2026-04-13T05:54:33Zhttps://recercat.cat/oai/request

oai:recercat.cat:11351/135572025-10-24T10:24:58Zcom_2072_378070com_2072_378040col_2072_378092

00925njm 22002777a 4500 dc Mengel, Eugen author Patterson, Marc author Da Riol, Rosalia M. author Deodato, Federica author Gautschi, Matthias author del Toro, Mireia author 2025-08-21T08:42:47Z 2025-08-21T08:42:47Z 2025-06 Arimoclomol; NPC clinical severity scale; Niemann-Pick disease type C Arimoclomol; Escala de gravetat clínica de la NPC; Malaltia de Niemann-Pick tipus C Arimoclomol; Escala de gravedad clínica de la NPC; Enfermedad de Niemann-Pick tipo C Background In the 12-month, randomized, double-blind, placebo-controlled Phase 2/3 NPC-002 study (NCT02612129), arimoclomol significantly reduced annual disease progression versus placebo, measured by the 5-domain NPC Clinical Severity Scale (5DNPCCSS). Arimoclomol has been approved in the US for treatment of Niemann-Pick disease type C (NPC) in combination with miglustat. This paper introduces the rescored 4-domain NPCCSS (R4DNPCCSS) as a post-hoc primary endpoint in NPC-002, discusses its validation, and presents the results of the post-hoc primary analysis. Methods To more accurately assess changes in disease course over a 12-month time period in a heterogeneous group of patients, the Cognition domain was removed from the 5DNPCCSS and the Swallow domain was rescored to reflect linearity in disease progression. Rescoring of the Swallow domain was based on input from clinical NPC and swallow experts from a qualitative interview-based study (N = 12), resulting in the R4DNPCCSS. To supplement prior validation analyses, data supporting the overall validity and reliability of the R4DNPCCSS was gathered through additional analyses of construct and convergent validity. The NPC-002 prespecified primary efficacy endpoint analysis based on the 5DNPCCSS score change from baseline to 12 months was repeated with R4DNPCCSS. Results Construct validity analysis demonstrated high agreement between the R4DNPCCSS domain scores and the Clinical Global Impression Scale of Severity (CGI-S) and NPC Clinical Database (NPC-cdb) scores. Convergent validity was confirmed by strong correlations between the R4DNPCCSS domains and corresponding items on the Scale for Assessment and Rating of Ataxia (SARA), 9-hole peg test (9-HPT), and Video Fluoroscopic Swallowing Study (VFSS) performance tests. The NPC-002 post-hoc primary analysis showed a mean standard error (SE) change in R4DNPCCSS score of 0.35 (0.40) with arimoclomol (N = 34) versus 2.05 (0.54) with placebo (N = 16), and a treatment effect in favor of arimoclomol over placebo of −1.70 (p = 0.0155). In the miglustat subgroup analysis, mean (SE) change in R4DNPCCSS score was −0.23 (1.02) with arimoclomol (N = 22) versus 1.92 (3.37) with placebo (N = 12), representing a treatment effect of −2.21 (p = 0.0077). Conclusion The R4DNPCCSS is a valid and reliable measure of disease progression demonstrating consistent outcomes with the prespecified 5DNPCCSS endpoint. Arimoclomol significantly slowed disease progression through 12 months as measured by the R4DNPCCSS versus placebo. The research was funded by Zevra Therapeutics Inc. http://hdl.handle.net/11351/13557 Avaluació de resultats (Assistència sanitària) Malalties per dipòsit lisosòmic - Tractament ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT::Diagnosis::Prognosis::Treatment Outcome DISEASES::Nervous System Diseases::Central Nervous System Diseases::Brain Diseases::Brain Diseases, Metabolic::Brain Diseases, Metabolic, Inborn::Lysosomal Storage Diseases, Nervous System::Sphingolipidoses::Niemann-Pick Diseases::Niemann-Pick Disease, Type C Other subheadings::Other subheadings::Other subheadings::/drug therapy CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Physiological Effects of Drugs::Protective Agents::Neuroprotective Agents Other subheadings::Other subheadings::/therapeutic use TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS::diagnóstico::pronóstico::resultado del tratamiento ENFERMEDADES::enfermedades del sistema nervioso::enfermedades del sistema nervioso central::enfermedades cerebrales::enfermedades cerebrales metabólicas::enfermedades cerebrales metabólicas congénitas::enfermedades por almacenamiento lisosómico del sistema nervioso::esfingolipidosis::enfermedades de Niemann-Pick::enfermedad de Niemann-Pick tipo c Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::efectos fisiológicos de los fármacos::sustancias protectoras::fármacos neuroprotectores Otros calificadores::Otros calificadores::/uso terapéutico Efficacy results from a 12-month double-blind randomized trial of arimoclomol for treatment of Niemann-Pick disease type C (NPC): Presenting a rescored 4-domain NPC Clinical Severity Scale