Randomized Trials: Design, Subjects, and Randomization Clay Johnston, MD, PhD Neurology and...

Randomized Trials: Design, Randomized Trials: Design, Subjects, and RandomizationSubjects, and Randomization

Clay Johnston, MD, PhDClay Johnston, MD, PhD

Neurology and EpidemiologyNeurology and Epidemiology

Randomized Trials: the Randomized Trials: the EvidenceEvidence in in “Evidence-Based”“Evidence-Based”

• TodayToday

– Randomized trials: why bother?Randomized trials: why bother?

– RandomizationRandomization

• Adaptive designs

– Selection of participants (Inclusion/exclusion)Selection of participants (Inclusion/exclusion)

– Design options for trialsDesign options for trials

• Factorial designs

• Cross-over designs

• Matched pairs

• Cluster or group randomization

Randomized Controlled Trial (RCT)Randomized Controlled Trial (RCT)

An experiment in which subjects are randomly An experiment in which subjects are randomly allocated into groups, usually called allocated into groups, usually called studystudy and and controlcontrol groups, to receive or not to receive an groups, to receive or not to receive an experimental preventive or therapeutic procedure, experimental preventive or therapeutic procedure, maneuver, or intervention. The results are maneuver, or intervention. The results are assessed by assessed by rigorousrigorous comparison of rates of comparison of rates of disease, death, recovery, or other appropriate disease, death, recovery, or other appropriate outcome in the study and control groups, outcome in the study and control groups, respectively.respectively.

Number of randomized trials published*Number of randomized trials published*

* Based on Medline search restricted to “Randomized clinical trials”* Based on Medline search restricted to “Randomized clinical trials”

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

1986 1991 1996 2001 2006

Disadvantages of RCTsDisadvantages of RCTs

• Expensive: typically in $ millionsExpensive: typically in $ millions

• Time Consuming: typically yearsTime Consuming: typically years

• Can only answer a single questionCan only answer a single question

• May not apply to most patients in practiceMay not apply to most patients in practice

• May not be practicalMay not be practical

• Generally very difficult to get fundedGenerally very difficult to get funded

• Time consuming, organizationally complexTime consuming, organizationally complex

Class dismissed.Class dismissed.

Alternatives to RCTsAlternatives to RCTs(30 second Epi. Course)(30 second Epi. Course)

• Case-control studiesCase-control studies

– Compare those with and without diseaseCompare those with and without disease

• Cross-sectional studiesCross-sectional studies

– Compare rates of risk factor among those with and Compare rates of risk factor among those with and without disease at a single time point.without disease at a single time point.

• Cohort studies (prospective)Cohort studies (prospective)

– Identify those with and without risk factorIdentify those with and without risk factor

– Follow forward in time to seeFollow forward in time to see who gets disease who gets disease

• Case-control, cross-sectional, and cohort studies are Case-control, cross-sectional, and cohort studies are observationalobservational (not experimental) (not experimental)

Reasons for doing RCTsReasons for doing RCTs

• Only study design that can prove causationOnly study design that can prove causation

– Rodney Dangerfield syndrome for Rodney Dangerfield syndrome for observational researchersobservational researchers

• Required by FDA (and others) for Required by FDA (and others) for new drugsnew drugs and and some devicessome devices

• Most influential to clinical practiceMost influential to clinical practice

Example: Estrogen Replacement TherapyExample: Estrogen Replacement Therapyin post-menopausal womenin post-menopausal women

• Important therapeutic questionImportant therapeutic question

• Applies to ~30 million women in USApplies to ~30 million women in US

• Prempro Prempro (estrogen/progestin combo)(estrogen/progestin combo)may have been most prescribed drug in USmay have been most prescribed drug in US

• Potentially huge impact on public healthPotentially huge impact on public health

• Complex: ERT effects multiple diseases Complex: ERT effects multiple diseases

Estrogen Replacement Therapy (ERT)Estrogen Replacement Therapy (ERT)

DiseaseDisease Effect on Risk*Effect on Risk*

Coronary heart diseaseCoronary heart disease Decrease by 40 - 80%Decrease by 40 - 80%Osteoporosis (hip fx)Osteoporosis (hip fx) Decrease by 30 - 60%Decrease by 30 - 60%Breast cancerBreast cancer Increase by 10 - 20%Increase by 10 - 20%Endometrial cancerEndometrial cancer Increase by 700%Increase by 700%

Alzheimer’sAlzheimer’s Decrease by ?Decrease by ?

Pulmonary embolism &Pulmonary embolism & Increase by 200 - 300%Increase by 200 - 300%deep vein thrombosisdeep vein thrombosis

* From observational (case-control and cohort) studies* From observational (case-control and cohort) studies

Nurses Health Study (NEJM, 9/12/91)Nurses Health Study (NEJM, 9/12/91)

• Prospective cohort study, n = 48,470Prospective cohort study, n = 48,470

• 337,000 person years of follow-up337,000 person years of follow-up

Risk of MajorRisk of MajorEstrogen UseEstrogen Use Coronary Disease*Coronary Disease* Relative Relative Risk**Risk**

Never UsedNever Used 1.41.4 1.01.0

Current userCurrent user 0.60.6 0.56 (0.40-0.56 (0.40-0.80)0.80)

Former userFormer user 1.31.3 0.83 (0.65-0.83 (0.65-1.05)1.05)

* Events per 1000 women-years of follow-up* Events per 1000 women-years of follow-up** Relative Risk (95% CI) compared to never users** Relative Risk (95% CI) compared to never users

Meta-analysis of ERT, Published 4/10/97Meta-analysis of ERT, Published 4/10/97

““Benefits (for CHD, osteoporosis) outweigh Benefits (for CHD, osteoporosis) outweigh risks (breast cancer) and side effects…risks (breast cancer) and side effects…

All post-menopausal women should All post-menopausal women should be taking ERT”*be taking ERT”*

* CNN, 4/10/97* CNN, 4/10/97

Virtually all estrogen results wereVirtually all estrogen results werebased on observational databased on observational data

• Women chose to take ERTWomen chose to take ERT

• Are ERT users different from non-users?Are ERT users different from non-users?– AgeAge– Health statusHealth status– More exerciseMore exercise– Health behaviors (see Dr.)Health behaviors (see Dr.)– SESSES

• Try to adjust in analysis, but may not be possibleTry to adjust in analysis, but may not be possible

• Randomized trials alleviate these problemsRandomized trials alleviate these problems

Heart and Estrogen-Progestin Heart and Estrogen-Progestin Replacement Study (HERS)Replacement Study (HERS)

• Secondary prevention of heart diseaseSecondary prevention of heart disease

• HRT (Prempro) vs. placebo (4-5 years)HRT (Prempro) vs. placebo (4-5 years)

• 2763 women with established heart disease2763 women with established heart disease

– Postmenopausal, < 80 years, mean age 67Postmenopausal, < 80 years, mean age 67

• 20 clinical centers in U.S./UCSF Coordinating 20 clinical centers in U.S./UCSF Coordinating centercenter

• Funding by Wyeth-Ayerst (post-NIH refusal)Funding by Wyeth-Ayerst (post-NIH refusal)

• Results: JAMA: 8/98Results: JAMA: 8/98

HERS: Summary of resultsHERS: Summary of results

EndpointEndpoint PlaceboPlacebo HRTHRT RRRR PP

New CHDNew CHD 176176 172172 0.990.990.910.91

Any fractureAny fracture 138138 130130 0.950.950.700.70

Conclusion: RandomizedConclusion: Randomized trials can lead to big trials can lead to big surprises!surprises!

Women’s Health Initiative Women’s Health Initiative HRT study (7/10/02)HRT study (7/10/02)

• Randomized trial (2)Randomized trial (2)

– 16,608 women with uterus (ERT + progestin vs. placebo)16,608 women with uterus (ERT + progestin vs. placebo)

– ~11,000 women without uterus (ERT alone vs. placebo)~11,000 women without uterus (ERT alone vs. placebo)

• Ages 50-79, mean age 64Ages 50-79, mean age 64

• Represent broad range of U.S. womenRepresent broad range of U.S. women

• 40 clinical centers40 clinical centers

WHI E+P study: 7/10/02WHI E+P study: 7/10/02

• Combination therapy arm stopped early (3 years)Combination therapy arm stopped early (3 years)

– Mean 5.2 years of follow-upMean 5.2 years of follow-up

– Overall, health risks outweigh benefitsOverall, health risks outweigh benefits

– Significant increased risk for invasive breast cancer HRT Significant increased risk for invasive breast cancer HRT usersusers

WHI E + P: Coronary Heart DiseaseWHI E + P: Coronary Heart Disease

years 1 2 3 4 5 6

HERS/WHI Trials: Take HomeHERS/WHI Trials: Take Home

• Observational studies can be wrong.Observational studies can be wrong.

– Cohort studies can be wrongCohort studies can be wrong

– Meta-analysis of observational studies can Meta-analysis of observational studies can be wrong.be wrong.

• What went wrong with observational studies of What went wrong with observational studies of HRT?HRT?

Major Observational Study LimitationMajor Observational Study Limitation

• CHARMCHARM

– Candesartan in Heart failure: Candesartan in Heart failure: Assessment of Reduction in Mortality Assessment of Reduction in Mortality and morbidity and morbidity

– Compared those taking vs. not taking Compared those taking vs. not taking either drug or placeboeither drug or placebo

– 35% RRR in all-cause mortality35% RRR in all-cause mortality

• For drug and placebo.

• Take homeTake home

– Confounders are impossible to fully Confounders are impossible to fully identifyidentify

Lancet 2005, 366:2005Lancet 2005, 366:2005

CLINICAL TRIALS IN THE NEWS:CLINICAL TRIALS IN THE NEWS:

• Lots of trials of things other than drugsLots of trials of things other than drugs

• Surgical techniquesSurgical techniques

• Weight lossWeight loss

Clinical Trials in the News:Clinical Trials in the News:JAMA 1/5/05JAMA 1/5/05

Vs.Vs.Vs.Vs. VsVs..

RCT of 4 Popular Weight Loss ProgramsRCT of 4 Popular Weight Loss Programs

• CompareCompare

– Atkins (low carbohydrate)Atkins (low carbohydrate)

– Weight Watchers (low calorie/portion size)Weight Watchers (low calorie/portion size)

– Zone (high protein/low-glycemic load)Zone (high protein/low-glycemic load)

– Ornish (very low fat)Ornish (very low fat)JAMA 1/5/05

VsVs..

Diet study: DesignDiet study: Design

N =160N =160

Randomize to 1 of 4 dietsRandomize to 1 of 4 diets

Follow for 12 monthsFollow for 12 months

Endpoints: Endpoints:

• Weight loss

• Heart disease risk factors (cholesterol, BP, triglycerides)

JAMA 1/5/05

Diet study: Results at 12 monthsDiet study: Results at 12 months

YearYear AtkinsAtkins ZoneZone Weight Weight OrnishOrnish

watchers .watchers .

Weight (kg)Weight (kg) -3.9-3.9 -4.9-4.9 -4.6-4.6 -6.6-6.6

LDL (mg/dL)LDL (mg/dL) -13.5 -13.5 -18.1-18.1 -14.2-14.2 -25.2-25.2

SBP (mm/Hg)SBP (mm/Hg) 0.3 0.3 2.12.1 -4.1-4.1 0.90.9

JAMA 1/5/05

Diet study: SummaryDiet study: Summary

• All diets lead to modest reductions in weight and All diets lead to modest reductions in weight and

cardiac risk factorscardiac risk factors

• Poor compliance for all diets, especially Atkins and Poor compliance for all diets, especially Atkins and

OrnishOrnish

– Those who adhered well had better resultsThose who adhered well had better results

JAMA 1/5/05

Examples of major Examples of major breakthroughs from RCTsbreakthroughs from RCTs

• Protease inhibitors and AIDSProtease inhibitors and AIDS

• Aspirin and heart diseaseAspirin and heart disease

• Lipid lowering (statins) and heart Lipid lowering (statins) and heart diseasedisease

NINDS TrialsNINDS TrialsTable 2. Impact of Clinical Trials with Published Information on Societal Cost s and Benefits*

References 10 Year Projections of Impact

Trial Title Societal

Cost Quality of Life Utilization

Quality-Adjusted Life

Years Treatment Costs Net Value Randomized Indomethacin Germinal Matrix/Intraventricular Hemorrhage Prevention Trial

42 42 43, 44 146,837 $ (92,857,340) $ 6,003,009,978

Diazepam for Acute Repetitive Seizures 45 NA 46, 47 $ (891,839,458) $ 890,276,155

Recombinant Beta Interferon as Treatment for Multiple Sclerosis

48 48-50 51 4,038 $ 955,140,007 $ (800,131,189)

Asymptomatic Carotid Artery Stenosis Collaborative Study

52 52 44, 53-55 92,820 $ 4,288,862,203 $ (590,564,802)

Stroke Prevention In Atrial Fibrillation I 56 56 57-60 35,457 $ 145,402,116 $ 1,267,774,453

North American Symptomatic Carotid Endarterectomy Trial

61 61 54, 55, 62 49,304 $ 256,977,048 $ 1,666,447,880

Tissue Plasminogen Activator in Ischemic Stroke

63 63 64, 65 134,066 $ (1,084,314,904) $ 6,469,781,905

Extracranial/Intracranial Arterial Anastomosis Study

66 NA 67 $ (325,476,690) $ 296,277,864

Total 462,522 $ 3,251,892,981 $ 15,202,872,245

*Negative numbers are in parentheses and represent soci etal cost savings. NA = not available. Net value includes cost of trial, treatment costs, and quality-adjusted life years valued at 2004 per capita gross domestic product ($40,310). Costs were inflated to 2004 dollars with the medical care portion of the Consumer Price Index.

So you want to do a randomized So you want to do a randomized trial…trial…

Steps in a “Classical”Steps in a “Classical” Randomized, Controlled Trail (RCT) Randomized, Controlled Trail (RCT)

11.. Select participants Select participants

2. Measure baseline variables2. Measure baseline variables

3. Randomize (to 1 or more treatments)3. Randomize (to 1 or more treatments)

4. Apply intervention4. Apply intervention

5/6. Follow-up--measure outcomes5/6. Follow-up--measure outcomes

Most commonly: one treatment vs. controlMost commonly: one treatment vs. control

Can be used for various types of outcomes (binary, Can be used for various types of outcomes (binary, continuous)continuous)

RandomizationRandomization

• Key element of RCT’sKey element of RCT’s

• Assures equal distribution of both...Assures equal distribution of both...

– Measured/known confoundersMeasured/known confounders

– Unmeasured/unknown confoundersUnmeasured/unknown confounders

• Important to do wellImportant to do well

– True random allocationTrue random allocation

– Tamper-proof (no peeking, altering order of Tamper-proof (no peeking, altering order of participants, etc)participants, etc)

• Simple randomizationSimple randomization

– Low techLow tech

– High techHigh tech

Other types of randomizationOther types of randomization

• Blocking*: equal after each n assignmentsBlocking*: equal after each n assignments

– e.g., block size of 4, treatments a and be.g., block size of 4, treatments a and b

abab aabb abba baba bbaa baababab aabb abba baba bbaa baab

– Randomly choose blocksRandomly choose blocks

– Assure relatively equal number of ppts. to Assure relatively equal number of ppts. to each treatment each treatment

– Disadvantages of blocking (in unblinded Disadvantages of blocking (in unblinded trials)trials)

– Size of block: 2 treatments--4 or 6Size of block: 2 treatments--4 or 6

– Very commonly usedVery commonly used

*Formally: random, permuted blocks*Formally: random, permuted blocks

Randomized blocks to Randomized blocks to balance prognostic variablesbalance prognostic variables

• Stratified permuted blocksStratified permuted blocks

– Blocks within strata of prognostic variableBlocks within strata of prognostic variable

– e.g., Stroke prevention after TIA. Time from event e.g., Stroke prevention after TIA. Time from event a key predictora key predictor

– StratumStratum

<12 hour: aabb baba …<12 hour: aabb baba …

>=12 hour: baab abab ….>=12 hour: baab abab ….

– Limited number of risk factors Limited number of risk factors

– Very commonly used in multicenter studies to Very commonly used in multicenter studies to balance within clinical centerbalance within clinical center

• Fancier techniques for assuring balanceFancier techniques for assuring balance

– Adaptive randomizationAdaptive randomization

Adaptive RandomizationAdaptive Randomization

• Various designs that reduce the total number of subjects Various designs that reduce the total number of subjects necessary when comparing multiple groupsnecessary when comparing multiple groups

– Determine assignment on the fly based on prior dataDetermine assignment on the fly based on prior data

– Often used for dose findingOften used for dose finding

• Simple designs based on a priori decision rulesSimple designs based on a priori decision rules

– Eg, go to next highest dose if no side effects in first 4 Eg, go to next highest dose if no side effects in first 4 treatedtreated

• Complex designs based on recalculation of oddsComplex designs based on recalculation of odds

– ASTIN trial of 15 doses of neutrophil inhibitory factor ASTIN trial of 15 doses of neutrophil inhibitory factor (Stroke, 2003)(Stroke, 2003)

Implementation of randomizationImplementation of randomization

• Less challenging for blinded studiesLess challenging for blinded studies

– Sealed envelopes in fixed order at clinical sitesSealed envelopes in fixed order at clinical sites

– List of drug numbersList of drug numbers

• a b a b b b a a• 1 2 3 4 5 6 7 8• Clinic receives bottles labeled only by numbers--

assign in order

– IVRS: Interactive Voice Response SystemIVRS: Interactive Voice Response System

• Unblinded studies: important to keep next Unblinded studies: important to keep next assignment secret assignment secret

– Problem with blocks within strataProblem with blocks within strata

Randomization: SummaryRandomization: Summary

• Key element of clinical trialsKey element of clinical trials

• Not really very complicated (usually)Not really very complicated (usually)

Who to Study: Who to Study: Principles for Inclusion/exclusionPrinciples for Inclusion/exclusion

• Widest possible generalizabilityWidest possible generalizability

• Sufficiently high event rate (for power to Sufficiently high event rate (for power to be adequate)be adequate)

• Population in whom intervention likely to Population in whom intervention likely to be effective and safebe effective and safe

• Ease of recruitmentEase of recruitment

• Likelihood of compliance with treatment Likelihood of compliance with treatment and F/Uand F/U

Who to Study: Who to Study: Principles for Inclusion/exclusionPrinciples for Inclusion/exclusion

Homogeneity --------------------HeterogeneityHomogeneity --------------------Heterogeneity

Explicit criteria for inclusion in a trialExplicit criteria for inclusion in a trial

• Typically written as “inclusion/exclusion” criteria in Typically written as “inclusion/exclusion” criteria in protocolprotocol

• Generally, the more explicit the betterGenerally, the more explicit the better

– Want centers or investigators to be consistentWant centers or investigators to be consistent

• Examples of exclusion criteria decisionsExamples of exclusion criteria decisions

1. Women with heart disease vs. Women with 1. Women with heart disease vs. Women with CABG surgery or documented MI by ECG (criteria) CABG surgery or documented MI by ECG (criteria) or enzymes (criteria)or enzymes (criteria)

2. Users of estrogen vs Use of oral ERT (.625 mg 2. Users of estrogen vs Use of oral ERT (.625 mg prempro) for more than 3 months over last 24 mos.prempro) for more than 3 months over last 24 mos.

Valid reasons to exclude participantsValid reasons to exclude participants

• Treatment would be unsafeTreatment would be unsafe

– Adverse experience from active treatmentAdverse experience from active treatment

– ““Risk” of placeboRisk” of placebo

• Active treatment cannot/unlikely to be effectiveActive treatment cannot/unlikely to be effective

– No risk of outcomeNo risk of outcome

– Disease type unlikely to respondDisease type unlikely to respond

– Competing/interfering treatment (history of?)Competing/interfering treatment (history of?)

• Unlikely to adhere or follow-upUnlikely to adhere or follow-up

• Practical problemsPractical problems

Enrollment rates in stroke trialsEnrollment rates in stroke trials

Ebselen 1MAST-E 2FISS 3FIST 4ASK 5Nimodipine 6Nalmefene 7Citicoline 8Aspirin 9STAT 10ATLANTIS 11ECASS 12MAST-I 13NINDS-TPA 14Enlimomab 15Aptiganel 16RANTTAS 17EST 18ECASS II 19Citicoline II 20PASS 21ANS 22TRUST 23TOAST 24SPIRIT 25TAIST 26GAIN 27GAIN-I 28WARSVISPPROGRESS

Legend: Average recruitment per site per month as a function of the maximum time from stroke to enrollment. ESPS-2CAPRIE

order based on the total number of subjects enrolled. Note: The x-axis is log scale. IST CAST

Named studies are ones that enrolled more than 2000 subjects. Other studies are numbered in ascending

Ave

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s P

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Site

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.125 1 2 90 1800

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2728 WARS

VISP

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ESPS-2

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CAST

Example of Inclusions/Exclusions in Example of Inclusions/Exclusions in ProtocolProtocol

• Inclusion CriteriaInclusion Criteria

– Male or female Male or female >> 40 years 40 years

– TIA (TIA (>> 10 minutes) or minor acute ischemic stroke (NIHSS 10 minutes) or minor acute ischemic stroke (NIHSS << 2 at time of randomization) occurring less than 24 2 at time of randomization) occurring less than 24 hours before randomizationhours before randomization

– Informed consent signedInformed consent signed

– Able to have MRI scan within 24 hours of symptoms onsetAble to have MRI scan within 24 hours of symptoms onset

• Exclusion CriteriaExclusion Criteria

– Related to absolute contraindications to the use of clopidogrel and/or ASA:Related to absolute contraindications to the use of clopidogrel and/or ASA:

• History of drug allergy to thienopyridine derivatives or ASA• Severe uncontrolled hypertension (SBP > 160 mm Hg or DBP > 110 mm Hg on two or more measures over the last 6

months)• History of clinically significant or persistent thrompocytopenia• History of clinically significant or persistent neutropenia• Women of child-bearing potential who are not following an effective method of contraception• Women who are breast-feeding

Example of Inclusions/Exclusions in Example of Inclusions/Exclusions in ProtocolProtocol

• Inclusion CriteriaInclusion Criteria

– Male or female Male or female >> 40 years 40 years

– TIA (TIA (>> 10 minutes) or minor acute ischemic stroke (NIHSS 10 minutes) or minor acute ischemic stroke (NIHSS << 2 at time of randomization) 2 at time of randomization) occurring less than 24 hours before randomizationoccurring less than 24 hours before randomization

– Informed consent signedInformed consent signed

– Able to have MRI scan within 24 hours of symptoms onsetAble to have MRI scan within 24 hours of symptoms onset

• Exclusion CriteriaExclusion Criteria

– Related to absolute contraindications to the use of clopidogrel and/or ASA:Related to absolute contraindications to the use of clopidogrel and/or ASA:

– Related to concomitant or planned medication(s) / treatment(s):Related to concomitant or planned medication(s) / treatment(s):

– Related to TIA/Stroke characteristics:Related to TIA/Stroke characteristics:

– Related to the presence of other medical problems that would either interfere with Related to the presence of other medical problems that would either interfere with participation in the trial or lead to inability to complete the trial:participation in the trial or lead to inability to complete the trial:

Design-a-trial: Design-a-trial: Inclusion criteria options for HRTInclusion criteria options for HRT

• Study HRT and prevention of heart disease, 4 years (HERS-like)Study HRT and prevention of heart disease, 4 years (HERS-like)

– Women over age 50 yearsWomen over age 50 years

– Women over 60 yearsWomen over 60 years

– Women over 75 yearsWomen over 75 years

– Women with existing heart diseaseWomen with existing heart disease

• Generalizability?Generalizability?

• Feasible sample size?Feasible sample size?

• Population amenable to intervention?Population amenable to intervention?

• Logistic difficulties (recruitment? cost? adherence)Logistic difficulties (recruitment? cost? adherence)

HERS inclusion optionsHERS inclusion options

• HERS trial options (event rate)HERS trial options (event rate)

– Women over age 50 years (0.1%/year)Women over age 50 years (0.1%/year)

– Women over 60 years (0.5%/year)Women over 60 years (0.5%/year)

– Women over 75 years (1%/year)Women over 75 years (1%/year)

– Women with existing heart disease Women with existing heart disease (4%/year)(4%/year)

HERS inclusion optionsHERS inclusion options

• HERS trial options (event rate) [n required]HERS trial options (event rate) [n required]

– Women over age 50 years (0.1%/year) Women over age 50 years (0.1%/year)

[55,000][55,000]

– Women over 60 years (0.5%/year) [45,000]Women over 60 years (0.5%/year) [45,000]

– Women over 75 years (1%/year) [34,000]Women over 75 years (1%/year) [34,000]

– Women with existing heart disease (4%/year) Women with existing heart disease (4%/year)

[3,000][3,000]

(Choose last option as most practical: (Choose last option as most practical: common to generalize from secondary to common to generalize from secondary to primary prevention)primary prevention)

Exclusions/inclusions examplesExclusions/inclusions examples

• Important impact on generalizability of both Important impact on generalizability of both efficacy and safetyefficacy and safety

• Example: Primary Stroke Prevention TrialExample: Primary Stroke Prevention Trial

– Chlorthalidone vs. placeboChlorthalidone vs. placebo

– Stroke rates dramatically increase with Stroke rates dramatically increase with ageage

• Stroke more common than MI after age 65

– Who should we include?Who should we include?

• Age cut-off?

• Atrial fibrillation?

Inclusion, Exclusion: ConclusionInclusion, Exclusion: Conclusion

• Many factors to balance in deciding who to includeMany factors to balance in deciding who to include

• Generally not a clear cut or single correct decisionGenerally not a clear cut or single correct decision

– Many academics have simplistic understanding Many academics have simplistic understanding of issuesof issues

Alternative RCT designs: Alternative RCT designs: Large-simple vs. standardLarge-simple vs. standard

• Large simple: less information on more peopleLarge simple: less information on more people

– Balance loss of precision with sample sizeBalance loss of precision with sample size

– Cost per patient with number of patientsCost per patient with number of patients

– Example:Example:

• Primary Prevention of Stroke Trial

• COMMIT: 45,852 patients in China, adding clopidogrel to aspirin in acute MI

• Standard: lots of info on fewStandard: lots of info on few

– Example: CASTIA trialExample: CASTIA trial

Alternative RCT designs: Alternative RCT designs: Factorial designFactorial design

• Test of more than one treatment (vs. placebo)Test of more than one treatment (vs. placebo)

• Each drug alone and in combinationEach drug alone and in combination

• Allows multiple hypotheses in single trialAllows multiple hypotheses in single trial

• EfficientEfficient

• Example: Physician’s Health StudyExample: Physician’s Health Study

– Test aspirin ==> MI Test aspirin ==> MI

– beta carotene ==> cancerbeta carotene ==> cancer

Factorial design: Physician’s Heath Factorial design: Physician’s Heath StudyStudy

PlaceboPlaceboPlaceboPlacebo

AspirinAspirinAspirinAspirin

Beta-Beta-carotenecarotene


Aspirin plusAspirin plus


Aspirin plusAspirin plus


Aspirin vs. Aspirin vs. no aspirin no aspirin (MI)(MI)

Aspirin vs. Aspirin vs. no aspirin no aspirin (MI)(MI)

Beta carotene Beta carotene vs. no beta vs. no beta carotene carotene (cancer)(cancer)

Beta carotene Beta carotene vs. no beta vs. no beta carotene carotene (cancer)(cancer)

Music, imagery, touch, and prayer as adjuncts to Music, imagery, touch, and prayer as adjuncts to interventional cardiac care: the Monitoring and Actualisation interventional cardiac care: the Monitoring and Actualisation

of Noetic Trainings (MANTRA) II randomised study of Noetic Trainings (MANTRA) II randomised study

Factorial design: Primary Stroke Factorial design: Primary Stroke Prevention TrialPrevention Trial

PlaceboPlaceboPlaceboPlacebo

K CitrK CitrK CitrK Citr

Chlorthal.Chlorthal.Chlorthal.Chlorthal.

Chlorthal. Chlorthal. plusplus

K CitrK Citr

Chlorthal. Chlorthal. plusplus

K CitrK Citr

3-way factorial design of WHI3-way factorial design of WHI

HRT vs. no HRT vs. no HRTHRT

HRT vs. no HRT vs. no HRTHRT

Low fat vs. Low fat vs. regular dietregular diet

Low fat vs. Low fat vs. regular dietregular diet

Calcium vs. no

Calcium vs. no

calcium

calcium

Calcium vs. no

Calcium vs. no

calcium

calcium

Factorial design issuesFactorial design issues

• Do treatments interact?Do treatments interact?

– Effect of chlorthalidone likely greater with Effect of chlorthalidone likely greater with potassium citrate on boardpotassium citrate on board

– HRT may increase calcium effect on bone HRT may increase calcium effect on bone

• Must test for interaction of treatments Must test for interaction of treatments

– If present, power is lower: large sample If present, power is lower: large sample requiredrequired

– May require more complicated stopping rulesMay require more complicated stopping rules

– May require more complicated analysis plan May require more complicated analysis plan (eg, logistic regression)(eg, logistic regression)

A Factorial Trial of Six Interventions for the A Factorial Trial of Six Interventions for the Prevention of Postoperative Nausea and VomitingPrevention of Postoperative Nausea and Vomiting

• One third of patients have post-op N/VOne third of patients have post-op N/V

• 5200 patients randomized to test 6 5200 patients randomized to test 6 individual medicationsindividual medications

– 2^6 = 64 combinations2^6 = 64 combinations

• Ondansetron

• Dexamethosone

• Droperidol

• Propofol vs. other

• Nitrogen vs. nitrous oxide

• Remifentanil vs. fentanyl

Apfel, C. C. et al. N Engl J Med 2004;350:2441-2451


Study Design

A Factorial Trial of Six Interventions for the A Factorial Trial of Six Interventions for the Prevention of Postoperative Nausea and VomitingPrevention of Postoperative Nausea and Vomiting

• ResultsResults

– Ondensetron, dexamethasone, and Ondensetron, dexamethasone, and droperidol each reduced N/V by 26%droperidol each reduced N/V by 26%

– Propofol by 19%Propofol by 19%

– Nitrogen by 12%Nitrogen by 12%

– All agents acted independentlyAll agents acted independently

• RR associated with combined interventions could be estimated by multiplying individual RRs.


Factorial design conclusionsFactorial design conclusions

• Factorial designs are seductive but Factorial designs are seductive but complicated complicated – Some attraction in combining a low-risk Some attraction in combining a low-risk

hypothesis with a high-risk hypothesishypothesis with a high-risk hypothesis

• Must weigh benefits in efficiency against Must weigh benefits in efficiency against compounded uncertainty and complexitycompounded uncertainty and complexity

Cross-over designsCross-over designs

• Both treatments are administered Both treatments are administered sequentially to all subjectssequentially to all subjects

• Subject serves as own control, random Subject serves as own control, random orderorder

• Compare treatment period vs. control Compare treatment period vs. control periodperiod

– Increases power by reducing person-to-Increases power by reducing person-to-person variabilityperson variability

Cross-over designsCross-over designs

• Diuretic vs. beta blocker for blood pressureDiuretic vs. beta blocker for blood pressure

– 1/2 get d followed by bb1/2 get d followed by bb

– 1/2 get bb followed by d1/2 get bb followed by d

• Migraine prophylaxisMigraine prophylaxis

– Rx x 3 months followed by placeboRx x 3 months followed by placebo

– Placebo x 3 months followed by RxPlacebo x 3 months followed by Rx

• Atrial Overdrive Pacing in sleep apneaAtrial Overdrive Pacing in sleep apnea

– AOP x 1 month followed by low-rate pacingAOP x 1 month followed by low-rate pacing

– Low-rate pacing x 1 month followed by AOPLow-rate pacing x 1 month followed by AOP

Cross-over assumptions/limitationsCross-over assumptions/limitations

• Transient outcomes onlyTransient outcomes only

• No order effectsNo order effects

–No carry-over effectsNo carry-over effects

–Need quick response and quick Need quick response and quick resolutionresolution

• ““Wash out” period helpfulWash out” period helpful

• More commonly used in phase I/IIMore commonly used in phase I/II

Matched Pair RandomizationMatched Pair Randomization

• One of each pair to each treatmentOne of each pair to each treatment

• Reduces risk of imbalanced randomizationReduces risk of imbalanced randomization

• Allows smaller sample sizeAllows smaller sample size

Matched Pair RandomizationMatched Pair Randomization

• Example: two eyes within an individual (one Example: two eyes within an individual (one to each treatment)to each treatment)–Diabetic Retinopathy studyDiabetic Retinopathy study

• Example: Filter for carotid arteries in Example: Filter for carotid arteries in patients with atrial fibrillationpatients with atrial fibrillation–Random side of interventionRandom side of intervention

• Example: Quality Improvement in Stroke Example: Quality Improvement in Stroke Prevention (QUISP) trialPrevention (QUISP) trial–Randomize paired Kaiser facilitiesRandomize paired Kaiser facilities

Matched Pair Randomization IssuesMatched Pair Randomization Issues

• Not necessary when sample size makes Not necessary when sample size makes balanced randomization likelybalanced randomization likely

–Loss in efficiencyLoss in efficiency

• May not be feasibleMay not be feasible

• Arguments about how to analyze the dataArguments about how to analyze the data

–Maintaining the match vs. breaking itMaintaining the match vs. breaking it

Cluster or grouped randomizationCluster or grouped randomization

• Randomize groups to treatmentsRandomize groups to treatments

• Often useful especially for public health-Often useful especially for public health-type interventionstype interventions

• May be only way to study a questionMay be only way to study a question

– Intervention is at the group levelIntervention is at the group level

–Cross-contamination between individualsCross-contamination between individuals


• ExamplesExamples

–Quality Improvement in Stroke Prevention Quality Improvement in Stroke Prevention (QUISP) trial(QUISP) trial

–DTC Advertising TrialDTC Advertising Trial

• Randomize matched cities

–Cities to public health risk factor reduction Cities to public health risk factor reduction (5 Cities Project)(5 Cities Project)


• Sample size complex: true n is between n Sample size complex: true n is between n clusters and n individuals (closer to clusters)clusters and n individuals (closer to clusters)

–Tendency to underestimate necessary Tendency to underestimate necessary sample sizesample size

• Analysis complexAnalysis complex

–Must account for clusteringMust account for clustering

–Mixed models bestMixed models best

Randomized Trials: the Randomized Trials: the EvidenceEvidence in in “Evidence-Based”“Evidence-Based”

• TodayToday

– Randomized trials: why bother?Randomized trials: why bother?

– RandomizationRandomization

• Adaptive designs

– Selection of participants (Inclusion/exclusion)Selection of participants (Inclusion/exclusion)

– Design options for trialsDesign options for trials

• Factorial designs

• Cross-over designs

• Matched pairs

• Cluster or group randomization

Previews of coming attractionsPreviews of coming attractions

• Statistical issues in randomized trialsStatistical issues in randomized trials

Randomized Trials: Design, Subjects, and Randomization Clay Johnston, MD, PhD Neurology and...

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Transcript of Randomized Trials: Design, Subjects, and Randomization Clay Johnston, MD, PhD Neurology and...