Randomized, Parallel Group, Active Controlled Trial
Public Title of Study
A clinical study to estimate the safety, tolerability and efficacy of two medications for treatment of complicated intraabdominal infections in adults.
Scientific Title of Study
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.
Trial Acronym
Secondary IDs if Any
Secondary ID
Identifier
101,307
Other
2008-005604-54
EudraCT
NCT00752219
ClinicalTrials.gov
NXL104/2002
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study) Modification(s)
Name
Sunil Garg
Designation
Affiliation
Address
INC GVKBIO Pvt Ltd
14th Floor, Tower B, Building No 14
DLF Cyber City, Phase III
Gurgaon Gurgaon HARYANA 122002 India
Amrita Institute of Medical Sciences, Institutional Ethics Committee
Submittted/Under Review
Bangalore Central Ethics Committee
Approved
C.S.M. Medical University - Ethics Committee
Submittted/Under Review
Ethical Committee, Bangalore Medical College and Research Institute
Approved
Independent Ethics Committee, CHL Apollo Hospial
Approved
M.S. Ramaiah Medical College and Teaching Hospital, Ethical Review Board
Approved
Medisurge Ethics Committee
Approved
S. R. Kalla Memorial Ethical Committee for Human Research
Approved
Sir Ganga Ram Hospital, Institutional Ethical Committee
Submittted/Under Review
St. John's Medical College Hospital, Institutional Ethical Review Board
Approved
Regulatory Clearance Status from DCGI
Status
Approved/Obtained
Health Condition / Problems Studied
Health Type
Condition
Patients
Complicated Intra-abdominal Infection (cIAI).
Complicated IAI are the infections requiring surgical intervention and which extend beyond the hollow viscus into the peritoneal space. ,
Intervention / Comparator Agent
Type
Name
Details
Intervention
Ceftazidime/NXL104 (study drug) plus Metronidazole
500mg NXL104/2000mg ceftazidime plus metronidazole 500mg intravenous, every 8 hrs, 5 to 14 days
Comparator Agent
Meropenem
1000mg, every 8 hrs, 5 to14 days
Inclusion Criteria
Age From
Age To
Gender
Details
1. 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 year
OR
 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.
2. For Intraoperative/postoperative enrollment
Patients 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 wall
b. diverticular disease with perforation or abscess
c. appendiceal perforation or peri-appendiceal abscess
d. acute gastric and duodenal perforations, only if operated on > 24 hours after perforation occurs
e. traumatic perforation of the intestines, only if operated on > 12 hours after perforation occurs
f. secondary peritonitis (but not spontaneous bacterial peritonitis associated with cirrhosis and chronic ascites)
g. intra-abdominal abscess (including of liver and spleen)
AND
Specimens from the surgical intervention are sent for culture and susceptibility testing
AND
Infection 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. 2) 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.
3. For Preoperative Enrollment
The 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°C
2)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)Hypoxemia
6)Altered mental status
AND
b.Physical findings consistent with Intra-abdominal infection, such as:
1)Abdominal pain and/or tenderness, with or without rebound
2)Localized or diffuse abdominal wall rigidity
3)Mass
4)Ileus
AND
c.Supportive radiologic imaging findings of intra-abdominal infection such as perforated intraperitoneal abscess detected on CT scan, MRI, or ultrasound
AND
d.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 testing
AND
f.Infection is caused or presumed to be caused by mircroorganisms susceptible to the intravenous study medications (ceftazidime/NXL104 plus metronidazole or meropenem)
ExclusionCriteria
Details
1. 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.
2. Patient with abdominal wall abscess or small bowel obstruction without perforation or ischemic bowel without perforation.
3. Patient with simple cholecystitis; or gangrenous cholecystitis without rupture; or simple appendicitis; or acute suppurative cholangitis; or infected necrotizing pancreatitis or pancreatic abscess
4. Patient whose surgery will include staged abdominal repair, or ?open abdomen? technique, or marsupialization.
5. Patient known at study entry to have intra-abdominal infections that are caused by pathogens resistant to the study antimicrobial agents.
6. Patient with evidence of sepsis with shock not responding to intravenous fluid challenge or anticipated to require the administration of vasopressors for > 12 hours.
7. Patient with perinephric infections.
8. Female patient with infection of the genital tract.
9. 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 inadequate
b) findings of infection were documented at surgery
c) operative intervention is intended no more than 24 hours after study entry
d) specimens for bacterial cultures and susceptibility testing are taken at operative intervention
e) no further nonstudy antibacterials are administered after enrollment
18.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/mm3. 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 interventions
c.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.
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Centralized
Blinding/Masking
Participant, Investigator, Outcome Assessor and Date-entry Operator Blinded
Primary Outcome
Outcome
TimePoints
Safety and Effficacy
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).
Secondary Outcome
Outcome
TimePoints
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.
Target Sample Size
Total Sample Size="0" Sample Size from India="" Final Enrollment numbers achieved (Total)= "" Final Enrollment numbers achieved (India)=""
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Brief Summary
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.