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

NCT02762617 | Terminated Phase 1 DMC FDA Drug

• 2 other identifiers: 2015-5591U19AI103461
• Study Type: interventional
• Target: 17
• Locations: 2 countries
• Sites: 2

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.

Conditions

Healthy; HIV

Keywords

Healthy Volunteers; Women's Health

Outcome Measures

Primary Outcomes (1)

• Proportion of women in each arm experiencing adverse events (AEs)

  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

  Duration of study - 12 weeks (84 days)

Secondary Outcomes (15)

• Assessment of TDF levels in cervicovaginal fluid (CVF) - Cmax

  Days 28, 42, 56, 70, and 84 after TDF ring insertion

• Assessment of TDF levels in cervicovaginal fluid (CVF) - Tmax

  Days 28, 42, 56, 70, and 84 after TDF ring insertion

• Assessment of TDF levels in cervicovaginal fluid (CVF) - AUC

  Days 28, 42, 56, 70, and 84 after TDF ring insertion

• Assessment of TFV (tenofovir) levels in cervicovaginal fluid and plasma - Cmax

  Days 28, 42, 56, 70, and 84 after TDF ring insertion

• Assessment of TFV (tenofovir) levels in cervicovaginal fluid and plasma - Tmax

  Days 28, 42, 56, 70, and 84 after TDF ring insertion

Other Outcomes (27)

• Assessment of TDF levels in CVF - Cmax

  1 Hour, 4 Hours, and Day 1 after TDF ring insertion

• Assessment of TDF levels in CVF - Tmax

  1 Hour, 4 Hours, and Day 1 after TDF ring insertion

• Assessment of TDF levels in CVF - AUC

  1 Hour, 4 Hours, and Day 1 after TDF ring insertion

Study Arms (2)

TDF IVR group

EXPERIMENTAL

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

Placebo IVR group

PLACEBO COMPARATOR

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)

Interventions

Tenofovir disoproxil fumarate intravaginal ring DRUG

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.

Also known as: TDF IVR

TDF IVR group

Placebo intravaginal ring (IVR) DRUG

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.

Also known as: Placebo

Placebo IVR group

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Marla Keller: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (2)

Albert Einstein College of Medicine

The Bronx, New York, 10461, United States

Location

Kenya Medical Research Institute, Partners in Prevention, University of Nairobi

Nairobi, 00202, Kenya

Location

Related Publications (2)

• Keller MJ, Mesquita PM, Marzinke MA, Teller R, Espinoza L, Atrio JM, Lo Y, Frank B, Srinivasan S, Fredricks DN, Rabe L, Anderson PL, Hendrix CW, Kiser PF, Herold BC. A phase 1 randomized placebo-controlled safety and pharmacokinetic trial of a tenofovir disoproxil fumarate vaginal ring. AIDS. 2016 Mar 13;30(5):743-51. doi: 10.1097/QAD.0000000000000979.

  PMID: 26605514 RESULT

• Keller MJ, Wood L, Billingsley JM, Ray LL, Goymer J, Sinclair S, McGinn AP, Marzinke MA, Frank B, Srinivasan S, Liu C, Atrio JM, Espinoza L, Mugo N, Spiegel HML, Anderson PL, Fredricks DN, Hendrix CW, Marrazzo J, Bosinger SE, Herold BC. Tenofovir disoproxil fumarate intravaginal ring for HIV pre-exposure prophylaxis in sexually active women: a phase 1, single-blind, randomised, controlled trial. Lancet HIV. 2019 Aug;6(8):e498-e508. doi: 10.1016/S2352-3018(19)30145-6. Epub 2019 Jul 15.

  PMID: 31320290 DERIVED

Study Officials

• Marla J Keller, MD

  Albert Einstein College of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: April 22, 2016
• First Posted: May 5, 2016
• Study Start: February 24, 2017
• Primary Completion: October 17, 2017
• Study Completion: October 17, 2017
• Last Updated: August 21, 2018

Record last verified: 2018-08

Locations

US (1); KE (1)