This is a prospective, open label, two-centre, randomized, controlled, two-stage, phase Ib/IIa study to evaluate the safety, tolerability, PK, drug-drug interaction and bactericidal activity of BTZ-043 administered orally once daily over 14 days to participants with newly diagnosed, uncomplicated, smear-positive, drug-susceptible pulmonary tuberculosis:
Stage 1 is an escalating dose design in up to eight cohorts receiving different doses of BTZ-043 to define a safe dose corridor for BTZ-043. The focus of this stage is on adverse events, PK and a food-effect PK-evaluation .
Stage 2 is a parallel group comparison of 4 arms receiving different treatment regimens: three arms to receive BTZ-043 in different doses within the safe corridor defined in stage 1, compared to one arm receiving Rifampicin, Isoniazid, Pyrazinamide, and Ethambutol as a control. This stage is focusing on adverse effects, early bactericidal activity (EBA), PK and an evaluation of PK drug-drug interaction potential.
A total of up to 77 male and female patients, aged ≥ 18 - 64 years, with newly diagnosed, smear positive, drug sensitive pulmonary tuberculosis will be enrolled.
Allocation of patients will be carried out in two stages:
Stage 1: for each cohort 3 patients will be enrolled, treated and followed-up accordingly, starting with cohort 1. In a Trial Steering Committee (TSC) meeting, decision will be made on the dose in the next cohort.
Dose escalation steps to be followed, if no safety concerns arise:
- Cohort 1: patients to receive 250 mg BTZ-043
- Cohort 2: patients to receive 500 mg BTZ-043
- Cohort 3: patients to receive 750 mg BTZ-043
- Cohort 4: patients to receive 1000 mg BTZ-043
- Cohort 5: patients to receive 1250 mg BTZ-043
- Cohort 6: patients to receive 1500 mg BTZ-043
- Cohort 7: patients to receive 1750 mg BTZ-043
- Cohort 8: patients to receive 2000 mg BTZ-043
Patients receiving the investigational drug in cohorts 1 - 8 will take BTZ-043 in fasting state for 13 days and after a pre-defined high-fat, high-caloric meal on day 14.
After all patients of a current cohort have completed at least 7 days of dosing, the TSC, composed of the national principal investigator (PI), the trial statistician, the sponsor representative and two independent scientists, will review safety data, including clinical, lab and electrocardiography (ECG) data, to assess whether dose limiting toxicity of BTZ-043, as defined below, has been observed in any participant. Depending on the outcome, the TSC will then decide on dose escalation, or on enrolling more participants to the same or a lower dose in the following cohort, according to dose escalation and stopping rules.
After the end of stage 1, the TSC will decide which of the BTZ-043 doses, which are deemed to not exceed the acceptable toxicity level, are to be moved to stage 2.
Stage 2: after the highest possible dose of the investigational drug, that has proven to be safe within the 1st stage, is identified, all remaining patients will be recruited and randomised to receive one of three different doses of BTZ-043 or to control treatment with Rifafour e-275® at a ratio of 3:3:3:2 favouring the experimental treatment.
Stage 2 is focusing on adverse effects, early bactericidal activity (EBA), PK and an evaluation of PK drug-drug interaction potential.
Allocation of patients:
- Arm 1: patients to receive BTZ-043 in a higher dose
- Arm 2: patients to receive BTZ-043 in a medium dose
- Arm 3: patients to receive BTZ-043 in a lower dose
- Control Arm 4: patients to receive Rifafour e-275® as control treatment
Participants will take in BTZ-043 in either fasted or fed state, depending on which state has shown to lead to higher exposure during the 1st stage.
Additional measurements in the 2nd stage in BTZ-arms 1 to 3 only:
• Drug-drug interactions will be investigated: patients, who have been randomized to BTZ-043 arms, will additionally be randomized to receive either a probe drug cocktail, with drugs specifically metabolized by certain enzymes, or dolutegravir at a ratio of 2:1. Probe drugs or Dolutegravir (DTG) will be given pre-BTZ on day 0 and on day 14.
After the course of study drugs is completed (on day 14), all patients (in stage 1 and stage 2) will be referred to a government clinic to complete their course of tuberculosis (TB) according to national standards for a total of 6 months of first-line therapy.
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