Phase IIa, 90-Day Safety, Adherence, and Acceptability Study of Intravaginal Rings Releasing Tenofovir With and Without Levonorgestrel Among Women in Western Kenya
试验速览
- 阶段
- 2 期
- 发起方
- 入组人数
- 50
- 试验地点
- 1
- 主要终点
- Mucosal safety
研究概览
简要总结
The purpose of the study is to evaluate the safety, pharmacokinetics and pharmacodynamics of, and the tolerability and acceptance of an intravaginal ring (IVR) delivering both tenofovir and levonorgestrel (TFV/LNG) and an IVR delivering TFV only, compared to a placebo IVR, in women in Western Kenya.
详细描述
This Phase 2a clinical trial will evaluate the safety, pharmacokinetics and pharmacodynamics of, and the tolerability and adherence to two novel intravaginal rings (IVRs). The tenofovir/levonorgestrel (TFV/LNG) IVR and TFV IVRs are designed to provide HIV (and HSV-2) prevention with and without contraceptive for pregnancy prevention, respectively. Women will be protected from pregnancy by abstinence from vaginal intercourse or agreeing to consistently use condoms; concurrent use of a non-hormonal copper intrauterine device is permitted.
The study will enroll healthy, HIV-negative, non-pregnant, menstruating women aged 18-34 years, inclusive, and not currently infected with hepatitis B virus, who are assessed to be at lower risk for HIV. The goal is to enroll fifty (50) women in Western Kenya. The participants will be randomized 2:2:1 to use one of the following continuous delivery IVRs: twenty (20) women to use the TFV/LNG IVR; ten (10) women to use the TFV IVR; and ten (10) women to use the placebo IVR. Participants will attend up to ten (10) routine study visits that may include physical and pelvic exams, collection of venous blood, vaginal fluid and cervical mucus, and behavioral questionnaires. A subset of twenty (20) women will participate in in-depth interviews.
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, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 34 Years（Adult）
- 性别
- Female
- 接受健康志愿者
- 是
入选标准
- •Female, aged 18-34 years, inclusive
- •General good health (by history and per clinician 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), uterus, and cervix
- •Not pregnant or planning to become pregnant
- •Pre-screening HIV risk score ≤4
- •Currently having regular menstrual cycles (approximately 24-35 days) OR with a history of having regular menstrual cycles before contraceptive use, by report, and resumed some menstruation or spotting (with biochemical confirmation of ovulation)
- •Willing to undergo Visual Inspection with Lugol's Iodine (VILI) for cervical abnormalities during pelvic exam
- •Willing to abstain from use of vaginal products other than the study product, including tampons (except for during menses) , menstrual cups, vaginally inserted cloths or other materials, spermicides, lubricants, and douches for the whole study
- •Willing to abstain from any vaginal intercourse starting 48 hours before certain study visits
- •Vaginal and cervical anatomy that, in the opinion of the clinician, lends itself to easy genital tract sample collection and is absent of vesicles and ulcers
- •No use of hormonal contraceptives within the following periods specified for each type of contraception method:
- •Oral contraceptives (combined or progestin-only), contraceptive patch or contraceptive vaginal ring in at least two (2) months
- •Last DMPA injection received at least four (4) months ago and has resumed regular menstruation
- •Hormonal IUD/IUS removed at least four (4) months ago and has resumed regular menstruation
- •Hormonal implant removed at least six (6) months ago and has resumed regular menstruation
- •Willing to refrain from using any hormonal contraceptives for the entire study and to use only study-provided non-spermicidal male condoms with or without a study-provided Cu-IUD
- •P4 ≥3.0 ng/ml
- •Estimated glomerular filtration rate (eGFR) ≥90ml/min/1.73m2
- •Willing to give voluntary consent and sign/mark an informed consent form
- •Willing and able to comply with protocol requirements
排除标准
- •Body mass index (BMI) ≥30 kg/m
- •History of hysterectomy
- •Currently pregnant or within less than three (3) calendar months of the last pregnancy outcome.
- •Currently breastfeeding or having breastfed an infant in the last two (2) months, or planning to breastfeed during the course of the study
- •Contraindication to any study products-LNG, TFV, or excipient ingredients
- •Contraindication to LNG
- •In the last three (3) months, diagnosed with or treated for any STI or pelvic inflammatory disease
- •Positive test for HIV-1, syphilis, Trichomonas vaginalis (TV), Neisseria gonorrhea (GC), Chlamydia trachomatis (CT) or HBsAg
- •Nugent score greater than or equal to 7 or a symptomatic BV clinical diagnosis as defined by Amsel's criteria
- •Suspected breast cancer or other progestin-sensitive cancer
- •Suspected hepatic disease, including cirrhosis or viral hepatitis
- •History of bleeding or coagulation problems
- •Known current drug or alcohol abuse which could impact study compliance
- •Grade 2 or higher laboratory abnormality, per 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
- •Use of any concomitant medications
- •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
- •Labial elongation (due to pulling practices and use of botanicals or caustic agents)
- •Abnormal finding on laboratory or physical examination or a social or medical condition in the volunteer which, in the opinion of the site co-PI(s), would make participation in the study unsafe or would complicate interpretation of data
- •Currently using, or has used within the preceding one (1) month, emtricitabine/tenofovir disoproxil fumarate (TDF/FTC or Truvada®) or any other tenofovir product, and/or has plans to use a non-study tenofovir product in any form during the study
研究组 & 干预措施
TFV/LNG IVR (10mg/20μg) (Continuous)
Tenofovir/Levonorgestrel Intravaginal Ring
干预措施: TFV/LNG IVR (Drug)
TFV IVR (10mg) (Continuous)
Tenofovir Intravaginal Ring
干预措施: TFV IVR (Drug)
Placebo IVR (Non-eluting)
Placebo Intravaginal Ring
干预措施: Placebo IVR (Drug)
结局指标
主要结局
Mucosal safety
时间窗: Change from Baseline to up to 90 days of IVR use
Changes in cervicovaginal mucosa by visual inspection
Safety Laboratory Assessments- complete blood counts
时间窗: Change from Baseline to up to 90 days of IVR use
Number of participants with abnormal complete blood counts
Treatment-emergent adverse events (TEAEs)
时间窗: Change from Baseline to up to 90 days of IVR use
Participants with Grade 2 or higher local female genital TEAEs as defined by DAIDS Table for Grading the Severity of Adult and Pediatric AEs (version 2.1) and DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events Addendum 1 Female Genital Grading Table for Use in Microbicide Studies
Safety Laboratory Assessments- lipids
时间窗: Change from Baseline to up to 90 days of IVR use
Number of participants with abnormal lipids
Safety Laboratory Assessments- Serum chemistry
时间窗: Change from Baseline to up to 90 days of IVR use
Number of participants with abnormal serum chemistry
次要结局
- Maximum CV fluid concentration(6 and 24 hours post-IVR insertion; Menstrual cycle 1 day 14; Menstrual cycle 1 day 21-25; Menstrual cycle 2 day 21-25; Menstrual cycle 3, day 14; Day 90 of IVR use; and 24 hours post-IVR use (anticipated cycle length is 28 days))
- Confirmation of Ovulation(Pre-IVR insertion; Menstrual cycle 1, day 20-25; Menstrual cycle 2, day 20-25; Day 90 of IVR use (anticipated cycle length is 28 days))
- Cervicovaginal (CV) fluid cytokines- IL-8(Change from Baseline to Day 90 of IVR use)
- Changes in endogenous vaginal bacteria- Nugent score(Change from Baseline to Day 90 of IVR use)
- Cervicovaginal (CV) fluid cytokines-IL-1α(Change from Baseline to Day 90 of IVR use)
- Tolerability - Somatic and non-specific non-treatment emergent adverse events(Baseline; 6 and 24 hours post-IVR insertion; Menstrual cycle 1, day 14; Menstrual cycle 1, day 21-25; Menstrual cycle 2, day 21-25; Menstrual cycle 3, day 14; 90 days of IVR use; 24 hours post IVR use (anticipated cycle length is 28 days))
- Acceptability - Quantitative assessment of acceptability based on Questionnaires administered pre- and post-IVR use(Screening; 90 days of IVR use)
- Percent (%) inhibition of HIV resulting from product use (Anti-HIV activity)(Baseline, Day 90 of IVR use)
- Adherence - Drug concentrations(Baseline; 6 and 24 hours post-IVR insertion; Menstrual cycle 1, day 14; Menstrual cycle 1, day 21-25; Menstrual cycle 2, day 21-25; Menstrual cycle 3, day 14; 90 days of IVR use; 24 hours post-IVR use (anticipated cycle length is 28 days))
- Adherence - Residual drug concentrations(Day 90 of IVR use)
- Maximum blood concentrations (Cmax)(Baseline; 6 and 24 hours post IVR insertion; Menstrual cycle 1, day 14; Menstrual cycle 1,day 21-25; Menstrual cycle 2, day 21-25; Menstrual cycle 3, day 14; Day 90 IVR use; 24 hours post-IVR use (anticipated cycle length is 28 days))
- Percent (%) inhibition of HSV resulting from product use (Anti-HSV activity)(Baseline, Day 90 of IVR use)
- Cervical mucus assessment and quality score(Menstrual cycle 1, day 14; Menstrual cycle 3, day 14 (anticipated cycle length is 28 days))
- Changes in endogenous vaginal bacteria(Change from Baseline to Day 90 of IVR use)
- qPCR of Ring Microbiota(Day 90 of IVR use)
- Tolerability - Self-reported complaints of changes in menstrual cycle(Screening; Menstrual cycle 1, day 14; Menstrual cycle 1, day 21-25; Menstrual cycle 2, day 21-25; Menstrual cycle 3, day 14; Day 90 of IVR use; 24 hours post-IVR use (anticipated cycle length is 28 days))
- Adherence - Percentage of discontinuations(Up to Day 90 of IVR use)