Table 2.
Summary of Primary and Secondary Efficacy Endpoints (Microbiological Modified Intent-to-Treat Population)
| Endpoint | Patients, No. (%) |
Difference, % (95% CI) | |
|---|---|---|---|
| Ceftazidime-Avibactam (n = 393) | Doripenem (n = 417) | ||
| FDA co-primary endpoints | |||
| Patient-assessed symptomatic resolutiona at day 5b | 276 (70.2) | 276 (66.2) | 4.0 (−2.39 to 10.42) |
| Combined patient-assessed symptomatic resolutionc and favorable per-patient microbiological response at TOCb | 280 (71.2) | 269 (64.5) | 6.7 (.30 to 13.12) |
| Per-patient favorable microbiological response at TOC | 304 (77.4) | 296 (71.0) | 6.4 (.33 to 12.36) |
| Patient-reported symptomatic resolution at TOC | 332 (84.5) | 360 (86.3) | −1.9 (−6.78 to 3.02) |
| EMA primary endpoint | |||
| Per-patient favorable microbiological response at TOCd | 304 (77.4) | 296 (71.0) | 6.4 (.33 to 12.36) |
| Secondary endpoints | |||
| Microbiological | |||
| Per-patient favorable microbiological response at EOT (IV) | 374 (95.2) | 395 (94.7) | 0.4 (−2.7 to 3.56) |
| Per-patient favorable microbiological response at LFU | 268 (68.2) | 254 (60.9) | 7.3 (.68 to 13.81) |
| Per-patient favorable microbiological response at TOC in patients with a ceftazidime-nonsusceptible pathogene | 47/75 (62.7) | 51/84f (60.7) | 2.0 (−13.18 to 16.89) |
| Per-patient favorable microbiological response at LFU in patients with a ceftazidime-nonsusceptible pathogene | 46/75 (61.3) | 38/84 (45.2) | 16.1 (.50 to 30.89) |
| Per-patient favorable microbiological response at TOC in patients with a ceftazidime-susceptible pathogene | 256/316 (81.0) | 238/326 (73.0) | 8.0 (1.50 to 14.48) |
| Per-patient favorable microbiological response at LFU in patients with a ceftazidime-susceptible pathogene | 221/316 (69.9) | 209/326 (64.1) | 5.8 (−1.46 to 13.05) |
| Clinical | |||
| Investigator-determined clinical cure | |||
| EOT (IV) | 378 (96.2) | 407 (97.6) | −1.4 (−4.07 to 1.02) |
| TOC | 355 (90.3) | 377 (90.4) | −0.1 (−4.23 to 4.03) |
| LFU | 335 (85.2) | 350 (83.9) | 1.3 (−3.71 to 6.30) |
| Sustained clinical cure at LFU in patients who were cured at TOC | 330/355 (93.0) | 345/377 (91.5) | 1.4 (−2.5 to 5.4) |
| Investigator-determined clinical cure at TOC in patients with a ceftazidime-susceptible pathogene | 287/316 (90.8) | 295/326 (90.5) | 0.3 (−4.3 to 4.9) |
| Investigator-determined clinical cure at TOC in patients with a ceftazidime-nonsusceptible pathogene | 67/75 (89.3) | 75/84f (89.3) | 0.0 (−10.4 to 10.1) |
Denominators are the total numbers in each group unless shown otherwise.
Abbreviations: CI, confidence interval; EMA, European Medicines Agency; EOT (IV), end of intravenous therapy; FDA, US Food and Drug Administration; LFU, late follow--up (45–52 days after randomization); TOC, test of cure (21–25 days after randomization).
a Symptomatic resolution of symptoms of frequency, urgency, dysuria, and suprapubic pain with resolution or improvement in flank pain, based on the patient-reported symptom assessment questionnaire (PSAQ).
b Co-primary endpoints for the FDA. The sponsor concluded noninferiority if the lower limit of the 95% CI at TOC was greater than −12.5%. The FDA noninferiority margin was a lower limit of the 95% CI greater than −10.0%.
c Symptomatic resolution of all symptoms (frequency, urgency, dysuria, suprapubic pain, and flank pain) based on the PSAQ.
d Primary endpoint for the EMA. The sponsor concluded noninferiority if the lower limit of the 95% CI at TOC was greater than −12.5%.
e Ceftazidime nonsusceptibility was defined as a central microbiology reference laboratory minimum inhibitory concentration ≥8 µg/mL for Enterobacteriaceae or ≥16 µg/mL for Pseudomonas aeruginosa, or local laboratory disk diffusion diameter (from a 30 μg ceftazidime disk) of ≤20 mm for Enterobacteriaceae and ≤17 mm for P. aeruginosa. Nine patients were not included in either subset (ceftazidime-nonsusceptible or ceftazidime-susceptible) because no susceptibility tests were performed (6 patients) or baseline blood or urine susceptibility results were missing (3 bacteremic patients).
f One patient in the doripenem group had 2 ceftazidime-nonsusceptible pathogens isolated at baseline.