This is a phase 2B/C, open label platform study that will compare the efficacy, safety of experimental regimens with a standard control regimen in participants with newly diagnosed, drug sensitive pulmonary tuberculosis.

In stage 1, participants will be randomly allocated to the control or one of the 2 rifampicin-containing experimental regimens in the ratio 1:1:1.

In stage 2, the experimental arm 4 containing BTZ-043 will be added. The allocation ratio will be changed to co-enrol the remaining participants in arms 1- 3 simultaneously with arm 4 in a ratio of 1:1:1:2. When arms 1-2 are fully enrolled and arm 4 is not, further participants will be randomized 1:1 to control and experimental arm 4. Not all countries will participate in stage 2.

In stage 3, participants will be allocated in parallel to control arm treatment (now designated arm 7) or the experimental arms 5 and 6, favouring arm 5, 2:1:1 over arms 6 and control. This stage will start after completion of recruitment in the stages 1 and 2. Enrolment of participants into arm 5 will proceed following review of data from the ENABLE/UNITE-03 (NCT06748937), non-clinical safety data and after endorsement by the DSMB. Thus, arm 5 recruitment might start after arms 6 and 7, which may require an increase in the control arm sample size to ensure controls are recruited concomitantly.

This open label, phase 2B/C , randomized, controlled platform trial, will evaluate experimental arms including regimens with optimized doses of rifampicin, pyrazinamide, and moxifloxacin; a regimen with BTZ-043 combined first-line anti-TB drugs; a regimen with alpibectir-boosted ethionamide replacing isoniazid in combination with first-line anti-TB durgs, and a bedaquiline sparing regimen containing new anti-TB drugs (ganfeborole, BTZ-043 and delpazolid) in adults with newly diagnosed, drug sensitive, smear-positive pulmonary tuberculosis

A total of up to 390 (270 for stage 1 and 2, and 120 for stage 3, respectively) adult (≥ 18 years of age) participants will be enrolled.

In case of a high number of dropouts or non-evaluable participants, it may be necessary to recruit more participants into the study.

Also, if the stage 2 starts later than stage 1, it may be necessary to increase the number of control arm participants to achieve a 1:1 ratio of concomitantly recruited control and arm 4 participants until the recruitment for arm 4 is completed (see sample size considerations).

Stage 3 will start after stages 1 and 2 complete recruitment.

Inclusion Criteria:

1. Provide written, informed consent prior to all trial-related procedures including HIV testing.

2. Male or female, aged between 18 and 65 years, inclusive.

3. Body weight (in light clothing and with no shoes) between 40 and 90 kg, inclusive.

4. Newly diagnosed, previously untreated, drug susceptible pulmonary TB: presence of MTB complex and rapid molecular tests result confirming susceptibility to RIF and INH such as GeneXpert and/or HAIN MTBDR plus. Participants who had a previous history of TB may be enrolled in this trial, if they:

   • had a good treatment response in the opinion of the investigator; i.e. TB symptoms improved sufficiently or resolved suggesting a cure of the past episode; AND
   • no persistent microbiological positivity is seen (in case microbiological results are available); AND - their treatment course was completed AND
   • the last dose of treatment was more than 3 months ago.

5. A chest X-ray (no older than 2 weeks) which shows abnormalities that, in the opinion of the Investigator, are consistent with TB.

6. Sputum positive on microscopy from concentrated sputum for acid-fast bacilli (at least 1+ on the IUATLD/WHO scale) AND/OR positive GeneXpert MTB/RIF Ultra® semi-quantitative result "medium" or "high" on at least one sputum sample.

7. The participant understands the interaction between the study drugs and certain foods and is willing to forgo the consumption of those foods for the period of study medication.

8. The participant is not of child-bearing potential or is willing to use effective methods of contraception when engaging in heterosexual intercourse, as defined below:

   1. Non-childbearing potential:

   i. Female participant/sexual partner of male participant: Bilateral oophorectomy, and/or hysterectomy or bilateral tubal ligation more than 12 months ago and/or has been postmenopausal with a history of no menses for at least 12 consecutive months and confirmed by a FSH test.

   ii. Male participant/sexual partner of female participant: Vasectomised or has had a bilateral orchidectomy minimally three months prior to screening iii. Male participants having a pregnant female partner or a male sexual partner: At least one barrier method has to be used in this case.

   b. Effective contraception methods: i. Female participants: Two methods, including methods that the participant's sexual partner(s) use. At least one must be a barrier method. Contraception must be practised for at least until 12 weeks after the last dose of experimental treatment. For stage 3, female participants of child-bearing potential must have used contraception if any sexual intercourse has occurred after last menses or within the last 3 weeks (whichever is later) before participation, and agree to use non-user dependent contraception: depo-provera injection* or an intrauterine device additional to one barrier method.

   *Including a back-up method of contraception for at least 7 days to prevent unintended pregnancy if injection has been administered within the first 5 days of their menstrual cycle. Otherwise, a back-up barrier method of contraception is required for one month to prevent unintended pregnancy.

   ii. Male participants: Two methods, including methods that the participant's female sexual partner(s) use. At least one must be a barrier method. Effective contraception must be ensured for at least 12 weeks after the last dose of experimental treatment.

   Exclusion Criteria:

1. Circumstances that raise doubt about free, unconstrained consent to study participation (e.g., person in detention or person with mental disability)

2. Poor general condition where delay in treatment cannot be tolerated or death within four months is likely.

3. Circumstances (in the opinion of the investigator) that raise doubt about ability to complete the follow-up during the study period.

4. The participant is pregnant or breast-feeding or planning to become pregnant in the study period.

5. The participant is infected with HIV with a CD4 count <220 cells/mm3. If >220 cells/mm3, participants will be included only if any of the following is applicable:

   • The participant is antiretroviral (ARV) naïve and able to postpone commencing HIV treatment for 2 months after the trial has started and then restrict regimens to those mentioned in section on ARVs or

   • The participant is ARV experienced (has been on ARV´s a minimum of 5 months), AND: ARV treatment is compliant to, or can be modified as described in the section on Antiretroviral Therapy

6. The participant has a known intolerance to any of the study drugs or concomitant disorders or conditions for which study drugs or standard TB treatment are contraindicated.

7. The participant has a history of, or current evidence of clinically relevant cardiovascular metabolic, gastrointestinal, neurological, hepato-biliary, renal, psychiatric or endocrine diseases, malignancy, or any other condition that will influence treatment response, study adherence or survival in the judgement of the investigator, especially:

   a. Neuropathy, or significant psychiatric disorder like depression or schizophrenia; especially if treatment for those has ever been required or is anticipated to be required b. Evidence of clinically significant extra-pulmonary TB (e.g. miliary TB, TB meningitis, but not limited lymph node involvement) c. Serious lung conditions other than TB, or significant respiratory impairment in the discretion of the investigator d. Uncontrolled diabetes mellitus or diabetes mellitus receiving/requiring treatment with metformin or sulfonylureas e. Cardiovascular disease such as myocardial infarction, heart failure, coronary heart disease, arrhythmia, tachyarrhythmia, or pulmonary hypertension f. Uncontrolled arterial hypertension (systolic blood pressure ≥150 mmHg and/or diastolic blood pressure of ≥95 mmHg on two occasions during screening. An attempt at antihypertensive treatment during the screening period is permitted).

   g. Long QT syndrome or family history of long QT syndrome or family history of sudden death of unknown or cardiac-related cause h. Alcohol, regular opiate, or other drug abuse that is sufficient to significantly compromise the safety or cooperation of the participant, that includes substances prohibited by the protocol or has led to significant organ damage at the discretion of the investigator; AND/OR any abuse of methamphetamine.

   i. History of optic neuropathy j. Vitiligo

8. Any of the following laboratory findings at screening:

   a. Serum amino aspartate transferase (AST) and/or alanine aminotransferase (ALT) >3x the upper limit of normal (ULN), b. Serum alkaline phosphatase or y-glutamyl transferase > 2.5x the ULN, c. Serum total bilirubin level >1.5x the ULN d. Estimated creatinine clearance -eCrCl (using the CKD-EPI 2021 creatinine formula):

   - Stage 1: Lower than 30 ml/min)

   - Stage 2: Lower than 30ml/min or lower than 60 ml/min in participants living with HIV

   - Stage 3: Lower than 80ml/min e. Proteins in urine dipstick >=2+ f. Haemoglobin level <7.0 g/dl g. Platelet count <50,000/mm3, h. Serum potassium below 3 mmol/l, persisting after correction.

9. ECG findings in the screening ECG: (one or more):

   1. QTcF of >450 milliseconds
   2. Atrioventricular (AV) block with PR interval > 200 milliseconds
   3. QRS complex > 120 milliseconds
   4. Any other changes in the ECG that are clinically relevant as per discretion of the investigator

10. Restricted medication:

    1. Treatment with any other investigational drug within 2 month prior to enrolment or enrolment into other clinical (intervention) trials during participation.
    2. Previous anti-TB treatment with drugs active against MTB within the last 3 months prior to screening.
    3. Unable or unwilling to abide by the requirements regarding restricted medication or have taken restricted medication. Restricted medication includes the following drug classes, with relevant timing of intake, and possible exceptions. Exceptions may be permissible after discussion with the sponsor medical expert.

Currently exploring data sharing via the TB CAPT research data repository.

This study will be open-label, participants and physicians will be aware of treatment allocation. To ensure unbiased assessment of efficacy endpoints, the personnel assessing participants' outcomes, like the microbiology laboratory staff, will remain blinded to treatment assignment throughout the whole study. Every effort will be made to maintain this blinding.