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

Phase 2Active Not RecruitingNCT05122026

The Aurum Institute NPC252 enrolled

Overview

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.

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.

Eligibility

Sex: FEMALEMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Age \> 18 years 2. Weight \> 50 kg 3. Documented HIV infection 4. At least 4 weeks of ART and virally suppressed on dolutegravir plus two NRTIs 5. Undetectable HIV-1 viral load 6. Pregnancy at 20-34 weeks as confirmed by ultrasound 7. Singleton pregnancy Exclusion Criteria: 1. Confirmed or suspected TB disease 2. Likely to move from the study area during the study period 3. Known exposure to pulmonary TB cases with known or suspected resistance to isoniazid or rifampicin in the source case 4. TB treatment within the past year 5. TB preventive therapy within the last year 6. Sensitivity or intolerance to isoniazid or rifamycins 7. On nevirapine, etravirine, rilpivirine, PI-based, or raltegravir-containing ART regimens 8. Suspected acute hepatitis or known chronic liver disease; HBsAg positivity; severe hepatic impairment 9. Alanine aminotransferase (ALT) ≥ 3 times the upper limit of normal (ULN) 10. Total bilirubin ≥ 2.5 times the ULN 11. Absolute neutrophil count (ANC) \< 750 cells/mm3 12. Creatinine clearance \< 50 ml/min 13. Self-reported alcohol use exceeding 21 units per week 14. Karnofsky status \< 80 15. On prohibited medications e.g. dofetilide

Outcomes

Primary Outcomes

Mortality

Maternal all-cause mortality (both groups)

Time frame: from study entry at Week 0 through post partum Week 24, to be reported at end of trial

Targeted serious adverse events (SAEs)

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)

Time frame: from study entry at Week 0 through post partum Week 12, to be reported at end of trial

PK sampling of Dolutegravir - Cl/F parameter

Oral clearance in the presence or absence of 1HP or 3HP (both groups)

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

PK sampling of Dolutegravir - AUC parameter

Area under the plasma drug concentration-time curve (AUC) in the presence or absence of 1HP or 3HP (both groups)

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

PK sampling of Dolutegravir - Ctau parameter

Trough concentration (Ctau) in the presence or absence of 1HP or 3HP (both groups)

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

Secondary Outcomes

HIV-1 RNA viral load- maternal

Maternal HIV-1 RNA viral load (copies/ml) (both groups)

Time frame: HIV viral load to be measured at Screening, Week 3, at Delivery, and post partum Week 12, to be reported at end of trial

DTG Dose selection

Dose options for DTG with 1HP or 3HP derived by simulation using nonlinear mixed effects models (both groups)

Time frame: 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.

PK sampling of RPT - AUC parameter

Area under curve (AUC) in participants taking 1HP (Group 1)

Time frame: PK sampling at Week 3 (Day 17 ) to be reported at end of trial

PK sampling of RPT - Ctau parameter

Trough concentration (Ctau) in participants taking 1HP (Group 1)

Time frame: PK sampling at Week 3 (Day 17 ) to be reported at end of trial

Adverse Events- maternal

Grade 3 or higher maternal adverse events (AE) (all groups)

Time frame: from study entry at Week 0 through post partum Week 12, to be reported at end of trial

Adverse Events- pregnancy

Grade 3 or higher pregnancy adverse events (AE) (all groups)

Time frame: from study entry at Week 0 through post partum Week 12, to be reported at end of trial

Adverse Events- infant

Grade 3 or higher infant adverse events (AE) (all groups)