Phase I One-month Safety, PK, PD, and Acceptability Study of IVR Releasing TFV and LNG or TFV Alone

Phase I One-Month Safety, Pharmacokinetic, Pharmacodynamic, and Acceptability Study of Intravaginal Rings Releasing Tenofovir and Levonorgestrel or Tenofovir Alone

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.

Study Overview

• Status: Completed
• Conditions: HIV; Contraception
• Intervention / Treatment: Drug: TFV IVR; Drug: TFV/LNG IVR; Other: Placebo IVR

• Study Type: Interventional
• Enrollment (Actual): 86
• Phase: Phase 1

Contacts and Locations

Study Locations

• Dominican Republic
  • Santo Domingo, Dominican Republic
    • Profamilia
• United States
  • Virginia
    • Norfolk, Virginia, United States, 23507
      • Eastern Virginia Medical School

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TFV IVR; TFV IVR is an intravaginal ring 55.0 mm in diameter, consisting of single segment of polyurethane tubing with an outer diameter of 5.5 mm and filled with white TFV-containing paste. Used for one month, the IVR delivers 8-10 mg/day TFV.	Drug: TFV IVR; Other Names: Tenofovir Intravaginal Ring
Experimental: TFV/LNG IVR; TFV/LNG IVR is an intravaginal ring 55.0 mm in diameter, consisting of two segments of polyurethane tubing with an outer diameter of 5.5 mm: a longer segment containing white TFV paste and a shorter one (20 mm) with a white LNG core. Used for one month, the IVR delivers 8-10 mg/day TFV and 20 μg/day LNG.	Drug: TFV IVR; Other Names: Tenofovir Intravaginal Ring; Drug: TFV/LNG IVR; Other Names: Tenofovir Levonorgestrel Intravaginal Ring
Placebo Comparator: Placebo Intravaginal Ring; 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.	Other: Placebo IVR; Other Names: Placebo Intravaginal Ring

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of treatment-emergent adverse events	Number of treatment-emergent adverse events	IVR Day 1, 2, ~8, ~16-18; 24 hours and 1-2 weeks post-IVR insertion and 1-2 weeks after IVR removal
Systemic laboratory tests	Changes in Systemic laboratory tests	Baseline and IVR Day ~16-18
Cervicovaginal ulcerations, abrasions, edema, and other findings	Development of cervicovaginal ulcerations, abrasions, edema, and other findings as assessed by naked eye and colposcopic visualization of the cervicovaginal epithelium	Baseline, IVR Day 2, ~8 and ~16-18
Soluble markers of innate mucosal immunity and inflammatory response in cervicovaginal lavage (CVL) fluid	Changes in soluble markers of innate mucosal immunity and inflammatory response in CVL fluid	Baseline and IVR Day ~16-18
HIV-1 target immune cell phenotype and HIV-1 activation/proliferation marker in cervicovaginal tissue (biopsy)	Changes in HIV-1 target immune cell phenotype and HIV-1 activation/proliferation marker in cervicovaginal tissue (biopsy)	Baseline and IVR Day ~16-18
Microflora (semi-quantitative vaginal culture and/or unculturable bacteria)	Changes microflora (semi-quantitative vaginal culture and/or unculturable bacteria)	Baseline and IVR Day ~16-18
Vaginal pH	Changes in vaginal pH	Baseline and IVR Day ~16-18
Nugent Score	Changes in Nugent Score	Baseline and IVR Day ~16-18

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
TFV concentrations in plasma	TFV concentrations in plasma	Baseline; 1, 2, 4 and 8 hrs post-IVR insertion; IVR Day 2, ~8, ~16-18; 24 hours post-IVR removal
TFV concentrations in cervicovaginal fluid (aspirate and swab)	TFV concentrations in cervicovaginal fluid (aspirate and swab)	1, 2, 4 or 8 hours post-IVR insertion (randomized time point); IVR Day 2, ~8, ~16-18; 24 hours post-IVR removal
TFV concentrations in genital tissue (biopsy)	TFV concentrations in genital tissue (biopsy)	IVR Day 2, ~16-18; 24 or 72 hours post-IVR removal (randomized time point)
Tenofovir diphosphate (TFV-DP) concentrations in peripheral blood mononuclear cells (PBMCs)	TFV-DP concentrations in PBMCs	IVR Day ~16-18
TFV-DP concentrations in genital tissue (biopsy)	TFV-DP concentrations in genital tissue (biopsy)	IVR Day 2, ~16-18; 24 or 72 hours post-IVR removal (randomized time point)
LNG concentration in blood (including SHBG)	LNG concentration in blood (including SHBG)	Baseline; 1, 2, 4 and 8 hrs post-IVR insertion; IVR Day 2, ~8, ~16-18; 24 hours post-IVR removal
LNG concentration in vaginal secretions (swabs)	LNG concentration in vaginal secretions (swabs)	Baseline; IVR Day~8
LNG concentration in cervical mucus	LNG concentration in cervical mucus	IVR Day ~8, ~16-18; 24 hours post-IVR removal
Weight of returned IVRs	Weight of returned IVRs	IVR Day ~16-18 (post-removal)
Amount of drug remaining in returned IVRs	Amount of drug remaining in returned IVRs	IVR Day ~16-18 (post-removal)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cervical mucus assessment and sperm migration on the Simplified Slide test	Surrogates of contraceptive efficacy - Cervical mucus assessment	IVR Day ~8
Ovulation by P4	Surrogates of contraceptive efficacy - Ovulation by P4	IVR Day ~16-18
Follicular development by serum estradiol concentration	Surrogates of contraceptive efficacy - Follicular development by serum estradiol concentration	IVR Day ~8, ~16-18
Acceptability of IVR	Acceptability of IVR as measured by a composite of the following factors: Discontinuations, Expulsions, Removals, Visible changes (such as discoloration) as documented on photographs of returned IVRs, Responses to key questions on acceptability questionnaire	IVR Day ~16-18 (post-removal)
Pharmacodynamics	Pharmacodynamics - Anti-herpes simplex virus (HSV)-2 and Anti-HIV-1 activities in the CVL. Anti-HIV and anti-HSV activity as a percent of anti-HIV and anti-HSV activity before exposure to test product	Baseline, IVR Day ~16-18
Pharmacodynamics	TFV anti-HIV efficacy in cervicovaginal tissues. Comparison of cervicovaginal tissue permissiveness to ex vivo infection with HIV-1 BaL between the control cycle and treatment cycle.	Baseline, IVR Day ~16-18
Pharmacodynamic surrogates of LNG in endometrium	Findings on endometrial biopsy: Histology, Markers of endometrial function	Baseline, IVR Day ~16-18
Endometrial thickness	Endometrial thickness as assessed by transvaginal ultrasound	Baseline, IVR Day ~16-18
Cervicovaginal epithelial histology and epithelial integrity in cervicovaginal tissue (biopsy)	Cervicovaginal epithelial histology (thickness and number of cell layers) and epithelial integrity, as measured immuno-histochemistry (IHC) of epithelial junction proteins in cervicovaginal tissue (biopsy)	Baseline, IVR Day ~16-18
Markers of mucosal alteration and inflammation (e.g., expression of COX-2) in cervicovaginal and endometrial tissue	Markers of mucosal alteration and inflammation (e.g., expression of COX-2) in cervicovaginal and endometrial tissue	Baseline, IVR Day ~16-18
Microbial growth on swabs obtained from returned IVRs and microbial levels in returned IVRs	Microbial growth on swabs obtained from returned IVRs and microbial levels in returned IVRs	IVR Day ~16-18 (post-removal)
Level of association of TFV levels between less-invasive swabs and the more invasive biopsies, and possibly between swabs and aspirates	Level of association of TFV levels between less-invasive swabs and the more invasive biopsies, and possibly between swabs and aspirates	IVR Day 2, ~16-18; 24 hours post-IVR removal
Characterization of returned IVRs for physicochemical properties and potential chemical and/or biological measures of adherence	Characterization of returned IVRs for physicochemical properties and potential chemical and/or biological measures of adherence	IVR Day ~16-18 (post-removal)

Collaborators and Investigators

• Sponsor: CONRAD
• Investigators: Study Chair: Jill Schwartz, MD, CONRAD; Study Director: Chris Mauck, MD, CONRAD

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: July 14, 2014
• First Submitted That Met QC Criteria: September 8, 2014
• First Posted (Estimate): September 10, 2014

Study Record Updates

• Last Update Posted (Estimate): January 11, 2016
• Last Update Submitted That Met QC Criteria: January 8, 2016
• Last Verified: January 1, 2016

More Information

Terms related to this study

• Keywords: HIV; Contraception; Prevention; LNG; IVR
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; Tenofovir; Levonorgestrel
• Other Study ID Numbers: A13-128