Clinical trial NCT05686356: A Pan-TB Regimen Targeting Host and Microbe
Official title: A Novel 4-month Pan-TB Regimen Targeting Both Host and Microbe (panTB-HM)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Tuberculosis
Lead sponsor: The Aurum Institute NPC
Sponsor class: OTHER
Collaborators: name: Ludwig-Maximilians - University of Munich
name: Stichting Katholieke Universiteit
name: Wits Health Consortium (Pty) Ltd
name: Instituto Nacional de Saúde, Mozambique
name: National Institute for Medical Research, Tanzania
name: University of Stellenbosch
name: Sequella, Inc.
name: Global Alliance for TB Drug Development
First posted: 2023-01-17
Enrollment: 352
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


Eligibility criteria: 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

Primary outcomes:
measure: The proportion of patients achieving durable (non-relapsing) cure
timeFrame: Assessed after 1 year of post-treatment follow-up
Secondary outcomes:
measure: The proportion of subjects with TE ALT increases, graded according to severity
timeFrame: From day 1 through 4 weeks post end-of-treatment
measure: The proportion of subjects with TE increases in transaminases and bilirubin meeting Hy's criteria for serious liver injury
timeFrame: From day 1 through 4 weeks post end-of-treatment
measure: The proportion of subjects with TE AEs, according to seriousness
timeFrame: From day 1 through 4 weeks post end-of-treatment
measure: The number of TE AEs per treatment arm, according to seriousness
timeFrame: From day 1 through 4 weeks post end-of-treatment
measure: The proportion of subjects requiring temporary or permanent treatment discontinuation due to safety or tolerability concerns
timeFrame: From day 1 through 4 weeks post end-of-treatment
measure: FEV1 and FVC at 1, 2, 6, and 18 months after initiation of treatment
timeFrame: 1, 2, 6, and 18 months after initiation of treatment
measure: FEV1 and FVC slope during 6 and 18 months after initiation of treatment
timeFrame: 6 and 18 months after initiation of treatment
measure: FEV1/FVC ratio at 1, 2, 6, and 18 months after initiation of treatment
timeFrame: 1, 2, 6, and 18 months after initiation of treatment
measure: The proportion of subjects with sputum cultures showing growth of MTB at 1, 2, 3, and 4 months after initiation of treatment
timeFrame: 1, 2, 3, and 4 months after initiation of treatment
measure: The hazard ratio for stable culture conversion through the 4th month of treatment
timeFrame: through the 4th month of treatment
measure: The proportion of subjects with treatment failure
timeFrame: More than 1 specimen showing growth of MTB during the final 6 weeks of treatment
measure: The proportion of subjects with relapse
timeFrame: At week 72 for the control arm and at week 64 for the experimental arms
Other outcomes:
measure: The proportion of subjects with non-TB cardiac or pulmonary AEs during the 18 months after TB diagnosis, according to seriousness.
timeFrame: During the 18 months after TB diagnosis
measure: The plasma concentration (AUC) of sutezolid and its main metabolite
timeFrame: Month 1
measure: The plasma concentration (Cmax and Cmin) of sutezolid and its main metabolite
timeFrame: Month 1
measure: The plasma concentration (T>MIC) of sutezolid and its main metabolite
timeFrame: Month 1
Locations:
city: Maputo
country: Mozambique
facility: Instituto Nacional de Saúde
city: Johannesburg
country: South Africa
facility: Clinical HIV Research Unit
state: Gauteng
city: Tembisa
country: South Africa
facility: The Aurum Institute: Tembisa Clinical Research Centre
state: Gauteng
city: Rustenburg
country: South Africa
facility: The Aurum Institute, Rustenburg Clinical Research Centre
state: North West Provice
city: George
country: South Africa
facility: TASK Eden
state: Western Cape
city: Durban
country: South Africa
facility: Clinical HIV Research Unit
city: Klerksdorp
country: South Africa
facility: The Aurum Institute, Gavin J Churchyard Legacy Centre (Klerksdorp Clinical Research Centre)
city: Mbeya
country: Tanzania
facility: NIMR-Mbeya Medical Research Centre
Study officials:
affiliation: The Aurum Institute NPC
name: Professor Robert Wallis, MD
role: PRINCIPAL_INVESTIGATOR
References: