E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
acute ischemic stoke
Based on the results of preclinical studies, enecadin is expected to play an important role in the treatment of acute ischemic stroke and to ameliorate the outcome and prognosis of patients either in combination with or without thrombolytic therapy. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 8.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061256 |
E.1.2 | Term | Ischaemic stroke |
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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 |
Main objective of this study is to investigate the tolerability of enecadin given as slow i.v.-infusion on three consecutive days in three dose-tiers in patients with acute ischemic stroke within a time-window of nine hours after onset of symptoms.
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E.2.2 | Secondary objectives of the trial |
Furthermore the pharmacokinetics of enecadin in male and female patients with acute ischemic stroke will be assessed.
Trends in efficacy will be evaluated until day 30 of study participation.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients able to understand trial related information, scope of the trial and consequences of trial participation and to give Informed Consent. If the patient is unable to write, Informed Consent can be given orally and documented by an impartial witness. 2. The patient is male of female and aged between 18 and 85 years (extremes included) (in Austria according to local legislation) 3. Treatment onset within 9 hours after onset of stroke symptoms. If the exact onset of stroke is unclear, but the onset of stroke symptoms was definitely less than 8 hours before arrival at the hospital, then the patient can be considered eligible for the study (this provides 1 hour for eligibility determination prior to receipt of randomised therapy). 4. Score of 3-20 on the NIHSS with clinical signs suggestive of ischemic stroke; level of consciousness score: 0 or 1 (conscious patients). 5. For female patients: post-menopausal or surgically sterile (post-menopausal: age ≥55 years and last menses ≥3 years ago).
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E.4 | Principal exclusion criteria |
1. Participation in any investigational study in the previous 30 days. 2. Any terminal illness that is serious or advanced (patient is not expected to survive more than 1 year). 3. Patients unable to understand trial related information. 4. History, clinical presentation or suspicion of intracerebral haemorrhage (ICH), subarachnoid haemorrhage (SAH), arterio-venous (AV) malformation, aneurysm, or cerebral neoplasm. CT/MRI scan consistent with haemorrhagic stroke. 5. Suspected acute basilar artery occlusion. 6. Stroke or a serious head injury in the previous 6 weeks. 7. Spontaneously improving neurological signs since stroke onset. 8. Seizure at the onset of stroke. 9. QTcF interval >450 ms, history of drug-induced Torsade de Pointes, or presence of a familial long QT syndrome. 10. Bradycardia less than 50 bpm. 11. Resting pulse >110 bpm after at least 3 min rest. 12. History or evidence of clinically relevant arrhythmias (atrial fibrillation, frequent or complex ventricular extrasystoles, ventricular tachycardia, ventricular pre-excitation syndromes). 13. Significant cardiac conduction disturbances (AV block grades 2 and 3), complete right or left bundle branch block. 14. Patients with an implanted pacemaker. 15. Myocardial infarction within the previous 3 months 16. Any unstable or severe heart disease (e.g. clinically overt heart failure (NYHA III-IV), unstable angina pectoris). 17. Severe chronic uncontrolled arterial hypertension. 18. Relevant serum hypokalemia (< 3.6 mmol/L). 19. Acute uncontrolled hypertension defined by a blood pressure >220 mmHg systolic or >110 mmHg diastolic on at least 2 separate occasions at least 10 minutes apart, or requiring aggressive treatment to reduce the blood pressure to values within the limits. The definition of “aggressive treatment” is left to the discretion of the responsible Investigator. 20. Relevant hepatic dysfunction (total bilirubin >1.8 mg/dL or 30 µmol/L, ALT, AST or GGT >3x the upper limit) 21. Known hypersensitivity to the study drug or components of the preparation. 22. Use of concomitant and prior medications as defined in section 11.2 (e.g. drugs prolonging myocardial repolarization (e.g. Class IA and Class III antiarrhythmic agents (amiodarone, sotalol, quinidine), antibiotics known to prolong the QT interval (e.g. macrolides), antipsychotics known to polong the QT interval). 23. Any other condition that could to the discretion of the Investigator impose hazards to the patient if study therapy was initiated, including clinically important deviations from the normal ranges of the assessed laboratory parameters.
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety Parameters
The following safety endpoints will be assessed in an exploratory manner: · qualitative and quantitative 12-lead ECG parameters (e.g. QTc interval, RR interval, Heart rate, PR interval, QRS duration and qualitative parameters (wave form), arrhythmias), · qualitative and quantitative 24 h-12-lead ECG parameters (e.g. QTc interval, RR interval, Heart rate, PR interval, QRS duration and qualitative parameters (wave form), arrhythmias, additionally Short Term Variability of QT), · clinical laboratory, · incidence of (serious) adverse events, · mortality, · vital signs.
Pharmacokinetic Parameters
Enecadin plasma concentration data will be obtained in 100% of the patients of each dose-tier. The patients will be genotyped regarding CYP2D6 alleles and a metabolizer phenotype will be predicted based on the genotyping results. Peak plasma concentration (Cmax) and time to peak plasma concentration (tmax) will be obtained for all patients. Area under the curve (AUC), and apparent terminal half-life (t1/2) shall be calculated where possible.
Efficacy Parameters
Trends in efficacy parameters will be evaluated using outcome measures based on the NIHSS, the Modified Rankin Scale (MRS) and the Barthel Index (BI). |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
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 | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 23 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
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
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last visit of last subject |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
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 | 2 |