(Stroke. 2000;31:82.)
© 2000 American Heart Association, Inc.
Original Contributions |
Results in 95 Hemorrhagic Stroke Patients Included in CLASS, a Controlled Trial of Clomethiazole Versus Placebo in Acute Stroke Patients
From the Stroke Research Unit, Department of Neurology, Karolinska Hospital, Stockholm, Sweden (N.G.W.); Stroke Unit, Department of Neurology, University Hospital La Paz, Universidad Autónoma de Madrid, Spain (E.D.-T.); Hopital Maisonneuve Rosemont, Montreal, Canada (J.T.); Quinta de Salud la Alianza, Servicio de Neurologia, Barcelona, Spain (A.A.); Service de Neurologie Vasculaire, Hôpital Roger Salengro, Lille, France (D.L.); and AstraZeneca, Södertälje, Sweden (T.A., E.G.).
Correspondence to N.G. Wahlgren, MD, The Stroke Research Unit, Department of Neurology, Karolinska Hospital, S-171 76 Stockholm, Sweden. E-mail nilsgw{at}neuro.ks.se
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Background and Purpose—Clomethiazole is a neuroprotective drug that enhances
-aminobutyrate type A (GABAA) receptor activity. Its
efficacy and safety were tested in the CLomethiazole Acute Stroke Study
(CLASS). The protocol allowed a CT scan to be done after randomization
but within 7 days of stroke onset to minimize delays before start of
treatment. Ninety-five of the 1360 patients randomized were diagnosed
as having intracranial hemorrhage rather than ischemic
stroke. Safety results for clomethiazole compared with placebo in this
group are reported. Methods—The study included patients with a clinical diagnosis of acute hemispheric cerebral infarction. Treatment was a 24-hour intravenous infusion of 75 mg/kg clomethiazole or placebo. Patients with intracranial hemorrhage discovered on a postrandomization CT were withdrawn from study treatment if treatment was ongoing, and all patients were followed up to 90 days.
Results—Ninety-four patients received treatment, 47 in each
group. The hemorrhage was classified as
intracerebral in 89 patients (94%). Mortality at 90
days was 19.1% in the clomethiazole group and 23.4% in the placebo
group. Sedation was the most common adverse event, occurring at a
higher incidence in clomethiazole-treated patients (clomethiazole 53%,
placebo 17%), followed by rhinitis and coughing. The incidence and
pattern of serious adverse events was similar between the treatment
groups. The percentage of patients reaching relative functional
independence on the Barthel Index (score 
60) at 90 days was 59.6% in
the clomethiazole group and 53.2% in the placebo group.
Conclusions—Clomethiazole appears safe to administer to hemorrhagic stroke patients compared with placebo. These results would obviate the need for a CT scan before therapy is initiated in acute stroke. The safety of clomethiazole in hemorrhagic stroke patients will be further evaluated in a prospective study that is under way in North America.
Key Words: cerebral ischemia • clinical trials • clomethiazole • hemorrhage • neuroprotection
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Clomethiazole (Zendra, AstraZeneca) is a neuroprotective drug that has been shown to be effective in several animal models of cerebral ischemia.1 2 3 4 5 6 The compound enhances
-aminobutyrate type A (GABAA) receptor
activity,7 8 9 and this is a plausible mechanism for its
neuroprotective effect. The efficacy and safety of clomethiazole were
tested in a double-blind, placebo-controlled study that recruited 1360
patients with a clinical diagnosis of acute hemispheric cerebral
infarction (CLomethiazole Acute Stroke Study [CLASS]). There was no
statistically significant difference between the treatment groups in
functional outcome for all patients treated.10 However,
for 545 patients classified before randomization as having total
anterior circulation syndrome, the percentage who reached relative
functional independence (Barthel Index score 60) was 40.8% for
clomethiazole and 29.8% for placebo, a relative benefit of 37%
(nominal P=0.008).11 It is widely believed
that it is important to start acute stroke treatment as soon as
possible after onset of the stroke. To minimize delays in the hospital,
the study did not require a CT scan before randomization; however, one
had to be performed within the first 7 days after randomization. This
resulted in the inclusion of patients with a diagnosis of intracranial
hemorrhage. We report here on the safety of clomethiazole
versus placebo in patients with intracranial hemorrhage. |
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
The study was performed in accordance with the Declaration of Helsinki, and the protocol was approved by the local ethics committees. All patients or their relatives gave informed consent. A full description of the study design, inclusion and exclusion criteria, treatment regimen, assessments, statistical methods, and study group members has been given elsewhere.10 In brief, 1360 patients were recruited at 85 centers in 7 European countries and Canada. Patients were included if they were aged 40 to 90 years and were conscious, with a clinical diagnosis of acute hemispheric cerebral infarction and onset of symptoms in the 12 hours before randomization. They had to score
40 on the sum of the Scandinavian Neurological
Stroke Scale (SSS) long-term items12 and 14 for the sum
of the SSS motor items of arm, hand, and leg at baseline. Patients were
randomized to either clomethiazole or placebo (75 mg/kg), which was
administered as a 15-minute loading infusion (8% of total dose)
followed by a maintenance infusion to 24 hours. If patients
became excessively sedated, the infusion was interrupted and then
resumed at half the previous rate. A CT scan was required within 7 days of stroke onset. When this was done before randomization, patients with a diagnosis of intracranial hemorrhage were excluded. Patients diagnosed with intracranial hemorrhage after a postrandomization CT scan were withdrawn from treatment if treatment was ongoing. All patients were followed up to 90 days.
Hemorrhage on the CT scan was classified as subdural hematoma, intracerebral hemorrhage, or subarachnoid hemorrhage. More than 1 category could be recorded. Patients with CT evidence of infarction and hemorrhagic transformation (as judged by the investigator) were not classified as having intracranial hemorrhage.
Assessments of body temperature, ECG, laboratory tests, and plasma
sampling were made at baseline and at the end of the infusion. Patients
were assessed at baseline and regularly during the infusion for adverse
events, blood pressure, and level of sedation. Sedation was assessed by
use of a sedation scale used in a previous dose-escalation
trial.13 Serious adverse events (SAEs) were defined as
those that resulted in death, hospitalization, or permanent or
significant disability or that were life threatening or required
medical or surgical intervention. Information on all SAEs was collected
up to 7 days after randomization, and data on those SAEs that were
believed to be related to treatment were collected for 90 days during
the first half of the study recruitment period. The protocol was then
amended owing to regulatory requirements, and all data on SAEs were
collected up to day 90. Functional and neurological outcomes were
assessed with the Barthel Index14 and the
SSS,12 respectively, at 7, 30, 60, and 90 days. The
primary end point was the percentage of patients scoring 60 on the
Barthel Index (relative functional independence) at 90 days.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Recruitment and Baseline Characteristics
Ninety-five (7%) of the 1360 patients randomized to CLASS were classified as having intracranial hemorrhage. One patient randomized to the clomethiazole group did not receive treatment because an intracerebral hemorrhage was found on the CT scan before treatment could be started. Therefore, 94 patients were included in the analysis of all patients treated (47 in each treatment group). All but 1 of these patients (in the clomethiazole group) were randomized before the results of the CT scans were known.
The hemorrhage was classified as intracerebral in 89 patients (94%). Of the remaining patients, 2 had subdural hematomas, 1 had subarachnoid hemorrhage, and 1 had mixed intracerebral and subarachnoid hemorrhage in the clomethiazole group, and 1 patient in the placebo group had mixed intracerebral and subarachnoid hemorrhage.
The mean age of patients classified as having an intracranial hemorrhage was 73.6±9.1 years compared with 71.2±11.2 years for the ischemic stroke patients (n=1254), and these patients had slightly worse scores on the SSS-58 scale (hemorrhagic: median 26 points, interquartile range 17 to 33; ischemic: median 28 points, interquartile range 19 to 38).
The demographic and baseline characteristics of patients in the 2
treatment groups were reasonably well balanced for age and severity on
the SSS-58 scale. Mean time since onset of symptoms was 1 hour shorter
in the clomethiazole group, and there were some differences in the
medical history (Table 1
). Mean
blood pressure was slightly higher in the clomethiazole group (Table 1).
|
Dose Administered
The mean dose administered in the clomethiazole group was
58.1 mg/kg compared with 62.4 mg/kg for the placebo group. The latter
was calculated from the volume administered. There were 15 withdrawals
(32%) from each treatment group. The main reason for withdrawal was
diagnosis of hemorrhage during the 24-hour treatment period,
which was a protocol-specified criterion for withdrawal. This occurred
in 10 clomethiazole patients (21%) and 12 placebo patients (20%). The
second most common reason for withdrawal was the occurrence of adverse
events, which occurred in 4 clomethiazole patients (9%) and 3 placebo
patients (6%). All of these adverse events were related to reduced
consciousness, eg, sedation or coma.
Safety
Mortality at 90 days was slightly lower for patients treated with
clomethiazole than for those treated with placebo (clomethiazole
19.1%, placebo 23.4%), but the difference between groups was not
statistically significant (OR 0.78, 95% CI 0.29 to 2.09;
P=0.614), and there was no difference between the
Kaplan-Meier estimates of the survival distribution (data not shown).
The most common primary cause of death was damage due to initial stroke
(6 patients in the clomethiazole group and 4 in the placebo group).
Mortality at 30 days was 17.0% in the clomethiazole group and 14.9%
in the placebo group. The incidence of adverse events during treatment
is shown in Table 2. Somnolence (which
includes the term sedation), rhinitis, and coughing were the most
common adverse events, and these occurred at a higher rate in the
clomethiazole group. The incidence of SAEs was similar in both
treatment groups (8 clomethiazole patients, 5 placebo patients), and
there was no obvious difference between the treatment groups in the
type of adverse events reported. The most common event was cerebral
hemorrhage (3 clomethiazole patients, 1 placebo patient), and
these cases corresponded with the initial diagnosis of the illness.
Clomethiazole produced a mild lowering of systolic blood
pressure during treatment compared with placebo. The mean difference
between the treatment groups for the change from baseline to the
minimum value at any time during treatment was 7 mm Hg (SE 4.3;
P=0.105) for systolic and 0 mm Hg (SE 2.6) for
diastolic blood pressure. There were no differences between
the treatment groups for mean laboratory test values, including
coagulation tests, or mean ECG times.
|
Functional and Neurological Outcomes
The outcome on the Barthel Index at 90 days is shown in the
Figure. Twenty-eight (59.6%) of 47
clomethiazole-treated patients and 25 (53.2%) of 47 placebo patients
scored 60 on the Barthel Index, an absolute difference of 6.4%
(OR=1.3, 95% CI 0.57 to 2.94). At the 95 cutpoint, the difference
between the groups was 14.9 percentage units to the advantage of
clomethiazole. On the SSS-48 scale, the median absolute change from
baseline to last rating was 16 points for clomethiazole patients and 13
points for placebo patients.
|
|
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Stroke patients with a diagnosis of intracranial hemorrhage are usually excluded from clinical trials of putative acute stroke therapies. This was also done in CLASS if a prerandomization CT scan was performed, but a prerandomization scan was not a requirement. As a result, 7% of the patients randomized had intracranial hemorrhage. This is the first report of the safety and tolerability of a neuroprotective drug compared with placebo in patients with acute hemorrhagic stroke.
The patients included in the study were slightly older and scored only
2 points worse on the SSS than the ischemic stroke group.
Correspondingly, the 90-day mortality rate of 23.4% in the placebo
group was similar to that for patients with ischemic stroke who
received placebo (19.4%).10 The 30-day mortality rate of
15% in the hemorrhagic stroke group is relatively low compared with
most series of these patients, in whom the mortality rate at 1 month
ranges from 35% to 50%.15 16 17 Similarly, functional
outcome in this study was relatively good, with 53% of hemorrhagic
patients who were treated with placebo reaching relative functional
independence at 90 days, in contrast to a figure of 25% reported in
previous series after 4 months of follow up.17 It is
likely that the better outcome in the present study is due to a
large extent to the exclusion of patients with reduced consciousness
and symptoms of brain stem stroke.17
Sedation was the most common adverse event produced by clomethiazole, but the incidence of some respiratory adverse events was also increased. The pattern and incidence of adverse events was very similar to that reported for all patients.10 Clomethiazole also produced a mild lowering of systolic blood pressure. This was similar to what was seen in all patients in whom it was not associated with a worse outcome.18 The incidence of SAEs was similar between the treatment groups, and there was no difference in mortality.
Hemorrhagic patients constituted a small subgroup of all patients randomized, and the study was not powered to detect a difference between treatment groups in functional outcome for this subgroup. There were indications of a better functional outcome in hemorrhagic stroke patients treated with clomethiazole compared with placebo, but this might be due to imbalances in severity and prognostic factors at baseline. A much larger study is required to test the efficacy of clomethiazole in hemorrhagic stroke.
We conclude that clomethiazole appears safe to administer to hemorrhagic stroke patients, and in contrast to thrombolytics, it should not be necessary to obtain the results of a CT scan before clomethiazole treatment for acute stroke is begun. The safety of the drug is being further studied in a prospective study that is under way in North America in which the volume of hemorrhage is also being measured.19
|
Acknowledgments |
|---|
This trial was sponsored by Astra Arcus AB, Södertälje, Sweden, the manufacturer of Zendra (clomethiazole).
|
Footnotes |
|---|
AstraZeneca, the manufacturer of Zendra (clomethiazole), provided funding for this study.
Received July 6, 1999; revision received October 5, 1999; accepted October 8, 1999.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
1. Cross AJ, Jones JA, Baldwin Ma, Green AR. Neuroprotective activity of clomethiazole following transient forebrain ischemia in the gerbil. Br J Pharmacol. 1991;104:406–411.[Medline] [Order article via Infotrieve]
2. Cross AJ, Jones JA, Snares M, Jostell K-G, Bredberg U, Green AR. The protective action of chlormethiazole against ischaemia-induced neurogeneration in gerbils when infused at doses having little sedative or anticonvulsant activity. Br J Pharmacol. 1995;114:1625–1630.[Medline] [Order article via Infotrieve]
3. Sydserff SG, Cross AJ, Green AR. The neuroprotective effect of chlormethiazole on ischaemic neuronal damage following permanent middle cerebral artery ischaemia in the rat. Neurodegeneration. 1995;4:323–328.[Medline] [Order article via Infotrieve]
4. Sydserff SG, Cross AJ, West KJ, Green AR. The effect of chlormethiazole on ischaemic neuronal damage in a model of transient focal ischaemia. Br J Pharmacol. 1995;114:1631–1635.[Medline] [Order article via Infotrieve]
5. Snape MF, Baldwin HA, Cross AJ, Green AR. The effects of chlormethiazole and nimodipine on cortical infarct area after focal cerebral ischaemia in the rat. Neuroscience. 1993;53:837–844.[Medline] [Order article via Infotrieve]
6. Marshall JWB, Cross AJ, Murray TK, Ridley RM. Functional benefit from clomethiazole treatment after focal cerebral ischaemia in a non-human primate species. Stroke. 1998;29:330. Abstract.
7. Cross AJ, Stirling JM, Robinson TN, Bowen DM, Francis PT, Green AR. The modulation by clomethiazole of the GABAA receptor complex in rat brain. Br J Pharmacol. 1989;98:284–290.[Medline] [Order article via Infotrieve]
8. Hales TB, Lambert JJ. Modulation of GABAA and glycine receptors by chlormethiazole. Eur Pharmacol. 1992;210:239–246.
9. Moody EJ, Skolnick P. Clomethiazole: neurochemical actions at the gamma-aminobutyric acid complex. Br J Pharmacol. 1989;164:153–158.
10.
Wahlgren NG, Ranasinha KW, Rosolacci T, Franke CL, von
Erven PMM, Ashwood T, Claesson L, for the CLASS Study Group.
Clomethiazole Acute Stroke Study (CLASS): results of a randomised
controlled trial of clomethiazole versus placebo in 1360 acute stroke
patients. Stroke. 1999;30:21–28.
11. Wahlgren NG, Bornhov S, Sharma A, Cederin B, Rosolacci T, Ashwood T, Claesson L, for the CLASS Study Group. The Clomethiazole Acute Stroke Study (CLASS): efficacy results in 545 patients classified as total anterior circulation syndrome (TACS). J Stroke Cerebrovasc Dis. 1999;8:1–10.
12.
Scandinavian Stroke Study Group. Multicenter
trial of hemodilution in ischemic stroke, I: results in the
total study population. Stroke. 1987;18:691–699.
13. Wester P, Strand T, Wahlgren NG, Ashwood T, Osswald G. An open study of clomethiazole in patients with acute cerebral infarction. Cerebrovasc Dis. 1998;8:188–190.[Medline] [Order article via Infotrieve]
14. Mahoney FI, Barthel DW. Functional evaluation: the Barthel Index. Md Med J. 1965;14:61–65.
15.
Fogelholm R, Nuutila M, Vuorela A-L. Primary
haemorrhage in the Jyväskulä region, Central
Finland, 1985–89: incidence, case fatality rate, and functional
outcome. J Neurol Neurosurg Psychiatry. 1992;55:546–552.
16. Broderick JP, Brott T, Tomsick T, Miller R, Huster G. Intracerebral haemorrhage more than twice as common as subarachnoid hemorrhage. J Neurosurg. 1993;78:188–191.[Medline] [Order article via Infotrieve]
17.
Anderson CS, Chakera TMH, Stewart-Wynne EG, Jamrozik
KD. Spectrum of primary intracerebral
haemorrhage in Perth, Western Australia, 1989–90: incidence
and outcome. J Neurol Neurosurg Psychiatry. 1994;57:936–940.
18. Wahlgren NG. The Clomethiazole Acute Stroke Study (CLASS): safety results in 1356 patients with acute hemispheric stroke. Neurology. 1998;50(suppl 4):A212.
19. Lyden PD, Ashwood T, Claesson L, Odergren T, Friday GH, Martin-Munley S. The clomethiazole acute stroke study in ischemic, hemorrhagic and t-PA treated stroke: design of a phase III trial in the U.S. and Canada. J Stroke Cerebrovasc Dis. 1998;7:435–441.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  H. P. Adams Jr, G. del Zoppo, M. J. Alberts, D. L. Bhatt, L. Brass, A. Furlan, R. L. Grubb, R. T. Higashida, E. C. Jauch, C. Kidwell, et al. Guidelines for the Early Management of Adults With Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Circulation, May 22, 2007; 115(20): e478 - e534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. P. Adams Jr, G. del Zoppo, M. J. Alberts, D. L. Bhatt, L. Brass, A. Furlan, R. L. Grubb, R. T. Higashida, E. C. Jauch, C. Kidwell, et al. Guidelines for the Early Management of Adults With Ischemic Stroke: A Guideline From the American Heart Association/ American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists Stroke, May 1, 2007; 38(5): 1655 - 1711. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||