Clinical trial NCT05122026: 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
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: HIV Seropositivity
Pregnancy
Tuberculosis Infection
Keywords: Dolutegravir
3HP
Rifapentine
pharmacokinetic
TB preventive treatment
Lead sponsor: The Aurum Institute NPC
Sponsor class: OTHER
Collaborators: name: Johns Hopkins University
name: Weill Medical College of Cornell University
name: University of Washington
First posted: 2021-11-16
Enrollment: 252
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Participants will be randomized 1:1 to receive either 1HP or 3HP
Primary purpose: PREVENTION

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Mortality
timeFrame: from study entry at Week 0 through post partum Week 24, to be reported at end of trial
measure: Targeted serious adverse events (SAEs)
timeFrame: from study entry at Week 0 through post partum Week 12, to be reported at end of trial
measure: PK sampling of Dolutegravir - Cl/F parameter
timeFrame: 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
measure: PK sampling of Dolutegravir - AUC parameter
timeFrame: 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
measure: PK sampling of Dolutegravir - Ctau parameter
timeFrame: 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:
measure: HIV-1 RNA viral load- maternal
timeFrame: HIV viral load to be measured at Screening, Week 3, at Delivery, and post partum Week 12, to be reported at end of trial
measure: DTG Dose selection
timeFrame: 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.
measure: PK sampling of RPT - AUC parameter
timeFrame: PK sampling at Week 3 (Day 17 ) to be reported at end of trial
measure: PK sampling of RPT - Ctau parameter
timeFrame: PK sampling at Week 3 (Day 17 ) to be reported at end of trial
measure: Adverse Events- maternal
timeFrame: from study entry at Week 0 through post partum Week 12, to be reported at end of trial
measure: Adverse Events- pregnancy
timeFrame: from study entry at Week 0 through post partum Week 12, to be reported at end of trial
measure: Adverse Events- infant
timeFrame: from Delivery through post partum Week 24, to be reported at end of trial
measure: HIV infection- infant
timeFrame: from Delivery through post partum Week 24, to be reported at end of trial
measure: Infant growth parameters- HAZ
timeFrame: from Delivery through post partum Week 24, to be reported at end of trial
measure: Infant growth parameters- WAZ
timeFrame: from Delivery through post partum Week 24, to be reported at end of trial
measure: Infant growth parameters- HCAZ
timeFrame: from Delivery through post partum Week 24, to be reported at end of trial
measure: TB disease-maternal
timeFrame: from study entry at Week 0 through post partum Week 24, to be reported at end of trial
measure: TB disease-infant
timeFrame: from Delivery through post partum Week 24, to be reported at end of trial
measure: Treatment adherence- HP
timeFrame: 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
Other outcomes:
Locations:
city: Tembisa
country: South Africa
facility: The Aurum Institute: Tembisa Clinical Research Centre
state: Gauteng
city: Klerksdorp
country: South Africa
facility: Peri Natal HIV Research Unit - Klerksdorp Tshepong Hospital
state: North-West
city: Cape Town
country: South Africa
facility: FAMily Centre for Research with Ubuntu (FAMCRU)
Study officials:
affiliation: Aurum Institute
name: Dr Vaneshree Govender
role: PRINCIPAL_INVESTIGATOR
References: