Clinical Trials Register

Summary
EudraCT Number:	2018-002800-16
Sponsor's Protocol Code Number:	C3591024
National Competent Authority:	Slovakia - SIDC (Slovak)
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2019-10-01
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

Slovakia - SIDC (Slovak)

A.2

EudraCT number

2018-002800-16

A.3

Full title of the trial

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

Nezaslepené, nerandomizované, multicentrické klinické skúšanie fázy 2A, pozostávajúce z 2 častí, hodnotiace farmakokinetiku, bezpečnosť a znášanlivosť jednorazovej a opakovaných dávok ceftazidímu a avibaktámu u novorodencov a dojčiat od narodenia do menej ako 3 mesiacov veku, ktorí vyžadujú intravenóznu antibiotickú liečbu pri podozrení na infekcie alebo potvrdených infekciách vyvolaných gramnegatívnymi patogénmi

A.3.1

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

Treatment for infections due to Gram-Negative Pathogens Infection in infants from birth to 3 months old.

Liečba infekcií spôsobených gramnegatívnymi patogénmi u detí od narodenia do 3 mesiacov veku.

A.4.1

Sponsor's protocol code number

C3591024

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.
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	ceftazidime 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	Avibactam sodium
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

Infections with suspected or confirmed Gram-negative pathogens

E.1.1.1

Medical condition in easily understood language

Infections requiring treatment with intravenous antibiotic

E.1.1.2

Therapeutic area

Diseases [C] - Bacterial Infections and Mycoses [C01]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10032531
E.1.2	Term	Other specified bacterial infections in conditions classified elsewhere and of unspecified site
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

Part A Primary Objective: To characterize the pharmacokinetics (PK) of a single intravenous dose of CAZ-AVI in hospitalized neonates and infants from birth to <3 months.

Part B Primary Objective: To evaluate the safety and tolerability of CAZ-AVI for the treatment of aerobic Gram-negative infection in neonates and infants from birth to <3 months.

E.2.2

Secondary objectives of the trial

Part A Secondary Objective:
To evaluate the safety and tolerability of a single intravenous dose of CAZ-AVI in hospitalized neonates and infants from birth to <3 months

Part B Secondary Objectives:
To evaluate the pharmacokinetic profile of multiple intravenous doses of CAZ-AVI in hospitalized neonates and infants from birth to <3 months.
To evaluate the efficacy of CAZ-AVI for the treatment of aerobic Gram-negative infection in neonates and infants from birth to <3 months.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
Inclusion Criteria for All Subjects:
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.
2.Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3.Male or female neonates and infants with age at Screening:
a.Cohort 1: Full term infants (gestational age ≥37 weeks) with chronological age >28 days to <3 months (89 days) or pre-term infants with corrected age* >28 days to <3 months (89 days). A maximum of 3 pre-term corrected age infants may be enrolled in each part (A and B) of Cohort 1. Sites will be notified in writing if this limit is reached.
b.Cohort 2: Full term neonates (gestational age ≥37 weeks) from birth to ≤28 days.
c.Cohort 3: Pre-term neonates (gestational age ≥26 to <37 weeks) from birth to ≤28 days.
Gestational age is the time elapsed between the first day of the last menstrual period and birth.
*Corrected age is the age of the infant from the expected date of delivery, calculated by subtracting the number of weeks born before 40 weeks of gestation from the chronological age (Engle, 2004). Corrected age (in weeks) = chronological age in weeks – (40 – gestational age in weeks). See Protocol (Appendix 2) for calculation of corrected age in days and alternative perinatal age terminologies.
Inclusion Criteria for Part A Subjects Only:
1.Hospitalized and receiving intravenous antibacterial therapy for the treatment of a suspected or confirmed bacterial infection.
Inclusion Criteria for Part B Subjects Only:
1.Hospitalized with suspected or confirmed aerobic Gram-negative bacterial infection requiring intravenous antibacterial therapy.
2.Subjects must meet at least 1 clinical and 1 laboratory criterion or meet at least 2 of the clinical criteria:
Clinical Criteria:
a.Hypothermia (<36˚C) OR fever (>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 ≤4.0 × 109/L OR ≥20.0 × 109/L;
b.Immature to total neutrophil ratio >0.2;
c.Platelet count ≤100 × 109/L;
d.C-reactive protein (CRP) >15 mg/L OR procalcitonin ≥2 ng/mL;
e.Hyperglycemia OR Hypoglycemia;
f.Metabolic acidosis.

E.4

Principal exclusion criteria

Subjects with any of the following characteristics/conditions will not be included in the study:
Exclusion Criteria for 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 ß-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 ≥2 times the upper limit of normal (ULN) for age OR urine output <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 (see Section 5.5.2 of the protocol).
8.Evidence of progressively fatal underlying disease, or life expectancy of ≤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 central nervous system (CNS) infection (eg, meningitis, brain abscess, subdural abscess).
3.Anticipated need for antibacterial therapy longer than 14 days (eg, osteomyelitis, endocarditis). 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 nonstudy 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.

E.5 End points

E.5.1

Primary end point(s)

Part A
•CAZ and AVI plasma concentrations by nominal sampling time.

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

E.5.1.1

Timepoint(s) of evaluation of this end point

Timepoints for each endpoint are listed with the endpoint.

E.5.2

Secondary end point(s)

English Part A
• Safety and tolerability endpoints include adverse events (AEs), serious adverse events (SAEs), deaths, discontinuations due to AEs and laboratory abnormalities.
Part B
• CAZ and AVI plasma concentrations by nominal sampling time.
• Efficacy outcome measures will include:
- All cause mortality.
- Clinical outcome at EOIV, EOT, TOC and LFU.
- Cure defined as clinical improvement and no need for further antibacterial treatment, 7 to 14 days after end of treatment.
- Microbiological eradication 7 to 14 days after end of treatment (micro Intent to Treat analysis set).
- Emergent infections.

E.5.2.1

Timepoint(s) of evaluation of this end point

Timepoints for each endpoint are listed with the endpoint.

English 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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

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)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

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

China

Czech Republic

Estonia

Greece

Hungary

India

Italy

Philippines

Slovakia

Taiwan

United States

E.8.7

Trial has a data monitoring committee

Yes

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

LVLS

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)

Yes

F.1.1.2.1

Number of subjects for this age range:

F.1.1.3

Newborns (0-27 days)

Yes

F.1.1.3.1

Number of subjects for this age range:

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)

F.1.1.6

Adolescents (12-17 years)

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	PENTA ID Innovation srl
G.4.3.4	Network Country	Italy

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-12-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-10-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-11-18

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