1 Case Studies in Prevention Trial Design Deborah Donnell, PhD SCHARP Vaccine and Infectious Disease Institute Fred Hutchinson Cancer Research Center

1

Case Studies in Prevention Trial Case Studies in Prevention Trial DesignDesign

Case Studies in Prevention Trial Case Studies in Prevention Trial DesignDesign

Deborah Donnell, PhDDeborah Donnell, PhD

SCHARPSCHARP

Vaccine and Infectious Disease InstituteVaccine and Infectious Disease Institute

Fred Hutchinson Cancer Research CenterFred Hutchinson Cancer Research Center

2

Case StudiesCase StudiesCase StudiesCase Studies

HPTN035 – Microbicide 4 armHPTN035 – Microbicide 4 arm

HPTN039 – HSV-2 AcyclovirHPTN039 – HSV-2 Acyclovir

HPTN052 – Discordant couples HAART HPTN052 – Discordant couples HAART

HPTN058 – IDU treatment SuboxoneHPTN058 – IDU treatment Suboxone

Tom Fleming – Tom Fleming – University of WashingtonUniversity of Washington

Jim Hughes – Jim Hughes – University of WashingtonUniversity of Washington

Barbra Richardson – Barbra Richardson – University of WashingtonUniversity of Washington

Ben MBen Mââsse – sse – FHCRCFHCRC

Ying Chen - Ying Chen - FHCRCFHCRC

3

“How can we be so different and feel so much alike?” mused Flitter“And how can we feel so different and be so much alike?” wondered Pip.

4

Selection criteriaSelection criteriaSelection criteriaSelection criteria

Randomized Clinical TrialsRandomized Clinical Trials

HIV seroconversion endpointHIV seroconversion endpoint

Approved and in the fieldApproved and in the field

Biomedical interventionsBiomedical interventions

Long-term adherence for on-going riskLong-term adherence for on-going risk

5

HPTN035: Microbicide TrialHPTN035: Microbicide TrialHPTN035: Microbicide TrialHPTN035: Microbicide Trial

Population: Women at sexual risk for HIVPopulation: Women at sexual risk for HIV

4 arms: gel arms blinded4 arms: gel arms blinded

ActiveActive InactiveInactive

Arm 1: Pro 2000Arm 1: Pro 2000 Arm 3: Placebo GelArm 3: Placebo Gel

vs.vs.

Arm 2: BufferGelArm 2: BufferGel Arm 4: Condom Only Arm 4: Condom Only

Intended Mechanism: Intended Mechanism:

Microbicide = “Kill the microbe”Microbicide = “Kill the microbe”

Protect/enhance natural defensesProtect/enhance natural defenses

Hypothesis: Hypothesis:

Active vs. Placebo Gel reduces HIV infection by 33%Active vs. Placebo Gel reduces HIV infection by 33%

Active Gel vs. condom only reduces HIV infection by 33%Active Gel vs. condom only reduces HIV infection by 33%

6

HPTN039 : Acyclovir to prevent HPTN039 : Acyclovir to prevent HIV acquisitionHIV acquisition

HPTN039 : Acyclovir to prevent HPTN039 : Acyclovir to prevent HIV acquisitionHIV acquisition

Population:Population:

HSV-2+, HIV uninfectedHSV-2+, HIV uninfected

Women (in Southern Africa)Women (in Southern Africa)

MSM (in Americas)MSM (in Americas)

Two arms, double blindedTwo arms, double blinded

Arm1: Acyclovir twice daily Arm1: Acyclovir twice daily

Arm 2: Placebo twice dailyArm 2: Placebo twice daily

Intended mechanism:Intended mechanism:

HSV-2 a suspected cofactor in HIV acquisitionHSV-2 a suspected cofactor in HIV acquisition

Daily Acyclovir reduces herpes activation Daily Acyclovir reduces herpes activation

reduced lesions and/or lymphocyte activationreduced lesions and/or lymphocyte activation

reducing risk of HIV acquisitionreducing risk of HIV acquisition


Daily Acyclovir will reduce HIV acquisition by 50%Daily Acyclovir will reduce HIV acquisition by 50%

7

HPTN052: Delayed vs. HPTN052: Delayed vs. Immediate HAART in Discordant Immediate HAART in Discordant

CouplesCouples

HPTN052: Delayed vs. HPTN052: Delayed vs. Immediate HAART in Discordant Immediate HAART in Discordant

CouplesCouplesPopulation: Population:

Discordant couples (index HIV infected; partner HIV uninfected) with Discordant couples (index HIV infected; partner HIV uninfected) with CD4 350-550 in indexCD4 350-550 in index

Two arm; unblindedTwo arm; unblinded

Arm 1: Immediate HAART for indexArm 1: Immediate HAART for index

Arm 2: HAART initiated when clinically indicated for indexArm 2: HAART initiated when clinically indicated for index

Mechanism: Immediate therapyMechanism: Immediate therapyPotential benefitsPotential benefits

Partner: Lower risk of early transmissionPartner: Lower risk of early transmissionIndex : More sustained virologic response Index : More sustained virologic response

Lower risk of irreversible CD4 dropLower risk of irreversible CD4 drop


Index on immediate vs. delayed strategy reduces HIV transmission to Index on immediate vs. delayed strategy reduces HIV transmission to partner by 37%.partner by 37%.

Potential risksPotential risks Partner : Transmission of resistant virusPartner : Transmission of resistant virus Index : Longer course of ART may Index : Longer course of ART may

reduce treatment optionsreduce treatment options Poorer adherence/high resistancePoorer adherence/high resistance

8

HPTN058: Suboxone treatment HPTN058: Suboxone treatment in in

opiate injectorsopiate injectors

HPTN058: Suboxone treatment HPTN058: Suboxone treatment in in

opiate injectorsopiate injectorsTargeted population: Targeted population:

Active opiate injectors (China and Thailand)Active opiate injectors (China and Thailand)

Two arm, unblindedTwo arm, unblinded

Arm 1: One year of Suboxone substitution therapyArm 1: One year of Suboxone substitution therapy

+ one year counseling support+ one year counseling support

Arm 2: Suboxone detoxification Arm 2: Suboxone detoxification

+ one year counseling support + one year counseling support

Intended Mechanism: Biomedical + Behavioral Intended Mechanism: Biomedical + Behavioral

Biomedical support for cessation of injection drug useBiomedical support for cessation of injection drug use

Counseling support for long term behavior changeCounseling support for long term behavior change

Hypothesis:Hypothesis:

One year of Suboxone treatment and counseling will reduce death One year of Suboxone treatment and counseling will reduce death and HIV infection rate at 2 years by 42%and HIV infection rate at 2 years by 42%

9

ComparisonsComparisonsComparisonsComparisons

1.1. Proof of Concept vs. Efficacy trialProof of Concept vs. Efficacy trial

2.2. Effect sizeEffect size

3.3. Adherence requirementsAdherence requirements

4.4. Durability of effectDurability of effect

10

Proof of Concept vs Effectiveness Proof of Concept vs Effectiveness

(aka Phase IIb vs Phase III)(aka Phase IIb vs Phase III)

Proof of Concept vs Effectiveness Proof of Concept vs Effectiveness

(aka Phase IIb vs Phase III)(aka Phase IIb vs Phase III)

HPTN035 – Microbicide HPTN035 – Microbicide Phase II/IIb Phase II/IIb ?? ? ?

HPTN039 – Acyclovir HPTN039 – Acyclovir Phase III Phase III 90%90% 2.5% 2.5%

HPTN052 – HAART strategyHPTN052 – HAART strategy Phase III Phase III 90 %90 % 2.5% 2.5%

HPTN058 – Suboxone for IDUHPTN058 – Suboxone for IDU Phase III Phase III 90%90% 2.5% 2.5%

Power Size

11

What is a Phase IIb design, anyway, What is a Phase IIb design, anyway, and when would you use it?and when would you use it?

12

Goal of a clinical trialGoal of a clinical trialGoal of a clinical trialGoal of a clinical trial

Obtain a reliable answer to a clinically relevant Obtain a reliable answer to a clinically relevant questionquestion

Clinically relevant improvement in clinically relevant Clinically relevant improvement in clinically relevant endpointendpoint

Definitive (Phase III) Definitive (Phase III)

vs. vs.

Proof of concept (Phase IIb)Proof of concept (Phase IIb)

13

Phase III

0% 33%

15

Phase IIIPhase III

0% 33% 22%

10%10%

256 endpoints

2.5%

16

Why consider a Phase IIb ?Why consider a Phase IIb ?Why consider a Phase IIb ?Why consider a Phase IIb ?

No reliable information about efficacy No reliable information about efficacy

risk of taking too long, risk of taking too long,

using too many resources on something that may not work, using too many resources on something that may not work, or something in early development: or something in early development:

……take a two step approach to establish proof of concepttake a two step approach to establish proof of concept

Phase IIb questions: Phase IIb questions:

1.1. Does this look like it might work? Does this look like it might work?

2.2. Does this not work at all ? Does this not work at all ?

3.3. Does this work better than we hoped?Does this work better than we hoped?

17

Phase IIIPhase III

Phase IIbPhase IIb

0%

0%

15%

33% 22%

33%

Fleming TR, Richardson BA, JID 2004.

256 endpoints

96 endpoints

18

Phase IIIPhase III

Phase IIbPhase IIb

0%

0%

15%

33% 22%

33% 52%

12%

20%

256 endpoints

96 endpoints

10%2.5%

19

Phase IIIPhase III

Phase IIbPhase IIb

0%

0%

15%

33% 22%

33% 52%

256 endpoints

96 endpoints

10%2.5%

10%2.5%

20

Phase IIIPhase III

Phase IIbPhase IIb

0%

0%

15%

33% 22%

33% 52%

256 endpoints

96 endpoints

21

Factors in play for Phase IIb vs. Factors in play for Phase IIb vs. Phase III: Risk and ResourcesPhase III: Risk and Resources

Factors in play for Phase IIb vs. Factors in play for Phase IIb vs. Phase III: Risk and ResourcesPhase III: Risk and Resources

Maturity/Definitiveness of the intervention and its intended Maturity/Definitiveness of the intervention and its intended mechanismmechanism

Microbicide vs. Acyclovir; Suboxone; HAARTMicrobicide vs. Acyclovir; Suboxone; HAART

State of results in the fieldState of results in the field

Success in other settings: perinatal vs. microbicidesSuccess in other settings: perinatal vs. microbicides

Effectiveness on intended mediators; surrogatesEffectiveness on intended mediators; surrogates

Concurrent trialsConcurrent trials

ResourcesResources

Participants, staff and money to conduct a high quality trialParticipants, staff and money to conduct a high quality trial

23






24

Targeted Effectiveness in HIV Targeted Effectiveness in HIV PreventionPrevention


HPTN035 – Microbicide 33% vs. 0%

Phase II/IIb

HPTN039 – Acyclovir 49% vs. 0%

Phase III

HPTN052 – HAART strategy 37% vs. 0%

Phase III

HPTN058 – Suboxone for IDU 42% vs.

0% Phase III

3100 96

[256]

3300 93

1750 cpls ~188

1500 ~132

Number of Number of peoplepeople

Number Number of Eventsof Events

Targeted Targeted EffectivenessEffectiveness

25


What is plausible ?What is plausible ?


What is plausible ?What is plausible ?HPTN035 – Microbicide 33% vs. 0%

Phase II/IIb

HPTN039 – Acyclovir 49% vs. 0%

Phase III

HPTN052 – HAART strategy 37% vs. 0%

Phase III

HPTN058 – Suboxone for IDU 42% vs. 0% Phase III

No evidence of efficacy Time off drug in pregnancy

Condom use and adherence

Highly effective in treating HSV2 Time off drug in pregnancy

Proven to reduce viral loadConcept proven in perinatal trials

Crossover to HAART

Effective in treating opiate dependence HIV: 50% reduction

Death: 25% effective reduction

Targeted Effectiveness

26


Is it relevant for implementation?Is it relevant for implementation?


Is it relevant for implementation?Is it relevant for implementation?

HPTN035 – Microbicide 33%

Phase II/IIb

HPTN039 – Acyclovir 49%

Phase III

HPTN052 – HAART strategy 37% Phase III

HPTN058 – Suboxone for IDU 42%

Phase III

Low cost, low tech, low risk

Woman controlled

Low cost

Lifetime prophylaxis

High cost/infrastructure needs

Significant side effects

High cost/infrastructure needs

Targeted Targeted EffectivenessEffectiveness

27






28

Burden of Adherence Burden of Adherence Burden of Adherence Burden of Adherence

HPTN035 – Microbicide

Phase II/IIb

HPTN039 – Acyclovir

Phase III

HPTN052 – HAART strategy

Phase III

HPTN058 – Suboxone for IDU Phase III

With each sex act 12 – 30 mo

Twice daily pill 12 – 18 mo

Daily HAART regimen 5 – 7 yrs

Three times/week (DOT) 1 yr

DurationDurationAdherenceAdherence

29

Best Achievable Adherence for Best Achievable Adherence for EffectivenessEffectiveness

Best Achievable Adherence for Best Achievable Adherence for EffectivenessEffectiveness


Phase II/IIb


Phase III


Phase III


With each sex act 83-85% adherence83-85% adherence

87-92% 87-92% retentionretention

Twice daily pill 90-95% 90-95% adherenceadherence

91-96% 91-96% retentionretention

Daily HAART regimen NA

Three times/week (DOT) NA

Self reported Self reported AdherenceAdherence

Targeted Targeted AdherenceAdherence

30

Effectiveness vs. EfficacyEffectiveness vs. Efficacy(a.k.a. “Intent to Treat”(ITT) vs. “Per Protocol” (a.k.a. “Intent to Treat”(ITT) vs. “Per Protocol”

(PP))(PP))

Effectiveness vs. EfficacyEffectiveness vs. Efficacy(a.k.a. “Intent to Treat”(ITT) vs. “Per Protocol” (a.k.a. “Intent to Treat”(ITT) vs. “Per Protocol”

(PP))(PP))Biological efficacy (Theoretical: Does the intended Biological efficacy (Theoretical: Does the intended mechanism, when delivered, work?) mechanism, when delivered, work?)

vs. vs.

Effectiveness (Does the intervention, with best Effectiveness (Does the intervention, with best achievable adherence, as delivered in clinical trial, achievable adherence, as delivered in clinical trial, work?) work?)

vs. vs.

Implemented (Real world: Does the intervention, when Implemented (Real world: Does the intervention, when made available to people, work)made available to people, work)

31

Illustration: MicrobicidesIllustration: MicrobicidesIllustration: MicrobicidesIllustration: Microbicides

Biological Efficacy: Biological Efficacy:

Unprotected vaginal sex with HIV infected manUnprotected vaginal sex with HIV infected man

Biological Efficacy (“Per protocol”) Biological Efficacy (“Per protocol”)

Woman supplied with gel, with monthly counseling support Woman supplied with gel, with monthly counseling support for use of condoms and gel, who uses gel consistentlyfor use of condoms and gel, who uses gel consistently..

Effectiveness (ITT)Effectiveness (ITT)

Woman offered an ongoing supply of gel, with monthly Woman offered an ongoing supply of gel, with monthly counseling support for use of condoms and gel.counseling support for use of condoms and gel.

32

Randomization and Randomization and EffectivenessEffectiveness

Randomization and Randomization and EffectivenessEffectiveness

Randomized trials are the gold standard for objective evidence

Effectiveness is the most relevant prevention measure

Treatment

Placebo

Balanced in Risk factors: measured

and unmeasured

R

33

Post-Randomization Selection Post-Randomization Selection BiasBias

Post-Randomization Selection Post-Randomization Selection BiasBias

Treatment

Placebo

Adherent

Risk factors: measured

and unmeasured

Treatment

Placebo

Treatment

Placebo

Non-Adhere

nt

R

35

Examples of ITT vs. Examples of ITT vs. Per Protocol analysisPer Protocol analysisExamples of ITT vs. Examples of ITT vs. Per Protocol analysisPer Protocol analysis

MIRA (July 2007)MIRA (July 2007)

Intent to treat: Intent to treat: RR = 1.05 (RR = 1.05 (CI: 0.84, 1.32)0.84, 1.32)

Per-protocol (last sex act): Per-protocol (last sex act): RR = 0.90 (RR = 0.90 (CI: 0.68, 1.17)0.68, 1.17)

Per-protocol (consistent use): Per-protocol (consistent use): RR = 0.83 (RR = 0.83 (CI: 0.61,1.14)0.61,1.14)

Acyclovir trial in Mwanza (Aug 2007)Acyclovir trial in Mwanza (Aug 2007)

Intent to treatIntent to treat RR = 1.02RR = 1.02

P-P (Pregnancy censored)P-P (Pregnancy censored) RR = 1.08 (CI: 0.64-1.83)RR = 1.08 (CI: 0.64-1.83)

P-P (90% adherent) P-P (90% adherent) RR = 0.58 (CI: 0.25-1.38) RR = 0.58 (CI: 0.25-1.38)

STEP trial (Nov 2007)STEP trial (Nov 2007)

ITT: Vaccine vs. PlaceboITT: Vaccine vs. Placebo 24 vs. 2124 vs. 21

Per-protocol: Per-protocol: 19 vs. 1119 vs. 11

36






37

Targeted Duration for Targeted Duration for EffectivenessEffectiveness

Targeted Duration for Targeted Duration for EffectivenessEffectiveness


Phase II/IIb


Phase III


Phase III


With each sex act 12-30 mo

Twice daily pill 12-18 mo

Daily HAART regimen 5-7yrs

Three times/week (DOT) 1yr

DurationDurationTargeted Targeted AdherenceAdherence

38

HPTN035Microbicide

HPTN039 Acyclovir

HPTN052HAART strategy

HPTN058Suboxone IDU

Years

0 1 2 3 4 5 6 7

0 1 2 3 4 5 6 7

0 1 2 3 4 5 6 7

0 1 2 3 4 5 6 7

39

Duration of effectDuration of effectDuration of effectDuration of effect

Survival design maxim of “fixed number of events”

88 events: mean 3.3 years with 300 people

88 events: mean 1 year with 1000 people

Equivalent assuming proportional hazards

Inherent in design

Longevity of effect

Estimate effect is “average” reduction in infection (weighted by time on study)

Real world vs. Clinical trial setting

Intended use

Associated safety data

Adherence over time

Retention

40

Non-proportional Hazard Non-proportional Hazard DesignsDesigns

Non-proportional Hazard Non-proportional Hazard DesignsDesigns

HPTN052 – HAART strategyHPTN052 – HAART strategy

Immediate strategy likely to have early advantage; Immediate strategy likely to have early advantage;

Delayed strategy may defray this with better viral control from Delayed strategy may defray this with better viral control from conserved treatment options;conserved treatment options;

Delayed strategy may be “almost as good” as immediate for Delayed strategy may be “almost as good” as immediate for preventing transmission over 5-7 yearspreventing transmission over 5-7 years

Trial designed with long follow-up, i.e. estimate decreased HR over 5-7 Trial designed with long follow-up, i.e. estimate decreased HR over 5-7 years, to deliberately average out the early effectyears, to deliberately average out the early effect

HPTN058 – IDU SuboxoneHPTN058 – IDU Suboxone

Likely early advantage while on suboxone (up to 1 year); Likely early advantage while on suboxone (up to 1 year); potentially defrayed when suboxone removedpotentially defrayed when suboxone removed

Trial assesses difference in cumulative survival at 2 yearsTrial assesses difference in cumulative survival at 2 years

Interim monitoring requires special attentionInterim monitoring requires special attention

42

ConclusionConclusionConclusionConclusion

Trial design requires good collaborationTrial design requires good collaboration

Determining design parameters: effectiveness, duration, endpoint Determining design parameters: effectiveness, duration, endpoint analysisanalysis

Resources are finite but we need definitive answersResources are finite but we need definitive answers

Givens:Givens:

Clinically relevant questionsClinically relevant questions

Definitive answersDefinitive answers

Role of adherence in achieving success requires ITTRole of adherence in achieving success requires ITT

VariablesVariables

Design depend on the prevention modalityDesign depend on the prevention modality

Strategies for advancing the science differ because of the scienceStrategies for advancing the science differ because of the science

Each prevention modality has its own idiomEach prevention modality has its own idiom

43

“How can we be so different and feel so much alike?” mused Flitter“And how can we feel so different and be so much alike?” wondered Pip.

“I wish you could see in the dark, too.”“We wish you could land on your feet,” Flitter replied.

Documents

1 Case Studies in Prevention Trial Design Deborah Donnell, PhD SCHARP Vaccine and Infectious Disease Institute Fred Hutchinson Cancer Research Center