E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
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 | Information not present in EudraCT |
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.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
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 | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 48 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
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 | 8 |
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 | 8 |