Phase I One-month Safety, PK, PD, and Acceptability Study of IVR Releasing TFV and LNG or TFV Alone

NCT02235662 | Completed Phase 1

• 1 other identifier: A13-128
• Study Type: interventional
• Target: 86
• Locations: 2 countries
• Sites: 2

Brief Summary

The purpose of the study is to evaluate the safety of the TFV/LNG intravaginal ring (IVR), TFV-only IVR, and placebo IVR, evaluate pharmacokinetics (PK) of TFV and LNG, evaluate pharmacodynamic (PD) surrogates of contraceptive efficacy of LNG, and to evaluate acceptability of the IVRs.

Conditions

HIV; Contraception

Keywords

HIV; LNG; IVR; Contraception; Prevention

Outcome Measures

Primary Outcomes (8)

• Number of treatment-emergent adverse events

  Number of treatment-emergent adverse events

  IVR Day 1, 2, ~8, ~16-18; 24 hours and 1-2 weeks post-IVR insertion and 1-2 weeks after IVR removal

• Systemic laboratory tests

  Changes in Systemic laboratory tests

  Baseline and IVR Day ~16-18

• Cervicovaginal ulcerations, abrasions, edema, and other findings

  Development of cervicovaginal ulcerations, abrasions, edema, and other findings as assessed by naked eye and colposcopic visualization of the cervicovaginal epithelium

  Baseline, IVR Day 2, ~8 and ~16-18

• Soluble markers of innate mucosal immunity and inflammatory response in cervicovaginal lavage (CVL) fluid

  Changes in soluble markers of innate mucosal immunity and inflammatory response in CVL fluid

  Baseline and IVR Day ~16-18

• HIV-1 target immune cell phenotype and HIV-1 activation/proliferation marker in cervicovaginal tissue (biopsy)

  Changes in HIV-1 target immune cell phenotype and HIV-1 activation/proliferation marker in cervicovaginal tissue (biopsy)

  Baseline and IVR Day ~16-18

• Microflora (semi-quantitative vaginal culture and/or unculturable bacteria)

  Changes microflora (semi-quantitative vaginal culture and/or unculturable bacteria)

  Baseline and IVR Day ~16-18

• Vaginal pH

  Changes in vaginal pH

  Baseline and IVR Day ~16-18

• Nugent Score

  Changes in Nugent Score

  Baseline and IVR Day ~16-18

Secondary Outcomes (10)

• TFV concentrations in plasma

  Baseline; 1, 2, 4 and 8 hrs post-IVR insertion; IVR Day 2, ~8, ~16-18; 24 hours post-IVR removal

• TFV concentrations in cervicovaginal fluid (aspirate and swab)

  1, 2, 4 or 8 hours post-IVR insertion (randomized time point); IVR Day 2, ~8, ~16-18; 24 hours post-IVR removal

• TFV concentrations in genital tissue (biopsy)

  IVR Day 2, ~16-18; 24 or 72 hours post-IVR removal (randomized time point)

• Tenofovir diphosphate (TFV-DP) concentrations in peripheral blood mononuclear cells (PBMCs)

  IVR Day ~16-18

• TFV-DP concentrations in genital tissue (biopsy)

  IVR Day 2, ~16-18; 24 or 72 hours post-IVR removal (randomized time point)

Other Outcomes (13)

• Cervical mucus assessment and sperm migration on the Simplified Slide test

  IVR Day ~8

• Ovulation by P4

  IVR Day ~16-18

• Follicular development by serum estradiol concentration

  IVR Day ~8, ~16-18

Study Arms (3)

TFV IVR

EXPERIMENTAL

TFV IVR is an intravaginal ring 55.0 mm in diameter, consisting of single segment of polyurethane tubing with an outer diameter of 5.5 mm and filled with white TFV-containing paste. Used for one month, the IVR delivers 8-10 mg/day TFV.

Drug: TFV IVR

TFV/LNG IVR

EXPERIMENTAL

TFV/LNG IVR is an intravaginal ring 55.0 mm in diameter, consisting of two segments of polyurethane tubing with an outer diameter of 5.5 mm: a longer segment containing white TFV paste and a shorter one (20 mm) with a white LNG core. Used for one month, the IVR delivers 8-10 mg/day TFV and 20 μg/day LNG.

Drug: TFV IVR; Drug: TFV/LNG IVR

Placebo Intravaginal Ring

PLACEBO COMPARATOR

Intravaginal ring 55.0 mm in diameter, consisting of two segments of polyurethane tubing with an outer diameter of 5.5 mm containing no active experimental ingredients. Used for one month.

Other: Placebo IVR

Interventions

TFV IVR DRUG

Also known as: Tenofovir Intravaginal Ring

TFV IVR; TFV/LNG IVR

TFV/LNG IVR DRUG

Also known as: Tenofovir Levonorgestrel Intravaginal Ring

TFV/LNG IVR

Placebo IVR OTHER

Also known as: Placebo Intravaginal Ring

Placebo Intravaginal Ring

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
• 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)
• Currently having regular menstrual cycles of 26-35 days by participant report
• History of Pap smears and follow-up consistent with standard medical practice as outlined in the study manual or willing to undergo a Pap smear
• Protected from pregnancy by one of the following: 1) Sterilization of either partner. Note: Women protected from pregnancy by sterilization of either partner must abstain from vaginal intercourse from 48 hours prior to Visit 3 until the sixth day after the last study visit; or 2) Willing to abstain from vaginal intercourse from Visit 1 until the sixth day after the last study visit.
• Willing to abstain from any other vaginal activity and the use of vaginal product other than the study product including tampons, spermicides, lubricants, and douches starting 48 hours before Visit 3 until the sixth day after the last study visit
• Vaginal and cervical anatomy that, in the opinion of the investigator, lends itself to easy colposcopy and genital tract sample collection
• Negative urine pregnancy test
• P4 ≥3 ng/ml
• Willing to give voluntary consent, sign an informed consent form and comply with study procedures as required by the protocol

You may not qualify if:

• History of hysterectomy
• Currently pregnant or within two calendar months from the last pregnancy outcome. Note: If recently pregnant must have had at least two spontaneous menses since pregnancy outcome.
• Use of any hormonal contraceptive method in the last 3 months (oral, transdermal, transvaginal, implant, or hormonal intrauterine contraceptive device)
• Injection of Depo-Provera in the last 10 months
• Use of copper intrauterine device (IUD) after Visit 1
• Currently breastfeeding or having breastfed an infant in the last two months, or planning to breastfeed during the course of the study
• History of sensitivity/allergy to any component of: TFV 1% gel, topical anesthetic, or allergy to both silver nitrate and Monsel's solution.
• Contraindication to LNG
• In the last six months, diagnosed with or treated for any sexually transmitted infection (STI) or pelvic inflammatory disease. Note: Women with a history of genital herpes or condylomata who have been asymptomatic for at least six months may be considered for eligibility.
• Nugent score greater than or equal to 7 or symptomatic bacterial vaginosis (BV) as defined by Amsel's criteria
• Positive test for Trichomonas vaginalis, Neisseria gonorrhea (GC), Chlamydia trachomatis (CT), HIV, or Hepatitis B surface antigen (HBsAg)
• Known bleeding disorder that could lead to prolonged or continuous bleeding with biopsy
• Chronic or acute vulvar or vaginal symptoms (pain, irritation, spotting, etc.)
• Known current drug or alcohol abuse which could impact study compliance
• Grade 2 or higher laboratory abnormality, per the August 2009 update of the Division of AIDS, National Institute of Allergy and Infectious Disease (DAIDS) Table for Grading the Severity of Adverse Events, or clinically significant laboratory abnormality as determined by the clinician

Sponsors & Collaborators

• CONRAD: lead

Study Sites (2)

Eastern Virginia Medical School

Norfolk, Virginia, 23507, United States

Location

Profamilia

Santo Domingo, Dominican Republic, Dominican Republic

Location

Related Publications (2)

• Thurman AR, Schwartz JL, Ravel J, Gajer P, Marzinke MA, Yousefieh N, Anderson SM, Doncel GF. Vaginal microbiota and mucosal pharmacokinetics of tenofovir in healthy women using tenofovir and tenofovir/levonorgestrel vaginal rings. PLoS One. 2019 May 20;14(5):e0217229. doi: 10.1371/journal.pone.0217229. eCollection 2019.

  PMID: 31107913 DERIVED

• Thurman AR, Schwartz JL, Brache V, Clark MR, McCormick T, Chandra N, Marzinke MA, Stanczyk FZ, Dezzutti CS, Hillier SL, Herold BC, Fichorova R, Asin SN, Rollenhagen C, Weiner D, Kiser P, Doncel GF. Randomized, placebo controlled phase I trial of safety, pharmacokinetics, pharmacodynamics and acceptability of tenofovir and tenofovir plus levonorgestrel vaginal rings in women. PLoS One. 2018 Jun 28;13(6):e0199778. doi: 10.1371/journal.pone.0199778. eCollection 2018.

  PMID: 29953547 DERIVED

Study Officials

• Jill Schwartz, MD

  CONRAD

  STUDY CHAIR

• Chris Mauck, MD

  CONRAD

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 14, 2014
• First Posted: September 10, 2014
• Study Start: October 1, 2014
• Primary Completion: December 1, 2015
• Study Completion: December 1, 2015
• Last Updated: January 11, 2016

Record last verified: 2016-01

Locations

US (1); DO (1)