Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials

van Eijk, Ruben P A, Jones, Ashley R, Sproviero, William, Shatunov, Aleksey, Shaw, Pamela J, Leigh, Nigel, Young, Carolyn A, Shaw, Christopher E, Mora, Gabriele, Mandrioli, Jessica, Borghero, Giuseppe, Volanti, Paolo, Diekstra, Frank P, van Rheenen, Wouter, Verstraete, Esther, Eijkemans, Marinus J C, Veldink, Jan H, Chio, Adriano, Al-Chalabi, Ammar, van den Berg, Leonard H, van Es, Michael A and Unset (2017) Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials. Neurology, 89 (18). pp. 1915-1922. ISSN 1526-632X

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Abstract

OBJECTIVE

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.

METHODS

Individual participant data were obtained from 3 randomized trials investigating the efficacy of lithium carbonate. We matched clinical data with data regarding the UNC13A and C9orf72 genotype. Our primary outcome was survival at 12 months. On an exploratory basis, we assessed whether the effect of lithium depended on the genotype.

RESULTS

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; p = 0.96). Both the UNC13A and C9orf72 genotype were independent predictors of survival (HR 2.4, 95% CI 1.3-4.3; p = 0.006 and HR 2.5, 95% CI 1.1-5.2; p = 0.032, respectively). The effect of lithium was different for UNC13A carriers (p = 0.027), but not for C9orf72 carriers (p = 0.22). The 12-month survival probability for UNC13A carriers treated with lithium carbonate improved from 40.1% (95% CI 23.2-69.1) to 69.7% (95% CI 50.4-96.3).

CONCLUSIONS

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
Schools and Departments: Brighton and Sussex Medical School > Neuroscience
Subjects: R Medicine > R Medicine (General) > R852 Research. Experimentation > R853.C55 Clinical trials
R Medicine > RC Internal medicine > RC0321 Neurosciences. Biological psychiatry. Neuropsychiatry > RC0346 Neurology. Diseases of the nervous system Including speech disorders
Depositing User: Patricia Butler
Date Deposited: 23 Jan 2018 16:09
Last Modified: 23 Jan 2018 16:10
URI: http://sro.sussex.ac.uk/id/eprint/73090

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