CLOMETHIAZOILE STROKE STUDY FACT SHEET (CLASS-I)
    
Study Name: The Clomethiazole Acute Stroke Study in Ischemic Stroke (CLASS-1):
A Double Blind, Parallel Group, Multinational, Multicenter Study of the
Efficacy and Safety of IN. Clomethiazole Compared to Placebo in Patients with
Acute Ischemic Stroke.
    
    Background: Acute ischemic stroke accounts for 85% of all strokes. A new
classification of drugs called neuroprotectors are being tested for acute
ischemic stroke. This protocol is designed to test the safety and efficacy of
Clomethiazole. This drug has been used internationally (not in the U.S. or
Canada) for more than 30 years for treatment of agitation, sleep disturbances,
alcohol withdrawal symptoms, pre-eclamptic toxemia, delirium tremens, status
epilepticus and as a sleep cover agent during regional anesthesia. The GABA-A
receptor complex has been identified as the site of action for clomethiazole.
The precise mechanism of neuroprotective effect of clomethiazole has not been
determined, but it is believed to be the interaction with the GABA-A receptor
complex. It is not FDA approved except for use in stroke research.
    
Design, This is a randomized, double-blind, multinational (U.S. and Canada),
multicenter, placebo-controlled study to demonstrate the safety and efficacy
of clomethiazole on functional and neurological recovery when given to
patients with acute ischemic stroke within 12 hours of onset of symptoms. The
study will include a total of 1200 patients enrolled at 100-120 centers
throughout the U.S. and Canada. Approximately 12 patients will be enrolled at
this site.
    
Study Population:
Inclusion Criteria:
    1)   Men or Women 18-90 years of age (inclusive);
    2)   Clinical diagnosis of acute ischemic stroke. Patient must have
         symptoms of higher cortical dysfunction, homonymous visual field
         defect and limb weakness contralateral to the infarct;
    3)   Treatment initiated within 12 hours of onset of symptoms. For
         patients who awake with deficits, the time of onset is defined as the
         time at which they were last known to be symptom free;
    4)   The sum scores on items 5, 6 and 12 on the NIH Stroke Scale must be
         > 3 at baseline;
    5)   Symptoms must be present for at least an hour and not rapidly
         improving suggesting a transient ischemic attack;
    6)   Patient must be fully conscious before start of treatment;
    7)   Patient must have been functionally independent prior to their present
         illness;
    8)   Written informed consent must be obtained.
    
    Exclusion Criteria:
    1)   Evidence from CT scan or other prerandornization investigations of a
         diagnosis other than acute ischemic stroke which may have caused the
         symptoms, (e.g. intracranial hemorrhage or tumor);
    2)   Severe concurrent illness with life expectancy of less than 6 months;
    3)   Acute onset or acute exacerbation of chronic or severe respiratory
         insufficiency, (e.g. asthma, bronchitis, emphysema);
    4)   Known severe hepatic or severe renal disorder;
    5)   Systolic blood pressure <100 mmHg;
    6)   Residual neurological sequelae from a previous or concurrent illness,
         or from pre-stroke trauma making neurological and functional
         assessment of the present illness difficult or impossible;
    7)   Seizure at onset of stroke;
    8)   Known hypersensitivity to clomethiazole (Heminevrin);
    9)   Known or suspected alcohol or drug dependence, or known abuse of
         alcohol within the last 24 hours;
    10)  Breast-feeding or pregnant women and women of childbearing potential,
         unless a negative pregnancy test has been obtained prior to
         randomization;
    11)  Treatment since admission to the hospital with thrombolytic agents,
         nimodipine, pentoxifylline, or any other experimental or empirical
         treatments for stroke;
    12)  Treatment since admission to the hospital with medications for cerebral
         edema due to stroke;
    13)  Treatment with aggressive hypertensive therapy;
    14)  Treatment in the last week with sedative drugs or neuroleptics where
         the dose regimen and the time of the last dose may produce residual
         sedation, or treatment with a sleep-inducing drug Wthin the last 8
         hours;
    15)  Previous inclusion in the present study or concurrent inclusion in
         another clinical study.
    
Specific Procedures: The study consists of a 15 minute loading dose followed
by a 23.75 hour infusion of domethiazole or placebo. The patient is then
re-examined at 7 days or discharge, 1 month, 2 months and 3 months after
enrollment into the study. Telephone evaluations at 1, 3, 6, 9, and 12 months
will also be performed by the Technology Assessment Group.
    
    Risks Involved: In a pilot study of three doses of clomethiazole (10, 75, and 100mg/kg) given
    to acute ischemic stroke patients, the most common adverse events were mild sedation, sneezing
    and injection site thrombophlebitis. In a safety analysis of clomethiazole, more serious adverse
    events were reported in patients receiving clomethiazole, but these were related to the known
    sedative effects of the drug. Other possible side effects were nasal irritation, eye irritation,
    headache, increased secretions from the nose and throat and irritation at the infusion site. A
    small decrease in blood pressure was observed in clomethiazole-treated patients, but this was
    not associated with a worse outcome. There may be unknown risks because this is an
    experimental drug. The patient will be medically treated for any adverse event by the medical staff
    as needed.
    
    Questions? Please call Dr. Gregory Larkin (principal investigator) at x5772 or pager 1582,
    Susan Mathias, CRNP (Stroke Study Coordinator) at x5827 or pager 1065, Pam Cockley, RN
    (Stroke Study Co-coordinator) at x5766 or page~r 591-6503, or contact the DEM Stroke IVID/RN
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    on call (24 hour call) x8222.