A 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.

Study Overview
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Brief Summary
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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.

Detailed Description
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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

Official Title
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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

Conditions
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Complicated Intra-abdominal Infection, Hosptial Acquired Pneumonia, Ventilator Associated Pneumonia

Intervention / Treatment
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* Drug: ATM-AVI
* Drug: MTZ
* Drug: MER
* Drug: COL


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: All subjects: Male or female from 18 years of age Provision of informed consent Confirmed diagnosis of HAP/VAP or cIAI requiring iv antibiotic treatment 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: 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 Surgical intervention within 24 hours (before or after) the administration of the first dose of study drug Additional for HAP/VAP: Onset symptoms > 48h after admission to or <7 days after discharge from an inpatient care facility New or worsening infiltrate on CXR or CT scan Clinical signs and symptoms and laboratory findings consistent with HAP/VAP Respiratory specimen obtained for Gram stain and culture following onset of symptoms and prior to randomisation Exclusion criteria: All subjects: APACHE II score > 30 Confirmed or suspected infection caused by Gram-negative species not expected to respond to study drug, or Gram-positive species Receipt of >24 hr systemic antibiotic within 48h prior to randomisation (exception in case of treatment failure) 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 Known Clostridium difficle associated diarrhoea Requirement for effective concomitant systemic antibacterials or antifungals Creatinine clearance ≤15 ml/min or requirement or expectation for renal replacement therapy Acute hepatitis, cirrhosis, acute hepatic failure, chronic hepatic failure 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 Patient has a total bilirubin >2 × ULN, unless isolated hyperbilirubinemia is directly related to infectious process or due to known Gilbert's disease 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 Absolute neutrophil count <500/mm3 Pregnant or breastfeeding or if of child bearing potential, not using a medically accepted effective method of birth control. Any other condition that may confound the results of the study or pose additional risks to the subject Unlikely to comply with protocol History of epilepsy or seizure disorders excluding febrile seizures of childhood Additional for cIAI 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 Simple cholecystitis, gangrenous cholecystitis without rupture, simple appendicitis, acute suppurative cholangitis, infected necrotizing pancreatitis, pancreatic abscess Prior liver, pancreas or small-bowel transplant Staged abdominal repair (STAR), open abdomen technique or marsupialisation Additional for HAP/VAP APACHE II score < 10 Known or high likelihood of Gram-positive monomicrobial infection Lung abscess, pleural empyema, post-obstructive pneumonia Lung or heart transplant Myasthenia gravis

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Prospective, Randomized, Multicenter, Open Label, Central Assessor Blinded, Parallel Group, Comparative Study
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aztreonam-Avibactam ± Metronidazole<br>All patients randomised to this arm will receive ATM-AVI; all patients with cIAI will receive MTZ for anaerobic cover | Drug: ATM-AVI<br>* (Creatinine clearance > 50 mL/min) 6500 mg ATM/2167 mg (loading dose, extended loading dose and maintenance dose) by iv infusion on Day 1 followed by a total daily dose of 6000 mg ATM/2000 mg AVI (Creatinine clearance 31 - 50 mL/min) 4250 mg ATM/1417 mg AVI on Day 1 (loading dose, extended loading dose, maintenance dose) followed by total daily dose 3000 mg ATM/1000 mg AVI (Creatinine clearance 16 - 30 mL/min) 2700 mg ATM/900 mg AVI on Day 1 (loading dose, extended loading dose maintenance dose), followed by total daily dose 2025 mg ATM/675 mg AVI<br>Drug: MTZ<br>* For cIAI only; 500 mg/100 mL metronidazole iv infusion over 1hr q8h<br>|
| Active Comparator: Meropenem ± Colistin<br>All patients randomised to this arm will receive MER; addition of COL will be at investigator's discretion in line with local practice | Drug: MER<br>* Where pathogen initially not suspected of being MER-resistant: (Creatinine clearance > 50 mL/min) 1000 mg meropenem by 30 min iv infusion q8h (Creatinine clearance 26 - 50 mL/min) 1000mg meropenem by 30 min iv infusion q12h (Creatinine clearance 16 - 25 mL/min) 500 mg meropenem by 30 min iv infusion q12h Where pathogen initially suspected of being MER-resistant (Creatinine clearance > 50 mL/min) 2000 mg meropenem by 180 min iv infusion q8h (Creatinine clearance 26 - 50 mL/min) 2000 mg meropenem by 180 min iv infusion q12h (Creatinine clearance 16 - 25 mL/min) 1000 mg meropenem by 180 min iv infusion q12h<br>Drug: COL<br>* Loading dose 9 million IU by 30 -60 min iv infusion (6 million IU where weight < 60 kg) followed by one of the following maintenance doses: (Creatinine clearance > 50 mL/min) after a 12h interval, commence maintenance dosing 9 million IU daily in 2 or 3 divided doses by 30 -60 min iv infusions. (Creatinine clearance 31 - 50 mL/min) After a 24 hr interval, commence maintenance dosing of 6 million IU daily in 2 divided doses by 30 -60 min iv infusion (Creatinine clearance 21 - 30 mL/min) After a 24 hr interval, commence maintenance dosing 5 million IU daily in 2 divided doses by 30 -60 min iv infusion (Creatinine clearance 16 - 20 mL/min) after a 24 hr interval, commence maintenance dosing 4 million IU daily in 2 divided doses by 30 -60 min iv infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects with clinical cure in the ITT and CE analysis sets | Proportion of subjects meeting the criteria for clinical cure | Test of Cure (TOC) visit, Day 28 +/- 3 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of subjects with clinical cure in the m-ITT and ME analysis sets | Proportion of subjects meeting the criteria for clinical cure | Test of Cure (TOC) visit, Day 28 (+/- 3 days) | 
| Proportion of subjects with clinical cure by infection type in the ITT and CE analysis sets. | Proportion of subjects meeting the criteria for clinical cure | Test of Cure (TOC) visit, Day 28 (+/- 3 days) | 
| Proportion of subjects with clinical cure for subjects with MBL positive pathogens in the micro ITT and ME analysis sets. | Proportion of subjects meeting the criteria for clinical cure | Test of Cure (TOC) visit, Day 28 (+/- 3 days) | 
| Proportion of subjects with a favorable per subject microbiological response in the micro ITT and ME analysis sets. | Proportion of subjects with a favourable microbiological response (aggregate of eradication + presumed eradication) | Test of Cure (TOC) visit, Day 28 (+/- 3 days) | 
| Proportion of subjects who died | Daily mortality assessment | Day 28 | 
| PK of ATM | Plasma concentration of ATM | Days 1 and 4 | 
| PK/PD relationship between exposure and clinical response for ATM AVI±MTZ in the popPK analysis set | Correlation between plasma concentration of ATM and clinical cure | Test of Cure (TOC) visit, Day 28 (+/- 3 days) | 
| PK of AVI | Plasma concentration of AVI | Days 1 and 4 | 
| PK/PD relationship between exposure and clinical response for ATM/AVI +/- MTZ in the popPK analysis set | Correlation between concentration of AVI and clinical cure | Test of Cure (TOC) days 28 (+/- 3 days) | 
| PK/PD relationship between exposure and microbiological response for ATM/AVI+/-MTZ in the popPK analysis set | Correlation between plasma concentration of ATM and microbiological response | Test of Cure (TOC) visit, Days 28 (+/- 3 days) | 
| PK/PD relationship between exposure and microbiological response for ATM/AVI+/-MTZ in the popPK analysis set | Correlation between plasma concentration of AVI and microbiological response | Test of Cure (TOC) visit, day 28 (+/- 3 days) | 
| Description of safety in terms of adverse events | Descriptive summary of adverse events | Throughout study to Late Follow Up visit (Day 45 +/- 3 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Complicated intra-abdominal infection, Hosptial acquired pneumonia, Ventilator associated pneumonia, Gram negative infections, Metallo-beta lactamase, Multi drug resistant pathogens