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
Overview
- Phase
- Phase 1
- Intervention
- Rifapentine
- Conditions
- HIV Seropositivity
- Sponsor
- The Aurum Institute NPC
- Enrollment
- 252
- Locations
- 3
- Primary Endpoint
- Mortality
- Status
- Active, not recruiting
- Last Updated
- 4 months ago
Overview
Brief Summary
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.
Detailed Description
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. Arm 2: 3HP (n=126): Participants will start twice-daily DTG on Day 0, and will receive once-weekly HP for 12 total doses starting on Day 1. HIV VL will be measured at baseline (screening), week 3 (Day 17), at delivery, and at post-partum week 12. Safety labs: CBC, U\&E, creatinine, PT/INR, and LFTs will be obtained at screening for everyone and at follow-up visits, if clinically indicated; CBCs and LFTs will be drawn at delivery. The first 25 participants enrolled to Arm 2 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 3HP, and before the morning dose of DTG. Additional sparse PK sampling for DTG will be performed on Day 17 prior to DTG dosing (72 hours after the 3rd dose of HP) and on Day 52 prior to DTG dosing (72 hours after the 8th dose of HP). There will not be plasma collection on Day 17 for RPT PK in Arm 2, because specimen collection would be 72 hours after the weekly HP dose and a RPT level will likely not be detectable. Interim analysis will occur when 25 participants each from Arms 1 and 2 have completed the Week 3 (Day 17) sparse PK visit. Ongoing enrolment will not be paused during the interim analysis, which will assess DTG PK, safety, and VL data. Enrollment will be paused if accrual to each arm reaches 101 participants before the interim analysis has been completed. Once results are available, then enrollment will restart with dosing (daily vs. BID) based on the DTG PK results.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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
Exclusion Criteria
- •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
Arms & Interventions
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
Intervention: Rifapentine
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
Intervention: Isoniazid
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
Intervention: Rifapentine
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
Intervention: Isoniazid
Outcomes
Primary Outcomes
Mortality
Time Frame: 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)
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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)
Secondary Outcomes
- 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)