Phase I, 90-Day Safety, Pharmacokinetic, And Pharmacodynamic Study Of Intravaginal Rings Releasing Tenofovir And Levonorgestrel
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 66
- 试验地点
- 2
- 主要终点
- Percentage of women with Treatment-emergent adverse events
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 是
入选标准
- •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
- •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
排除标准
- •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
- •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
研究组 & 干预措施
TFV/LNG IVR (8-10mg/20μg) (Continuous)
TFV/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).
干预措施: TFV/LNG IVR (Drug)
TFV/LNG IVR (8-10mg/20μg) (Interrupted)
TFV/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).
干预措施: TFV/LNG IVR (Drug)
Placebo (Continuous)
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. Used for 90 days (continuous).
干预措施: Placebo (Drug)
Placebo (Interrupted)
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. Used for 90 days (3x28 days interrupted).
干预措施: Placebo (Drug)
结局指标
主要结局
Percentage of women with Treatment-emergent adverse events
时间窗: Day 90
Treatment-emergent adverse events (TEAEs)
Changes in systemic laboratory values
时间窗: Change from Baseline at Day 90
Systemic laboratory values
Changes in endogenous vaginal bacteria
时间窗: Change from Baseline at Day 90
Endogenous vaginal bacteria in cervicovaginal fluid
Microbial growth
时间窗: Day 90
Microbial growth on returned IVRs
Changes in cervicovaginal mucosa by visual inspection
时间窗: Change from Baseline at Day 90
Mucosal safety
Changes in soluble markers
时间窗: Change from Baseline at Day 90
Soluble markers in cervicovaginal fluid
Changes in inflammatory markers in cervicovaginal tissue
时间窗: Change from Baseline at Day 90
Inflammatory markers in cervicovaginal tissue
次要结局
- Surrogates of contraceptive efficacy of Mucus(Day 30)
- Surrogates of contraceptive efficacy of Sperm(Day 30)
- Ovulation(Changes from baseline at day 90)
- Follicular Development(Changes from baseline at day 90)
- Antiviral activity in CV Fluid--HSV-2(Changes from baseline at day 90)
- Changes in Antiviral Activity(Changes from baseline at day 90)
- Forgiveness--TFV(Day 32 and 63; and 48 or 72 hours or 5 days after IVR removal (randomized time point))
- Maximum Plasma Concentrations [Cmax](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))
- Maximum CV Tissue Concentrations(Changes from baseline at day 90; and 48 or 72 hours or 5 days after IVR removal (randomized time point))
- Acceptability--IDI(During first month of IVR use and Day 90)
- Maximum CV Fluid Concentrations(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))
- Maximum Rectal Fluid Concentrations(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))
- Maximum CV Tissue Metabolite Concentrations(Changes from baseline at day 90; and 48 or 72 hours or 5 days after IVR removal (randomized time point))
- Maximum Serum Concentrations of LNG(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))
- Residual Drug Concentrations(Day 90)
- Antiviral activity in CV Fluid--HIV(Changes from baseline at day 90)
- Bleeding Patterns(Baseline through Day 90 of IVR use)
- Forgiveness--LNG(Day 32 and 63; and 48 or 72 hours or 5 days after IVR removal (randomized time point))
- Acceptability--Qualitative(Baseline, Day 28 and 90)
- Adherence(Baseline, Day 28 and 90)