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Lithium in patients with amyotrophic lateral sclerosis (LiCALS): a phase 3 multicentre, randomised, double-blind, placebo-controlled trial

Lookup NU author(s): Dr Nick Steen, Professor David BurnORCiD, Dr Tien Kheng Khoo, Dr Hisham Hamdalla

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Abstract

Background Lithium has neuroprotective effects in cell and animal models of amyotrophic lateral sclerosis (ALS), and a small pilot study in patients with ALS showed a significant effect of lithium on survival. We aimed to assess whether lithium improves survival in patients with ALS.Methods The lithium carbonate in amyotrophic lateral sclerosis (LiCALS) trial is a randomised, double-blind, placebo-controlled trial of oral lithium taken daily for 18 months in patients with MS. Patients aged at least 18 years who had ALS according to the revised El Escorial criteria, had disease duration between 6 and 36 months, and were taking riluzole were recruited from ten centres in the UK. Patients were randomly assigned (1:1) to receive either lithium or matched placebo tablets. Randomisation was via an online system done at the level of the individual by block randomisation with randomly varying block sizes, stratified by study centre and site of disease onset (limb or bulbar). All patients and assessing study personnel were masked to treatment assignment. The primary endpoint was the rate of survival at 18 months and was analysed by intention to treat. This study is registered with Eudract, number 2008-006891-31.Findings Between May 26, 2009, and Nov 10, 2011, 243 patients were screened, 214 of whom were randomly assigned to receive lithium (107 patients) or placebo (107 patients). Two patients discontinued treatment and one died before the target therapeutic lithium concentration could be achieved. 63 (59%) of 107 patients in the placebo group and 54(50%) of 107 patients in the lithium group were alive at 18 months. The survival functions did not differ significantly between groups (Mantel-Cox log-rank chi(2) on 1 df=1.64; p=0.20). After adjusting for study centre and site of onset using logistic regression, the relative odds of survival at 18 months (lithium vs placebo) was 0.71 (95% CI 0.40-1.24). 56 patients in the placebo group and 61 in the lithium group had at least one serious adverse event.Interpretation We found no evidence of benefit of lithium on survival in patients with ALS, but nor were there safety concerns, which had been identified in previous studies with less conventional designs. This finding emphasises the importance of pursuing adequately powered trials with clear endpoints when testing new treatments.


Publication metadata

Author(s): Allen C, Counsell C, Farrin A, Al-Chalabi A, Dickie B, Leigh PN, Murphy CL, Payan C, Reynolds G, Shaw P, Steen IN, Thornhill M, Waters J, Zajicek J, Shaw PJ, Young CA, Morrison KE, Dhariwal S, Hornabrook R, Savage L, Burn DJ, Khoo TK, Kelly J, Dougherty A, Wijesekera L, Ellis CM, O'Hanlon K, Panicker J, Pate L, Ray P, Wyatt L, Young CA, Copeland L, Ealing J, Hamdalla H, Leroi I, Murphy C, O'Keeffe F, Oughton E, Partington L, Paterson P, Rog D, Sathish A, Sexton D, Smith J, Vanek H, Dodds S, Williams TL, Clarke J, Eziefula C, Howard R, Orrell R, Sidle K, Sylvester R, Barrett W, Merritt C, Talbot K, Turner MR, Talbot K, Williams C, Williams J, Cosby C, Hanemann CO, Imam I, Phillips C, Timings L, Crawford SE, Hewamadduma C, Hibberd R, Hollinger H, McDermott C, Mills G, Rafiq M, Taylor A, Waines E, Walsh T, Addison-Jones R, Birt J, Hare M, Majid T, UKMND-LiCALS Study Grp

Publication type: Article

Publication status: Published

Journal: Lancet Neurology

Year: 2013

Volume: 12

Issue: 4

Pages: 339-345

Print publication date: 01/04/2013

Online publication date: 27/02/2013

ISSN (print): 1474-4422

ISSN (electronic): 1474-4465

Publisher: Elsevier

URL: http://dx.doi.org/10.1016/S1474-4422(13)70037-1

DOI: 10.1016/S1474-4422(13)700374


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