Safety, PK, and PD Study of IVRs Releasing TFV and LNG (TFV/LNG IVR)

Phase I, 90-Day Safety, Pharmacokinetic, And Pharmacodynamic Study Of Intravaginal Rings Releasing Tenofovir And Levonorgestrel

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.

Study Overview

• Status: Completed
• Conditions: Contraceptive Usage; Anti-Infective Agents; Anti-Retroviral Agents
• Intervention / Treatment: Drug: TFV/LNG IVR; Drug: Placebo

Detailed Description

The purpose of this multi-center Phase I protocol, titled Phase I, 90-Day Safety, Pharmacokinetic, and Pharmacodynamic Study of Intravaginal Rings Releasing Tenofovir and Levonorgestrel is to assess the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the Tenofovir/Levonorgestrel Intravaginal Ring (TFV/LNG IVR).

The study will enroll healthy, non-pregnant, ovulatory, HIV-uninfected women aged 18 to 50 with a body mass index (BMI) less than 30 kg/m2, regular menstrual cycles (approximately 26-35 days) by participant report, and willing to use non-spermicidal condoms for sex and follow other study restrictions. Women will be protected from pregnancy by abstinence from vaginal intercourse or agreeing to consistently use condoms.

The enrollment goal is for approximately 60 participants to complete the study. A subset of approximately 20 women will be selected for an in-depth interview to take place during the first month of IVR use and again after 90 days of use.

Women will be randomized to one of four arms: TFV/LNG IVR (8-10mg per day/20μg per day) for 90 days (Continuous), TFV/LNG IVR (8-10mg per day/20μg per day) for 3x28 days (Interrupted), placebo IVR for 90 days (Continuous), or placebo IVR for 3x28 days (Interrupted) and will undergo blood, cervicovaginal and rectal fluid sample collections, and cervicovaginal tissue collections for PK and PD assessments before, during and after 90 days of continuous or interrupted IVR use.

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 1

Contacts and Locations

Study Locations

• Dominican Republic
  • Santo Domingo, Dominican Republic
    • Profamilia
• United States
  • Virginia
    • Norfolk, Virginia, United States, 23507-1627
      • Eastern Virginia Medical School

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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.)
• Known current drug or alcohol abuse which could impact study compliance
• Grade 2 or higher laboratory abnormality, per the 2014 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
• Systemic use in the last two weeks or anticipated use during the study of any of the following: corticosteroids, antibiotics, anticoagulants or other drugs known to prolong bleeding and/or clotting, antifungals, or antivirals or antiretrovirals (e.g. acyclovir, valacyclovir, Viread®, Atripla®, Emtriva®, or Complera®), or CYP3A4 inducers or inhibitors as detailed in the Study Manual (e.g., St. John's Wort or erythromycin).

Note: Participants should avoid non-steroidal anti-inflammatory drugs (NSAIDs) except for treatment of dysmenorrhea during menses. Participants may use acetaminophen on an as-needed but not daily basis during the study.

• Participation in any other investigational trial with use of a drug/device within the last 30 days or planned participation in any other investigational trial with use of a drug/device during the study
• History of gynecological procedures (including genital piercing) on the external genitalia, vagina, or cervix within the last 14 days
• Abnormal finding on laboratory or physical examination or a social or medical condition in the volunteer which, in the opinion of the investigator, would make participation in the study unsafe or would complicate interpretation of data

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TFV/LNG IVR (8-10mg/20μg) (Continuous); 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; Used for 90 days (Continuous or Interrupted); Other Names: Tenofovir/Levonorgestrel Intravaginal Ring
Experimental: TFV/LNG IVR (8-10mg/20μg) (Interrupted); 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; Used for 90 days (Continuous or Interrupted); Other Names: Tenofovir/Levonorgestrel Intravaginal Ring
Placebo Comparator: Placebo (Continuous); 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; Used for 90 days (Continuous or Interrupted)
Placebo Comparator: Placebo (Interrupted); 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; Used for 90 days (Continuous or Interrupted)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Plasma Concentrations [Cmax]	Maximum Plasma Concentrations [Cmax] of TFV and LNG	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	Maximum CV Fluid Concentrations of TFV	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	Maximum Rectal Fluid Concentrations of TFV	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	Maximum CV Tissue Concentrations of TFV	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	Maximum CV Tissue Concentrations of TFV-DP	Changes from baseline at day 90; and 48 or 72 hours or 5 days after IVR removal (randomized time point)
Maximum Serum Concentrations of LNG	Maximum Serum Concentrations of LNG	Baseline, 1, 2, 4, and 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)
Residual Drug Concentrations	Residual drug (TFV and LNG) in returned IVRs	Day 90
Surrogates of contraceptive efficacy of Mucus	Surrogates of contraceptive efficacy: Cervical mucus assessment (Cervical mucus quality [score of >10])	Day 30
Surrogates of contraceptive efficacy of Sperm	Surrogates of contraceptive efficacy: Cervical mucus assessment (Sperm migration on the Simplified Slide test)	Day 30
Ovulation	Ovulation by serum progesterone (P4)	Changes from baseline at day 90
Follicular Development	Effect on follicular development by serum estradiol concentration	Changes from baseline at day 90
Antiviral activity in CV Fluid--HIV	Anti-HIV-1 activity in CV fluid	Changes from baseline at day 90
Antiviral activity in CV Fluid--HSV-2	Anti-HSV-2 activity in CV fluid	Changes from baseline at day 90
Changes in Antiviral Activity	Comparison of HIV-1 ex vivo infection in CV tissue (EVMS only) at baseline and after 90 days of IVR use	Changes from baseline at day 90
Bleeding Patterns	Participant self-report of bleeding	Baseline through Day 90 of IVR use
Forgiveness--LNG	Decay of LNG during 3-day periods of non-use in interrupted regimen, and after 90 days of IVR use	Day 32 and 63; and 48 or 72 hours or 5 days after IVR removal (randomized time point)
Forgiveness--TFV	Decay of TFV during 3-day periods of non-use in interrupted regimen, and after 90 days of IVR use	Day 32 and 63; and 48 or 72 hours or 5 days after IVR removal (randomized time point)
Acceptability--Qualitative	Responses to key questions on acceptability and psychosocial questionnaire(s) (all participants), and feedback during in-depth interviews (subset of participants)	Baseline, Day 28 and 90
Acceptability--IDI	Responses to key questions on acceptability and psychosocial questionnaire(s) (all participants), and feedback during in-depth interviews (subset of participants)	During first month of IVR use and Day 90
Adherence	Percentage of participants with Discontinuations/Expulsions/Removals by self-report	Baseline, Day 28 and 90

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Antiviral activity in Rectal Fluid--HIV	Anti-HIV-1 activity in rectal fluid	Changes from baseline at day 90
Antiviral activity in Rectal Fluid--HSV-2	Anti-HSV-2 activity in rectal fluid	Changes from baseline at day 90
Changes in Antiviral Activity--HSV-2	Comparison of HSV-2 ex vivo infection in CV tissue (EVMS-only) at baseline and after 90 days of IVR use, as possible	Changes from baseline at day 90
Qualitative TFV measurement	Qualitative measure of TFV in a vaginal swab	Day 90
Adherence Marker in returned vaginal ring-analytic	Analytical measures of drug or placebo products	Day 90
Adherence marker in returned ring--bioassay	Characterization of returned IVRs (active and placebo) via objective IVR biomarkers (e.g., residual glycerin content and bioassay) and residual drug (TFV and LNG), as feasible	Day 90
Adherence marker in returned ring--correlation	Correlation of IVR removal scale factors and objective biomarkers of IVR use	Day 90
Adherence marker in returned ring--correlation	Correlation of baseline user characteristics and objective biomarkers of IVR use	Day 90

Collaborators and Investigators

• Sponsor: CONRAD
• Collaborators: United States Agency for International Development (USAID); Agility Clinical, Inc.
• Investigators: Study Director: study director, CONRAD

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 28, 2017
• Primary Completion (Actual): December 26, 2018
• Study Completion (Actual): December 26, 2018

Study Registration Dates

• First Submitted: August 23, 2017
• First Submitted That Met QC Criteria: September 8, 2017
• First Posted (Actual): September 12, 2017

Study Record Updates

• Last Update Posted (Actual): July 23, 2019
• Last Update Submitted That Met QC Criteria: July 22, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: HIV; Contraception; Prevention; LNG; TFV; IVR
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; Tenofovir; Levonorgestrel
• Other Study ID Numbers: A15-138

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No