Clinical trial NCT03762382: Tenofovir/Levonorgestrel Intravaginal Ring and Tenofovir Intravaginal Ring
Official title: Phase IIa, 90-Day Safety, Adherence, and Acceptability Study of Intravaginal Rings Releasing Tenofovir With and Without Levonorgestrel Among Women in Western Kenya
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: HIV
Contraception
Prevention
Anti-Retroviral Agent
Keywords: Intravaginal Ring
HIV Prevention
Tenofovir
Levonorgestrel
Pregnancy Prevention
Lead sponsor: CONRAD
Sponsor class: OTHER
Collaborators: name: Kenya Medical Research Institute
name: University of Washington
name: Centers for Disease Control and Prevention
First posted: 2018-12-03
Enrollment: 50
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 34
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Treatment-emergent adverse events (TEAEs)
timeFrame: Change from Baseline to up to 90 days of IVR use
measure: Safety Laboratory Assessments- Serum chemistry
timeFrame: Change from Baseline to up to 90 days of IVR use
measure: Safety Laboratory Assessments- lipids
timeFrame: Change from Baseline to up to 90 days of IVR use
measure: Safety Laboratory Assessments- complete blood counts
timeFrame: Change from Baseline to up to 90 days of IVR use
measure: Mucosal safety
timeFrame: Change from Baseline to up to 90 days of IVR use
Secondary outcomes:
measure: Maximum blood concentrations (Cmax)
timeFrame: 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)
measure: Maximum CV fluid concentration
timeFrame: 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)
measure: Percent (%) inhibition of HIV resulting from product use (Anti-HIV activity)
timeFrame: Baseline, Day 90 of IVR use
measure: Percent (%) inhibition of HSV resulting from product use (Anti-HSV activity)
timeFrame: Baseline, Day 90 of IVR use
measure: Cervical mucus assessment and quality score
timeFrame: Menstrual cycle 1, day 14; Menstrual cycle 3, day 14 (anticipated cycle length is 28 days)
measure: Confirmation of Ovulation
timeFrame: 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)
measure: Cervicovaginal (CV) fluid cytokines-IL-1α
timeFrame: Change from Baseline to Day 90 of IVR use
measure: Cervicovaginal (CV) fluid cytokines- IL-8
timeFrame: Change from Baseline to Day 90 of IVR use
measure: Changes in endogenous vaginal bacteria
timeFrame: Change from Baseline to Day 90 of IVR use
measure: Changes in endogenous vaginal bacteria- Nugent score
timeFrame: Change from Baseline to Day 90 of IVR use
measure: qPCR of Ring Microbiota
timeFrame: Day 90 of IVR use
measure: Tolerability - Somatic and non-specific non-treatment emergent adverse events
timeFrame: 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)
measure: Tolerability - Self-reported complaints of changes in menstrual cycle
timeFrame: 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)
measure: Adherence - Drug concentrations
timeFrame: 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)
measure: Adherence - Residual drug concentrations
timeFrame: Day 90 of IVR use
measure: Adherence - Percentage of discontinuations
timeFrame: Up to Day 90 of IVR use
measure: Acceptability - Quantitative assessment of acceptability based on Questionnaires administered pre- and post-IVR use
timeFrame: Screening; 90 days of IVR use
Other outcomes:
measure: Qualitative assessment of acceptability and adherence influences through In-depth interviews
timeFrame: Between Menstrual cycle 2, day 21-25 and Menstrual cycle 3, day 14 (anticipated cycle length is 28 days)
Locations:
city: Kisumu
country: Kenya
facility: Kenya Medical Research Institute, Center for Global Health Research
state: Kisumu County
Study officials:
affiliation: University of Washington
name: Nelly R. Mugo, MBChB
role: PRINCIPAL_INVESTIGATOR
References:
citation: Thurman AR, Schwartz JL, Brache V, Clark MR, McCormick T, Chandra N, Marzinke MA, Stanczyk FZ, Dezzutti CS, Hillier SL, Herold BC, Fichorova R, Asin SN, Rollenhagen C, Weiner D, Kiser P, Doncel GF. Randomized, placebo controlled phase I trial of safety, pharmacokinetics, pharmacodynamics and acceptability of tenofovir and tenofovir plus levonorgestrel vaginal rings in women. PLoS One. 2018 Jun 28;13(6):e0199778. doi: 10.1371/journal.pone.0199778. eCollection 2018.
citation: McLellan-Lemal E, Deaton SR, Betts JE, Ondenge K, Mudhune V, O'Connor SM, Nyagol B, Thurman AR, Doncel GF, Allen SA, Heffron R, Mugo NR; Kisumu Combined Ring Study (KCRS) Team. Acceptability of an intravaginal ring for simultaneously preventing HIV infection and pregnancy: Qualitative findings of the Kisumu Combined Ring Study, 2019. Contemp Clin Trials. 2022 Nov;122:106935. doi: 10.1016/j.cct.2022.106935. Epub 2022 Sep 23.
citation: Dabee S, Mugo N, Mudhune V, McLellan-Lemal E, Peacock S, O'Connor S, Njoroge B, Nyagol B, Thurman AR, Ouma E, Ridzon R, Wiener J, Haugen HS, Gasper M, Feng C, Allen SA, Doncel GF, Jaspan HB, Heffron R; Kisumu Combined Ring Study Team. Genital microbiota of women using a 90 day tenofovir or tenofovir and levonorgestrel intravaginal ring in a placebo controlled randomized safety trial in Kenya. Sci Rep. 2022 Jul 14;12(1):12040. doi: 10.1038/s41598-022-13475-9.