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Neuroprotection disappointment yet aGAIN
CORRESPONDENCE
5 days. Since the UV exposure required to produce duct damage is not great, and is encountered even in British sunshine, let alone after sun-bed UV exposure, it is incorrect to assume that thermal collapse is “. . . not because patients have ceased to sweat, but because, with occlusive clothing, their sweat cannot evaporate”.1 In addition to avoiding unnecessarily heavy exertion and clothing, avoidance of (or tolerance training for) sun exposure sufficient to produce even minor scaling, especially in unacclimatised individuals with a low skin tolerance to UV, is prophylactically critical. Sam Shuster East Gables, 42 Double Street, Framlingham IP13 9BN, UK 1
2
Porter AMW. The death of a British officercadet from heat illness. Lancet 2000; 355: 569–71. Shuster S. Duct disruption, a new explanation of miliaria. Acta Derm Venerol (Stockh) 1997; 77: 1–3.
Neuroprotection disappointment yet aGAIN Sir—Kennedy Lees and colleagues (June 3, p 1949)1 present yet another phase III clinical trial (Glycine Antagonist [gavestinel] in Neuroprotection [GAIN] International) of a neuroprotective drug (gavestinel, GV150526) that fails to show any benefit at all in stroke patients, despite a 50% reduction in infarct volume in preclinical studies.2 The recurrent failure of apparently promising new drugs to improve functional outcome after stroke has been the subject of increasing speculation. A list of failings in the design of the clinical trials (which were articled in GAIN) has been suggested as the main reason.3 The appropriateness of animal models has also been questioned, but the recently introduced guidelines for preclinical assessment of neuroprotectants (STAIR)4 will hopefully lead to better minimum standards for drug testing (too recent for gavestinel). However, we feel that more fundamental sources of bias in the preclinical assessment of neuroprotectants, so far overlooked (even in STAIR4), could explain the large discrepancies between trials in animals and trials in human beings. In clinical trials, as exemplified by GAIN, it is standard practice to go to great lengths to avoid bias: randomised treatment allocation; balanced randomisation on key baseline variables; masked treatment allocation; masked assessment of outcome (preferably by an
THE LANCET • Vol 356 • August 12, 2000
independent outcome assessor); and use of intention-to-treat analyses. Also, in the assessment of any treatment, we should never rely on the results of just one trial, but carry out a methodologically rigorous systematic review and meta-analysis of all the available randomised evidence and guard against publication bias (ie, unpublished negative experiments). Have any of these points been given such careful attention in preclinical studies? Is it possible to ensure adequate masking of treatment allocation or outcome assessment within the laboratory environment where the same staff may be involved in the administration of test drug, dayto-day care of the (often very small) number of animals, and the assessment of outcome? Given the considerable pressure on laboratories to develop stroke treatments, the potential for bias in outcome assessment with any prior knowledge of treatment allocation is substantial. For example, the size of the observed reductions in infarct volume with gavestinel seem almost biologically implausible. It is imperative that preclinical study methodology be made more rigorous. It is unethical to subject thousands more patients to the risk (and intrusion into their privacy) of participating in more trials based on the results of misleading preclinical testing. At least in the case of gavestinel and several other neuroprotectants one could say “at least they did no harm”. Or did they? The commercially sponsored neuroprotection trials have occupied the research time of hundreds of the most active and organised stroke centres in the world for several years,5 further delaying the implementation of an effective stroke treatment. The question the neuroprotection trialists should be asking themselves is not “has the neuroprotection hypothesis been disproved?” but “what basic methodological flaw or flaws allow preclinical studies to provide such inadequate and probably overoptimistic data?” *J M Wardlaw, C P Warlow, P A G Sandercock, M S Dennis, R I Lindley Departments of *Clinical Neurosciences and Geriatrics, University of Edinburgh, Western General Hospitals, Edinburgh EH4 2XU, UK 1
2
Lees KR, Asplund K, Carolei A, et al. Glycine antagonist (gavestinel) in neuroprotection (GAIN International) in patients with acute stroke: a randomised controlled trial. Lancet 2000; 355: 1949–54. Di Fabio R Cugola A, Donati D, et al. Identification and pharmacological characterisation of GB150526, a novel glycine antagonist as a potent
3
4
5
neuroprotective agent. Drugs Future 1998; 23: 62–69. DeGraba TJ, Pettigrew LC. Why do neuroprotective drugs work in animals but not in humans? Neurol Clinics 2000; 19: 475–93. Stroke Therapy Academic Industry Roundtable (STAIR). Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 1999; 30: 2752–58. Dorman PJ, Counsell C, Sandercock PAG. Reports of randomised trials in acute stroke, 1955 to 1995. What proportions were commercially sponsored? Stroke 1999; 30: 1995–98.
Sleep attacks in Parkinson’s disease Sir—Anthony Schapira (April 15, p 1332)1 and J J Ferreira and colleagues (p 1333) present studies of sleep episodes in patients with Parkinson’s disease who are taking the dopamine agonists pergolide,1,2 bromocriptine, lisuride, or piribedil.2 Frucht and colleagues3 had already described sleep attacks in patients taking pramipexole and ropinirole, two newer dopamine agonists with D2 and D3 receptor activity. It was speculated that the sedating effect of pramipexole and ropinirole may be a result of their stronger D3 receptor activity when compared with other dopamine agonists. However, the observations by Schapira1 and Ferreira and colleagues2 suggest that sedation may be rather a class effect of dopamine agonists. We report on a patient with Parkinson’s disease, who developed excessive daytime sleepiness under monotherapy with a relatively low dose of ropinirole, which resolved after switching to an equivalent dose of pergolide. This man aged 63 years presented with resting tremor of the right leg at the age of 59 years. In response to a low dose of levodopa (150 mg per day) the patient developed transient mild sedation and gastrointestinal side-effects and thus decided to stop treatment. 2 years after onset of disease he had mild bilateral disease. Ropinirole, up to a daily dose of 6 mg, was well tolerated, apart from intermittent mild daytime sleepiness. After a further increase to a dose of 9 mg per day, signs of parkinsonism improved (with a reduction in motor score on the Unified Parkinson’s Disease Rating Scale from 11 to 1). However, during the next months the patient gradually developed excessive daytime sleepiness and was noticed to fall asleep while reading, watching television, and during conversations, with at least five episodes of unplanned sleep per day. Daytime sleepiness immediately disappeared after switching overnight from ropinirole to
597
For personal use only. Not to be reproduced without permission of The Lancet.
5 days. Since the UV exposure required to produce duct damage is not great, and is encountered even in British sunshine, let alone after sun-bed UV exposure, it is incorrect to assume that thermal collapse is “. . . not because patients have ceased to sweat, but because, with occlusive clothing, their sweat cannot evaporate”.1 In addition to avoiding unnecessarily heavy exertion and clothing, avoidance of (or tolerance training for) sun exposure sufficient to produce even minor scaling, especially in unacclimatised individuals with a low skin tolerance to UV, is prophylactically critical. Sam Shuster East Gables, 42 Double Street, Framlingham IP13 9BN, UK 1
2
Porter AMW. The death of a British officercadet from heat illness. Lancet 2000; 355: 569–71. Shuster S. Duct disruption, a new explanation of miliaria. Acta Derm Venerol (Stockh) 1997; 77: 1–3.
Neuroprotection disappointment yet aGAIN Sir—Kennedy Lees and colleagues (June 3, p 1949)1 present yet another phase III clinical trial (Glycine Antagonist [gavestinel] in Neuroprotection [GAIN] International) of a neuroprotective drug (gavestinel, GV150526) that fails to show any benefit at all in stroke patients, despite a 50% reduction in infarct volume in preclinical studies.2 The recurrent failure of apparently promising new drugs to improve functional outcome after stroke has been the subject of increasing speculation. A list of failings in the design of the clinical trials (which were articled in GAIN) has been suggested as the main reason.3 The appropriateness of animal models has also been questioned, but the recently introduced guidelines for preclinical assessment of neuroprotectants (STAIR)4 will hopefully lead to better minimum standards for drug testing (too recent for gavestinel). However, we feel that more fundamental sources of bias in the preclinical assessment of neuroprotectants, so far overlooked (even in STAIR4), could explain the large discrepancies between trials in animals and trials in human beings. In clinical trials, as exemplified by GAIN, it is standard practice to go to great lengths to avoid bias: randomised treatment allocation; balanced randomisation on key baseline variables; masked treatment allocation; masked assessment of outcome (preferably by an
THE LANCET • Vol 356 • August 12, 2000
independent outcome assessor); and use of intention-to-treat analyses. Also, in the assessment of any treatment, we should never rely on the results of just one trial, but carry out a methodologically rigorous systematic review and meta-analysis of all the available randomised evidence and guard against publication bias (ie, unpublished negative experiments). Have any of these points been given such careful attention in preclinical studies? Is it possible to ensure adequate masking of treatment allocation or outcome assessment within the laboratory environment where the same staff may be involved in the administration of test drug, dayto-day care of the (often very small) number of animals, and the assessment of outcome? Given the considerable pressure on laboratories to develop stroke treatments, the potential for bias in outcome assessment with any prior knowledge of treatment allocation is substantial. For example, the size of the observed reductions in infarct volume with gavestinel seem almost biologically implausible. It is imperative that preclinical study methodology be made more rigorous. It is unethical to subject thousands more patients to the risk (and intrusion into their privacy) of participating in more trials based on the results of misleading preclinical testing. At least in the case of gavestinel and several other neuroprotectants one could say “at least they did no harm”. Or did they? The commercially sponsored neuroprotection trials have occupied the research time of hundreds of the most active and organised stroke centres in the world for several years,5 further delaying the implementation of an effective stroke treatment. The question the neuroprotection trialists should be asking themselves is not “has the neuroprotection hypothesis been disproved?” but “what basic methodological flaw or flaws allow preclinical studies to provide such inadequate and probably overoptimistic data?” *J M Wardlaw, C P Warlow, P A G Sandercock, M S Dennis, R I Lindley Departments of *Clinical Neurosciences and Geriatrics, University of Edinburgh, Western General Hospitals, Edinburgh EH4 2XU, UK 1
2
Lees KR, Asplund K, Carolei A, et al. Glycine antagonist (gavestinel) in neuroprotection (GAIN International) in patients with acute stroke: a randomised controlled trial. Lancet 2000; 355: 1949–54. Di Fabio R Cugola A, Donati D, et al. Identification and pharmacological characterisation of GB150526, a novel glycine antagonist as a potent
3
4
5
neuroprotective agent. Drugs Future 1998; 23: 62–69. DeGraba TJ, Pettigrew LC. Why do neuroprotective drugs work in animals but not in humans? Neurol Clinics 2000; 19: 475–93. Stroke Therapy Academic Industry Roundtable (STAIR). Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 1999; 30: 2752–58. Dorman PJ, Counsell C, Sandercock PAG. Reports of randomised trials in acute stroke, 1955 to 1995. What proportions were commercially sponsored? Stroke 1999; 30: 1995–98.
Sleep attacks in Parkinson’s disease Sir—Anthony Schapira (April 15, p 1332)1 and J J Ferreira and colleagues (p 1333) present studies of sleep episodes in patients with Parkinson’s disease who are taking the dopamine agonists pergolide,1,2 bromocriptine, lisuride, or piribedil.2 Frucht and colleagues3 had already described sleep attacks in patients taking pramipexole and ropinirole, two newer dopamine agonists with D2 and D3 receptor activity. It was speculated that the sedating effect of pramipexole and ropinirole may be a result of their stronger D3 receptor activity when compared with other dopamine agonists. However, the observations by Schapira1 and Ferreira and colleagues2 suggest that sedation may be rather a class effect of dopamine agonists. We report on a patient with Parkinson’s disease, who developed excessive daytime sleepiness under monotherapy with a relatively low dose of ropinirole, which resolved after switching to an equivalent dose of pergolide. This man aged 63 years presented with resting tremor of the right leg at the age of 59 years. In response to a low dose of levodopa (150 mg per day) the patient developed transient mild sedation and gastrointestinal side-effects and thus decided to stop treatment. 2 years after onset of disease he had mild bilateral disease. Ropinirole, up to a daily dose of 6 mg, was well tolerated, apart from intermittent mild daytime sleepiness. After a further increase to a dose of 9 mg per day, signs of parkinsonism improved (with a reduction in motor score on the Unified Parkinson’s Disease Rating Scale from 11 to 1). However, during the next months the patient gradually developed excessive daytime sleepiness and was noticed to fall asleep while reading, watching television, and during conversations, with at least five episodes of unplanned sleep per day. Daytime sleepiness immediately disappeared after switching overnight from ropinirole to
597
For personal use only. Not to be reproduced without permission of The Lancet.