1. health and fitness
2. disease
3. heart disease

ITHS BOOTCAMP
CLINICAL TRIALS II
SEPTEMBER 20, 2010
JEFFREY L. PROBSTFIELD, MD
DIRECTOR, CLINICAL TRIALS SERVICE UNIT
DIRECTOR, KL2 PROGRAM, ITHS
PROFESSOR OF MEDICINE (CARDIOLOGY)
EQUIPOSE AND THE ETHICS
OF CLINICAL RESEARCH
Benjamin Freedman, PhD
EQUIPOSE
“ - a state of genuine uncertainty
on the part of the (all) clinical
investigator(s) regarding the
comparative therapeutic merits of
each arm in a trial.”
NEJM 1987; 317:141-145
SAMPLE SIZE ADJUSTMENT FOR
REDUCED ADHERENCE
Key Point - Adherence correction term-sample
size formula, a squared function.
2N = σ2(zα + zβ)2 ÷ (µ
µ1 - µ2)2(1-p)2
p = Reduction in Adherence
k = Increase in Sample Size
p
k
.01 1.02
.05 1.11
.10 1.23
.20 1.56
.30 2.04
.50 4.00
DROPOUTS (%) AT FIRST AND LAST
VISIT POSTRANDOMIZATION IN
LONGLONG-TERM STUDIES
TRIAL
BHAT
AMIS
UKP
CAPS
LRC-CPPT
B-MC
% DROPOUTS
TIME OF VISITS
3.5, 15
3, 6
18, 30
4, 9
1, 1.8, 6.1
2, 4, 0.6
1 mo, 36 mos
1 mo, 36 mos
6 mos, 77 mos
3 mos, 12 mos
2 wks, 4 wks, 86 mos
2 wks, 4 wks, 86 mos
LRC: ANALYSIS FOR PREDICTORS
OF ADHERENCE
Adherence after first month associated with p<0.01
–Adherence in first month most powerful predictor
–Smoking status
–Age
–Extent of Psychological Distress
Multiple regression analysis: adherence in first month is
best predictor of subsequent (r=.59 or r²=.34);
r²=.36 with smoking and other factors added.
No statistical association with adherence in first year of:
–Exercise
-Overall risk status
–Weight
-Motivational level
–Vitamin consumption
“RUNRUN-IN”
IN” PERIOD
• Pre-randomization procedure
• Single blind
• Placebo used
• Test for "pill-taking behavior”
“TESTTEST-DOSING”
DOSING” PERIOD
• Pre-randomization procedure
• Single blind
• Active drug used
• Identify those with severe adverse effects
GENERALIZIBILITY
MECHANISMS IN DEVELOPMENT OF
PARTICIPANT NONNON-ADHERENCE
• Lack motivation
• Lack of knowledge (disease, intervention)
• Rejects medical diagnosis
• Denies significance of disease process
• Self-debate over intervention regimen
• Rejects intervention regimen
MEDICAL THERAPEUTICS TEAM
Psychologist-Behaviorist
Nurse-Clinician
Therapeutic Plan
Participant
(Patient)
Physician
Physician
Assistant
Intervention Schedule
Dietitian-Nutritionist
WORST CASE ANALYSIS
HYPERTENSION IN ELDERLY:STROKE
PREVENTION 5,000 PARTICIPANTS, 5 YRS
FOLLOWFOLLOW-UP
ENDPOINT STATUS
Active Treatment
Documented
Strokes
Stroke Status
Unknown
TOTALS
ALTERNATIVE
END OF TRIAL
Placebo
p Value
95
125
< .04
25
120
120
25
150
125
ns
PRINCIPLES AND GOALS: PARTICIPANT
COUNSELING IN DROPOUT RECOVERY
Principles for Counseling
Corresponding Goals
1. To establish contact with
participants
1. To maintain contact with
participants.
2. To “undercut” participant’s
resistance for reinstitution of some
aspect of the trial protocol.
2. To complete as much of the trial
protocol as possible.
3. To convey a caring attitude to the
3. To resolve any somatic, adverse
participant about his overall health
drug effects, or behavioral
status and the importance of health
problems preventing protocol
care to these participants.
adherence.
4. To maximize the participant’s
4. To reinstate the protocol in small
opportunities for success of
increments using informal
protocol completion using
contracts and shaping.
standardized behavioral techniques.
5. To give positive reinforcement for
fulfillment of protocol activities
5. To emphasize the positive
contribution at any level of
protocol adherence.
6. To resume study drug at a low but
definite priority for the participant.
6. To restore and maintain study
power.
DISTRIBUTION OF ADHERENCE PROBLEMS
IN A CADRE OF DROPOUTS AND OTHERS
IN AN RCT
Type of Problem
Adverse effects
Percent
Dropouts Others*
19
22
Medical problems
11
20
Psychosocial problems
69
58
* Those who experienced either a 10% drop in medication adherence or a 10 day delay from their
clinic visit window
RESULTS OF PROGRAM FOR RECOVERY
OF DROPOUTS AT
BAYLORBAYLOR-METHODIST CLINIC OF CPPT
• 94 % were recovered for some regular visit
with clinic personnel (90% within 6 months )
• Remaining participant was contacted
regularly by telephone
• 3% recidivism
• 70% reinstituted study medication
• Average adherence: study medication 35 %
FACTORS AFFECTING ADHERENCE
TO INTERVENTIONS
Effect on Adherence
Negative
Low social class
“Blue collar:
occupation
Social isolation
Regimen Supervised
Therapy duration
Parental
Number of drugs
administration
Dosing frequency
Symptomatic drugs
Cardiac drugs
Respiratory drugs
Diabetic drugs
Illness
Disability
Severity of
symptoms
Severity of illness
Psychiatric illness
Patient
Positive
Education
No Effect
Age
Sex
Race
Adverse effect
Disease duration
Clinical
improvement
Concurrent illness
SIGNS AND SYMPTOMS: POTENTIAL
NON--ADHERENCE: “ RED FLAGS”
NON
FLAGS” (1)
1.
2.
3.
4.
5.
6.
7.
8.
Missed visits
Difficulty in reaching by phone or failure to return calls
Rescheduling appointment twice (change in behavior)
Complaints about office visits
Impatience during clinic visit
Length of time (mandatory) at each visit
“Distance” during interview
Length of time since participation in study was
discussed between physician and participant
9. Humor dealing with negative aspects of trial medication
SIGNS AND SYMPTOMS: POTENTIAL
NON--ADHERENCE: “ RED FLAGS”
NON
FLAGS” (2)
10. Sarcasm about trial or study medication
11. Any expression by participant that he/she may
discontinue study medication
12. Unusual or unexplained change in adherence to study
medication
13. Unconcern by participant about adherence rate
14. Reassignment to new primary-care manager
15. Reassignment to other new clinic personnel
16. Illness with increased attention to “trial related disease”
17. Hospitalization for any reason
18. Any major change in life style which is imminent
HEALTH BEHAVIOR COUNSELING
AND ADHERENCE MANAGEMENT
• Systematic - Approach to problem identification
• Targeted - Identify and resolve problems
• Data Based - Collect information on behaviors
• Adaptable - Approaches and solutions, tailored
• Generic - Useful for clinical trials and practice
Russell et al, AJM 1985;78:277-282
NEGOTIATION!!!!
“IN BUSINESS AS IN LIFE-YOU DON’T GET WHAT YOU DESERVE-YOU GET WHAT YOU NEGOTIATE!”
CHESTER KARRASS-IN-FLIGHT ADD
“NEGOTIATED ADHERENCE
REGIMENS”
REGIMENS”
(Informal Contracts)
• Reduced Dose
• “Drug Holiday”
• Follow-up only
• Final assessment at trial end
INFORMAL CONTRACTS
“THE ART OF THE DEAL”
DEAL”
• Implied circumstance between two people.
• Trust level is critical.
• “Professional (staff)=Person(participant)”
– Trust equation is not equal.
• Will be seen as binding on you by participant.
– Can’t just discuss contract-must ask
permission.
• Refusal to discuss means identification of old.
• Frequency of contract discussion- an issue.
RECHALLANGE:
RESTARTING
STUDY MEDICATION
•
•
•
•
•
INFORMAL CONTRACT -BE CAUTIOUS.
What was the reason for stopping?
Has that reason gone away?
Can you make small steps to your goal?
Part of a “Win, Win” is participant success
WHAT IS A PI?
“Principal Investigator”
or “Practically Invisible”
Clinical sites most successful where the PI
is engaged and actively involved.
Coordinators-- be proactive and identify
activities where PI can help you!
“ALTERATION OF NATURAL
HISTORY”
HISTORY” TRIAL
• Enrolled group must do the intervention
• Looking for efficacy on clinical outcomes
• e.g., Phase IV trials
“INTENTION TO TREAT”
TREAT” - “ONCE
IN ALWAYS COUNTED”
COUNTED” - No. 1
Issue:Avoid Bias
Fundamental Point: FFD
Excluding randomize subjects from
analysis and sub-grouping on the basis of
outcome or response variables can lead to
biased results. This bias can be of unknown
magnitude or direction.
“INTENTION TO TREAT,”
“ONCE IN, ALWAYS COUNTED” (2)
“Preserves the benefits of randomization by including
all randomized patients based on their original
allocation.”
Safeguards against:
Erroneous claims of efficacy by exclusion of those
who do not adhere to the protocol
BOTTOM LINE:
MINIMUM ACCEPTABLE
ADHERENCE
Know primary outcome status on every
randomized participant.
Human behavior will allow few to purposely
harm a worthy scientific project.
EFFICACY ANALYSIS
(ON TREATMENT)
•
•
•
•
•
Expected in pharmaceutical industry
Precisely describe - denominator not same
True estimate benefit between two analyses
Should be reported without p-value
Crucial in non-inferiority trials
HIPPA
HEALTH INSURANCE PRIVACY AND
PORTABILITY ACT
Cl Trials 2008
PARTICIPANT WITHDRAWAL
• POSSIBLE MAJOR THREAT TO ITT
• MUST ANTICIPATE
• IN CONSENT-MANDITORY LAST CONTACT
• IRB POSITION-PRIVACY PROTECTION
• CLINICAL CENTER STAFF-ACTIVE ROLE
• ESPECIALLY PI
Cl Trials 2008
CLINICAL TRIALS OVERVIEW
FUNDAMENTAL POINT: SURVIVAL ANALYSIS
Survival analysis methods are important in trials where
participants are entered over a period of time and have various
lengths of follow-up. These methods permit the comparisons of
the entire survival experience during the follow-up and may be
used for the analysis of time to any dichotomous response
variable such as a nonfatal event or an adverse effect.
CLINICAL TRIALS OVERVIEW
SURVIVAL ANALYSIS
• Estimation of the Survival Curve
eg. Kaplan - Meier
• Comparison of Two Survival Curves
Point-by-point comparison
Comparison of median survival time
eg. Mantel - Haenszel - Gehan
• Generalizations
• Covariate Adjustment
Kaplan-Meier Rates
Primary Outcome Ramipril vs Placebo
0.2
Ramipril
Placebo
0.15
0.1
0.05
0
0
500
1000
1500
Days of Follow-up
RR=078(0.70-0.86)
P=0.000002
CLINICAL TRIALS OVERVIEW
FUNDAMENTAL POINT: MONITORING RESPONSE VARIABLES
During the trial, response variables need to be monitored for early
dramatic benefits or potential harmful effects. Preferably,
monitoring should be done by a person or group independent of
the investigators. Although many techniques are available to
assist in monitoring, none of them should be used as the sole
basis for the decision to stop or continue the trial.
CLINICAL TRIALS OVERVIEW
MONITORING RESPONSE VARIABLES
Data and Safety Monitoring Committee (Board)
•Repeated Testing for Significance
•Decisions for Early Termination
•Statistical Methods Used in Monitoring
Classical Sequential Methods
Group Sequential Methods
Flexible Group Sequential Methods
“Spending the Alpha”
Boundaries - Setting them A-priori
Asymmetrical
MONITORING BOUNDARIIES
OVER TIME
5
4.76
Ramipril versus Placebo
4.5
↑
3
Benefit
4
2
Z
2.75
4.31
2.32
1.51
1
CLINICAL TRIALS OVERVIEW
FUNDAMENTAL POINT: ISSUES IN DATA ANALYSIS
Excluding randomized participants or observed outcomes
from analysis and sub-grouping on the basis of outcome or
response variables can lead to biased results of unknown
magnitude or direction.
Mar. 99
Nov. 99
Nov. 98
Nov. 97
Aug. 96
Oct. 95
-1
Jan. 94
0
CLINICAL TRIALS OVERVIEW
ISSUES IN DATA ANALYSIS
• Which Participants Should Be Analyzed?
Intention to treat
By treatment analysis - Non-adherence
• Withdrawals
• Ineligibility
• Poor quality or missing data
• Competing events
• Covariate adjustment - Baseline, surrogates
• Subgroup analysis
• Not counting some outcomes
• Comparison and multiple variables
• “Cutpoints” categorical analysis
• Meta-analysis of multiple studies
CLINICAL TRIALS OVERVIEW
FUNDAMENTAL POINT: CLOSEOUT
The closeout of a clinical trial is usually a fairly complex
process that requires careful planning, if it is to be
accomplished in an orderly fashion.
CLINICAL TRIALS OVERVIEW
CLOSEOUT
“You must account for every participant’s primary outcome status”
Termination Procedures
Post Study Follow-up
Data Clean-up and Verification
Storage of Study Material
Dissemination of Results
CLINICAL TRIALS OVERVIEW
FUNDAMENTAL POINT: REPORTING AND INTERPRETING
OF RESULTS
The investigators have an obligation to review their study
and its findings critically and to present sufficient
information so that readers can properly evaluate the trial.
CLINICAL TRIALS OVERVIEW
REPORTING AND INTERPRETING OF RESULTS
“As broadly as possible”
Guidelines for reporting
Interpretation
Publication
“Did the trial go as planned?”
Compare with other studies
Clinical implications
Potential Annual Global Impact
Ramipril: Assume HOPE Results
If 1/4 of eligible patients with vascular disease in
developing countries and 1/2 in developed countries
are given Ramipril:
• approximately 1 to 1.5 million deaths, myocardial
infarction, stroke or revascularization procedures will
be prevented globally every year
• Plus impact on CHF, diabetic complications and
prevention of diabetes, which will prevent an additional
0.5 to 0.6 million such events/year
Total benefit of about 2 million events prevented
CLINICAL TRIALS OVERVIEW
FUNDAMENTAL POINT: MULTICENTER TRIALS
Anyone responsible for organizing and conducting a multicenter study should have a full understanding of the
complexity of the undertaking. Problems in conduct of the
trial most often originate from inadequate and unclear
communication between the participating investigators, all of
whom must agree to follow a common study protocol.
CLINICAL TRIALS OVERVIEW
MULTICENTER TRIALS
Reasons
Conduct
METAMETA-ANALYSIS
• A systematic way of combining data to get a
more precise estimate of the effect of a therapy.
• Positives
- Combine all available data.
- Larger numbers of events available.
- Estimate of therapeutic benefits possible.
• Negatives
- Loss of equipoise.
- Outcome numbers may be small.
- Uncritical examination.
• Importance
- Sample size estimates.
- FDA submissions.
- Medical policy formulation.
LIMITATION OF METAMETA-ANALYSIS
• Numbers small.
• Number of outcomes (deaths) small.
• Selection of arrhythmias - problematic.
• Potentially biased patient selection.
• Duration of follow:
- Generally covered hospital stay.
- Limited long-term.
HOW DO WE USE METAMETA-ANALYSIS, SMALL
TO MODERATE SIZED TRIALS AND LARGE
SIMPLE TRIALS
Sequence of Investigations
Meta-analysis - 1991
Moderate Size Trial - 1992
Mega Trial - 1995
Large Trial-2002
Subject - Effect of magnesium on mortality in immediate
post infarction.
INITIAL METAMETA-ANALYSIS - MAGNESIUM
AND DEATH RATE POST MI
• 7 trials: 1301 participants
• 657 (25) magnesium
• 644 (53) controls
• 55% reduction in mortality
• 95% CI 0.28-0.71, p<0.001
• Biologically plausible result:
• Ventricular arrhythmia reduced 7 versus 109
• Adverse effects rare
7 TRIALS’
TRIALS’S CHARACTERISTICS
•
•
•
•
•
•
•
All randomized.
6 blinded.
Baseline characteristics balanced.
Treatment usually started within 12 hours.
99.4% follow-up for mortality (8 patients).
Dosage varied 30-90 mmols.
Infusion over 24-48 hours.
- Some bolus injections.
• Baseline and follow-up Mg levels similar.
• 1 year mortality 20% vs 32% from 2 studies.
MAGNESIUM TRIAL METAMETA-ANALYSIS
MAGNESIUM TRIAL METAMETA-ANALYSIS
Leicester Intravenous Magnesium
Intervention Trial LIMITLIMIT-2
• 2316 patients with suspected acute MI
• Blinded placebo controlled
• 8 mmol over 5 minutes; 65 mmol over 24 hrs
• Primary outcome - total mortality @ 28 days
• 99.3% ascertainment
• 24% reduction (95% CI = 0.57 - 0.99, 2p = 0.04)
• 25% reduction in left ventricular failure
(95% CI = 0.61 - 0.91, 2p = 0.009)
• 65% confirmation of MI in both groups
Randomization of Patients Admitted to CCU
(September, 1987 to February, 1992)
n(%)
Total CCU admissions during study
4,508
Randomised to trial
2,316
Not Randomised
2192
Reason for non-randomisation
AMI not suspected
Previously randomised
660 (30.1)
454 (20.7)
Consent not obtainable/refused
272 (12.4)
Incomplete heart block
158 (7.2)
Died on admission
67 (3.0)
Entered another trial
34 (1.5)
Trial pack unavailable
30 (1.3)
Creatinine > 300 µmol/l
19 (0.8)
Bradycardia
14 (0.6)
Given magnesium therapeutically
Reason not recorded
LIMITLIMIT- 2
9 (0.4)
475 (21.7)
MAGNESIUM TRIAL METAMETA-ANALYSIS
ISIS 4: INTERNATIONAL STUDY OF
INFARCT SURVIVAL
•
•
•
•
•
58,050 Participants
Entry - up to 24 hours after onset of chest pain.
No contraindications to other therapies
2x2x2 factorial design
Treatments vs. Placebo
- 1 month, up to 100 mg/d captopril
- 1 month, controlled-release nitrate 60 mg/d
- 24 hours magnesium.
8 mmols bolus
72 mmols infusion
ISIS 4: INTERNATIONAL STUDY
OF INFARCT SURVIVAL
Primary endpoint all arms: total mortality
Results:
• 7% reduction: captopril
• No change: mononitrate
• No change: magnesium
• No significant interactions between treatments
ISIS 4: CLINICAL EVENTS IN HOSPITALS
(up to day 35 or earlier discharge)
Magnesium comparison
Magnesium n(%)
No randomized
29,011
Control n(%)
29,039
No with discharge form
28,527
28,534
Infarction confirmed
26,264 (92.1)
26,261 (92.0)
1,134 (4.0)
1,129 (4.0)
Ventricular fibrillation
992 (3.5)
1,087 (3.8)
Other cardiac arrest
916 (3.2)
829 (2.9)
2°° / 3°° heart block
1,115 (3.9)
1,068 (3.7)
Heart failure
Day 0-1
5,069 (17.8)
3,079 (10.8)
4,730 (16.6)†
2,695 (9.4)‡
Cardiogenic shock
Day 0-1
1,306 (4.6)
741 (2.6)
1,173 (4.1)*
638 (2.2)*
Profound hypotension
requiring termination of study
treatment
Day 0-1
2267 (7.9)
1,952 (6.8)‡
1,265 (4.4)
953 (3.3)‡
Any profound hypotension
4,781 (16.8)
4,300 (15.1)‡
Reinfarction
* 2p<0.01; † 2p<0.001; ‡ 2p<0.0001
MORTALITY IN DAYS 00-35
SUBDIVIDED BY OTHER RANDOMLY
ALLOCATED STUDY TREATMENTS
SYSTEMATIC OVERVIEW OF EFFECTS ON
SHORTSHORT-TERM MORTALITY OF STARTING
INTRAVENOUS MAGNESIUM EARLY IN
ACUTE MYOCARDIAL INFARCTION
WHAT WENT WRONG?
WHAT SHOULD WE BELIEVE?
• Increase in deaths ISIS-4
(p 0.07, 95% CI = +12-0%)
No convergence or divergence - 1 year
• 23,000 given bolus within 6 hours
7.9% magnesium, 7.6% control
• 17,000 no fibrinolytic therapy - no change
• ISIS an open trial - no apparent problems
• Previous meta-analysis and clinical trial small numbers
99% CI in LIMIT-2 - no benefit
MAGIC
(MAGNESIUM IN CORONARIES)
•
•
•
•
•
•
Design and Context
Randomised/ Double Blind
6213 participants-Acute STEMI
Magnesium Sulfate/Placebo
2g IV bolus (15min) 17g infusion (24hr)
30 day all cause mortality
Strata: 65 and older (rep)/any age (no rep)
Lancet 2002;360:1189-1196
MAGIC
(MAGNESIUM IN CORONARIES)
•
•
•
•
•
•
•
ACM (prim)
Stratum 1
Stratum 2
MI (Yes/No)
Reper (Y/N)
<65/>65
New onset HF
Mg
475
161
311
131/344
131/344
74/237
597
Lancet 2002;360:1189-1196
P
472
175
300
136/336
125/347
67/233
562
CUMULATIVE METAMETA-ANALYSIS
Lau et al – NE&M 1992:327: 248-254
“The Performance Of Updating A Meta-Analysis Every
Time A New Trial Appears”
• Goal – Evaluating the results as a continuum.
• Outcome – Supply practitioners with up-to-date
information
• Methods – “Fixed effects model”
( Mantel-Haenszel Statistic)
_ “Random effects model”
(DerSimonian-Laird Statistic)
• Methods Evaluation – Little difference in results
• Recommendation – Use both methods
THROMBOLYTIC TRIALS
LARGE, SIMPLE TRIALS
YUSUF, COLLINS AND PETO
“Ask an important question, answer it reliably”
Statistics in Medicine 1984;3:409-420
LARGE, SIMPLE TRIALS
•
•
•
•
•
•
Identification of effective treatments
Disease common
Treatment widely practicable
Concentrate on major vs minor outcomes
Stratification does not improve
No need to subcategorize participants
If no reliable answer yet-effect moderate
Statistics in Medicine 1984;3:409-420
EXPECTED EFFECTS OF TRIAL SIZE
ON TRIAL RESULTS
Total no. of deaths in (Approx. no. of patients
randomized if risk
trial
(treated + control)
≅ 10%)
Approx. probability of
failing to achieve 1
P<0.01 significance if
true risk reduction is
≅ 1/4
Comments that
might be made of
size before trial
begins
0-50
(under 500)
over 0.9
Utterly inadequate
50-150
(1000)
0.7-0.9
Probably inadequate
150-350
(3000)
0.3-0.7
Possibly adequate,
possibly not
350-650
(6000)
0.1-0.3
Probably adequate
over 650
(10,000)
under 0.1
Definitely adequate
Effects of trial size on trial results. Relationship
between the total number of deaths in the two
treatment groups and the result actually attained
No. of trials resulting in:
Statistical
power
P<0.05
against
Non-sigt.
againts
Non-sigt.
favorable
P<0.05
favourable
(255)
Utterly
inadequate
0
5
5
0
50-150
(861)
Probably
inadequate
0
1
9
1
150-350
(2925)
Possibly
adequate,
possibly not
0
0
1
2
350-650
(No such β-bl.
trials exist)
Problably
adequate
-
-
-
-
over 650
(No such β-bl.
trials exist)
Definitely
adequate
-
-
-
-
TOTAL
(866)
Inadequate
separately,
adequate only
in aggregate
0
6
15
3
Total no. of
deaths in trial
β-bl. ± plac.)
(β
(Mean no. of
patients
randomized)
0-50