Protocol HVTN 505 Phase 2b, randomized, placebo-controlled test-of- concept trial to evaluate the safety and efficacy of a multiclade HIV-1 DNA plasmid vaccine followed by a multiclade HIV-1 recombinant adenoviral vector vaccine in HIV-uninfected, adenovirus type 5 neutralizing antibody negative, circumcised men and male-to-female (MTF) transgender persons, who have sex with men DAIDS Document ID 10753 BB IND 13971 held by DAIDS Clinical trial sponsored by Division of AIDS (DAIDS) National Institute of Allergy and Infectious Diseases (NIAID) National Institutes of Health (NIH) Department of Health and Human Services (DHHS) Bethesda, Maryland, USA Vaccine provided by Dale and Betty Bumpers Vaccine Research Center (VRC), NIAID, NIH Bethesda, Maryland, USA July 21, 2014 HVTN 505, Version 6.0 HVTN 505, Version 6.0 / July 21, 2014 At the first planned interim analysis for efficacy futility, conducted under Version 4 of the protocol on April 22, 2013, the DSMB recommended that the trial be stopped for efficacy futility. A total of 71 HIV infections had been diagnosed in the MITT cohort (41 among vaccine recipients, 30 among placebo recipients). Of these, 48 constituted primary endpoints (Week 28+ HIV infections diagnosed on or after Day 196 post-enrollment); 27 occurred among vaccine recipients and 21 among placebo recipients. There was no statistically significant difference in the rate of HIV infection between treatment arms, either in the Week 28+ cohort (estimated hazard ratio = 1.25; 95% CI: 0.71 to 2.20; p = 0.446) or in the MITT cohort (hazard ratio = 1.33; 95% CI: 0.83 to 2.13; p = 0.230). However, given that the number of HIV infections was larger in the vaccine arm, and given that there was a trend toward the hazard ratio increasing over time since enrollment (p = 0.09), the DSMB recommended, and the study team agreed, to continue to follow all participants beyond the Month 24 visit (the terminal visit in Version 4 of the protocol). Under Version 5 of the protocol, participants were followed post-unblinding to 48 months post-enrollment. Additional interim analyses were conducted at six-month intervals to evaluate the HIV-1 acquisition rate in the two treatment arms, and to evaluate conditional power to detect an increased rate of acquisition in the vaccine arm as compared to the placebo arm. At the second interim analysis, conducted on March 24, 2014 under Version 5 of the protocol, the study oversight group recommended that the protocol be revised to reduce the frequency of post-unblinding follow-up visits. A total of 109 HIV infections had been diagnosed in the MITT cohort to 48 months post-enrollment (53 among vaccine recipients and 56 among placebo recipients). There was no statistically significant difference in the rate of HIV-1 infection between treatment arms, either including all follow-up to 48 months post-enrollment (estimated hazard ratio = 0.92; 95% CI: 0.63 to 1.34; p = 0.65), or restricting follow-up to 24 months post- enrollment (estimated hazard ratio = 1.09; 95% CI: 0.72 to 1.66; p = 0.68). Given these data, there was very low power (< 1%) to detect an increased rate of HIV-1 infection in the vaccine vs. placebo arm, if the study were to continue following participants as specified under Version 5 of the protocol. As described in Sections 8.2 and 8.2.1, under Version 6 of the protocol participants will continue to be followed to 48 months post- enrollment, with an additional health contact at 60 months, but with study visits only annually following Month 24. The goal of this extended follow-up is to continue to monitor the rate of HIV-1 acquisition in the two treatment arms. To this end, the rate of study dropout will also continue to be evaluated in each treatment arm. The objectives of the study have been modified accordingly. Assessing the rates of study dropout and of HIV infection in the vaccine vs. placebo arms are now the primary objectives (see Section 5.2). Assessing the impact of vaccination on post-infection endpoints and on immunogenicity; assessing modification of vaccine effects by host immune genetic and other factors; and assessing immune correlates of risk are now exploratory objectives (see Section 5.4). HVTN505_v6.0_FINAL.docx / Page 2 of 112 HVTN 505, Version 6.0 / July 21, 2014 Contents 1 Ethical considerations .............................................................................................. 5 2 IRB/IEC review considerations ............................................................................... 7 2.1 Risks to participants ...................................................................................... 7 2.2 Risk/benefit balance ...................................................................................... 7 2.3 Subject selection ............................................................................................ 8 2.4 Informed consent ........................................................................................... 9 2.5 Safety monitoring .......................................................................................... 9 2.6 Privacy/confidentiality .................................................................................. 9 3 Overview ................................................................................................................ 11 3.1 Protocol Team ............................................................................................. 14 4 Background and rationale ...................................................................................... 15 4.1 HIV epidemic and epidemiology ................................................................. 15 4.2 Ad5 nAb assays ........................................................................................... 28 4.3 Study vaccines ............................................................................................. 28 4.4 Non-clinical and natural history data that provide evidence of potential vaccine activity ............................................................................................ 31 4.5 Potential benefit of VL reduction as a vaccination outcome ....................... 34 4.6 Experience with the VRC vaccine regimen ................................................. 37 5 Objectives and endpoints of the unblinded extended follow-up phase .................. 48 5.1 Primary objective and endpoints ................................................................. 48 5.2 Exploratory objectives ................................................................................. 48 6 Statistical considerations ........................................................................................ 50 6.1 Overview ..................................................................................................... 50 6.2 Objectives .................................................................................................... 50 6.3 Endpoints ..................................................................................................... 51 6.4 Sample size rationale ................................................................................... 52 6.5 Sampling design for assessing prophylactic ARV use ................................ 52 6.6 Statistical analysis ....................................................................................... 52 6.7 Monitoring of trial ....................................................................................... 55 7 Selection and withdrawal of participants ............................................................... 56 7.1 Inclusion criteria .......................................................................................... 56 7.2 Exclusion criteria ......................................................................................... 57 7.3 Co-enrollment of HVTN 505 participants ................................................... 58 7.4 Participant termination from the study ........................................................ 59 8 Clinical procedures ................................................................................................ 60 8.1 Informed consent ......................................................................................... 60 8.2 Follow-up visits for HIV-uninfected participants ....................................... 61 8.3 Procedures for HIV-1–infected participants ................................................ 62 8.4 HIV risk reduction counseling ..................................................................... 63 8.5 Visit windows and missed visits .................................................................. 64 8.6 Early termination visit ................................................................................. 64 9 HIV-1 infection assessment and clinical response ................................................. 65 9.1 HIV-1 symptom assessment ........................................................................ 65 9.2 HIV-1 testing during post-unblinding follow-up ......................................... 65 9.3 Endpoint adjudication .................................................................................. 65 9.4 HIV-1 infection during the study................................................................. 66 HVTN505_v6.0_FINAL.docx / Page 3 of 112 HVTN 505, Version 6.0 / July 21, 2014 9.5 Medical care for participants who become HIV-1–infected ........................ 66 10 Laboratory .............................................................................................................