Pulmonary TuberculosesPhase 1/2NCT04044001
BTZ-043 - Multiple Ascending Dose (MAD) to Evaluate Safety, Tolerability and Early Bactericidal Activity (EBA)
A Phase 1/2 study testing BTZ-043, Rifafour e-275® and Probe Drug Cocktail in people with Pulmonary Tuberculoses and Other Specified Pulmonary Tuberculosis, run by Michael Hoelscher at 2 sites in South Africa.
Trial 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… Read more about this study
- Who is it for?
- Ages 18 to 64 years
- Conditions the study is for
- Pulmonary Tuberculoses, Other Specified Pulmonary Tuberculosis
- What is being tested?
- BTZ-043, Rifafour e-275® and Probe Drug Cocktail
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 78 participants
- Where
- 2 sitesSouth Africa
- Study dates
- 15 Nov 2019to 31 May 2022
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 64 years
- All sexes
- No healthy volunteers
- Adult
General inclusion criteria:
- 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. Disease-specific inclusion criteria:
- 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.
General exclusion criteria:
- 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. Disease-specific exclusion criteria:
- 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 Laboratory exclusion criteria at screening:
- Serum amino aspartate transferase (AST) and/or alanine aminotransferase (ALT) activity >2x the upper limit of normal (ULN)
- serum alkaline phosphatase (ALP) or y-glutamyl transferase (GGT) > 2x the ULN
- serum total bilirubin level >1.5 times the ULN
- estimated creatinine clearance (eCrCl) using the Cockcroft and Gault formula level lower than 60 mls/min
- haemoglobin level <8.0 g/dL
- platelet count <100,000/mm3
- serum potassium below the lower level of normal (LLN) for the laboratory ECG-specific exclusion criteria:
- corrected QT interval (QTc)F of > 450 milliseconds (ms)
- Atrioventricular (AV) block with PR interval > 200 ms
- QRS complex > 120 ms
- any other changes in the ECG that are clinically relevant as per discretion of the investigator Restricted medication:
- Treatment with drugs active against Mycobacterium Tuberculosis (MTB) within the last 3 months prior to screening
- 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)
Trial locations and contacts
2 sites in 1 country.
South Africa2 sites
TASK Applied Sciences Clinical Research Centre
Cape Town, 7530
University of Cape Town Lung Institute (UCTLI)
Cape Town, 7700
About this study
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
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.
Read the 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.
- Being tested
- BTZ-043, Rifafour e-275®, Probe Drug Cocktail, Dolutegravir 50mg Tab
- 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
- Medical subject headings
- Tuberculosis, Pulmonary, Tuberculosis, Gram-Positive Bacterial Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BTZ-043Drug
BTZ-043 (250mg per tablet)
Rifafour e-275®Drug
Also called Isoniazid, Rifampicin, Pyrazinamide, Ethambutol (HRZE)
Rifafour e-275® (150mg rifampicin, 75mg isoniazid, 400mg pyrazinamide, 275 mg ethambutol per tablet)
Probe Drug CocktailDrug
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
Dolutegravir 50mg TabDrug
Also called Tivicay®
1 tablet à 50mg Dolutegravir will be given to randomly selected patients after inclusion on Day 1 and on Day 14 once orally.
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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 Receives: 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 Receives: 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 Receives: 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 Receives: 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 Receives: 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 Receives: 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 Receives: 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. Receives: 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. Receives: 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. Receives: 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 Receives: Drug: Rifafour e-275® |
What is being measured
The primary outcome is the main question the study is designed to answer.
Safety and Tolerability of BTZ-043
Safety and tolerability of BTZ-043 was assessed by evaluation of Adverse Events (AEs) during treatment- and follow-up phase (Clinical observations, Vital signs, Serum chemistry, hematology and coagulation parameters with baseline measurements. Electrocardiography (ECG), including heart rate, PR interval, QRS, QT interval, QTcF; change of QTcF from baseline; morphological abnormalities).
Measured: Day 1 to Day 22
Secondary outcomes (2)
Bactericidal Activity Endpoint - MGIT Time to Positivity (log10 (h))
Liquid culture is inoculated with overnight sputum of the participants. Upon growth of Mycobacteria, the color of the medium is changing due to changes in pH. This is measured photometric and the time of the change in color is recorded. The more bactera are inoculated, the quicker the change ind color and the time to positivity.
Overnight sputum is collected on Day -1, Day 0, Day 2, Day 3, Day 4, Day 6, Day 8, Day 11 and Day 14 to be able to follow the decrease in bacterial load over time.
Measured: Day -1 to Day 14. Change from Day -1 to Day 2, Day 2 - Day 14 and Day -1 to Day 14 have been assessed.
Bactericidal Activity Endpoint - CFU
Overnight sputum was plated on solid medium. Decrease in log 10 CFU (No. of colony forming untis) over time was assessed.
Overnight sputum is collected on Day -1, Day 0, Day 2, Day 3, Day 4, Day 6, Day 8, Day 11 and Day 14 to be able to follow the decrease in bacterial load over time.
Measured: Day -1 to Day 14. Change from Day -1 to Day 2, Day 2 - Day 14 and Day -1 to Day 14 have been assessed.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Aug 2019
- Study start15 Nov 2019
- Primary completion3 Mar 2022
- Study completion31 May 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Pulmonary TuberculosesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- 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 blind
- Who is masked
- Outcomes assessor
- Enrolment
- 78 participants (actual)
Sponsor and investigators
- Lead sponsor
- Michael Hoelscher
- Sponsor type
- University, hospital or other
- Collaborators
- European and Developing Countries Clinical Trials Partnership (EDCTP), Radboud University Medical Center, German Federal Ministry of Education and Research
- Responsible party
- Sponsor-investigator, Michael Hoelscher, Ludwig-Maximilians - University of Munich
- Investigators
- Michael Hoelscher, Prof, Study director, University Hospital, LMU Munich, Division of Infectious Diseases and Tropical MedicineAndreas Diacon, Prof, Principal investigator, TASK Applied Science Clinical Research Centre
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04044001
- Sponsor's protocol ID
- PanACEA-BTZ-043-02
- Status last verified
- Aug 2026
- First submitted
- 29 Jul 2019
- Last updated
- 31 Aug 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
McClean MCW, Koele SE, Dreisbach J, Mirold-Mei S, Njeleka F, Mapamba D, Mtafya B, Phillips PPJ, De Jager VR, Dawson R, Narunsky K, Diacon AH, Svensson EM, Heinrich N, Casale FP, Hoelscher M. Modeling Treatment Response in Tuberculosis Early Bactericidal Activity Trials. CPT Pharmacometrics Syst Pharmacol. 2026 Aug;15(8):e70311. doi: 10.1002/psp4.70311.
PubMed 42568101Heinrich 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.
PubMed 39793592
Study at a glance
From the registry record, last updated by the sponsor on 31 Aug 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT04044001
- Acronym / sponsor ID
- PanACEA-BTZ-043-02
- Keywords
- Tuberculosis, Pulmonary, Randomized Controlled Trial (RCT), BTZ-043, Tuberculosis, Antitubercular Agents, Gram-positive Bacterial Infections, Escalating dose, Drug-sensitive TB
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 78 participants (actual)
- Lead sponsor
- Michael HoelscherUniversity, hospital or other
- Collaborators
- European and Developing Countries Clinical Trials Partnership (EDCTP), Radboud University Medical Center, German Federal Ministry of Education and Research
- Study start
- 15 Nov 2019 (actual)
- Primary completion
- 3 Mar 2022 (actual)
- Study completion
- 31 May 2022 (actual)
- First posted
- 2 Aug 2019 (actual)
- Results
- Posted 31 Aug 2026
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 12
- 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.
| Arm | Type | Receives |
|---|---|---|
| Stage 1 - Cohort 1 (BTZ 250) | Experimental | Drug: BTZ-043Patients will receive 1 tablet of BTZ-043 orally once daily, containing 250mg BTZ-043 from Day 1 through to Day 14 |
| Stage 1 - Cohort 2 (BTZ 500) | Experimental | Drug: BTZ-043Patients 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 3 (BTZ 750) | Experimental | Drug: BTZ-043Patients 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 4 (BTZ 1000) | Experimental | Drug: BTZ-043Patients 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) | Experimental | Drug: BTZ-043Patients 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 6 (BTZ 1500) | Experimental | Drug: BTZ-043Patients 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) | Experimental | Drug: BTZ-043Patients 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 1 - Cohort 8 (BTZ 2000) | Experimental | Drug: BTZ-043Patients 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 2 - Arm 1 (BTZ high) | Experimental | Drug: BTZ-043, Drug: Probe Drug Cocktail, Drug: Dolutegravir 50mg TabPatients 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) | Experimental | Drug: BTZ-043, Drug: Probe Drug Cocktail, Drug: Dolutegravir 50mg TabPatients 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) | Experimental | Drug: BTZ-043, Drug: Probe Drug Cocktail, Drug: Dolutegravir 50mg TabPatients 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) | Active comparator | Drug: 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 |
Who may qualify
- Ages
- 18 to 64 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BTZ-043BTZ-043 (250mg per tablet) | Drug | 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®Also: Isoniazid, Rifampicin, Pyrazinamide, Ethambutol (HRZE)Rifafour e-275® (150mg rifampicin, 75mg isoniazid, 400mg pyrazinamide, 275 mg ethambutol per tablet) | Drug | Stage 2 - Arm 4 (control) |
| Probe Drug CocktailA 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 | Stage 2 - Arm 1 (BTZ high), Stage 2 - Arm 2 (BTZ medium), Stage 2 - Arm 3 (BTZ low) |
| Dolutegravir 50mg TabAlso: Tivicay®1 tablet à 50mg Dolutegravir will be given to randomly selected patients after inclusion on Day 1 and on Day 14 once orally. | Drug | Stage 2 - Arm 1 (BTZ high), Stage 2 - Arm 2 (BTZ medium), Stage 2 - Arm 3 (BTZ low) |
Primary outcome
Safety and Tolerability of BTZ-043
Time frame: Day 1 to Day 22
Safety and tolerability of BTZ-043 was assessed by evaluation of Adverse Events (AEs) during treatment- and follow-up phase (Clinical observations, Vital signs, Serum chemistry, hematology and coagulation parameters with baseline measurements. Electrocardiography (ECG), including heart rate, PR interval, QRS, QT interval, QTcF; change of QTcF from baseline; morphological abnormalities).
2 secondary outcomes
Bactericidal Activity Endpoint - MGIT Time to Positivity (log10 (h))
Time frame: Day -1 to Day 14. Change from Day -1 to Day 2, Day 2 - Day 14 and Day -1 to Day 14 have been assessed.
Bactericidal Activity Endpoint - CFU
Time frame: Day -1 to Day 14. Change from Day -1 to Day 2, Day 2 - Day 14 and Day -1 to Day 14 have been assessed.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 31 Aug 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 42568101McClean MCW, Koele SE, Dreisbach J, Mirold-Mei S, Njeleka F, Mapamba D, Mtafya B, Phillips PPJ, De Jager VR, Dawson R, Narunsky K, Diacon AH, Svensson EM, Heinrich N, Casale FP, Hoelscher M. Modeling Treatment Response in Tuberculosis Early Bactericidal Activity Trials. CPT Pharmacometrics Syst Pharmacol. 2026 Aug;15(8):e70311. doi: 10.1002/psp4.70311.
- Derived from this study: PubMed 39793592Heinrich 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
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
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing BTZ-043, Rifafour e-275® and Probe Drug Cocktail in people with Pulmonary Tuberculoses and Other Specified Pulmonary Tuberculosis, run by Michael Hoelscher at 2 sites in South Africa.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 31 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 31 Aug 2026). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Safety and Tolerability of BTZ-043 (time frame: Day 1 to Day 22). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04044001, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Aug 2026.