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 (DOLPHIN Moms)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Pregnancy; HIV Seropositivity; Tuberculosis Infection
• Intervention / Treatment: Drug: Rifapentine; Drug: Isoniazid

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 Type: Interventional
• Enrollment (Estimated): 252
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• South Africa
  • Cape Town
    • Cape Town, Cape Town, South Africa, 7505
      • Family Centre for Research with Ubuntu (FAMCRU)
  • Gauteng
    • Tembisa, Gauteng, South Africa, 1632
      • The Aurum Institute: Tembisa Clinical Research Centre
  • North West
    • Klerksdorp, North West, South Africa, 2571
      • Peri Natal HIV Research Unit - Klerksdorp Tshepong Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1: One month of daily isoniazid and rifapentine (4 weeks); DTG 50 mg orally BIDDTG 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 BIDDTG 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: The Aurum Institute NPC
• Collaborators: Johns Hopkins University; Weill Medical College of Cornell University; University of Washington
• Investigators: Principal Investigator: Dr Vaneshree Govender, Aurum Institute

Study record dates

Study Major Dates

• Study Start (Actual): January 17, 2024
• Primary Completion (Actual): October 24, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: October 26, 2021
• First Submitted That Met QC Criteria: November 4, 2021
• First Posted (Actual): November 16, 2021

Study Record Updates

• Last Update Posted (Estimated): December 12, 2025
• Last Update Submitted That Met QC Criteria: December 5, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: pharmacokinetic; Dolutegravir; 3HP; Rifapentine; TB preventive treatment
• Additional Relevant MeSH Terms: Blood-Borne Infections; Latent Infection; Urogenital Diseases; Genital Diseases; Immune System Diseases; Infections; RNA Virus Infections; Virus Diseases; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Actinomycetales Infections; Mycobacterium Infections; HIV Infections; Tuberculosis; Latent Tuberculosis; HIV Seropositivity; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Hydrazines; Isonicotinic Acids; Acids, Heterocyclic; Isoniazid; rifapentine
• Other Study ID Numbers: IRB00299011; 3HP-MOMS-AUR1-6-351 (Other Identifier: The Aurum Institute)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No