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| ID | Type | Description | Link |
|---|---|---|---|
| RFA-PS-17-005 | Other Grant/Funding Number | U.S. Centers for Disease Control and Prevention | |
| AID-OAA-A-14-000010 | Other Grant/Funding Number | USAID |
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| Name | Class |
|---|---|
| Kenya Medical Research Institute | OTHER |
| University of Washington | OTHER |
| Centers for Disease Control and Prevention | FED |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| TFV/LNG IVR (10mg/20μg) (Continuous) | Experimental | Tenofovir/Levonorgestrel Intravaginal Ring |
|
| TFV IVR (10mg) (Continuous) | Experimental | Tenofovir Intravaginal Ring |
|
| Placebo IVR (Non-eluting) | Placebo Comparator | Placebo Intravaginal Ring |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| TFV/LNG IVR | Drug | 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. |
|
| 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 |
| 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) |
| Measure | Description | Time Frame |
|---|---|---|
| Qualitative assessment of acceptability and adherence influences through In-depth interviews | In-depth interviews | Between Menstrual cycle 2, day 21-25 and Menstrual cycle 3, day 14 (anticipated cycle length is 28 days) |
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:
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:
Healthy, non-pregnant females of reproductive potential, ovulating and not using non-study hormonal contraception during the study period.
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| Name | Affiliation | Role |
|---|---|---|
| Nelly R. Mugo, MBChB | University of Washington | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Kenya Medical Research Institute, Center for Global Health Research | Kisumu | Kisumu County | 40100 | Kenya |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29953547 | Background | 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. | |
| 37383290 |
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Data sharing will comply with CDC's current Policy on Public Health Research and Non-research Data Management and Access. Except for the analyses outlined in the study protocol, all future requests to perform new analyses on data or specimens from this study protocol will require (1) agreement of all Parties owning or jointly owning the data and (2) Ethics Committee approval.
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| ID | Term |
|---|---|
| D000068698 | Tenofovir |
| ID | Term |
|---|---|
| D063065 | Organophosphonates |
| D009943 | Organophosphorus Compounds |
| D009930 | Organic Chemicals |
| D000225 | Adenine |
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|
| TFV IVR | Drug | TFV IVR is an intravaginal ring that releases approximately 8-10mg/day of TFV to be used for 90 continuous days. |
|
|
| Placebo IVR | Drug | Placebo IVR is an intravaginal ring containing no active experimental ingredients to be used for 90 continuous 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 |
| Derived |
| Mugo NR, Mudhune V, Heffron R, Thomas KK, McLellan-Lemal E, Njoroge B, Peacock S, O'Connor SM, Nyagol B, Ouma E, Ridzon R, Wiener J, Isoherranen N, Erikson DW, Ouattara LA, Yousefieh N, Jacot TA, Haaland RE, Morrison SA, Haugen HS, Thurman AR, Allen SA, Baeten JM, Samandari T, Doncel GF. Randomized controlled phase IIa clinical trial of safety, pharmacokinetics and pharmacodynamics of tenofovir and tenofovir plus levonorgestrel releasing intravaginal rings used by women in Kenya. Front Reprod Health. 2023 Jun 13;5:1118030. doi: 10.3389/frph.2023.1118030. eCollection 2023. |
| 36162740 | Derived | 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. |
| 35835755 | Derived | 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. |
| D011687 |
| Purines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |