QUESTIONS AND ANSWERS

Transcription

1 CONTACT: Lisa Rossi (mobile) QUESTIONS AND ANSWERS ASPIRE A Study to Prevent Infection with a Ring for Extended Use The Big Picture 1. What is the aim of ASPIRE? ASPIRE A Study to Prevent Infection with a Ring for Extended Use, also known as MTN-020, is a Phase III clinical trial that seeks to determine whether a woman s use of a vaginal ring containing the antiretroviral (ARV) drug dapivirine is a safe and effective method for protecting against HIV through vaginal sex. Vaginal rings are products designed to allow for the slow delivery of a drug or multiple drugs to cells inside the vagina over a period of weeks or months. The dapivirine ring being tested in ASPIRE is designed to be replaced every four weeks. As a potential method to protect women from acquiring HIV during sex, rings represent another option besides microbicide gels, which are intended to be used at the time of sex, some even daily. In addition to testing the ring s safety and effectiveness, ASPIRE is assessing whether women and their partners like using the ring, and, importantly, whether women are able and actually willing to use such a product. Andrew Loxely ASPIRE is being conducted in parallel with a second trial, The Ring Study, led by the International Partnership for Microbicides (IPM), which developed the ring. As sister studies, the two trials are designed to provide the strength of evidence to support potential licensure of the dapivirine vaginal ring for preventing HIV in women. 2. What is unique about ASPIRE? ASPIRE represents a major step forward in the evaluation of a promising female-controlled method that potentially could provide women with discreet, long-acting protection against HIV. Building on IPM s previous research and as a complement to The Ring Study, ASPIRE is a critical component in a strategy that seeks to license the dapivirine ring. Significantly, ASPIRE and The Ring Study are the first effectiveness trials of a vaginal ring for HIV prevention and also of an ARV-based HIV prevention product using a drug other than tenofovir or a tenofovir combination. 3. Why is this study important? Of the more than 35 million people living with HIV, greater than half are women. Most women acquire HIV through heterosexual intercourse. In fact, women are twice as likely as men to acquire HIV during vaginal sex, due in part to biological factors that make them more susceptible. Young women are especially vulnerable. In southern Africa, young women are up to eight times more likely to become infected with HIV than young men. Efforts to promote abstinence, monogamy and the use of male condoms have not been enough to stop the HIV epidemic nor are these practical methods in most settings. There is an urgent need for effective prevention strategies that women can control themselves, and that they are willing and able to actually use. Toward this end, vaginal microbicides are HIV prevention products being developed especially for use by women to help reduce their risk of HIV infection. Clinical trials to date have primarily focused on microbicides formulated as vaginal gels, with a gel based on the ARV tenofovir the most studied. In the CAPRISA 004 study, tenofovir gel used before and after sex reduced the risk of HIV infection by 39 percent compared to a placebo gel. However, tenofovir gel was not effective in another study called VOICE Vaginal and Oral Interventions to Control the Epidemic which was designed to test its daily use (as well as daily use of an ARV tablet). An analysis of blood samples at the end of the trial indicated that most women had not used their assigned study products daily as recommended. In the meantime, a Phase III trial, FACTS 001, is testing the same tenofovir gel regimen used in CAPRISA 004 (before and after sex), with results expected early Some women may prefer taking a daily ARV tablet; some may prefer using a vaginal gel in association with sex, while others may prefer a microbicide in the form of a vaginal ring, which can be used monthly. Different approaches will appeal to different women, with the one that best suits individual needs or lifestyle more likely to be used. This is

2 important, because no matter how effective a given product or approach may be, it can have no benefit if it s not used or not used correctly. And this is why it s critical that researchers, like those conducting ASPIRE, investigate different strategies to ensure that women have different options for protecting themselves from HIV. 4. Who is conducting and funding the study? ASPIRE is a study of the Microbicide Trials Network (MTN), an HIV/AIDS clinical trials network funded by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Mental Health (NIMH) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, all of the U.S. National Institutes of Health (NIH). Jared Baeten, M.D., Ph.D., of the University of Washington, U.S., is protocol chair; and Thesla Palanee, Ph.D., of the Wits Reproductive Health and HIV Institute, South Africa, is protocol co-chair. As the regulatory sponsor and license holder of the dapivirine ring, IPM is providing both the placebo rings and the rings containing dapivirine for use in ASPIRE. 5. When did the trial begin and how long will it last? ASPIRE was launched in August 2012 and completed participant enrollment in June Researchers expect to complete the study July 2015, with results available early How many women are taking part in ASPIRE and where? ASPIRE has enrolled 2,629 participants at 15 MTN-affiliated clinical research sites in Malawi, Uganda, South Africa and Zimbabwe. 7. What is a vaginal ring? Vaginal rings are flexible products that fit comfortably high up inside the vagina and allow for the slow, continuous delivery of a drug or multiple drugs over a period of weeks or months. In the U.S. and Europe, vaginal ring products are licensed for both contraception delivery and hormone replacement. 8. What exactly is the dapivirine vaginal ring? Researchers conducting ASPIRE are testing a vaginal ring containing 25mg of the ARV dapivirine. The ring is made of an elastic silicone material that measures 56mm (about 2 ¼ inches) in diameter and is 7.7mm thick (3/8 inch). The dapivirine ring is designed to be replaced every four weeks. When placed inside the vagina, the ring slowly releases the drug over time. Dapivirine, also known as TMC-120, is a type of ARV called a non-nucleoside reverse transcriptase inhibitor (NNRTI). NNRTIs bind to and disable HIV s reverse transcriptase enzyme, a protein that HIV needs to make copies of itself. Dapivirine was initially being developed as an oral therapeutic agent to be used in the treatment of HIV, but because of its favorable safety profile and physical and chemical properties it was decided that dapivirine was better suited for development as a microbicide for HIV prevention. As such, in 2004, IPM, a nonprofit product development partnership based in Silver Spring, Md., received a royalty-free license to develop dapivirine for use as a microbicide in developing countries through an agreement with Janssen R&D Ireland. Since then, 16 clinical safety studies of dapivirine, formulated as either a vaginal gel or a vaginal ring, have been conducted by IPM and its partners. 9. How is ASPIRE designed? ASPIRE is a Phase III trial designed to evaluate the safety and effectiveness of the dapivirine vaginal ring for preventing the sexual transmission of HIV in women. Participants are randomly assigned to use either the dapivirine ring or a placebo ring that looks the same but contains no active drug. Participants insert a new ring every four weeks at their monthly clinic visit, and will use their assigned product for at least one year. As part of the study, all participants receive ongoing HIV risk reduction counseling, condoms and diagnosis and treatment of sexually transmitted infections (STIs). In addition to determining the ring s safety and effectiveness, ASPIRE is designed to assess women s adherence to and acceptability of the ring. Researchers will also try to determine if there is a relationship between drug levels in cells and tissue and HIV acquisition, as well as the nature and frequency of HIV drug resistance among those women who, despite the HIV prevention measures provided to all participants, acquire HIV during the study. The study was originally designed to enroll up to 3,476 women, a calculation based in part on a background HIV incidence rate of 3.9 percent in trial site communities when the protocol was being developed. However, results of the VOICE study, reported seven months into ASPIRE, found HIV incidence in a very similar population to be much higher, at 5.7 percent. Adjusting for both the higher HIV incidence as well as the fact that the study has more women than expected using the ring well beyond one year, the team determined a target enrollment of 2,600 participants 2

3 3 would be sufficient to meet the study s objectives. Because the ASPIRE protocol is designed to accommodate new information as it becomes available, both the Study Monitoring Committee and the independent Data Safety and Monitoring Board (DSMB) that conducts routine reviews of the study were in agreement. 10. What other studies have been conducted of the dapivirine vaginal ring? ASPIRE is the culmination of a large body of research led by IPM looking at the dapivirine ring as an alternative HIV prevention option for women. These studies have shown the ring can deliver high concentrations of active drug to vaginal tissue for a month or longer, with only trace amounts of drug being absorbed elsewhere in the body. Studies have also found that use of the dapivirine ring is safe and well-tolerated by women, and that among women in Africa, the ring itself is highly acceptable as a potential method for HIV prevention. In studies to date, the most common side effect associated with the dapivirine ring has been headache. Some women have also experienced vaginal discomfort or bleeding between menstrual periods. As part of its strategy to license the ring, IPM is conducting The Ring Study, also known as IPM 027, in parallel with ASPIRE. The Ring Study, which began enrolling women in April 2012, will collect additional long-term safety and efficacy data about the dapivirine ring among approximately 1,950 women at six sites in South Africa and one in Uganda. Several smaller studies of the ring are taking place, including studies being conducted by the MTN to evaluate the ring s safety in adolescents and postmenopausal women, and others that IPM is conducting looking at condom compatibility and drug interactions. 11. Why the need for both ASPIRE and The Ring Study? As sister studies, ASPIRE and The Ring Study are designed to collect the strength of evidence needed by regulatory authorities to consider potential licensure of the dapivirine vaginal ring for preventing HIV in women. By conducting the trials in parallel, researchers will be able to obtain answers to key questions more quickly. Combined, the two trials will involve more than 4,500 women. 12. Will ASPIRE participants have access to the dapivirine ring if it s found safe and effective in ASPIRE? Should ASPIRE finds the dapivirine ring safe and effective for reducing the risk of HIV among the women in the study, former ASPIRE participants would be invited to take part in an open-label follow-on trial, MTN-025, which would provide women access to the dapivirine ring. The primary aim of MTN-025, which is currently in development, would be to gather additional data on the safety of and adherence to the ring, information that will help understand issues important for broader implementation of the ring should it receive regulatory approval. 13. What are plans for the dapivirine ring after these studies? If the results of a package of studies, of which ASPIRE and The Ring Study are the centerpiece, find the ring is safe and effective, IPM intends to seek product approval from the European Medicines Agency, the U.S. Food and Drug Administration (FDA) and the South African Medicines Control Council (MCC) and other African regulatory agencies. If the ring is subsequently 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. At the Trial Site 14. What kind of approvals were needed to conduct the study? ASPIRE underwent extensive and rigorous review by NIAID and the U.S. FDA. Moreover, before any site could begin the study, approvals were required of government and regulatory authorities in the trial site country and by the site s Institutional Review Board (IRB) or Ethics Committee (EC). IRBs and ECs ensure that studies are scientifically valid and ethically sound and provide oversight throughout the duration of the trial. 15. Who may participate in ASPIRE? Women between the ages of 18 and 45 who are sexually active and HIV-negative were eligible to enroll in ASPIRE, provided they met other study inclusion criteria. For instance, women who are pregnant or breastfeeding, or intend on getting pregnant, cannot participate in ASPIRE. 16. Do women participating in ASPIRE provide informed consent? Yes. Women who volunteered to join ASPIRE were educated about all the study procedures, any possible risks, benefits and alternatives to participation as well as the study s time requirements. Study staff also explained that - women do not have to take part in the study and can leave it at any time, without consequence. This process is called more-

4 4 informed consent and it occurred prior to screening, again at enrollment, and continues throughout the duration of the study. Information is provided in simple terms and translated into local languages. 17. Are women taught how to insert and remove the ring? Participants learn how to insert and remove the ring when they first enroll into the study and receive additional guidance at monthly follow-up visits as needed. Site staff also counsel participants on how to reinsert the ring should it come out accidentally between visits and on its correct use. 18. What is being done to ensure the safety of participants in ASPIRE? ASPIRE was designed based on rigorous international medical practice and ethical standards and is being conducted with numerous measures to protect the safety and well-being of participants. Potential volunteers were carefully screened by study staff to ensure that only women for whom it would be safe to participate were enrolled. Clinical teams at the trial sites perform thorough evaluations of participants at each study visit. A team at the MTN statistical and data management center (SDMC) assesses incoming reports on a daily basis; and an ASPIRE protocol safety review team (PSRT) provides regular monthly oversight. The PSRT includes three additional MTN physicians two specializing in infectious diseases and HIV and the other in obstetrics and gynecology whose sole responsibilities are to ensure that everything possible is being done to monitor and protect the safety of participants. Regular reviews are also conducted by an independent Data and Safety Monitoring Board (DSMB) that oversees clinical trials funded by NIAID to ensure that participants are not being adversely affected by the study or study products. If the DSMB has any safety concerns, it may, at any time, recommend that the study modify its procedures or be discontinued. It may also recommend stopping the trial if the evidence clearly shows a product s effectiveness or that it is not effective in the study s participants. 19. What happens if a participant becomes HIV-positive while in ASPIRE? A comprehensive HIV prevention package is provided to all women throughout the trial. This includes HIV riskreduction counseling, free condoms, regular HIV testing and testing for and treatment of other sexually transmitted infections (STIs). Despite these intensive efforts, some participants could acquire HIV while in the study. Women who test positive for HIV are taken off study product immediately because continuing its use could increase the risk of the virus becoming resistant to dapivirine and similar ARVs; and they are counseled and referred by study staff to local HIV care and support services. Women will are encouraged to remain in the ASPIRE study and continue with routine study visits and invited to participate in another MTN study called MTN-015. MTN-015 does not provide HIV treatment, but frequent laboratory tests indicating how the disease is progressing and how women are responding to treatment may help local treatment providers better manage their clinical care. 20. How could a woman become HIV-positive while taking part in an HIV prevention trial? In sub-saharan Africa, a woman s risk for acquiring HIV through sexual intercourse is greater than in any other part of the world. Participants in HIV prevention trials like ASPIRE are reminded of the fact that the product being tested has not been proven effective and that not all women in the study may be using an active product. To reduce the risk of HIV for women participating in its trials, MTN researchers provide trial participants free condoms, frequent HIV testing and HIV risk-reduction counseling, including on the correct and consistent use of condoms, and provide routine testing and treatment for STIs. Despite these intensive, ongoing efforts, a woman who participates in a trial like ASPIRE could acquire HIV if she has unprotected sex with a partner who is infected with the virus. 21. Is there concern that women who become HIV-infected will develop drug resistance to dapivirine? It s important to understand that drug resistance is possible only in someone infected with HIV, and the study s primary interest is in reducing HIV risk in all participants. However, if, despite the study s efforts, a woman becomes infected, safeguards are in place to minimize the potential for drug resistance. For instance, women in ASPIRE are tested for HIV at every monthly visit. If a test indicates that a woman has acquired HIV, staff will immediately stop her use of study product, because its continued use could potentially increase the chance virus will become resistant to the drug. Women testing positive for HIV are monitored for resistance, even after stopping product, so that if identified, it can be managed appropriately by those treating the infection. Although dapivirine is not used in the treatment of HIV, ARV drugs in the same class as dapivirine (NNRTIs) are. At the same time, a potential advantage dapivirine may have is that it remains potent even in the presence of common HIV strains with resistance. The ASPIRE trial will help to understand the nature and frequency of drug resistance among women who become infected while enrolled in the study.

5 22. Will ASPIRE provide antiretroviral therapy, or ART, to women who acquire HIV? MTN receives funding to conduct clinical trials only, and is not permitted to provide HIV treatment. However, all MTN trial sites are required to have agreements with local service providers so that if a study participant acquires HIV she can be referred to the appropriate services and care in her community. In addition, site staff offer women the opportunity to participate in another MTN study, MTN-015. As a long-term observational study, MTN-015 does not provide HIV treatment, but frequent laboratory tests indicating how the disease is progressing and how women are responding to treatment may help local treatment providers better manage their clinical care. 23. What is adherence and why is it so important? In the context of HIV prevention research, adherence refers to a person s willingness or ability to correctly and consistently follow a prescribed regimen. When participants use the study product as directed in an HIV prevention trial, researchers can determine with greater certainty whether the product prevents HIV. For example, adherence to product use was very high in the Partners PrEP Study, which provided especially convincing evidence that daily use of an ARV tablet (tenofovir or Truvada) can be highly effective among heterosexual couples in whom one of the partners has HIV. Yet, neither the FEM-PrEP nor the VOICE studies found Truvada effective among young, predominately single women, most of whom had not followed the daily pill-taking regimen as instructed. No matter how effective a given product or approach may be, there s no benefit if it s not used.women who need safe and effective HIV prevention methods must also be willing and able to use them. As such, a finding of low adherence in a clinical trial could also be an indicator of the kinds of challenges that women may face in the real world. 24. What is being done in ASPIRE to ensure women actually use the ring? First, it s important to point out that the dapivirine ring being evaluated in ASPIRE is a longer-acting product to be used by women for four weeks at time which may be easier and more convenient for women to use consistently. Still, site staff go to great effort to help trial participants and local communities better understand the importance of correct and consistent product use and the impact that non-adherence can have on the findings of a research study. Although in VOICE adherence was estimated to be about 90 percent based on what participants themselves had reported and on counts of unused applicators and leftover pills, blood tests conducted at the end of the trial revealed that only about 25 percent of the women had actually used product regularly. As such, ASPIRE trial staff (many of whom also were involved in conducting VOICE) are working on ways to better understand women s social contexts, perceptions about HIV risk and their motives for taking part in ASPIRE, and encouraging participants to be open about any difficulties they are having with using the ring. ASPIRE is also monitoring adherence while the trial is underway so that challenges with use can be addressed as they occur, and in a way that preserves the blinded, placebo-controlled nature of the study. Participant blood samples and used rings are being tested on a routine basis to determine use of the ring and the data is pooled according to trial sites or the study overall. 25. How is adherence being measured in ASPIRE? Information about adherence to product use is being collected using different measures in ASPIRE, including through face-to-face interviews and the use of Audio-Computer Assisted Self Interviewing (ACASI), which allows participants to answer questions about condom use, sexual behavior and product use. Tests of used rings and of blood and vaginal fluid samples taken from participants during the study will also help determine how well participants followed the study regimens by measuring the amount of drug present. A special test that can determine how much drug remains in used rings may be especially useful. Once the dapivirine ring is placed in the vagina it releases drug slowly over the four weeks it is intended to be worn. A ring that still contains active drug indicates little or no use, whereas a ring depleted or nearly depleted of drug indicates it was used all or most of the time. 26. What happens to women who become pregnant or are breastfeeding? Researchers don t yet know how dapivirine might affect a woman s pregnancy or the development of her fetus, so trial participants must not be planning to become pregnant during the study and must use effective contraception and have monthly pregnancy tests. If a participant becomes pregnant during the study, she will stop use of the ring, but can remain in the study and continue with all trial site visits. She will also be referred by study staff to available sources of medical care and other services that she or her baby may need. Depending on the timing of pregnancy relative to the study s progress, some women may be able to resume using the ring, provided they are no longer breastfeeding. Women who become pregnant will also be invited to participate in an observational study, MTN 016, or EMBRACE (Evaluation of Maternal and Baby Outcome Registry After Chemoprophylactic Exposure. 5

6 6 27. What are the medical benefits for women participating in the study? Study participants receive free laboratory tests and physical and pelvic exams, HIV prevention counseling and free condoms. STI risk-reduction counseling, testing and treatment are provided at no charge to women. HIV testing and STI treatment is also be provided to their partners. In addition, ASPIRE provides effective barrier and hormonal contraception and monthly pregnancy and HIV testing. For medical issues that become apparent during trial participation and fall beyond the scope of management of the clinical trial site, women are referred to local service providers for ongoing treatment, management and care. 28. If women in ASPIRE use condoms, how will you know if the ring is effective for preventing HIV? As in all HIV prevention trials, researchers conducting ASPIRE provide participants free condoms and HIV riskreduction counseling, including on the use of condoms, as well as routine testing and treatment for STIs. Yet, women cannot always convince their partners to use condoms or to use them all the time. So, despite all that is provided to study participants, the reality is that some women will still acquire HIV, and this will be true among women in both study groups those assigned to use dapivirine ring and those assigned to use a placebo ring with no active product. If at the end of the study there is a fewer number of women in the group using the active product who get infected compared to the placebo group, that will indicate to researchers that the product was instrumental in preventing HIV. 29. What if another HIV prevention approach becomes widely available during this trial would women in the trial have access? As part of the study participants receive a comprehensive HIV prevention package that includes condoms, riskreduction counseling and treatment for STIs. If, during the course of the study, other new prevention strategies are found to be effective and are also incorporated into national HIV prevention policies, study participants will be counseled about these interventions, and either offered them by the site or referred to local centers with appropriate expertise, in accordance with WHO/UNAIDS guidelines and local HIV prevention practice and standards. 30. Why is ASPIRE only being conducted in Africa? The MTN has clinical trial sites in many parts of the world, but not all of these sites are in places where the rates of new HIV infections for women are as high as they are in Africa. In places where the risk for HIV infection is high, researchers can determine more quickly and with greater certainty whether a certain product is working. More importantly, women in sub-saharan Africa represent the largest and fastest growing at-risk population for HIV, and they have the most to gain if this trial or any other trial identifies a safe and effective method for preventing HIV. 31. How is ASPIRE involving the community? True community participation in HIV prevention research requires a level of ownership throughout the research process. Understanding the purpose, methods and limitations of clinical research is also vital for meaningful community input into study design and implementation. As such, all MTN trial sites have active community engagement programs with local non-governmental organizations, activist groups, journalists, local physicians, health department officials and other stakeholders; and during the development of an MTN protocol and throughout implementation, trial site Community Advisory Boards (CABs) play an especially important role. At a broader level, MTN s Community Working Group (CWG), comprised of community educators and CAB members from each clinical research site, has and will continue to be actively involved in the development of community education strategies and in providing input about different study procedures. As the trial was being designed, leading African advocates and civil society representatives were also consulted. The MTN values their continued engagement, especially in the context of a changing HIV prevention trials landscape. # # # More information and materials about ASPIRE is available at About the Microbicide Trials Network The Microbicide Trials Network (MTN) is an HIV/AIDS clinical trials network established in 2006 by the National Institute of Allergy and Infectious Diseases with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, all components of the U.S. National Institutes of Health. Based at Magee-Womens Research Institute and the University of Pittsburgh, the MTN brings together international investigators and community and industry partners whose work is focused on the development and rigorous evaluation of promising microbicides products applied inside the vagina or rectum that are intended to prevent the sexual transmission of HIV from the earliest phases of clinical study to large-scale trials that support potential licensure of these products for widespread use. More information about the MTN is available at 27-June-2014