CTRI/2018/09/015762 [Registered on: 19/09/2018] Trial Registered Prospectively
Last Modified On:
29/04/2024
Post Graduate Thesis
No
Type of Trial
Interventional
Type of Study
Drug
Study Design
Randomized, Parallel Group, Active Controlled Trial
Public Title of Study
A Study to Determine the Effect of Aztreonam-Avibactam Versus Meropenem for the Treatment of Serious Infections Due to Gram Negative Bacteria.
Scientific Title of Study
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
Site Relationship and Excellence Partner (Director), GSSO, Clinical Development & Operations
Affiliation
Pfizer Limited
Address
The Capital, 1802/1901, Plot No. C - 70, G Block, Bandra Kurla Complex, Bandra (East), Mumbai, India.
Mumbai MAHARASHTRA 400051 India
Phone
91-8826422322
Fax
91-22-265225993
Email
seema.pai@pfizer.com
Source of Monetary or Material Support
Pfizer Limited, The Capital, 1802/1901, Plot No. C - 70, G Block, Bandra Kurla Complex, Bandra (East), Mumbai - 400051, India.
Primary Sponsor
Name
Pfizer Limited
Address
The Capital, 1802/1901, Plot No. C - 70, G Block, Bandra Kurla Complex, Bandra (East), Mumbai - 400051, India.
Type of Sponsor
Pharmaceutical industry-Global
Details of Secondary Sponsor
Name
Address
Pfizer Limited
The Capital, 1802/1901, Plot No. C - 70, G Block, Bandra Kurla Complex, Bandra (East), Mumbai - 400051, India.
Countries of Recruitment
Argentina Brazil Bulgaria China Croatia Czech Republic Greece Hungary India Israel Italy Malaysia Mexico Peru Philippines Republic of Korea Romania Russian Federation South Africa Spain Taiwan Thailand Turkey Ukraine United States of America Viet Nam Chile
Artemis Health Sciences Institutional Ethics Committee
Approved
Drug Trial Ethics Committee, Ethics Committee Office, Basement Hero DMC Heart Institute, Dayanand Medical College and Hospital, Ludhiana-141001, Punjab, India
Approved
ETHICS COMMITTEE OF BANGALORE MEDICAL COLLEGE AND RESEARCH INSTITUTE, Bangalore Medical College and Research Institute 1st Floor K.R Road Bengaluru-560002 Karnataka India
Approved
ETHICS COMMITTEE, M S Ramaiah Medical College and Hospitals, M S Ramaiah Nagar, MSRIT Post, Bangalore-560054
Approved
Institutional Ethics Committee Amrita Institute of Medical Sciences and Research Centre Peeliyadu Road, Ponekkara, Edappally, Ernakulam, Kerala 682041, India
Approved
Institutional Ethics Committee Lata Mangeshkar Medical Foundation’s Deenanath Mangeshkar Hospital and Research Centre Off Karve Road, Erandawane, Pune 411004
Approved
Institutional Ethics committee, Govt. Medical College, 4th Floor, Golden Jubilee Annex, Institute of Meternal and Child Health, Kozhikode-673 008, Kerala, India
Approved
Institutional Ethics Committee, King George Hospital
Approved
Institutional Ethics Committee-Clinical Studies No: 21, Greams Lane, Off Greams Road, Chennai, Tamil Nadu 600006
Approved
Institutional Human Ethics Committee, JSS Medical College and Hospital 3rd Floor JSS Medical College Mysore-570015 Karnataka
Approved
King Georges Medical University, Office of Research Cell, Administrative Block, King George’s Medical University, U.P., Lucknow- 226003, India
Approved
Manipal Academy of Higher Education Ethics Committee, Mezzanine floor of Old KMC Library Building, Near KMC Dean Office, Manipal University, Manipal – 576104
Approved
S.R.Kalla Memorial Ethical Committee for Human Research, S.R.Kalla Memorial Gastro & General Hospital, 78-79 Dhuleshwar Garden, Behind HSBC Bank, Sardar Patel Marg, C-Scheme Jaipur-302001, Rajasthan, India.
Approved
Sahyadri Hospitals Ltd Ethics committee, Sahyadri Clinical Research and Development Center 33/34B, Makarand Bhave Path, Karve road Pune 411004
(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
Comparator Agent
Colistin (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
Comparator Agent
Meropenem (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
Intervention
Metronidazole (MTZ)
For cIAI only; 500 mg/100 mL metronidazole iv infusion over 1hr q8h
Inclusion Criteria
Age From
18.00 Year(s)
Age To
99.00 Year(s)
Gender
Both
Details
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
ExclusionCriteria
Details
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 ß-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 is equals to 15 ml per 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 greater than 3 X ULN. Patients with AST and or or ALT up to 5 X ULN are eligible if acute and documented by the investigator as being directly related infectious process
10. Patient has a total bilirubin greater than 2 X ULN unless isolated hyperbilirubinemia is directly related to infectious process or due to known Gilberts disease.
11. ALP greater than 3 X ULN. Patients with values greater than 3 X ULN and Less than 5 X ULN are eligible if acute and directly related to the infectious process being treated
12. Absolute neutrophil count less than 500 per 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 h
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
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Centralized
Blinding/Masking
Open Label
Primary Outcome
Outcome
TimePoints
proportion of subjects with clinical cure in the ITT and CE analysis sets
Test of Cure (TOC) visit, Day 28 ± 3 days
Secondary Outcome
Outcome
TimePoints
Description of safety in terms of adverse events
Throughout study to Late Follow Up visit (Day 45 ± 3 days)
PK of ATM
Days 1 and 4
PK of AVI
Days 1 and 4
PK/PD relationship between exposure and clinical response for ATM AVI±MTZ in the popPK analysis set
Test of Cure (TOC) visit, Day 28 ± 3 days
Proportion of subjects who died
Day 28
Proportion of subjects with a favorable per subject microbiological response in the micro ITT and ME analysis sets
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
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.
Test of Cure (TOC) visit, Day 28± 3 days
Proportion of subjects with clinical cure in the m-ITT and ME analysis sets
Test of Cure (TOC) visit, Day 28± 3 days
PK/PD relationship between exposure and microbiological response for ATM/AVI±MTZ in the popPK analysis set
Test of Cure (TOC) visit, Day 28± 3 days
PK/PD relationship between exposure and clinical response for ATM/AVI ± MTZ in the popPK analysis set
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Brief Summary
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.