Abstract
BackgroundNiemann-Pick disease type C (NPC) is an ultra-rare, progressive, genetic disease leading to impaired lysosomal function and neurodegeneration causing serious morbidity and shortened life expectancy.The Niemann-Pick type C Clinical Severity Scale (NPCCSS) is a 17 domain, disease-specific, clinician-reported outcome measure of disease severity and progression. An abbreviated 5-domain NPCCSS scale has been developed (measuring Ambulation, Swallow, Cognition, Speech, and Fine Motor Skills) and the scale reliability has been established. Additional psychometric properties and meaningful change of the scale need, however, to be assessed.MethodsMixed method studies were conducted to ascertain which NPCCSS domains were most important, as well as to explore meaningful change: 1) surveys in caregivers/patients (n = 49) and 2) interviews with clinicians (n = 5) as well as caregivers/patients (n = 28). Clinical trial data (n = 43) assessed construct validity and meaningful change through an anchor-based approach.ResultsDomains identified as most important by clinicians, caregivers, and patients (independent of current age, age of onset, and disease severity) were Ambulation, Swallow, Cognition, Speech, and Fine Motor Skills, indicating content validity of the 5-domain NPCCSS.Criterion validity was shown with the 5-domain NPCCSS being highly correlated with the 17-item NPCCSS total score (excluding hearing domains), r2 = 0.97. Convergent validity was demonstrated against the 9 Hole Peg Test, r2 = 0.65 (n = 31 patients), and the Scale for Assessment and Rating of Ataxia (SARA), r2 = 0.86 (n = 49 patients). Any change was seen as meaningful by patients/caregivers across domains. Meaningful change using trial data and interviews with NPC experts (n = 5) and patients/caregivers (n = 28) suggested that a 1-category change on a domain is equivalent to 1-point change or greater in the 5-domain NPCCSS total score.ConclusionsQualitative and quantitative data support content and construct validity of the 5-domain NPCCSS score as a valid endpoint in NPC trials. A 1-category change on any domain is equivalent to 1-point change or greater in the 5 domain NPCCSS total score, representing a clinically meaningful transition and reflecting loss of complex function and increased disability.Trial registration NCT02612129. Registered 23 November 2015, https://clinicaltrials.gov/ct2/show/NCT02612129
Highlights
Niemann-Pick disease type C (NPC) is an ultra-rare, progressive, genetic disease leading to impaired lysosomal function and neurodegeneration causing serious morbidity and shortened life expectancy.The Niemann-Pick type C Clinical Severity Scale (NPCCSS) is a 17 domain, disease-specific, clinician-reported outcome measure of disease severity and progression
Meaningful change using trial data and interviews with NPC experts (n = 5) and patients/caregivers (n = 28) suggested that a 1-category change on a domain is equiva‐ lent to 1-point change or greater in the 5-domain NPCCSS total score
A 1-category change on any domain is equivalent to 1-point change or greater in the 5 domain NPCCSS total score, representing a clinically meaningful transition and reflecting loss of complex function and increased disability
Summary
Niemann-Pick disease type C (NPC) is an ultra-rare, progressive, genetic disease leading to impaired lysosomal function and neurodegeneration causing serious morbidity and shortened life expectancy.The Niemann-Pick type C Clinical Severity Scale (NPCCSS) is a 17 domain, disease-specific, clinician-reported outcome measure of disease severity and progression. Four of the major domains (Ambulation, Fine Motor Skills, Swallow, and Speech) were modified from a disability scale developed by Iturriaga et al, [8] (Seizures and Ocular movements were later added to this scale [9]); additional clinical findings frequently observed in NPC (Cognition, Eye Movement, Hearing, Memory, and Seizures) were added to form the 9 major domains. These reflect the major neurological features of NPC. Other important but less frequent clinical aspects of NPC were included as minor domains (Auditory Brainstem Response, Behavior, Gelastic Cataplexy, Hyperreflexia, Incontinence, Narcolepsy, Psychiatric, and Respiratory Status)
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