Table 2.
Primary and Secondary Prospective Efficacy Endpoints (in the Modified Microbiologic Intent-to-Treat Population) and Secondary Prospective Safety Endpoints (in the Safety Population)
| IMI/REL (n = 21) | Colistin + IMI (n = 10) | Unadjusted Difference | Adjusted Differencea | ||||
|---|---|---|---|---|---|---|---|
| Endpoint | n | % (95% CI)b | n | % (95% CI)a | % | % | 90% CI |
| Primary endpoint | |||||||
| Favorable overall responsec | 15 | 71.4 (49.8, 86.4) | 7 | 70.0 (39.2, 89.7) | 1.4 | –7.3 | (–27.5, 21.4) |
| Hospital-acquired bacterial pneumonia/ ventilator-associated bacterial pneumonia | 7/8 | 87.5 (50.8, 99.9) | 2/3 | 66.7 | 20.8 | ||
| Complicated intraabdominal infection | 0/2d | 0.0 | 0/2e | 0.0 | 0.0 | ||
| Complicated urinary tract infection | 8/11 | 72.7 (42.9, 90.8) | 5/5 | 100.0 (51.1, 100.0) | –27.3 (–52.8, 12.8) | ||
| Secondary endpoints | |||||||
| Favorable clinical response (day 28) | 15f | 71.4 (49.8, 86.4) | 4g | 40.0 (16.7, 68.8) | 31.4 | 26.3 | (1.3, 51.5) |
| 28-day all-cause mortality | 2 | 9.5 (1.4, 30.1) | 3 | 30.0 (10.3, 60.8) | –20.5 | –17.3 | (–46.4, 6.7) |
| Treatment-emergent nephrotoxicityh | 3/29 | 10.3 (2.8, 27.2) | 9/16 | 56.3 (33.2, 76.9) | –45.9 (–69.1, –18.4) | ||
CIs are not presented if the number of patients with assessment was <4.
Abbreviations: CI, confidence interval; IMI, imipenem/cilastatin; IMI/REL, imipenem/cilastatin plus relebactam.
aBased on the Miettinen and Nurminen method stratified by infection site.
bBased on the Agresti and Coull method.
cOverall response defined as hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HAP/VAP), survival through day 28; complicated intraabdominal infection (cIAI), clinical response at day 28; complicated urinary tract infection (cUTI), composite clinical and microbiological response 5–9 days after the end of therapy (EOT).
dOne of these patients had cIAI due to Citrobacter freundii encoding Klebsiella pneumoniae carbapenemase KPC-2 and the plasmid-borne AmpC CMY-48; this patient died on day 3 due to pneumonia, with the cIAI not deemed contributory to this death (indeterminate overall response). The other patient had cIAI due to Pseudomonas. aeruginosa encoding the chromosomal AmpC PDC-30, with persistence at the on-therapy visit (OTX) and failure at EOT, the on-therapy visit (EFU), and day 28 (unfavorable overall response).
eOne of these patients had cIAI due to P. aeruginosa encoding the chromosomal AmpC PDC-1, with indeterminate response at OTX, response of “improved” at EOT, and indeterminate response at EFU and day 28 (indeterminate overall response). The other patient had cIAI due to P. aeruginosa isolate encoding the chromosomal AmpC PDC-39, with investigator-assessed response of “improved” at OTX, “cure” at EOT, and “sustained cure” at EFU and day 28; based on prospectively defined rules, prior to unblinding the patient was imputed as having had an unfavorable overall response due to having received confounding, protocol-prohibited antibacterial therapy.
fTwo HAP/VAP patients with favorable overall response (ie, alive at day 28) had an unfavorable clinical response at day 28, while 2 cUTI patients had favorable clinical response at day 28 but (due to lack of microbiologic response) did not have a favorable overall response.
gOf 3 patients with favorable overall response (defined differently for each infection type, see footnote “c”) but lack of day 28 favorable clinical response, 1 patient with HAP/VAP experienced confirmed clinical failure but was still alive by day 28, 1 patient with HAP/VAP due to P. aeruginosa and Delftia acidovorans had an indeterminate clinical response (ie, extenuating circumstances precluded response classification, but the patient still required mechanical ventilation and had hypoxemia) but was still alive by day 28, and 1 patient with cUTI was lost to follow-up by day 28 but had favorable composite clinical and microbiological response 5–9 days after EOT.
hAssessed in evaluable safety population patients (IMI/REL, n = 29; colistin + IMI, n = 16).