1. health and fitness
2. disease
3. aids and hiv

Journal of Thrombosis and Haemostasis, 11: 1119–1127
DOI: 10.1111/jth.12202
ORIGINAL ARTICLE
Randomized, controlled, parallel-group trial of routine
prophylaxis vs. on-demand treatment with sucrose-formulated
recombinant factor VIII in adults with severe hemophilia A
(SPINART)
M. J. MANCO-JOHNSON,* C. L. KEMPTON,† M. T. REDING,‡ T. LISSITCHKOV,§ S. GORANOV,¶
L . G E R C H E V A , * * L . R U S E N , † † M . G H I N E A , ‡ ‡ V . U S C A T E S C U , § § V . R E S C I A ¶ ¶ and W . H O N G * * *
*University of Colorado, Aurora, CO; †Emory University, Atlanta, GA; ‡University of Minnesota, Minneapolis, MN, USA; §NSHAT
Haematology, Sofia; ¶UMHAT Sveti Georgi, Plovdiv; **UMHAT Sveta Marina, Varna, Bulgaria; ††S.C. SANADOR SRL, Bucharest;
‡‡Constanta Clinical Hospital, Constanta; §§Institutul Clinic Fundeni, Bucharest, Romania; ¶¶Instituto Dr Ruben Davoli, Rosario, Argentina;
and ***Bayer HealthCare Pharmaceuticals, Montville, NJ, USA
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To cite this article: Manco-Johnson MJ, Kempton CL, Reding MT, Lissitchkov T, Goranov S, Gercheva L, Rusen L, Ghinea M, Uscatescu V,
Rescia V, Hong W. Randomized, controlled, parallel-group trial of routine prophylaxis vs. on-demand treatment with sucrose-formulated
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were enrolled and analyzed (n = 42 per group; mean age,
30.6 years; median treatment duration, 1.7 years). The
median number of total bleeding episodes and total bleeding episodes per year were significantly lower with prophylaxis than with on-demand treatment (total, 0 vs. 54.5;
total per year, 0 vs. 27.9; both P < 0.0001). No treatmentrelated adverse events occurred, and no patients developed
FVIII inhibitors. Conclusions: Routine prophylaxis with
rFVIII-FS leads to a significant reduction in bleeding as
compared with on-demand treatment. Adverse events were
consistent with the established rFVIII-FS safety profile.
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Summary. Background: The benefits of routine prophylaxis vs. on-demand treatment with factor VIII products
have not been evaluated in controlled clinical trials in
older patients with hemophilia A. Objectives: To report
results from a preplanned analysis of data from the first
year of the 3-year SPINART study, which compares routine prophylaxis with on-demand treatment with sucroseformulated recombinant FVIII (rFVIII-FS). Patients/
Methods: SPINART is an open-label, randomized, controlled, parallel-group, multinational trial. Males aged 12–
50 years with severe hemophilia A, 150 days of exposure to FVIII, no FVIII inhibitors, no prophylaxis for
> 12 consecutive months in the past 5 years and 6–24
bleeding episodes in the preceding 6 months were randomized 1 : 1 to rFVIII-FS prophylaxis (25 IU kg 1, three
times weekly) or on-demand treatment. The primary efficacy endpoint, number of total bleeding episodes in the
intent-to-treat population, was analyzed after the last
patient had completed 1 year of follow-up. A negative
binomial model was used for the primary endpoint analysis; analysis of variance was used for confirmatory analysis
of annualized bleeding rates. Results: Eighty-four patients
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recombinant factor VIII in adults with severe hemophilia A (SPINART). J Thromb Haemost 2013; 11: 1119–27.
Correspondence: Marilyn Manco-Johnson, Department of Pediatrics,
Hemophilia and Thrombosis Center, University of Colorado at Denver and Children’s Hospital Colorado, 13199 East Montview Blvd,
Suite 100, Anschutz Medical Campus, Aurora, CO 80045, USA.
Tel. +1 303 724 0365; fax: +1 303 724 0078.
E-mail: [email protected]
Received 30 November 2012
Manuscript handled by: M. Greaves
Final decision: M. Greaves, 15 March 2013
Keywords: hemophilia A, on demand, prophylaxis,
sucrose-formulated recombinant factor VIII.
Introduction
Patients with severe hemophilia A have factor VIII
plasma levels < 1% of normal, and experience recurrent
spontaneous or trauma-related bleeding episodes. Bleeding into soft tissue and joints is common, and places
patients at risk for disabling hemophilic arthropathy [1].
Treatment of severe hemophilia A entails replacement
therapy with exogenous FVIII, either on demand at the
first sign of bleeding, or with routine FVIII infusions to
prevent bleeding (prophylaxis). On-demand treatment can
stop bleeding, relieve pain, and restore joint motion, but
does not prevent arthropathy [2,3].
Patients treated prophylactically receive regular FVIII
infusions to maintain an FVIII level of 1% [4]. Considerable experience with prophylaxis has been gained
internationally since the 1960s [5–8]. Given the well-established benefits of primary prophylaxis [9,10] (continuous
© 2013 International Society on Thrombosis and Haemostasis
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1120 M. J. Manco-Johnson et al
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FVIII inhibitor activity or history, no prophylaxis for
> 12 consecutive months in the past 5 years (there was no
limit on the duration of prophylaxis during this period,
provided that it did not exceed 12 consecutive months),
and 6–24 documented bleeding events or treatments in
the previous 6 months. Key exclusion criteria included
bleeding disorders other than hemophilia A, thrombocytopenia (platelet count of < 100 000 mm 3), abnormal
renal function or active hepatic disease, use of immunomodulatory agents in the preceding 3 months, and an
absolute CD4 lymphocyte cell count of < 200 cells mm 3.
The study protocol and all amendments were reviewed
and approved by the independent ethics committee or
institutional review board at each site. The study was
conducted in accordance with Declaration of Helsinki
principles and International Conference on Harmonization Good Clinical Practice guidelines. All patients provided written informed consent before participating in
any study procedure. For patients aged < 18 years, consent was obtained from the patient and the parent or
legal guardian, with patient assent.
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Study design
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SPINART is a randomized, controlled, parallel-group,
open-label phase 3b/4 trial designed to evaluate the
effects of routine prophylaxis with rFVIII-FS as compared with on-demand treatment in adolescents and
adults with severe hemophilia A. Patients were randomly
assigned 1 : 1 to prophylaxis or on-demand treatment.
Randomization was centralized and managed by use of a
customized interactive voice response system. Patients
were stratified on the basis of the presence or absence of
target joints (defined as a joint in which bleeding has
occurred on four or more occasions during the previous
6 months) and bleeding frequency within the preceding
6 months (< 15 or 15 annualized bleeding episodes).
Patients completed a 6-week screening process, followed by a 3-year treatment phase (Fig. 1). On-demand
treatment was administered on the basis of investigator
clinical recommendations. Prophylaxis was begun at a
thrice-weekly dose of 25 IU kg 1. In patients with 12
bleeding episodes per year, the dose could be increased by
5 IU kg 1 at the end of year 1 and year 2 to a maximum
dose of 30 or 35 IU kg 1, respectively. All patients underwent magnetic resonance imaging (MRI) joint assessment
at baseline, and will do so again at year 3. Physical joint
examinations and HRQoL assessments were performed at
baseline, and are evaluated yearly thereafter. Testing for
FVIII inhibitors occurs at screening, month 3, and
years 1, 2, and 3; inhibitor testing is also performed
whenever inhibitor development is clinically suspected.
Patients were provided with and trained in the use of
an electronic patient diary to record all infusions, bleeding episodes, and associated data (e.g, bleeding episode
location, type, and severity; pain; injection date and time;
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prophylaxis started before age 3 years and before the
second joint bleeding episode [11]), prophylaxis for severe
hemophilia is recommended by the World Federation of
Hemophilia [11] and the US National Hemophilia Foundation [12]. As compared with on-demand treatment,
primary prophylaxis can decrease bleeding frequency and
prevent arthropathy [2,9]. Patients receiving prophylaxis
have significantly better physical function, better healthrelated quality of life (HRQoL) and less pain than those
treated on demand [13,14].
The goal of secondary prophylaxis (started after age
3 years or after two or more joint bleeding episodes but
before the onset of arthropathy [11]) is to maintain joint
function and prevent arthropathy. A goal of tertiary prophylaxis (started after the onset of arthropathy [11]) is to
prevent or slow the progression of arthropathy. The benefits of secondary and tertiary prophylaxis are less clear than
those of primary prophylaxis, primarily because of a lack
of long-term prospective data. Most studies of secondary
and tertiary prophylaxis in severe hemophilia A are limited
by retrospective or uncontrolled designs, small sample
sizes, and heterogeneity of patients, treatments, and collected data [15–17]. The prospective Evaluation Study on
Prophylaxis: a Randomized Italian Trial (ESPRIT) compared prophylaxis with on-demand treatment in patients
with severe hemophilia aged 1–7 years who had no evidence of joint damage [18], but only one prospective, randomized study comparing prophylaxis with on-demand
treatment in adolescents and adults has been published
[19]. Evidence of the benefits of secondary or tertiary prophylaxis in adults is particularly limited, because most
long-term data come from pediatric studies [8,9,20–22].
Sucrose-formulated recombinant FVIII (rFVIII-FS) has
been shown to be highly effective in decreasing bleeding
and joint damage when used as primary prophylaxis in
children with severe hemophilia A and no joint damage
at baseline [9]. SPINART is a randomized controlled trial
comparing routine prophylaxis and on-demand treatment
with rFVIII-FS in adults with severe hemophilia A. We
present data from a preplanned analysis of bleeding frequency (primary efficacy endpoint) and preliminary safety
data from the first year of this 3-year study.
Methods
Patients
SPINART (ClinicalTrials.gov identifier: NCT00623480) is
being conducted at 31 centers (USA, 23; Bulgaria, 3;
Romania, 3; Argentina, 2). Males aged 12–50 years (aged
18–50 years in Bulgaria and Romania) with severe hemophilia A (FVIII:C < 1%) were eligible. A maximum of
10% of patients with FVIII:C of 1–2% could be enrolled
if they showed clinical severity and met all other inclusion
criteria. Additional key inclusion criteria were 150
exposure days with any FVIII product, no measurable
© 2013 International Society on Thrombosis and Haemostasis
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Routine prophylaxis vs. on demand in adults 1121
Screening
(6 weeks)
Treatment Phase (3 years)
Primary Endpoint: 1 year
Prophylaxis (rFVIII-FS 25 IU/kg* 3 times per week)
Randomization
N = 84 (1:1)
On Demand (rFVIII-FS per investigator recommendations)
Joint MRI
Joint MRI
Joint Exam, QoL
Baseline
Joint Exam, QoL
Year 1
Joint Exam, QoL
Year 2
Joint Exam, QoL
Year 3
Continuous log of bleeding and infusion data via electronic patient diary
Fig. 1. Study design. MRI, magnetic resonance imaging; QoL, quality of life; rFVIII-FS, sucrose-formulated recombinant factor VIII. *Escalation by 5 IU kg 1 to a maximum of 30 or 35 IU kg 1 was allowed for patients with 12 bleeding episodes after 1 and 2 years, respectively.
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of 40 patients needed to be enrolled in each treatment
group.
A preplanned analysis of bleeding frequency, the primary endpoint, was conducted after the last patient had
completed 1 year of follow-up. Data are presented for
the intent-to-treat (ITT) population, defined as all randomized patients who received any study treatment.
Between-group comparisons for bleeding frequency were
made within the framework of a negative binomial
regression model, accounting for different follow-up times
of patients who discontinued prematurely via an offset
variable. The model also included the two variables (presence or absence of target joints; and number of previous
annualized bleeding episodes [ 15 or < 15]) considered
as stratification factors in the randomization. A sensitivity analysis of annualized bleeding rates was conducted
by use of analysis of variance with the stratification variables included in the model. All inferential statistical
comparisons were based on two-sided tests with
alpha = 0.05. All statistical analyses were performed with
SAS system version 9.1 or higher (SAS Institute, Cary,
NC, USA). Statistical modeling of bleeding frequencies
was performed with the GENMOD procedure implemented in SAS.
The safety population was identical to the ITT population. No inferential statistical comparison was conducted
for safety data, which are summarized descriptively.
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reason for treatment; number of vials; lot numbers; and
infusion-related health issues). Bleeding severity was selfrated, with no specific guidance provided on how to categorize bleeding episodes; pain severity was evaluated with
the Short-Form McGill Pain Questionnaire [23]. Data
entered in the electronic patient diary were transmitted
directly to the study database.
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Efficacy assessments
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The primary efficacy endpoint was the number of total
bleeding episodes in each treatment group after all patients
had completed 1 year of treatment. Secondary endpoints, which will be reported at study conclusion, were
mean change from baseline to year 3 on the MRI scale, the
Colorado Adult Joint Assessment Scale, and the HaemoQoL-A physical functioning domain [24]. Other endpoints
presented here are the annualized number of joint, spontaneous and trauma-related bleeding episodes and FVIII use.
Safety assessments
Adverse events (AEs) were recorded at each study visit
and assessed for seriousness, severity, and relationship to
study drug. The presence of FVIII inhibitors was assessed
with the Nijmegen-modified Bethesda assay.
Statistical analysis
Sample size was determined on the assumption that
patients in the on-demand group would average 30 bleeding episodes per year (based on an average of 20 bleeding
episodes in the SPINART protocol and 40 from Collins
et al. [15]) and that the prophylaxis group would average
six bleeding episodes per year (20% of the frequency in
the on-demand group; data on file, Bayer). To detect
between-group differences with 90% power, a minimum
Results
From March 2008 to the data cut-off point (27 September 2011), 84 patients were randomly assigned to prophylaxis (n = 42) or on-demand treatment (n = 42) with
rFVIII-FS; 68 patients were continuing in the study at
the time of this analysis (Fig. 2). Seven patients in each
treatment group had discontinued; two patients in the
prophylaxis group had completed all 3 years of treatment.
© 2013 International Society on Thrombosis and Haemostasis
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1122 M. J. Manco-Johnson et al
Screened
N = 106
Reasons for screening failure
Protocol violation, n = 18
Withdrawn consent, n = 2
Lost to follow-up, n = 1
Adverse event, n = 1
Randomized
N = 84
Prophylaxis
n = 42
On demand
n = 42
Premature
termination
n=7
Completed
study*
n=2
Premature
termination
n=7
Reasons for withdrawal
Withdrawn consent, n = 4
Lost to follow-up, n = 1
Protocol violation, n = 1
Site closed, n = 1
Reasons for withdrawal
Noncompliance with study medication,
n=4
Withdrawn consent, n = 2
Insufficient therapeutic effect, n = 1
Ongoing
n = 33
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Ongoing
n = 35
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Completed
study n = 0
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All 84 randomized patients met the criteria for the ITT
population and had evaluable data.
Baseline demographics and disease characteristics were
similar between treatment groups (Table 1). Most patients
(91%) were white; the mean age for all patients was
30.6 years (range, 15–50 years). Seventy percent of
patients had one or more target joints, and the median
number of bleeding episodes in the year before study
entry was 18.0.
The median number of days in the study was 605.5
(range, 111–1106 days) with on-demand treatment and
625.5
(range,
161–1109 days)
with
prophylaxis
(~ 1.7 years for both groups); the median number of
exposure days was 73.5 (range, 1–203 days) and 204.5
(range, 42–478 days), respectively.
Adherence to prophylaxis was generally good. In the
prophylaxis group, mean adherence with the thrice-weekly
dosing regimen was 78% (median, 79%; range, 31–
102%). Overall, 75% of patients were 80% adherent,
and two patients (5%) were fully adherent (that is, they
infused rFVIII-FS at least three times weekly throughout
the study). The mean number of days between infusions
was ~ 2.9, reflecting a mean of 2.4 infusions per week
(median, 2.4; interquartile range, 2.3–2.5).
The median number of infusions per patient was 73.5
in the on-demand group and 206.0 in the prophylaxis
group. The median total dose per infusion was
28.0 IU kg 1 (range, 12–52 IU kg 1) with on-demand
treatment and 26.6 IU kg 1 (range, 20–31 IU kg 1) with
prophylaxis; the median total dose per year was
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Fig. 2. Patient disposition. *‘Completed study’ refers to the entire planned 3-year study period. Two patients in the prophylaxis group had
completed study treatment by the data analysis cut-off date of 27 September 2011.
Table 1 Baseline demographic and disease characteristics
On demand
(n = 42)
Age (years)
Median
29.0
Range
17–48
Race, n (%)
White
38 (90.5)
Asian
1 (2.4)
Hispanic
3 (7.1)
Factor VIII level, n (%)
< 1%
42 (100)
1.1%
0
1.3%
0
Presence of target joints, n (%)
Yes
31 (73.8)
No
11 (26.2)
Target joints, n
Median
1.5
Range
0–7
Bleeding episodes in last 6 months, n
Median
12.0
Range
6–24
Bleeding episodes in last 12 months, n
Median
19.5
Range
8–47
Bleeding episodes in last 12 months, n (%)*
< 15
10 (23.8)
15
32 (76.2)
Prophylaxis
(n = 42)
29.0
15–50
38 (90.5)
1 (2.4)
3 (7.1)
39 (92.9)
2 (4.8)
1 (2.4)
28 (66.7)
14 (33.3)
1.0
0–5
9.0
2–23
17.0
6–42
14 (33.3)
27 (64.3)
*Baseline data were not available for one patient in the prophylaxis
group.
© 2013 International Society on Thrombosis and Haemostasis
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Routine prophylaxis vs. on demand in adults 1123
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Cumulative percentage of patients
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A 100
Cumulative percentage of patients
The distribution of bleeding episodes in the prophylaxis
and on-demand groups is shown in Fig. 3A. The median
numbers of total bleeding episodes and total bleeding episodes per year were significantly lower with rFVIII-FS
prophylaxis than with on-demand treatment (0 vs. 54.5
and 0 vs. 27.9, respectively; P < 0.0001). The mean standard deviation (SD) numbers of total bleeding episodes and total bleeding episodes per year were 4.2 10.8 and 2.0 4.5, respectively, with prophylaxis, and
52.7 34.8 and 30.5 19.5, respectively, with ondemand treatment. The ratio of the bleeding frequency
estimated from the negative binomial regression model
was 14.7 (95% CI, 8.1–26.5; P < 0.0001) for on demand
versus prophylaxis, indicating that patients treated on
demand experienced 14.7 times as many bleeding episodes
compared with patients treated with prophylaxis. This
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Efficacy
corresponds to a 93% (95% CI, 88%–96%; P < 0.0001)
decrease in bleeding frequency with routine prophylaxis.
Consistent with the primary analysis results, there was a
94% reduction in the mean annual bleed rate (bleed/
patient/year): 30.5 in the on-demand group versus 2.0 in
the prophylaxis group.
Twenty-two patients (52%) receiving prophylaxis had
no bleeding episodes vs. one patient (2%) treated on
demand. The median time to the first bleeding episode
during the study was numerically longer with prophylaxis
than with on-demand treatment (88 vs. 3 days).
Most bleeding was into joints, and most joint bleeding
episodes were in target joints. The distribution of joint
bleeding episodes is shown in Fig. 3B. The median numbers of joint bleeding episodes and joint bleeding episodes
per year were lower with prophylaxis than with ondemand treatment (0 vs. 40.0 and 0 vs. 21.2, respectively).
The mean SD numbers of joint bleeding episodes and
joint bleeding episodes per year were 3.5 9.9 and
1.7 4.2, respectively, with prophylaxis, and 40.7 26.2
and 24.2 17.1, respectively, with on-demand treatment.
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1362.7 IU kg 1 (range, 46–4419 IU kg 1) and 3298.2
IU kg 1 (range, 1259–4486 IU kg 1), respectively.
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60
or
40
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20
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*P
0
20
0
75
125
50
100
Number of total bleeds
Prophylaxis
On demand
pi
25
40
0
150
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0
< 0.0001
60
50
75
Number of joint bleeds
On demand
100
100
125
Prophylaxis
100
80
60
40
20
*P
< 0.0001
0
0
20
80
40
60
Number of total bleeds per year
On demand
Prophylaxis
100
Cumulative percentage of patients
Cumulative percentage of patients
25
80
60
40
20
0
0
20
60
40
Number of joint bleeds per year
On demand
Prophylaxis
Fig. 3. Cumulative distribution curves for all patients in the prophylaxis and on-demand groups. (A) The range of total bleeding episodes. (B)
The range of joint bleeding episodes. Horizontal lines indicate median and interquartile values. *On demand vs. prophylaxis, adjusted for stratification variables (presence/absence of target joints and number of previous bleeding episodes).
© 2013 International Society on Thrombosis and Haemostasis
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1124 M. J. Manco-Johnson et al
Prophylaxis patients also experienced fewer annualized
spontaneous (median, 0 vs. 16.3) and trauma-related
(median, 0 vs. 6.4) bleeding events. For joint bleeding episodes, the between-group difference corresponded to a
93% decrease per year for patients receiving prophylaxis
as compared with those receiving on-demand treatment.
Large decreases in the number of bleeding episodes were
seen in the prophylaxis group, regardless of baseline
patient characteristics (Table 2). Based on self-ratings of
2363 bleeding events in the on-demand group and 196 in
the prophylaxis group, bleeding severity was mild in 17%
and 44% of the on-demand and prophylaxis groups,
respectively; moderate in 58% and 36%, respectively; and
severe in 19% and 7%, respectively. Severity data are missing for 150 on-demand and 24 prophylaxis bleeding events.
dicitis, anemia, dehydration, fibula fracture, humerus
fracture, hemarthrosis [in two patients], joint stiffness,
osteoarthritis, and stab wound) were reported by eight
patients (19%) treated on demand, and five SAEs (appendicitis, impacted tooth, infection related to knee replacement, migraine, and suicidal ideation) were reported by
three patients (7%) on prophylaxis. None of the AEs,
including SAEs, were considered to be treatment-related
by the investigators. No deaths occurred during the study,
and no patients developed FVIII inhibitors.
Discussion
SPINART is the first prospective, controlled trial to use a
randomized, parallel-group design to compare outcomes
with routine prophylaxis with those with on-demand treatment with rFVIII-FS in adults with severe hemophilia A.
The SPINART findings extend to adults the results from
the Joint Outcome Study [9], which definitively demonstrated that children receiving rFVIII-FS prophylaxis have
significantly fewer bleeding episodes, including joint bleeding episodes, than those treated on demand [9].
Primary data from the first year of the 3-year SPINART study demonstrated that routine prophylaxis is
Safety
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Twenty-nine patients (69%) in the on-demand group and
17 (41%) in the prophylaxis group experienced one or
more treatment-emergent AEs. Most AEs in both groups
were mild or moderate, and they occurred in 5% of
patients; AEs were consistent with the established
rFVIII-FS safety profile. Ten serious AEs (SAEs) (appen-
Table 2 Bleeding episodes per year overall and by baseline patient characteristics
Age (years)
< 18
1
n
Median [quartiles]
(range)
Patients with no
bleeding episodes (%)
27.9
[16.5, 45.7]
(0–82.8)*
2.4
42
0
[0, 0.9]
(0–19.2)
52
0
2
100
4.8
19
0
21
0
[0, 0]
(0–0)
0.6
[0, 0.9]
(0–15.4)
0
[0, 1.0]
(0–19.2)
0
14
64.3
3.1
27
0
[0, 1.0]
(0–19.2)
0.6
[0, 0.9]
(0–15.4)
0
28
50.0
9.1
14
0.3
[0, 0.8]
(0–15.4)
0
[0, 3.3]
(0–19.2)
or
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Patients with no
bleeding episodes (%)
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Overall
Prophylaxis
Median [quartiles]
(range)
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On demand
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16.5
[16.5, 16.5]
(16.5–16.5)
18 to < 30
21
34.7
[16.6, 42.9]
(0–61.2)
30
20
24.9
[16.8, 46.1]
(3.3–82.8)
Number of bleeding episodes in last 12 months†
< 15
10
20.5
[9.3, 37.3]
(2.9–47.0)
15
32
30.3
[16.5, 46.0]
(0–82.8)
Presence of target joints
Yes
31
34.7
[24.2, 46.5]
(4.0–82.8)
No
11
15.6
[3.3, 17.6]
(0–66.9)
42.1
57.1
44.4
57.1
*A minimum value of 0 occurred because one patient in the on-demand group withdrew consent before experiencing a bleeding episode. †Baseline data were not available for one patient in the prophylaxis group.
© 2013 International Society on Thrombosis and Haemostasis
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Routine prophylaxis vs. on demand in adults 1125
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analysis, 92% of patients infused 90% of prescribed
doses; in SPINART, 75% of patients infused 80% of
prescribed doses).
FVIII trough levels were not measured during the treatment period in SPINART. Permitted increases in the
fixed-dose prophylaxis regimen were made on the basis of
the number of bleeding episodes per year, and not on the
basis of pharmacokinetic parameters or FVIII trough levels. Trough level data in adults receiving prophylaxis with
rFVIII-FS, the same product as used in SPINART, have
been reported by Collins et al. [15]. SPINART focused
on clinical outcomes, including the bleeding episode data
presented here and the relationship between prophylaxis
and joint outcome scores, which will be analyzed at study
conclusion. The focus on joint outcomes in adults parallels the focus of the Joint Outcome Study in children [9].
Furthermore, although adherence to prophylaxis was generally good, most patients infused rFVIII-FS at a slightly
longer interval than prescribed (2.9 days actual vs.
2.3 days prescribed), but little relationship was seen with
breakthrough bleeding. This finding supports clinical
practice, in which adults often base prophylaxis schedules
on anticipated event-based bleeding risk and knowledge
of their individual bleeding pattern rather than on pharmacokinetic measurements.
Good bleeding control in some patients with severe
hemophilia A might be achieved with doses lower than
those prescribed in SPINART (25 IU kg 1 three times
weekly). The dose used by Collins et al. (20–40 IU three
times weekly) resulted in median FVIII trough levels of
6.0 and 4.0 IU dL 1 at 48 and 72 h, respectively, after
the last prophylactic infusion [15]. In the Valentino et al.
study [19], median trough levels were 3.0 IU dL 1 with
standard prophylaxis and 1.0 IU dL 1 with the pharmacokinetic-tailored regimen. However, in a third study,
based on pharmacokinetic measurements in 99 patients
receiving rAHF-PFM, Collins et al. [25] estimated that
even patients who were fully adherent to a standard prophylaxis regimen of 30 IU kg 1 three times weekly would
spend a median of 10 h per week with FVIII levels
< 1.0 IU dL 1, and showed that time spent below this
level predicted breakthrough bleeding.
Whereas some publications suggest that bleeding and
joint damage can be prevented even when FVIII trough
levels are < 1% [6,26,27], others suggest that some patients
will have repeated bleeding episodes despite maintenance
of a 1% trough level, and many patients continue to have
joint bleeding even with trough levels of 3% [26,27].
Collins et al. [15], who achieved a reduction in bleeding
episodes with higher than expected trough levels, suggested that good outcomes might be possible in many
patients with prophylaxis doses lower than those used in
their study, which would have the advantage of decreasing
overall FVIII consumption and associated costs. However,
despite the cost savings possible with the use of lower
doses, higher doses may be desirable to ensure adequate
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significantly more effective than on-demand treatment in
reducing bleeding frequency in older patients with severe
hemophilia A. After a median treatment period of
1.7 years, the number of total bleeding episodes was significantly lower with prophylaxis than with on-demand
treatment. The confirmatory analysis showed that the
median number of total bleeding episodes per year was
also significantly lower with prophylaxis than with ondemand treatment. Results were similar for all types of
bleeding episodes, with the number of joint, spontaneous
and trauma-related bleeding episodes being considerably
lower with prophylaxis than with on-demand treatment.
When bleeding occurred, the most common self-reported
ratings of severity were mild (44%) for prophylaxis
patients and moderate (58%) for on-demand patients,
perhaps because of residual FVIII circulating in plasma
when breakthrough bleeding occurred.
The SPINART results are consistent with bleeding data
reported by Collins et al. [15]. In this open-label, prospective, one-group sequential study, 20 previously treated
patients aged 30–45 years received rFVIII-FS on demand
for 6 months, and were then switched to rFVIII-FS prophylaxis (20–40 IU kg 1 three times weekly) for 7 months.
At study end, the median numbers of bleeding episodes
(all, joint, spontaneous, and trauma-related) were significantly lower during secondary prophylaxis than during ondemand treatment (all P < 0.0001) [15]. Our results are also
consistent with those from the open-label Valentino et al.
study, in which 66 patients aged 7–59 years with moderately severe to severe hemophilia A were initially treated
on demand for 6 months, and then randomly assigned to
one of two prophylaxis regimens for 12 months. Valentino
et al. [19] showed that prophylaxis with antihemophilic factor (recombinant), the plasma/albumin-free method
(rAHF-PFM; ADVATE; Baxter Healthcare, Westlake
Village, CA, USA), administered according to either a standard (20–40 IU kg 1 every 2 days) or pharmacokinetictailored (20–80 IU kg 1 every 3 days) regimen, significantly
decreased the annualized bleeding rate as compared with
on-demand treatment (P < 0.0001). Similar significant
decreases with prophylaxis vs. on-demand treatment were
seen for joint, spontaneous and trauma-related bleeding episodes. Unlike in the 3-year SPINART study, comparison
between the on-demand and prophylaxis groups was a secondary objective in the Valentino et al. study (the primary
endpoint was a parallel-group comparison of the two different prophylaxis regimens).
Annual FVIII consumption levels in SPINART were
lower than those reported by Valentino et al. [19]
(3298 IU kg 1 per year in SPINART vs. 5768 and
5198 IU kg 1 per year for standard and tailored prophylaxis, respectively). This consumption difference probably
reflects the higher median dose per infusion in the Valentino et al. [19] trial (31.4 IU kg 1 for standard prophylaxis and 43.0 for tailored prophylaxis vs. 26.6 IU kg 1in
SPINART), as well as greater adherence (in a post hoc
© 2013 International Society on Thrombosis and Haemostasis
11/06/2014
1126 M. J. Manco-Johnson et al
nications, Inc. (Chadds Ford, PA, USA) and was funded
by Bayer HealthCare.
The SPINART study investigators are as follows.
Argentina: M. Pierdominici and V. Rescia. Bulgaria: L.
Gercheva, S. Goranov, and T. Lissitchkov. Romania: M.
Ghinea, L. Rusen, and V. Uscatescu. USA: J. Bernstein,
A. Cohen, M. Escobar, E. Eyster, J. Gill, C. Kempton,
D. Macfarlane, M. Manco-Johnson, W. Mitchell, R. Najasubramanian, M. Ragni, M. Reding, A. Schmaier, A.
Shapiro, V. Sharma, A. Soni, K. Stine, A. Stopeck, H.
Wahid, C. Walsh, B. Wicklund, and A. Zakarija.
Disclosure of Conflict of Interests
CD
R
C. L. Kempton is a consultant for Bayer. W. Hong is an
employee of Bayer HealthCare Pharmaceuticals. M. J.
Manco-Johnson and M. T. Reding have been advisory
board participants for Bayer. L. Gercheva, S. Goranov,
T. Lissitchkov, L. Rusen, M. Ghinea, V. Uscatescu and
V. Rescia have no conflicts of interest to declare.
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FVIII levels in all patients and to help prevent subclinical
joint bleeding, which can occur in the absence of obvious
clinical bleeding [9,28]. Ultimately, individualized prophylaxis dosing regimens may be the best means of balancing
efficacy and factor consumption.
The benefits of prophylaxis in patients with severe
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In conclusion, in adults with severe hemophilia A, routine prophylaxis with rFVIII-FS was more effective than
on-demand treatment in controlling bleeding episodes,
including bleeding into joints. SPINART is ongoing; a
complete evaluation of all efficacy endpoints, including
MRI results, joint assessment, HRQoL, and final safety
data, will be available after the study concludes. Final
results obtained after 3 years of study will provide a more
comprehensive picture of the benefits of routine prophylaxis in adults.
Addendum
M. J. Manco-Johnson, C. L. Kempton, M. T. Reding, T.
Lissitchkov, S. Goranov, L. Gercheva, L. Rusen, M. Ghinea, V. Uscatescu, and V. Rescia are principal investigators for the SPINART study. W. Hong is responsible for
overseeing the conduct of the study. All authors made
substantial contributions to the study design, data acquisition, or data analysis and interpretation. Each author
contributed to the development of the manuscript,
reviewed and commented on each draft, and approved
the final draft.
Acknowledgements
This study was funded by Bayer HealthCare AG, Leverkusen, Germany. Medical writing assistance was provided
by K. L. Zimmermann of Complete Healthcare Commu-
© 2013 International Society on Thrombosis and Haemostasis
11/06/2014
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