Abstract
Background
Experimental studies have shown that ischaemic insults cause excess release of excitatory amino acid (EAA) neurotransmitters, particularly glutamate. Glutamate re‐uptake is impaired under ischaemic conditions. In preclinical models of stroke, antagonists of excitatory amino acids or of glutamate release protect against ischaemic injury, even when administered after the ischaemic insult. Lubeluzole is a benzothiazole derivative that has shown neuroprotective properties in different experimental models inhibiting glutamate release, nitric oxide (NO) synthesis and blocking voltage‐gated Na+ and Ca2+ ion channels.
Objectives
The objective of this review is to assess the effectiveness and safety of lubeluzole given in the acute phase of acute ischaemic stroke.
Search methods
We searched the Cochrane Stroke Group trials register, the Cochrane Controlled Trials Register (CENTRAL/CCTR), MEDLINE, EMBASE, Pascal BioMed (1996 to 2001) and Current Contents CCSearch (1996 to 2001). We contacted Janssen Research Foundation to identify further studies.
Selection criteria
All randomised unconfounded trials comparing intravenous lubeluzole with placebo or open control in patients with a clinical syndrome definitely considered as an acute stroke in whom CT scanning showed an infarct or was normal.
Data collection and analysis
Two reviewers independently selected trials for inclusion, assessed trial quality and extracted the data.
Main results
Five trials involving a total of 3510 patients were included. The quality of the trials did not vary considerably. Sensitivity/subgroups analysis was not completely performed because of lack of data. Lubeluzole given at the doses of 5, 10 and 20 mg/day for five days was tested against a placebo‐control group. There was no evidence that lubeluzole given at any dose either reduced the odds of death from all causes (odds ratio (OR) 0.93, 95% confidence interval (CI) 0.79 to 1.09) or reduced the odds of being dead or dependent at the end of follow up (OR 1.04, 95% CI 0.91 to 1.19). On the other hand, given at any dose, lubeluzole was associated with a significant excess of heart‐conduction disorders (Q‐T prolonged > 450 msec) at the end of follow up (OR 1.43, 95% CI 1.09 to 1.87).
Authors' conclusions
Lubeluzole, given in the acute phase of ischaemic stroke, is not associated with a significant reduction of death or dependency at the end of scheduled follow‐up period but seems to be associated with a significant increase of heart‐conduction disorders (Q‐T prolonged > 450 msec).
Keywords: Humans, Acute Disease, Brain Ischemia, Brain Ischemia/drug therapy, Neuroprotective Agents, Neuroprotective Agents/therapeutic use, Piperidines, Piperidines/therapeutic use, Thiazoles, Thiazoles/therapeutic use
Plain language summary
Lubeluzole for acute ischaemic stroke
Lubeluzole is not effective in patients with acute ischaemic stroke. After a stroke, where a part of the brain suffers from reduced blood supply, an excess of chemicals known as excitatory amino acid neurotransmitters is produced. This excess can cause some brain cells to be damaged or to die (permanent cell damage is called cerebral infarction). Drugs which block the effects of these amino acids can protect against the cerebral infarct. The review focuses on the effects of lubeluzole, an inhibitor of excitatory amino acids. The review of trials did not find any benefit of lubeluzole in humans either to prevent death after acute ischaemic stroke or to reduce disability from it. Moreover, lubeluzole may cause heart‐conduction disorders.
Background
Despite the fact that ischaemic stroke is still the third leading cause of death in developed countries, and the first leading cause of long term disability in survivors, only aspirin and thrombolysis (in highly selected patients within three hours of stroke onset) are treatments of proven efficacy for the acute phase of the disease (Gubitz 2001; Wardlaw 2001). Other strategies are currently being considered, both from the point of view of circulatory impairment (e.g. antithrombotics, thrombolytics) and from the point of view of neuroprotection of the ischaemic brain. Experimental studies have shown that ischaemic insults cause excess release of excitatory amino acid (EAA) neurotransmitters, particularly glutamate. Glutamate acts at post‐synaptic receptors to promote calcium and sodium permeability and to activate intracellular second messenger systems. Glutamate re‐uptake is impaired under ischaemic conditions. In preclinical models of stroke, antagonists of excitatory amino acids or of glutamate release protect against ischaemic injury, even when administered after the ischaemic insult. Administration of EAA antagonist drugs may be neuroprotective after acute stroke in man, and this should be reflected in improved clinical outcome (Lees 1997).
EAA antagonist drugs fall into several categories, and have ancillary properties which may influence their efficacy and safety as neuroprotective agents. Most compounds act through mechanisms which remain under investigation, and clinical experience is limited. Lubeluzole is a benzothiazole derivative that has shown neuroprotective properties in different experimental models inhibiting glutamate release, nitric oxide (NO) synthesis and blocking voltage‐gated Na+ and Ca2+ ion channels (Haseldonckx 1997; Scheller 1997).
Lubeluzole, like all neuroprotective drugs, is likely to be administered after some degree of permanent ischaemic damage to neurons has already occurred. The agent is intended to salvage only cells which are ischaemic. Thus if fewer neurones are permanently damaged, the degree of long‐term neurological impairment and disability should be reduced; such a reduction in disability may also be associated with a corresponding reduction in the risk of death. The greater the delay between the onset of stroke symptoms and the start of treatment, the less scope there is for benefit (De Keyser 1997).
The aim of this review is therefore to assess the available evidence from randomised controlled trials of lubeluzole in the treatment of acute ischaemic stroke.
Objectives
The objective of this review is to assess the effectiveness and safety of lubeluzole given in the acute phase of acute ischaemic stroke. In other words, to test the hypotheses: (1) among patients with acute ischaemic stroke, whether intravenous lubeluzole reduces the proportion of patients dead or dependent at final follow up; (2) among patients with acute ischaemic stroke, whether intravenous lubeluzole is associated with serious adverse events (ECG abnormalities, myocardial infarction, any other cardiovascular event).
Methods
Criteria for considering studies for this review
Types of studies
We sought to identify all truly randomised unconfounded trials, in patients with acute ischaemic stroke comparing intravenous lubeluzole with placebo or open control.
Types of participants
We sought trials in which all patients with a clinical syndrome definitely considered as an acute stroke in whom CT scanning showed an infarct, or was normal, were included. Patients at any age, sex and severity could be included.
Types of interventions
The only agent considered for this review was lubeluzole, given intravenously at any dose, compared with placebo or open control, without including data from dose ranging studies. These latter studies generally only include a small number of patients in each dose tier. It is well recognised that imbalance in baseline characteristics may make interpretation of the effect of treatment on clinical outcome very difficult to interpret in such studies. On the other hand, such differences generally do not interfere with any pharmacodynamic assessment made during such studies.
Types of outcome measures
The main outcomes of interest were: (1) death from any cause at the end of the scheduled treatment period; (2) death from any cause at the end of the scheduled trial follow up; (3) death from specific causes (e.g. death from stroke, and death from cardiac events) at the end of the scheduled trial follow up; (4) the proportion of survivors who were dependent from any cause at the end of the scheduled trial follow up (that is, the patient is dependent on help from other people in activities of daily living). If the results were expressed as scale scores, these were dichotomised into dependent/independent; (5) the number of patients who were dead or dependent at the end of the scheduled trial follow up; (6) the frequency of serious adverse events divided into: ECG abnormality (heart‐conduction disorders (Q‐T prolonged > 450 msec), heart‐rhythm disorders (atrial fibrillation, ventricular tachycardia, ventricular fibrillation, torsade de pointes)), myocardial infarction and any other cardiovascular event.
Search methods for identification of studies
See: 'Specialized register' section in Cochrane Stroke Group
Relevant trials were identified in the Cochrane Stroke Group Trials Register, which was last searched by the Review Group Co‐ordinator in December 2000. Additional searches of electronic databases were made as follows:
Cochrane Controlled Trials Register (The Cochrane Library Issue 3, 2001): text word: lubeluzole
MEDLINE (1966 to 2001) SilverPlatter: text word: lubeluzole
EMBASE (1980 to 2001) BIDS: Emtree Heading. Lubeluzole (added to the vocabulary in 1997): text word: lubeluzole
An additional search of the Data Bank of Genoa University Internet System was undertaken (www.sba.unige.it/cgi‐erl/webspirs.cgi). This system allowed us to consult the following medical databases:
PASCAL BIOMED (1996 to 2001) in English: text word: lubeluzole
CURRENT CONTENTS CCSEARCH ® 7 Editions (1996 to 2001): text word: lubeluzole
We contacted the pharmaceutical company that manufactured Lubeluzole and sponsored the phase III clinical trials (Janssen Research Foundation), but received no additional or unpublished data.
We also checked all references listed in the papers found.
Data collection and analysis
The reviewers independently selected the trials for inclusion in the review. Disagreements were resolved by discussion. Both reviewers evaluated the trials' quality and excluded those of poor quality. We assessed the methodology of included trials focusing on details of the randomisation method, blinding, numbers of patients screened for inclusion in relation to numbers enrolled, whether intention‐to‐treat (ITT) analyses were possible from the published data and the number of patients lost to follow up. Data were extracted independently by the reviewers and cross‐checked. Any discrepancy was resolved by discussion and the decision documented. Data were sought on the number of patients with each outcome measure (where available) by allocated treatment group. To allow an ITT analysis, the data were sought regardless of compliance, whether or not the patient was subsequently deemed ineligible, or otherwise excluded from follow up. To assess efficacy under optimal but unbiased conditions we aimed to perform an on‐treatment (per‐protocol) analysis. Comparison between drug and control group was based on the Peto fixed‐effect model for the main endpoint. We aimed, if the data permitted, to do sub‐group exploratory analyses to assess the effects of the drug on cortical versus non‐cortical stroke and on separate time windows. In the light of the reported effects on cardiac conduction (Q‐T prolonged > 450 msec) we performed a post‐hoc analysis on death from cardiac events. The incidence of ECG abnormalities and any vascular effects and other adverse events was also explored.
Furthermore, we had planned, if appropriate, to perform the following sensitivity/subgroup analyses: (1) all patients, and only patients with CT before randomisation; (2) all strokes, whether or not definitely ischaemic; (3) only patients with CT‐confirmed ischaemic stroke (CT could be performed after randomisation); (4) all trials and only blinded trials; (5) effects of the length of treatment; (6) effects of different doses either on outcome or on frequency of serious adverse events; (7) patients randomised within three (if possible) or six hours compared with all patients randomised in all trials; (8) effects of sex; (9) effects of different degree of disability.
Results
Description of studies
Five trials involving a total of 3510 patients were included. Summary details of the trials are given in Characteristics of included studies. Two trials were excluded for reasons given in Characteristics of excluded studies. One trial (LUB‐USA‐6 1998) involving combination therapy with lubeluzole and t‐PA is currently awaiting assessment before inclusion in this review. The age of patients in the included studies ranged from 19 to 96 years (mean 70.7 years): there was a slight preponderance of males (1820 ‐ 52%). Characteristics of included studies gives, for each trial, details of patients excluded after randomisation.
All trials compared a bolus dose of 7.5 mg of lubeluzole over one hour followed by a maintenance dose of 10 mg/day for five days with a placebo group. In two trials an additional arm was tested: in the former (LUB‐INT‐7 1996), a dose of 3.75 mg of lubeluzole over one hour followed by 5 mg/day for five days was compared with a placebo group; in the latter (LUB‐INT‐4 1995), a dose of 15 mg of lubeluzole over one hour followed by 20 mg/day for five days was compared with a placebo group too.
In all trials Lubeluzole was administered within six hours from the acute stroke; in one trial (LUB‐INT‐13 1996) a stratified randomisation permitted recruitment of patients presenting six to eight hour from the onset of the acute stroke. All trials routinely performed CT head scan within 24 hours from the start of treatment. The duration of follow up was generally short, ranging from four to 12 weeks.
All trials used the Barthel Score to assess functional outcome: 0 to 70 score for dependent patients, 75 to 100 score for independent ones.
Risk of bias in included studies
(1) Randomisation ‐ all the trials included were randomised. (2) Type of allocation concealment ‐ in all trials allocation concealment was adequate (level A). (3) Patient and assessor blindness ‐ in all trials placebo was used, in all cases the assessment was blind. (4) Intention‐to‐treat analysis ‐ all trials were evaluated according to an intention‐to‐treat analysis.
Effects of interventions
We present data ‐ where available ‐ for both 'any dose of lubeluzole versus placebo' and '10 mg versus placebo', since the latter dose was the most widely tested. In particular we couldn't assess the effect of dose of lubeluzole on outcome because we were unable to extract data to permit either direct or indirect comparisons of the effect of different doses.
We present data for both 'all randomised patients' and 'patients with a CT‐confirmed ischaemic stroke' as specified in the protocol.
Death from any causes at the end of scheduled treatment
Two trials including data from 2507 patients (71% of patients included in the overall review) evaluated death at the end of scheduled treatment. Treatment with lubeluzole 10 mg/day for five days was not associated with a significant reduction in the odds of being dead at one week (Peto odds ratio (OR) 0.97, 95% confidence interval (CI) 0.67 to 1.39).
Death from any cause at the end of scheduled follow‐up period
Data from all included trials were available for this outcome.
All randomised patients
Lubeluzole given at any dose was not associated with a significant reduction in death from all causes at the end of the scheduled follow up (OR 0.93, 95% CI 0.79 to 1.09). An analysis restricted to a comparison of lubeluzole 10 mg versus placebo gave very similar results (OR 0.90, 95% CI 0.76 to 1.06).
Patients with CT‐confirmed ischaemic stroke
Lubeluzole given at any dose was not associated with a significant reduction in death from all causes at the end of the scheduled follow up (OR 0.99, 95% CI 0.81 to 1.20). An analysis restricted to a comparison of lubeluzole 10 mg versus placebo gave very similar results (OR 0.94, 95% CI 0.77 to 1.15).
Death from specific causes at the end of scheduled follow‐up period
Death from stroke
Lubeluzole given at any dose was not associated with a significant reduction in death from stroke at the end of the scheduled follow up (OR 1.06, 95% CI 0.86 to 1.32). An analysis restricted to a comparison of lubeluzole 10 mg versus placebo gave very similar results (OR 1.04, 95% CI 0.84 to 1.29).
Death from cardiac events
Lubeluzole given at any dose was not associated with a significant reduction in death from cardiac events at the end of the scheduled follow‐up (OR 1.16, 95% CI 0.81 to 1.65). An analysis restricted to a comparison of lubeluzole 10 mg versus placebo gave very similar results (OR 1.11, 95% CI 0.77 to 1.59).
Dependency among survivors at the end of scheduled follow‐up period
Four trials including randomised data from 3464 patients (99% of patients included in the overall review) evaluated functional outcome at the end of scheduled follow‐up period. The Barthel Score, dichotomised into dependent (0 to 70) and independent (75 to 100), was used as the measure of functional outcome in all trials considered.
All randomised patients
Lubeluzole given at any dose was not associated with a significant difference in functional outcome at the end of the scheduled follow up (OR 1.10, 95% CI 0.95 to 1.26). An analysis restricted to a comparison of lubeluzole 10 mg versus placebo gave very similar results (OR 1.11, 95% CI 0.96 to 1.28).
Patients with CT‐confirmed ischaemic stroke
Lubeluzole given at any dose was not associated with a significant difference in functional outcome at the end of the scheduled follow up (OR 1.07, 95% CI 0.90 to 1.27). An analysis restricted to a comparison of lubeluzole 10 mg versus placebo gave very similar results (OR 1.07, 95% CI 0.90 to 1.27).
Death or dependency at the end of scheduled follow‐up period
All randomised patients
Lubeluzole given at any dose was not associated with a significant reduction in the odds of being dead or dependent at the end of the scheduled follow up (OR 1.04, 95% CI 0.91 to 1.19). An analysis restricted to a comparison of lubeluzole 10 mg versus placebo gave very similar results (OR 1.03, 95% CI 0.90 to 1.18).
Patients with CT‐confirmed ischaemic stroke
Lubeluzole given at any dose was not associated with a significant reduction in the odds of being dead or dependent at the end of the scheduled follow up (OR 1.06, 95% CI 0.90 to 1.25). An analysis restricted to a comparison of lubeluzole 10 mg versus placebo gave very similar results (OR 1.05, 95% CI 0.89 to 1.24).
Frequency of serious adverse events (ECG abnormalities, myocardial infarction, any other cardiovascular variable) at the end of scheduled follow‐up period
Data from all included trials were available for this outcome. However, we were unable to determine what proportion of these events were fatal. The safety analysis of lubeluzole was performed analysing all randomised patients and grouping serious adverse events into four categories as follows.
Heart‐conduction disorders (Q‐T prolonged > 450 msec)
(1) Lubeluzole given at any dose was associated with a significant increase in the odds of having heart‐conduction disorders (Q‐T prolonged > 450 msec) at the end of the scheduled follow up (OR 1.43, 95% CI 1.09 to 1.87). (2) Lubeluzole given at the dose of 10 mg/day for five days was associated with a significant increase in the odds of having heart‐conduction disorders at the end of the scheduled follow up (OR 1.43, 95% CI 1.09 to 1.88).
Heart‐rhythm disorders (atrial fibrillation, ventricular tachycardia, ventricular fibrillation, torsade de pointes)
(1) Lubeluzole given at any dose was not associated with a significant increase in the odds of having heart‐rhythm disorders at the end of the scheduled follow up (OR 1.28, 95% CI 0.97 to 1.69). (2) Lubeluzole given at the dose of 10 mg/day for five days was not associated with a significant increase in the odds of having heart‐rhythm disorders at the end of the scheduled follow up (OR 1.18, 95% CI 0.89 to 1.58).
Myocardial infarction
(1) Lubeluzole given at any dose was not associated with a significant increase in the odds of having myocardial infarction at the end of the scheduled follow up (OR 1.20, 95% CI 0.45 to 3.21). (2) Lubeluzole given at the dose of 10 mg/day for five days was not associated with a significant increase in the odds of having myocardial infarction at the end of the scheduled follow up (OR 1.46, 95% CI 0.53 to 4.02).
Any others cardiovascular events such as heart failure and pulmonary embolism
(1) Lubeluzole given at any dose was not associated with a significant increase in the odds of having any other cardiovascular events such as heart failure or pulmonary embolism at the end of the scheduled follow up (OR 0.73, 95% CI 0.46 to 1.14). (2) Lubeluzole given at the dose of 10 mg/day for five days was not associated with a significant increase in the odds of having any others cardiovascular events such as heart failure and pulmonary embolism at the end of the scheduled follow up (OR 0.69, 95% CI 0.44 to 1.08).
Sensitivity/subgroup analysis
We were unable to extract the appropriate data for either on‐treatment analysis or any of the pre‐specified sensitivity or subgroup analysis from the publications (apart from the subgroup analysis performed on CT‐confirmed ischaemic stroke patients).
Discussion
Acute stroke treatments should aim to reduce the risk of both death as well as survival with disability, lest patients survive their acute stroke only to remain severely disabled. The present review does not provide evidence that lubeluzole, given at any of the doses tested, started within eight hours and continued for up to five days from the onset of acute ischaemic stroke, reduces the risk of death or disability at the end of the scheduled follow‐up period. The results were similar whether the analyses were for all patients randomised or when analyses were restricted to patients with ischaemic stroke only. It did not appear that lubeluzole had any material effect on death from stroke or death from cardiac events. However the review did indicate that lubeluzole seemed to be associated with a significant increase in the odds of having heart‐conduction disorders (Q‐T prolonged, > 450 msec) (OR 1.36, 95% CI 1.09 to 1.87) and with an almost significant increase in heart‐rhythm disorders. On the other hand, there was no clear evidence on an effect on the occurrence of myocardial infarction, pulmonary embolism or other cardiovascular events.
These conclusions appear quite robust, but we cannot exclude the possibility of modest benefit from lubeluzole. Much larger scale trials would be required to detect such benefit reliably (Dorman 1996). Other authors have suggested that inadequate pre‐clinical studies or inappropriate phase III clinical trial design may have contributed to the failure of neuroprotective trials to show benefit in man (Muir 1999; STAIR 1999). However, before performing any further clinical trials of lubeluzole, an individual patient data meta‐analysis of the phase III trials would be important to identify potential reasons for the apparent overall lack of benefit.
Authors' conclusions
Implications for practice.
There is no evidence from this systematic review that lubeluzole, given at any dose in patients with acute ischaemic stroke has any effect on death, or death or dependency after a follow up of 12 weeks. Moreover, lubeluzole may significantly increase the odds of developing heart‐conduction disorders. These data do not support the use of lubeluzole for the routine treatment of patients with acute stroke.
Implications for research.
The trials included in this review were designed to have sufficient statistical power to detect fairly large clinical benefits from lubeluzole. The available data reliably exclude such large effects, but cannot exclude a more modest 10% relative reduction or relative increase in the odds of death or dependency. Much larger trials with 10,000 patients or more would be need to reliably confirm or refute such benefit.
What's new
| Date | Event | Description |
|---|---|---|
| 30 August 2010 | Review declared as stable | The Cochrane Stroke Group Trials Register was last searched for this review on 27 July 2010. No new relevant trials were found. The Cochrane Stroke Group Editorial Board believes that it is very unlikely that there will be any further trials in this topic area. |
History
Protocol first published: Issue 1, 2000 Review first published: Issue 1, 2002
| Date | Event | Description |
|---|---|---|
| 1 September 2008 | Amended | Converted to new review format. |
Acknowledgements
None
Data and analyses
Comparison 1. Lubeluzole vs Placebo.
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
|---|---|---|---|---|
| 1 Death from all causes at the end of scheduled treatment | 2 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 1.1 All randomised patients (Lubeluzole 10 mg/day) | 2 | 2507 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.97 [0.67, 1.39] |
| 2 Death from all causes at the end of scheduled follow‐up period | 5 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 2.1 All randomised patients (Lubeluzole 5, 10 and 20 mg/day vs Placebo) | 5 | 3510 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.93 [0.79, 1.09] |
| 2.2 All randomised patients (Lubezole 10 mg/day vs Placebo) | 5 | 3415 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.90 [0.76, 1.06] |
| 2.3 Patients with CT‐confirmed ischaemic stroke (Lubeluzole 5, 10 and 20 mg/day vs Placebo) | 5 | 2471 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.99 [0.82, 1.21] |
| 2.4 Patients with CT‐confirmed ischaemic stroke (Lubeluzole 10 mg/day vs Placebo) | 5 | 2372 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.94 [0.77, 1.15] |
| 3 Death from stroke at the end of scheduled follow‐up period | 5 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 3.1 All randomised patients (Lubeluzole 5, 10 and 20 mg/day vs Placebo) | 5 | 3510 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.06 [0.86, 1.32] |
| 3.2 All randomised patients (Lubeluzole 10 mg/day vs Placebo) | 5 | 3415 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.04 [0.84, 1.29] |
| 4 Death from cardiac events at the end of scheduled follow‐up period | 5 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 4.1 All randomised patients (Lubeluzole 5, 10 and 20 mg/day vs Placebo) | 5 | 3510 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.16 [0.81, 1.65] |
| 4.2 All randomised patients (Lubeluzole 10 mg/day vs Placebo) | 5 | 3415 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.11 [0.77, 1.59] |
| 5 Dependency among survivors at the end of scheduled follow‐up period (Lubeluzole 10 and 20 mg/day vs Placebo) | 4 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 5.1 All randomised patients | 4 | 3464 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.10 [0.95, 1.26] |
| 5.2 Patients with CT‐confirmed ischaemic stroke | 4 | 2403 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.07 [0.90, 1.27] |
| 6 Dependency among survivors at the end of scheduled follow‐up period (Lubeluzole 10 mg/day vs Placebo) | 4 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 6.1 All randomised patients | 4 | 3384 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.11 [0.96, 1.28] |
| 6.2 Patients with CT‐confirmed ischaemic stroke | 4 | 2327 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.07 [0.90, 1.27] |
| 7 Death or dependency at the end of the scheduled follow up period | 4 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 7.1 All randomised patients (Lubeluzole 10 and 20 mg/day vs Placebo) | 4 | 3464 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.04 [0.91, 1.19] |
| 7.2 All randomised patients (Lubeluzole 10 mg/day vs Placebo) | 4 | 3384 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.03 [0.90, 1.18] |
| 7.3 Patients with CT‐confirmed ischaemic stroke (Lubeluzole 10 and 20 mg/day vs Placebo) | 4 | 2407 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.06 [0.90, 1.25] |
| 7.4 Patients with CT‐confirmed ischaemic stroke (Lubeluzole 10 mg/day vs Placebo) | 4 | 2341 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.05 [0.89, 1.24] |
| 8 Heart‐conduction disorders at the end of scheduled follow‐up period | 4 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 8.1 Lubeluzole 5, 10 and 20 mg vs Placebo | 4 | 3269 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.43 [1.09, 1.87] |
| 8.2 Lubeluzole 10 mg vs Placebo | 4 | 3257 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.43 [1.09, 1.88] |
| 9 Heart‐rhythm disorders at the end of scheduled follow‐up period | 5 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 9.1 Lubeluzole 5, 10 and 20 mg vs Placebo | 5 | 3501 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.28 [0.97, 1.69] |
| 9.2 Lubeluzole 10 mg vs Placebo | 5 | 3379 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.18 [0.89, 1.58] |
| 10 Myocardial infarction at the end of scheduled follow‐up period | 5 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 10.1 Lubeluzole 5, 10 and 20 mg vs Placebo | 5 | 3501 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.20 [0.45, 3.21] |
| 10.2 Lubeluzole 10 mg vs Placebo | 5 | 3409 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 1.46 [0.53, 4.02] |
| 11 Any other cardiovascular event (heart failure,pulmonary embolism,etc) at the end of scheduled follow‐up period | 5 | Peto Odds Ratio (Peto, Fixed, 95% CI) | Subtotals only | |
| 11.1 Lubeluzole 5, 10 and 20 mg vs Placebo | 5 | 3501 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.73 [0.46, 1.14] |
| 11.2 Lubeluzole 10 mg vs Placebo | 5 | 3409 | Peto Odds Ratio (Peto, Fixed, 95% CI) | 0.69 [0.44, 1.08] |
1.1. Analysis.
Comparison 1 Lubeluzole vs Placebo, Outcome 1 Death from all causes at the end of scheduled treatment.
1.2. Analysis.
Comparison 1 Lubeluzole vs Placebo, Outcome 2 Death from all causes at the end of scheduled follow‐up period.
1.3. Analysis.
Comparison 1 Lubeluzole vs Placebo, Outcome 3 Death from stroke at the end of scheduled follow‐up period.
1.4. Analysis.
Comparison 1 Lubeluzole vs Placebo, Outcome 4 Death from cardiac events at the end of scheduled follow‐up period.
1.5. Analysis.
Comparison 1 Lubeluzole vs Placebo, Outcome 5 Dependency among survivors at the end of scheduled follow‐up period (Lubeluzole 10 and 20 mg/day vs Placebo).
1.6. Analysis.
Comparison 1 Lubeluzole vs Placebo, Outcome 6 Dependency among survivors at the end of scheduled follow‐up period (Lubeluzole 10 mg/day vs Placebo).
1.7. Analysis.
Comparison 1 Lubeluzole vs Placebo, Outcome 7 Death or dependency at the end of the scheduled follow up period.
1.8. Analysis.
Comparison 1 Lubeluzole vs Placebo, Outcome 8 Heart‐conduction disorders at the end of scheduled follow‐up period.
1.9. Analysis.
Comparison 1 Lubeluzole vs Placebo, Outcome 9 Heart‐rhythm disorders at the end of scheduled follow‐up period.
1.10. Analysis.
Comparison 1 Lubeluzole vs Placebo, Outcome 10 Myocardial infarction at the end of scheduled follow‐up period.
1.11. Analysis.
Comparison 1 Lubeluzole vs Placebo, Outcome 11 Any other cardiovascular event (heart failure,pulmonary embolism,etc) at the end of scheduled follow‐up period.
Characteristics of studies
Characteristics of included studies [ordered by study ID]
LUB‐INT‐13 1996.
| Methods | Multicenter Double blind Exclusion after randomisation: 416 pts (210 from the Lubeluzole group and 206 from the Placebo group) Losses to FU: 9 (2 Lubeluzole group, 7 Placebo group) | |
| Participants | 5 countries 1786 pts (intention‐to‐treat analysis) 857 pts (target population): stroke pts with a 0‐ to 6‐hour inclusion time window, with the exclusion of pts aged > 75 years with a severe stroke Mean age:71.2 49.5% male CT before or within 24 hours from the start of treatment | |
| Interventions | Rx: 7.5 mg Lubeluzole over 1 hour followed by 10 mg/day Control = placebo ASA, ticlopidine, dipyridamole, anticoagulants allowed Duration: 5 days | |
| Outcomes | Death at the end of scheduled treatment period (28 days) and at the end of scheduled trial follow‐up (84 days) Functional status (Barthel Index) Neurology recovery (ESS) General outcome (Modified Rankin Scale) | |
| Notes | Ex: < 18 years, uncounsciousness, complete resolution of acute deficit by time of study, cognitive or psychiatric disorders, Barthel < 70 before stroke, life expectancy < 12 weeks, serious ventricular arrhythmias, second or third degree AV‐block, QT interval > 450 msec, acute heart failure, recent myocardial infarction, thrombolytic therapy FU: 28 days | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Low risk | A ‐ Adequate |
LUB‐INT‐4 1995.
| Methods | Multicenter Double blind Exclusions after randomisation: 39 (ICH and vertebro‐basilar ischaemic stroke) Losses to FU: none | |
| Participants | 7 countries (34 centers) 232 pts (intention‐to‐treat analysis) 193 pts (target population) Median age 71 yrs 50.2% male CT within 24 hours from the start of treatment | |
| Interventions | Rx: (1) 7.5 mg Lubeluzole over 1 hour followed by 10 mg/day, (2) 15 mg Lubeluzole over 1 hour followed by 20 mg/day Control: placebo ASA, ticlopidine, heparin allowed as prophylaptic agents Duration: 5 days | |
| Outcomes | Death at the end of scheduled trial follow up (28 days) Functional status by Bathel Index | |
| Notes | Ex: pts < 50 yrs, stroke recurrences, pts. uncounsciousness, stroke over 6 hours, heart failure, myocardial infarction < 6 weeks, serious ventricular arrhythmias; QT interval > 400 msec FU: 28 days | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Low risk | A ‐ Adequate |
LUB‐INT‐5 1997.
| Methods | Multicenter Double blind Exclusion after randomisation: 50 (CT inconsistent with ischaemic stroke) Losses to FU: 7 (5 Lubeluzole group, 2 Placebo group) | |
| Participants | 11 countries (10 European and Australia) 725 pts (intention‐to‐treat analysis) 675 (target population) Mean age: 70 yrs 63% male CT within 24 hours from the start of treatment | |
| Interventions | Rx: 7.5 mg Lubeluzole over 1 hour followed by 10 mg/day Control: placebo ASA, ticlopidine, anticoagulants allowed Duration: 5 days | |
| Outcomes | Death at the end of scheduled trial follow up (84 days) Functional status by Bathel Index Residual disability by Rankin scale | |
| Notes | Ex: pts < 18 yrs, stroke recurrences, pts. uncounsciousness, stroke over 6 hours, heart failure, myocardial infarction < 6 weeks, serious ventricular arrhythmias; QT interval > 450 msec FU: 84 days | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Low risk | A ‐ Adequate |
LUB‐INT‐7 1996.
| Methods | Multicenter Double blind Exclusion after randomisation: 9 (1 investigator erroneously doubled the speed of infusion for 3 pts in each 3 treatment group) Losses to FU: none | |
| Participants | 4 countries 46 pts (intention‐to‐treat analysis) 37 pts (target population) Mean age: 68.6 yrs Male 60.8% CT before or immediately after from the start of treatment | |
| Interventions | Rx: (1) 3.75 mg Lubeluzole over 1 hour followed by 5 mg/day, (2) 7.5 mg Lubeluzole over 1 hour followed by 10 mg/day Control:placebo Duration: 5 days | |
| Outcomes | Cardiovascular safety evaluated by corrected QT interval (QTc), linear corrected QT interval (QTlc), QT dispersion (analysis on correctly dosed pts) Mortality for all causes at the end of scheduled trial follow‐up (28 days) | |
| Notes | Ex: < 18 years, uncounsciousness, serious ventricular arrhythmias, second or third degree AV‐block, QT interval > 450 msec, acute heart failure, recent acute myocardial infarction, cognitive or psychiatric disorders, experimental stroke medication, history of severe drug allergy, life‐threatening concurrent illness. FU: 7 days (for safety evaluation) 30 days (for mortality) | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Low risk | A ‐ Adequate |
LUB‐INT‐9 1997.
| Methods | Multicenter Double blind Exclusion after randomisation: 21 (13 haemorrhagic, 2 functional psychogenic reaction, 2 brain tumors, 1 migraine syndrome, 1 possible MS, 1 dystrophic calcification) Losses to FU: 13 (3 Lubeluzole group, 10 Placebo group) | |
| Participants | 2 countries (US, Canada) 721 pts (intention‐to‐treat analysis) 700 pts (target population) Mean age: 70.5 yrs 52.1% male CT within 3 (US) and 24 (Canada) hours from the start of treatment | |
| Interventions | Rx: 7.5 mg Lubeluzole over 1 hour followed by 10 mg/day Control: placebo ASA, ticlopidine, anticoagulants allowed Duration: 5 days | |
| Outcomes | Death at the end of scheduled trial follow up (84 days) Functional status by Bathel Index Residual disability by Rankin scale | |
| Notes | Ex: pts < 18 yrs, stroke recurrences, pts. uncounsciousness, stroke over 6 hours, heart failure, myocardial infarction < 6 weeks, serious ventricular arrhythmias; QT interval > 400 msec FU: 84 days | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Allocation concealment? | Low risk | A ‐ Adequate |
Ex: exclusion criteria FU: follow up Rx: treatment
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| De Keyser 1997a | Single masked, dose ranging study |
| De Keyser 1997b | Single masked, dose ranging study |
Contributions of authors
Dr Massimo Conti and Professor Carlo Gandolfo independently checked the quality of all the studies, extracted and cross‐checked the data. Dr Massimo Conti wrote the protocol, carried out searches, performed the analyses, and drafted and wrote the review. Professor Peter Sandercock commented on the protocol, analyses and the draft review. Professor Carlo Gandolfo commented on each draft of the protocol and review, and gave general advice. He is the Guarantor of the review.
Sources of support
Internal sources
15.000.000 (Liras) from University of Genoa and Italian Ministery of University, Italy.
External sources
No sources of support supplied
Declarations of interest
None
Stable (no update expected for reasons given in 'What's new')
References
References to studies included in this review
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De Keyser 1997a {published data only}
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Additional references
De Keyser 1997
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