lecture 3 hypothesis

7/28/2019 Lecture 3 Hypothesis

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Sheryl F. Kelsey lecture 3-hypothesis 1

Design of Clinical TrialsEpidemiology 2181

Clinical Protocol

September 16, 2004

Sheryl F. Kelsey, Ph.D


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HYPOTHESIS

Patient selection

Intervention (treatment)

Endpoint (timeframe)


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STUDY POPULATION - PATIENT SELECTION

Unambiguous Entry CriteriaInclusion

Exclusion

Impact

Study design

Ability to generalize

Subject recruitment


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ELIGIBILITY CRITERIA

Inclusion criteria are used to roughlyoutline 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 communitiesmust 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, highlikelihood 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


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Impact of eligibility criteria on

recruitment of participants should beconsidered 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

hospitalvolunteer - 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 J AMA 1997

Hypothesis

Project TREAT (Trial for early alcohol treatment) was designedto test the efficacy of brief physician advise in reducing alcohol

use and health care utilization in problem drinkers

Patient Selection

Inclusionmen > 14 drinks/week (168g alcohol)

women > 11 drinks/week (132g alcohol)Exclusion

Pregnant< 18 years>65 years

alcohol treatment - previous yearalcohol withdrawal symptoms - prior yearadvise of physician within 3 months re: alcohol use> 50 drinks/weeksuicidal


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BYPASS ANGIOPLASTY

REVASCULARIZATION INVESTIGATION

(BARI)

Hypothesis: Among selected

symptomatic patients with multivesselcoronary disease suitable for either

PTCA or CABG, an initial strategy of

PTCA does not result in a poorer five-year survival than CABG.


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Sheryl F. Kelseylecture 3-hypothesis

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BARI - PATIENT SELECTION

Inclusion Criteria:Clinically severe angina or objectiveevidence of ischemia.

Need for a revascularization procedure Angiographically documentedmultivessel coronary disease

Suitability for both PTCA and CABG Informed consent

EXCLUSION CRITERIA


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Sheryl F. Kelseylecture 3-hypothesis

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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 patientssuitability for each procedure according to their technical expertiseand considerations of patient safety.

EXCLUSION CRITERIA:


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SUBGROUPSWhy important?

Tailor treatment

Treatment interaction

Typical subgroups defined by:

Age, gender, race

Prognostic categories High risk

Statistical power

Controversiesgender and racefishing - astrological signbiologic plausibilityspecify in advance

INTERVENTION (TREATMENT)


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INTERVENTION (TREATMENT)Drug dosage regimens

fixedflexible

side effectresponse- dummy dosage

responses for masked trialsSurgical treatments

guidelinesBehavioralnutritionexercisesmoking cessation

weight losscombinationAlternative TherapiesHealth Care DeliveryTREATMENT 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 seedsplacebo


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BEHAVIORAL PLACEBO SIMULATES

Non-specific effects

Therapist attention, interest and

concern

Reputation, expensiveness, and

impressiveness of treatment

Characteristics of setting

NHLBI TYPE II CORONARY INVENTION STUDY


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NHLBI TYPE II CORONARY INVENTION STUDY

Gastroinestinal

Belching/bloating 8 11.1 9 12.7 1 1.4 3 4.4 3 5.3 3 5.1

Constipation 1 1.4 2 2.8 0 0.0 1 1.5 2 3.5 3 5.1

Gas 15 20.8 11 15.5 2 2.9 5 7.4 4 7.0 3 5.1

Heartburn 12 16.7 10 14.1 0 0.0 1 1.5 0 0.0 3 5.1

Other

Abdominal pain 3 4.2 5 7.0 0 0.0 1 1.5 0 0.0 2 3.4

Drowsiness 4 5.6 8 11.3 0 0.0 2 2.9 1 1.8 5 8.5

Itching 7 9.7 5 7.0 1 1.4 1 1.5 0 0.0 1 1.7

Leg cramps 6 8.3 9 12.7 2 2.9 4 5.9 1 1.8 5 8.5

Nervousness 16 22.2 18 25.4 1 1.4 3 4.4 3 5.3 5 8.5

Rash 3 4.2 3 4.2 0 0.0 1 1.5 0 0.0 1 1.7

Weakness 5 6.9 3 4.2 0 0.0 1 1.5 0 0.0 3 5.1

Placebo Colestyramine

(=72) (n=71)

No. of No. ofpatients % patients %

Placebo colestyramine

(n=70) (n=68)

No. of No. of

patients % patients %

Placebo Colestyramine

(n=57) (n=69)

No. of No. of

patients % patients %

Incidence of moderate and severe side effects by treatment

Baseline First year Five years

1984 Circulation


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BLINDING (MASKING)

single

double

Drugs

placebos

pills, injections, IV administration

SurgerySham surgery - ethical?

Behavioral not possible

Deception - Not ethicalPick best control group


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UNMASKING

Safety measures

Review of data

GuessingAsking patients at the end of the trial

Telling patients


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HOW TO MINIMIZE BIASIN UNMASKED TRIAL

Masked Evaluation


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EXAMPLE: PROBLEM ALCOHOL DRINKERS

Intervention

Two 10 - 15 minute counseling sessions byphysicians

scripted workbook - prevalence ofproblem drinking, adverse effects,

drinking cues

follow-up by nurses

Control

general health bookletMasked? 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 atsix months

What should be the control?

ENDPOINTS OUTCOME RESPONSE


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ENDPOINTS-OUTCOME-RESPONSE

VARIABLETypical endpoints

mortality

death from specific causeincidence of a diseasesymptomatic reliefclinical findinglaboratory measurement

Pick one primary

Specify secondary endpoints

Type of data

yes or no (dead or alive, success or failure)dichotomouscontinuoustime to event (censoring)frequency of events

ENDPOINT ISSUES


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Combinations - Composite Endpointsex: death or retransplantation

death or Ca recurrence

death or nonfatal MI

One event per subject

Good endpoints

Primary response must be capable of being assessedin everyone - minimize missing data

Measured in the same way (angiography vs RVG forLeft Ventricular function)

Uniform assessment

Reliability

When does participation end if achieve endpoint

ENDPOINT ISSUES


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COMPOSITE ENDPOINT

Example:

Death Stroke MI Hemmorhage Primary Secondary

1.0 1.0 .5 .4

Patient

1

1 1.0

2 0 0

3 1 1.0

4

1.5

5 1 4

6 0 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

SURROGATE ENDPOINTS


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SURROGATE ENDPOINTS

Motivation: need for rapid reliable evaluation of promising newinterventions

Substitute for a clinically meaningful endpoint (feel good, functionbetter, live longer)

A laboratory measurement or physical sign

Cheaper, faster, easier

Requirementscorrelate with true clinical outcomecapture effect of treatment on clinical outcome

ConsiderationsPhase II vs. Phase IIISeverity of disease and alternativesCost of wrong treatment

SURROGATE ENDPOINTS EXAMPLES


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SURROGATE ENDPOINTS - EXAMPLES

CD4 lymphocyte count - test anti-retroviral agentsfor 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 andtrue endpoint may not be causal, but

coincidental to a third factor

Other unfavorable effects of the

treatment

Surrogate may correlate with one

clinical endpoint, but not others


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SURROGATE ARRHYTHMIA EXAMPLE

Coronary arrhythmias are associatedwith sudden death

Drugs developed to suppress

arrhythmias Approved for special use

Increased off label use

Little data on mortality effect

CARDIAC ARRHYTHMIA SUPPRESSION TRIAL


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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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CAST-1

EARLY INTERIM RESULTS

Drug Placebo P

N 730 725

Follow-up 203 300

(average days)

Sudden death 33 9 .0006

Total death 56 22 .0003

lecture 3 hypothesis

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