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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
TRIPLE
Enrollment
50
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.
TFV IVR is an intravaginal ring that releases approximately 8-10mg/day of TFV to be used for 90 continuous days.
Placebo IVR is an intravaginal ring containing no active experimental ingredients to be used for 90 continuous days.
Kenya Medical Research Institute, Center for Global Health Research
Kisumu, Kisumu County, Kenya
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
Time frame: Change from Baseline to up to 90 days of IVR use
Safety Laboratory Assessments- Serum chemistry
Number of participants with abnormal serum chemistry
Time frame: Change from Baseline to up to 90 days of IVR use
Safety Laboratory Assessments- lipids
Number of participants with abnormal lipids
Time frame: 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
Time frame: Change from Baseline to up to 90 days of IVR use
Mucosal safety
Changes in cervicovaginal mucosa by visual inspection
Time frame: Change from Baseline to up to 90 days of IVR use
Maximum blood concentrations (Cmax)
Maximum plasma concentration of TFV and maximum serum concentration of LNG
Time frame: 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
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Maximum CV fluid concentration of TFV
Time frame: 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)
Time frame: 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)
Time frame: 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
Time frame: Menstrual cycle 1, day 14; Menstrual cycle 3, day 14 (anticipated cycle length is 28 days)
Confirmation of Ovulation
Serum progesterone (P4) level.
Time frame: 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.
Time frame: Change from Baseline to Day 90 of IVR use
Cervicovaginal (CV) fluid cytokines- IL-8
Changes in IL-8 in CV fluid.
Time frame: Change from Baseline to Day 90 of IVR use
Changes in endogenous vaginal bacteria
Changes in endogenous vaginal bacteria in CV fluid
Time frame: Change from Baseline to Day 90 of IVR use
Changes in endogenous vaginal bacteria- Nugent score
Changes in Nugent score (score 0-10)
Time frame: Change from Baseline to Day 90 of IVR use
qPCR of Ring Microbiota
Microbial growth on returned IVRs.
Time frame: 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.)
Time frame: 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
Time frame: 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.
Time frame: 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.
Time frame: Day 90 of IVR use
Adherence - Percentage of discontinuations
Percentage of IVR discontinuations
Time frame: 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.
Time frame: Screening; 90 days of IVR use