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

Pregnancy Clinical Trial

— DOLPHIN Moms  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05122026
• Other study ID #: IRB00299011
• Secondary ID: 3HP-MOMS-AUR1-6-
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: January 17, 2024
• Est. completion date: March 31, 2025

Study information

• Verified date: March 2024
• Source: The Aurum Institute NPC
• Contact: Jayajothi Moodley
• Phone: +27826593766
• Email: JMoodley[@]auruminstitute.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 252
• Est. completion date: March 31, 2025
• Est. primary completion date: December 31, 2024
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• HIV Seropositivity
• Latent Tuberculosis
• Pregnancy
• Tuberculosis
• Tuberculosis Infection

Intervention

Drug:
• Rifapentine
As included in arm/group description
• Isoniazid
As included in arm/group description

Locations

Country	Name	City	State
South Africa	FAMily Centre for Research with Ubuntu (FAMCRU)	Cape Town
South Africa	Peri Natal HIV Research Unit - Klerksdorp Tshepong Hospital	Klerksdorp	North-West
South Africa	The Aurum Institute: Tembisa Clinical Research Centre	Tembisa	Gauteng

Sponsors (4)

Lead Sponsor	Collaborator
The Aurum Institute NPC	Johns Hopkins University, University of Washington, Weill Medical College of Cornell University

Country where clinical trial is conducted

South Africa, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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.
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	HIV infection- infant	Infant HIV infection (all groups)	from Delivery through post partum Week 24, to be reported at end of trial
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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