BTZ-043 – Multiple Ascending Dose (MAD) to Evaluate Safety, Tolerability and Early Bactericidal Activity (EBA)

Overview

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.

Full Title of Study: “A Prospective Phase Ib/IIa, Active-controlled, Randomized, Open-label Study to Evaluate the Safety, Tolerability, Extended Early Bactericidal Activity and Pharmacokinetics of Multiple Oral Doses of BTZ-043 Tablets in Subjects With Newly Diagnosed, Uncomplicated, Smear-positive, Drug-susceptible Pulmonary Tuberculosis”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Sequential Assignment
    • Primary Purpose: Treatment
    • Masking: Single (Outcomes Assessor)
  • Study Primary Completion Date: August 2021

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.

Interventions

  • Drug: BTZ-043
    • BTZ-043 (250mg per tablet)
  • Drug: Rifafour e-275®
    • Rifafour e-275® (150mg rifampicin, 75mg isoniazid, 400mg pyrazinamide, 275 mg ethambutol per tablet)
  • Drug: Probe Drug Cocktail
    • 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
  • Drug: Dolutegravir 50mg Tab
    • 1 tablet à 50mg Dolutegravir will be given to randomly selected patients after inclusion on Day 1 and on Day 14 once orally.

Arms, Groups and Cohorts

  • Experimental: Stage 1 – Cohort 1 (BTZ 250)
    • Patients will receive 1 tablet of BTZ-043 orally once daily, containing 250mg BTZ-043 from Day 1 through to Day 14
  • Experimental: Stage 1 – Cohort 2 (BTZ 500)
    • 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
  • Experimental: Stage 1 – Cohort 3 (BTZ 750)
    • 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
  • Experimental: Stage 1 – Cohort 4 (BTZ 1000)
    • 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
  • Experimental: Stage 1 – Cohort 5 (BTZ 1250)
    • 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
  • Experimental: Stage 1 – Cohort 6 (BTZ 1500)
    • 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
  • Experimental: Stage 1 – Cohort 7 (BTZ 1750)
    • 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
  • Experimental: Stage 1 – Cohort 8 (BTZ 2000)
    • 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
  • Experimental: Stage 2 – Arm 1 (BTZ high)
    • 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.
  • Experimental: Stage 2 – Arm 2 (BTZ medium)
    • 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.
  • Experimental: Stage 2 – Arm 3 (BTZ low)
    • 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.
  • Active Comparator: Stage 2 – Arm 4 (control)
    • 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

Clinical Trial Outcome Measures

Primary Measures

  • Safety and tolerability of BTZ-043
    • Time Frame: 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 Measures

  • Bactericidal Activity Endpoint – MGIT
    • Time Frame: 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
    • Time Frame: Day -1 to Day 14
    • • changes in solid media colony forming units (CFU) from baseline
  • Bactericidal Activity Endpoint – LAM
    • Time Frame: Day -1 to Day 14
    • • changes in sputum lipoarabinomannan (LAM) concentration from baseline
  • Bactericidal Activity Endpoint – MBLA
    • Time Frame: Day -1 to Day 14
    • • changes in sputum molecular bacterial load assay (MBLA) from baseline
  • Pharmacokinetic Endpoint – BTZ-043 – AUC
    • Time Frame: 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
    • Time Frame: 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
    • Time Frame: 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)
  • Pharmacokinetic Endpoint – BTZ-043 – Cmin
    • Time Frame: 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
    • Time Frame: 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
    • Time Frame: 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
    • Time Frame: 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)
    • Time Frame: 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
    • Time Frame: 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
    • Time Frame: 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
    • Time Frame: 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
    • Time Frame: 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
    • Time Frame: 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
    • Time Frame: 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.

Participating in This Clinical Trial

General inclusion criteria:

1. Provide written, informed consent prior to all trial-related procedures including HIV testing. 2. Understand and willing to comply with the study procedures. 3. Male or female adults, aged 18 up to and including 64 years. 4. Body weight ≥ 40 kg. 5. 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:

6. Newly diagnosed, previously untreated, drug-susceptible pulmonary TB 7. Chest X-ray which is consistent with TB 8. Ability to produce an adequate volume of sputum (at least 10ml estimated overnight production) 9. ≥ 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:

1. Poor general condition, where delay in treatment cannot be tolerated or death within three months is likely, as assessed by the investigator. 2. The patient is pregnant or breast-feeding. Disease-specific exclusion criteria:

3. The patient is infected with HIV. 4. 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. 5. Treatment with any other investigational drug within 1 month prior to enrolment or enrolment into other clinical (intervention) trials during participation. 6. 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: 1. Clinically significant evidence of severe 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. Neuropathy, epilepsy or significant psychiatric disorder 4. Any diabetes mellitus 5. Cardiovascular disease, such as myocardial infarction, heart failure, coronary heart disease, arrhythmia, tachyarrhythmia, or pulmonary hypertension 6. Current or history of hypertension (systolic blood pressure >135 mmHg and/or diastolic blood pressure of >85 mmHg) AND/OR ever received antihypertensive treatment) 7. Long QT syndrome or family history of long QT syndrome or sudden death of unknown or cardiac-related cause 8. 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: 7. Serum amino aspartate transferase (AST) and/or alanine aminotransferase (ALT) activity >2x the upper limit of normal (ULN) 8. serum alkaline phosphatase (ALP) or y-glutamyl transferase (GGT) > 2x the ULN 9. serum total bilirubin level >1.5 times the ULN 10. estimated creatinine clearance (eCrCl) using the Cockcroft and Gault formula level lower than 60 mls/min 11. haemoglobin level <8.0 g/dL 12. platelet count <100,000/mm3 13. serum potassium below the lower level of normal (LLN) for the laboratory ECG-specific exclusion criteria:

14. corrected QT interval (QTc)F of > 450 milliseconds (ms) 15. Atrioventricular (AV) block with PR interval > 200 ms 16. QRS complex > 120 ms 17. any other changes in the ECG that are clinically relevant as per discretion of the investigator Restricted medication: 18. Treatment with drugs active against Mycobacterium Tuberculosis (MTB) within the last 3 months prior to screening 19. 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)

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 64 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Michael Hoelscher
  • Collaborator
    • European and Developing Countries Clinical Trials Partnership (EDCTP)
  • Provider of Information About this Clinical Study
    • Sponsor-Investigator: Michael Hoelscher, Prof. Dr. Michael Hoelscher – Ludwig-Maximilians – University of Munich
  • Overall Official(s)
    • Michael Hoelscher, Prof, Study Director, University Hospital, LMU Munich, Division of Infectious Diseases and Tropical Medicine
    • Andreas Diacon, Prof, Principal Investigator, TASK Applied Science Clinical Research Centre
  • Overall Contact(s)
    • Norbert Heinrich, MD, +49894400, heinrich@lrz.uni-muenchen.de

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