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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT03279120
Other study ID # A15-138
Secondary ID
Status Completed
Phase Phase 1
First received
Last updated
Start date September 28, 2017
Est. completion date December 26, 2018

Study information

Verified date July 2019
Source CONRAD
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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.


Recruitment information / eligibility

Status Completed
Enrollment 66
Est. completion date December 26, 2018
Est. primary completion date December 26, 2018
Accepts healthy volunteers Accepts Healthy Volunteers
Gender Female
Age group 18 Years to 50 Years
Eligibility 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 Design


Intervention

Drug:
TFV/LNG IVR
Used for 90 days (Continuous or Interrupted)
Placebo
Used for 90 days (Continuous or Interrupted)

Locations

Country Name City State
Dominican Republic Profamilia Santo Domingo
United States Eastern Virginia Medical School Norfolk Virginia

Sponsors (3)

Lead Sponsor Collaborator
CONRAD Agility Clinical, Inc., United States Agency for International Development (USAID)

Countries where clinical trial is conducted

United States,  Dominican Republic, 

Outcome

Type Measure Description Time frame Safety issue
Other Antiviral activity in Rectal Fluid--HIV Anti-HIV-1 activity in rectal fluid Changes from baseline at day 90
Other Antiviral activity in Rectal Fluid--HSV-2 Anti-HSV-2 activity in rectal fluid Changes from baseline at day 90
Other 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
Other Qualitative TFV measurement Qualitative measure of TFV in a vaginal swab Day 90
Other Adherence Marker in returned vaginal ring-analytic Analytical measures of drug or placebo products Day 90
Other 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
Other Adherence marker in returned ring--correlation Correlation of IVR removal scale factors and objective biomarkers of IVR use Day 90
Other Adherence marker in returned ring--correlation Correlation of baseline user characteristics and objective biomarkers of IVR use Day 90
Primary Percentage of women with Treatment-emergent adverse events Treatment-emergent adverse events (TEAEs) Day 90
Primary Changes in systemic laboratory values Systemic laboratory values Change from Baseline at Day 90
Primary Changes in cervicovaginal mucosa by visual inspection Mucosal safety Change from Baseline at Day 90
Primary Changes in soluble markers Soluble markers in cervicovaginal fluid Change from Baseline at Day 90
Primary Changes in inflammatory markers in cervicovaginal tissue Inflammatory markers in cervicovaginal tissue Change from Baseline at Day 90
Primary Changes in endogenous vaginal bacteria Endogenous vaginal bacteria in cervicovaginal fluid Change from Baseline at Day 90
Primary Microbial growth Microbial growth on returned IVRs Day 90
Secondary 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)
Secondary 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)
Secondary 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)
Secondary 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)
Secondary 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)
Secondary 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)
Secondary Residual Drug Concentrations Residual drug (TFV and LNG) in returned IVRs Day 90
Secondary Surrogates of contraceptive efficacy of Mucus Surrogates of contraceptive efficacy: Cervical mucus assessment (Cervical mucus quality [score of >10]) Day 30
Secondary Surrogates of contraceptive efficacy of Sperm Surrogates of contraceptive efficacy: Cervical mucus assessment (Sperm migration on the Simplified Slide test) Day 30
Secondary Ovulation Ovulation by serum progesterone (P4) Changes from baseline at day 90
Secondary Follicular Development Effect on follicular development by serum estradiol concentration Changes from baseline at day 90
Secondary Antiviral activity in CV Fluid--HIV Anti-HIV-1 activity in CV fluid Changes from baseline at day 90
Secondary Antiviral activity in CV Fluid--HSV-2 Anti-HSV-2 activity in CV fluid Changes from baseline at day 90
Secondary 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
Secondary Bleeding Patterns Participant self-report of bleeding Baseline through Day 90 of IVR use
Secondary 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)
Secondary 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)
Secondary 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
Secondary 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
Secondary Adherence Percentage of participants with Discontinuations/Expulsions/Removals by self-report Baseline, Day 28 and 90
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