Clinical trial NCT00331890: ICTUS Study: International Citicoline Trial on Acute Stroke
Official title: Citicoline in the Treatment of Acute Ischemic Stroke. An International Randomized Multicenter Placebo-controlled Study
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Acute Stroke
Cerebral Infarction
Keywords: Neuroprotection
Acute ischemic stroke
Cerebral infarction
Lead sponsor: Ferrer Internacional S.A.
Sponsor class: INDUSTRY
First posted: 2006-05-31
Enrollment: 2298
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Total recovery at three months of onset, based on a global test analysis including NIHSS, mRS and Barthel Index
timeFrame: 3 months
Secondary outcomes:
measure: mRS at 3 months
timeFrame: 3 months
measure: Barthel Index at 3 months
timeFrame: 3 months
measure: Safety and tolerability
timeFrame: 3 months
Other outcomes:
Locations:
city: Altenburg
country: Germany
facility: Klinikum AltenburgerLand GmbH
city: Bielefeld
country: Germany
facility: Neurologie EVKB
city: Dusseldorf
country: Germany
facility: Neurologische Klinik Heinrich-Heine Universität
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen
city: Greifswald
country: Germany
facility: Ernst-Moritz-Arndt-Universität Greifswald
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Heidelberg
country: Germany
facility: Neurologische Klinik Universitatsklinikum Heidelberg
city: Ingolstadt
country: Germany
facility: Klinikum Ingolstadt
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
city: Minden
country: Germany
facility: Johannes Wesling Klinikum Minden
city: München
country: Germany
facility: Klinikum Großhadern der Universität München
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Almada
country: Portugal
facility: Hospital Garcia de Orta, EPE
city: Almada
country: Portugal
facility: Hospital Garcia de Orta
city: Amadora - Sintra
country: Portugal
facility: Hospital Fernando Fonseca
city: Braga
country: Portugal
facility: Hospital Sao Marcos
city: Coimbra
country: Portugal
facility: Hospitais da Universidade Coimbra
city: Coimbra
country: Portugal
facility: Centro Hospitalar de Coimbra
city: Lisbon
country: Portugal
facility: Hospital de Sao Jose
city: Lisbon
country: Portugal
facility: Hospital de Santa Maria
city: Porto
country: Portugal
facility: Hospital de Santo Antonio
city: Porto
country: Portugal
facility: Hospital de Sao Joao
city: Santa Maria da Feira
country: Portugal
facility: Hospital Sao Sebastiao
city: Setubal
country: Portugal
facility: Centro Hospitalar de Setúbal
city: Setúbal
country: Portugal
facility: Centro Hospitalar de Setúbal, EPE
city: Vila Real
country: Portugal
facility: Hospital Sao Pedro
city: Palma de Mallorca
country: Spain
facility: Hospital Son Dureta
state: Baleares
city: Badalona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol
state: Barcelona
city: Hospitalet de Llobregat
country: Spain
facility: Hospital Universitario de Bellvitge
state: Barcelona
city: Mataro
country: Spain
facility: Hospital de Mataro
state: Barcelona
city: Sabadell
country: Spain
facility: Consorci Hospitalari Parc Tauli
state: Barcelona
city: Sant Joan Despi
country: Spain
facility: Hospital Moises Broggi
state: Barcelona
city: Santiago de Compostela
country: Spain
facility: Hospital Clinico Universitario de Santiago
state: La Coruña
city: Pamplona
country: Spain
facility: Hospital de Navarra
state: Navarra
city: Vigo
country: Spain
facility: Hospital Meixoeiro
state: Pontevedra
city: Barakaldo
country: Spain
facility: Hospital de Cruces
state: Vizcaya
city: Bilbao
country: Spain
facility: Hospital de Basurto
state: Vizcaya
city: Albacete
country: Spain
facility: Hospital General de Albacete
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu I Sant Pau
city: Barcelona
country: Spain
facility: Hospital Sagrat Cor
city: Barcelona
country: Spain
facility: Hospital Vall d´Hebron
city: Burgos
country: Spain
facility: Hospital General Yague
city: Caceres
country: Spain
facility: Hospital San Pedro de Alcantara
city: Girona
country: Spain
facility: Hospital de Girona Dr. Josep Trueta
city: Leon
country: Spain
facility: Hospital de Leon
city: Lleida
country: Spain
facility: Hospital Universitari Arnau de Vilanova
city: Lleida
country: Spain
facility: Hospital Arnau de Vilanova
city: Lugo
country: Spain
facility: Complejo Hospitalario Xeral Calde
city: Madrid
country: Spain
facility: Hospital de La Princesa
city: Madrid
country: Spain
facility: Hospital Universitario Gregorio Marañon
city: Madrid
country: Spain
facility: Hospital Ramon y Cajal
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Madrid
country: Spain
facility: Hospital Central de Defensa (del Aire)
city: Santander
country: Spain
facility: Hospital Marqués de Valdecilla
city: Santander
country: Spain
facility: Hospital Marqués de Valdecilla
city: Sevilla
country: Spain
facility: Hospital Virgen Macarena
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio
city: Sevilla
country: Spain
facility: Hospital Universitario Nuestra Señora De Valme
city: Valencia
country: Spain
facility: Hospital Universitario La Fe
city: Valencia
country: Spain
facility: Hospital Clinico Universitario
city: Valencia
country: Spain
facility: Hospital General Universitario de Valencia
city: Valladolid
country: Spain
facility: Hospital Clínico de Valladolid
city: Valladolid
country: Spain
facility: Hospital Universitario
Study officials:
affiliation: Hospital Universitari Germans Trias i Pujol, Badalona (Spain)
name: Antoni Dávalos, MD, PhD
role: STUDY_CHAIR
References:
citation: 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.
citation: 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.