E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Thrombus in acute ischemic stroke of the middle cerebral artery |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10008190 |
E.1.2 | Term | Cerebrovascular accident |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 of Plasmin (Human) in escalating doses in patients with acute MCA ischemic stroke given within 9 hours of stroke symptom onset. |
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E.2.2 | Secondary objectives of the trial |
• To determine the proportion of Treatment Successes - the proportion of patients with treatment success defined as partial or full recanalization as designated by a score of 2a, 2b, or 3 on the Thrombosis In Cerebral Infarction (TICI) scale |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. 18 through 85 years of age, inclusive
2. Male and female patients
3. New focal, potentially disabling neurologic deficit clinically localized to the MCA distribution
4. Catheter Arteriography - Complete occlusion or contrast penetration with minimal perfusion of either the M1 segment and/or M2 segment and/or M2 division of the MCA (M1, M2, or M1-2 only) as assessed by arteriography (Section 3.2.3.1)
5. Intra-arterial (IA) therapy with Plasmin must be completed within 9 hours of stroke onset (e.g., Plasmin infusion must start: a) within 8.5 hours of stroke onset in cohorts 1, 2a, 2b and 3a; b) within 8 hours of stroke onset in cohort 3b
6. An NIHSS score of ≥4 and ≤25, except for isolated aphasia
7. Women of child-bearing potential must practice a highly effective method of contraception (oral, injectable or implanted hormonal methods of contraception, placement of an intrauterine device [IUD] or intrauterine system [IUS], condom or occlusive cap with spermicidal foam/gel/film/cream/suppository, male sterilization, or true abstinence) throughout the study and must have a negative pregnancy test prior to study entry
8. Willing and able to provide written informed consent or have an authorized representative able to provide written informed consent on behalf of the patient in accordance with local law and institutional policy |
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E.4 | Principal exclusion criteria |
1. Patient is eligible for IV administration of tissue plasminogen activator (e.g.
alteplase)
2. Previous treatment for this event with mechanical embolectomy or cerebral angioplasty / stenting of target lesion
3. Treatment with any PA (e.g., streptokinase (e.g., Streptase®, Kabikinase®), anistreplase (Eminase®), alteplase (e.g., Activase®), reteplase (e.g., Retavase®), tenecteplase (TNKase™), UK (Abbokinase)) within the last 48 hours
4. Therapy with a Glycoprotein IIb/IIIa inhibitor (e.g. abciximab) in the 5 days prior to study enrollment or at any time during the study
5. Clinical evidence of significant medical, neurologic, or psychiatric disease that may confound the study outcome assessments
6. Women who are pregnant or lactating or, if of child-bearing potential, unwilling to practice a highly effective method of contraception (oral, injectable or implanted hormonal methods of contraception, placement of an intrauterine device [IUD] or intrauterine system [IUS] condom or occlusive cap with spermicidal foam/gel/film/cream/suppository, male sterilization, or true abstinence) throughout the study
7. Participation in another treatment clinical study within 30 days prior to entry
8. History of intracranial procedures or intracranial or systemic bleeding within the last year
9. Previous history of intracranial neoplasm (except meningioma)
10. History of stroke in previous 6 weeks
11. Within 48 hours, major or minor surgery, biopsy of a parenchymal organ, or major trauma/injury with internal injuries, lumbar puncture or hemorrhage
12. Catheter Arteriography - Inability for whatever reason (e.g. arterial stenosis, vessel tortuosity) to access the target lesion and achieve contact between the microcatheter and the proximal aspect of the target thrombus
13. Acute ICH of any degree or location
14. Evidence of active bleeding/hemorrhage or acute trauma on physical examination
15. Coma or severe obtundation with fixed eye deviation and complete hemiplegia. Coma is defined as 2 or more points in the NIHSS Level of Consciousness exam item.
16. An NIHSS score > 25
17. Significant intracranial mass effect leading to midline shift
18. Acute hypodense/hyperintense parenchymal lesion or effacement of cerebral sulci in more than one third of the MCA distribution as confirmed during pre-study imaging
19. Seizures at onset of stroke symptoms
20. Uncontrolled hypertension defined by a systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg on 3 separate occasions at least 10 minutes apart or requiring intravenous antihypertensive treatment by continuous infusion to reduce blood pressure to within these limits
21. Known hereditary or acquired hemorrhagic diathesis with baseline international normalized ratio (INR) > 1.7, activated partial thromboplastin time (aPTT) > 1.5 times normal, or baseline platelet count <100 x 109/L
22. Presence of an unsecured aneurysm
23. Clinical presentation suggestive of subarachnoid hemorrhage, even if initial imaging study is normal
24. Suspected lacunar stroke
25. Proximal stenosis with complete occlusion or simultaneous stenting / angioplasty, if deemed necessary by the interventionalist. Stenosis that does not impair accessibility to the primary lesion is allowed.
26. Known or presumed septic embolus
27. Creatinine ≥ 2.0 mg/dL or patient on renal dialysis
28. Previous severe or anaphylactic or anaphylactoid reaction to contrast agent, streptokinase, or blood products |
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E.5 End points |
E.5.1 | Primary end point(s) |
Incidence of Symptomatic Intracranial Hemorrhage (SICH, as defined by SITS-MOST criteria) summarized by dose cohort.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
24 hour ± 6 hr post treatment |
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E.5.2 | Secondary end point(s) |
Proportion of patients with a score of Category 2a, 2b or 3 on the TICI scale as determined by the Central Reading Facility on Arteriogram #2 or Arteriogram #3. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 | 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) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
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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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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 | 7 |
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 | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Austria |
France |
Germany |
Israel |
Serbia |
Slovakia |
Spain |
United Kingdom |
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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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LPLV is day 90 of the last patient enrolled in the final cohort |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |