Frequently Asked Questions
The Ring Study and ASPIRE: The basics
What are The Ring Study and ASPIRE?
The Ring Study and ASPIRE are Phase III clinical trials that evaluated whether a monthly vaginal ring containing the antiretroviral (ARV) drug dapivirine is effective in preventing HIV in women and safe for long-term use. The trials also sought to assess whether women find the ring practical and easy to use. Together, these “sister” studies have involved more than 4,500 women volunteers across southern and eastern Africa, where women are at high risk of HIV.
The Ring Study (IPM 027) is led by the International Partnership for Microbicides (IPM), the nonprofit that developed the dapivirine ring, and enrolled 1,959 HIV-negative women ages 18-45 in South Africa and Uganda. ASPIRE (MTN-020), was led by IPM’s clinical trial partner the Microbicide Trials Network (MTN), and enrolled, 2,629 HIV-negative women ages 18-45 in Malawi, South Africa, Uganda and Zimbabwe.
What is dapivirine and how does it work in a vaginal ring?
Dapivirine is a potent ARV that belongs to a class of ARVs known as non-nucleoside reverse transcriptase inhibitors, or NNRTIs, which work against HIV-1 by blocking its ability to make copies of itself once inside a healthy cell. IPM began developing dapivirine as a microbicide in 2004, when it received a royalty-free license from Janssen Sciences Ireland UC that expanded to an exclusive worldwide rights agreement in 2014.
IPM explored various vaginal formulations containing dapivirine. Vaginal rings are flexible products that provide continuous and controlled release of a drug or multiple drugs to vaginal tissue over a period of weeks or months. Vaginal rings are currently used for other medical purposes, such as contraception and hormone replacement. IPM adapted this commonly used technology to develop the dapivirine vaginal ring for HIV prevention.
IPM’s ring is made of a flexible silicone material with dapivirine dispersed throughout the matrix. The ring delivers the drug directly to the site of potential infection, with low absorption elsewhere in the body. Women can insert and remove the rings themselves.
Who conducted and funded these studies?
The Ring Study is led by IPM, in partnership with seven research centers in South Africa and Uganda. IPM’s work is made possible through generous support from the Ministry of Foreign Affairs of Denmark, Flanders Department of Foreign Affairs, Irish Aid, the Ministry of Foreign Affairs of the Netherlands, the Norwegian Agency for Development Cooperation (Norad), the United Kingdom Department for International Development (DFID), the American people through the United States Agency for International Development (USAID) through the President’s Emergency Plan for AIDS Relief (PEPFAR), and the Bill & Melinda Gates Foundation.
ASPIRE was conducted by MTN and 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).
When did the trials begin and end?
Because two Phase III trials are usually needed for a product to be considered for regulatory approval, these “sister” studies were designed to take place concurrently to keep the timeline to potential licensure and rollout as short as possible. The ASPIRE study began in August 2012 and completed follow-up in 2015. The Ring Study began in April 2012 and was scheduled to complete follow-up in 2016. The study is reporting results early after its independent data and safety monitoring board recommended the study data be analyzed because sufficient information had been collected to determine the ring’s efficacy. In March 2016, The Ring Study will commence closing its placebo arm in South Africa following guidance from the regulatory authority in that country, based on the safety and efficacy findings from both studies. IPM is seeking similar approval in Uganda.
What were the trial designs?
Both The Ring Study and ASPIRE are randomized, double-blinded and placebo-controlled. Women enrolled in either study were randomly assigned to use either the dapivirine ring or a placebo ring that contained no active drug, and received a new ring at every monthly clinic visit. Neither the women nor the researchers knew the group assignments.
The Ring Study has a 2:1 randomization, meaning that for every two women who used the dapivirine ring, one woman used a placebo ring. Because The Ring Study was designed to assess the ring’s long-term safety, women in that study use their randomly assigned ring for at least two years. In March 2016, The Ring Study will commence moving all women still enrolled in the placebo group to the active group. The ASPIRE study had a 1:1 randomization, and women used their randomly assigned ring for at least one year.
Both studies also assessed how well women liked using the ring (acceptability) and consistency of ring use (adherence). In addition, both studies collected data on the rates of sexually transmitted infections (STIs), HIV-2 infection, and pregnancy occurring during the study as well as the frequency of drug resistance in women who become HIV-1 positive during the trial. All women in the two studies received ongoing HIV risk-reduction and safe sex counseling, free male condoms, STI treatment and other medical services.
What are the topline results of The Ring Study and ASPIRE?
The Ring Study and ASPIRE each found that the monthly dapivirine ring helped reduce the risk of HIV infection in women. The ring was also found to be safe in both studies.
In The Ring Study, which used a 2:1 randomization, of the 1,300 participants who used the dapivirine ring, 77 acquired HIV; of the 650 who used a placebo ring, 56 acquired HIV (31 percent efficacy). In ASPIRE, which used a 1:1 randomization, of the 1,308 participants who used the dapivirine ring, 71 acquired HIV; of the 1,306 who used a placebo ring, 97 acquired HIV (27 percent efficacy).
Notably, HIV protection appeared to increase with age and consistency of ring use, or adherence. ASPIRE showed that the ring reduced HIV risk by 61 percent in women older than age 25. In women older than age 21, ASPIRE showed that HIV risk was cut by more than half, which was supported by a trend in The Ring Study also showing higher efficacy for women in that age group. In addition, women older than 21 appear to have used the ring most consistently, which may help explain why protection was higher for them. Little to no protection was seen in either study among women ages 18-21. IPM and MTN are working to understand how ring use, and biological and other factors may have influenced different levels of protection by age.
What is the significance of the results? Why are these trials important for women?
This is the first time two studies have confirmed efficacy for a microbicide, an important achievement for women’s health. Globally, HIV/AIDS is a leading cause of death among women, taking an especially high toll in sub-Saharan Africa, where women account for nearly 60 percent of all people living with HIV and face some of the highest rates of HIV infection in the world. Women are particularly vulnerable to infection due to a mix of biological, economic and social factors, and urgently need a range of self-initiated prevention methods that match their individual needs and fit within the context of their lives. We hope the monthly dapivirine ring can join daily oral PrEP in expanding women’s prevention options.
How do The Ring Study and ASPIRE fit into IPM’s ring licensure program?
The Ring Study and ASPIRE make up the centerpiece of IPM’s Dapivirine Ring Licensure Program. As the ring’s developer and regulatory sponsor, IPM designed the licensure program to provide the strength of evidence required by regulatory authorities to support the ring’s potential licensure. In addition to the two Phase III studies, the clinical component of IPM’s licensure program includes several smaller studies to examine the ring’s safety in adolescents and women over 45, condom compatibility, possible drug interactions and use during menses and with tampons.
What’s next for the dapivirine ring?
IPM plans to submit the comprehensive dossier of evidence regulators require to license the product for public use in Q1 2017, once all data on the ring have been compiled. IPM is committed to working closely with governments, donors, communities and civil society partners to fully understand the findings from the ring studies and determine how the ring could best strengthen HIV prevention programs. In addition, IPM is planning to conduct an open-label extension (OLE) follow-on study to provide former Ring Study participants with the dapivirine ring while it is under regulatory review. Discussions will take place on a similar OLE study for former ASPIRE participants.
Ring Study results in detail
How did The Ring Study determine whether the ring helped prevent HIV?
As noted, women in the ring studies were randomly assigned to the active group receiving the dapivirine ring or a placebo group. In addition, all women participating in the trials received HIV risk-reduction counselling, free male condoms, STI testing and treatment, and other medical services. When sufficient data had been collected, we compared the rates of HIV infection in each arm to determine whether women who used the active ring had a lower rate of infection. This tells us whether the ring worked to help prevent HIV.
Why are there different analyses?
Previous HIV clinical trials have shown that there are many factors that could influence the efficacy of a prevention product. Analyzing the data in different ways is a standard and scientifically valid way to ensure that we understand the role of these factors, and helps us to build on the results to improve future research and development efforts.
What is being done to understand the difference in results by age?
IPM is now analyzing all of the data from The Ring Study to fully understand the results, including the differences in outcome by age, and expect to report the results of those additional analyses over the coming months. These data will also be reviewed with similar analyses of ASPIRE data.
What role did adherence play in the levels of HIV protection seen in The Ring Study?
The ASPIRE study found that HIV protection was greater in age groups that also showed more consistent ring use. Incidence of HIV was cut by more than half (56 percent) among women 21 and older, who also appeared to use the ring most consistently. These findings were supported by a post-hoc analysis in The Ring Study that showed a strong trend toward higher efficacy (37 percent) with lower levels of drug remaining in used rings, a marker of adherence. Taken together, these data suggest that the ring must be used continuously to achieve protection — and that protection can be achieved with consistent use. We are now conducting additional analyses to fully understand the results, which we expect to make available later this year.
How was adherence measured in The Ring Study? Was it the same for ASPIRE?
The Ring Study and ASPIRE both used objective methods to gauge participant adherence, such as measuring the amount of dapivirine remaining in used rings as well as drug levels in plasma and vaginal fluid samples. We also collected data from questionnaires and in-depth interviews.
Were there differences in results by country?
The Ring Study is taking place in two countries, South Africa and Uganda, with the majority of its participants located in South Africa. Because there are fewer participants in Uganda and few infections among those participants, differences by country in The Ring Study cannot be meaningfully calculated. ASPIRE showed no differences in protection by country.
What were the safety results? Were there side effects?
Both studies found the ring to be safe, with no statistical difference in safety concerns between the active and placebo arms. The monthly dapivirine ring has no known major side effects and has been found to be safe and well-tolerated in both Phase III trials and seven smaller safety studies. Previous IPM studies have shown that absorption of dapivirine is largely confined to vaginal tissue with low systemic exposure, which may help minimize side effects.
Was drug resistance seen in The Ring Study?
Both The Ring Study and ASPIRE found no evidence that use of the dapivirine ring increased the presence of ARV-resistant HIV virus.
How can you know the ring helped prevent HIV if the participants used condoms?
As in all HIV prevention trials, researchers provided participants free male condoms and HIV risk-reduction counseling, among other measures, for reducing their risk of HIV. However, condom use is not always a realistic option for many women, so the reality is that some women will still acquire HIV. This is true across study groups. So, at the end of the study, comparing the number of women in the group using the active product who become infected with the number who become infected in the placebo group is still a reliable way to indicate whether or not the product helped protect against HIV.
Implications and next steps
Will former Ring Study and ASPIRE participants have access to the dapivirine ring?
IPM is planning to conduct an open-label extension (OLE) follow-on study called DREAM that would provide previous Ring Study participants with the dapivirine ring and help answer critical questions about the product and its use while it is under regulatory review for licensure. NIAID, the primary NIH institute that funds MTN, will be convening a panel of experts to provide advice on a possible similar OLE study called HOPE that would provide the dapivirine ring to former ASPIRE participants. It is our expectation that knowledge of the ring’s safety and efficacy could help encourage its use, as seen in oral PrEP OLEs.
When would DREAM and HOPE start? Who would participate?
Pending regulatory and ethics approvals, we expect DREAM to begin in Q2 2016. Former Ring Study participants who have remained HIV-negative and meet other eligibility criteria will be invited to participate. Discussions on HOPE are scheduled to take place in March.
What other studies of the dapivirine ring are you conducting?
IPM is currently conducting a number of smaller supporting studies to inform the potential use of the ring should it be approved. These studies evaluate the ring’s safety and pharmacokinetics with factors such as menses and with tampon use, and potential interactions with commonly used medications to treat infections. IPM is also partnering with MTN to conduct a supporting study to assess the ring’s safety in adolescent girls, now ongoing, and a planned study assessing pharmacokinetics when the ring is used by lactating women.
Is IPM seeking regulatory approval for the ring’s licensure?
Yes. IPM plans to submit the comprehensive dossier of evidence regulators require to license the product for public use in Q1 2017, once all data on the ring have been compiled.
Where and when will the dapivirine ring be available for widespread use?
IPM plans to seek regulatory approval in Q1 2017, once all data on the ring have been compiled. Pending approvals, the dapivirine ring could be available to women in trial populations through open-label extension studies in 2016 and commercially available in some countries as soon as 2018. In alignment with our mission, the first phase of the dapivirine ring’s rollout would be in the eight African countries with the highest HIV incidence among women globally, pending regulatory approvals in those countries.
How much will the ring cost?
IPM is a nonprofit organization, and our goal is to ensure that women who can most benefit from the ring can access it affordably. We are prioritizing potential roll-out of the ring in Africa, where women are at greatest risk. The ring’s ultimate cost will vary from country to country, and depend on factors such as the scale of manufacturing, delivery and packaging. We are working with donors, governments and commercial manufacturers and other partners to develop the lowest and most cost-effective process possible. Partnerships and financing mechanisms being researched right now will play a vital role in keeping costs to women low. IPM is also developing a three-month dapivirine ring that would further lower the cost to women, who would need just four rings per year.
What are the potential benefits of the dapivirine ring?
The dapivirine ring is the first long-acting HIV prevention product shown to safely help prevent HIV, and was specifically designed for women. It is discreet, allowing women to use the tool on their own, without partner negotiation. Previous IPM studies found that women find the ring highly acceptable, and both women and their male partners report that it does not interfere with sexual pleasure. Given the continuing high rates of new infections among women, especially in sub-Saharan Africa, the dapivirine ring could be an important new self-initiated prevention option.
How does the ring fit into a comprehensive HIV prevention package alongside condoms, PrEP and TasP?
As seen in the ring studies, HIV incidence rates among women in sub-Saharan Africa remain alarmingly high, underscoring the need for different and multiple prevention options to meet women’s diverse needs and help end the epidemic. The monthly dapivirine ring reduced new infections by up to 56 percent in women over 21, with additional data showing a clear trend toward increased efficacy with more consistent use. As seen with PrEP, knowing a product’s efficacy can help encourage its use. That’s why it’s so critical now to make multiple methods available, and to educate women, communities and health workers about their options. We hope that, if approved, the long-acting dapivirine ring could join daily PrEP in expanding new self-initiated options for women as part of a comprehensive HIV prevention package that includes male and female condoms, TasP and other strategies.
Now that the efficacy of a microbicide for HIV prevention has been confirmed in two clinical trials, what are the implications for other microbicide products?
As the first vaginal ring to effectively deliver an ARV, the results of the two Phase III studies open the door to further development of microbicides for HIV and multipurpose prevention. IPM is developing a three-month dapivirine ring that would allow women to replace the ring less frequently; three-month combination rings that leverage multiple ARVs to potentially increase efficacy; a three-month ring that would simultaneously prevent HIV and unintended pregnancy; and other new formulations such as films, tablets and rectal gels.
At the trial site
What was done to ensure The Ring Study was conducted ethically?
All studies of IPM products closely adhere to international, national and local ethical standards, and national regulatory standards. Our studies — and the way in which they are conducted — are also approved in advance by the appropriate regulatory authorities and independent ethics committees. In addition, a process called “informed consent,” which follows the internationally accepted Good Clinical Practice guidelines, ensures that volunteers clearly understand the potential benefits and risks of the clinical study before they decide to enroll. Volunteers are also informed that they can withdraw from clinical trials at any point during their participation.
Did women provide informed consent to participate in the study?
Yes, all women who volunteered to participate in The Ring Study provided informed consent before enrolling in the study. The informed consent process is crucial to ensuring all participants receive detailed information about the study, and understand the potential risks and benefits of participation. Informed consent occurred at the first screening visit, again when a participant decided to enroll, and was revisited throughout the duration of the study. Women could choose to leave the study at any point for any reason, with no consequence. Informed consent forms and any other study-related materials were translated into appropriate local languages for each site. For non-literate volunteers, informed consent documents and other written materials were read to the participant in her preferred local language. These participants indicated consent verbally and provided a thumbprint, as verified by an impartial witness.
How did you know the ring was safe to use in The Ring Study?
Protecting the health and safety of the women who volunteer for the study is IPM’s top priority. Before participants in clinical studies use any new product, extensive preclinical studies are conducted in the laboratory and in animals to identify the product’s safety profile. Only products that are proven safe in these preclinical tests progress to clinical studies. Prior to the start of The Ring Study and ASPIRE, IPM completed six clinical safety studies of different formulations of the dapivirine ring, all of which showed the ring to be safe and well-tolerated.
What was done to ensure the safety of Ring Study participants during the study?
The Ring Study was approved by national regulatory agencies and local ethics committees before research centers began the study. IPM closely monitored the study to ensure that all operational and safety procedures were implemented according to the study protocol. In addition, study participants received medical treatment at the research centers or were referred to local health services as appropriate for medical conditions. Participants also received regular medical exams, HIV and STI testing and risk reduction counseling, and access to free male condoms at every study visit.
In addition, an independent Data Safety Monitoring Board (DSMB) conducted regular reviews of the study data to ensure the safety of participants at all times. If any safety concerns arose or if the study became unable to answer its main objectives, the DSMB could, at any time, recommend modifying or stopping the study to protect the safety and well-being of the participants. The DSMB for The Ring Study found no concerns about safety, quality of conduct or study integrity in any of its regular reviews of the study.
Why was The Ring Study conducted in Africa?
For HIV prevention trials to accurately show whether the product being tested is effective, they must take place in areas with a high incidence of HIV. As a result, efficacy studies like The Ring Study and ASPIRE must recruit participants from communities heavily affected by HIV, including in sub-Saharan Africa where women are at the greatest risk of infection. It is important that the trials involve the women who will later be using the product so that we know if it is safe and acceptable to them, and if they are willing and able to use it regularly. The high incidence rates we saw in both studies underscore the high risk faced by the women in these communities — and the urgent need to find effective prevention solutions. For clinical trials evaluating products for safety and how they act in the body, microbicide developers also recruit from many communities throughout and outside Africa, including Europe and the United States.
Were women taught to use the ring?
Participants learned how to insert and remove the ring when they first enrolled into the study and received additional guidance on its correct use at monthly follow-up visits. Site staff also counseled participants on how to reinsert the ring should it come out accidentally between visits. Participants were encouraged to return to the clinic at any time if they had any difficulty using the ring.
How was adherence promoted in The Ring Study and ASPIRE?
Both The Ring Study and ASPIRE worked closely with research centers to offer an in-depth adherence program to support participants. Research centers offered individualized adherence counseling and an array of community events designed to seek input, engage in dialogue and raise awareness about the key role of adherence in the dapivirine ring studies. Engaging men was an important part of the adherence strategy, as many women wished to involve their partner when using the ring as seen in previous IPM acceptability studies. Since launching in 2012, The Ring Study alone has held more than 200 adherence events, male engagement workshops, women’s health days, trainings and other events involving women and men in the wider communities where the studies were conducted.
How were male partners involved in The Ring Study?
Each of the research centers participating in The Ring Study held a range of outreach activities to raise awareness and involve male partners about HIV prevention, the ring and the study. These included individual counseling, couples counseling, workshops involving male partners, advocacy events and more.
How were trial site communities involved in The Ring Study?
IPM and its research center partners implemented a wide range of programs to engage diverse community members. Information about microbicides and clinical trials was provided in local languages not only to trial participants but also to key stakeholders, including local officials, women’s groups, medical professionals, the media, traditional leaders, ministries of health and others. Community Advisory Boards (CABs)/Community Advisory Groups (CAGs) at each trial site convened diverse community members to serve as a link between the research centers and the broader community. These CABs/CAGs played a vital role, providing feedback to the research centers throughout the conduct of the study and keeping their respective communities informed of the study’s progress. In addition, community members were invited to participate in outreach activities and events such as women’s and youth health awareness days, advocacy workshops, community sporting events, workshops and dialogues to engage men and more.
What medical services did women participating in The Ring Study receive?
Women received ongoing HIV risk-reduction counseling, male condoms, diagnosis and treatment of sexually transmitted infections (STIs), pregnancy testing and family planning services, as well as treatment or referrals for medical conditions. Women in either study who tested positive for HIV immediately stopped using the ring and were referred to local health facilities for care and treatment, with an option to enroll in a follow-up study to assess the ring’s impact, if any, on HIV treatment outcomes.
What happened if a woman became pregnant during the study?
Pregnant women and women who were breastfeeding at the time of screening were not eligible to enroll in the study. Women who volunteered for the study were required to be on a stable method of contraception, and those who enrolled received ongoing contraceptive counseling and access to free condoms, and were tested for pregnancy at each study visit. If a woman became pregnant during the study, she stopped using the ring immediately and was referred to a local health facility for prenatal services.
What happened if a woman became HIV-positive during the study?
Women in the study received ongoing and thorough counseling on reducing their risk of acquiring HIV and other STIs, and were provided with condoms at each visit to the research center. All participants were strongly encouraged to use a male condom during sex. However, using a condom is not always possible and a woman could acquire HIV if she has unprotected sex with a partner who is infected with the virus.
If a participant became HIV-positive during the study, she immediately stopped using the ring to minimize the possibility of developing resistance to dapivirine and other similar drugs. She was also counseled and referred for support services, and for appropriate HIV-related care and treatment at local health facilities. Each research center has strong linkages and referral agreements in place with local organizations that provide support and medical services. Women who become HIV-positive during The Ring Study also had the option to enroll in a separate long-term follow-up study to assess the impact, if any, of the microbicide on HIV treatment outcomes.