ICTUS Study: International Citicoline Trial on Acute Stroke

NCT ID: NCT00331890

Last Updated: 2012-06-20

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 2298 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2006-10-31
• Study Completion Date: 2012-03-31

Brief 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

Detailed 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.

Conditions

Acute Stroke; Cerebral Infarction

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Active

Receives active drug

Group Type: EXPERIMENTAL

Citicoline

Intervention Type: DRUG

1g/12h iv during 3 days and then orally until complete 6 weeks of treatment

Placebo

Receives a placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

As active drug

Interventions

Citicoline

1g/12h iv during 3 days and then orally until complete 6 weeks of treatment

Intervention Type: DRUG

Placebo

As active drug

Intervention Type: DRUG

Other Intervention Names

CDP-choline

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ferrer Internacional S.A.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Antoni Dávalos, MD, PhD

Role: STUDY_CHAIR

Hospital Universitari Germans Trias i Pujol, Badalona (Spain)

Locations

Klinikum AltenburgerLand GmbH

Altenburg, , Germany

Neurologie EVKB

Bielefeld, , Germany

Neurologische Klinik Heinrich-Heine Universität

Düsseldorf, , 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, , Germany

Hospital de Sao Jose

Lisbon, Lisbon District, Portugal

Hospital de Sao Joao

Porto, Porto District, Portugal

Hospital Garcia de Orta, EPE

Almada, , Portugal

Hospital Garcia de Orta

Almada, , Portugal

Hospital Fernando Fonseca

Amadora - Sintra, , Portugal

Hospital Sao Marcos

Braga, , Portugal

Hospitais da Universidade Coimbra

Coimbra, , Portugal

Centro Hospitalar de Coimbra

Coimbra, , Portugal

Hospital de Santa Maria

Lisbon, , Portugal

Hospital de Santo Antonio

Porto, , Portugal

Hospital Sao Sebastiao

Santa Maria da Feira, , Portugal

Centro Hospitalar de Setúbal, EPE

Setúbal, , Portugal

Centro Hospitalar de Setúbal

Setúbal, , Portugal

Hospital Sao Pedro

Vila Real, , Portugal

Hospital General de Albacete

Albacete, Albacete, Spain

Hospital Son Dureta

Palma de Mallorca, Balearic Islands, Spain

Hospital Universitari Germans Trias i Pujol

Badalona, Barcelona, Spain

Hospital del Mar

Barcelona, Barcelona, Spain

Hospital de la Santa Creu I Sant Pau

Barcelona, Barcelona, Spain

Hospital Sagrat Cor

Barcelona, Barcelona, Spain

Hospital Vall d´Hebron

Barcelona, Barcelona, Spain

Hospital Universitario de Bellvitge

L'Hospitalet de Llobregat, Barcelona, Spain

Hospital de Mataro

Mataró, Barcelona, Spain

Consorci Hospitalari Parc Tauli

Sabadell, Barcelona, Spain

Hospital Moises Broggi

Sant Joan Despí, Barcelona, Spain

Hospital General Yague

Burgos, Burgos, Spain

Hospital San Pedro de Alcantara

Cáceres, Caceres, Spain

Hospital de Girona Dr. Josep Trueta

Girona, Girona, Spain

Hospital Clinico Universitario de Santiago

Santiago de Compostela, La Coruña, Spain

Hospital de Leon

León, Leon, Spain

Hospital Arnau de Vilanova

Lleida, Lleida, Spain

Complejo Hospitalario Xeral Calde

Lugo, Lugo, Spain

Hospital de La Princesa

Madrid, Madrid, Spain

Hospital Universitario Gregorio Marañon

Madrid, Madrid, Spain

Hospital Ramon y Cajal

Madrid, Madrid, Spain

Hospital Clinico San Carlos

Madrid, Madrid, Spain

Hospital Universitario La Paz

Madrid, Madrid, Spain

Hospital Central de Defensa (del Aire)

Madrid, Madrid, Spain

Hospital de Navarra

Pamplona, Navarre, Spain

Hospital Meixoeiro

Vigo, Pontevedra, Spain

Hospital Virgen Macarena

Seville, Sevilla, Spain

Hospital Universitario Virgen del Rocio

Seville, Sevilla, Spain

Hospital Universitario Nuestra Señora De Valme

Seville, Sevilla, Spain

Hospital Universitario La Fe

Valencia, Valencia, Spain

Hospital Clinico Universitario

Valencia, Valencia, Spain

Hospital General Universitario de Valencia

Valencia, Valencia, Spain

Hospital Universitario

Valladolid, Valladolid, Spain

Hospital de Cruces

Barakaldo, Vizcaya, Spain

Hospital de Basurto

Bilbao, Vizcaya, Spain

Hospital Universitari Arnau de Vilanova

Lleida, , Spain

Hospital Marqués de Valdecilla

Santander, , Spain

Hospital Marqués de Valdecilla

Santander, , Spain

Hospital Clínico de Valladolid

Valladolid, , Spain

Countries

Germany; Portugal; Spain

References

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.

Reference Type: BACKGROUND

PMID: 18637642 (View on PubMed)

Davalos A, Alvarez-Sabin J, Castillo J, Diez-Tejedor E, Ferro J, Martinez-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 ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial). Lancet. 2012 Jul 28;380(9839):349-57. doi: 10.1016/S0140-6736(12)60813-7. Epub 2012 Jun 11.

Reference Type: RESULT

PMID: 22691567 (View on PubMed)

Other Identifiers

GF-ICTUS-04

Identifier Type: -

Identifier Source: org_study_id