Clinical Trials Register

Summary
EudraCT Number:	2005-004825-25
Sponsor's Protocol Code Number:	GF-ICTUS-04
National Competent Authority:	Portugal - INFARMED
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2006-05-17
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

Portugal - INFARMED

A.2

EudraCT number

2005-004825-25

A.3

Full title of the trial

CITICOLINE IN THE TREATMENT OF ACUTE ISCHEMIC STROKE. AN INTERNATIONAL RANDOMIZED MULTICENTER PLACEBO-CONTROLLED STUDY

CITICOLINA NO TRATAMENTO DO ACIDENTE VASCULAR CEREBRAL ISQUÉMICO AGUDO. ESTUDO INTERNACIONAL, MULTICÊNTRICO, ALEATORIZADO, CONTROLADO COM PLACEBO

A.3.1

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

CITICOLINE IN THE TREATMENT OF ACUTE ISCHEMIC STROKE. AN INTERNATIONAL RANDOMIZED MULTICENTER PLACEBO-CONTROLLED STUDY

CITICOLINA NO TRATAMENTO DO ACIDENTE VASCULAR CEREBRAL ISQUÉMICO AGUDO. ESTUDO INTERNACIONAL, MULTICÊNTRICO, ALEATORIZADO, CONTROLADO COM PLACEBO

A.3.2

Name or abbreviated title of the trial where available

ICTUS study

A.4.1

Sponsor's protocol code number

GF-ICTUS-04

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	Ferrer Grupo S.A.
B.1.3.4	Country	Spain
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	FERRER INTERNACIONAL
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ANAGRAM-ESIC,S.L.
B.5.2	Functional name of contact point	Project Leader
B.5.3	Address:
B.5.3.1	Street Address	Comte Urgell 143
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08036
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034934515250
B.5.5	Fax number	0034934516631
B.5.6	E-mail	m.cardona@anagram-esic.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	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	Citicoline
D.3.2	Product code	Citicoline
D.3.4	Pharmaceutical form	Coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Citicoline
D.3.9.1	CAS number	33818-15-4
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.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	Somazina 1g injectable solution
D.2.1.1.2	Name of the Marketing Authorisation holder	FERRER INTERNACIONAL S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Injection
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	Citicoline
D.3.9.1	CAS number	987-78-0
D.3.10	Strength
D.3.10.1	Concentration unit	g gram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Injection
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Acute ischemic stroke

ACIDENTE VASCULAR CEREBRAL ISQUÉMICO

E.1.1.1

Medical condition in easily understood language

Stroke

AVC

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

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

The primary objective of this study is to confirm the effects on recovery at 3 months of oral citicoline 2000 mg/d/6 weeks, after 6 weeks of treatment and 6 weeks of follow-up, in patients with moderate-to-severe acute ischemic strokes (baseline NIHSS over 8) in comparison with placebo. Recovery will be evaluated using a primary end-point incorporating 3 components: neurological (National Institute of Health Stroke Scale (NIHSS) less or equal than 1), disability (MRS less or equal than 1), and activities of daily life (Barthel Index higher or equal than 95). These three components will be averaged using Generalized Estimating Equations (GEE).

E.2.2

Secondary objectives of the trial

Comparison of % of patients with MRS less or equal than 1 at week 12
Comparison of % of patients with NIHSS less or equal than 1 at week 12
Comparison of % of patients with Barthel Index higher or equal than 95% at week 12
Comparison of the distribution of the MRS scores at week 12
Absolute difference in the NIHSS between baseline and 3 months
The same analyses will be performed at Weeks 1 and 6
Assessment of citicoline safety and tolerability.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female, 18 years old.
2. Patients must be treated within 24 hours of their initial stroke symptoms onset. The time between hospital admittance and randomization must be inferior or equal to 12 hours and the time between randomization and the administration of the first dose must be inferior or equal to 1 hour. In the case of inpatients suffering a stroke (in-hospital stroke), the hospital arrival time will be the time of symptoms onset. In the case of unknown time of symptoms onset (i.e. awake stroke), the time of stroke onset will be considered as the last time when the patient was asymptomatic.
3. Patients with a measurable focal neurological deficit lasting for a minimum of 60 minutes. This deficit must persist from onset and up to the time of treatment without clinically significant improvement (independent of the use of rTPA). At the inclusion, patient must have a NIHSS score ≥ 8.
4. Patients must have a CT scan and/or conventional MRI compatible with the clinical diagnosis of acute ischemic stroke prior to being randomized.
5. Patients must have an acute ischemic stroke with symptoms, on clinical examination, suggestive of a stroke referable to the middle cerebral artery territory.
6. At inclusion, NIHSS score ³ 8, with at least 2 of these points from sections 5 & 6 (motor).
7. Immediately (i.e. minutes) pre-stroke, MRS £ 1 (no symptoms at all, or no significant disability despite symptoms; able to carry out all usual duties and activities). [History of past stroke does not, by itself, preclude study entrance].
8. Women of childbearing potential must have a negative pregnancy test prior to enrolment.
9. Signed informed consent (following a full explanation of the nature and purpose of this study, the patient or legal guardian(s) or representative(s) must consent to participate by signing the Informed Consent document).

E.4

Principal exclusion criteria

1. Patients in coma: patients having a score of 2 or higher in the items regarding the level of consciousness in the NIHSS (1a).
2. CT or conventional MRI evidence of brain tumor, cerebral edema with a clinically significant mass midline shift with compression of the ventricles, brainstem or cerebellar infarction, subarachnoid and/or intracerebral and/or intraventricular hemorrhage.
3. History of ventricular dysrhythmias, acute myocardial infarction within 72 hours prior to enrolment, unstable angina, decompensated congestive heart failure or any other acute, severe, uncontrollable or sustained cardiovascular condition that, in the Investigator’s opinion, may interfere with effective participation in the study.
4. Previous disorders that may confound the interpretation of the neurological scales.
5. Drug addiction-related disorders.
6. Pre existing dementia, when dementia implies a disability, measured as an score of 2 or higher in the previous MRS.
7. Pre existing medical condition that, in the Investigator’s opinion, may interfere with the patient's suitability and participation in the study.
8. Patients participating in another clinical trial or receiving a non-approved drug (clinical investigational drug) less than 30 days prior to screening.
9. Patients under current treatment with citicoline.

E.5 End points

E.5.1

Primary end point(s)

The primary objective of this study is to confirm the results obtained with the PDS, that is: to determine the effects on recovery at 3 months of oral citicoline 2000 mg/d/6 weeks, after 6 weeks of treatment and 6 weeks of follow-up, in patients with moderate-to-severe acute ischemic strokes (baseline NIHSS higher than 8) in comparison with placebo.
Recovery will be evaluated using a primary end-point incorporating 3 components: neurological (National Institute of Health Stroke Scale (NIHSS) less or equal than 1), disability (MRS less or equal than 1), and activities of daily life (Barthel Index higher or equal than 95). These three components will be averaged using GEE.
The trial will be considered positive, if under the Intent-To-Treat basis, the positive GEE analysis is associated to a positive trend in the single scales used for the analysis, that is p between 0.1 and 0.05 (or and OR equal or higher than 1.1).

E.5.1.1

Timepoint(s) of evaluation of this end point

Recovery will be evaluated using a primary end-point incorporating 3 components: neurological (National Institute of Health Stroke Scale (NIHSS) less or equal than 1), disability (MRS less or equal than 1), and activities of daily life (Barthel Index higher or equal than 95).

El objectivo principal

E.5.2

Secondary end point(s)

Not applicable

E.5.2.1

Timepoint(s) of evaluation of this end point

Not applicable

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

Yes

E.6.6

Pharmacokinetic

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)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

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

Yes

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

Germany

Spain

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

The end of the trial is the last visit of the last subject undergoing the trial

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

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)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

1170

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

1430

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

Yes

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Patients with neurological deficits from stroke

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

2600

F.4.2

For a multinational trial

F.4.2.1

In the EEA

2600

F.4.2.2

In the whole clinical trial

2600

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)

Os habituais neste tipo de doentes

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

2006-12-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2005-04-07

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2012-05-22

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