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Safety and Pharmacokinetics (PK) of a Polyurethane Tenofovir Disoproxil Fumarate (TDF) Vaginal Ring (TDF IVR-002) (TDF IVR-002)

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ClinicalTrials.gov Identifier: NCT02762617
Recruitment Status : Terminated (Safety-related)
First Posted : May 5, 2016
Last Update Posted : August 21, 2018
Sponsor:
Collaborator:
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
Marla Keller, Albert Einstein College of Medicine

Brief Summary:

This prospective, two-site, two-arm, randomized, single-blind, placebo-controlled trial will examine the safety and pharmacokinetics (PK) of a polyurethane tenofovir disoproxil fumarate (TDF) vaginal ring when used continuously for 84 consecutive days by sexually active women.

The primary objective is to assess the safety of TDF vaginal rings when used continuously for 84 days by healthy, HIV-uninfected, sexually active women, as compared with a placebo vaginal ring.


Condition or disease Intervention/treatment Phase
Healthy HIV Drug: Tenofovir disoproxil fumarate intravaginal ring Drug: Placebo intravaginal ring (IVR) Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 17 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Prevention
Official Title: Phase 1 Safety and Pharmacokinetic Study of a Polyurethane Tenofovir Disoproxil Fumarate Vaginal Ring in Sexually Active Women (TDF IVR-002)
Actual Study Start Date : February 24, 2017
Actual Primary Completion Date : October 17, 2017
Actual Study Completion Date : October 17, 2017

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: TDF IVR group

The Tenofovir Disoproxil Fumarate intravaginal ring (TDF-IVR) is a white (with clear segment), flexible torus-shaped device with an inner core which contains the experimental drug, TDF, and sodium chloride. The intravaginal ring is worn continuously for 28 days and replaced with new rings twice (every 28 days) for total of 84 days (3 months).

Participants will be stratified by site and will be randomized in a 3:1 ratio (TDF:Placebo).

Drug: Tenofovir disoproxil fumarate intravaginal ring
The TDF IVR is formulated using preformed flexible tubing, comprised of biomedical medical grade hydrophilic, aliphatic polyurethane, and an inner core compartment comprised of 86% (w/w) TDF and 14% (w/w) sodium chloride. The ring will be inserted by the study clinician and worn for 28 day intervals for a total of 3 months (84 days). The ring will be removed and replaced with a new ring at each 28 day interval.
Other Name: TDF IVR

Placebo Comparator: Placebo IVR group

The placebo intravaginal ring (IVR) is a clear, flexible torus-shaped device with an inner core which contains sodium chloride. The intravaginal ring is worn continuously for 28 days and replaced with new rings twice (every 28 days) for total of 84 days (3 months).

Participants will be stratified by site and will be randomized in a 3:1 ratio (TDF:Placebo).

Drug: Placebo intravaginal ring (IVR)
The Placebo IVR is formulated using preformed flexible tubing, comprised of biomedical medical grade hydrophilic, aliphatic polyurethane, and an inner core compartment comprised of sodium chloride. The ring will be inserted by the study clinician and worn for 28 day intervals for a total of 3 months (84 days). The ring will be removed and replaced with a new ring at each 28 day interval.
Other Name: Placebo




Primary Outcome Measures :
  1. Proportion of women in each arm experiencing adverse events (AEs) [ Time Frame: Duration of study - 12 weeks (84 days) ]

    Genitourinary events Grade 2 or higher as defined by the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events judged to be related to study product.

    Adverse events Grade 2 or higher as defined by the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events



Secondary Outcome Measures :
  1. Assessment of TDF levels in cervicovaginal fluid (CVF) - Cmax [ Time Frame: Days 28, 42, 56, 70, and 84 after TDF ring insertion ]
    Analysis for routine PK parameters: Maximum Concentration (Cmax)

  2. Assessment of TDF levels in cervicovaginal fluid (CVF) - Tmax [ Time Frame: Days 28, 42, 56, 70, and 84 after TDF ring insertion ]
    Analysis for routine PK parameters: Time to Maximum Concentration (Tmax)

  3. Assessment of TDF levels in cervicovaginal fluid (CVF) - AUC [ Time Frame: Days 28, 42, 56, 70, and 84 after TDF ring insertion ]
    Analysis for routine PK parameters: Area Under the Curve (AUC)

  4. Assessment of TFV (tenofovir) levels in cervicovaginal fluid and plasma - Cmax [ Time Frame: Days 28, 42, 56, 70, and 84 after TDF ring insertion ]
    Analysis for routine PK parameters (Cmax)

  5. Assessment of TFV (tenofovir) levels in cervicovaginal fluid and plasma - Tmax [ Time Frame: Days 28, 42, 56, 70, and 84 after TDF ring insertion ]
    Analysis for routine PK parameters (Tmax)

  6. Assessment of TFV (tenofovir) levels in cervicovaginal fluid and plasma - AUC [ Time Frame: Days 28, 42, 56, 70, and 84 after TDF ring insertion ]
    Analysis for routine PK parameters (AUC)

  7. Assessment of TFV-DP (tenofovir diphosphate) levels in dried blood spots (DBS) - Cmax [ Time Frame: Days 28, 56, and 84 after TDF ring insertion ]
    Analysis for routine PK parameters (Cmax)

  8. Assessment of TFV-DP (tenofovir diphosphate) levels in dried blood spots (DBS) - Tmax [ Time Frame: Days 28, 56, and 84 after TDF ring insertion ]
    Analysis for routine PK parameters (Tmax)

  9. Assessment of TFV-DP (tenofovir diphosphate) levels in dried blood spots (DBS) - AUC [ Time Frame: Days 28, 56, and 84 after TDF ring insertion ]
    Analysis for routine PK parameters (AUC)

  10. Assessment of TFV levels in cervical tissue - Cmax [ Time Frame: Days 28, 56 (US participants only), and 84 after TDF ring insertion ]
    Analysis for routine PK parameters (Cmax)

  11. Assessment of TFV levels in cervical tissue - Tmax [ Time Frame: Days 28, 56 (US participants only), and 84 after TDF ring insertion ]
    Analysis for routine PK parameters (Tmax)

  12. Assessment of TFV levels in cervical tissue - AUC [ Time Frame: Days 28, 56 (US participants only), and 84 after TDF ring insertion ]
    Analysis for routine PK parameters (AUC)

  13. Assessment of TFV-DP levels in cervical tissue - Cmax [ Time Frame: Days 28, 56 (US participants only), and 84 after TDF ring insertion ]
    Analysis for routine PK parameters (Cmax)

  14. Assessment of TFV-DP levels in cervical tissue - Tmax [ Time Frame: Days 28, 56 (US participants only), and 84 after TDF ring insertion ]
    Analysis for routine PK parameters (Tmax)

  15. Assessment of TFV-DP levels in cervical tissue - AUC [ Time Frame: Days 28, 56 (US participants only), and 84 after TDF ring insertion ]
    Analysis for routine PK parameters (AUC)


Other Outcome Measures:
  1. Assessment of TDF levels in CVF - Cmax [ Time Frame: 1 Hour, 4 Hours, and Day 1 after TDF ring insertion ]
    Analysis for routine PK parameters (Cmax)

  2. Assessment of TDF levels in CVF - Tmax [ Time Frame: 1 Hour, 4 Hours, and Day 1 after TDF ring insertion ]
    Analysis for routine PK parameters (Tmax)

  3. Assessment of TDF levels in CVF - AUC [ Time Frame: 1 Hour, 4 Hours, and Day 1 after TDF ring insertion ]
    Analysis for routine PK parameters (AUC)

  4. Assessment of TFV levels in CVF and tissue - Cmax [ Time Frame: 1 Hour, 4 Hours, and Day 1 after TDF ring insertion ]
    Analysis for routine PK parameters (Cmax)

  5. Assessment of TFV levels in CVF and tissue - Tmax [ Time Frame: 1 Hour, 4 Hours, and Day 1 after TDF ring insertion ]
    Analysis for routine PK parameters (Tmax)

  6. Assessment of TFV levels in CVF and tissue - AUC [ Time Frame: 1 Hour, 4 Hours, and Day 1 after TDF ring insertion ]
    Analysis for routine PK parameters (AUC)

  7. Assessment of TFV-DP levels in tissue - Cmax [ Time Frame: 1 Hour, 4 Hours, and Day 1 after TDF ring insertion ]
    Analysis for routine PK parameters (Cmax)

  8. Assessment of TFV-DP levels in tissue - Tmax [ Time Frame: 1 Hour, 4 Hours, and Day 1 after TDF ring insertion ]
    Analysis for routine PK parameters (Tmax)

  9. Assessment of TFV-DP levels in tissue - AUC [ Time Frame: 1 Hour, 4 Hours, and Day 1 after TDF ring insertion ]
    Analysis for routine PK parameters (AUC)

  10. Assessment of TFV levels in plasma, CVF, and tissue - Cmax [ Time Frame: Days 7, 14, and 21 after TDF ring insertion ]
    Analysis for routine PK parameters (Cmax)

  11. Assessment of TFV levels in plasma, CVF, and tissue - Tmax [ Time Frame: Days 7, 14, and 21 after TDF ring insertion ]
    Analysis for routine PK parameters (Tmax)

  12. Assessment of TFV levels in plasma, CVF, and tissue - AUC [ Time Frame: Days 7, 14, and 21 after TDF ring insertion ]
    Analysis for routine PK parameters (AUC)

  13. Assessment of TDF levels in CVF - Cmax [ Time Frame: Days 7, 14, and 21 after TDF ring insertion ]
    Analysis for routine PK parameters (Cmax)

  14. Assessment of TDF levels in CVF - Tmax [ Time Frame: Days 7, 14, and 21 after TDF ring insertion ]
    Analysis for routine PK parameters (Tmax)

  15. Assessment of TDF levels in CVF - AUC [ Time Frame: Days 7, 14, and 21 after TDF ring insertion ]
    Analysis for routine PK parameters (AUC)

  16. Assessment of TFV-DP levels in tissue - Cmax [ Time Frame: Days 7, 14, and 21 after TDF ring insertion ]
    Analysis for routine PK parameters (Cmax)

  17. Assessment of TFV-DP levels in tissue - Tmax [ Time Frame: Days 7, 14, and 21 after TDF ring insertion ]
    Analysis for routine PK parameters (Tmax)

  18. Assessment of TFV-DP levels in tissue - AUC [ Time Frame: Days 7, 14, and 21 after TDF ring insertion ]
    Analysis for routine PK parameters (AUC)

  19. Assessment of TFV-DP levels in tissue - Cmax [ Time Frame: 5-7 days after ring removal ]
    Analysis for routine PK parameters (Cmax)

  20. Assessment of TFV-DP levels in tissue - Tmax [ Time Frame: 5-7 days after ring removal ]
    Analysis for routine PK parameters (Tmax)

  21. Assessment of TFV-DP levels in tissue - AUC [ Time Frame: 5-7 days after ring removal ]
    Analysis for routine PK parameters (AUC)

  22. Assessment of TDF levels in CVF - Cmax [ Time Frame: 10-12 days after ring removal (US participants only) ]
    Analysis for routine PK parameters (Cmax)

  23. Assessment of TDF levels in CVF - Tmax [ Time Frame: 10-12 days after ring removal (US participants only) ]
    Analysis for routine PK parameters (Tmax)

  24. Assessment of TDF levels in CVF - AUC [ Time Frame: 10-12 days after ring removal (US participants only) ]
    Analysis for routine PK parameters (AUC)

  25. Assessment of TFV levels in CVF and plasma - Cmax [ Time Frame: 10-12 days after ring removal (US participants only) ]
    Analysis for routine PK parameters (Cmax)

  26. Assessment of TFV levels in CVF and plasma - Tmax [ Time Frame: 10-12 days after ring removal (US participants only) ]
    Analysis for routine PK parameters (Tmax)

  27. Assessment of TFV levels in CVF and plasma - AUC [ Time Frame: 10-12 days after ring removal (US participants only) ]
    Analysis for routine PK parameters (AUC)



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age 18-45 years (inclusive) at screening.
  • General good health (by volunteer history and per investigator discretion) without any clinically significant systemic disease (including, but not limited to significant liver disease/hepatitis, gastrointestinal disease, kidney disease, thyroid disease, osteoporosis or bone disease, and diabetes).
  • Able and willing to provide written informed consent to be screened for and take part in the study.
  • Able and willing to provide adequate locator information.
  • Able and willing to avoid receptive vaginal and anal intercourse for 1 week after each biopsy.
  • HIV-uninfected based on testing performed by study staff during screening procedures (per applicable algorithm in Appendix II).
  • Using a copper IUD or any hormonal contraceptive method, other than an IVR, for a minimum of 2 months and intending to use the same method for the duration of study participation.
  • Per participant report, sexually active, defined as having vaginal intercourse at least once in the month prior to screening.
  • Have a regular sex partner and willing to have at least 4 sex acts per month for the duration of the study. Sex act is defined as penile-vaginal penetrative intercourse. Study staff will provide condoms to all study participants. Participants will not be restricted from engaging in oral sex.
  • Has not used pre- or post-exposure prophylaxis for HIV exposure in the 3 months prior to Screening.
  • Per participant report at Screening and Enrollment, agrees not to participate in other research studies involving drugs, medical devices, or vaginal products for the duration of study participation.
  • At Screening, participant states she is able and willing to refrain from taking traditional herbs or medicines and is willing to refrain from inserting any non-study vaginal products or objects into the vagina, including but not limited to, spermicides, diaphragms, contraceptive vaginal rings, vaginal medications, vaginal probiotics/pre-biotics, menstrual cups, cervical caps (or any other vaginal barrier method), douches, lubricants, vaginal drying agents and sex toys (vibrators, dildos, etc.). Tampons may be used, but for menses only.
  • Vaginal and cervical anatomy that, in the opinion of the investigator, lends itself to easy genital tract sample collection.

Exclusion Criteria:

Women must meet none of the following criteria prior to genital sampling at Enrollment:

Participant report of any of the following at Screening:

  • Sex in the past 3 months or any possibility of sex during study participation with a partner who is HIV+ or with a partner of unknown HIV status.
  • Known adverse reaction to polyurethane or to any components of the study product or allergy to both silver nitrate and Monsel's solution.
  • Active hepatitis B infection.
  • Chronic, recurrent, and/or acute vulvar or vaginal symptoms (pain, irritation, spotting, etc.).
  • Known bleeding disorder that could lead to prolonged or continuous bleeding with biopsy.
  • Intending to become pregnant during the period of study participation.
  • Currently breastfeeding or planning to breastfeed during the course of the study.
  • Menopause.
  • History of unexplained or unresolved intermenstrual bleeding in the 3 months prior to screening.
  • History of gynecological procedures (including genital piercing) on the external genitalia, vagina or cervix in the last 14 days.
  • Hysterectomy.
  • Women using contraceptive IVRs because the study product is an IVR.
  • Systemic use in the last 2 weeks or anticipated use during the study period of any of the following: corticosteroids, anticoagulants or ARVs.
  • Plans to relocate away from the study site area during the period of study participation.
  • Grade 1 or higher laboratory abnormality, as defined by the DAIDS Table for Grading the Severity of Adult and Pediatric AEs, Version 2.0, Nov 2014.
  • At Screening or Enrollment, is pregnant (based on urine pregnancy test).
  • In the last three months, diagnosed with or treated for any STI. Note: Women with a history of condylomata or genital herpes may be considered for eligibility as long as there are no lesions on exam. HSV 1 and 2 serologies will be obtained. Participants will be included regardless of the results of these serologies.
  • Reproductive tract infection (RTI) or pelvic inflammatory disease (PID) requiring treatment per local guidelines in Kenya and Centers for Disease Control and Prevention (CDC) guidelines in the US at Screening or Enrollment.

Note: Otherwise eligible women diagnosed with symptomatic vulvovaginal candidiasis (VVC), symptomatic bacterial vaginosis (BV) or urinary tract infection (UTI) will be eligible if Visit 2 (Enrollment) is scheduled after all symptoms have resolved and at least two weeks after completing treatment. Women with recurrent VVC and symptomatic BV despite treatment will be offered another course of treatment and will not be eligible.

  • Positive test for Trichomonas vaginalis, Neisseria gonorrhea or Chlamydia trachomatis at screening.
  • Positive test for hepatitis B (defined as positive for hepatitis B surface antigen).
  • Reactive serologic test for syphilis at screening (per local guidelines). Note: Women with a history of syphilis that was not acquired and/or treated within the past 3 months and that has been appropriately treated may be considered for eligibility.
  • At Screening or Enrollment, has a clinically apparent Grade 1 or higher pelvic exam finding (observed by study clinician or designee) per the DAIDS Table for Grading the Severity of Adult and Pediatric AEs, Addendum 1, Female Genital Grading Table for Use in Microbicide Studies.

Note: Cervical friability bleeding associated with speculum insertion and/or specimen collection judged to be within the range of normal according to the clinical judgment of the PL/designee is considered expected non-menstrual bleeding and is not exclusionary.

- Pap result Grade 2 or higher according to the Female Genital Grading Table for Use in Microbicide Studies Addendum 1 to the DAIDS Table for Grading Adult and Pediatric AEs, Version 1.0, December 2004 (Clarification dated August 2009).

Note: Women 21 years of age or older with a documented normal result within the 12 months prior to enrollment need not have Pap smear during the screening period. Women with a Grade 1 abnormal Pap smear 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.

  • At Screening, has severe pelvic relaxation such that either the vaginal walls or the uterine cervix descend beyond the vaginal introitus with Valsalva maneuver.
  • Has any condition that, in the investigator's opinion, would preclude informed consent, make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02762617


Locations
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United States, New York
Albert Einstein College of Medicine
Bronx, New York, United States, 10461
Kenya
Kenya Medical Research Institute, Partners in Prevention, University of Nairobi
Nairobi, Kenya, 00202
Sponsors and Collaborators
Marla Keller
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
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Principal Investigator: Marla J Keller, MD Albert Einstein College of Medicine

Publications of Results:
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Responsible Party: Marla Keller, Professor, Albert Einstein College of Medicine
ClinicalTrials.gov Identifier: NCT02762617     History of Changes
Other Study ID Numbers: 2015-5591
U19AI103461 ( U.S. NIH Grant/Contract )
First Posted: May 5, 2016    Key Record Dates
Last Update Posted: August 21, 2018
Last Verified: August 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Marla Keller, Albert Einstein College of Medicine:
Healthy Volunteers
Women's Health

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