Validation of the 5-domain Niemann-Pick type C Clinical Severity Scale

Marc C Patterson, Lucy Lloyd-Price, Christina Guldberg, Helen Doll, Claire Burbridge, Michael Chladek, Christine íDali, Eugen Mengel, Tara Symonds, Marc C Patterson, Lucy Lloyd-Price, Christina Guldberg, Helen Doll, Claire Burbridge, Michael Chladek, Christine íDali, Eugen Mengel, Tara Symonds

Abstract

Background: 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. 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.

Methods: Mixed 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.

Results: Domains 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.

Conclusions: Qualitative 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://ichgcp.net/clinical-trials-registry/NCT02612129.

Keywords: Arimoclomol; ClinRO; NPCCSS; Niemann-pick type C clinical severity scale; Validation.

Conflict of interest statement

CG and CD are employees of Orphazyme A/S. TS, MP, LLP, HD, CB, MC, and EM declare no competing interests.

References

    1. Hammond N, Munkacsi A, Sturley S. The complexity of a monogenic neurodegenerative disease: more than two decades of therapeutic driven research into Niemann-Pick type C disease. Biochim Biophy Acta Mol Cell Biol Lipids. 2019;1864:1109–1123. doi: 10.1016/j.bbalip.2019.04.002.
    1. Vanier M. Niemann-Pick disease type C. Orphanet J Rare Dis. 2010;5:16. doi: 10.1186/1750-1172-5-16.
    1. Naureckiene S, Sleat D, Lackland H, et al. Identification of HE1 as the second gene of Niemann-Pick C disease. Science. 2000;290:2298–2301. doi: 10.1126/science.290.5500.2298.
    1. Lloyd-Evans E, Platt F. Lipids on trial: the search for the offending metabolite in Niemann-Pick Type C Disease. Traffic. 2010;11(4):419–428. doi: 10.1111/j.1600-0854.2010.01032.x.
    1. Platt F, d'Azzo A, Davidson B, Neufeld E, Tifft C. Lysosomal storage diseases. Nat Rev Dis Primers. 2018;4(1):27. doi: 10.1038/s41572-018-0025-4.
    1. Geberhiwot T, Moro A, Dardis A, et al. Consensus clinical management guidelines for Niemann-Pick Disease Type C. Orphanet J Rare Dis. 2018;13(1):50. doi: 10.1186/s13023-018-0785-7.
    1. Yanjanin N, Velez J, Gropman A, et al. Linear clinical progression, independent of age of onset, in Niemann-Pick Disease, Type C. Am J Med Genet B Neuropsychiatr Genet. 2010;153B(1):132–140.
    1. Iturriaga C, Pineda M, Fernandez-Valero E, Vanier M, Coll M. Niemann-Pick C Disease in Spain: clinical spectrum and development of a disability scale. J Neurol Sci. 2006;249(1):1–6. doi: 10.1016/j.jns.2006.05.054.
    1. Pineda M, Perez-Poyato M, O'Callaghan M, et al. Clinical experience with miglustat therapy in pediatric patients with Niemann-Pick disease type C: a case series. Mol Genet Metab. 2010;99(4):358–366. doi: 10.1016/j.ymgme.2009.11.007.
    1. Shin J, Epperson K, Yanjanin N, et al. Defining natural history: assessment of the ability of college students to aid in characterizing clinical progression of Niemann-Pick Disease, Type C. PLoS ONE. 2011;6(10):e23666. doi: 10.1371/journal.pone.0023666.
    1. Ory D, Ottinger E, Farhat N, et al. Intrathecal 2-hydroxypropyl-β-cyclodextrin decreases neurological disease progression in Niemann-Pick Disease, Type C1: a non-randomised, open-label, Phase 1–2 trial. Lancet. 2017;390(10104):1758–1768. doi: 10.1016/S0140-6736(17)31465-4.
    1. Cortina-Borja M, Vruchte D, Mengel E, et al. Annual severity increment score as a tool for stratifying patients with Niemann-Pick Disease Type C and for recruitment to clinical trials. Orphanet J Rare Dis. 2018;13(1):143. doi: 10.1186/s13023-018-0880-9.
    1. A Parseghian. Niemann-Pick type C patient and caregiver voices: externally-led, patient-focused drug development meeting (2019). Available at: . Accessed June 8, 2020.
    1. Mengel E, Bembi B, Toro Md, Deodato F, Gauschi M. Clinical disease progression and biomarkers in Nieman Pick disease type C: a prospective cohort study. Orphanet J Rare Dis. 2020;pending acceptance.
    1. Mengel E, Patterson M, Dariol M, Deodato F, Gautschi M, Grunewald S. Efficacy and safety of arimoclomol in patients with Niemann-Pick type C: results from a double blind, randomized, placebo-controlled phase 2/3 study of a novel treatment. Lancet Neurol. 2020;pending acceptance.
    1. Kellor M. Hand strength and dexterity. Am J Occup Ther. 1971;25:77–83.
    1. Schmitz-Hübsch T, Du Montcel ST, Baliko L, et al. Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology. 2006;66(11):1717–1720. doi: 10.1212/01.wnl.0000219042.60538.92.
    1. Guy W. ECDEU Assessment Manual for Psychopharmacology, revised. DHEW Pub. No. (ADM)76–338. Rockville, MD: National Institute of Mental Health; 1976.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅