To evaluate the 2-week bactericidal activity, pharmacokinetics, safety and tolerability of sanfetrinem cilexetil in participants with rifampicin-susceptible pulmonary tuberculosis.
A single-centre, open-label, clinical trial in two stages. Stage 1 will recruit 20 participants followed by a recruitment pause and an interim analysis to determine if sanfetrinem cilexetil has early bactericidal activity (EBA). Should EBA be demonstrated, stage 2 will focus on optimising sanfetrinem cilexetil. All treatments will be administered orally (PO) on days 1-14. The treatments are: Stage 1: * Sanfetrinem cilexetil 1.6 g PO 12-hourly * Rifampicin 35 mg/kg PO once daily (OD)\* An interim analysis is planned after stage 1 to review the pharmacokinetics (PK), safety, tolerability and EBA of sanfetrinem cilexetil. Results of stage 1 will determine whether stage 2 should proceed and if any modifications in dose, duration or combinations are required for Stage 2. If deemed possible, a PK-EBA model will be derived using only stage 1 from which clinical trial simulations will be conducted to inform the design of stage 2. If EBA is not demonstrated, the study will be stopped after stage 1. Stage 2: * Rifampicin 35 mg/kg po OD\* * Sanfetrinem cilexetil 2.4 g PO OD Five of the rifampicin 35 mg/kg arm participants will be recruited in stage 1 and the remainder in stage 2. Participants on rifampicin will serve as control for the EBA quantitative mycobacteriology. The study will not be blinded but the mycobacteriology laboratory staff performing the endpoint assays will remain blinded until analysis of the EBA results.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
54
Sanfetrinem cilexetil powder, weighed for dose and administered as a suspension in water. Amx/CA 250/125 mg tablets Rifampicin 150 mg, 300 mg and 600 mg tablets or capsules
Rifampicin will be administered at a dose of 35 mg/kg once daily for 14 days with or without sanfetrinem cilexetil.
TASK Clinical Research Centre
Cape Town, Western Cape, South Africa
Rate of change in mycobacterium tuberculosis (Mtb) load in sputum from pre-treatment to Day 14 on-treatment, based on colony forming unit (CFU) count on solid culture media (7H11 agar plates)
Early bactericidal activity (EBA) will be determined, per treatment arm, as the rate of change in log10 CFU count per ml sputum over the treatment period day 0 to day 14, and described using linear, bi-linear or non-linear regression of log10CFU count over time and relation to drug exposure.
Time frame: 14 days
Rate of change in mycobacterium tuberculosis (Mtb) load in sputum from pre-treatment to Day 14 on-treatment, based on time to positive (TTP) culture in the BACTEC MGIT 960 liquid culture system
EBA will be determined, per treatment arm, by the rate of change in time to culture positivity (TTP) over the treatment period day 0 to day 14, and described using linear, bi-linear or non-linear regression of TTD over time and relation to drug exposure
Time frame: 14 days
Number of patients with abnormal safety and tolerability findings following the study regimens, administered for 14 days
The pooled incidence of the following events will be summarized by treatment group for further analysis: 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 early withdrawal; Incidence of TEAEs leading to death 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 early withdrawal; Incidence of TEAEs leading to death
Time frame: 14 days
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