Safety, PK, and PD Study of IVRs Releasing TFV and LNG

NCT03279120 | Completed Phase 1 FDA Drug

• 1 other identifier: A15-138
• Study Type: interventional
• Target: 66
• Locations: 2 countries
• Sites: 2

Brief Summary

This multi-center Phase I study is designed to characterize the safety, PK, and PD of TFV/LNG IVR to assess systemic and genital tract bioavailability in healthy women. The IVRs to be used in the study are TFV/LNG IVR (8-10mg per day/20μg per day) or placebo IVR. Samples will be obtained before, during and after 90 days of continuous or interrupted IVR use.

Conditions

Anti-Infective Agents; Anti-Retroviral Agents; Contraceptive Usage

Keywords

HIV; LNG; TFV; IVR; Contraception; Prevention

Outcome Measures

Primary Outcomes (7)

• Percentage of women with Treatment-emergent adverse events

  Treatment-emergent adverse events (TEAEs)

  Day 90

• Changes in systemic laboratory values

  Systemic laboratory values

  Change from Baseline at Day 90

• Changes in cervicovaginal mucosa by visual inspection

  Mucosal safety

  Change from Baseline at Day 90

• Changes in soluble markers

  Soluble markers in cervicovaginal fluid

  Change from Baseline at Day 90

• Changes in inflammatory markers in cervicovaginal tissue

  Inflammatory markers in cervicovaginal tissue

  Change from Baseline at Day 90

• Changes in endogenous vaginal bacteria

  Endogenous vaginal bacteria in cervicovaginal fluid

  Change from Baseline at Day 90

• Microbial growth

  Microbial growth on returned IVRs

  Day 90

Secondary Outcomes (20)

• Maximum Plasma Concentrations [Cmax]

  Baseline, 8 hours post-IVR insertion, Day 2 or 3 or 4 (randomized time point), 10, 21, 28, 32, 42, 53, 59, 63, 73, 84, 90; and 48 or 72 hours or 5 days after IVR removal (randomized time point)

• Maximum CV Fluid Concentrations

  2 and 8 hours post-IVR insertion, Day 2 or 3 or 4 (randomized time point), 10, 21, 32, 42, 53, 63, 73, 84; and 48 or 72 hours or 5 days after IVR removal (randomized time point)

• Maximum Rectal Fluid Concentrations

  Day 2 or 3 or 4 (randomized time point), 21, 53, 84; and 48 or 72 hours or 5 days after IVR removal (randomized time point)

• Maximum CV Tissue Concentrations

  Changes from baseline at day 90; and 48 or 72 hours or 5 days after IVR removal (randomized time point)

• Maximum CV Tissue Metabolite Concentrations

  Changes from baseline at day 90; and 48 or 72 hours or 5 days after IVR removal (randomized time point)

Other Outcomes (8)

• Antiviral activity in Rectal Fluid--HIV

  Changes from baseline at day 90

• Antiviral activity in Rectal Fluid--HSV-2

  Changes from baseline at day 90

• Changes in Antiviral Activity--HSV-2

  Changes from baseline at day 90

Study Arms (4)

TFV/LNG IVR (8-10mg/20μg) (Continuous)

EXPERIMENTAL

TFV/LNG IVR is an intravaginal ring 55.0 mm in diameter, consisting of two segments of polyurethane tubing with an outer cross-sectional diameter of 5.5 mm: a longer segment (135 mm) containing white to off-white TFV paste and a shorter one (34 mm) with a translucent LNG core. Used for 90 days (continuous).

Drug: TFV/LNG IVR

TFV/LNG IVR (8-10mg/20μg) (Interrupted)

EXPERIMENTAL

TFV/LNG IVR is an intravaginal ring 55.0 mm in diameter, consisting of two segments of polyurethane tubing with an outer cross-sectional diameter of 5.5 mm: a longer segment (135 mm) containing white to off-white TFV paste and a shorter one (34 mm) with a translucent LNG core. Used for 90 days (3x28 days interrupted).

Drug: TFV/LNG IVR

Placebo (Continuous)

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. Used for 90 days (continuous).

Drug: Placebo

Placebo (Interrupted)

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. Used for 90 days (3x28 days interrupted).

Drug: Placebo

Interventions

TFV/LNG IVR DRUG

Used for 90 days (Continuous or Interrupted)

Also known as: Tenofovir/Levonorgestrel Intravaginal Ring

TFV/LNG IVR (8-10mg/20μg) (Continuous); TFV/LNG IVR (8-10mg/20μg) (Interrupted)

Placebo DRUG

Used for 90 days (Continuous or Interrupted)

Placebo (Continuous); Placebo (Interrupted)

Eligibility Criteria

• Age: 18 Years - 50 Years
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Female, age 18-50 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) and with an intact gastrointestinal tract, uterus, and cervix.
• Currently having regular menstrual cycles (approximately 26-35 days) by participant report
• History of Pap smears and follow-up consistent with standard clinical practice as outlined in the Study Manual or willing to undergo a Pap smear at Visit 1
• Protected from pregnancy by one of the following:
• Sterilization of either partner
• Abstinence from vaginal intercourse
• Consistent use of non-spermicidal condoms
• Willing to abstain from use of vaginal products (other than the study product and condoms) including tampons (except for menses), spermicides, lubricants, and douches for the whole study
• Willing to abstain from any vaginal and anal intercourse/activity starting 48 hours before cervical mucus collection, as possible, and 48 hours before Visits 4 and 29, and for 5 days after tissue collection
• Vaginal and cervical anatomy that, in the opinion of the investigator, lends itself to easy genital tract sample collection
• Negative urine pregnancy test
• P4 ≥3 ng/ml
• Willing to give voluntary consent and sign an informed consent form
• Willing and able to comply with protocol requirements

You may not qualify if:

• BMI ≥ 30 kg/m2
• 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 IUD
• 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 the study products, topical anesthetic, or to both silver nitrate and Monsel's solution
• Contraindication to LNG
• In the last three months, diagnosed with or treated for any 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 (TV), Neisseria gonorrhea (GC), Chlamydia trachomatis (CT), HIV-1, or Hepatitis B surface antigen (HBsAg)
• Known bleeding disorder, including deep vein thrombosis (DVT) and pulmonary embolism (PE), or those that could lead to prolonged or continuous bleeding with biopsy
• Chronic or acute vulvar or vaginal symptoms (pain, irritation, spotting/bleeding, discharge, etc.)

Sponsors & Collaborators

• CONRAD: lead
• United States Agency for International Development (USAID): collaborator
• Agility Clinical, Inc.: collaborator

Study Sites (2)

Eastern Virginia Medical School

Norfolk, Virginia, 23507-1627, United States

Location

Profamilia

Santo Domingo, Dominican Republic

Location

Related Publications (3)

• Thurman AR, Brache V, Cochon L, Ouattara LA, Chandra N, Jacot T, Yousefieh N, Clark MR, Peet M, Hanif H, Schwartz JL, Ju S, Marzinke MA, Erikson DW, Parikh U, Herold BC, Fichorova RN, Tolley E, Doncel GF. Randomized, placebo controlled phase I trial of the safety, pharmacokinetics, pharmacodynamics and acceptability of a 90 day tenofovir plus levonorgestrel vaginal ring used continuously or cyclically in women: The CONRAD 138 study. PLoS One. 2022 Oct 10;17(10):e0275794. doi: 10.1371/journal.pone.0275794. eCollection 2022.

  PMID: 36215267 DERIVED

• Tolley EE, Zissette S, Taylor J, Hanif H, Ju S, Schwarz J, Thurman A, Tyner D, Brache V, Doncel GF. Acceptability of a Long-Acting, Multipurpose Vaginal Ring: Findings from a Phase I Trial in the U.S. and Dominican Republic. J Womens Health (Larchmt). 2022 Sep;31(9):1343-1352. doi: 10.1089/jwh.2021.0394. Epub 2022 Apr 1.

  PMID: 35363574 DERIVED

• Thurman AR, Ravel J, Gajer P, Marzinke MA, Ouattara LA, Jacot T, Peet MM, Clark MR, Doncel GF. Vaginal Microbiota and Mucosal Pharmacokinetics of Tenofovir in Healthy Women Using a 90-Day Tenofovir/Levonorgestrel Vaginal Ring. Front Cell Infect Microbiol. 2022 Mar 8;12:799501. doi: 10.3389/fcimb.2022.799501. eCollection 2022.

  PMID: 35350436 DERIVED

MeSH Terms

Conditions

Contraception Behavior

Interventions

Tenofovir

Condition Hierarchy (Ancestors)

Reproductive Behavior; Behavior

Intervention Hierarchy (Ancestors)

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

Study Officials

• study director

  CONRAD

  STUDY DIRECTOR

Study Design

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

Study Record Dates

• First Submitted: August 23, 2017
• First Posted: September 12, 2017
• Study Start: September 28, 2017
• Primary Completion: December 26, 2018
• Study Completion: December 26, 2018
• Last Updated: July 23, 2019

Record last verified: 2019-07

Data Sharing

• IPD Sharing: Will not share

Locations

DO (1); US (1)