Optimization of a Tenofovir Enema for HIV Prevention

NCT02750540 | Completed Phase 1 DMC

• 3 other identifiers: IRB00097186DAIDS ES 120675U19AI113127
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 3

Brief Summary

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).

Conditions

HIV Prevention

Keywords

Tenofovir enema

Outcome Measures

Primary Outcomes (11)

• Occurrence of adverse events Grade 2 or higher, using Division of AIDS Adverse Events Grading Tables

  Adverse events occurring between dosing and day 7 for each of 3 doses during the study (each will be assessed as a unique dose related event period lasting 7 days) will be assessed according to the following scale: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Potentially Life-Threatening

  A total number of adverse events will be assessed through study completion, time period of up to 9 months

• Area under the curve of tenofovir concentration matrix at 1 hr post dose

  TFV-DP concentration will be measured at 1 hr post dose in order to assess target concentrations in colonic mucosal mononuclear cells (MMC) for each study product

  1 hr post dose

• Area under the curve of tenofovir concentration matrix at 3 hr post dose

  TFV-DP concentration will be measured at 3 hr post dose in order to assess target concentrations in colonic mucosal mononuclear cells (MMC) for each study product

  3 hr post dose

• Area under the curve of tenofovir concentration matrix at 6 hr post dose

  TFV-DP concentration will be measured at 6 hr post dose in order to assess target concentrations in colonic mucosal mononuclear cells (MMC) for each study product

  6 hr post dose

• Area under the curve of tenofovir concentration matrix at 12 hr post dose

  TFV-DP concentration will be measured at 12 hr post dose in order to assess target concentrations in colonic mucosal mononuclear cells (MMC) for each study product

  12 hr post dose

• Area under the curve of tenofovir concentration matrix at 24 hr post dose

  TFV-DP concentration will be measured at 24 hr post dose in order to assess target concentrations in colonic mucosal mononuclear cells (MMC) for each study product

  24 hr post dose

• Area under the curve of tenofovir concentration matrix at 72 hr post dose

  TFV-DP concentration will be measured at 72 hr post dose in order to assess target concentrations in colonic mucosal mononuclear cells (MMC) for each study product

  72 hr post dose

• Area under the curve of tenofovir concentration matrix at 168 hr post dose

  TFV-DP concentration will be measured at 168 hr post dose in order to assess target concentrations in colonic mucosal mononuclear cells (MMC) for each study product

  168 hr post dose

• Proportion of subjects who consider the tenofovir study products acceptable for use as assessed by a behavioral questionnaire

  For each product, descriptive statistics of overall product acceptability will be generated (i.e., mean and standard deviation for continuous variables and proportion of subjects who consider the products acceptable -- with score 3 or greater). In addition, a futility test will be conducted for each product to screen out non-acceptable product(s) and identify the product(s) with potential for being acceptable to users in a future study. The acceptability of each product is defined as a mean score of 3 on 4-point continuous acceptability measure (1=completely unacceptable; 2=somewhat unacceptable; 3=somewhat acceptable; 4=highly acceptable) that is defined in this study as the minimal clinically meaningful threshold for product acceptability.

  After each TFV enema product (at 1 to 6 hours post dose)

• Proportion of subjects who consider using the saline enemas at home acceptable as assessed by a behavioral questionnaire

  Descriptive statistics of overall product acceptability will be generated (i.e., mean and standard deviation for continuous variables and proportion of subjects who consider the products acceptable -- with score 3 or greater). In addition, a futility test will be conducted for each product to screen out non-acceptable product(s) and identify the product(s) with potential for being acceptable to users in a future study. The acceptability of each product is defined as a mean score of 3 on 4-point continuous acceptability measure (1=completely unacceptable; 2=somewhat unacceptable; 3=somewhat acceptable; 4=highly acceptable) that is defined in this study as the minimal clinically meaningful threshold for product acceptability.

  Within 30 days after completing the low dose TFV enema use and high dose TFV enema use in clinic

• Proportion of subjects who consider all enema study products acceptable for use as assessed by a behavioral questionnaire

  Descriptive statistics of overall product acceptability will be generated (i.e., mean and standard deviation for continuous variables and proportion of subjects who consider the products acceptable -- with score 3 or greater). In addition, a futility test will be conducted for each product to screen out non-acceptable product(s) and identify the product(s) with potential for being acceptable to users in a future study. The acceptability of each product is defined as a mean score of 3 on 4-point continuous acceptability measure (1=completely unacceptable; 2=somewhat unacceptable; 3=somewhat acceptable; 4=highly acceptable) that is defined in this study as the minimal clinically meaningful threshold for product acceptability.

  At the end of each subject's study participation, after all 3 products have been administered in clinic and at home, which is up to 1 month after the last product is administered at home. The total period of study depends on interim data analysis.

Study Arms (5)

Product A dose

ACTIVE COMPARATOR

Product A will contain tenofovir (TFV) 220 mg in 125 mL iso-osmolar solution: Participants will have a single dose administered in clinic or a research unit, followed by various specimen collections over 8 days, according to individual sampling schedule assigned to each participant; specimens will be collected on Day 1, 2, 4, and 8.

Drug: Tenofovir enema

Product B dose

ACTIVE COMPARATOR

Product B will contain tenofovir (TFV) \*660 mg in 125 mL iso-osmolar solution: Participants will have a single dose administered in clinic or a research unit, followed by various specimen collections over 8 days, according to individual sampling schedule assigned to each participant; specimens will be collected on Day 1, 2, 4, and 8.

Drug: Tenofovir enema

Product C dose

ACTIVE COMPARATOR

Product C will contain tenofovir (TFV) \*660 mg in 125 mL hypo-osmolar solution at half the osmolarity of iso-osmolar solution: Participants will have a single dose administered in clinic or a research unit, followed by various specimen collections over 8 days, according to individual sampling schedule assigned to each participant; specimens will be collected on Day 1, 2, 4, and 8.

Drug: Tenofovir enema

Take-home normal saline (NS) enema

PLACEBO COMPARATOR

The normal saline (NS) solution will be provided following administration of Product A which is iso-osmolar. The volume of NS enema (120 mL) was selected to approximately match that of Product A (125 mL)

Other: Saline enema

Take-home half normal saline (½ NS) enema

PLACEBO COMPARATOR

The ½ normal saline (½ NS) solution will be provided following administration of Product C which is hypo-osmolar. The volume of the ½ NS enema (120 mL) was selected to approximately match that of Product C (125 mL)

Other: Saline enema

Interventions

Tenofovir enema DRUG

Product A dose; Product B dose; Product C dose

Saline enema OTHER

Take-home half normal saline (½ NS) enema; Take-home normal saline (NS) enema

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• years of age or older at screening
• Willing and able to communicate in English
• Willing and able to provide written informed consent to take part in the study
• Willing and able to provide adequate locator information
• Understand and agree to local Sexually Transmitted Infection (STI) reporting requirements
• Biologically male
• HIV-1 uninfected at screening as documented by Combo Ag/Ab HIV-1/HIV-2 immunoassay (refer to Appendix II for confirmatory testing algorithm)
• Available to return for all study visits, barring unforeseen circumstances
• 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)
• Per participant report at screening, experience with receiving or self-administering an enema or douche in the past year.
• 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.
• Willing to refrain from aspirin and NSAID use for one week before and after each study biopsy visit
• Willing and able to use condoms provided by the study for all Receptive Anal Intercourse (RAI) for the duration of participation
• Agrees not to participate in other research studies involving drugs and/ or medical devices for the duration of the study

You may not qualify if:

• History of chronic Hepatitis B infection, as documented by positive HBsAg at screening
• ≥ 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
• 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)
• History of an underlying cardiac arrhythmia or renal disease (including creatinine clearance \<50 mL/min using Cockcroft-Gault equation)
• History of severe or recent cardiac or pulmonary event
• History of aortic aneurysm
• History of significant gastrointestinal bleeding
• 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®)
• Use of systemic or anorectal immunomodulatory medications within 4 weeks of enrollment or planned use at any time during study participation
• 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.
• 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
• Known allergic reaction to TFV or other components of the test articles
• Current known HIV-infected partners
• History of recurrent urticaria
• 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

Sponsors & Collaborators

• Johns Hopkins University: lead
• University of California, Los Angeles: collaborator
• University of Pittsburgh: collaborator
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (3)

Center for Prevention Research, University of California Los Angeles

Los Angeles, California, 90024, United States

Location

The Johns Hopkins University

Baltimore, Maryland, 21287, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

Related Publications (2)

• Giguere R, Balan IC, Lentz C, Dolezal C, Carballo-Dieguez A, Fuchs EJ, Anton P, McGowan I, Ho K, Weld E, Hendrix CW. Acceptability of a rectal microbicide douche for HIV prevention: a mixed-methods analysis of a first-in-human formulation pilot study. Sex Transm Infect. 2025 Jan 29;101(1):49-54. doi: 10.1136/sextrans-2024-056209.

  PMID: 39237135 DERIVED

• Weld ED, McGowan I, Anton P, Fuchs EJ, Ho K, Carballo-Dieguez A, Rohan LC, Giguere R, Brand R, Edick S, Bakshi RP, Parsons T, Manohar M, Seigel A, Engstrom J, Elliott J, Jacobson C, Bagia C, Wang L, Al-Khouja A, Hartman DJ, Bumpus NN, Spiegel HML, Marzinke MA, Hendrix CW. Tenofovir Douche as HIV Preexposure Prophylaxis for Receptive Anal Intercourse: Safety, Acceptability, Pharmacokinetics, and Pharmacodynamics (DREAM 01). J Infect Dis. 2024 Apr 12;229(4):1131-1140. doi: 10.1093/infdis/jiad535.

  PMID: 38019657 DERIVED

Study Officials

• Ethel D Weld, MD, PhD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 11, 2016
• First Posted: April 25, 2016
• Study Start: October 1, 2016
• Primary Completion: May 1, 2019
• Study Completion: May 1, 2019
• Last Updated: February 7, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)