Comment
Clinical trials for multiple system atrophy Published Online December 8, 2014 http://dx.doi.org/10.1016/ S1474-4422(14)70311-4 See Articles page 145
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Multiple system atrophy is a neurodegenerative disorder characterised by autonomic, extrapyramidal, pyramidal, or cerebellar features, or a combination of these features.1,2 At present, no medications are able to slow the relentless disease progression, and treatment of symptoms is inadequate. Thus, novel disease modifying and symptomatic therapies are needed. In The Lancet Neurology, Werner Poewe and colleagues present results of a 48-week randomised, controlled, multicentre trial evaluating the potential disease modifying and symptomatic effects of 1 mg/day of rasagiline versus placebo in 174 patients with the parkinsonian subtype of multiple system atrophy.3 The primary outcome was change from baseline to 48 weeks in the Unified Multiple System Atrophy Rating Scale (UMSARS)4 score (sum of parts I and II), and several secondary outcome measures were assessed, including putaminal mean diffusivity on MRI in a subset of patients. The study did not show that this regimen was effective in the slowing of disease progression or improvement of symptoms. This report could affect clinical practice because it does not provide evidence for the use of rasagiline in patients with the parkinsonian subtype of multiple system atrophy. Despite the negative results, the data add to physicians’ understanding of the natural history5 and cognitive decline6 of multiple system atrophy, and further support the potential of an imaging outcome7 that could facilitate future trials. Furthermore, the design and outcomes of this study raise several points relevant to future trials of multiple system atrophy. First, in terms of preclinical data, although rasagiline was shown to be neuroprotective in a mouse model of multiple system atrophy,8 the lack of clinical translation raises questions about the predictive value of this model. However, the dose equivalence of rasagiline in the trial was several times lower than that assessed in the preclinical model. As with most neurodegenerative diseases, the absence of an adequate animal model hinders drug development and highlights the need for improved disease models. A further challenge in development of therapies for multiple system atrophy is the incomplete understanding of the underlying pathophysiology. Second, with respect to the study population, Poewe and colleagues enrolled patients who had an average time from symptom onset to baseline assessment of
3·9 years (SD 2·4). Because cellular loss precedes clinical manifestations, disease progression might have been too advanced to be influenced by a neuroprotective effect of rasagiline. In addition, some degree of diagnostic uncertainty exists in early multiple system atrophy.1 These two points underscore the need for a validated biomarker to facilitate early diagnosis and to improve diagnostic accuracy. Although the present study included only patients with the parkinsonian form of multiple system atrophy, the additional inclusion of patients with the cerebellar subtype in disease modification trials might be reasonable presuming the underlying pathophysiology is similar and the outcome measure is sensitive to change in both disease subsets. Third, when considering the trial design for a rare disorder such as multiple system atrophy, efficiency is crucial, and the completion of enrolment in 11 months at 40 clinical sites is laudable. Based on available natural history data, Poewe and colleagues’ study was powered to detect a 5 point difference in change on the UMSARS (sum of parts I and II). However, the clinical importance to a patient of a 5 point difference is unknown; no definition of the minimal clinically important change on this scale is available. Longitudinal clinical data should permit this value to be determined and enable future studies to be powered on a change that is clinically meaningful to patients. Additionally, a preplanned interim analysis for futility should be considered in future efficacy trials;9 if a trial were deemed futile and stopped early, patients would avoid potential risks of an investigational agent, study costs would be reduced, and a larger patient pool would be available for enrolment in other trials. Fourth, patient retention in the study was challenging, with 21 (25%) of 84 patients withdrawing early in the rasagiline group and 15 (17%) of 90 patients doing so in the placebo group, which required imputation for some missing data. This rate of loss to follow-up suggests that careful consideration should be given to the selection of the primary outcome measure of long trials to ensure that primary outcome data are available at study completion. One approach to improve collection of follow-up data on the primary outcome might be remote assessments.10 A key unmet need in the field of multiple system atrophy therapeutics is the identification of biomarkers that allow early diagnosis and improve diagnostic www.thelancet.com/neurology Vol 14 February 2015
Comment
accuracy, track disease progression, and ideally change in response to treatment. The MRI substudy suggests that such measures might be on the horizon and highlights the value of exploring potential biomarkers within clinical trials. With advances in our understanding of the pathogenesis of multiple system atrophy, new therapies might soon be available for testing, and the present study will aid in the approach to future clinical trials aimed at slowing this devastating neurological disease.
2 3
4
5 6
Wendy R Galpern
7
National Institute of Neurological Disorders and Stroke, National Institutes of Health, 6001 Executive Boulevard, #2225, Bethesda, MD 20892, USA [email protected]
8
I declare no competing interests. 1
Gilman S, Wenning GK, Low PA, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008; 71: 670–76.
9
10
Stefanova N, Bucke P, Duerr S, Wenning GK. Multiple system atrophy: an update. Lancet Neurol 2009; 8: 1172–78. Poewe W, Seppi K, Fitzer-Attas CJ, et al. Efficacy of rasagiline in patients with the parkinsonian variant of multiple system atrophy: a randomised, placebo-controlled trial. Lancet Neurol 2014; published online Dec 8. http://dx.doi.org/10.1016/S1474-4422(14)70288-1. Wenning GK, Tison F, Seppi K, et al. Development and validation of the Unified Multiple System Atrophy Rating Scale (UMSARS). Mov Disord 2004; 19: 1391–402. Wenning GK, Geser F, Krismer F, et al. The natural history of multiple system atrophy: a prospective European cohort study. Lancet Neurol 2013; 12: 264–74. Stankovic I, Krismer F, Jesic A, et al. Cognitive impairment in multiple system atrophy: a position statement by the Neuropsychology Task Force of the MDS Multiple System Atrophy (MODIMSA) study group. Mov Disord 2014; 29: 857–67. Brooks DJ, Seppi K. Proposed neuroimaging criteria for the diagnosis of multiple system atrophy. Mov Disord 2009; 24: 949–64. Stefanova N, Poewe W, Wenning GK. Rasagiline is neuroprotective in a transgenic model of multiple system atrophy. Exp Neurol 2008; 210: 421–27. Low PA, Robertson D, Gilman S, et al. Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2014; 13: 268–75. Achey M, Aldred JL, Aljehani N, et al. The past, present, and future of telemedicine for Parkinson’s disease. Mov Disord 2014; 29: 871–83.
Prevention of cardiomyopathy in Duchenne muscular dystrophy Duchenne muscular dystrophy is a severe X-linked disease due to loss of dystrophin in skeletal and cardiac muscle. Boys develop progressive weakness and lose the ability to walk by 10 years of age, then develop dilated cardiomyopathy, a leading cause of death. In this context, Subha V Raman and colleagues1 present a placebo-controlled randomised trial in 42 boys from three US centres with Duchenne muscular dystrophy treated with either eplerenone or placebo in association with background angiotensin-converting-enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Two patterns of cardiac involvement are recognised in Duchenne muscular dystrophy: a left ventricular wall motion abnormality, which is frequent in the early stage of the disease, and dilated cardiomyopathy,2,3 which is more frequent in the second decade of life, the age of the patients recruited in the study by Raman and colleagues.1 To prolong survival in boys presenting with a restrictive ventilatory defect and sleep-related hypoxyaemia, ventilatory support and aggressive respiratory management are required.2 Prolonged survival owing to improvement in clinical care, such as non-invasive positive pressure ventilation, has led to an increased incidence of cardiomyopathy.3 www.thelancet.com/neurology Vol 14 February 2015
In some patients, the progression of Duchenne muscular dystrophy is responsive to corticosteroids, which can prolong walking ability by about a year and improve quality of life, although the benefits and severity of sideeffects are variable. In 2004, a European Neuromuscular Centre workshop recommended daily steroids as the gold standard, on the basis of their benefit on skeletal and respiratory muscle function,4,5 but other regimens are under investigation. Results from a retrospective analysis showed that steroid-naive patients aged 10 years or younger were four times more likely to have decreased cardiac function than patients in the same age group who had received steroids, whereas patients older than 10 years who had not received steroids were 15-times more likely to have decreased cardiac function than patients in this age group who had taken steroids.6 In a small randomised trial, early ACEI (ie, perindopril) monotherapy in 9·5–13·0 year-old boys with Duchenne muscular dystrophy delayed the onset and the progression of left ventricular dysfunction, monitored by decline in ejection fraction.7 The beneficial effect of combined β-blockers and ACEI was established in 56 wheelchair-bound patients (mean age 19·5 years [SD 5·8] at study entry) with a 5-year survival of 93% and 7-year survival of 84%8. In the study by Raman
Published Online December 30, 2014 http://dx.doi.org/10.1016/ S1474-4422(14)70326-6 See Articles page 153
127
Clinical trials for multiple system atrophy Published Online December 8, 2014 http://dx.doi.org/10.1016/ S1474-4422(14)70311-4 See Articles page 145
126
Multiple system atrophy is a neurodegenerative disorder characterised by autonomic, extrapyramidal, pyramidal, or cerebellar features, or a combination of these features.1,2 At present, no medications are able to slow the relentless disease progression, and treatment of symptoms is inadequate. Thus, novel disease modifying and symptomatic therapies are needed. In The Lancet Neurology, Werner Poewe and colleagues present results of a 48-week randomised, controlled, multicentre trial evaluating the potential disease modifying and symptomatic effects of 1 mg/day of rasagiline versus placebo in 174 patients with the parkinsonian subtype of multiple system atrophy.3 The primary outcome was change from baseline to 48 weeks in the Unified Multiple System Atrophy Rating Scale (UMSARS)4 score (sum of parts I and II), and several secondary outcome measures were assessed, including putaminal mean diffusivity on MRI in a subset of patients. The study did not show that this regimen was effective in the slowing of disease progression or improvement of symptoms. This report could affect clinical practice because it does not provide evidence for the use of rasagiline in patients with the parkinsonian subtype of multiple system atrophy. Despite the negative results, the data add to physicians’ understanding of the natural history5 and cognitive decline6 of multiple system atrophy, and further support the potential of an imaging outcome7 that could facilitate future trials. Furthermore, the design and outcomes of this study raise several points relevant to future trials of multiple system atrophy. First, in terms of preclinical data, although rasagiline was shown to be neuroprotective in a mouse model of multiple system atrophy,8 the lack of clinical translation raises questions about the predictive value of this model. However, the dose equivalence of rasagiline in the trial was several times lower than that assessed in the preclinical model. As with most neurodegenerative diseases, the absence of an adequate animal model hinders drug development and highlights the need for improved disease models. A further challenge in development of therapies for multiple system atrophy is the incomplete understanding of the underlying pathophysiology. Second, with respect to the study population, Poewe and colleagues enrolled patients who had an average time from symptom onset to baseline assessment of
3·9 years (SD 2·4). Because cellular loss precedes clinical manifestations, disease progression might have been too advanced to be influenced by a neuroprotective effect of rasagiline. In addition, some degree of diagnostic uncertainty exists in early multiple system atrophy.1 These two points underscore the need for a validated biomarker to facilitate early diagnosis and to improve diagnostic accuracy. Although the present study included only patients with the parkinsonian form of multiple system atrophy, the additional inclusion of patients with the cerebellar subtype in disease modification trials might be reasonable presuming the underlying pathophysiology is similar and the outcome measure is sensitive to change in both disease subsets. Third, when considering the trial design for a rare disorder such as multiple system atrophy, efficiency is crucial, and the completion of enrolment in 11 months at 40 clinical sites is laudable. Based on available natural history data, Poewe and colleagues’ study was powered to detect a 5 point difference in change on the UMSARS (sum of parts I and II). However, the clinical importance to a patient of a 5 point difference is unknown; no definition of the minimal clinically important change on this scale is available. Longitudinal clinical data should permit this value to be determined and enable future studies to be powered on a change that is clinically meaningful to patients. Additionally, a preplanned interim analysis for futility should be considered in future efficacy trials;9 if a trial were deemed futile and stopped early, patients would avoid potential risks of an investigational agent, study costs would be reduced, and a larger patient pool would be available for enrolment in other trials. Fourth, patient retention in the study was challenging, with 21 (25%) of 84 patients withdrawing early in the rasagiline group and 15 (17%) of 90 patients doing so in the placebo group, which required imputation for some missing data. This rate of loss to follow-up suggests that careful consideration should be given to the selection of the primary outcome measure of long trials to ensure that primary outcome data are available at study completion. One approach to improve collection of follow-up data on the primary outcome might be remote assessments.10 A key unmet need in the field of multiple system atrophy therapeutics is the identification of biomarkers that allow early diagnosis and improve diagnostic www.thelancet.com/neurology Vol 14 February 2015
Comment
accuracy, track disease progression, and ideally change in response to treatment. The MRI substudy suggests that such measures might be on the horizon and highlights the value of exploring potential biomarkers within clinical trials. With advances in our understanding of the pathogenesis of multiple system atrophy, new therapies might soon be available for testing, and the present study will aid in the approach to future clinical trials aimed at slowing this devastating neurological disease.
2 3
4
5 6
Wendy R Galpern
7
National Institute of Neurological Disorders and Stroke, National Institutes of Health, 6001 Executive Boulevard, #2225, Bethesda, MD 20892, USA [email protected]
8
I declare no competing interests. 1
Gilman S, Wenning GK, Low PA, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008; 71: 670–76.
9
10
Stefanova N, Bucke P, Duerr S, Wenning GK. Multiple system atrophy: an update. Lancet Neurol 2009; 8: 1172–78. Poewe W, Seppi K, Fitzer-Attas CJ, et al. Efficacy of rasagiline in patients with the parkinsonian variant of multiple system atrophy: a randomised, placebo-controlled trial. Lancet Neurol 2014; published online Dec 8. http://dx.doi.org/10.1016/S1474-4422(14)70288-1. Wenning GK, Tison F, Seppi K, et al. Development and validation of the Unified Multiple System Atrophy Rating Scale (UMSARS). Mov Disord 2004; 19: 1391–402. Wenning GK, Geser F, Krismer F, et al. The natural history of multiple system atrophy: a prospective European cohort study. Lancet Neurol 2013; 12: 264–74. Stankovic I, Krismer F, Jesic A, et al. Cognitive impairment in multiple system atrophy: a position statement by the Neuropsychology Task Force of the MDS Multiple System Atrophy (MODIMSA) study group. Mov Disord 2014; 29: 857–67. Brooks DJ, Seppi K. Proposed neuroimaging criteria for the diagnosis of multiple system atrophy. Mov Disord 2009; 24: 949–64. Stefanova N, Poewe W, Wenning GK. Rasagiline is neuroprotective in a transgenic model of multiple system atrophy. Exp Neurol 2008; 210: 421–27. Low PA, Robertson D, Gilman S, et al. Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2014; 13: 268–75. Achey M, Aldred JL, Aljehani N, et al. The past, present, and future of telemedicine for Parkinson’s disease. Mov Disord 2014; 29: 871–83.
Prevention of cardiomyopathy in Duchenne muscular dystrophy Duchenne muscular dystrophy is a severe X-linked disease due to loss of dystrophin in skeletal and cardiac muscle. Boys develop progressive weakness and lose the ability to walk by 10 years of age, then develop dilated cardiomyopathy, a leading cause of death. In this context, Subha V Raman and colleagues1 present a placebo-controlled randomised trial in 42 boys from three US centres with Duchenne muscular dystrophy treated with either eplerenone or placebo in association with background angiotensin-converting-enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). Two patterns of cardiac involvement are recognised in Duchenne muscular dystrophy: a left ventricular wall motion abnormality, which is frequent in the early stage of the disease, and dilated cardiomyopathy,2,3 which is more frequent in the second decade of life, the age of the patients recruited in the study by Raman and colleagues.1 To prolong survival in boys presenting with a restrictive ventilatory defect and sleep-related hypoxyaemia, ventilatory support and aggressive respiratory management are required.2 Prolonged survival owing to improvement in clinical care, such as non-invasive positive pressure ventilation, has led to an increased incidence of cardiomyopathy.3 www.thelancet.com/neurology Vol 14 February 2015
In some patients, the progression of Duchenne muscular dystrophy is responsive to corticosteroids, which can prolong walking ability by about a year and improve quality of life, although the benefits and severity of sideeffects are variable. In 2004, a European Neuromuscular Centre workshop recommended daily steroids as the gold standard, on the basis of their benefit on skeletal and respiratory muscle function,4,5 but other regimens are under investigation. Results from a retrospective analysis showed that steroid-naive patients aged 10 years or younger were four times more likely to have decreased cardiac function than patients in the same age group who had received steroids, whereas patients older than 10 years who had not received steroids were 15-times more likely to have decreased cardiac function than patients in this age group who had taken steroids.6 In a small randomised trial, early ACEI (ie, perindopril) monotherapy in 9·5–13·0 year-old boys with Duchenne muscular dystrophy delayed the onset and the progression of left ventricular dysfunction, monitored by decline in ejection fraction.7 The beneficial effect of combined β-blockers and ACEI was established in 56 wheelchair-bound patients (mean age 19·5 years [SD 5·8] at study entry) with a 5-year survival of 93% and 7-year survival of 84%8. In the study by Raman
Published Online December 30, 2014 http://dx.doi.org/10.1016/ S1474-4422(14)70326-6 See Articles page 153
127
