A prospective, multicenter, double-blind, randomized, comparative study to estimate the safety, tolerability and efficacy of NXL104/ceftazidime plus metronidazole vs. meropenem in the treatment of complicated intra-abdominal infections (cIAI) in hospitalized adults.

Novexel SA10 个研究点分布在 1 个国家目标入组 0 人开始时间: 2009年2月3日最近更新: 2014年10月9日

试验速览

阶段: 2 期
状态: 已完成
发起方: Novexel SA
试验地点: 10
主要终点: Safety and Effficacy

研究概览研究设计入排标准结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

This is a prospective, multicenter, double-blind, randomized, two arm, parallel group (1:1) study to estimate the efficacy, safety, and tolerability of NXL104/ceftazidime plus metronidazole vs. meropenem in the treatment of adults with cIAI. cIAI are those requiring surgical intervention and which extend beyond the hollow viscus into the peritoneal space. The minimum duration of therapy is 5 days, and the suggested maximum duration of therapy is 14 days. Each patient is expected to complete the study, including follow-up, within approximately 8 weeks. The entire study duration is expected to be approximately 1 year. Study medication includes 500mg NXL104/2000mg ceftazidime plus metronidazole 500mg that will be given intravenously every 8hr and 1000mg meropenem will be given intravenously every 8hr. In order to maintain blinding, a placebo to metronidazole (100mL 0.9% saline) will be administered every 8 hours to patients randomized to meropenem. After at least 5 days of parenteral therapy, if clinical improvement is clearly demonstrated IV antimicrobial therapy may be discontinued at the discretion of the investigator. If antibiotic therapy is required beyond 14 days, the medical monitor should be contacted.Approximately 200 hospitalized adult patients (18 to 65 years of age) with a presumed (preoperative) or definitive (intraoperative or postoperative) diagnosis of cIAI will be studied globally. Diagnosis of infection will be based on the patient?s clinical syndrome and intraoperative findings, including intraoperative cultures. Operative intervention includes open laparotomy, laparoscopic procedure, and percutaneous drainage procedure. All patients will undergo a preliminary evaluation within the 24 hour period prior to initiation of intravenous study antibiotic therapy.The primary efficacy assessment is the clinical response in the microbiologically evaluable population at the Test of Cure visit, 2 weeks post-therapy. Other than India (10 sites), this trial is being conducted in Bulgaria (5 sites), France (3 sites), Lebanon (5 sites), Poland (5 sites), Romania (5 sites), Russia (5 sites) and USA (8 sites)Approximately, 50 patients are to be enrolled from India, out of the 200 pateints to be enrolled globally.

研究设计

分配方式: Computer generated randomization
盲法: Participant, Investigator, Outcome Assessor and Date-entry Operator Blinded

入排标准

入选标准

•For 18 to 65 years of age Women are authorized to participate in this clinical study if they meet the following criteria: Has been surgically sterilized or post menopausal for at least one yearOR Is of childbearing potential, and all of the following conditions are met:-had normal menstrual periods for the 3 months prior to study entry, and-has a negative serum pregnancy test (serum -hCG) within 1 day prior to enrollment.
•must be willing to practice double barrier methods of birth control (e.g., condoms or diaphragms together with spermicidal foam or gel) during treatment and for at least 28 days after dosing with study medication.
•Oral contraceptives should not be used as the sole method of birth control, because the effect of NXL104 on the efficacy of oral contraceptives has not yet been established.
•For Intraoperative/postoperative enrollmentPatients may be enrolled intraoperatively or postoperatively upon visual confirmation (presence of pus within the abdominal cavity) of an intra-abdominal infection.
•Surgical intervention includes open laparotomy, percutaneous drainage of an abscess, or laparoscopic surgery.
•Diagnoses considered eligible for this study are those in which there is evidence of intraperitoneal infection.
•The patient must have one of the following diagnoses:a.
•cholecystitis with gangrenous rupture or perforation or progression of the infection beyond the gallbladder wallb.
•diverticular disease with perforation or abscessc.
•appendiceal perforation or peri-appendiceal abscessd.
•acute gastric and duodenal perforations, only if operated on > 24 hours after perforation occurse.
•intra-abdominal abscess (including of liver and spleen)ANDSpecimens from the surgical intervention are sent for culture and susceptibility testingANDInfection is caused or presumed to be caused by mircroorganisms susceptible to the intravenous study medications (ceftazidime/NXL104 plus metronidazole or meropenem) Note: 1) infections limited to the hollow viscus, such as simple cholecystitis and simple appendicitis, are not eligible.
•Ischemic bowel disease without perforation is not eligible.
•Acute suppurative cholangitis and acute necrotizing pancreatitis are not eligible.
•Postoperative (or intraoperative) enrollment of patients is encouraged.
•If, however, preoperative data are available that strongly suggest an appropriate diagnosis for entry (e.g., rupture of intraperitoneal abscess on CT or MRI), then these patients may be enrolled preoperatively.
•For Preoperative EnrollmentThe following clinical criteria must be met, and the patient?s infection must be confirmed by a surgical intervention within 24 hours of entry:a.
•Evidence of systemic inflammatory response, with at least one of the following:1)Fever (temperature > 37.8°C; > 38°C tympanic; > 38.3°C rectal; or hypothermia with a core body temperature < 35°C2)Elevated WBC (> 10,500/mm3)3)Drop in blood pressure (however, systolic BP must be > 90 mm Hg without pressor support)4)Increased pulse (HR > 90) and respiratory rates (> 20)5)Hypoxemia6)Altered mental statusANDb.Physical findings consistent with Intra-abdominal infection, such as:1)Abdominal pain and/or tenderness, with or without rebound2)Localized or diffuse abdominal wall rigidity3)Mass4)IleusANDc.Supportive radiologic imaging findings of intra-abdominal infection such as perforated intraperitoneal abscess detected on CT scan, MRI, or ultrasoundANDd.requirement for surgical intervention, including open laparotomy, percutaneous drainage of an abscess, or laparoscopic surgery;AND e.Specimens from the surgical intervention are sent for culture and susceptibility testingANDf.Infection is caused or presumed to be caused by mircroorganisms susceptible to the intravenous study medications (ceftazidime/NXL104 plus metronidazole or meropenem).

排除标准

•Patient diagnosed with traumatic bowel perforation with surgery within 12 hours; perforation of gastroduodenal ulcers with surgery within 24 hours.
•Other intra-abdominal processes in which the primary etiology is not likely to be infectious.
•Patient with abdominal wall abscess or small bowel obstruction without perforation or ischemic bowel without perforation.
•Patient with simple cholecystitis; or gangrenous cholecystitis without rupture; or simple appendicitis; or acute suppurative cholangitis; or infected necrotizing pancreatitis or pancreatic abscess
•Patient whose surgery will include staged abdominal repair, or ?open abdomen?
•technique, or marsupialization.
•Patient known at study entry to have intra-abdominal infections that are caused by pathogens resistant to the study antimicrobial agents.
•Patient with evidence of sepsis with shock not responding to intravenous fluid challenge or anticipated to require the administration of vasopressors for > 12 hours.
•Patient with perinephric infections.
•Female patient with infection of the genital tract.
•Patient with indwelling peritoneal catheter.10.Patient with history of serious allergy, hypersensitivity (e.g., anaphylaxis), or any serious reaction to carbapenem or cephalosporin antibiotics or other beta lactam antibiotics.11.Patient with APACHE II score > 25 (see appendix 6).12.Patient who is considered unlikely to survive the 6- to 8-week study period.13.Patient who is unlikely to respond to 5 to 14 days of antibiotic therapy.14.Patient with rapidly progressive or terminal illness, including acute hepatic failure or respiratory failure.
•15.Male patient who is not willing to abstain from sexual intercourse with a fertile woman without use of a condom/spermicide while taking the study drug and for at least 90 days after treatment with study drug.16.Female patient who is pregnant or breastfeeding, or fertile woman not practicing adequate methods of contraception (as defined in inclusion criteria); or planning to become pregnant within 1 month of the study.17.Patient who received systemic antibacterial agents within the 72-hour period prior to study entry, unless either of the following pertains:?Patient treated with nonstudy systemic antibiotic consisting of postoperative (or postdrainage) therapy of no more than 24 hours of an appropriate antimicrobial regimen for patients not considered to have failed a previous regimen;?Patient is considered to have failed the previous treatment regimen.
•In this case, preoperative treatment of any duration with nonstudy systemic antimicrobial therapy for peritonitis or abscess is permitted provided that;a) the treatment regimen has been administered for at least 72 hours and is thought to have been inadequateb) findings of infection were documented at surgeryc) operative intervention is intended no more than 24 hours after study entryd) specimens for bacterial cultures and susceptibility testing are taken at operative interventione) no further nonstudy antibacterials are administered after enrollment18.Patient who needs effective concomitant systemic antibacterials (other than vancomycin for documented Methicillin Resistant S.
•aureus or Enteroccal infections) in addition to those designated in the 2 study groups.
•19.Patient with concurrent infection that may interfere with the evaluation of response to the study antibiotic.20.Patient with a BMI > 45 kg/m2.21.Patient with Hematocrit <30% or Hemoglobin <10 g/dL.22.Patient with absolute neutrophil count (ANC) less than 1500/mm
•Patient with ANC as low as 1000/mm3 may be enrolled if this is directly related to the acute infection.23.Patient with Platelet count <100,000/mm3.24.Patient with Coagulation (prothrombin time [PT] and partial thromboplastin time [PTT] and/or INR) tests >1.5 times the upper limit of the range of normal values (ULN) used by the laboratory performing the test.
•Patients who are on anticoagulant therapy with values >1.5 times ULN may be enrolled provided these values are stable within the therapeutic range.25.Patient with an estimated creatinine clearance < 50mL/min by Cockcroft-Gault formula.
•If a patient is dehydrated he/she should be rehydrated and creatinine re-measured before calculating creatinine clearance.26.Patient with abnormal liver function: a.Alanine transaminase (ALT), Aspartate transaminase (AST) > 3 times ULN values used by the laboratory performing the test.
•Patients with elevations of AST and/or ALT up to 5 times ULN are eligible if these elevations are acute and directly related to the infectious process being treated.
•This must be documented.b.Bilirubin >3.0 times ULN, unless isolated hyperbilirubinemia is directly related to the acute infection or known Gilbert?s disease.c.Alkaline Phosphatase >3.0 times ULN.
•Patients with values >3.0 times ULN and <5.0 times ULN are eligible if this value is historically stable.
•d.Acute hepatitis, chronic hepatitis, cirrhosis, acute hepatic failure, or acute decompensation of chronic hepatic failure should be excluded.27.Immunocompromised patient, such as: a.HIV infection, with either an AIDS-defining condition (e.g., Kaposi?s sarcoma, Pneumocystis carinii pneumonia) or a CD4+ T-lymphocyte count < 200/mm3 b.metastatic or hematological malignancy requiring chemotherapeutic interventionsc.splenectomized patient or patient with known hyposplenia or asplenia d.receiving maintenance corticosteroid therapy (> 20 mg/day equivalent prednisolone)28.Patients who participated in any other clinical study that involves the administration of an investigational medication at the time of presentation, during the course of the study, or during the 30 days prior to study start.29.Patient or legal representative unable to provide written informed consent for any reason.
•30.Patient is in a situation or has a condition that, in the investigator?s opinion, may interfere with optimal participation in the study.31.Patient unlikely to comply with protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study.32.Patient who has previously been treated with the investigational product (NXL104).33.Patient with known inflammatory bowel disease.34.Patient who has received more than one dose of ceftazidime for treatment of this infection.35.Patient who had been previously enrolled in this study.

结局指标

主要结局

Safety and Effficacy

时间窗: The primary safety variable will be the incidence of adverse experiences.The primary analysis variable for efficacy will be the clinical outcome at the early follow-up, Test of Cure (TOC) Visit, performed 2 weeks post-therapy in the microbiologically evaluable population. The stratified Mantel Haenszel test, accounting for baseline disease severity (Apache II score <=10 vs >10 and <25), will be used to determine treatment effect on clinical outcome (cured vs. failure).

次要结局

Efficacy(The secondary analysis variables for efficacy will include, (i) The clinical response in baseline microbiologically evaluable patients with cIAI at the end of IV therapy and at the late follow-up 4 to 6 weeks post-therapy. (ii)The clinical response in clinically evaluable patients with cIAI at the end of IV therapy, at the Test of Cure visit, and at the late follow-up 4 to 6 weeks post-therapy. (iii) The microbiological response in patients with cIAI at the end of IV therapy, at the Test of Cure visit and at the late follow-up 4 to 6 weeks post-therapy. Additional analysis variables for efficacy and safety will be defined in a Statistical Analysis Plan (SAP) prior to finalization of the database.)

研究者

发起方

Novexel SA

研究点 (10)

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