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

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ClinicalTrials.gov Identifier: NCT02235662
Recruitment Status : Completed
First Posted : September 10, 2014
Last Update Posted : January 11, 2016
Sponsor:
Information provided by (Responsible Party):
CONRAD

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.

Condition or disease Intervention/treatment Phase
HIV Contraception Drug: TFV IVR Drug: TFV/LNG IVR Other: Placebo IVR Phase 1

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 86 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Phase I One-Month Safety, Pharmacokinetic, Pharmacodynamic, and Acceptability Study of Intravaginal Rings Releasing Tenofovir and Levonorgestrel or Tenofovir Alone
Study Start Date : October 2014
Actual Primary Completion Date : December 2015
Actual Study Completion Date : December 2015

Resource links provided by the National Library of Medicine


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 Name: 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 Name: Tenofovir Intravaginal Ring

Drug: TFV/LNG IVR
Other Name: 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 Name: Placebo Intravaginal Ring




Primary Outcome Measures :
  1. Number of treatment-emergent adverse events [ Time Frame: IVR Day 1, 2, ~8, ~16-18; 24 hours and 1-2 weeks post-IVR insertion and 1-2 weeks after IVR removal ]
    Number of treatment-emergent adverse events

  2. Systemic laboratory tests [ Time Frame: Baseline and IVR Day ~16-18 ]
    Changes in Systemic laboratory tests

  3. Cervicovaginal ulcerations, abrasions, edema, and other findings [ Time Frame: Baseline, IVR Day 2, ~8 and ~16-18 ]
    Development of cervicovaginal ulcerations, abrasions, edema, and other findings as assessed by naked eye and colposcopic visualization of the cervicovaginal epithelium

  4. Soluble markers of innate mucosal immunity and inflammatory response in cervicovaginal lavage (CVL) fluid [ Time Frame: Baseline and IVR Day ~16-18 ]
    Changes in soluble markers of innate mucosal immunity and inflammatory response in CVL fluid

  5. HIV-1 target immune cell phenotype and HIV-1 activation/proliferation marker in cervicovaginal tissue (biopsy) [ Time Frame: Baseline and IVR Day ~16-18 ]
    Changes in HIV-1 target immune cell phenotype and HIV-1 activation/proliferation marker in cervicovaginal tissue (biopsy)

  6. Microflora (semi-quantitative vaginal culture and/or unculturable bacteria) [ Time Frame: Baseline and IVR Day ~16-18 ]
    Changes microflora (semi-quantitative vaginal culture and/or unculturable bacteria)

  7. Vaginal pH [ Time Frame: Baseline and IVR Day ~16-18 ]
    Changes in vaginal pH

  8. Nugent Score [ Time Frame: Baseline and IVR Day ~16-18 ]
    Changes in Nugent Score


Secondary Outcome Measures :
  1. TFV concentrations in plasma [ Time Frame: Baseline; 1, 2, 4 and 8 hrs post-IVR insertion; IVR Day 2, ~8, ~16-18; 24 hours post-IVR removal ]
    TFV concentrations in plasma

  2. TFV concentrations in cervicovaginal fluid (aspirate and swab) [ Time Frame: 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 cervicovaginal fluid (aspirate and swab)

  3. TFV concentrations in genital tissue (biopsy) [ Time Frame: IVR Day 2, ~16-18; 24 or 72 hours post-IVR removal (randomized time point) ]
    TFV concentrations in genital tissue (biopsy)

  4. Tenofovir diphosphate (TFV-DP) concentrations in peripheral blood mononuclear cells (PBMCs) [ Time Frame: IVR Day ~16-18 ]
    TFV-DP concentrations in PBMCs

  5. TFV-DP concentrations in genital tissue (biopsy) [ Time Frame: IVR Day 2, ~16-18; 24 or 72 hours post-IVR removal (randomized time point) ]
    TFV-DP concentrations in genital tissue (biopsy)

  6. LNG concentration in blood (including SHBG) [ Time Frame: Baseline; 1, 2, 4 and 8 hrs post-IVR insertion; IVR Day 2, ~8, ~16-18; 24 hours post-IVR removal ]
    LNG concentration in blood (including SHBG)

  7. LNG concentration in vaginal secretions (swabs) [ Time Frame: Baseline; IVR Day~8 ]
    LNG concentration in vaginal secretions (swabs)

  8. LNG concentration in cervical mucus [ Time Frame: IVR Day ~8, ~16-18; 24 hours post-IVR removal ]
    LNG concentration in cervical mucus

  9. Weight of returned IVRs [ Time Frame: IVR Day ~16-18 (post-removal) ]
    Weight of returned IVRs

  10. Amount of drug remaining in returned IVRs [ Time Frame: IVR Day ~16-18 (post-removal) ]
    Amount of drug remaining in returned IVRs


Other Outcome Measures:
  1. Cervical mucus assessment and sperm migration on the Simplified Slide test [ Time Frame: IVR Day ~8 ]
    Surrogates of contraceptive efficacy - Cervical mucus assessment

  2. Ovulation by P4 [ Time Frame: IVR Day ~16-18 ]
    Surrogates of contraceptive efficacy - Ovulation by P4

  3. Follicular development by serum estradiol concentration [ Time Frame: IVR Day ~8, ~16-18 ]
    Surrogates of contraceptive efficacy - Follicular development by serum estradiol concentration

  4. Acceptability of IVR [ Time Frame: IVR Day ~16-18 (post-removal) ]
    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

  5. Pharmacodynamics [ Time Frame: Baseline, IVR Day ~16-18 ]
    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

  6. Pharmacodynamics [ Time Frame: Baseline, IVR Day ~16-18 ]
    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.

  7. Pharmacodynamic surrogates of LNG in endometrium [ Time Frame: Baseline, IVR Day ~16-18 ]
    Findings on endometrial biopsy: Histology, Markers of endometrial function

  8. Endometrial thickness [ Time Frame: Baseline, IVR Day ~16-18 ]
    Endometrial thickness as assessed by transvaginal ultrasound

  9. Cervicovaginal epithelial histology and epithelial integrity in cervicovaginal tissue (biopsy) [ Time Frame: Baseline, IVR Day ~16-18 ]
    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)

  10. Markers of mucosal alteration and inflammation (e.g., expression of COX-2) in cervicovaginal and endometrial tissue [ Time Frame: Baseline, IVR Day ~16-18 ]
    Markers of mucosal alteration and inflammation (e.g., expression of COX-2) in cervicovaginal and endometrial tissue

  11. Microbial growth on swabs obtained from returned IVRs and microbial levels in returned IVRs [ Time Frame: IVR Day ~16-18 (post-removal) ]
    Microbial growth on swabs obtained from returned IVRs and microbial levels in returned IVRs

  12. Level of association of TFV levels between less-invasive swabs and the more invasive biopsies, and possibly between swabs and aspirates [ Time Frame: IVR Day 2, ~16-18; 24 hours post-IVR removal ]
    Level of association of TFV levels between less-invasive swabs and the more invasive biopsies, and possibly between swabs and aspirates

  13. Characterization of returned IVRs for physicochemical properties and potential chemical and/or biological measures of adherence [ Time Frame: IVR Day ~16-18 (post-removal) ]
    Characterization of returned IVRs for physicochemical properties and potential chemical and/or biological measures of adherence



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
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

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): NCT02235662


Locations
United States, Virginia
Eastern Virginia Medical School
Norfolk, Virginia, United States, 23507
Dominican Republic
Profamilia
Santo Domingo, Dominican Republic
Sponsors and Collaborators
CONRAD
Investigators
Study Chair: Jill Schwartz, MD CONRAD
Study Director: Chris Mauck, MD CONRAD

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: CONRAD
ClinicalTrials.gov Identifier: NCT02235662     History of Changes
Other Study ID Numbers: A13-128
First Posted: September 10, 2014    Key Record Dates
Last Update Posted: January 11, 2016
Last Verified: January 2016

Keywords provided by CONRAD:
HIV
LNG
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