Stroke and Critical Care Research Center Current Clinical Trial

"Study of Acute ViprinexTM for Emergency Stroke: A Randomized, Double-Blind, Placebo-Controlled Study of Ancrod (Viprinex™) in Subjects Beginning Treatment within 6 Hours of the Onset of Acute, Ischemic Stroke"

Sponsor: Neurobiological Technologies, Inc. (NTI)

List of Investigators

Objective

The primary objective is to determine whether ancrod (Viprinex™) begun intravenously within 6 hours of stroke onset confers statistically significant benefit in reducing the incidence of disability at 90 days.

Goals

The primary objective is to determine whether ancrod (Viprinex™) begun intravenously within 6 hours of stroke onset confers statistically significant benefit in reducing the incidence of disability at 90 days. The study seeks to determine whether a brief (2-3 hr) IV infusion of ancrod begun within 6 hrs of stroke onset is

• Safe (acceptable mortality and symptomatic intracranial hemorrhage (ICH) rate) and
• Effective (functional endpoint based on the Barthel Index (BI) or or modified Rankin Score (mRS))

Subject Type

Adult subjects with acute, ischemic stroke with no hemorrhagic component on pre-treatment CT and with moderate-severe deficits [baseline NIH Stroke Scale (NIHSS) score of 5-25] who are considered not suitable to receive intravenous tPA within 3 hours of stroke onset.

What is Ancrod?

Ancrod is an investigational drug that is derived from snake venom. Ancrod acts to reduce fibrinogen in the blood. Fibrinogen is a naturally occurring substance in the blood that is involved in blood clotting, the likely cause of stroke. Reducing the fibrinogen in the blood reduces clotting and also improves blood flow within and to the brain. These actions may help limit the amount of damage that can be caused by stroke.

Patient Recruitment

Subject will be chosen from the patients, arriving with a new stroke in the ER. The stroke neurologist on call is always paged during this situation.

Inclusion Criteria

1. Sudden onset of an ischemia related neurological deficit involving the carotid, vertebrobasilar, or cerebral artery territories.
2. Diagnosis of stroke based on a physical examination conducted by a neurologist (defined as a physician with at least two years of specialty training in neurology) and included in the center's Form FDA 1572. (A stroke diagnosis made by a non-neurologist physician included in the center's Form FDA 1572 will be accepted if the sponsor approves this physician's qualifications and experience for diagnosing stroke in advance. Otherwise, the diagnosis must be confirmed by a neurologist within 24 hours of subject enrollment.)
3. Administration of ancrod is to begin within 6 hours (0 360 min) of recognized onset of stroke symptoms; symptoms must last longer than 30 minutes, must not have significantly improved, and must be distinguished from an episode of generalized ischemia (e.g., syncope), active seizure, or migraine disorder. To insure that deficits beginning during sleep had not been present for more than 6 hours, such subjects must have been observed to be deficit free within 6 hours of the time treatment is to begin.
4. No conditions other than stroke to which the subject's sudden clinical deterioration could have been attributed (e.g., pneumonia, systemic febrile infection), or which might interfere with the neurological evaluation (e.g., ipsilateral focal neurological deficits from old brain lesions, demyelinating disease, superimposed encephalopathy, or multi infarct dementia).
5. Adult subjects (at least 18 years old), who are not candidates for t-PA treatment
6. Men or women, but women must not be pregnant or lactating; women of child bearing potential must have a negative pregnancy test before receiving Viprinex™.
7. Baseline NIH Stroke Scale score of 5-25 to identify subjects with moderate severe strokes.
8. Prestroke BI >- 70 to exclude subjects with relatively severe prestroke disability.
9. Written consent by the subject (or his/her representative if the subject is unable to sign personally) obtained and noted in the subject's chart.

Exclusion Criteria

Note that other than the pretreatment fibrinogen level, an INR and/or aPTT in circumstances addressed in Exclusion Criterion #15, the pretreatment CT scan, and in premenopausal women urine pregnancy testing, laboratory test results are not required to satisfy exclusion criteria for this study. If results of these tests are available, they may be used by the investigator in determining whether the subject violates any of the following exclusion criteria.

1. Clinical or CT evidence of intracranial extravascular blood (e.g., cerebral hemorrhage, hemorrhagic infarction, subdural hematoma) or potentially progressive intracranial lesion (e.g., neoplasm, abscess) on head CT scan taken before treatment. CT evidence of the index ischemic stroke will not exclude subjects, but investigators should be fully satisfied that they have determined the time of symptom onset if there is extensive change related to the index stroke (e.g., hypodensity or obliteration of the gray/white junction exceeding 33% of the putative MCA distribution).
2. Stroke known or strongly suspected to be caused by an arterial dissection.
3. Unconscious or comatose state.
4. Seizures at or since onset of neurological deficit (in an effort to exclude subjects whose deficits are caused by "Todd's paralysis"). Seizures after study entry do not warrant discontinuation of study drug or termination of observations.
5. Stroke (ischemic or hemorrhagic) within the previous 6 weeks.
6. Improvement in the clinical deficit suggesting a resolving TIA based, for example, on documented improvement in NIHSS of >- 3 points in the 30 min prior to beginning study drug, undocumented clinical observations, or other evidence of rapid clinical improvement.
7. Ipsilateral focal neurological deficits from prior lesions that would complicate subject evaluation.
8. Anticipated emergency surgery (including angioplasty) or general anesthesia.
9. Recent (<- 24 hours) or anticipated arterial puncture at a noncompressible site.
10. Current stroke occurring <- 14 days after major surgery or <- 30 days after carotid endarterectomy.
11. Hypertension, considered severe and uncontrolled by history or with serious complications, such as hypertensive encephalopathy at any time; or as detected on physical examination at Screening on the basis of a diastolic BP > 105 mmHg or systolic BP > 185 mmHg that is not lowered to satisfy these criteria by a regimen such as that immediately following.

    If antihypertensives are used prior to starting the ancrod infusion to lower the BP to <- 185/105 mmHg, the following regimen is recommended:

    For systolic BP > 230 mmHg and/or	Diastolic BP > 120 mmHg	labetalol 20 mg IV over 1-2 min
    For systolic BP > 185 mmHg and <- 230 mm Hg and/or	Diastolic BP > 105 mmHg and <- 120 mmHg	Labetalol 10 mg IV over 1-2 min

    The dose may be repeated and/or doubled every 10 min, up to 150 mg. Alternatively, following the first bolus of labetalol, an IV infusion of 2 8 mg/min labetalol may be initiated and continued until the desired BP is reached. Subjects treated with antihypertensives to lower the BP prior to study enrollment should be carefully monitored and treated gently as needed during the first 24 hours to avoid rebound hypertension.

12. Hypotension (systolic BP < 90 mm Hg).
13. Severe bradycardia (heart rate less than 40 beats/min at any time between stroke onset and treatment).
14. Baseline plasma fibrinogen level < 100 mg/dl.
Although the duration of the ancrod infusion depends on the pretreatment fibrinogen level, the protocol does not require that subject entry be stratified with respect to the fibrinogen level, and study drug treatment can be started before the pretreatment fibrinogen is reported. If a pretreatment plasma fibrinogen value < 100 mg/dL is reported after subject randomization, study drug infusion should be stopped.
15. Known disorder of platelet function or coagulation abnormality. Use of anticoagulants such as warfarin, heparin, low-molecular weight heparin or heparinoids, or abciximab (or similar antiplatelet agents) within 3 days or planned use of an anticoagulant within 5 days after beginning study medication. Subjects who received warfarin or heparin but who are believed to be inadequately anticoagulated may be treated if their pretreatment INR is < 1.5 and if their pretreatment aPTT is <- 45 sec or the local laboratory's upper limit of normal, whichever is higher.
16. Use of a thrombolytic agent (e.g., rt-PA, urokinase, streptokinase) within the prior 3 days or planned use of a thrombolytic agent within 5 days after beginning study drug. Thrombolytic agents should not have been used within the prior 3 days to maintain patency of indwelling catheters.
17. Known or suspected thrombocytopenia or anemia (except that a platelet count >- 100,000 per cubic millimeter or hematocrit >- 30%, respectively, will permit subject enrollment).
18. Major hemostatic deficit as a result of other illness, e.g., uremia.
19. Unstable angina pectoris or an acute myocardial infarction that might require thrombolytic therapy or surgery; suspected pericarditis placing subject at risk of a hemorrhagic pericardial effusion; or subacute bacterial endocarditis.

Download the Schedule of Activities and Assessments in pdf format:AcuteVirprinexStudy_Schedule.pdf

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