Lithium in patients with amyotrophic lateral sclerosis (LiCALS)

a phase 3 multicentre, randomised, double-blind, placebo-controlled trial

A. Al-Chalabi, C.M. Allen, C. E. Counsell, A. Farrin, B.G. Dickie, J.B. Kelly, P.N. Leigh, C.L. Murphy, C.A.M. Payan, G. Reynolds, P.J. Shaw, I.N. Steen, M. Thornhill, J. Waters, J. Zajicek, C. A. Young, Karen E. Morrison, S. Dhariwal, R. Hornabrook, L. Savage & 60 others D. J. Burn, T. K. Khoo, J Kelly, A. Dougherty, L. Wijesekera, M. Thornhill, C. M. Ellis, K. O'Hanlon, J. Panicker, L. Pate, P. Ray, L. Wyatt, L. Copeland, J. Ealing, H. Hamdalla, I. Leroi, C. Murphy, F. O'Keeffe, E. Oughton, L. Partington, P. Paterson, D. Rog, A. Sathish, D. Sexton, J. Smith, H. Vanek, S. Dodds, T. L. Williams, J. Clarke, C. Eziefula, R. Howard, R. Orrell, K. Sidle, R. Sylvester, W. Barrett, C. Merritt, K. Talbot, M. R. Turner, C. Whatley, C. Williams, J. Williams, C. Cosby, C. O. Hanemann, I. Imam, C. Phillips, L. Timings, S. E. Crawford, C. Hewamadduma, R. Hibberd, H. Hollinger, C. McDermott, G. Mills, M. Rafiq, A. Taylor, E. Waines, T. Walsh, R. Addison-Jones, J. Birt, M. Hare, T. Majid

Research output: Contribution to journalArticle

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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 ALS. 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 χ2 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. Funding: The Motor Neurone Disease Association of Great Britain and Northern Ireland.
Original languageEnglish
Pages (from-to)339-345
Number of pages7
JournalThe Lancet neurology
Volume12
Issue number4
DOIs
Publication statusPublished - 1 Apr 2013

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Lithium Carbonate
Amyotrophic Lateral Sclerosis
Lithium
Placebos
Survival
Random Allocation
Riluzole
Online Systems
Northern Ireland
Motor Neuron Disease
Neuroprotective Agents
Therapeutics

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Lithium in patients with amyotrophic lateral sclerosis (LiCALS) : a phase 3 multicentre, randomised, double-blind, placebo-controlled trial. / Al-Chalabi, A.; Allen, C.M.; Counsell, C. E.; Farrin, A.; Dickie, B.G.; Kelly, J.B.; Leigh, P.N.; Murphy, C.L.; Payan, C.A.M.; Reynolds, G.; Shaw, P.J.; Steen, I.N.; Thornhill, M.; Waters, J.; Zajicek, J.; Young, C. A.; Morrison, Karen E.; Dhariwal, S.; Hornabrook, R.; Savage, L.; Burn, D. J.; Khoo, T. K.; Kelly, J; Dougherty, A.; Wijesekera, L.; Thornhill, M.; Ellis, C. M.; O'Hanlon, K.; Panicker, J.; Pate, L.; Ray, P.; Wyatt, L.; 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, T. L.; Clarke, J.; Eziefula, C.; Howard, R.; Orrell, R.; Sidle, K.; Sylvester, R.; Barrett, W.; Merritt, C.; Talbot, K.; Turner, M. R.; Whatley, C.; Williams, C.; Williams, J.; Cosby, C.; Hanemann, C. O.; Imam, I.; Phillips, C.; Timings, L.; Crawford, S. E.; 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.

In: The Lancet neurology, Vol. 12, No. 4, 01.04.2013, p. 339-345.

Research output: Contribution to journalArticle

Al-Chalabi, A, Allen, CM, Counsell, CE, Farrin, A, Dickie, BG, Kelly, JB, Leigh, PN, Murphy, CL, Payan, CAM, Reynolds, G, Shaw, PJ, Steen, IN, Thornhill, M, Waters, J, Zajicek, J, Young, CA, Morrison, KE, Dhariwal, S, Hornabrook, R, Savage, L, Burn, DJ, Khoo, TK, Kelly, J, Dougherty, A, Wijesekera, L, Thornhill, M, Ellis, CM, O'Hanlon, K, Panicker, J, Pate, L, Ray, P, Wyatt, L, 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, Whatley, C, 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 2013, 'Lithium in patients with amyotrophic lateral sclerosis (LiCALS): a phase 3 multicentre, randomised, double-blind, placebo-controlled trial', The Lancet neurology, vol. 12, no. 4, pp. 339-345. https://doi.org/10.1016/S1474-4422(13)70037-1
Al-Chalabi, A. ; Allen, C.M. ; Counsell, C. E. ; Farrin, A. ; Dickie, B.G. ; Kelly, J.B. ; Leigh, P.N. ; Murphy, C.L. ; Payan, C.A.M. ; Reynolds, G. ; Shaw, P.J. ; Steen, I.N. ; Thornhill, M. ; Waters, J. ; Zajicek, J. ; Young, C. A. ; Morrison, Karen E. ; Dhariwal, S. ; Hornabrook, R. ; Savage, L. ; Burn, D. J. ; Khoo, T. K. ; Kelly, J ; Dougherty, A. ; Wijesekera, L. ; Thornhill, M. ; Ellis, C. M. ; O'Hanlon, K. ; Panicker, J. ; Pate, L. ; Ray, P. ; Wyatt, L. ; 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, T. L. ; Clarke, J. ; Eziefula, C. ; Howard, R. ; Orrell, R. ; Sidle, K. ; Sylvester, R. ; Barrett, W. ; Merritt, C. ; Talbot, K. ; Turner, M. R. ; Whatley, C. ; Williams, C. ; Williams, J. ; Cosby, C. ; Hanemann, C. O. ; Imam, I. ; Phillips, C. ; Timings, L. ; Crawford, S. E. ; 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. / Lithium in patients with amyotrophic lateral sclerosis (LiCALS) : a phase 3 multicentre, randomised, double-blind, placebo-controlled trial. In: The Lancet neurology. 2013 ; Vol. 12, No. 4. pp. 339-345.
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title = "Lithium in patients with amyotrophic lateral sclerosis (LiCALS): a phase 3 multicentre, randomised, double-blind, placebo-controlled trial",
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 ALS. 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 χ2 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. Funding: The Motor Neurone Disease Association of Great Britain and Northern Ireland.",
author = "A. Al-Chalabi and C.M. Allen and Counsell, {C. E.} and A. Farrin and B.G. Dickie and J.B. Kelly and P.N. Leigh and C.L. Murphy and C.A.M. Payan and G. Reynolds and P.J. Shaw and I.N. Steen and M. Thornhill and J. Waters and J. Zajicek and Young, {C. A.} and Morrison, {Karen E.} and S. Dhariwal and R. Hornabrook and L. Savage and Burn, {D. J.} and Khoo, {T. K.} and J Kelly and A. Dougherty and L. Wijesekera and M. Thornhill and Ellis, {C. M.} and K. O'Hanlon and J. Panicker and L. Pate and P. Ray and L. Wyatt and L. Copeland and J. Ealing and H. Hamdalla and I. Leroi and C. Murphy and F. O'Keeffe and E. Oughton and L. Partington and P. Paterson and D. Rog and A. Sathish and D. Sexton and J. Smith and H. Vanek and S. Dodds and Williams, {T. L.} and J. Clarke and C. Eziefula and R. Howard and R. Orrell and K. Sidle and R. Sylvester and W. Barrett and C. Merritt and K. Talbot and Turner, {M. R.} and C. Whatley and C. Williams and J. Williams and C. Cosby and Hanemann, {C. O.} and I. Imam and C. Phillips and L. Timings and Crawford, {S. E.} and C. Hewamadduma and R. Hibberd and H. Hollinger and C. McDermott and G. Mills and M. Rafiq and A. Taylor and E. Waines and T. Walsh and R. Addison-Jones and J. Birt and M. Hare and T. Majid",
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TY - JOUR

T1 - Lithium in patients with amyotrophic lateral sclerosis (LiCALS)

T2 - a phase 3 multicentre, randomised, double-blind, placebo-controlled trial

AU - Al-Chalabi, A.

AU - Allen, C.M.

AU - Counsell, C. E.

AU - Farrin, A.

AU - Dickie, B.G.

AU - Kelly, J.B.

AU - Leigh, P.N.

AU - Murphy, C.L.

AU - Payan, C.A.M.

AU - Reynolds, G.

AU - Shaw, P.J.

AU - Steen, I.N.

AU - Thornhill, M.

AU - Waters, J.

AU - Zajicek, J.

AU - Young, C. A.

AU - Morrison, Karen E.

AU - Dhariwal, S.

AU - Hornabrook, R.

AU - Savage, L.

AU - Burn, D. J.

AU - Khoo, T. K.

AU - Kelly, J

AU - Dougherty, A.

AU - Wijesekera, L.

AU - Thornhill, M.

AU - Ellis, C. M.

AU - O'Hanlon, K.

AU - Panicker, J.

AU - Pate, L.

AU - Ray, P.

AU - Wyatt, L.

AU - Copeland, L.

AU - Ealing, J.

AU - Hamdalla, H.

AU - Leroi, I.

AU - Murphy, C.

AU - O'Keeffe, F.

AU - Oughton, E.

AU - Partington, L.

AU - Paterson, P.

AU - Rog, D.

AU - Sathish, A.

AU - Sexton, D.

AU - Smith, J.

AU - Vanek, H.

AU - Dodds, S.

AU - Williams, T. L.

AU - Clarke, J.

AU - Eziefula, C.

AU - Howard, R.

AU - Orrell, R.

AU - Sidle, K.

AU - Sylvester, R.

AU - Barrett, W.

AU - Merritt, C.

AU - Talbot, K.

AU - Turner, M. R.

AU - Whatley, C.

AU - Williams, C.

AU - Williams, J.

AU - Cosby, C.

AU - Hanemann, C. O.

AU - Imam, I.

AU - Phillips, C.

AU - Timings, L.

AU - Crawford, S. E.

AU - Hewamadduma, C.

AU - Hibberd, R.

AU - Hollinger, H.

AU - McDermott, C.

AU - Mills, G.

AU - Rafiq, M.

AU - Taylor, A.

AU - Waines, E.

AU - Walsh, T.

AU - Addison-Jones, R.

AU - Birt, J.

AU - Hare, M.

AU - Majid, T.

PY - 2013/4/1

Y1 - 2013/4/1

N2 - 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 ALS. 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 χ2 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. Funding: The Motor Neurone Disease Association of Great Britain and Northern Ireland.

AB - 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 ALS. 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 χ2 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. Funding: The Motor Neurone Disease Association of Great Britain and Northern Ireland.

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U2 - 10.1016/S1474-4422(13)70037-1

DO - 10.1016/S1474-4422(13)70037-1

M3 - Article

VL - 12

SP - 339

EP - 345

JO - The Lancet neurology

JF - The Lancet neurology

SN - 1474-4422

IS - 4

ER -