Brief Summary:
To evaluate the 2-week bactericidal activity, pharmacokinetics, safety and tolerability of sanfetrinem cilexetil in participants with rifampicin-susceptible pulmonary tuberculosis.
Detailed Description:
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 3.2 g PO OD
- Sanfetrinem cilexetil 800 mg PO 12-hourly
- Sanfetrinem cilexetil 800 mg PO 8-hourly
- Sanfetrinem cilexetil 1.6 g plus amoxicillin/clavulanic acid (Amx/CA) 250mg/125 mg, PO 12-hourly
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Sanfetrinem cilexetil 1.6 g 12-hourly plus rifampicin 35 mg/kg 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 both as control for the EBA quantitative mycobacteriology and allow evaluation of pharmacodynamic-pharmacodynamic (PD-PD) interaction between rifampicin and sanfetrinem.
The study will not be blinded but the mycobacteriology laboratory staff performing the endpoint assays will remain blinded until analysis of the EBA results.