Clinical trial NCT03279120: Safety, PK, and PD Study of IVRs Releasing TFV and LNG
Official title: Phase I, 90-Day Safety, Pharmacokinetic, And Pharmacodynamic Study Of Intravaginal Rings Releasing Tenofovir And Levonorgestrel
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Anti-Infective Agents
Anti-Retroviral Agents
Contraceptive Usage
Keywords: HIV
LNG
TFV
IVR
Contraception
Prevention
Lead sponsor: CONRAD
Sponsor class: OTHER
Collaborators: name: United States Agency for International Development (USAID)
name: Agility Clinical, Inc.
First posted: 2017-09-12
Enrollment: 66
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Percentage of women with Treatment-emergent adverse events
timeFrame: Day 90
measure: Changes in systemic laboratory values
timeFrame: Change from Baseline at Day 90
measure: Changes in cervicovaginal mucosa by visual inspection
timeFrame: Change from Baseline at Day 90
measure: Changes in soluble markers
timeFrame: Change from Baseline at Day 90
measure: Changes in inflammatory markers in cervicovaginal tissue
timeFrame: Change from Baseline at Day 90
measure: Changes in endogenous vaginal bacteria
timeFrame: Change from Baseline at Day 90
measure: Microbial growth
timeFrame: Day 90
Secondary outcomes:
measure: Maximum Plasma Concentrations [Cmax]
timeFrame: 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)
measure: Maximum CV Fluid Concentrations
timeFrame: 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)
measure: Maximum Rectal Fluid Concentrations
timeFrame: 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)
measure: Maximum CV Tissue Concentrations
timeFrame: Changes from baseline at day 90; and 48 or 72 hours or 5 days after IVR removal (randomized time point)
measure: Maximum CV Tissue Metabolite Concentrations
timeFrame: Changes from baseline at day 90; and 48 or 72 hours or 5 days after IVR removal (randomized time point)
measure: Maximum Serum Concentrations of LNG
timeFrame: 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)
measure: Residual Drug Concentrations
timeFrame: Day 90
measure: Surrogates of contraceptive efficacy of Mucus
timeFrame: Day 30
measure: Surrogates of contraceptive efficacy of Sperm
timeFrame: Day 30
measure: Ovulation
timeFrame: Changes from baseline at day 90
measure: Follicular Development
timeFrame: Changes from baseline at day 90
measure: Antiviral activity in CV Fluid--HIV
timeFrame: Changes from baseline at day 90
measure: Antiviral activity in CV Fluid--HSV-2
timeFrame: Changes from baseline at day 90
measure: Changes in Antiviral Activity
timeFrame: Changes from baseline at day 90
measure: Bleeding Patterns
timeFrame: Baseline through Day 90 of IVR use
measure: Forgiveness--LNG
timeFrame: Day 32 and 63; and 48 or 72 hours or 5 days after IVR removal (randomized time point)
measure: Forgiveness--TFV
timeFrame: Day 32 and 63; and 48 or 72 hours or 5 days after IVR removal (randomized time point)
measure: Acceptability--Qualitative
timeFrame: Baseline, Day 28 and 90
measure: Acceptability--IDI
timeFrame: During first month of IVR use and Day 90
measure: Adherence
timeFrame: Baseline, Day 28 and 90
Other outcomes:
measure: Antiviral activity in Rectal Fluid--HIV
timeFrame: Changes from baseline at day 90
measure: Antiviral activity in Rectal Fluid--HSV-2
timeFrame: Changes from baseline at day 90
measure: Changes in Antiviral Activity--HSV-2
timeFrame: Changes from baseline at day 90
measure: Qualitative TFV measurement
timeFrame: Day 90
measure: Adherence Marker in returned vaginal ring-analytic
timeFrame: Day 90
measure: Adherence marker in returned ring--bioassay
timeFrame: Day 90
measure: Adherence marker in returned ring--correlation
timeFrame: Day 90
measure: Adherence marker in returned ring--correlation
timeFrame: Day 90
Locations:
city: Norfolk
country: United States
facility: Eastern Virginia Medical School
state: Virginia
city: Santo Domingo
country: Dominican Republic
facility: Profamilia
Study officials:
affiliation: CONRAD
name: study director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.