DOLPHIN Moms: 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

Sponsor

The Aurum Institute NPC (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05122026

Collaborator

Johns Hopkins University (Other), Weill Medical College of Cornell University (Other), University of Washington (Other)

252

Enrollment

Location

Arms

26.1

Anticipated Duration (Months)

9.7

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
HIV Seropositivity Pregnancy Tuberculosis Infection	Drug: Rifapentine Drug: Isoniazid	Phase 1/Phase 2

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

252 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Participants will be randomized 1:1 to receive either 1HP or 3HPParticipants will be randomized 1:1 to receive either 1HP or 3HP

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

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

Anticipated Study Start Date :

Oct 30, 2022

Anticipated Primary Completion Date :

Oct 30, 2024

Anticipated Study Completion Date :

Dec 31, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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	Drug: Rifapentine As included in arm/group description Other Names: Priftin Drug: Isoniazid As included in arm/group description Other Names: Winthrop Isoniazid
Experimental: 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	Drug: Rifapentine As included in arm/group description Other Names: Priftin Drug: Isoniazid As included in arm/group description Other Names: Winthrop Isoniazid

Arm

Intervention/Treatment

Experimental: 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

Drug: Rifapentine

As included in arm/group description

Other Names:

Priftin

Drug: Isoniazid

As included in arm/group description

Other Names:

Winthrop Isoniazid

Experimental: 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

Drug: Rifapentine

As included in arm/group description

Other Names:

Priftin

Drug: Isoniazid

As included in arm/group description

Other Names:

Winthrop Isoniazid

Outcome Measures

Primary Outcome Measures

Mortality [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) [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 [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 - AUC parameter [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)
PK sampling of Dolutegravir - Ctau parameter [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)

Secondary Outcome Measures

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]
Maternal HIV-1 RNA viral load (copies/ml) (both groups)
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.]
Dose options for DTG with 1HP or 3HP derived by simulation using nonlinear mixed effects models (both groups)
PK sampling of RPT - AUC parameter [PK sampling at Week 3 (Day 17 ) to be reported at end of trial]
Area under curve (AUC) in participants taking 1HP (Group 1)
PK sampling of RPT - Ctau parameter [PK sampling at Week 3 (Day 17 ) to be reported at end of trial]
Trough concentration (Ctau) in participants taking 1HP (Group 1)
Adverse Events- maternal [from study entry at Week 0 through post partum Week 12, to be reported at end of trial]
Grade 3 or higher maternal adverse events (AE) (all groups)
Adverse Events- pregnancy [from study entry at Week 0 through post partum Week 12, to be reported at end of trial]
Grade 3 or higher pregnancy adverse events (AE) (all groups)
Adverse Events- infant [from Delivery through post partum Week 24, to be reported at end of trial]
Grade 3 or higher infant adverse events (AE) (all groups)
HIV infection- infant [from Delivery through post partum Week 24, to be reported at end of trial]
Infant HIV infection (all groups)
Infant growth parameters- HAZ [from Delivery through post partum Week 24, to be reported at end of trial]
Height-for-age z-score (all groups)
Infant growth parameters- WAZ [from Delivery through post partum Week 24, to be reported at end of trial]
Weight-for-age z-score (WAZ) (all groups)
Infant growth parameters- HCAZ [from Delivery through post partum Week 24, to be reported at end of trial]
Head circumference-for-age z-score (HCAZ) (all groups)
TB disease-maternal [from study entry at Week 0 through post partum Week 24, to be reported at end of trial]
confirmed maternal TB disease (all groups)
TB disease-infant [from Delivery through post partum Week 24, to be reported at end of trial]
confirmed or suspected infant TB disease (all groups)
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]
Proportion of doses taken for 1HP and 3HP regimens

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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