- Assess and compare the safety of ethylene-vinyl acetate (EVA) IVRs containing 182 mg vicriviroc (MK-4176), or 30 mg MK-2048, or 182 mg vicriviroc (MK-4176) + 30 mg MK-2048 (MK-2048A), when used continuously for 28 days by healthy, HIV-uninfected, sexually abstinent women, as compared with the placebo IVR
- Examine systemic and local pharmacokinetics (PK) of vicriviroc (MK-4176) and MK-2048 in vaginal fluid, plasma and cervical tissue during and after 28 days continuous use of an IVR containing 182 mg vicriviroc (MK-4176), or 30 mg MK-2048, or 182 mg vicriviroc (MK-4176) + 30 mg MK-2048 (MK-2048A)
MTN-027 was a multi-site, single-blind, four-arm, randomized, placebo-controlled Phase 1 safety and PK trial of the vicriviroc (MK-4176) IVR, the MK-2048 IVR, the MK-2048A IVR, and the Placebo VR. The combination IVR (MK-2048A IVR) combines two different classes of antiretroviral agents - a CCR5-receptor antagonist, VCV (MK-4176), with an integrase inhibitor, MK-2048. The study enrolled 48 healthy, 18-45-year-old women who were HIV-uninfected, non-pregnant, sexually abstinent, and using adequate contraception. Women were randomized to four study regimens in a 1:1:1:1 ratio. The IVR was used continuously for approximately 28 consecutive days. The design of MTN-027 allowed for safety comparisons of each study product to a placebo and provided data on relative safety among active products. Additionally, data related to the absorption and distribution of the drug(s) were collected. MTN-027 and MTN-028 were the first clinical trials to test an integrase inhibitor as a microbicide.
MTN-027 completed follow-up on March 7, 2016. The primary manuscript was published in Clinical Infectious Diseases on October 4, 2018. A total of two papers have been published from this study.
There was no difference in related genitourinary adverse events between treatment arms compared to placebo. VCV and MK-2048 released from single or combination VRs both achieved peak concentrations in vaginal fluids, which were substantially higher compared to plasma (200× for VCV, 30× for MK-2048) and rectal fluid. In an ex vivo challenge assay, the antiviral activity of VCV and/or MK-2048 was not correlated with tissue-associated drug concentrations. Most women (77%) were fully adherent to 28 days of continuous VR use and found the VR acceptable. These data highlight the need to assess the adequacy of drug dosing in the IVR and to measure genital tissue drug concentrations to develop more precise concentration-response relationships.
US Eunice Kennedy Shriver National Institute of Child Health and Human Development
US National Institute of Mental Health
US National Institutes of Health
Phase I, multi-site, four-arm, randomized (1:1:1:1), single-blind, placebo-controlled trial