Clinical Trials Register

Summary
EudraCT Number:	2012-002836-97
Sponsor's Protocol Code Number:	240193
National Competent Authority:	Estonia - SAM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-09-12
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

Estonia - SAM

A.2

EudraCT number

2012-002836-97

A.3

Full title of the trial

Pharmacokinetics of penicillin, ampicillin and gentamicin in near- term and full-term neonates

Ampitsilliini, penitsilliini ja gentamütsiini farmakokineetika vastsündinutel gestatsioonivanusega üle 32 rasedusnädala

A.3.1

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

Distribution, metabolism and excretion of ampicillin, penicillin and gentamicin after intravenous administration to near-term or term neoantes

Ampitsilliini, penitsilliini ja gentamütaiini jatumine, metabolism ja eritumine pärast veenisisest manustamist vastsündinutele, kes on sündinud raseduset kestusega üle 32 nädala

A.4.1

Sponsor's protocol code number

240193

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Tartu University Hospital
B.1.3.4	Country	Estonia
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Archimedes Foundation
B.4.2	Country	Estonia
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Tartu University Hospital
B.5.2	Functional name of contact point	Children`s Clinic
B.5.3	Address:
B.5.3.1	Street Address	N.Lunini 6
B.5.3.2	Town/ city	Tartu
B.5.3.3	Post code	51014
B.5.3.4	Country	Estonia
B.5.4	Telephone number	+3727319552
B.5.6	E-mail	helgi.padari@kliinikum.ee

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	Standacillin 1 g
D.2.1.1.2	Name of the Marketing Authorisation holder	Sandoz GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Estonia
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.3.1	Product name	ampicillin
D.3.4	Pharmaceutical form	Powder for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous bolus use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ampicillinum
D.3.9.1	CAS number	69-53-4
D.3.9.3	Other descriptive name	AMPICILLIN
D.3.9.4	EV Substance Code	SUB05487MIG
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	1000
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.IMP: 2
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	PENICILLIN G SODIUM SANDOZ
D.2.1.1.2	Name of the Marketing Authorisation holder	Sandoz GmbH
D.2.1.2	Country which granted the Marketing Authorisation	Estonia
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.3.1	Product name	Benzylpenicillin
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous bolus use (Noncurrent) Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BENZYLPENICILLIN PROCAINE
D.3.9.1	CAS number	6130-64-9
D.3.9.4	EV Substance Code	SUB00752MIG
D.3.10	Strength
D.3.10.1	Concentration unit	IU international unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1000000
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.IMP: 3
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	GENTAMICIN KRKA
D.2.1.1.2	Name of the Marketing Authorisation holder	KRKA d.d., Novo Mesto
D.2.1.2	Country which granted the Marketing Authorisation	Estonia
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.3.1	Product name	gentamicin
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous bolus use (Noncurrent) Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	GENTAMICIN SULFATE
D.3.9.1	CAS number	1405-41-0
D.3.9.4	EV Substance Code	SUB02327MIG
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	40
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

neonatal sepsis, pneumonia and meningitis

vastsündinu sepsis, pneumoonia ja meningiit

E.1.1.1

Medical condition in easily understood language

inflammation of bloodstream, lungs and brain membranes in neonates

vastsündinute vere, kopsude ja ajukelme põletik

E.1.1.2

Therapeutic area

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

MedDRA Classification

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 describe the PK of ampicillin, penicillin G and gentamicin in neonates with suspected or proven neonatal sepsis or pneumonia and GA of ≥ 32 week in order to define optimal dosing regimen of the studied antibiotics.

E.2.2

Secondary objectives of the trial

1) To describe the safety of ampicillin, penicillin G and gentamicin in neonates with GA ≥32 weeks
2) To describe the PK of ampicillin, penicillin G and gentamicin in CSF of neonates with suspected or proven bacterial meningitis and of GA ≥32 weeks
3)To describe the bronchoalveolar lavage fluid (BALF) concentrations of ampicillin, penicillin G and gentamicin achieved with the dosing regimen used in the study in neonates with GA ≥32 weeks requiring invasive ventilator support

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. GA ≥ 32 weeks
2. PNA < 28 days
3. Informed consent (IC) given by parents or guardian
4. Central venous or arterial catheter placed or will be placed on clinical indication
5. Treatment with intravenous ampicillin or penicillin G with or without gentamicin for suspected or proven neonatal sepsis, defined as at least two clinical and at least two laboratory criteria as listed below. In neonates with positive blood culture yielding a known pathogen (apart from CoNS for wich at least 2 positive blood cultures will be required) for the diagnosis of sepsis will be based on the presence of one clinical and one laboratory criterion.
Clinical criteria:
• hyper- or hypothermia or temperature instability,
• reduced urinary output or hypotension or mottled skin or impaired peripheral perfusion
• apnea or increased oxygen requirement or increased requirement for ventilator support,
• bradycardia spells or tachycardia or rhythm instability,
• feeding intolerance or abdominal distension,
• lethargy or hypotonia or irritability,
• skin and subcutaneous lesions such as petechial rash or sclerema
Laboratory criteria:
• white blood cells (WBC) count < 4 or > 21 x 109 cells/L,
• immature to total neutrophil ratio (I/T) > 0.2,
• platelet count < 100 x 109/L,
• C-reactive protein (CRP) > 15 mg/L,
• glucose intolerance when receiving normal glucose amounts (8-15 g/kg/day) as expressed by blood glucose values > 180 mg/dL or hypoglycemia (< 40 mg/dL) confirmed at least two times,
• acidosis as characterized by base excess (BE) < -10 mmol/L or lactate with value above 2 mmol/L.
6. No major malformations
7. Likely survival for more than 24 h from inclusion into the study

E.4

Principal exclusion criteria

1. GA < 32 weeks
2. PNA > 28 days
3. Informed consent not given by parents or guardian
4. No central venous or arterial catheter in place
5. Known hypersensitivity to study drug
6. Likely to be infected with organisms resistant to study antibiotics
7. Participation in any other study, apart from observational studies involving only data registration on clinical treatment

E.5 End points

E.5.1

Primary end point(s)

The PK endpoints are Cmax, Cmin, Tmax, , CLssdrug, T1/2, Vd
The secondary PK endpoints are drug concentration in BALF (ELF + AM) and CSF with AUCELF, AUCCSF calculated if feasible; and renal drug clearance (ClRdrug)
PD endpoints: T>MIC for penicillin and ampicillin and Cmax/MIC for gentamicin in plasma

E.5.1.1

Timepoint(s) of evaluation of this end point

pharmacokinetic sampling visit

E.5.2

Secondary end point(s)

Safety endpoints, what include the description of all adverse events (AE) experienced by infants receiving study drugs:
Clinical and laboratory AE will be recorded until end of therapy (EOT) visit and graded according to the need for a specific medical intervention.
Renal function parameters (creatinine, urea) will be recorded at least once before and once during treatment with the study regimen (EOT visit inclusive).
Clinical evaluation for seizures will be performed throughout the treatment with the study drug with EEG performed at the discretion of the treating physician.
Neurological evaluation by cerebral ultrasound undertaken as clinically indicated at any time during treatment with the study regimen (EOT visit inclusive).

E.5.2.1

Timepoint(s) of evaluation of this end point

All study patients will be monitored continuously plus additional evaluation at pharmacokinetic sampling visit and end of therapy visit

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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)

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

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

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

neonates are not able for consent

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

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2012-12-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-07-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-08-27

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