CompletedNCT03279120TFV/LNG IVRUpdated Jul 23, 2019

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

A Phase 1 interventional study of TFV/LNG IVR and Placebo in Anti-Infective Agents, Anti-Retroviral Agents and Contraceptive Usage, sponsored by CONRAD. Completed at 2 sites in 2 countries. Open to female participants aged 18 Years to 50 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2019-07-23.

Sponsored by CONRAD · Phase 1, Interventional, and Prevention

Phase: Phase 1
Study type: Interventional
Enrollment: 66
Allocation: Randomized
Ages: 18 Years to 50 Years
Sex: Female

Study 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.

Read the 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.

Conditions studied

Anti-Infective Agents
Anti-Retroviral Agents
Contraceptive Usage

Keywords

HIV
LNG
TFV
IVR
Contraception
Prevention

Who can participate

Ages eligible: 18 Years to 50 Years
Sexes eligible: Female
Accepts healthy volunteers: Yes

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

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 design

Phase: Phase 1
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Triple (Participant, Investigator, Outcomes assessor)
Enrollment: 66 participants (actual)

Study arms

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
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
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
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

Interventions

DrugTFV/LNG IVR
Used for 90 days (Continuous or Interrupted)
Also known as: Tenofovir/Levonorgestrel Intravaginal Ring
DrugPlacebo
Used for 90 days (Continuous or Interrupted)

What researchers measure

Primary outcomes

Percentage of women with Treatment-emergent adverse events
Treatment-emergent adverse events (TEAEs)
Time frame: Day 90
Changes in systemic laboratory values
Systemic laboratory values
Time frame: Change from Baseline at Day 90
Changes in cervicovaginal mucosa by visual inspection
Mucosal safety
Time frame: Change from Baseline at Day 90
Changes in soluble markers
Soluble markers in cervicovaginal fluid
Time frame: Change from Baseline at Day 90
Changes in inflammatory markers in cervicovaginal tissue
Inflammatory markers in cervicovaginal tissue
Time frame: Change from Baseline at Day 90
Changes in endogenous vaginal bacteria
Endogenous vaginal bacteria in cervicovaginal fluid
Time frame: Change from Baseline at Day 90
Microbial growth
Microbial growth on returned IVRs
Time frame: Day 90

Secondary outcomes

Maximum Plasma Concentrations [Cmax]
Maximum Plasma Concentrations \[Cmax\] of TFV and LNG
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: Day 90
Surrogates of contraceptive efficacy of Mucus
Surrogates of contraceptive efficacy: Cervical mucus assessment (Cervical mucus quality \[score of \>10\])
Time frame: Day 30
Surrogates of contraceptive efficacy of Sperm
Surrogates of contraceptive efficacy: Cervical mucus assessment (Sperm migration on the Simplified Slide test)
Time frame: Day 30
Ovulation
Ovulation by serum progesterone (P4)
Time frame: Changes from baseline at day 90
Follicular Development
Effect on follicular development by serum estradiol concentration
Time frame: Changes from baseline at day 90
Antiviral activity in CV Fluid--HIV
Anti-HIV-1 activity in CV fluid
Time frame: Changes from baseline at day 90
Antiviral activity in CV Fluid--HSV-2
Anti-HSV-2 activity in CV fluid
Time frame: 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
Time frame: Changes from baseline at day 90
Bleeding Patterns
Participant self-report of bleeding
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: 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)
Time frame: During first month of IVR use and Day 90
Adherence
Percentage of participants with Discontinuations/Expulsions/Removals by self-report
Time frame: Baseline, Day 28 and 90

Other outcomes

Antiviral activity in Rectal Fluid--HIV
Anti-HIV-1 activity in rectal fluid
Time frame: Changes from baseline at day 90
Antiviral activity in Rectal Fluid--HSV-2
Anti-HSV-2 activity in rectal fluid
Time frame: 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
Time frame: Changes from baseline at day 90
Qualitative TFV measurement
Qualitative measure of TFV in a vaginal swab
Time frame: Day 90
Adherence Marker in returned vaginal ring-analytic
Analytical measures of drug or placebo products
Time frame: 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
Time frame: Day 90
Adherence marker in returned ring--correlation
Correlation of IVR removal scale factors and objective biomarkers of IVR use
Time frame: Day 90
Adherence marker in returned ring--correlation
Correlation of baseline user characteristics and objective biomarkers of IVR use
Time frame: Day 90

Study locations

2 sites

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

References and documents

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. PubMed 36215267 ↗
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. PubMed 35363574 ↗
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. PubMed 35350436 ↗

Individual participant data

Plan to share: No

Registry details

Key details

Study ID: NCT03279120
Lead sponsor: CONRAD
Collaborators: United States Agency for International Development (USAID), Agility Clinical, Inc.
Responsible party: Sponsor
First posted: Sep 12, 2017
Start date: Sep 28, 2017
Primary completion: Dec 26, 2018
Completion: Dec 26, 2018
Last update: Jul 23, 2019

Study contacts

study director

study director · CONRAD

Oversight

FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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