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CTRI Number  CTRI/2020/02/023439 [Registered on: 19/02/2020] Trial Registered Prospectively
Last Modified On: 08/04/2020
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Single Arm Study 
Public Title of Study   Study of ceftazidime and avibactam in neonates and infants from birth to less than 3 months of age who is having infection or can have infaction and require antibiotic treatment. 
Scientific Title of Study   A Phase 2A, 2-Part, Open-Label, Non-Randomized, Multicenter, Single And Multiple Dose Trial to Evaluate Pharmacokinetics, Safety And Tolerability of Ceftazidime And Avibactam In Neonates And Infants From Birth To Less Than 3 Months of Age With Suspected or Confirmed Infections Due to Gram-Negative Pathogens Requiring Intravenous Antibiotic Treatment. 
Trial Acronym   
Secondary IDs if Any  
Secondary ID  Identifier 
2018 002800-16  EudraCT 
C3591024 (Final Protocol Amendment 01, 27 June 2019  Protocol Number 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name   
Designation   
Affiliation   
Address 




 
Phone    
Fax    
Email    
 
Details of Contact Person
Scientific Query  
Name  Dr Karan Thakkar 
Designation  Site Relationship and Excellence Partner 
Affiliation  Pfizer Limited 
Address  The Capital, 1802, Plot No. C-70, G Block, Bandra Kurla Complex,Bandra(E)

Mumbai
MAHARASHTRA
400051
India 
Phone  7045788858  
Fax    
Email  Karan.thakkar@pfizer.com  
 
Details of Contact Person
Public Query  
Name  Dr Seema Pai 
Designation  Director (Site Relationship and Excellence Partner) 
Affiliation  Pfizer Limited 
Address  The Capital, 1802, Plot No. C-70, G Block, Bandra Kurla Complex,Bandra(E)

Mumbai
MAHARASHTRA
400051
India 
Phone  8826422322  
Fax    
Email  Seema.Pai@pfizer.com  
 
Source of Monetary or Material Support  
Pfizer Inc. 235 East 42nd Street, New York, NY 10017 
 
Primary Sponsor  
Name  Pfizer Inc 
Address  235 East 42nd Street, New York, NY 10017 
Type of Sponsor  Pharmaceutical industry-Global 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     Czech Republic
Estonia
Greece
Hungary
India
Italy
Philippines
Slovakia
Taiwan
United Kingdom
United States of America  
Sites of Study  
No of Sites = 2  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
Dr Leslie Lewis  Kasturba Medical College and Hospital  Pediatric Department. Kasturba Medical College and Hospital Madhav Nagar, Manipal, Karnataka-576104, India
Udupi
KARNATAKA 		 9449208476

leslie.lewis@manipal.edu 
Dr Mohit Sahni  Nirmal Hospital Pvt. Ltd.  Neonatel & Pediatric Department, Nirmal Hospital Pvt. Ltd. Ring Road, Surat,395002, Gujarat, India
Surat
GUJARAT 		 9099079394

drmohitssahni@gmail.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 2  
Name of Committee  Approval Status 
Institutional Ethics committee, Kasturba Medical College and Hospital  Approved 
Nirmal Hospital Private Limited Ethics Committee  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Approved/Obtained 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  (1) ICD-10 Condition: B968||Other specified bacterial agents as the cause of diseases classified elsewhere,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Intervention  Ceftazidime-Avibactam (CAZ-AVI)  Drug: Part A: Single Dose Ceftazidime-Avibactam, Cohorts 1-3 Single intravenous infusion of ceftazidime-avibactam over 2 hours Drug: Part B: Multiple-dose Ceftazidime-Avibactam, Cohorts 1-3 Multiple intravenous infusions of ceftazidime-avibactam over 2 hours, repeated every 8 hours up to 14 days 
Comparator Agent  NIL  NIL 
 
Inclusion Criteria  
Age From  1.00 Day(s)
Age To  88.00 Day(s)
Gender  Both 
Details  1. Male or female neonates and infants with age at Screening:
a. Cohort 1: Full term (or pre-term corrected age), age greater than 28 days to less than 3 months
b. Cohort 2: Full term, age birth to less than or equal to 28 days
c. Cohort 3: Pre-term, age birth to less than or equal to 28 days
2. Part A: Hospitalized and receiving intravenous antibacterial therapy for the treatment of a suspected or confirmed bacterial infection.
3. Part B: Hospitalized with suspected or confirmed aerobic Gram-negative bacterial infection requiring intravenous antibacterial therapy,
a. plus Must meet at least 1 clinical and 1 laboratory criterion OR
b. Meet at least 2 of the clinical criteria
Clinical Criteria:
a. Hypothermia (less than 36°C) OR fever (greater than 38.5°C);
b. Bradycardia OR tachycardia OR rhythm instability;
c. Urine output 0.5 to 1 mL/kg/h OR hypotension OR mottled skin OR impaired peripheral perfusion;
d. Petechial rash OR sclerema neonatorum;
e. New onset or worsening of apnea episodes OR tachypnea episodes OR increased oxygen requirements OR requirement for ventilation support;
f. Feeding intolerance OR poor suckling OR abdominal distension;
g. Irritability;
h. Lethargy;
i. Hypotonia.
Laboratory Criteria:
a. White blood cell count less than or equal to 4.0 × 109/L OR greater than or equal to 20.0 × 109/L;
b. Immature to total neutrophil ratio greater than 0.2;
c. Platelet count less than or equal to 100 × 109/L;
d. C reactive protein (CRP) greater than 15 mg/L OR procalcitonin greater than or equal to 2 ng/mL;
e. Hyperglycemia OR Hypoglycemia;
f. Metabolic acidosis 
 
ExclusionCriteria 
Details  Exclusion Criteria (All Subjects):
1. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the Investigator, or subjects who are Pfizer employees, including their family members, directly involved in the conduct of the study.
2. Participation in another clinical study involving investigational drug(s) within 30 days prior to study entry and/or during this study participation or have previously participated in the current study or in another study of CAZ-AVI (in which an active agent was received).
3. Use of potent inhibitors of organic anion transporters OAT1 and/or OAT3 (eg, probenecid, p-aminohippuric acid (PAH), or teriflunomide) are prohibited. This prohibition of OAT1 and/or OAT3 inhibitors also applies to the mothers of any neonates or infants who are breast feeding during the trial.
4. Other acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study.
5. Documented history of any hypersensitivity or allergic reaction to any beta-lactam antibiotic.
6. Refractory septic shock within 24 hours before screening that does not resolve after 60 minutes of vasopressor therapy.
7. Moderate or severe renal impairment defined as serum creatinine greater than or equal to 2 times the upper limit of normal (ULN) for age OR urine output less than 0.5 mL/kg/h (measured over at least 8 hours) OR requirement for dialysis. Deterioration of renal function after enrollment during Part B of the study will be handled on a case-by-case basis in discussion with the Medical Monitor.
8. Evidence of progressively fatal underlying disease, or life expectancy of less than or equal to 60 days.
9. Documented history of seizure.
10. Active acute viral hepatitis or acute hepatic failure.
11. Known Clostridium difficile associated diarrhea.
12. Requiring or currently taking antiretroviral therapy for human immunodeficiency virus (HIV) or known HIV positive mother.
13. Any condition (eg, cystic fibrosis, urea cycle disorders), antepartum/peripartum factors, or procedures that would, in the opinion of the Investigator, make the subject unsuitable for the study, place a subject at risk, or compromise the quality of data.
14. Treatment with ceftazidime within 12 hours of CAZ-AVI administration.

Exclusion Criteria for Part A Subjects Only:
1. Subject received a blood or a blood component transfusion within 24 hours of the start of CAZ AVI infusion.
2. Subject is expected to be discharged less than 24 hours after the start of CAZ AVI infusion.

Exclusion Criteria for Part B Subjects Only:
1. At study entry, subject has confirmed or strongly suspected infection with a pathogen known to be resistant to CAZ-AVI or only a Gram-positive pathogen or viral, fungal, or parasitic pathogens as the sole cause of infection.
2. Confirmed or suspected CNS infection (meningitis, brain abscess, subdural abscess etc.)
3. Anticipated need for antibacterial therapy longer than 14 days (osteomyelitis, endocarditis etc.). This applies to both study treatment with CAZ AVI as well as adjunctive IV antibacterial treatment for suspected co infection with Gram positive organisms or multi drug resistant Gram negative organisms.
4. Receipt of more than 24 hours of non study systemic antibacterial treatment for Gram negative organisms after culture and before administration of study doses of CAZ AVI. Empiric coverage with an aminoglycoside for suspected multidrug resistant organisms is permitted, provided CAZ AVI is initiated within 24 hours after culture.
5. Intravenous treatment with chloramphenicol within 24 hours of administration of study doses of CAZ AVI.
6. Subject is expected to be discharged less than 48 hours after the start of CAZ AVI infusion.


 
 
Method of Generating Random Sequence   Not Applicable 
Method of Concealment   Centralized 
Blinding/Masking   Open Label 
Primary Outcome  
Outcome  TimePoints 
Part A: Ceftazidime and avibactam plasma conc. by nominal sampling time using appropriate descriptive statistics, eg, no., mean, SD, minimum, median, maximum, geometric mean, and coefficient of variation
Part B: Number of subjects with adverse events (AEs) and Serious Adverse Events (SAEs)
Part B: Number of deaths reported for study subjects
Part B: Number of subjects discontinued due to adverse events (AEs)
Part B: Number of subjects with clinically significant abnormal laboratory results 		 Part A: Day 1-2
Part B: Day 1 until Late Follow-up Visit (up to a maximum study duration of 49 days) 
 
Secondary Outcome  
Outcome  TimePoints 
Part A:AEs & SAEs; Deaths; Discontinuation due to AEs & No. of subj. with abnormal lab results; Part B: Drug plasma conc. by using statistics; Efficacy Assessments: All-cause mortality ; Clinical outcome, clinical imprmnt., clinical failure, or indeterminate at End-of-IV, EoT, Test-of-Cure & Late f-up Visits; Cure defined as clinical imprmnt. & no need for further antibacterial treatment, 7-14 days after EoT ; Microbiological eradication 7 to 14 days after EoT & Emergent infections.   Part A: Day 1 until Late Follow-up Visit (up to a maximum study duration of 35 days).
Part B: Day 2 until Late Follow-up Visit (up to a maximum study duration of 49 days)
 
 
Target Sample Size   Total Sample Size="48"
Sample Size from India="4" 
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 2 
Date of First Enrollment (India)   10/03/2020 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  10/03/2020 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="1"
Months="0"
Days="0" 
Recruitment Status of Trial (Global)   Not Yet Recruiting 
Recruitment Status of Trial (India)  Not Yet Recruiting 
Publication Details   NIL 
Individual Participant Data (IPD) Sharing Statement

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

Brief Summary   This study will assess the pharmacokinetics, safety, and tolerability of single and multiple doses of intravenous ceftazidime-avibactam in hospitalized infants and neonates from 26 weeks gestation to 3 months of age. In Part A of the study all patients will receive a single dose of ceftazidime-avibactam. In Part B all patients will received multiple doses of ceftazidime-avibactam. Efficacy will be assessed in the infants and neonates receiving multiple doses of ceftazidime-avibactam. 
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