Clinical Trials Register

Summary
EudraCT Number:	2011-001521-25
Sponsor's Protocol Code Number:	NEOMERO-2
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:	2011-09-19
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

Estonia - SAM

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 multicenter phase II trial

A.3.1

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

Meropenem in meningitis in children up to 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

NEOMERO-2

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 ONLUS
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 COMMUNITY
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 Onlus
B.5.2	Functional name of contact point	Fondazione PENTA Onlus
B.5.3	Address:
B.5.3.1	Street Address	c/o Dipartimento di Pediatria, 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	+390498213585
B.5.5	Fax number	+390498753865
B.5.6	E-mail	management@neomero.org

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.3.2	Product code	NA
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.3.9.4	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 from chemical synthesis

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

Bacterial meningitis in children up to 90 days of age

E.1.1.1

Medical condition in easily understood language

Bacterial infection of the meningis in neonates and children up to 90 days of age

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	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10004049
E.1.2	Term	Bacterial meningitis
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 study the pharmacokinetics (plasma and cerebrospinal fluid) of meropenem in infants ≤ 90 days of postnatal age with probable or confirmed bacterial meningitis and to characterize the safety profile of meropenem in the treatment of infants ≤ 90 days of postnatal age with probable or confirmed bacterial meningitis.

Studiare la farmacocinetica del Meropenem (nel plasma e nel liquido cefalo-rachidiano) nei neonati e bambini di età ≤ 90 giorni con meningite batterica probabile o confermata e caratterizzare il profilo di sicurezza del Meropenem nel trattamento dei neonati e bambini di età ≤ 90 giorni con meningite batterica probabile o confermata.

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 response according to this • To evaluate mucosal colonization by resistant organisms before and after treatment with meropenem • To evaluate bacterial eradication

• Descrivere l’efficacia del Meropenem al giorno 3, alla fine della terapia assegnata, al test di cura ed alla visita di follow up • Valutare la sopravvivenza alla visita di follow up • Valutare ulteriori episodi di meningite (ricadute o nuove infezioni) nel periodo tra il test di cura e le visite di follow-up • Definire gli organisimi che causano la meningite neonatale • Descrivere la sensibilità agli antibiotici degli organismi causanti la meningite e sulla base di essa descrivere la risposta clinica e microbiologica • Valutare la colonizzazione delle mucose da parte di organismi resistenti prima e dopo il trattamento con Meropenem • Valutare l’eradicazione batterica

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

PHARMACOGENETICS:
Version 4 Date 2014/03/31
Title:Genetic determinants of susceptibility to sepsis/meningitis and to differential responses to Meropemen
Objectives: investigating genetic factors modulating differential susceptibility to sepsis and meningitis. The substudy will be separated in two stages, one “hypothesis-driven” (candidate gene approach) and the other one “hypothesis-driving” (genome wide scan).

FARMACOGENETICA:
Versione 4 Data 31/03/2014
Titolo: Determinanti di suscettibilità a sepsi/meningite ed a differenti risposte a Meropenem.
Obiettivi: indagare i fattori genetici che modulano la differente suscettibilità a sepsi e meningite. Il sottostudio comprenderà 2 fasi: approccio del gene candidato e mappatura dell'intero genoma.

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 (clinical signs of meningitis are: fever or hypothermia or temperature instability PLUS 1 or more neurological findings e.g. coma, seizures, neck stiffness, apnoea, bulging fontanelle) OR CSF pleocytosis (≥ 20 cells / mm3 OR a positive Gram stain of CSF).

• Consenso informato firmato dai genitori/tutori • Età cronologica ≤90 giorni • La presenza di segni clinici indicativi di meningite batterica (segni clinici di meningite sono: febbre o ipotermia o instabilità della temperatura corporea PIU’ uno o più segni neurologici come per esempio coma, convulsioni, rigidità del collo, apnea, fontanella bombata) O pleiocitosi del liquor (≥ 20 cell/mm3) O positività alla colorazione Gram del liquor.

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

• Presenza di un dispositivo liquorale • Meningite virale o fungina provata • Malformazioni congenite severe, se la previsione di vita non è superiore a 3 mesi • Altre situazioni in cui il medico curante ritenga necessario un diverso regime di terapia antibiotica • Intolleranza nota o controindicazioni al farmaco in studio • Partecipazione a qualsiasi altro studio clinico con farmaci sperimentali • Insufficienza renale e necessità di emofiltrazione o dialisi peritoneale • Meningite causata da un organismo resistente al 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. Clinical and biological adverse events will be recorded until FU visit.

• La farmacocinetica (nel plasma e liquido cefalo-rachidiano) del Meropenem nei neonati e bambini di età ≤ 90 giorni con meningite batterica probabile o confermata; • Gli eventi avversi (clinici e biologici) nei neonati e bambini in trattamento con Meropenem. Gli eventi avversi saranno registrati/riportati fino alla visita di follow up.

E.5.1.1

Timepoint(s) of evaluation of this end point

Within day 45 of enrolment

Entro il giorno 45 dall’arruolamento

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 (see appendix B) of the abnormalities that defined BM at entry and no occurrence of any new clinical or laboratory abnormalities requiring a new course of antibiotic 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 assessed 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)

• Un outcome favorevole definito come un paziente con i seguenti criteri alla visita del test di cura, 2 giorni dopo la fine della terapia antibiotica assegnata: è vivo con risoluzione clinica e batteriologica delle anomalie che hanno caratterizzato la meningite batterica all’ingresso nello studio e assenza di nuovi segni clinici o laboratoristici che richiedano un ulteriore ciclo di terapia antibiotica e alcuna modificazione della terapia iniziale con Meropenem (per più di 24 ore) • La risposta clinica, bioumorale e microbiologica al giorno 3, alla fine della terapia antibiotica assegnata, alla visita del test di cura e alla visita di follow up • La sopravvivenza alla visita di follow up • La funzionalità uditiva valutata tramite potenziali evocati uditivi tra il completamento della terapia antibiotica e la visita di follow up • La valutazione neurologica tramite ecografia cerebrale (e qualora questa fosse persistentemente patologica, tramite RMN o TAC) entro la visita del follow up • Gli organisimi che causano la meningite neonatale • La sensibilità agli antibiotici degli organismi causanti la meningite • La colonizzazione delle mucose da parte di batteri resistenti agli antibiotici o funghi all’arruolamento, alla fine della terapia antibiotica assegnata e alla visita del follow up/alla dimissione (nell’occasione che avviene prima nel tempo)

E.5.2.1

Timepoint(s) of evaluation of this end point

Within day 45 of enrolment

entro il giorno 45 dall’arruolamento

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

Yes

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.8.2.4

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

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

"Last patient - Last follow-up visit at day 45"

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 of age

neonati e bambini di età fino a 90 giorni inclusi

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"

"Nessuno"

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

2011-12-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-09-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-12-10

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