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).

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.

Eligibility Criteria:
Inclusion Criteria:

1. 18 years of age or older at screening
2. Willing and able to communicate in English
3. Willing and able to provide written informed consent to take part in the study
4. Willing and able to provide adequate locator information
5. Understand and agree to local Sexually Transmitted Infection (STI) reporting requirements
6. Biologically male
7. HIV-1 uninfected at screening as documented by Combo Ag/Ab HIV-1/HIV-2 immunoassay (refer to Appendix II for confirmatory testing algorithm)
8. Available to return for all study visits, barring unforeseen circumstances
9. Per participant report at screening, a history of consensual Receptive Anal Intercourse (RAI) at least five times in lifetime and at least once in the prior 3 months (Required to ensure that participants are sufficiently sexually active to complete take-home enema study requirements)
10. Per participant report at screening, experience with receiving or self-administering an enema or douche in the past year.
11. Willing to abstain from insertion of anything (drug/medication, penis, object, sex toy, or enema including take-home enema) into the anorectum for 72 hours before and after each research unit study product exposure and 7 days after each flexible sigmoidoscopy with biopsy collection.
12. Willing to refrain from aspirin and NSAID use for one week before and after each study biopsy visit
13. Willing and able to use condoms provided by the study for all Receptive Anal Intercourse (RAI) for the duration of participation
14. Agrees not to participate in other research studies involving drugs and/ or medical devices for the duration of the study

Exclusion Criteria:

1. History of chronic Hepatitis B infection, as documented by positive HBsAg at screening
2. ≥ Grade 2 laboratory abnormality at baseline as defined by The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 2.0 dated November 2014
3. Significant colorectal symptom(s) as determined by medical history or by participant self-report (including but not limited to presence of any unresolved injury, infectious or inflammatory condition of the local mucosa, history of inflammatory bowel disease, presence of symptomatic external hemorrhoids, and presence of any painful anorectal conditions that would be tender to manipulation)
4. At screening or within the past 2 months: participant-reported symptoms and/or clinical or laboratory diagnosis of active rectal or reproductive tract infection requiring treatment per current Centers for Disease Control and Prevention (CDC) guidelines or symptomatic urinary tract infection (UTI). Infections requiring treatment include Chlamydia (CT), gonorrhea (GC), syphilis, active Herpes Simplex Virus (HSV) lesions, chancroid, genital sores or ulcers, and, if clinically indicated, genital warts. Note that HSV seropositivity with no active genital lesions is not an exclusion criterion, since treatment is not required.
5. History of an underlying cardiac arrhythmia or renal disease (including creatinine clearance \<50 mL/min using Cockcroft-Gault equation)
6. History of severe or recent cardiac or pulmonary event
7. History of aortic aneurysm
8. History of significant gastrointestinal bleeding
9. Current use of warfarin or heparin or other anticoagulant medications associated with increased risk for bleeding following mucosal biopsy (e.g., daily high dose aspirin \[\>81 mg\], NSAIDs, or Pradaxa®)
10. Use of systemic or anorectal immunomodulatory medications within 4 weeks of enrollment or planned use at any time during study participation
11. Use of pre-exposure (PrEP) and post-exposure (PEP) prophylaxis for HIV exposure within 3 weeks of enrollment or planned use within 3 weeks prior to any study visit with PK sampling.
12. Per participant report, use of any rectally administered products containing N-9 (including condoms) or investigational products within 4 weeks of enrollment, or planned use of either at any time during study participation
13. Known allergic reaction to TFV or other components of the test articles
14. Current known HIV-infected partners
15. History of recurrent urticaria
16. For JHU only: Participants whose whole body (Effective Dose Equivalent or EDE) radiation exposure, per the investigator's records and/or participant report, exceeds 5000 Millirem (mRem)/year
17. Symptoms suggestive of acute HIV seroconversion at screening and enrollment
18. Any other condition or prior therapy that, in the opinion of the investigator, would preclude informed consent, make study participation unsafe, make the individual unsuitable for the study or unable to comply with the study requirements. Such conditions may include, but are not limited to, current or recent history of severe, progressive, or uncontrolled substance abuse, or renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, neurological, or cerebral disease.