Pharmacokinetics and Safety of Double-dose Dolutegravir When Used With Rifapentine for HIV-associated Tuberculosis

NCT05630872 | Completed Phase 2 Results FDA Drug

• 1 other identifier: A5406
• Study Type: interventional
• Target: 30
• Locations: 2 countries
• Sites: 4

Brief Summary

A5406 hypothesized that dolutegravir (DTG) 50 mg taken twice daily provides adequate exposures to maintain viral suppression when dosed with rifapentine (RPT) 1200 mg for HIV-associated tuberculosis (TB).

Conditions

HIV-associated Tuberculosis

Outcome Measures

Primary Outcomes (1)

• Model-simulated 5th Percentile and Corresponding 95% Confidence Interval of DTG Cmin at 50 mg BID When Co-administered With Daily RPT 1200 mg Plus HZM

  Model-simulated 5th percentile and corresponding 95% confidence interval of dolutegravir (DTG) minimum concentrations (Cmin) at 50 mg BID (twice daily) when co-administered with daily rifapentine (RPT) 1200 mg plus HZM (isoniazid, pyrazinamide, and ethambutol). Pharmacokinetic parameters were estimated using nonlinear mixed-effects modelling (FOCE-I). The final model was used to simulate 10000 individuals, incorporating parameter uncertainty. Covariates included fat-free mass on disposition parameters, rifapentine on clearance and bioavailability, and baseline unconjugated bilirubin on clearance. Measurements were taken at steady state, which was assumed to be achieved after at least 5 half-lives.

  Measured at week 8 and week 21. Samples were drawn pre-dose and at 1, 2, 4, 6, 8-10, and 24 hours (but prior to next dose) post-dosing.

Secondary Outcomes (10)

• DTG Minimum Concentration (Cmin)

  Measured at week 8 and week 21; Samples were drawn pre-dose and at 1, 2, 4, 6, 8-10, and 24 hours (but prior to next dose) post-dosing.

• DTG Maximum Concentration (Cmax)

  Measured at week 8 and week 21; Samples were drawn pre-dose and at 1, 2, 4, 6, 8-10, and 24 hours (but prior to next dose) post-dosing.

• DTG Area Under the Concentration-time Curve (AUC0-24)

  Measured at week 8 and week 21; Samples were drawn pre-dose and at 1, 2, 4, 6, 8-10, and 24 hours (but prior to next dose) post-dosing.

• DTG Clearance

  Measured at week 8 and week 21; Samples were drawn pre-dose and at 1, 2, 4, 6, 8-10, and 24 hours (but prior to next dose) post-dosing.

• DTG Terminal Half Life

  Measured at week 8 and week 21; Samples were drawn pre-dose and at 1, 2, 4, 6, 8-10, and 24 hours (but prior to next dose) post-dosing.

Study Arms (1)

Adults with HIV and newly diagnosed DS-TB not currently on ART

EXPERIMENTAL

Participants received daily rifapentine-moxifloxacin plus isoniazid and pyrazinamide for 8 weeks followed by daily rifapentine-moxifloxacin plus isoniazid for 9 weeks (referred to as 2HPZM/2HPM) for anti-TB therapy at study entry. DTG-based ART at 50 mg BID was started after 6 weeks of TB therapy and continued for 2 weeks after completion of TB therapy. Two weeks after completion of TB therapy DTG was reduced to standard dose 50 mg QD.

Drug: Dolutegravir (DTG) 50 mg orally BID (~12 hours apart) plus TDF/3TC; Drug: DTG 50 mg orally QD plus TDF/3TC; Drug: 2HPZM; Drug: 2HPM

Interventions

2HPZM DRUG

Daily regimen of rifapentine 1200mg, moxifloxacin 400mg, isoniazid 300mg, and pyrazinamide at standard doses adjusted for body weight from study entry through study week 8.

Adults with HIV and newly diagnosed DS-TB not currently on ART

Dolutegravir (DTG) 50 mg orally BID (~12 hours apart) plus TDF/3TC DRUG

Dolutegravir (DTG) 50 mg orally BID (\~12 hours apart) plus TDF/3TC, from study week 6 until 2 weeks after completion of TB treatment: Morning dose DTG 50 mg QD plus TDF/3TC from study-supplied ART regimen. Evening dose: DTG 50 mg orally QD from study-supplied source.

Adults with HIV and newly diagnosed DS-TB not currently on ART

DTG 50 mg orally QD plus TDF/3TC DRUG

DTG 50 mg orally QD plus TDF/3TC from two weeks after completion of TB treatment to end of study (week 48).

Adults with HIV and newly diagnosed DS-TB not currently on ART

2HPM DRUG

Daily regimen of rifapentine 1200mg, moxifloxacin 400mg, and isoniazid 300mg from study week 8 through study week 17.

Adults with HIV and newly diagnosed DS-TB not currently on ART

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Weight ≥40 kg.
• Ability and willingness of participant or legal guardian/representative to provide informed consent.
• Documentation of HIV-1 status.
• CD4+ cell count ≥50 cells/mm3 obtained within 30 days prior to study entry at any network-approved non-US laboratory that is IQA certified.
• ART-naïve or not on ART for 12 consecutive weeks prior to TB diagnosis.
• Willingness and eligibility to start DTG-based ART at 6 weeks, with a window of ±1 week, after starting TB treatment, with no intention to change ART for the duration of the study.
• Documentation of pulmonary TB.
• Willingness to start 2HPZM/2HPM therapy for DS-TB.
• The following laboratory values obtained within 30 days prior to study entry:
• Absolute neutrophil count (ANC) \>750 cells/mm3
• Hemoglobin ≥7.4 g/dL
• Platelet count ≥50,000/mm3
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) \<2.5 X the upper limit of normal (ULN)
• Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) \<2.5 x ULN
• Total bilirubin ≤1.5 x ULN

You may not qualify if:

• Breastfeeding, pregnant, or plans to become pregnant.
• Known allergy/sensitivity or any hypersensitivity to components of the study drugs, or their formulations.
• Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
• Requirement for ongoing use of drugs that are known to have significant drug-drug interactions with DTG or RPT.
• Known history of acute intermittent porphyria.
• Previous treatment for active TB disease within 6 months preceding initiation of study drugs.
• More than 5 days of treatment directed against active TB for the current TB episode preceding study entry.
• At the time of study entry, documentation of an M. tuberculosis isolate from the current or previous treatment episode known to be resistant to RIF or INH.
• Known history of prolonged QT syndrome.
• Known cirrhosis, a history of decompensated liver disease (ascites, hepatic encephalopathy, or esophageal varices).
• Documentation of severe opportunistic infections, in the opinion of the site investigator, within 3 months of study entry.
• Documentation of severe extra-pulmonary TB (e.g., meningitis, osteomyelitis, disseminated TB) at the time of screening.
• Acute gout at the time of screening.

Sponsors & Collaborators

• ViiV Healthcare: collaborator
• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Mylan Inc.: collaborator

Study Sites (4)

University of Cape Town Lung Institute (UCTLI) CRS (Site # 31792)

Mowbray, Cape Town, Western Cape, 7700, South Africa

Location

Durban International CRS (Site # 11201)

Wentworth, Durban, 4052, South Africa

Location

South African Tuberculosis Vaccine Initiative (SATVI) CRS (Site # 31793)

Worcester, Western Cape, 6850, South Africa

Location

Thai Red Cross AIDS Research Centre (TRC-ARC) CRS (Site # 31802)

Bangkok, 10330, Thailand

Location

Related Links

• The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017
• Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), Version 2.0

MeSH Terms

Interventions

dolutegravir

Results Point of Contact

• Title: ACTG Clinicaltrials.gov Coordinator
• Organization: ACTG Network Coordinating Center, Social and Scientific Systems, a DLH Holdings Company

ACTGCT.gov@dlhcorp.com

(301) 628-3348

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 18, 2022
• First Posted: November 30, 2022
• Study Start: February 13, 2024
• Primary Completion: May 7, 2025
• Study Completion: November 12, 2025
• Last Updated: July 20, 2026
• Results First Posted: July 20, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Beginning 3 months following publication and available throughout period of funding of the ACTG (Advancing Clinical Therapeutics Globally) by NIH.
• Access Criteria: * With whom? Researchers who provide a methodologically sound proposal for use of the data that is approved by the ACTG. * For what types of analyses? To achieve aims in the proposal approved by the ACTG. * By what mechanism will data be made available? Researchers may submit a request for access to data using the AIDS Clinical Trials Group "Data Request" form at: https://actgnetwork.org/submit-a-proposal/. Researchers of approved proposals will need to sign an ACTG Data Use Agreement before receiving the data.

Locations

ZA (3); TH (1)