Supplementary Materials
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Supplementary Materials A multicenter, double-blind, randomized, comparison study of the efficacy and safety of tigecycline to imipenem/cilastatin to treat complicated intra-abdominal infections in hospitalized subjects in China Yijian Chen*, Demei Zhu*, Yingyuan Zhang, Yongjie Zhao, Gang Chen, Ping Li, Lihong Xu, Ping Yan, M. Anne Hickman, Xiajun Xu, Margaret Tawadrous, Michele Wible * These authors contributed equally to this study. Contents Supplementary Table 1. Inclusion and exclusion criteria .................................................................... 2 Supplementary Table 2. Summary of MIC data for baseline isolates with number of subjects ≥5 for either antibiotic for the microbiologically evaluable (ME) population................................................... 7 Supplementary Table 3. Adverse events of special interest ................................................................. 8 Supplementary Table 4. Incidence of laboratory test abnormalitiesa in ≥10% of subjects in either treatment group in the safety analysis set ............................................................................................. 10 Supplementary Table 5. Study center information ............................................................................. 11 1 Supplementary Table 1. Inclusion and exclusion criteria Inclusion criteria Eligible subjects were expected to meet the following criteria: • Hospitalized male or female patients, at least 18 years of age. • Patients of childbearing potential had to agree to use a highly effective contraception method throughout the study and for at least 28 days after the last dose of assigned treatment. A subject was of childbearing potential if, in the opinion of the investigator, he/she was biologically capable of having children and was sexually active. Female subjects who were not of childbearing potential (must have met at least 1 of the following criteria): had undergone hysterectomy or bilateral oophorectomy, had medically confirmed ovarian failure or were medically confirmed to be post-menopausal (cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause) • Subjects were required to be candidates for or have had a laparotomy, laparoscopy or percutaneous drainage of an intra-abdominal abscess within 24 hours of enrolment. Subjects could have been enrolled preoperatively, however, investigational products should not have been given unless there was a strong suspicion (elevated white blood cell [WBC], elevated bands counts, or fever, or highly suggestive radiographic findings etc.) or a confirmed diagnosis of an intra-abdominal infection (presence of pus within the abdominal cavity) and the baseline intra-abdominal culture was obtained or planned to be obtained from the infected site. • cIAI of less than 2 weeks duration, such as: − An intra-abdominal abscess. − Appendicitis complicated by perforation (grossly visible) and abscess or periappendicular abscess. − Perforated diverticulitis complicated by abscess formation or fecal contamination. 2 − Complicated cholecystitis with evidence of perforation or empyema. − Perforation of the large or small intestine with abscess or fecal contamination. − Purulent peritonitis. − Gastric or duodenal ulcer perforation with symptoms lasting at least 24 hours before operation. − Traumatic bowel perforation with symptoms lasting at least 12 hours before operation. • Minimal clinical criteria at the time of intra-abdominal infection diagnosis or highly suspected intra-abdominal infection that included the presence of either: − Fever defined as an oral temperature ≥38.0°C, axillary temperature ≥37.5°C, or a rectal temperature ≥38.5°C, or hypothermia defined as an oral temperature <35.5°C, axillary temperature <35.0°C, or a rectal temperature <36.0°C. − Leukocytosis defined as WBC count >10,000/mm3, or leucopenia defined as WBC <5000/mm3, or >10% immature (band) forms. • Plus at least 1 of the following: − Localized or diffuse abdominal wall rigidity and /or involuntary guarding, abdominal tenderness or abdominal pain. − Nausea or vomiting or ileus. − Radiographic, scintigraphic, sonographic, computed tomography (CT) or magnetic resonance imaging (MRI) studies suggesting a perforated viscus, an intra-abdominal abscess, or other focus of intra-abdominal infection. • Evidence of a personally signed and dated informed consent document (ICD) indicating that the subject (or a legal representative) had been informed of all pertinent aspects of the study. If any subject was unable to give consent, it may have been obtained from the subject’s legal representative if in accordance with local laws and regulations. Subject would then sign an ICD as soon as possible. 3 • Subjects who were willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. Exclusion Criteria Subjects were ineligible to participate in this study if any of the following criteria were met: • Any concomitant condition that, in the opinion of the investigator, precluded an evaluation of a response or made it unlikely that the contemplated course of therapy or follow-up visits could have been completed. • Active or treated leukemia or systemic malignancy that required treatment with chemotherapy, immunotherapy, radiation therapy, or other antineoplastic therapy within the 3 months before entry into the study, or any metastatic malignancy to the abdomen with life expectancy less than 6 months. • Anticipated length of antibiotic therapy less than 5 days or the likelihood that the subject would not complete the course of treatment. • Presence of any uncontrolled central nervous system disease, including epilepsy or unexplained seizures. • Concomitant treatment with ganciclovir. • Known or suspected hypersensitivity to tigecycline, tetracycline agents, imipenem, cilastatin, or other compounds related to these classes of antibacterial agents. • Organ function failure. − Hepatic function: . Aspartate aminotransferase (AST) or alanine aminotransferase (ALT), or alkaline phosphatase (ALP) >10 × the upper limit of normal (ULN) of the local laboratory reference range. Bilirubin >3 × ULN, unless isolated hyperbilirubinemia was directly related to the acute process. Acute hepatic failure or acute decompensation of chronic hepatic failure. − Renal Function: Calculated creatinine clearance (ClCR) less than 4 2 41 mL/min/1.73 m after adequate hydration. ClCR may have been calculated from the serum creatinine (SCR) concentration by the following equation: . Male: ClCR mL/min = (140-age) × weight (kg) / [72 × SCR (mg/dL)] . Female: ClCR mL/min = 0.85 × ClCR derived by above formula. Body surface area (BSA) (m2) = (weight[kg])0.425 × (height [cm])0.725 × 0.007184 2 . ClCR / BSA × 1.73 = mL/min/1.73 m − Bone Marrow function: . Neutropenia defined as absolute neutrophil count (ANC) <1000/mm3 . Thrombocytopenia defined as platelet count <35,000/mm3 • Intra-abdominal infection known to be caused by 1 or more organism(s) which were not susceptible to either of the test articles (eg, methicillin-resistant staphylococci [methicillin-resistant Staphylococcus aureus, methicillin-resistant Staphylococcus epidermidis], or Pseudomonas aeruginosa) and which, in the investigator’s opinion, required treatment with an additional antibacterial agent. • Receipt of more than 24 hours of non-study systemic antibiotics within 72 hours before enrolment should have been excluded except for subjects declared prior failures. A subject may have been declared a prior failure if he/she received more than 72 hours of systemic non-study antibacterial therapy prior to study entry and declared a clinical or microbiological failure. An intra-abdominal culture had to be obtained from the infected site. • Previous participation in this study. • Participation in other studies within 4 weeks before the current study began and/or during study participation. • Anticipation of leaving the fascia or deep muscular layers open or expectation of planned abdominal re-exploration either in or out of the operating room. • Subjects suspected preoperatively to have had a diagnosis of spontaneous bacterial 5 peritonitis, simple cholecystitis, gangrenous cholecystitis without rupture, simple appendicitis, acute suppurative cholangitis, pancreatic abscess, or infected necrotizing pancreatitis. • Weight less than 40 kg. • Life expectation less than 30 days. • Immunosuppressive therapy that, in the opinion of the investigator, would have decreased the subject’s ability to eradicate the infection, including use of high-dose corticosteroids (eg, 40 mg or more prednisone or equivalent per day) or known diagnosis of acquired immunodeficiency syndrome (AIDS). • Administration of intraoperative antibacterial irrigants or peritoneal antibacterial agents (eg, irrigants, antibiotic-impregnated sponges). • Presence of infection requiring systemic antimicrobial therapy at a site other than the abdomen (eg, urinary tract). • Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that might increase the risk associated with study participation or investigational product administration or might interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study. • Subjects who were investigational site staff members or relatives of those site staff members or subjects who were the Sponsor employees directly involved in the conduct