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Clinical Protocol and Population Considerations
HVTN 705/HPX2008 Clinical Protocol and Population Considerations Research reported in this publication was supported by the National Institute of Allergy And Infectious Diseases of the National Institutes of Health under Award Number UM1A The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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Study objectives and design
11/7/2018
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Soluble trimeric gp140 Env protein co-formulated with Alum
Mixture of 4 mosaic Ad26 constructs + gp140 Clade C boost Double Prime Double Boost Ad26.Mos4.HIV Ad26 vectors with Mosaic gag-pol or env inserts Ad26.Mos1.Gag-Pol Ad26.Mos2.Gag-Pol Ad26.Mos1.Env Ad26.Mos2S.Env Co-formulated 1:1:1:1 Ad26.Mos4.HIV Ad26 vectors with Mosaic gag-pol or env inserts Ad26.Mos1.Gag-Pol Ad26.Mos2.Gag-Pol Ad26.Mos1.Env Ad26.Mos2S.Env Co-formulated 1:1:1:1 gp140 Clade C Soluble trimeric gp140 Env protein co-formulated with Alum + prime 3 12 months 6 boost
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Clade C gp140 (250 mcg + adjuvant)
Schema Group N Month 0 Month 3 Month 6 Month 12 1 1300 Ad26.Mos4.HIV + Clade C gp140 (250 mcg + adjuvant) 2 Placebo Total: 2600 female participants Anticipated enrollment: 14 months Anticipated total study duration: 50 months (includes enrollment and follow-up)
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Phase 2b HVTN 705/HPX2008 Trial Schema
Ad = Ad26.Mos4.HIV Pr = Clade C gp140 HIV negative volunteers enrolled and tested for HIV every 3 months for a maximum of 36 months Ad Ad AdPr AdPr Vaccine 2nd stage (24-36) N=1,300 N=2,600 Women 1:1 randomization +/-14 mo recruitment Placebo 2nd stage (24-36) N=1,300 Mo Mo. 7 Wk 28 (PP infections) Mo. 24 Wk 104 2 years Mo. 36 Wk 156 3 years
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Efficacy Objectives Primary Objective*
Assess VE to prevent HIV-1 infection through 24 months If positive VE, assess durability of VE to prevent HIV infection through 36 months Secondary Objectives Assess immune correlates of risk and of VE Sieve analysis of breakthrough viruses integrated with the correlates analysis *Primary analysis counts infections post-month 7 in participants who received the first 3 vaccinations per protocol Key secondary analyses count all HIV-1 infections post Month 0
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Two-Stage Design to Assess VE to Prevent HIV-1 Infection
Stage 1: Assess VE to prevent infection through 24 months Stage 2: Assess VE to prevent infection through 36 months [VE(7-36)] Begins when the last participant reaches Month 24 Adaptive: Stage 2 occurs if, and only if, reject H0: VE(7-24) ≤ 0% in Stage 1 If Stage 2 occurs, the Oversight Group will have the opportunity to recommend continuing the trial for longer-term assessment of VE Sample size selected to achieve 90% power to reject H0: VE(7-24) ≤ 0% if VE(7-24) = 50%
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Rationale for Two-Stage Design
Durable protection is important for a vaccine to have major public health impact to avert HIV-1 infections Vaccines tend to protect best against exposures occurring proximal to the immunizations If there is no VE over the first 24 months, we can reasonably predict there would be no VE to 36 months, such that Stage 2 would be unnecessary But if there is positive VE over the first 24 months, a critical question is whether the protection is sustained, which needs continued follow-up for evaluation
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Correlates Analysis Correlates of risk analysis from RV144 trial and NHP challenge models suggest similarities and differences in correlates between the ALVAC-based (HVTN 702) and Ad26- based (HVTN 705) regimens HVTN 702 and HVTN 705 trials are harmonized in timing of specimen collection, laboratory assays and analysis This approach substantially increases power to evaluate correlates within and across trials 11/7/2018
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Under design alternative Est. VE(7-24)=50% and Est. VE(7-36) = 50%
Combining HVTN 702 and 705 Women for Improving Power of Correlates Analysis Combining HVTN 702 female cohort with HVTN 705 increases projected number of vaccine group infected cases 2.24-fold from HVTN 705 alone Under design alternative Est. VE(7-24)=50% and Est. VE(7-36) = 50% Follow-up Period Infected Cases Uninfected Controls Total 7−24 Months = 74 = 371 445 7−36 Months = 124 = 618 742
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Study population and sites
11/7/2018
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New HIV Infections in Southern and East Africa
2015 11/7/2018
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HIV Prevalence by age and sex, South Africa, 2012
Gap Report, UNAIDS 2014 11/7/2018
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Sites: HVTN 705/HPX2008 Ndola Lusaka -ZEHRP Lilongwe Lusaka -Matero
Seke South Soshanguve Medunsa Elandsdoorn Rustenburg Mamelodi Soweto – Kliptown Tembisa Soweto – Baragwanath Maputo Klerksdorp Ladysmith Isipingo Verulam Chatsworth eThekwini Cape Town-Emavundleni Cape Town-Khayelitsha Bloemfontein Mthatha Masiphumelele 7/20/2017
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HVTN 705 Sites and Investigators
RSA: Durban - Chatsworth Logashvari Naidoo RSA: Masiphumelele Katherine Gill RSA: Bloemfontein Zaheer Hoosain RSA: Elandsdoorn Robert Moraba RSA: Mamelodi Tasneem Vally Zambia: Ndola Mubiana Inambao Zambia: Lusaka-ZEHRP William Kilembe Mozambique: Maputo Illesh Jani Zimbabwe: Harare - Seke South Zvavahere (Mike) Chirenje Zambia: Lusaka - Matero Michael Herce Malawi: Lilongwe Mina Hosseinipour RSA: Soweto - Bara Fatima Laher RSA: Cape Town - Emavundleni Linda-Gail Bekker RSA: Durban - Isipingo Logashvari Naidoo RSA: Durban - eThekwini Kathryn Mngadi RSA: Klerksdorp Craig Innes RSA: Soshanguve Mookho Mahlaleha RSA: Tembisa Modulakgotla Sebe RSA: Ladysmith Philip Kotze RSA: Soweto - Kliptown Nicole Hunt RSA: Durban - Verulam Anamika Premrajh RSA: Cape Town - Khayelitsha Graeme Meintjes RSA: Rustenburg William Brumskine RSA: Medunsa Maphoshane Nchabeleng RSA: Mthatha Lungiswa S. Mtingi-Nkonzombi 9/6/2016
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HIV Incidence in the Placebo Arm of Efficacy Trials in Women in Africa
Years Age HIV Incidence/100 py Phambili 2007 18-35 yrs 5.9 FACTS 001 18-30 yrs 4.0 VOICE 18-45 yrs 5.7 ASPIRE 4.5 The Ring Study 6.1 Fem-PrEP 5.0 Overall incidence over the 6 studies: /100 py Protocol assumes 16% lower incidence: 4.2/100 py Accommodates PrEP 90% efficacy in 15% of person-time 11/7/2018
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Site development 11/7/2018
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Training the Community staff
Regional Workshop, June 5th – June 7th, 2017 Selected topics, developed by experienced southern African site staff: HVTN Overview Recruitment strategies HIV Vaccines 101 Basic science of HVTN 705 Developing outreach materials and key messages Timing: 5 months prior to 1st trial start date 11/7/2018
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Community Stakeholder meeting
Regional Workshop, June 8th – June 9th, 2017 Selected topics, developed by experienced southern African site staff: HIV Vaccines 101 HIV Prevention overview HVTN 705 overview Group Activities Questions/Discussions 11/7/2018
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Training the Clinic Staff: Protocol-specific
Regional Training, 3 days Selected topics: Scheduling within visit windows Study materials review Safety monitoring Randomization Case Report Form completion Enrollment/follow-up visit scenarios Timing: ~4 weeks prior to first trial start date Planned for week of 3rd October 2017 Repeated for new sites 11/7/2018
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Staff Training, HVTN Website
Select trainings available for download: All protocol-specific training Curriculum developed by experienced network members Clinical Research Basics Clinical Management Laboratory Epidemiology Basics Clinical Procedures Trial Operations Regulatory Oversight & Ethics Community Engagement Vaccinology/Immunology 11/7/2018
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Staff Support: Acute & Ongoing
On-site technical assistance, based in RSA 3 Clinical Trials/Program Managers 2 Regional Medical Liaison 2 Community Engagement Training Managers Webinars HVTN Core Training Unit HVTN Conferences, 2-3 times per year Break-out meetings 11/7/2018
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HVTN 705 Acknowledgments 11/7/2018 Chair Glenda Gray, PHRU Cochair
Frank Tomaka, Janssen Kathy Mngadi, CAPRISA Susan Buchbinder, SFDPH PTL / CMM Philipp Mann, HVTN PTL & Study Responsible Physician Ludo Lavreys, Janssen Medical Officer Edith Swann, DAIDS, NIAID Julia Hutter, DAIDS, NIAID Statistician Alexander Luedtke, SCHARP Michal Juraska, SCHARP Steven Nijs, Janssen Peter Gilbert, SCHARP Lab Lead Zelda Euler, Janssen John Hural, HVTN Julie McElrath, HVTN Nicole Frahm, HVTN Compound Dev. Team Lead Maria Grazia Pau, Janssen SDMC Jessica Andriesen GCDO Program Leader Chris McShane, Janssen Medical Writer Anick Vandingenen DAIDS Carl Dieffenbach Dale Hu Mary Marovich BMGF Emilio Emini Nina Russel Peggy Johnston Pervin Anklesaria MHRP Christina Polyak Julie Ake Merlin Robb Nelson Michael Ragon Dan Barouch CDM Gina Escamilla Olive Yuan, Janssen Clinic Coordinator Mmathapelo Masala Yajna Duki Communications Unit Jim Maynard Community Engagement Unit Nandi Luthuli CSS Jill Zeller CTM Caroline Borremans, Janssen Carrie Sopher Lab Georgia Tomaras Jenny Hendriks, Janssen Medical Safety Officer Raphael Roten, Janssen PDM Meg Trahey Ryan Jensen Pharmacist Nayri Khairalla RCSL Keitumetse Diphoko REG Lorenz Scheppler, Janssen Rachael McClennen RML Simba Takuva SRA Brittany Sanchez Carla Truyers, Janssen CAB Rep Audry Tasaranarwo Sibusiso Mngadi CER Rep Charles Chasakara Ivy Kaunda Editor Erik Schwab Lab Ops On Ho Study Responsible Physician backup Richard De Rooij, Janssen 11/7/2018
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Thank you to all the study participants, site investigators, clinic coordinators, CER teams, and site pharmacists. HVTN 705 Sites: Bloemfontein Lusaka - Matero Cape Town - Emavundleni Mamelodi Cape Town - Khayelitsha Maputo Durban - Chatsworth Masiphumelele Durban - eThekwini Medunsa Durban - Isipingo Mthatha Durban - Tongaat Ndola Durban - Verulam Rustenburg Elandsdoorn Soshanguve Harare - Seke South Soweto - Bara Klerksdorp Soweto - Kliptown Ladysmith Tembisa Lilongwe 11/7/2018
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