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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Anti-Infective Agents, Anti-Retroviral Agents, Contraceptive Usage

Intervention / Treatment
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* Drug: TFV/LNG IVR
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HIV, LNG, TFV, IVR, Contraception, Prevention