van Eijk, Ruben PA, Jones, Ashley R, Sproviero, William, Shatunov, Aleksey 
ORCID: 0000-0002-2671-8040, Shaw, Pamela J, Leigh, P Nigel, Young, Carolyn A ORCID: 0000-0001-6971-8203, Shaw, Christopher E, Mora, Gabriele, Mandrioli, Jessica et al (show 12 more authors)
(2017)
Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials.
NEUROLOGY, 89 (18).
pp. 1915-1922.
Abstract
<h4>Objective</h4>To assess whether genetic subgroups in recent amyotrophic lateral sclerosis (ALS) trials responded to treatment with lithium carbonate, but that the treatment effect was lost in a large cohort of nonresponders.<h4>Methods</h4>Individual participant data were obtained from 3 randomized trials investigating the efficacy of lithium carbonate. We matched clinical data with data regarding the <i>UNC13A</i> and <i>C9orf72</i> genotype. Our primary outcome was survival at 12 months. On an exploratory basis, we assessed whether the effect of lithium depended on the genotype.<h4>Results</h4>Clinical data were available for 518 of the 606 participants. Overall, treatment with lithium carbonate did not improve 12-month survival (hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.7-1.4; <i>p</i> = 0.96). Both the <i>UNC13A</i> and <i>C9orf72</i> genotype were independent predictors of survival (HR 2.4, 95% CI 1.3-4.3; <i>p</i> = 0.006 and HR 2.5, 95% CI 1.1-5.2; <i>p</i> = 0.032, respectively). The effect of lithium was different for <i>UNC13A</i> carriers (<i>p</i> = 0.027), but not for <i>C9orf72</i> carriers (<i>p</i> = 0.22). The 12-month survival probability for <i>UNC13A</i> carriers treated with lithium carbonate improved from 40.1% (95% CI 23.2-69.1) to 69.7% (95% CI 50.4-96.3).<h4>Conclusions</h4>This study incorporated genetic data into past ALS trials to determine treatment effects in a genetic post hoc analysis. Our results suggest that we should reorient our strategies toward finding treatments for ALS, start focusing on genotype-targeted treatments, and standardize genotyping in order to optimize randomization and analysis for future clinical trials.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | For UKMND-LiCALS and LITALS Study Group, Amyotrophic Lateral Sclerosis, Lithium Carbonate, Proteins, Nerve Tissue Proteins, Neuroprotective Agents, Proportional Hazards Models, Pharmacogenetics, Genotype, Randomized Controlled Trials as Topic, C9orf72 Protein |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 08 Feb 2019 12:01 |
| Last Modified: | 19 Jan 2023 01:04 |
| DOI: | 10.1212/WNL.0000000000004606 |
| Open Access URL: | http://10.0.4.188/WNL.0000000000004606 |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3032525 |
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