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Coital Pharmacokinetics/Pharmacodynamics (PK/PD) of Tenofovir Gel

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by CONRAD
Sponsor:
Collaborators:
Information provided by (Responsible Party):
CONRAD
ClinicalTrials.gov Identifier:
NCT01687205
First received: August 27, 2012
Last updated: April 11, 2014
Last verified: April 2014
  Purpose

Study Objectives:

  • To assess the impact of coitus (and semen) on the pharmacokinetics of tenofovir 1% gel in female genital tract secretions, vaginal and cervical tissue and rectal tract secretions
  • To assess the impact of coitus (and semen) on pharmacodynamics of luminal drug by measuring the anti-HIV-1 activity in CVL samples

Study Summary:

MTN-011 will enroll heterosexual monogamous, sexually active couples, in which both partners are healthy and HIV-negative. The female participants must be between the ages of 21-46 (inclusive) and currently using effective non-barrier contraception. Male participants must be 21 years of age or older. This Phase 1 expanded safety study will assess tenofovir PK in the genital tract secretions (CVL), rectal (rectal sponge) and both intracellular and extracellular tissue compartments (vaginal biopsy) in the absence of, or following coitus. Pharmacodynamics (antiviral activity) will also be assessed in CVL. MTN-011 will study the timing in which coitus might have the greatest impact on these variables, which is when gel is applied shortly prior to coitus in the absence of a drug reservoir.

In Stage 1, MTN-011 will examine PK/PD in response to a single dose of 1% tenofovir gel applied shortly before sex and compare to PK/PD assessments following a single gel application without sex. Additionally, data obtained from a visit in which participants do not dose with gel and do not have sex will serve as an additional control for the pharmacodynamic (PD) studies of the antiviral activity in CVL. If tenofovir retains its antiviral activity following sex, then the anti-HIV activity in CVL collected at the visit in which female participants dose with gel and have sex should be comparable to that of CVL collected at the visit in which females dose with gel and then do not engage in intercourse and significantly greater than the endogenous anti-HIV activity in CVL obtained at the visit in which participants do not dose with gel but do have sex and the visit in which no gel is administered and sex does occur. An interim analysis will be performed after the completion of enrollment and follow-up procedures for Stage 1. If a difference is detected (25% decrease in PK) between the pharmacokinetic data or in the antiviral activity (PD) at the Gel/Sex Visit vs. Gel/No Sex Visit Stage 2 of the study will commence and begin enrolling.

If Stage 1 demonstrates an impact of coitus and semen on PK/PD when a single 1% tenofovir dose is applied shortly prior to sex, coitus and semen may not have the same impact on PK/PD in the setting of daily gel application due to continual accumulation of drug in cervicovaginal tissue over time. Thus Stage 2 will compare PK/PD after 7 daily doses of gel in the absence of sex to that of the PK/PD after the couple engages in sex.


Condition Intervention Phase
Pharmacokinetics of 1% Tenofovir Gel Following Coitus
Pharmacodynamics of 1% Tenofovir Gel Following Coitus
Drug: 1% Tenofovir Gel
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Official Title: Phase 1 Evaluation of the Impact of Coitus on Pharmacokinetics and Pharmacodynamics of Tenofovir 1% Gel Following Pericoital or Daily Gel Dosing

Resource links provided by NLM:


Further study details as provided by CONRAD:

Primary Outcome Measures:
  • Pharmacokinetics of tenofovir 1% gel [ Time Frame: Visits 3b, 4b, 5b, 6b and 7b in group 1. Visits 3b, 5, 7b and 9 in group 2. ] [ Designated as safety issue: No ]
    To assess the impact of coitus (and semen) on the pharmacokinetics of tenofovir 1% gel in female genital tract secretions, vaginal and cervical tissue and rectal tract secretions

  • Pharmacodynamics of luminal drug [ Time Frame: Visits 2b, 3b, 4b, 5b, 6b and 7b in group 1. Visits 3b, 5, 7b and 9 in group 2. ] [ Designated as safety issue: No ]
    To assess the impact of coitus (and semen) on pharmacodynamics of luminal drug by measuring the anti-HIV-1 activity in CVL samples


Secondary Outcome Measures:
  • Acceptability [ Time Frame: Visit 7b for group 1. Visit 9 for group 2. ] [ Designated as safety issue: No ]
    To assess the acceptability of the MTN-011 trial to male and female participants


Other Outcome Measures:
  • Impact of coitus and/or tenofovir on the genital tract mucosal environment [ Time Frame: Visits 1, 2b, 3b, 4b, 5b, 6b and 7b in group 1. Visits 1, 3b, 5, 7b and 9 in group 2. ] [ Designated as safety issue: No ]
  • Semen biomarker [ Time Frame: Visits 1, 2b, 3b, 5b and 7b in group 1. Visits 1, 3b, 5, 7b and 9 in group 2. ] [ Designated as safety issue: No ]
    To determine whether a semen biomarker can be used to estimate the volume of ejaculate within CVL

  • Retained drug levels in the lumen [ Time Frame: Visits 1, 2b, 3b, 4b, 5b, 6b and 7b in group 1. Visits 1, 3b, 5, 7b and 9 in group 2. ] [ Designated as safety issue: No ]
    To assess whether sufficient drug is retained in the lumen in the absence of or following coitus to inhibit HSV-2 as an additional surrogate biomarker of pharmacodynamics


Estimated Enrollment: 80
Study Start Date: November 2012
Estimated Study Completion Date: September 2014
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Group 1
Single Dose/BAT Cohort
Drug: 1% Tenofovir Gel
Active Comparator: Group 2
Multiple Dose Cohort
Drug: 1% Tenofovir Gel

  Eligibility

Ages Eligible for Study:   21 Years to 46 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

Men and women in Group 1 and Group 2 must meet the following criteria to be eligible for inclusion in the study:

  1. Able and willing to provide the following:

    • Written informed consent to be screened for and take part in the study
    • Adequate locator information, as defined in site SOPs
  2. Per participant report, at low risk for HIV/STI. Low risk is defined as:

    • No STIs in the 6 months prior to Screening
    • No non-therapeutic intravenous drug use in the 18 months prior to Screening
    • In a mutually monogamous relationship with a partner of the opposite sex for 6 months prior to Screening and the intent to stay in this relationship for the next 4 months
  3. At Screening and Enrollment, both partners independently report not using barrier contraception and/or barrier protection as part of normal coital routine and report the intent to continue said sexual practice for the duration of study participation
  4. HIV-uninfected based upon testing performed by study staff at Screening (per protocol algorithm)
  5. Agrees not to participate in other research studies involving drugs, medical devices, or genital and rectal products, or large blood draw studies during study participation
  6. Women must also meet the following criteria:

    • Age 21 through 46 years (inclusive) at Screening, verified per site SOPs
    • Pap result in the 12 calendar months prior to Screening consistent with Grade 0 according to the Female Genital Grading Table for Use in Microbicide Studies Addendum 1 to the DAIDS Table for Grading Adult and Pediatric Adverse Events, Version 1.0, December 2004 (Clarification dated August 2009), or satisfactory evaluation with no treatment required of non-Grade 0 Pap result per American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines in the 12 calendar months prior to the Screening Visit

    Note: Women with a documented normal result within the 12 months prior to screening need not have a Pap smear during the screening period. Women with abnormal Pap smears can be enrolled upon completion of the initial phase of evaluation if no current treatment is indicated (based on local standard of care for management of abnormal cervical cytology). Need for a repeat Pap within 6 months does not preclude enrollment prior to that result becoming available.

    • Must be currently using effective non-barrier contraception, other than a contraceptive vaginal ring, for at least three months prior to Screening (i.e., oral contraceptive, patch, injectable hormones, subdermal implants, intrauterine device, female or male sterilization) and intending to use this method for the course of the study
    • Per participant report, regular menstrual cycles with at least 21 days between menses (does not apply to participants who report using a progestin-only method of contraception at screening, e.g., Depo-Provera)

    Note: This criterion is not applicable to participants using continuous combination oral contraceptive pills, as the absence of regular menstrual cycles is an expected, normal consequence in this context.

    • Anatomy sufficient for performing pelvic examinations and for collecting vaginal and cervical specimens
    • Female participants must also agree to abstain from intercourse (oral, anal, or penile-vaginal) and other vaginal practices (e.g., masturbation, douching, tampon use, application of lubricants/spermicides or other related practices) 72 hours prior to each follow-up visit. Group 2 participants must agree to also abstain from the aforementioned practices throughout the at-home gel use period
  7. Men must also meet the following criteria:

    • Age 21 or older at Screening, verified per site SOPs
    • Agree to abstain from intercourse (oral, anal, or penile-vaginal) and other penile practices (e.g., masturbation, application of lubricants/spermicides or other related practices) 72 hours prior to each follow-up visit. Group 2 participants must also agree to refrain from intercourse (oral, anal, or penile-vaginal) throughout their partner's at-home gel use period

Exclusion Criteria:

Men and women who meet any of the following criteria will be excluded from the study. Previous participation in Group 1 or Group 2 of the MTN-011 clinical trial is not exclusionary.

  1. Participant report of any of the following:

    • Known allergy to the study product (ever)
    • Post-exposure prophylaxis (PEP) for HIV exposure within 6 months prior to Screening
    • Participation in any other research study involving drugs, medical devices, or genital products 30 days or less prior to Enrollment
    • Plans to relocate away from the study site in the next 4 months
    • History of domestic violence with current partner (ever)
    • Systemic or topical antimicrobials within the last 7 days prior to Enrollment
    • Currently using or planning to use pharmacologic immune modulator(s)
  2. At Screening or Enrollment, symptomatic urinary tract infection (UTI)

    Note: Otherwise eligible participants diagnosed with UTI during screening are offered treatment and may be enrolled after completing treatment and all symptoms have resolved as long as treatment is completed and all symptoms have resolved within 30 days of obtaining informed consent for Screening/Enrollment.

  3. At Screening, has a positive hepatitis B surface antigen (HBsAg) test result
  4. At Screening or Enrollment, has an STI or reproductive tract infection (RTI) requiring treatment per current CDC guidelines
  5. Genital signs and/or symptoms of Grade 2 or higher

    Note: For female participants, cervical bleeding associated with speculum insertion and/or specimen collection judged to be within the range of normal according to the clinical judgment of the IoR/designee is considered expected non-menstrual bleeding and is not exclusionary.

    Note: Otherwise eligible participants with exclusionary genital findings may be enrolled after the findings have improved to a non-exclusionary severity grading or resolved as long as treatment is completed and all symptoms have resolved within 30 days of obtaining informed consent for Screening/Enrollment.

  6. Has any other condition that, in the opinion of the IoR/designee, would preclude informed consent, make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives
  7. Women who meet any of the following criteria will be excluded from the study:

    • Participant report (or clinical finding) of the following:

      • Last pregnancy outcome 90 days or less prior to Enrollment
      • Currently pregnant

    Note: Self-reported pregnancy is adequate for exclusion from the study. A documented negative pregnancy test performed by study staff is required for inclusion.

    • Currently breastfeeding
    • Intends to become pregnant in the next 4 months
    • Gynecologic or genital procedure (e.g., tubal ligation, dilation and curettage) within the prior 30 days to Enrollment

    Note: This does not include biopsy for the evaluation of an abnormal pap result or endometrial biopsy that occurred more than 7 days prior to Enrollment.

    • Any of the following laboratory abnormalities at Screening:

      • Hemoglobin less than 10.0 g/dl
      • Platelet count less than 100,000/mm3

    Note: Otherwise eligible participants with an exclusionary test may be re-tested during the screening process

    • Use of a vaginal douche or other intravaginal products (excluding tampon use) in the 30 days prior to Enrollment
    • Currently menopausal or perimenopausal
  8. Men who meet any of the following criteria will be excluded from the study:

    • Participant report of penile procedures (e.g. biopsy, circumcision) within 42 days prior to Enrollment
    • For uncircumcised men, per participant report, treatment of candidal balanoposthitis/ balanitis within 30 days prior to Enrollment
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01687205

Locations
United States, Ohio
Case Western Reserve University Recruiting
Cleveland, Ohio, United States, 44106
Contact: Robert A. Salata, MD    216-844-3287    robert.salata@case.edu   
Principal Investigator: Robert A. Salata, MD         
United States, Pennsylvania
Magee-Womens Hospital of UPMC Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Beatrice A. Chen, MD    412-641-1403    chenba@upmc.edu   
Principal Investigator: Beatrice A. Chen, MD, MPH         
Sponsors and Collaborators
CONRAD
Investigators
Study Chair: Betsy Herold, MD Albert Einstein College of Medicine of Yeshiva University
Principal Investigator: Beatrice A. Chen, MD, MPH Magee-Womens Hospital of UPMC
Principal Investigator: Robert A. Salata, MD Case Western Reserve University
  More Information

No publications provided

Responsible Party: CONRAD
ClinicalTrials.gov Identifier: NCT01687205     History of Changes
Other Study ID Numbers: MTN-011, 5UM1AI068633-06, 11825
Study First Received: August 27, 2012
Last Updated: April 11, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Tenofovir
Tenofovir disoproxil
Anti-HIV Agents
Anti-Infective Agents
Anti-Retroviral Agents
Antiviral Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Nucleic Acid Synthesis Inhibitors
Pharmacologic Actions
Reverse Transcriptase Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014