Phase I One-month Safety, PK, PD, and Acceptability Study of IVR Releasing TFV and LNG or TFV Alone

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the safety of the TFV/LNG intravaginal ring (IVR), TFV-only IVR, and placebo IVR, evaluate pharmacokinetics (PK) of TFV and LNG, evaluate pharmacodynamic (PD) surrogates of contraceptive efficacy of LNG, and to evaluate acceptability of the IVRs.

Official Title
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Phase I One-Month Safety, Pharmacokinetic, Pharmacodynamic, and Acceptability Study of Intravaginal Rings Releasing Tenofovir and Levonorgestrel or Tenofovir Alone

Conditions
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HIV, Contraception

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-45 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) Currently having regular menstrual cycles of 26-35 days by participant report History of Pap smears and follow-up consistent with standard medical practice as outlined in the study manual or willing to undergo a Pap smear Protected from pregnancy by one of the following: 1) Sterilization of either partner. Note: Women protected from pregnancy by sterilization of either partner must abstain from vaginal intercourse from 48 hours prior to Visit 3 until the sixth day after the last study visit; or 2) Willing to abstain from vaginal intercourse from Visit 1 until the sixth day after the last study visit. Willing to abstain from any other vaginal activity and the use of vaginal product other than the study product including tampons, spermicides, lubricants, and douches starting 48 hours before Visit 3 until the sixth day after the last study visit Vaginal and cervical anatomy that, in the opinion of the investigator, lends itself to easy colposcopy and genital tract sample collection Negative urine pregnancy test P4 ≥3 ng/ml Willing to give voluntary consent, sign an informed consent form and comply with study procedures as required by the protocol Exclusion Criteria: 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 intrauterine device (IUD) after Visit 1 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: TFV 1% gel, topical anesthetic, or allergy to both silver nitrate and Monsel's solution. Contraindication to LNG In the last six months, diagnosed with or treated for any sexually transmitted infection (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, Neisseria gonorrhea (GC), Chlamydia trachomatis (CT), HIV, or Hepatitis B surface antigen (HBsAg) Known bleeding disorder that could lead to prolonged or continuous bleeding with biopsy Chronic or acute vulvar or vaginal symptoms (pain, irritation, spotting, etc.) Known current drug or alcohol abuse which could impact study compliance Grade 2 or higher laboratory abnormality, per the August 2009 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, antivirals (e.g., acyclovir or valacyclovir) or antiretrovirals (e.g., Viread, Atripla®, Emtriva®, Complera®). Note: Participants should avoid non-steroidal anti-inflammatory drugs (NSAIDs) except for treatment of dysmenorrhea during menses. Participants may use Tylenol® on an as-needed but not daily basis during the study Participation in any other investigational trial (device, drug, or vaginal trial) within the last 30 days or planned participation in any other investigational trial 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 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: 45 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TFV IVR<br>TFV IVR is an intravaginal ring 55.0 mm in diameter, consisting of single segment of polyurethane tubing with an outer diameter of 5.5 mm and filled with white TFV-containing paste. Used for one month, the IVR delivers 8-10 mg/day TFV. | Drug: TFV IVR<br> <br> * Other names: Tenofovir Intravaginal Ring;|
| Experimental: TFV/LNG IVR<br>TFV/LNG IVR is an intravaginal ring 55.0 mm in diameter, consisting of two segments of polyurethane tubing with an outer diameter of 5.5 mm: a longer segment containing white TFV paste and a shorter one (20 mm) with a white LNG core. Used for one month, the IVR delivers 8-10 mg/day TFV and 20 μg/day LNG. | Drug: TFV IVR<br> <br> * Other names: Tenofovir Intravaginal Ring;Drug: TFV/LNG IVR<br> <br> * Other names: Tenofovir Levonorgestrel Intravaginal Ring;|
| Placebo Comparator: Placebo Intravaginal Ring<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. | Other: Placebo IVR<br> <br> * Other names: Placebo Intravaginal Ring;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of treatment-emergent adverse events | Number of treatment-emergent adverse events | IVR Day 1, 2,  8,  16-18; 24 hours and 1-2 weeks post-IVR insertion and 1-2 weeks after IVR removal | 
| Systemic laboratory tests | Changes in Systemic laboratory tests | Baseline and IVR Day  16-18 | 
| Cervicovaginal ulcerations, abrasions, edema, and other findings | Development of cervicovaginal ulcerations, abrasions, edema, and other findings as assessed by naked eye and colposcopic visualization of the cervicovaginal epithelium | Baseline, IVR Day 2,  8 and  16-18 | 
| Soluble markers of innate mucosal immunity and inflammatory response in cervicovaginal lavage (CVL) fluid | Changes in soluble markers of innate mucosal immunity and inflammatory response in CVL fluid | Baseline and IVR Day  16-18 | 
| HIV-1 target immune cell phenotype and HIV-1 activation/proliferation marker in cervicovaginal tissue (biopsy) | Changes in HIV-1 target immune cell phenotype and HIV-1 activation/proliferation marker in cervicovaginal tissue (biopsy) | Baseline and IVR Day  16-18 | 
| Microflora (semi-quantitative vaginal culture and/or unculturable bacteria) | Changes microflora (semi-quantitative vaginal culture and/or unculturable bacteria) | Baseline and IVR Day  16-18 | 
| Vaginal pH | Changes in vaginal pH | Baseline and IVR Day  16-18 | 
| Nugent Score | Changes in Nugent Score | Baseline and IVR Day  16-18 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TFV concentrations in plasma | TFV concentrations in plasma | Baseline; 1, 2, 4 and 8 hrs post-IVR insertion; IVR Day 2,  8,  16-18; 24 hours post-IVR removal | 
| TFV concentrations in cervicovaginal fluid (aspirate and swab) | TFV concentrations in cervicovaginal fluid (aspirate and swab) | 1, 2, 4 or 8 hours post-IVR insertion (randomized time point); IVR Day 2,  8,  16-18; 24 hours post-IVR removal | 
| TFV concentrations in genital tissue (biopsy) | TFV concentrations in genital tissue (biopsy) | IVR Day 2,  16-18; 24 or 72 hours post-IVR removal (randomized time point) | 
| Tenofovir diphosphate (TFV-DP) concentrations in peripheral blood mononuclear cells (PBMCs) | TFV-DP concentrations in PBMCs | IVR Day  16-18 | 
| TFV-DP concentrations in genital tissue (biopsy) | TFV-DP concentrations in genital tissue (biopsy) | IVR Day 2,  16-18; 24 or 72 hours post-IVR removal (randomized time point) | 
| LNG concentration in blood (including SHBG) | LNG concentration in blood (including SHBG) | Baseline; 1, 2, 4 and 8 hrs post-IVR insertion; IVR Day 2,  8,  16-18; 24 hours post-IVR removal | 
| LNG concentration in vaginal secretions (swabs) | LNG concentration in vaginal secretions (swabs) | Baseline; IVR Day 8 | 
| LNG concentration in cervical mucus | LNG concentration in cervical mucus | IVR Day  8,  16-18; 24 hours post-IVR removal | 
| Weight of returned IVRs | Weight of returned IVRs | IVR Day  16-18 (post-removal) | 
| Amount of drug remaining in returned IVRs | Amount of drug remaining in returned IVRs | IVR Day  16-18 (post-removal) | 

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