Evaluating Distribution of a Tenofovir Douche With Tap Water Douching and Simulated Receptive Anal Intercourse

DREAM-02 is a phase 1, open label study to evaluate different sequences of tap water douching and simulated receptive anal intercourse (sRAI) in the presence of a tenofovir douche designed to confer protection from Human Immunodeficiency Virus (HIV) acquisition. DREAM-02 will assess the safety and pharmacokinetics (PK) of different sequences of administration of tap water (H2O) and rectal tenofovir (TFV) douches to more accurately represent the community practice of commonly using cleansing douches prior to RAI, and occasionally after RAI. DREAM-02 results are essential to gain understanding of Tenofovir diphosphate (TFV-DP) concentrations at various anatomic distances in the colon, and how those concentrations may be modified by sRAI, seminal fluid, and sequence of cleansing tap water douches.

DREAM-02 is proposed as the next step in the development of an on demand, behaviorally-congruent rectal tenofovir (TFV) microbicide to prevent HIV acquisition via unprotected receptive anal intercourse (RAI). The DREAM Program has previously established that (1) no TFV pro-drug provides significantly superior colon tissue pharmacokinetics in pre-clinical models (mice and macaques), (2) a single rectal TFV douche protects macaques from repeated low dose rectal simian/human immunodeficiency virus (SHIV) challenge and is superior to oral daily dosing of TFV disoproxil fumarate (TDF), (3) it takes only 1-3 hours for a single 125 mL hypotonic rectal douche with a concentration of 5.28 mg/mL of TFV (660 mg total)to exceed by 100-fold the steady-state colon tissue TFV diphosphate (TFV-DP) concentrations associated with \>90% protection (83 femtomoles/ million \[fmol/106\] Mucosal Mononuclear Cells (MMC) in oral daily dosing studies), and (4) DREAM behavioral survey research indicates very common use of one to several rectal douches in series prior to Unprotected Receptive Anal Intercourse (URAI). DREAM-02 will assess the safety and PK of different sequences of administration of tap water (H2O) and rectal TFV douches to more accurately represent the community practice of commonly using cleansing douches prior to RAI, and occasionally after RAI, based on investigators' DREAM behavioral survey results. DREAM-02 results are essential to gain understanding of TFV-DP concentrations at various distances from the anal verge, and how those concentrations may be modified by sRAI, seminal fluid, and sequence of cleansing tap water douches. The sequences of douche administration are selected to evaluate the impact of either a TFV rectal douche or H2O douche administered prior to, or following simulated sexual intercourse with ejaculation. The first sequence of administration will replicate administration of the dose that achieved the greatest tissue TFV-DP concentrations in DREAM-01 (660 mg TFV in 125 mL half-normal saline; TFV 5.28 mg/mL), then followed by simulated receptive anal intercourse (sRAI) and administration of autologous seminal fluid via a catheter embedded in an artificial phallus (Sequence A). Sequence B will evaluate the administration of the TFV rectal douche administered prior to sRAI and ejaculation followed by a cleansing H2O douche. Lastly, Sequence C will evaluate the administration of a cleansing H2O douche prior to sRAI and ejaculation followed by the TFV rectal douche. Investigators hypothesize that douching after sex will increase the distribution of HIV surrogates within the lower GI tract and may lead to a mismatch of drug and HIV surrogate distribution, possibly, reducing rectal douche effectiveness. This information will be essential to the design of phase 2 extended safety studies of investigators' TFV douche, especially with regard to providing guidance for research participants and study counselors. Since DREAM-02 and DREAM-03 will use the same TFV douche product, DREAM-02 will provide data complementary to the 3 dose sequences planned for DREAM-03, and in the first arm of this protocol replicates the same product/conditions as used in the highest dose escalation step of DREAM-01, but with the addition of sRAI and exposure to autologous seminal fluid. Therefore, bridging data from DREAM-01, DREAM-02, and DREAM-03, as well as data from other DREAM Projects will inform the design and labeling of an optimal TFV douche for further clinical testing. It is anticipated that the study will take approximately six months to complete study enrollment, and that each participant will be in the study for approximately six months from the time of screening.