Background: Clinical trials of new antibacterial agents in pts with carbapenem-resistant infections are critical but challenging to conduct. One challenge is identifying the study population by microbiological (micro) criteria; pts need to be identified locally to initiate effective treatment rapidly, but data standardization requires central laboratory confirmation. REL is a novel β-lactamase inhibitor that can restore imipenem activity against many imipenem-NS gram-negative pathogens. Here we compare a supplemental analysis population based on local microbiology data (SmMITT eligibility) with the primary analysis population (mMITT) from the RESTORE-IMI 1 trial (NCT02452047) of IMI/REL vs IMI+CST.
Methods: Randomized, active-controlled, double-blind, phase 3 trial enrolled adults with hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP), complicated intra-abdominal infection (cIAI), or complicated urinary tract infection (cUTI). Pts were mMITT-eligible if pathogens were imipenem-NS (but CST- and IMI/REL-susceptible) based on central lab minimum inhibitory concentration (MIC). SmMITT comprised mMITT plus all pts who met inclusion criteria only based on local lab MIC.
Results: The SmMITT population (n=41 [28 IMI/REL; 13 IMI+CST]) comprised 31 from mMITT plus 10 based on local MIC; 12/41 (29%) had HABP/VABP, 8/41 (20%) cIAI, and 21/41 (51%) cUTI. The majority of differences in central vs local MIC were 1-2 dilutions; similar numbers of pts were excluded from mMITT due to imipenem susceptibility (n=5) or IMI/REL-NS (n=4); 1 patient was CST-NS. Baseline characteristics, including infecting pathogens, were comparable in SmMITT and mMITT (SmMITT: 68% male; 46% ≥65 y; 24% APACHE II score >15; 22% creatinine clearance <60 mL/min). Rates of efficacy outcomes (overall response, day 28 clinical response, day 28 mortality) were comparable between populations, except that response rates in pts with cIAI were higher in SmMITT (Table).
Conclusion: Consistency of results was demonstrated across 2 analysis populations in a trial of resistant pathogens. This analysis provides results supportive of expected future clinical use of IMI/REL when treatment decisions will be made based on local lab results.
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