This study was a phase 3, multicenter, open-label trial of hospitalized Chinese patients at least 18 years of age who were candidates for or had undergone a laparotomy, laparoscopy, or percutaneous drainage of an intra-abdominal abscess and had a known or suspected diagnosis of cIAI. Specific enrollment criteria are outlined in Table 1. Following approval of the study protocol by the institutional review board or ethical review committee at each participating center, each patient or his or her legal representative provided written informed consent prior to undergoing any study procedures.
Patients were randomly assigned using a computerized enrollment system in a 1:1 ratio to receive tigecycline (initial 100-mg dose given by intravenous [IV] infusion over a 30-minute period, followed by 50 mg IV every 12 hours) or IV imipenem/cilastatin (500 mg/500 mg every 6 hours or dose-adjusted based on weight and creatinine clearance). Patients were to receive study drug for up to 2 weeks, unless deemed a treatment failure after at least 4 doses of tigecycline or 8 doses of imipenem/cilastatin.
Baseline aerobic and anaerobic cultures from the primary intra-abdominal site of infection and two sets of blood cultures were obtained within 24 hours of the first dose of study drug.
At serial visits throughout the study, the clinical status of the patient’s intra-abdominal infection was assessed based upon the presence or absence of the following signs and symptoms: fever; localized or diffuse abdominal wall rigidity or involuntary guarding; abdominal tenderness or pain; ileus or hypoactive bowel sounds; nausea or vomiting. The clinical response to study drug was determined by the investigator at the test-of-cure (TOC) visit (12-37 days after therapy) and categorized as cure, failure, or indeterminate.
Microbiologic response by patient was categorized at the TOC visit as eradication, persistence, superinfection (i.e., the emergence of a new isolate was documented at the site of infection with worsening signs and symptoms of infection), or indeterminate. The microbiologic response for each baseline isolate at the TOC visit was categorized as eradication, persistence, or indeterminate.
All patients who received at least one dose of study drug were evaluated for safety. Safety was assessed from clinical observations and findings from serial electrocardiograms (ECGs), serum chemistry, hematology, coagulation, and urinalysis tests. Adverse events (AEs) were recorded throughout the study period, up to and including the TOC visit or 14 days after last dose of study medication (whichever was longer), and were subjectively rated by the investigator as to their severity and relationship to the study drug. Investigators also recorded whether the AE resulted in temporary or permanent discontinuation and whether any remedial action was taken. Serious AEs (SAEs; i.e., those that were life-threatening, led to prolongation of the existing hospitalization, caused persistent or significant disability or incapacity, led to cancer, or death) were also recorded.
Three primary populations of patients were assessed for safety, clinical, and bacteriologic outcomes; the modified intent-to-treat (mITT), microbiologic modified ITT (m-mITT), and the microbiologically evaluable (ME) populations. ITT patients who received at least one dose of study drug were included in the mITT population. Patients in the mITT population who had clinical evidence of complicated intra-abdominal infection comprised the clinical-mITT (c-mITT) population. The m-mITT population consisted of patients in the c-mITT population who had ≥1 isolate identified at the baseline assessment. Clinically evaluable (CE) patients were c-mITT patients who met all inclusion/exclusion criteria; did not receive concomitant antibiotics after the baseline intra-abdominal culture was obtained through the test-of-cure visit; received no more than 1 dose of a prohibited antibacterial treatment after the baseline intra-abdominal culture was obtained but before the first dose of study drug; received at least 5 days of study drug and between 80% and 120% of planned doses; had a test-of-cure visit 12 to 37 days after the last dose of study drug. Those patients included in the microbiologically evaluable (ME) population were CE patients who had at least one identifiable baseline bacterial isolate(s) taken from the primary site of infection that was susceptible to both study drugs and who had a microbiologic response assigned, i.e., eradication, persistence, or superinfection, at the TOC visit.
This trial was designed to enroll 200 patients. By assuming an evaluability rate of 50%, this would allow for the evaluation of 100 ME patients. The expected percentage of patients with a favorable clinical response (cure) was 70% at the TOC assessment. With a sample size of 50 evaluable patients in a treatment group, if 35 patients showed a favorable clinical response, then the 2-sided exact 95% CI would equal 55.4, 82.1.
The primary efficacy endpoints were clinical response at the TOC visit for the m-mITT and ME populations. Microbiological response at the TOC visit by patient and isolate was performed as a secondary analysis. Because the study was not powered to demonstrate non-inferiority between tigecycline and imipenem/cilastatin, no formal statistical analysis was performed for the primary and secondary efficacy endpoints of this study. Two-sided 95% confidence intervals (CIs) were calculated for the response rates in each treatment group for descriptive purposes using the “exact” method of Clopper and Pearson. Two-sided 95% CIs for differences between groups were calculated based on the asymptotic method corrected for continuity, except for differences in subgroup analyses where the Wilson score method corrected for continuity was used. Secondary efficacy analyses included the determination of susceptibility to tigecycline (MIC50, MIC90) and the development of decreased susceptibility (at least a 4-fold increase in MIC from baseline). Susceptibility was analyzed by using the Fisher exact test.
A post-hoc Cochran-Mantel-Haenszel analysis (stratified by protocol) was performed on the 2 co-primary efficacy endpoints to evaluate equality across the current trial and the 2 global cIAI studies [16]. The Breslow-Day test was used to evaluate equality across the strata with a P value of < 0.05 indicating statistical significance from study to study with respect to clinical response.
The Global Biostatistics and Programming Department of Wyeth Research performed all statistical analyses.
