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Progression of atypical parkinsonian syndromes: PROSPECT-M-UK study implications for clinical trials
The advent of clinical trials of disease-modifying agents for neurodegenerative disease highlights the need for evidence-based end point selection. Here we report the longitudinal PROSPECT-M-UK study of progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), multiple system atrophy (MSA)...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10393398/ https://www.ncbi.nlm.nih.gov/pubmed/36975168 http://dx.doi.org/10.1093/brain/awad105 |
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author | Street, Duncan Jabbari, Edwin Costantini, Alyssa Jones, P Simon Holland, Negin Rittman, Timothy Jensen, Marte T Chelban, Viorica Goh, Yen Y Guo, Tong Heslegrave, Amanda J Roncaroli, Federico Klein, Johannes C Ansorge, Olaf Allinson, Kieren S J Jaunmuktane, Zane Revesz, Tamas Warner, Thomas T Lees, Andrew J Zetterberg, Henrik Russell, Lucy L Bocchetta, Martina Rohrer, Jonathan D Burn, David J Pavese, Nicola Gerhard, Alexander Kobylecki, Christopher Leigh, P Nigel Church, Alistair Hu, Michele T M Houlden, Henry Morris, Huw Rowe, James B |
author_facet | Street, Duncan Jabbari, Edwin Costantini, Alyssa Jones, P Simon Holland, Negin Rittman, Timothy Jensen, Marte T Chelban, Viorica Goh, Yen Y Guo, Tong Heslegrave, Amanda J Roncaroli, Federico Klein, Johannes C Ansorge, Olaf Allinson, Kieren S J Jaunmuktane, Zane Revesz, Tamas Warner, Thomas T Lees, Andrew J Zetterberg, Henrik Russell, Lucy L Bocchetta, Martina Rohrer, Jonathan D Burn, David J Pavese, Nicola Gerhard, Alexander Kobylecki, Christopher Leigh, P Nigel Church, Alistair Hu, Michele T M Houlden, Henry Morris, Huw Rowe, James B |
author_sort | Street, Duncan |
collection | PubMed |
description | The advent of clinical trials of disease-modifying agents for neurodegenerative disease highlights the need for evidence-based end point selection. Here we report the longitudinal PROSPECT-M-UK study of progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), multiple system atrophy (MSA) and related disorders, to compare candidate clinical trial end points. In this multicentre UK study, participants were assessed with serial questionnaires, motor examination, neuropsychiatric and MRI assessments at baseline, 6 and 12 months. Participants were classified by diagnosis at baseline and study end, into Richardson syndrome, PSP-subcortical (PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (PSP-frontal, PSP-speech and language and PSP-CBS subtypes), MSA-parkinsonism, MSA-cerebellar, CBS with and without evidence of Alzheimer’s disease pathology and indeterminate syndromes. We calculated annual rate of change, with linear mixed modelling and sample sizes for clinical trials of disease-modifying agents, according to group and assessment type. Two hundred forty-three people were recruited [117 PSP, 68 CBS, 42 MSA and 16 indeterminate; 138 (56.8%) male; age at recruitment 68.7 ± 8.61 years]. One hundred and fifty-nine completed the 6-month assessment (82 PSP, 27 CBS, 40 MSA and 10 indeterminate) and 153 completed the 12-month assessment (80 PSP, 29 CBS, 35 MSA and nine indeterminate). Questionnaire, motor examination, neuropsychiatric and neuroimaging measures declined in all groups, with differences in longitudinal change between groups. Neuroimaging metrics would enable lower sample sizes to achieve equivalent power for clinical trials than cognitive and functional measures, often achieving N < 100 required for 1-year two-arm trials (with 80% power to detect 50% slowing). However, optimal outcome measures were disease-specific. In conclusion, phenotypic variance within PSP, CBS and MSA is a major challenge to clinical trial design. Our findings provide an evidence base for selection of clinical trial end points, from potential functional, cognitive, clinical or neuroimaging measures of disease progression. |
format | Online Article Text |
id | pubmed-10393398 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-103933982023-08-02 Progression of atypical parkinsonian syndromes: PROSPECT-M-UK study implications for clinical trials Street, Duncan Jabbari, Edwin Costantini, Alyssa Jones, P Simon Holland, Negin Rittman, Timothy Jensen, Marte T Chelban, Viorica Goh, Yen Y Guo, Tong Heslegrave, Amanda J Roncaroli, Federico Klein, Johannes C Ansorge, Olaf Allinson, Kieren S J Jaunmuktane, Zane Revesz, Tamas Warner, Thomas T Lees, Andrew J Zetterberg, Henrik Russell, Lucy L Bocchetta, Martina Rohrer, Jonathan D Burn, David J Pavese, Nicola Gerhard, Alexander Kobylecki, Christopher Leigh, P Nigel Church, Alistair Hu, Michele T M Houlden, Henry Morris, Huw Rowe, James B Brain Original Article The advent of clinical trials of disease-modifying agents for neurodegenerative disease highlights the need for evidence-based end point selection. Here we report the longitudinal PROSPECT-M-UK study of progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), multiple system atrophy (MSA) and related disorders, to compare candidate clinical trial end points. In this multicentre UK study, participants were assessed with serial questionnaires, motor examination, neuropsychiatric and MRI assessments at baseline, 6 and 12 months. Participants were classified by diagnosis at baseline and study end, into Richardson syndrome, PSP-subcortical (PSP-parkinsonism and progressive gait freezing subtypes), PSP-cortical (PSP-frontal, PSP-speech and language and PSP-CBS subtypes), MSA-parkinsonism, MSA-cerebellar, CBS with and without evidence of Alzheimer’s disease pathology and indeterminate syndromes. We calculated annual rate of change, with linear mixed modelling and sample sizes for clinical trials of disease-modifying agents, according to group and assessment type. Two hundred forty-three people were recruited [117 PSP, 68 CBS, 42 MSA and 16 indeterminate; 138 (56.8%) male; age at recruitment 68.7 ± 8.61 years]. One hundred and fifty-nine completed the 6-month assessment (82 PSP, 27 CBS, 40 MSA and 10 indeterminate) and 153 completed the 12-month assessment (80 PSP, 29 CBS, 35 MSA and nine indeterminate). Questionnaire, motor examination, neuropsychiatric and neuroimaging measures declined in all groups, with differences in longitudinal change between groups. Neuroimaging metrics would enable lower sample sizes to achieve equivalent power for clinical trials than cognitive and functional measures, often achieving N < 100 required for 1-year two-arm trials (with 80% power to detect 50% slowing). However, optimal outcome measures were disease-specific. In conclusion, phenotypic variance within PSP, CBS and MSA is a major challenge to clinical trial design. Our findings provide an evidence base for selection of clinical trial end points, from potential functional, cognitive, clinical or neuroimaging measures of disease progression. Oxford University Press 2023-03-28 /pmc/articles/PMC10393398/ /pubmed/36975168 http://dx.doi.org/10.1093/brain/awad105 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Article Street, Duncan Jabbari, Edwin Costantini, Alyssa Jones, P Simon Holland, Negin Rittman, Timothy Jensen, Marte T Chelban, Viorica Goh, Yen Y Guo, Tong Heslegrave, Amanda J Roncaroli, Federico Klein, Johannes C Ansorge, Olaf Allinson, Kieren S J Jaunmuktane, Zane Revesz, Tamas Warner, Thomas T Lees, Andrew J Zetterberg, Henrik Russell, Lucy L Bocchetta, Martina Rohrer, Jonathan D Burn, David J Pavese, Nicola Gerhard, Alexander Kobylecki, Christopher Leigh, P Nigel Church, Alistair Hu, Michele T M Houlden, Henry Morris, Huw Rowe, James B Progression of atypical parkinsonian syndromes: PROSPECT-M-UK study implications for clinical trials |
title | Progression of atypical parkinsonian syndromes: PROSPECT-M-UK study implications for clinical trials |
title_full | Progression of atypical parkinsonian syndromes: PROSPECT-M-UK study implications for clinical trials |
title_fullStr | Progression of atypical parkinsonian syndromes: PROSPECT-M-UK study implications for clinical trials |
title_full_unstemmed | Progression of atypical parkinsonian syndromes: PROSPECT-M-UK study implications for clinical trials |
title_short | Progression of atypical parkinsonian syndromes: PROSPECT-M-UK study implications for clinical trials |
title_sort | progression of atypical parkinsonian syndromes: prospect-m-uk study implications for clinical trials |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10393398/ https://www.ncbi.nlm.nih.gov/pubmed/36975168 http://dx.doi.org/10.1093/brain/awad105 |
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