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Rare inherited diseases merit disease-specific trials
Comment
Rare inherited diseases merit disease-specific trials Inherited cerebellar ataxias need therapeutic interventions. A key question is how to run conclusive therapeutic trials. Patient groups are very small, and the risk of being underpowered to test efficacy is important. Cerebellar ataxias, which include a multitude of different, rare genetic entities, are a difficult set of diseases for such studies. In The Lancet Neurology, Romano and colleagues1 present the results of a 12-month, three-centre, double-blind, placebocontrolled trial of riluzole, given at a dose of 50 mg twice daily. The study included 20 patients with Friedreich’s ataxia (10 assigned to riluzole and 10 assigned to placebo), 21 with spinocerebellar ataxia type 1 (11 riluzole and 10 placebo), 16 with spinocerebellar ataxia type 2 (seven riluzole and nine placebo), and one patient each with spinocerebellar ataxia types 6 and 8 (both assigned to riluzole) and type 10 (assigned to placebo). Riluzole had a positive effect based on a decrease in Scale for the Assessment and Rating of Ataxia (SARA) scores (maximum score=40) in 14 (50%) of 28 of the treated patients compared with three (11%) of 27 who received placebo (odds ratio [OR] 8·00, 95% CI 1·95–32·83; p=0·002). This difference in worsening of the cerebellar score should be considered a success, and the investigators are to be congratulated. However, the clinician eager to treat patients is left with some important questions about the design of trials for rare diseases. Is it appropriate to mix different forms of ataxias in a therapeutic trial? We know from natural history studies that the mean SARA score increases at different rates according to genotype (2·18 points per year for spinocerebellar ataxia type 1, 1·40 for spinocerebellar ataxia type 2, and 1·36 for Friedreich’s ataxia; in spinocerebellar ataxia type 6, evolution of the score is not linear).2–4 Confounding factors for SARA evolution are age at inclusion and the presence of other neurological signs.3 The effect size, the sensitivity to change, of SARA remains small (<0·2),5 and this limitation has to be taken into account. Can we include presymptomatic individuals? Five (10%) of the participants who completed the trial had SARA scores of 4 or less. Since a score of 4 is the threshold for differentiating people without manifest ataxia from those with manifest ataxia,6 they could be carriers without cerebellar symptoms. SARA progression does
not seem to be predictable in this group because they had disease durations ranging from 1 to 11 years, and the symptom progression profiles of presymptomatic mutation carriers are not well known. Clinicians are waiting for the follow-up results of the European prospective study of individuls at risk for spinocerebellar ataxia (RISCA) initiative to know more about whether mutation carriers without motor symptoms have sufficient changes in clinical features over time to be included in randomised trials.7,8 The underlying mutations (exonic CAG repeat expansions in spinocerebellar ataxia types 1 and 2 and intronic GAA repeat expansions in Friedreich’s ataxia) are important factors for onset and survival, which are inversely correlated with CAG and GAA repeat length.9,10 Should the interpretation of the results from Romano and colleagues’ study1 have taken different repeats lengths into account? And does the underlying physiopathological mechanism play a part in the response to treatment? The mechanisms of ataxias include mitochondrial dysfunction (Friedreich’s ataxia), abnormal signal transduction (spinocerebellar ataxia type 1), abnormal RNA metabolism and regulation of translation (spinocerebellar ataxia type 2), and channelopathies (spinocerebellar ataxia type 6).11 The neuronal population that degenerates also varies according to genotype. The mechanism of action of riluzole is not known and could differ depending on the underlying disease cause. To take into account the large variety of known and unknown confounding factors in disease progression and treatment response, trials in rare inherited diseases should: be disease-specific, and account for genetic forms of disease and, when applicable, the size of the causative repeat expansion; include randomisation that takes into account the clinical forms of the disease and the number of premanifest individuals; rely on international collaborations to recruit cohorts of sufficient size; and include outcome measures other than SARA that have larger effect sizes. Additionally, future investigators could include qualitative assessments and specific quality of life questionnaires to assess general well being. International efforts to improve trial design for rare diseases have been made. Statistical considerations (frequentist vs Bayesian approaches) and the search for
www.thelancet.com/neurology Published online August 26, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00217-3
Lancet Neurol 2015 Published Online August 26, 2015 http://dx.doi.org/10.1016/ S1474-4422(15)00217-3 See Online/Articles http://dx.doi.org/10.1016/ S1474-4422(15)00201-X
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Comment
biomarkers are certainly important. Markers that allow tracking of disease progression and change in response to treatment are needed. Imaging markers that have shown short-term effect sizes of greater than 1 in similar disorders should be used.12 Change in individual slopes of markers or clinical parameters could be calculated in run-in trials and multimodal integration of biomarkers could be used to detect changes over time. The next step is to determine exactly which subgroups of patients with cerebellar ataxia respond to riluzole and could therefore benefit from treatment.
APHP, Department of Genetics, Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle Épinière, ICM, University Hospital Pitié-Salpêtrière, Paris, France [email protected] I declare no competing interests.
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Alexandra Durr
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Romano S, Coarelli G, Marcotulli C, et al. Riluzole in patients with hereditary cerebellar ataxia: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2015; published online Aug 26. http://dx.doi.org/10.1016/ S1474-4422(15)00201-X.
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Jacobi H, Bauer P, Giunti P, et al. The natural history of spinocerebellar ataxia type 1, 2, 3, and 6: a 2-year follow-up study. Neurology 2011; 77: 1035–41. Tezenas du Montcel S, Charles P, Goizet C, et al. Factors influencing disease progression in autosomal dominant cerebellar ataxia and spastic paraplegia. Arch Neurol 2012; 69: 500–08. Marelli C, Figoni J, Charles P, et al. Annual change in Friedreich’s ataxia evaluated by the Scale for the Assessment and Rating of Ataxia (SARA) is independent of disease severity. Mov Disord 2012; 27: 135–38. Chan E, Charles P, Ribai P, et al. Quantitative assessment of the evolution of cerebellar signs in spinocerebellar ataxias. Mov Disord 2011; 26: 534–38. Schmitz-Hübsch T, Tezenas du Montcel S, Baliko L, et al. Reliability and validity of the International Cooperative Ataxia Rating Scale: a study in 156 spinocerebellar ataxia patients. Mov Disord 2006; 21: 699–704. Jacobi H, Reetz K, du Montcel ST, et al. Biological and clinical characteristics of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 in the longitudinal RISCA study: analysis of baseline data. Lancet Neurol 2013; 12: 650–58. Maas RP, van Gaalen J, Klockgether T, van de Warrenburg BP. The preclinical stage of spinocerebellar ataxias. Neurology 2015; 85: 96–103. Tezenas du Montcel S, Durr A, Rakowicz M, et al. Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6. J Med Genet 2014; 51: 479–86. Monin ML, Tezenas du Montcel S, Marelli C, et al. Survival and severity in dominant cerebellar ataxias. Ann Clin Transl Neurol 2015; 2: 202–07. Orr HT. Cell biology of spinocerebellar ataxia. J Cell Biol 2012; 197: 167–77. Hobbs NZ, Farmer RE, Rees EM, et al. Short-interval observational data to inform clinical trial design in Huntington’s disease. J Neurol Neurosurg Psychiatry 2015; published online Feb 10. DOI:10.1136/jnnp-2014-309768.
www.thelancet.com/neurology Published online August 26, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00217-3
Rare inherited diseases merit disease-specific trials Inherited cerebellar ataxias need therapeutic interventions. A key question is how to run conclusive therapeutic trials. Patient groups are very small, and the risk of being underpowered to test efficacy is important. Cerebellar ataxias, which include a multitude of different, rare genetic entities, are a difficult set of diseases for such studies. In The Lancet Neurology, Romano and colleagues1 present the results of a 12-month, three-centre, double-blind, placebocontrolled trial of riluzole, given at a dose of 50 mg twice daily. The study included 20 patients with Friedreich’s ataxia (10 assigned to riluzole and 10 assigned to placebo), 21 with spinocerebellar ataxia type 1 (11 riluzole and 10 placebo), 16 with spinocerebellar ataxia type 2 (seven riluzole and nine placebo), and one patient each with spinocerebellar ataxia types 6 and 8 (both assigned to riluzole) and type 10 (assigned to placebo). Riluzole had a positive effect based on a decrease in Scale for the Assessment and Rating of Ataxia (SARA) scores (maximum score=40) in 14 (50%) of 28 of the treated patients compared with three (11%) of 27 who received placebo (odds ratio [OR] 8·00, 95% CI 1·95–32·83; p=0·002). This difference in worsening of the cerebellar score should be considered a success, and the investigators are to be congratulated. However, the clinician eager to treat patients is left with some important questions about the design of trials for rare diseases. Is it appropriate to mix different forms of ataxias in a therapeutic trial? We know from natural history studies that the mean SARA score increases at different rates according to genotype (2·18 points per year for spinocerebellar ataxia type 1, 1·40 for spinocerebellar ataxia type 2, and 1·36 for Friedreich’s ataxia; in spinocerebellar ataxia type 6, evolution of the score is not linear).2–4 Confounding factors for SARA evolution are age at inclusion and the presence of other neurological signs.3 The effect size, the sensitivity to change, of SARA remains small (<0·2),5 and this limitation has to be taken into account. Can we include presymptomatic individuals? Five (10%) of the participants who completed the trial had SARA scores of 4 or less. Since a score of 4 is the threshold for differentiating people without manifest ataxia from those with manifest ataxia,6 they could be carriers without cerebellar symptoms. SARA progression does
not seem to be predictable in this group because they had disease durations ranging from 1 to 11 years, and the symptom progression profiles of presymptomatic mutation carriers are not well known. Clinicians are waiting for the follow-up results of the European prospective study of individuls at risk for spinocerebellar ataxia (RISCA) initiative to know more about whether mutation carriers without motor symptoms have sufficient changes in clinical features over time to be included in randomised trials.7,8 The underlying mutations (exonic CAG repeat expansions in spinocerebellar ataxia types 1 and 2 and intronic GAA repeat expansions in Friedreich’s ataxia) are important factors for onset and survival, which are inversely correlated with CAG and GAA repeat length.9,10 Should the interpretation of the results from Romano and colleagues’ study1 have taken different repeats lengths into account? And does the underlying physiopathological mechanism play a part in the response to treatment? The mechanisms of ataxias include mitochondrial dysfunction (Friedreich’s ataxia), abnormal signal transduction (spinocerebellar ataxia type 1), abnormal RNA metabolism and regulation of translation (spinocerebellar ataxia type 2), and channelopathies (spinocerebellar ataxia type 6).11 The neuronal population that degenerates also varies according to genotype. The mechanism of action of riluzole is not known and could differ depending on the underlying disease cause. To take into account the large variety of known and unknown confounding factors in disease progression and treatment response, trials in rare inherited diseases should: be disease-specific, and account for genetic forms of disease and, when applicable, the size of the causative repeat expansion; include randomisation that takes into account the clinical forms of the disease and the number of premanifest individuals; rely on international collaborations to recruit cohorts of sufficient size; and include outcome measures other than SARA that have larger effect sizes. Additionally, future investigators could include qualitative assessments and specific quality of life questionnaires to assess general well being. International efforts to improve trial design for rare diseases have been made. Statistical considerations (frequentist vs Bayesian approaches) and the search for
www.thelancet.com/neurology Published online August 26, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00217-3
Lancet Neurol 2015 Published Online August 26, 2015 http://dx.doi.org/10.1016/ S1474-4422(15)00217-3 See Online/Articles http://dx.doi.org/10.1016/ S1474-4422(15)00201-X
1
Comment
biomarkers are certainly important. Markers that allow tracking of disease progression and change in response to treatment are needed. Imaging markers that have shown short-term effect sizes of greater than 1 in similar disorders should be used.12 Change in individual slopes of markers or clinical parameters could be calculated in run-in trials and multimodal integration of biomarkers could be used to detect changes over time. The next step is to determine exactly which subgroups of patients with cerebellar ataxia respond to riluzole and could therefore benefit from treatment.
APHP, Department of Genetics, Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle Épinière, ICM, University Hospital Pitié-Salpêtrière, Paris, France [email protected] I declare no competing interests.
2
3
4
5 6
7
8
Alexandra Durr
1
2
Romano S, Coarelli G, Marcotulli C, et al. Riluzole in patients with hereditary cerebellar ataxia: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2015; published online Aug 26. http://dx.doi.org/10.1016/ S1474-4422(15)00201-X.
9
10 11 12
Jacobi H, Bauer P, Giunti P, et al. The natural history of spinocerebellar ataxia type 1, 2, 3, and 6: a 2-year follow-up study. Neurology 2011; 77: 1035–41. Tezenas du Montcel S, Charles P, Goizet C, et al. Factors influencing disease progression in autosomal dominant cerebellar ataxia and spastic paraplegia. Arch Neurol 2012; 69: 500–08. Marelli C, Figoni J, Charles P, et al. Annual change in Friedreich’s ataxia evaluated by the Scale for the Assessment and Rating of Ataxia (SARA) is independent of disease severity. Mov Disord 2012; 27: 135–38. Chan E, Charles P, Ribai P, et al. Quantitative assessment of the evolution of cerebellar signs in spinocerebellar ataxias. Mov Disord 2011; 26: 534–38. Schmitz-Hübsch T, Tezenas du Montcel S, Baliko L, et al. Reliability and validity of the International Cooperative Ataxia Rating Scale: a study in 156 spinocerebellar ataxia patients. Mov Disord 2006; 21: 699–704. Jacobi H, Reetz K, du Montcel ST, et al. Biological and clinical characteristics of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 in the longitudinal RISCA study: analysis of baseline data. Lancet Neurol 2013; 12: 650–58. Maas RP, van Gaalen J, Klockgether T, van de Warrenburg BP. The preclinical stage of spinocerebellar ataxias. Neurology 2015; 85: 96–103. Tezenas du Montcel S, Durr A, Rakowicz M, et al. Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6. J Med Genet 2014; 51: 479–86. Monin ML, Tezenas du Montcel S, Marelli C, et al. Survival and severity in dominant cerebellar ataxias. Ann Clin Transl Neurol 2015; 2: 202–07. Orr HT. Cell biology of spinocerebellar ataxia. J Cell Biol 2012; 197: 167–77. Hobbs NZ, Farmer RE, Rees EM, et al. Short-interval observational data to inform clinical trial design in Huntington’s disease. J Neurol Neurosurg Psychiatry 2015; published online Feb 10. DOI:10.1136/jnnp-2014-309768.
www.thelancet.com/neurology Published online August 26, 2015 http://dx.doi.org/10.1016/S1474-4422(15)00217-3