Lecture 3 Hypothesis
-
Upload
saad-motawea -
Category
Documents
-
view
226 -
download
0
Transcript of Lecture 3 Hypothesis
-
7/28/2019 Lecture 3 Hypothesis
1/36
Sheryl F. Kelsey lecture 3-hypothesis 1
Design of Clinical TrialsEpidemiology 2181
Clinical Protocol
September 16, 2004
Sheryl F. Kelsey, Ph.D
-
7/28/2019 Lecture 3 Hypothesis
2/36
Sheryl F. Kelsey lecture 3-hypothesis 2
HYPOTHESIS
Patient selection
Intervention (treatment)
Endpoint (timeframe)
-
7/28/2019 Lecture 3 Hypothesis
3/36
Sheryl F. Kelsey lecture 3-hypothesis 3
STUDY POPULATION - PATIENT SELECTION
Unambiguous Entry CriteriaInclusion
Exclusion
Impact
Study design
Ability to generalize
Subject recruitment
-
7/28/2019 Lecture 3 Hypothesis
4/36
Sheryl F. Kelsey lecture 3-hypothesis 4
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
-
7/28/2019 Lecture 3 Hypothesis
5/36
Sheryl F. Kelsey lecture 3-hypothesis 5
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.
-
7/28/2019 Lecture 3 Hypothesis
6/36
Sheryl F. Kelsey lecture 3-hypothesis 6
PATIENT SELECTION - WHO?
Homogeneous vs heterogeneous, highlikelihood to detect an effect
Potential to benefit high risk group
Concomitant disease
competing risk
Expected to comply
-
7/28/2019 Lecture 3 Hypothesis
7/36
Sheryl F. Kelsey lecture 3-hypothesis 7
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
-
7/28/2019 Lecture 3 Hypothesis
8/36
Sheryl F. Kelsey lecture 3-hypothesis 8
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
-
7/28/2019 Lecture 3 Hypothesis
9/36
Sheryl F. Kelsey lecture 3-hypothesis 9
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
-
7/28/2019 Lecture 3 Hypothesis
10/36
Sheryl F. Kelsey lecture 3-hypothesis 10
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
-
7/28/2019 Lecture 3 Hypothesis
11/36
Sheryl F. Kelsey lecture 3-hypothesis 11
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.
-
7/28/2019 Lecture 3 Hypothesis
12/36
Sheryl F. Kelseylecture 3-hypothesis
12
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
-
7/28/2019 Lecture 3 Hypothesis
13/36
Sheryl F. Kelseylecture 3-hypothesis
13
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:
-
7/28/2019 Lecture 3 Hypothesis
14/36
Sheryl F. Kelsey lecture 3-hypothesis 14
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)
-
7/28/2019 Lecture 3 Hypothesis
15/36
Sheryl F. Kelsey lecture 3-hypothesis 15
INTERVENTION (TREATMENT)Drug dosage regimens
fixedflexible
side effectresponse- dummy dosage
responses for masked trialsSurgical treatments
guidelinesBehavioralnutritionexercisesmoking cessation
weight losscombinationAlternative TherapiesHealth Care DeliveryTREATMENT STRATEGY
-
7/28/2019 Lecture 3 Hypothesis
16/36
Sheryl F. Kelsey lecture 3-hypothesis 16
CONTROLS
Placebo
Standard Treatment
Usual Care (Best Medical Care)
Wait list controls
CONCOMITANT MEDICAL CARE
Specify in Protocol
-
7/28/2019 Lecture 3 Hypothesis
17/36
Sheryl F. Kelsey lecture 3-hypothesis 17
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
-
7/28/2019 Lecture 3 Hypothesis
18/36
Sheryl F. Kelsey lecture 3-hypothesis 18
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
-
7/28/2019 Lecture 3 Hypothesis
19/36
Sheryl F. Kelsey lecture 3-hypothesis 19
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
-
7/28/2019 Lecture 3 Hypothesis
20/36
Sheryl F. Kelsey lecture 3-hypothesis 20
BLINDING (MASKING)
single
double
Drugs
placebos
pills, injections, IV administration
SurgerySham surgery - ethical?
Behavioral not possible
Deception - Not ethicalPick best control group
-
7/28/2019 Lecture 3 Hypothesis
21/36
Sheryl F. Kelsey lecture 3-hypothesis 21
UNMASKING
Safety measures
Review of data
GuessingAsking patients at the end of the trial
Telling patients
-
7/28/2019 Lecture 3 Hypothesis
22/36
Sheryl F. Kelsey lecture 3-hypothesis 22
HOW TO MINIMIZE BIASIN UNMASKED TRIAL
Masked Evaluation
-
7/28/2019 Lecture 3 Hypothesis
23/36
Sheryl F. Kelsey lecture 3-hypothesis 23
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
-
7/28/2019 Lecture 3 Hypothesis
24/36
Sheryl F. Kelsey lecture 3-hypothesis 24
EXAMPLE: BARI
Test of treatment strategies
CABG
PTCA
Crossover
Concomitant therapy
Specified in protocol
Risk factors: hypertension, lipids, smoking
-
7/28/2019 Lecture 3 Hypothesis
25/36
Sheryl F. Kelsey lecture 3-hypothesis 25
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
-
7/28/2019 Lecture 3 Hypothesis
26/36
Sheryl F. Kelsey lecture 3-hypothesis 26
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
-
7/28/2019 Lecture 3 Hypothesis
27/36
Sheryl F. Kelsey lecture 3-hypothesis 27
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
-
7/28/2019 Lecture 3 Hypothesis
28/36
Sheryl F. Kelsey lecture 3-hypothesis 28
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
-
7/28/2019 Lecture 3 Hypothesis
29/36
Sheryl F. Kelsey lecture 3-hypothesis 29
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
-
7/28/2019 Lecture 3 Hypothesis
30/36
Sheryl F. Kelsey lecture 3-hypothesis 30
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
-
7/28/2019 Lecture 3 Hypothesis
31/36
Sheryl F. Kelsey lecture 3-hypothesis 31
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
-
7/28/2019 Lecture 3 Hypothesis
32/36
Sheryl F. Kelsey lecture 3-hypothesis 32
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
-
7/28/2019 Lecture 3 Hypothesis
33/36
Sheryl F. Kelsey lecture 3-hypothesis 33
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
-
7/28/2019 Lecture 3 Hypothesis
34/36
Sheryl F. Kelsey lecture 3-hypothesis 34
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
-
7/28/2019 Lecture 3 Hypothesis
35/36
Sheryl F. Kelsey lecture 3-hypothesis 35
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
-
7/28/2019 Lecture 3 Hypothesis
36/36
Sheryl F. Kelsey lecture 3-hypothesis 36
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