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

NCT04044001 | Completed Phase 1 DMC

• 1 other identifier: PanACEA-BTZ-043-02
• Study Type: interventional
• Target: 77
• Locations: 1 country
• Sites: 2

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.

Conditions

Pulmonary Tuberculoses; Other Specified Pulmonary Tuberculosis

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

Outcome Measures

Primary Outcomes (1)

• Safety and tolerability of BTZ-043

  Safety and tolerability of BTZ-043 will be assessed by evaluation of Adverse Events (AEs) during treatment- and follow-up phase

  Day 1 to Day 22

Secondary Outcomes (18)

• Bactericidal Activity Endpoint - MGIT

  Day -1 to Day 14

• Bactericidal Activity Endpoint - CFU

  Day -1 to Day 14

• Bactericidal Activity Endpoint - LAM

  Day -1 to Day 14

• Bactericidal Activity Endpoint - MBLA

  Day -1 to Day 14

• Pharmacokinetic Endpoint - BTZ-043 - AUC

  Day 1, 12 and 14

Study Arms (12)

Stage 1 - Cohort 1 (BTZ 250)

EXPERIMENTAL

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

Stage 1 - Cohort 2 (BTZ 500)

EXPERIMENTAL

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

Stage 1 - Cohort 3 (BTZ 750)

EXPERIMENTAL

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

Stage 1 - Cohort 4 (BTZ 1000)

EXPERIMENTAL

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

Stage 1 - Cohort 5 (BTZ 1250)

EXPERIMENTAL

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

Stage 1 - Cohort 6 (BTZ 1500)

EXPERIMENTAL

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

Stage 1 - Cohort 7 (BTZ 1750)

EXPERIMENTAL

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

Stage 1 - Cohort 8 (BTZ 2000)

EXPERIMENTAL

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

Stage 2 - Arm 1 (BTZ high)

EXPERIMENTAL

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; Drug: Probe Drug Cocktail; Drug: Dolutegravir 50mg Tab

Stage 2 - Arm 2 (BTZ medium)

EXPERIMENTAL

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; Drug: Probe Drug Cocktail; Drug: Dolutegravir 50mg Tab

Stage 2 - Arm 3 (BTZ low)

EXPERIMENTAL

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; Drug: Probe Drug Cocktail; Drug: Dolutegravir 50mg Tab

Stage 2 - Arm 4 (control)

ACTIVE COMPARATOR

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®

Interventions

BTZ-043 DRUG

BTZ-043 (250mg per tablet)

Stage 1 - Cohort 1 (BTZ 250); Stage 1 - Cohort 2 (BTZ 500); Stage 1 - Cohort 3 (BTZ 750); Stage 1 - Cohort 4 (BTZ 1000); Stage 1 - Cohort 5 (BTZ 1250); Stage 1 - Cohort 6 (BTZ 1500); Stage 1 - Cohort 7 (BTZ 1750); Stage 1 - Cohort 8 (BTZ 2000); Stage 2 - Arm 1 (BTZ high); Stage 2 - Arm 2 (BTZ medium); Stage 2 - Arm 3 (BTZ low)

Rifafour e-275® DRUG

Rifafour e-275® (150mg rifampicin, 75mg isoniazid, 400mg pyrazinamide, 275 mg ethambutol per tablet)

Also known as: Isoniazid, Rifampicin, Pyrazinamide, Ethambutol (HRZE)

Stage 2 - Arm 4 (control)

Probe Drug Cocktail DRUG

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

Stage 2 - Arm 1 (BTZ high); Stage 2 - Arm 2 (BTZ medium); Stage 2 - Arm 3 (BTZ low)

Dolutegravir 50mg Tab DRUG

1 tablet à 50mg Dolutegravir will be given to randomly selected patients after inclusion on Day 1 and on Day 14 once orally.

Also known as: Tivicay®

Stage 2 - Arm 1 (BTZ high); Stage 2 - Arm 2 (BTZ medium); Stage 2 - Arm 3 (BTZ low)

Eligibility Criteria

• Age: 18 Years - 64 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Provide written, informed consent prior to all trial-related procedures including HIV testing.
• Understand and willing to comply with the study procedures.
• Male or female adults, aged 18 up to and including 64 years.
• Body weight ≥ 40 kg.
• 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.
• Newly diagnosed, previously untreated, drug-susceptible pulmonary TB
• Chest X-ray which is consistent with TB
• Ability to produce an adequate volume of sputum (at least 10ml estimated overnight production)
• ≥ 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.

You may not qualify if:

• Poor general condition, where delay in treatment cannot be tolerated or death within three months is likely, as assessed by the investigator.
• The patient is pregnant or breast-feeding.
• The patient is infected with HIV.
• 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.
• Treatment with any other investigational drug within 1 month prior to enrolment or enrolment into other clinical (intervention) trials during participation.
• 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:
• Clinically significant evidence of severe TB (e.g. miliary TB, TB meningitis, excluding limited lymph node involvement)
• Serious lung conditions other than TB or significant respiratory impairment in the discretion of the investigator
• Neuropathy, epilepsy or significant psychiatric disorder
• Any diabetes mellitus
• Cardiovascular disease, such as myocardial infarction, heart failure, coronary heart disease, arrhythmia, tachyarrhythmia, or pulmonary hypertension
• Current or history of hypertension (systolic blood pressure \>135 mmHg and/or diastolic blood pressure of \>85 mmHg) AND/OR ever received antihypertensive treatment)
• Long QT syndrome or family history of long QT syndrome or sudden death of unknown or cardiac-related cause
• 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
• Serum amino aspartate transferase (AST) and/or alanine aminotransferase (ALT) activity \>2x the upper limit of normal (ULN)

Sponsors & Collaborators

• Michael Hoelscher: lead
• European and Developing Countries Clinical Trials Partnership (EDCTP): collaborator
• Radboud University Medical Center: collaborator
• German Federal Ministry of Education and Research: collaborator

Study Sites (2)

TASK Applied Sciences Clinical Research Centre

Cape Town, 7530, South Africa

Location

University of Cape Town Lung Institute (UCTLI)

Cape Town, 7700, South Africa

Location

Related Publications (1)

• Heinrich N, de Jager V, Dreisbach J, Gross-Demel P, Schultz S, Gerbach S, Kloss F, Dawson R, Narunsky K, Matt L, Wildner L, McHugh TD, Fuhr U, Aldana BH, Mouhdad C, Brake LT, Boeree MJ, Aarnoutse RE, Svensson EM, Gong X, P J Phillips P, Diacon AH, Hoelscher M; PanACEA-TB consortium. Safety, bactericidal activity, and pharmacokinetics of the antituberculosis drug candidate BTZ-043 in South Africa (PanACEA-BTZ-043-02): an open-label, dose-expansion, randomised, controlled, phase 1b/2a trial. Lancet Microbe. 2025 Feb;6(2):100952. doi: 10.1016/j.lanmic.2024.07.015. Epub 2025 Jan 7.

  PMID: 39793592 DERIVED

MeSH Terms

Conditions

Tuberculosis, Pulmonary; Tuberculosis; Gram-Positive Bacterial Infections

Interventions

2-(2-methyl-1,4-dioxa-8-azaspiro(4.5)dec-8-yl)-8-nitro-6-(trifluoromethyl)-4H-1,3-benzothiazin-4-one; Isoniazid; Rifampin; Pyrazinamide; Ethambutol; dolutegravir

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Rifamycins; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Lactams, Macrocyclic; Macrocyclic Compounds; Polycyclic Compounds; Pyrazines; Ethylenediamines; Diamines; Polyamines; Amines

Study Officials

• Michael Hoelscher, Prof

  University Hospital, LMU Munich, Division of Infectious Diseases and Tropical Medicine

  STUDY DIRECTOR

• Andreas Diacon, Prof

  TASK Applied Science Clinical Research Centre

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: Laboratory staff, analysing and evaluating the sputum and safety blood samples of the participants will be blinded to the treatment cohort/arm.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Prof. Dr. Michael Hoelscher

Model Details: 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.

Study Record Dates

• First Submitted: July 29, 2019
• First Posted: August 2, 2019
• Study Start: November 15, 2019
• Primary Completion: March 3, 2022
• Study Completion: May 31, 2022
• Last Updated: August 10, 2022

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will not share

Locations

ZA (2)