A PHASE 3 PROSPECTIVE, RANDOMIZED, MULTICENTER, OPEN-LABEL, CENTRAL ASSESSOR-BLINDED, PARALLEL GROUP, COMPARATIVE STUDY TO DETERMINE THE EFFICACY, SAFETY AND TOLERABILITY OF AZTREONAM-AVIBACTAM (ATM-AVI) ±METRONIDAZOLE (MTZ) VERSUS MEROPENEM±COLISTIN (MER±COL) FOR THE TREATMENT OF SERIOUS INFECTIONS DUE TO GRAM NEGATIVE BACTERIA, INCLUDING METALLO-Β-LACTAMASE (MBL) - PRODUCING MULTIDRUG RESISTANT PATHOGENS, FOR WHICH THERE ARE LIMITED OR NO TREATMENT OPTIONS

C3601002

A Phase 3 comparative study to determine the efficacy, safety and tolerability of Aztreonam-Avibactam (ATM-AVI) ± Metronidazole (MTZ) versus Meropenem (MER) ± Colistin (COL) for the treatment of serious infections due to Gram negative bacteria.

2018-04-05

2023-02-23

2023-02-23

Completed

Early phase I

422

Inclusion Criteria: All subjects: 1. Male or female from 18 years of age 2. Provision of informed consent 3. Confirmed diagnosis of HAP/VAP or cIAI requiring iv antibiotic treatment 4. Female patients are authorized to participate in this clinical study if criteria concerning pregnancy avoidance stated in the protocol are met and negative pregnancy test Additional for cIAI: 1. Diagnosis of cIAI, EITHER: Intra-operative/postoperative enrolment with visual confirmation of cIAI. OR Preoperative enrollment with evidence of systemic inflammatory response, physical and radiological findings consistent with cIAI; confirmation of cIAI at time of surgery within 24 hours of study entry 2. Surgical intervention within 24 hours (before or after) the administration of the first dose of study drug Additional for HAP/VAP: 1. Onset symptoms \> 48h after admission to or \<7 days after discharge from an inpatient care facility 2. New or worsening infiltrate on CXR or CT scan 3. Clinical signs and symptoms and laboratory findings consistent with HAP/VAP 4. Respiratory specimen obtained for Gram stain and culture following onset of symptoms and prior to randomisation Exclusion criteria: All subjects: 1. APACHE II score \> 30 2. Confirmed or suspected infection caused by Gram-negative species not expected to respond to study drug, or Gram-positive species 3. Receipt of \>24 hr systemic antibiotic within 48h prior to randomisation (exception in case of treatment failure) 4. History of serious allergy, hypersensitivity (eg, anaphylaxis), or any serious reaction to aztreonam, carbapenem,monobactam or other β-lactam antibiotics, avibactam, nitroimidazoles or metronidazole, or any of the excipients of the study drugs 5. Known Clostridium difficle associated diarrhoea 6. Requirement for effective concomitant systemic antibacterials or antifungals 7. Creatinine clearance ≤15 ml/min or requirement or expectation for renal replacement therapy 8. Acute hepatitis, cirrhosis, acute hepatic failure, chronic hepatic failure 9. Hepatic disease as indicated by AST or ALT \>3 × ULN. Patients with AST and/or ALT up to 5 × ULN are eligible if acute and documented by the investigator as being directly related infectious process 10. Patient has a total bilirubin \>2 × ULN, unless isolated hyperbilirubinemia is directly related to infectious process or due to known Gilbert's disease 11. ALP \>3 × ULN. Patients with values \>3 × ULN and \<5 x ULN are eligible if acute and directly related to the infectious process being treated 12. Absolute neutrophil count \<500/mm3 13. Pregnant or breastfeeding or if of child bearing potential, not using a medically accepted effective method of birth control. 14. Any other condition that may confound the results of the study or pose additional risks to the subject 15. Unlikely to comply with protocol 16. History of epilepsy or seizure disorders excluding febrile seizures of childhood Additional for cIAI 1. Diagnosis of abdominal wall abscess; small bowel obstruction or ischemic bowel disease without perforation; traumatic bowel perforation with surgery within 12 hours of diagnosis; perforation of gastroduodenal ulcer with surgery \< 24 hours of diagnosis primary etiology is not likely to be infectious 2. Simple cholecystitis, gangrenous cholecystitis without rupture, simple appendicitis, acute suppurative cholangitis, infected necrotizing pancreatitis, pancreatic abscess 3. Prior liver, pancreas or small-bowel transplant 4. Staged abdominal repair (STAR), open abdomen technique or marsupialisation Additional for HAP/VAP 1. APACHE II score \< 10 2. Known or high likelihood of Gram-positive monomicrobial infection 3. Lung abscess, pleural empyema, post-obstructive pneumonia 4. Lung or heart transplant 5. Myasthenia gravis

{'studyType': 'INTERVENTIONAL', 'phases': ['PHASE3'], 'designInfo': {'allocation': 'RANDOMIZED', 'interventionModel': 'PARALLEL', 'interventionModelDescription': 'Prospective, Randomized, Multicenter, Open Label, Central Assessor Blinded, Parallel Group, Comparative Study', 'primaryPurpose': 'TREATMENT', 'maskingInfo': {'masking': 'SINGLE', 'maskingDescription': "An independent adjudication committee (central blinded assessor) will be convened at regular intervals during the study. The adjudication committee will be blinded to study treatment and will review the clinical response assessments at each visit. In case of a discrepancy with the Investigator's assignment of clinical response, the adjudication committee's assessment will prevail.\n\nIn addition, for cIAI subjects classified as a clinical failure, and all cIAI subjects classified as a cure who undergo another procedure (eg, another surgical procedure) subsequent to randomization, the expert panel will review the adequacy of the surgical source control.", 'whoMasked': ['OUTCOMES_ASSESSOR']}}, 'enrollmentInfo': {'count': 422, 'type': 'ACTUAL'}}

2024-05-07