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

HIV Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02235662
• Other study ID #: A13-128
• Status: Completed
• Phase: Phase 1
• First received: July 14, 2014
• Last updated: January 8, 2016
• Start date: October 2014
• Est. completion date: December 2015

Study information

• Verified date: January 2016
• Source: CONRAD
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationDominican Republic: Consejo Nacional de Bioetica en Salud
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 86
• Est. completion date: December 2015
• Est. primary completion date: December 2015
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 45 Years

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Contraception
• HIV

Intervention

Drug:
• TFV IVR

• TFV/LNG IVR

Other:
• Placebo IVR

Locations

Country	Name	City	State
Dominican Republic	Profamilia	Santo Domingo
United States	Eastern Virginia Medical School	Norfolk	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
CONRAD

Countries where clinical trial is conducted

United States,  Dominican Republic, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Cervical mucus assessment and sperm migration on the Simplified Slide test	Surrogates of contraceptive efficacy - Cervical mucus assessment	IVR Day ~8	No
Other	Ovulation by P4	Surrogates of contraceptive efficacy - Ovulation by P4	IVR Day ~16-18	No
Other	Follicular development by serum estradiol concentration	Surrogates of contraceptive efficacy - Follicular development by serum estradiol concentration	IVR Day ~8, ~16-18	No
Other	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)	No
Other	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	No
Other	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	No
Other	Pharmacodynamic surrogates of LNG in endometrium	Findings on endometrial biopsy: Histology, Markers of endometrial function	Baseline, IVR Day ~16-18	No
Other	Endometrial thickness	Endometrial thickness as assessed by transvaginal ultrasound	Baseline, IVR Day ~16-18	No
Other	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	Yes
Other	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	Yes
Other	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)	Yes
Other	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	No
Other	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)	No
Primary	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	Yes
Primary	Systemic laboratory tests	Changes in Systemic laboratory tests	Baseline and IVR Day ~16-18	Yes
Primary	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	Yes
Primary	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	Yes
Primary	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	Yes
Primary	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	Yes
Primary	Vaginal pH	Changes in vaginal pH	Baseline and IVR Day ~16-18	Yes
Primary	Nugent Score	Changes in Nugent Score	Baseline and IVR Day ~16-18	Yes
Secondary	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	No
Secondary	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	No
Secondary	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)	No
Secondary	Tenofovir diphosphate (TFV-DP) concentrations in peripheral blood mononuclear cells (PBMCs)	TFV-DP concentrations in PBMCs	IVR Day ~16-18	No
Secondary	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)	No
Secondary	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	No
Secondary	LNG concentration in vaginal secretions (swabs)	LNG concentration in vaginal secretions (swabs)	Baseline; IVR Day~8	No
Secondary	LNG concentration in cervical mucus	LNG concentration in cervical mucus	IVR Day ~8, ~16-18; 24 hours post-IVR removal	No
Secondary	Weight of returned IVRs	Weight of returned IVRs	IVR Day ~16-18 (post-removal)	No
Secondary	Amount of drug remaining in returned IVRs	Amount of drug remaining in returned IVRs	IVR Day ~16-18 (post-removal)	No