Comment

High-calorie diets in amyotrophic lateral sclerosis Wills and colleagues reported that the two highcalorie diets were well tolerated and seemed to be safe—notably, participants who received the highcarbohydrate hypercaloric diet had fewer adverse events than did those in the other groups (23 events vs 42 in the control group and 48 in the high-fat hypercaloric diet group), though not significantly so, and significantly fewer serious adverse events than did those on the control diet (none vs nine). These are key findings that pave the way for a large-scale interventional study of diet in patients with amyotrophic lateral sclerosis. The investigators also assessed survival as an exploratory endpoint, and reported that none of nine patients assigned to the high-carbohydrate hypercaloric diet died during the 5 month followup, compared with three (43%) of seven patients assigned to the control group (log-rank p=0·03) and one (13%) of eight in the high-fat hypercaloric diet group. The survival component of this study is the crucial issue. The ease with which dietary changes can be made by patients, and the apparent safety of calorie augmentation shown, mean that the reported survival benefit of the high-carbohydrate hypercaloric diet might be regarded as sufficient evidence to change to such a diet, either through the recommendation of a neurologist, or as a self-prescribed treatment. But should high-carbohydrate, high-calorie diets now be prescribed to patients with amyotrophic lateral sclerosis? Good background evidence supports the

www.thelancet.com Published online February 28, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60270-1

Published Online February 28, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)60270-1 See Online/Articles http://dx.doi.org/10.1016/ S0140-6736(14)60222-1

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Amyotrophic lateral sclerosis has a cumulative lifetime risk of about one in 400,1 has no effective treatment, and is a greatly feared diagnosis because it progressively paralyses voluntary muscles, including those used for breathing, potentially leaving an affected person in a so-called locked-in state until they die from respiratory failure. Not surprisingly, amyotrophic lateral sclerosis is the most common reason why people attempt suicide or seek assisted suicide.2,3 Therefore, any therapy that might improve survival is seized upon by patients and doctors alike. However, the findings of clinical trials of treatments for this disease need to be put into perspective, particularly those of small phase 2 trials, because results can suggest a benefit that is not later confirmed.4–7 In The Lancet, Anne-Marie Wills and colleagues8 report important findings of a well executed but small randomised controlled phase 2 trial examining increased calorie intake in patients with amyotrophic lateral sclerosis, an approach rapidly gaining interest because of its simplicity, apparent safety, and potential benefit. Because dietary change does not need a prescription, and could be practised by almost anyone, the safety of a high-calorie diet in these patients should be confirmed, and safety and tolerability were the primary endpoints of the study. The researchers randomly assigned 24 people with amyotrophic lateral sclerosis who were already using gastrostomy feeding to one of three diets: calorie intake tailored to match calorie expenditure (isocaloric diet), a high-carbohydrate diet designed to provide an excess of calories, and a high-fat diet also designed to provide an excess of calories. The reasons why a high-calorie diet might be an effective treatment for amyotrophic lateral sclerosis are related to the mounting evidence that this disease induces a hypermetabolic state,9 and that countering the increased metabolism might improve outcomes. This theory is supported by studies showing that high-calorie diets improve survival in mice with amyotrophic lateral sclerosis.10 Furthermore, people with amyotrophic lateral sclerosis tend to consume fewer calories than they need,11 and mild obesity and high fasting serum lipid concentrations at diagnosis are associated with longer survival in people with the disease,12,13 whereas malnourishment is associated with a worse prognosis.14

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intervention, and now the results of this study show that it is safe and apparently improves survival. However, the study was too small to provide survival results that can be relied on for clinical decisions. Experience with lithium and other trial therapies in amyotrophic lateral sclerosis shows that apparent benefit in phase 2 studies can be misleading.4–7 Participants in the study had already lost an average of 20% of their bodyweight before receiving the study diet, and gastrostomy feeding tends to occur in the later stages of amyotrophic lateral sclerosis, also restricting how easily the findings can be generalised. For example, a different or larger effect on safety or survival might be noted if the intervention was implemented earlier in the disease course, and the surprising absence of benefit from the high-lipid, high-calorie diet might have been a result of late intervention. Even in terms of safety, the trial size meant that the study was only powered to detect a high level of harm. Therefore, as the investigators suggest, a large phase 3 trial to examine survival in each of the three diets at an earlier disease stage is essential. Unfortunately, such a study might now be difficult to undertake because patients might take it upon themselves to make the dietary changes as a result of these findings, such that a control group could not be guaranteed, even in a patient-directed trial design such as that suggested by the patient network PatientsLikeMe.15 I will not be changing my advice to patients on the basis of this study, but am eager to see the results of a large phase 3 trial. Wills and colleagues8 have taken the first steps needed to provide evidence for a potentially robust, non-pharmacological treatment for amyotrophic lateral sclerosis that is well tolerated and easy to administer, but the work that they have started must be finished before any solid conclusions can be drawn.

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Ammar Al-Chalabi King’s College London, Institute of Psychiatry, London SE5 8AF, UK [email protected] I have received personal fees from Biogen Idec, Cytokinetics, GlaxoSmithKline, Chronos Therapeutics, and Daval International, all unrelated to the topic of this Comment. 1

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Johnston CA, Stanton BR, Turner MR, al. Amyotrophic lateral sclerosis in an urban setting: a population based study of inner city London. J Neurol 2006; 253: 1642–43. Fang F, Valdimarsdóttir U, Fürst CJ, et al. Suicide among patients with amyotrophic lateral sclerosis. Brain 2008; 131: 2729–33. Maessen M, Veldink JH, van den Berg LH, Schouten HJ, van der Wal G, Onwuteaka-Philipsen BD. Requests for euthanasia: origin of suffering in ALS, heart failure, and cancer patients. J Neurol 2010; 257: 1192–98. Fornai F, Longone P, Cafaro L, et al. Lithium delays progression of amyotrophic lateral sclerosis. Proc Natl Acad Sci USA 2008; 105: 2052–57. UKMND-LiCALS Study Group. Lithium in patients with amyotrophic lateral sclerosis (LiCALS): a phase 3 multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2013; 12: 339–45. Rudnicki SA, Berry JD, Ingersoll E, et al. Dexpramipexole effects on functional decline and survival in subjects with amyotrophic lateral sclerosis in a phase II study: subgroup analysis of demographic and clinical characteristics. Amyotroph Lateral Scler Frontotemporal Degener 2013; 14: 44–51. Cudkowicz ME, van den Berg LH, Shefner JM, et al, for the EMPOWER investigators. Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial. Lancet Neurol 2013; 12: 1059–67. Wills A-M, Hubbard J, Macklin EA, et al, for the MDA Clinical Research Network. Hypercaloric enteral nutrition in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet 2014; published online Feb 28. http://dx.doi.org/10.1016/S01406736(14)60222-1. Bouteloup C, Desport JC, Clavelou P, et al. Hypermetabolism in ALS patients: an early and persistent phenomenon. J Neurol 2009; 256: 1236–42. Dupuis L, Oudart H, Rene F, Gonzalez de Aguilar JL, Loeffler JP. Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model. Proc Natl Acad Sci USA 2004; 101: 11159–64. Kasarskis EJ, Berryman S, Vanderleest JG, Schneider AR, McClain CJ. Nutritional status of patients with amyotrophic lateral sclerosis: relation to the proximity of death. Am J Clin Nutr 1996; 63: 130–37. Dupuis L, Corcia P, Fergani A, et al. Dyslipidemia is a protective factor in amyotrophic lateral sclerosis. Neurology 2008; 70: 1004–09. Dorst J, Kuhnlein P, Hendrich C, Kassubek J, Sperfeld AD, Ludolph AC. Patients with elevated triglyceride and cholesterol serum levels have a prolonged survival in amyotrophic lateral sclerosis. J Neurol 2011; 258: 613–17. Marin B, Desport JC, Kajeu P, et al. Alteration of nutritional status at diagnosis is a prognostic factor for survival of amyotrophic lateral sclerosis patients. J Neurol Neurosurg Psychiatry 2011; 82: 628–34. Wicks P, Vaughan T, Heywood J. Subjects no more: what happens when trial participants realize they hold the power? BMJ 2014; 348: g368.

www.thelancet.com Published online February 28, 2014 http://dx.doi.org/10.1016/S0140-6736(14)60270-1

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