A multi-centre, randomized, open-label clinical trial. All treatments will be administered orally (PO) on days 1-14.
15 participants will be recruited into each treatment arm in two sequential cohorts. Each cohort will have participants enrolled onto the experimental regimen(s) or the standard of care (SOC; HRZE) control arm.
• Cohort 1 aims to generate safety data for a higher dose of alpibectir plus ethionamide 125 mg and 250 mg (arm 1: A45E125 and arm2: A45E250).
Once 5 participants have enrolled into arms 1 and 2 each, and completed 14 days of treatment, an interim safety review will be conducted to determine whether the study can advance to cohort 2.
• Cohort 2 will investigate safety of alpibectir and ethionamide (A45E250) in combination with rifampicin, pyrazinamide and ethambutol (A45E250RZE).
Participants on HRZE will serve as control for the EBA quantitative mycobacteriology in each cohort, and additionally as a safety benchmark for the A45E250RZE arm. The study is not statistically powered to make between arm comparisons of activity or safety. The treatment will not be blinded but the mycobacteriology laboratory staff performing the endpoint assays will remain blinded until analysis of the EBA results.
Provide written, informed consent prior to all trial-related procedures and willing to adhere to all required study procedures and restrictions for the duration of the trial.
Male or female, aged between 18 and 65 years, inclusive.
Body weight (in light clothing and with no shoes) between 40 and 90 kg, inclusive.
Newly diagnosed and untreated for this episode of pulmonary TB.
Evidence of clinically significant conditions or findings, other than TB, that might compromise safety or the interpretation of trial endpoints, per discretion of the investigator.
Poor general condition where any delay in treatment cannot be tolerated per discretion of the investigator.
History of epilepsy, seizures or other neuropsychiatric disorders that might compromise safety or the interpretation of trial endpoints, per discretion of the investigator.
Cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice (with the exception of Gilbert's syndrome or asymptomatic gallstones).
Sequential
Alpibectir 45 mg once daily (OD) plus Ethionamide 125 mg OD
DrugCohort 1 Arm 1
Alpibectir 45 mg OD plus Ethionamide 250 mg OD
DrugCohort 1 Arm 2
Isoniazid, rifampicin, pyrazinamide and ethambutol fixed dose combination, weight based
DrugActive Comparator
Alpibectir 45 mg OD plus Ethionamide 250 mg OD plus Rifampicin 10 mg/kg OD plus Ethambutol 20 mg/kg OD plus Pyrazinamide 25 mg/kg OD
DrugCohort 2 Arm 4
EBA-TTP (0-14)
The EBA TTP (0-14) as determined by the rate of change in log10TTP in sputum over the period day 0 (baseline sample) to Day 14 will be described using linear, bi-linear, or non-linear functions using nonlinear mixed effects modelling of log10TTP over time. Estimates of rates of change including uncertainties for each treatment group will be given and graphically illustrated.
EBA CFU (0-14)
The EBA CFU (0-14) as determined by the rate of change in log10CFU per ml sputum over the period day 0 to day 14 will be described using linear, bi-linear, or non-linear functions using nonlinear mixed effects modelling as dictated by the data of log10CFU over time. Estimates of rates of change including uncertainties for each treatment group will be given and graphically illustrated.
EBA (0-2) and EBA (2-14)
The EBA (0-2) and EBA (2-14) determined by the rate of change in The EBA (0-2) and EBA (2-14) determined by the rate of change in log10CFU and log10TTP over time.
Safety and tolerability
The incidence of the following events will be summarized by treatment group: * Incidence of treatment-emergent adverse events (TEAEs). * Incidence of TEAEs by Severity. * Incidence of drug related TEAEs. * Incidence of Serious TEAEs. * Incidence of TEAEs leading to treatment discontinuation. * Incidence of TEAEs leading to early withdrawal from the study. * Incidence of TEAEs leading to death. Descriptive summary statistics will be presented for other safety variables: laboratory parameters, physical examination, vital signs, concomitant medication
PK analysis - Cmax
Maximum observed plasma drug concentration (Cmax),
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TASK Applied Science
Lead sponsor
Innovative Medicines Initiative
Collaborator
