1. What is the aim of MTN-013/IPM 026?
MTN-013/IPM 026 is a Phase I study that aims to evaluate the safety of a vaginal ring being developed as a possible method for protecting women against HIV infection 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. MTN-013/IPM 026 is the first clinical trial of a vaginal ring containing two antiretroviral (ARV) drugs: dapivirine and maraviroc. Because each works against HIV in a different way, it is thought that a ring with both agents may offer greater protection against HIV than a ring containing either drug alone. Before researchers can conduct a trial to determine whether the dapivirine-maraviroc ring is effective in preventing HIV, they first must know that it is safe and acceptable for women to use. In addition, it is important to know how much of each drug is taken up by the cells usually targeted by HIV and whether drug levels are sustained throughout the four weeks that the ring is worn.
MTN-013/IPM 026 will involve 48 HIV-negative women who will be randomly assigned to use either the combination dapivirine-maraviroc ring, a ring containing maraviroc alone, a ring that contains dapivirine alone, or one with no active product. The dapivirine-only ring has already been studied extensively and is to be evaluated in a Phase III effectiveness trial called ASPIRE that is expected to begin May or June 2012, as well as in another large study called The Ring Study. The maraviroc-only and dapivirine-maraviroc rings, on the other hand, are being tested in humans for the first time in MTN-013/IPM 026.
2. What is unique about MTN-013/IPM 026?
In testing a vaginal ring containing maraviroc, MTN-013/ IPM 026 is the first clinical trial of a vaginal microbicide based on a type of ARV called an entry inhibitor. Entry inhibitors block HIV from being able to enter human cells. To date, all other clinical trials of ARV-based microbicides have focused on ARVs called nucleoside or non-nucleoside reverse transcriptase inhibitors (NRTIs or NNRTIs).These include tenofovir (an NRTI) formulated as a vaginal gel and dapivirine (an NNRTI) formulated as either a vaginal gel or a ring. MTN-013/ IPM 026 is also the first clinical study of a vaginal microbicide containing two active drugs. A ring with two drugs, each having a different mechanism of action against HIV, potentially may be more effective in defending against HIV than a ring with a single drug. Similarly, to be effective, the treatment of HIV typically requires at least three drugs used in combination.
3. Why is this study important?
Of the 34 million people living with HIV, half are women. The majority of women acquire HIV through unprotected heterosexual intercourse with an infected partner. 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 condoms have not been enough to stop the HIV epidemic nor are these methods practical in most settings. There is an urgent need for effective prevention strategies that women can control themselves. Toward this end, 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 a gel based on the ARV tenofovir having been studied the most. . Tenofovir gel was found safe and effective in reducing the risk of HIV in women who used it before and after vaginal sex in a study called CAPRISA 004. Yet, researchers conducting another trial called VOICE stopped testing tenofovir gel after an interim data review determined that while safe, it was not effective among the women in the study who were asked to use the gel every day.Tenofovir gel continues to be evaluated in FACTS 001, a Phase III trial testing the same regimen of tenofovir gel used in CAPRISA 004. But for some women, a microbicide in the form of a vaginal ring, which can be used monthly, may be more suited to their particular needs or lifestyles, and therefore, more likely to be used. A product only has a chance of being effective if it is used and used properly. Of the vaginal rings being developed for HIV prevention, the dapivirine ring is the farthest along, with two large-scale trials set to launch by May or June 2012. MTN-013/ IPM 026 represents an important step toward the development of a safe and effective product that employs a drug that works differently than either dapivirine or tenofovir. Moreover, the study is important for determining whether a combination ring can be considered for further study in larger clinical trials.
4. Who is conducting and funding the study?
MTN-013/IPM 026 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 Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health (NIMH), all components of the U.S. National Institutes of Health (NIH). NIAID and NIMH are the main sponsors of the study. As co-sponsor and the developer of the rings being tested in the trial, the International Partnership for Microbicides (IPM), a non-profit product development partnership based in Silver Spring, Maryland, is providing the study products for free. Leading the study is Beatrice A. Chen, M.D., M.P.H., of the University of Pittsburgh School of Medicine and Magee-Womens Hospital of UPMC, who is protocol chair; with Lori Panther, M.D., M.P.H., of the Fenway Institute and Harvard University in Boston, as protocol co-chair.
5. Where is MTN-013/IPM 026 being conducted?
MTN-013/IPM 026 is being conducted at three NIAID-funded clinical research sites affiliated with the MTN: the University of Pittsburgh, Fenway Institute and the University of Alabama at Birmingham.
6. When did the trial begin and how long will it last?
The study began screening potential participants in November 2011 and is expected to take less than a year to complete, with results available early 2013.
7. What is the difference between a vaginal microbicide and a vaginal ring?
Microbicides are products designed to prevent or reduce the sexual transmission of HIV or other sexually transmitted infections (STIs) when applied topically inside the vagina or rectum. A microbicide can be formulated in many ways, such as a vaginal or rectal gel or cream, or as a vaginal ring that once inserted releases the active ingredient gradually over time. Vaginal rings that are being developed for HIV prevention are seen as alternatives to microbicides formulated as a gel, which would be used every day or at the time of sex. Different microbicide products are being tested in clinical trials, including in trials being conducted by the MTN, although none is currently approved or available for general use. The rings that are being developed for HIV prevention have a similar look and feel to vaginal ring products that are used for contraceptive delivery or hormone replacement and licensed in both the U.S. and Europe.
8. What rings are being studied in MTN-013/IPM 026?
Researchers conducting MTN-013/IPM 026 are testing three vaginal rings: a ring that contains 25mg of the ARV dapivirine; a ring that contains 100mg of the ARV maraviroc; and a ring containing both a 25-mg dose of dapivirine and a 100-mg dose of maraviroc. A fourth ring, a placebo, contains no active drug. Each of the rings is made of silicone elastomer and measure 56mm (about 2 ¼ inches) in diameter and 7.7mm thick (¼inch).
Dapivirine, also known as TMC120, is a type of ARV that inhibits the ability of HIV to replicate. Dapivirine was initially being tested by Tibotec Pharmaceuticals, one of the Janssen pharmaceutical companies, as an oral therapeutic agent to be used in the treatment of HIV, but it was determined to be a more promising drug for prevention of HIV infection. In 2004, Tibotec assigned a royalty-free license to IPM to develop dapivirine as a vaginal microbicide for the prevention of HIV in developing countries. Since then, 15 clinical safety studies of dapivirine, formulated as either a vaginal gel or a vaginal ring, have been conducted by IPM and its partners (most studies have been in women, with one study in men, MTN-012/IPM 10, conducted by the MTN.). Studies of the dapivirine ring show that it 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. Furthermore, studies to date have found 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. In mid-2012, the MTN expects to launch ASPIRE, a Phase III trial of the dapivirine ring that will enroll approximately 3,476 women at sites in Malawi, Uganda, South Africa, Zambia and Zimbabwe. As part of its strategy to license the dapivirine ring, IPM will conduct The Ring Study (IPM 027) in parallel with the ASPIRE, and collect long-term safety and efficacy data among approximately 1,650 women at multiple research centers in Africa.
Maraviroc is an ARV marketed under the trade names Selzentry® in the United States and Celsentri® in Europe for use in combination with other oral ARVs for treating people infected with HIV. It works by blocking a molecule, called a receptor, on the surface of cells that the most common strains of HIV use for gaining entry. IPM is developing maraviroc as a topical microbicide for women in developing countries through a 2008 non-exclusive, royalty-free licensing agreement now held by ViiV Healthcare. Because maraviroc is licensed as an oral drug, there is extensive preclinical and clinical safety information as well as data on its efficacy since being approved for treatment of HIV in 2007. IPM considers maraviroc a highly promising compound because it is active against HIV strains that are resistant to other ARVs. IPM has completed several preclinical studies of maraviroc and is exploring its development as a microbicide formulated as a vaginal ring both alone and in combination with dapivirine or tenofovir. The MTN-013/IPM 026 study will be the first time that a maraviroc-based microbicide will be evaluated in humans.
Combination dapivirine-maraviroc ring
IPM has conducted extensive preclinical studies of a dapivirine-maraviroc vaginal ring, that combined with the large portfolio and clinical experience using maraviroc in the treatment setting and the encouraging research on the dapivirine ring to date, support its further evaluation in a Phase I clinical study.
9. How is MTN-013/IPM 026 designed?
MTN-013/IPM 026 is a Phase I study that will enroll 48 HIV-negative women between the ages of 18 and 40 who agree to use contraception and remain sexually abstinent throughout their participation in the trial. Participants will be randomized to use one of the four rings being tested in the trial: a combination dapivirine-maraviroc ring, dapivirine-only ring, maraviroc-only ring, or a placebo ring with no active drug. Women will insert the ring into the vagina themselves (or with the assistance of a clinician) on the day they enroll and will remove it after 28 days of use.
To determine if the rings are safe and how much of the drug or drugs is absorbed in the blood, vaginal fluid and cervical tissue, different tests will be performed daily in the first week and weekly thereafter. Each study visit will include a physical exam, and pelvic exams will be performed at other intervals during the study and small tissue samples of the cervix will be taken. Similar tests and procedures will be conducted at regular intervals during a 24-day follow-up period after the ring has been removed.
To assess women’s adherence to and acceptability of the ring, participants will be asked questions about what they liked or didn’t like about the ring, whether it was easy to insert and remove, whether they were aware of the ring or found it comfortable during daily activities and about their willingness to use a vaginal ring in the future, if one were available, to protect against HIV infection.
10. What will be done to ensure the safety of participants in MTN-013/IPM 026?
MTN-013/IPM 026 was designed according to the most rigorous international medical practice and ethical standards and includes numerous measures, beginning at the site level, intended to protect the safety and well-being of participants. Potential volunteers will be carefully screened by study staff to ensure that only women for whom it would be safe to participate are enrolled. Site staff will provide continuous close safety monitoring of all study participants. As with all NIH-funded studies, MTN-013/IPM 026 incorporates a multi-tiered safety review process that includes strict national and international standards and procedures for monitoring and reporting. Prior to implementation, the protocol underwent extensive and rigorous review by NIAID, the U.S. Food and Drug Administration and the institutional review boards (IRBs) at each trial site. IRBs ensure that studies are scientifically valid and ethically conducted and they provide oversight throughout the duration of a trial.
Because this is the first study of the maraviroc ring and dapivirine-maraviroc ring, participants will be strongly urged to remain sexually abstinent during the study.
11. Will women participating in the study provide informed consent?
Yes. Women who volunteer to join MTN-013/IPM 026 will be educated about all the study procedures, any possible risks, benefits and alternatives to participation as well as the study’s time requirements. Study staff will also explain that women do not have to take part in the study and can leave it at any time, without consequence. This process is called “informed consent” and it will occur prior to screening, again at enrollment, and continue throughout the duration of the study.
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More information and materials about MTN-013/IPM 026 and other MTN clinical trials is available at http://www.mtnstopshiv.org/news