The Clomethiazole Acute Stroke Study (CLASS): Safety Results in 1,356 Patients With Acute Hemispheric Stroke Nils Gunnar Wahlgren, MD, PhD, Jordi Matias-Guiu, MD, PhD, Jose´ Miguel Lainez, MD, Felix Veloso, MD, Kingsley Ranasinha, MD, FRCP, Eva Grossman, MD, and Timothy Ashwood, PhD for the CLASS Study Group
The Clomethiazole Acute Stroke Study (CLASS) showed no difference in outcome between patients treated with clomethiazole or placebo for all patients treated, but a beneficial effect in patients classified as a total anterior circulation syndrome (TACS). These are patients with clinical symptoms of a large stroke. Safety and tolerability data are reported here with emphasis on the safety of treating stroke patients with a sedative drug. In total, 1,356 patients were eligible for safety analysis. Mortality at 90 days was equal between the treatment groups (clomethiazole, 19.5%; placebo, 19.7%). Clomethiazole was generally well-tolerated. The most common adverse event was sedation (clomethiazole, 53%; placebo, 10%). Clomethiazole also produced some respiratory adverse events (e.g., rhinitis and increased sputum). Serious adverse events associated with sedation were more commonly reported in the clomethiazole group during treatment. However, the incidence was low. There was no difference in the incidence of serious adverse events between the treatment groups for pulmonary conditions, cardiovascular conditions, or other conditions. Clomethiazole produced a small decrease in blood pressure, but this was not associated with a worse outcome. Safety and tolerability in TACS patients was similar to that for all patients treated with the exception that these patients were more sensitive to the sedative effects of the drug. Despite this, mortality was slightly lower, and functional outcome was better in clomethiazole-treated TACS patients compared with placebo. In conclusion, clomethiazole was generally well-tolerated. The sedation observed did not increase the risk for complications, such as pulmonary serious adverse events or affect the outcome in a negative way. Clomethiazole appeared to be safe to use in stroke patients in general and in patients with a large stroke. The efficacy and safety in large strokes will be studied further in a new study, which is ongoing. Key Words: Cerebral ischemia—Clinical trials—Clomethiazole—Safety—Neuroprotection.
A number of neuroprotective drugs have been tested in randomized trials in acute stroke. Several have produced clinically significant adverse events, which may have led to a choice of a suboptimal dose level in terms of the
From the Stroke Research Unit, Department of Neurology, Karolinska Hospital, Stockholm, Sweden; Servicio de Neurologia, Hospital General Universitario de Alicante, Alicante, Spain; Servicio de Neurocirugia, Hospital Gen. Univ. de Valencia, Valencia, Spain; Plains Health Centre Regina, SK, Canada; Epsom General Hospital, Epsom, United Kingdom; and Astra Arcus AB, So¨derta¨lje, Sweden. Received September 23, 1999; accepted January 6, 2000. Supported by Astra Arcus AB, So¨derta¨lje, Sweden. Address reprint requests to Nils Gunnar Wahlgren, MD, PhD, The Stroke Research Unit, Department of Neurology, Karolinska Hospital, S-171 76 Stockholm, Sweden. Copyright r 2000 by National Stroke Association 1052-3057/00/0904-0002$3.00/0 doi:10.1053/jscd.2000.7236
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neuroprotective effect.1-3 Some substances even appeared to be harmful, producing a worse outcome compared with placebo.4-6 Clomethiazole (Zendra; AstraZeneca, So¨derta¨lje, Sweden) is also a neuroprotective drug. It protects against neuronal damage in animal models of focal and global ischaemia.7-12 However, it differs mechanistically from other neuroprotectants, which have been tested, because it enhances gamma aminobutyric acid receptor subtype A (GABAA ) receptor activity.13-15 Clomethiazole, therefore, has sedative properties, although it is possible to produce powerful neuroprotection in animals at doses, which have little sedative effect.8 There is no evidence that drug-induced sedation per se will adversely affect the clinical outcome of stroke patients. However, sedation should not compromise respiratory function or preclude adequate monitoring of the patients neurological status to detect a deterioration of the stroke or a
Journal of Stroke and Cerebrovascular Diseases, Vol. 9, No. 4 ( July-August), 2000: pp 158-165
SAFETY RESULTS FOR CLOMETHIAZOLE IN ACUTE STROKE
complication, such as cerebral edema. Furthermore, the onset of early rehabilitation should not be delayed, as this is one of the key factors for success at the stroke unit.16 Excessive or prolonged sedation should, therefore, be avoided. An open dose escalation study found a dose of 75 mg/kg clomethiazole given as an intravenous infusion over 24 hours was the maximum tolerated without producing excessive sedation. This dose produced a mean plasma concentration in man of 13 µmol/L, which corresponds well to concentrations that are neuroprotective in animal models.17 This dose was, therefore, considered suitable for further use in clinical efficacy trials in acute stroke patients and was tested in the clomethiazole acute stroke study (CLASS). This was a double-blind placebocontrolled study of the efficacy and safety of the drug in 1,360 patients with acute hemispheric stroke.18 In the main efficacy analysis, there was no statistically significant difference between clomethiazole and placebo on the primary outcome measure, which was the percentage of patients scoring 60 or more on the Barthel index (relative functional independence). Patients were classified before randomization into stroke syndromes according to Bamford et al.19 In a post hoc analysis of a subset of patients classified as a total anterior circulation syndrome (TACS, n ⫽ 545), 40.8% of clomethiazole patients reached relative functional independence compared with 29.8% in the placebo group. These patients had symptoms of higher cerebral dysfunction, motor weakness, and homonymous visual field deficit at baseline and have been shown by others to be at high risk of a large volume of brain infarction.20 We hypothesize that clomethiazole is effective in patients with clinical symptoms of a large ischemic stroke. This is currently being tested in a further study.21 We report here the safety and tolerability results from CLASS with special emphasis on the safety of treating stroke patients with a drug with sedative properties through a comparison of serious adverse event incidence and mortality rates. Results are presented primarily for all patients treated, but some features of safety in TACS patients will be highlighted.
Patients and Methods A complete description of the patients and methods together with the names of the principal investigators of the CLASS study group is given elsewhere.18 A brief summary of the patients recruited and efficacy measures is given below plus full details of safety measures. Patients 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 representatives gave informed consent. Inclusion criteria
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were patients aged 40 to 90 with a clinical diagnosis of an ischemic hemispheric cerebral infarction and with stroke onset in the last 12 hours. Patients had to be functionally independent before the stroke and conscious with a hemiparesis and a Scandinavian Stroke Scale (SSS) score of 40 points or less on the 48 point long-term items scale.22 A computed tomography (CT) scan was not required before inclusion, but had to be performed within 7 days. Patients were excluded if they had any disorder interfering with the neurological or functional assessment, a life-threatening concurrent illness, severe respiratory insufficiency, hepatic or renal disorder, or diastolic blood pressure ⬍50 or ⬎130 mm Hg. Treatment Patients received a loading infusion of clomethiazole (8% of total dose) or placebo over 15 minutes followed by a maintenance infusion. The maintenance infusion continued until the total infusion time (loading plus maintenance) was 24 hours. Flow rates were adjusted to body weight. The target dose was 75 mg/kg. The patient’s level of sedation was carefully and regularly monitored during the infusion using a 6 graded sedation scale as follows: 1, fully awake; 2, drowsy, but answers when spoken to; 3, answers slowly when spoken to; 4, reacts when spoken to, but does not answer; 5, reacts only to painful stimuli; 6, does not react to painful stimuli. If the patient became markedly sedated, (score ⱖ4), the infusion was interrupted and then resumed again at half the previous rate once the patient scored 3 or less. This stop/reduction procedure was repeated if required. If the patient was still markedly sedated within 2 hours of stopping the infusion, the study drug was not restarted. Sedation scores ⱖ3 were recorded as adverse events. Assessments All adverse events were collected during the 24-hour treatment period. Unresolved adverse events were followed up at day 7. All serious adverse events (i.e., those that resulted in death, hospitalization, permanent or significant disability or were life-threatening, or required medical or surgical intervention) were collected up to 7 days. Events believed to be related to treatment were collected for 90 days (none were reported) during the first half of the study recruitment period. Thereafter, the protocol was amended due to regulatory requirements, and all serious adverse events were collected up to day 90. All deaths were reported irrespective of relationship to treatment. The primary cause of death was classified according to a scheme based on that used in the International Stroke Trial.23 An independent data monitoring committee reviewed all serious adverse events when 200, 450, and 900 patients had been randomized and followed for 7 days.
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Assessments for body temperature, electrocardiogram (ECG) and laboratory tests (clinical chemistry and hematology) were made before (baseline) and at the end of the treatment (24 hours). Abnormal laboratory tests were followed up until normalized or otherwise explained. Thrombophlebitis was collected as a checklist symptom at baseline and after treatment. Pulse, blood pressure, sedation score, and adverse events were assessed before treatment, at 15, 30, and 60 minutes during the first hour, then every 3 hours for half of the treatment time and finally every 6 hours until the end of treatment. Sedation score were also recorded at 3, 6, 12, and 24 hours postinfusion. All ECGs were evaluated centrally by an external consultant. All patients were followed to 90 days. The primary efficacy variable was relative functional independence defined as the proportion of patients scoring ⱖ60 on the Barthel Index24 at 90 days. Statistical Methods Mortality was appropriately summarized as rates and compared between treatment groups. Survival distributions were estimated using the Kaplan-Meier method and assessed for a difference between treatment groups with the log-rank test. Incidences of adverse events were compared between treatment groups using the chi-square/ Fisher’s exact test, as appropriate. Analysis of variance models were used in the comparison of cardiovascular assessments. Spearman’s rank correlation coefficient was used for assessing the relationship between blood pressure fall and functional outcome, as measured by the Barthel index. All deaths were treated as a category worse than a Barthel score of 0 in this analysis. All reported P values are nominal and not corrected for multiplicity.
Results The study randomized 1,360 patients. All patients who received treatment (n ⫽ 1,356) were eligible for safety analysis, (clomethiazole, n ⫽ 679; placebo, n ⫽ 677). One patient randomized to clomethiazole and 3 randomized to placebo never received any study drug. The TACS subgroup constituted 40% of the patients included in the study (clomethiazole, n ⫽ 287; placebo, n ⫽ 258). Demographic and baseline characteristics have been presented elsewhere.18 They were well-balanced between the treatment groups. Mortality The overall mortality was 19.5% in the clomethiazole group and 19.7% in the placebo group (odd-ratio [OR] ⫽ 0.99; 95% confidence interval [CI], 0.76 to 1.29, P ⫽ .924). There was no difference between the KaplanMeier estimates of the survival distributions (P ⫽ .951, log-rank test).
The primary cause of death for all patients treated is summarized in Table 1. The most common primary causes of death were damage due to the initial stroke followed by bronchopneumonia. There were no significant differences between the treatment groups for any cause of death for all patients treated. Adverse Events General. Treatment emergent adverse events (i.e., those not seen at baseline or with an increased intensity during treatment) were reported by 543 (80%) of the patients in the clomethiazole group and 364 (54%) in the placebo group. Adverse events were generally few (1 to 2) in most patients. They caused withdrawal from treatment in 106 (15.6%) clomethiazole patients compared with 29 (4.2%) placebo patients. Somnolence (this includes the term, sedation) and rhinitis were the most common adverse events occurring at a higher incidence in the clomethiazole group (Table 2). Other adverse events with a higher incidence in the clomethiazole group, in order of decreasing incidence were coughing, yawning, increased sputum, hiccups, injection site reaction, conjunctivitis, lacrimation abnormal, and thrombophlebitis. Vomiting was more common in patients treated with placebo. Thrombophlebitis recorded on the checklist was present in 213 (31%) patients in the clomethiazole group and 35 (5%) patients in the placebo group. The intensity of the reaction was mild in most cases, and most were resolved within the first 7 days. Psychotomimetic adverse events were rare. For example, hallucinations occurred in 3 patients (0.4%) in each treatment group. Sedation. Somnolence was reported as an adverse event in about half (53%) of the clomethiazole-treated patients, compared with 10% of patients in the placebo group (Table 2). This was the most common adverse event leading to withdrawal from treatment, which occurred in 90 patients (13%) treated with clomethiazole compared with 21 patients (3%) treated with placebo.
Table 1. Primary cause of death in all patients
Primary cause of death Damage initial stroke Bronchopneumonia Nonvascular disease Ischemic or unknown recurrent stroke Coronary heart disease Recurrent hemorrhage stroke Pulmonary embolism Other vascular disease Unknown Total
Clomethiazole (n ⫽ 679)
Placebo (n ⫽ 677)
53 (8%) 27 (4%) 11 (2%)
50 (7%) 19 (3%) 14 (2%)
11 (2%) 7 (1%) 4 (1%) 7 (1%) 4 (1%) 8 (1%) 132 (19%)
15 (2%) 10 (1%) 2 (⬍1%) 4 (1%) 9 (1%) 10 (1%) 133 (19%)
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Table 2. Treatment emergent adverse events in all patients during treatment
Preferred term
Clomethiazole (%) (n ⫽ 679)
Placebo (%) (n ⫽ 677)
Somnolence (including sedation) Rhinitis Fever Headache Hypertension Coughing Yawning Sputum increased Agitation Hiccup Tachycardia Progressive stroke Urinary incontinence Nausea Vomiting Dyspnea Injection site reaction Pain Hypotension Conjunctivitis Pruritus Lacrimation abnormal Fibrillation atrial Leukocytosis Thrombophlebitis* Paraesthesia
357 (52.6) 128 (18.9) 115 (16.9) 81 (11.9) 52 (7.7) 46 (6.8) 44 (6.5) 35 (5.2) 35 (5.2) 29 (4.3) 28 (4.1) 26 (3.8) 24 (3.5) 23 (3.4) 22 (3.2) 22 (3.2) 22 (3.2) 19 (2.8) 19 (2.8) 16 (2.4) 15 (2.2) 14 (2.1) 13 (1.9) 12 (1.8) 12 (1.8) 11 (1.6)
68 (10.0) 21 (3.1) 91 (13.4) 67 (9.9) 44 (6.5) 21 (3.1) 14 (2.1) 14 (2.1) 26 (3.8) 10 (1.5) 20 (3.0) 19 (2.8) 14 (2.1) 24 (3.5) 49 (7.2) 23 (3.4) 7 (1.0) 20 (3.0) 12 (1.8) 3 (0.4) 6 (0.9) 4 (0.6) 9 (1.3) 8 (1.2) 1 (0.1) 6 (0.9)
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reduction) was 30% in all patients. The incidence of excessive sedation increased over the 24-hour treatment period. At 24 hours postinfusion, most clomethiazoletreated patients were no longer sedated. The percentage scoring 3 or more was clomethiazole, 11% and placebo, 3%. Serious adverse events. During treatment, cerebral conditions associated with sedation, such as somnolence, coma, and stupor were more frequently reported in the clomethiazole group, although the incidence was low (Table 4). Cerebral edema was also more often reported as a serious adverse event during treatment with clomethiazole. The incidence of fatal events due to this condition up to day 7 was similar in both treatment groups, with 12 deaths in patients treated with clomethiazole and 11 deaths in placebo-treated patients. There was no difference in the incidence of serious adverse events between the treatment groups for pulmonary conditions, cardiovascular conditions, or other conditions during the 24-hour treatment period or the follow-up period up to 90 days. Cardiovascular There was an increase in pulse during treatment with clomethiazole compared with placebo. The mean difference between the treatment groups for the change from baseline to a maximum value at any time during treatment was 4 bpm (standard error [SE], 0.8; P ⬍ .001). Table 4. Serious adverse events in all patients (cerebral conditions)
NOTE: Events of any severity reported by more than 10 patients on clomethiazole are shown. *Also recorded on a checklist.
The sedative effects of clomethiazole were also measured on the sedation scale. Approximately 50% of all patients scored 3 or more, as their maximum during the maintenance infusion, compared with 10% in the placebo group (Table 3). The percentage of clomethiazole-treated patients reaching a level of excessive sedation as defined by the protocol (score ⱖ4) (i.e., sedation requiring a dose Table 3. Maximum sedation scores during the maintenance infusion in all patients
Sedation score
Clomethiazole (%) (n ⫽ 679)
Placebo (%) (n ⫽ 677)
1, fully awake 2, drowsy but answers 3, answers slowly 4, does not answer* 5, reacts only to pain 6, does not react to pain
17 33 19 23 7 ⬍1
54 37 5 3 2 ⬍1
*Patients scoring ⱖ4 were required to have a dose reduction according to the protocol.
Clomethiazole (%) (n ⫽ 679)
Progressive stroke Somnolence Coma Stupor Cerebral edema Cerebral incarceration Cerebral hemorrhage Intracranial hemorrhage Cerebrovascular disorder Convulsions grand mal Hydrocephalus Intracranial hypertension Total *Start of infusion.
Placebo (%) (n ⫽ 677)
0*-24 hours
Day 2-7
0*-24 hours
Day 2-7
22 (3.2) 7 (1) 5 (0.7) 2 (0.3) 8 (1.2)
12 (1.8) 0 (0) 1 (0.1) 1 (0.1) 11 (1.6)
2 (0.3)
2 (0.3)
1 (0.1)
1 (0.1)
4 (0.6)
3 (0.4)
2 (0.3)
0 (0)
0 (0)
1 (0.1)
1 (0.1)
0 (0)
2 (0.3)
4 (0.6)
2 (0.3)
9 (1.3)
0 (0) 0 (0)
0 (0) 0 (0)
0 (0) 0 (0)
1 (0.1) 1 (0.1)
1 (0.1) 53 (7.8)
0 (0) 35 (5.2)
21 (3.1) 14 (2) 0 (0) 0 (0) 3 (0.4) 1 (0.1) 0 (0) 0 (0) 2 (0.3) 12 (1.8)
0 (0) 0 (0) 32 (4.7) 39 (5.7)
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204 (30%); placebo, 133 (20%). Despite this, outcome did not appear worse on clomethiazole in this cohort. There were 119 of 204 clomethiazole patients (58.3%) and 70 of 133 placebo patients (52.6%) who scored 60 or more on Barthel index at 90 days. Laboratory Tests, ECG, and Body Temperature For laboratory tests, including coagulation tests, changes in mean values between baseline and after treatment and the incidence of outliers showed no difference between the treatment groups. Changes in ECG times and the incidence of new ECG abnormalities after treatment were also similar in the 2 treatment groups (data not shown). The mean values of body temperature before and after treatment were similar between the treatment groups, although fever was more often reported as an adverse event in the clomethiazole group.
Figure 1. Blood pressure over time in all patients. Clomethiazole, n ⫽ 679; placebo, n ⫽ 677.
Safety in TACS Compared With non-TACS Patients Mortality. Mortality in TACS patients was 28.6% in the clomethiazole group and 32.2% in the placebo group (OR, 0.84; 95% CI, 0.59 to 1.22; P ⫽ .361). The difference between the groups was not significant. Similarly, there was no statistically significant difference in Kaplan-Meier estimates of the survival distribution (P ⫽ .335, log-rank test). For non-TACS patients, the mortality in the clomethiazole group was 12.8% and in the placebo group, 11.9%. (OR, 1.08; 95% CI, 0.71 to 1.64, P ⫽ .72). There was no statistically significant difference in Kaplan-Meier estimates of the survival distribution (P ⫽ .673, log-rank test). The primary cause of death for TACS and non-TACS patients is summarized in Table 5. Damage due to the initial stroke and bronchopneumonia were the most common causes in both treatment groups. There were no significant differences between the treatment groups for any cause of death for either TACS or non-TACS patients. Sedation. In the TACS group, sedation was recorded as an adverse event for 68% in the clomethiazole group and 16% in the placebo group. For the non-TACS patients, the
There was a mild reduction in blood pressure during the infusion (Fig 1), which was slightly greater in the clomethiazole group. The mean difference between the treatment groups for the change from baseline to the minimum value at any time during treatment for systolic blood pressure was 6 mmHg (SE, 1.1; P ⬍ .001). The corresponding figure for diastolic blood pressure was 2 mmHg (SE, 0.7; P ⬍ .01). An analysis of whether a decrease in systolic or diastolic blood pressure was associated with a worse functional recovery did not show any such relationship. Spearman’s rank correlation between the maximum decrease in systolic blood pressure and the Barthel index score at 90 days was 0.07 (not significant [NS]) in the clomethiazole group and ⫺0.01 (NS) in the placebo group. There were more patients experiencing a fairly large decrease in systolic blood pressure in the clomethiazole group. The number experiencing a decrease of 37 mm Hg or more (upper quartile of distribution) compared with baseline at anytime during treatment were clomethiazole,
Table 5. Primary cause of death in TACS and non-TACS TACS
Non-TACS
Primary cause of death
Clomethiazole (%) (n ⫽ 287)
Placebo (%) (n ⫽ 258)
Clomethiazole (%) (n ⫽ 392)
Placebo (%) (n ⫽ 419)
Damage initial stroke Bronchopneumonia Nonvascular disease Ischemic or unknown recurrent stroke Coronary heart disease Recurrent hemorrhage stroke Pulmonary embolism Other vascular disease Unknown Total
34 (12) 18 (6) 9 (3) 5 (2) 5 (2) 3 (1) 2 (⬍1) 2 (⬍1) 4 (1) 82 (29)
37 (14) 11 (4) 8 (3) 8 (3) 7 (3) 1 (⬍1) 1 (⬍1) 5 (2) 5 (2) 83 (32)
19 (5) 9 (2) 2 (⬍1) 6 (1) 2 (⬍1) 1 (⬍1) 5 (1) 2 (⬍1) 4 (1) 50 (13)
13 (3) 8 (2) 6 (1) 7 (2) 3 (⬍1) 1 (⬍1) 3 (⬍1) 4 (1) 5 (1) 50 (12)
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corresponding figures are clomethiazole, 41% and placebo, 6%. The recordings of the maximum sedation scores during the maintenance infusion for the 2 groups is presented in Table 6. The percentage of patients on clomethiazole reaching a level of excessive sedation (score ⱖ4) was 46% in TACS patients and 19% in the non-TACS patients. The number of patients in the TACS group who withdrew early from treatment due to sedation were 53 (19%) in the clomethiazole group and 10 (3%) in the placebo group compared with clomethiazole, 37 (9%) and placebo, 11 (3%) in the non-TACS group. At 24 hours postinfusion, most clomethiazole-treated patients were no longer sedated. The percentage scoring 3 or more among TACS patients was clomethiazole, 17%; placebo, 12%. The corresponding figures for non-TACS patients were clomethiazole, 7% and placebo, 3%. Adverse events other than sedation showed similar incidences in TACS and non-TACS groups, and the cardiovascular measurements did not differ between these groups.
Discussion Clomethiazole was, in general, well-tolerated in this study. As expected, sedation was the most commonly reported adverse event, but this could be managed using a simple scheme that monitored the level of sedation. The majority of patients did not reach a level of excessive sedation at any time, and most completed the 24-hour treatment period. Although there were some dose reductions due to sedation, this was driven by the protocol, which required dose reductions in patients with excessive sedation and treatment withdrawal if excessive sedation lasted more than 2 hours. Almost all patients had little or no sedation 24 hours after the end of treatment. TACS patients were more sensitive to the sedative effects of clomethiazole. Some TACS patients, however, developed reduced consciousness as a symptom of the stroke during the 24-hour treatment period, as reflected by the higher incidence of sedation in the placebo TACS compared with non-TACS patients. There may thus be an interaction between the sedative properties of the drug and the
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development of reduced consciousness as part of the disease process in this group of patients. During treatment, there were more serious adverse events reported on clomethiazole compared with placebo. These were mostly due to cerebral conditions, were related to the sedative properties of the drug (e.g., coma, stupor), and were of low incidence. A slightly larger number of cases of cerebral edema were reported on clomethiazole during the treatment period. The reports were often based on clinical signs, such as reduced consciousness, which may be explained by the sedative effects of clomethiazole. The latter may also lead to increased monitoring by CT scan in clomethiazole-treated patients compared with those treated with placebo, resulting in the detection of signs of edema on the scan more often in this group. There was no difference in mortality between the treatment groups at 1 week for either the cases of cerebral edema or the other cerebral conditions. Clomethiazole produced respiratory adverse events such as rhinitis and increased sputum. However, there was no overrepresentation in the number of serious adverse events of pulmonary conditions at anytime during the study period. The mean blood pressure in both treatment groups decreased slightly during the 24-hour treatment period. A decrease in blood pressure from the value at the time of presentation to hospital has been reported by others,25,26 although the mechanism for the elevation of blood pressure at admission is not clear. The decrease in systolic and diastolic blood pressure was slightly larger for patients treated with clomethiazole. In addition, some patients in both treatment groups experienced a substantial decrease of systolic blood pressure. The percentage was somewhat larger in the clomethiazole group. The decreased blood pressure could be due to the sedative effects of the drug. Earlier investigations in volunteers have detected increased heart rate, but no consistent effect on blood pressure during clomethiazole treatment.27-29 Wahlgren et al6 have shown that a decrease in blood pressure in the acute phase in patients treated with nimodipine, when
Table 6. Maximum sedation scores during the maintenance infusion in TACS and non-TACS patients Clomethiazole
Sedation score 1, fully awake 2, drowsy but answers 3, answers slowly 4, does not answer* 5, reacts only to pain 6, does not react to pain Missing
Placebo
TACS (%) (n ⫽ 287)
Non-TACS (%) (n ⫽ 392)
TACS (%) (n ⫽ 259)
Non-TACS (%) (n ⫽ 419)
11 24 19 34 11 ⬍1
22 40 19 14 5 0 1
40 44 8 4 3 ⬍1
62 32 3 2 1 0
*Patients scoring ⱖ4 were required to have a dose reduction according to the protocol.
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given as an intravenous (IV) infusion, was associated with a poorer outcome compared with patients treated with placebo. Recently, Chamorro et al30 found that complete recovery in ischemic stroke is facilitated by moderate blood pressure reduction when brain edema develops. We could find no evidence that the blood pressure changes in this study were associated with a worse outcome, presumably because the mean blood pressure changes were much smaller than in the nimodipine study. It is also likely that the effect on outcome may be different depending on whether a decrease in blood pressure is caused by reduction of peripheral arterial resistance, sedation, or relief of sympathetic activation on arrival at the hospital. In all patients, functional outcome and the incidence and causes of mortality were very similar in patients treated with clomethiazole compared with placebo, even though clomethiazole produced a moderate degree of sedation and some respiratory adverse events. There are, therefore, no findings that indicate that the sedation observed increased the risk for complications or affected outcome in a negative way. We conclude that a dose of 75 mg/kg clomethiazole using a dose reduction schedule in patients who become excessively sedated is a safe treatment. This contrasts with the safety and tolerability profile of some other neuroprotective drugs with different mechanisms of action to clomethiazole. For example, the competitive N-methyl-D-aspartate (NMDA) antagonist, selfotel, produced marked psychotomimetic effects and increased mortality due to cerebral causes,1,4 while IV administration of the calcium channel blocker, nimodipine, produced a worse outcome associated with a pronounced decrease of the blood pressure.6 In TACS patients, the incidence of excessive sedation was higher compared with non-TACS patients, and yet the percentage of TACS patients reaching relative functional independence was 40.8% on clomethiazole compared with 29.8% on placebo,18 while mortality was slightly lower compared with placebo. These findings need to be confirmed, as they are based on a posthoc subgroup analysis, but they indicate that the sedation observed did not worsen outcome, and that clomethiazole is also safe to administer to TACS patients. A new study selecting patients with a symptom profile similar to TACS patients to test the hypothesis that clomethiazole is efficacious is, therefore, justified and is ongoing.21 In the new study, the dosage regimen has been modified based on pharmacokinetic modelling to reduce the number of dose reductions and withdrawals due to sedation, while maintaining drug plasma concentrations that are effective in animal models.
References 1. Grotta J, Clark W, Coull B, et al. Safety and tolerability of the glutamate antagonist CGS 19755 (Selfotel) in patients with acute ischemic stroke. Results of a phase IIa randomised trial. Stroke 1995;26:602-605.
N.G. WAHLGREN ET AL. 2. Diener HC, Hacke W, Hennerici M, et al. Lubeluzole in acute ischemic stroke: A double-blind, placebo-controlled phase II trial. Stroke 1996;27:76-81. 3. Hacke W, Lees KR, Timmerhuis T, et al. Cardiovascular safety of lubeluzole (Prosynapt) in patients with acute ischemic stroke. Cerebrovasc Dis 1998;8:247-254. 4. Davis SM, Albers GW, Diener HC, et al. Termination of acute stroke studies involving selfotel treatment. Lancet 1997;349:32. 5. The Enlimomab Acute Stroke Trial Investigators. The enlimomab acute stroke trial: final results. Cerebrovasc Dis 1998;18: (suppl 4; abstr). 6. Wahlgren NG, MacMahon DG, De Keyser J, et al. Intravenous Nimodipine West European Stroke Trial (INWEST) of nimodipine in the treatment of acute ischemic stroke. Cerebrovasc Dis 1994;4:204-210. 7. Cross AJ, Jones JA, Baldwin MA, et al. Neuroprotective activity of clomethiazole following transient forebrain ischemia in the gerbil. Br J Pharmacol 1991;104:406-411. 8. Cross AJ, Jones JA, Snares M, et al. 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. 9. 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. 10. Sydserff SG, Cross AJ, West KJ, et al. The effect of chlormethiazole on ischaemic neuronal damage in a model of transient focal ischaemia. Br J Pharmacol 1995;114:1631-1635. 11. Snape MF, Baldwin HA, Cross AJ, et al. The effects of chlormethiazole and nimodipine on cortical infarct area after focal cerebral ischaemia in the rat. Neuroscience 1993;53:837-844. 12. Marshall JWB, Cross AJ, Murray TK, et al. Functional benefit from clomethiazole treatment after focal cerebral ischaemia in a non-human primate species. Stroke 1998; 29:330 (abstr). 13. Cross AJ, Stirling JM, Robinson TN, et al. The modulation by clomethiazole of the GABAA receptor complex in rat brain. Br J Pharmacol 1989;98:284-290. 14. Hales TB, Lambert JJ. Modulation of GABAA and glycine receptors by chlormethiazole. Eur J Pharmacol 1992;210: 239-246. 15. Moody EJ, Skolnick P. Clomethiazole: Neurochemical actions at the gamma-aminobutyric acid receptor complex. Br J Pharmacol 1989;164:153-158. 16. Strand T, Asplund K, Eriksson S, et al. A non intensive stroke unit reduces functional disability and the need for long term hospitalisation. Stroke 1985;16:29-34. 17. Wester P, Strand T, Wahlgren NG, et al. An open study of clomethiazole in patients with acute cerebral infarction. Cerebrovasc Dis 1998;8:188-190. 18. Wahlgren NG, Ranasinha KW, Rosolacci T, et al. 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. 19. Bamford J, Sandercock P, Dennis M, et al. Classification and natural history of clinically identifiable subtypes of cerebral infarction. Lancet 1991;337:1521-1526.
SAFETY RESULTS FOR CLOMETHIAZOLE IN ACUTE STROKE 20. Lindgren A, Norrving B, Rudling O, et al. Comparison of clinical and neurological findings in first-ever stroke. A population based study. Stroke 1994;25:1371-1377. 21. Lyden PD, Ashwood T, Claesson L, et al. 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;7:435441. 22. Scandinavian Stroke Study Group. Multicenter trial of hemodilution in ischemic stroke. I: Results in the total study population. Stroke 1987;18:691-699. 23. International Stroke Trial Collaboration Group. The International Stroke Trial (IST): A randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischemic stroke. Lancet 1997;349:15691581. 24. Mahoney FI, Barthel DW. Functional evaluation. The Barthel index. MD State Med 1965;14:61-65.
165 25. Carlberg C, Asplund K, Ha¨gg E. Factors influencing admission blood pressure in patients with acute stroke. Stroke 1991;22:527-530. 26. Morfis L, Schwartz RS, Poulos R, et al. Blood pressure changes in acute cerebral infarction and hemorrhage. Stroke 1997;28:1401-1405. 27. Wilson J, Stephen GW, Scott DB. A study of the cardiovascular effects of chlormethiazole. Br J Anaesth 1969;41:840-843. 28. Seow LT, Mather LE, Roberts JG. An integrated study of pharmacokinetics and pharmacodynamics of chlormethiazole in healthy young volunteers. Eur J Clin Pharmacol 1981;19:263-269. 29. Seow LT, Roberts JG, Mather LE, et al. Two-stage infusion of chlormethiazole for basal sedation. Br J Anaesth 1981;53:1203-1210. 30. Chamorro A, Vila N, Ascaso C, et al. Blood pressure and functional recovery in acute ischemic stroke. Stroke 1998;29:1850-1853.
The Clomethiazole Acute Stroke Study (CLASS) showed no difference in outcome between patients treated with clomethiazole or placebo for all patients treated, but a beneficial effect in patients classified as a total anterior circulation syndrome (TACS). These are patients with clinical symptoms of a large stroke. Safety and tolerability data are reported here with emphasis on the safety of treating stroke patients with a sedative drug. In total, 1,356 patients were eligible for safety analysis. Mortality at 90 days was equal between the treatment groups (clomethiazole, 19.5%; placebo, 19.7%). Clomethiazole was generally well-tolerated. The most common adverse event was sedation (clomethiazole, 53%; placebo, 10%). Clomethiazole also produced some respiratory adverse events (e.g., rhinitis and increased sputum). Serious adverse events associated with sedation were more commonly reported in the clomethiazole group during treatment. However, the incidence was low. There was no difference in the incidence of serious adverse events between the treatment groups for pulmonary conditions, cardiovascular conditions, or other conditions. Clomethiazole produced a small decrease in blood pressure, but this was not associated with a worse outcome. Safety and tolerability in TACS patients was similar to that for all patients treated with the exception that these patients were more sensitive to the sedative effects of the drug. Despite this, mortality was slightly lower, and functional outcome was better in clomethiazole-treated TACS patients compared with placebo. In conclusion, clomethiazole was generally well-tolerated. The sedation observed did not increase the risk for complications, such as pulmonary serious adverse events or affect the outcome in a negative way. Clomethiazole appeared to be safe to use in stroke patients in general and in patients with a large stroke. The efficacy and safety in large strokes will be studied further in a new study, which is ongoing. Key Words: Cerebral ischemia—Clinical trials—Clomethiazole—Safety—Neuroprotection.
A number of neuroprotective drugs have been tested in randomized trials in acute stroke. Several have produced clinically significant adverse events, which may have led to a choice of a suboptimal dose level in terms of the
From the Stroke Research Unit, Department of Neurology, Karolinska Hospital, Stockholm, Sweden; Servicio de Neurologia, Hospital General Universitario de Alicante, Alicante, Spain; Servicio de Neurocirugia, Hospital Gen. Univ. de Valencia, Valencia, Spain; Plains Health Centre Regina, SK, Canada; Epsom General Hospital, Epsom, United Kingdom; and Astra Arcus AB, So¨derta¨lje, Sweden. Received September 23, 1999; accepted January 6, 2000. Supported by Astra Arcus AB, So¨derta¨lje, Sweden. Address reprint requests to Nils Gunnar Wahlgren, MD, PhD, The Stroke Research Unit, Department of Neurology, Karolinska Hospital, S-171 76 Stockholm, Sweden. Copyright r 2000 by National Stroke Association 1052-3057/00/0904-0002$3.00/0 doi:10.1053/jscd.2000.7236
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neuroprotective effect.1-3 Some substances even appeared to be harmful, producing a worse outcome compared with placebo.4-6 Clomethiazole (Zendra; AstraZeneca, So¨derta¨lje, Sweden) is also a neuroprotective drug. It protects against neuronal damage in animal models of focal and global ischaemia.7-12 However, it differs mechanistically from other neuroprotectants, which have been tested, because it enhances gamma aminobutyric acid receptor subtype A (GABAA ) receptor activity.13-15 Clomethiazole, therefore, has sedative properties, although it is possible to produce powerful neuroprotection in animals at doses, which have little sedative effect.8 There is no evidence that drug-induced sedation per se will adversely affect the clinical outcome of stroke patients. However, sedation should not compromise respiratory function or preclude adequate monitoring of the patients neurological status to detect a deterioration of the stroke or a
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complication, such as cerebral edema. Furthermore, the onset of early rehabilitation should not be delayed, as this is one of the key factors for success at the stroke unit.16 Excessive or prolonged sedation should, therefore, be avoided. An open dose escalation study found a dose of 75 mg/kg clomethiazole given as an intravenous infusion over 24 hours was the maximum tolerated without producing excessive sedation. This dose produced a mean plasma concentration in man of 13 µmol/L, which corresponds well to concentrations that are neuroprotective in animal models.17 This dose was, therefore, considered suitable for further use in clinical efficacy trials in acute stroke patients and was tested in the clomethiazole acute stroke study (CLASS). This was a double-blind placebocontrolled study of the efficacy and safety of the drug in 1,360 patients with acute hemispheric stroke.18 In the main efficacy analysis, there was no statistically significant difference between clomethiazole and placebo on the primary outcome measure, which was the percentage of patients scoring 60 or more on the Barthel index (relative functional independence). Patients were classified before randomization into stroke syndromes according to Bamford et al.19 In a post hoc analysis of a subset of patients classified as a total anterior circulation syndrome (TACS, n ⫽ 545), 40.8% of clomethiazole patients reached relative functional independence compared with 29.8% in the placebo group. These patients had symptoms of higher cerebral dysfunction, motor weakness, and homonymous visual field deficit at baseline and have been shown by others to be at high risk of a large volume of brain infarction.20 We hypothesize that clomethiazole is effective in patients with clinical symptoms of a large ischemic stroke. This is currently being tested in a further study.21 We report here the safety and tolerability results from CLASS with special emphasis on the safety of treating stroke patients with a drug with sedative properties through a comparison of serious adverse event incidence and mortality rates. Results are presented primarily for all patients treated, but some features of safety in TACS patients will be highlighted.
Patients and Methods A complete description of the patients and methods together with the names of the principal investigators of the CLASS study group is given elsewhere.18 A brief summary of the patients recruited and efficacy measures is given below plus full details of safety measures. Patients 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 representatives gave informed consent. Inclusion criteria
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were patients aged 40 to 90 with a clinical diagnosis of an ischemic hemispheric cerebral infarction and with stroke onset in the last 12 hours. Patients had to be functionally independent before the stroke and conscious with a hemiparesis and a Scandinavian Stroke Scale (SSS) score of 40 points or less on the 48 point long-term items scale.22 A computed tomography (CT) scan was not required before inclusion, but had to be performed within 7 days. Patients were excluded if they had any disorder interfering with the neurological or functional assessment, a life-threatening concurrent illness, severe respiratory insufficiency, hepatic or renal disorder, or diastolic blood pressure ⬍50 or ⬎130 mm Hg. Treatment Patients received a loading infusion of clomethiazole (8% of total dose) or placebo over 15 minutes followed by a maintenance infusion. The maintenance infusion continued until the total infusion time (loading plus maintenance) was 24 hours. Flow rates were adjusted to body weight. The target dose was 75 mg/kg. The patient’s level of sedation was carefully and regularly monitored during the infusion using a 6 graded sedation scale as follows: 1, fully awake; 2, drowsy, but answers when spoken to; 3, answers slowly when spoken to; 4, reacts when spoken to, but does not answer; 5, reacts only to painful stimuli; 6, does not react to painful stimuli. If the patient became markedly sedated, (score ⱖ4), the infusion was interrupted and then resumed again at half the previous rate once the patient scored 3 or less. This stop/reduction procedure was repeated if required. If the patient was still markedly sedated within 2 hours of stopping the infusion, the study drug was not restarted. Sedation scores ⱖ3 were recorded as adverse events. Assessments All adverse events were collected during the 24-hour treatment period. Unresolved adverse events were followed up at day 7. All serious adverse events (i.e., those that resulted in death, hospitalization, permanent or significant disability or were life-threatening, or required medical or surgical intervention) were collected up to 7 days. Events believed to be related to treatment were collected for 90 days (none were reported) during the first half of the study recruitment period. Thereafter, the protocol was amended due to regulatory requirements, and all serious adverse events were collected up to day 90. All deaths were reported irrespective of relationship to treatment. The primary cause of death was classified according to a scheme based on that used in the International Stroke Trial.23 An independent data monitoring committee reviewed all serious adverse events when 200, 450, and 900 patients had been randomized and followed for 7 days.
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Assessments for body temperature, electrocardiogram (ECG) and laboratory tests (clinical chemistry and hematology) were made before (baseline) and at the end of the treatment (24 hours). Abnormal laboratory tests were followed up until normalized or otherwise explained. Thrombophlebitis was collected as a checklist symptom at baseline and after treatment. Pulse, blood pressure, sedation score, and adverse events were assessed before treatment, at 15, 30, and 60 minutes during the first hour, then every 3 hours for half of the treatment time and finally every 6 hours until the end of treatment. Sedation score were also recorded at 3, 6, 12, and 24 hours postinfusion. All ECGs were evaluated centrally by an external consultant. All patients were followed to 90 days. The primary efficacy variable was relative functional independence defined as the proportion of patients scoring ⱖ60 on the Barthel Index24 at 90 days. Statistical Methods Mortality was appropriately summarized as rates and compared between treatment groups. Survival distributions were estimated using the Kaplan-Meier method and assessed for a difference between treatment groups with the log-rank test. Incidences of adverse events were compared between treatment groups using the chi-square/ Fisher’s exact test, as appropriate. Analysis of variance models were used in the comparison of cardiovascular assessments. Spearman’s rank correlation coefficient was used for assessing the relationship between blood pressure fall and functional outcome, as measured by the Barthel index. All deaths were treated as a category worse than a Barthel score of 0 in this analysis. All reported P values are nominal and not corrected for multiplicity.
Results The study randomized 1,360 patients. All patients who received treatment (n ⫽ 1,356) were eligible for safety analysis, (clomethiazole, n ⫽ 679; placebo, n ⫽ 677). One patient randomized to clomethiazole and 3 randomized to placebo never received any study drug. The TACS subgroup constituted 40% of the patients included in the study (clomethiazole, n ⫽ 287; placebo, n ⫽ 258). Demographic and baseline characteristics have been presented elsewhere.18 They were well-balanced between the treatment groups. Mortality The overall mortality was 19.5% in the clomethiazole group and 19.7% in the placebo group (odd-ratio [OR] ⫽ 0.99; 95% confidence interval [CI], 0.76 to 1.29, P ⫽ .924). There was no difference between the KaplanMeier estimates of the survival distributions (P ⫽ .951, log-rank test).
The primary cause of death for all patients treated is summarized in Table 1. The most common primary causes of death were damage due to the initial stroke followed by bronchopneumonia. There were no significant differences between the treatment groups for any cause of death for all patients treated. Adverse Events General. Treatment emergent adverse events (i.e., those not seen at baseline or with an increased intensity during treatment) were reported by 543 (80%) of the patients in the clomethiazole group and 364 (54%) in the placebo group. Adverse events were generally few (1 to 2) in most patients. They caused withdrawal from treatment in 106 (15.6%) clomethiazole patients compared with 29 (4.2%) placebo patients. Somnolence (this includes the term, sedation) and rhinitis were the most common adverse events occurring at a higher incidence in the clomethiazole group (Table 2). Other adverse events with a higher incidence in the clomethiazole group, in order of decreasing incidence were coughing, yawning, increased sputum, hiccups, injection site reaction, conjunctivitis, lacrimation abnormal, and thrombophlebitis. Vomiting was more common in patients treated with placebo. Thrombophlebitis recorded on the checklist was present in 213 (31%) patients in the clomethiazole group and 35 (5%) patients in the placebo group. The intensity of the reaction was mild in most cases, and most were resolved within the first 7 days. Psychotomimetic adverse events were rare. For example, hallucinations occurred in 3 patients (0.4%) in each treatment group. Sedation. Somnolence was reported as an adverse event in about half (53%) of the clomethiazole-treated patients, compared with 10% of patients in the placebo group (Table 2). This was the most common adverse event leading to withdrawal from treatment, which occurred in 90 patients (13%) treated with clomethiazole compared with 21 patients (3%) treated with placebo.
Table 1. Primary cause of death in all patients
Primary cause of death Damage initial stroke Bronchopneumonia Nonvascular disease Ischemic or unknown recurrent stroke Coronary heart disease Recurrent hemorrhage stroke Pulmonary embolism Other vascular disease Unknown Total
Clomethiazole (n ⫽ 679)
Placebo (n ⫽ 677)
53 (8%) 27 (4%) 11 (2%)
50 (7%) 19 (3%) 14 (2%)
11 (2%) 7 (1%) 4 (1%) 7 (1%) 4 (1%) 8 (1%) 132 (19%)
15 (2%) 10 (1%) 2 (⬍1%) 4 (1%) 9 (1%) 10 (1%) 133 (19%)
SAFETY RESULTS FOR CLOMETHIAZOLE IN ACUTE STROKE
Table 2. Treatment emergent adverse events in all patients during treatment
Preferred term
Clomethiazole (%) (n ⫽ 679)
Placebo (%) (n ⫽ 677)
Somnolence (including sedation) Rhinitis Fever Headache Hypertension Coughing Yawning Sputum increased Agitation Hiccup Tachycardia Progressive stroke Urinary incontinence Nausea Vomiting Dyspnea Injection site reaction Pain Hypotension Conjunctivitis Pruritus Lacrimation abnormal Fibrillation atrial Leukocytosis Thrombophlebitis* Paraesthesia
357 (52.6) 128 (18.9) 115 (16.9) 81 (11.9) 52 (7.7) 46 (6.8) 44 (6.5) 35 (5.2) 35 (5.2) 29 (4.3) 28 (4.1) 26 (3.8) 24 (3.5) 23 (3.4) 22 (3.2) 22 (3.2) 22 (3.2) 19 (2.8) 19 (2.8) 16 (2.4) 15 (2.2) 14 (2.1) 13 (1.9) 12 (1.8) 12 (1.8) 11 (1.6)
68 (10.0) 21 (3.1) 91 (13.4) 67 (9.9) 44 (6.5) 21 (3.1) 14 (2.1) 14 (2.1) 26 (3.8) 10 (1.5) 20 (3.0) 19 (2.8) 14 (2.1) 24 (3.5) 49 (7.2) 23 (3.4) 7 (1.0) 20 (3.0) 12 (1.8) 3 (0.4) 6 (0.9) 4 (0.6) 9 (1.3) 8 (1.2) 1 (0.1) 6 (0.9)
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reduction) was 30% in all patients. The incidence of excessive sedation increased over the 24-hour treatment period. At 24 hours postinfusion, most clomethiazoletreated patients were no longer sedated. The percentage scoring 3 or more was clomethiazole, 11% and placebo, 3%. Serious adverse events. During treatment, cerebral conditions associated with sedation, such as somnolence, coma, and stupor were more frequently reported in the clomethiazole group, although the incidence was low (Table 4). Cerebral edema was also more often reported as a serious adverse event during treatment with clomethiazole. The incidence of fatal events due to this condition up to day 7 was similar in both treatment groups, with 12 deaths in patients treated with clomethiazole and 11 deaths in placebo-treated patients. There was no difference in the incidence of serious adverse events between the treatment groups for pulmonary conditions, cardiovascular conditions, or other conditions during the 24-hour treatment period or the follow-up period up to 90 days. Cardiovascular There was an increase in pulse during treatment with clomethiazole compared with placebo. The mean difference between the treatment groups for the change from baseline to a maximum value at any time during treatment was 4 bpm (standard error [SE], 0.8; P ⬍ .001). Table 4. Serious adverse events in all patients (cerebral conditions)
NOTE: Events of any severity reported by more than 10 patients on clomethiazole are shown. *Also recorded on a checklist.
The sedative effects of clomethiazole were also measured on the sedation scale. Approximately 50% of all patients scored 3 or more, as their maximum during the maintenance infusion, compared with 10% in the placebo group (Table 3). The percentage of clomethiazole-treated patients reaching a level of excessive sedation as defined by the protocol (score ⱖ4) (i.e., sedation requiring a dose Table 3. Maximum sedation scores during the maintenance infusion in all patients
Sedation score
Clomethiazole (%) (n ⫽ 679)
Placebo (%) (n ⫽ 677)
1, fully awake 2, drowsy but answers 3, answers slowly 4, does not answer* 5, reacts only to pain 6, does not react to pain
17 33 19 23 7 ⬍1
54 37 5 3 2 ⬍1
*Patients scoring ⱖ4 were required to have a dose reduction according to the protocol.
Clomethiazole (%) (n ⫽ 679)
Progressive stroke Somnolence Coma Stupor Cerebral edema Cerebral incarceration Cerebral hemorrhage Intracranial hemorrhage Cerebrovascular disorder Convulsions grand mal Hydrocephalus Intracranial hypertension Total *Start of infusion.
Placebo (%) (n ⫽ 677)
0*-24 hours
Day 2-7
0*-24 hours
Day 2-7
22 (3.2) 7 (1) 5 (0.7) 2 (0.3) 8 (1.2)
12 (1.8) 0 (0) 1 (0.1) 1 (0.1) 11 (1.6)
2 (0.3)
2 (0.3)
1 (0.1)
1 (0.1)
4 (0.6)
3 (0.4)
2 (0.3)
0 (0)
0 (0)
1 (0.1)
1 (0.1)
0 (0)
2 (0.3)
4 (0.6)
2 (0.3)
9 (1.3)
0 (0) 0 (0)
0 (0) 0 (0)
0 (0) 0 (0)
1 (0.1) 1 (0.1)
1 (0.1) 53 (7.8)
0 (0) 35 (5.2)
21 (3.1) 14 (2) 0 (0) 0 (0) 3 (0.4) 1 (0.1) 0 (0) 0 (0) 2 (0.3) 12 (1.8)
0 (0) 0 (0) 32 (4.7) 39 (5.7)
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204 (30%); placebo, 133 (20%). Despite this, outcome did not appear worse on clomethiazole in this cohort. There were 119 of 204 clomethiazole patients (58.3%) and 70 of 133 placebo patients (52.6%) who scored 60 or more on Barthel index at 90 days. Laboratory Tests, ECG, and Body Temperature For laboratory tests, including coagulation tests, changes in mean values between baseline and after treatment and the incidence of outliers showed no difference between the treatment groups. Changes in ECG times and the incidence of new ECG abnormalities after treatment were also similar in the 2 treatment groups (data not shown). The mean values of body temperature before and after treatment were similar between the treatment groups, although fever was more often reported as an adverse event in the clomethiazole group.
Figure 1. Blood pressure over time in all patients. Clomethiazole, n ⫽ 679; placebo, n ⫽ 677.
Safety in TACS Compared With non-TACS Patients Mortality. Mortality in TACS patients was 28.6% in the clomethiazole group and 32.2% in the placebo group (OR, 0.84; 95% CI, 0.59 to 1.22; P ⫽ .361). The difference between the groups was not significant. Similarly, there was no statistically significant difference in Kaplan-Meier estimates of the survival distribution (P ⫽ .335, log-rank test). For non-TACS patients, the mortality in the clomethiazole group was 12.8% and in the placebo group, 11.9%. (OR, 1.08; 95% CI, 0.71 to 1.64, P ⫽ .72). There was no statistically significant difference in Kaplan-Meier estimates of the survival distribution (P ⫽ .673, log-rank test). The primary cause of death for TACS and non-TACS patients is summarized in Table 5. Damage due to the initial stroke and bronchopneumonia were the most common causes in both treatment groups. There were no significant differences between the treatment groups for any cause of death for either TACS or non-TACS patients. Sedation. In the TACS group, sedation was recorded as an adverse event for 68% in the clomethiazole group and 16% in the placebo group. For the non-TACS patients, the
There was a mild reduction in blood pressure during the infusion (Fig 1), which was slightly greater in the clomethiazole group. The mean difference between the treatment groups for the change from baseline to the minimum value at any time during treatment for systolic blood pressure was 6 mmHg (SE, 1.1; P ⬍ .001). The corresponding figure for diastolic blood pressure was 2 mmHg (SE, 0.7; P ⬍ .01). An analysis of whether a decrease in systolic or diastolic blood pressure was associated with a worse functional recovery did not show any such relationship. Spearman’s rank correlation between the maximum decrease in systolic blood pressure and the Barthel index score at 90 days was 0.07 (not significant [NS]) in the clomethiazole group and ⫺0.01 (NS) in the placebo group. There were more patients experiencing a fairly large decrease in systolic blood pressure in the clomethiazole group. The number experiencing a decrease of 37 mm Hg or more (upper quartile of distribution) compared with baseline at anytime during treatment were clomethiazole,
Table 5. Primary cause of death in TACS and non-TACS TACS
Non-TACS
Primary cause of death
Clomethiazole (%) (n ⫽ 287)
Placebo (%) (n ⫽ 258)
Clomethiazole (%) (n ⫽ 392)
Placebo (%) (n ⫽ 419)
Damage initial stroke Bronchopneumonia Nonvascular disease Ischemic or unknown recurrent stroke Coronary heart disease Recurrent hemorrhage stroke Pulmonary embolism Other vascular disease Unknown Total
34 (12) 18 (6) 9 (3) 5 (2) 5 (2) 3 (1) 2 (⬍1) 2 (⬍1) 4 (1) 82 (29)
37 (14) 11 (4) 8 (3) 8 (3) 7 (3) 1 (⬍1) 1 (⬍1) 5 (2) 5 (2) 83 (32)
19 (5) 9 (2) 2 (⬍1) 6 (1) 2 (⬍1) 1 (⬍1) 5 (1) 2 (⬍1) 4 (1) 50 (13)
13 (3) 8 (2) 6 (1) 7 (2) 3 (⬍1) 1 (⬍1) 3 (⬍1) 4 (1) 5 (1) 50 (12)
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corresponding figures are clomethiazole, 41% and placebo, 6%. The recordings of the maximum sedation scores during the maintenance infusion for the 2 groups is presented in Table 6. The percentage of patients on clomethiazole reaching a level of excessive sedation (score ⱖ4) was 46% in TACS patients and 19% in the non-TACS patients. The number of patients in the TACS group who withdrew early from treatment due to sedation were 53 (19%) in the clomethiazole group and 10 (3%) in the placebo group compared with clomethiazole, 37 (9%) and placebo, 11 (3%) in the non-TACS group. At 24 hours postinfusion, most clomethiazole-treated patients were no longer sedated. The percentage scoring 3 or more among TACS patients was clomethiazole, 17%; placebo, 12%. The corresponding figures for non-TACS patients were clomethiazole, 7% and placebo, 3%. Adverse events other than sedation showed similar incidences in TACS and non-TACS groups, and the cardiovascular measurements did not differ between these groups.
Discussion Clomethiazole was, in general, well-tolerated in this study. As expected, sedation was the most commonly reported adverse event, but this could be managed using a simple scheme that monitored the level of sedation. The majority of patients did not reach a level of excessive sedation at any time, and most completed the 24-hour treatment period. Although there were some dose reductions due to sedation, this was driven by the protocol, which required dose reductions in patients with excessive sedation and treatment withdrawal if excessive sedation lasted more than 2 hours. Almost all patients had little or no sedation 24 hours after the end of treatment. TACS patients were more sensitive to the sedative effects of clomethiazole. Some TACS patients, however, developed reduced consciousness as a symptom of the stroke during the 24-hour treatment period, as reflected by the higher incidence of sedation in the placebo TACS compared with non-TACS patients. There may thus be an interaction between the sedative properties of the drug and the
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development of reduced consciousness as part of the disease process in this group of patients. During treatment, there were more serious adverse events reported on clomethiazole compared with placebo. These were mostly due to cerebral conditions, were related to the sedative properties of the drug (e.g., coma, stupor), and were of low incidence. A slightly larger number of cases of cerebral edema were reported on clomethiazole during the treatment period. The reports were often based on clinical signs, such as reduced consciousness, which may be explained by the sedative effects of clomethiazole. The latter may also lead to increased monitoring by CT scan in clomethiazole-treated patients compared with those treated with placebo, resulting in the detection of signs of edema on the scan more often in this group. There was no difference in mortality between the treatment groups at 1 week for either the cases of cerebral edema or the other cerebral conditions. Clomethiazole produced respiratory adverse events such as rhinitis and increased sputum. However, there was no overrepresentation in the number of serious adverse events of pulmonary conditions at anytime during the study period. The mean blood pressure in both treatment groups decreased slightly during the 24-hour treatment period. A decrease in blood pressure from the value at the time of presentation to hospital has been reported by others,25,26 although the mechanism for the elevation of blood pressure at admission is not clear. The decrease in systolic and diastolic blood pressure was slightly larger for patients treated with clomethiazole. In addition, some patients in both treatment groups experienced a substantial decrease of systolic blood pressure. The percentage was somewhat larger in the clomethiazole group. The decreased blood pressure could be due to the sedative effects of the drug. Earlier investigations in volunteers have detected increased heart rate, but no consistent effect on blood pressure during clomethiazole treatment.27-29 Wahlgren et al6 have shown that a decrease in blood pressure in the acute phase in patients treated with nimodipine, when
Table 6. Maximum sedation scores during the maintenance infusion in TACS and non-TACS patients Clomethiazole
Sedation score 1, fully awake 2, drowsy but answers 3, answers slowly 4, does not answer* 5, reacts only to pain 6, does not react to pain Missing
Placebo
TACS (%) (n ⫽ 287)
Non-TACS (%) (n ⫽ 392)
TACS (%) (n ⫽ 259)
Non-TACS (%) (n ⫽ 419)
11 24 19 34 11 ⬍1
22 40 19 14 5 0 1
40 44 8 4 3 ⬍1
62 32 3 2 1 0
*Patients scoring ⱖ4 were required to have a dose reduction according to the protocol.
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given as an intravenous (IV) infusion, was associated with a poorer outcome compared with patients treated with placebo. Recently, Chamorro et al30 found that complete recovery in ischemic stroke is facilitated by moderate blood pressure reduction when brain edema develops. We could find no evidence that the blood pressure changes in this study were associated with a worse outcome, presumably because the mean blood pressure changes were much smaller than in the nimodipine study. It is also likely that the effect on outcome may be different depending on whether a decrease in blood pressure is caused by reduction of peripheral arterial resistance, sedation, or relief of sympathetic activation on arrival at the hospital. In all patients, functional outcome and the incidence and causes of mortality were very similar in patients treated with clomethiazole compared with placebo, even though clomethiazole produced a moderate degree of sedation and some respiratory adverse events. There are, therefore, no findings that indicate that the sedation observed increased the risk for complications or affected outcome in a negative way. We conclude that a dose of 75 mg/kg clomethiazole using a dose reduction schedule in patients who become excessively sedated is a safe treatment. This contrasts with the safety and tolerability profile of some other neuroprotective drugs with different mechanisms of action to clomethiazole. For example, the competitive N-methyl-D-aspartate (NMDA) antagonist, selfotel, produced marked psychotomimetic effects and increased mortality due to cerebral causes,1,4 while IV administration of the calcium channel blocker, nimodipine, produced a worse outcome associated with a pronounced decrease of the blood pressure.6 In TACS patients, the incidence of excessive sedation was higher compared with non-TACS patients, and yet the percentage of TACS patients reaching relative functional independence was 40.8% on clomethiazole compared with 29.8% on placebo,18 while mortality was slightly lower compared with placebo. These findings need to be confirmed, as they are based on a posthoc subgroup analysis, but they indicate that the sedation observed did not worsen outcome, and that clomethiazole is also safe to administer to TACS patients. A new study selecting patients with a symptom profile similar to TACS patients to test the hypothesis that clomethiazole is efficacious is, therefore, justified and is ongoing.21 In the new study, the dosage regimen has been modified based on pharmacokinetic modelling to reduce the number of dose reductions and withdrawals due to sedation, while maintaining drug plasma concentrations that are effective in animal models.
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