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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, P 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.
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  • van Eijk RPA; From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdo
  • Jones AR; From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdo
  • Sproviero W; From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdo
  • Shatunov A; From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdo
  • Shaw PJ; From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdo
  • Leigh PN; From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdo
  • Young CA; From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdo
  • Shaw CE; From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdo
  • Mora G; From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdo
  • Mandrioli J; From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdo
  • Borghero G; From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdo
  • Volanti P; From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdo
  • Diekstra FP; From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdo
  • van Rheenen W; From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdo
  • Verstraete E; From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdo
  • Eijkemans MJC; From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdo
  • Veldink JH; From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdo
  • Chio A; From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdo
  • Al-Chalabi A; From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdo
  • van den Berg LH; From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdo
  • van Es MA; From the Department of Neurology, Brain Centre Rudolf Magnus (R.P.A.v.E., F.P.D., W.v.R., J.H.V., L.H.v.d.B., M.A.v.E.), and Department of Biostatistics and Research Support (M.J.C.E.), University Medical Centre Utrecht, the Netherlands; Maurice Wohl Clinical Neuroscience Institute and United Kingdo
Neurology ; 89(18): 1915-1922, 2017 Oct 31.
Article en En | MEDLINE | ID: mdl-28978660
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.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Farmacogenética / Ensayos Clínicos Controlados Aleatorios como Asunto / Fármacos Neuroprotectores / Esclerosis Amiotrófica Lateral Tipo de estudio: Clinical_trials / Prognostic_studies / Systematic_reviews Idioma: En Revista: Neurology Año: 2017 Tipo del documento: Article
Texto completo
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Farmacogenética / Ensayos Clínicos Controlados Aleatorios como Asunto / Fármacos Neuroprotectores / Esclerosis Amiotrófica Lateral Tipo de estudio: Clinical_trials / Prognostic_studies / Systematic_reviews Idioma: En Revista: Neurology Año: 2017 Tipo del documento: Article