Disease progression modeling of the North Star Ambulatory Assessment for Duchenne Muscular Dystrophy
Abstract Duchenne muscular dystrophy (DMD) is a rare genetic disorder caused by decreased or absent dystrophin gene leading to progressive muscle degeneration and weakness in young boys. Disease progression models for the North Star Ambulatory Assessment (NSAA), a functional measurement widely used...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-03-01
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| Series: | CPT: Pharmacometrics & Systems Pharmacology |
| Online Access: | https://doi.org/10.1002/psp4.12921 |
| _version_ | 1797870767374860288 |
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| author | Jennifer E. Hibma Priya Jayachandran Srividya Neelakantan Lutz O. Harnisch |
| author_facet | Jennifer E. Hibma Priya Jayachandran Srividya Neelakantan Lutz O. Harnisch |
| author_sort | Jennifer E. Hibma |
| collection | DOAJ |
| description | Abstract Duchenne muscular dystrophy (DMD) is a rare genetic disorder caused by decreased or absent dystrophin gene leading to progressive muscle degeneration and weakness in young boys. Disease progression models for the North Star Ambulatory Assessment (NSAA), a functional measurement widely used to assess outcomes in clinical trials, were developed using a longitudinal population modeling approach. The relationship between NSAA total score over time, loss of ambulation, and potential covariates that may influence disease progression were evaluated. Data included individual participant observations from an internal placebo‐controlled phase II clinical trial and from the external natural history database for male patients with DMD obtained through the Cooperative International Neuromuscular Research Group (CINRG). A modified indirect response model for NSAA joined to a loss of ambulation (LOA) time‐to‐event model described the data well. Age was used as the independent variable because ambulatory function is known to vary with age. The NSAA and LOA models were linked using the dissipation rate constant parameter from the NSAA model by including the parameter as a covariate on the hazard equation for LOA. No covariates were identified. The model was then used as a simulation tool to explore various clinical trial design scenarios. This model contributes to the quantitative understanding of disease progression in DMD and may guide model‐informed drug development decisions for ongoing and future DMD clinical trials. |
| first_indexed | 2024-04-10T00:32:37Z |
| format | Article |
| id | doaj.art-eec9b2ee80954fc29c1fa3a1f3337e51 |
| institution | Directory Open Access Journal |
| issn | 2163-8306 |
| language | English |
| last_indexed | 2024-04-10T00:32:37Z |
| publishDate | 2023-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | CPT: Pharmacometrics & Systems Pharmacology |
| spelling | doaj.art-eec9b2ee80954fc29c1fa3a1f3337e512023-03-14T20:14:27ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062023-03-0112337538610.1002/psp4.12921Disease progression modeling of the North Star Ambulatory Assessment for Duchenne Muscular DystrophyJennifer E. Hibma0Priya Jayachandran1Srividya Neelakantan2Lutz O. Harnisch3Global Product Development Pfizer Inc. La Jolla California USAGlobal Product Development Pfizer Inc. Cambridge Massachusetts USAGlobal Product Development Pfizer Inc. Cambridge Massachusetts USAGlobal Product Development Pfizer Inc. Sandwich, Kent UKAbstract Duchenne muscular dystrophy (DMD) is a rare genetic disorder caused by decreased or absent dystrophin gene leading to progressive muscle degeneration and weakness in young boys. Disease progression models for the North Star Ambulatory Assessment (NSAA), a functional measurement widely used to assess outcomes in clinical trials, were developed using a longitudinal population modeling approach. The relationship between NSAA total score over time, loss of ambulation, and potential covariates that may influence disease progression were evaluated. Data included individual participant observations from an internal placebo‐controlled phase II clinical trial and from the external natural history database for male patients with DMD obtained through the Cooperative International Neuromuscular Research Group (CINRG). A modified indirect response model for NSAA joined to a loss of ambulation (LOA) time‐to‐event model described the data well. Age was used as the independent variable because ambulatory function is known to vary with age. The NSAA and LOA models were linked using the dissipation rate constant parameter from the NSAA model by including the parameter as a covariate on the hazard equation for LOA. No covariates were identified. The model was then used as a simulation tool to explore various clinical trial design scenarios. This model contributes to the quantitative understanding of disease progression in DMD and may guide model‐informed drug development decisions for ongoing and future DMD clinical trials.https://doi.org/10.1002/psp4.12921 |
| spellingShingle | Jennifer E. Hibma Priya Jayachandran Srividya Neelakantan Lutz O. Harnisch Disease progression modeling of the North Star Ambulatory Assessment for Duchenne Muscular Dystrophy CPT: Pharmacometrics & Systems Pharmacology |
| title | Disease progression modeling of the North Star Ambulatory Assessment for Duchenne Muscular Dystrophy |
| title_full | Disease progression modeling of the North Star Ambulatory Assessment for Duchenne Muscular Dystrophy |
| title_fullStr | Disease progression modeling of the North Star Ambulatory Assessment for Duchenne Muscular Dystrophy |
| title_full_unstemmed | Disease progression modeling of the North Star Ambulatory Assessment for Duchenne Muscular Dystrophy |
| title_short | Disease progression modeling of the North Star Ambulatory Assessment for Duchenne Muscular Dystrophy |
| title_sort | disease progression modeling of the north star ambulatory assessment for duchenne muscular dystrophy |
| url | https://doi.org/10.1002/psp4.12921 |
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