A Pan-TB Regimen Targeting Host and Microbe

Tuberculosis Clinical Trial

— panTB-HM  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05686356
• Other study ID #: AUR1-1-312
• Secondary ID: 242066986RIA2019
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: July 28, 2023
• Est. completion date: September 30, 2025

Study information

• Verified date: November 2023
• Source: The Aurum Institute NPC
• Contact: Professor Robert Wallis
• Phone: +1 (860) 271-6745
• Email: rwallis[@]auruminstitute.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 352
• Est. completion date: September 30, 2025
• Est. primary completion date: September 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

Related Conditions & MeSH terms

• Tuberculosis

Intervention

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.
• N-acetyl cysteine
NAC will be given at a dose of 1800 mg BID in arm 3
• Pretomanid
Pretomanid will be given at its approved dose
• Bedaquiline
Bedaquiline will be given at its approved dose

Combination Product:
• Rifafour
Fixed dose combination tablets for TB treatment will be given at approved doses

Locations

Country	Name	City	State
Mozambique	Instituto Nacional de Saúde	Maputo
South Africa	Clinical HIV Research Unit	Durban
South Africa	Clinical HIV Research Unit	Johannesburg	Gauteng
South Africa	The Aurum Institute: Tembisa Clinical Research Centre	Tembisa	Gauteng
Tanzania	NIMR-Mbeya Medical Research Centre	Mbeya

Sponsors (9)

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

Countries where clinical trial is conducted

Mozambique,  South Africa,  Tanzania, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	The plasma concentration (AUC) of sutezolid and its main metabolite		Month 1
Other	The plasma concentration (Cmax and Cmin) of sutezolid and its main metabolite		Month 1
Other	The plasma concentration (T>MIC) of sutezolid and its main metabolite		Month 1
Primary	The proportion of patients achieving durable (non-relapsing) cure		Assessed after 1 year of post-treatment follow-up
Secondary	The proportion of subjects with TE ALT increases, graded according to severity		From day 1 through 4 weeks post end-of-treatment
Secondary	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
Secondary	The proportion of subjects with TE AEs, according to seriousness		From day 1 through 4 weeks post end-of-treatment
Secondary	The number of TE AEs per treatment arm, according to seriousness		From day 1 through 4 weeks post end-of-treatment
Secondary	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
Secondary	FEV1 and FVC at 1, 2, 6, and 18 months after initiation of treatment		1, 2, 6, and 18 months after initiation of treatment
Secondary	FEV1 and FVC slope during 6 and 18 months after initiation of treatment		6 and 18 months after initiation of treatment
Secondary	FEV1/FVC ratio at 1, 2, 6, and 18 months after initiation of treatment		1, 2, 6, and 18 months after initiation of treatment
Secondary	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
Secondary	The hazard ratio for stable culture conversion through the 4th month of treatment		through the 4th month of treatment
Secondary	The proportion of subjects with treatment failure		More than 1 specimen showing growth of MTB during the final 6 weeks of treatment
Secondary	The proportion of subjects with relapse		At week 72 for the control arm and at week 64 for the experimental arms