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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04044001
Recruitment Status : Recruiting
First Posted : August 2, 2019
Last Update Posted : December 10, 2019
Sponsor:
Collaborators:
European and Developing Countries Clinical Trials Partnership (EDCTP)
Radboud University
German Federal Ministry of Education and Research
Information provided by (Responsible Party):
Michael Hoelscher, Ludwig-Maximilians - University of Munich

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.


Condition or disease Intervention/treatment Phase
Pulmonary Tuberculoses Other Specified Pulmonary Tuberculosis Drug: BTZ-043 Drug: Rifafour e-275® Drug: Probe Drug Cocktail Drug: Dolutegravir 50mg Tab Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 77 participants
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)
Masking Description: Laboratory staff, analysing and evaluating the sputum and safety blood samples of the participants will be blinded to the treatment cohort/arm.
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : November 15, 2019
Estimated Primary Completion Date : October 2020
Estimated Study Completion Date : November 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

Arm Intervention/treatment
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
Drug: BTZ-043
BTZ-043 (250mg per tablet)

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
Drug: BTZ-043
BTZ-043 (250mg per tablet)

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
Drug: BTZ-043
BTZ-043 (250mg per tablet)

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
Drug: BTZ-043
BTZ-043 (250mg per tablet)

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
Drug: BTZ-043
BTZ-043 (250mg per tablet)

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
Drug: BTZ-043
BTZ-043 (250mg per tablet)

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
Drug: BTZ-043
BTZ-043 (250mg per tablet)

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
Drug: BTZ-043
BTZ-043 (250mg per tablet)

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.
Drug: BTZ-043
BTZ-043 (250mg 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.
Other Name: Tivicay®

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.
Drug: BTZ-043
BTZ-043 (250mg 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.
Other Name: Tivicay®

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.
Drug: BTZ-043
BTZ-043 (250mg 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.
Other Name: Tivicay®

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
Drug: Rifafour e-275®
Rifafour e-275® (150mg rifampicin, 75mg isoniazid, 400mg pyrazinamide, 275 mg ethambutol per tablet)
Other Name: Isoniazid, Rifampicin, Pyrazinamide, Ethambutol (HRZE)




Primary Outcome Measures :
  1. 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 Outcome Measures :
  1. 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

  2. Bactericidal Activity Endpoint - CFU [ Time Frame: Day -1 to Day 14 ]
    • changes in solid media colony forming units (CFU) from baseline

  3. Bactericidal Activity Endpoint - LAM [ Time Frame: Day -1 to Day 14 ]
    • changes in sputum lipoarabinomannan (LAM) concentration from baseline

  4. Bactericidal Activity Endpoint - MBLA [ Time Frame: Day -1 to Day 14 ]
    • changes in sputum molecular bacterial load assay (MBLA) from baseline

  5. 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)

  6. 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)

  7. 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)

  8. 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)

  9. 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)

  10. 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)

  11. 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)

  12. 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)

  13. 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

  14. 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

  15. 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.

  16. 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.

  17. 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.

  18. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 64 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04044001


Contacts
Layout table for location contacts
Contact: Norbert Heinrich, MD +49894400 ext 59805 heinrich@lrz.uni-muenchen.de
Contact: Susanne Schultz, MD, MSc +49894400 ext 58907 susanne.schultz@lrz.uni-muenchen.de

Locations
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South Africa
TASK Applied Sciences Clinical Research Centre Recruiting
Cape Town, South Africa, 7530
Contact: Lize Greyling, MD    +2721917 ext 1044    dr.lize@task.org.za   
University of Cape Town Lung Institute (UCTLI) Recruiting
Cape Town, South Africa, 7700
Contact: Rodney A Dawson, Prof    +2721406 ext 6850    rodney.dawson@uct.ac.za   
Sponsors and Collaborators
Michael Hoelscher
European and Developing Countries Clinical Trials Partnership (EDCTP)
Radboud University
German Federal Ministry of Education and Research
Investigators
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Study Director: Michael Hoelscher, Prof University Hospital, LMU Munich, Division of Infectious Diseases and Tropical Medicine
Principal Investigator: Andreas Diacon, Prof TASK Applied Science Clinical Research Centre

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Responsible Party: Michael Hoelscher, Prof. Dr. Michael Hoelscher, Ludwig-Maximilians - University of Munich
ClinicalTrials.gov Identifier: NCT04044001    
Other Study ID Numbers: PanACEA-BTZ-043-02
First Posted: August 2, 2019    Key Record Dates
Last Update Posted: December 10, 2019
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Michael Hoelscher, Ludwig-Maximilians - University of Munich:
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
Additional relevant MeSH terms:
Layout table for MeSH terms
Tuberculosis
Tuberculosis, Pulmonary
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Rifampin
Isoniazid
Pyrazinamide
Ethambutol
Dolutegravir
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP2C8 Inducers
Cytochrome P-450 CYP2C19 Inducers
Cytochrome P-450 CYP2C9 Inducers
Cytochrome P-450 CYP3A Inducers
Fatty Acid Synthesis Inhibitors
Hypolipidemic Agents