BTZ-043 Dose Evaluation in Combination and Selection

Exclusion Criteria

• •Circumstances that raise doubt about free, unconstrained consent to study participation (e.g. in a prisoner or person suffering from an intellectual disability).
• •Poor general condition, where delay in treatment cannot be tolerated, or death within three months is likely, as assessed by the investigator.
• •Poor social condition which would result in a high likelihood of not completing the trial 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 at screening
• •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 a combination of tenofovir, lamivudine and dolutegravir (TDF/3TC/DTG) for a minimum of 6 months prior to the screening visit.
• •The patient 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.
• •The patient has received treatment with any other investigational drug within 1 month prior 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 relevant cardiovascular, metabolic, gastrointestinal, neurological, ophthalmological, 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:
• •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 in the discretion of the investigator
• •3. Peripheral neuropathy (as evaluated by the Brief Peripheral Neuropathy Score).
• •4. Significant psychiatric disorder like depression or schizophrenia; especially if treatment for those has ever been required in the last five years or is anticipated to be required.
• •5. An established diagnosis of diabetes mellitus.
• •6. Cardiovascular disease, such as myocardial infarction, heart failure, coronary heartdisease, arrhythmia, tachyarrhythmia, or pulmonary hypertension.
• •7. Current (as measured on two occasions during screening) or history of hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure of ≥90 mmHg) on two occasions. Controlled hypertension is permitted if the patients receive only the allowed anti-hypertensives.
• •8. Long QT syndrome or family history of long QT syndrome or sudden death of unknown or cardiac-related cause.
• •9. Alcohol or other drug abuse, that is sufficient to significantly compromise the safety or cooperation of the patient, includes substances prohibited by the protocol, or has led to significant organ damage, at the discretion of the investigator. An isolated positive test for cannabinoids does not fulfil this exclusion 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 the Cockcroft 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 of the investigator
• •Any of the following regarding concomitant medications at screening:
• •1. Previous treatment with first- and second-line anti-TB drugs within the last 3 months prior to screening.
• •2. Treatment with any other investigational drug (including vaccines) within 1 month prior to enrolment or enrolment into other clinical (interventional) trials during participation.
• •3. Unable or unwilling to only take the allowed concomitant medications for this studyand ensuring an appropriate washout period
• •4. Unable or unwilling to abide to the dietary restrictions required in this study