This is a phase 2B/C, open label platform study that will compare the efficacy, safety of experimental regimens with a standard control regimen in participants with newly diagnosed, drug sensitive pulmonary tuberculosis. In stage 1, participants will be randomly allocated to the control or one of the 2 rifampicin-containing experimental regimens in the ratio 1:1:1. In stage 2, the experimental arm 4 containing BTZ-043 will be added. The allocation ratio will be changed to co-enrol the remaining participants in arms 1- 3 simultaneously with arm 4 in a ratio of 1:1:1:2. When arms 1-2 are fully enrolled and arm 4 is not, further participants will be randomized 1:1 to control and experimental arm 4. Not all countries will participate in stage 2. In stage 3, participants will be allocated in parallel to control arm treatment (now designated arm 7) or the experimental arms 5 and 6, favouring arm 5, 2:1:1 over arms 6 and control. This stage will start after completion of recruitment in the stages 1 and 2. Enrolment of participants into arm 5 will proceed following review of data from the ENABLE/UNITE-03 (NCT06748937), non-clinical safety data and after endorsement by the DSMB. Thus, arm 5 recruitment might start after arms 6 and 7, which may require an increase in the control arm sample size to ensure controls are recruited concomitantly.
This open label, phase 2B/C , randomized, controlled platform trial, will evaluate experimental arms including regimens with optimized doses of rifampicin, pyrazinamide, and moxifloxacin; a regimen with BTZ-043 combined first-line anti-TB drugs; a regimen with alpibectir-boosted ethionamide replacing isoniazid in combination with first-line anti-TB durgs, and a bedaquiline sparing regimen containing new anti-TB drugs (ganfeborole, BTZ-043 and delpazolid) in adults with newly diagnosed, drug sensitive, smear-positive pulmonary tuberculosis A total of up to 390 (270 for stage 1 and 2, and 120 for stage 3, respectively) adult (≥ 18 years of age) participants will be enrolled. In case of a high number of dropouts or non-evaluable participants, it may be necessary to recruit more participants into the study. Also, if the stage 2 starts later than stage 1, it may be necessary to increase the number of control arm participants to achieve a 1:1 ratio of concomitantly recruited control and arm 4 participants until the recruitment for arm 4 is completed (see sample size considerations). Stage 3 will start after stages 1 and 2 complete recruitment.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
390
BTZ-043 1000mg once daily in arms 4 and 6.
Rifampicin will be dosed in a fixed high-dose (2100 mg for arms 1 and 2) or a weight-banded regular dose (10 mg/kg) in arm 3, 5 and 7.
Isoniazid will be dosed at fixed dose of 300mg in arms 1 and 2, and regular dose of 5 mg/kg in arm 3 and 7.
Pyrazinamide will be dosed in a fixed regular dose in arm 1 (1600 mg), a weight banded high dose in arm 2 (2000/2400 mg) or a weight-banded regular dose (25 mg/kg) in arm 3, 5 and 7.
Moxifloxacin will be dosed at 600 mg orally once daily in arms 1-2.
Alpibectir 45 mg OD plus Ethionamide 500 mg OD combined with rifampicin pyrazinamide and ethambutol at standard weight-banded doses in arm 5.
Ganfeborole 20 mg OD in arm 6
Delpazolid 1200mg OD in arm 6
Pretomanid 20mg OD in arm 6.
Ethambutol 20mg/Kg OD in arm 3, 5 and 7
Ethionamide 500mg OD in arm 5.
Centre de Recherches Médicales de Lambaréné (CERMEL)
Lambaréné, Gabon
COMPLETEDKamuzu College of Health Sciences (formerly College of Medicine)
Blantyre, Malawi
RECRUITINGInstituto Nacional de Saúde (INS)
Maputo, Mozambique
RECRUITINGIsango Lethemba TB Research Unit. Clinical HIV Research Unit (CHRU), Wits Health Consortium.
Port Elizabeth, Eastern Cape, South Africa
NOT_YET_RECRUITINGTASK Applied Sciences Clinical Research Centre
Cape Town, South Africa
RECRUITINGUniversity of Cape Town Lung Institute
Cape Town, South Africa
NOT_YET_RECRUITINGNational Institute for Medical Research (NIMR-MMRC)
Mbeya, Mbeya, Tanzania
RECRUITINGIfakara Health Institute (IHI)
Bagamoyo, Tanzania
RECRUITINGKilimanjaro Clinical Research Institute (KCRI)
Moshi, Tanzania
RECRUITINGMakerere University Lung Institute Limited
Kampala, Uganda
RECRUITINGTime to stable culture conversion to negative in liquid media
The primary efficacy endpoint of arms 1 and 2 will be time to stable culture conversion to negative in liquid media defined as the time from enrolment to the first of two negative weekly sputum cultures without an intervening positive culture in liquid media, in comparison to arm 3. The efficacy of BTZ-043 will be evaluated by measuring the change in mycobacterial load over time on treatment as quantified by time to positivity in BD MGIT 960® liquid culture described by non-linear mixed-effects methodology, in comparison to arm 3.
Time frame: Day 01- Week 26
Change in Mycobacterial load (Stage 3)
The efficacy of the arms 5 and 6 (Stage 3) will be evaluated by measuring the change in mycobacterial load over time on treatment as quantified by time to positivity in BD MGIT 960® liquid culture described by non-linear mixed-effects methodology, in comparison to arm 7 using the TTP0-8 or 12 weeks slope.
Time frame: Baseline until week 12 of treatment.
Relapse - free survival at 12 months after randomization
To assess treatment efficacy based on proportion of patients with relapse free outcome at 12 months after randomization. Sustained cure at 12 months (52 weeks) after randomization without a failure or relapse event is achieved when all the following criteria are met: * known to be alive at or after 48 weeks after randomization; * having Sustained Culture Negativity at 48 weeks after randomization; * not having met criteria for Failure or Relapse event (see below); * not in need of TB treatment and having had no substantial treatment modifications or additional treatment for TB outside of the pre-specified treatment strategies.
Time frame: Day 01-364
Frequency of all adverse events (serious and non-serious)
To assess the frequency, severity, and type of adverse events (AEs), and AE related treatment discontinuations.
Time frame: Day 01-182
Frequency of adverse events of Grade 3 severity (severe) or higher
Severity of AEs will be classified following the U.S. National Institutes of Health Common Terminology Criteria for Adverse Events 5.0 (CTCAE). The minimum grade is 1 (Mild) and the maximum grade is 5 (Death related to AE). Higher scores mean a worse outcome.
Time frame: Day 01-182
Frequency of adverse events possibly, probably or definitely related to study drug
To assess the frequency, severity, and type of adverse events (AEs), and AE related treatment discontinuations.
Time frame: Day 01-182
Frequency of treatment discontinuations or interruptions related to adverse events/serious adverse event
To assess the frequency, severity, and type of adverse events (AEs), and AE related treatment discontinuations.
Time frame: Day 01-182
Changes in ECG intervals of PR, RR, QRS, QT, Fridericia-corrected QT [QTcF]
* Proportion of participants with QTcF \> 500ms in ECGs on treatment * Proportion of participants who have a QTcF prolongation of grade 3 or higher
Time frame: Day 01-182
Area under the plasma concentration curve from dosing to the end of the dosing interval (AUC 0-24) predicted from limited pharmacokinetic sampling.
For RIF, PZA, MXF, and IHN (arms 1-3), and BTZ-043, RIF, INH and PZA (arm 4) in all participants with limited pharmacokinetic sampling strategy being done on WK 02 (Day 14 ± 2 Days).
Time frame: Day 14
The observed maximum concentration (Cmax)
For RIF, PZA, MXF, and IHN (arms 1-3), and BTZ-043, RIF, INH and PZA (arm 4) in all participants with limited pharmacokinetic sampling strategy being done on WK 02 (Day 14 ± 2 Days).
Time frame: Day 14
Time to reach Cmax (Tmax)
For RIF, PZA, MXF, and IHN (arms 1-3), and BTZ-043, RIF, INH and PZA (arm 4) in all participants with limited pharmacokinetic sampling strategy being done on WK 02 (Day 14 ± 2 Days).
Time frame: Day 14
Minimum observed plasma concentration 24 hours following the last dose (Cmin)
For RIF, PZA, MXF, and IHN (arms 1-3), and BTZ-043, RIF, INH and PZA (arm 4) in all participants with limited pharmacokinetic sampling strategy being done on WK 02 (Day 14 ± 2 Days).
Time frame: Day 14.
DTG and TFD concentration
concentrations will be compared at screening and at week 2. More time points may be determined if leftover samples are available. Timing of last DTG and TFD dose intake will be recorded.
Time frame: Day 01-15
Identification of M. tuberculosis complex and Rifampicin (RIF) resistance by PCR (GeneXpert Ultra MTB/RIF®/GeneXpert XDR/HAIN MTBDRplus or similar)
Cultures grown from the screening period, and the last sputum sample with mycobacteriological growth will be assessed. This test is qualitative, therefore the result will be: Detected, not detected or indeterminate.
Time frame: Day 01-182
Identification of M. tuberculosis complex and Isoniazid (INH) resistance by PCR (GeneXpert Ultra MTB/RIF®/GeneXpert XDR/HAIN MTBDRplus or similar)
Cultures grown from the screening period, and the last sputum sample with mycobacteriological growth will be assessed. This test is qualitative, therefore the result will be: Detected, not detected or indeterminate.
Time frame: Day 01-182
Minimum inhibitory concentrations (MIC) of study drugs the patient was receiving
Cultures grown from the screening period, and the last sputum sample with mycobacteriological growth will be assessed.
Time frame: Day 01-182
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.