A Study to Prevention Infection with a Ring for Extended Use

1. A Study to Prevention Infection with a Ring for Extended Use [INSERT NAME] [INSERT CRS/INSTITUTION]

2. AStudy to Prevent Infection with a Ring for Extended Use

3. at a Glance • A Phase III trial of a vaginal ring that contains an antiretroviral (ARV) drug called dapivirine • A vaginal ring is a new and different approach for HIV prevention in women • Being conducted by the Microbicide Trials Network (MTN) and will involve about 3,476 women at several sites in Africa • MTN is also leading VOICE • Many of the same trial sites for VOICE will be conducting ASPIRE • Results are expected late 2014 or early 2015

4. at a Glance • Funded by the U.S. National Institutes of Health • The International Partnership for Microbicides(IPM) developed the dapivirine ring • IPM is also leading The Ring Study • Both ASPIRE and The Ring Study are designed to provide the kind of information needed to support potential licensure of the ring

5. Why a vaginal ring? • Vaginal rings are flexible products that fit comfortably high up inside the vagina where they release a drug slowly over time • They stay in place during sex and are not usually felt by the partner • Vaginal ring products are licensed for both contraception delivery and hormone replacement in some countries • The vaginal ring being tested in ASPIRE is not for contraception. It contains an ARV developed to treat HIV that also has promise for preventing HIV

6. Why are we conducting ? To answer these questions: • Can the ring protect against HIV? • Is it safe to use? • Will women like using it? • Will women actually use it? Women need safe and effective HIV prevention products!

7. Overview • Background and rationale • Design and objectives • Who may participate and what’s involved • Safety monitoring • The current microbicide landscape • Summary and Conclusions

8. Background and Rationale

9. Developing a range of HIV prevention options for women Vaginal film Tablet Vaginal gel Vaginal ring Injectable • Goals: long acting, safe, effective, low cost and user-friendly • Maximize choice & optimize effectiveness

10. Are all women the same? • Some women may favor a daily tablet • Some women may prefer using a gel, such as before and after sex • Some women may prefer wearing a vaginal ring that she replaces once a month • It’s about giving women choice – a product that best suits a woman’s needs and lifestyles is more likely to be used • Only if it is used does it have a chance of being effective

11. ARVs and HIV Prevention • ARVs are drugs that when used in combination are safe and effective for treating HIV • Generally three different ARVs are needed to suppress virus • For prevention, the idea is that one – maybe two ARVs – can protect an HIV-uninfected person if exposed to HIV (e.g., through unprotected sex) • The ARV will already be in the blood and/or vaginal tissue and will hamper HIV’s ability to establish infection

12. Different Approaches • Oral pre-exposure prophylaxis (PrEP) • Involves taking an ARV tablet by mouth • Vaginal microbicides • Involves use of a vaginal product - gel or ring - that contains an ARV • Other formulations are being developed, like a film

13. What do we know so far about ARVs for prevention? • Some trials have found ARV-based prevention is effective • Partners PrEP in serodiscordant couples – with Truvada,tenofovir • iPrEx in men who have sex with men – with Truvada • CDC TDF2 study in heterosexual men and women – with Truvada • CAPRISA 004 in women – with tenofovir gel (used before/after sex) • And some trials have found these not to be effective • FEM-PrEP in women – with Truvada • VOICE in women – with tenofovir and with tenofovir gel (used daily) • Other trials don’t have results yet • FACTS 001 in women – with tenfovir gel (used before/after sex); Results expected in 2014 • VOICE in women – with Truvada; Results expected early 2013

14. What do we know so far about ARVs for prevention? • Safety has not been an issue in any trial so far • ARV drug resistance rare among those who acquired HIV • Results of Partners PrEP, iPrEx and CAPRISA 004 show there is greater protection with regular use • In FEM-PrEP, less than half the women took the daily tablet – too few to measure whether Truvada prevented HIV Remember! • Even if a product is active against HIV, if for whatever reason it’s not used, it can’t help prevent HIV

15. About the dapivirine ring • Flexible ring made of an elastic silicone material • Measures 56 mm (2 ¼”) in diameter and 7.7 mm (3/8”) thick • Designed for 28-day use • When inside the vagina, the ring releases dapivirine slowly over time

16. Developed by Tibotec Pharmaceuticals for treating HIV Studies showed a favorable safety profile and that it was effective in reducing the “viral load” At the same time, Tibotec was looking at a very similar drug (etravirine) that was equally promising It had to decide the one to develop further for treatment and the one it would donate for prevention Dapivirine can be manufactured at lower cost Tibotec assigned a royalty-free license to IPM in 2004 to develop it as a microbicide for HIV prevention Dapivirine

17. Clinical safety of the ring • To date, 25 phase I/II trials of dapivirine (in oral, gel, and ring form) have been conducted • Studies of the ring have shown that high levels of drug can be delivered throughout the cervix and vagina for up to one month and that the ring is safe and women find using the ring acceptable • These studies support moving the ring into Phase III testing to determine its large-scale safety and effectiveness in protecting against HIV

18. Phase III Sister Studies • The Ring Study • 1,650 women • Trial sites in South Africa and Rwanda • Started enrolling in April2012 • ASPIRE • 3,476 women • Trial sites in South Africa, Uganda, Zambia, Zimbabwe, Malawi • Started screening in July 2012

19. ASPIRE Study Design and Objectives

20. Study Design Women will replace the ring every 4 weeks while in the study - over the course of at least 1 year

21. Two PrimaryObjectives • Is the ring effective in preventing HIV? • When used for a month at a time? • Is the ring safe to use? • When used for a month at a time?

22. How will we know it’s effective? • At the end of the study we will compare the number of HIV infections that occurred among women in the group using the dapivirine ring with the number of HIV infections in the group using a placebo ring • We hope to see a minimum of 60% fewer infections compared to the placebo

23. How will we know it’s safe? • Participants’ health assessed at each monthly study visit • We will compare the number, frequency and type of side effects/problems between the two groups • Were they related to use of the product or not?

24. Secondary Objectives • Will women find it acceptable to use? • Will women actually use the ring, and use it properly? • If a women becomes infected, will drug resistance be a problem?

25. How will we know if she likes the ring – and is using it? • Participants will be asked questions by staff and will use ACASI (Audio Computer-Assisted Self-Interview) and by questionnaire • Looking to know: • Does she have discomfort? • Is the ring noticeable during daily activity or sex? • Is her partner aware of the ring during sex? • How easy is it to insert and remove? • Did she take the ring out or did it come out on its own? • If so, why? And how long was it out? • More objective measures of adherence include tests that to assess drug levels in blood or vaginal fluid

26. Is drug resistance a concern? • Our first goal is to prevent HIV • All women receive HIV and risk reduction counseling and condoms every month • All women are tested for HIV every month • If she tests positive, we will stop product immediately to reduce the risk for resistance • Although resistance has been rare in prevention trials involving tenofovir-based products, we need to closely monitor women and better understand possible risks • Studies of the dapivirine ring indicate that very little of the drug gets absorbed into the blood, so resistance is less likely to be a concern than with oral ARVs

27. Who may participate and what’s involved?

28. Proposed Sites • Malawi • Blantyre • Lilongwe • South Africa • Cape Town • Durban (7 sites) • Johannesburg • Uganda • Kampala • Zambia • Lusaka • Zimbabwe • Harare (3 sites)

29. Who may participate? HIV-uninfected, sexually active women who : • Are between ages of 18 to 45 • Are not pregnant, breastfeeding, or intending to become pregnant; and agree to use an effective contraceptive method during their participation • Have no medical conditions that would make their participation unsafe • Are not currently participating or have recently participated in research study involving drugs, devices, vaginal products or vaccines

30. Informed Consent • Women must also be able and willing to provide written informed consent • To be screened for the study • To enroll in the study • To have leftover specimens stored for future research • Materials are translated into local languages to help ensure understanding and inclusiveness • Informed consent is a continuous process throughout the study

31. Study Visits and Procedures • Women will be seen monthly • HIV and pregnancy testing • HIV/STI risk reduction, contraceptive counseling and provision of condoms • Clinical follow up on symptoms as needed • Adherence interviews and counseling • Informed consent as needed • Receive and insert a new ring • At quarterly visits, behavioral and social harms assessments, physical exam and additional safety labs also conducted • At semiannual visits pelvic exams and STI tests also conducted

32. Learning how to use the ring • Women will learn how to insert and remove the ring on the day they are enrolled • Staff will explain that the ring should remain in place until the next monthly visit, when she will remove the ring and insert a new one • Staff will remind women at each visit how the ring is inserted and removed • A woman can ask for help at anytime, and she will have educational materials she can take home

33. 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 when she is no longer breastfeeding

34. HIV • All women receive HIV and risk reduction counseling, condoms, and treatment for STIs at each clinic visit • Women who acquire HIV will need to stop using the ring but can remain in the study to continue follow-up visits • Counseling and testing for her partner will be offered and she will be referred to local care and support services • All sites required to have procedures for care and support and referral agreements with HIV primary care and ART providers • Resistance testing is done for those who acquire HIV; if identified, this information may help to better manage her care • If she is confirmed HIV+, she will be invited to join MTN-015, a long-term observational study

35. Safety Monitoring

36. Many Layers of Safety Monitoring

37. At the local and site level • IRBs/ECs must review and approve protocol and any subsequent amendments; and provide oversight throughout the study • Site clinicians monitor safety and wellbeing of participants at each monthly visit • Clinical and laboratory evaluations and questions about key symptoms • HIV and pregnancy testing • Counseling on safe use of the product and practices • If there is ever any question about safety, staff will stop a participant’s use of the ring

38. External Safety Monitoring: DSMBs • A Data Safety Monitoring Board (DSMB) is a group of independent experts that conducts routine reviews of data while a trial is ongoing • A DSMB looks at “blinded” data at several time points during a trial – about two times a year • Are there safety concerns? • Will the trial be able to answer the study questions? • Do any of study questions already have clear answers? • Should the trial keep going, stop early or be modified? • Also may evaluate emergent data from other trials

39. The DSMB for • Routine reviews of ASPIRE will be conducted by a National Institute of Allergy and Infectious Diseases DSMB with expertise in international HIV prevention trials • The majority of its members are from developing countries • Decisions whether to continue, stop or modify the study are based on: • Pre-determined statistical parameters and stopping rules set by the study team and the DSMB • International ethical principles and standards

40. The Current Microbicide Landscape

41. As moves forward… • ASPIRE expects to be completed by 2014, and have results late 2014, early 2015 • We are committed to open communication and discussion throughout ASPIRE about: • The clinical trial process • Progress and milestones • Possible outcomes and their implications • Especially important to talk about: • DSMB reviews of ASPIRE • DSMB reviews of The Ring Study • Other HIV prevention trials, e.g., VOICE • New HIV prevention guidelines or products

42. 2012-13 Microbicide Studies and Sites • ASPIRE – dapivirine ring • Malawi, Uganda, South Africa, Zambia, Zimbabwe • The Ring Study – dapivirine ring • Rwanda, South Africa • FACTS 001 – tenofovir gel • South Africa • CAPRISA 008 – tenofovir gel • South Africa We need to be mindful of the entire landscape!

43. What if the landscape changes? • What happens when VOICE results are available? • What if Truvada becomes more widely available? • WHO and UNAIDS are discussing PrEP guidelines • Depending on timing, changes to ASPIRE may be required. • We will follow all relevant national policies • Will former participants at ASPIRE sites have access to Truvada through an “open-label” trial? • Plans are to conduct CHOICE, but this will depend on the results of VOICE (early 2013)

44. What if the ring is effective? • If both ASPIRE and The Ring Study find the ring safe and effective, IPM intends to seek product approval from regulatory agencies • If the ring is approved, IPM is committed to making it available at the lowest possible cost in countries where women urgently need tools to protect themselves against sexual transmission of HIV • Participants in both studies will likely have access prior to the ring’s availability through an open-access trial

45. Summary

46. Summary and Final Thoughts • Women need more than one option for HIV prevention • ASPIRE is testing a new approach called a vaginal ring that women replace once a month. The active drug in the ring is dapivirine • Results are expected late 2014/early 2015: • Can the ring protect against HIV? • Is it safe to use? • Will women like using it? • Will women actually use it? • ASPIRE, and its sister study, The Ring Study, are designed to support possible licensure of the ring for HIV prevention • Open communication is key to success

47. 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

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

49. Acknowledgements MTN is funded by NIAID (5UM1 AI068633-07), NICHD and NIMH, all of the U.S. National Institutes of Health