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

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

Study Overview

• Status: Recruiting
• Conditions: HIV-associated Tuberculosis
• Intervention / Treatment: 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

Detailed Description

This is an open-label, single arm, phase II, multicenter PK study to investigate the effect of daily RPT 1200 mg on DTG exposure in participants with HIV-associated TB. Adults with HIV with newly diagnosed DS-TB who are not currently on ART will be recruited around the time of DS TB diagnosis. At study entry, the 2HPZM/2HPM regimen will be initiated for anti-tuberculosis (anti-TB) therapy and continued for 17 weeks.

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• South Africa
  • Cape Town, Western Cape
    • Mowbray, Cape Town, Western Cape, South Africa, 7700
      • Recruiting
      • University of Cape Town Lung Institute (UCTLI) CRS (Site # 31792)
      • Contact: Catrien C Drinkwater; Phone Number: +27 21-4066850; Email: catrien.drinkwater@uct.ac.za
  • Durban RSA
    • Westridge, Durban RSA, South Africa, 4091
      • Not yet recruiting
      • Durban International CRS (Site # 11201)
      • Contact: Rosie Mngqibisa; Phone Number: 27-31-2611093; Email: mngqibisa@ecarefoundation.com
  • Western Province
    • Worcester, Western Province, South Africa, 6850
      • Not yet recruiting
      • South African Tuberculosis Vaccine Initiative (SATVI) CRS (Site # 31793)
      • Contact: Lynnett Stone; Phone Number: +27 23-342-5400; Email: lynnett.stone@uct.ac.za
• Thailand
  • Bangkok, Thailand, 6850
    • Not yet recruiting
    • Thai Red Cross AIDS Research Centre (TRC-ARC) CRS (Site # 31802)
    • Contact: Parawee Thongpaeng; Phone Number: 66-2-6523040; Email: parawee.t@hivnat.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Individuals ≥18 years of age at study entry.
2. Weight ≥40 kg.
3. Body mass index (BMI) >18.5 kg/m2.
4. Ability and willingness of participant or legal guardian/representative to provide informed consent.
5. Documentation of HIV-1 status.
6. CD4+ cell count ≥100 cells/mm3 obtained within 30 days prior to study entry at any network-approved non-US laboratory that is IQA certified.
7. ART-naïve or not on ART for 12 consecutive weeks prior to TB diagnosis.
8. 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.
9. Documentation of pulmonary TB.
10. Willingness to start 2HPZM/2HPM therapy for DS-TB.

11. 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
    • Creatinine <1.3 x ULN
12. For participants who can become pregnant, negative serum or urine pregnancy test at screening within 30 days prior to entry and within 48 hours prior to entry.
13. Participants who can become pregnant must agree not to participate in the conception process and if participating in sexual activity that could lead to pregnancy, must agree to use one reliable nonhormonal method of contraception.
14. Documentation of Karnofsky performance score ≥50 within 30 days prior to entry.

Exclusion Criteria:

1. Breastfeeding, pregnant, or plans to become pregnant.
2. Known allergy/sensitivity or any hypersensitivity to components of the study drugs, or their formulations.
3. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
4. Requirement for ongoing use of drugs that are known to have significant drug-drug interactions with DTG or RPT.
5. Known history of acute intermittent porphyria.
6. Previous treatment for active TB disease.
7. More than 5 days of treatment directed against active TB for the current TB episode preceding study entry.
8. 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.
9. Known history of prolonged QT syndrome.
10. Known cirrhosis, a history of decompensated liver disease (ascites, hepatic encephalopathy, or esophageal varices).
11. Documentation of severe opportunistic infections, in the opinion of the site investigator, within 3 months of study entry.
12. Documentation of severe extra-pulmonary TB (e.g., meningitis, osteomyelitis, disseminated TB) at the time of screening.
13. Acute gout at the time of screening.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Adults with HIV and newly diagnosed DS-TB not currently on ART; Participants will receive 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-tuberculosis (anti-TB) therapy at study entry. DTG-based ART at 50 mg twice daily (BID) will be started after 6 weeks of TB therapy and will be continued for 2 weeks after completion of TB therapy. Two weeks after completion of TB therapy DTG will be reduced to standard dose 50 mg once daily (QD).

Drug: Dolutegravir (DTG) 50 mg orally BID (~12 hours apart) plus TDF/3TC; 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 ARV regimen. Evening dose: DTG 50 mg orally QD from study-supplied source.; Drug: DTG 50 mg orally QD plus TDF/3TC; DTG 50 mg orally QD plus TDF/3TC from two weeks after completion of TB treatment to end of study (week 48).; Drug: 2HPZM; Daily rifapentine-moxifloxacin plus isoniazid and pyrazinamide regimen; Drug: 2HPM; Daily rifapentine-moxifloxacin plus isoniazid regimen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Model-simulated 5th percentile and corresponding 95% confidence interval of DTG minimum concentrations (Cmin) at 50 mg BID when co-administered with daily RPT 1200 mg plus HZM	48 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DTG minimum concentration (Cmin)	Model-derived participant- and week-specific estimate of DTG Cmin	48 Weeks
DTG minimum concentration (Cmax)	Model-derived participant- and week-specific estimate of DTG Cmax	48 Weeks
DTG area under the concentration-time curve (AUC0-24)	Model-derived participant- and week-specific estimate of DTG AUC0-24	48 Weeks
Number of participants who experience Grade 3 or higher AEs		Weeks 6-17
Number of participants who have a diagnosis of rifamycin hypersensitivity		Weeks 6-17
Number of participants who experience ALT ≥3xULN with symptoms/jaundice or ALT ≥5xULN		Weeks 6-17
Number of participants who prematurely discontinue study drugs DTG and/or RPT		Weeks 6-17
Proportion of participants with HIV-1 viral load below 50 copies/mL		Weeks 10, 14, 21, and 30

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: ViiV Healthcare; Mylan Inc.

Study record dates

Study Major Dates

• Study Start (Actual): February 13, 2024
• Primary Completion (Estimated): October 31, 2024
• Study Completion (Estimated): May 31, 2025

Study Registration Dates

• First Submitted: November 18, 2022
• First Submitted That Met QC Criteria: November 18, 2022
• First Posted (Actual): November 30, 2022

Study Record Updates

• Last Update Posted (Estimated): March 4, 2024
• Last Update Submitted That Met QC Criteria: February 29, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; HIV Integrase Inhibitors; Integrase Inhibitors; Lamivudine; Dolutegravir
• Other Study ID Numbers: A5406

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie results in the publication, after deidentification.
• IPD Sharing Time Frame: Beginning 3 months following publication and available throughout period of funding of the AIDS Clinical Trials Group by NIH.
• IPD Sharing Access Criteria: With whom? Researchers who provide a methodologically sound proposal for use of the data that is approved by the AIDS Clinical Trials Group.; For what types of analyses? To achieve aims in the proposal approved by the AIDS Clinical Trials Group.; 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 AIDS Clinical Trials Group Data Use Agreement before receiving the data.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

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