Clinical Trials

MainTitle

Tenofovir/Levonorgestrel Intravaginal Ring and Tenofovir Intravaginal Ring

This study has been enrolling by invitation
Sponsor
CONRAD

Collaborator
Kenya Medical Research Institute
University of Washington
Centers for Disease Control and Prevention

Information provided by (Responsible Party)
CONRAD
ClinicalTrials.gov Identifier
NCT03762382

First received: November 16, 2018
Last updated: January 29, 2019
Last Verified: November 2018
History of Changes
Purpose

Purpose

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.

Condition Intervention Phase
HIV
Contraception
Prevention
Anti-Retroviral Agent

Drug : TFV/LNG IVR
Drug : TFV IVR
Drug : Placebo IVR
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Prevention
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

Further study details as provided by CONRAD:

Primary Outcome Measures

  • Treatment-emergent adverse events (TEAEs) [ Time Frame: Change from Baseline to up to 90 days of IVR use ]
    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
  • Safety Laboratory Assessments [ Time Frame: Change from Baseline to up to 90 days of IVR use ]
    Number of participants with abnormal serum chemistry
  • Safety Laboratory Assessments [ Time Frame: Change from Baseline to up to 90 days of IVR use ]
    Number of participants with abnormal lipids
  • Safety Laboratory Assessments [ Time Frame: Change from Baseline to up to 90 days of IVR use ]
    Number of participants with abnormal complete blood counts
  • Mucosal safety [ Time Frame: Change from Baseline to up to 90 days of IVR use ]
    Changes in cervicovaginal mucosa by visual inspection
Secondary Outcome Measures:
  • Maximum blood concentrations (Cmax) [ 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 plasma concentration of TFV and maximum serum concentration of LNG
  • Maximum CV fluid concentration [ 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) ]
    Maximum CV fluid concentration of TFV
  • Percent (%) inhibition of HIV resulting from product use (Anti-HIV activity) [ Time Frame: Baseline, Day 90 of IVR use ]
    Anti-HIV and anti-HSV-2 activity in CV fluid (inhibition in cell assay)
  • Percent (%) inhibition of HSV resulting from product use (Anti-HSV activity) [ Time Frame: Baseline, Day 90 of IVR use ]
    Anti-HSV-2 activity in CV fluid (inhibition in cell assay)
  • Cervical mucus assessment and quality score [ Time Frame: Menstrual cycle 1, day 14; Menstrual cycle 3, day 14 (anticipated cycle length is 28 days) ]
    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
  • Confirmation of Ovulation [ 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) ]
    Serum progesterone (P4) level.
  • Cervicovaginal (CV) fluid cytokines [ Time Frame: Change from Baseline to Day 90 of IVR use ]
    Changes in IL-1α in CV fluid.
  • Cervicovaginal (CV) fluid cytokines [ Time Frame: Change from Baseline to Day 90 of IVR use ]
    Changes in IL-8 in CV fluid.
  • Changes in endogenous vaginal bacteria [ Time Frame: Change from Baseline to Day 90 of IVR use ]
    Changes in endogenous vaginal bacteria in CV fluid
  • Changes in endogenous vaginal bacteria [ Time Frame: Change from Baseline to Day 90 of IVR use ]
    Changes in Nugent score (score 0-10)
  • qPCR of Ring Microbiota [ Time Frame: Day 90 of IVR use ]
    Microbial growth on returned IVRs.
  • Tolerability - Somatic and non-specific non-treatment emergent adverse events [ 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) ]
    Subjective and objective assessment of new complaints (e.g., headache, nausea, weight change, breast tenderness, etc.)
  • Tolerability - Self-reported complaints of changes in 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) ]
    Percentage of women with changes in regularity of menstrual cycle
  • Adherence - 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) ]
    Plasma, serum, and vaginal fluid drug concentrations.
  • Adherence - Residual drug concentrations [ Time Frame: Day 90 of IVR use ]
    Residual drug (TFV and LNG) concentrations in returned TFV/LNG and TFV IVRs and residual excipients in returned placebo IVRs.
  • Adherence - Percentage of discontinuations [ Time Frame: Up to Day 90 of IVR use ]
    Percentage of IVR discontinuations
  • Acceptability - Quantitative assessment of acceptability based on Questionnaires administered pre- and post-IVR use [ Time Frame: Screening; 90 days of IVR use ]
    Changes in responses to questionnaires pre- and post-IVR use on attitudes toward and perspectives of IVR use.
Other Outcome Measures:
  • Qualitative assessment of acceptability and adherence influences through In-depth interviews [ Time Frame: Between Menstrual cycle 2, day 21-25 and Menstrual cycle 3, day 14 (anticipated cycle length is 28 days) ]
    In-depth interviews

Estimated Enrollment: 50
Study Start Date: December 12, 2018
Estimated Study Completion Date: June 2019
Estimated Primary Completion Date: May 2019 (Final data collection date for primary outcome measure)

Arms Assigned Interventions
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 Name: 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 Name: 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.

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

Eligibility

Ages Eligible for Study: 18 Years to 34 Years  
Sexes Eligible for Study: Female  
Accepts Healthy Volunteers: Yes  

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

contacts and locations

Contacts and Locations

Choosing to participate in a study is an important personal decision.Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below.For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT03762382

Locations

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

Sponsors and Collaborators

CONRAD
Kenya Medical Research Institute
University of Washington
Centers for Disease Control and Prevention

Investigators

Principal Investigator: Nelly R. Mugo, MBChB University of Washington
More Information

More Information


Responsible Party: CONRAD  
ClinicalTrials.gov Identifier: NCT03762382   History of Changes  
Other Study ID Numbers: Protocol B17-144  
  RFA-PS-17-005  
  AID-OAA-A-14-000010  
Study First Received: November 16, 2018  
Last Updated: January 29, 2019  
Individual Participant Data    
Plan to Share IPD: No  

Studies a U.S. FDA-regulated Drug Product: Yes  
Studies a U.S. FDA-regulated Device Product: No  

Keywords provided by CONRAD:

Intravaginal Ring
HIV Prevention
Tenofovir
Levonorgestrel
Pregnancy Prevention

Additional relevant MeSH terms:
Tenofovir
Levonorgestrel

ClinicalTrials.gov processed this data on July 19, 2019
This information is provided by ClinicalTrials.gov.