ICTUS Study: International Citicoline Trial on Acute Stroke

Acute Stroke Clinical Trial

— ICTUS  

Official title:

Citicoline in the Treatment of Acute Ischemic Stroke. An International Randomized Multicenter Placebo-controlled Study

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00331890
• Other study ID #: GF-ICTUS-04
• Status: Terminated
• Phase: Phase 3
• First received: May 30, 2006
• Last updated: June 19, 2012
• Start date: October 2006
• Est. completion date: March 2012

Study information

• Verified date: June 2012
• Source: Ferrer Internacional S.A.
• Contact: n/a
• Is FDA regulated: No
• Health authority: Spain: Spanish Agency of MedicinesPortugal: National Pharmacy and Medicines InstituteGermany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial Summary

Citicoline is a safe drug approved in some countries for the treatment of acute ischemic stroke. The drug has shown some evidence of efficacy in a pooled analysis, based on four clinical trials done in USA with oral citicoline.The purpose of the study is confirm the results obtained in the pooled analysis, that is, evidence of efficacy in the treatment of acute ischemic stroke

Description:

The stroke or brain attack is one of the main health problems in developed countries. It is the third cause for death and the main cause of disability in adults. Cerebral infarction makes up 80 % of all the types of strokes.

After a stroke, different evolutions and outcomes can be observed, and there are several factors that may influence the outcome, such as age, cognitive impairment, and psycho-social factors. The most important prognostic factors for acute ischemic stroke are the volume of the cerebral infarction and the severity of the baseline neurological deficit.

In recent years, stroke has been considered a real medical emergency, and for this reason several clinical trials have been conducted to find effective therapies. Among pharmacological therapies, there are two possible ways to treat ischemic strokes: treatments directed to recanalize the occluded artery, such as thrombolysis, and the neuroprotective drugs.

None of the neuroprotective drugs have attained the international approval for this indication. Among the reasons for the failures obtained with the different drugs tested, we must highlight the problems derived from the toxicity of the drugs and from the evaluation criteria, as well as the therapeutic window used.

To evaluate a drug in the treatment of acute ischemic stroke, one must be very careful when defining the schedule of the clinical trial, and which variable or variables may be considered as primary endpoints. Several endpoints have been used in the different clinical trials developed, although the most used are those referring to the functional status and the degree of disability of the patients, normally set at 3 months after the stroke.

After the onset of an ischemic stroke in the brain, there is a cascade of events that are responsible for neuronal disruption, neuronal membrane breakdown and/or neuronal apoptosis, specifically in the penumbra area. Therapies acting by blocking the ischemic cascade, at least partially, and/or stabilizing neuronal membranes are believed to be beneficial protecting the brain from the progressive effects of ischemia. Among the neuroprotective drugs, there is a new class of drugs, of which the main representative is citicoline. Citicoline monosodium is an exogenous form of CDP-Choline, which is essential for the biosynthesis of membrane phospholipids. The mechanisms of action of citicoline include the stimulation of the biosynthesis of phospholipids of the neuronal membrane, the inhibition of the activity of some phospholipases, the restoration of some enzymatic activities bound to neuronal membranes, and the elevation of brain levels of some catecholamines.

The previous clinical trials performed with citicoline were no conclusive, with some positive results. In all these studies, citicoline was found to have a similar safety profile as compared with placebo.

The variety of outcomes and results of the different trials made it difficult to arrive at a consensus on the efficacy of the drug. That is the reason why a Pooling Data Analysis using updated individual patient data was done, with the main objective to determine the effects of citicoline on the improvement, functional and neurological, of patients with acute ischemic stroke treated with different doses of citicoline for 6 weeks and with a follow-up period of 6 weeks. The results obtained in this Pooling Data Analysis showed that the odds ratio of achieving a complete recovery was 33 % higher in citicoline-treated patients than in placebo-treated patients, with the best response obtained with the dose of 2000 mg/d/6 weeks.

The primary objective of this study 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 equal or higher than 8) in comparison with placebo.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 2298
• Est. completion date: March 2012
• Est. primary completion date: February 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Male or female, >18 years old

• Patients must be treated within 24 hours of their initial stroke symptoms onset.

• Patients with a measurable focal neurological deficit lasting for a minimum of 60 minutes.

• Patients must have a CT scan and/or conventional MRI compatible with the clinical diagnosis of acute ischemic stroke prior to being randomized.

• Patients must have an acute ischemic stroke referable to the middle cerebral artery territory

• At inclusion, NIHSS score > 7, with at least 2 of these points from sections 5 & 6 (motor)

• Immediately (i.e. minutes) pre-stroke, MRS < 2

• Women of childbearing potential must have a negative pregnancy test prior to enrolment

• Signed informed consent

Exclusion Criteria:

• Patients in coma: patients having a score of 2 or higher in the items regarding the level of consciousness in the NIHSS (1a)

• 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

• 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

• Previous disorders that may confound the interpretation of the neurological scales

• Drug addiction-related disorders

• Pre existing dementia, when dementia implies a disability, measured as an score of 2 or higher in the previous MRS

• Pre existing medical condition that, in the Investigator's opinion, may interfere with the patient's suitability and participation in the study

• Patients participating in another clinical trial or receiving a non-approved drug (clinical investigational drug) less than 30 days prior to screening

• Patients under current treatment with citicoline

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Acute Stroke
• Cerebral Infarction
• Infarction
• Stroke

Intervention

Drug:
• Citicoline
1g/12h iv during 3 days and then orally until complete 6 weeks of treatment
• Placebo
As active drug

Locations

Country	Name	City	State
Germany	Klinikum AltenburgerLand GmbH	Altenburg
Germany	Neurologie EVKB	Bielefeld
Germany	Neurologische Klinik Heinrich-Heine Universität	Dusseldorf
Germany	Universitätsklinikum Erlangen	Erlangen
Germany	Ernst-Moritz-Arndt-Universität Greifswald	Greifswald
Germany	Universitätsklinikum Hamburg-Eppendorf	Hamburg
Germany	Neurologische Klinik Universitatsklinikum Heidelberg	Heidelberg
Germany	Klinikum Ingolstadt	Ingolstadt
Germany	Universitätsklinikum Leipzig	Leipzig
Germany	Johannes Wesling Klinikum Minden	Minden
Germany	Klinikum Großhadern der Universität München	München
Germany	Universitätsklinikum Münster	Münster
Portugal	Hospital Garcia de Orta	Almada
Portugal	Hospital Garcia de Orta, EPE	Almada
Portugal	Hospital Fernando Fonseca	Amadora - Sintra
Portugal	Hospital Sao Marcos	Braga
Portugal	Centro Hospitalar de Coimbra	Coimbra
Portugal	Hospitais da Universidade Coimbra	Coimbra
Portugal	Hospital de Santa Maria	Lisbon
Portugal	Hospital de Sao Jose	Lisbon
Portugal	Hospital de Santo Antonio	Porto
Portugal	Hospital de Sao Joao	Porto
Portugal	Hospital Sao Sebastiao	Santa Maria da Feira
Portugal	Centro Hospitalar de Setúbal	Setubal
Portugal	Centro Hospitalar de Setúbal, EPE	Setúbal
Portugal	Hospital Sao Pedro	Vila Real
Spain	Hospital General de Albacete	Albacete
Spain	Hospital Universitari Germans Trias i Pujol	Badalona	Barcelona
Spain	Hospital de Cruces	Barakaldo	Vizcaya
Spain	Hospital de la Santa Creu I Sant Pau	Barcelona
Spain	Hospital del Mar	Barcelona
Spain	Hospital Sagrat Cor	Barcelona
Spain	Hospital Vall d´Hebron	Barcelona
Spain	Hospital de Basurto	Bilbao	Vizcaya
Spain	Hospital General Yague	Burgos
Spain	Hospital San Pedro de Alcantara	Caceres
Spain	Hospital de Girona Dr. Josep Trueta	Girona
Spain	Hospital Universitario de Bellvitge	Hospitalet de Llobregat	Barcelona
Spain	Hospital de Leon	Leon
Spain	Hospital Arnau de Vilanova	Lleida
Spain	Hospital Universitari Arnau de Vilanova	Lleida
Spain	Complejo Hospitalario Xeral Calde	Lugo
Spain	Hospital Central de Defensa (del Aire)	Madrid
Spain	Hospital Clinico San Carlos	Madrid
Spain	Hospital de La Princesa	Madrid
Spain	Hospital Ramon y Cajal	Madrid
Spain	Hospital Universitario Gregorio Marañon	Madrid
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital de Mataro	Mataro	Barcelona
Spain	Hospital Son Dureta	Palma de Mallorca	Baleares
Spain	Hospital de Navarra	Pamplona	Navarra
Spain	Consorci Hospitalari Parc Tauli	Sabadell	Barcelona
Spain	Hospital Moises Broggi	Sant Joan Despi	Barcelona
Spain	Hospital Marqués de Valdecilla	Santander
Spain	Hospital Marqués de Valdecilla	Santander
Spain	Hospital Clinico Universitario de Santiago	Santiago de Compostela	La Coruña
Spain	Hospital Universitario Nuestra Señora De Valme	Sevilla
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Hospital Virgen Macarena	Sevilla
Spain	Hospital Clinico Universitario	Valencia
Spain	Hospital General Universitario de Valencia	Valencia
Spain	Hospital Universitario La Fe	Valencia
Spain	Hospital Clínico de Valladolid	Valladolid
Spain	Hospital Universitario	Valladolid
Spain	Hospital Meixoeiro	Vigo	Pontevedra

Sponsors (1)

Lead Sponsor	Collaborator
Ferrer Internacional S.A.

Countries where clinical trial is conducted

Germany,  Portugal,  Spain, 

References & Publications (2)

Bolland K, Whitehead J, Cobo E, Secades JJ. Evaluation of a sequential global test of improved recovery following stroke as applied to the ICTUS trial of citicoline. Pharm Stat. 2009 Apr-Jun;8(2):136-49. doi: 10.1002/pst.344. — View Citation

Dávalos A, Alvarez-Sabín J, Castillo J, Díez-Tejedor E, Ferro J, Martínez-Vila E, Serena J, Segura T, Cruz VT, Masjuan J, Cobo E, Secades JJ; International Citicoline Trial on acUte Stroke (ICTUS) trial investigators. Citicoline in the treatment of acute — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Total recovery at three months of onset, based on a global test analysis including NIHSS, mRS and Barthel Index		3 months	No
Secondary	mRS at 3 months		3 months	No
Secondary	Barthel Index at 3 months		3 months	No
Secondary	Safety and tolerability		3 months	Yes

External Links

•   Protocol reviewed by The Lancet
•   Register of stroke trials