Clinical Trials Register

Summary
EudraCT Number:	2011-001521-25
Sponsor's Protocol Code Number:	11.0173
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-03-21
Trial 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

UK - MHRA

A.2

EudraCT number

2011-001521-25

A.3

Full title of the trial

Pharmacokinetics and safety of meropenem in infants below 90 days of age (inclusive) with probable and confirmed meningitis: a European multicentre phase I-ll trial.

A.3.1

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

How well does meropenem treat meningitis in infants below and including 90 days of age

A.3.2

Name or abbreviated title of the trial where available

NEOMERO2

A.4.1

Sponsor's protocol code number

11.0173

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/001/2010

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	FONDAZIONE PENTA
B.1.3.4	Country	Italy
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	European Commission
B.4.2	Country	European Union
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	FONDAZIONE PENTA
B.5.2	Functional name of contact point	c/o Dipartimento di Pediatria
B.5.3	Address:
B.5.3.1	Street Address	Via Giustiniani 3
B.5.3.2	Town/ city	Padova
B.5.3.3	Post code	35128
B.5.3.4	Country	Italy
B.5.4	Telephone number	0390498213585
B.5.5	Fax number	0390498753865
B.5.6	E-mail	management@neomero.org
B.Sponsor: 2
B.1.1	Name of Sponsor	St George's University of London
B.1.3.4	Country	United Kingdom
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	European Commission
B.4.2	Country	European Union
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	St George's University of London
B.5.2	Functional name of contact point	Joint Research Office
B.5.3	Address:
B.5.3.1	Street Address	Ground Floor, Hunter Wing, Cranmer Terrace
B.5.3.2	Town/ city	London
B.5.3.3	Post code	SW17 0RE
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	004402087254986
B.5.5	Fax number	004402087250794
B.5.6	E-mail	trials@sgul.ac.uk

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	No
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	Meropenem
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	Yes
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	MEROPENEM
D.3.9.1	CAS number	96036-03-2
D.3.9.3	Other descriptive name	Sterile dry mixture of sterile Meropenem trihydrate and sterile Sodium Carbonate lyophilized blended
D.3.9.4	EV Substance Code	SUB08778MIG
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	100
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	Yes
D.3.11.13.1	Other medicinal product type	Antibiotic substance

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

Proven or suspected bacterial meningitis in neonates and infants up to 90 days of age.

E.1.1.1

Medical condition in easily understood language

Meningitis in neonates and infants.

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	15.0
E.1.2	Level	LLT
E.1.2	Classification code	10004049
E.1.2	Term	Bacterial meningitis
E.1.2	System Organ Class	10021881 - Infections and infestations

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 study the pharmacokinetics (plasma and cerebrospinal fluid) of meropenem in infants ≤ 90 days of postnatal age with probable or confirmed bacterial meningitis (BM);
• To characterise the safety profile of meropenem in the treatment of infants ≤ 90 days of postnatal age with probable or confirmed bacterial meningitis.

E.2.2

Secondary objectives of the trial

• To describe the efficacy of meropenem on day 3, at end of allocated treatment (EOAT), at test of cure (TOC) and at follow up (FU);
• To evaluate survival at FU;
• To evaluate further episodes of meningitis (relapse or new infection) occurring between TOC and FU visits;
• To define the organisms causing neonatal meningitis;
• To describe the antibacterial susceptibility of meningitis-causing organisms and to describe the clinical and microbiological responses according to this;
• To evaluate mucosal colonization by resistant organisms before and after treatment with meropenem;
• To evaluate bacterial eradication;
• To evaluate functional genetic parameters that may affect response to therapy.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

• Microbiology sub-study: gut colonisation with resistant microorganisms in neonates and infants treated with meropenem for bacterial meningitis (Protocol V2.0; 08-07-2011)
• Genetic determinants of susceptibility to meningitis and differential responses to meropenem. (Protocol V2.0; 08-07-2011)

E.3

Principal inclusion criteria

• Informed consent form signed by the parents/carers
• Chronological age below 90 days inclusive
• The presence of:
- clinical signs consistent with Bacterial Meningitis (fever or hypothermia or temperature instability PLUS 1 or more neurological findings among coma, seizures, neck stiffness, apnoea, bulging fontanelle),
- OR CSF pleocytosis (≥ 20 cells/mm3)
- OR a positive Gram stain of CSF.

Notes:
1. Where the initial results of the lumbar puncture do not support a diagnosis of meningitis e.g. where the cell count is < 20 cells/mm3, but the subsequent CSF culture (or PCR (see later)) is positive for a significant pathogen, then the infant will still be eligible for recruitment when these results become known.
2. Where the early lumbar puncture is deferred, for example, because the infant is clinically unstable, but the delayed lumbar puncture supports a diagnosis of meningitis (as above), then the infant will still be eligible for recruitment.
3. If the lumbar puncture is traumatic, the “normal” ratio of 500 RBC: 1 WBC will be used to evaluate the CSF WCC result.

E.4

Principal exclusion criteria

• Presence of a CSF device
• Proven viral or fungal meningitis
• Severe congenital malformations if the infant is not to expect to survive for more than 3 months
• Other situations where the treating physician considers a different empiric antibiotic regimen necessary
• Known intolerance or contraindication to the study medication
• Participation in any other clinical study of an investigational medicinal product
• Renal failure and requirement of haemofiltration or peritoneal dialysis
• Meningitis with an organism known to be resistant to meropenem

E.5 End points

E.5.1

Primary end point(s)

- The PK of meropenem (plasma and CSF) in infants ≤ 90 days of age diagnosed with probable and confirmed BM
- Adverse Events experienced by infants receiving meropenem.

E.5.1.1

Timepoint(s) of evaluation of this end point

Meropenem PK wil be studied in steady state on the 3rd study day. Clinical and biological adverse events will be recorded until follow-up visit on Day 45+/- 3.

E.5.2

Secondary end point(s)

- A favourable outcome defined at Test of Cure visit (TOC), 2 days after EOAT as an infant fulfilling the following criteria: Alive with clinical and bacteriological resolution of the abnormalities that defined BM at entry and no occurrence of any abnormalities that defined BM at entry requiring a new course of antbiotic therapy and no modification of the initial meropenem therapy (for more than 24 hours).
- Clinical, biological and microbiological response at day 3, at EOAT, at TOC and at FU
- Survival at FU visit
- Auditory function as asessed by brain-stem auditory evoked potentials between COT and FU visits
- Neurological evaluation as assessed by cerebral ultrasound (and if persistently abnormal, by MRI or CT) at any time up until the FU visit;
- The organisms causing neonatal meningitis
- The antibiotic susceptibility of bacteria causing BM
- Mucosal colonisation with antibiotic resistant bacteria or fungi at enrolment, EOAT and FU / discharge (whichever is earlier)
- Genetic parameters which can affect response to therapy.

E.5.2.1

Timepoint(s) of evaluation of this end point

- End of allocated treatment (EOAT) - the point in time when allocated therapy or meningitis is stopped, that means the last day of allocated treatment.
- TOC visit is performed 2+/- 1 days after EOAT.
- Follow up (FU) visit is performed at Day 45 +/- 3.

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

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)

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.8.3

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

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

IDMC performs an interim review of the trial's progress including updated figures on recruitment, data quality, and main safety outcomes. Based on its review, the IDMC will provide within 15 days after each of its meetings a written report with recommendations to the Sponsor regarding study modification, continuation or termination.

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

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

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Neonates and infants up to 90 days.

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)

Trial subject will continue to be looked after and followed up under the normal hospital care.

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

2012-05-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-01-25

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-12-12

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