Overview

This is a phase 2B, open label study, that will compare the safety and efficacy of three experimental regimens consisting of bedaquiline and delamanid in combination with different doses of BTZ-043, a novel antibiotic, in adult participants with newly diagnosed, drug-sensitive pulmonary tuberculosis. Participants will be assigned to receive either one of the three BTZ-043-containing regimens or a comparator regimen consisting of bedaquiline, delamanid and moxifloxacin. The objective is to find the optimal dose of BTZ-043 with the highest efficacy and safety to be used in subsequent studies.

Eligibility

Inclusion Criteria:

• Provide written, informed consent prior to all trial-related procedures, including HIV testing.
• 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 and body 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 to rifampicin 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 father children OR consent to use effective methods of contraception when engaging in heterosexual intercourse, as defined below:
  1. Non-childbearing potential: i) 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 as per medical history.

        ii) Sexual partner(s) of female participant: vasectomy OR bilateral orchidectomy at least
        three months prior to screening as per medical history.
        b. Effective contraception methods: i) Two methods, including methods used by patient's
        sexual partner(s). At least one must be a barrier method. Contraception must be practised
        for at least until 12 weeks after the last dose of BTZ-043.
        - MALE PARTICIPANTS: Inability to father children AND/OR inability of partner(s) to
        conceive, OR consent to use effective methods of contraception when engaging in
        heterosexual intercourse, as defined below:
        c. Non-childbearing potential: i) Sexual partner(s) 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 as per medical history.
        ii) Vasectomy OR bilateral orchidectomy at least three months prior to screening as per
        medical history.
        iii) Female pregnant sexual partner of a male participant: agree to use at least one
        barrier method.
        iv) Male sexual partner of male participant: agree to use at least one barrier method for
        at 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's
        female sexual partner(s). At least one must be a barrier method. Effective contraception
        must 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 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