| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Complicated intra-abdominal infections (cIAI) in hospitalised adults |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10021881 |
| E.1.2 | Term | Infections and infestations |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10056570 |
| E.1.2 | Term | Intra-abdominal infection |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To estimate the efficacy of NXL104/ceftazidime plus metronidazole with respect to the clinical response in baseline microbiologically evaluable patients with cIAI at the Test of Cure (TOC) visit, 2 weeks post-treatment, compared to meropenem. |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the safety and tolerability profile of NXL104/ceftazidime plus metronidazole in the treatment of cIAI in adults.
2. To estimate the efficacy of NXL104/ceftazidime plus metronidazole with respect to the clinical response in baseline microbiologically evaluable patients with cIAI at the end of IV therapy and at the late follow-up visit at 4 to 6 weeks post-treatment compared to meropenem.
3. To estimate the clinical response of NXL104/ceftazidime plus metronidazole at the end of IV therapy, at the Test of Cure visit, and at the late follow up visit, 4 to 6 weeks post therapy compared to meropenem.
4. To estimate the microbiological response of NXL104/ceftazidime plus metronidazole in with cIAI at the end of IV therapy, at the Test of Cure visit, and at the late follow-up 4 to 6weeks post-therapy, compared to meropenem. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. 18 to 90 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 β-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. 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 provided that there is extension beyond the organ with evidence of intraperitoneal involvement)
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) |
|
| E.4 | Principal exclusion criteria |
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. Patients with suspected amebic liver abscess.
11. Patient with history of serious allergy, hypersensitivity (e.g., anaphylaxis), or any serious reaction to carbapenem or cephalosporin antibiotics or other beta lactam antibiotics.
12. Patient with APACHE II score > 25 (see appendix 6).
13. Patient who is considered unlikely to survive the 6- to 8-week study period.
14. Patient who is unlikely to respond to 5 to 14 days of antibiotic therapy.
15. 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 with new infection (not considered a treatment failure) may receive no more than 24 hours of total antibiotic therapy [preoperatively (prophylaxis) and/or postoperatively];
• 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) operative intervention that is just completed or is intended no more than 24 hours after study entry
c) findings of infection were documented at surgery
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 vancomycin, linezolid, or daptomycin for 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 [45]. If a patient is dehydrated he/she should be rehydrated and creatinine re-measured before calculating creatinine clearance. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy assessment is the clinical response in the microbiologically evaluable population at the Test of Cure visit, 2 weeks post-therapy. The primary safety variable will be the incidence of adverse experiences. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 12 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 12 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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