Please select the eligibility criteria that correspond to the clinical trial below.
Title: International, Multicenter, Double-Blind, Placebo-Controlled, Randomized Phase I/II Trial of Desmoteplase in the Indication of Acute Ischemic Stroke
Brief Summary: The purpose of this study was to explore trends in safety and efficacy, and to find the optimal dose for the subsequent phase III trial. The decision to initiate the phase III trial will depend on both safety (incidence of symptomatic intracranial hemorrhage) and efficacy (reperfusion measured by MRI and correlating with clinical outcome) profiles. The safety (incidence of symptomatic intracranial haemorrhage) and efficacy (reperfusion measured by MRI and correlating with clinical outcome) profiles gained from this study were the basis of planning the phase III.


Options:
A: Inclusion Criteria:

* scoring 4 to 20 on the National Institute of Health Stroke Scale (NIHSS)
* showing a perfusion-diffusion mismatch on MRI of 20 %
* enrolment within a 3 h to 9 h time window after symptom onset.
* 18-85 years of age

Exclusion Criteria:

* Participation in any interventional trial in the previous 30 days.
* Women in the childbearing age.
* Any history of intracranial hemorrhage, subarachnoid hemorrhage, neoplasm, arteriovenous malformation or aneurysm.
* Conditions that, according to the judgment of the investigator, might impose an additional risk to any individual stroke patient when receiving study medication (this applied to patients on platelet-function inhibitors as well).
* MRI exclusion criteria: Evidence of ICH, Evidence of SAH, Signs of extensive early infarction on DWI assessed by evidence of involvement of \>1/3 of the middle cerebral artery (MCA) territory. No perfusion deficit, Internal carotid artery (ICA) occlusion ipsilateral to stroke lesion without additional ipsilateral MCA, anterior cerebral artery (ACA) or posterior cerebral artery (PCA) occlusion. Any intracranial pathology that would interfere with the MRI assessment of acute ischemic stroke.
B: Inclusion Criteria:

* Female or male inpatients.
* Age: 18-80 years.
* If female, patient must not be pregnant
* Clinical diagnosis of ischemic stroke causing a measurable neurological deficit defined as impairment of language, motor function, cognition and/or gaze,vision or neglect. Ischemic stroke is defined as an event characterized by the sudden onset of an acute focal neurologic deficit presumed to be due to cerebral ischemia after CT scan excludes haemorrhage.
* Onset of symptoms within 3 hours prior to initiation of rt-PA administration.
* Stroke symptoms are to be present for at least 30 minutes and have not significantly improved before treatment. Symptoms must be distinguishable from an episode of generalized ischemia (i.e. syncope), seizure or migraine disorder.
* Patient is willing to participate voluntarily and to sign a written patient informed consent. Informed consent will be obtained from each patient or the subject's legally authorized representative or relatives, or deferred where applicable, according to the regulatory and legal requirements of the participating country.
* Patients who are unable to sign but who are able to understand the meaning of participation in the study may give an oral witnessed informed consent. These patients have to make clear undoubtful that they are willing to participate voluntarily and must be able to understand an explanation of the contents of the information sheet. A written consent has to be obtained as soon as possible.
* Willingness and ability to comply with the protocol.

Exclusion Criteria:

* Evidence of intracranial haemorrhage (ICH) on the CT-scan
* Violation of inclusion criteria not approved by clinical study director or study safety officer
* Failure to perform or to evaluate screening or baseline examinations
* Hospitalisation (except for study purposes) or change of concomitant medication 4 weeks prior to screening or during screening period
* Participation in another therapeutic clinical trial 3 months before baseline
* Patients with any history of prior stroke and concomitant diabetes
* Prior stroke within the last 3 months
* Platelet count of below 100x103/mm3
* Blood glucose \<50 or \>400 mg/dl (\<2.77 or \>22.15 mmol/L)
* Known haemorrhagic diathesis
* Manifest or recent severe or dangerous bleeding
* Known bacterial endocarditis, pericarditis
* Acute pancreatitis
* Documented ulcerative gastrointestinal disease during the last 3 months, oesophageal varices, arterial-aneurysm, arterial/venous malformation
* Neoplasm with increased bleeding risk
* Severe liver disease, including hepatic failure, cirrhosis, portal hypertension, oesaphageal varices) and active hepatitis
* Major surgery or significant trauma in past 3 months
* Lab values seriously abnormal, and/or more than 2 lab values abnormal not approved by clinical study director or study safety officer
* Serious drug allergies
* Hypersensitivity to one of the components of the drug
* Severe renal impairment
* Systolic blood pressure \>185 mmHg or diastolic blood pressure \>110 mmHg, or aggressive management (IV medication) necessary to reduce BP to these limits
* Recent (less than 10 days) traumatic external heart massage, obstetrical delivery, recent puncture of a non-compressible blood-vessel (e.g. subclavian or jugular vein puncture)
* Chronic intoxication or chronic substance use disorder with pharmaceuticals, drugs, alcohol or industrial poisons
* Symptoms of ischemic attack began more than 3 hours prior to start of thrombolytic therapy or if time of symptom onset is unknown
* Minor neurological deficit or symptoms rapidly improving before start of infusion
* Severe stroke as assessed clinically (e.g. NIHSS \>25) and/or by appropriate imaging techniques
* Epilepsy or epileptic seizure at onset of stroke
* Symptoms suggestive of subarachnoid haemorrhage, even if the CT-scan is normal
* Known history of or suspected intracranial haemorrhage
* Suspected subarachnoid haemorrhage or condition after subarachnoid hemorrhage from aneurysm
* Any history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal surgery)
* Haemorrhagic retinopathy, e.g. in diabetes (vision disturbances may indicate haemorrhagic retinopathy)
* Administration of heparin within the previous 48 hours and a thromboplastin time exceeding the upper limit of normal for laboratory
* Patients receiving oral anticoagulants, e.g. warfarin sodium
* Special attention should be given to possible additive effects when used in conjunction with anti-depressants or MAO-inhibitors
* Cerebrolysin should not be mixed with balanced amino acid solutions in an infusion
C: Inclusion Criteria:

1. Patients presenting with hemispheric acute ischaemic stroke
2. Patient, family member or legally responsible person depending on local ethics requirements has given informed consent
3. Patient's age is ≥18 years
4. Treatment onset can commence within ≥ 3 - 9 hours after stroke onset according to registered product information, or within 4.5 - 9 hours according to locally accepted guidelines\*.

   (\*Guidelines are currently under international review - advisory statement issued by the Stroke Council, American Heart Association and American Stroke Association)
5. Patients who wake with stroke may be included if neurological and other exclusion criteria are satisfied. These 'wake up' strokes are defined as having no symptoms at sleep onset, but stroke symptoms on waking. The time of stroke onset is to be taken as the mid-point between sleep onset (or last known to be normal) and time of waking. The maximum time window for randomisation is then 9 hours from the mid-point as described.
6. NIHSS score of ≥ 4 - 26 with clinical signs of hemispheric infarction.
7. Penumbral mismatch - A "hypo-perfusion to core" volume ratio of greater than 1.2 and an absolute difference greater than 10mL (using a MR or CT Tmax \> 6 second delay) between perfusion lesion and MR-DWI or CT-CBF core lesion.
8. An ischaemic core lesion volume of less than or equal to 70 ml using MR-DWI or CT-CBF \*\* Patients may be consented before or after penumbral screening depending upon local practice. The entire cohort of patients consented onto the study will be followed up with clinical assessments and biomarker studies regardless of eligibility for randomisation to treatment based on penumbral mismatch criteria

Exclusion Criteria:

1. Intracranial haemorrhage (ICH) identified by CT or MRI
2. Rapidly improving symptoms, particularly if in the judgment of the managing clinician that the improvement is likely to result in the patient having an NIHSS score of \< 4 at randomization
3. Pre-stroke MRS score of ≥ 2 (indicating previous disability)
4. Contra indication to imaging with MR with contrast agents
5. Infarct core \>1/3 MCA territory qualitatively
6. Participation in any investigational study in the previous 30 days
7. Any terminal illness such that patient would not be expected to survive more than 1 year
8. Any condition that could impose hazards to the patient if study therapy is initiated or affect the participation of the patient in the study (this applies to patients with severe microangiopathy such as haemolytic uremic syndrome or thrombotic thrombocytopenic purpura). The judgment is left to the discretion of the Investigator.
9. Pregnant women (clinically evident)
10. Previous stroke within last three months
11. Recent past history or clinical presentation of ICH, subarachnoid haemorrhage (SAH), arterio-venous (AV) malformation, aneurysm, or cerebral neoplasm. At the discretion of each Investigator.
12. Current use of oral anticoagulants or a prolonged prothrombin time (INR \> 1.7) if the patient is on warfarin
13. Use of heparin, except for low dose subcutaneous heparin, in the previous 48 hours and an activated prolonged partial thromboplastin time exceeding the upper limit of the local laboratory normal range.
14. Use of glycoprotein IIb - IIIa inhibitors within the past 72 hours. Use of single or dual agent oral platelet inhibitors (clopidogrel and/or low-dose aspirin) prior to study entry is permitted.
15. Clinically significant hypoglycaemia.
16. Uncontrolled hypertension defined by a blood pressure \> 185 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 within these limits. The definition of "aggressive treatment" is left to the discretion of the responsible Investigator.
17. Hereditary or acquired haemorrhagic diathesis
18. Gastrointestinal or urinary bleeding within the preceding 21 days
19. Major surgery within the preceding 14 days which poses risk in the opinion of the investigator.
20. Exposure to a thrombolytic agent within the previous 72 hours
21. Clinically deemed eligible for Endovascular Clot Retrieval (ECR) treatment by the treating team
D: Inclusion Criteria:

* scoring 4 to 20 on the National Institute of Health Stroke Scale (NIHSS)
* showing a perfusion-diffusion mismatch on MRI of 20 %
* enrolment within a 3 h to 9 h time window after symptom onset.
* 18-85 years of age

Exclusion Criteria:

* Participation in any interventional trial in the previous 30 days.
* Women in the childbearing age.
* Any history of intracranial hemorrhage, subarachnoid hemorrhage, neoplasm, arteriovenous malformation or aneurysm.
* Conditions that, according to the judgment of the investigator, might impose an additional risk to any individual stroke patient when receiving study medication (this applied to patients on platelet-function inhibitors as well).
* MRI exclusion criteria: Evidence of ICH, Evidence of SAH, Signs of extensive early infarction on DWI assessed by evidence of involvement of \>1/3 of the middle cerebral artery (MCA) territory. No perfusion deficit, Internal carotid artery (ICA) occlusion ipsilateral to stroke lesion without additional ipsilateral MCA, anterior cerebral artery (ACA) or posterior cerebral artery (PCA) occlusion. Any intracranial pathology that would interfere with the MRI assessment of acute ischemic stroke.

Answer: A