A Pan-TB Regimen Targeting Host and Microbe

NCT05686356 | Active Not Recruiting Phase 2 DMC

• 4 other identifiers: AUR1-1-312242066986RIA2019AMR-2647
• Study Type: interventional
• Target: 352
• Locations: 3 countries
• Sites: 8

Brief Summary

This project will develop the first regimen meeting WHO criteria for a pan-TB indication, ie, not requiring knowledge of RIF susceptibility. The regimen will test sutezolid at 2 dose levels, with the approved anti-TB drugs bedaquiline and pretomanid, in a phase 2c trial. It will also test whether the addition of N-acetylcysteine (NAC), a re-purposed host-directed WHO essential medicine, can protect the lung and liver against oxidative damage, preserve lung function, and accelerate the eradication of MTB infection by replenishing glutathione (GSH).

Conditions

Tuberculosis

Outcome Measures

Primary Outcomes (1)

• The proportion of patients achieving durable (non-relapsing) cure

  Assessed after 1 year of post-treatment follow-up

Secondary Outcomes (12)

• The proportion of subjects with TE ALT increases, graded according to severity

  From day 1 through 4 weeks post end-of-treatment

• The proportion of subjects with TE increases in transaminases and bilirubin meeting Hy's criteria for serious liver injury

  From day 1 through 4 weeks post end-of-treatment

• The proportion of subjects with TE AEs, according to seriousness

  From day 1 through 4 weeks post end-of-treatment

• The number of TE AEs per treatment arm, according to seriousness

  From day 1 through 4 weeks post end-of-treatment

• The proportion of subjects requiring temporary or permanent treatment discontinuation due to safety or tolerability concerns

  From day 1 through 4 weeks post end-of-treatment

Other Outcomes (4)

• The proportion of subjects with non-TB cardiac or pulmonary AEs during the 18 months after TB diagnosis, according to seriousness.

  During the 18 months after TB diagnosis

• The plasma concentration (AUC) of sutezolid and its main metabolite

  Month 1

• The plasma concentration (Cmax and Cmin) of sutezolid and its main metabolite

  Month 1

Study Arms (4)

Arm 1 (S1200BP)

EXPERIMENTAL

Sutezolid 1200mg QD plus bedaquiline and pretomanid for 4 months

Drug: Sutezolid; Drug: Pretomanid; Drug: Bedaquiline

Arm 2 (S1600BP)

EXPERIMENTAL

Sutezolid 1600mg QD plus bedaquiline and pretomanid for 4 months

Drug: Sutezolid; Drug: Pretomanid; Drug: Bedaquiline

Arm 3 (S1600BPN)

EXPERIMENTAL

Sutezolid 1600mg QD plus bedaquiline pretomanid and N-acetyl cysteine for 4 months

Drug: Sutezolid; Drug: N-acetyl cysteine; Drug: Pretomanid; Drug: Bedaquiline

Arm 4 (HRZE)

ACTIVE COMPARATOR

Rifafour (2HRZE/4HR)

Combination Product: Rifafour

Interventions

Sutezolid DRUG

Sutezolid will be given at a dose of 1200mg QD in arm 1 and at a dose of 1600mg QD in arms 2 and 3.

Arm 1 (S1200BP); Arm 2 (S1600BP); Arm 3 (S1600BPN)

N-acetyl cysteine DRUG

NAC will be given at a dose of 1800 mg BID in arm 3

Also known as: NAC

Arm 3 (S1600BPN)

Pretomanid DRUG

Pretomanid will be given at its approved dose

Arm 1 (S1200BP); Arm 2 (S1600BP); Arm 3 (S1600BPN)

Bedaquiline DRUG

Bedaquiline will be given at its approved dose

Arm 1 (S1200BP); Arm 2 (S1600BP); Arm 3 (S1600BPN)

Rifafour COMBINATION_PRODUCT

Fixed dose combination tablets for TB treatment will be given at approved doses

Arm 4 (HRZE)

Eligibility Criteria

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

You may qualify if:

• Aged 18 to 65 years
• Willing and able to provide signed written consent prior to undertaking any trial-related procedures, or, in the case of illiteracy, witnessed oral consent
• Body weight (in light clothing without shoes) between 30 and 90 kg.
• Radiographic evidence of pulmonary tuberculosis
• Positive Xpert TB/RIF (original or Ultra) for MTB
• RIF susceptibility diagnosed by Xpert TB/RIF, with subsequent culture confirmation
• If sexually active, willing to use an effective contraceptive method for the duration of tuberculosis treatment
• HIV-1 seronegative, or if HIV-1 seropositive, CD4 T cell count ≥100/µl and either receiving ART or willing to start ART during study participation
• SARS-CoV-2 PCR or antigen test negative, or if positive, either fully vaccinated against Covid-19 or with D-dimer \<0.8 ug/ml
• Willing to adhere to a diet excluding tyramine-rich foods (certain mold-ripened cheeses and cured meats), and to avoid eating grapefruits and pomelos

You may not qualify if:

• Any condition for which participation in the trial, as judged by the investigator, could compromise the well-being of the subject or prevent, limit or confound protocol specified assessments
• Current or imminent (within 24 hr) treatment for malaria.
• Pregnant or nursing
• Is critically ill, and in the judgment of the investigator has a diagnosis likely to result in death during the trial or the follow-up period.
• TB meningitis or spondylitis, or other forms of severe tuberculosis with high risk of a poor outcome as judged by the investigator.
• History of allergy or hypersensitivity to any of the trial therapies or related substances.
• Having participated in other clinical trials with investigational agents within 8 weeks prior to trial start or currently enrolled in an investigational trial.
• Prior TB treatment in the preceding 6 months
• Angina pectoris requiring treatment with nitroglycerin or other nitrates
• Cardiac arrhythmia requiring medication, or any clinically significant ECG abnormality, in the opinion of the investigator
• History of unstable Diabetes Mellitus requiring hospitalization for hyper- or hypo-glycaemia within the past year prior to start of screening.
• Use of systemic corticosteroids within the past 28 days.
• Patients requiring treatment with medications not compatible with rifampin, such as HIV-1 protease inhibitors
• Patients requiring treatment with antidepressants, including MAO inhibitors and SSRIs.
• Subjects with any of the following abnormal laboratory values:

Sponsors & Collaborators

• The Aurum Institute NPC: lead
• Ludwig-Maximilians - University of Munich: collaborator
• Stichting Katholieke Universiteit: collaborator
• Wits Health Consortium (Pty) Ltd: collaborator
• Instituto Nacional de Saúde, Mozambique: collaborator
• National Institute for Medical Research, Tanzania: collaborator
• University of Stellenbosch: collaborator
• Sequella, Inc.: collaborator
• Global Alliance for TB Drug Development: collaborator

Study Sites (8)

Instituto Nacional de Saúde

Maputo, Mozambique

Location

Clinical HIV Research Unit

Durban, Durban, 4015, South Africa

Location

Clinical HIV Research Unit

Johannesburg, Gauteng, 2092, South Africa

Location

The Aurum Institute: Tembisa Clinical Research Centre

Tembisa, Gauteng, 1632, South Africa

Location

The Aurum Institute, Gavin J Churchyard Legacy Centre (Klerksdorp Clinical Research Centre)

Klerksdorp, Klerksdorp, 2571, South Africa

Location

The Aurum Institute, Rustenburg Clinical Research Centre

Rustenburg, North West Provice, 0299, South Africa

Location

TASK Eden

George, Western Cape, 6529, South Africa

Location

NIMR-Mbeya Medical Research Centre

Mbeya, Tanzania

Location

MeSH Terms

Conditions

Tuberculosis

Interventions

PNU-100480; Acetylcysteine; pretomanid; bedaquiline

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Cysteine; Amino Acids, Sulfur; Sulfur Compounds; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Professor Robert Wallis, MD

  The Aurum Institute NPC

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 18, 2022
• First Posted: January 17, 2023
• Study Start: July 28, 2023
• Primary Completion: January 1, 2026
• Study Completion: January 1, 2026
• Last Updated: May 28, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will share

Locations

MO (1); TA (1); ZA (6)