Tenofovir/Levonorgestrel Intravaginal Ring and Tenofovir Intravaginal Ring

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

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.

Study Overview

• Status: Unknown
• Conditions: HIV; Contraception; Prevention; Anti-Retroviral Agent
• Intervention / Treatment: Drug: TFV/LNG IVR; Drug: TFV IVR; Drug: Placebo IVR

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.

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• Kenya
  • Kisumu County
    • Kisumu, Kisumu County, Kenya, 40100
      • Kenya Medical Research Institute, Center for Global Health Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 34 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TFV/LNG IVR (10mg/20μg) (Continuous); Tenofovir/Levonorgestrel Intravaginal Ring	Drug: TFV/LNG IVR; 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.; Other Names: Tenofovir/Levonorgestrel Intravaginal Ring
Experimental: TFV IVR (10mg) (Continuous); Tenofovir Intravaginal Ring	Drug: TFV IVR; TFV IVR is an intravaginal ring that releases approximately 8-10mg/day of TFV to be used for 90 continuous days.; Other Names: Tenofovir Intravaginal Ring
Placebo Comparator: Placebo IVR (Non-eluting); Placebo Intravaginal Ring	Drug: Placebo IVR; Placebo IVR is an intravaginal ring containing no active experimental ingredients to be used for 90 continuous days.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	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)

Collaborators and Investigators

• Sponsor: CONRAD
• Collaborators: University of Washington; Centers for Disease Control and Prevention; Kenya Medical Research Institute
• Investigators: Principal Investigator: Nelly R. Mugo, MBChB, University of Washington

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 12, 2018
• Primary Completion (Actual): August 20, 2019
• Study Completion (Anticipated): April 1, 2020

Study Registration Dates

• First Submitted: November 16, 2018
• First Submitted That Met QC Criteria: November 30, 2018
• First Posted (Actual): December 3, 2018

Study Record Updates

• Last Update Posted (Actual): January 14, 2020
• Last Update Submitted That Met QC Criteria: January 13, 2020
• Last Verified: January 1, 2020

More Information

Terms related to this study

• Keywords: Tenofovir; HIV Prevention; Levonorgestrel; Intravaginal Ring; Pregnancy Prevention
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; Tenofovir; Levonorgestrel
• Other Study ID Numbers: Protocol B17-144; 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)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No