Clinical Trials Register

Summary
EudraCT Number:	2018-002841-12
Sponsor's Protocol Code Number:	C3591025
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:
Date on which this record was first entered in the EudraCT database:	2021-01-05
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2018-002841-12

A.3

Full title of the trial

A Phase 1, Open-Label, Single-Dose Study To Assess The Pharmacokinetics, Safety And Tolerability Of Ceftazidime-Avibactam (Caz-Avi) In Children From 3 Months To Less Than 18 Years Of Age Who Are Hospitalized And Receiving Systemic Antibiotic Therapy For Suspected Or Confirmed Nosocomial Pneumonia, Including Ventilator-Associated Pneumonia

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Treatment for Hospital-acquired pneumonia

A.4.1

Sponsor's protocol code number

C3591025

A.5.4

Other Identifiers

Name:

IND Number

Number:

101,307

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/340/2018

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Pfizer Inc. 235 East 42nd Street, New York, New York 10017
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Pfizer Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Pfizer Inc.
B.5.2	Functional name of contact point	Clinical Trials.gov Call Center
B.5.3	Address:
B.5.3.1	Street Address	235 East 42nd Street
B.5.3.2	Town/ city	New York
B.5.3.3	Post code	10017
B.5.3.4	Country	United States
B.5.4	Telephone number	18007181021
B.5.5	Fax number	13037391119
B.5.6	E-mail	clinicaltrials.gov_Inquiries@pfizer.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Zavicefta
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Ireland Pharmaceuticals
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.4	Pharmaceutical form	Powder for concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ceftazidime pentahydrate
D.3.9.1	CAS number	78439-06-2
D.3.9.2	Current sponsor code	CAZ
D.3.9.3	Other descriptive name	CCI 20263BQ, 113/4 pentahydrate
D.3.9.4	EV Substance Code	SUB01134MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2000
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Avibactam sodium
D.3.9.1	CAS number	1192491-61-4
D.3.9.2	Current sponsor code	AVI
D.3.9.3	Other descriptive name	CCI 20263BQ, 1132/4 pentahydrate
D.3.9.4	EV Substance Code	SUB179984
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	500
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Suspected Or Confirmed Nosocomial Pneumonia, Including Ventilator-Associated Pneumonia

E.1.1.1

Medical condition in easily understood language

Hospital-acquired pneumonia

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10052596
E.1.2	Term	Nosocomial pneumonia
E.1.2	System Organ Class	100000004862

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To characterize the pharmacokinetics (PK) of a single intravenous dose of CAZ-AVI in pediatric subjects aged 3 months to less than 18 years who are receiving systemic antibiotic therapy for suspected or confirmed nosocomial pneumonia, including ventilator-associated pneumonia.

E.2.2

Secondary objectives of the trial

To evaluate the safety and tolerability of a single intravenous dose of CAZ-AVI in pediatric subjects aged 3 months to less than 18 years with nosocomial pneumonia, including ventilator-associated pneumonia.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Evidence of a personally signed and dated informed consent document indicating that the subject’s parent(s), legal guardian, or legally acceptable representative has been informed of all pertinent aspects of the study. As appropriate per local requirements informed assent of subjects must also be documented.
2. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Male or female children age ≥3 months to <18 years at Screening:
a. Cohort 1: age 12 years to <18 years;
b. Cohort 2: age 6 years to <12 years;
c. Cohort 3: age 2 years to <6 years;
d. Cohort 4: age 3 months to <2 years (must be born ≥37 weeks gestational age).
4. Hospitalized, receiving systemic antibiotic therapy for the treatment of a suspected or confirmed HAP, including VAP, meeting the following criteria, and expected to require hospitalization until after the follow-up evaluations are completed on Day 3 (48 hours after the end of infusion):
a. Onset of symptoms ≥48 hours after admission or <7 days after discharge from an inpatient acute or chronic care facility;
b. Evidence of new or worsening infiltrate as demonstrated on chest X-ray or other imaging modality that has been performed as part the subject's regular medical care;
c. At least 1 of the following systemic signs prior to the initiation of treatment for Nosocomial Pneumonia:
i. Fever (temperature >38°C) or hypothermia (rectal/core temperature <35°C);
ii. White blood cell (WBC) count >10,000 cells/mm3, or WBC count <4,500 cells/mm3, or >15% band forms.
d. At least 2 of the following respiratory signs or symptoms:
i. A new onset of cough (or worsening of cough).
ii. Production of purulent sputum or endotracheal secretions.
iii. Auscultatory findings consistent with pneumonia/pulmonary consolidation (eg, rales, rhonchi, bronchial breath sounds, dullness to percussion, egophony).
iv. Dyspnea, tachypnea or hypoxemia (O2 saturation <90% or PaO2<60 mmHg while breathing room air).
v. A need for mechanical ventilation or, for already ventilated subjects, acute changes made in the ventilator support system to enhance oxygenation, as determined by, for example arterial blood gas or worsening PaO2/FiO2.
5. Likely to survive the current illness or hospitalization.
6. Sufficient IV access (peripheral or central) to receive study drug and dedicated access for PK sampling.

E.4

Principal exclusion criteria

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 other studies involving investigational drug(s) within 30 days prior to study entry and/or during study participation.
3. Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior 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.
4. Past or current history of epilepsy or seizure disorder (excluding childhood febrile seizures).
5. Severe renal impairment defined as creatinine clearance (CrCL) ≤30 mL/min/1.73 m2 calculated using the child’s measured height (length) and serum creatinine with the Bedside Schwartz equation (Schwartz, Munoz, et al., 2009):
CrCL (mL/min/1.73 m2) = 0.413 x height (cm) / serum creatinine (mg/dL)
6. Documented history of any hypersensitivity or allergic reaction to any β-lactam antibiotic.
7. Pregnant female subjects; breastfeeding female subjects; fertile male subjects and female subjects of childbearing potential who are sexually active and unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for at least 28 days after the last dose of CAZ-AVI.
8. Acute hepatitis in the prior 6 months, a prior history of cirrhosis, acute hepatic failure, or acute decompensation of chronic hepatic failure; and/or any of the following blood test results, for any individual, when assessed for eligibility:
a. Bilirubin >3 × upper limit of normal (ULN), unless isolated hyperbilirubinemia is directly related to the acute infection or due to known Gilbert’s disease;
b. ALT or AST >3 × ULN values used by the laboratory performing the test.
Subjects with values >3 × ULN and <5 × ULN are eligible if this value is acute and directly related to the infectious process being treated. This must be documented;
c. ALP >3 × ULN. Subjects with values >3 × ULN and <5 × ULN are eligible if this value is acute and directly related to the infectious process being treated. This must be documented.
9. Any condition (eg, septic shock, burns, cystic fibrosis, acute hemodynamic instability, including those conditions not responding to pressor support) that would make the patient, in the opinion of the Investigator, unsuitable for the study (eg, would place a patient at risk; compromise the quality of the data; or interfere with the absorption, distribution, metabolism, or excretion of CAZ-AVI).
10. Receipt of a blood or blood component or scheduled for transfusion within the PK sampling period (eg, red blood cells, fresh frozen plasma, platelets) transfusion during the 24-hour period before enrollment.
11. Body mass index (BMI) below the 5th percentile or above the 95th percentile for height, age, and weight except for children <2 years of age as BMI is not considered a screening tool for healthy weight in children under 2 years of age.
12. Treatment with ceftazidime within 12 hours of CAZ-AVI administration or treatment with ceftazidime within 24 hours of CAZ-AVI administration in subjects with renal impairment (CrCL ≤50 mL/min/1.73 m2).
13. Treatment with potent inhibitors of OAT1 and/or OAT3 (eg, probenecid, p-aminohippuric acid (PAH), or teriflunomide).

E.5 End points

E.5.1

Primary end point(s)

CAZ and AVI Plasma concentrations by nominal time.
CAZ and AVI PK parameters calculated by non-compartmental analysis (Cohorts 1 and 2 only).

E.5.1.1

Timepoint(s) of evaluation of this end point

Timepoints for each endpoint are listed with the endpoint.
Blood samples for PK analyses (0.5 mL per sample) will be obtained over 22 hours following the CAZ AVI infusion for Cohort 1 (7 samples), over 13 hours for Cohort 2 (6 samples), and over 6 hours for Cohorts 3 and 4 (4 samples).

E.5.2

Secondary end point(s)

Safety and tolerability endpoints include adverse events (AEs), serious adverse events (SAEs), deaths, discontinuations due to AEs and laboratory abnormalities.

E.5.2.1

Timepoint(s) of evaluation of this end point

Timepoints for each endpoint are listed with the endpoint.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Pharmacokinetics, Safety and Tolerability study in children

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Australia

Brazil

Canada

Chile

Mexico

New Zealand

Russian Federation

Turkey

United States

Austria

Belgium

France

Germany

Ireland

Italy

Netherlands

Poland

Romania

Spain

Switzerland

United Kingdom

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The end of the study is defined as the LVLS undergoing the study or the date of study closure in the case of early study termination, whichever date is later.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-01-29

Ethics Committee Opinion of the trial application

Withdrawn

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-09-11

P. End of Trial
P.	End of Trial Status

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IMP with orphan designation in the indication
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