Tenofovir/Levonorgestrel Intravaginal Ring and Tenofovir Intravaginal Ring

Study Overview
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Brief Summary
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The purpose of the study is to evaluate the safety, pharmacokinetics and pharmacodynamics of, and the tolerability and acceptance of an intravaginal ring (IVR) delivering both tenofovir and levonorgestrel (TFV/LNG) and an IVR delivering TFV only, compared to a placebo IVR, in women in Western Kenya.

Detailed Description
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This Phase 2a clinical trial will evaluate the safety, pharmacokinetics and pharmacodynamics of, and the tolerability and adherence to two novel intravaginal rings (IVRs). The tenofovir/levonorgestrel (TFV/LNG) IVR and TFV IVRs are designed to provide HIV (and HSV-2) prevention with and without contraceptive for pregnancy prevention, respectively. Women will be protected from pregnancy by abstinence from vaginal intercourse or agreeing to consistently use condoms; concurrent use of a non-hormonal copper intrauterine device is permitted. The study will enroll healthy, HIV-negative, non-pregnant, menstruating women aged 18-34 years, inclusive, and not currently infected with hepatitis B virus, who are assessed to be at lower risk for HIV. The goal is to enroll fifty (50) women in Western Kenya. The participants will be randomized 2:2:1 to use one of the following continuous delivery IVRs: twenty (20) women to use the TFV/LNG IVR; ten (10) women to use the TFV IVR; and ten (10) women to use the placebo IVR. Participants will attend up to ten (10) routine study visits that may include physical and pelvic exams, collection of venous blood, vaginal fluid and cervical mucus, and behavioral questionnaires. A subset of twenty (20) women will participate in in-depth interviews.

Official Title
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Phase IIa, 90-Day Safety, Adherence, and Acceptability Study of Intravaginal Rings Releasing Tenofovir With and Without Levonorgestrel Among Women in Western Kenya

Conditions
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HIV, Contraception, Prevention, Anti-Retroviral Agent

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female, aged 18-34 years, inclusive General good health (by history and per clinician 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), uterus, and cervix Not pregnant or planning to become pregnant Pre-screening HIV risk score ≤4 Currently having regular menstrual cycles (approximately 24-35 days) OR with a history of having regular menstrual cycles before contraceptive use, by report, and resumed some menstruation or spotting (with biochemical confirmation of ovulation) Willing to undergo Visual Inspection with Lugol's Iodine (VILI) for cervical abnormalities during pelvic exam Willing to abstain from use of vaginal products other than the study product, including tampons (except for during menses) , menstrual cups, vaginally inserted cloths or other materials, spermicides, lubricants, and douches for the whole study Willing to abstain from any vaginal intercourse starting 48 hours before certain study visits Vaginal and cervical anatomy that, in the opinion of the clinician, lends itself to easy genital tract sample collection and is absent of vesicles and ulcers No use of hormonal contraceptives within the following periods specified for each type of contraception method: Oral contraceptives (combined or progestin-only), contraceptive patch or contraceptive vaginal ring in at least two (2) months Last DMPA injection received at least four (4) months ago and has resumed regular menstruation Hormonal IUD/IUS removed at least four (4) months ago and has resumed regular menstruation Hormonal implant removed at least six (6) months ago and has resumed regular menstruation Willing to refrain from using any hormonal contraceptives for the entire study and to use only study-provided non-spermicidal male condoms with or without a study-provided Cu-IUD P4 ≥3.0 ng/ml Estimated glomerular filtration rate (eGFR) ≥90ml/min/1.73m2 Willing to give voluntary consent and sign/mark an informed consent form Willing and able to comply with protocol requirements Exclusion Criteria: Body mass index (BMI) ≥30 kg/m History of hysterectomy Currently pregnant or within less than three (3) calendar months of the last pregnancy outcome. Currently breastfeeding or having breastfed an infant in the last two (2) months, or planning to breastfeed during the course of the study Contraindication to any study products-LNG, TFV, or excipient ingredients Contraindication to LNG In the last three (3) months, diagnosed with or treated for any STI or pelvic inflammatory disease Positive test for HIV-1, syphilis, Trichomonas vaginalis (TV), Neisseria gonorrhea (GC), Chlamydia trachomatis (CT) or HBsAg Nugent score greater than or equal to 7 or a symptomatic BV clinical diagnosis as defined by Amsel's criteria Suspected breast cancer or other progestin-sensitive cancer Suspected hepatic disease, including cirrhosis or viral hepatitis History of bleeding or coagulation problems Known current drug or alcohol abuse which could impact study compliance Grade 2 or higher laboratory abnormality, per 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 Use of any concomitant medications 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 Labial elongation (due to pulling practices and use of botanicals or caustic agents) Abnormal finding on laboratory or physical examination or a social or medical condition in the volunteer which, in the opinion of the site co-PI(s), would make participation in the study unsafe or would complicate interpretation of data Currently using, or has used within the preceding one (1) month, emtricitabine/tenofovir disoproxil fumarate (TDF/FTC or Truvada®) or any other tenofovir product, and/or has plans to use a non-study tenofovir product in any form during the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 34 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 (10mg/20μg) (Continuous)<br>Tenofovir/Levonorgestrel Intravaginal Ring | Drug: TFV/LNG IVR<br>* TFV/LNG IVR is an intravaginal ring that releases approximately 8-10 mg/day of TFV and approximately 20ug/day of LNG to be used for 90 continuous days.<br>* Other names: Tenofovir/Levonorgestrel Intravaginal Ring;|
| Experimental: TFV IVR (10mg) (Continuous)<br>Tenofovir Intravaginal Ring | Drug: TFV IVR<br>* TFV IVR is an intravaginal ring that releases approximately 8-10mg/day of TFV to be used for 90 continuous days.<br>* Other names: Tenofovir Intravaginal Ring;|
| Placebo Comparator: Placebo IVR (Non-eluting)<br>Placebo Intravaginal Ring | Drug: Placebo IVR<br>* Placebo IVR is an intravaginal ring containing no active experimental ingredients to be used for 90 continuous days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-emergent adverse events (TEAEs) | Participants with Grade 2 or higher local female genital TEAEs as defined by DAIDS Table for Grading the Severity of Adult and Pediatric AEs (version 2.1) and DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events Addendum 1 Female Genital Grading Table for Use in Microbicide Studies | Change from Baseline to up to 90 days of IVR use | 
| Safety Laboratory Assessments- Serum chemistry | Number of participants with abnormal serum chemistry | Change from Baseline to up to 90 days of IVR use | 
| Safety Laboratory Assessments- lipids | Number of participants with abnormal lipids | Change from Baseline to up to 90 days of IVR use | 
| Safety Laboratory Assessments- complete blood counts | Number of participants with abnormal complete blood counts | Change from Baseline to up to 90 days of IVR use | 
| Mucosal safety | Changes in cervicovaginal mucosa by visual inspection | Change from Baseline to up to 90 days of IVR use | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum blood concentrations (Cmax) | Maximum plasma concentration of TFV and maximum serum concentration of LNG | Baseline; 6 and 24 hours post IVR insertion; Menstrual cycle 1, day 14; Menstrual cycle 1,day 21-25; Menstrual cycle 2, day 21-25; Menstrual cycle 3, day 14; Day 90 IVR use; 24 hours post-IVR use (anticipated cycle length is 28 days) | 
| Maximum CV fluid concentration | Maximum CV fluid concentration of TFV | 6 and 24 hours post-IVR insertion; Menstrual cycle 1 day 14; Menstrual cycle 1 day 21-25; Menstrual cycle 2 day 21-25; Menstrual cycle 3, day 14; Day 90 of IVR use; and 24 hours post-IVR use (anticipated cycle length is 28 days) | 
| Percent (%) inhibition of HIV resulting from product use (Anti-HIV activity) | Anti-HIV and anti-HSV-2 activity in CV fluid (inhibition in cell assay) | Baseline, Day 90 of IVR use | 
| Percent (%) inhibition of HSV resulting from product use (Anti-HSV activity) | Anti-HSV-2 activity in CV fluid (inhibition in cell assay) | Baseline, Day 90 of IVR use | 
| Cervical mucus assessment and quality score | Cervical mucus assessment and quality score (total summary score 0-15) as defined by WHO laboratory manual for the Examination and processing of human semen Fifth Edition, Appendix 5 | Menstrual cycle 1, day 14; Menstrual cycle 3, day 14 (anticipated cycle length is 28 days) | 
| Confirmation of Ovulation | Serum progesterone (P4) level. | Pre-IVR insertion; Menstrual cycle 1, day 20-25; Menstrual cycle 2, day 20-25; Day 90 of IVR use (anticipated cycle length is 28 days) | 
| Cervicovaginal (CV) fluid cytokines-IL-1α | Changes in IL-1α in CV fluid. | Change from Baseline to Day 90 of IVR use | 
| Cervicovaginal (CV) fluid cytokines- IL-8 | Changes in IL-8 in CV fluid. | Change from Baseline to Day 90 of IVR use | 
| Changes in endogenous vaginal bacteria | Changes in endogenous vaginal bacteria in CV fluid | Change from Baseline to Day 90 of IVR use | 
| Changes in endogenous vaginal bacteria- Nugent score | Changes in Nugent score (score 0-10) | Change from Baseline to Day 90 of IVR use | 
| qPCR of Ring Microbiota | Microbial growth on returned IVRs. | Day 90 of IVR use | 
| Tolerability - Somatic and non-specific non-treatment emergent adverse events | Subjective and objective assessment of new complaints (e.g., headache, nausea, weight change, breast tenderness, etc.) | Baseline; 6 and 24 hours post-IVR insertion; Menstrual cycle 1, day 14; Menstrual cycle 1, day 21-25; Menstrual cycle 2, day 21-25; Menstrual cycle 3, day 14; 90 days of IVR use; 24 hours post IVR use (anticipated cycle length is 28 days) | 
| Tolerability - Self-reported complaints of changes in menstrual cycle | Percentage of women with changes in regularity of menstrual cycle | Screening; Menstrual cycle 1, day 14; Menstrual cycle 1, day 21-25; Menstrual cycle 2, day 21-25; Menstrual cycle 3, day 14; Day 90 of IVR use; 24 hours post-IVR use (anticipated cycle length is 28 days) | 
| Adherence - Drug concentrations | Plasma, serum, and vaginal fluid drug concentrations. | Baseline; 6 and 24 hours post-IVR insertion; Menstrual cycle 1, day 14; Menstrual cycle 1, day 21-25; Menstrual cycle 2, day 21-25; Menstrual cycle 3, day 14; 90 days of IVR use; 24 hours post-IVR use (anticipated cycle length is 28 days) | 
| Adherence - Residual drug concentrations | Residual drug (TFV and LNG) concentrations in returned TFV/LNG and TFV IVRs and residual excipients in returned placebo IVRs. | Day 90 of IVR use | 
| Adherence - Percentage of discontinuations | Percentage of IVR discontinuations | Up to Day 90 of IVR use | 
| Acceptability - Quantitative assessment of acceptability based on Questionnaires administered pre- and post-IVR use | Changes in responses to questionnaires pre- and post-IVR use on attitudes toward and perspectives of IVR use. | Screening; 90 days of IVR use | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Intravaginal Ring, HIV Prevention, Tenofovir, Levonorgestrel, Pregnancy Prevention