MTN-008 Expanded Safety Study of Tenofovir Gel in Pregnant and Breastfeeding Women
1. What is the aim of MTN-008?
MTN-008 aims to find out whether a vaginal microbicide gel containing the antiretroviral drug tenofovir is safe for women to use daily for one week during late-stage pregnancy and while breastfeeding. As the first clinical trial of tenofovir gel conducted among breastfeeding women and only the second among pregnant women, MTN-008 is part of a comprehensive research program that is designed to take incremental steps toward determining whether the gel can safely and effectively protect women against HIV infection during all stages of pregnancy and motherhood. The overall goal of the program is to develop HIV prevention products women can use throughout their lives. MTN-008, a Phase I study, is a follow-up to MTN-002, which found that a single dose of tenofovir gel given to pregnant women hours before giving birth by scheduled Cesarean delivery was safe and well-tolerated by both mother and infant. Based on these reassuring findings, researchers are increasing the dosage to daily use for one week during both at-term and close-to-term pregnancy. They plan to evaluate the safety of the drug and assess how much active drug is absorbed during pregnancy and subsequently transferred to the fetus. In breastfeeding mothers, the researchers will measure drug levels in breast milk and assess whether the drug is transferred to the baby.
2. What is a microbicide?
Microbicides are products being developed to prevent or reduce the risk of HIV or other sexually transmitted infections when used in the vagina or rectum. If proven effective, microbicides could help prevent HIV infection in women in developing countries where it most often is spread through unprotected heterosexual intercourse despite efforts to promote abstinence, monogamy and the use of condoms. Unlike condoms, microbicides provide an HIV prevention strategy that is not controlled by one’s sexual partner. A microbicide can be formulated in many ways, such as a gel or cream, or as a ring that releases the active ingredient gradually over time. Several microbicides have been tested in clinical trials, but none has been approved or available for widespread use.
3. What is tenofovir gel?
Tenofovir gel is a vaginal microbicide that researchers are hopeful may be the first to be approved for HIV prevention. In its tablet form, tenofovir is a common treatment for HIV when used in combination with other antiretroviral (ARV) drugs and it is increasingly being used to treat HIV-positive women who are pregnant. Both the tablet and gel forms of tenofovir were developed by Gilead Sciences, Inc., of Foster City, Calif., U.S., which assigned rights for the topical gel to CONRAD, of Arlington, Va., and the International Partnership for Microbicides of Silver Spring, Md. in December 2006. In a recent study called CAPRISA 004, HIV-negative women who used tenofovir gel before and after sex had 39 percent fewer HIV infections than women who used a placebo gel. This study and earlier trials also found the gel well-tolerated and safe. The Microbicide Trials Network (MTN) is conducting a major large-scale trial called VOICE –Vaginal and Oral Interventions to Control the Epidemic – that is testing whether daily use of tenofovir gel, or daily use of an ARV tablet, can reduce women’s risk for HIV among 5,000 women in southern Africa. The U.S. Food and Drug Administration (FDA) has indicated it will consider approving tenofovir gel as an HIV prevention method for women based primarily on its review of the results of CAPRISA 004 and VOICE, which are expected in 2013.
4. Why is this study important?
Nearly 16 million women around the world are living with HIV, which represents close to half of all people who are infected. Most of these women acquired HIV from unprotected vaginal sex. Vaginal microbicides are primarily intended for use by sexually active women of reproductive age, yet there is very little information
about whether these products can be safely used by pregnant and breastfeeding women, most of whom remain sexually active and continue to be at risk for HIV. In fact, some studies suggest that women may be particularly susceptible to HIV during pregnancy due to heightened immune responses or hormonal changes that affect the mucosal lining in the vagina. Because women often continue to use medications during pregnancy, knowing whether microbicides are safe to use in this population before they become readily available also is vitally important. MTN-008 will provide critical information about the safety of tenofovir gel during pregnancy and lactation, which the FDA considers essential to its decision whether to approve the gel.
5. How is this study unique?
MTN-008 is the second study of tenofovir gel in pregnancy, and the first in breastfeeding women. It is a follow-up study to MTN-002, which found that a single dose of tenofovir gel given to pregnant women hours before giving birth by scheduled Cesarean delivery was safe and well-tolerated by both mother and infant. Based on reassuring safety results from the single-dose study, researchers are now increasing the dosage to daily use for one week during both at-term and close-to-term pregnancy. They also are studying its use in women who are breastfeeding.
6. Who is conducting and funding MTN-008?
MTN-008 is being conducted by a team of researchers working with the Microbicide Trials Network (MTN), a clinical trials network established and funded in 2006 by the National Institute of Allergy and Infectious Diseases (NIAID) with co-funding from the National Institute of Mental Health and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), all components of the U.S. National Institutes of Health (NIH). The study, which is funded by NIAID and NICHD, is being led by Richard Beigi, M.D., M.Sc., of the University of Pittsburgh School of Medicine and Magee-Womens Hospital of the University of Pittsburgh Medical Center.
7. Where is the trial being conducted?
MTN-008 is being conducted at Magee-Womens Hospital of the University of Pittsburgh Medical Center and the University of Alabama, Birmingham (UAB). The first participants were enrolled in April 2011.
8. How is MTN-008 designed?
MTN-008 is a Phase I expanded safety study looking at the daily use of tenofovir gel for one week by women in the third trimester of pregnancy, and the daily use of the gel for one week by breastfeeding mothers four to 26 weeks after they have given birth. The study will include approximately 105 HIV-negative mother-infant pairs (90 pairs in the pregnancy group and 15 pairs in the nursing group). For the pregnancy group, researchers will initially enroll 45 pregnant women between 37 and 39 weeks gestation and randomize them to receive tenofovir gel or a placebo gel. The women will apply their assigned study product (tenofovir gel or placebo gel) daily for seven consecutive days, and undergo evaluation for side effects. Provided there are no safety concerns, researchers will then enroll a second group of 45 pregnant women who will follow the same seven-day regimen. The second group of women will enter the study earlier in their third trimester – between 34 and 36 weeks gestation. For the group of breastfeeding women, all 15 participants who are enrolled will use tenofovir gel daily for seven days.
9. What tests and procedures do women undergo as part of the study?
The tests and procedures performed during the study will include urine and blood tests, vaginal and cervical fluid collection, and pelvic exams and physicals to determine how the drug is absorbed and distributed in the body. Once a woman gives birth, researchers also will measure the presence of the gel’s active ingredient in the umbilical cord blood. Additionally, in the group of breastfeeding women, the presence of active drug will be measured in breast milk and in blood samples from both mother and infant.
10. How can you test pregnant and nursing women? Is it ethical?
Products like tenofovir gel are specifically intended for use by sexually active women – the very women who are most likely to become pregnant. Women need HIV prevention products they can safely use throughout their lives, including when they are pregnant and nursing. Researchers can’t know whether promising products will be safe and effective to use during pregnancy unless trials are carefully conducted that include pregnant and nursing women. Studies like MTN-008 are designed and implemented with the highest ethical standards and consider the safety and well-being of this special population.
11. Is tenofovir gel safe to give during pregnancy? What about risks to the baby?
MTN-008 researchers are taking a very careful and step-wise approach to investigating this question in pregnant and breastfeeding women. They would not be conducting MTN-008 without reassuring safety results from earlier studies and MTN-002, which found that a single dose of tenofovir gel given to pregnant women prior to scheduled Cesarean delivery resulted in only trace amounts of active drug in their bloodstream, and in the amniotic fluid and umbilical cord blood. In MTN-002, the drug levels measured in umbilical cord blood were 40 times lower than drug levels measured in studies of HIV-infected women who took the tablet form of tenofovir while they were pregnant. Researchers of these other studies found very low amounts of tenofovir in the babies of HIV-positive mothers who took the tablet during pregnancy, and neither mothers nor babies had any complications or problems thought to be related to use of the drug.
12. What is being done to ensure the safety of the participants?
MTN-008 was designed according to the most rigorous international medical practice and ethical standards and includes numerous measures to protect the safety and well-being of participants. As with all MTN studies, MTN-008 incorporates a multi-tiered safety review process for monitoring and reporting. This process includes clinicians evaluating participants at the trial sites; a team at the statistical and data management center (SDMC) that assesses incoming reports on a daily basis; three MTN physicians – two specializing in infectious diseases and HIV and the other in obstetrics and gynecology – who review summary reports and any concerns raised by site clinicians or the SDMC; monthly reviews by a protocol safety review team; and periodic review by a study monitoring committee.
13. Do women participating in the study provide informed consent?
Written informed consent is obtained from all study participants before screening and enrollment. The process ensures that women understand the procedures, as well as possible risks and benefits of the study. Women are under no obligation to participate and are aware they can leave the study at any time, without consequence.
14. What approvals were required to conduct the study?
The study underwent extensive and rigorous review by NIAID, NICHD and the U.S. Food and Drug Administration. The study also was reviewed by the Institutional Review Boards (IRBs) at the University of Pittsburgh and UAB to ensure that it is scientifically valid and ethically conducted. The IRBs at both universities will provide oversight throughout the duration of the study.
# # #
More information about MTN-008 and other MTN studies can be found at http://www.mtnstopshiv.org/news.
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.
20-June-2011
See Also
20-Jun-2011
