BTZ-043 Dose Evaluation in Combination and Selection

Inclusion Criteria:

• Provide written, informed consent prior to all trial-related procedures, including HIVtesting.
• Male or female, aged 18 up to (and including) 64 years.
• Body weight (in light clothing and with no shoes) within the range of 30 to 100kg andbody mass index within the range of 15 to 40kg/m2.
• Newly diagnosed, previously untreated current episode of drug-susceptible pulmonary TB (presence of MTB complex with rapid molecular test result confirming susceptibility torifampicin and isoniazid such as "GeneXpert" and/or "HAIN MTBDR plus").
• ≥ 1 sputum sample from concentrated spot sputum positive in GeneXpert MTB/RIF Ultra®,with semi-quantitative result at least "medium" or higher.
• FEMALE PARTICIPANTS: Inability to conceive AND/OR inability of partner(s) to fatherchildren OR consent to use effective methods of contraception when engaging inheterosexual intercourse, as defined below: a. Non-childbearing potential: i) Bilateral oophorectomy AND/OR hysterectomy ORbilateral tubal ligation more than 12 months ago, AND/OR has been postmenopausal witha history of no menses for at least 12 consecutive months as per medical history. ii) Sexual partner(s) of female participant: vasectomy OR bilateral orchidectomy at leastthree months prior to screening as per medical history.

b. Effective contraception methods: i) Two methods, including methods used by patient'ssexual partner(s). At least one must be a barrier method. Contraception must be practisedfor at least until 12 weeks after the last dose of BTZ-043.

• MALE PARTICIPANTS: Inability to father children AND/OR inability of partner(s) toconceive, OR consent to use effective methods of contraception when engaging inheterosexual intercourse, as defined below: c. Non-childbearing potential: i) Sexual partner(s) of male participant: Bilateraloophorectomy 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 consecutivemonths as per medical history. ii) Vasectomy OR bilateral orchidectomy at least three months prior to screening as permedical history. iii) Female pregnant sexual partner of a male participant: agree to use at least onebarrier method. iv) Male sexual partner of male participant: agree to use at least one barrier method forat least until 12 weeks after the last dose of BTZ-043 for protection of the partner. d. Effective contraception methods: ii) Two methods, including methods used by patient'sfemale sexual partner(s). At least one must be a barrier method. Effective contraceptionmust be ensured for at least 16 weeks after the last dose of BTZ-043

Exclusion Criteria:

• Circumstances that raise doubt about free, unconstrained consent to studyparticipation (e.g. in a prisoner or person suffering from an intellectualdisability).
• Poor general condition, where delay in treatment cannot be tolerated, or death withinthree months is likely, as assessed by the investigator.
• Poor social condition which would result in a high likelihood of not completing thetrial until the final visit.
• The patient is pregnant or breast-feeding.
• The patient is HIV antibody positive (known, or on a test performed at screening),unless:

1. The patient has a viral load (VL) < 200 copies/mL on a test performed atscreening
2. The patient has a CD4 cell count > 200 cells/mm3 at screening
3. The patient is experienced on antiretroviral therapy (ART), and is on acombination of tenofovir, lamivudine and dolutegravir (TDF/3TC/DTG) for a minimumof 6 months prior to the screening visit.

• The patient has a known intolerance to any of the study drugs or concomitant disordersor conditions for which study drugs or standard TB treatment are contraindicated.
• The patient has received treatment with any other investigational drug within 1 monthprior to enrolment, or is planning to be enrolled into other clinical (intervention)trials during participation.
• The patient has a history of or current evidence of clinically relevantcardiovascular, metabolic, gastrointestinal, neurological, ophthalmological,psychiatric or endocrine diseases, malignancy or any other condition, that willinfluence treatment response, study adherence or survival in the judgement of theinvestigator, especially:

1. Clinically significant evidence of severe or extra-thoracic TB (e.g., miliary TB,TB meningitis, excluding limited lymph node involvement)
2. Serious lung conditions other than TB or significant respiratory impairment inthe discretion of the investigator
3. Peripheral neuropathy (as evaluated by the Brief Peripheral Neuropathy Score).
4. Significant psychiatric disorder like depression or schizophrenia; especially iftreatment for those has ever been required in the last five years or isanticipated to be required.
5. An established diagnosis of diabetes mellitus.
6. Cardiovascular disease, such as myocardial infarction, heart failure, coronaryheartdisease, arrhythmia, tachyarrhythmia, or pulmonary hypertension.
7. Current (as measured on two occasions during screening) or history ofhypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressureof ≥90 mmHg) on two occasions. Controlled hypertension is permitted if thepatients receive only the allowed anti-hypertensives.
8. Long QT syndrome or family history of long QT syndrome or sudden death of unknownor cardiac-related cause.
9. Alcohol or other drug abuse, that is sufficient to significantly compromise thesafety or cooperation of the patient, includes substances prohibited by theprotocol, or has led to significant organ damage, at the discretion of theinvestigator. An isolated positive test for cannabinoids does not fulfil thisexclusion criterion.
10. Chronic kidney disease (CKD) or any other history of renal impairment.

• Any of the following laboratory findings at screening:

1. serum amino aspartate transferase (AST) and/or alanine aminotransferase (ALT)activity >3x the ULN
2. serum alkaline phosphatase (ALP) >3x the ULN
3. serum total bilirubin level >1.5 times the ULN
4. estimated creatinine clearance (eCrCl) < 60 mls/min (calculated using theCockcroft and Gault formula
5. haemoglobin level <8.0 g/dL
6. platelet count <50,000/mm3
7. albumin < 2.8 g/dl
8. serum potassium <3.5 mmol/L (not excluded if subsequently corrected)
9. serum magnesium < 0.5mmol/L (not excluded if subsequently corrected)

• Any of the following ECG findings at screening:

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

• Any of the following regarding concomitant medications at screening:

1. Previous treatment with first- and second-line anti-TB drugs within the last 3months prior to screening.
2. Treatment with any other investigational drug (including vaccines) within 1 monthprior to enrolment or enrolment into other clinical (interventional) trialsduring participation.
3. Unable or unwilling to only take the allowed concomitant medications for thisstudyand ensuring an appropriate washout period
4. Unable or unwilling to abide to the dietary restrictions required in this study