E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10055221 |
E.1.2 | Term | Ischemic 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 |
To evaluate the safety and efficacy of microplasmin administered intravenously in patients with acute ischemic stroke |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Acute ischemic stroke (defined as a measurable neurological deficit of sudden onset considered secondary to focal cerebral ischemia and not otherwise attributable to ICH or other condition), with onset within 12 hours before start of study drug administration (Onset is defined as the time the patient was last seen in a normal state, or bedtime for unwitnessed strokes occurring during the night). 2. Evidence of perfusion defect of at least 2 cm in diameter, as assessed by MRI (PWI) corresponding to the acute stroke syndrome. The PWI will be assessed by relative mean transit time (MTT) images. 3. Ability to initiate study drug administration within 1 hour of completion of MRI and within 12 hours of stroke onset. 4. Male or female age 18-85 (inclusive) 5. Patients with baseline NIHSS >= 4 and =< 22 6. Prior to inclusion in the study and following a full explanation of the nature and purpose of the study, the patient or the patient’s legal representative must consent/assent to participate by signing the Informed Consent document. 7. Women of child-bearing potential must have a negative pregnancy test prior to enrolment and be using a reliable form of contraception 8. Patients must be ambulatory prior to stroke onset. |
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E.4 | Principal exclusion criteria |
General exclusion criteria 1. Participation in another study with an investigational drug or device within the previous 30 days, prior participation in the present study, or planned participation in another trial within the timeframe of the current trial 2. Symptoms suggestive of subarachnoid hemorrhage, even if CT scan or MRI is negative for hemorrhage 3. Women known to be pregnant, lactating, or having a positive or indeterminate pregnancy test
Stroke related exclusion criteria 4. Neurological deficit that has led to stupor or coma (NIHSS Level Of Consciousness Item 1a score >or=2) 5. High clinical suspicion of septic embolus 6. Thrombosis involving cerebral veins 7. Rapidly improving neurological signs at any time before initiation of study drug administration
Imaging related exclusion criteria 8. Hemorrhagic transformation or intracerebral hemorrhage observed on baseline CT of the brain or gradient recalled echo (GRE) magnetic resonance imaging 9. CT or MRI evidence of nonvascular cause for the neurological symptoms 10. Ischemic lesion consistent with lacunar stroke 11. PWI not obtained or uninterpretable 12. No MTT defect corresponding to acute stroke deficit 13. Large hypodensity on CT involving > 1/3 of the MCA territory 14. Baseline DWI volume > 1/3 of the MCA territory 15. Signs of mass effect causing shift of midline structures on CT or MRI 16. Unable to undergo MRI (i.e., ferrous implants, cardiac pacemakers, agitation, claustrophobia or known sensitivity to MRI contrast agents)
Safety related exclusion criteria 17. Congenital or acquired coagulopathy causing either of the following a. activated partial thromboplastin time prolongation greater than 2 seconds above the ULN for local laboratory b. International normalized ratio of 1.4 or more. 18. Uncontrolled hypertension defined as a systolic blood pressure > 180 mm Hg or a diastolic blood pressure > 100 mm Hg on 3 separate occasions at least 10 minutes apart or requiring continuous IV therapy. 19. History of stroke within the previous 3 months 20. Seizures at any time between stroke onset to planned initiation of study drug 21. History of intracranial hemorrhage 22. History of surgery, lumbar puncture, biopsy or trauma to internal organs within the previous 30 days. 23. Major trauma at the time of stroke 24. Head trauma within the previous 90 days. 25. Known bleeding diathesis. 26. Baseline platelet count < 100 X 10 9/L. 27. Blood glucose > 400mg/dl or <50 mg/dl if administration of glucose does not rapidly reverse neurological deficit
Exclusion criteria that may potentially interfere with outcome assessment 28. Life expectancy <3 months 29. Other serious illness that in the opinion of the investigator may confound clinical assessment (e.g. hepatic, cardiac, or renal failure, advanced cancer)
Exclusion criteria related to concomitant medication 30. If treatment with tPA is indicated (IN THE 0-3 POST-STROKE TIME WINDOW) 31. Treatment with rtPA or any other thrombolytic agent for the qualifying stroke 32. Administration of intra-arterial or systemic thrombolytic therapy in previous 7 days 33. Need for antiplatelet agent, unfractionated or heparin-related products, direct thrombin inhibitor, oral anticoagulant within 24 hours after treatment bolus. 34. Treatment with low molecular weight heparin, direct thrombin inhibitor, or GPIIb/IIIa antagonists within 48 hours prior to randomisation 35. Treatment with vitamin-K antagonists or heparin (or heparin-related compounds) which results in either an INR>1.4 or an aPTT>2 times control (ULN for the hospital laboratory) |
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E.5 End points |
E.5.1 | Primary end point(s) |
SAFETY EVALUATIONS/CRITERIA The safety profile of three dose regimens of microplasmin administered intravenously in patients with acute ischemic stroke will be defined based on the rate of occurrence of:
Safety parameters: • Intracranial hemorrhage*, • Major bleeding **, • Bleeding other than major, • Serious and non-serious adverse events***, • Allergic reactions, • Hypotension, or other vital sign alterations during treatment • Immunology (Microplasmin and Staphylokinase antibody assays) • Laboratory data • Markers of systemic lysis (fibrinogen, plasminogen, D-dimer, PT and aPTT) and complement activation (C3, C4 and CH50)
* Asymptomatic (by CT at 24 hours and GRE at 7 days) or symptomatic (accompanied by NIHSS decrease of > 2 points WITHIN 36 HOURS).The CT scan may be replaced by an MRI if this is consistent with local standards; however, if bleeding is evident on the MRI, a CT-scan MUST be performed. ** In the context of this study, major bleeding is defined as any bleeding event resulting in death; any retroperitoneal hemorrhage; overt bleeding associated with a need for transfusion of 2 or more units of blood or which requires surgical intervention; overt bleeding associated with a decrease from baseline in hemoglobin of at least 2.0 g/dL; clinical intracranial hemorrhage. *** In the context of this study, an increase in NIHSS score of 4 points or more from the baseline score is defined as a Serious Adverse Event.
EFFICACY EVALUATIONS/CRITERIA
Efficacy parameters: • NIHSS total score at 30 days (or last rating) adjusted for baseline NIHSS total score. Proportion of patients who achieve an NIHSS total score at 30 days (or last rating) of 1 or less or who show an improvement from baseline in NIHSS total score of at least 8 points or more. • Change from baseline in NIHSS at day 7 • Barthel Index and Modified Rankin scale at day 30 • Change in infarct size as measured by MRI on day 7 • Change from baseline in surrogate markers NSE and S100 and MMP-2, MMP-9 and TIMP-1 • Proportion achieving reperfusion (measured as): o Reduction of PWI abnormality (at 8 +/- 4 hours) by > 30 percent. (For perfusion defects < 10 ml, reperfusion will be defined as absence of perfusion deficit on the follow up MRI). o 2 point improvement on the adapted Thrombolysis in Myocardial Infarction Scale using MRA o Either of the above
ADDITIONAL EVALUATIONS • Pharmacokinetic measurements. • Pharmacodynamic measurements (α2-antiplasmin) |
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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 | 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 | 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 | Yes |
E.8.1.7.1 | Other trial design description |
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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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
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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The end of the trial is defined as the last visit of the last subject, unless the Safety Committee recommends premature termination of the trial as a result of safety concerns. |
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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 | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |