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Analysis of the KIFAP3 gene in amyotrophic lateral sclerosis: a multicenter survival study.

ABSTRACT: Sporadic amyotrophic lateral sclerosis is a multifactorial disease of environmental and genetic origin. In a previous large multicenter genome wide study, common genetic variation in the Kinesin-Associated Protein 3 (KIFAP3) gene (rs1541160) was reported to have a significant effect on survival in amyotrophic lateral sclerosis patients. However, this could not be replicated in 3 smaller independent cohorts. We conducted a large multicenter multivariate survival analysis (n = 2362) on the effect of genetic variation in rs1541160. The previously reported beneficial genotype did not show a significant improvement in survival in this patient group.

SUBMITTER: van Doormaal PT

PROVIDER: S-EPMC5496711 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Analysis of the KIFAP3 gene in amyotrophic lateral sclerosis: a multicenter survival study.

van Doormaal Perry T C PT Ticozzi Nicola N Gellera Cinzia C Ratti Antonia A Taroni Franco F Chiò Adriano A Calvo Andrea A Mora Gabriele G Restagno Gabriella G Traynor Bryan J BJ Birve Anna A Lemmens Robin R van Es Michael A MA Saris Christiaan G J CG Blauw Hylke M HM van Vught Paul W J PW Groen Ewout J N EJ Corrado Lucia L Mazzini Letizia L Del Bo Roberto R Corti Stefania S Waibel Stefan S Meyer Thomas T Ludolph Albert C AC Goris An A van Damme Philip P Robberecht Wim W Shatunov Aleksey A Fogh Isabella I Andersen Peter M PM D'Alfonso Sandra S Hardiman Orla O Cronin Simon S Rujescu Dan D Al-Chalabi Ammar A Landers John E JE Silani Vincenzo V van den Berg Leonard H LH Veldink Jan H JH

Neurobiology of aging 20140419 10

Sporadic amyotrophic lateral sclerosis is a multifactorial disease of environmental and genetic origin. In a previous large multicenter genome wide study, common genetic variation in the Kinesin-Associated Protein 3 (KIFAP3) gene (rs1541160) was reported to have a significant effect on survival in amyotrophic lateral sclerosis patients. However, this could not be replicated in 3 smaller independent cohorts. We conducted a large multicenter multivariate survival analysis (n = 2362) on the effect ...[more]

PMID: 24838185

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Project description:BackgroundA randomized, placebo-controlled phase III study (AB10015) previously demonstrated that orally administered masitinib (4.5 mg/kg/day) slowed rate of functional decline, with acceptable safety, in amyotrophic lateral sclerosis (ALS) patients having an ALS Functional Rating Scale-revised (ALSFRS-R) progression rate from disease onset to baseline of <1.1 points/month. Here we assess long-term overall survival (OS) data of all participants from study AB10015 and test whether a signal in OS is evident in an enriched patient population similar to that prospectively defined for confirmatory study AB19001.MethodsSurvival status of all patients originally randomized in AB10015 was collected from participating investigational sites. Survival analysis (using the multivariate log-rank test and Cox proportional hazards model, with stratification factors as covariates) was performed on the intention-to-treat population and enriched subgroups, which were defined according to initial randomization, baseline ALSFRS-R progression rate and baseline disease severity.ResultsA significant survival benefit of 25 months (p = 0.037) and 47% reduced risk of death (p = 0.025) was observed for patients receiving 4.5 mg/kg/day masitinib (n = 45) versus placebo (n = 62) in an enriched cohort with ⩾2 on each baseline ALSFRS-R individual component score (i.e. prior to any complete loss or severe impairment of functionality) and post-onset ALSFRS-R progression rate <1.1 (i.e. exclusion of very fast progressors) [median OS of 69 versus 44 months, respectively; hazard ratio, 0.53 [95% CI (0.31-0.92)]]. This corresponds to the population enrolled in confirmatory phase III study, AB19001.ConclusionsAnalysis of long-term OS (75 months average follow-up from diagnosis) indicates that oral masitinib (4.5 mg/kg/day) could prolong survival by over 2 years as compared with placebo, provided that treatment starts prior to severe impairment of functionality.This trial was registered at www.ClinicalTrials.gov under identifier NCT02588677 (28 October 2015).

Dataset Information

Analysis of the KIFAP3 gene in amyotrophic lateral sclerosis: a multicenter survival study.

Publications

Analysis of the KIFAP3 gene in amyotrophic lateral sclerosis: a multicenter survival study.

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