REJUVENATE’s First Publication
The research and results coming from COMBACTE can be mined for years to come. In these series, we look back on the very first scientific papers per project and study produced in our consortium. COMBACTE-CARE's REJUVENATE is a Phase II, prospective, open-label, single-arm, dose-confirming multicenter study. The trial was set up to test the optimal dosing and safety of a new combinational drug, aztreonam-avibactam (ATM-AVI). It is a beta-lactam-beta-lactamase inhibitor combination, intended to treat serious Gram-negative bacterial infections in patients with limited or no treatment options. A total of 40 adult patients with a diagnosis of complicated intra-abdominal infection and the need for a surgical intervention were enrolled.
REJUVENATE published its first paper in 2019, on the pharmacokinetics and safety of aztreonam-avibactam for the treatment of complicated intra-abdominal infections. The paper was published in the Journal of Antimicrobial Chemotherapy. Read the abstract below.
ABSTRACT
OBJECTIVES
To investigate pharmacokinetics (PK) and safety (primary objectives) and efficacy (secondary objective) of the investigational monobactam/β-lactamase inhibitor combination aztreonam/avibactam in patients with complicated intra-abdominal infection (cIAI).
METHODS
This Phase 2a open-label, multicentre study (NCT02655419; EudraCT 2015-002726-39) enrolled adults with cIAI into sequential cohorts for 5-14 days treatment. Cohort 1 patients received an aztreonam/avibactam loading dose of 500/137 mg (30 min infusion), followed by maintenance doses of 1500/410 mg (3 h infusions) q6h; Cohort 2 received 500/167 mg (30 min infusion), followed by 1500/500 mg (3 h infusions) q6h. Cohort 3 was an extension of exposure at the higher dose regimen. Doses were adjusted for creatinine clearance of 31-50 mL/min (Cohorts 2 + 3). All patients received IV metronidazole 500 mg q8h. PK, safety and efficacy were assessed.
RESULTS
Thirty-four patients (Cohort 1, n = 16; Cohorts 2 + 3, n = 18) comprised the modified ITT (MITT) population. Mean exposures of aztreonam and avibactam in Cohorts 2 + 3 were consistent with those predicted to achieve joint PK/pharmacodynamic target attainment in >90% patients. Adverse events (AEs) were similar between cohorts. The most common AEs were hepatic enzyme increases [n = 9 (26.5%)] and diarrhoea [n = 5 (14.7%)]. Clinical cure rates at the test-of-cure visit overall were 20/34 (58.8%) (MITT) and 14/23 (60.9%) (microbiological-MITT population).
CONCLUSIONS
Observed AEs were consistent with the known safety profile of aztreonam monotherapy, with no new safety concerns identified. These data support selection of the aztreonam/avibactam 500/167 mg (30 min infusion) loading dose and 1500/500 mg (3 h infusions) maintenance dose q6h regimen, in patients with creatinine clearance >50 mL/min, for the Phase 3 development programme.
Related updates
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COMBACTE is proud to announce a significant milestone achieved in COMBACTE-CARE. The European Medicines Agency (EMA) has recommended granting a market...
