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CTRI Number  CTRI/2014/05/004622 [Registered on: 26/05/2014] Trial Registered Prospectively
Last Modified On: 28/05/2020
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Randomized, Parallel Group, Multiple Arm Trial 
Public Title of Study   A clinical trial to study the safety, efficacy and tolerability of the drug Ceftazidime-Avibactam(CAZ-AVI) versus Meropenem in patients with Nosocomial Pneumonia(NP) including Ventilator Associated Pneumonia(VAP). 
Scientific Title of Study   Phase III, Randomized, Multicentre, Double-blind, Double-dummy,Parallel-group Comparative Study to Determine the Efficacy, Safety And Tolerability of Ceftazidime-Avibactam (CAZ-AVI) Versus Meropenem in the Treatment of Nosocomial Pneumonia (NP) Including Ventilator-Associated Pneumonia (VAP) in Hospitalised Adults 
Trial Acronym  REPROVE 
Secondary IDs if Any  
Secondary ID  Identifier 
D4281C00001  ClinicalTrials.gov 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name   
Designation   
Affiliation   
Address 




 
Phone    
Fax    
Email    
 
Details of Contact Person
Scientific Query
Modification(s)  
Name  Dr Bhavesh Kotak 
Designation  Vice President- Medical and Regulatory Affairs 
Affiliation  AstraZeneca Pharma India Ltd. 
Address  AstraZeneca Pharma India Ltd., Block N1, 12th Floor, Manyata Embassy Business Park, Rachenahalli, Outer Ring Road, Bangalore - 560045

Bangalore
KARNATAKA
560045
India 
Phone  0918067748514  
Fax  0918023622015  
Email  Bhavesh.Kotak@astrazeneca.com  
 
Details of Contact Person
Public Query
Modification(s)  
Name  Ms Ranju Sharma 
Designation  Senior Clinical Research Manager and Country Head 
Affiliation  AstraZeneca Pharma India Ltd. 
Address  Block N1, 12th Floor, Manyata Embassy Business Park, Rachenahalli, Outer Ring Road, Bangalore - 560045

Bangalore
KARNATAKA
560045
India 
Phone  0918067748518  
Fax  0918023622052  
Email  Ranju.Sharma@astrazeneca.com  
 
Source of Monetary or Material Support  
AstraZeneca AB, 151 85 Södertälje, Sweden. 
 
Primary Sponsor  
Name  AstraZeneca AB  
Address  151 85 Södertälje, Sweden. 
Type of Sponsor  Pharmaceutical industry-Global 
 
Details of Secondary Sponsor  
Name  Address 
AstraZeneca Pharma India Ltd  "Avishkar", P.B. No 2483, Off Bellary Road, Hebbal, Bangalore – 560024 Karnataka, India 
 
Countries of Recruitment     Argentina
Brazil
Bulgaria
Chile
China
Czech Republic
France
Hungary
India
Italy
Japan
Mexico
Peru
Poland
Republic of Korea
Russian Federation
South Africa
Spain
Turkey
Ukraine
United Kingdom
Viet Nam  
Sites of Study  
No of Sites = 9  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Suresh Ramasubban  Apollo Gleneagles Hospital  No. 58, Canal Circular Road Kolkata-700 054, West Bengal
Kolkata
WEST BENGAL 		 03323203040
03323205184
drsuresh@hotmail.com 
Dr V Ramasubramanian  Apollo Hospitals (Main),   21, Greams Lane, Off Greams Road, Chennai - 600006, Tamilnadu
Chennai
TAMIL NADU 		 04428294735
04428294449
idisdoc@gmail.com 
Dr K R Raveendra  Bangalore Medical College and Research Institute  Room No 72/A, 2nd Floor, New C Block, Victoria Hospital, Fort, Bangalore – 560002, Karnataka
Bangalore
KARNATAKA 		 0919448134587
08026706260
drkrraveendra@gmail.com 
Dr Prachee Sathe  Dept. of Critical Care Medicine  Main building, 1st floor ICU, Ruby Hall Clinic, 40 Sassoon road, Pune-411001, Maharashtra
Pune
MAHARASHTRA 		 02066455495
02066455628
prachee.sathe@gmail.com 
Dr Omender Singh  Director of Critical Care Max Super Speciality Hospital  1 Press Enclave Road, Saket New Delhi-110 017
South
DELHI 		 919810734246
01126565060
Omender.critical@gmail.com 
Dr P A Mahesh  JSS Hospital   Dept of Pulmonology M.G. Road, Mysore -570 004, Karnataka
Mysore
KARNATAKA 		 08212548356
08212548368
mahesh1971in@yahoo.com 
Dr Arun Narayan  M S Ramaiah Medical College and Hospitals  MSRIT Post, New BEL road, Bangalore-560054
Bangalore
KARNATAKA 		 08023601923
08023601983
drarunnarayan@gmail.com 
Dr Yatin Mehta  Medanta-The Medicity   Medanta-The Medicity Sector – 38, Gurgaon - 122 001,
Gurgaon
HARYANA 		 01244855100
01244834111
Yatin.Mehta@Medanta.org 
Dr Narendra Khippal  S.M.S Medical College & Hospital  Subhash Nagar Shopping Center, Shastri Nagar Jaipur – 302016,
Jaipur
RAJASTHAN 		 01412711299
01414007619
drnkhippal@rediffmail.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 9  
Name of Committee  Approval Status 
Ethical Review Board  Approved 
Ethics Committee Apollo Hospital  Approved 
Ethics Committee of Bangalore Medical   Approved 
Institution Ethics Committee  Approved 
Institution Ethics Committee JSS Medical College  Approved 
Institutional Ethics Committee   Approved 
Max Healthcare Ethics Committee  Approved 
Medanta Independent Ethics Committee  Approved 
Office of the Ethics Committee  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Approved/Obtained 
 
Health Condition / Problems Studied
Modification(s)  
Health Type  Condition 
Patients  Nosocomial Pneumonia (NP) Ventilator Associated Pneumonia (VAP) , (1) ICD-10 Condition: J189||Pneumonia, unspecified organism,  
 
Intervention / Comparator Agent
Modification(s)  
Type  Name  Details 
Intervention  Ceftazidime-Avibactam  Ceftazidime plus avibactam for 7-14 days treatment; Intravenous infusion 
Comparator Agent  Meropenem  Meropenem for 7-14 days treatment; Intravenous infusion 
 
Inclusion Criteria  
Age From  18.00 Year(s)
Age To  90.00 Year(s)
Gender  Both 
Details  • 18 to 90 years of age inclusive.

• Females can participate if surgically sterile or completed menopause; if able to have children, must have negative serum pregnancy test, agree not to attempt pregnancy and use acceptable contraception while receiving study therapy and for 1 week after last dose of IV study therapy.

• Onset of symptoms more than or equal to 48 hours after admission or less than 7 days after discharge from an inpatient acute or chronic care facility.

• New or worsening infiltrate on chest X-ray obtained within 48 hours prior to randomization.

• At least 1 of the following systemic signs: Fever (temperature more than 38 degree C) or hypothermia (rectal/core temperature less than 35 degree C); White blood cell count more than10,000 cells/mm3, or White blood cell count less than 4500 cells/mm3, or more than15% band forms. 
 
ExclusionCriteria 
Details  • Pulmonary disease that precludes evaluation of therapeutic response (including, but not limited to, lung cancer, active tuberculosis, cystic fibrosis, granulomatous disease, fungal pulmonary infection or recent pulmonary embolism).

• Patients with lung abscess, pleural empyema or post obstructive pneumonia.

• Patients with an estimated creatinine clearance 16ml/min by Cockcroft Gault formula or patients expected to require haemodialysis or other renal support while on study therapy.

• Acute hepatitis in the prior 6 months, cirrhosis, acute hepatic failure or acute decompensation of chronic hepatic failure.

• Patients receiving hemodialysis or peritoneal dialysis. 
 
Method of Generating Random Sequence   Computer generated randomization 
Method of Concealment   Centralized 
Blinding/Masking   Double Blind Double Dummy 
Primary Outcome  
Outcome  TimePoints 
The proportion of patients with clinical cure in the clinically modified intent-to-treat and clinically evaluable analysis sets (co-primary analyses)  Up to 25 days from randomization

21st - 25th day from randomization 
 
Secondary Outcome  
Outcome  TimePoints 
The proportion of patients with clinical cure in the microbiologically modified intent-to-treat, microbiologically evaluable and extended Microbiologically evaluable analysis sets  Up to 25 days from randomization

21st - 25th day from randomization
 
The proportion of patients with clinical cure in clinically modified intent-to-treat, clinically evaluable, microbiologically modified intent-to-treat, microbiologically evaluable, extended microbiologically evaluable analysis sets  up to 14 days from randomization 
The proportion of patients with a favorable per-patient microbiologic response in microbiologically modified intent-to-treat, microbiologically evaluable, extended microbiologically evaluable analysis sets  up to 14 days from randomization and 21 to 25 from randomization 
The proportion of favorable per-pathogen microbiologic responses in microbiologically modified intent-to-treat, microbiologically evaluable and extended microbiologically evaluable analysis sets  up to 14 days from randomization and 21 to 25 from randomization 
The proportion of favorable per-pathogen microbiologic responses by minimum inhibitory concentration categories in microbiologically modified intent-to-treat, microbiologically evaluable and extended-microbiologically evaluable analysis sets  up to 14 days from randomization and 21 to 25 from randomization 
The proportion of patients with clinical cure in patients with pathogens resistant to ceftazidime in clinically evaluable, clinically modified intent-to-treat, microbiologically evaluable analysis sets  up to 14 days from randomization and 21 to 25 from randomization 
Proportion of patients with a favorable per-patient microbiologic response in patients with pathogens resistant to ceftazidime in microbiologically modified intent-to-treat, microbiologically evaluable, extended microbiologically evaluable analysis sets  up to 14 days from randomization and 21 to 25 from randomization 
The proportion of favorable per-pathogen microbiologic responses in patients with pathogens resistant to ceftazidime in microbiologically modified intent-to-treat, microbiologically evaluable and extended microbiologically evaluable analysis sets  up to 14 days from randomization and 21 to 25 from randomization 
The proportion of patients with death due to any cause (all-cause mortality) in the clinically evaluable, clinically modified intent-to-treat and microbiologically modified intent-to-treat analysis sets  at Day 21 to 25 from randomization and Day 28 from randomization 
The proportion of patients discharged from hospital in the clinically evaluable, clinically modified intent-to-treat and microbiologically modified intent-to-treat analysis sets  up to 25 days from randomization

21st - 25th day from randomization
 
Safety and tolerability by incidence and severity of adverse events and serious adverse events, mortality, reasons for discontinuations of study therapy, vital signs, physical exams, electrocardiogram parameters, and clinical laboratory tests  up to 28 days from randomization 
 
Target Sample Size   Total Sample Size="1600"
Sample Size from India="100" 
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" 
Phase of Trial   Phase 3 
Date of First Enrollment (India)   19/06/2014 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  13/04/2013 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="3"
Months="0"
Days="0" 
Recruitment Status of Trial (Global)
Modification(s)  		 Closed to Recruitment of Participants 
Recruitment Status of Trial (India)  Closed to Recruitment of Participants 
Publication Details    
Individual Participant Data (IPD) Sharing Statement

Will individual participant data (IPD) be shared publicly (including data dictionaries)?  

Brief Summary  

Short description of the primary purpose of the protocol, including a brief statement of the study hypothesis. Include publication/s details (link/reference), if any.
This is a prospective, randomized, multicenter, double-blind, double-dummy parallel-group, comparative study to determine the efficacy, safety, and tolerability of CAZ-AVI versus meropenem in the treatment of adults with NP, including Ventilator Associated Pneumonia.


The following hypotheses will be assessed during this study:
• Intravenous CAZ-AVI will demonstrate clinical efficacy comparable with that of IV meropenem as treatment for patients with NP
• The safety and tolerability profile of CAZ-AVI administered intravenously is acceptable.


This study will randomize 1120 eligible Non-VAP patients.
Additionally, VAP patients will be recruited such that between 25% and 30% of the total number of patients recruited are VAP in nature. So a minimum total of 1494 patients (1120 Non-VAP plus 374 VAP) and a maximum total of 1600 patients (1120 Non-VAP plus 480 VAP) with NP including VAP will be recruited into this study from approximately 22 countries. From India, a total of 100 patients will be randomised from approximately 12 sites. The recruitment in India is expected to start from May 2014.

 
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