BTZ-043 - Multiple Ascending Dose (MAD) to Evaluate Safety, Tolerability and Early Bactericidal Activity (EBA)
Pulmonary Tuberculoses, Other Specified Pulmonary Tuberculosis
About this trial
This is an interventional treatment trial for Pulmonary Tuberculoses focused on measuring Tuberculosis, Pulmonary, Randomized Controlled Trial (RCT), BTZ-043, Tuberculosis, Antitubercular Agents, Gram-positive Bacterial Infections, Escalating dose, Drug-sensitive TB, Early Bactericidal Activity (EBA), Drug-drug-interaction, Pharmacokinetics (PK), Safety, Tolerability, Bactericidal Activity
Eligibility Criteria
General inclusion criteria:
- Provide written, informed consent prior to all trial-related procedures including HIV testing.
- Understand and willing to comply with the study procedures.
- Male or female adults, aged 18 up to and including 64 years.
- Body weight ≥ 40 kg.
Participants are either unable to conceive/father children AND/OR they will be using two effective methods of contraception, including methods used by the patient's sexual partner(s). At least one to be a barrier method.
Disease-specific inclusion criteria:
- Newly diagnosed, previously untreated, drug-susceptible pulmonary TB
- Chest X-ray which is consistent with TB
- Ability to produce an adequate volume of sputum (at least 10ml estimated overnight production)
- ≥ 1 sputum sample from concentrated sputum positive for acid-fast bacilli on microscopy (at least 1+ on the International Union Against Tuberculosis and Lung Disease/World Health Organization (IUATLD/WHO) scale) from either a spot sputum or overnight sputum sample.
General exclusion criteria:
- Poor general condition, where delay in treatment cannot be tolerated or death within three months is likely, as assessed by the investigator.
The patient is pregnant or breast-feeding.
Disease-specific exclusion criteria:
- The patient is infected with HIV.
- 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.
- Treatment with any other investigational drug within 1 month prior to enrolment or enrolment into other clinical (intervention) trials during participation.
The patient has a history of or current evidence of clinically relevant cardiovascular metabolic, gastrointestinal, neurological, 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:
- Clinically significant evidence of severe TB (e.g. miliary TB, TB meningitis, excluding limited lymph node involvement)
- Serious lung conditions other than TB or significant respiratory impairment in the discretion of the investigator
- Neuropathy, epilepsy or significant psychiatric disorder
- Any diabetes mellitus
- Cardiovascular disease, such as myocardial infarction, heart failure, coronary heart disease, arrhythmia, tachyarrhythmia, or pulmonary hypertension
- Current or history of hypertension (systolic blood pressure >135 mmHg and/or diastolic blood pressure of >85 mmHg) AND/OR ever received antihypertensive treatment)
- Long QT syndrome or family history of long QT syndrome or sudden death of unknown or cardiac-related cause
- 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
Laboratory exclusion criteria at screening:
- Serum amino aspartate transferase (AST) and/or alanine aminotransferase (ALT) activity >2x the upper limit of normal (ULN)
- serum alkaline phosphatase (ALP) or y-glutamyl transferase (GGT) > 2x the ULN
- serum total bilirubin level >1.5 times the ULN
- estimated creatinine clearance (eCrCl) using the Cockcroft and Gault formula level lower than 60 mls/min
- haemoglobin level <8.0 g/dL
- platelet count <100,000/mm3
serum potassium below the lower level of normal (LLN) for the laboratory
ECG-specific exclusion criteria:
- corrected QT interval (QTc)F of > 450 milliseconds (ms)
- Atrioventricular (AV) block with PR interval > 200 ms
- QRS complex > 120 ms
any other changes in the ECG that are clinically relevant as per discretion of the investigator
Restricted medication:
- Treatment with drugs active against Mycobacterium Tuberculosis (MTB) within the last 3 months prior to screening
Requires medication as included in the following drug classes within 2 weeks prior to the first dose of study treatment:
- medication that prolongs the QTc interval
- Cytochrome P450 (CYP450) inhibitors or inducers, including grapefruit containing foods / beverages and St. John's Wort
- Antacids or antipeptic drugs (antacids, H2 blockers, proton pump inhibitors)
Sites / Locations
- TASK Applied Sciences Clinical Research Centre
- University of Cape Town Lung Institute (UCTLI)
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm 7
Arm 8
Arm 9
Arm 10
Arm 11
Arm 12
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Experimental
Active Comparator
Stage 1 - Cohort 1 (BTZ 250)
Stage 1 - Cohort 2 (BTZ 500)
Stage 1 - Cohort 3 (BTZ 750)
Stage 1 - Cohort 4 (BTZ 1000)
Stage 1 - Cohort 5 (BTZ 1250)
Stage 1 - Cohort 6 (BTZ 1500)
Stage 1 - Cohort 7 (BTZ 1750)
Stage 1 - Cohort 8 (BTZ 2000)
Stage 2 - Arm 1 (BTZ high)
Stage 2 - Arm 2 (BTZ medium)
Stage 2 - Arm 3 (BTZ low)
Stage 2 - Arm 4 (control)
Patients will receive 1 tablet of BTZ-043 orally once daily, containing 250mg BTZ-043 from Day 1 through to Day 14
Patients will receive 2 tablets of BTZ-043 orally once daily, each containing 250mg BTZ-043 (500 mg in total) from Day 1 through to Day 14
Patients will receive 3 tablets of BTZ-043 orally once daily, each containing 250mg BTZ-043 (750 mg in total) from Day 1 through to Day 14
Patients will receive 4 tablets of BTZ-043 orally once daily, each containing 250mg BTZ-043 (1000 mg in total) from Day 1 through to Day 14
Patients will receive 5 tablets of BTZ-043 orally once daily, each containing 250mg BTZ-043 (1250 mg in total) from Day 1 through to Day 14
Patients will receive 6 tablets of BTZ-043 orally once daily, each containing 250mg BTZ-043 (1500 mg in total) from Day 1 through to Day 14
Patients will receive 7 tablets of BTZ-043 orally once daily, each containing 250mg BTZ-043 (1750 mg in total) from Day 1 through to Day 14
Patients will receive 8 tablets of BTZ-043 orally once daily, each containing 250mg BTZ-043 (2000 total) from Day 1 through to Day 14
Patients will receive a higher dose of BTZ-043, that has proven to be safe in stage 1 orally once daily from Day 1 through to Day 14. The dose of BTZ-043 will be determined after review of safety data from stage 1.
Patients will receive a medium dose of BTZ-043, that has proven to be safe in stage 1 orally once daily from Day 1 through to Day 14. The dose of BTZ-043 will be determined after review of safety data from stage 1.
Patients will receive a lower dose of BTZ-043, that has proven to be safe in stage 1 orally once daily from Day 1 through to Day 14. The dose of BTZ-043 will be determined after review of safety data from stage 1.
Patients will receive a standard dose of Rifafour e-275® orally once daily according to body weight from Day 1 through to Day 14. Each tablet of Rifafour e-275® contains 150mg rifampicin, 75mg isoniazid, 400mg pyrazinamide and 275mg ethambutol. The daily doses will be given to fasting patients, in accordance with South African Guidelines for treatment of TB. The total number of tablets will be based on the body weight at screening: participants weighing 38 - 54 kg: 3 tablets participants weighing 55 - 70 kg: 4 tablets participants weighing >70 kg: 5 tablets