Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials
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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.
GLOSSARY
- ALS=
- amyotrophic lateral sclerosis;
- ALSFRS-R=
- Amyotrophic Lateral Sclerosis Functional Rating Scale–revised;
- CI=
- confidence interval;
- GWAS=
- genome-wide association studies;
- HR=
- hazard ratio;
- IPD=
- individual participant data;
- SNP=
- single nucleotide polymorphism
Footnotes
↵* These principal investigators contributed equally to this work.
Members of the UKMND-LiCALS and LITALS Study Group are listed at Neurology.org.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was funded by Research Councils UK.
Supplemental data at Neurology.org
Editorial, page 1850
- Received May 19, 2017.
- Accepted in final form August 18, 2017.
- Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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