Clinical Trials

Antiretrovirals as Microbicides: Tenofovir Gel

Tenofovir is a nucleotide reverse transcriptase inhibitor (NRTI) that prevents viral replication in susceptible cells.  CONRAD, along with the International Partnership for Microbicides, has been granted a co-exclusive license by Gilead Sciences to develop, manufacture and, if proven effective, distribute tenofovir in developing countries.  A safety and pharmacokinetic study of tenofovir vaginal gel in women completed in April 2008 showed tenofovir concentrations to be low in blood plasma and high in cervicovaginal fluids and tissues up to 24 hours following exposure.  A male tolerance study of tenofovir gel carried out in 2006 showed that penile exposure to tenofovir for 7 days was well tolerated.  CONRAD supervised the manufacture of clinical supplies of tenofovir gel for CAPRISA 004, a Phase IIb clinical trial in South Africa that showed tenofovir gel to be 39% effective in reducing a woman’s risk of becoming infected with HIV during sex.   Additionally, CONRAD supplies tenofovir gel for several Microbicide Trials Network (MTN) clinical trials, including the Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial (MTN-003), which began in fall 2009 and is comparing oral tenofovir and tenofovir gel for the prevention of HIV in women.

Antiretrovirals as Microbicides: UC781 Gel

UC781 is a tight-binding non-nucleoside reverse transcriptase inhibitor (NNRTI) with excellent anti-HIV microbicidal properties.  CONRAD licensed UC781 from Chemtura for development and public sector marketing and along with its partners, conducted studies testing the safety of UC781 gel use in women, penile tolerance to the gel and rectal safety. While the single entity gel was found to be well tolerated and safe in these initial safety studies, the positive results of the CAPRISA 004 tenofovir gel trial combined with difficulties encountered formulating UC781 in alternative dosage forms (e.g., rings and films) and in combination with tenofovir led to a strategic decision in 2010 to discontinue UC781 development work.

Inflammatory Markers

A study of inflammatory markers in women using vaginal products randomized women to use either the universal HEC placebo, cellulose sulfate (CS) or nonoxynol-9 twice daily for 14 days.  New safety endpoints studied in this trial include soluble and cellular markers of inflammation in cervicovaginal lavage (CVL) fluid, biopsy specimens, and cytobrush specimens, as well as changes in pH, vaginal microflora, colposcopic findings, histopathological measures, and antiviral activity of the CVL supernatant.  Preliminary analysis showed that nonoxynol-9 was associated with an inflammatory pattern of results, while CS was not. After vaginal use, CS retained its anti-HIV activity.

Influence of Hormonal Contraception on Microbicide Safety Endpoints

Alterations in cervicovaginal immunity (innate immunity, inflammation, epithelial integrity and microbiota) may affect the risk of HIV acquisition.  Effective contraception is required or strongly encouraged for Phase IIb/III microbicide trials, yet the effect of contraception on vaginal immunity is poorly understood.  Two studies are underway that will help answer these questions about the effect of contraception on HIV acquisition.  The first study will analyze swabs taken from participants in a large clinical trial completed in 2004 to link biomarkers to HIV acquisition and examine changes by contraceptive method.  A second study will enroll 180 women desiring to start hormonal or intrauterine contraception and will assess the effects of contraceptive methods on the persistence of tenofovir within the mucosa and changes in markers of mucosal safety following vaginal use of 1% tenofovir gel.

Gel Imaging and Acceptability

An imaging study at Johns Hopkins University will compare the distribution, concentration and persistence of one or two spreading gels through 24 hours after application.  A dose of gel will be inserted into the participant’s vagina and images taken at different time points.  In an acceptability study at Brown University, women will test a spreading gel and a bolus gel, both in the hand and in the vagina and then rate them on specific, verified acceptability scales and dimensions, including leakage, application process, covert use and sexual pleasure.

HIV Incidence in India

CONRAD is working with the Indian Council of Medical Research to identify high HIV incidence sites where clinical trials of HIV prevention technologies, including vaginal microbicides, could be conducted.  The study population of this cross-sectional trial may include up to 9,000 sexually active high-risk women, 18-45 years old (six sites enrolling up to 1,500 women per site).