Design of Clinical Trials Epidemiology 2181 Clinical Protocol

September 16, 2004 Sheryl F. Kelsey, Ph.D

Sheryl F. Kelsey

lecture 3-hypothesis

HYPOTHESIS
Patient selection
Intervention (treatment) Endpoint (timeframe)

Sheryl F. Kelsey

lecture 3-hypothesis

STUDY POPULATION - PATIENT SELECTION

Unambiguous Entry Criteria Inclusion Exclusion

Impact Study design Ability to generalize Subject recruitment

Sheryl F. Kelsey

lecture 3-hypothesis

ELIGIBILITY CRITERIA
Inclusion

criteria are used to roughly outline the intended patient population.

Exclusion criteria are used to fine-tune the intended patient population: safety, feasibility, practicality Dont duplicate
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WHY EXPLICITLY DEFINE A STUDY POPULATION?

The medical and scientific communities must know to what people the findings apply. Knowledge of the study population helps other investigators assess the studys merit and appropriateness. In order for other investigators to be able to replicate the study.
Only small trials are likely to be repeated, but these are the ones, in general, that most need confirmation.
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PATIENT SELECTION - WHO?

Homogeneous vs heterogeneous, high likelihood to detect an effect Potential to benefit high risk group Concomitant disease competing risk Expected to comply
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EXCLUSION CRITERIA MAY BE BASED ON MINIMIZING THE RISK OF ADVERSE EVENTS

Drug interactions

Seizure history Pregnant women Gastric bleeding history of major gastric bleed

Sheryl F. Kelsey

lecture 3-hypothesis

 Impact of eligibility criteria on recruitment of participants should be considered when deciding on these criteria. If entrance criteria are properly determined in the beginning of a study, there should be no need to change them. The reason for each criteria should be carefully examined during the planning phase of the study. Appeals Committees not advisable
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GENERALIZABILITY
Nonrandom Patient selection criteria plus Screening/recruitment - relate to generalizability Clinical - Internal validity - randomized comparison Statistical inference Scientific inference Generalize a treatment difference when everything else is unbiased. Characterize age, gender, race, blood sugar level - can we extrapolate? Other factors geography hospital volunteer - why do some do so - healthier, better adherence? - logs and registries IMPACT ON RECRUITMENT
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BRIEF PHYSICIAN ADVISE FOR PROBLEM ALCOHOL DRINKERS, FLEMING ET AL JAMA 1997
Hypothesis Project TREAT (Trial for early alcohol treatment) was designed to test the efficacy of brief physician advise in reducing alcohol use and health care utilization in problem drinkers Patient Selection Inclusion men > 14 drinks/week (168g alcohol) women > 11 drinks/week (132g alcohol) Exclusion Pregnant < 18 years >65 years alcohol treatment - previous year alcohol withdrawal symptoms - prior year advise of physician within 3 months re: alcohol use > 50 drinks/week suicidal
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BYPASS ANGIOPLASTY REVASCULARIZATION INVESTIGATION (BARI)

Hypothesis: Among selected symptomatic patients with multivessel coronary disease suitable for either PTCA or CABG, an initial strategy of PTCA does not result in a poorer fiveyear survival than CABG.
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BARI - PATIENT SELECTION

Inclusion Criteria: Clinically severe angina or objective evidence of ischemia. Need for a revascularization procedure Angiographically documented multivessel coronary disease Suitability for both PTCA and CABG

Informed consent
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EXCLUSION CRITERIA:

Primary congenital heart disease Primary valvular heart disease Primary myocardial heart disease (including patients with a ventricular aneurysm, which requires surgery) Prior PTCA or CABG Age 80 years Age < 17 years Left main stenosis 50% Noncardiac illness that is expected to limit survival Extensive ascending aortic calcification Contraindication to CABG or PTCA because of a coexisting clinical condition. Primary coronary spasm Suspected or known pregnancy Enrollment in a competing clinical trial Geographically inaccessible or unable to return for follow-up Inability to understand or cooperate with protocol requirements Final Eligibility: The surgeon and angioplasty operator assess the patients suitability for each procedure according to their technical expertise and considerations of patient safety.
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SUBGROUPS
Why important? Tailor treatment Treatment interaction Typical subgroups defined by: Age, gender, race Prognostic categories High risk Statistical power Controversies gender and race fishing - astrological sign biologic plausibility specify in advance
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INTERVENTION (TREATMENT)
Drug dosage regimens fixed flexible side effect response - dummy dosage responses for masked trials Surgical treatments guidelines Behavioral nutrition exercise smoking cessation weight loss combination Alternative Therapies Health Care Delivery TREATMENT STRATEGY
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CONTROLS
Placebo Standard Treatment Usual Care (Best Medical Care) Wait list controls

CONCOMITANT MEDICAL CARE Specify in Protocol

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THE POWERFUL PLACEBO

33% will respond to placebo Medical placebo produce side effects and carryover affects that mimic medication

Surgical placebo
Acupuncture placebo Percutaneous coronary intervention radiation seeds placebo
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BEHAVIORAL PLACEBO SIMULATES

Non-specific effects

Therapist attention, interest and concern

Reputation, expensiveness, and impressiveness of treatment Characteristics of setting

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NHLBI TYPE II CORONARY INVENTION STUDY

Incidence of moderate and severe side effects by treatment

Baseline
Placebo (=72) No. of patients % Gastroinestinal Belching/bloating Constipation Gas Heartburn Other Abdominal pain 3 4.2 5 7.0 0 8 1 15 12 11.1 1.4 20.8 16.7 9 2 11 10 12.7 2.8 15.5 14.1 1 0 2 0 Colestyramine (n=71) No. of patients %

First year
Placebo (n=70) No. of patients % colestyramine (n=68) No. of patients %

Five years
Placebo (n=57) No. of patients % Colestyramine (n=69) No. of patients %

1.4 0.0 2.9 0.0 0.0

3 1 5 1 1

4.4 1.5 7.4 1.5 1.5

3 2 4 0 0

5.3 3.5 7.0 0.0 0.0

3 3 3 3 2

5.1 5.1 5.1 5.1 3.4

Drowsiness
Itching Leg cramps Nervousness Rash Weakness
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4
7 6 16 3 5

5.6
9.7 8.3 22.2 4.2 6.9

8
5 9 18 3 3

11.3
7.0 12.7 25.4 4.2 4.2

0
1 2 1 0 0

0.0
1.4 2.9 1.4 0.0 0.0

2
1 4 3 1 1

2.9
1.5 5.9 4.4 1.5

1
0 1 3 0

1.8
0.0 1.8 5.3 0.0 0.0

5
1 5 5 1 3
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8.5
1.7 8.5 8.5 1.7 5.1

lecture 3-hypothesis

1.5 0 1984 Circulation

BLINDING (MASKING)
single double Drugs placebos pills, injections, IV administration Surgery Sham surgery - ethical? Behavioral not possible Deception - Not ethical Pick best control group
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UNMASKING
Safety measures

Review of data
Guessing

Asking patients at the end of the trial

Telling patients

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HOW TO MINIMIZE BIAS

IN UNMASKED TRIAL
Masked Evaluation

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EXAMPLE: PROBLEM ALCOHOL DRINKERS Intervention

Two 10 - 15 minute counseling sessions by physicians scripted workbook - prevalence of problem drinking, adverse effects, drinking cues

follow-up by nurses

Control
general health booklet Masked? No, but masked evaluation
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EXAMPLE: BARI
Test of treatment strategies CABG PTCA Crossover

Concomitant therapy
Specified in protocol Risk factors: hypertension, lipids, smoking

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Hypothesis
Aerobic exercise - group sessions twice per week - for kids with cystic fibrosis has a beneficial effect on lung function at six months

What should be the control?

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ENDPOINTS-OUTCOME-RESPONSE VARIABLE
Typical endpoints mortality death from specific cause incidence of a disease symptomatic relief clinical finding laboratory measurement Pick one primary Specify secondary endpoints Type of data yes or no (dead or alive, success or failure) dichotomous continuous time to event (censoring) frequency of events
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ENDPOINT ISSUES
Combinations - Composite Endpoints ex: death or retransplantation death or Ca recurrence death or nonfatal MI One event per subject Good endpoints Primary response must be capable of being assessed in everyone - minimize missing data Measured in the same way (angiography vs RVG for Left Ventricular function)

Uniform assessment
Reliability When does participation end if achieve endpoint
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COMPOSITE ENDPOINT
Example:
Death Stroke MI Hemmorhage Primary Secondary

1.0 Patient 1 2 3 4

1.0

.5

.4

1 0 1

1.0 0 1.0 1

.5
5
Sheryl F. Kelsey

lecture 3-hypothesis

1 0

4 0
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PROBLEM ALCOHOL DRINKERS

Issue: No primary endpoint specified

Average drinks per week

Health utilization, hospital days and emergency

room visits
6, 12 month telephone interview by personnel

from different clinic

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BARI
Endpoints

Primary: Mortality
Secondary: Myocardial infarction, angina, cost, quality of life, exercise stress test results

Masked evaluations of cause of death, ECG

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SURROGATE ENDPOINTS
Motivation: need for rapid reliable evaluation of promising new interventions Substitute for a clinically meaningful endpoint (feel good, function better, live longer) A laboratory measurement or physical sign Cheaper, faster, easier Requirements correlate with true clinical outcome capture effect of treatment on clinical outcome Considerations Phase II vs. Phase III Severity of disease and alternatives Cost of wrong treatment
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SURROGATE ENDPOINTS - EXAMPLES

CD4 lymphocyte count - test anti-retroviral agents for HIV, Virus Smoking cessation - lung cancer Bone density - osteoporosis

Angiographic progression of atherosclerosis clinical CAD

Proliferation of breast tissue - breast cancer Blood pressure - stroke, myocardial infarction
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SURROGATE: CONCERNS

Relationship between surrogate and true endpoint may not be causal, but coincidental to a third factor

Other unfavorable treatment

effects

of

the

Surrogate may correlate with one clinical endpoint, but not others
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Sheryl F. Kelsey

SURROGATE ARRHYTHMIA EXAMPLE

Coronary arrhythmias are associated with sudden death Drugs developed to suppress arrhythmias Approved for special use Increased off label use Little data on mortality effect

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CARDIAC ARRHYTHMIA SUPPRESSION TRIAL (CAST-1)

Two drugs (Encainide, Flecainide) Randomized, double masked, placebo control Testing if suppression of arrhythmias in MI patients reduces sudden death total mortality Run-in period Expected a 30% reduction in mortality 1455 patients randomized 3 years average follow-up
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Sheryl F. Kelsey

CAST-1 EARLY INTERIM RESULTS

Drug
N 730

Placebo
725

Follow-up 203 (average days)

Sudden death Total death
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300

33 56

9 22
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.0006 .0003
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