Study of Combinations of Novel Promising Drugs for Pulmonary Tuberculosis

Inclusion Criteria: * To be eligible to participate in this trial, an individual must meet all the following criteria: 1. Provide written informed consent. 2. Male or female aged 18-65 (inclusive) 3. Clinical evidence of active TB disease, meeting either or both of the following criteria: 1. Symptoms consistent with pulmonary TB at screening AND/OR 2. Imaging findings consistent with active pulmonary TB on chest X-ray performed at screening or within 15 days prior to screening. 4. At least one sputum specimen produced at screening tested on either of the following: Xpert MTB/XDR and Ultra with: * positive for M. tb * a semi-quantitative result of 'medium' (cycle threshold value of \>16-22) or 'high' (cycle threshold value of \>16-22) AND * does not show rifampicin and/or isoniazid resistance. OR a. Sputum smear * Sputum positive for tubercle bacilli (at least 1+ on the IUATLD/WHO scale on smear microscopy) AND o Sensitive to rifampicin and isoniazid by rapid sputum-based test. 5. Able to produce a spot sputum with a volume of at least 4 ml. 6. Body weight within the range of 30 to 100 kgs and body mass index within the range of 15 to 40 kg/m2. 7. Newly diagnosed and untreated for this episode of TB. 8. Individuals with a history of TB may be enrolled in this trial if they meet the following criteria: 1. had a good treatment response in the opinion of the investigator (previous TB symptoms improved sufficiently or resolved) AND 2. completed their previous TB treatment AND 3. received their last dose of treatment more than 6 months before trial treatment AND • remained clinically well after completing treatment for their previous TB. 9. Willing to abstain from alcohol and tyramine containing foods for the treatment duration. 10. Willing to comply with study visits, all study procedures and treatment observation. Exclusion Criteria: * An individual who meets any of the following criteria will be excluded from participation in this trial: 1. Taken more than 1 daily dose of medication with anti-tuberculous activity during the 14 days prior to randomisation (isoniazid, rifampicin, pyrazinamide, ethambutol, linezolid, moxifloxacin, levofloxacin or amikacin). 2. Known or suspected extra-thoracic TB, miliary TB or disseminated TB (in the judgement of the investigator; note uncomplicated pleural effusion occupying \<50% of hemithorax or concomitant intra- or extra-thoracic lymphadenopathy are not exclusions). 3. Severe clinical pulmonary TB e.g. respiratory failure or complications, likely to require hospital admission in the opinion of the investigator. 4. Poor general condition (Karnofsky score ≤50) OR where any delay in treatment cannot be tolerated in the opinion of the investigator. 5. Active malignancy requiring systemic therapy, radiotherapy or palliative therapy. 6. History of myocardial infarction, coronary heart disease or congestive cardiac failure; long QT syndrome or clinically significant arrhythmias; pulmonary hypertension; any known congenital cardiac problems; family history of long QT syndrome or sudden death from unknown or cardiac related cause; uncontrolled arterial hypertension (not excluded if this is corrected prior to randomisation). 7. Cardiac valve abnormalities identified on echocardiogram. 8. History of vitiligo. 9. History of, or ongoing, inflammatory skin disorder such as leprosy, eczema, psoriasis, lichen planus, or other skin rash that would, in the opinion of the investigator, compromise the participant's safety or outcome in the trial. 10. History of seizure(s). 11. History of vascular aneurysm. 12. Symptomatic peripheral neuropathy causing greater than minimal interference with usual social and functional activities. 13. History of optic neuritis. 14. Current alcohol or illicit drug use sufficient to compromise the safety of the participant or research staff or compromise adherence to study procedures, in the opinion of the investigator. 15. Any current or recent use of amphetamines or methamphetamines evident on toxicity screen. 16. Any other medically or socially significant condition (e.g. psychiatric illness, chronic diarrhoeal disease, metabolic condition, other cardiovascular disease not listed under criterion 6), that would, in the opinion of the investigator, compromise the participant's safety or outcome in the trial; or lead to poor compliance with study visits and protocol requirements; or compromise the interpretation of trial safety and efficacy endpoints. 17. Women who are currently pregnant or breast-feeding. 18. Women of childbearing potential (WOCBP) who have had sexual intercourse without contraception after last menses or within the last 3 weeks (whichever is later); or, if unwilling to disclose this information, unable to provide two negative pregnancy tests 8 days apart during the screening period and on day 1 prior to randomisation . 19. WOCBP unwilling or unable to use appropriate non-user dependent contraception during the study intervention period and for at least 6 months after the last dose of study intervention; and unwilling to commit to refrain from donating eggs (ova, oocytes) for the purpose of reproduction during this period 20. Men who are unwilling to use a condom during the study period and for at least 90 days after the last dose of study drug to prevent pregnancy, unless they have had a vasectomy; and are unwilling to commit to refrain from donating fresh unwashed semen. 21. Known allergy to one or more of the study drugs. 22. Taking a concomitant medication that has a known or predicted interaction with any of the study drugs to which the participant might be randomised The participant need not be excluded if: 1. the concomitant medication can be stopped or replaced with an alternative non-interacting medication, if needed AND 2. the investigator judges there to be no residual clinical risk to the participant after stopping the concomitant medication (taking into account the washout period of 5x the half-life of the concomitant medication and the duration of the effect of the interaction on levels of study medication). 23. Taking a concomitant medication that is known to prolong the QTc interval. The participant need not be excluded if the concomitant medication can be stopped or replaced with an alternative medication, if needed, and the duration of the QTc prolongation is expected to resolve prior to dosing of study medication (taking into account the washout period of 5x the half-life of the concomitant medication). 24. Treatment with any immunosuppressive drugs within the 2 weeks prior to screening (taking systemic corticosteroids for less than 5 consecutive days and stopped at or prior to screening is not an exclusion; topical or inhaled steroids that are taken at a dose below the threshold considered to have systemic immunosuppressive effects are not excluded). 25. Participation in other clinical intervention trials with an investigational agent within 8 weeks prior to the first dosing day in this trial. 26. 12-lead ECGs at screening or at baseline shows QTcF \>450 ms (men) or \>460 ms (women) calculated by Fridericia's formula; and/or any other clinically significant abnormality such as arrhythmia or ischaemia. 27. Any of the following laboratory parameters at screening: 1. Hemoglobin \< 9 g/dl 2. Platelet count \< 100 x 109 cells/L 3. Absolute neutrophil count \<1 000 cells/μL 4. eGFR \<75 ml/min, calculated using race free CKD EPI 2021 eGFR normalised by body surface area through additional inclusion of weight AND height parameters (not excluded if corrected to above this level) 5. Alanine Aminotransferase (ALT) or Aspartate Aminotransferase (AST) \> 3 times the upper limit of normal (ULN) 6. Total bilirubin \> 1.5 times the ULN 7. Serum potassium \<3.5 mmol/L (not excluded if corrected to above this level) 8. Serum magnesium \< 0.50mmol/L (not excluded if corrected to above this level) 9. Serum calcium (corrected for albumin level) \< 2.10 mmol/L (not excluded if corrected to above this level). 10. HbA1C \>8.0% 28. Hepatitis B surface antigen positive (known, or on a test performed at screening), hepatitis A IgM and hepatitis C antibodies. (Participants with positive hepatitis C antibodies but negative PCR can be allowed in the trial) 29. Human Immunodeficiency Virus (HIV) antibody positive (known, or on test performed at screening) unless ALL of the following conditions are met: 1. Viral load (HIV-RNA) below 200 copies/mL on the last test, done within the previous 90 days (or at screening if no test performed in the previous 90 days). 2. CD4 count \> 200 cells/mm3 on the last test, done within the previous 90 days (or at screening if no test performed in the previous 90 days). 3. The participant has been taking a regimen of dolutegravir (DTG), tenofovir (TFV) and lamivudine(3TC)/emtricitabine for at least 6 months prior to screening with good adherence. 30. For Part B only: Participants unwilling or unable to disclose information regarding their last unprotected sexual intercourse (UPSI), or whose responses are considered unreliable or non-compliant by the Investigator.