EBA, Safety and Tolerability of Sanfetrinem Cilexetil

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.

Inclusion criteria

• Participants are required to meet all of the following criteria in order to be randomized.

• Provide written, informed consent prior to all trial-related procedures.
• 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, previously untreated, rifampicin-susceptible pulmonary TB.
• A chest X-ray picture taken at screening which, in the opinion of the investigator, is consistent with TB.
• Sputum positive on direct microscopy for acid-fast bacilli on at least one sputum sample (at least 1+ on the IUATLD/WHO scale) or GeneXpert cycle threshold of medium or high.
• Ability to produce an adequate volume of sputum as estimated from an overnight sputum collection sample (estimated 10 ml or more).
• Be of non-childbearing potential or using effective methods of birth control, as defined below:

Non-childbearing potential:

Female participant/ female sexual partner - bilateral oophorectomy

• bilateral tubal ligation
• hysterectomy
• postmenopausal with no menses for at least 12 consecutive months Male participant/ male sexual partner - vasectomy
• bilateral orchidectomy more than three months prior to screening

Effective birth control methods:

• Participant is not heterosexually active or practicing sexual abstinence
• Double barrier method which can include a male condom, diaphragm, cervical cap, or female condom (male and female condoms should not be used together); or
• Barrier method combined with hormone-based contraceptives or an intra-uterine device for the female partner.

Exclusion criteria

• Participants will be excluded from participation if they fulfil any of the following criteria.

• 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.
• Clinically significant evidence of extrathoracic TB, as judged by the investigator.
• History of allergy to any of the trial IP/s or related substances i.e. β-lactams and penicillin, as confirmed by the clinical judgement of the investigator.
• Alcohol or drug abuse, that in the opinion of the investigator, is sufficient to compromise the safety or cooperation of the participant.
• HIV positive ONLY IF:

• CD4 < 250cells/mm3
• On ART
• Participation in other clinical studies with investigational agents within 8 weeks prior to trial start (with the exception of COVID-19 vaccines).
• Female participant who is pregnant, breast-feeding, or planning to conceive a child within the anticipated period of trial participation. Male participant planning to conceive a child within the anticipated period of participating in the trial.
• Treatment received with any drug active against M.tb (including but not limited to isoniazid, ethambutol, amikacin, cycloserine, fluoroquinolones, rifabutin, rifampicin, streptomycin, kanamycin, para-aminosalicylic acid, rifapentine, pyrazinamide, thioacetazone, capreomycin, thioamides), or with immunosuppressive medications such as TNF-alpha inhibitors within 2 weeks prior to screening, or systemic corticosteroids for more than 7 days within 2 weeks prior to screening.
• Participants with the following toxicities at screening as defined by the enhanced CTCEA toxicity table

• creatinine >1.5 times upper limit of normal [ULN];
• haemoglobin <8.0 g/dL;
• platelets <50x109 cells/L;
• serum potassium <3.0 mmol/L;
• aspartate aminotransferase (AST) ≥3.0 x ULN;
• alanine aminotransferase (ALT) ≥3.0 x ULN;
• Total white cell count <1.5 cells/L
• For participants undergoing PET/CT, the following are excluded:

• Participants with diabetes (Type 1 or 2) with point of care HbA1c above 6.5, or random glucose over 11.1 mmol/L.