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Prozac (LY110140)
These clinical study results are supplied for informational purposes only in the interests of scientific disclosure. They are not intended to substitute for the FDA-approved
package insert or other approved labeling. The approved drug label can be found at http://pi.Lilly.com/us/prozac-pi.pdf
Therapeutic
Area
Neuroscience
Alias
Indication
Trial ID
Trial Title
B1Y-MC-HCCJ
Pediatric Depression
236
Fluoxetine: Fluoxetine Versus Placebo in Adolescent Depressed Patients
Neuroscience
B1Y-MC-X065
Pediatric Depression
375
Neuroscience
B1Y-MC-HCIU
Pediatric Depression
1545
Neuroscience
Neuroscience
B1Y-MC-HCJE
B1Y-MC-HCJW
Pediatric Depression
Pediatric Depression
2201
3032
Neuroscience
B1Y-PU-S012
Major Depressive Disorder
6334
Neuroscience
B1Y-GH-S013
Major Depressive Disorder
6706
Fluoxetine Versus Placebo in the Acute Treatment of Major Depressive
Disorder in Children and Adolescents
Pharmacokinetic Assessment of Fluoxetine and Norfluoxetine in Preadolescent
and Adolescent Patients
Fluoxetine Versus Placebo in Childhood/Adolescent Depression
Fluoxetine Versus Placebo in the Treatment of Children and Adolescents with
Obsessive-Compulsive Disorder
Enteric-Coated Hydrochlorate Fluoxetine Administered Once Weekly during
the Maintenance Treatment of the Major Depressive Disorder
Depression with Lack of Motivation; Comparison Between Fluoxetine and
Trazodone
Page 1 of 1
Trial
Phase
3
3
4
3
3
4
4
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CT Registry ID#236
Page 1
Summary ID#236
Clinical Study Summary: Study B1Y-MC-HCCJ
Title of Study: Fluoxetine: Fluoxetine versus Placebo in Adolescent Depressed Patients
Investigator(s): This single-center study included one principal investigator.
Study Center(s): This study was conducted at one study center in one country.
Phase of Development: 3
Length of Study: 2 years
Date first patient enrolled: March 1984
Date last patient completed: March 1986
Objectives: To evaluate the safety and efficacy of fluoxetine in adolescent patients with major depressive
disorder comparing fluoxetine with placebo.
Study Design:
This was a single center, randomized, double-blind, parallel study of adolescent patients with major
depressive disorder comparing fluoxetine with placebo. All patients received placebo on a single-blind
basis for approximately one week, but not less than four days nor more than ten days (Study Period 1), to
eliminate placebo-reactors from the study group. The study drug, ie fluoxetine or placebo, was
administered on a double-blind basis for six weeks (Study Period 2). The study included 40 patients who
had not responded to placebo during Study Period 1. Responses were assessed by analyzing the following
psychiatric scales: Hamilton Psychiatric Rating Scale for Depression (HAMD), Clinical Global
Impressions (CGI), Raskin Depression Scale, Covi Anxiety Scale, Self-Rating Symptom Scale (SCL-58),
Patient’s Global Impressions (PGI), Efficacy Index, and Adverse Experience Form.
Patients who had not experienced a serious adverse event during the main study were included in a twelve
week open-label extension period. Patients within the Fluoxetine group continued to receive study drug.
Administration of study drug to patients within the placebo group was discontinued. Long term efficacy
and safety were evaluated for patients in both groups. Responses were assessed based on the criteria listed
above.
Number of Patients:
Planned: 50 patients
Randomized: 21 fluoxetine (males 9, females 12), 19 placebo (males 9, females 10)
Completed: 15 fluoxetine, 15 placebo
Enrollment was discontinued before 50 patients were enrolled due to slow rate of recruitment
Diagnosis and Main Criteria for Inclusion: All patients satisfied the criteria for major depressive
disorder according to DSM III (Diagnostic and Statistical Manual of Mental Disorder [3rd Edition]),
HAMD score was at least 20, the Raskin Depression Scale was at least 8, and the Raskin Depression Scale
exceeded the Covi Anxiety Scale score. The patients were male and female outpatients or inpatients, 12 to
17 years of age with an educational level and degree of understanding such that they could communicate
intelligently with the investigator and nurse.
Test Product, Dose, and Mode of Administration: Fluoxetine hydrochloride 20-60 mg/day, given orally
twice daily as fluoxetine 10 mg capsules.
Duration of Treatment:
Fluoxetine: 6 weeks, plus 12 week extension period (if applicable)
Placebo: 6 weeks
Reference Therapy, Dose, and Mode of Administration: Placebo capsules given orally twice daily
(Study Periods 1 and 2 only)
Fluoxetine Hydrochloride
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Page 2
Variables:
Efficacy: Change in psychiatric test score served as the primary efficacy criterion. Efficacy was
determined by comparing baseline (Visit 1) HAMD, CGI, Raskin, Covi Anxiety Scale, and SCL-58 scores
with scores obtained at the end of the active medication periods (Study Period 2) or those obtained at
termination from the study. Study Period 1 was an initial wash-out period to eliminate placebo-responders
from the study and to establish baseline values. Study Period 2 was a six-week, double-blind treatment
period. Subsequent evaluations were scheduled at one week intervals and concluded at Visit 8. The
HAMD, CGI, Raskin Depression Scale, Covi Anxiety Scale, and SCL-58 were evaluated at admission and
at all follow-up visits. PGI, Efficacy Index and Adverse Experiences were evaluated at all follow-up visits.
Safety: Clinical laboratory tests (hematology, urinalysis and clinical chemistry), an electrocardiogram
and a physical examination were performed at the admission visit and within 48 hours following the end of
study drug therapy. Fluoxetine and desmethylfluoxetine levels were quantitated from plasma samples
collected at admission and at visit 8. Pulse, temperature, blood pressure, and weight were recorded at each
visit.
Evaluation Methods:
Statistical: Analysis of Variance (ANOVA) was used to assess significant treatment effects for
continuous efficacy and safety data. Within-patient treatment efficacy was assessed using the Wilcoxan
signed rank statistic. Treatment and investigator effects were tested at the a =.05 level of significance.
Treatment-by-investigator interactions were tested at the a =.10 level of significance. Categorical efficacy
and safety data were analyzed using the chi-squared tests with appropriate degrees of freedom.
Summary:
Patient Demographics: The majority of patients were female (55% [22/40]) and Caucasian (100% [40/40]).
Mean patient age was 15.58 years. Treatment groups were comparable at baseline with respect to
demographics.
Efficacy: There was no statistically significant difference in the mean change in HAMD-17 and HAMD-21
scores between fluoxetine-treated patients and placebo-treated patients. There was a statistically significant
(p<.001) improvement in HAMD17 and HAMD21 total scores, measured from baseline to endpoint in the
fluoxetine and placebo treatment groups (Table HCCJ.1 and Table HCCJ.2).
There was no statistically significant difference in the mean change in CGI-Improvement and Raskin Total
scores between fluoxetine-treated patients and placebo-treated patients. There was a statistically significant
(p<.001) improvement in CGI-Improvement (Table HCCJ.3) and Raskin Total scores (Table HCCJ.4),
measured from baseline to endpoint in the fluoxetine and placebo treatment groups.
There was a statistically significant (p<.001) improvement in Covi Anxiety Scale Total scores (Table
HCCJ.5), measured from baseline to endpoint in the fluoxetine treated group. There was also a significant
(p=.001) improvement in Covi scores measured from baseline to endpoint in the placebo-treated group.
There was no statistically significant difference in the mean change in Covi Anxiety Scale Total scores
between fluoxetine-treated patients and placebo-treated patients.
There was a statistically significant (p<.001) improvement in SCL Total 1-58 scores (Table HCCJ.6),
measured from baseline to endpoint, in the fluoxetine treated group. There was no statistically significant
improvement in SCL Total 1-58 scores in the placebo-treated group. There was no statistically significant
difference in the mean change in SCL scores between fluoxetine-treated patients and placebo-treated
patients.
Fluoxetine Hydrochloride
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Page 3
Safety: No deaths were reported among the patients enrolled in this study. Fluoxetine-treated patients had
significantly higher rates of treatment emergent tremor (28.6% versus 0.0%), and insomnia (23.8% versus
0.0%) as compared to placebo-treated patients. Ten patients discontinued from the study (adverse event 2
[9.5%] fluoxetine, 0 [0.0%] placebo; lack of efficacy 1 [4.8%] fluoxetine, 3 [15.8] placebo; patient decision
1 [4.8%] fluoxetine, 1 [5.3%] placebo; protocol requirement 1 [4.8%] fluoxetine; 0 [0.0%] placebo; and
physician decision 1 [4.8%] fluoxetine, 0 [0.0%] placebo). Table HCCJ.7 summarizes treatment-emergent
adverse events by body system.
Fluoxetine-treated patients had a statistically significant (p<.001) greater loss of weight than placebotreated patients during the main study.
In summary, 40 adolescent patients with major depressive disorder were randomized in a double-blind,
parallel study to evaluate the efficacy and safety of fluoxetine compared with placebo. On the basis of
baseline to endpoint improvement in HAMD17 and HAMD21, CGI-Improvement, Raskin Total, and Covi
Anxiety Scale Total scores, fluoxetine was no more effective than placebo in alleviating symptoms of
depression in adolescents..
Fluoxetine Hydrochloride
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Table HCCJ.1.
Page 4
Summary of Efficacy Changes from Baseline to Endpoint
HAMD17 Total Score
Study B1Y-MC-HCCJ
Fluoxetine Hydrochloride
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Table HCCJ.2.
Page 5
Summary of Efficacy Changes from Baseline to Endpoint
HAMD21 Total Score
Study B1Y-MC-HCCJ
Fluoxetine Hydrochloride
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Table HCCJ.3.
Page 6
Summary of Efficacy Changes from Baseline to Endpoint
CGI-Improvement
Study B1Y-MC-HCCJ
Fluoxetine Hydrochloride
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Table HCCJ.4.
Page 7
Summary of Efficacy Changes from Baseline to Endpoint
Raskin Total Score
Study B1Y-MC-HCCJ
Fluoxetine Hydrochloride
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Table HCCJ.5.
Page 8
Summary of Efficacy Changes from Baseline to Endpoint
COVI Total Score
Study B1Y-MC-HCCJ
Fluoxetine Hydrochloride
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Table HCCJ.6.
Page 9
Summary of Efficacy Changes from Baseline to Endpoint
SCL Total Score
Study B1Y-MC-HCCJ
Fluoxetine Hydrochloride
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Table HCCJ.7.
Page 10
Treatment-Emergent Adverse Events
By Body System
Study B1Y-MC-HCCJ
Fluoxetine Hydrochloride
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CT Registry ID#236
Fluoxetine Hydrochloride
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Fluoxetine Hydrochloride
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CT Registry ID#236
Fluoxetine Hydrochloride
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CT Registry ID#236
Fluoxetine Hydrochloride
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CT Registry ID#236
Fluoxetine Hydrochloride
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CT Registry ID#236
Fluoxetine Hydrochloride
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CT Registry ID#236
Fluoxetine Hydrochloride
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CT Registry ID#236
Fluoxetine Hydrochloride
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Fluoxetine Hydrochloride
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CT Registry ID#375
Page 1
Synopsis ID#375
Clinical Study Synopsis: Study B1Y-MC-X065
Title of Study: Fluoxetine Versus Placebo in the Acute Treatment of Major Depressive Disorder in
Children and Adolescents
Investigator(s): This single-center study included one principal investigator.
Study Center(s): This study was conducted at one study center in one country.
Publication(s) Based on the Study: Please refer to the clinical trial registry website for publications on
this compound.
Phase of Development: 3
Length of Study: 11 months/ 3 years
Date first patient enrolled: 10 April 1991
Date last patient completed: 28 February 1995
Objectives:
Primary Objective: Based on a responder analysis of the Children's Depression Rating Scale-Revised
(CDRS-R), to test the hypothesis that fluoxetine 20 mg/day is more effective than placebo in the treatment
of children (aged 8 to <13 years) and adolescents (aged 13 to ≤18 years) diagnosed with Diagnostic and
Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R) major depression as measured
by response rates on the CDRS-R after up to 8 weeks. Response was defined as a decrease of at least 30%
in the CDRS-R total score from baseline to endpoint.
Secondary Objectives: To compare the efficacy of fluoxetine 20 mg/day with placebo in the treatment of
childhood and adolescent depression as measured by the mean change in CDRS-R total and subtotal scores;
remission rates on the CDRS-R; change in mean CDRS-R total scores over time; response rates on the
Clinical Global Impressions of Improvement (CGI-Improvement) scale; recovery rates; mean scores on the
Clinical Global Impressions of Severity scale (CGI-Severity), CGI-Improvement scale, Brief Psychiatric
Rating Scale for Children (BPRS-C), Beck Depression Inventory (BDI), and Children’s Depression
Inventory (CDI); response and remission rates on the CDRS-R, for those patients who completed at least
4 weeks of treatment; and monitoring of adverse events, vital signs, and laboratory analytes; and to
determine if there were any differences in the efficacy and safety of fluoxetine between subgroups defined
by age and gender.
Study Design: Single-center, double-blind, randomized, parallel-group, placebo-controlled study.
This was a study comparing the efficacy and safety of fluoxetine 20 mg/day and placebo for the acute
treatment (8 weeks) of major depressive disorder (MDD), as defined by the DSM-III-R, in children and
adolescents.
Study Period I was a single-blind, placebo wash-out period that lasted for 1 to 2 weeks. Patients were
evaluated at the end of the first (and second) week(s) for placebo response.
Study Period II was a double-blind, acute treatment period during which patients were randomized to
receive either fluoxetine 20 mg/day or placebo for 8 weeks. Patients were seen at weekly intervals.
Number of Patients:
Planned: 40 fluoxetine, 40 placebo
Randomized: 48 fluoxetine (male 26, female 22), 48 placebo (male 26, female 22)
Children (8 to <13): fluoxetine 24, placebo 24, total: 48;
Adolescents (13 to ≤18): fluoxetine 24, placebo 24, total 48.
Completed: 33 fluoxetine, 25 placebo
Fluoxetine hydrochloride
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Diagnosis and Main Criteria for Inclusion: Outpatients with non-psychotic, MDD, single or recurrent
episodes according to the DSM-III-R, aged 8 to 18 years, normal intelligence as assessed clinically or by
psychomotor testing if evidence of IQ <80, and were willing and able to provide informed consent (parent
and patient). Diagnosis of major depressive disorder (MDD) was also dependent on patients having a
Children's Depression Rating Scale-Revised (CDRS-R) total score >40 at study entry. Diagnosis of MDD
and comorbid diagnoses was decided at a consensus meeting of the clinical investigators. At this meeting,
the clinical investigators systematically reviewed data from interviews, parent and child self-report
measures, and additional information (eg, CDRS-R scores indicative of depression).
Test Product, Dose, and Mode of Administration: Fluoxetine 20 mg capsules, given orally once daily
Duration of Treatment:
Fluoxetine: 8 weeks
Placebo: 8 weeks
Reference Therapy, Dose, and Mode of Administration: Placebo given orally once daily.
Variables:
Efficacy: Primary efficacy analysis was response on the CDRS-R. Secondary analyses included
additional evaluations of CDRS-R, CGI-Improvement, CGI-Severity, BPRS-C, BDI, and CDI scales.
Safety: Safety was evaluated through the reporting and collection of concomitant medications, vital
signs, routine laboratory testing, and adverse event data (solicited and non-solicited).
Evaluation Methods:
Statistical: For analyses of continuous data, treatment groups were compared using last-observationcarried-forward (LOCF) in Type III sums of squares from an analysis of variance (ANOVA) with treatment
in the model. For analyses of categorical data, Fisher's exact test was used.
All tests of hypotheses were tested at a two-sided, .05 significance level. All total and subtotal scores from
rating scales were derived from individual items. All analyses were performed on an intent-to-treat basis.
Only patients with baseline and postbaseline measurements for the primary efficacy analysis were included
in the analyses of all efficacy scales.
Summary:
The safety and efficacy of fluoxetine was assessed following 8 weeks of fixed-dose therapy of fluoxetine
20 mg/day versus placebo in 96 pediatric patients diagnosed with MDD, as defined by the DSM-III-R.
This study was conducted as an investigator-initiated trial and was exempt for the Investigational New
Drug Application for fluoxetine.
Baseline demographic characteristics for all randomized patients are summarized in Table X065.1. The
patients randomized in this study were predominantly Caucasian (79%). The mean age of patients in the
study was 12.8 years (range = 7.2 to 17.8 years). Of the 96 patients randomized to treatment, 44 (46%)
were female and 52 (54%) were male. The mean height of patients was 152 cm (range = 66 to 180 cm) and
the mean weight of patients was 52 kg (range = 23 to 120 kg).
Ninety-six patients were randomized to treatment in this study, with 48 being treated with fluoxetine 20 mg
once daily and 48 being treated with placebo. A total of 58 patients (33 fluoxetine, 25 placebo) completed
the entire study. Nineteen placebo-treated patients discontinued the study due to lack of efficacy as
compared with 6 fluoxetine-treated patients (p=.005). In addition, 13 randomized patients discontinued
from the study (adverse events [5 patients], protocol requirements [5 patients], patient decision [2 patients],
and physician decision [1 patient]). The treatment groups were balanced with respect to demographic
characteristics and psychiatric evaluations at baseline.
Fluoxetine hydrochloride
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Fluoxetine 20 mg/day was statistically superior to placebo in the treatment of MDD in this pediatric
population as demonstrated by response on the CDRS-R total score, defined as at least a 30% reduction
from baseline, when patients were treated for up to 8 weeks (p=.013) and for at least 4 weeks (p=.031).
The observed response rates on the CDRS-R total score (58% fluoxetine, 32% placebo, Table X065.3,
Figure X065.1) and the CGI-Improvement scores (56% fluoxetine, 34% placebo, Table X065.10) are
similar to the rates seen in adults with depression.
The CGI-Improvement and CGI-Severity showed similar results. Endpoint (p=.015) and response analyses
(p=.040) for CGI-Improvement scores demonstrated the statically superiority of fluoxetine treatment over
placebo treatment. In addition, the mean change in CGI-Severity scores from baseline to endpoint was
statistically significant for fluoxetine-treated patients as compared with placebo-treated patients (p=.003).
Table X065.2 summarizes the analyses of the efficacy variables that demonstrated statistical superiority of
fluoxetine treatment over placebo.
Greater attrition from the placebo treatment group was seen due to failure to respond to treatment as
compared with fluoxetine-treated patients. Despite this differential rate of attrition, LOCF analysis of mean
CDRS-R total scores over time indicates that fluoxetine treatment was statistically significantly superior to
placebo treatment after 3 weeks (Visit 5) of treatment. This treatment effect persisted for the duration of
the study.
Of the 96 randomized patients in this study, 92 (96%) reported at least 1 treatment-emergent solicited
adverse event, and 85 (89%) reported at least 1 non-solicited adverse event. There were no statistically
significant differences in frequencies of adverse events reported in fluoxetine-treated patients as compared
with placebo-treated patients (Table X065.13).
Two serious adverse events of suicide attempt occurred in patients receiving fluoxetine treatment during
the study. Both events were considered to have unknown causality as determined by the principal
investigator and occurred early in the study (after 12 and 15 days of therapy, respectively). One patient
discontinued from the study as a result. Four additional fluoxetine-treated patients were discontinued from
the study due to adverse events. Two patients were discontinued for hypomania, 1 for increased
impulsivity, and 1 for rash. Three of the events (increased impulsivity, rash, and 1 event of hypomania)
were considered possibly related to fluoxetine treatment. No placebo-treated patients discontinued due to
adverse events.
One patient was discontinued from the study after receiving 15 days of fluoxetine treatment due to a suicide
attempt. The patient was hospitalized after intentional overdose including Pamprin, Momentum, and
Dibromm following a fight with her boyfriend. She was treated in the emergency room and admitted to the
psychiatric unit. The event was considered to have unknown causality as determined by the principal
investigator.
Fluoxetine hydrochloride
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A second patient was hospitalized for a suicide attempt after receiving 12 days of fluoxetine treatment. The
patient intentionally overdosed on unknown pills, possibly including ibuprofen and phenergan. The patient
was treated in the emergency room and released. The event was considered to have unknown causality as
determined by the principal investigator. The patient remained in the study and completed the entire
protocol.
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Table X065.1.
Variable
-----------------Origin
No. Patients
African Descent
Caucasian
Hispanic
Other
Age (yrs)
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
Page 5
Baseline Patient Characteristics
All Randomized Patients
B1Y-MC-X065
Flx 20mg
(N=48)
-------------
48
4
35
8
1
(8.3)
(72.9)
(16.7)
(2.1)
48
12.67
13.00
2.73
7.56
17.84
Placebo
(N=48)
-------------
48
4
41
2
1
(8.3)
(85.4)
(4.2)
(2.1)
48
13.00
12.98
2.78
7.16
17.80
Total
(N=96)
-------------
96
8
76
10
2
p-Value
-------------
.195*
(8.3)
(79.2)
(10.4)
(2.1)
96
12.84
12.98
2.75
7.16
17.84
.559**
Age Category
No. Patients
Adolesc(13-18yr)
Child(8-12yr)
48
24 (50.0)
24 (50.0)
48
24 (50.0)
24 (50.0)
96
48 (50.0)
48 (50.0)
1.00*
Gender
No. Patients
Female
Male
48
22 (45.8)
26 (54.2)
48
22 (45.8)
26 (54.2)
96
44 (45.8)
52 (54.2)
1.00*
RMP.B1YP.JCLLIB2(DES1EM05)
RMP.B1YO.X065REP(DES1EM05)
* Frequencies are analyzed using a Fishers-Exact test.
** Means are analyzed using a Type III Sum of Squares analysis of variance
(ANOVA): PROC GLM model=treatment.
XDES0001
Fluoxetine hydrochloride
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Table X065.1.
Page 6
Baseline Patient Characteristics
All Randomized Patients
B1Y-MC-X065 (continued)
Flx 20mg
(N=48)
-------------
Placebo
(N=48)
-------------
Total
(N=96)
-------------
Height (cm)
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
Unspecified
37
149.93
149.00
20.58
66.00
180.00
7
39
153.93
153.00
12.59
137.00
180.00
7
76
151.99
153.00
16.96
66.00
180.00
14
.307**
Weight (kg)
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
44
54.07
51.00
21.82
23.00
120.00
46
50.83
49.00
15.48
26.00
99.00
90
52.41
50.00
18.81
23.00
120.00
.418**
Variable
------------------
Socioeconomic Status
No. Patients
Professional
Skilled
Semi/Unskilled
48
13 (27.1)
17 (35.4)
18 (37.5)
48
16 (33.3)
18 (37.5)
14 (29.2)
96
29 (30.2)
35 (36.5)
32 (33.3)
p-Value
-------------
.665*
RMP.B1YP.JCLLIB2(DES1EM05)
RMP.B1YO.X065REP(DES1EM05)
* Frequencies are analyzed using a Fishers-Exact test.
** Means are analyzed using a Type III Sum of Squares analysis of variance
(ANOVA): PROC GLM model=treatment.
XDES0001
Fluoxetine hydrochloride
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Table X065.1.
Variable
-----------------Family Structure
No. Patients
Both Parents
Nat. Mother
Other
Nat.Mthr/Stpfthr
Nat. Father
Nat.Fthr/Stpmthr
Other Relatives
Adoptive Parents
Page 7
Baseline Patient Characteristics
All Randomized Patients
B1Y-MC-X065 (concluded)
Flx 20mg
(N=48)
-------------
48
20
16
2
6
1
2
0
1
(41.7)
(33.3)
(4.2)
(12.5)
(2.1)
(4.2)
(2.1)
Placebo
(N=48)
-------------
48
23
12
0
9
0
2
1
1
(47.9)
(25.0)
(18.8)
(4.2)
(2.1)
(2.1)
Total
(N=96)
-------------
96
43
28
2
15
1
4
1
2
p-Value
-------------
.715*
(44.8)
(29.2)
(2.1)
(15.6)
(1.0)
(4.2)
(1.0)
(2.1)
RMP.B1YP.JCLLIB2(DES1EM05)
RMP.B1YO.X065REP(DES1EM05)
* Frequencies are analyzed using a Fishers-Exact test.
** Means are analyzed using a Type III Sum of Squares analysis of variance
(ANOVA): PROC GLM model=treatment.
XDES0001
Fluoxetine hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
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CT Registry ID#375
Table X065.2.
Page 8
Variable Analyzed
Efficacy Variable Analyzed
p-Value
Response, at least a 30% reduction in CDRS-R Total score from baseline (at endpoint)
Response, at least a 30% reduction in CDRS-R Total score from baseline (after at least
4 weeks of treatment)
Mean change from baseline to endpoint in CDRS-R Total score
Mean change from baseline to endpoint in CDRS-R Mood Subtotal score
Mean change from baseline to endpoint in CDRS-R Somatic Subtotal score
Mean change from baseline to endpoint in CDRS-R Behavior Subtotal score
Endpoint analysis of CGI-Improvement score
Response, CGI-Improvement score of 1 or 2 at endpoint
Mean change from baseline to endpoint in CGI-Severity score
.013
.031
.002
<.001
.001
.028
.015
.040
.003
Abbreviations: CGI-Improvement = clinical global impressions of improvement; CGI-Severity = clinical
global impressions of severity; CDRS = Children's Depression Rating Scale-Revised.
Fluoxetine hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
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CT Registry ID#375
Table X065.3.
Page 9
CDRS-R Total Score
Number of Patients Meeting Criteria for Response
All Randomized Patients
B1Y-MC-X065
Protocol: B1Y-MC-X065
Outcome Variable: RESPONSE - 30% REDUCTION FROM BASELINE
Therapy
-- -----------------A. Flx 20mg
B. Placebo
N
------48
47
NO
n
%
------ ---------20
41.7
32
68.1
YES
n
%
------ ---------28
58.3
15
31.9
COMPARISON OF TREATMENT GROUPS
STATISTICS
-----------------------------Fisher's exact test
(2-tailed)
Pearson's chi-square test
df=1
Cochran-Mantel-Haenszel
general association test
df=1
VALUE
P-VALUE
----------- ----------0.013
6.7
<0.01
6.6
0.010
RMP.B1YP.JCLLIB2(EFS1EM01)
RMP.B1YO.X065REP(EFS1EM01)
XEFS0001
Fluoxetine hydrochloride
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Page 10
Percent Patients Meeting Response Criteria
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
>=60
>=50
>=40
>=30
>=20
>=10
>=0
Percent Change in CDRS-R Total Score from Baseline
Flx 20 mg
Figure X065.1.
Placebo
CDRS-R Total Score Percent Change Distribution, All
Randomized Patients, B1Y-MC-X065.
Fluoxetine hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
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Fluoxetine hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Table X065.4.
Approved by Lilly 15 November 2004
CDRS-R Scores
Change from Baseline to Endpoint
All Randomized Patients
B1Y-MC-X065
Baseline
Mean
SD
---------------
Endpoint
Mean
SD
--------------
Change
Mean
SD
----------------
Variable
-------------------------
Therapy
---------
n
--
p-Value *1
----------
TOTAL
Flx 20mg
Placebo
48
47
58.9
57.5
10.4
10.4
38.7
47.0
14.6
16.9
-20.2
-10.5
13.5
15.9
.002
MOOD SUBTOTAL
Flx 20mg
Placebo
48
47
15.1
14.6
3.5
3.1
9.3
12.0
3.6
4.7
-5.8
-2.6
4.1
4.9
<.001
SOMATIC SUBTOTAL
Flx 20mg
Placebo
48
47
20.3
18.7
3.9
3.8
13.7
15.7
6.0
5.2
-6.6
-2.9
5.4
5.3
.001
SUBJECTIVE SUBTOTAL
Flx 20mg
Placebo
48
47
11.3
11.6
2.8
3.6
7.8
9.2
3.1
3.9
-3.5
-2.4
3.2
4.3
.147
BEHAVIOR SUBTOTAL
Flx 20mg
Placebo
48
47
12.2
12.6
2.8
2.9
7.9
10.1
3.7
4.4
-4.3
-2.6
3.7
3.9
.028
*1 Type III Sums of Squares from an analysis of variance (ANOVA): PROC GLM model=treatment.
RMP.B1YP.JCLLIB2(LAS3EM13)
RMP.B1YO.X065REP(PRCNEM13)
CT Registry ID#375
Page 11
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Page 12
60
CDRS-R Total Score
55
50
45
40
35
30
Baseline
3
4
5
6
7
8
9
10
9
10
Visit
Flx 20 mg
Placebo
0
CDRS-R Total Change from Baseline
Baseline
3
4
5
6
7
8
-5
-10
-15
-20
-25
Visit
Flx 20 mg
Figure X065.2.
Placebo
CDRS-R Total Score versus Visit by Treatment Group for all
Observed Cases, All Randomized Patients, B1Y-MC-X065.
Fluoxetine hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
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Table X065.5.
Page 13
CDRS-R Total Score
Mean Change From Baseline to Visit 10
All Randomized Patients
B1Y-MC-X065
Treatment
Group
n
Observed
Mean
Fluoxetine 20 mg
Placebo
34
25
-24.2
-18.2
p-Value
n
LOCF
Mean
.106
48
47
-20.2
-10.5
p-Value
.002
Abbreviations: LOCF = last observation carried forward.
Fluoxetine hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
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Table X065.6.
Page 14
CDRS-R Total Score
Repeated Measures Model Parameters
All Randomized Patients
B1Y-MC-X065
Parameter
Treatment
Visit
Treatment-by-Visit
Contrast between Treatment, Change
from Baseline to Visit 10
ndf
ddf
F-Test Value
p-Value
1
8
8
1
83.1
73.9
73.9
64.6
2.28
22.5
1.38
6.86
.135
<.001
.220
.011
Abbreviations: ddf = denominator degrees of freedom; ndf = numerator degrees of freedom.
Fluoxetine hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
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Table X065.7.
Visit
1 and 2
3
4
5
6
7
8
9
10
Page 15
CDRS-R Total Score
Repeated Measures Least-Squares Means
All Randomized Patients
B1Y-MC-X065
Fluoxetine 20 mg
LS Mean
p-Valuea
58.9
-7.7
-12.8
-14.3
-16.5
-19.4
-20.2
-20.1
-21.3
<.001
<.001
<.001
<.001
<.001
<.001
<.001
<.001
Placebo
LS Mean
p-Valuea
57.5
-5.1
-8.6
-10.4
-12.8
-12.2
-14.2
-13.6
-12.3
.001
<.001
<.001
<.001
<.001
<.001
<.001
<.001
a
Within treatment change from baseline.
Abbreviation: LS = least-squares.
Fluoxetine hydrochloride
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Table X065.8.
Page 16
CDRS-R Total Score
Number of Patients Meeting Criteria for Remission
All Randomized Patients
B1Y-MC-X065
Protocol: B1Y-MC-X065
Outcome Variable: REMISSION - SCORE <=28
Therapy
-- -----------------A. Flx 20mg
B. Placebo
N
------48
47
NO
n
%
------ ---------33
68.8
38
80.9
YES
n
%
------ ---------15
31.3
9
19.1
COMPARISON OF TEATMENT GROUPS
STATISTICS
-----------------------------Fisher's exact test
(2-tailed)
Pearson's chi-square test
df=1
Cochran-Mantel-Haenszel
general association test
df=1
VALUE
P-VALUE
----------- ----------0.238
1.8
0.175
1.8
0.177
RMP.B1YP.JCLLIB2(EFS1EM02)
RMP.B1YO.X065REP(EFS1EM02)
XEFS0001
Fluoxetine hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
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Table X065.9.
Variable
-----------------CGI-Improvement
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
Page 17
CGI-Improvement Scores
Endpoint Analysis
All Randomized Patients
B1Y-MC-X065
Flx 20mg
(N=48)
-------------
Placebo
(N=48)
-------------
Total
(N=96)
-------------
48
2.5
2.0
1.3
1.0
5.0
47
3.2
3.0
1.5
1.0
6.0
95
2.9
3.0
1.4
1.0
6.0
p-Value
-------------
.015**
RMP.B1YP.JCLLIB2(DES1EM02)
RMP.B1YO.X065REP(DES1EM02)
** Means are analyzed using a Type III Sum of Squares analysis of variance
(ANOVA): PROC GLM model=treatment.
XDES0001
Fluoxetine hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
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Table X065.10.
Page 18
CGI-Improvement Score
Number of Patients Meeting Criteria for Response
All Randomized Patients
B1Y-MC-X065
Protocol: B1Y-MC-X065
Outcome Variable: RESPONSE - SCORE = 1 OR 2
Therapy
-- -----------------A. Flx 20mg
B. Placebo
N
------48
47
NO
n
%
------ ---------21
43.8
31
66.0
YES
n
%
------ ---------27
56.3
16
34.0
COMPARISON OF TREATMENT GROUPS
STATISTICS
-----------------------------Fisher's exact test
(2-tailed)
Pearson's chi-square test
df=1
Cochran-Mantel-Haenszel
general association test
df=1
P-VALUE
----------0.040
0.030
0.031
RMP.B1YP.JCLLIB2(EFS1EM03)
RMP.B1YO.X065REP(EFS1EM03)
XEFS0001
Fluoxetine hydrochloride
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Table X065.11.
Page 19
CDRS-R Total and CGI-Improvement Scores
Number of Patients Meeting Criteria for Recovery
All Randomized Patients
B1Y-MC-X065
Protocol: B1Y-MC-X065
Outcome Variable: RECOVERY - CDRS-R <=28 AND CGI-IMPROVEMENT = 1 OR 2
Therapy
-- -----------------A. Flx 20mg
B. Placebo
N
------48
47
NO
n
%
------ ---------34
70.8
38
80.9
YES
n
%
------ ---------14
29.2
9
19.1
COMPARISON OF TREATMENT GROUPS
STATISTICS
-----------------------------Fisher's exact test
(2-tailed)
Pearson's chi-square test
df=1
Cochran-Mantel-Haenszel
general association test
df=1
VALUE
P-VALUE
----------- ----------0.339
1.3
0.254
1.3
0.257
RMP.B1YP.JCLLIB2(EFS1EM04)
RMP.B1YO.X065REP(EFS1EM04)
XEFS0001
Fluoxetine hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
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Fluoxetine hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Table X065.12.
Approved by Lilly 15 November 2004
Secondary Efficacy Variable Scores
Change From Baseline to Endpoint
All Randomized Patients
B1Y-MC-X065
Baseline
Mean
SD
---------------
Endpoint
Mean
SD
--------------
Change
Mean
SD
----------------
Variable
-------------------------
Therapy
---------
n
--
p-Value *1
----------
CGI Severity
Flx 20mg
Placebo
48
47
5.1
4.9
0.8
0.8
3.1
3.9
1.5
1.7
-2.0
-1.1
1.4
1.6
.003
BPRS-C Total
Flx 20mg
Placebo
47
47
26.3
24.7
7.9
8.5
18.0
20.0
9.9
10.1
-8.4
-4.7
8.4
12.0
.087
BDI Total
Flx 20mg
Placebo
23
19
17.6
14.8
12.0
8.6
11.7
9.6
13.6
10.3
-5.9
-5.2
9.8
8.7
.795
CDI Total
Flx 20mg
Placebo
23
20
16.1
17.8
10.5
13.2
10.3
13.4
10.4
8.6
-5.8
-4.4
8.8
7.9
.594
*1 Type III Sums of Squares from analysis of variance (ANOVA): PROC GLM model=treatment
RMP.B1YP.JCLLIB2(LAS3EM23)
RMP.B1YO.X065REP(PRCNEM23)
CT Registry ID#375
Page 20
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Table X065.13.
Page 21
Treatment-Emergent Solicited Adverse EventsSide-Effects
Checklist
Incidence by Decreasing Frequency (Ordered by Fluoxetine)
All Randomized Patients
B1Y-MC-X065
Event Classification
-------------------------------PATIENTS WITH >= 1 TESS
PATIENTS WITH NO TESS
14. COLD OR SNIFFLES
24. SLEEPING
06. DIARRHEA
08. MUSCLE CRAMPS
09. BEING SICK TO YOUR STOMACH
07. STOMACHACHES
21. SITTING STILL
23. FEELING SLEEPY
32. PAYING ATTENTION
16. DIZZINESS
26. GETTING ALONG WITH PARENTS
03. DRY MOUTH AND LIPS
22. TIREDNESS
30. NOT BEING HAPPY
15. HEADACHE
18. SHAKINESS
27. GETTING ALONG WITH KIDS
28. CRYING
13. RASHES
25. BAD DREAMS
12. ITCHY OR SCRATCHY SKIN
20. DOING THINGS WITH YOUR HANDS
31. BEING SAD
04. WETNESS IN MOUTH
19. PRONOUNCING WORDS
29. GETTING MAD
01. EATING
02. DRINKING
05. CONSTIPATION
17. PLAYING SPORTS
10. WETTING THE BED
11. URINATING
Flx 20mg
(N=48)
n (%)
--------47 (97.9)
1 (2.1)
22 (45.8)
17 (35.4)
16 (33.3)
15 (31.3)
15 (31.3)
14 (29.2)
14 (29.2)
14 (29.2)
14 (29.2)
13 (27.1)
13 (27.1)
12 (25.0)
12 (25.0)
12 (25.0)
11 (22.9)
11 (22.9)
11 (22.9)
11 (22.9)
10 (20.8)
10 (20.8)
9 (18.8)
9 (18.8)
9 (18.8)
8 (16.7)
8 (16.7)
8 (16.7)
7 (14.6)
7 (14.6)
7 (14.6)
7 (14.6)
4 (8.3)
3 (6.3)
Placebo
(N=48)
n (%)
--------45 (93.8)
3 (6.3)
22 (45.8)
15 (31.3)
9 (18.8)
10 (20.8)
18 (37.5)
16 (33.3)
13 (27.1)
11 (22.9)
9 (18.8)
13 (27.1)
12 (25.0)
10 (20.8)
14 (29.2)
12 (25.0)
12 (25.0)
6 (12.5)
11 (22.9)
14 (29.2)
5 (10.4)
9 (18.8)
9 (18.8)
9 (18.8)
11 (22.9)
5 (10.4)
7 (14.6)
12 (25.0)
8 (16.7)
8 (16.7)
7 (14.6)
7 (14.6)
3 (6.3)
3 (6.3)
Total
(N=96)
n (%)
--------92 (95.8)
4 (4.2)
44 (45.8)
32 (33.3)
25 (26.0)
25 (26.0)
33 (34.4)
30 (31.3)
27 (28.1)
25 (26.0)
23 (24.0)
26 (27.1)
25 (26.0)
22 (22.9)
26 (27.1)
24 (25.0)
23 (24.0)
17 (17.7)
22 (22.9)
25 (26.0)
15 (15.6)
19 (19.8)
18 (18.8)
18 (18.8)
20 (20.8)
13 (13.5)
15 (15.6)
20 (20.8)
15 (15.6)
15 (15.6)
14 (14.6)
14 (14.6)
7 (7.3)
6 (6.3)
p-Value*
--------.617
.617
1.00
.829
.162
.352
.668
.826
1.00
.642
.339
1.00
1.00
.809
.819
1.00
1.00
.285
1.00
.642
.261
1.00
1.00
1.00
.802
.552
1.00
.452
1.00
1.00
1.00
1.00
1.00
1.00
1 Treatment-Emergent Solicited = was present at baseline and worsened as defined by
increase in score on the side-effect checklist or a new occurrence after baseline.
Baseline is the highest score of item at visit 1 and 2.
RMP.B1YT.JCLLIB2(AES2E28A)
RMP.B1YO.X065REP(AES2E28A)
* Frequencies are analyzed using a Fisher's Exact test.
XAES0002
Fluoxetine hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
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CT Registry ID#1545
Page 1
Summary ID#1545
Clinical Study Summary: Study B1Y-MC-HCIU
Title of Study: Pharmacokinetic Assessment of Fluoxetine and Norfluoxetine in Preadolescent and
Adolescent Patients
Investigator(s): This single-center study included one principal investigator.
Study Center(s): There were two study centers coordinated through a single site.
Phase of Development: 4
Length of Study: 12 months
Date first patient enrolled: 16 September 1997
Date last patient completed: 06 October 1998
Objectives:
Primary Objectives: To assess the pharmacokinetics of fluoxetine 20 mg/day and its metabolite,
norfluoxetine, in preadolescent and adolescent patients diagnosed with major depressive disorder (MDD),
depressive disorder not otherwise specified, dysthymic disorder, or obsessive-compulsive disorder (OCD)
as defined by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV).
To compare the steady-state plasma concentrations achieved and pharmacokinetics attained in
preadolescent and adolescent patients on a fixed dose of fluoxetine 20 mg/day with the steady-state plasma
concentrations achieved and pharmacokinetics attained in adult patients from prior pharmacokinetic
studies.
Secondary Objective: To assess the adverse event profile of fluoxetine and norfluoxetine in preadolescent
and adolescent patients.
Study Design: Open-label, single-site, fixed-dose, acute and steady-state pharmacokinetic study.
This was an open-label, single-site, 60-day (58 to 62 days) treatment study to assess the pharmacokinetic
profiles of fluoxetine 20 mg/day and its metabolite, norfluoxetine, in 22 preadolescents and adolescents
with major depressive disorder (MDD), depressive disorder not otherwise specified (NOS), dysthymic
disorder, or obsessive compulsive disorder (OCD) as defined by the DSM-IV.
Study Period I was a screening, wash out, and study preparation phase that lasted 2 to 28 days. Patients
were evaluated for eligibility and did not receive study medication during this study period.
Study Period II was an open-label treatment phase during which patients received a fixed dose of fluoxetine
20 mg/day for 58 to 62 days. Patients were seen at 9 full visits and 2 partial visits during this study period.
Up to 10 blood samples were obtained from each patient for pharmacokinetic analysis. Figure HCIU.1
illustrates the study design.
Number of Patients:
Enrolled: fluoxetine 20 mg/day: 22.
Completed: fluoxetine 20 mg/day: 19.
Diagnosis and Main Criteria for Inclusion: Female or male in- or out-patients between the ages of 6 and
17 years with psychiatric diagnosis of MDD, depressive disorder NOS, dysthymic disorder, or OCD as
defined by the DSM-IV.
Test Product, Dose, and Mode of Administration: Fluoxetine 20 mg, given orally once daily as
fluoxetine capsules, 20 mg
Fluoxetine Hydrochloride
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Page 2
Duration of Treatment: 60 days
Reference Therapy, Dose, and Mode of Administration: Not applicable
Variables:
Pharmacokinetic: Plasma concentrations, absorption rate constant, apparent oral clearance, apparent
volume of distribution, accumulation profile, steady-state concentrations.
Safety: Adverse events, laboratory analytes, vital signs, and electrocardiograms (ECGs).
Evaluation Methods:
Statistical: Observed fluoxetine and norfluoxetine concentrations were summarized using descriptive
statistics (mean, coefficient of variation, number of observations). Estimates of the pharmacokinetic
parameters and error terms for fluoxetine were obtained by fitting the concentration-time by means of the
nonlinear mixed-effects modeling program (NONMEM, version V) with PREDPP (version V).
Baseline demographic data, incidence rates of concomitant medications, and exposure to study medication
were analyzed using summary statistics. Incidence rates for treatment-emergent adverse events were
analyzed by decreasing frequency, body system and event, and maximum severity. Laboratory analytes
were evaluated for mean change from baseline to endpoint using a Wilcoxon Signed-Rank procedure. The
proportion of patients with abnormal laboratory values at Visit 8 and Visit 12 were summarized. Vital
signs were analyzed for mean change from baseline to endpoint using the Wilcoxon Signed-Rank
procedure. Electrocardiogram results were presented as the proportion of patients with normal and
abnormal electrocardiograms at baseline and endpoint.
Summary:
Demographics/Disposition: Twenty-three patients were screened, and 22 patients were enrolled into Study
Period I. Fourteen males (64%) and 8 females (36%) enrolled into Study Period I. Of these, 10 were
preadolescents (46%: 7 males, 3 females) and 12 were adolescents (55%: 7 males and 5 females). Twentytwo patients entered Study Period II and received fluoxetine 20 mg/day. Three patients did not complete
the study, discontinuing during Study Period II (2 for patient decision and 1 for physician decision).
Nineteen patients completed the study. The distribution at study completion consisted of 9 preadolescents
(7 males, 2 females) and 10 adolescents (6 males, 4 females). Table HCIU.1 summarizes patient
characteristics.
Concomitant Medications: Seventeen of the 22 patients (77%) received at least one concomitant
medication during the study. The most common concomitant medications were ibuprofen, a non-steroidal
anti-inflammatory, and methylphenidate hydrochloride, used in the treatment of attention deficit
hyperactivity disorder (ADHD) (exclusion criteria excluded patients taking other psychotropic drugs, with
the exception of patients who have been maintained on a stable dose of a psychostimulant used to manage
ADHD). The majority of the concomitant medications used during the study were for the treatment of
colds (viral infections) and allergies. Of note, Patient 121 initiated treatment with sertraline 50 mg daily at
Visit 3, after receiving one dose of study medication; he voluntarily discontinued from the study at that
time.
Plasma Concentrations: Table HCIU.2 shows the steady-state plasma concentrations for fluoxetine and
norfluoxetine. Overall, the plasma steady-state concentrations of fluoxetine indicated similar ranges of
observed concentrations and high between-subject variability in both preadolescents and adolescents.
Overall, the plasma steady-state concentrations of norfluoxetine in preadolescents and adolescents
indicated high between-subject variability. The range of observed norfluoxetine concentrations in
preadolescents spanned a 4.5-fold range, indicating high between-subject variability.
Fluoxetine Hydrochloride
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Page 3
Population Pharmacokinetic Parameters: The population estimate for Ka was 0.67 hr-1; however, the
model was unable to define a between-patient variability term for this parameter. The population estimates
for V/F and CL/F in pediatric patients were 1480 L and 11.8 L/hr, respectively and both were influenced by
the fraction absorbed. The volume of distribution was large, suggesting distribution of fluoxetine outside
the plasma compartment. Typical of fluoxetine pharmacokinetics in adults, the between-subject variability
in oral clearance in pediatric patients was high. On the basis of current data, the between-subject
variability for V/F and CL/F was estimated as 44.2% and 85.7%, respectively.
Comparison Between Adult and Pediatric Population: Table HCIU.2 shows overall steady-state
concentrations for fluoxetine and norfluoxetine in adults and pediatrics patients. The between-subject
variability in both populations was large although overall plasma levels between the two populations were
similar. The observed differences between fluoxetine and norfluoxetine plasma concentrations in
preadolescents and adolescents can be attributed to body weight. The overall exposure for pediatric
patients was comparable to that observed in adults. The extent of accumulation and time to reach steadystate in pediatric and adult populations were similar (Figure HCIU.2).
Exposure: Patients were exposed to fluoxetine 20 mg QD for an average of 54 days during this study.
Adverse Events: Of the 22 patients enrolled in the study, 16 (73%) reported at least one TEAE (Table
HCIU.6). No patients reported serious adverse events or discontinued due to an adverse event. The most
common adverse events (occurring with a frequency ≥10% in the entire population) were rhinitis (32%),
headache (27%), insomnia (23%), diarrhea (18%), anorexia (14%), and personality disorder (14%).
Laboratory Values: In the mean change from baseline to endpoint analysis, there were some statistically
significant differences (Table HCIU.7). A categorical distribution with respect to reference ranges (low, in
range, and high) was performed at baseline, Visit 8, and Visit 12. Several patients had out-of-range values;
however, the investigator and Lilly clinical research physician did not consider these values to be clinically
significant.
Vital Signs: There were no statistically significant changes in mean sitting heart rate, sitting diastolic
blood pressure, sitting systolic blood pressure, or weight from baseline to endpoint (Table HCIU.8). There
was a statistically significant difference from baseline for height (p=.032, Wilcoxon Signed-Rank test). On
average, patients grew 0.5 cm over the course of this study. Although not statistically significant, a mean
decrease of 0.4 kg in weight was observed for these patients over the course of the study (p=.187).
ECGs: At endpoint, there were 4 patients with abnormal ECGs (Table HCIU.9). Over the course of the
study, 3 patients with normal ECGs at baseline had abnormal ECGs at endpoint, 3 patients with abnormal
ECGs at baseline had normal ECGs at endpoint, and 1 patient had abnormal ECGs at both baseline and
endpoint.
In summary, a clear relationship between efficacy and plasma concentrations of fluoxetine has not been
established for these disease states. Consequently, extrapolation from plasma exposure data to efficacy for
pediatric patients is not possible. Potential dosage adjustments in pediatric patients should be based on
observed efficacy and tolerability.
Fluoxetine Hydrochloride
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CT Registry ID#1545
Page 4
Study Period I
No Therapy
Study Period II
Open Label
Screening
Wash out
Phase
Acute Treatment and
Pharmacokinetic Phase
(20-28 hours after first dose)
(58-62 days)
(10-12 days)
(2-28 days)
Week
Visit
Fluoxetine 20 mg/day
-1 / -4
0
1
2
3
1
2
3 4
5 6
7
2 3 4
5
4
5
8
6
7
8
9
10
11
12
7
8
9
10
Sample
1
6
Boxed numbers indicate required samples. Other samples were optional.
Figure HCIU.1.
Study design for B1Y-MC-HCIU.
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
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CT Registry ID#1545
Table HCIU.1.
Variable
------------------
Page 5
Summary of Baseline Patient Characteristics
All Enrolled Patients
B1Y-MC-HCIU
Flx 20mg
(N=22)
-------------
Sex: No. (%)
No. Patients
Female
Male
22
8 (36.4)
14 (63.6)
Origin: No. (%)
No. Patients
AFRICAN DESCENT
CAUCASIAN
HISPANIC
OTHER
22
1
18
2
1
Age: Yrs.
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
Age Group
No. Patients
Adolescent
Preadolescent
(4.5)
(81.8)
(9.1)
(4.5)
22
12.58
12.37
2.95
6.27
17.23
22
12 (54.5)
10 (45.5)
Height: cm
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
Average Weight: kg
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
22
153.08
153.42
14.92
121.92
182.88
22
53.05
54.33
20.17
21.27
93.24
RMP.B1YP.JCLLIB2(DES1IU03)
RMP.B1YO.HCIUREP(DES1IU03)
XDES0001
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
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CT Registry ID#1545
Table HCIU.1.
Variable
------------------
Page 6
Summary of Baseline Patient Characteristics (concluded)
All Enrolled Patients
B1Y-MC-HCIU
Flx 20mg
(N=22)
-------------
Body Mass Index: BMI=kg/(m x m)
No. Patients
22
Mean
21.85
Median
22.24
Standard Dev.
5.80
Minimum
14.22
Maximum
35.84
Body Surface Area: BSA=(m x m)
No. Patients
22
Mean
1.48
Median
1.52
Standard Dev.
0.34
Minimum
0.86
Maximum
1.98
RMP.B1YP.JCLLIB2(DES1IU03)
RMP.B1YO.HCIUREP(DES1IU03)
XDES0001
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
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CT Registry ID#1545
Table HCIU.2.
Page 7
Observed Fluoxetine and Norfluoxetine Concentrations at
Steady-Statea in Pediatric Patients
Category
Fluoxetine
Overall Pediatric
Preadolescents
Adolescents
Overall Adult
B1Y-MC-HCFB
B1Y-MC-HCFC
Norfluoxetine
Overall Pediatric
Preadolescents
Adolescents
Overall Adult
B1Y-MC-HCFB
B1Y-MC-HCFC
Mean (ng/mL)
SD
%CV
Range (ng/mL)
126.6
170.9
86.3
96.9
62.2
137.3
75.0
73.3
51.6
54.0
33.0
45.5
59.2
42.9
59.8
55.8
53.0
35.1
28-312
28-312
30-203
19-199
19-109
63-199
151.8
195.0
112.5
110.5
120.9
98.2
76.3
89.2
30.4
57.9
72.0
38.7
50.3
45.8
27.0
52.4
59.6
39.8
48-310
68-310
48-163
45-244
49-244
50-158
Abbreviations: CV = coefficient of variation; SD = standard deviation.
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
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CT Registry ID#1545
Page 8
Table HCIU.3.
Observed Fluoxetine Concentrations at Steady-Statea
in Pediatric Patients
Pharmacokinetic Dataset
B1Y-MC-HCIU
Category
Mean (ng/mL)
All Patients
Preadolescents
Adolescents
126.6
170.9
86.3
SD
%CV
Range (ng/mL)
75.0
73.3
51.6
59.2
42.9
59.8
28-312
28-312
30-203
Gender
Male
Female
130.9
119.5
64.1
94.5
48.9
79.1
28-243
30-312
Male
Female
151.3
216.6
65.1
83.5
43.0
38.6
28-243
155-312
59.3
28.7
55.3
46.8
57-203
30-96
Preadolescents
Adolescents
Male
Female
107.2
61.2
Depression (n=18)
OCD (n=2)
Depression & OCD (n=1)
115.8
257.2
59.6
62.2
-
53.7
-
28-243
203-312
-
Preadolescents
Depression (n=9)
OCD (n=1)
Depression & OCD (n=0)
155.2
311.6
57.4
-
37.0
-
28-243
-
76.3
202.8
59.6
37.8
-
49.5
-
30-134
-
Disease State
Overall
Adolescents
Depression (n=9)
OCD (n=1)
Depression & OCD (n=1)
Abbreviations: CV = coefficient of variation; OCD = obsessive-compulsive disorder; SD = standard
deviation.
aBased on graphical evaluation, patients were assumed to be at steady-state within 3 to 4 weeks.
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
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Page 9
Table HCIU.4.
Observed Norfluoxetine Concentrations at Steady-Statea
in Pediatric Patients
Pharmacokinetic Dataset
B1Y-MC-HCIU
Category
Mean (ng/mL)
All Patients
SD
%CV
Range (ng/mL)
Preadolescents
Adolescents
151.8
195.0
112.5
76.3
89.2
30.4
50.3
45.8
27.0
48-310
68-310
48-163
Male
Female
155.6
145.6
79.7
75.5
51.2
51.8
68-290
48-310
Male
Female
192.3
201.4
94.8
93.7
49.3
46.5
68-290
143-310
Male
Female
112.9
112.1
19.5
42.8
17.2
38.2
85-140
48-163
Depression (n=18)
OCD (n=2)
Depression & OCD (n=1)
147.2
207.7
122.6
72.1
-
49.0
-
48-290
106-310
-
Preadolescents
Depression (n=9)
OCD (n=1)
Depression & OCD (n=0)
182.3
309.5
-
84.5
-
46.4
-
68-290
-
Adolescents
Depression (n=9)
OCD (n=1)
Depression & OCD (n=1)
112.2
105.8
122.6
33.7
-
30.0
-
48-163
-
Gender
Preadolescents
Adolescents
Disease State
Overall
Abbreviations: CV = coefficient of variation; OCD = obsessive-compulsive disorder; - = not applicable; SD
= standard deviation.
aBased on graphical evaluation, patients were assumed to be at steady-state within 3 to 4 weeks.
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
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CT Registry ID#1545
Table HCIU.5.
Page 10
One-Compartment Population Pharmacokinetic Model
for Fluoxetine in Pediatric Patients
Pharmacokinetic Dataset
B1Y-MC-HCIU
Parameter
Estimatesa
(% SEE)b
Between-Patient Variability, ω;
as %CV
(%SEE)
Ka (hr-1)
CL/F (L/hr)
V/F (L)
0.666 (35.7)
11.8 (16.7)
1480 (14.4)
-2
85.7 (26)
44.2 (37)
Residual Error,σ, as %CV,
24.3 (27)
(%SEE)
Abbreviations: CL/F = oral clearance; Ka = absorption rate constant; %SEE = standard errors of the
NONMEM estimates expressed as % of estimate; V/F = apparent volume of distribution.
a
First-order method with conditional estimation.
b
Not estimated with adequate precision.
Fluoxetine Hydrochloride
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CT Registry ID#1545
Table HCIU.6.
Page 11
Treatment-Emergent Adverse Events
Incidence by Decreasing Frequency
All Enrolled Patients
B1Y-MC-HCIU
Event Classification
-----------------------PATIENTS WITH >= 1 TESS
PATIENTS WITH NO TESS
RHINITIS
HEADACHE
INSOMNIA
DIARRHEA
ANOREXIA
PERSONALITY DISORDER
ABDOMINAL PAIN
ASTHENIA
FLU SYNDROME
ABNORMAL DREAMS
ANXIETY
DEPRESSION
DYSMENORRHEA
DYSPEPSIA
ECCHYMOSIS
FEVER
HOSTILITY
HYPERKINESIA
INCREASED SALIVATION
MYALGIA
NAUSEA
PHARYNGITIS
THINKING ABNORMAL
TOOTH DISORDER
Flx 20mg
(N=22)
n (%)
--------16 (72.7)
6 (27.3)
7 (31.8)
6 (27.3)
5 (22.7)
4 (18.2)
3 (13.6)
3 (13.6)
2 (9.1)
2 (9.1)
2 (9.1)
1 (4.5)
1 (4.5)
1 (4.5)
1 (4.5)
1 (4.5)
1 (4.5)
1 (4.5)
1 (4.5)
1 (4.5)
1 (4.5)
1 (4.5)
1 (4.5)
1 (4.5)
1 (4.5)
1 (4.5)
RMP.B1YP.JCLLIB2(AES2IU36)
RMP.B1YO.HCIUREP(AES2IU36)
XAES0002
Fluoxetine Hydrochloride
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Page 12
Plasma Fluoxetine Concentration (ng/mL)
350
300
250
200
150
100
50
0
0
1
2
3
4
5
6
7
8
9
10
9
10
Time (weeks)
3
4
5 6
7
8
9
10
11
6
7
12
Plasma Norfluoxetine Concentration (ng/mL)
Visit
350
300
250
200
150
100
50
0
0
1
2
3
4
5
8
Time (weeks)
3
4
5 6
7
8
9
10
11
12
Visit
Pre-Adolescent Pediatric Patients (HCIU)
Adolescent Pediatric Patients (HCIU)
Adult Patients (HCFB)
Adult Patients (HCFC)
For clarity, only unidirectional error bars are presented.
Figure HCIU.2.
Mean (standard deviation) observed fluoxetine and
norfluoxetine plasma concentrations.
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
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Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Table HCIU.7.
Approved by Lilly 15 November 2004
Clinical Laboratory Analysis
Change From Baseline to Endpoint, Statistically Significant Results
All Enrolled Patients With Baseline and Postbaseline Data
B1Y-MC-HCIU
Clinical Laboratory
Test
Leukocyte count (bill/L)
Segmented neutrophils
(bill/L)
Monocytes (bill/L)
GGT (U/L)
Creatinine (µmol/L)
Calcium (mmol/L)
Total protein (g/L)
n
Mean
Baseline
Median
SD
Mean
Endpoint
Median
SD
Mean
Change
Median
SD
p-value*
21
7.68
7.48
2.06
6.58
6.37
1.48
-1.10
-1.18
2.04
0.027
21
21
21
21
21
21
4.33
0.50
12.38
77.90
2.39
73.50
4.27
0.47
13.00
70.70
2.37
73.00
1.59
0.15
2.73
14.70
0.09
3.50
3.67
0.41
11.43
74.90
2.34
72.00
3.26
0.36
11.00
79.60
2.32
73.00
1.31
0.14
2.42
13.00
0.10
4.30
-0.66
-0.09
-0.95
-2.90
-0.05
-1.50
-0.90
-0.11
-1.00
0.00
-0.03
-2.00
1.37
0.16
1.94
8.50
0.10
2.70
0.033
0.016
0.025
0.034
0.039
0.023
Abbreviations: GGT = gamma-glutamyl transferase; SD = standard deviation.
* Within-treatment p-value = location shift from zero of the change from baseline as tested by the Wilcoxon Signed-Rank procedure.
CT Registry ID#1545
Page 13
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Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Table HCIU.8.
Vital Signs
Change From Baseline to Endpoint
All Enrolled Patients With Baseline and Postbaseline Data
B1Y-MC-HCIU
Variable analyzed:
No.
--1)
Therapy
-------Flx 20mg
No.
--1)
Therapy
-------Flx 20mg
Approved by Lilly 15 November 2004
n
--22
SITTING HEART RATE (PULSE) (SI_HR)
Baseline
------------------------------Mean
Median
SD
--------- --------- --------84.636
85.500
10.870
p-Values
------Within
Group*1
------.113
Endpoint
------------------------------Mean
Median
SD
--------- --------- --------81.045
79.500
15.831
Change
------------------------------Mean
Median
SD
--------- --------- ---------3.591
-5.000
13.088
*1 The significance of a location shift from zero of the change from baseline within a treatment group is tested by the Wilcoxon
Signed Rank procedure.
RMP.B1YP.JCLLIB2(LAS3IU15)
RMP.B1YO.HCIUREP(LAS3IU15)
XLAS0003
CT Registry ID#1545
Page 14
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Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Table HCIU.8.
Vital Signs (continued)
Change From Baseline to Endpoint
All Enrolled Patients With Baseline and Postbaseline Data
B1Y-MC-HCIU
Variable analyzed:
No.
--1)
Therapy
-------Flx 20mg
No.
--1)
Therapy
-------Flx 20mg
Approved by Lilly 15 November 2004
n
--22
SITTING DIASTOLIC BLOOD PRESSURE (SI_DIABP)
Baseline
------------------------------Mean
Median
SD
--------- --------- --------67.636
65.000
11.206
p-Values
------Within
Group*1
------.407
Endpoint
------------------------------Mean
Median
SD
--------- --------- --------69.182
69.000
8.122
Change
------------------------------Mean
Median
SD
--------- --------- --------1.545
3.000
11.628
*1 The significance of a location shift from zero of the change from baseline within a treatment group is tested by the Wilcoxon
Signed Rank procedure.
RMP.B1YP.JCLLIB2(LAS3IU15)
RMP.B1YO.HCIUREP(LAS3IU15)
XLAS0003
CT Registry ID#1545
Page 15
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Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Table HCIU.8.
Vital Signs (continued)
Change From Baseline to Endpoint
All Enrolled Patients With Baseline and Postbaseline Data
B1Y-MC-HCIU
Variable analyzed:
No.
--1)
Therapy
-------Flx 20mg
No.
--1)
Therapy
-------Flx 20mg
Approved by Lilly 15 November 2004
n
--22
SITTING SYSTOLIC BLOOD PRESSURE (SI_SYSBP)
Baseline
------------------------------Mean
Median
SD
--------- --------- --------113.227
112.000
15.817
p-Values
------Within
Group*1
------.602
Endpoint
------------------------------Mean
Median
SD
--------- --------- --------110.636
110.000
12.693
Change
------------------------------Mean
Median
SD
--------- --------- ---------2.591
-2.500
16.727
*1 The significance of a location shift from zero of the change from baseline within a treatment group is tested by the Wilcoxon
Signed Rank procedure.
RMP.B1YP.JCLLIB2(LAS3IU15)
RMP.B1YO.HCIUREP(LAS3IU15)
XLAS0003
CT Registry ID#1545
Page 16
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Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Table HCIU.8.
Vital Signs (continued)
Change From Baseline to Endpoint
All Enrolled Patients With Baseline and Postbaseline Data
B1Y-MC-HCIU
Variable analyzed:
No.
--1)
Therapy
-------Flx 20mg
No.
--1)
Therapy
-------Flx 20mg
Approved by Lilly 15 November 2004
n
--22
WEIGHT IN KG (WEIGHTKG)
Baseline
------------------------------Mean
Median
SD
--------- --------- --------53.384
54.431
20.271
p-Values
------Within
Group*1
------.187
Endpoint
------------------------------Mean
Median
SD
--------- --------- --------53.025
54.885
20.187
Change
------------------------------Mean
Median
SD
--------- --------- ---------0.359
-0.227
1.041
*1 The significance of a location shift from zero of the change from baseline within a treatment group is tested by the Wilcoxon
Signed Rank procedure.
RMP.B1YP.JCLLIB2(LAS3IU15)
RMP.B1YO.HCIUREP(LAS3IU15)
XLAS0003
CT Registry ID#1545
Page 17
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Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Table HCIU.8.
Vital Signs (concluded)
Change From Baseline to Endpoint
All Enrolled Patients With Baseline and Postbaseline Data
B1Y-MC-HCIU
Variable analyzed:
No.
--1)
Therapy
-------Flx 20mg
No.
--1)
Therapy
-------Flx 20mg
Approved by Lilly 15 November 2004
n
--22
HEIGHT IN CM (HEIGHT)
Baseline
------------------------------Mean
Median
SD
--------- --------- --------153.162
154.051
15.064
p-Values
------Within
Group*1
------.032
Endpoint
------------------------------Mean
Median
SD
--------- --------- --------153.624
154.305
14.768
Change
------------------------------Mean
Median
SD
--------- --------- --------0.462
0.000
1.042
*1 The significance of a location shift from zero of the change from baseline within a treatment group is tested by the Wilcoxon
Signed Rank procedure.
RMP.B1YP.JCLLIB2(LAS3IU15)
RMP.B1YO.HCIUREP(LAS3IU15)
XLAS0003
CT Registry ID#1545
Page 18
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CT Registry ID#1545
Table HCIU.9.
Page 19
Electrocardiograms
Change From Baseline to Endpoint
All Enrolled Patients With Baseline and Postbaseline Data
B1Y-MC-HCIU
Flx 20mg
(N=22)
n (%)
--------14 (63.6)
3 (13.6)
17 (77.3)
BASECG
(Visit: 1)
-----------1Normal
ENDECG
(Visit: 12)
-----------1Normal
2Abnormal
Total
2Abnormal
1Normal
2Abnormal
3Missing
Total
3 (13.6)
1 (4.5)
1 (4.5)
5 (22.7)
Total
1Normal
2Abnormal
3Missing
Total*
17 (77.3)
4 (18.2)
1 (4.5)
22
RMP.B1YP.JCLLIB2(DES2IU16)
RMP.B1YO.HCIUREP(DES2IU16)
BASECG: Patient ECG (Visit: 1)
ENDECG: Patient ECG (Visit: 12)
Note: N = Total number of patients in the therapy treatment group.
*Note: The number of patients may be less than N due to
patients having a missing value for either variable.
XDES0002
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
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CT Registry ID#2201
Page 1
Summary ID#2201
Clinical Study Summary: Study B1Y-MC-HCJE
Title of Study: Fluoxetine Versus Placebo in Childhood/Adolescent Depression
Investigator(s): This multicenter study included 19 principal investigators, 15 of whom randomized
patients.
Study Center(s): This study was conducted at 20 study centers, 16 of which randomized patients, in one
country.
Phase of Development: 3
Length of Study: 8 months / 1 year
Date first patient enrolled: 27 April 1998
Date last patient completed: 16 December 1999
Objectives:
Primary Objective: Based on a responder analysis of the Children's Depression Rating Scale-Revised
(CDRS-R), to test the hypothesis that fluoxetine 20 mg/day was more effective than placebo in the acute
treatment of child (aged 8 to <13 years) and adolescent outpatients (aged 13 to <18 years) diagnosed with
Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) major depression as
measured by response rates on the CDRS-R. Response was defined as a decrease of at least 30% in the
CDRS-R total score from baseline to endpoint.
Secondary Objectives: To compare the efficacy of continued fluoxetine 20 mg/day with fluoxetine 40 to
60 mg/day among the nonresponders to 20 mg/day following acute treatment; to compare the efficacy of
fluoxetine 20 to 60 mg/day with placebo in subchronic treatment as measured by response rates on the
CDRS-R after up to 19 weeks; to compare the efficacy of fluoxetine 20 mg/day (acute) and fluoxetine 20 to
60 mg/day (subchronic) with placebo as measured by the mean change in CDRS-R, Clinical Global
Impression of Severity (CGI-Severity), Clinical Global Impression of Improvement (CGI-Improvement),
the KIDDE Schedule for Affective Disorders and Schizophrenia–Present and Lifetime (K-SADS-PL)
(Affective Disorders module only), Montgomery-Asberg Depression Rating Scale (MADRS), Beck
Depression Inventory (BDI), and Children’s Depression Inventory (CDI) scores from baseline to endpoint;
to compare the effects of fluoxetine 20 mg/day (acute) and fluoxetine 20 to 60 mg/day (subchronic) with
placebo on symptoms of anxiety as measured by mean changes in the Hamilton Anxiety Rating Scale
(HAMA) scores from baseline to endpoint; to compare the safety of fluoxetine 20 mg/day (acute) and
fluoxetine 20 mg/day to 60 mg/day (subchronic) with placebo.
Study Design: Multicenter, double-blind, randomized, parallel-group, placebo-controlled study.
Fluoxetine was compared with placebo for efficacy and safety in children and adolescents diagnosed with
major depressive disorder (MDD) according to DSM-IV criteria.
The study consisted of six study periods, as described below. Overall, the study was divided into three
phases for the purposes of data analysis: a 9-week acute treatment phase (Study Period III through Study
Period IV), a 19-week subchronic treatment phase (Study Period III through Study Period V), and a 32week relapse prevention phase (Study Period VI).
Study Period I was a diagnostic evaluation period that lasted for 2 weeks.
Study Period II was a single-blind, placebo wash-out period that lasted for 1 week. Placebo responders
were discontinued from the study.
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Study Period III was a double-blind adaptation period that lasted for 1 week. Patients were randomized to
receive either fluoxetine 10 mg/day or placebo.
Study Period IV was a double-blind, fixed-dose acute treatment period that lasted for 8 weeks. Patients
randomized to fluoxetine received 20 mg/day during this period.
Study Period V was a double-blind, nonresponder rerandomization period that lasted for 10 weeks.
Patients were evaluated for response at Visit 10 and Visit 12. Responders at Visit 10 remained on
fluoxetine 20 mg/day or placebo. Fluoxetine nonresponders were rerandomized to either remain on
fluoxetine 20 mg/day or to receive fluoxetine 40 mg/day with an option to titrate to 60 mg/day at Visit 12.
Placebo nonresponders remained on placebo.
Study Period VI was a double-blind, relapse prevention period that lasted for 32 weeks. Fluoxetine
responders were rerandomized to either continue on the current fluoxetine dose or placebo. Placebo
responders remained on placebo.
The six study periods are presented in Figures HCJE.1 and HCJEr.2.
Number of Patients:
Planned: 220 patients; 110 patients per treatment group
Randomized: 109 fluoxetine (male 55, female 54), 110 placebo (male 56, female 54)
Children (8 to <13): fluoxetine 61, placebo 61, total 122;
Adolescents (13 to <18): fluoxetine 48, placebo 49, total 97.
Completed: 90 fluoxetine, 68 placebo completed Study Periods III to IV.
Completed: 40 fluoxetine, 35 placebo completed Study Periods III to V.
Completed: 10 fluoxetine/fluoxetine, 8 fluoxetine/placebo, 17 placebo/placebo completed Study Period
VI.
Diagnosis and Main Criteria for Inclusion: Outpatients with a primary diagnosis of nonpsychotic MDD
(single or recurrent episode) according to the DSM-IV, aged 8 to <18 years, and were willing and able to
provide informed consent (parent and patient). Diagnosis of MDD was dependent on evaluation of the
Missouri Assessment of Genetics Interview for Children (MAGIC) or Diagnostic Interview for Children
and Adolescents (DICA). Patients were required to have a Children's Depression Rating Scale-Revised
(CDRS-R) score >40 and a rating of at least moderate on the Clinical Global Impression of Severity (CGISeverity) scale at study entry.
Test Product, Dose, and Mode of Administration: Fluoxetine 10 mg to 60 mg, given orally once daily
as 10 mg and 20 mg fluoxetine capsules
Duration of Treatment: Acute treatment phase: (9 weeks)
Subchronic treatment phase: 19 weeks
Relapse prevention phase: 32 weeks
Total duration of treatment: 51 weeks
Reference Therapy, Dose, and Mode of Administration: Placebo capsules given orally once daily
Variables:
Efficacy: Primary efficacy analysis was response on the CDRS-R. Secondary analyses included
additional evaluations of CDRS-R, CGI-Improvement, CGI-Severity, BDI, CDI, MADRS, HAMA, Global
Assessment of Functioning (GAF) Current Functioning, and the Affective Disorders module of the KSADS-PL.
Safety: Safety was evaluated through the reporting of concomitant medications, vital signs, routine
laboratory testing, electrocardiograms (ECGs), and adverse event data (solicited and non-solicited).
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Evaluation Methods:
Statistical: Analyses were conducted on an intent-to-treat basis unless otherwise specified. All tests of
hypotheses were considered statistically significant if the two-sided p-value was less than .05. For analyses
of continuous data, treatment groups were compared using last-observation-carried-forward (LOCF) with
Type III sums of squares from an analysis of variance (ANOVA) with treatment in the model. For analyses
of categorical data, Fisher's exact test was used.
An ANOVA (Type III sums of squares) with the term treatment in the model was used when comparing
change scores or endpoint scores between treatments. Analyses were performed on both the original and
the rank-transformed data. The analysis of the original data was considered primary unless there was
evidence to suggest non-normality. As secondary analyses, an ANOVA with treatment, investigator,
gender, age category, and the treatment-by-investigator interaction in the model was used. Fisher's exact
test was used to compare percentages. Logistic regression models with treatment, investigator, gender, age
category, and the treatment-by-investigator interaction were also used to compare percentages, but were
considered secondary. The repeated measures analysis of variance was performed using a mixed-model
approach with the dependent variable being the baseline and postbaseline CDRS-R total scores. The
independent factors were treatment, investigator, treatment-by-investigator interaction, visit as the withinsubject factor, and treatment-by-visit interaction. If the treatment-by-investigator interaction was not
statistically significant at the level .10, then this interaction effect was excluded from the model. All main
effects and interaction tests were made using the approximate F test reported by SAS PROC MIXED. An
unstructured covariance matrix was used.
Summary:
This double-blind, placebo-controlled study of the efficacy of fluoxetine versus placebo in the treatment of
MDD in children and adolescents consisted of three study phases. Results from the 9-week acute treatment
phase (Study Periods III through IV), the 19-week subchronic treatment phase (Study Periods III through
V), and the 32-week relapse prevention phase are presented in this report.
Two hundred nineteen patients were randomized to treatment in this study, with 109 patients receiving
fluoxetine and 110 patients receiving placebo. One hundred fifty-eight (72%) patients completed acute
treatment (90, 83% fluoxetine-treated; 68, 62% placebo-treated). Seventy-five (34%) patients completed
subchronic treatment (40, 37% fluoxetine-treated; 35, 32% placebo-treated). The treatment groups were
balanced with respect to demographic characteristics and psychiatric evaluations at baseline. Patient
baseline characteristics are presented in Table HCJE.1 (acute treatment phase) and Table HCJE.2 (relapseprevention phase)
In the acute phase, 65% of fluoxetine-treated patients met response criteria as compared with 54% of
placebo-treated patients, a difference that was not statistically significant (p=.093). Statistically
significantly more fluoxetine-treated patients had decreases in CDRS-R total score of 20%, 40%, 50%, and
60% from baseline as compared with placebo-treated patients. Statistical significance was also achieved in
favor of fluoxetine treatment for CDRS-R total score mean change (-22 fluoxetine, -15 placebo; p<.001),
and for remission (p<.01) and recovery (p<.01) analyses for CDRS-R. In addition, endpoint (p=.025) and
response (p=.028) analyses of CGI-Improvement scores demonstrated the statistical superiority of
fluoxetine treatment over placebo treatment (Table HCJE.3).
Efficacy variables that demonstrated statistical superiority of fluoxetine treatment over placebo treatment
during the acute treatment phase are summarized below in Table HCJE.4.
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Twice as many patients treated at the higher dose levels demonstrated response on the CDRS-R as
compared with patients who remained on fluoxetine 20 mg/day that was a nonsignificant difference (71%
fluoxetine 40 mg or 60 mg, 36% fluoxetine 20 mg; p=.128). Patients receiving fluoxetine 40 mg or 60
mg/day demonstrated a nonsignificant mean change in CDRS-R total score (-9.4 fluoxetine 40 mg or
60 mg, -1.5 fluoxetine 20 mg; p=.099).
Fluoxetine 20 to 60 mg/day was found to be statistically superior to placebo when patients were treated
subchronically, as supported by the observed response rates on the CDRS-R total score (75% fluoxetine,
60% placebo; p=.026) and CDRS-R total score mean change (-23 fluoxetine, -19 placebo; p=.021). The
analysis of mean change in CGI-Severity scores similar results (p=.025). (Table HCJE.5, Table HCJE.6,
Table HCJE.7, Figure HCJE.3, Figure HCJE.4, Figure HCJE.5, Table HCJE.8, Table HCJE.9). Table
HCJE.10 summarizes CDRS-R total score for the relapse-prevention phase.
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Pharmacokinetic results showed that observed fluoxetine plasma concentrations in children were 2-fold
higher than those in adolescents, and observed norfluoxetine plasma concentrations in children were 1.5fold higher than in those in adolescents. Differences between fluoxetine and norfluoxetine plasma
concentrations in children and adolescents may be attributed to body weight.
A total of nine serious adverse events occurred during Study Periods I through V; three of these occurred
prior to randomization. Six serious advents occurred following randomization (two in fluoxetine-treated
patients, four in placebo-treated patients). Twenty-three patients (1 not randomized, 11 fluoxetine-treated,
11 placebo-treated) discontinued due to an adverse event during Study Periods I through V. No statistically
significant differences were observed between treatment groups in discontinuations due to adverse events
during either acute or subchronic treatment, and no event that led to discontinuation occurred in more than
1 fluoxetine-treated patient. There were no serious adverse events reported during the relapse prevention
phase (Study Period VI). Three patients (1 fluoxetine/fluoxetine treated and 2 placebo/placebo treated)
discontinued due to an adverse event during Study Period VI. No statistically significant differences were
observed between treatment groups in discontinuations due to adverse events during the relapse prevention
phase.
Headache was the only non-solicited adverse event reported by more fluoxetine-treated patients than
placebo-treated patients (p=.017 and .014 for the acute treatment phase and subchronic treatment phase,
respectively). All other reported adverse events were not significantly different between fluoxetine-treated
and placebo-treated patients (Table HCJE.11, Table HCJE.13, Table HCJE.15, and Table HCJE.16). Table
HCJE.12 and Table HCJE.14 summarize treatment-emergent adverse events for the relapse prevention
phase.
Fluoxetine-treated patients demonstrated a statistically significantly greater decrease in alkaline
phosphatase levels as compared with placebo-treated patients. No fluoxetine-treated patients had a
decrease in alkaline phosphatase that was outside normal range. Lesser increases in both weight and height
were also observed in fluoxetine-treated patients during subchronic treatment. There were no statistically
significant differences between Flx/Flx and Flx/Plc patients for mean change in any laboratory value or in
the incidence of any treatment-emergent abnormal laboratory value during the relapse prevention phase.
Two independent, blinded analyses of ECG interval changes did not reveal clinically significant changes in
any ECG parameter.
Subgroup analyses of efficacy and safety endpoints indicated that there were no differences in the
effectiveness or safety profile for subgroups based on age category, gender, or family history of depression.
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Subchronic Treatment Phase
Acute Treatment Phase
60 mg/day
Nonresponders 40 mg/day
Nonresponders 20 mg/day
Fluoxetine 20 mg/day
Responders 20 mg/day
Fluoxetine 10 mg/day
No Drug
Placebo
Placebo
Visit 1 2
Week -3 -2
I
3
-1
4
0
II
III
Figure HCJE.1.
5
1
6
2
7
3
8
5
9
7
10
9
11
11
12
13
IV
13
15
14
17
15
19
V
Study Design for Study Periods I through V.
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Long-Term Treatment Phase (Study Periods III-VI)
Relapse Prevention Phase (Study Period VI)
Fluoxetine 20 to 60 mg/day
Fluoxetine
20 to 60
mg/day
Placebo
Placebo
Placebo
Rerandomization (1:1) at Visit 16
Visit 15
Week 19
16
21
17
23
18
25
19
27
20
29
21
31
V
Figure HCJE.2.
22
35
23
39
24
43
25
47
26
51
VI
Study Design for Study Period VI.
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Table HCJE.1.
Variable
-----------------Origin
No. Patients
Caucasian
East, SE Asian
African American
Hispanic
Other
Age
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
Page 8
Baseline Patient Characteristics
All Randomized Patients
B1Y-MC-HCJE
Flx 20
(N=109)
-------------
109
96
1
6
3
3
(88.1)
(0.9)
(5.5)
(2.8)
(2.8)
109
12.70
12.56
2.46
8.26
17.52
Placebo
(N=110)
-------------
110
84
0
8
10
8
(76.4)
(7.3)
(9.1)
(7.3)
110
12.69
12.50
2.67
8.01
17.85
Total
(N=219)
-------------
219
180
1
14
13
11
p-Value
-------------
.071*
(82.2)
(0.5)
(6.4)
(5.9)
(5.0)
219
12.70
12.56
2.56
8.01
17.85
.983**
Age Category
No. Patients
8 - < 13 yrs.
13 - < 18 yrs.
109
61 (56.0)
48 (44.0)
110
61 (55.5)
49 (44.5)
219
122 (55.7)
97 (44.3)
1.00*
Gender
No. Patients
Female
Male
109
54 (49.5)
55 (50.5)
110
54 (49.1)
56 (50.9)
219
108 (49.3)
111 (50.7)
1.00*
Height(cm)
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
Unspecified
108
155.53
156.21
14.55
124.46
187.96
1
110
153.98
154.94
13.05
121.92
182.88
0
218
154.75
154.94
13.80
121.92
187.96
1
.409**
RMP.B1YP.JCLLIB2(DES1JEAA)
RMP.B1YO.HCJEREP(DES1JEAA)
* Frequencies are analyzed using a Fishers-Exact test.
** Means are analyzed using a Type III Sum of Squares analysis of variance
(ANOVA): PROC GLM model=treatment.
XDES0001
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Table HCJE.1.
Variable
-----------------Weight(kg)
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
Unspecified
Page 9
Baseline Patient Characteristics
All Randomized Patients
B1Y-MC-HCJE (concluded)
Flx 20
(N=109)
-------------
Placebo
(N=110)
-------------
Total
(N=219)
-------------
108
57.06
53.30
19.33
20.87
102.97
1
110
56.85
55.57
19.96
26.76
140.61
0
218
56.96
54.43
19.61
20.87
140.61
1
p-Value
-------------
.937**
RMP.B1YP.JCLLIB2(DES1JEAA)
RMP.B1YO.HCJEREP(DES1JEAA)
* Frequencies are analyzed using a Fishers-Exact test.
** Means are analyzed using a Type III Sum of Squares analysis of variance
(ANOVA): PROC GLM model=treatment.
XDES0001
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Table HCJE.2.
Page 10
Baseline Patient Characteristics
All Patients Entering Study Period VI
Variable
------------------
Flx/Flx
(N=20)
-----------
Origin
No. Patients
Caucasian
East, SE Asian
African American
20
17 (85.0)
1 (5.0)
2 (10.0)
Age
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
20
13.45
13.70
2.38
8.91
17.52
Flx/Plc
(N=20)
-----------
20
20 (100)
0
0
20
11.65
10.90
2.48
8.26
16.27
Total
(N=40)
-----------
40
37 (92.5)
1 (2.5)
2 (5.0)
40
12.55
12.25
2.57
8.26
17.52
p-Value
-----------
.231*
.025**
Age Category
No. Patients
8 - < 13 yrs.
13 - < 18 yrs.
20
8 (40.0)
12 (60.0)
20
13 (65.0)
7 (35.0)
40
21 (52.5)
19 (47.5)
.205*
Gender
No. Patients
Female
Male
20
9 (45.0)
11 (55.0)
20
11 (55.0)
9 (45.0)
40
20 (50.0)
20 (50.0)
.752*
Height(cm)
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
Unspecified
20
160.65
162.56
11.42
142.24
182.88
0
19
150.53
147.32
14.19
124.46
175.26
1
39
155.72
157.48
13.67
124.46
182.88
1
.019**
Weight(kg)
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
20
61.85
60.78
18.42
34.02
102.97
20
58.35
54.88
21.48
25.85
96.16
40
60.10
57.15
19.83
25.85
102.97
.584**
Flx/Flx: patients who received fluoxetine treatment during Study Periods III-V
and were rerandomized to fluoxetine treatment during Study Period VI.
Flx/Plc: patients who received fluoxetine treatment during Study Periods III-V
and were rerandomized to placebo treatment during Study Period VI.
RMP.B1YP.JCLLIB3(DES1JERA)
RMP.B1YO.HCJEREP(DES1JERA)
* Frequencies are analyzed using a Fishers-Exact test.
** Means are analyzed using a Type III Sum of Squares analysis of variance
(ANOVA): PROC GLM model=treatment.
XDES0001
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Table HCJE.2.
Variable
-----------------Origin
No. Patients
Caucasian
African American
Hispanic
Other
Age
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
Page 11
Baseline Patient Characteristics
All Patients Entering Study Period VI
(concluded)
Plc/Plc
(N=35)
-----------
35
28
3
2
2
(80.0)
(8.6)
(5.7)
(5.7)
35
12.43
11.98
2.83
8.01
17.62
Age Category
No. Patients
8 - < 13 yrs.
13 - < 18 yrs.
35
21 (60.0)
14 (40.0)
Gender
No. Patients
Female
Male
35
16 (45.7)
19 (54.3)
Height(cm)
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
Unspecified
33
155.56
157.48
13.43
132.08
182.88
2
Weight(kg)
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
35
55.45
56.25
16.99
28.12
85.73
Plc/Plc: patients who received placebo treatment during Study Periods III-V
and continued receiving placebo treatment during Study Period VI.
RMP.B1YP.JCLLIB3(DES1JERA)
RMP.B1YO.HCJEREP(DES1JERA)
XDES0001
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Table HCJE.3.
Page 12
Efficacy Variables Analyzed
Acute Therapy Phase
Study B1Y-MC-HCJE
Efficacy Variable Analyzed
p-Value
Response, at least a 20% reduction in CDRS-R Total score from baseline (at endpoint)
Response, at least a 40% reduction in CDRS-R Total score from baseline (at endpoint)
Remission, CDRS-R endpoint score ≤28
Recovery, CDRS-R score ≤28 and CGI-Improvement score of 1 or 2 at endpoint
Mean change from baseline to endpoint in CDRS-R Total score
Mean change from baseline to endpoint in CDRS-R Mood subtotal score
Mean change from baseline to endpoint in CDRS-R Somatic subtotal score
Mean change from baseline to endpoint in CDRS-R Behavior subtotal score
Mean change from baseline to endpoint in CDRS-R Subjective subtotal score
Endpoint analysis of CGI-Improvement score
Response, CGI-Improvement score of 1 or 2 at endpoint
Mean change from baseline to endpoint in CGI-Severity score
Mean change from baseline to endpoint in MADRS score
.002
.002
<.01
<.01
<.001
.002
.004
<.001
.026
.025
.028
<.001
.023
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Table HCJE.4.
Page 13
Efficacy Variables Analyzed
Subchronic Treatment Phase
Study B1Y-MC-HCJE
Efficacy Variable Analyzed
p-Value
Response, at least a 30% reduction in CDRS-R Total score from baseline (at endpoint)
Mean change from baseline to endpoint in CDRS-R Total score
Mean change from baseline to endpoint in CDRS-R Behavior subtotal score
Mean change from baseline to endpoint in CGI-Severity score
.026
.021
.011
.025
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Table HCJE.5.
Page 14
Categorical Efficacy Analyses
All Randomized Patients
B1Y-MC-HCJE
Measure
CDRS-R Total Responseb
CDRS-R Total Remissionc
CGI-Improvement Responsed
Recovery Ratee
Acute Treatment
(Study Periods III-IV)
Flx 20
Placebo
(%)
(%)
p-Valuea
65
41
52
39
54
20
37
20
.093
<.01
.028
<.01
Subchronic Treatment
(Study Periods III-V)
Flx 20-60 Placebo
(%)
(%)
p-Valuea
75
51
63
51
60
46
52
46
.026
.493
.099
.493
aFisher’s
exact test.
30% or greater reduction in CDRS-R total score from baseline to endpoint.
cRemission- endpoint CDRS-R total score ≤28.
dCGI-Improvement Response- endpoint score of 1 (very much improved) or 2 (much improved).
eRecovery- CDRS-R total score ≤28 combined with an endpoint CGI-Improvement score of 1 (very much
improved) or 2 (much improved).
Abbreviations: CDRS-R = Children’s Depression Rating Scale-Revised; CGI = Clinical Global
Impression; Flx = fluoxetine.
bResponse-
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Table HCJE.6.
Page 15
Continuous Efficacy Analyses
All Randomized Patients
B1Y-MC-HCJE
Measure
Acute Treatment
(Study Periods III-IV)
p-Value
Subchronic Treatment
(Study Periods III-V)
p-Value
<.001
.002
.004
.026
<.001
.025
<.001
.700
.822
.023
.115
.176
.021
.055
.181
.078
.011
.323
.025
1.00
.068
.212
.669
.803
CDRS-R Total Mean Change
CDRS-R Mood Subtotal Mean Change
CDRS-R Somatic Subtotal Mean Change
CDRS-R Subjective Subtotal Mean Change
CDRS-R Behavior Subtotal Mean Change
CGI-Improvement Endpoint Score
CGI-Severity Mean Change
BDI Total Mean Change
CDI Total Mean Change
MADRS Total Mean Change
HAMA Total Mean Change
GAF: Current Functioning Mean Change
Abbreviations: BDI = Beck Depression Inventory; CDI = Children’s Depression Inventory; CDRS-R =
Children’s Depression Rating Scale-Revised; CGI = Clinical Global Impression; GAF = Global
Assessment of Functioning; HAMA = Hamilton Anxiety Rating Scale; MADRS = Montgomery-Asberg
Depression Rating Scale.
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Table HCJE.7.
Page 16
CDRS-R Total Score
Number of Patients Meeting Criteria for Response
All Randomized Patients
Acute Treatment Phase (Study Period IV)
B1Y-MC-HCJE
Protocol: B1Y-MC-HCJE
Outcome Variable: RESPONSE - 30% REDUCTION FROM BASELINE
Stratification Variable: INVESTIGATOR (number of strata = 14)
Therapy
-- -----------------A. Flx 20
B. Placebo
NO
n
%
------ ---------38
34.9
47
46.5
N
------109
101
YES
n
%
------ ---------71
65.1
54
53.5
Comparison of All Treatments
STATISTICS
-----------------------------Fisher's exact test
(2-tailed)
Pearson's chi-square test
df=1
# Cochran-Mantel-Haenszel
general association test
df=1
P-VALUE
----------0.093
0.085
0.077
#: Stratification variable included.
Investigators 6 and 17 are pooled into Investigator 999
RMP.B1YP.JCLLIB2(EFS1JEMA)
RMP.B1YO.HCJEREP(EFS1JEMA)
XEFS0001
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
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CT Registry ID#2201
Page 17
Percent Patients Meeting Response Criteria
100%
*
90%
*
80%
70%
60%
*
50%
*
40%
30%
*
20%
10%
0%
>=70
>=60
>=50
>=40
>=30
>=20
>=10
>=0
Percent Change in CDRS-R Total Score from Baseline
Fluoxetine
Placebo
*Statistically significant difference between treatment groups.
Figure HCJE.3.
Percent change distribution in CDRS-R total score for all
randomized patients during the acute treatment phase
(Study Period IV) of B1Y-MC-HCJE.
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
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CT Registry ID#2201
Table HCJE.8.
Page 18
CDRS-R Total Score
Number of Patients Meeting Criteria for Remission
All Randomized Patients
Acute Treatment Phase (Study Period IV)
B1Y-MC-HCJE
Protocol: B1Y-MC-HCJE
Outcome Variable: REMISSION - SCORE <=28
Stratification Variable: INVESTIGATOR (number of strata = 14)
Therapy
-- -----------------A. Flx 20
B. Placebo
NO
n
%
------ ---------64
58.7
81
80.2
N
------109
101
YES
n
%
------ ---------45
41.3
20
19.8
COMPARISON OF TREATMENT GROUPS
STATISTICS
-----------------------------Fisher's exact test
(2-tailed)
Pearson's chi-square test
df=1
# Cochran-Mantel-Haenszel
general association test
df=1
VALUE
P-VALUE
----------- ----------<0.01
11.3
<0.01
12.0
<0.01
#: Stratification variable included.
Investigators 6 and 17 are pooled into Investigator 999
RMP.B1YP.JCLLIB2(EFS1JEME)
RMP.B1YO.HCJEREP(EFS1JEME)
XEFS0001
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
Return to list of Prozac studies
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Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Table HCJE.9.
Approved by Lilly 15 November 2004
CDRS-R Scores
Change from Baseline to Endpoint
All Randomized Patients
Acute Treatment Phase (Study Periods III-IV)
B1Y-MC-HCJE
n
--
Baseline
Mean
SD
---------------
Endpoint
Mean
SD
--------------
Change
Mean
SD
----------------
Variable
-------------------------
Therapy
---------
p-Value *1
----------
TOTAL
Flx 20
Placebo
109
105
57.1
55.1
9.9
11.8
35.1
40.2
13.5
13.5
-22.1
-14.9
14.4
13.3
<.001
MOOD SUBTOTAL
Flx 20
Placebo
109
105
15.9
15.4
4.0
4.8
9.4
11.2
4.7
5.0
-6.6
-4.3
5.3
5.4
.002
SOMATIC SUBTOTAL
Flx 20
Placebo
109
105
17.2
17.0
4.5
4.3
10.7
12.6
4.2
4.9
-6.5
-4.5
5.2
4.8
.004
SUBJECTIVE SUBTOTAL
Flx 20
Placebo
109
105
11.1
10.8
3.0
3.3
7.2
7.9
2.9
2.5
-3.9
-2.9
3.6
3.1
.026
BEHAVIOR SUBTOTAL
Flx 20
Placebo
109
105
12.9
11.9
2.9
3.2
7.8
8.6
4.0
3.7
-5.1
-3.3
3.7
3.7
<.001
*1 Type III Sums of Squares from an analysis of variance (ANOVA): PROC GLM model=treatment.
RMP.B1YP.JCLLIB2(LAS3JEAA)
RMP.B1YO.HCJEREP(LAS3JEAA)
CT Registry ID#2201
Page 19
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CT Registry ID#2201
Page 20
0
CDRS-R Total Change from Baseline
4
5
6
7
8
9
10
-5
-10
*
-15
-20
*
*
-25
*
*
*
-30
Visit
Fluoxetine
Placebo
*Statistically significant difference between treatment groups.
Figure HCJE.4.
CDRS-R total score versus visit (observed cases) by
treatment group for the acute treatment phase (Study
Periods III-IV) of B1Y-MC-HCJE.
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
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CT Registry ID#2201
Page 21
0
CDRS-R Total Change from Baseline
4
5
6
7
8
9
10
*
*
-5
-10
*
-15
-20
*
*
*
-25
Visit
Fluoxetine
Placebo
*Statistically significant difference between treatment groups.
Figure HCJE.5.
CDRS-R total score versus visit (LOCF) by treatment group
for the acute treatment phase (Study Periods III-IV) of B1YMC-HCJE.
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
Return to list of Prozac studies
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Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Table HCJE.10.
Approved by Lilly 15 November 2004
CDRS-R Total Score
Change From Baseline (Visit 15) to Endpoint (Visits 16-26)
All Patients Entering Study Period VI
Relapse Prevention Phase (Study Period VI)
Baseline
Mean
SD
---------------
Endpoint
Mean
SD
--------------
Change
Mean
SD
----------------
Variable
-------------------------
Therapy
---------
n
--
p-Value *1
----------
CDRS-R Total
Flx/Flx
Flx/Plc
20
20
21.9
24
3.4
3.7
30.1
38.6
12.2
13.1
8.2
14.7
12.4
14.5
.139
Mood Subtotal
Flx/Flx
Flx/Plc
20
20
5.5
5.9
1.4
1.4
7.8
11.4
4.3
4.9
2.3
5.5
4.6
5.1
.048
Somatic Subtotal
Flx/Flx
Flx/Plc
20
20
6.7
8.1
1.4
1.9
9.4
11.1
4.4
3.4
2.7
3.1
4.4
4.3
.803
Subjective Subtotal
Flx/Flx
Flx/Plc
20
20
5.0
5.3
0.9
1.2
5.5
8.1
1.6
3.6
0.5
2.8
1.5
3.9
.018
Behavior Subtotal
Flx/Flx
Flx/Plc
20
20
4.7
4.8
1.7
1.3
7.4
8.1
4.1
2.9
2.7
3.4
3.9
3.3
.578
* 1 Type III Sums of Squares from an analysis of variance (ANOVA): PROC GLM model=treatment.
Flx/Flx: patients who received fluoxetine treatment during Study Periods III-V
and were rerandomized to fluoxetine treatment during Study Period VI.
Flx/Plc: patients who received fluoxetine treatment during Study Periods III-V
and were rerandomized to placebo treatment during Study Period VI.
RMP.B1YP.JCLLIB3(LAS3JESA)
RMP.B1YO.HCJEREP(LAS3JESA)
CT Registry ID#2201
Page 22
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Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Table HCJE.10.
Approved by Lilly 15 November 2004
CDRS-R Total Score
Change From Baseline (Visit 15) to Endpoint (Visits 16-26)
All Patients Entering Study Period VI
Relapse Prevention Phase (Study Period VI)
(concluded)
Baseline
Mean
SD
---------------
Endpoint
Mean
SD
--------------
Change
Mean
SD
----------------
Variable
-------------------------
Therapy
---------
n
--
p-Value *1
----------
CDRS-R Total
Plc/Plc
34
24.6
3.0
26.4
9.5
1.9
9.8
N/A
Mood Subtotal
Plc/Plc
34
6.5
1.4
7.6
4.3
1.1
3.8
N/A
Somatic Subtotal
Plc/Plc
34
7.5
1.6
8.4
3.1
1.0
3.7
N/A
Subjective Subtotal
Plc/Plc
34
5.9
1.7
5.7
2.1
-0.1
1.5
N/A
Behavior Subtotal
Plc/Plc
34
4.7
1.2
4.6
2.3
-0.1
2.3
N/A
Plc/Plc: patients who received placebo treatment during Study Periods III-V
and continued receiving placebo treatment during Study Period VI.
RMP.B1YP.JCLLIB3(LAS3JESA)
RMP.B1YO.HCJEREP(LAS3JESA)
CT Registry ID#2201
Page 23
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CT Registry ID#2201
Table HCJE.11.
Page 24
Treatment-Emergent Non-Solicited Adverse Events
Incidence by Decreasing Frequency (Ordered by Fluoxetine)
(Fluoxetine Incidence Greater than 1%)
All Randomized Patients
Acute Treatment Phase (Study Periods III-IV)
B1Y-MC-HCJE
Event Classification
------------------------PATIENTS WITH >= 1 TESS
PATIENTS WITH NO TESS
HEADACHE
RHINITIS
ABDOMINAL PAIN
PHARYNGITIS
ACCIDENTAL INJURY
DIARRHEA
DIZZINESS
RASH
ANOREXIA
COUGH INCREASED
NAUSEA
NERVOUSNESS
ASTHENIA
PAIN
VOMITING
FEVER
ABNORMAL DREAMS
EPISTAXIS
DRY MOUTH
DYSMENORRHEA
EAR PAIN
FLU SYNDROME
INSOMNIA
PRURITUS
AGITATION
BACK PAIN
CHEST PAIN
CONSTIPATION
DYSPEPSIA
ECCHYMOSIS
NECK PAIN
SINUSITIS
SOMNOLENCE
TREMOR
AKATHISIA
ALLERGIC REACTION
ANXIETY
ASTHMA
CHILLS
Flx 20
(N=109)
n (%)
---------94 (86.2)
15 (13.8)
33 (30.3)
24 (22.0)
17 (15.6)
16 (14.7)
13 (11.9)
11 (10.1)
10 (9.2)
10 (9.2)
9 (8.3)
9 (8.3)
9 (8.3)
9 (8.3)
8 (7.3)
8 (7.3)
8 (7.3)
7 (6.4)
6 (5.5)
5 (4.6)
4 (3.7)
4 (3.7)
4 (3.7)
4 (3.7)
4 (3.7)
4 (3.7)
3 (2.8)
3 (2.8)
3 (2.8)
3 (2.8)
3 (2.8)
3 (2.8)
3 (2.8)
3 (2.8)
3 (2.8)
3 (2.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
Placebo
(N=110)
n (%)
---------80 (72.7)
30 (27.3)
18 (16.4)
21 (19.1)
16 (14.5)
9 (8.2)
8 (7.3)
11 (10.0)
4 (3.6)
4 (3.6)
6 (5.5)
7 (6.4)
8 (7.3)
6 (5.5)
6 (5.5)
9 (8.2)
8 (7.3)
5 (4.5)
3 (2.7)
1 (0.9)
5 (4.5)
3 (2.7)
3 (2.7)
3 (2.7)
5 (4.5)
5 (4.5)
0
5 (4.5)
2 (1.8)
2 (1.8)
4 (3.6)
2 (1.8)
0
2 (1.8)
3 (2.7)
0
0
2 (1.8)
0
0
0
Total
(N=219)
n (%)
---------174 (79.5)
45 (20.5)
51 (23.3)
45 (20.5)
33 (15.1)
25 (11.4)
21 (9.6)
22 (10.0)
14 (6.4)
14 (6.4)
15 (6.8)
16 (7.3)
17 (7.8)
15 (6.8)
14 (6.4)
17 (7.8)
16 (7.3)
12 (5.5)
9 (4.1)
6 (2.7)
9 (4.1)
7 (3.2)
7 (3.2)
7 (3.2)
9 (4.1)
9 (4.1)
3 (1.4)
8 (3.7)
5 (2.3)
5 (2.3)
7 (3.2)
5 (2.3)
3 (1.4)
5 (2.3)
6 (2.7)
3 (1.4)
2 (0.9)
4 (1.8)
2 (0.9)
2 (0.9)
2 (0.9)
p-Value*
---------.019
.019
.017
.619
.852
.143
.261
1.00
.106
.106
.437
.615
.806
.437
.594
1.00
1.00
.569
.332
.119
1.00
.721
.721
.721
1.00
1.00
.122
.721
.683
.683
1.00
.683
.122
.683
1.00
.122
.247
1.00
.247
.247
.247
RMP.B1YP.JCLLIB2(AES2JEKS)
RMP.B1YO.HCJEREP(AES2JEKS)
* Frequencies are analyzed using a Fisher's Exact test.
XAES0002
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
Return to list of Prozac studies
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CT Registry ID#2201
Table HCJE.11.
Page 25
Treatment-Emergent Non-Solicited Adverse Events
Incidence by Decreasing Frequency (Ordered by Fluoxetine)
(Fluoxetine Incidence Greater than 1%)
All Randomized Patients
Acute Treatment Phase (Study Periods III-IV)
B1Y-MC-HCJE (concluded)
Event Classification
------------------------DEPRESSION
DRY SKIN
EYE DISORDER
GASTROENTERITIS
HOSTILITY
HYPERKINESIA
INFECTION
OTITIS EXTERNA
PERSONALITY DISORDER
PHOTOSENSITIVITY REACTION
SLEEP DISORDER
SPEECH DISORDER
THIRST
WEIGHT LOSS
Flx 20
(N=109)
n (%)
---------2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
Placebo
(N=110)
n (%)
---------1 (0.9)
1 (0.9)
0
0
5 (4.5)
0
2 (1.8)
1 (0.9)
1 (0.9)
0
0
2 (1.8)
2 (1.8)
1 (0.9)
Total
(N=219)
n (%)
---------3 (1.4)
3 (1.4)
2 (0.9)
2 (0.9)
7 (3.2)
2 (0.9)
4 (1.8)
3 (1.4)
3 (1.4)
2 (0.9)
2 (0.9)
4 (1.8)
4 (1.8)
3 (1.4)
p-Value*
---------.622
.622
.247
.247
.446
.247
1.00
.622
.622
.247
.247
1.00
1.00
.622
RMP.B1YP.JCLLIB2(AES2JEKS)
RMP.B1YO.HCJEREP(AES2JEKS)
* Frequencies are analyzed using a Fisher's Exact test.
XAES0002
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
Return to list of Prozac studies
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CT Registry ID#2201
Table HCJE.12.
Page 26
Treatment-Emergent Non-Solicited Adverse Events
Incidence by Decreasing Frequency (Ordered by Fluoxetine)
All Patients Entering Study Period VI
Relapse Prevention Phase (Study Period VI)
Event Classification
-----------------------PATIENTS WITH >= 1 TESS
PATIENTS WITH NO TESS
ACCIDENTAL INJURY
BRONCHITIS
FLU SYNDROME
INFECTION
RHINITIS
VOMITING
ABDOMINAL PAIN
COUGH INCREASED
ECCHYMOSIS
FEVER
PAIN
PHARYNGITIS
SINUSITIS
BACK PAIN
CHILLS
CYST
DYSPEPSIA
EAR PAIN
HEADACHE
INCREASED APPETITE
INSOMNIA
NAIL DISORDER
Flx/Flx
(N=20)
n (%)
--------14 (70.0)
6 (30.0)
3 (15.0)
3 (15.0)
3 (15.0)
3 (15.0)
3 (15.0)
3 (15.0)
2 (10.0)
2 (10.0)
2 (10.0)
2 (10.0)
2 (10.0)
2 (10.0)
2 (10.0)
1 (5.0)
1 (5.0)
1 (5.0)
1 (5.0)
1 (5.0)
1 (5.0)
1 (5.0)
1 (5.0)
1 (5.0)
Flx/Plc
(N=20)
n (%)
--------12 (60.0)
8 (40.0)
1 (5.0)
0
1 (5.0)
0
2 (10.0)
2 (10.0)
0
0
1 (5.0)
1 (5.0)
0
0
1 (5.0)
1 (5.0)
1 (5.0)
0
0
0
3 (15.0)
1 (5.0)
1 (5.0)
0
Total
(N=40)
n (%)
--------26 (65.0)
14 (35.0)
4 (10.0)
3 (7.5)
4 (10.0)
3 (7.5)
5 (12.5)
5 (12.5)
2 (5.0)
2 (5.0)
3 (7.5)
3 (7.5)
2 (5.0)
2 (5.0)
3 (7.5)
2 (5.0)
2 (5.0)
1 (2.5)
1 (2.5)
1 (2.5)
4 (10.0)
2 (5.0)
2 (5.0)
1 (2.5)
p-Value*
--------.741
.741
.605
.231
.605
.231
1.00
1.00
.487
.487
1.00
1.00
.487
.487
1.00
1.00
1.00
1.00
1.00
1.00
.605
1.00
1.00
1.00
Flx/Flx: patients who received fluoxetine treatment during Study Periods III-V
and were rerandomized to fluoxetine treatment during Study Period VI.
Flx/Plc: patients who received fluoxetine treatment during Study Periods III-V
and were rerandomized to placebo treatment during Study Period VI.
RMP.B1YP.JCLLIB2(AES2JETB)
RMP.B1YO.HCJEREP(AES2JETB)
* Frequencies are analyzed using a Fisher's Exact test.
XAES0002
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
Return to list of Prozac studies
Return to list of Lilly drugs
CT Registry ID#2201
Table HCJE.12.
Page 27
Treatment-Emergent Non-Solicited Adverse Events
Incidence by Decreasing Frequency (Ordered by Fluoxetine)
All Patients Entering Study Period VI
Relapse Prevention Phase (Study Period VI)
(continued)
Event Classification
-----------------------NAUSEA
SWEATING
SYNCOPE
TENDON DISORDER
VASODILATATION
ANOREXIA
CONJUNCTIVITIS
DEPRESSION
DIARRHEA
DIZZINESS
DYSMENORRHEA
EMOTIONAL LABILITY
HYPERKINESIA
MYALGIA
NERVOUSNESS
OTITIS MEDIA
POSTURAL HYPOTENSION
SKIN DISCOLORATION
ULCERATIVE STOMATITIS
WEIGHT GAIN
Flx/Flx
(N=20)
n (%)
--------1 (5.0)
1 (5.0)
1 (5.0)
1 (5.0)
1 (5.0)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Flx/Plc
(N=20)
n (%)
--------1 (5.0)
0
0
0
0
1 (5.0)
1 (5.0)
2 (10.0)
2 (10.0)
2 (10.0)
1 (5.0)
1 (5.0)
1 (5.0)
2 (10.0)
2 (10.0)
1 (5.0)
1 (5.0)
1 (5.0)
1 (5.0)
2 (10.0)
Total
(N=40)
n (%)
--------2 (5.0)
1 (2.5)
1 (2.5)
1 (2.5)
1 (2.5)
1 (2.5)
1 (2.5)
2 (5.0)
2 (5.0)
2 (5.0)
1 (2.5)
1 (2.5)
1 (2.5)
2 (5.0)
2 (5.0)
1 (2.5)
1 (2.5)
1 (2.5)
1 (2.5)
2 (5.0)
p-Value*
--------1.00
1.00
1.00
1.00
1.00
1.00
1.00
.487
.487
.487
1.00
1.00
1.00
.487
.487
1.00
1.00
1.00
1.00
.487
Flx/Flx: patients who received fluoxetine treatment during Study Periods III-V
and were rerandomized to fluoxetine treatment during Study Period VI.
Flx/Plc: patients who received fluoxetine treatment during Study Periods III-V
and were rerandomized to placebo treatment during Study Period VI.
RMP.B1YP.JCLLIB2(AES2JETB)
RMP.B1YO.HCJEREP(AES2JETB)
* Frequencies are analyzed using a Fisher's Exact test.
XAES0002
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
Return to list of Prozac studies
Return to list of Lilly drugs
CT Registry ID#2201
Table HCJE.12.
Page 28
Treatment-Emergent Non-Solicited Adverse Events
Incidence by Decreasing Frequency (Ordered by Fluoxetine)
All Patients Entering Study Period VI
Relapse Prevention Phase (Study Period VI)
(concluded)
Event Classification
-----------------------PATIENTS WITH >= 1 TESS
PATIENTS WITH NO TESS
FLU SYNDROME
COUGH INCREASED
FEVER
PHARYNGITIS
RHINITIS
ABDOMINAL PAIN
ACCIDENTAL INJURY
SINUSITIS
DIARRHEA
HYPERKINESIA
INCREASED APPETITE
NERVOUSNESS
PAIN
SOMNOLENCE
VOMITING
ALLERGIC REACTION
ANXIETY
ARTHRALGIA
ASTHENIA
BACK PAIN
CONJUNCTIVITIS
DEPRESSION
DRY SKIN
EAR PAIN
EUPHORIA
HEADACHE
INFECTION
INSOMNIA
INTENTIONAL INJURY
MOUTH ULCERATION
OTITIS MEDIA
PRURITUS
RASH
SURGICAL PROCEDURE
SYNCOPE
Plc/Plc
(N=35)
n (%)
--------22 (62.9)
13 (37.1)
6 (17.1)
4 (11.4)
4 (11.4)
4 (11.4)
4 (11.4)
3 (8.6)
3 (8.6)
3 (8.6)
2 (5.7)
2 (5.7)
2 (5.7)
2 (5.7)
2 (5.7)
2 (5.7)
2 (5.7)
1 (2.9)
1 (2.9)
1 (2.9)
1 (2.9)
1 (2.9)
1 (2.9)
1 (2.9)
1 (2.9)
1 (2.9)
1 (2.9)
1 (2.9)
1 (2.9)
1 (2.9)
1 (2.9)
1 (2.9)
1 (2.9)
1 (2.9)
1 (2.9)
1 (2.9)
1 (2.9)
Plc/Plc: patients who received placebo treatment during Study Periods III-V
and continued receiving placebo treatment during Study Period VI.
RMP.B1YP.JCLLIB2(AES2JETB)
RMP.B1YO.HCJEREP(AES2JETB)
XAES0002
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
Return to list of Prozac studies
Return to list of Lilly drugs
CT Registry ID#2201
Table HCJE.13.
Page 29
Treatment-Emergent Solicited Adverse Events
Side-Effects Checklist
Incidence by Decreasing Frequency (Ordered by Fluoxetine)
All Randomized Patients
Acute Treatment Phase (Study Periods III-IV)
B1Y-MC-HCJE
Event Classification
-------------------------------PATIENTS WITH >= 1 TESS
PATIENTS WITH NO TESS
23. FEELING SLEEPY
22. TIREDNESS
15. HEADACHE
26. GETTING ALONG WITH PARENTS
32. PAYING ATTENTION
14. COLD OR SNIFFLES
31. BEING SAD
29. GETTING MAD
30. NOT BEING HAPPY
09. BEING SICK TO YOUR STOMACH
24. SLEEPING
Flx 20
(N=109)
n (%)
---------105 (96.3)
4 (3.7)
52 (47.7)
50 (45.9)
49 (45.0)
43 (39.4)
43 (39.4)
41 (37.6)
41 (37.6)
40 (36.7)
40 (36.7)
39 (35.8)
39 (35.8)
Placebo
(N=110)
n (%)
---------100 (90.9)
10 (9.1)
47 (42.7)
46 (41.8)
41 (37.3)
45 (40.9)
31 (28.2)
50 (45.5)
32 (29.1)
47 (42.7)
34 (30.9)
33 (30.0)
45 (40.9)
Total
(N=219)
n (%)
---------205 (93.6)
14 (6.4)
99 (45.2)
96 (43.8)
90 (41.1)
88 (40.2)
74 (33.8)
91 (41.6)
73 (33.3)
87 (39.7)
74 (33.8)
72 (32.9)
84 (38.4)
p-Value*
---------.165
.165
.499
.587
.273
.891
.088
.273
.199
.408
.394
.390
.488
1 Treatment-Emergent = was present at baseline (Visit 4) and worsened as defined by
increase in score on the side-effects checklist at any postbaseline visit (Visits 5-10)
or new occurrence after baseline.
RMP.B1YP.JCLLIB2(AES2JEKI)
RMP.B1YO.HCJEREP(AES2JEKI)
* Frequencies are analyzed using a Fisher's Exact test.
XAES0002
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
Return to list of Prozac studies
Return to list of Lilly drugs
CT Registry ID#2201
Table HCJE.13.
Page 30
Treatment-Emergent Solicited Adverse Events
Side-Effects Checklist
Incidence by Decreasing Frequency (Ordered by Fluoxetine)
All Randomized Patients
Acute Treatment Phase (Study Periods III-IV)
B1Y-MC-HCJE (continued)
Event Classification
-------------------------------28. CRYING
07. STOMACHACHES
16. DIZZINESS
27. GETTING ALONG WITH KIDS
03. DRY MOUTH AND LIPS
01. EATING
21. SITTING STILL
08. MUSCLE CRAMPS
12. ITCHY OR SCRATCHY SKIN
25. BAD DREAMS
06. DIARRHEA
18. SHAKINESS
13. RASHES
Flx 20
(N=109)
n (%)
---------39 (35.8)
37 (33.9)
34 (31.2)
33 (30.3)
32 (29.4)
31 (28.4)
30 (27.5)
27 (24.8)
27 (24.8)
27 (24.8)
22 (20.2)
21 (19.3)
17 (15.6)
Placebo
(N=110)
n (%)
---------39 (35.5)
43 (39.1)
23 (20.9)
31 (28.2)
38 (34.5)
35 (31.8)
42 (38.2)
34 (30.9)
32 (29.1)
27 (24.5)
19 (17.3)
23 (20.9)
18 (16.4)
Total
(N=219)
n (%)
---------78 (35.6)
80 (36.5)
57 (26.0)
64 (29.2)
70 (32.0)
66 (30.1)
72 (32.9)
61 (27.9)
59 (26.9)
54 (24.7)
41 (18.7)
44 (20.1)
35 (16.0)
p-Value*
---------1.00
.484
.092
.768
.469
.659
.114
.366
.543
1.00
.607
.866
1.00
1 Treatment-Emergent = was present at baseline (Visit 4) and worsened as defined by
increase in score on the side-effects checklist at any postbaseline visit (Visits 5-10)
or new occurrence after baseline.
RMP.B1YP.JCLLIB2(AES2JEKI)
RMP.B1YO.HCJEREP(AES2JEKI)
* Frequencies are analyzed using a Fisher's Exact test.
XAES0002
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
Return to list of Prozac studies
Return to list of Lilly drugs
CT Registry ID#2201
Table HCJE.13.
Page 31
Treatment-Emergent Solicited Adverse Events
Side-Effects Checklist
Incidence by Decreasing Frequency (Ordered by Fluoxetine)
All Randomized Patients
Acute Treatment Phase (Study Periods III-IV)
B1Y-MC-HCJE (concluded)
Event Classification
-------------------------------17. PLAYING SPORTS
02. DRINKING
19. PRONOUNCING WORDS
20. DOING THINGS WITH YOUR HANDS
04. WETNESS IN MOUTH
11. URINATING
05. CONSTIPATION
10. WETTING THE BED
Flx 20
(N=109)
n (%)
---------17 (15.6)
14 (12.8)
13 (11.9)
13 (11.9)
10 (9.2)
10 (9.2)
9 (8.3)
3 (2.8)
Placebo
(N=110)
n (%)
---------20 (18.2)
20 (18.2)
28 (25.5)
19 (17.3)
19 (17.3)
12 (10.9)
10 (9.1)
5 (4.5)
Total
(N=219)
n (%)
---------37 (16.9)
34 (15.5)
41 (18.7)
32 (14.6)
29 (13.2)
22 (10.0)
19 (8.7)
8 (3.7)
p-Value*
---------.719
.351
.015
.339
.110
.823
1.00
.721
1 Treatment-Emergent = was present at baseline (Visit 4) and worsened as defined by
increase in score on the side-effects checklist at any postbaseline visit (Visits 5-10)
or new occurrence after baseline.
RMP.B1YP.JCLLIB2(AES2JEKI)
RMP.B1YO.HCJEREP(AES2JEKI)
* Frequencies are analyzed using a Fisher's Exact test.
XAES0002
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
Return to list of Prozac studies
Return to list of Lilly drugs
CT Registry ID#2201
Table HCJE.14..
Page 32
Treatment-Emergent Solicited Adverse Events
Incidence by Decreasing Frequency (Ordered by Fluoxetine)
All Patients Entering Study Period VI
Relapse Prevention Phase (Study Period VI)
Event Classification
-------------------------------PATIENTS WITH >= 1 TESS
PATIENTS WITH NO TESS
15. HEADACHE
21. SITTING STILL
07. STOMACHACHES
16. DIZZINESS
26. GETTING ALONG WITH PARENTS
01. EATING
03. DRY MOUTH AND LIPS
06. DIARRHEA
09. BEING SICK TO YOUR STOMACH
14. COLD OR SNIFFLES
23. FEELING SLEEPY
24. SLEEPING
08. MUSCLE CRAMPS
12. ITCHY OR SCRATCHY SKIN
13. RASHES
17. PLAYING SPORTS
18. SHAKINESS
19. PRONOUNCING WORDS
22. TIREDNESS
25. BAD DREAMS
27. GETTING ALONG WITH KIDS
28. CRYING
29. GETTING MAD
30. NOT BEING HAPPY
31. BEING SAD
32. PAYING ATTENTION
02. DRINKING
05. CONSTIPATION
20. DOING THINGS WITH YOUR HANDS
Flx/Flx
(N=20)
n (%)
--------15 (75.0)
5 (25.0)
5 (25.0)
5 (25.0)
4 (20.0)
4 (20.0)
4 (20.0)
3 (15.0)
3 (15.0)
3 (15.0)
3 (15.0)
3 (15.0)
2 (10.0)
2 (10.0)
1 (5.0)
1 (5.0)
1 (5.0)
1 (5.0)
1 (5.0)
1 (5.0)
1 (5.0)
1 (5.0)
1 (5.0)
1 (5.0)
1 (5.0)
1 (5.0)
1 (5.0)
1 (5.0)
0
0
0
Flx/Plc
(N=20)
n (%)
--------18 (90.0)
2 (10.0)
4 (20.0)
2 (10.0)
4 (20.0)
1 (5.0)
3 (15.0)
2 (10.0)
2 (10.0)
0
4 (20.0)
2 (10.0)
2 (10.0)
0
5 (25.0)
3 (15.0)
1 (5.0)
3 (15.0)
1 (5.0)
0
3 (15.0)
1 (5.0)
3 (15.0)
3 (15.0)
5 (25.0)
4 (20.0)
3 (15.0)
5 (25.0)
2 (10.0)
3 (15.0)
3 (15.0)
Total
(N=40)
n (%)
--------33 (82.5)
7 (17.5)
9 (22.5)
7 (17.5)
8 (20.0)
5 (12.5)
7 (17.5)
5 (12.5)
5 (12.5)
3 (7.5)
7 (17.5)
5 (12.5)
4 (10.0)
2 (5.0)
6 (15.0)
4 (10.0)
2 (5.0)
4 (10.0)
2 (5.0)
1 (2.5)
4 (10.0)
2 (5.0)
4 (10.0)
4 (10.0)
6 (15.0)
5 (12.5)
4 (10.0)
6 (15.0)
2 (5.0)
3 (7.5)
3 (7.5)
p-Value*
--------.407
.407
1.00
.407
1.00
.342
1.00
1.00
1.00
.231
1.00
1.00
1.00
.487
.182
.605
1.00
.605
1.00
1.00
.605
1.00
.605
.605
.182
.342
.605
.182
.487
.231
.231
1 Treatment-Emergent = was present at baseline (highest score for item of visits 4-15)
and worsened as defined by increase in score on the Side-Effects Checklist at any
postbaseline visit (Visits 16-26)or new occurrence after baseline.
Flx/Flx: patients who received fluoxetine treatment during Study Periods III-V
and were rerandomized to fluoxetine treatment during Study Period VI.
Flx/Plc: patients who received fluoxetine treatment during Study Periods III-V
and were rerandomized to placebo treatment during Study Period VI.
RMP.B1YP.JCLLIB2(AES2JETA)
RMP.B1YO.HCJEREP(AES2JETA)
* Frequencies are analyzed using a Fisher's Exact test.
XAES0002
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
Return to list of Prozac studies
Return to list of Lilly drugs
CT Registry ID#2201
Table HCJE.14.
Page 33
Treatment-Emergent Solicited Adverse Events
Incidence by Decreasing Frequency (Ordered by Fluoxetine)
All Patients Entering Study Period VI
Relapse Prevention Phase (Study Period VI)
(concluded)
Event Classification
-------------------------------PATIENTS WITH >= 1 TESS
PATIENTS WITH NO TESS
14. COLD OR SNIFFLES
03. DRY MOUTH AND LIPS
15. HEADACHE
06. DIARRHEA
23. FEELING SLEEPY
27. GETTING ALONG WITH KIDS
01. EATING
08. MUSCLE CRAMPS
09. BEING SICK TO YOUR STOMACH
13. RASHES
16. DIZZINESS
21. SITTING STILL
22. TIREDNESS
29. GETTING MAD
18. SHAKINESS
24. SLEEPING
28. CRYING
31. BEING SAD
32. PAYING ATTENTION
05. CONSTIPATION
07. STOMACHACHES
12. ITCHY OR SCRATCHY SKIN
17. PLAYING SPORTS
19. PRONOUNCING WORDS
25. BAD DREAMS
26. GETTING ALONG WITH PARENTS
30. NOT BEING HAPPY
02. DRINKING
04. WETNESS IN MOUTH
10. WETTING THE BED
20. DOING THINGS WITH YOUR HANDS
Plc/Plc
(N=35)
n (%)
--------28 (80.0)
7 (20.0)
8 (22.9)
7 (20.0)
7 (20.0)
5 (14.3)
5 (14.3)
5 (14.3)
4 (11.4)
4 (11.4)
4 (11.4)
4 (11.4)
4 (11.4)
4 (11.4)
4 (11.4)
4 (11.4)
3 (8.6)
3 (8.6)
3 (8.6)
3 (8.6)
3 (8.6)
2 (5.7)
2 (5.7)
2 (5.7)
2 (5.7)
2 (5.7)
2 (5.7)
2 (5.7)
2 (5.7)
1 (2.9)
1 (2.9)
1 (2.9)
1 (2.9)
1 Treatment-Emergent = was present at baseline (highest score for item of visits 4-15)
and worsened as defined by increase in score on the Side-Effects Checklist at any
postbaseline visit (Visits 16-26)or new occurrence after baseline.
Plc/Plc: patients who received placebo treatment during Study Periods III-V
and continued receiving placebo treatment during Study Period VI.
RMP.B1YP.JCLLIB2(AES2JETA)
RMP.B1YO.HCJEREP(AES2JETA)
XAES0002
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
Return to list of Prozac studies
Return to list of Lilly drugs
CT Registry ID#2201
Table HCJE.15.
Page 34
Treatment-Emergent Non-Solicited Adverse Events
Incidence by Decreasing Frequency (Ordered by Fluoxetine)
(Fluoxetine Incidence Greater than 1%)
All Randomized Patients
Subchronic Treatment Phase (Study Periods III-V)
B1Y-MC-HCJE
Event Classification
------------------------PATIENTS WITH >= 1 TESS
PATIENTS WITH NO TESS
HEADACHE
RHINITIS
ABDOMINAL PAIN
PHARYNGITIS
ACCIDENTAL INJURY
COUGH INCREASED
DIARRHEA
RASH
DIZZINESS
NERVOUSNESS
VOMITING
ANOREXIA
ASTHENIA
FEVER
PAIN
NAUSEA
ABNORMAL DREAMS
BACK PAIN
DRY MOUTH
EAR PAIN
INSOMNIA
PRURITUS
EPISTAXIS
HOSTILITY
INFECTION
PERSONALITY DISORDER
SOMNOLENCE
AGITATION
ALLERGIC REACTION
DYSMENORRHEA
DYSPEPSIA
ECCHYMOSIS
FLU SYNDROME
HYPERKINESIA
PHOTOSENSITIVITY REACTION
SINUSITIS
AKATHISIA
ASTHMA
CHEST PAIN
Flx
(N=109)
n (%)
---------101 (92.7)
8 (7.3)
37 (33.9)
34 (31.2)
22 (20.2)
21 (19.3)
19 (17.4)
16 (14.7)
14 (12.8)
13 (11.9)
11 (10.1)
11 (10.1)
11 (10.1)
10 (9.2)
10 (9.2)
10 (9.2)
10 (9.2)
9 (8.3)
7 (6.4)
6 (5.5)
6 (5.5)
6 (5.5)
6 (5.5)
6 (5.5)
5 (4.6)
5 (4.6)
5 (4.6)
5 (4.6)
5 (4.6)
4 (3.7)
4 (3.7)
4 (3.7)
4 (3.7)
4 (3.7)
4 (3.7)
4 (3.7)
4 (3.7)
4 (3.7)
3 (2.8)
3 (2.8)
3 (2.8)
Placebo
(N=110)
n (%)
---------87 (79.1)
23 (20.9)
21 (19.1)
29 (26.4)
22 (20.0)
14 (12.7)
10 (9.1)
9 (8.2)
13 (11.8)
10 (9.1)
8 (7.3)
6 (5.5)
12 (10.9)
9 (8.2)
7 (6.4)
8 (7.3)
12 (10.9)
11 (10.0)
3 (2.7)
5 (4.5)
6 (5.5)
3 (2.7)
5 (4.5)
6 (5.5)
2 (1.8)
5 (4.5)
5 (4.5)
2 (1.8)
4 (3.6)
0
2 (1.8)
4 (3.6)
5 (4.5)
2 (1.8)
3 (2.7)
1 (0.9)
1 (0.9)
2 (1.8)
0
0
2 (1.8)
Total
(N=219)
n (%)
---------188 (85.8)
31 (14.2)
58 (26.5)
63 (28.8)
44 (20.1)
35 (16.0)
29 (13.2)
25 (11.4)
27 (12.3)
23 (10.5)
19 (8.7)
17 (7.8)
23 (10.5)
19 (8.7)
17 (7.8)
18 (8.2)
22 (10.0)
20 (9.1)
10 (4.6)
11 (5.0)
12 (5.5)
9 (4.1)
11 (5.0)
12 (5.5)
7 (3.2)
10 (4.6)
10 (4.6)
7 (3.2)
9 (4.1)
4 (1.8)
6 (2.7)
8 (3.7)
9 (4.1)
6 (2.7)
7 (3.2)
5 (2.3)
5 (2.3)
6 (2.7)
3 (1.4)
3 (1.4)
5 (2.3)
p-Value*
---------.006
.006
.014
.458
1.00
.202
.076
.143
.840
.517
.483
.218
1.00
.815
.462
.632
.823
.815
.215
.768
1.00
.332
.768
1.00
.280
1.00
1.00
.280
.748
.060
.446
1.00
1.00
.446
.721
.212
.212
.446
.122
.122
.683
RMP.B1YP.JCLLIB2(AES2JEKL)
RMP.B1YO.HCJEREP(AES2JEKL)
* Frequencies are analyzed using a Fisher's Exact test.
XAES0002
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
Return to list of Prozac studies
Return to list of Lilly drugs
CT Registry ID#2201
Table HCJE.15.
Page 35
Treatment-Emergent Non-Solicited Adverse Events
Incidence by Decreasing Frequency (Ordered by Fluoxetine)
(Fluoxetine Incidence Greater than 1%)
All Randomized Patients
Subchronic Treatment Phase (Study Periods III-V)
B1Y-MC-HCJE (concluded)
Event Classification
------------------------CONSTIPATION
CONTACT DERMATITIS
DEPRESSION
MYALGIA
NECK PAIN
SPEECH DISORDER
TREMOR
ACUTE BRAIN SYNDROME
ANXIETY
BRONCHITIS
CHILLS
DRY SKIN
EAR DISORDER
EUPHORIA
EYE DISORDER
GASTROENTERITIS
INCREASED APPETITE
NECK RIGIDITY
OTITIS EXTERNA
SLEEP DISORDER
SURGICAL PROCEDURE
SWEATING
THINKING ABNORMAL
THIRST
TOOTH DISORDER
WEIGHT LOSS
YAWN
Flx
(N=109)
n (%)
---------3 (2.8)
3 (2.8)
3 (2.8)
3 (2.8)
3 (2.8)
3 (2.8)
3 (2.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
2 (1.8)
Placebo
(N=110)
n (%)
---------6 (5.5)
0
2 (1.8)
6 (5.5)
1 (0.9)
2 (1.8)
1 (0.9)
0
0
2 (1.8)
1 (0.9)
3 (2.7)
1 (0.9)
0
0
0
3 (2.7)
1 (0.9)
1 (0.9)
0
2 (1.8)
0
1 (0.9)
2 (1.8)
0
1 (0.9)
0
Total
(N=219)
n (%)
---------9 (4.1)
3 (1.4)
5 (2.3)
9 (4.1)
4 (1.8)
5 (2.3)
4 (1.8)
2 (0.9)
2 (0.9)
4 (1.8)
3 (1.4)
5 (2.3)
3 (1.4)
2 (0.9)
2 (0.9)
2 (0.9)
5 (2.3)
3 (1.4)
3 (1.4)
2 (0.9)
4 (1.8)
2 (0.9)
3 (1.4)
4 (1.8)
2 (0.9)
3 (1.4)
2 (0.9)
p-Value*
---------.499
.122
.683
.499
.369
.683
.369
.247
.247
1.00
.622
1.00
.622
.247
.247
.247
1.00
.622
.622
.247
1.00
.247
.622
1.00
.247
.622
.247
RMP.B1YP.JCLLIB2(AES2JEKL)
RMP.B1YO.HCJEREP(AES2JEKL)
* Frequencies are analyzed using a Fisher's Exact test.
XAES0002
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
Return to list of Prozac studies
Return to list of Lilly drugs
CT Registry ID#2201
Table HCJE.16.
Page 36
Treatment-Emergent Solicited Adverse Events
Side-Effects Checklist
Incidence by Decreasing Frequency (Ordered by Fluoxetine)
All Randomized Patients
Subchronic Treatment Phase (Study Periods III-V)
B1Y-MC-HCJE
Event Classification
-------------------------------PATIENTS WITH >= 1 TESS
PATIENTS WITH NO TESS
15. HEADACHE
23. FEELING SLEEPY
22. TIREDNESS
14. COLD OR SNIFFLES
26. GETTING ALONG WITH PARENTS
07. STOMACHACHES
28. CRYING
31. BEING SAD
32. PAYING ATTENTION
24. SLEEPING
29. GETTING MAD
Flx
(N=109)
n (%)
---------107 (98.2)
2 (1.8)
57 (52.3)
56 (51.4)
55 (50.5)
51 (46.8)
51 (46.8)
48 (44.0)
47 (43.1)
47 (43.1)
47 (43.1)
45 (41.3)
45 (41.3)
Placebo
(N=110)
n (%)
---------101 (91.8)
9 (8.2)
44 (40.0)
49 (44.5)
48 (43.6)
56 (50.9)
48 (43.6)
49 (44.5)
44 (40.0)
36 (32.7)
37 (33.6)
50 (45.5)
51 (46.4)
Total
(N=219)
n (%)
---------208 (95.0)
11 (5.0)
101 (46.1)
105 (47.9)
103 (47.0)
107 (48.9)
99 (45.2)
97 (44.3)
91 (41.6)
83 (37.9)
84 (38.4)
95 (43.4)
96 (43.8)
p-Value*
---------.059
.059
.079
.345
.345
.590
.685
1.00
.682
.127
.166
.586
.497
1 Treatment-Emergent = was present at baseline (Visit 4) and worsened as defined by
increase in score on the side-effects checklist at any postbaseline visit (Visits 5-15)
or new occurrence after baseline.
RMP.B1YP.JCLLIB2(AES2JEKK)
RMP.B1YO.HCJEREP(AES2JEKK)
* Frequencies are analyzed using a Fisher's Exact test.
XAES0002
Fluoxetine Hydrochloride
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Table HCJE.16.
Page 37
Treatment-Emergent Solicited Adverse Events
Side-Effects Checklist
Incidence by Decreasing Frequency (Ordered by Fluoxetine)
All Randomized Patients
Subchronic Treatment Phase (Study Periods III-V)
B1Y-MC-HCJE (continued)
Event Classification
-------------------------------09. BEING SICK TO YOUR STOMACH
30. NOT BEING HAPPY
16. DIZZINESS
08. MUSCLE CRAMPS
01. EATING
03. DRY MOUTH AND LIPS
21. SITTING STILL
27. GETTING ALONG WITH KIDS
12. ITCHY OR SCRATCHY SKIN
25. BAD DREAMS
06. DIARRHEA
18. SHAKINESS
17. PLAYING SPORTS
Flx
(N=109)
n (%)
---------44 (40.4)
44 (40.4)
38 (34.9)
35 (32.1)
34 (31.2)
34 (31.2)
34 (31.2)
34 (31.2)
32 (29.4)
30 (27.5)
28 (25.7)
26 (23.9)
19 (17.4)
Placebo
(N=110)
n (%)
---------39 (35.5)
39 (35.5)
32 (29.1)
42 (38.2)
39 (35.5)
42 (38.2)
43 (39.1)
33 (30.0)
36 (32.7)
35 (31.8)
23 (20.9)
24 (21.8)
21 (19.1)
Total
(N=219)
n (%)
---------83 (37.9)
83 (37.9)
70 (32.0)
77 (35.2)
73 (33.3)
76 (34.7)
77 (35.2)
67 (30.6)
68 (31.1)
65 (29.7)
51 (23.3)
50 (22.8)
40 (18.3)
p-Value*
---------.488
.488
.387
.396
.567
.321
.258
.884
.662
.555
.428
.750
.861
1 Treatment-Emergent = was present at baseline (Visit 4) and worsened as defined by
increase in score on the side-effects checklist at any postbaseline visit (Visits 5-15)
or new occurrence after baseline.
RMP.B1YP.JCLLIB2(AES2JEKK)
RMP.B1YO.HCJEREP(AES2JEKK)
* Frequencies are analyzed using a Fisher's Exact test.
XAES0002
Fluoxetine Hydrochloride
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Table HCJE.16.
Page 38
Treatment-Emergent Solicited Adverse Events
Side-Effects Checklist
Incidence by Decreasing Frequency (Ordered by Fluoxetine)
All Randomized Patients
Subchronic Treatment Phase (Study Periods III-V)
B1Y-MC-HCJE (concluded)
Event Classification
-------------------------------13. RASHES
19. PRONOUNCING WORDS
02. DRINKING
20. DOING THINGS WITH YOUR HANDS
04. WETNESS IN MOUTH
05. CONSTIPATION
11. URINATING
10. WETTING THE BED
Flx
(N=109)
n (%)
---------18 (16.5)
18 (16.5)
16 (14.7)
15 (13.8)
11 (10.1)
11 (10.1)
10 (9.2)
3 (2.8)
Placebo
(N=110)
n (%)
---------25 (22.7)
33 (30.0)
21 (19.1)
25 (22.7)
24 (21.8)
14 (12.7)
13 (11.8)
5 (4.5)
Total
(N=219)
n (%)
---------43 (19.6)
51 (23.3)
37 (16.9)
40 (18.3)
35 (16.0)
25 (11.4)
23 (10.5)
8 (3.7)
p-Value*
---------.308
.025
.471
.115
.026
.672
.660
.721
1 Treatment-Emergent = was present at baseline (Visit 4) and worsened as defined by
increase in score on the side-effects checklist at any postbaseline visit (Visits 5-15)
or new occurrence after baseline.
RMP.B1YP.JCLLIB2(AES2JEKK)
RMP.B1YO.HCJEREP(AES2JEKK)
* Frequencies are analyzed using a Fisher's Exact test.
XAES0002
Fluoxetine Hydrochloride
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CT Registry ID#3032
Page 1
Summary ID#3032
Clinical Study Summary: Study B1Y-MC-HCJW
Title of Study: Fluoxetine Versus Placebo in the Treatment of Children and Adolescents with ObsessiveCompulsive Disorder
Investigator(s): This multicenter study included 21 principal investigators.
Study Center(s): This study was conducted at 21 study centers in one country.
Phase of Development: 3
Length of Study: 10 months
Date first patient enrolled: 17 March 1999
Date last patient completed: 1 February 2000
Objectives:
Primary Objective: To test the hypothesis that fluoxetine 20 mg to 60 mg daily is more effective than
placebo in the acute treatment of children and adolescents with obsessive compulsive disorder (OCD)
during 13 weeks of double-blind-therapy, using the Children’s Yale-Brown Obsessive Compulsive Scale
(CY-BOCS) as the primary efficacy measure.
Secondary Objectives: to compare the efficacy of fluoxetine 20 mg to 60 mg daily with placebo using the
Clinical Global Impressions of Improvement (CGI-Improvement), Clinical Global Impressions of Severity
(CGI-Severity), Patient’s Global Impressions of Improvement (PGI-Improvement), OCD Impact, and
National Institute of Mental Health (NIMH) Global OCD scales; to compare efficacy on symptoms of
secondary anxiety in children and adolescents with OCD as measured by changes in mean
Multidimensional Anxiety Scale for Children (MASC) scores; to compare efficacy on symptoms of
secondary depression in children and adolescents with OCD as measured by changes in mean Children’s
Depression Rating Scale-Revised (CDRS-R) scores; to compare safety through monitoring of vital signs,
laboratory values, concomitant medications, and treatment-emergent adverse events.
Study Design: Multicenter, double-blind, randomized, parallel-group, placebo-controlled study.
This was a study comparing the efficacy and safety of fluoxetine 20 to 60 mg/day and placebo for the acute
treatment (13 weeks) of OCD, as defined by the Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition (DSM-IV), in children and adolescents.
Study Period I was a 1-week (3 to 14 days) screening phase during which patients were evaluated for study
eligibility. Patients received no study medication during this period.
Study Period II was a 13-week, double-blind acute treatment phase during which patients were randomized
(2:1) to treatment groups of fluoxetine and placebo. Patients randomized to fluoxetine treatment received
fluoxetine 10 mg/day for the first 2 weeks of the study and then were increased to a dose of 20 mg/day for
an additional 2 weeks. At Visit 6 and Visit 8 (at Week 4 and Week 7, respectively), a patient’s dose of
fluoxetine could be increased to 40 mg/day or 60 mg/day on the basis of response and tolerability. If
patients on the higher doses experienced signs of intolerance, the investigator reduced their dose to the next
lower dose level (from 60 mg/day to 40 mg/day or from 40 mg/day to 20 mg/day). Once a patient’s dose
was reduced, the patient remained on that dose for the remainder of the study. Patients who were unable to
tolerate fluoxetine 20 mg/day were discontinued from the study. Figure HCJW.1 illustrates the study
design.
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Page 2
Number of Patients:
Planned: sample size of 90 patients
Randomized: 71 fluoxetine (male 34, female 37), 32 placebo (male 15, female 17)
Children (7 to <13): fluoxetine 51, placebo 24, total 75;
Adolescents (13 to <18): fluoxetine 20, placebo 8, total 28
Completed: 49 fluoxetine, 20 placebo
Diagnosis and Main Criteria for Inclusion: Outpatients with a primary psychiatric diagnosis of OCD
according to the DSM-IV aged 7 to <18 years. Patients were required to have a CY-BOCS score ≥16 and
CGI-Severity score ≥4 at Visit 1 and Visit 2. At study entry, patients were also required to have a score ≥7
on the NIMH Global OCD scale and a score ≤40 on the CDRS-R.
Test Product, Dose, and Mode of Administration: Fluoxetine 20 mg to 60 mg, administered orally once
daily as 10 mg and 20 mg fluoxetine capsules
Duration of Treatment: 13 weeks
Reference Therapy, Dose, and Mode of Administration: Placebo capsules administered orally once
daily
Variables:
Efficacy: Primary efficacy analysis was the last-observation-carried-forward (LOCF) change from
baseline to endpoint in CY-BOCS total score. Response, defined as a 40% reduction or greater on the CYBOCS total score from baseline to endpoint, was also evaluated. Secondary analyses included evaluations
of CY-BOCS Obsessions and Compulsions subtotal scores, CGI-Severity scores, CGI-Improvement scores
on clinician and parent versions, Patient Global Impressions scores, NIMH Global OCD scores, OCD
Impact total scores, CDRS-R total and subtotal scores, and MASC total and subtotal scores.
Safety: Safety was evaluated through the reporting and collection of concomitant medications, vital
signs, routine laboratory testing, and adverse event data.
Evaluation Methods:
Statistical: For analyses of continuous efficacy data, treatment groups were compared using LOCF in
Type III sums of squares from an analysis of variance (ANOVA) with treatment, investigator, and
treatment-by-investigator as independent factors in the model. For analyses of continuous safety data, the
treatment groups were compared using LOCF in Type III sums of squares from an ANOVA with treatment
and investigator in the model. For analyses of categorical data, Fisher’s exact test was used. Response was
evaluated across treatment groups using an exact Mantel-Haenszel test with investigator as the stratification
variable. The LOCF change from baseline to endpoint in CY-BOCS total score was the primary efficacy
measurement. A repeated measures ANOVA was conducted on the CY-BOCS total score and the
Obsessions and Compulsions subtotal scores in order to assess temporal changes over time. For subgroup
analyses, the Breslow-Day test for homogeneity of odds ratio was used. Investigators with fewer than 2
randomized patients per treatment group were pooled for statistical analysis.
Summary:
The safety and efficacy of fluoxetine was assessed following 13 weeks of acute therapy of fluoxetine 20 to
60 mg/day versus placebo in 103 pediatric patients diagnosed with OCD, as defined by the DSM-IV.
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Page 3
Patient Disposition/Demographics (Table HCJW.1): One hundred three patients ages 7-18 years were
randomized to treatment in this study using a 2:1 ratio of fluoxetine:placebo. Seventy-one patients were
randomized to fluoxetine treatment and 32 to placebo treatment. A total of 69 patients (49 fluoxetine,
20 placebo) completed the entire study. The average duration of illness prior to study entry was
approximately 5 years, and few patients presented with secondary comorbid psychiatric disorders at
baseline (major depressive disorder [MDD] 5%, depressive disorder not otherwise specified 3%, attention
deficit hyperactivity disorder 2%, and dysthymic disorder 1%). Patients randomized to treatment had OCD
that was moderate in severity, as evidenced by mean baseline CY-BOCS total scores of 24.5 for fluoxetinetreated patients and 26.3 for placebo-treated patients. There were no statistically significant differences
across treatment groups in any of the baseline demographic, physical, or disease characteristics examined.
The average mean and modal doses of fluoxetine administered during the study were 24.6 mg/day and 30.1
mg/day, respectively.
Efficacy (Tables HCJW.2, through HCJW.12): Fluoxetine 20 mg/day to 60 mg/day treatment produced
greater reductions from baseline to endpoint in the CY-BOCS total score as compared with placebo
treatment (p=.026). Fluoxetine-treated patients demonstrated higher rates of response, defined as at least a
40% reduction from baseline to endpoint, as compared with placebo-treated patients (fluoxetine 49%,
placebo 25%, p=.030, Mantel-Haenszel exact test). Fluoxetine treatment resulted in reductions in the CYBOCS Obsessions subtotal score as compared with placebo treatment that did not reach statistical
significance. In the analysis of CY-BOCS Compulsions subtotal score, the reduction was statistically
significant in favor of fluoxetine treatment (p=.015).
Repeated measures analyses of CY-BOCS total, Obsessions, and Compulsions scores were performed to
assess temporal changes in score over the course of the study. These analyses were consistent with the
primary analyses of change from baseline to endpoint. Greater improvement on CY-BOCS total score was
observed for fluoxetine treatment compared with placebo treatment as early as Week 5 (p=.086), becoming
statistically significant at Week 7 (p=.022). The observed treatment effect persisted for the remainder of
the study.
In all of the secondary analyses of OCD-specific efficacy scales (clinician-rated NIMH Global OCD scale
and patient-rated OCD Impact scale) and global measures of disease (clinician- and parent-rated CGIImprovement, PGI-Improvement, and CGI-Severity), fluoxetine treatment resulted in statistically
significantly (p<.02) greater improvements as compared with placebo treatment.
On most secondary measures of depression (CDRS-R total and subtotal scores) and anxiety (MASC total
and subtotal scores), fluoxetine-treated patients experienced numerically, but not statistically, greater
improvements as compared with placebo-treated patients, likely due to the fact that patients began the study
with baseline levels of depression and/or anxiety that were in the low to normal range. In addition, the
incidence of secondary comorbid psychiatric disorders at baseline was low (e.g., the highest incidence was
5% for MDD) as was the number of patients who reported either disorder as a historical diagnosis (8% for
anxiety, 6% for depression).
Safety (Table HCJW.13): No deaths occurred in this study. Of the 103 randomized patients, 80 (78%)
reported at least 1 treatment-emergent adverse event (TEAE). There were no statistically significant
differences in frequencies of TEAEs reported in fluoxetine-treated patients as compared with placebotreated patients.
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Page 4
One serious adverse event of elevated liver enzymes was noted in a fluoxetine-treated patient after 28 days
of treatment following an intentional overdose of acetaminophen tablets. She was hospitalized and
subsequently discontinued from the study. The investigator did not consider this event to be related to the
patient’s fluoxetine treatment. A total of 7 patients (5 fluoxetine, 2 placebo) were discontinued from the
study due to nonserious clinically significant adverse events. Two of the events (headache and
nervousness) that occurred in fluoxetine-treated patients were considered to be related to active treatment,
while the other three events (hyperkinesia, manic reaction, and somnolence) were considered to be possibly
related, as determined by the respective investigators. Two placebo-treated patients were discontinued
from the study due to adverse events of hyperkinesia and nervousness. While blinded, the investigators felt
that the events were possibly related to active treatment. There were no statistically significant differences
between treatment groups with respect to adverse events that led to discontinuation.
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Page 5
Study
Period I
Study Period II
60mg/day*
Fluoxetine
40 mg/day *
40 mg/day*
20 mg/day
20 mg/day
No Rx
10 mg/day
Placebo
Week
-1
0
1
2
3
4
5
Visit
1
2
3
4
5
6
7
6
7
8
8
9
10
11
9
12
13
10
↑
Randomization
* If dose increases to 40 or 60 mg daily are poorly tolerated, the dose may be reduced by 20 mg
once during the study following Visit 6.
Figure HCJW.1.
Study design for B1Y-MC-HCJW.
Fluoxetine Hydrochloride
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CT Registry ID#3032
Table HCJW.1.
Variable
------------------
Baseline Patient Characteristics
All Randomized Patients
B1Y-MC-HCJW
Flx
(N=71)
-------------
Gender: No. (%)
No. Patients
Female
Male
71
37 (52.1)
34 (47.9)
Age (yrs)
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
Age Category: No.
No. Patients
7 - < 13 yrs.
13 - < 18 yrs.
Origin: No. (%)
No. Patients
Caucasian
East, SE Asian
African Descent
Hispanic
Other
Height (cm)
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
Unspecified
Page 6
Placebo
(N=32)
-------------
32
17 (53.1)
15 (46.9)
71
11.42
11.07
2.95
7.03
17.72
Total
(N=103)
-------------
103
54 (52.4)
49 (47.6)
32
11.41
11.60
2.79
7.01
17.93
p-Value
-------------
1.00*
103
11.42
11.27
2.89
7.01
17.93
.847**
(%)
71
51 (71.8)
20 (28.2)
32
24 (75.0)
8 (25.0)
103
75 (72.8)
28 (27.2)
.814*
71
62
0
2
4
3
32
27
1
0
3
1
103
89
1
2
7
4
.538*
(87.3)
(2.8)
(5.6)
(4.2)
69
146.67
144.78
16.55
116.84
185.42
2
(84.4)
(3.1)
(9.4)
(3.1)
32
144.41
144.78
14.31
116.84
172.21
0
(86.4)
(1.0)
(1.9)
(6.8)
(3.9)
101
145.95
144.78
15.84
116.84
185.42
2
.574**
Investigators 1,4,7,8,9,12,13,17,19,20, 21, and 22 are pooled into Investigator 999
RMP.B1YP.JCLLIB2(DES1JWAD)
RMP.B1YO.HCJWREP(DES1JWAD)
* Frequencies are analyzed using a Fishers-Exact test.
** Means are analyzed using a Type III Sum of Squares analysis of variance
(ANOVA): PROC GLM model=investigator and treatment.
XDES0001
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CT Registry ID#3032
Table HCJW.1.
Variable
-----------------Weight (kg)
No. Patients
Mean
Median
Standard Dev.
Minimum
Maximum
Page 7
Baseline Patient Characteristics
All Randomized Patients
B1Y-MC-HCJW (concluded)
Flx
(N=71)
-------------
Placebo
(N=32)
-------------
Total
(N=103)
-------------
71
46.19
41.28
20.87
20.87
102.06
32
41.55
40.82
13.64
19.96
77.11
103
44.75
41.28
18.97
19.96
102.06
p-Value
-------------
.287**
Investigators 1,4,7,8,9,12,13,17,19,20, 21, and 22 are pooled into Investigator 999
RMP.B1YP.JCLLIB2(DES1JWAD)
RMP.B1YO.HCJWREP(DES1JWAD)
* Frequencies are analyzed using a Fishers-Exact test.
** Means are analyzed using a Type III Sum of Squares analysis of variance
(ANOVA): PROC GLM model=investigator and treatment.
XDES0001
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CT Registry ID#3032
Table HCJW.2.
CY-BOCS Total Score
Change from Baseline to Endpoint
All Randomized Patients
B1Y-MC-HCJW
Variable analyzed:
No.
--1)
2)
No.
--1)
2)
Page 8
Change in Total Score (CYBOCTOT)
Baseline
Endpoint
Change
-------------------- -------------------- -------------------Therapy n
Mean Median
SD
Mean Median
SD
Mean Median
SD
------- --- ------ ------ ------ ------ ------ ------ ------ ------ -----Flx
71
24.5
24.0
5.1
15.0
15.0
9.6
-9.5
-9.0
9.2
Placebo 32
26.3
25.5
4.6
21.1
23.0
8.4
-5.2
-4.5
7.4
Therapy
------Flx
Placebo
------------ p-Values ----------Pairwise*3
-----Within InterGroup*1 action*2 Overall*2 vs.(2)
------- -------- --------- -----<.001
.494
.026
.026
<.001
*1 The significance of a location shift from zero of the change from baseline
within a treatment group is tested by the Wilcoxon Signed Rank procedure.
*2 Type III Sums of Squares from an analysis of variance (ANOVA): PROC GLM
model=investigator and treatment for the overall p-Value and
model=investigator, treatment, and interaction for the interaction p-Value.
*3 Least-squares mean option in PROC GLM from the ANOVA using the mean square
for error.
Note: Each investigator has at least one patient in each treatment group.
Investigators 1,4,7,8,9,12,13,17,19,20, 21, and 22 are pooled into Investigator 999
RMP.B1YP.JCLLIB2(LAS3JWAT)
RMP.B1YO.HCJWREP(LAS3JWAT)
XLAS0003
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Table HCJW.3.
Page 9
CY-BOCS Total Score
Number of Patients Meeting Criteria for Response
All Randomized Patients
B1Y-MC-HCJW
Protocol: B1Y-MC-HCJW
Outcome Variable: RESPONSE-40% REDUCTION FROM BASELINE
Stratification Variable: INVESTIGATOR (number of strata = 10)
Therapy
-- -----------------A. Flx
B. Placebo
NO
n
%
------ ---------36
50.7
24
75.0
N
------71
32
YES
n
%
------ ---------35
49.3
8
25.0
COMPARISON OF TREATMENT GROUPS
STATISTICS
-----------------------------Fisher's exact test
(2-tailed)
Pearson's chi-square test
df=1
# Cochran-Mantel-Haenszel
general association test
df=1
VALUE
P-VALUE
----------- ----------0.030
5.354
0.021
5.011
0.025
#: Stratification variable included.
Investigators 1,4,7,8,9,12,13,17,19,20, 21, and 22 are pooled into Investigator 999
RMP.B1YO.HCJWREP(EFS1JWBD)
XEFS0001
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Table HCJW.4.
CY-BOCS Obsessions Score
Change from Baseline to Endpoint
All Randomized Patients
B1Y-MC-HCJW
Variable analyzed:
No.
--1)
2)
No.
--1)
2)
Page 10
Change in Obsession Score (CYBOCOBS)
Baseline
Endpoint
Change
-------------------- -------------------- -------------------Therapy n
Mean Median
SD
Mean Median
SD
Mean Median
SD
------- --- ------ ------ ------ ------ ------ ------ ------ ------ -----Flx
71
11.9
12.0
3.3
7.2
7.0
5.1
-4.7
-4.0
4.8
Placebo 32
12.6
12.5
3.1
9.6
10.0
4.8
-3.0
-3.0
4.3
Therapy
------Flx
Placebo
------------ p-Values ----------Pairwise*3
-----Within InterGroup*1 action*2 Overall*2 vs.(2)
------- -------- --------- -----<.001
.216
.102
.102
<.001
*1 The significance of a location shift from zero of the change from baseline
within a treatment group is tested by the Wilcoxon Signed Rank procedure.
*2 Type III Sums of Squares from an analysis of variance (ANOVA): PROC GLM
model=investigator and treatment for the overall p-Value and
model=investigator, treatment, and interaction for the interaction p-Value.
*3 Least-squares mean option in PROC GLM from the ANOVA using the mean square
for error.
Note: Each investigator has at least one patient in each treatment group.
Investigators 1,4,7,8,9,12,13,17,19,20, 21, and 22 are pooled into Investigator 999
RMP.B1YP.JCLLIB2(LAS3JWAU)
RMP.B1YO.HCJWREP(LAS3JWAU)
XLAS0003
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Table HCJW.5.
CY-BOCS Compulsions Score
Change from Baseline to Endpoint
All Randomized Patients
B1Y-MC-HCJW
Variable analyzed:
No.
--1)
2)
No.
--1)
2)
Page 11
Change in Compulsions Score (CYBOCCOM)
Baseline
Endpoint
Change
-------------------- -------------------- -------------------Therapy n
Mean Median
SD
Mean Median
SD
Mean Median
SD
------- --- ------ ------ ------ ------ ------ ------ ------ ------ -----Flx
71
12.6
12.0
2.9
7.8
8.0
5.0
-4.8
-4.0
5.0
Placebo 32
13.7
14.0
2.5
11.5
12.0
4.7
-2.2
-1.0
4.5
Therapy
------Flx
Placebo
------------ p-Values ----------Pairwise*3
-----Within InterGroup*1 action*2 Overall*2 vs.(2)
------- -------- --------- -----<.001
.588
.015
.015
.013
*1 The significance of a location shift from zero of the change from baseline
within a treatment group is tested by the Wilcoxon Signed Rank procedure.
*2 Type III Sums of Squares from an analysis of variance (ANOVA): PROC GLM
model=investigator and treatment for the overall p-Value and
model=investigator, treatment, and interaction for the interaction p-Value.
*3 Least-squares mean option in PROC GLM from the ANOVA using the mean square
for error.
Note: Each investigator has at least one patient in each treatment group.
Investigators 1,4,7,8,9,12,13,17,19,20, 21, and 22 are pooled into Investigator 999
RMP.B1YP.JCLLIB2(LAS3JWAV)
RMP.B1YO.HCJWREP(LAS3JWAV)
XLAS0003
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
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CT Registry ID#3032
Table HCJW.6.
Page 12
CY-BOCS Total, Obsessions, and Compulsions Scores
Repeated Measures Analyses: AIC for the Full Model
All Randomized Patients
B1Y-MC-HCJW
Covariance Structure
Unstructured
Heterogeneous Toeplitz
Heterogeneous Compound Symmetric
Heterogeneous AR(1)
CY-BOCS
Total
CY-BOCS
Obsessions
CY-BOCS
Compulsions
-2285.63
-2294.63
-2384.89
-2297.98
-1916.42
-1912.93
-1966.03
-1927.86
-1845.46
-1860.01
-1964.00
-1859.52
Data for this table were taken from RMP.B1YSHCHG.SASPGM (REPR01WA, REPR02WA, and
REPR03WA).
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
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CT Registry ID#3032
Table HCJW.7.
Source
Page 13
CY-BOCS Total Score
Repeated Measures Analysis: Significance Level of Fixed
Effects from the Full and Reduced Models
All Randomized Patients
B1Y-MC-HCJW
Full Model
p-Value
Reduced Model
p-Value
.003
.016
.690
<.001
.561
<.001
.006
--<.001
.561
Investigator
Treatment
Investigator x Treatment
Visit
Treatment x Visit
Table HCJW.8.
Visit
Week from
Randomization
2
3
4
5
6
7
8
9
10
0
1
2
3
4
5
7
9
13
CY-BOCS Total Score
Repeated Measures Analysis
Treatment-by-Visit LS Means from the Reduced Model
All Randomized Patients
B1Y-MC-HCJW
Fluoxetine
LS Mean (SE)
24.8
22.7
20.9
18.5
17.9
17.2
15.9
15.1
14.3
(0.6)
(0.7)
(0.8)
(0.9)
(1.0)
(1.0)
(1.1)
(1.1)
(1.1)
Placebo
LS Mean (SE)
26.3
24.7
23.8
21.7
21.3
21.6
21.3
20.8
20.1
(0.8)
(0.9)
(1.2)
(1.3)
(1.4)
(1.5)
(1.6)
(1.7)
(1.7)
Fluoxetine vs Placebo
Change from Baseline p-Value
--.504
.220
.225
.216
.086
.022
.034
.034
Abbreviations: CY-BOCS = Children’s Yale-Brown Obsessive Compulsive Scale; LS = least squares, SE
= standard error.
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
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CT Registry ID#3032
Table HCJW.9.
Page 14
CY-BOCS Obsessions Score
Repeated Measures Analysis: Significance Level of Fixed
Effects from the Full and Reduced Models
All Randomized Patients
B1Y-MC-HCJW
Source
Full Model
p-Value
Reduced Model
p-Value
.101
.087
.613
<.001
.761
.154
.045
--<.001
.756
Investigator
Treatment
Investigator x Treatment
Visit
Treatment x Visit
Abbreviations: CY-BOCS = Children’s Yale-Brown Obsessive Compulsive Scale.
Table HCJW.10.
CY-BOCS Obsessions Score
Repeated Measures Analysis
Treatment-by-Visit LS Means from the Reduced Model
All Randomized Patients
B1Y-MC-HCJW
Visit
Week from
Randomization
2
3
4
5
6
7
8
9
10
0
1
2
3
4
5
7
9
13
Fluoxetine
LS Mean (SE)
12.1
10.9
10.1
9.0
8.5
8.1
7.6
7.2
6.9
Placebo
LS Mean (SE)
(0.5)
(0.5)
(0.5)
(0.6)
(0.5)
(0.5)
(0.6)
(0.6)
(0.6)
12.7
11.8
11.4
9.9
9.9
10.0
9.7
9.3
9.1
(0.6)
(0.6)
(0.7)
(0.8)
(0.8)
(0.7)
(0.8)
(0.8)
(0.9)
Fluoxetine vs Placebo
Change from Baseline p-Value
--.423
.213
.603
.241
.098
.065
.102
.122
Abbreviations: CY-BOCS = Children’s Yale-Brown Obsessive Compulsive Scale; LS = least squares, SE =
standard error.
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
Return to list of Prozac studies
Return to list of Lilly drugs
CT Registry ID#3032
Table HCJW.11.
Page 15
CY-BOCS Compulsions Score
Repeated Measures Analysis: Significance Level of Fixed
Effects from the Full and Reduced Models
All Randomized Patients
B1Y-MC-HCJW
Source
Full Model
p-Value
Reduced Model
p-Value
.002
.004
.201
<.001
.168
.002
.001
--<.001
.184
Investigator
Treatment
Investigator x Treatment
Visit
Treatment x Visit
Abbreviations: CY-BOCS = Children’s Yale-Brown Obsessive Compulsive Scale.
Table HCJW.12.
CY-BOCS Compulsions Score
Repeated Measures Analysis
Treatment-by-Visit LS Means from the Reduced Model
All Randomized Patients
B1Y-MC-HCJW
Visit
Week from
Randomization
2
3
4
5
6
7
8
9
10
0
1
2
3
4
5
7
9
13
Fluoxetine
LS Mean (SE)
12.6
11.7
10.7
9.4
9.4
8.9
8.1
7.7
7.1
Placebo
LS Mean (SE)
(0.3)
(0.4)
(0.4)
(0.5)
(0.5)
(0.5)
(0.5)
(0.6)
(0.6)
13.6
12.8
12.3
11.7
11.2
11.3
11.2
11.3
10.7
(0.5)
(0.6)
(0.6)
(0.7)
(0.7)
(0.8)
(0.8)
(0.8)
(1.0)
Fluoxetine vs Placebo
Change from Baseline p-Value
--0.823
0.370
0.113
0.358
0.157
0.035
0.014
0.027
Abbreviations: CY-BOCS = Children’s Yale-Brown Obsessive Compulsive Scale; LS = least squares, SE
= standard error.
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
Return to list of Prozac studies
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CT Registry ID#3032
Table HCJW.13.
Page 16
Treatment-Emergent Adverse Events by Body System
Incidence by Decreasing Frequency (Ordered by Fluoxetine)
All Randomized Patients
B1Y-MC-HCJW
Body System: Overall
Event Classification
----------------------------PATIENTS WITH >= 1 TESS
PATIENTS WITH NO TESS
Flx
(N=71)
n (%)
---------53 (74.6)
18 (25.4)
Placebo
(N=32)
n (%)
---------27 (84.4)
5 (15.6)
Total
(N=103)
n (%)
---------80 (77.7)
23 (22.3)
p-Value*
Flx
(N=71)
n (%)
---------40 (56.3)
31 (43.7)
20 (28.2)
11 (15.5)
8 (11.3)
7 (9.9)
4 (5.6)
4 (5.6)
3 (4.2)
3 (4.2)
2 (2.8)
2 (2.8)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
0
Placebo
(N=32)
n (%)
---------19 (59.4)
13 (40.6)
9 (28.1)
6 (18.8)
2 (6.3)
2 (6.3)
1 (3.1)
0
0
3 (9.4)
4 (12.5)
1 (3.1)
0
1 (3.1)
1 (3.1)
0
0
1 (3.1)
Total
(N=103)
n (%)
---------59 (57.3)
44 (42.7)
29 (28.2)
17 (16.5)
10 (9.7)
9 (8.7)
5 (4.9)
4 (3.9)
3 (2.9)
6 (5.8)
6 (5.8)
3 (2.9)
1 (1.0)
2 (1.9)
2 (1.9)
1 (1.0)
1 (1.0)
1 (1.0)
p-Value*
---------.317
.317
Body System: BODY AS A WHOLE
Event Classification
----------------------------PATIENTS WITH >= 1 TESS
PATIENTS WITH NO TESS
HEADACHE
ABDOMINAL PAIN
FEVER
PAIN
ACCIDENTAL INJURY
FLU SYNDROME
ALLERGIC REACTION
ASTHENIA
INFECTION
UNEXPECTED BENEFIT
CHEST PAIN
INTENTIONAL INJURY
NECK PAIN
OVERDOSE
PHOTOSENSITIVITY REACTION
MALAISE
---------.832
.832
1.00
.776
.720
.717
1.00
.308
.550
.372
.073
1.00
1.00
.527
.527
1.00
1.00
.311
RMP.B1YP.JCLLIB2(AES2JWCU)
RMP.B1YO.HCJWREP(AES2JWCU)
* Frequencies are analyzed using a Fisher's Exact test.
XAES0002
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
Return to list of Prozac studies
Return to list of Lilly drugs
CT Registry ID#3032
Table HCJW.13.
Page 17
Treatment-Emergent Adverse Events by Body System
Incidence by Decreasing Frequency (Ordered by Fluoxetine)
All Randomized Patients
B1Y-MC-HCJW (continued)
Body System: CARDIOVASCULAR SYSTEM
Event Classification
----------------------------PATIENTS WITH >= 1 TESS
PATIENTS WITH NO TESS
MIGRAINE
Flx
(N=71)
n (%)
---------0
71 (100)
0
Placebo
(N=32)
n (%)
---------1 (3.1)
31 (96.9)
1 (3.1)
Total
(N=103)
n (%)
---------1 (1.0)
102 (99.0)
1 (1.0)
p-Value*
Flx
(N=71)
n (%)
---------29 (40.8)
42 (59.2)
9 (12.7)
9 (12.7)
7 (9.9)
6 (8.5)
3 (4.2)
2 (2.8)
2 (2.8)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
0
0
0
0
Placebo
(N=32)
n (%)
---------12 (37.5)
20 (62.5)
1 (3.1)
4 (12.5)
2 (6.3)
3 (9.4)
1 (3.1)
0
0
0
0
2 (6.3)
0
0
0
0
1 (3.1)
1 (3.1)
1 (3.1)
1 (3.1)
Total
(N=103)
n (%)
---------41 (39.8)
62 (60.2)
10 (9.7)
13 (12.6)
9 (8.7)
9 (8.7)
4 (3.9)
2 (1.9)
2 (1.9)
1 (1.0)
1 (1.0)
3 (2.9)
1 (1.0)
1 (1.0)
1 (1.0)
1 (1.0)
1 (1.0)
1 (1.0)
1 (1.0)
1 (1.0)
p-Value*
---------.311
.311
.311
Body System: DIGESTIVE SYSTEM
Event Classification
----------------------------PATIENTS WITH >= 1 TESS
PATIENTS WITH NO TESS
DIARRHEA
NAUSEA
ANOREXIA
VOMITING
DYSPEPSIA
INCREASED APPETITE
THIRST
ESOPHAGEAL ULCER
FLATULENCE
GASTROINTESTINAL DISORDER
GINGIVITIS
LIVER FUNCTION TESTS ABNORMAL
STOMATITIS
TOOTH CARIES
CONSTIPATION
DYSPHAGIA
GASTROENTERITIS
MELENA
---------.829
.829
.167
1.00
.717
1.00
1.00
1.00
1.00
1.00
1.00
.227
1.00
1.00
1.00
1.00
.311
.311
.311
.311
RMP.B1YP.JCLLIB2(AES2JWCU)
RMP.B1YO.HCJWREP(AES2JWCU)
* Frequencies are analyzed using a Fisher's Exact test.
XAES0002
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
Return to list of Prozac studies
Return to list of Lilly drugs
CT Registry ID#3032
Table HCJW.13.
Page 18
Treatment-Emergent Adverse Events by Body System
Incidence by Decreasing Frequency (Ordered by Fluoxetine)
All Randomized Patients
B1Y-MC-HCJW (continued)
Body System: METABOLIC AND NUTRITIONAL DISORDERS
Event Classification
----------------------------PATIENTS WITH >= 1 TESS
PATIENTS WITH NO TESS
EDEMA
Flx
(N=71)
n (%)
---------0
71 (100)
0
Placebo
(N=32)
n (%)
---------1 (3.1)
31 (96.9)
1 (3.1)
Total
(N=103)
n (%)
---------1 (1.0)
102 (99.0)
1 (1.0)
p-Value*
Placebo
(N=32)
n (%)
---------2 (6.3)
30 (93.8)
1 (3.1)
1 (3.1)
Total
(N=103)
n (%)
---------5 (4.9)
98 (95.1)
4 (3.9)
1 (1.0)
p-Value*
---------.311
.311
.311
Body System: MUSCULOSKELETAL SYSTEM
Event Classification
----------------------------PATIENTS WITH >= 1 TESS
PATIENTS WITH NO TESS
TWITCHING
MYALGIA
Flx
(N=71)
n (%)
---------3 (4.2)
68 (95.8)
3 (4.2)
0
---------.645
.645
1.00
.311
RMP.B1YP.JCLLIB2(AES2JWCU)
RMP.B1YO.HCJWREP(AES2JWCU)
* Frequencies are analyzed using a Fisher's Exact test.
XAES0002
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
Return to list of Prozac studies
Return to list of Lilly drugs
CT Registry ID#3032
Table HCJW.13.
Page 19
Treatment-Emergent Adverse Events by Body System
Incidence by Decreasing Frequency (Ordered by Fluoxetine)
All Randomized Patients
B1Y-MC-HCJW (continued)
Body System: NERVOUS SYSTEM
Event Classification
----------------------------PATIENTS WITH >= 1 TESS
PATIENTS WITH NO TESS
HYPERKINESIA
INSOMNIA
NERVOUSNESS
SOMNOLENCE
AGITATION
ANXIETY
DIZZINESS
TREMOR
PERSONALITY DISORDER
AKATHISIA
AMNESIA
APATHY
EMOTIONAL LABILITY
HOSTILITY
MANIC REACTION
SLEEP DISORDER
THINKING ABNORMAL
ABNORMAL DREAMS
DEPRESSION
NEUROSIS
Flx
(N=71)
n (%)
---------29 (40.8)
42 (59.2)
9 (12.7)
9 (12.7)
7 (9.9)
5 (7.0)
3 (4.2)
3 (4.2)
3 (4.2)
3 (4.2)
2 (2.8)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
0
0
0
Placebo
(N=32)
n (%)
---------15 (46.9)
17 (53.1)
1 (3.1)
3 (9.4)
5 (15.6)
0
0
1 (3.1)
2 (6.3)
0
0
0
0
0
0
0
0
1 (3.1)
0
1 (3.1)
1 (3.1)
1 (3.1)
Total
(N=103)
n (%)
---------44 (42.7)
59 (57.3)
10 (9.7)
12 (11.7)
12 (11.7)
5 (4.9)
3 (2.9)
4 (3.9)
5 (4.9)
3 (2.9)
2 (1.9)
1 (1.0)
1 (1.0)
1 (1.0)
1 (1.0)
1 (1.0)
1 (1.0)
2 (1.9)
1 (1.0)
1 (1.0)
1 (1.0)
1 (1.0)
p-Value*
Flx
(N=71)
n (%)
---------26 (36.6)
45 (63.4)
19 (26.8)
10 (14.1)
6 (8.5)
1 (1.4)
1 (1.4)
1 (1.4)
0
0
Placebo
(N=32)
n (%)
---------12 (37.5)
20 (62.5)
8 (25.0)
5 (15.6)
2 (6.3)
0
0
0
2 (6.3)
1 (3.1)
Total
(N=103)
n (%)
---------38 (36.9)
65 (63.1)
27 (26.2)
15 (14.6)
8 (7.8)
1 (1.0)
1 (1.0)
1 (1.0)
2 (1.9)
1 (1.0)
p-Value*
---------.668
.668
.167
.750
.508
.321
.550
1.00
.645
.550
1.00
1.00
1.00
1.00
1.00
1.00
1.00
.527
1.00
.311
.311
.311
Body System: RESPIRATORY SYSTEM
Event Classification
----------------------------PATIENTS WITH >= 1 TESS
PATIENTS WITH NO TESS
RHINITIS
PHARYNGITIS
COUGH INCREASED
EPISTAXIS
LUNG DISORDER
SINUSITIS
ASTHMA
BRONCHITIS
---------1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
.094
.311
RMP.B1YP.JCLLIB2(AES2JWCU)
RMP.B1YO.HCJWREP(AES2JWCU)
* Frequencies are analyzed using a Fisher's Exact test.
XAES0002
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
Return to list of Prozac studies
Return to list of Lilly drugs
CT Registry ID#3032
Table HCJW.13.
Page 20
Treatment-Emergent Adverse Events by Body System
Incidence by Decreasing Frequency (Ordered by Fluoxetine)
All Randomized Patients
B1Y-MC-HCJW (continued)
Body System: SKIN AND APPENDAGES
Event Classification
----------------------------PATIENTS WITH >= 1 TESS
PATIENTS WITH NO TESS
RASH
PRURITUS
EXFOLIATIVE DERMATITIS
SWEATING
URTICARIA
CONTACT DERMATITIS
DRY SKIN
Flx
(N=71)
n (%)
---------8 (11.3)
63 (88.7)
4 (5.6)
2 (2.8)
1 (1.4)
1 (1.4)
1 (1.4)
0
0
Placebo
(N=32)
n (%)
---------2 (6.3)
30 (93.8)
0
0
0
0
0
1 (3.1)
1 (3.1)
Total
(N=103)
n (%)
---------10 (9.7)
93 (90.3)
4 (3.9)
2 (1.9)
1 (1.0)
1 (1.0)
1 (1.0)
1 (1.0)
1 (1.0)
p-Value*
Flx
(N=71)
n (%)
---------5 (7.0)
66 (93.0)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
Placebo
(N=32)
n (%)
---------1 (3.1)
31 (96.9)
0
0
1 (3.1)
0
0
Total
(N=103)
n (%)
---------6 (5.8)
97 (94.2)
1 (1.0)
1 (1.0)
2 (1.9)
1 (1.0)
1 (1.0)
p-Value*
---------.720
.720
.308
1.00
1.00
1.00
1.00
.311
.311
Body System: SPECIAL SENSES
Event Classification
----------------------------PATIENTS WITH >= 1 TESS
PATIENTS WITH NO TESS
AMBLYOPIA
CONJUNCTIVITIS
EAR PAIN
EYE DISORDER
OTITIS MEDIA
---------.663
.663
1.00
1.00
.527
1.00
1.00
RMP.B1YP.JCLLIB2(AES2JWCU)
RMP.B1YO.HCJWREP(AES2JWCU)
* Frequencies are analyzed using a Fisher's Exact test.
XAES0002
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
Return to list of Prozac studies
Return to list of Lilly drugs
CT Registry ID#3032
Table HCJW.13.
Page 21
Treatment-Emergent Adverse Events by Body System
Incidence by Decreasing Frequency (Ordered by Fluoxetine)
All Randomized Patients
B1Y-MC-HCJW (concluded)
Body System: UROGENITAL SYSTEM
Event Classification
----------------------------PATIENTS WITH >= 1 TESS
PATIENTS WITH NO TESS
URINARY FREQUENCY
MENORRHAGIA
DYSMENORRHEA
HEMATURIA
URINARY INCONTINENCE
URINARY TRACT INFECTION
Flx
(N=71)
n (%)
---------7 (9.9)
64 (90.1)
3 (4.2)
2 (2.8)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
Placebo
(N=32)
n (%)
---------0
32 (100)
0
0
0
0
0
0
Total
(N=103)
n (%)
---------7 (6.8)
96 (93.2)
3 (2.9)
2 (1.9)
1 (1.0)
1 (1.0)
1 (1.0)
1 (1.0)
p-Value*
---------.096
.096
.550
1.00
1.00
1.00
1.00
1.00
RMP.B1YP.JCLLIB2(AES2JWCU)
RMP.B1YO.HCJWREP(AES2JWCU)
* Frequencies are analyzed using a Fisher's Exact test.
XAES0002
Fluoxetine Hydrochloride
Copyright © 2004 Eli Lilly and Company. All rights reserved.
Approved by Lilly 15 November 2004
Return to list of Prozac studies
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CT Registry ID#6334
Page 1
Summary ID# 6334
Clinical Study Summary: Study B1Y-PU-S012
Enteric-Coated Hydrochlorate Fluoxetine Administered
Once Weekly During the Maintenance Treatment of
Major Depressive Disorder
Date summary approved by Lilly: 08 November 2006
Brief Summary of Results
Study B1Y-PU-S012 (S012) was an open-label, prospective, multicenter, noncontrolled,
outpatient study spanning 24 weeks that included patients with a diagnosis of major
depressive disorder (MDD), as defined by the Diagnostic and Statistical Manual of
Mental Disorders 4th Edition (DSM-IV) criteria, who had previously responded to an
acute phase of 20 mg/day of fluoxetine for a minimum of 8 weeks and were switched to
90 mg/week of enteric-coated fluoxetine.
The primary objective of Study S012 was to determine the relapse rate in patients
responding to 20 mg/day of fluoxetine who were transitioned to 90 mg/week of entericcoated fluoxetine for 24 weeks.
Secondary objectives were to determine the changes on the Hamilton Depression Scale –
17 (HAMD17) Items and the Clinical Global Impression of Severity (CGI-S) Scale in
relation to the basal scores, and to determine the rate of adverse events (AEs) in patients
who received extension treatment with 90 mg of fluoxetine weekly and to determine the
rate of AEs which showed up during the extension treatment with 90 mg fluoxetine
weekly. The main results were as follows:
•
No relapses were registered after switching to fluoxetine weekly.
•
The decrease of the total score from baseline to endpoint of the HAMD17 was
statistically significant (mean change: 2.07; p<.001).
Fluoxetine
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•
Statistically significant results were reported for sub-score anxiety/somatization
(mean change: 0.64; p=.001) and CGI-S (mean change: 0.52; p<.001).
•
The analysis of fluoxetine on sleep (Items 4 to 6 of HAMD17) showed a
statistically significant difference from baseline to endpoint (mean change: 0.6;
p<.001).
•
One patient was discontinued from the study due to AEs (nausea, vomiting, and
increase of alanine transaminase [ALT/SGPT] and aspartate transaminase
[AST/SGOT]).
•
No statistically significant changes in vital signs or electrocardiograms (ECGs)
were registered during this study.
Title of Study: Enteric-Coated Hydrochlorate Fluoxetine Administered Once Weekly During the
Maintenance Treatment of Major Depressive Disorder
Investigator(s): This multicenter study included 15 principal investigators.
Study Center(s): This study was conducted at 14 study centers in 3 countries.
Length of Study: 15 months
Phase of Development: 4
Date of first patient visit: 19 December 2001
Date of first patient enrolled: 02 January 2002
Date of last patient completed: 13 March 2003
Objectives:
Primary:
• To determine the relapse rate in patients responding to 20 mg/day of fluoxetine who had been
transitioned to a 90 mg enteric-coated fluoxetine once weekly dose for 24 weeks.
Secondary:
• To determine the changes in score on the HAMD17 Items, and on the CGI-S Scale in relation to
the basal scores of patients who received extension treatment with 90 mg of fluoxetine weekly.
• To determine the rate of AEs with 90-mg fluoxetine weekly administered, which occurred
during extension treatment. To achieve this, the AEs spontaneously reported by patients were
considered as well as laboratory test findings.
Study Design: This was an open-label, prospective, multicenter, noncontrolled, outpatient study of 24
weeks that included patients with a diagnosis of MDD as defined by the DSM-IV criteria that had
previously responded to an acute phase of 20 mg/day of fluoxetine for a minimum of 8 weeks and were
switched to 90-mg enteric-coated fluoxetine weekly. See Figure 1 for details of study design.
Number of Patients:
Planned: 100
Enrolled: 98
Completed: 94
Diagnosis and Main Criteria for Inclusion: Male or female ambulatory patients between the ages of
16- and 65-years-old with a diagnosis of MDD as defined by the DSM-IV criteria who had previously
responded to an acute phase of 20 mg/day of fluoxetine for a minimum of 8 weeks, with a HAMD17
Score ≤9 (in Visits 1 and 2) and CGI-S Score ≤2 (in Visits 1 and 2), and who gave signed informed
consent were enrolled in this study.
Study Drug, Dose, and Mode of Administration: Enteric-coated fluoxetine 90 mg given orally once a
week as one 90-mg capsule.
Comparator, Dose, and Mode of Administration: No comparator was used in this study.
Fluoxetine
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Duration of Treatment: 24 weeks.
Fluoxetine Frequency: 24 weeks (1x/wk).
Variables:
Efficacy: The main efficacy variable was the percentage of patients who relapsed at the end of the24week period of maintenance treatment. Secondary measurements of efficacy included HAMD17 and
CGI-S scores.
Safety: Safety measures included: physical examinations, vital signs, weight, clinical history,
reporting of AEs (nonserious and serious), as well as ECGs, hematological analyses, blood chemistry
and thyroid function tests, in Visits 2 and 13, and if the patient presented a relapse.
Evaluation Methods:
Statistical: For the efficacy analysis, the recurrence rate and the confidence level was estimated at
95% after 24 weeks of extension treatment with weekly 90 mg fluoxetine. Additionally, the free
recurrence period was determined using the Kaplan-Meier method and was compared with the clinical
features through the proportional risk model of Wilcoxon rank. Adverse events (AEs) were defined as
events which occurred or got worse during Period II of the trial. Period II of the trial was the baseline
for the definition of AEs that arose during the extension treatment. Adverse events (AEs) during the
extension phase were analyzed using Pearson’s chi-square test. The change or variation of the
laboratory values between Period I and Period II were analyzed using the repetitive measures method.
Period II
Period I
Initial
Evaluation and
Selection
2-9 days
Visit 1
Figure 1.
Fluoxetine
Open treatment period with fluoxetine 90 mg/week
Suspension of
Fluoxetine
20 mg/day
weekly
3-7 days
Visit 2
Visit 3
biweekly
Visit 6
monthly
Visit 10
Visit 13
Illustration of study design for protocol B1Y-PU-S012.
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Results:
Patient Demographics
Ninety-eight patients were enrolled in Study S012. The mean age was 45-years-old
(ranging from 20 to 71 years old) and 79% were female. Eighty-four percent were
Hispanic, 14% Caucasian, 1% Black and 1% Asian. The mean age of illness onset was
39 years old ± 12.6 years. Fifty-eight percent had recurrent depression and 76% had
previous treatment. See Table 1 for details of clinical characteristics.
Table 1.
Clinical Characteristics (n=98)
Clinical Characteristic
N°.
%
None
41
42
1 to 2
33
34
3 or more
24
24
Personal antecedents
46
47
Familial antecedents
57
58
Familiar psychiatric antecedent
22
22
Familiar major depression antecedent
18
18
No
26
24
Yes
74
76
Previous depressive episodes
Pathological antecedents
Previous treatment
Measures done in Visit 1, when the patients were receiving fluoxetine 20 mg daily, were
considered as baseline. The baseline CGI-S, HAMD17 and anxiety/somatization scores
are shown below (see Table 2.). The baseline means and standard deviation (SD) of the
efficacy measures were: HAMD17: 4.02 (SD 3), CGI-S: 1.7 (SD 0.7) and
anxiety/somatization sub score: 1.62 (SD 1.3).
Fluoxetine
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Table 2.
Page 5
Baseline Measures (n=98)
Baseline Measures
N°
%
Normal, not at all ill
42
43
Borderline ill
44
45
Mildly ill
11
11
Moderately ill
1
1
Score < 9
94
96
Score > 9
4
4
98
100
CGI
HAMD17
Anxiety/somatization sub-score
<7
Patient Disposition
Ninety-four patients (96%) completed the study. One patient withdrew from the study
due to AEs (nausea, vomiting, and increase of ALT/SGPT and AST/SGOT), and another
patient withdrew from the study after Visit 2 without explanation. Two patients were
missing in the follow-up period: 1 patient was lost to follow-up after Visit 1 and another
one after Visit 7.
Primary Efficacy Measure
The primary objective of Study S012 was to determine the relapse rate in patients
responding to 20 mg/day of fluoxetine who had been transitioned to a 90-mg entericcoated fluoxetine weekly dose for 24 weeks. A relapse was defined as when the patient
fulfilled the DSM-IV of MDD or had HAMD17 scores >9 and CGI-S scores >2, in 4,
consecutive, nonprogrammed weekly visits. No relapses were registered after switching
to fluoxetine weekly.
The reappearance of significant depressive symptoms was defined as an increase of at
least 50% in HAMD17 during the evaluation or a score ≥12 in HAMD17. Two patients
presented reappearance of depressive symptoms with values of HAMD17=12 at Visit 4.
In both cases these scores decreased to 9 and 8, respectively, at Visit 6.
Fluoxetine
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Secondary Efficacy Measures/Safety
The statistical analysis of the secondary efficacy measures scales showed statistically
significant decreases in scores from baseline to endpoint. The decrease of the total score
from baseline to endpoint of the HAMD17 was statistically significant (mean change:
-2.07; p<.001). Similar results were observed in the anxiety/somatization subscore (mean
change: -0.64; p=.001) and CGI-S score (mean change: -0.52; p<.001). Multivariate
analysis of variance (MANOVA) revealed statistical differences in HAMD17 total scores,
anxiety/somatization sub-scores and CGI-S scores (see Table 3).
Table 3.
Statistical Analysis of the Secondary Measures of Efficacy
Efficacy Measures
Baseline Mean
Change to
Media (SD)
(SD)
Endpoint
HAMD17 Total Score
4.02 (3.0)
-2.70
<.001
Anxiety/Somatization
1.62 (1.3)
-0.64
=.001
CGI-S
1.70 (0.7)
-0.52
<.001
p-Value
The statistical analysis by repeated measures of the items about sleep and genital
symptoms, extracted from HAMD17, were similar to those found in anxiety/somatization
sub-scores. In the analysis of the effect of fluoxetine weekly on sleep (Items 4 to 6 of
HAMD17), the mean score at Visit 1 was 0.8 ± 1.0. The analysis of sleep showed a
statistically significant difference from baseline to endpoint (mean change: 0.6; p<.001).
The analysis of changes in the score of Item 14 of HAMD17 (genital symptoms) showed
no statistically significant difference from baseline to endpoint (see Figure 2).
Fluoxetine
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Sub-scales of HAMD17
Score
3.0
Insomnia
2.5
SG
Anxiety
2.0
1.5
1.0
0.5
0.0
1
2
3
4
5
6
7
8
9
10
11
12
13
Visit
Insomnia items p<0.001
Genital symptoms (SG) p=0.071
Anxiety/somatization items: p=0.013
Figure 2.
Sub-scales of HAMD17.
Safety
The AE analysis included all patients. Seventy-six percent of patients reported at least
one AE. The most frequent AEs were headache (41%), anxiety (37%), somnolence
(21%), nausea (19%), and insomnia (17%). One patient was discontinued due to nausea,
vomiting, and increases of alanine transaminase (ALT/SGPT) and aspartate transaminase
(AST/SGOT). Sixty-three patients (64%) required concomitant medication(s), and 14%
required anxiolytic medication(s). Details of the AEs registered are presented (see Table
4).
Fluoxetine
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Table 4.
Page 8
Spontaneous Adverse Events Registered During the Study
(n=98)
Adverse Events
N
Percentage
Cephalea
26
41
Anxiety
23
37
Somnolence
13
21
Nausea and Dizziness
12
19
Insomnia
11
17
Diarrhea
7
11
Nervousness
7
11
Weight Gain
7
11
Dry Mouth
7
11
Hypochondriasis
3
5
Depressive Mood
2
3
Abdominal Pain
2
3
Arterial Hypertension
1
2
No AEs on vital signs or ECGs were reported during this study.
Fluoxetine
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Summary ID # 6706
Clinical Study Summary: Study B1Y-GH-S013
Depression with Lack of Motivation; Comparison
Between Fluoxetine and Trazodone
Date summary approved by Lilly: 26 October 2006
Brief Summary of Results
Study B1Y-GH-S013 (S013) was a multicenter, outpatient, open-label, Phase 4 study of
patients with depression treated with fluoxetine or trazodone. The primary objective was
to assess the efficacy of fluoxetine in treating depressed patients who had anergic
symptoms and to compare it with trazodone in a randomized, open clinical setting. The
efficacy was assessed using the baseline in the Hamilton depression rating
scale (HAM-D) for a decrease in the score and the percentage (decrease rate) of the
retardation factor.
The secondary objectives were to evaluate the general efficacy of fluoxetine and
trazodone in treating depression with retardation with the HAM-D total score as an index;
use the medical outcomes Short-Form 36 Health Survey (SF-36) to evaluate the change
in the quality of life (QOL) of depressed patients treated with fluoxetine and trazodone;
use the HAM-D to evaluate item 13 of lack of energy/fatigue (general somatic
symptoms), items related to energy in the Symptom Checklist-90-Revision (SCL-90-R;
reduced energy or retardation; retardation of thought, speaking, or action; difficulty doing
anything; lack of interest; hard to concentrate), and items related to chronic fatigue or
reduced energy in order to assess the efficacy of fluoxetine and trazodone in treating the
fatigue and reduced energy that accompany depression; and use the linking and deleting
tests to evaluate the change in gnosia of depressed patients during fluoxetine and
trazodone treatment.
The main results were as follows:
•
The reduction from baseline in the HAM-D retardation score and SCL-90-R score for
fluoxetine and trazodone was statistically significant at Weeks 1 through 6 when
compared with baseline (p<.01).
Fluoxetine
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•
The reduction from baseline in the HAM-D retardation score and SCL-90-R score
was greater for patients in the fluoxetine group at Weeks 4 and 6 compared with the
trazodone group; the difference was statistically significant (p<.01).
•
Patients in both treatment groups had a statistically significant reduction in HAM-D
total score, HAM-D sleep factor score, and HAM-D anxiety factor score with
treatment compared with baseline (p<.01).
•
The reduction in the HAM-D total score and HAM-D anxiety factor score was greater
for patients in the fluoxetine group at Week 6 compared with the trazodone group; the
difference was statistically significant (p<.01 and p<.05, respectively).
•
The energy-related symptom scores and QOL scores, based on SF-36, were
significantly improved from baseline in the fluoxetine and trazodone treatment
groups; the decreases in SF-36 energy-related symptoms and score of SF-36 QOL
were statistically significant (p<.01). The improvement in scores from baseline was
greater in the fluoxetine group compared with the trazodone group (p<.01).
•
The score in the grooved pegboard test was significantly improved (that is, decreased)
from baseline in the fluoxetine and trazodone treatment groups; the decrease was
statistically significant (p<.05 in the trazodone group; p<.01 in the fluoxetine group).
•
The improvement (that is, increase) from baseline in the trail-making test score was
statistically significant in the fluoxetine group (p<.01).
•
There was no difference in cognitive function from baseline for either treatment
group.
•
The most frequently reported adverse events (AEs) for patients in the fluoxetine
group were insomnia, tachycardia, gastrointestinal symptoms, and anticholinergic
effect. Of 61 patients in the fluoxetine group, 34% reported at least 1 AE.
•
The most frequently reported AEs for patients in the trazodone group were
anticholinergic effect, tachycardia, tiredness, and gastrointestinal symptoms. Of
59 patients in the trazodone group, 39% reported at least 1 AE.
•
There were no statistically significant differences in adverse events between the
treatment groups.
•
One patient in the fluoxetine group had an elevated alanine aminotransferase (ALT)
level during the study. There were no other laboratory value changes noted.
Fluoxetine
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Title of Study: Depression with Lack of Motivation; Comparison of Fluoxetine and Trazodone
Investigator(s): This multicenter study included 4 principal investigators.
Study Center(s): This study was conducted at 4 study centers in 1 country.
Length of Study: 12 months
Phase of Development: 4
Date of first patient enrolled: October 2002
Date of last patient completed: October 2003
Objectives: The primary objective of this study was to assess the efficacy of fluoxetine in treating
depressed patients who had anergic symptoms and to compare it with trazodone in a randomized, open
clinical setting. The efficacy was assessed using the baseline in the HAM-D for a decrease in the score and
the percentage (decrease rate) of the retardation factor.
The secondary objectives of this study were to evaluate the general efficacy of fluoxetine and trazodone in
treating depression with retardation with the HAM-D total score as an index; use the medical outcomes
SF-36 to evaluate the change in the QOL of depressed patients treated with fluoxetine and trazodone; use
the HAM-D to evaluate item 13 of lack of energy/fatigue (general somatic symptoms), items related to
energy in the SCL-90-R (reduced energy or retardation; retardation of thought, speaking, or action;
difficulty doing anything; lack of interest; hard to concentrate), and items related to chronic fatigue or
reduced energy in order to assess the efficacy of fluoxetine and trazodone in treating the fatigue and
reduced energy that accompany depression; and use the linking and deleting tests to evaluate the change in
gnosia of depressed patients during fluoxetine and trazodone treatment.
Study Design: This was a multicenter, open-label, outpatient, Phase 4 study.
Number of Patients:
Planned: 120 patients total
Entered: 120 patients total (61 patients in fluoxetine group; 59 patients in trazodone group)
Completed: 113patients total (58 in fluoxetine group and 55 in trazodone group, respectively)
Diagnosis and Main Criteria for Inclusion: Male or female patients with clinically diagnosed severe
depression (DSM-IV); HAM-D total score ≥18 on 17 items; HAM-D score ≥8 on items 1, 7, 8, and 14; no
serious or unstable illness; aged ≥18 years; and who gave written informed consent were eligible to
participate in this study.
Study Drug, Dose, and Mode of Administration: Fluoxetine 20 mg/day was administered orally during
the first and second weeks of treatment. The dose could be increased up to 80 mg/day based on clinical
judgment.
Reference Therapy, Dose, and Mode of Administration: Trazodone 50 mg/day was administered orally
for the first 3 days of treatment and increased to 100 mg/day for Days 4 through 7. The dose could then be
increased up to 300 mg/day based on clinical judgment.
Duration of Treatment: After a 7- to 14-day washout period, patients were randomized to 6 weeks of
treatment with fluoxetine or trazodone. Treatment was discontinued for violation of study protocol, patient
pregnancy, unacceptable toxicity, or patient’s or investigator’s decision.
Variables:
Efficacy: This study used the first 17 items of HAM-D as the primary measure for evaluating therapeutic
efficacy. This study also used the total HAM-D score as the secondary therapeutic efficacy index.
Safety: Safety was evaluated based on vital sign measurements (blood pressure, pulse rate), laboratory
values, physical examinations, pregnancy testing (as appropriate), and AEs. Additional tools to evaluate
safety were the SF-36 and SCL-90-R.
Fluoxetine
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Evaluation Methods:
Primary analyses were done on an intent-to-treat basis (ITT); ITT analysis included all patient data, even if
the patient did not take the assigned treatment, did not receive the correct treatment, or did not follow the
protocol. All patient AE data, reasons for study termination, and status of termination based on AEs were
analyzed.
Overall, 120 patients were entered into the study (61 patients in the fluoxetine group; 59 patients in the
trazodone group). Efficacy analysis was performed for 58 patients (95.1%) in the fluoxetine group and
55 patients (93.2%) in the trazodone group. Safety analysis was performed on the 120 patients admitted to
the study (that is, informed consent obtained).
Analysis of variance (ANOVA) was used to assess continuous data. Categorized data was analyzed using
Pearson chi-square test. The carryover method was used to analyze the average change from baseline to
end of study. Reasons for study termination were compared between treatment groups using the simple
table method. Sex, age, disease characteristics and origins, and other baseline characteristics were
summarized according to treatment group. Analysis of therapeutic efficacy was conducted using ANOVA.
Fisher’s exact test was used to analyze the frequency of AEs and changes in laboratory values.
Results:
Patient Demographics
The treatment groups were comparable for sex, age, and HAM-D scores (total and
retardation) (see Table 1).
Table 1.
Baseline Patient Demographics and Other Characteristics
Fluoxetine Group
Trazodone Group
N = 61
N = 59
Sex
Male
27 (44.3%)
29 (49.2%)
Female
34 (55.7%)
30 (50.8%)
Age (years)
Mean ± SD
37.2±14.0
37.4±13.0
HAM-D score (total)
Mean ± SD
29.5±6.5
29.1±7.9
HAM-D retardation score
Mean ± SD
10.9±1.9
10.8±1.9
Abbreviations: HAM-D = Hamilton depression rating scale; N = total population; SD = standard deviation.
Parameter
Patient Disposition
The ITT group included those patients who had at least one assessment after study drug
administration. Efficacy analysis was conducted on the ITT group; 7 patients (3 patients
in the fluoxetine group; 4 in the trazodone group) were excluded from efficacy analysis
because posttreatment data were not obtained. As such, efficacy analysis was performed
for 58 patients (95.1%) in the fluoxetine group and 55 patients (93.2%) in the trazodone
group. Safety analysis was performed on the 120 patients admitted to the study (that
is, informed consent obtained).
Fluoxetine
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Primary Efficacy Measures
The primary objective was to assess the efficacy of fluoxetine in treating depressed
patients who had anergic symptoms and to compare it with trazodone in a randomized,
open clinical setting. The efficacy was assessed using the baseline in the HAM-D for a
decrease in the score and the percentage (decrease rate) of the retardation factor. The
reduction from baseline in the HAM-D retardation score and SCL-90-R score for
fluoxetine and trazodone was statistically significant at Weeks 1 through 6 when
compared with baseline (p<.01). The reduction from baseline in the HAM-D retardation
score and SCL-90-R score was greater for patients in the fluoxetine group at Weeks 4 and
6 compared with the trazodone group; the difference was statistically significant (p<.01).
Table 2 provides an overview of HAM-D retardation scores and SCL-90-R scores by
treatment group.
Table2.
HAM-D Retardation Factor Score and Total Score of
SCL-90-R Energy-Related Items
Assessments
Patients Baseline
Week 1
Week 2
Week 4
Week 6
HAM-D Retardation factor score
Fluoxetine
Assessed
58
10.9±1.9
9.8±2.2*
7.7±2.1*
5.2±2.5*
3.6±2.5*
7.4±3.4#
Reduced
1.1±1.4
3.2±2.2
5.7±3.2#
Trazodone
Assessed
55
10.8±1.9
9.6±2.1*
8.1±2.6*
6.6±2.1*
5.8±3.5*
Reduced
1.2±1.8
2.7±2.0
4.2±3.5
5.0±4.1
Total Score of SCL-90-R energy related items
Fluoxetine
Assessed
58
8.1±3.0
7.2±2.6*
5.9±2.7*
4.1±2.7*
2.8±2.6*
#
5.3±3.3#
Reduced
0.9±1.7
2.2±2.2
4.0±3.0
Trazodone
Assessed
55
8.2±2.8
7.3±2.7*
6.1±2.6*
5.2±2.7*
4.5±2.9*
Reduced
0.9±1.7
2.1±2.7
3.1±3.5
3.7±3.9
*comparison with baseline assessment, p<.01; #comparison between fluoxetine and trazodone treatment
groups, p<.01.
Abbreviations: HAM-D = Hamilton depression rating scale; SCL-90-R = Symptom Checklist-90-Revision.
Secondary Efficacy Measures
The secondary objectives were to evaluate the general efficacy of fluoxetine and
trazodone in treating depression with retardation with the HAM-D total score as an index;
use the medical outcomes SF-36 to evaluate the change in the QOL of depressed patients
treated with fluoxetine and trazodone; use the HAM-D to evaluate item 13 of lack of
energy/fatigue (general somatic symptoms), items related to energy in the SCL-90-R
(reduced energy or retardation; retardation of thought, speaking, or action; difficulty
doing anything; lack of interest; hard to concentrate), and items related to chronic fatigue
or reduced energy in order to assess the efficacy of fluoxetine and trazodone in treating
the fatigue and reduced energy that accompany depression; and use the linking and
deleting tests to evaluate the change in gnosia of depressed patients during fluoxetine and
trazodone treatment.
HAM-D Total Score, HAM-D Sleep Factor Score, and HAM-D Anxiety Factor
Score
Fluoxetine
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Patients in both treatment groups had a statistically significant reduction in HAM-D total
score, HAM-D sleep factor score, and HAM-D anxiety factor score with treatment
compared with baseline (p<.01). The reduction in the HAM-D total score and HAM-D
anxiety factor score was greater for patients in the fluoxetine group at Week 6 compared
with the trazodone group; the difference was statistically significant (p<.01 and p<.05,
respectively). Table 3 provides an overview of HAM-D total score, HAM-D sleep factor
score, and HAM-D anxiety factor score by treatment group.
Table 3.
HAM-D Total Score, HAM-D Sleep Factor Score, and HAM-D
Anxiety Factor Score
Assessments
Patients Baseline
Week 1
Week 2
Week 4
Week 6
HAM-D total score
Fluoxetine
Assessed
58
29.5±6.5
25.1±6.4*
19.4±6.4* 13.2±7.0* 8.8±7.0*
Reduced
4.4±5.2
10.1±6.8
16.3±8.7
20.7±9.5#
Trazodone
Assessed
55
29.1±7.9
23.5±7.1*
19.0±7.7* 15.0±8.2* 13.7±8.9*
Reduced
5.6±5.9
10.1±8.6
14.1±9.9
15.4±11.1
HAM-D Sleep factor score
Fluoxetine
Assessed
58
4.6±1.5
3.4±1.9*
2.6±1.8*
1.8±1.6*
1.2±1.4*
Reduced
1.2±1.9
2.1±2.0
2.9±2.0
3.5±1.9
Trazodone
Assessed
55
4.4±1.7
2.9±1.8*
1.8±1.8*
1.4±1.5*
1.3±1.6*
Reduced
1.6±1.4
2.6±1.8
3.0±1.8
3.1±1.9
HAM-D Anxiety factor score
Fluoxetine
Assessed
58
6.9±3.3
6.1±2.7*
4.9±2.8*
3.5±2.6*
2.5±2.3*
Reduced
0.8±1.8
2.0±2.3
3.4±2.9
4.4±3.5#
Trazodone
Assessed
55
7.1±3.2
5.8±2.8*
5.0±3.0*
4.0±2.8*
3.9±2.9*
Reduced
1.3±1.8
2.0±2.5
3.1±2.9
3.2±3.7
*comparison with baseline assessment, p<.01; #comparison between fluoxetine and trazodone treatment
groups, p<.01.
Abbreviations: HAM-D = Hamilton depression rating scale.
Energy-Related Symptoms and Quality of Life
The energy-related symptom scores and QOL scores, based on SF-36, were significantly
improved from baseline in the fluoxetine and trazodone treatment groups; the decreases
in SF-36 energy-related symptoms and score of SF-36 QOL were statistically significant
(p<.01). The improvement in scores from baseline was greater in the fluoxetine group
compared with the trazodone group (p<.01). Table4 provides an overview of the mean
SF-36 Scores and cognitive function assessment scores.
Fluoxetine
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CT Registry ID#6706
Table 4.
Page 7
Mean SF-36 Scores and Cognitive Function Assessments
Patients
Baseline
Week 6
Improvement
Score of SF-36 energy-related symptoms
Fluoxetine group
52
31.3±6.6
11.9±8.0**
19.4±9.0#
Trazodone group
52
29.9±6.0
19.4±10.6**
10.5±11.4
Score of SF-36 QOL
Fluoxetine group
52
15.7±3.8
6.5±4.3**
9.3±4.9#
Trazodone group
52
14.8±3.4
10.1±5.3**
4.7±5.7
Score of Grooved Pegboard Test
Fluoxetine group
52
86.4±61.5
60.6±31.3**
17.0±24.1
Trazodone group
52
86.5±63.1
69.7±40.1*
8.9±28.7
Score of Trail-Making Test
Fluoxetine group
52
105.5±35.6
120.4±34.5**
14.9±12.4
Trazodone group
52
102.8±34.6
108.0±33.8
5.2±24.9
*comparison with baseline assessment, p<.05; **comparison with baseline assessment, p<.01; #comparison
between fluoxetine and trazodone groups, p<.01.
Abbreviations: QOL = quality of life; SF-36 = 36-item short-form health survey.
Grooved Pegboard Test and Trail-Making Test
The score in the grooved pegboard test was significantly improved (that is, decreased)
from baseline in the fluoxetine and trazodone treatment groups; the decrease was
statistically significant (p<.05 in the trazodone group; p<.01 in the fluoxetine group).
The improvement (that is, increase) from baseline in the trail-making test score was
statistically significant in the fluoxetine group (p<.01) (see Table 4).
Safety
The primary safety measure was the assessment of tolerability of fluoxetine and
trazodone in patients with depression.
Adverse Events
There were no deaths reported during this study. The most frequently reported AEs for
patients in the fluoxetine group were insomnia, tachycardia, gastrointestinal symptoms,
and anticholinergic effect. Of 61 patients in the fluoxetine group, 34% reported at least
1 AE. The most frequently reported AEs for patients in the trazodone group were
anticholinergic effect, tachycardia, tiredness, and gastrointestinal symptoms. Of
59 patients in the trazodone group, 39% reported at least 1 AE. There were no
statistically significant differences in AEs between the treatment groups. Table 5
provides an overview of AEs by treatment group.
Fluoxetine
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CT Registry ID#6706
Table 5.
Page 8
Adverse Events; by Treatment Group
Adverse Events by Treatment Group; Percent of Patients
Fluoxetine
Adverse Event
Group
Adverse Event
N = 61
Any adverse event
34%
Any adverse event
Insomnia
16%
Anticholinergic effect
Tachycardia
11%
Tachycardia
Gastrointestinal symptoms
6.5%
Tiredness
Anticholinergic effect
6.5%
Gastrointestinal symptoms
Abbreviations: N = total population.
Trazodone
Group
N = 59
39%
18%
10%
6.7%
6.7%
Laboratory Values
One patient in the fluoxetine group had an elevated ALT level of 117 U/L during the
study. There were no other laboratory value changes noted.
Exposure to Study Drug
Patients were randomized to treatment with fluoxetine (20 to 80 mg/day) or trazodone
(100 to 300 mg/day). The mean prescribed dose for patients in the fluoxetine group was
21.6±5.9 mg/day; the mean prescribed dose for patients in the trazodone group was
130.2±43.6 mg/day.
Fluoxetine
Copyright © 2006 Eli Lilly and Company. All rights reserved.