Pharmacy and Poisons Board: Applications

List Applications

Protocol No:

ECCT/23/10/02

Date of Protocol:

04-05-2023

Study Title:	A Phase I Randomized, Placebo-Controlled, Double-Blind Study to Assess Safety, Pharmacokinetics, and Modeled Pharmacodynamics of a Vaginal Insert Containing Tenofovir Alafenamide and Elvitegravir
Study Objectives:	Primary Objective Safety To evaluate the urogenital and systemic safety of the TAF/EVG insert (20/16 mg) administered vaginally in multiple doses, with emphasis on adverse events developing in the cervicovaginal tract Secondary Objectives Pharmacokinetics (PK) To characterize the multi-compartmental PK profile of the TAF/EVG insert administered vaginally in multiple doses *Modeled in vitro* PD To characterize the anti-HIV activity of the TAF/EVG insert in CVF administered vaginally in multiple doses To characterize the anti-HSV activity of the TAF/EVG insert in CVF administered vaginally in multiple doses Acceptability To explore user experiences and identify product attributes considered likely to challenge and/or facilitate future sustained use of the TAF/EVG insert applied vaginally Subclinical Safety and Vaginal Microbiome To characterize changes from baseline in soluble and cellular CV mucosal markers after multiple dose vaginal administration of the TAF/EVG insert To characterize changes from baseline in the vaginal microbiota after multiple dose vaginal administration of the TAF/EVG insert Exploratory Objective Modeled in vitro PD** To characterize the anti-HIV activity of the TAF/EVG insert in CVT administered vaginally in multiple doses.
Laymans Summary:	Adolescent girls and young women (AGYW) from sub-Saharan Africa (SSA), aged 15-24, remain at substantial risk of acquiring HIV and bear the burden of the HIV-1 epidemic, with more than 59% of new infections occurring in women in sub-Saharan Africa (SSA). The daily requirement for the pre-exposure prophylaxis (PrEP) medication for people at risk for Human Immunodeficiency Virus (HIV) and the systemic side effects have made it difficult, particularly for AGYW, to adhere to daily intake of tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) for HIV-1 prevention. The development of topical inserts for the prevention of sexually transmitted infections (STIs), particularly HIV, represents a promising alternative to oral and parenteral PrEP dosage forms. A topical vaginal insert that contains tenofovir alafenamide (TAF) and elvitegravir (EVG) is being developed for the prevention of HIV and HSV acquisition. Topical vaginal inserts have the potential for increased adherence as they are easy to store and transport, discreet, and convenient and easy to use. The main aim of this clinical trial is to evaluate the urogenital and systemic safety of the TAF/EVG insert administered vaginally in multiple doses, with emphasis on adverse events developing in the cervicovaginal tract.
Abstract of Study:	Background: Adolescent girls and young women (AGYW) bear the burden of the HIV-1 epidemic, with more than 59% of new infections occurring in women in sub-Saharan Africa (SSA). The daily dosing requirement and systemic side effects, primarily gastrointestinal (GI), have made it difficult, particularly for AGYW, to adhere to daily tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) for HIV-1 prevention. In SSA, adolescents and young people desire and even prefer on-demand HIV prevention options. Across multiple end-user studies a subset of women consistently indicate a preference for on-demand HIV and multipurpose prevention technologies (MPT) over daily use and even longer-acting products. Recent acceptability data from the contraceptive field, among AGYW in both high- and low-income countries, indicate that many prefer an on-demand, female controlled, peri-coital contraceptive, rather than a daily regimen or even a long-acting product. While there are several US Food and Drug Administration (FDA) approved antivirals to reduce HSV-2 shedding from an infected individual’s genital tract and reduce the duration of painful HSV-2 flare ups, there is no approved HSV-2 primary prevention product. HSV-2 is the most common cause of genital ulcers and is the most prevalent viral sexually transmitted infection (STI) in the US and world-wide, with an estimated 417 million people worldwide living with HSV-2. SSA is the most severely affected region of the world with up to 80% of sexually active women infected with HSV-2 by age 35 years. There are substantial data that HSV-2 and HIV-1 infections are synergistic, with asymptomatic shedding of HSV-2 causing increased susceptibility to HIV-1 and increased shedding of HSV-2 among HIV-1 infected individuals. The development of an HIV-1 and HSV-2 primary prevention MPT would have a significant public health impact, especially for AGYW. The objectives of this study will be to examine the safety, Pharmacokinetics, modelled Pharmacodynamics, and acceptability of inserts containing the combination of Tenofovir Alafenamide (TAF) and Elvitegravir (EVG) applied vaginally in HIV-1 negative low-risk women aged 18 – 50 years. Although long-acting pre-exposure prophylaxis (PrEP) regimens, such as injectables and implants, will likely improve adherence over daily pill ingestion, there is clear evidence that many individuals do not want to use continuous systemically administered products and want discreet, on demand, user-controlled products. Topical inserts have the potential for increased adherence as they are easy to store and transport, discreet, and convenient and easy to use. Vaginal or rectal administration of HIV prevention products provides local absorption of drug, enhanced bioavailability, high concentration at portals of virus entry, decreased systemic side effects, and reduced dosing frequency, all of which would increase adherence and persistence.