Jared Baeten, MD PhD Thesla Palanee, PhD Site trainings 2012 OVERVIEW Jared Baeten, MD PhD Thesla Palanee, PhD Site trainings 2012

Overview Background and rationale Dapivirine for HIV prevention MTN-020/ASPIRE overview MTN-020/ASPIRE sites, timelines, goals MTN-020 and IPM 027 Lessons learned and thinking ahead

Background and Rationale

MTN-020 / ASPIRE A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Phase III Safety and Effectiveness Trial of a Vaginal Matrix Ring Containing Dapivirine for the Prevention of HIV-1 Infection in Women

A Study to Prevent Infection with a MTN-020 / ASPIRE A Study to Prevent Infection with a Ring for Extended Use

Antiretrovirals for HIV prevention Right drug (safe, effective, ideally not overlapping treatment) Right place (sufficient concentrations at site of exposure) Right time (present when exposed, user-independent adherence) 6

Tenofovir for HIV prevention: successes and challenges During the past two years, large studies of oral and topical tenofovir-based PrEP have demonstrated efficacy for HIV protection: Trial PrEP regimen Population Reduction in HIV risk CAPRISA 004 Peri-coital tenofovir gel Women 39% iPrEx Daily oral FTC/TDF Men who have sex with men 44% TDF2 Young heterosexuals 62% Partners PrEP Daily oral TDF and FTC/TDF HIV serodiscordant couples 67% (TDF) 75% (FTC/TDF) 7

Tenofovir for HIV prevention: successes and challenges However, not all trials of tenofovir-based PrEP have found HIV protection: No efficacy for daily oral FTC/TDF in FEM-PrEP trial and for daily tenofovir gel and daily TDF in VOICE study, both studies of women with high HIV incidence Across PrEP studies, adherence is likely an important driver of HIV protection Vaginal rings provide slow, continuous delivery of a drug or multiple drugs to cells inside the vagina over a period of weeks or months. Marketed vaginal ring products include those used for contraceptive delivery and hormone replacement. However, vaginal rings can also be used as a vehicle for delivering potent ARV drugs into the vagina to prevent HIV infection. Because they could be used for one month at a time, vaginal rings may offer a long-acting and convenient prevention option for women. 8

Developing a range of options for antiretroviral-based HIV prevention Pill Gel Vaginal film Vaginal ring Injectable Landmark health research is a process of continued development. Tenofovir is critical first proof on a future pathway. Goals: long acting, safe, effective, low cost and user- friendly Maximize choice & optimize effectiveness 9

Vaginal ring for HIV prevention: advantages and considerations Long acting: Monthly or longer Could potentially improve adherence Better adherence  better effectiveness Easy to use, comfortable Flexible ring, can be self-inserted Rarely felt by women or male partners Little or no impact on sexual activity Suitable for a wide range of settings Relatively low manufacturing cost Good safety and acceptability data Potential for drug combinations For example, contraception, in the future

Dapivirine Vaginal Ring for HIV Prevention

Dapivirine (TMC 120) Dapivirine is a di-amino-pyrimidine (DAPY) substituted highly potent non-nucleoside reverse transciptase inhibitor (NNRTI) of HIV-1 replication Initially developed and tested as oral antiretroviral treatment agent by Tibotec Potent activity both in vitro and in vivo

Dapivirine ring Flexible ring made of an elastic silicone material Off white, platinum-catalyzed Measures 56 mm (about 2 ½”) in diameter and 7.7 mm (3/4”) thick Designed for monthly use Developed by the International Partnership for Microbicides (IPM)

Dapivirine vaginal ring composition Tested for description, weight, tensile strength, ID, assay, content uniformity, impurities, dissolution and microbial limits

Dapivirine safety studies 11 oral dosing studies, for HIV treatment (N=211) 9 studies in healthy volunteers 2 studies in HIV-infected patients 8 vaginal gel studies, for HIV prevention (N=774) 6 vaginal ring studies, for HIV prevention (N=393) Ring-001: 1 trial Ring-002: 2 trials Ring-003: 1 trial Ring-004: 3 trials

IPM dapivirine Ring-004 trials Description Phase Countries N IPM 024 Safety and PK (28 days) I Belgium 16 (8:8) IPM 013 (56/57 days) 48 (36:12) IPM 015 (84 days) I/II Kenya Malawi Tanzania South Africa 280 (140:140)

Ring-004 safety and pharmacokinetic studies IPM 024 : Phase 1 Study, 16 Women, 4 weeks, Belgium (2009) Desired sustainable release, PK properties, no safety concerns Vaginal fluid levels on Day 28 at least 4000 times higher than the in vitro inhibitory concentration in cervical tissues; plasma levels <1 ng/mL IPM 013 : Phase 1 study, 48 women, 8 weeks, Belgium (2010) Multiple dosing of monthly rings well tolerated, no safety concerns PK data support sustained release over a 35-day period Vaginal fluid levels on Day 35 at least 3000 times higher than the in vitro 99% inhibitory concentration in cervical tissue, Plasma levels < 1ng/ml IPM 015: Phase I/II study, 280 women, 12 weeks, Africa (2010- 2011) Active and placebo rings safe and well tolerated. Adverse events probably or possible related to ring use were similar for dapivirine and placebo Plasma levels <1ng/mL; ring residual levels found that ~4mg dapivirine is released from Ring-004 over 28 days

IPM 015: ring acceptability Ring was comfortable : 97% Ring not felt during daily activities : 89% Willing to use if effective : 97% Prefer to wear ring every day : 97% Prefer ring use during menses : 69% Concerned ring might fall out : 16% Concerned ring might get lost in body : 22% Male partner did not feel ring during sex : 63% Male partner felt ring, but no problem: 22% Male partner felt ring might be or definitely a problem : 1%

IPM 015: safety data Dapivirine N=140 n (%) Placebo SAEs 1 (0.7) 4 (2.9) HIV seroconversions 3 (2.1) Positive pregnancy tests 2 (1.4) Non-serious AEs resulting in product discontinuation AEs definitely related to product AEs possibly/probably related to product 30 (21.4) 31 (22.1)

IPM 015: ring adherence Frequency of ring use Perfect adherence (ring never came out for >1 day) : 92% Ring removals Median number of times ring came out : 1 time per visit interval Frequency decreased over time Most frequent activity for involuntary expulsion: urination/ defecation Most common reason for removal: cleaning Had sex during the time that the ring was out : 17% - 36%

Dapivirine ring for HIV prevention: Ring-004 SAFETY: Safe and well-tolerated No related SAEs, AEs similar in treatment and placebo groups PK: High vaginal, low systemic concentrations Sustained release for at least 35 days Acceptability High willingness, good adherence, most common reason for removal = menses

ASPIRE: Design, Objectives, and Overview

ASPIRE Study Design

Primary Objectives EFFECTIVENESS To determine the effectiveness of dapivirine (25 mg) administered in a silicone elastomer vaginal matrix ring, when inserted once every 4 weeks, in preventing HIV infection among healthy sexually active HIV-uninfected women Primary Effectiveness Outcome: HIV seroconversion

Primary Objectives SAFETY To assess the safety of dapivirine (25 mg) administered in a silicone elastomer vaginal matrix ring, when inserted once every 4 weeks over the investigational product use period Primary Safety Outcomes: Grade 2 adverse events (AEs) judged to be related to study product Grade 3 and 4 AEs All serious adverse events  

Secondary Objectives Acceptability Adherence Drug resistance Self-report Adherence Including ring expulsions & removals Drug resistance In HIV-1 seroconverters Relationship between drug concentrations and HIV-1 seroconversion Concentrations of dapivirine in blood and self-collected vaginal swabs

Exploratory Objectives Describe changes in the genital microenvironment Changes in candidate biomarkers of safety and efficacy Assess correlation of steady-state drug concentrations and adherence measures Assess delayed seroconversion 4 week post-product completion visit

Behavioral components Quantitative assessments CRFs ACASI Qualitative component Subset of 6 sites (35-40♀/site) / ~5% sub-sample (~n=200) Serial IDIs (M3; Y1 and/or PUEV) Single IDIs with serconverters/ product discontinuers Post PUEV FGDs (2 per site) Adherence Counseling & Education (ACE) Modeled after NSC and VASP (use experience, needs focused) Integrates product adherence and visit retention Main trial conducted at 17 sites in 5 countries Qualitative data collected at 6 sites in 4 countries: MU-JHU (Kampala, Uganda) Spilhaus (Harare, Zimbabwe) UNC Lilongwe (Lilongwe, Malawi) WRHI (Johannesburg, South Africa) DTHF (Cape Town, South Africa) MRC Chatsworth (Durban, South Africa)

Participants 3476 sexually active HIV-uninfected women who are non-pregnant, contracepting, and 18-45 years of age Accrual will require approximately 12 months, with total study duration approximately 24 months Designed so that all participants will achieve 12 months on study product

Follow-up Monthly follow-up, including: HIV serologic testing Contraceptive counseling and provision Clinical safety assessment Study produce provision and adherence counseling Physical and pelvic examination, laboratory safety assessment (every 3-6 months)

Pregnancy Women who become pregnant while in the study will need to stop using the ring but can remain in the study to continue with follow-up visits Women will be referred for appropriate care and invited to join MTN-016, an observational registry study that aims to understand if product use has an effect on pregnancy outcomes She may be able to rejoin ASPIRE after her pregnancy

HIV acquisition Sites are required to have procedures for care and support for participants who acquire HIV and referral agreements with HIV primary care and ART providers The study product will be discontinued immediately Antiretroviral resistance testing will be done Seroconverters will be invited to join MTN-015 MTN-015 is a long-term observational study / registry of seroconverters from MTN studies

Sites, Timelines, and Goals

Proposed sites Blantyre Lilongwe Malawi Cape Town Durban (8 sites) Johannesburg South Africa Kampala Uganda Lusaka Zambia Harare (3 sites) Zimbabwe

Timeline 2011 Initiate site IRB and regulatory approval process 2012 IRB/regulatory approvals, trainings, enrollments begin Q3 2013 Enrollments and follow-up continue 2014 End of participant follow-up 2015 Results 35

The Big Five Accrual Retention Adherence Clinical and Laboratory There is a reason why the african big five have appropriately earned this title.  The elephant, lion, cape buffalo, leopard, and rhino are among the most dangerous and difficult animals for an experienced hunter to attain- however with careful considered strategy- even these animals can be captured. The Big Five of MTN 020 are as above. There isn’t one that is more powerful than the other and with considered strategy and support from today the highest quality is achievable. Clinical and Laboratory Participant Safety Data Quality and Timeliness

Design efficiencies Accrual Large number of sites, modest sample size = achievable number of recruitments Focus will be on protocol adherence during screening and enrollment – i.e., really trying to enroll only those who will return as scheduled for follow-up Follow-up Streamlined data collection and study procedures = reduced time spent in clinic Allowances for efficiencies for individual women – protocol provisions for extra ring dispensing and off-site visits 37

Design efficiencies (2) Retention Focus from day one from participant one : resource and attention allocation will be critical No retention = no adherence Provision of services on-site Contraception : expanding method mix and convenience Partner HIV testing, STI evaluation/referral 38

MTN-020 and IPM 027

Until end of study (12-24 months) MTN-020 and IPM 027 MTN-020 IPM 027 Design endpoint driven fixed time No. of participants 3,476 1,650 Randomization 1:1 2:1 Age 18-45 yrs Product use period Until end of study (12-24 months) 24 months fixed Person-years follow-up (all / Dapivirine Vaginal Ring) 4,396 / 2,198 3,150 / 2,100 HIV-1 seroconversions 120 80 Power for 50% effect 97% 83%

Similarities Very similar primary, secondary, and exploratory objectives and endpoints

Similarities Very similar primary, secondary, and exploratory objectives and endpoints Key goals are identical: efficient enrollment, high retention, promotion of product use/adherence, definitively testing whether this product is safe and effective

Differences Sample size (3476 vs. 1650) Follow-up (open-ended vs. fixed 24 months) Randomization (1:1 vs. 1:2) Sample collection (somewhat different repositories), laboratory testing (027 has more tests), pregnancy (027 will terminate at pregnancy)

Coordination MTN-020 and IPM 027 teams have worked tirelessly to ensure that data collection, counseling/clinical management, oversight are moving in parallel MTN-020 and IPM 027 are coordinated within single regulatory/investigational new drug applications (FDA, EMA)

Dapivirine ring for HIV prevention Dapivirine ring has shown safety and acceptability in phase I and phase II trials but its large-scale safety and its effectiveness for HIV protection are unknown These studies will provide the definitive data to determine whether dapivirine vaginal ring will have the strength of evidence to support potential licensure

Key Considerations for Optimization of Implementation

Everything else flows from these Numbers that matter 3476 = total number of women enrolled >95% = retention, product distribution 100% = attention to data quality, safety Everything else flows from these

Getting to 3476 To date, have defined site targets for start-up These are clearly not set in stone and will flux depending on timing of site initiation A portion of 3476 not currently assigned at all – pending early performance Period of accrual is about 12 months, driven by quality and appropriate pacing

Lessons learned… #1. Efficiency matters Efficient and focused start-up Targeted participant visits Attention to what is important for a quality study

Lessons learned… #2. Adherence is key Products don’t work if they aren’t used How will we set up a culture in ASPIRE so that women can accurately report non-use?

Lessons learned… #3. Retention is adherence Missed visit = month of zero adherence

Lessons learned… #4. We all work together – all parts of the study are all our business Recruitment QC/QA Retention Regulatory Adherence Safety Monitoring Sample collection Space/facilities Staff morale Study drug/pharmacy Community/outreach Contraception Communications Lab-clinic interface Lab quality Monitoring follow-up

Lessons learned… #5. Metrics and competition are healthy Retention #s Data quality #s

Lessons learned… #6. Bigger is not always better Smaller sites / new sites can be models of success

Lessons learned… #7. No one knows how to do this perfectly Cross-site, cross-team sharing is important Some of our ideas: job-specific list servs, biweekly calls with FHI360, regular protocol team meetings that focus on site-led presentations Talk with each other…

Lessons learned… #8. Talk with participants We have much to learn from them

Lessons learned… #9. Stakeholder and community involvement is ongoing Continuous contact

Lessons learned… #10. It takes a team We are all in this together

Malawi College of Medicine – JHU Research Project ASPIRE TEAM Malawi College of Medicine – JHU Research Project UNC Project - Malawi

Acknowledgements MTN is funded by NIAID (5U01AI068633), NICHD and NIMH, all of the U.S. National Institutes of Health