- Evaluate the systemic safety of vaginally-formulated tenofovir 1% gel
RMP-02/MTN-006 was a Phase 1, partially-blinded, placebo-controlled trial designed to evaluate the safety, acceptability, pharmacokinetics and pharmacodynamics of rectal administration of tenofovir 1% vaginally formulated gel and oral tenofovir (TDF) in healthy men and women. This tenofovir gel formulation was originally designed for vaginal use. The primary objective of this trial was to evaluate the systemic safety profile of vaginally formulated tenofovir 1% gel, applied rectally, during a single exposure, followed by once-daily rectal administration for 7 days, as compared to a single oral dose of tenofovir. In addition to acceptability, RMP-02/MTN-006 assessed concentrations of tenofovir in tissue, rectal fluid, intracellular (both peripheral blood mononuclear cells (PBMC)) and mucosal mononuclear cells (MMC), and plasma.
Determining whether the intracellular levels of tenofovir diphosphate concentrations in presumptive mucosal target cells are similar using topical or oral formulations will impact clinical trials and drug development plans for prevention of HIV among populations for whom receptive anal intercourse is a route of HIV exposure. This was a joint project of the MTN and the Integrated Preclinical Clinical Program (IPCP) in Topical Microbicides funded by the Division of AIDS. This study was the first MTN trial to leverage the IPCP in Topical Microbicides through collaboration with the UCLA IPCP on rectal microbicides.
MTN-006 completed follow-up on July 1, 2010. Preliminary results were reported at the annual Conference on Retroviruses and opportunistic Infections (CROI) held on February 27- March 2, 2011, in Boston, MA. The primary manuscript was published online in AIDS Research and Human Retroviruses in October 2012. A total of three papers have been published from this study.
No serious AEs were reported. However, AEs were significantly increased with 7-day TFV gel use, most prominently with gastrointestinal AEs (p=0.002). Only 25% of participants liked the TFV gel. Likelihood of use "if somewhat protective" was ∼75% in both groups. Indices of mucosal damage showed minimal changes. Tissue TFV diphosphate (TFV-DP) C(max) 30 min after single rectal exposure was 6-10 times greater than single oral exposure; tissue TFV-DP was 5.7 times greater following 7-day versus single rectal exposure. In vivo exposure correlated with significant ex vivo tissue infectibility suppression [single-rectal: p=0.12, analysis of covariance (ANCOVA) p=0.006; 7-day rectal: p=0.02, ANCOVA p=0.005]. Tissue PK-PD was significantly correlated (p=0.002). We conclude that rectal dosing with TFV 1% gel resulted in greater TFV-DP tissue detection than oral dosing with reduced ex vivo biopsy infectibility, enabling PK-PD correlations. On the basis of increased gastrointestinal AEs, rectally applied, vaginally formulated TFV was not entirely safe or acceptable, suggesting the need for alternative rectal-specific formulations.
US National Institutes of Health
Phase 1, randomized, two-site, partially-blinded, placebo controlled study