Glenda Gray on behalf of HVTN 503

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					Update on the STEP (HVTN 502) trial and the
Phambili study (HVTN 503)



  Glenda Gray on behalf of HVTN 503
  Prepared for Ministry of Health, 14 Nov, 2007
                                 Outline

•   STEP & Phambili trial design (Glenda Gray)

•   An update on STEP data (Gavin Churchyard)

•   The rational for and steps taken to pause & unblind Phambili
    (Glenda Gray)

•   Interacting with the IRBS & Communities (Maphoshane
    Nchabeleng)

•   Assessing participant understanding of reasons for unblinding
    (Linda-Gail Bekker)

•   PAVE 100 (Koleka Mlisana)
•   The partners are Merck, HVTN, NIAID & SAAVI (503)
•   Performed phase 1 and 2 trials to evaluate safety and immunogenicity
    (collaboration with RSA began with epidemiological studies initiated more
    than 5 years ago)
•   HVTN 050 (gag only) phase I/II conducted in sites in Malawi and South
    Africa as part of a multi-country trial
•   Data supported launch of two phase 2B trials
     – STEP – HVTN and Merck sites, clade B
     – Phambili – HVTN sites, clade C
                Potential Differences between a phase IIB-
                  TOC and phase III pivotal trial design
Design considerations                     Phase IIB-TOC trial design                 Pivotal phase III trial design


Statistical power and sample size         Designed to be of sufficient size to       Designed to be of sufficient size such
                                          have a high statistical power (90%) to     that there is 90% chance that the
                                          reject the null hypothesis that VE=0%      lower 95% confidence bound on the
                                          (at p=0.05) if the true vaccine efficacy   VE will exceed 30% (or minimum
                                          is more than 50%                           level considered to be of clinical
                                                                                     importance) if the true VE is 60%or
                                                                                     more


                                          Prototype
Vaccine                                                                              Expected final product


                                          Narrow-optimized for sensitivity
Population                                                                           As representative as possible for
                                          relating to the primary endpoint
                                                                                     licensure


                                          HIV infection and surrogate of clinical
                                                                                     HIV infection and surrogate of clinical
Primary Endpoint                          outcome
                                                                                     outcome




                                    WHO/UNAIDS/IAVI International Expert Group, AIDS,
                                    2007
                       Phase IIB-TOC and Phase III pivotal trials

Trial           STEP (HVTN           HVTN 503            USMHRP RV-144        VaxGen 004         Vaxgen 003
                502/MRK023)          (Phambili)
                                                         IIB-TOC              Piv otal III       Piv otal III
                IIB-TOC              IIB-TOC
                                                         (USD60-88 million)
                (USD33million)       (USD33million)
                                                                              (USD78million)     (USD52million)


Vaccine         MRK ad5 trivalent    MRK ad5 trivalent   ALVAC v CP-1521      AIDSVAX B/B, rgp   AIDSVAX B/E, rgp
                (gag/pol/nef)                            and AIDSVAX B/E,     120 B/B            120 B/E
                                     (gag/pol/nef)
                                                         rgp120 B/E
                                                                              (gp120)            (gp120)
                                                         (gag/pro/env
                                                         +gp120)

Population      MSM,HW, USA,         HM, HW,             HM, HW               MSM,HW, USA,       IDU
                Caribean, Latin                                               Canada and the
                                     South Africa        Thailand                                Thailand
                America, Australia                                            Netherlands




HIV infection   100                  120                 129                  368                211
endpoints


Sample size     3000                 3000                16 000               5 400              2550




                                                               WHO/UNAIDS/IAVI International Expert Group, AIDS,
                                                               2007
             STEP TRIAL: Phase IIb
             HVTN 502 / Merck 023

Ad5 vector expressing 3 internal HIV genes
   gag, pol, nef (clade B)
N= 3000 volunteers (low and high Ad5 titers)
Population: MSM, HS
Primary Endpoints
   Safety
   Reduction in HIV-1 infection
  rate and/or viral load at
  3 months post-diagnosis
Initiated Dec 2004; fully enrolled Mar 2007
           Phambili: Phase IIb
           HVTN503
Same Ad5 vector expressing 3 internal HIV genes
  gag, pol, nef (clade B)
N= 3000 volunteers in 5 sites in RSA
Population: Heterosexual
  Depends on immunogenicity in first 600
Primary Endpoints
  Safety
  Reduction in HIV-1 infection rate and/or viral load at 3 months post-
  diagnosis
Initiated Jan 2007; 801 enrolled
        DSMB 18th Sep: Futility Declared in STEP Trial

• Pre-defined futility cutoffs met at first interim analysis

• The STEP DSMB recommended that

   – No further injections be administered in the trial

   – Volunteers be encouraged to return for all protocol visits and tests so
     that the investigators can fully evaluate whether there is an increased
     risk of infection in vaccine recipients over time

   – The trial Oversight Committee determine the appropriate steps and
     timing of release of trial results to volunteers, investigators, those
     conducting related trials, relevant agencies, and the public
19th September: Stopping the steam train




                   801 enrolled (45% female):
                   •   3 vaccinations: 58
                   •   2 vaccinations: 501
                   •   I vaccination: 215
                   Age range:
                   •   18-20yrs: 30%
                   •   21-30yrs: 60%
                   •   31-35: 10%

				
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