Optimization of a Tenofovir Enema for HIV Prevention

DREAM-01 is an early phase 1, open label, dose-escalation and variable osmolarity study to compare the safety, pharmacokinetics (PK), pharmacodynamics (PD), and acceptability of 3 formulations of a tenofovir (TFV) enema. The goal of the study is to identify the dose and osmolarity of a TFV enema for human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) which achieves the desired colonic mucosal mononuclear cells (MMC) tenofovir diphosphate (TFV-DP) target concentrations that have previously been shown to confer protection from HIV acquisition in men who have sex with men (MSM). Each participant will undergo screening to evaluate eligibility. Baseline visit will assess safety, PD, and behavioral readout baselines. Three products described below (Product A, B, and C) are dosed sequentially as a dose-escalation within each subject. Safety, PK, PD, and behavioral readouts are assessed at specified times for one week after each dose, followed by a variable washout period before the next escalation dose. Johns Hopkins University (JHU) participants only will have SPECT/CT imaging to assess distribution and permeability of radiolabeled product. After two of the study product doses (Product A and Product C) and their respective sampling periods, a normal saline (NS) solution and ½ normal saline (½ NS) solution will be taken at home in the context of receptive anal intercourse. Study Duration: Participant accrual will take approximately 9 months and each participant will be on study for approximately 4-5 months. Total study duration is about 1 year. Study Products: Three study products administered sequentially and estimated to approximate TFV 1% gel (Product A), 3 times the concentration and dose of Product A (Product B), and 2 times concentration and dose of Product B (Product C) as defined below. At JHU only, the study product will also be radiolabeled with Technetium-99m-DTPA (99mTc-DTPA) for SPECT/CT imaging. Take-home enemas consisting of normal saline (NS) or ½ normal saline (½ NS) will be self-administered at home. * Product A: Enema formulation of TFV 1.76 mg/mL (220 mg in 125 mL) in iso-osmolar solution * Product B: Enema formulation of TFV 5.28 mg/mL (\*660 mg in 125 mL) in iso-osmolar solution * Product C: Rectal specific Enema formulation of TFV 5.28 mg/mL (\*660 mg in 125 mL) in hypo-osmolar solution * Take-home enema to follow Product A: 120 mL of normal saline (NS) solution * Take-home enema to follow Product C: ½ normal saline (½ NS) * Note: the planned 660 mg TFV dose in Product B and C may be adjusted lower or higher based on Product A results in order to more closely achieve target concentrations - this is indicated by \*660 mg, which will be used throughout the protocol to indicate the planned, but potentially modified Product B (or C as the case may be) dose.