RMP-02/MTN-006: Phase I Safety, Acceptability and Drug Absorption Study of the Vaginal Microbicide Tenofovir Gel Applied Rectally Compared to Oral Tenofovir
1. What is the aim of RMP-02/MTN-006?
RMP-02/MTN-006 is a Phase I trial involving both men and women that seeks to determine whether rectal use of a vaginal microbicide gel containing the antiretroviral (ARV) drug tenofovir is safe, and in particular, that its use does not cause cells in the rectum to become more vulnerable targets for HIV infection than they already are. The study represents an important step in efforts to curb the epic proportion of HIV infections attributed to unprotected anal sex. Receptive anal intercourse is common among men who have sex with men and there is increasing evidence that significant numbers of heterosexual women in both the developed and developing world also engage in the practice. According to conservative estimates, the risk of acquiring HIV through unprotected receptive anal sex is 20 times greater than unprotected vaginal sex. To date, the majority of microbicide research has focused on development of vaginal microbicides for preventing the sexual transmission of HIV in women. In the absence of a rectal-specific product, it is likely that both men and women will use the vaginal gel with anal sex. As such, in addition to safety, RMP-02/MTN-006 is looking to see the extent that active drug in the gel is absorbed by and distributed to the rectum and in blood and asking participants if they find the product acceptable and easy to use. In novel laboratory studies, researchers hope also to gain insight on the effectiveness of vaginal tenofovir gel for preventing HIV infection of target cells in rectal tissue.
2. Who is conducting and supporting the study?
RMP-02/MTN-006 is a study funded by the Division of AIDS (DAIDS) at the National Institute of Allergy and Infectious Diseases (NIAID), a component of the U.S. National Institutes of Health (NIH), through both the Integrated Preclinical/Clinical Program for HIV Topical Microbicides (IPCP-HTM) and the Microbicide Trials Network (MTN). The study represents a collaboration between the IPCP-HTM-funded Microbicide Development Program based at the University of California, Los Angeles (UCLA), which focuses on preclinical and early Phase I development of ARV-based rectal microbicides, and the MTN, based at the University of Pittsburgh. The MTN is an HIV/AIDS clinical trials network established and funded by DAIDS/NIAID with co-funding from the National Institute of Mental Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development, all components of NIH. Peter Anton, M.D., the director of the Center for Prevention Research at UCLA, is leading RMP-02/MTN-006, together with Ross Cranston, M.D., and Ian McGowan, M.D., Ph.D., at the University of Pittsburgh. As co-sponsors of RMP-02/MTN-006, CONRAD of Arlington, Virginia, USA; and Gilead Sciences, Inc., of Foster City, California, USA, are providing the study products free of charge.
3. When did the trial begin and how long will it last?
The study, which is being conducted at UCLA and the University of Pittsburgh, began enrolling participants in September 2009. A total of 18 men and women will be enrolled into the study, which is expected to take about a year to complete, with results available some time in 2010.
4. What is a microbicide?
Microbicides are substances designed to prevent or reduce the sexual transmission of HIV when applied topically on the inside of the vagina or rectum. A microbicide can be formulated in many ways, such as a gel or cream, or as a ring that would release the active ingredient over time. A handful of microbicide products are being tested in clinical trials although none is currently approved or available for use.
5. Why do men and women need rectal microbicides?
In the United States alone, anal intercourse is practiced in up to 90 percent of gay and other men who have sex with men, according to International Rectal Microbicides Advocates. Moreover, the practice is not limited to men. U.S. estimates and surveys in the United Kingdom indicate between 10 to 35 percent of heterosexual women have engaged in anal sex at least once. Globally, estimates suggest 5 to 10 percent of sexually active women are having anal sex. The risk of acquiring HIV through unprotected anal sex is at least 20 times greater than with unprotected vaginal sex and increases if other infections are already present in the rectal lining. Merely a single-cell thick, the lining of the rectum is a fragile barrier and, therefore, an easy point of entry to an abundant number of HIV target cells. By contrast, in the vagina, HIV must penetrate a slightly more protective layer of cells – about 40 cells in thickness – to reach a smaller population of target cells it can infect. While condoms are generally effective for protecting against HIV and other sexually transmitted infections, most acts of anal sex go unprotected. If found to be safe and effective, a rectal microbicide would represent an alternative method of protection for both men and women. As a lubricant, a microbicide gel could also enhance sexual pleasure, making regular and consistent use more likely.
6. Why is this study important?
The majority of microbicide research has focused on products for preventing HIV transmission through vaginal sex. Even though these products have been designed for vaginal use, it is generally assumed that if a vaginal microbicide were to be approved, it would be used by both men and women during anal sex, even without evidence on its rectal safety and effectiveness. As such, there is a need to evaluate the rectal safety profile of candidate vaginal microbicides. RMP-02/MTN-006 is the first rectal safety study of the vaginal formulation of tenofovir gel. Results will help researchers establish rectal safety standards for the vaginal preparation of tenofovir gel and help determine whether the vaginal gel is suitable for further study in larger clinical trials as a rectal microbicide. In addition, insight gained in the study into the gel’s potential efficacy as a rectal microbicide in humans will enable researchers to better design and hasten the pace of clinical trials.
7. What products are being studied in RMP-02/MTN-006?
Two products – tenofovir vaginal gel and oral tenofovir – are being studied in RMP-02/MTN-006. The active ingredient in tenofovir gel belongs to a class of ARVs called nucleotide/nucleoside reverse transcriptase inhibitors (NRTIs), which act against HIV by targeting a key enzyme the virus needs to copy its genetic material – an essential step for the virus to multiply and infect other cells. In its tablet form, tenofovir disoproxil fumarate, known by the brand name Viread®, is approved as a treatment for HIV infection when used in combination with other drugs and is widely prescribed and well tolerated by most people. Tenofovir is also under study for its potential to prevent HIV, an approach known as pre-exposure prophylaxis, or PrEP. PrEP trials thus far suggest the drug is safe to be used in trials of people without HIV.
Tenofovir gel is a candidate microbicide specifically developed to prevent the sexual transmission of HIV through vaginal intercourse and is currently being evaluated in two large Phase IIb trials in women. Laboratory and nonclinical studies have shown its potential for preventing HIV infection of target cells in vaginal and cervical tissue. Clinical safety studies performed have found it is well-tolerated and safe in both HIV-positive and HIV-negative women, and an expanded safety and acceptability trial found daily use of the gel over six months safe in and well-tolerated by sexually active HIV-negative women. Animal studies involving rectal application of tenofovir gel suggest it is safe. RMP-02/MTN-006 is the first clinical study in humans testing tenofovir gel in the rectum.
Both the oral and topical formulations of tenofovir were developed by Gilead Sciences, Inc., of Foster City, California, USA, which assigned a royalty-free license for the topical gel to the International Partnership for Microbicides of Silver Spring, Maryland, and CONRAD, of Arlington, Virginia, in December 2006.
8. How is RMP-02/MTN-006 designed?
RMP-02/MTN-006 will enroll 18 sexually abstinent, HIV-negative men and women. Participation involves two study regimens, one focused on oral tenofovir and the second on the rectal administration of either tenofovir gel or a placebo gel known as the hydroxyethyl cellulose (HEC) “universal placebo.” In the first part of the study, participants will be given a single oral dose of tenofovir and then undergo a series of tests and examinations over a two-week period, which will be followed by two weeks of “rest.” For the second part of the study, participants are randomized to one of two groups. One group will receive a single dose of vaginal tenofovir gel and the other group will receive a dose of placebo gel with no active ingredient. Both groups will go through the 14-day schedule of tests and two weeks without tests or study product. Participants will then be instructed to apply one dose of their assigned study gel rectally for six consecutive days, and they will return to the clinic to receive the seventh dose and undergo the final group of tests.
The tests and procedures performed at various time points of the study include blood tests, vaginal and rectal fluid collection and rectal exams and tissue collection using a standard procedure called sigmoidoscopy. Such tests will help researchers determine how much drug is being absorbed and remains in its active form over time in different parts of the body and to observe any changes to cells and tissue that may be due to use of the study drug. Repeating the same tests for both oral tenofovir and tenofovir gel will allow researchers to make comparisons of the two and determine which approach (if either) is likely to achieve optimal drug concentrations in the areas of the rectum where it is most critical for preventing HIV transmission. To explore the acceptability of tenofovir vaginal gel for rectal use, study participants will be asked about side effects and their likes and dislikes about both the gel and the applicator, which was designed for vaginal use. They will also be asked about the likelihood they would use rectal microbicides in the future, should one become available.
9. Why study an oral tablet in a microbicide trial?
Evaluating both approaches in a single trial is an efficient way to help researchers learn more about how a single dose of tenofovir gel differs from a single oral dose in terms of safety, absorption and distribution in the body. In addition, ARV-based prevention – as either a daily gel or tablet (PrEP) – is a promising HIV prevention approach being explored in clinical trials, so it is important to understand the safety of each in people who may engage in receptive anal intercourse.
10. The study intends also to study the effectiveness of tenofovir vaginal gel as a rectal microbicide, but this will be done in a laboratory. How is that possible?
A unique feature of RMP-02/MTN-006 are laboratory “explant” studies designed to assess whether tenofovir gel applied in the rectum can protect against HIV. Researchers will obtain small samples of rectal tissue from each participant at the beginning of the study and at different time points following their use of oral tenofovir and either tenofovir gel or placebo gel and then see how well the tissue is protected against infection when exposed to HIV. The studies will help researchers determine the extent that vaginal tenofovir gel may be effective against the sexual transmission of HIV in the rectum and will help inform decisions about the safety and suitability of the product for further study in larger clinical trials.
11. What is being done to ensure the safety of the participants?
RMP-02/MTN-006 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. As with all NIH-funded studies, RMP-02/MTN-006 incorporates a multi-tiered safety review process that includes strict national and international standards and procedures for monitoring and reporting. The protocol underwent extensive and rigorous review by NIAID, the U.S. Food and Drug Administration and the institutional review boards (IRBs) for both UCLA and the University of Pittsburgh. 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 tenofovir gel applied rectally, as an added precaution, participants will be strongly urged to remain sexually abstinent during the periods that study products are being evaluated.
12. Will participants in the study provide informed consent?
Written informed consent will be obtained from each study participant prior to screening and enrollment. This process ensures that individuals understand the procedures, as well as possible risks and benefits of the study. Participants are under no obligation to participate and may leave the study at any time, without consequence.
13. Are there other studies planned or underway that also focus on rectal microbicides?
As a complement to RMP-02/MTN-006, the MTN will soon begin a Phase I study called MTN-007 to evaluate the rectal safety and acceptability of vaginal tenofovir gel. The study will enroll approximately 60 men and women at the University of Pittsburgh, University of Alabama at Birmingham and Fenway Institute in Boston. Dr. McGowan, who is also co-principal investigator of the MTN, is leading the study with Kenneth Mayer, M.D., of the Fenway Institute. In other NIH-funded studies, Dr. McGowan is looking at rectal microbicide safety and acceptability in young black and Latino men who have sex with men, one of the highest at-risk groups in the United States.
Work is also underway to develop and eventually test rectal-specific products, which could be in preliminary clinical trials within the next few years. One effort, also funded by NIH and also being led by Dr. McGowan, aims to develop rectal formulations of tenofovir gel, another ARV-based microbicide called UC781 and the two combined. The IPCP-HTM-funded Microbicide Development Program at UCLA, which focuses specifically on investigating the preclinical and early Phase I development of ARV-based rectal microbicides, has already conducted one study of the vaginal formulation of UC781.
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11-May-10
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