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 | 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 |
To establish the safety of five dose levels (1.0, 2.5, 5.0, 7.5 and 10.0 mg/kg) of V10153 in patients with acute ischaemic stroke. |
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E.2.2 | Secondary objectives of the trial |
To compare recanalisation rates across dose levels. To compare clinical outcome between treatments by National Institue of Health Stroke Survey (NIHSS) at 24 hours, 5, 30 and 90 days and Modfied Rankin Score and Barthel Index at 5, 30 and 90 days. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Onset of new neurological signs of a stroke within 3 to 9 hours of the time to initiation of treatment with V10153. 2. Be aged 18 and over. 3. Provide written informed consent or appropriate surrogate consent and agree to comply with all protocol-specific procedures. (After it has been determined that a patient meets all of the clinical and CT scan inclusion criteria and none of the exclusion criteria, and after the study has been explained to the patient or the patient’s legal representative, he/she will be asked to sign a consent form prior to angiography, (unless angiography is standard of care)). 4. Cerebral CT scan to show findings of early ischaemic changes consistent with the clinical diagnosis and an ASPECT score of between 5 and 10 inclusive. 5. Have a NIHSS score > 5 - less than or equal to 20. 6. Patients with angiographic complete occlusion (TIMI 0) or penetration with minimal perfusion (TIMI 1) in any part of the middle cerebral artery (MCA), with that occlusion being consistent with the patient’s clinical presentation, (see Section 6.2.3 for TIMI definitions). Patients with tandem occlusions (carotid occlusion at bifurcation with thrombus in MCA) may also be enrolled.
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E.4 | Principal exclusion criteria |
Central Nervous System 1. Coma. 2. Stroke with unknown time of onset (unless last known to be well within the 9 hour window). 3. Minor symptoms and signs (< 6 points on the NIHSS) which are rapidly improving by the time of enrolment. 4. Major stroke symptoms and signs (> 20 on the NIHSS). 5. Basilar artery territory strokes. 6. Suspected lacunar or white matter stroke. 7. Any history of stroke (haemorrhagic, embolic, thrombotic or transient ischaemic attack) within the previous 6 weeks. 8. Any prior neurological event which would obscure the interpretation of the signal neurological deficits. 9. Any history of brain tumours (small incidental meningioma are permitted). 10. CT scan results in an ASPECT score of < 5, severe hypodensity lesion, haemorrhage of any degree, evidence of significant mass effect with midline shift due to large infarct, or subarachnoid haemorrhage. 11. CT angiogram shows no visible arterial occlusion in any part of the MCA. 12. Patients with van Sweiten Grade 4 (severe white matter disease).
Haemorrhagic Risk 1. Clinical presentation suggestive of subarachnoid haemorrhage, even if the initial CT scan is normal. 2. Previous known intracranial haemorrhage at any time, and/or subarachnoid haemorrhage. Patients with a known arteriovenous malformation or aneurysm with any evidence of associated haemorrhage. 3. Any recent invasive procedure (e.g. puncture of a non-compressible vessel (artery or vein) within 7 days of drug administration; surgery including ophthalmologic surgery, biopsy of a parenchymal organ, or lumbar puncture within 30 days of drug administration). 4. Trauma, including head trauma, with internal injuries or ulcerative wounds within 90 days of drug administration. 5. Active peptic ulcer disease within the 3 months prior to drug administration. 6. Any clinically significant active or recent haemorrhage within 30 days of drug administration. 7. Known hereditary or acquired haemorrhagic diathesis, e.g. activated Partial Thromboplastin Time (aPTT) greater than 1.5 times normal. 8. Treatment with heparin within 12 hours prior to drug administration other than a small amount for flushing intravenous cannulae. 9. Treatment with warfarin (unless the International Normalised Ratio (INR) is 1.5 or less) within 5 days prior to drug administration. 10. Treatment with low molecular weight heparin within 5 days prior to study drug administration. 11. Treatment with antiplatelet agents (dipyridamole, Aggrenox, ticlopidine) within 6 days prior to study drug administration with the exception of either aspirin (325 mgs or less daily) or clopidogrel (75 mgs, or less, daily) which are allowed, (but not both).
Laboratory 1. Baseline laboratory values which reveal platelets < 100,000/mm3, Haematocrit (Hct) or Packed Cell Volume (PCV) < 25 % or INR > 1.5. 2. If creatinine is known, exclude for serum creatinine > 2.5 times the upper limit of normal (ULN). 3. Haemoglobin < 10 g/dL = 100 g/L. 4. Haematocrit (Hct) or PCV < 25 %.
General 1. Positive urine pregnancy test, breast feeding or parturition within the previous 30 days. 2. Weight >135kg. 3.Uncontrolled hypertension at study entry, non-responsive to acute intravenous therapy. Uncontrolled hypertension is defined as mean systolic blood pressure > 180 mm Hg or diastolic blood pressure > 110 mm Hg on three repeated measures at least 5 minutes apart. 4. Blood glucose > 12.0 mmol/L. 5. Known serious sensitivity to contrast agents, or any condition in which CT angiography is contraindicated. 6. Myocardial infarction within 30 days prior to study drug administration. 7. Presumed septic embolus. 8. History of or current serious illness e.g., known chronic renal disease or renal insufficiency, known active inflammatory bowel disease, ulcerative colitis, or diverticular disease, active or recent alcohol or substance abuse, cancer, Human Immunodeficiency Virus (HIV), significant hepatic, pulmonary, endocrine, neurological, haematological disease or any other condition which the investigator considers would increase the risk to the patient or reduce the validity of the study. 9. Traumatic or prolonged cardiopulmonary resuscitation within 2 weeks prior to drug administration. 10. Patients participating in another clinical trial evaluating an investigational study drug or device within 4 weeks prior to drug administration. 11. Patients unwilling to participate or patients or their legal representative unable or unwilling to give informed consent. 12. Patients or their legal representatives who are unable to provide an adequate medical history, onset time of stroke and a complete list of concomitant medication. 13. Known prior exposure to aprotinin.
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary Safety: Safety determined through clinical assessment (intercranial haemorrhage (ICH), major systemic bleed, other serious adverse events (SAEs)).
Adverse Events.
Laboratory Variables.
Vital Signs.
ECG.
Primary Efficacy: Recanalisation rates from a blinded assessment of CT Angiograms at 0 and 2 hours will be compared between dose levels.
Secondary Efficacy: Clinical Outcome according to NIHSS at 24 hours, 5, 30 and 90 days, Modified Rankin Scale and Barthel Index at 5 days, 30 days and 90 days after treatment.
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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 | 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 | 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 | 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) | No |
E.8.2.2 | Placebo | No |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 | Information not present in EudraCT |
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 |
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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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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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |