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

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://clinicaltrials.gov/ct2/show/NCT02612129

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Validation of a short-form 5-domain Niemann-Pick type C clinical severity scale (5-domain NPCCSS)

Molecular Genetics and Metabolism ◽

10.1016/j.ymgme.2020.12.196 ◽

2021 ◽

Vol 132 (2) ◽

pp. S82-S83

Author(s):

Marc Patterson ◽

Lucy Lloyd-Price ◽

Christina Guldberg ◽

Stacie Hudgens ◽

Helen Doll ◽

...

Keyword(s):

Short Form ◽

Clinical Severity ◽

Severity Scale ◽

Type C ◽

Niemann Pick

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Impacts and Burden of Niemann Pick Type-C: A Patient and Caregiver Perspective

10.21203/rs.3.rs-144070/v1 ◽

2021 ◽

Author(s):

Eugen Mengel ◽

Marc C Patterson ◽

Michael Chladek ◽

Christina Guldberg ◽

Christine íDali ◽

...

Keyword(s):

Lived Experience ◽

Motor Skills ◽

Age Of Onset ◽

Fine Motor ◽

Fine Motor Skills ◽

Increased Risk ◽

Wide Range ◽

Type C ◽

Niemann Pick ◽

The Impact

Abstract Background Niemann-Pick disease type C (NPC) is a debilitating condition that impacts patients’ and caregivers’ quality of life (QOL) and reduces the patient’s life expectancy. Since there is little qualitative research from the perspective of patients and family caregivers, this study explored the impact of NPC on patients’ and caregivers’ daily lives to understand the burden of disease.Results A survey of caregivers for patients with NPC and adult patients with NPC (n = 49; patient age: 13 months – 65 years) assessed NPC severity, importance of NPC symptoms, and how symptoms impacted patients’ and caregivers’ activities of daily living (ADLs) and health-related QOL (HRQOL). Follow-up interviews with a subset of survey participants (n = 28) explored the ranking of NPC symptom importance and impact on ADLs and HRQOL.Findings indicated that the most important manifestations of NPC were ambulation, swallowing, speech, fine motor skills, and cognition, which were those that had the most significant impact on ADLs and HRQOL. A wide range of ADLs were affected by NPC, mainly eating/drinking and ability to perform daily tasks, including self-care, communicating, participating in school or work, and moving indoors as well as outside the home. Along with these impacts, there was an increased risk of experiencing dangerous or life-threatening situations leading to loss of patient independence and additional caregiver burden, often requiring changes in lifestyle such as giving up work. All aspects of patients’ and caregivers’ HRQOL were affected. Participants reported feelings of social isolation, loss of enjoyment in activities (patients), and feelings of sadness or worry (caregivers).ConclusionsAmbulation, swallowing, speech, fine motor skills, and cognition are important manifestations of NPC. ADLs and HRQOL were impaired in the majority of patients as well as their caregivers. The findings were independent of current age, age of onset of symptoms, and level of NPC disease-related disability; however, the impact increased at higher levels of disease disability. Knowing the impact of NPC on patients and caregivers is important for understanding the lived experience of NPC and for identifying potential areas of support.Trial registrationNCT02612129. Registered 23 November 2015, https://clinicaltrials.gov/ct2/show/NCT02612129

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Impacts and Burden of Niemann pick Type-C: a patient and caregiver perspective

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-02105-8 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Eugen Mengel ◽

Marc C. Patterson ◽

Michael Chladek ◽

Christina Guldberg ◽

Christine í Dali ◽

...

Keyword(s):

Lived Experience ◽

Motor Skills ◽

Age Of Onset ◽

Fine Motor ◽

Fine Motor Skills ◽

Increased Risk ◽

Wide Range ◽

Type C ◽

Niemann Pick ◽

The Impact

Abstract Background Niemann-Pick disease type C (NPC) is a debilitating condition that impacts patients’ and caregivers’ quality of life (QOL) and reduces the patient’s life expectancy. Since there is little qualitative research from the perspective of patients and family caregivers, this study explored the impact of NPC on patients’ and caregivers’ daily lives to understand the burden of disease. Results A survey of caregivers for patients with NPC and adult patients with NPC (n = 49; patient age: 13 months–65 years) assessed NPC severity, importance of NPC symptoms, and how symptoms impacted patients’ and caregivers’ activities of daily living (ADLs) and health-related QOL (HRQOL). Follow-up interviews with a subset of survey participants (n = 28) explored the ranking of NPC symptom importance and impact on ADLs and HRQOL. Findings indicated that the most important manifestations of NPC were ambulation, swallowing, speech, fine motor skills, and cognition, which were those that had the most significant impact on ADLs and HRQOL. A wide range of ADLs were affected by NPC, mainly eating/drinking and the ability to perform daily tasks, including self-care, communicating, participating in school or work, and moving indoors as well as outside the home. Along with these impacts, there was an increased risk of experiencing dangerous or life-threatening situations leading to loss of patient independence and additional caregiver burden, often requiring changes in lifestyle such as giving up work. All aspects of patients’ and caregivers’ HRQOL were affected. Participants reported feelings of social isolation, loss of enjoyment in activities (patients), and feelings of sadness or worry (caregivers). Conclusions Ambulation, swallowing, speech, fine motor skills, and cognition are important manifestations of NPC. ADLs and HRQOL were impaired in the majority of patients as well as their caregivers. The findings were independent of current age, age of onset of symptoms, and level of NPC disease-related disability; however, the impact increased at higher levels of disease disability. Knowing the impact of NPC on patients and caregivers is important for understanding the lived experience of NPC and for identifying potential areas of support.

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Consistently high agreement between independent raters of Niemann-Pick type C1 clinical severity scale in phase 2/3 trial

Pediatric Neurology ◽

10.1016/j.pediatrneurol.2021.11.009 ◽

2021 ◽

Author(s):

Nicole Farhat ◽

Laurie Bailey ◽

Katherine Friedmann ◽

Donald M. Bushnell ◽

Danielle Rodriguez ◽

...

Keyword(s):

Clinical Severity ◽

Phase 2 ◽

Severity Scale ◽

High Agreement ◽

Niemann Pick

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Niemann-Pick Type C Disease—Pathophysiology and Future Perspectives for Treatment

US Neurology ◽

10.17925/usn.2010.06.01.88 ◽

2010 ◽

Vol 06 (01) ◽

pp. 88 ◽

Cited By ~ 3

Author(s):

Cristin D Davidson ◽

Steven U Walkley ◽

◽

Keyword(s):

Motor Skills ◽

Therapeutic Option ◽

Disease Onset ◽

Cns Involvement ◽

Progressive Decline ◽

Inherited Metabolic Disorder ◽

Intellectual Function ◽

Lysosomal System ◽

Type C ◽

Niemann Pick

Niemann-Pick type C (NPC) disease is a rare and fatal inherited metabolic disorder that results in intracellular accumulation of cholesterol and glycolipids within the endosomal/lysosomal system. Central nervous system (CNS) involvement is especially prominent as evidenced by ataxia and progressive decline of motor skills and intellectual function. Defects in either the NPC1 or NPC2 protein, both of which are thought to be involved in the egress of cholesterol and other lipids out of the endosomal/lysosomal system, leads to NPC disease. The pathogenic cascade is not well understood, and currently there is no corrective therapy for NPC patients. However, some compounds tested in animal models of NPC disease have shown promise in slowing disease onset and progression, and administration of these drugs in combination has provided evidence of synergy and enhanced clinical benefit. This favorable outcome indicates that combinatorial therapies using small molecules likely represent the best therapeutic option available to NPC patients at this time.

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International consensus on clinical severity scale use in evaluating Niemann–Pick disease Type C in paediatric and adult patients: results from a Delphi Study

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-021-02115-6 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

William Evans ◽

Marc Patterson ◽

Frances Platt ◽

Christina Guldberg ◽

Toni Mathieson ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Practice ◽

Multiple Choice ◽

Clinical Severity ◽

Multiple Choice Questions ◽

Niemann Pick Disease ◽

First Choice ◽

Type C ◽

Niemann Pick ◽

Pick Disease

Abstract Background Several scales have been developed in the past two decades to evaluate Niemann–Pick disease Type C (NPC) severity in clinical practice and trials. However, a lack of clarity concerning which scale to use in each setting is preventing the use of standardised assessments across the world, resulting in incomparable data sets and clinical trial outcome measures. This study aimed to establish agreed approaches for the use of NPC severity scales in clinical practice and research. Methods A Delphi method of consensus development was used, comprising three survey rounds. In Round 1, participants were asked nine multiple-choice and open-ended questions to gather opinions on the six severity scales and domains. In Rounds 2 and 3, questions aimed to gain consensus on the opinions revealed in Round 1 using a typical Likert scale. Results Nineteen experts, active in NPC paediatric and adult research and treatment, participated in this study. Of these, 16/19 completed Rounds 1 and 2 and 19/19 completed Round 3. Consensus (defined as ≥ 70% agreement or neutrality, given the study aim to identify the severity scales that the clinical community would accept for international consistency) was achieved for 66.7% of the multiple-choice questions in Round 2 and 83% of the multiple-choice questions in Round 3. Consensus was almost reached (68%) on the use of the 5-domain NPCCSS scale as the first choice in clinical practice. Consensus was reached (74%) for the 17-domain NPCCSS scale as the first choice in clinical trial settings, but the domains measured in the 5-domain scale should be prioritised as the primary endpoints. Experts called for educational and training materials on how to apply the NPCCSS (17- and 5-domains) for clinicians working in NPC. Conclusions In achieving a consensus on the use of the 17-domain NPCCSS scale as the first choice for assessing clinical severity of NPC in clinical trial settings but prioritising the domains in the 5-domain NPCCSS scale for routine clinical practice, this study can help to inform future discussion around the use of the existing NPC clinical severity scales. For routine clinical practice, the study helps provide clarity on which scale is favoured by a significant proportion of a representative body of experts, in this case, the 5-domain NPCCSS scale.

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International Consensus on Clinical Severity Scale Use in Evaluating Niemann-pick Disease Type C in Paediatric and Adult Patients: Results From a Delphi Study

10.21203/rs.3.rs-240168/v1 ◽

2021 ◽

Author(s):

William Evans ◽

Marc Patterson ◽

Frances Platt ◽

Christina Guldberg ◽

Toni Mathieson ◽

...

Keyword(s):

Clinical Trial ◽

Clinical Practice ◽

Multiple Choice ◽

Clinical Severity ◽

Multiple Choice Questions ◽

Niemann Pick Disease ◽

First Choice ◽

Type C ◽

Niemann Pick ◽

Pick Disease

Abstract Background: Several scales have been developed in the past two decades to evaluate Niemann-Pick disease Type C (NPC) severity in clinical practice and trials. However, a lack of clarity concerning which scale to use in each setting is preventing the use of standardised assessments across the world, resulting in incomparable data sets and clinical trial outcome measures. This study aimed to establish agreed approaches for the use of NPC severity scales in clinical practice and research. Methods: A Delphi method of consensus development was used, comprising three survey rounds. In Round 1, participants were asked nine multiple-choice and open-ended questions to gather opinions on the six severity scales and domains. In Rounds 2 and 3, questions aimed to gain consensus on the opinions revealed in Round 1 using a typical Likert scale.Results: Nineteen experts, active in NPC paediatric and adult research and treatment, participated in this study. Of these, 16/19 completed Rounds 1 and 2 and 19/19 completed Round 3. Consensus (defined as ≥70% agreement or neutrality) was achieved for 66.7% of the multiple-choice questions in Round 2 and 83% of the multiple-choice questions in Round 3. Consensus was almost reached (68%) on the use of the 5-domain NPCCSS scale as the first choice in clinical practice. Consensus was reached (74%) for the 17-domain NPCCSS scale as the first choice in clinical trial settings, but the domains measured in the 5-domain scale should be prioritised as the primary endpoints. Experts called for educational and training materials on how to apply the NPCCSS (17- and 5-domains) for clinicians working in NPC.Conclusions: In achieving a consensus on the use of the 17-domain NPCCSS scale as the first choice for assessing clinical severity of NPC in clinical trial settings, but prioritising the domains in the 5-domain NPCCSS scale for routine clinical practice, this study can help to inform future discussion around the use of the existing NPC clinical severity scales. For routine clinical practice, the study helps provide clarity on which scale is favoured by a significant proportion of a representative body of experts, in this case, the 5-domain NPCCSS scale.

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