A Pan-TB Regimen Targeting Host and Microbe (panTB-HM)

A Novel 4-month Pan-TB Regimen Targeting Both Host and Microbe (panTB-HM)

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).

Study Overview

• Status: Recruiting
• Conditions: Tuberculosis
• Intervention / Treatment: Drug: Sutezolid; Drug: Pretomanid; Drug: Bedaquiline; Drug: N-acetyl cysteine; Combination product: Rifafour

• Study Type: Interventional
• Enrollment (Estimated): 352
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Professor Robert Wallis; Phone Number: +1 (860) 271-6745; Email: rwallis@auruminstitute.org
• Study Contact Backup: Name: Mr Don L Mudzengi; Phone Number: +27833697946; Email: dmudzengi@auruminstitute.org

Study Locations

• Mozambique
  • Maputo, Mozambique
    • Recruiting
    • Instituto Nacional de Saúde
    • Contact: Dr Emilia Fumane, MD; Email: emilia.fumane@ins.gov.mz
    • Principal Investigator: Celso Khosa, MD
• South Africa
  • Durban, South Africa, 4015
    • Recruiting
    • Clinical HIV Research Unit
    • Contact: Shakira Dr Rajaram; Phone Number: +27824221631; Email: shrajaram@witshealth.co.za
    • Contact: Nonhlanhla Gahima; Phone Number: +27877022581; Email: ngahima@witshealth.co.za
    • Principal Investigator: Shakira Rajaram, MD
  • Klerksdorp, South Africa, 2571
    • Not yet recruiting
    • The Aurum Institute, Gavin J Churchyard Legacy Centre (Klerksdorp Clinical Research Centre)
    • Contact: Mgcini Moyo, MD; Phone Number: +27615218350; Email: mmoyo@auruminstitute.org
    • Principal Investigator: Mgcini Moyo, MD
  • Gauteng
    • Johannesburg, Gauteng, South Africa, 2092
      • Recruiting
      • Clinical HIV Research Unit
      • Contact: Elizabeth Monari; Phone Number: +27812863310; Email: emonari@witshealth.co.za
      • Contact: Mohammed Dr Rassool, MD; Phone Number: +2711 276 8800; Email: mrassool@witshealth.co.za
      • Principal Investigator: Mohammed Dr Rassool, MD
    • Tembisa, Gauteng, South Africa, 1632
      • Recruiting
      • The Aurum Institute: Tembisa Clinical Research Centre
      • Contact: Don Mudzengi, MSc; Phone Number: +27 83 369 7946; Email: dmudzengi@auruminstitute.org
      • Contact: Salome Dr Charalambous, MD; Phone Number: +27 82 856 1146; Email: scharalambous@auruminstitute.org
      • Principal Investigator: Salome Charalambous, MD
  • North West Provice
    • Rustenburg, North West Provice, South Africa, 0299
      • Not yet recruiting
      • The Aurum Institute, Rustenburg Clinical Research Centre
      • Contact: William Brumskine, MD; Phone Number: +27723343575; Email: wbrumskine@auruminstitute.org
      • Principal Investigator: William Brumskine, MD
  • Western Cape
    • George, Western Cape, South Africa, 6529
      • Recruiting
      • TASK Eden
      • Contact: Alida van Deventer; Phone Number: +27448733395; Email: ida@task.org.za
      • Contact: Belinda Van Rooyen; Phone Number: +27448733395; Email: belinda.vr@task.org.za
      • Principal Investigator: Louis Botha, MD
• Tanzania
  • Mbeya, Tanzania
    • Recruiting
    • NIMR-Mbeya Medical Research Centre
    • Contact: Dr Nyanda Ntinginya, MD, Phd; Phone Number: +255 25 2503364; Email: nelias@nimr-mmrc.org
    • Contact: Dr Issa Sabi, MD, PhD; Email: isabi@nimr-mmrc.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Aged 18 to 65 years
2. Willing and able to provide signed written consent prior to undertaking any trial-related procedures, or, in the case of illiteracy, witnessed oral consent
3. Body weight (in light clothing without shoes) between 30 and 90 kg.
4. Radiographic evidence of pulmonary tuberculosis
5. Positive Xpert TB/RIF (original or Ultra) for MTB
6. RIF susceptibility diagnosed by Xpert TB/RIF, with subsequent culture confirmation
7. If sexually active, willing to use an effective contraceptive method for the duration of tuberculosis treatment
8. 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
9. 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
10. Willing to adhere to a diet excluding tyramine-rich foods (certain mold-ripened cheeses and cured meats), and to avoid eating grapefruits and pomelos

Exclusion Criteria:

1. 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
2. Current or imminent (within 24 hr) treatment for malaria.
3. Pregnant or nursing
4. 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.
5. TB meningitis or spondylitis, or other forms of severe tuberculosis with high risk of a poor outcome as judged by the investigator.
6. History of allergy or hypersensitivity to any of the trial therapies or related substances.
7. Having participated in other clinical trials with investigational agents within 8 weeks prior to trial start or currently enrolled in an investigational trial.
8. Prior TB treatment in the preceding 6 months
9. Angina pectoris requiring treatment with nitroglycerin or other nitrates
10. Cardiac arrhythmia requiring medication, or any clinically significant ECG abnormality, in the opinion of the investigator
11. History of unstable Diabetes Mellitus requiring hospitalization for hyper- or hypo-glycaemia within the past year prior to start of screening.
12. Use of systemic corticosteroids within the past 28 days.
13. Patients requiring treatment with medications not compatible with rifampin, such as HIV-1 protease inhibitors
14. Patients requiring treatment with antidepressants, including MAO inhibitors and SSRIs.

15. Subjects with any of the following abnormal laboratory values:

    1. HBsAg positive
    2. creatinine >2 mg/dL
    3. hemoglobin <8 g/dL
    4. platelets <100x109 cells/L
    5. serum potassium <3.5 mM/L
    6. alanine aminotransferase (ALT) ≥2.0 x ULN
    7. alkaline phosphatase (AP) >5.0 x ULN
    8. total bilirubin >1.5 mg/dL
    9. random blood glucose >200 mg/dL

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1 (S1200BP); Sutezolid 1200mg QD plus bedaquiline and pretomanid for 4 months	Drug: Sutezolid; 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.; Drug: Pretomanid; Pretomanid will be given at its approved dose; Drug: Bedaquiline; Bedaquiline will be given at its approved dose
Experimental: Arm 2 (S1600BP); Sutezolid 1600mg QD plus bedaquiline and pretomanid for 4 months	Drug: Sutezolid; 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.; Drug: Pretomanid; Pretomanid will be given at its approved dose; Drug: Bedaquiline; Bedaquiline will be given at its approved dose
Experimental: Arm 3 (S1600BPN); Sutezolid 1600mg QD plus bedaquiline pretomanid and N-acetyl cysteine for 4 months	Drug: Sutezolid; 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.; Drug: Pretomanid; Pretomanid will be given at its approved dose; Drug: Bedaquiline; Bedaquiline will be given at its approved dose; Drug: N-acetyl cysteine; NAC will be given at a dose of 1800 mg BID in arm 3; Other Names: NAC
Active Comparator: Arm 4 (HRZE); Rifafour (2HRZE/4HR)	Combination product: Rifafour; Fixed dose combination tablets for TB treatment will be given at approved doses

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
The proportion of patients achieving durable (non-relapsing) cure	Assessed after 1 year of post-treatment follow-up

Secondary Outcome Measures

Outcome Measure	Time Frame
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
FEV1 and FVC at 1, 2, 6, and 18 months after initiation of treatment	1, 2, 6, and 18 months after initiation of treatment
FEV1 and FVC slope during 6 and 18 months after initiation of treatment	6 and 18 months after initiation of treatment
FEV1/FVC ratio at 1, 2, 6, and 18 months after initiation of treatment	1, 2, 6, and 18 months after initiation of treatment
The proportion of subjects with sputum cultures showing growth of MTB at 1, 2, 3, and 4 months after initiation of treatment	1, 2, 3, and 4 months after initiation of treatment
The hazard ratio for stable culture conversion through the 4th month of treatment	through the 4th month of treatment
The proportion of subjects with treatment failure	More than 1 specimen showing growth of MTB during the final 6 weeks of treatment
The proportion of subjects with relapse	At week 72 for the control arm and at week 64 for the experimental arms

Other Outcome Measures

Outcome Measure	Time Frame
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
The plasma concentration (T>MIC) of sutezolid and its main metabolite	Month 1

Collaborators and Investigators

• Sponsor: The Aurum Institute NPC
• Collaborators: Ludwig-Maximilians - University of Munich; Global Alliance for TB Drug Development; University of Stellenbosch; Instituto Nacional de Saúde, Mozambique; National Institute for Medical Research, Tanzania; Sequella, Inc.; Stichting Katholieke Universiteit; Wits Health Consortium (Pty) Ltd
• Investigators: Principal Investigator: Professor Robert Wallis, MD, The Aurum Institute NPC

Study record dates

Study Major Dates

• Study Start (Actual): July 28, 2023
• Primary Completion (Estimated): September 30, 2025
• Study Completion (Estimated): September 30, 2025

Study Registration Dates

• First Submitted: December 18, 2022
• First Submitted That Met QC Criteria: January 13, 2023
• First Posted (Actual): January 17, 2023

Study Record Updates

• Last Update Posted (Estimated): May 15, 2024
• Last Update Submitted That Met QC Criteria: May 14, 2024
• Last Verified: May 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; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Anti-Bacterial Agents; Respiratory System Agents; Antioxidants; Antidotes; Antitubercular Agents; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine; Bedaquiline
• Other Study ID Numbers: AUR1-1-312; 24206 (Registry Identifier: Pan African Clinical Trials Registry (PACTR)); 6986 (Registry Identifier: South African Clinical Trials Registry (SANCTR)); RIA2019AMR-2647 (Other Grant/Funding Number: EDCTP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

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