To evaluate the early bactericidal activity (EBA), safety, tolerability and pharmacokinetics of meropenem administered intravenously three times a day, plus amoxycillin/CA administered orally three times a day; and of faropenem administered orally three times a day, plus amoxycillin/CA administered orally three times a day; for 14 consecutive days, in adult participants with newly diagnosed, smear positive pulmonary tuberculosis, in order to help establish proof-of-concept for carbapenem antibiotics as antituberculosis agents and to select the appropriate agent and route of administration for later stage clinical development.
A single-centre, open-label clinical trial including a total of 45 male or female participants (2 groups of 15 participants receiving an IMP and 1 group of 15 participants receiving Rifafour e-275), aged between 18 and 65 years (inclusive), with newly diagnosed, smear-positive, pulmonary tuberculosis will be enrolled into this trial. Treatment will be administered for 14 consecutive days in the following dosing schemes: 1. Meropenem 2g intravenously 8-hourly; plus amoxycillin/CA 500mg/125mg orally 8- hourly on days 1-14. 2. Faropenem 600mg orally 8-hourly; plus amoxycillin/CA 500mg/125mg orally 8-hourly on days 1-14. 3. The third arm will receive standard first line TB treatment as per the South African TB guidelines (Rifafour e-275) and is included as a control for the EBA quantitative mycobacteriology and to evaluate whether HRZE gives similar EBA results to that demonstrated in prior studies with this combination. The mycobacteriology laboratory will remain blinded until closure of the EBA results. Participants will be admitted to the in hospital facility for a period of up to 24 days. During this period they will await their screening results after which they will receive 14 day of IMP. on day 14 intensive PK sampling will be done. They will be discharged on day 15 to the clinic where they will continue on the national TB programme treatment regime. Participants will return to the clinical trial site 14 days after receipt of their last study drug. for a safety evaluation.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
46
To administer 2g daily 8 hourly for 14 days
To adminster 600mg 8 hourly daily for 14 days
To administer 625mg 8 hourly daily for 14 days together with the faropenem and meropenem
To be taken as per the National TB treatment programme for 14 days
TASK Foundation NPC
Cape Town, Western Cape, South Africa
Primary Endpoint (The EBA CFU(0-14) as determined by the rate of change in logCFU per ml sputum)
The EBA CFU(0-14) as determined by the rate of change in logCFU per ml sputum over the period Day 0 to Day 14 which will be described with at most 3 parameters from a linear, bi-linear or non-linear regression of logCFU on time
Time frame: 14 days
Efficacy (The EBA CFU(0-2) and EBA CFU(2-14) as determined by the rate of change of logCFU in sputum)
The EBA CFU(0-2) and EBA CFU(2-14) as determined by the rate of change of logCFU in sputum over the period Day 0 to Day 2 and Day 2 to Day 14, which will be described with at most 3 parameters from an appropriate function of logCFU on time. The EBA TTP(0-2), EBA TTP(0-14), and EBA TTP(2-14) in the Mycobacterial Growth Indicator Tube (BactecTM MGITTM 960) system as determined by the rate of change in TTP in sputum over the periods Day 0 to Day 2, Day 0 to Day 14, and will be described with at most 3 parameters from an appropriate function of TTP on time.
Time frame: 14 days
Safety and Tolerability (Incidence of treatment emergent adverse events (TEAEs)
will be presented by severity, IMP relatedness, seriousness, leading to early withdrawal and leading to death
Time frame: 28 days
Pharmacokinetics (The maximum observed plasma concentration (Cmax), time to reach Cmax (Tmax), the minimum observed plasma concentration (Cmin)
The maximum observed plasma concentration (Cmax), time to reach Cmax (Tmax), the minimum observed plasma concentration (Cmin) 24 hours following the intake if the first daily dosing on day 14, area under the plasma concentration time (t) curve from zero to 24 hours (AUC(0-24)) will be estimated for the following, on Day 14
Time frame: 14 days
Pharmacokinetics - Pharmacodynamics (descriptive analyses, and no inferential tests will be carried out, of EBA CFU(0-14), EBA CFU(0-2), and EBA CFU(2-14) vs. AUC(0-24) • Time over Minimum inhibitory concentrations (TMIC) (for meropenem; faropenem)
The EBA CFU(0-14), EBA CFU(0-2), and EBA CFU(2-14) vs. the following PK variables will be presented for meropenem and faropenem: * Cmax * AUC(0-24) * Time over Minimum inhibitory concentrations (TMIC) (for meropenem; faropenem) * These data will be presented as descriptive analyses, and no inferential tests will be carried out.
Time frame: 14 days
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