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Safety, PK, and PD Study of IVRs Releasing TFV and LNG (TFV/LNG IVR)

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ClinicalTrials.gov Identifier: NCT03279120
Recruitment Status : Recruiting
First Posted : September 12, 2017
Last Update Posted : November 28, 2017
Sponsor:
Collaborators:
United States Agency for International Development (USAID)
Agility Clinical, Inc.
Information provided by (Responsible Party):
CONRAD

Brief Summary:
This multi-center Phase I study is designed to characterize the safety, PK, and PD of TFV/LNG IVR to assess systemic and genital tract bioavailability in healthy women. The IVRs to be used in the study are TFV/LNG IVR (8-10mg per day/20μg per day) or placebo IVR. Samples will be obtained before, during and after 90 days of continuous or interrupted IVR use.

Condition or disease Intervention/treatment Phase
Anti-Infective Agents Anti-Retroviral Agents Contraceptive Usage Drug: TFV/LNG IVR Drug: Placebo Phase 1

Detailed Description:

The purpose of this multi-center Phase I protocol, titled Phase I, 90-Day Safety, Pharmacokinetic, and Pharmacodynamic Study of Intravaginal Rings Releasing Tenofovir and Levonorgestrel is to assess the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the Tenofovir/Levonorgestrel Intravaginal Ring (TFV/LNG IVR).

The study will enroll healthy, non-pregnant, ovulatory, HIV-uninfected women aged 18 to 50 with a body mass index (BMI) less than 30 kg/m2, regular menstrual cycles (approximately 26-35 days) by participant report, and willing to use non-spermicidal condoms for sex and follow other study restrictions. Women will be protected from pregnancy by abstinence from vaginal intercourse or agreeing to consistently use condoms.

The enrollment goal is for approximately 60 participants to complete the study. A subset of approximately 20 women will be selected for an in-depth interview to take place during the first month of IVR use and again after 90 days of use.

Women will be randomized to one of four arms: TFV/LNG IVR (8-10mg per day/20μg per day) for 90 days (Continuous), TFV/LNG IVR (8-10mg per day/20μg per day) for 3x28 days (Interrupted), placebo IVR for 90 days (Continuous), or placebo IVR for 3x28 days (Interrupted) and will undergo blood, cervicovaginal and rectal fluid sample collections, and cervicovaginal tissue collections for PK and PD assessments before, during and after 90 days of continuous or interrupted IVR use.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Phase I, 90-Day Safety, Pharmacokinetic, And Pharmacodynamic Study Of Intravaginal Rings Releasing Tenofovir And Levonorgestrel
Actual Study Start Date : September 28, 2017
Estimated Primary Completion Date : October 31, 2018
Estimated Study Completion Date : December 31, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: TFV/LNG IVR (8-10mg/20μg) (Continuous)
TFV/LNG IVR is an intravaginal ring 55.0 mm in diameter, consisting of two segments of polyurethane tubing with an outer cross-sectional diameter of 5.5 mm: a longer segment (135 mm) containing white to off-white TFV paste and a shorter one (34 mm) with a translucent LNG core. Used for 90 days (continuous).
Drug: TFV/LNG IVR
Used for 90 days (Continuous or Interrupted)
Other Name: Tenofovir/Levonorgestrel Intravaginal Ring

Experimental: TFV/LNG IVR (8-10mg/20μg) (Interrupted)
TFV/LNG IVR is an intravaginal ring 55.0 mm in diameter, consisting of two segments of polyurethane tubing with an outer cross-sectional diameter of 5.5 mm: a longer segment (135 mm) containing white to off-white TFV paste and a shorter one (34 mm) with a translucent LNG core. Used for 90 days (3x28 days interrupted).
Drug: TFV/LNG IVR
Used for 90 days (Continuous or Interrupted)
Other Name: Tenofovir/Levonorgestrel Intravaginal Ring

Placebo Comparator: Placebo (Continuous)
Intravaginal ring 55.0 mm in diameter, consisting of two segments of polyurethane tubing with an outer diameter of 5.5 mm containing no active experimental ingredients. Used for one month. Used for 90 days (continuous).
Drug: Placebo
Used for 90 days (Continuous or Interrupted)

Placebo Comparator: Placebo (Interrupted)
Intravaginal ring 55.0 mm in diameter, consisting of two segments of polyurethane tubing with an outer diameter of 5.5 mm containing no active experimental ingredients. Used for one month. Used for 90 days (3x28 days interrupted).
Drug: Placebo
Used for 90 days (Continuous or Interrupted)




Primary Outcome Measures :
  1. Percentage of women with Treatment-emergent adverse events [ Time Frame: Day 90 ]
    Treatment-emergent adverse events (TEAEs)

  2. Changes in systemic laboratory values [ Time Frame: Change from Baseline at Day 90 ]
    Systemic laboratory values

  3. Changes in cervicovaginal mucosa by visual inspection [ Time Frame: Change from Baseline at Day 90 ]
    Mucosal safety

  4. Changes in soluble markers [ Time Frame: Change from Baseline at Day 90 ]
    Soluble markers in cervicovaginal fluid

  5. Changes in inflammatory markers in cervicovaginal tissue [ Time Frame: Change from Baseline at Day 90 ]
    Inflammatory markers in cervicovaginal tissue

  6. Changes in endogenous vaginal bacteria [ Time Frame: Change from Baseline at Day 90 ]
    Endogenous vaginal bacteria in cervicovaginal fluid

  7. Microbial growth [ Time Frame: Day 90 ]
    Microbial growth on returned IVRs


Secondary Outcome Measures :
  1. Maximum Plasma Concentrations [Cmax] [ Time Frame: Baseline, 8 hours post-IVR insertion, Day 2 or 3 or 4 (randomized time point), 10, 21, 28, 32, 42, 53, 59, 63, 73, 84, 90; and 48 or 72 hours or 5 days after IVR removal (randomized time point) ]
    Maximum Plasma Concentrations [Cmax] of TFV and LNG

  2. Maximum CV Fluid Concentrations [ Time Frame: 2 and 8 hours post-IVR insertion, Day 2 or 3 or 4 (randomized time point), 10, 21, 32, 42, 53, 63, 73, 84; and 48 or 72 hours or 5 days after IVR removal (randomized time point) ]
    Maximum CV Fluid Concentrations of TFV

  3. Maximum Rectal Fluid Concentrations [ Time Frame: Day 2 or 3 or 4 (randomized time point), 21, 53, 84; and 48 or 72 hours or 5 days after IVR removal (randomized time point) ]
    Maximum Rectal Fluid Concentrations of TFV

  4. Maximum CV Tissue Concentrations [ Time Frame: Changes from baseline at day 90; and 48 or 72 hours or 5 days after IVR removal (randomized time point) ]
    Maximum CV Tissue Concentrations of TFV

  5. Maximum CV Tissue Metabolite Concentrations [ Time Frame: Changes from baseline at day 90; and 48 or 72 hours or 5 days after IVR removal (randomized time point) ]
    Maximum CV Tissue Concentrations of TFV-DP

  6. Maximum Serum Concentrations of LNG [ Time Frame: Baseline, 1, 2, 4, and 8 hours post-IVR insertion, Day 2 or 3 or 4 (randomized time point), 10, 21, 28, 32, 42, 53, 59, 63, 73, 84, 90; and 48 or 72 hours or 5 days after IVR removal (randomized time point) ]
    Maximum Serum Concentrations of LNG

  7. Residual Drug Concentrations [ Time Frame: Day 90 ]
    Residual drug (TFV and LNG) in returned IVRs

  8. Surrogates of contraceptive efficacy of Mucus [ Time Frame: Day 30 ]
    Surrogates of contraceptive efficacy: Cervical mucus assessment (Cervical mucus quality [score of >10])

  9. Surrogates of contraceptive efficacy of Sperm [ Time Frame: Day 30 ]
    Surrogates of contraceptive efficacy: Cervical mucus assessment (Sperm migration on the Simplified Slide test)

  10. Ovulation [ Time Frame: Changes from baseline at day 90 ]
    Ovulation by serum progesterone (P4)

  11. Follicular Development [ Time Frame: Changes from baseline at day 90 ]
    Effect on follicular development by serum estradiol concentration

  12. Antiviral activity in CV Fluid--HIV [ Time Frame: Changes from baseline at day 90 ]
    Anti-HIV-1 activity in CV fluid

  13. Antiviral activity in CV Fluid--HSV-2 [ Time Frame: Changes from baseline at day 90 ]
    Anti-HSV-2 activity in CV fluid

  14. Changes in Antiviral Activity [ Time Frame: Changes from baseline at day 90 ]
    Comparison of HIV-1 ex vivo infection in CV tissue (EVMS only) at baseline and after 90 days of IVR use

  15. Bleeding Patterns [ Time Frame: Baseline through Day 90 of IVR use ]
    Participant self-report of bleeding

  16. Forgiveness--LNG [ Time Frame: Day 32 and 63; and 48 or 72 hours or 5 days after IVR removal (randomized time point) ]
    Decay of LNG during 3-day periods of non-use in interrupted regimen, and after 90 days of IVR use

  17. Forgiveness--TFV [ Time Frame: Day 32 and 63; and 48 or 72 hours or 5 days after IVR removal (randomized time point) ]
    Decay of TFV during 3-day periods of non-use in interrupted regimen, and after 90 days of IVR use

  18. Acceptability--Qualitative [ Time Frame: Baseline, Day 28 and 90 ]
    Responses to key questions on acceptability and psychosocial questionnaire(s) (all participants), and feedback during in-depth interviews (subset of participants)

  19. Acceptability--IDI [ Time Frame: During first month of IVR use and Day 90 ]
    Responses to key questions on acceptability and psychosocial questionnaire(s) (all participants), and feedback during in-depth interviews (subset of participants)

  20. Adherence [ Time Frame: Baseline, Day 28 and 90 ]
    Percentage of participants with Discontinuations/Expulsions/Removals by self-report


Other Outcome Measures:
  1. Antiviral activity in Rectal Fluid--HIV [ Time Frame: Changes from baseline at day 90 ]
    Anti-HIV-1 activity in rectal fluid

  2. Antiviral activity in Rectal Fluid--HSV-2 [ Time Frame: Changes from baseline at day 90 ]
    Anti-HSV-2 activity in rectal fluid

  3. Changes in Antiviral Activity--HSV-2 [ Time Frame: Changes from baseline at day 90 ]
    Comparison of HSV-2 ex vivo infection in CV tissue (EVMS-only) at baseline and after 90 days of IVR use, as possible

  4. Qualitative TFV measurement [ Time Frame: Day 90 ]
    Qualitative measure of TFV in a vaginal swab

  5. Adherence Marker in returned vaginal ring-analytic [ Time Frame: Day 90 ]
    Analytical measures of drug or placebo products

  6. Adherence marker in returned ring--bioassay [ Time Frame: Day 90 ]
    Characterization of returned IVRs (active and placebo) via objective IVR biomarkers (e.g., residual glycerin content and bioassay) and residual drug (TFV and LNG), as feasible

  7. Adherence marker in returned ring--correlation [ Time Frame: Day 90 ]
    Correlation of IVR removal scale factors and objective biomarkers of IVR use

  8. Adherence marker in returned ring--correlation [ Time Frame: Day 90 ]
    Correlation of baseline user characteristics and objective biomarkers of IVR use



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.


Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   Female
Gender Based Eligibility:   Yes
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Female, age 18-50 years, inclusive
  • General good health (by volunteer history and per investigator 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) and with an intact gastrointestinal tract, uterus, and cervix.
  • Currently having regular menstrual cycles (approximately 26-35 days) by participant report
  • History of Pap smears and follow-up consistent with standard clinical practice as outlined in the Study Manual or willing to undergo a Pap smear at Visit 1
  • Protected from pregnancy by one of the following:
  • Sterilization of either partner
  • Abstinence from vaginal intercourse
  • Consistent use of non-spermicidal condoms
  • Willing to abstain from use of vaginal products (other than the study product and condoms) including tampons (except for menses), spermicides, lubricants, and douches for the whole study
  • Willing to abstain from any vaginal and anal intercourse/activity starting 48 hours before cervical mucus collection, as possible, and 48 hours before Visits 4 and 29, and for 5 days after tissue collection
  • Vaginal and cervical anatomy that, in the opinion of the investigator, lends itself to easy genital tract sample collection
  • Negative urine pregnancy test
  • P4 ≥3 ng/ml
  • Willing to give voluntary consent and sign an informed consent form
  • Willing and able to comply with protocol requirements

Exclusion Criteria:

  • BMI ≥ 30 kg/m2
  • History of hysterectomy
  • Currently pregnant or within two calendar months from the last pregnancy outcome.

Note: If recently pregnant, must have had at least two spontaneous menses since pregnancy outcome

  • Use of any hormonal contraceptive method in the last 3 months (oral, transdermal, transvaginal, implant, or hormonal intrauterine contraceptive device)
  • Injection of Depo-Provera in the last 10 months
  • Use of copper IUD
  • Currently breastfeeding or having breastfed an infant in the last two months, or planning to breastfeed during the course of the study
  • History of sensitivity/allergy to any component of the study products, topical anesthetic, or to both silver nitrate and Monsel's solution
  • Contraindication to LNG
  • In the last three months, diagnosed with or treated for any STI or pelvic inflammatory disease. Note: Women with a history of genital herpes or condylomata who have been asymptomatic for at least six months may be considered for eligibility.
  • Nugent score greater than or equal to 7 or symptomatic bacterial vaginosis (BV) as defined by Amsel's criteria
  • Positive test for Trichomonas vaginalis (TV), Neisseria gonorrhea (GC), Chlamydia trachomatis (CT), HIV-1, or Hepatitis B surface antigen (HBsAg)
  • Known bleeding disorder, including deep vein thrombosis (DVT) and pulmonary embolism (PE), or those that could lead to prolonged or continuous bleeding with biopsy
  • Chronic or acute vulvar or vaginal symptoms (pain, irritation, spotting/bleeding, discharge, etc.)
  • Known current drug or alcohol abuse which could impact study compliance
  • Grade 2 or higher laboratory abnormality, per the 2014 update of 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
  • Systemic use in the last two weeks or anticipated use during the study of any of the following: corticosteroids, antibiotics, anticoagulants or other drugs known to prolong bleeding and/or clotting, antifungals, or antivirals or antiretrovirals (e.g. acyclovir, valacyclovir, Viread®, Atripla®, Emtriva®, or Complera®), or CYP3A4 inducers or inhibitors as detailed in the Study Manual (e.g., St. John's Wort or erythromycin).

Note: Participants should avoid non-steroidal anti-inflammatory drugs (NSAIDs) except for treatment of dysmenorrhea during menses. Participants may use acetaminophen on an as-needed but not daily basis during the study.

  • 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
  • Abnormal finding on laboratory or physical examination or a social or medical condition in the volunteer which, in the opinion of the investigator, would make participation in the study unsafe or would complicate interpretation of data

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): NCT03279120


Contacts
Contact: Medical Director 703.524.4744 jschwartz@conrad.org
Contact: Project Manager 703.524.4744 sju@conrad.org

Locations
United States, Virginia
Eastern Virginia Medical School Recruiting
Norfolk, Virginia, United States, 23507-1627
Contact: Principal Investigator    703-446-5600    thurmaar@evms.edu   
Contact: Study Coordinator    703.446.5600    evansjl@evms.edu   
Dominican Republic
Profamilia Not yet recruiting
Santo Domingo, Dominican Republic
Contact: Vivian Brache         
Contact: Leila Cochon         
Sponsors and Collaborators
CONRAD
United States Agency for International Development (USAID)
Agility Clinical, Inc.

Responsible Party: CONRAD
ClinicalTrials.gov Identifier: NCT03279120     History of Changes
Other Study ID Numbers: A15-138
First Posted: September 12, 2017    Key Record Dates
Last Update Posted: November 28, 2017
Last Verified: September 2017
Individual Participant Data (IPD) Sharing Statement:
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:
HIV
LNG
TFV
IVR
Contraception
Prevention

Additional relevant MeSH terms:
Tenofovir
Levonorgestrel
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