panTB-HM: A Pan-TB Regimen Targeting Host and Microbe

• Sponsor: The Aurum Institute NPC (Other)
• Overall Status: Not yet recruiting
• CT.gov ID: NCT05686356
• Collaborator: Ludwig-Maximilians - University of Munich (Other), Stichting Katholieke Universiteit (Other), Wits Health Consortium (Pty) Ltd (Other), Instituto Nacional de Saúde, Mozambique (Other), National Institute for Medical Research, Tanzania (Other), University of Stellenbosch (Other), Sequella, Inc. (Industry), Global Alliance for TB Drug Development (Other)
• Enrollment: 352
• Locations: 4
• Arms: 4
• Anticipated Duration (Months): 33
• Patients Per Site: 88
• Patients Per Site Per Month: 2.7

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis	Drug: Sutezolid; Drug: N-acetyl cysteine; Drug: Pretomanid; Drug: Bedaquiline; Combination Product: Rifafour	Phase 2/Phase 3

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 352 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Novel 4-month Pan-TB Regimen Targeting Both Host and Microbe (panTB-HM)
• Anticipated Study Start Date: Jan 1, 2023
• Anticipated Primary Completion Date: Sep 30, 2025
• Anticipated Study Completion Date: Sep 30, 2025

Arms and Interventions

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: N-acetyl cysteine; NAC will be given at a dose of 1800 mg BID in arm 3; Other Names: NAC ; Drug: Pretomanid; Pretomanid will be given at its approved dose; Drug: Bedaquiline; Bedaquiline will be given at its approved dose
Active Comparator: Arm 4 (HRZE) Rifafour (2HRZE/4HR)	Combination Product: Rifafour; Fixed dose combination tablets for TB treatment will be given at approved doses

Outcome Measures

Primary Outcome Measures

1. The proportion of patients achieving durable (non-relapsing) cure [Assessed after 1 year of post-treatment follow-up]

Secondary Outcome Measures

1. The proportion of subjects with TE ALT increases, graded according to severity [From day 1 through 4 weeks post end-of-treatment]

2. 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]

3. The proportion of subjects with TE AEs, according to seriousness [From day 1 through 4 weeks post end-of-treatment]

4. The number of TE AEs per treatment arm, according to seriousness [From day 1 through 4 weeks post end-of-treatment]

5. 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]

6. FEV1 and FVC at 1, 2, 6, and 18 months after initiation of treatment [1, 2, 6, and 18 months after initiation of treatment]

7. FEV1 and FVC slope during 6 and 18 months after initiation of treatment [6 and 18 months after initiation of treatment]

8. FEV1/FVC ratio at 1, 2, 6, and 18 months after initiation of treatment [1, 2, 6, and 18 months after initiation of treatment]

9. 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]

10. The hazard ratio for stable culture conversion through the 4th month of treatment [through the 4th month of treatment]

11. The proportion of subjects with treatment failure [More than 1 specimen showing growth of MTB during the final 6 weeks of treatment]

12. The proportion of subjects with relapse [At week 72 for the control arm and at week 64 for the experimental arms]

Other Outcome Measures

1. 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]

2. The plasma concentration (AUC) of sutezolid and its main metabolite [Month 1]

3. The plasma concentration (Cmax and Cmin) of sutezolid and its main metabolite [Month 1]

4. The plasma concentration (T>MIC) of sutezolid and its main metabolite [Month 1]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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:

16. HBsAg positive

17. creatinine >2 mg/dL

18. hemoglobin <8 g/dL

19. platelets <100x109 cells/L

20. serum potassium <3.5 mM/L

21. alanine aminotransferase (ALT) ≥2.0 x ULN

22. alkaline phosphatase (AP) >5.0 x ULN

23. total bilirubin >1.5 mg/dL

24. random blood glucose >200 mg/dL

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Instituto Nacional de Saúde	Maputo		Mozambique
2	The Clinical HIV Research Unit	Johannesburg	Gauteng	South Africa	2092
3	The Aurum Institute: Tembisa Clinical Research Centre	Tembisa	Gauteng	South Africa	1632
4	NIMR-Mbeya Medical Research Centre	Mbeya		Tanzania

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Professor Robert Wallis, MD, The Aurum Institute NPC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: The Aurum Institute NPC
• ClinicalTrials.gov Identifier: NCT05686356
• Other Study ID Numbers: AUR1-1-312; 24206; 6986; RIA2019AMR-2647
• First Posted: Jan 17, 2023
• Last Update Posted: Jan 17, 2023
• Last Verified: Jan 1, 2023

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Tuberculosis; Acetylcysteine; Bedaquiline; N-monoacetylcystine

Study Results

No Results Posted as of Jan 17, 2023