BTZ-043 - Multiple Ascending Dose (MAD) to Evaluate Safety, Tolerability and Early Bactericidal Activity (EBA)
Condition: Pulmonary Tuberculoses; Other Specified Pulmonary Tuberculosis
MeSH terms: Tuberculosis; Tuberculosis, Pulmonary
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      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.

      The primary objective is to assess the safety and tolerability of BTZ-043 given over 14 days
      by evaluation of adverse events during treatment and follow-up period in patients with newly
      diagnosed, uncomplicated, smear-positive, drug-susceptible pulmonary tuberculosis.
    

Detailed description: 
      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.
    

Intervention name(s): BTZ-043; Rifafour e-275®; Probe Drug Cocktail; Dolutegravir 50mg Tab
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): BTZ-043 (250mg per tablet); Rifafour e-275® (150mg rifampicin, 75mg isoniazid, 400mg pyrazinamide, 275 mg ethambutol per tablet); A probe drug cocktail will be given to randomly selected patients after inclusion on Day 1 and on Day 14 once orally. The probe drug cocktail consists of
Caffeine: 1 tablet à 150mg
Tolbutamide: 1/4 tablet à 500mg
Dextromethorphan: 10 ml syrup à 15mg/5ml
Midazolam:2 ml solution à 5mg/5ml
Digoxin: 2 tablets à 0.25mg; 1 tablet à 50mg Dolutegravir will be given to randomly selected patients after inclusion on Day 1 and on Day 14 once orally.
Other intervention name(s): Isoniazid, Rifampicin, Pyrazinamide, Ethambutol (HRZE); Tivicay®
Intervention MeSH terms: Isoniazid; Pyrazinamide; Ethambutol; Dolutegravir
Allocation: Randomized
Intervention model: Sequential Assignment
Intervention model description: Stage 1: We will enrol patients sequentially in up to 8 cohorts of at least 3 patients to receive BTZ-043 in ascending doses. Patients in the first cohort will receive the lowest dose of 250mg of BTZ-043 for 14 days.
After each patient in a cohort has completed at least 7 days, a dosing recommendation for the next cohort will be made using the continual reassessment method (CRM) algorithm.
Stage 2: This will be a parallel group comparison of 4 treatment regimens. Patients will be randomized to receive either one of three doses of BTZ-043 within the therapeutic window defined in stage 1, or the control regimen of daily doses of Rifafour e-275®, adapted to body weight, for 14 days in the ratio 3:3:3:2.
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment
Keywords: 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