Rectal Microbicide Safety and Acceptability Trial of Topically Applied Tenofovir Compared With Oral Tablet

NCT00984971 | Completed Phase 1 DMC

• 2 other identifiers: DAIDS ID 10769RMP02-MTN006
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 2

Brief Summary

To date, the majority of microbicide research has focused on the assessment of the safety and effectiveness of vaginal microbicides used for the prevention of HIV transmission via the vaginal compartment. Receptive anal intercourse (RAI) is common among men who have sex with men (MSM), and there is increasing evidence that heterosexual women in the developed and developing world also practice anal sex. It can, therefore, be anticipated that once vaginal microbicides are licensed, they will be used in both the vaginal and rectal compartments. As a consequence, there is a need to evaluate both the rectal and vaginal safety profile of candidate microbicides. Therefore, the primary objective of this study is to evaluate the systemic safety of 1% vaginally formulated tenofovir gel applied rectally. In addition, this study will evaluate the immunotoxicity of the gel and evaluate its acceptability; it will also use the oral tenofovir disoproxil fumarate tablets (TDF), rectally-applied tenofovir gel,and a placebo gel to compare their systemic and compartmental pharmacokinetic (pK) profiles. This study was designed to address the following hypotheses:

• Vaginally-formulated tenofovir 1% topical gel when applied rectally will be safe using a combination of clinical and laboratory markers including assays specifically designed to measure mucosal toxicity
• Tenofovir will be detectable at different concentrations in the various anatomic compartments sampled for pharmacokinetics following single and 7-day topical exposures
• Exposure to tenofovir 1% gel will demonstrate prevention of ex vivo HIV-1 challenge using in vivo drug-exposed tissue as compared to baseline tissue samples
• Orally delivered, single dose, 300 mg tenofovir disoproxil fumarate tablets will have similar safety profiles using routine blood safety indices as have been established in other trials and will show no mucosal safety concerns
• The oral dose will have different multi-compartment concentration kinetics than the topical tenofovir and will also demonstrate preliminary (ex vivo) prevention using the explant infectivity assay
• Vaginally formulated tenofovir 1% topical gel applied rectally will be acceptable to participants, as indicated by a score in the upper one third of the 10-point Likert scale on intentionality to use in the product in the future

Conditions

HIV Prevention; HIV Infections

Keywords

Microbicides; Tenofovir; HIV seronegativity

Outcome Measures

Primary Outcomes (1)

• Grade 2 or higher clinical and laboratory adverse events as defined by the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Version 1.0,Dec 2004 and Addenda 1 and 3 to this table.

  Every study visit

Secondary Outcomes (1)

• Immunotoxicity, Pharmacokinetics, and Acceptability

  Immunotoxicity and pharmacokinetics: every study visit; acceptability: baseline and end of study

Study Arms (3)

Tenofovir

EXPERIMENTAL

Drug: Tenofovir

HEC Placebo

PLACEBO COMPARATOR

Drug: HEC Placebo

Open label tenofovir tablet

OTHER

Drug: Open label tenofovir tablet

Interventions

Tenofovir DRUG

Topical gel applied rectally

Tenofovir

HEC Placebo DRUG

Placebo gel applied rectally

HEC Placebo

Open label tenofovir tablet DRUG

All participants will undergo an open label tenofovir tablet single dose administration (i.e. Tenofovir Disoproxil Fumarate 300 mg, aka Viread®)

Open label tenofovir tablet

Eligibility Criteria

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

You may qualify if:

• ≥ Age of 18 at screening
• Willing and able to provide written informed consent for screening and enrollment
• HIV-1 uninfected at screening according to the standard DAIDS algorithm in Appendix II
• Willing and able to communicate in English
• Willing and able to provide adequate locator information, as defined in site standard operating procedures (SOP)
• Availability to return for all study visits, barring unforeseen circumstances
• Per participant report at screening, a history of consensual RAI at least once in the prior year
• Willing to abstain from insertion of anything rectally including sex toys, other than the study gel during the active phases of the study and for 5 days following biopsy collection
• Willing to abstain from sexual intercourse (rectal and vaginal) during the active phases of the study and for 5 days following biopsy collection
• Must agree to use study provided condoms for the duration of the study for vaginal and insertive anal intercourse
• Must be in general good health
• Must agree not to participate in other drug trials
• In addition to the criteria listed above, female participants must meet the following criteria:
• Post-menopausal or using (or willing to use) an acceptable form of contraception (e.g., barrier method, IUD, hormonal contraception, surgical sterilization, or vasectomization of male partner). If the female participant has female partners only, the method of contraception will be noted as a barrier method in the study documentation.

You may not qualify if:

• Abnormalities of the colorectal mucosa, or significant colorectal symptom(s), which in the opinion of the clinician represents a contraindication to biopsy (including but not limited to presence of any unresolved injury, infectious or inflammatory condition of the local mucosa, and presence of symptomatic external hemorrhoids)
• At screening, clinical or laboratory diagnosis of active rectal or reproductive tract infection requiring treatment per current Centers for Disease Control and Prevention (CDC) guidelines or urinary tract infection (UTI). Infections requiring treatment include symptomatic bacterial vaginosis, symptomatic vaginal candidiasis, other vaginitis, trichomoniasis, Chlamydia (CT), gonorrhea (GC), syphilis, active HSV lesions, chancroid, pelvic inflammatory disease, genital sores or ulcers, cervicitis, or symptomatic genital warts requiring treatment. Note that HSV-2 seropositive with no active lesions is allowed, since treatment is not required.
• Note: Allow one re-screening after documented treatment (30 days) in cases of GC/CT identified at screening
• At screening:
• Positive for hepatitis B surface antigen
• Hemoglobin \< 10.0 g/dL
• Platelet count \< 100,000/mm3
• White blood cell count less than 2,000 cells/mm3 or \> than 15,000 cells/mm3
• Calculated creatinine clearance less than 80 mL/min by the Cockcroft-Gault formula where creatinine clearance in mL/min (140- age in years) x (weight in kg) x (0.85 for females)/72 x (serum creatinine in mg/dL)
• Serum creatinine \> 1.3× the site laboratory upper limit of normal (ULN)
• ALT and/or AST \> 2.5× the site laboratory ULN
• +1 glucose or +1 protein on urinalysis (UA)
• History of bleeding problems (i.e. INR \> 1.5× the site laboratory ULN or PTT \> 1.25× the site laboratory ULN)
• History of significant gastrointestinal bleeding in the opinion of the investigator
• Allergy to methylparaben, propylparaben, sorbic acid

Sponsors & Collaborators

• CONRAD: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator
• Microbicide Trials Network: collaborator

Study Sites (2)

UCLA Center for HIV Prevention Research

Los Angeles, California, 90024, United States

Location

University of Pittsburgh Clinical Research Unit

Pittsburgh, Pennsylvania, 15213, United States

Location

Related Publications (4)

• Richardson-Harman N, Hendrix CW, Bumpus NN, Mauck C, Cranston RD, Yang K, Elliott J, Tanner K, McGowan I, Kashuba A, Anton PA. Correlation between compartmental tenofovir concentrations and an ex vivo rectal biopsy model of tissue infectibility in the RMP-02/MTN-006 phase 1 study. PLoS One. 2014 Oct 28;9(10):e111507. doi: 10.1371/journal.pone.0111507. eCollection 2014.

  PMID: 25350130 DERIVED

• Yang KH, Hendrix C, Bumpus N, Elliott J, Tanner K, Mauck C, Cranston R, McGowan I, Richardson-Harman N, Anton PA, Kashuba AD. A multi-compartment single and multiple dose pharmacokinetic comparison of rectally applied tenofovir 1% gel and oral tenofovir disoproxil fumarate. PLoS One. 2014 Oct 28;9(10):e106196. doi: 10.1371/journal.pone.0106196. eCollection 2014.

  PMID: 25350119 DERIVED

• Anton PA, Cranston RD, Kashuba A, Hendrix CW, Bumpus NN, Richardson-Harman N, Elliott J, Janocko L, Khanukhova E, Dennis R, Cumberland WG, Ju C, Carballo-Dieguez A, Mauck C, McGowan I. RMP-02/MTN-006: A phase 1 rectal safety, acceptability, pharmacokinetic, and pharmacodynamic study of tenofovir 1% gel compared with oral tenofovir disoproxil fumarate. AIDS Res Hum Retroviruses. 2012 Nov;28(11):1412-21. doi: 10.1089/aid.2012.0262. Epub 2012 Oct 9.

  PMID: 22943559 DERIVED

• Richardson-Harman N, Mauck C, McGowan I, Anton P. Dose-response relationship between tissue concentrations of UC781 and explant infectibility with HIV type 1 in the RMP-01 rectal safety study. AIDS Res Hum Retroviruses. 2012 Nov;28(11):1422-33. doi: 10.1089/AID.2012.0073. Epub 2012 Sep 20.

  PMID: 22900504 DERIVED

MeSH Terms

Conditions

HIV Infections

Interventions

Tenofovir

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: September 24, 2009
• First Posted: September 25, 2009
• Study Start: September 1, 2009
• Primary Completion: June 1, 2010
• Study Completion: July 1, 2010
• Last Updated: August 28, 2015

Record last verified: 2015-08

Locations

US (2)