Resumen

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.

Descripción detallada

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

Elegibilidad

Edad mínima: 18 YearsSexo: ALL

Criterios de inclusión

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

Criterios de exclusión

Myasthenia gravis
Lung or heart transplant
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

Intervenciones

drug

ATM-AVI

(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

drug

MTZ

For cIAI only; 500 mg/100 mL metronidazole iv infusion over 1hr q8h

drug

MER

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

drug

COL

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

Resumen

Descripción detallada

Elegibilidad

Criterios de inclusión

Criterios de exclusión

Intervenciones

ATM-AVI

MTZ

MER

COL

Ubicaciones

Sanatorio Britanico

Sanatorio Servicios Medicos SM

Hospital San Roque

Patrocinadores