A Pan-TB Regimen Targeting Host and Microbe

Phase 2

Recruiting

• Conditions: Tuberculosis
• Interventions: Drug: Sutezolid; Combination Product: Rifafour; Drug: N-acetyl cysteine; Drug: Pretomanid; Drug: Bedaquiline

• Registration Number: NCT05686356
• Lead Sponsor: The Aurum Institute NPC

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).

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2022-12-18
• Study First Submitted QC: 2023-01-13
• Study First Posted: 2023-01-17
• Study Start: 2023-07-28
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-03
• Last Update Posted: 2024-10-07
• Primary Completion: 2025-09-30
• Study Completion: 2025-09-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 352

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 3 (S1600BPN)	Sutezolid	Sutezolid 1600mg QD plus bedaquiline pretomanid and N-acetyl cysteine for 4 months
Arm 3 (S1600BPN)	Pretomanid	Sutezolid 1600mg QD plus bedaquiline pretomanid and N-acetyl cysteine for 4 months
Arm 2 (S1600BP)	Bedaquiline	Sutezolid 1600mg QD plus bedaquiline and pretomanid for 4 months
Arm 2 (S1600BP)	Sutezolid	Sutezolid 1600mg QD plus bedaquiline and pretomanid for 4 months
Arm 4 (HRZE)	Rifafour	Rifafour (2HRZE/4HR)
Arm 3 (S1600BPN)	N-acetyl cysteine	Sutezolid 1600mg QD plus bedaquiline pretomanid and N-acetyl cysteine for 4 months
Arm 1 (S1200BP)	Sutezolid	Sutezolid 1200mg QD plus bedaquiline and pretomanid for 4 months
Arm 1 (S1200BP)	Pretomanid	Sutezolid 1200mg QD plus bedaquiline and pretomanid for 4 months
Arm 1 (S1200BP)	Bedaquiline	Sutezolid 1200mg QD plus bedaquiline and pretomanid for 4 months
Arm 2 (S1600BP)	Pretomanid	Sutezolid 1600mg QD plus bedaquiline and pretomanid for 4 months
Arm 3 (S1600BPN)	Bedaquiline	Sutezolid 1600mg QD plus bedaquiline pretomanid and N-acetyl cysteine for 4 months

Primary Outcome Measures

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

Secondary Outcome Measures

Name	Time	Method
FEV1 and FVC at 1, 2, 6, and 18 months after initiation of treatment	1, 2, 6, and 18 months after initiation of treatment
The number of TE AEs per treatment arm, according to seriousness	From day 1 through 4 weeks post end-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 requiring temporary or permanent treatment discontinuation due to safety or tolerability concerns	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 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
FEV1 and FVC slope during 6 and 18 months after initiation of treatment	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
The proportion of subjects with TE ALT increases, graded according to severity	From day 1 through 4 weeks post end-of-treatment

Trial Locations

Locations (7)

Instituto Nacional de Saúde; 🇲🇿 Maputo, Mozambique

Clinical HIV Research Unit; 🇿🇦 Durban, South Africa

The Aurum Institute: Tembisa Clinical Research Centre; 🇿🇦 Tembisa, Gauteng, South Africa

The Aurum Institute, Rustenburg Clinical Research Centre; 🇿🇦 Rustenburg, North West Provice, South Africa

TASK Eden; 🇿🇦 George, Western Cape, South Africa

The Aurum Institute, Gavin J Churchyard Legacy Centre (Klerksdorp Clinical Research Centre); 🇿🇦 Klerksdorp, South Africa

NIMR-Mbeya Medical Research Centre; 🇹🇿 Mbeya, Tanzania