Clinical trial NCT02235662: Phase I One-month Safety, PK, PD, and Acceptability Study of IVR Releasing TFV and LNG or TFV Alone
Official title: Phase I One-Month Safety, Pharmacokinetic, Pharmacodynamic, and Acceptability Study of Intravaginal Rings Releasing Tenofovir and Levonorgestrel or Tenofovir Alone
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: HIV
Contraception
Keywords: HIV
LNG
IVR
Contraception
Prevention
Lead sponsor: CONRAD
Sponsor class: OTHER
First posted: 2014-09-10
Enrollment: 86
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of the study is to evaluate the safety of the TFV/LNG intravaginal ring (IVR), TFV-only IVR, and placebo IVR, evaluate pharmacokinetics (PK) of TFV and LNG, evaluate pharmacodynamic (PD) surrogates of contraceptive efficacy of LNG, and to evaluate acceptability of the IVRs.


Eligibility criteria: Inclusion Criteria:

* Age 18-45 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)
* Currently having regular menstrual cycles of 26-35 days by participant report
* History of Pap smears and follow-up consistent with standard medical practice as outlined in the study manual or willing to undergo a Pap smear
* Protected from pregnancy by one of the following: 1) Sterilization of either partner. Note: Women protected from pregnancy by sterilization of either partner must abstain from vaginal intercourse from 48 hours prior to Visit 3 until the sixth day after the last study visit; or 2) Willing to abstain from vaginal intercourse from Visit 1 until the sixth day after the last study visit.
* Willing to abstain from any other vaginal activity and the use of vaginal product other than the study product including tampons, spermicides, lubricants, and douches starting 48 hours before Visit 3 until the sixth day after the last study visit
* Vaginal and cervical anatomy that, in the opinion of the investigator, lends itself to easy colposcopy and genital tract sample collection
* Negative urine pregnancy test
* P4 ≥3 ng/ml
* Willing to give voluntary consent, sign an informed consent form and comply with study procedures as required by the protocol

Exclusion Criteria:

* 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 intrauterine device (IUD) after Visit 1
* 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: TFV 1% gel, topical anesthetic, or allergy to both silver nitrate and Monsel's solution.
* Contraindication to LNG
* In the last six months, diagnosed with or treated for any sexually transmitted infection (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, Neisseria gonorrhea (GC), Chlamydia trachomatis (CT), HIV, or Hepatitis B surface antigen (HBsAg)
* Known bleeding disorder that could lead to prolonged or continuous bleeding with biopsy
* Chronic or acute vulvar or vaginal symptoms (pain, irritation, spotting, etc.)
* Known current drug or alcohol abuse which could impact study compliance
* Grade 2 or higher laboratory abnormality, per the August 2009 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, antivirals (e.g., acyclovir or valacyclovir) or antiretrovirals (e.g., Viread, Atripla®, Emtriva®, Complera®). Note: Participants should avoid non-steroidal anti-inflammatory drugs (NSAIDs) except for treatment of dysmenorrhea during menses. Participants may use Tylenol® on an as-needed but not daily basis during the study
* Participation in any other investigational trial (device, drug, or vaginal trial) within the last 30 days or planned participation in any other investigational trial 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 which, in the opinion of the investigator, would make participation in the study unsafe or would complicate interpretation of data

Primary outcomes:
measure: Number of treatment-emergent adverse events
timeFrame: IVR Day 1, 2, ~8, ~16-18; 24 hours and 1-2 weeks post-IVR insertion and 1-2 weeks after IVR removal
measure: Systemic laboratory tests
timeFrame: Baseline and IVR Day ~16-18
measure: Cervicovaginal ulcerations, abrasions, edema, and other findings
timeFrame: Baseline, IVR Day 2, ~8 and ~16-18
measure: Soluble markers of innate mucosal immunity and inflammatory response in cervicovaginal lavage (CVL) fluid
timeFrame: Baseline and IVR Day ~16-18
measure: HIV-1 target immune cell phenotype and HIV-1 activation/proliferation marker in cervicovaginal tissue (biopsy)
timeFrame: Baseline and IVR Day ~16-18
measure: Microflora (semi-quantitative vaginal culture and/or unculturable bacteria)
timeFrame: Baseline and IVR Day ~16-18
measure: Vaginal pH
timeFrame: Baseline and IVR Day ~16-18
measure: Nugent Score
timeFrame: Baseline and IVR Day ~16-18
Secondary outcomes:
measure: TFV concentrations in plasma
timeFrame: Baseline; 1, 2, 4 and 8 hrs post-IVR insertion; IVR Day 2, ~8, ~16-18; 24 hours post-IVR removal
measure: TFV concentrations in cervicovaginal fluid (aspirate and swab)
timeFrame: 1, 2, 4 or 8 hours post-IVR insertion (randomized time point); IVR Day 2, ~8, ~16-18; 24 hours post-IVR removal
measure: TFV concentrations in genital tissue (biopsy)
timeFrame: IVR Day 2, ~16-18; 24 or 72 hours post-IVR removal (randomized time point)
measure: Tenofovir diphosphate (TFV-DP) concentrations in peripheral blood mononuclear cells (PBMCs)
timeFrame: IVR Day ~16-18
measure: TFV-DP concentrations in genital tissue (biopsy)
timeFrame: IVR Day 2, ~16-18; 24 or 72 hours post-IVR removal (randomized time point)
measure: LNG concentration in blood (including SHBG)
timeFrame: Baseline; 1, 2, 4 and 8 hrs post-IVR insertion; IVR Day 2, ~8, ~16-18; 24 hours post-IVR removal
measure: LNG concentration in vaginal secretions (swabs)
timeFrame: Baseline; IVR Day~8
measure: LNG concentration in cervical mucus
timeFrame: IVR Day ~8, ~16-18; 24 hours post-IVR removal
measure: Weight of returned IVRs
timeFrame: IVR Day ~16-18 (post-removal)
measure: Amount of drug remaining in returned IVRs
timeFrame: IVR Day ~16-18 (post-removal)
Other outcomes:
measure: Cervical mucus assessment and sperm migration on the Simplified Slide test
timeFrame: IVR Day ~8
measure: Ovulation by P4
timeFrame: IVR Day ~16-18
measure: Follicular development by serum estradiol concentration
timeFrame: IVR Day ~8, ~16-18
measure: Acceptability of IVR
timeFrame: IVR Day ~16-18 (post-removal)
measure: Pharmacodynamics
timeFrame: Baseline, IVR Day ~16-18
measure: Pharmacodynamics
timeFrame: Baseline, IVR Day ~16-18
measure: Pharmacodynamic surrogates of LNG in endometrium
timeFrame: Baseline, IVR Day ~16-18
measure: Endometrial thickness
timeFrame: Baseline, IVR Day ~16-18
measure: Cervicovaginal epithelial histology and epithelial integrity in cervicovaginal tissue (biopsy)
timeFrame: Baseline, IVR Day ~16-18
measure: Markers of mucosal alteration and inflammation (e.g., expression of COX-2) in cervicovaginal and endometrial tissue
timeFrame: Baseline, IVR Day ~16-18
measure: Microbial growth on swabs obtained from returned IVRs and microbial levels in returned IVRs
timeFrame: IVR Day ~16-18 (post-removal)
measure: Level of association of TFV levels between less-invasive swabs and the more invasive biopsies, and possibly between swabs and aspirates
timeFrame: IVR Day 2, ~16-18; 24 hours post-IVR removal
measure: Characterization of returned IVRs for physicochemical properties and potential chemical and/or biological measures of adherence
timeFrame: IVR Day ~16-18 (post-removal)
Locations:
city: Norfolk
country: United States
facility: Eastern Virginia Medical School
state: Virginia
city: Santo Domingo
country: Dominican Republic
facility: Profamilia
Study officials:
affiliation: CONRAD
name: Jill Schwartz, MD
role: STUDY_CHAIR
affiliation: CONRAD
name: Chris Mauck, MD
role: STUDY_DIRECTOR
References:
citation: Thurman AR, Schwartz JL, Ravel J, Gajer P, Marzinke MA, Yousefieh N, Anderson SM, Doncel GF. Vaginal microbiota and mucosal pharmacokinetics of tenofovir in healthy women using tenofovir and tenofovir/levonorgestrel vaginal rings. PLoS One. 2019 May 20;14(5):e0217229. doi: 10.1371/journal.pone.0217229. eCollection 2019.
citation: 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.