Diazepam to improve acute stroke outcome: results of the early GABA-Ergic activation study in stroke trial. a randomized double-blind placebo-controlled trial. The Clomethiazole Acute Stroke Study in tissue-type plasminogen activator-treated stroke (CLASS-T): final results. Clomethiazole acute stroke study (CLASS): results of a randomized, controlled trial of clomethiazole versus placebo in 1360 acute stroke patients. Clomethiazole Acute Stroke Study in ischemic stroke (CLASS-I): final results.
We tested whether diazepam, a GABA-ergic drug that also inhibits brain nitric monoxide formation, improves acute stroke prognosis.
                880 patients, randomized within 12 h of acute stroke, received diazepam 10 mg or placebo by rectiole, as soon as possible, followed by 10-mg tablets twice daily for 3 days. Primary outcome was independence (Rankin score <3) at 3 months; secondary outcome was complete recovery (Barthel index >or=95 or Rankin score <or=1).
                Intention-to-treat analyses on all 849 patients with full follow-up (50.4% on diazepam): odds ratio (OR) 1.14, 95% CI 0.87-1.49 for primary endpoint, and an OR of 1.26 (0.90-1.76) for complete recovery, both favoring diazepam. Adjusted analyses for all stroke patients (843): OR 1.20 (0.87-1.65), and 1.25 (0.89-1.74), respectively, and for all infarct patients (748): OR 1.31 (0.93-1.85), and 1.46 (1.02-2.09; p=0.037), respectively. Analyses restricted to cardioembolic infarct patients (200) showed treatment benefit for the primary outcome: OR 2.26, 95% CI 1.07-4.76, p=0.032, and complete recovery: OR 2.65, 95% CI 1.06-6.59, p=0.037. About one third of ischemic stroke patients had 'any adverse event', without any difference between treatment groups. In 95 intracerebral hemorrhage patients, frequency of pneumonia and death were higher in the diazepam group than in the placebo group: 35 and 10%, 22 and 12%, respectively.
                Although point estimates favored diazepam treatment in various analyses, our data did not confirm our primary hypothesis. Diazepam treatment seems beneficial in cardioembolic infarct patients, is safe in acute ischemic stroke, but may better be avoided in intracerebral hemorrhage.
                Copyright (c) 2006 S. Karger AG, Basel. To assess the safety of tissue-type plasminogen activator (t-PA) plus clomethiazole in patients with acute ischemic stroke and determine the feasibility of combination stroke therapy.
                Clomethiazole is a neuroprotectant that appeared to improve outcome in patients with clinical deficits of a major stroke (total anterior circulation syndrome [TACS]) in a previous study, the Clomethiazole Acute Stroke Study (CLASS). Combining a neuroprotectant such as clomethiazole with thrombolysis may augment the beneficial effects of the two agents. CLASS-t-PA (CLASS-T) was a pilot study to explore the safety of the combination and the feasibility of performing combination treatment in the setting of acute ischemic stroke.
                In a randomized, double-blind design (stratified for age, severity at admission, and time since onset of stroke), all patients received 0.9 mg/kg t-PA beginning within 3 hours of stroke onset and then either 68 mg/kg clomethiazole (n = 97) IV over 24 hours or placebo (n = 93) beginning within 12 hours of stroke onset. Patients were followed for 90 days. The main measures of safety were mortality and serious adverse events, and the main measure of functional outcome was the Barthel Index.
                The number of serious adverse event reports was 47 in the clomethiazole group and 48 in the placebo group. Death during the 90 days after treatment occurred in 15 clomethiazole and nine placebo patients (p = 0.26). Sedation was reported as an adverse event during therapy in 42% of clomethiazole patients vs 13% of placebo patients. The proportion of patients with TACS was 53% in the clomethiazole group and 41% in the placebo group. In the TACS subgroup, 52.9% of the clomethiazole patients scored a Barthel Index greater than 60 vs 44.7% of placebo patients (odds ratio 1.39; 95% CI 0.60 to 3.23).
                In this pilot study, there were no safety concerns related to the combination of t-PA and clomethiazole. The combination paradigm proved feasible, although many patients received clomethiazole several hours after thrombolysis; future studies must require prompt administration of the neuroprotectant either before or during administration of the thrombolytic. Patients with major strokes (TACS) may have the potential to benefit from the combination of t-PA and clomethiazole. The efficacy and safety of the neuroprotective drug clomethiazole was tested in a double blind placebo controlled trial in patients with a clinical diagnosis of acute hemispheric stroke.
                Patients with symptom onset of </=12 hours before the start of treatment were included in the study. Clomethiazole (75 mg/kg) or placebo was given as an intravenous infusion over a 24-hour period. Patients were followed up for 90 days. The primary efficacy variable was the proportion of patients reaching relative functional independence (>/=60 points on the Barthel Index) at 90 days.
                A total of 1360 patients were included. In the main efficacy analysis (n=1353), 56.1% of patients taking clomethiazole and 54.8% of placebo patients reached relative functional independence. The difference was not statistically significant. An analysis of the effect of time since onset of symptoms showed no difference between the treatment groups. Clomethiazole was generally well tolerated and appeared safe in the population studied. Sedation was the most common adverse event, leading to treatment withdrawal that occurred in 15.6% of clomethiazole-treated patients compared with 4.2% of placebo-treated patients. In a subgroup classified before randomization as having total anterior circulation syndrome (TACS) (n=545, or 40% of all randomized patients), the percentage of those reaching relative functional independence was 40.8% on clomethiazole and 29.8% on placebo, a difference of approximately 11 percentage units. TACS patients have clinical symptoms suggesting a "large" stroke.
                Clomethiazole had no adverse or beneficial effect on long-term outcome for all patients but produced sedation. The hypothesis that clomethiazole is effective in patients with large strokes will be tested in a further study. A previous trial (the Clomethiazole Acute Stroke Study) generated the hypothesis that clomethiazole is effective in patients with a major ischemic stroke (total anterior circulation syndrome), and this was tested in the present study.
                A total of 1198 patients with major ischemic stroke and a combination of limb weakness, higher cortical dysfunction, and visual field deficits were randomly assigned to clomethiazole (68 mg/kg IV over 24 hours) or placebo. The study drug was initiated within 12 hours of symptom onset. Functional outcome and neurological recovery were assessed at days 7, 30, and 90, with the proportion of patients with a Barthel Index > or =60 at last follow-up as the primary outcome measure.
                The patients were randomly assigned equally, and the two treatment groups were well matched for baseline characteristics, including stroke severity (mean National Institutes of Health Stroke Scale score 16.9+/-5.2). Ninety-six percent were classified as total anterior circulation syndrome. The proportion of patients reaching a Barthel Index score of > or =60 was 42% in the clomethiazole-treated group and 46% in the placebo-treated group (odds ratio, 0.81; 95% CI, 0.62 to 1.05; P=0.11). There was no evidence of efficacy on any secondary outcome variables (modified Rankin Score, National Institutes of Health Stroke Scale, Scandinavian Stroke Scale, and 30-day CT infarct volumes) compared with placebo. Subgroup analysis showed a similar lack of treatment effect in patients treated early (<6 hours) and in those treated later (6 to 12 hours). Somnolence was an expected pharmacological effect of clomethiazole, and this occurred during treatment as an adverse event in half of the patients randomly assigned to study drug.
                The target population was selected, and sufficient drug was given to produce the expected pharmacological effect in the brain. Clomethiazole does not improve outcome in patients with major ischemic stroke.
This review does not provide the evidence to support the use of GABA receptor agonists (chlormethiazole or diazepam) for the treatment of patients with acute ischemic or hemorrhagic stroke. Chlormethiazole appeared to be beneficial in improving functional independence in patients with TACS according to the subgroup analysis, but this result must be interpreted with great caution. More well-designed RCTs with large samples of TACS would be required for further confirmation. However, somnolence and rhinitis are frequent adverse events related to chlormethiazole.