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Tenofovir/Levonorgestrel Intravaginal Ring and Tenofovir Intravaginal Ring

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ClinicalTrials.gov Identifier: NCT03762382
Recruitment Status : Enrolling by invitation
First Posted : December 3, 2018
Last Update Posted : January 30, 2019
Sponsor:
Collaborators:
Kenya Medical Research Institute
University of Washington
Centers for Disease Control and Prevention
Information provided by (Responsible Party):
CONRAD

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.

Condition or disease Intervention/treatment Phase
HIV Contraception Prevention Anti-Retroviral Agent Drug: TFV/LNG IVR Drug: TFV IVR Drug: Placebo IVR Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
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
Actual Study Start Date : December 12, 2018
Estimated Primary Completion Date : May 2019
Estimated Study Completion Date : June 2019

Resource links provided by the National Library of Medicine


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 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.




Primary Outcome Measures :
  1. 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

  2. Safety Laboratory Assessments [ Time Frame: Change from Baseline to up to 90 days of IVR use ]
    Number of participants with abnormal serum chemistry

  3. Safety Laboratory Assessments [ Time Frame: Change from Baseline to up to 90 days of IVR use ]
    Number of participants with abnormal lipids

  4. Safety Laboratory Assessments [ Time Frame: Change from Baseline to up to 90 days of IVR use ]
    Number of participants with abnormal complete blood counts

  5. 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 :
  1. 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

  2. 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

  3. 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)

  4. 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)

  5. 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

  6. 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.

  7. Cervicovaginal (CV) fluid cytokines [ Time Frame: Change from Baseline to Day 90 of IVR use ]
    Changes in IL-1α in CV fluid.

  8. Cervicovaginal (CV) fluid cytokines [ Time Frame: Change from Baseline to Day 90 of IVR use ]
    Changes in IL-8 in CV fluid.

  9. Changes in endogenous vaginal bacteria [ Time Frame: Change from Baseline to Day 90 of IVR use ]
    Changes in endogenous vaginal bacteria in CV fluid

  10. Changes in endogenous vaginal bacteria [ Time Frame: Change from Baseline to Day 90 of IVR use ]
    Changes in Nugent score (score 0-10)

  11. qPCR of Ring Microbiota [ Time Frame: Day 90 of IVR use ]
    Microbial growth on returned IVRs.

  12. 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.)

  13. 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

  14. 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.

  15. 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.

  16. Adherence - Percentage of discontinuations [ Time Frame: Up to Day 90 of IVR use ]
    Percentage of IVR discontinuations

  17. 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:
  1. 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



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 34 Years   (Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Gender Eligibility Description:   Healthy, non-pregnant females of reproductive potential, ovulating and not using non-study hormonal contraception during the study period.
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03762382


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

Publications:
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Responsible Party: CONRAD
ClinicalTrials.gov Identifier: NCT03762382     History of Changes
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 )
First Posted: December 3, 2018    Key Record Dates
Last Update Posted: January 30, 2019
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
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.

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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:
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Levonorgestrel
Tenofovir
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Anti-HIV Agents
Contraceptive Agents, Female
Contraceptive Agents
Reproductive Control Agents
Physiological Effects of Drugs
Contraceptives, Oral, Synthetic
Contraceptives, Oral