ASPIRE – A Study to Prevent Infection with a Ring for Extended Use
Phase III Safety and Effectiveness Study of the Dapivirine Ring
Summary
· ASPIRE – A Study to Prevent Infection with a Ring for Extended Use, also known as MTN-020, is a Phase III study 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 the sexual transmission of HIV. The study will enroll approximately 3,476 women at several sites in Africa beginning mid-2012 and take approximately two years to conduct, with results anticipated late 2014 or early 2015.
· 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, 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 (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.
· The International Partnership for Microbicides (IPM) developed the dapivirine ring that will be tested in ASPIRE. IPM is also the regulatory sponsor and license holder of the product and will be conducting in parallel with ASPIRE another safety and effectiveness trial of dapivirine ring called The Ring Study, or IPM 027, which will enroll approximately 1,650 women.
· 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. As a potential method for preventing sexual transmission of HIV, rings are seen as an alternative to microbicide gels that are used every day or at the time of sex. The dapivirine ring being tested in ASPIRE is designed to be used by women for four weeks at a time.
· ASPIRE represents a major step forward in the evaluation of a promising female-controlled method, which is intended for extended use. 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 large-scale trials testing an ARV-based HIV prevention product using a drug other than tenofovir or tenofovir combined with the ARV emtricitabine.
Why This Study is Important
Of the more than 34 million people living with HIV, half are women. Three-quarters of the world’s HIV-positive women live in sub-Saharan Africa. The majority of women are acquiring HIV through heterosexual intercourse. In fact, women are twice as likely as their male partners to acquire HIV during 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 five 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.
Vaginal microbicides are HIV prevention products being developed especially for use by women to help reduce their risk of HIV infection through vaginal sex. To date, clinical trials have primarily focused on microbicides formulated as vaginal gels, with tenofovir gel being the most studied. In a trial called CAPRISA 004, HIV risk was reduced by 39 percent among women who used tenofovir gel before and after sex compared to women who used a placebo gel. However, VOICE – Vaginal and Oral Interventions to Control the Epidemic, which was designed to evaluate daily use of tenofovir gel, as well as daily use of an oral ARV tablet, stopped testing tenofovir gel after an interim review of study data determined that while safe it was no better than a placebo for protecting against HIV among the women in the trial. In the meantime, FACTS 001, a Phase III trial testing the same tenofovir gel regimen used in CAPRISA 004, continues to enroll women into that study, with results expected in 2014.
Experience in the area of female contraception has demonstrated that women’s preferences differ, and that a product that best suits a woman’s lifestyle and needs is more likely to be used. Only if a product is used and used properly does it have a chance of being effective. This is why it is important to investigate different HIV prevention strategies. Some women may prefer taking a tablet, or prefer using a vaginal microbicide gel; while others may prefer a vaginal ring that they replace monthly. ASPIRE is the culmination of a large body of research looking at the dapivirine ring as an alternative HIV prevention method for women. The study is designed to provide the strength of evidence to support potential licensure of the product. Positive results from ASPIRE, together with data from The Ring Study, a smaller safety and effectiveness trial that IPM will conduct in parallel, could lead to regulatory approval of the dapivirine ring for widespread use.
How the Study is Designed
ASPIRE is a Phase III trial designed to evaluate the safety and effectiveness of monthly use of the dapivirine vaginal ring for preventing the sexual transmission of HIV. The study will enroll approximately 3,476 HIV-negative women who will be randomly assigned to use either the dapivirine ring or a placebo ring that looks the same but contains no active drug. Participants will be instructed how to insert and remove the ring, which they will replace every four weeks. It is anticipated that women will use their assigned product for at least one year, some for as long as two years. As part of the study, all participants will receive ongoing HIV risk reduction counseling, condoms and diagnosis and treatment of sexually transmitted infections (STIs).
ASPIRE is also designed to assess women’s adherence to and acceptability of the ring. In women who acquire HIV during the study, researchers will try to determine if there is a relationship between drug levels in cells and tissues and HIV acquisition, as well as the nature and frequency of HIV drug resistance. The study is expected to be conducted at MTN-affiliated sites in Malawi, Uganda, South Africa, Zambia and Zimbabwe, pending in-country approvals.
About the Dapivirine Ring
Dapivirine, also known as TMC-120, belongs to a class of ARVs called non-nucleoside reverse transcriptase inhibitors (NNRTIs) that bind to and disable HIV’s reverse transcriptase enzyme, 
a protein that HIV needs to make copies of itself. Although dapivirine was initially being developed by Tibotec Pharmaceuticals, a subsidiary of Johnson & Johnson based in Belgium, as an oral therapeutic agent to be used in the treatment of HIV, dapivirine is a promising candidate for development as a microbicide due to its favorable safety profile as well as its physical and chemical properties. In 2004, Tibotec (now Janssen R&D Ireland, one of the Janssen pharmaceutical companies of Johnson & Johnson) assigned a royalty-free license to IPM, a non-profit product development partnership based in Silver Spring, Md., to develop dapivirine as a vaginal microbicide for the prevention of HIV in developing countries. 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.
a protein that HIV needs to make copies of itself. Although dapivirine was initially being developed by Tibotec Pharmaceuticals, a subsidiary of Johnson & Johnson based in Belgium, as an oral therapeutic agent to be used in the treatment of HIV, dapivirine is a promising candidate for development as a microbicide due to its favorable safety profile as well as its physical and chemical properties. In 2004, Tibotec (now Janssen R&D Ireland, one of the Janssen pharmaceutical companies of Johnson & Johnson) assigned a royalty-free license to IPM, a non-profit product development partnership based in Silver Spring, Md., to develop dapivirine as a vaginal microbicide for the prevention of HIV in developing countries. 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. Like vaginal rings that are used for contraception and hormone replacement in the U.S. and Europe, the dapivirine ring is made of an elastic silicone material. Its design allows for the delivery of dapivirine slowly over time. In fact, studies have shown that the ring can deliver high concentrations of active drug to vaginal tissue for a month or longer, with only trace amounts of the drug being absorbed elsewhere in the body. Studies to date have also shown that use of the dapivirine ring is safe and well-tolerated by women, and that among women in Africa, the vaginal ring itself is highly acceptable as a potential method for HIV prevention. Recently, results of a large trial among 280 participants in Kenya, Malawi, South Africa and Tanzania found the ring safe and acceptable to use.
As part of its strategy to license the ring, IPM will be conducting The Ring Study, or IPM 027, that will collect additional long-term safety and efficacy data about the dapivirine ring among approximately 1,650 women at multiple sites in Africa. The Ring Study will be conducted in parallel with MTN’s ASPIRE Phase III trial. If these studies find the daprivirine ring safe and effective, IPM intends to seek approval from the European Medicines Agency, the U.S. Food and Drug Administration and the South African Medicines Control Council and other African regulatory agencies to make the ring available for use as an HIV prevention method. 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 HIV.
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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 who are devoted to preventing or reducing the sexual transmission of HIV through the development and evaluation of products applied topically to mucosal surfaces or administered orally.
More information and materials about ASPIRE is available at http://www.mtnstopshiv.org/news/studies/mtn020
6-April-2012
See Also
