A Pan-TB Regimen Targeting Host and Microbe

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).

Inclusion Criteria:Aged 18 to 65 yearsWilling and able to provide signed written consent prior to undertaking any trial-related procedures, or, in the case of illiteracy, witnessed oral consentBody weight (in light clothing without shoes) between 30 and 90 kg.Radiographic evidence of pulmonary tuberculosisPositive Xpert TB/RIF (original or Ultra) for MTBRIF susceptibility diagnosed by Xpert TB/RIF, with subsequent culture confirmationIf sexually active, willing to use an effective contraceptive method for the duration of tuberculosis treatmentHIV-1 seronegative, or if HIV-1 seropositive, CD4 T cell count ≥100/µl and either receiving ART or willing to start ART during study participationSARS-CoV-2 PCR or antigen test negative, or if positive, either fully vaccinated against Covid-19 or with D-dimer <0.8 ug/mlWilling to adhere to a diet excluding tyramine-rich foods (certain mold-ripened cheeses and cured meats), and to avoid eating grapefruits and pomelosExclusion Criteria: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 assessmentsCurrent or imminent (within 24 hr) treatment for malaria.Pregnant or nursingIs 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.TB meningitis or spondylitis, or other forms of severe tuberculosis with high risk of a poor outcome as judged by the investigator.History of allergy or hypersensitivity to any of the trial therapies or related substances.Having participated in other clinical trials with investigational agents within 8 weeks prior to trial start or currently enrolled in an investigational trial.Prior TB treatment in the preceding 6 monthsAngina pectoris requiring treatment with nitroglycerin or other nitratesCardiac arrhythmia requiring medication, or any clinically significant ECG abnormality, in the opinion of the investigatorHistory of unstable Diabetes Mellitus requiring hospitalization for hyper- or hypo-glycaemia within the past year prior to start of screening.Use of systemic corticosteroids within the past 28 days.Patients requiring treatment with medications not compatible with rifampin, such as HIV-1 protease inhibitorsPatients requiring treatment with antidepressants, including MAO inhibitors and SSRIs.Subjects with any of the following abnormal laboratory values:HBsAg positivecreatinine >2 mg/dLhemoglobin <8 g/dLplatelets <100x109 cells/Lserum potassium <3.5 mM/Lalanine aminotransferase (ALT) ≥2.0 x ULNalkaline phosphatase (AP) >5.0 x ULNtotal bilirubin >1.5 mg/dLrandom blood glucose >200 mg/dL