A phase I study of a novel potential intravaginal microbicide, PRO 2000, in healthy sexually inactive women

Background: Although the male condom provides a reliable means of preventin g HIV transmission, a broader choice of methods is required particularly in circumstances where the negotiation of condom use is difficult. Developmen t of new products that may be effective as topical vaginal microbicides is the focus of a great deal of research activity currently. The novel agent P RO 2000, a naphthalene sulphonate derivative with in vitro activity against HIV and other sexually transmissible pathogens, is one such compound. We h ave studied the local and systemic safety and tolerance of a vaginal gel fo rmulation of this agent at two concentrations (0.5% and 4%) over a 2 week p eriod of daily exposure in two cohorts of healthy sexually abstinent women (one in London, UK, and the other in Antwerp, Belgium). Methods: This was a randomised, placebo controlled, double blind, three arm clinical trial conducted on two sites. Macroscopic evidence of genital epi thelial changes was sought using colposcopy and evidence of microscopic inf lammation was acquired using high vaginal biopsy from predetermined sires ( UK cohort only). Blood levels of PRO 2000 were measured and laboratory safe ty tests, including coagulation screens, were performed. The impact on vagi nal ecology was also assessed. Results: 73 women were enrolled across both sites (36 UK, 37 Belgium); 24, 24, 25 in the 4%, 0.5%, and placebo groups respectively. Of these, 70 compl eted 2 weeks' exposure to the study gel. Three tall in the 4% group) withdr ew owing to adverse events which were possibly or probably gel related. Cer vicovaginal abrasion was seen colposcopically in three subjects after 14 da ys of gel use (two in the 4% group and one in thr placebo group). Genital u lceration was not seen during gel use in any of the subjects who completed the study. Histological evaluation of vaginal biopsy samples (36 women only ) showed evidence of increased inflammatory signs in one participant of the 4.0% group. One volunteer in the placebo group had moderate inflammation a t screening and at follow up. Severe inflammation was not seen among any of the subjects tested. Plasma levels of PRO 2000 and laboratory safety tests showed no evidence of systemic absorption, No impact was seen on normal va ginal ecology in the UI( cohort where samples were taken 12 hours after the last gel application. Conclusion: In this phase I study PRO 2000 gel was found to be generally we ll tolerated with promising local and systemic safety profiles. The 0.5% ge l was better tolerated than the 4% gel as fewer genital epithelial adverse events were seen in the former. Phase II studies are about to begin in sexu ally active women.