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Anti-Infective AgentsPhase 1TFV/LNG IVRNCT03279120

Safety, PK, and PD Study of IVRs Releasing TFV and LNG

A Phase 1 study testing TFV/LNG IVR in people with Anti-Infective Agents and Anti-Retroviral Agents, run by CONRAD at 2 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 to 50 years, women onlyHealthy volunteers can take part
What is being tested?
TFV/LNG IVR
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
66 participants
Where
2 sitesin 2 countries
Study dates
28 Sep 2017to 26 Dec 2018
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 50 years
  • Women only
  • Healthy volunteers accepted
  • Adult

Who may be able to join

  • 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
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  • 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

Who cannot join

  • 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
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  • 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

Trial locations and contacts

2 sites in 2 countries.

2 sites in 2 countries

United States1 site

  • Eastern Virginia Medical School

    Norfolk, Virginia, 23507-1627

Other trials in United States

Dominican Republic1 site

  • Profamilia

    Santo Domingo

Other trials in Dominican Republic

About this study

Official title: Phase I, 90-Day Safety, Pharmacokinetic, And Pharmacodynamic Study Of Intravaginal Rings Releasing Tenofovir And Levonorgestrel

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.

Read the 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.

Being tested
TFV/LNG IVR, Placebo
Keywords
HIV, LNG, TFV, IVR, Contraception, Prevention
Medical subject headings
Contraception Behavior

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TFV/LNG IVRDrug

    Also called Tenofovir/Levonorgestrel Intravaginal Ring

    Used for 90 days (Continuous or Interrupted)

  • PlaceboDrug

    Used for 90 days (Continuous or Interrupted)

Study groups in NCT03279120
Study groupRoleWhat they receive
TFV/LNG IVR (8-10mg/20μg) (Continuous)ExperimentalTFV/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).
Receives: Drug: TFV/LNG IVR
TFV/LNG IVR (8-10mg/20μg) (Interrupted)ExperimentalTFV/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).
Receives: Drug: TFV/LNG IVR
Placebo (Continuous)Placebo comparatorIntravaginal 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).
Receives: Drug: Placebo
Placebo (Interrupted)Placebo comparatorIntravaginal 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).
Receives: Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Percentage of women with Treatment-emergent adverse events

    Treatment-emergent adverse events (TEAEs)

    Measured: Day 90

  2. Changes in systemic laboratory values

    Systemic laboratory values

    Measured: Change from Baseline at Day 90

  3. Changes in cervicovaginal mucosa by visual inspection

    Mucosal safety

    Measured: Change from Baseline at Day 90

  4. Changes in soluble markers

    Soluble markers in cervicovaginal fluid

    Measured: Change from Baseline at Day 90

  5. Changes in inflammatory markers in cervicovaginal tissue

    Inflammatory markers in cervicovaginal tissue

    Measured: Change from Baseline at Day 90

  6. Changes in endogenous vaginal bacteria

    Endogenous vaginal bacteria in cervicovaginal fluid

    Measured: Change from Baseline at Day 90

  7. Microbial growth

    Microbial growth on returned IVRs

    Measured: Day 90

Secondary outcomes (20)

  1. Maximum Plasma Concentrations [Cmax]

    Maximum Plasma Concentrations [Cmax] of TFV and LNG

    Measured: 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)

  2. Maximum CV Fluid Concentrations

    Maximum CV Fluid Concentrations of TFV

    Measured: 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)

  3. Maximum Rectal Fluid Concentrations

    Maximum Rectal Fluid Concentrations of TFV

    Measured: 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)

  4. Maximum CV Tissue Concentrations

    Maximum CV Tissue Concentrations of TFV

    Measured: Changes from baseline at day 90; and 48 or 72 hours or 5 days after IVR removal (randomized time point)

  5. Maximum CV Tissue Metabolite Concentrations

    Maximum CV Tissue Concentrations of TFV-DP

    Measured: Changes from baseline at day 90; and 48 or 72 hours or 5 days after IVR removal (randomized time point)

  6. Maximum Serum Concentrations of LNG

    Maximum Serum Concentrations of LNG

    Measured: 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)

  7. Residual Drug Concentrations

    Residual drug (TFV and LNG) in returned IVRs

    Measured: Day 90

  8. Surrogates of contraceptive efficacy of Mucus

    Surrogates of contraceptive efficacy: Cervical mucus assessment (Cervical mucus quality [score of >10])

    Measured: Day 30

  9. Surrogates of contraceptive efficacy of Sperm

    Surrogates of contraceptive efficacy: Cervical mucus assessment (Sperm migration on the Simplified Slide test)

    Measured: Day 30

  10. Ovulation

    Ovulation by serum progesterone (P4)

    Measured: Changes from baseline at day 90

  11. Follicular Development

    Effect on follicular development by serum estradiol concentration

    Measured: Changes from baseline at day 90

  12. Antiviral activity in CV Fluid--HIV

    Anti-HIV-1 activity in CV fluid

    Measured: Changes from baseline at day 90

  13. Antiviral activity in CV Fluid--HSV-2

    Anti-HSV-2 activity in CV fluid

    Measured: Changes from baseline at day 90

  14. Changes in Antiviral Activity

    Comparison of HIV-1 ex vivo infection in CV tissue (EVMS only) at baseline and after 90 days of IVR use

    Measured: Changes from baseline at day 90

  15. Bleeding Patterns

    Participant self-report of bleeding

    Measured: Baseline through Day 90 of IVR use

  16. Forgiveness--LNG

    Decay of LNG during 3-day periods of non-use in interrupted regimen, and after 90 days of IVR use

    Measured: Day 32 and 63; and 48 or 72 hours or 5 days after IVR removal (randomized time point)

  17. Forgiveness--TFV

    Decay of TFV during 3-day periods of non-use in interrupted regimen, and after 90 days of IVR use

    Measured: Day 32 and 63; and 48 or 72 hours or 5 days after IVR removal (randomized time point)

  18. Acceptability--Qualitative

    Responses to key questions on acceptability and psychosocial questionnaire(s) (all participants), and feedback during in-depth interviews (subset of participants)

    Measured: Baseline, Day 28 and 90

  19. Acceptability--IDI

    Responses to key questions on acceptability and psychosocial questionnaire(s) (all participants), and feedback during in-depth interviews (subset of participants)

    Measured: During first month of IVR use and Day 90

  20. Adherence

    Percentage of participants with Discontinuations/Expulsions/Removals by self-report

    Measured: Baseline, Day 28 and 90

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Sep 2017
  2. Study start28 Sep 2017
  3. Primary completion26 Dec 2018
  4. Study completion26 Dec 2018

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Investigator, Outcomes assessor
Enrolment
66 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03279120
Sponsor's protocol ID
A15-138
Acronym
TFV/LNG IVR
Status last verified
Jul 2019
First submitted
23 Aug 2017
Last updated
23 Jul 2019
Results posted
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Thurman AR, Brache V, Cochon L, Ouattara LA, Chandra N, Jacot T, Yousefieh N, Clark MR, Peet M, Hanif H, Schwartz JL, Ju S, Marzinke MA, Erikson DW, Parikh U, Herold BC, Fichorova RN, Tolley E, Doncel GF. Randomized, placebo controlled phase I trial of the safety, pharmacokinetics, pharmacodynamics and acceptability of a 90 day tenofovir plus levonorgestrel vaginal ring used continuously or cyclically in women: The CONRAD 138 study. PLoS One. 2022 Oct 10;17(10):e0275794. doi: 10.1371/journal.pone.0275794. eCollection 2022.

    PubMed 36215267

  • Tolley EE, Zissette S, Taylor J, Hanif H, Ju S, Schwarz J, Thurman A, Tyner D, Brache V, Doncel GF. Acceptability of a Long-Acting, Multipurpose Vaginal Ring: Findings from a Phase I Trial in the U.S. and Dominican Republic. J Womens Health (Larchmt). 2022 Sep;31(9):1343-1352. doi: 10.1089/jwh.2021.0394. Epub 2022 Apr 1.

    PubMed 35363574

  • Thurman AR, Ravel J, Gajer P, Marzinke MA, Ouattara LA, Jacot T, Peet MM, Clark MR, Doncel GF. Vaginal Microbiota and Mucosal Pharmacokinetics of Tenofovir in Healthy Women Using a 90-Day Tenofovir/Levonorgestrel Vaginal Ring. Front Cell Infect Microbiol. 2022 Mar 8;12:799501. doi: 10.3389/fcimb.2022.799501. eCollection 2022.

    PubMed 35350436

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing TFV/LNG IVR in people with Anti-Infective Agents and Anti-Retroviral Agents, run by CONRAD at 2 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 15 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 23 Jul 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States, Dominican Republic. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage of women with Treatment-emergent adverse events (time frame: Day 90). The study lists 7 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03279120, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Jul 2019.

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