Safety and Tolerability of 1 Month Daily (1HP) and 3 Months Weekly (3HP) Isoniazid and Rifapentine With Pharmacokinetics of Dolutegravir (DTG) in Pregnant People With HIV
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 252
- 试验地点
- 3
- 主要终点
- Mortality
研究概览
简要总结
Open-label, two-arm, randomized multicenter study to investigate the safety, tolerability, and pharmacokinetics (PK), and potential interactions between dolutegravir (DTG) and rifapentine (RPT) during pregnancy in people with HIV when RPT is given with isoniazid (INH) daily for 4 weeks (1HP) or weekly for 3 months (3HP) as part of tuberculosis (TB) preventive therapy (TPT). Adults (age ≥18) who are pregnant with a singleton pregnancy (confirmed by ultrasound) at a gestational age of 20-34 weeks and virally suppressed on an existing DTG-based plus two nucleoside reverse transcriptase inhibitors (NRTI) antiretroviral (ART) regimen for at least four weeks may participate.
详细描述
Enrolled participants will be randomized 1:1 to Arms 1 and 2.
Arm 1: 1HP (n=126):
Participants will start twice-daily DTG on Day 0, and will receive once-daily HP for 28 total doses, starting on Day 1. HIV viral load (VL) will be measured at baseline (screening), week 3 (Day 17), at delivery, and post-partum week 12. Safety labs: complete blood count (CBC), urea and electrolytes (U&E), creatinine, prothrombin time and international normalized ratio (PT/INR), and liver function tests (LFT) will be obtained at screening for everyone and at follow-up visits, if clinically indicated; CBCs and LFTs will be checked at delivery in all participants.
The first 25 participants enrolled to Arm 1 who consent to be in a PK substudy will participate in sparse PK blood collections for DTG. Sparse PK sampling for DTG will be performed on the morning of Day 1, before starting 1HP and before the morning dose of DTG. Additional sparse PK sampling for DTG will be performed prior to DTG dosing on Day 17 (to track with 72 hours after the 3rd dose of HP in Arm 2).
A plasma specimen for RPT PK will also be collected on Day 17.
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
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Age > 18 years
- •Weight > 50 kg
- •Documented HIV infection
- •At least 4 weeks of ART and virally suppressed on dolutegravir plus two NRTIs
- •Undetectable HIV-1 viral load
- •Pregnancy at 20-34 weeks as confirmed by ultrasound
- •Singleton pregnancy
排除标准
- •Confirmed or suspected TB disease
- •Likely to move from the study area during the study period
- •Known exposure to pulmonary TB cases with known or suspected resistance to isoniazid or rifampicin in the source case
- •TB treatment within the past year
- •TB preventive therapy within the last year
- •Sensitivity or intolerance to isoniazid or rifamycins
- •On nevirapine, etravirine, rilpivirine, PI-based, or raltegravir-containing ART regimens
- •Suspected acute hepatitis or known chronic liver disease; HBsAg positivity; severe hepatic impairment
- •Alanine aminotransferase (ALT) ≥ 3 times the upper limit of normal (ULN)
- •Total bilirubin ≥ 2.5 times the ULN
- •Absolute neutrophil count (ANC) < 750 cells/mm3
- •Creatinine clearance < 50 ml/min
- •Self-reported alcohol use exceeding 21 units per week
- •Karnofsky status < 80
- •On prohibited medications e.g. dofetilide
研究组 & 干预措施
Arm 1: One month of daily isoniazid and rifapentine (4 weeks)
-
DTG 50 mg orally BID
-
DTG 50 mg + 2 NRTI each morning (non-study)
-
2nd dose: DTG 50 mg each evening (during 1HP)
-
1HP: INH 300 mg + RPT 600 mg each morning for 4 weeks
干预措施: Rifapentine (Drug)
Arm 1: One month of daily isoniazid and rifapentine (4 weeks)
-
DTG 50 mg orally BID
-
DTG 50 mg + 2 NRTI each morning (non-study)
-
2nd dose: DTG 50 mg each evening (during 1HP)
-
1HP: INH 300 mg + RPT 600 mg each morning for 4 weeks
干预措施: Isoniazid (Drug)
Arm 2: Three months of once-weekly isoniazid and rifapentine (12 weeks)
-
DTG 50 mg orally BID
-
DTG 50 mg + 2 NRTI each morning (non-study)
-
2nd dose: DTG 50 mg each evening (during 3HP)
-
3HP: INH 900 mg + RPT 900 mg each week for 12 weeks
干预措施: Rifapentine (Drug)
Arm 2: Three months of once-weekly isoniazid and rifapentine (12 weeks)
-
DTG 50 mg orally BID
-
DTG 50 mg + 2 NRTI each morning (non-study)
-
2nd dose: DTG 50 mg each evening (during 3HP)
-
3HP: INH 900 mg + RPT 900 mg each week for 12 weeks
干预措施: Isoniazid (Drug)
结局指标
主要结局
Mortality
时间窗: from study entry at Week 0 through post partum Week 24, to be reported at end of trial
Maternal all-cause mortality (both groups)
Targeted serious adverse events (SAEs)
时间窗: from study entry at Week 0 through post partum Week 12, to be reported at end of trial
Premature discontinuation for toxicity or intolerance, Grade 3 or higher maternal bleeding, peripheral neuropathy, elevated LFTs), targeted pregnancy outcomes (fetal demise, stillbirth, preterm delivery (PTD) \<32 weeks, birthweight (BW) \<1500g, neonatal death \<28 days of age), or permanent discontinuation due to toxicity (both groups)
PK sampling of Dolutegravir - Cl/F parameter
时间窗: PK sampling at Week 1 (Day 1) and Week 3 (Day 17) for both groups, and at Week 8 (Day 52) for Group 2 (3HP arm), to be reported at end of trial
Oral clearance in the presence or absence of 1HP or 3HP (both groups)
PK sampling of Dolutegravir - Ctau parameter
时间窗: PK sampling at Week 1 (Day 1) and Week 3 (Day 17) for both groups, and at Week 8 (Day 52) for Group 2 (3HP arm), to be reported at end of trial
Trough concentration (Ctau) in the presence or absence of 1HP or 3HP (both groups)
PK sampling of Dolutegravir - AUC parameter
时间窗: PK sampling at Week 1 (Day 1) and Week 3 (Day 17) for both groups, and at Week 8 (Day 52) for Group 2 (3HP arm), to be reported at end of trial
Area under the plasma drug concentration-time curve (AUC) in the presence or absence of 1HP or 3HP (both groups)
次要结局
- PK sampling of RPT - AUC parameter(PK sampling at Week 3 (Day 17 ) to be reported at end of trial)
- HIV infection- infant(from Delivery through post partum Week 24, to be reported at end of trial)
- Infant growth parameters- HAZ(from Delivery through post partum Week 24, to be reported at end of trial)
- Infant growth parameters- WAZ(from Delivery through post partum Week 24, to be reported at end of trial)
- Treatment adherence- HP(from study entry at Week 0 through up to 8 weeks of 1HP (Group 1) or up to 16 weeks of 3HP (Group 2) , to be reported at end of trial)
- PK sampling of RPT - Ctau parameter(PK sampling at Week 3 (Day 17 ) to be reported at end of trial)
- DTG Dose selection(Dose selection will be determined at the interim analysis to be conducted when 25 participants from Arms 1 and 2 respectively have completed the Week 3 PK visit. Based upon these results, new enrollees will receive DTG either once or twice daily.)
- Adverse Events- pregnancy(from study entry at Week 0 through post partum Week 12, to be reported at end of trial)
- Adverse Events- infant(from Delivery through post partum Week 24, to be reported at end of trial)
- HIV-1 RNA viral load- maternal(HIV viral load to be measured at Screening, Week 3, at Delivery, and post partum Week 12, to be reported at end of trial)
- Adverse Events- maternal(from study entry at Week 0 through post partum Week 12, to be reported at end of trial)
- TB disease-maternal(from study entry at Week 0 through post partum Week 24, to be reported at end of trial)
- TB disease-infant(from Delivery through post partum Week 24, to be reported at end of trial)
- Infant growth parameters- HCAZ(from Delivery through post partum Week 24, to be reported at end of trial)