controlled clinical trials 9 sessions9 sessions grady (course director), black (lecturer), cummings...

Controlled Clinical TrialsControlled Clinical Trials

• 9 Sessions9 Sessions

• Grady (course director), Black (lecturer), Grady (course director), Black (lecturer), Cummings (lecturer)Cummings (lecturer)

• Logistics….Logistics….

TICR Professional Conduct StatementTICR Professional Conduct StatementClarifications for this classClarifications for this class

• I will maintain the highest standards of academic honestyI will maintain the highest standards of academic honesty

• I will neither give nor receive aid in examinations or I will neither give nor receive aid in examinations or assignments assignments unless such cooperation is expressly unless such cooperation is expressly permitted by the instructorpermitted by the instructor

• I will conduct research in an unbiased manner, reports I will conduct research in an unbiased manner, reports results truthfully, and credit ideas developed and work results truthfully, and credit ideas developed and work done by othersdone by others

• I will not use answer keys from prior yearsI will not use answer keys from prior years

• I will write answers in my own words, and, when I will write answers in my own words, and, when collaboration is permitted, collaboration is permitted, acknowledge collaborators acknowledge collaborators when answers are jointly formulatedwhen answers are jointly formulated

VideotapingVideotaping

• Lectures to be videotapedLectures to be videotaped

• On course website within 1-2 hours of lectureOn course website within 1-2 hours of lecture

• Remind me (and other lecturers) to repeat questions and Remind me (and other lecturers) to repeat questions and reiterate discussion for the tapereiterate discussion for the tape

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

Dennis Black, PhDDennis Black, PhD

Dept. of Epidemiology and BiostatisticsDept. of Epidemiology and Biostatistics

[email protected]@psg.ucsf.edu

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

• Outline for todayOutline for today

0. Randomized trials: why bother?0. Randomized trials: why bother?

1. Randomization1. Randomization

• Plain vanilla• Other flavors

2. Selection of participants (Inclusion/exclusion)2. Selection of participants (Inclusion/exclusion)

3. Design options for trials3. Design options for trials

• Vanilla• Factorial designs• Cross-over designs• Matched pairs• Cluster or group randomization

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

An An experimentexperiment in which subjects are in which subjects are randomly randomly allocatedallocated into groups, usually called 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.

Centre for Evidence-based Medicine, Oxfordhttp://www.cebm.net/index.aspx?o=1116

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

2010 update: 2010 update: 71,000 71,000 “randomized “randomized clinical trials”clinical trials”

2011 update: DBEYR2011 update: DBEYRAnywhere RCT: 60kAnywhere RCT: 60kTitle RCT: 6kTitle RCT: 6k

Google News “randomized studies”: 1/4/12Google News “randomized studies”: 1/4/12

Reasons NOT to do RCTsReasons NOT to do RCTs

• Expensive: total costs typically in $ millions (maybe Expensive: total costs typically in $ millions (maybe be as high as $200-$500 million)be as high as $200-$500 million)

• 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

So, why bother?So, why bother?

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

1. Case-control studies1. Case-control studies– Compare Vit E intake in those with and without Compare Vit E intake in those with and without

diseasedisease

2. Cross-sectional studies2. Cross-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.

3. Cohort studies (prospective)3. 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)

RQ: Does Vitamin E prevent prostate cancer?RQ: Does Vitamin E prevent prostate cancer?

Problems with observational studiesProblems with observational studies(e.g. cohort studies)(e.g. cohort studies)

Reasons for doing RCTsReasons for doing RCTs

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

• Most influential to clinical practiceMost influential to clinical practice

– Strongest evidence in “evidence-based”Strongest evidence in “evidence-based”

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

• Required more and more by payersRequired more and more by payers

Vitamin E, C and Selenium on Prostate Vitamin E, C and Selenium on Prostate Cancer in men (JAMA, 1/09)Cancer in men (JAMA, 1/09)

• 2 very large studies published together2 very large studies published together

– SELECT study (Lippman) is largest SELECT study (Lippman) is largest cancer prevention trial ever performed cancer prevention trial ever performed (n=35,533)(n=35,533)

– Also Gaziano study of prostate cancerAlso Gaziano study of prostate cancer

Vitamin E, C and Selenium on Prostate Vitamin E, C and Selenium on Prostate Cancer in men (JAMA 1/09)Cancer in men (JAMA 1/09)

• These studies have it all and are great These studies have it all and are great examples:examples:

– Interesting/popular research questions: Vit Interesting/popular research questions: Vit C and E for cancer preventionC and E for cancer prevention

– Surprising and impactful resultsSurprising and impactful results

– Large studiesLarge studies

– Early stoppingEarly stopping

– Multiple endpointsMultiple endpoints

– Subgroup analysesSubgroup analyses

– Factorial designFactorial design

• To be used throughout course (D. Black)To be used throughout course (D. Black)

Vitamin E, C and Selenium on Prostate Vitamin E, C and Selenium on Prostate Cancer: Background Cancer: Background

• Positive results in observational studies of anti-Positive results in observational studies of anti-oxidant use and cancer oxidant use and cancer

• 1994: ATBC (alpha-tocopherol/beta carotene) trial 1994: ATBC (alpha-tocopherol/beta carotene) trial showed 35% reduction in P.Ca in men taking vitamin e showed 35% reduction in P.Ca in men taking vitamin e (post-hoc analysis)(post-hoc analysis)

• 1996: 65% reduction in prostate cancer with selenium 1996: 65% reduction in prostate cancer with selenium (secondary analysis) (secondary analysis)

• Hope/belief: prostate cancer could be prevented by Hope/belief: prostate cancer could be prevented by anti-oxidantsanti-oxidants

• Many people taking anti-oxidantsMany people taking anti-oxidants


• Positive results in observational studies of anti-Positive results in observational studies of anti-oxidant use and cancer oxidant use and cancer

• 1994: ATBC (alpha-tocopherol/beta carotene) trial 1994: ATBC (alpha-tocopherol/beta carotene) trial showed 35% reduction in P.Ca in men taking vitamin e showed 35% reduction in P.Ca in men taking vitamin e (post-hoc analysis: main endpoint was lung CA)(post-hoc analysis: main endpoint was lung CA)

• 1996: 65% reduction in prostate cancer with selenium 1996: 65% reduction in prostate cancer with selenium (secondary analysis)(secondary analysis)

• Hope/belief: prostate cancer could be prevented by Hope/belief: prostate cancer could be prevented by anti-oxidantsanti-oxidants

• Many people taking anti-oxidantsMany people taking anti-oxidants

SELECT studySELECT study(Factorial design, 35,533 men) (JAMA, 1/7/09)(Factorial design, 35,533 men) (JAMA, 1/7/09)

PlaceboPlacebo Vit. EVit. E

SeleniumSelenium

Selenium + Selenium +

Vitamin EVitamin E

Selenium Selenium vs. no vs. no seleniumselenium

Vitamin E vs. No Vitamin E vs. No Vitamin EVitamin E


Selection:Selection:

• MenMen

• PSA <4 ng/mlPSA <4 ng/ml

• No P.Ca fromNo P.Ca from

DR examDR exam

SELECT studySELECT studyResults for Prostate Ca (Primary endpoint)Results for Prostate Ca (Primary endpoint)

SELECT Trial: FactoidsSELECT Trial: Factoids

• Non-significant Non-significant increasedincreased risk for prostate cancer in risk for prostate cancer in vitamin E vs. placebovitamin E vs. placebo

• Planned for 7 years, stopped early (“no possibility of Planned for 7 years, stopped early (“no possibility of benefit to planned degree”)benefit to planned degree”)

• No benefit for other cancer endpointsNo benefit for other cancer endpoints

• Interesting discussion (see Comments) of potential Interesting discussion (see Comments) of potential explanations of discrepancy with earlier resultsexplanations of discrepancy with earlier results

• Lots of other examples of “popular” treatments proven not Lots of other examples of “popular” treatments proven not beneficial or harmful in RCT’sbeneficial or harmful in RCT’s

•

SELECT + PH 2 Trials: Impact on patient SELECT + PH 2 Trials: Impact on patient care? Editorial in JAMA*care? Editorial in JAMA*

• Physicians should not recommend…Physicians should not recommend…vitamin e--or any other anti-oxidant vitamin e--or any other anti-oxidant supplements– to their patients”supplements– to their patients”

*JAMA, 1/7/09

Vitamin E, C and Selenium on Prostate Vitamin E, C and Selenium on Prostate Cancer in men (JAMA 1/09)Cancer in men (JAMA 1/09)

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

• Important therapeutic questionImportant therapeutic question

• Applies to 30 - 50 million women in USApplies to 30 - 50 million women in US

• Prempro Prempro (estrogen/progestin combo)(estrogen/progestin combo)may have been most prescribed drug in US in may have been most prescribed drug in US in 1990’s1990’s

• 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):Results from Results from ObservationalObservational Studies ~ 1996 Studies ~ 1996

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

1996: 100’s of observational studies with consistent results…. But no randomized trials at that timeBut no randomized trials at that time

1996: 100’s of observational studies with consistent results…. But no randomized trials at that timeBut no randomized trials at that time

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, adjusted for everything** Relative Risk (95% CI) compared to never users, adjusted for everything

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

As of 1997, virtually all estrogen results wereAs of 1997, virtually 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)

• First major RCT of estrogen (started 1992)First major RCT of estrogen (started 1992)

• 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 disease~ 2763 women with established heart disease

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

• 20 clinical centers in U.S./UCSF Coord center20 clinical centers in U.S./UCSF Coord center

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

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

HERS major outcome: No effect of HRT on heart HERS major outcome: No effect of HRT on heart disease (among women with existing CHD)disease (among women with existing CHD)

EndpointEndpoint PlaceboPlacebo HRTHRT RRRR PP

New CHDNew CHD 176176 172172 0.990.990.910.91

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

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

• Randomized trial (2) in wide range of women (w and Randomized trial (2) in wide range of women (w and w/o CHD)w/o CHD)

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

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

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

• Represent broad range of U.S. women, 40 centersRepresent broad range of U.S. women, 40 centers

• Follow-up planned for 8.5 years, to end in 2005Follow-up planned for 8.5 years, to end in 2005

* * only one component of WHI..more lateronly one component of WHI..more later

WHI E + P (stopped early 7/02): WHI E + P (stopped early 7/02): CHD 29% CHD 29% increaseincrease with HRT with HRT

years 1 2 3 4 5 6

HERS/WHI Trials: Take Home HERS/WHI Trials: Take Home messagemessage

• RCT’s can give definitive answers to clinical questionsRCT’s can give definitive answers to clinical questions

– HRT use has dramatically declinedHRT use has dramatically declined

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

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

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

• Take homeTake home

– Confounders (known + unknown) are impossible to fully Confounders (known + unknown) are impossible to fully identify and control for in non-randomized studiesidentify and control for in non-randomized studies

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

• RCT’s can give definitive answers to clinical RCT’s can give definitive answers to clinical questionsquestions

– HRT use has dramatically declinedHRT use has dramatically declined

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

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

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

• Take homeTake home

– Confounders (known + unknown) are Confounders (known + unknown) are impossible to fully identify and control for in impossible to fully identify and control for in non-randomized studiesnon-randomized studies

HRTHRT* Sort of* Sort of

“Epidemiology—Is It Time to Call It a Day? --Editors of The International Journal of Epi

Many non-drug trials…Many non-drug trials…

• Dietary InterventionDietary Intervention

• Surgical techniquesSurgical techniques

• Behavioral InterventionBehavioral Intervention

What to eat this morning?What to eat this morning?

Vs.Vs.Vs.Vs. VsVs..

Want to make an evidence-based decision..

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

• Compare 4 dietsCompare 4 diets

1. Atkins (low carbohydrate)1. Atkins (low carbohydrate)

2. Weight Watchers (low calorie/portion size)2. Weight Watchers (low calorie/portion size)

3. Zone (high protein/low-glycemic load)3. Zone (high protein/low-glycemic load)

4. Ornish (very low fat)4. 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

Small study, continuous endpointsSmall study, continuous endpoints

Diet study: SummaryDiet study: Summary

• All diets led to modest reductions in weight

and cardiac risk factors

• Poor compliance for all diets, especially

Atkins and Ornish

– Those who adhered well had better results

JAMA 1/5/05

Examples of major positive Examples of major positive breakthroughs from RCTsbreakthroughs from RCTs

• Protease inhibitors and AIDSProtease inhibitors and AIDS

• Aspirin and heart diseaseAspirin and heart disease

• Lipid lowering (statins) and heart diseaseLipid lowering (statins) and heart disease

• Bisphosphonates and fracture riskBisphosphonates and fracture risk

Many examples of trials with huge impact on Many examples of trials with huge impact on clinical practice and public healthclinical practice and public health

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)

*Hulley et al, Designing Clinical Research*Hulley et al, Designing Clinical Research

1. Randomization1. Randomization

RandomizationRandomization

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

• Assure equal distribution of both...Assure 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

RandomizationRandomizationWant balance in “Table 1”

Want balance in “Table 1”

Lippman et. al

Lippman et. al

Randomization:Randomization:The BasicsThe Basics

Cannot assure equal numbers per group or balance

Cannot assure equal numbers per group or balance

Randomized Permuted BlocksRandomized Permuted Blocks

• Blocking: equal after each 4 (or n) assignmentsBlocking: equal after each 4 (or 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 each Assure relatively equal number of ppts. to each treatment treatment

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

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

– Very commonly usedVery commonly used

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., Prostate cancer (PSA e.g., Prostate cancer (PSA << 5 vs. PSA > 5) 5 vs. PSA > 5)

– StratumStratum

PSA < 5: aabb baba …PSA < 5: aabb baba …

PSA > 5: baab abab ….PSA > 5: 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

• Probability of assignment to each Probability of assignment to each treatment depends on previous treatment depends on previous randomizationsrandomizations

Implementation of randomizationImplementation of randomization

• Less challenging for blinded studiesLess challenging for blinded studies

– 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

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

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

– Problem with randomized blocksProblem with randomized blocks

#001 #002

#003

Randomization: SummaryRandomization: Summary

• Key element of clinical trials (Rct’s)Key element of clinical trials (Rct’s)

– Insure balance for all factors at Insure balance for all factors at baselinebaseline

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

2. Selection of Patients2. Selection of Patients

Who to Study: Who to Study: Factors to Consider for Inclusion/exclusionFactors to Consider 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 (eg. CHD study): Who to Study (eg. CHD study): Principles for Inclusion/exclusionPrinciples for Inclusion/exclusion

Broad eligibility ------------------- Narrow elig.Broad eligibility ------------------- Narrow elig.

eg.eg. men or women >50men or women >50 men > 70men > 70

Generalizability:Generalizability: wide wide narrownarrow

Recruitment:Recruitment: easy easy difficultdifficult

Sample size:Sample size: large large small small

Valid reasons to exclude participantsValid reasons to exclude participants (Table 10.1, Hulley et. al.) (Table 10.1, Hulley et. al.)

• 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 treatmentCompeting/interfering treatment

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

• Practical problemsPractical problems

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

• Study HRT and prevention of heart disease, 4 yearsStudy HRT and prevention of heart disease, 4 years

– Women over age 50 years (WHI)Women over age 50 years (WHI)

– Women over 60 yearsWomen over 60 years

– Women over 75 yearsWomen over 75 years

– Women with existing heart disease (HERS)Women with existing heart disease (HERS)

• 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)

??

HRT Trial: sample size considerationsHRT Trial: sample size considerations

• HRT trial options (event rate)HRT trial options (event rate)

A. Women over age 50 years (0.1%/year)A. Women over age 50 years (0.1%/year)

B. Women over 60 years (0.5%/year)B. Women over 60 years (0.5%/year)

C. Women over 75 years (1%/year)C. Women over 75 years (1%/year)

D. Women with existing heart disease D. Women with existing heart disease (4%/year)(4%/year)

What sample size is required to reduce these What sample size is required to reduce these risks by 40%?risks by 40%?

??

HRT study inclusion optionsHRT study inclusion options

• HRT trial options (event rate) HRT trial options (event rate) [n required][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) Women over 60 years (0.5%/year) [45,000][45,000]

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

–Women with existing heart disease Women with existing heart disease

(4%/year) (4%/year) [3,000][3,000]

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

• Typically written as “inclusion/exclusion” Typically written as “inclusion/exclusion” criteria in protocolcriteria in protocol

• The more explicit the betterThe 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

- Women with heart disease - Women with heart disease (not very (not very specific)specific) vs. vs.

- Women with CABG surgery or documented - Women with CABG surgery or documented MI by ecg (criteria) or enzymes (criteria)MI by ecg (criteria) or enzymes (criteria)

Example: ProtocolExample: ProtocolPTH and alendronate (PaTH) in combination for the PTH and alendronate (PaTH) in combination for the

treatment of osteoporosistreatment of osteoporosis

3.6.1 3.6.1 Inclusion CriteriaInclusion Criteria

Women aged between 55 and 85 years of age.Women aged between 55 and 85 years of age.

Who are post-menopausal (have not had any menses in the last 5 years).Who are post-menopausal (have not had any menses in the last 5 years).

Have an evaluable bone mineral density scan (DXA) at the spine AND at the hip with a T-score Have an evaluable bone mineral density scan (DXA) at the spine AND at the hip with a T-score << -2.5 either at -2.5 either at the spine or the femoral neck or total hip the spine or the femoral neck or total hip

OR have a T-score OR have a T-score << –2.0 with at least one of the following risk factors for fracture: –2.0 with at least one of the following risk factors for fracture:

Age Age 65 years 65 years

History of post-menopausal fracture (non-vertebral or vertebral)History of post-menopausal fracture (non-vertebral or vertebral)

Maternal history of hip fracture.Maternal history of hip fracture.

Be willing and able to self-administer daily injections. ETCBe willing and able to self-administer daily injections. ETC

Example: ProtocolExample: ProtocolPTH and alendronate (PaTH) in combination for the PTH and alendronate (PaTH) in combination for the

treatment of osteoporosistreatment of osteoporosis• 3.6.2 3.6.2 Exclusion CriteriaExclusion Criteria• Have used estrogen (oral or patch) more than one month in the last 6 months or for more than 12 months in the last 2 years. Have used estrogen (oral or patch) more than one month in the last 6 months or for more than 12 months in the last 2 years.

• Have a history of more than 12 months of bisphosphonate use ever, or any use (> 4 weeks) within the past 12 months.Have a history of more than 12 months of bisphosphonate use ever, or any use (> 4 weeks) within the past 12 months.

• Have a history of rhPTH use ever.Have a history of rhPTH use ever.

• Have any major life-threatening illnesses.Have any major life-threatening illnesses.

• Have type 1 or uncontrolled type 2 diabetes mellitus (defined as hemoglobin A1C > 10.0), or currently using insulin.Have type 1 or uncontrolled type 2 diabetes mellitus (defined as hemoglobin A1C > 10.0), or currently using insulin.

• Have Vitamin D level < 15 nanograms /ml.Have Vitamin D level < 15 nanograms /ml.

• Have any history of kidney disease (creatinine > 2.0 mg/dl).Have any history of kidney disease (creatinine > 2.0 mg/dl).

• Have renal insufficiency (creatinine clearance < 40 mg/min).Have renal insufficiency (creatinine clearance < 40 mg/min).

• Have any history of kidney stones.Have any history of kidney stones.

• Have any history of hypercalcuria or currently have urine calcium/creatinine >300 mg.Have any history of hypercalcuria or currently have urine calcium/creatinine >300 mg.

• Have any history of hypercalcemia.Have any history of hypercalcemia.

• Have any history of sarcoidosis.Have any history of sarcoidosis.

• Have any history of hyperparathyroidism.Have any history of hyperparathyroidism.

• Have any history of active or treated tuberculosis or other granulomatous disorders.Have any history of active or treated tuberculosis or other granulomatous disorders.

• History of breast cancer, melanoma or hematologic malignancy which has required treatment within the last 10 years.History of breast cancer, melanoma or hematologic malignancy which has required treatment within the last 10 years.

• History of bone cancer or any other metabolic bone disease which has required treatment within the last 10 years.History of bone cancer or any other metabolic bone disease which has required treatment within the last 10 years.

• History of any other non-skin cancer which has required treatment within the last 10 years.History of any other non-skin cancer which has required treatment within the last 10 years.

• Have a documented history of symptomatic esophageal reflux, achalasia or esophageal stricture.Have a documented history of symptomatic esophageal reflux, achalasia or esophageal stricture.

• Be currently taking > 7.5 mg systemic prednisone or equivalent per day.Be currently taking > 7.5 mg systemic prednisone or equivalent per day.

• Be currently using > 2 puffs, 4 times / day of inhaled steroids.Be currently using > 2 puffs, 4 times / day of inhaled steroids.

• Be currently taking anticoagulants.Be currently taking anticoagulants.

• Be currently taking anticonvulsants( MORE)Be currently taking anticonvulsants( MORE)

• Have used Calcitonin within the past 3 months.Have used Calcitonin within the past 3 months.

• Have used Raloxifene in the last 6 months or for more than 12 months in the last 2 years.Have used Raloxifene in the last 6 months or for more than 12 months in the last 2 years.

• Have used Tamoxifen in the last 6 months or for more than 12 months in the last 2 years.Have used Tamoxifen in the last 6 months or for more than 12 months in the last 2 years.

• Have used fluoride for at least a month within the past 5 years.Have used fluoride for at least a month within the past 5 years.

• Be currently taking > 1000 IU/day Vitamin D or Vitamin D analogues or metabolites.Be currently taking > 1000 IU/day Vitamin D or Vitamin D analogues or metabolites.

• Be currently taking thyroid hormone replacement AND have a TSH < 0.1mIU/L.Be currently taking thyroid hormone replacement AND have a TSH < 0.1mIU/L.

Inclusion, Exclusion: SummaryInclusion, Exclusion: Summary

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

• Inclusion/exclusion criteria should be Inclusion/exclusion criteria should be clear and explicitclear and explicit

• Generally not a clear cut or single Generally not a clear cut or single correct decisioncorrect decision– Many people don’t appreciate the Many people don’t appreciate the

complexity of issuescomplexity of issues

3. Alternative Designs for RCT’s3. Alternative Designs for RCT’s

Alternative designs for RCT’s:Alternative designs for RCT’s:Quick surveyQuick survey

• Large, simple trialsLarge, simple trials

• Factorial designsFactorial designs

• Cross-over designsCross-over designs

• Matched pair designsMatched pair designs

• Cluster randomizationCluster randomization

Alternative RCT designs: Alternative RCT designs: “Large-simple” vs. standard“Large-simple” vs. standard

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

• 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

– Low cost per patientLow cost per patient

– Examples:Examples:

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

• Trials of vitamin D for fractures: 3000 patients recruited by mail/drug by mail/etc.

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 trial, efficientAllows multiple hypotheses in single trial, efficient

• ExamplesExamples

– Vitamin E and SeleniumVitamin E and Selenium

–Physician’s Health StudyPhysician’s Health Study

• Test aspirin ==> MI • beta carotene ==> cancer

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

PlaceboPlacebo

AspirinAspirin

Beta-Beta-carotenecarotene

Aspirin plusAspirin plus


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


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

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

HRT vs. no HRT vs. no HRT (CHD)HRT (CHD)

Low fat vs. regular Low fat vs. regular diet (breast cancer)diet (breast cancer)

Calcium vs. no

Calcium vs. no

calcium

calcium (fracture)

(fracture)

Physician’s Health II studyPhysician’s Health II study(Gaziano) (JAMA, 1/7/09)(Gaziano) (JAMA, 1/7/09)

PlaceboPlacebo

Vit. CVit. C

Vitamin EVitamin E

Vitamin E + Vitamin E +

Vitamin CVitamin C

Vitamin C Vitamin C vs. no vs. no Vitamin CVitamin C



Nerdy 2012 read of Nerdy 2012 read of methods: methods:

2 x 2 x 2 x 2 factorial2 x 2 x 2 x 2 factorial

3.3. Beta Carotene Beta Carotene

4.4. Multi-vitaminMulti-vitamin

Factorial design issuesFactorial design issues

• Do treatments Do treatments interactinteract??

– (WHI) Is calcium’s effect on fracture the same in those (WHI) Is calcium’s effect on fracture the same in those taking vs. not taking HRT?taking vs. not taking HRT?

• HRT 40% reduction

• Calcium 30% reduction

• HRT + Calcium= 70% reduction (additive)

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

– If present, power is lower: large sample requiredIf present, power is lower: large sample required

• May require more complicated stopping rulesMay require more complicated stopping rules

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

Physician’s Heath Study—Physician’s Heath Study—Interaction unlikelyInteraction unlikely

PlaceboPlacebo

AspirinAspirin


Aspirin plusAspirin plus




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

Factorial design conclusionsFactorial design conclusions

• Factorial designs are seductive but Factorial designs are seductive but complicated complicated

• 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 Diuretic vs. beta blocker for blood pressurepressure

– 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

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

Treatment BTreatment A

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

• Efficient design in some situationsEfficient design in some situations

• 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

–Cities to public health risk factor reduction Cities to public health risk factor reduction (5 Cities Project, 1970’s)(5 Cities Project, 1970’s)

–Medical practices to stop-smoking Medical practices to stop-smoking intervention (randomize med. prac.)intervention (randomize med. prac.)

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


• 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 complex but do-ableAnalysis complex but do-able–Must account for clusteringMust account for clustering–Mixed models bestMixed models best

• Very useful and underused designVery useful and underused design

• See you next week…See you next week…

controlled clinical trials 9 sessions9 sessions grady (course director), black (lecturer), cummings...

Documents

randomized clinical

number of randomized

tape slide

formulated slide

controlled clinical

group randomization

black lecturer

answer keys