BTZ-043 - Multiple Ascending Dose (MAD) to Evaluate Safety, Tolerability and Early Bactericidal Activity (EBA)
- Conditions
- Pulmonary TuberculosesOther Specified Pulmonary Tuberculosis
- Interventions
- Registration Number
- NCT04044001
- Lead Sponsor
- Michael Hoelscher
- Brief 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 77
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Stage 2 - Arm 2 (BTZ medium) Dolutegravir 50mg Tab 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. Stage 2 - Arm 3 (BTZ low) Dolutegravir 50mg Tab 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. Stage 2 - Arm 1 (BTZ high) Probe Drug Cocktail 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. Stage 2 - Arm 1 (BTZ high) Dolutegravir 50mg Tab 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. Stage 2 - Arm 2 (BTZ medium) Probe Drug Cocktail 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. Stage 2 - Arm 3 (BTZ low) Probe Drug Cocktail 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. Stage 2 - Arm 4 (control) Rifafour e-275® 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 Stage 1 - Cohort 2 (BTZ 500) BTZ-043 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 Stage 1 - Cohort 1 (BTZ 250) BTZ-043 Patients will receive 1 tablet of BTZ-043 orally once daily, containing 250mg BTZ-043 from Day 1 through to Day 14 Stage 1 - Cohort 4 (BTZ 1000) BTZ-043 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 Stage 1 - Cohort 5 (BTZ 1250) BTZ-043 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 Stage 1 - Cohort 3 (BTZ 750) BTZ-043 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 Stage 1 - Cohort 8 (BTZ 2000) BTZ-043 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 Stage 1 - Cohort 6 (BTZ 1500) BTZ-043 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 Stage 1 - Cohort 7 (BTZ 1750) BTZ-043 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 Stage 2 - Arm 1 (BTZ high) BTZ-043 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. Stage 2 - Arm 3 (BTZ low) BTZ-043 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. Stage 2 - Arm 2 (BTZ medium) BTZ-043 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.
- Primary Outcome Measures
Name Time Method Safety and tolerability of BTZ-043 Day 1 to Day 22 Safety and tolerability of BTZ-043 will be assessed by evaluation of Adverse Events (AEs) during treatment- and follow-up phase
- Secondary Outcome Measures
Name Time Method Bactericidal Activity Endpoint - MBLA Day -1 to Day 14 • changes in sputum molecular bacterial load assay (MBLA) from baseline
Pharmacokinetic Endpoint - BTZ-043 - AUC Day 1, 12 and 14 The PK of BTZ-043 and its two major metabolites BTZ-045S and M2 after a single dose and at steady state will be evaluated by measuring the area under the plasma concentration curve (AUC)
Pharmacokinetic Endpoint - BTZ-043 - Cmax Day 1, 12 and 14 The PK of BTZ-043 and its two major metabolites BTZ-045S and M2 after a single dose and at steady state will be evaluated by measuring the observed maximum concentration (Cmax)
Pharmacokinetic Endpoint - BTZ-043 - Tmax Day 1, 12 and 14 The PK of BTZ-043 and its two major metabolites BTZ-045S and M2 after a single dose and at steady state will be evaluated by measuring the time to reach Cmax (Tmax)
Bactericidal Activity Endpoint - MGIT Day -1 to Day 14 • changes in time to detection in the Mycobacteria Growth Indicator Tube (MGIT™) liquid media culture system from baseline
Bactericidal Activity Endpoint - CFU Day -1 to Day 14 • changes in solid media colony forming units (CFU) from baseline
Bactericidal Activity Endpoint - LAM Day -1 to Day 14 • changes in sputum lipoarabinomannan (LAM) concentration from baseline
Pharmacokinetic Endpoint - BTZ-043 - Cmin Day 1, 12 and 14 The PK of BTZ-043 and its two major metabolites BTZ-045S and M2 after a single dose and at steady state will be evaluated by measuring the minimum observed plasma concentration 24 hours following the last dose (Cmin)
Pharmacokinetic Endpoint - BTZ-043 - Cl Day 1, 12 and 14 The PK of BTZ-043 and its two major metabolites BTZ-045S and M2 after a single dose and at steady state will be evaluated by measuring the Clearance (Cl)
Pharmacokinetic Endpoint - BTZ-043 - Vd Day 1, 12 and 14 The PK of BTZ-043 and its two major metabolites BTZ-045S and M2 after a single dose and at steady state will be evaluated by measuring the Volume of distribution (Vd)
Pharmacokinetic Endpoint - BTZ-043 - T1/2 Day 1, 12 and 14 The PK of BTZ-043 and its two major metabolites BTZ-045S and M2 after a single dose and at steady state will be evaluated by measuring the Elimination half-life (T1/2)
Pharmacokinetic Endpoint - BTZ-043 - pharmacodynamics (PD) Day 1, 12 and 14 The PK of BTZ-043 and its two major metabolites BTZ-045S and M2 after a single dose and at steady state will be evaluated by measuring the Relation of efficacy measurements to pharmacokinetic indices of BTZ-043 and its metabolites (AUC, Cmax)
Pharmacokinetic Endpoint - Population PK AUC Day 1, 12 and 14 A population PK-analysis of BTZ-043 and its two major metabolites will be carried out by measuring the AUC and describing PK differences of BTZ-043 and its main metabolites between subjects to quantify inter-individual variability, suitable for evaluation of alternative dosing regimens
Pharmacokinetic Endpoint - Population PK Cmax Day 1, 12 and 14 A population PK-analysis of BTZ-043 and its two major metabolites will be carried out by measuring the Cmax and describing PK differences of BTZ-043 and its main metabolites between subjects to quantify inter-individual variability, suitable for evaluation of alternative dosing regimens
Pharmacokinetic Endpoint - Food Effect PK AUC Day 14 The effect of food on the exposure of the BTZ-043 and its two major metabolites will be determined by measuring the AUC of BTZ-043 and its main metabolites and by evaluating the change after a high fat high calorie meal in comparison to the AUC under fasting conditions during the 1st stage.
Pharmacokinetic Endpoint - Food Effect PK Cmax Day 14 The effect of food on the exposure of the BTZ-043 and its two major metabolites will be determined by measuring the Cmax of BTZ-043 and its main metabolites and by evaluating the change after a high fat high calorie meal in comparison to the Cmax under fasting conditions during the 1st stage.
Pharmacokinetic Endpoint - Probe Drugs PK AUC Day 0 and 14 The effect on BTZ-043 at steady state on hepatic enzyme and P-glycoprotein activity (induction vs. inhibition) will be evaluated by measuring changes in AUC of the probe drugs administered on day 0, and day 14 during the 2nd stage.
Pharmacokinetic Endpoint - Probe Drugs PK Cmax Day 0 and 14 The effect on BTZ-043 at steady state on hepatic enzyme and P-glycoprotein activity (induction vs. inhibition) will be evaluated by measuring changes in Cmax of the probe drugs administered on day 0, and day 14 during the 2nd stage.
Trial Locations
- Locations (2)
TASK Applied Sciences Clinical Research Centre
🇿🇦Cape Town, South Africa
University of Cape Town Lung Institute (UCTLI)
🇿🇦Cape Town, South Africa