Consistently High Agreement Between Independent Raters of Niemann-Pick Type C1 Clinical Severity Scale in Phase 2/3 Trial

Background: Niemann-Pick disease, type C1 (NPC1) is a rare neurodegenerative genetic disorder characterized by impaired intracellular transport of cholesterol and other lipids. The Niemann-Pick Disease, type C1 Severity Scale (NPC-SS) was developed to quantify neurological progression of NPC; it is used to monitor the natural history of disease progression and assess response to treatment. The objective of the study was to examine the interrater reliability of the NPC-SS in a phase 2/3 trial. Methods: Study data were from a multicenter, prospective, randomized, double-blind trial of adrabetadex in 56 subjects with NPC1. Clinical data recorded at each study site were distributed to two independent blinded central raters to generate a severity score. A composite four-item score was utilized as the primary clinical study end point, whereas a five-item focused score has been utilized in other NPC1 trials. Interrater reliability was assessed using two-way mixed models for instrument stability, Cohen kappa, weighted kappa, and percent agreement for the four-and five-item scores. Results: The frequency distribution and mean (S.D.) of the NPC-SS domain assessments by the raters were almost identical. Evaluation at the patient visit level showed wide variability between visits; however, weighted kappa calculation provided a lower variability between visits. The average kappa coefficients ranged between 0.69 and 0.89, indicating good to very good agreement between raters. Conclusions: These results support the NPC-SS, including derived four-and five-item composite scores, as reliable measures for use in a clinical trial setting. (c) 2021 Published by Elsevier Inc.