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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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HIV Seropositivity, Pregnancy, Tuberculosis Infection

Intervention / Treatment
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* Drug: Rifapentine
* Drug: Isoniazid


Participation Criteria
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Eligibility Criteria
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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 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomized 1:1 to receive either 1HP or 3HP
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: One month of daily isoniazid and rifapentine (4 weeks)<br>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 | Drug: Rifapentine<br>* As included in arm/group description<br>* Other names: Priftin;Drug: Isoniazid<br>* As included in arm/group description<br>* Other names: Winthrop Isoniazid;|
| Experimental: Arm 2: Three months of once-weekly isoniazid and rifapentine (12 weeks)<br>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 | Drug: Rifapentine<br>* As included in arm/group description<br>* Other names: Priftin;Drug: Isoniazid<br>* As included in arm/group description<br>* Other names: Winthrop Isoniazid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | Maternal all-cause mortality (both groups) | 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) | 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) | 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) | 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) | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HIV-1 RNA viral load- maternal | Maternal HIV-1 RNA viral load (copies/ml) (both groups) | 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) | 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) | 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) | 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) | 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) | 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) | from Delivery through post partum Week 24, to be reported at end of trial | 
| HIV infection- infant | Infant HIV infection (all groups) | from Delivery through post partum Week 24, to be reported at end of trial | 
| Infant growth parameters- HAZ | Height-for-age z-score (all groups) | from Delivery through post partum Week 24, to be reported at end of trial | 
| Infant growth parameters- WAZ | Weight-for-age z-score (WAZ) (all groups) | from Delivery through post partum Week 24, to be reported at end of trial | 
| Infant growth parameters- HCAZ | Head circumference-for-age z-score (HCAZ) (all groups) | from Delivery through post partum Week 24, to be reported at end of trial | 
| TB disease-maternal | confirmed maternal TB disease (all groups) | from study entry at Week 0 through post partum Week 24, to be reported at end of trial | 
| TB disease-infant | confirmed or suspected infant TB disease (all groups) | from Delivery through post partum Week 24, to be reported at end of trial | 
| Treatment adherence- HP | Proportion of doses taken for 1HP and 3HP regimens | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dolutegravir, 3HP, Rifapentine, pharmacokinetic, TB preventive treatment