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DMD Genotypes and Motor Function in Duchenne Muscular Dystrophy: A Multi-institution Meta-analysis With Implications for Clinical Trials

BACKGROUND AND OBJECTIVES: Clinical trials of genotype-targeted treatments in Duchenne muscular dystrophy (DMD) traditionally compare treated patients with untreated patients with the same DMD genotype class. This avoids confounding of drug efficacy by genotype effects but also shrinks the pool of e...

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Autores principales: Muntoni, Francesco, Signorovitch, James, Sajeev, Gautam, Lane, Henry, Jenkins, Madeline, Dieye, Ibrahima, Ward, Susan J., McDonald, Craig, Goemans, Nathalie, Niks, Erik H., Wong, Brenda, Servais, Laurent, Straub, Volker, Guglieri, Michela, de Groot, Imelda J.M., Chesshyre, Mary, Tian, Cuixia, Manzur, Adnan Y., Mercuri, Eugenio, Aartsma-Rus, Annemieke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Lippincott Williams & Wilkins 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10103111/
https://www.ncbi.nlm.nih.gov/pubmed/36725339
http://dx.doi.org/10.1212/WNL.0000000000201626
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author Muntoni, Francesco
Signorovitch, James
Sajeev, Gautam
Lane, Henry
Jenkins, Madeline
Dieye, Ibrahima
Ward, Susan J.
McDonald, Craig
Goemans, Nathalie
Niks, Erik H.
Wong, Brenda
Servais, Laurent
Straub, Volker
Guglieri, Michela
de Groot, Imelda J.M.
Chesshyre, Mary
Tian, Cuixia
Manzur, Adnan Y.
Mercuri, Eugenio
Aartsma-Rus, Annemieke
author_facet Muntoni, Francesco
Signorovitch, James
Sajeev, Gautam
Lane, Henry
Jenkins, Madeline
Dieye, Ibrahima
Ward, Susan J.
McDonald, Craig
Goemans, Nathalie
Niks, Erik H.
Wong, Brenda
Servais, Laurent
Straub, Volker
Guglieri, Michela
de Groot, Imelda J.M.
Chesshyre, Mary
Tian, Cuixia
Manzur, Adnan Y.
Mercuri, Eugenio
Aartsma-Rus, Annemieke
author_sort Muntoni, Francesco
collection PubMed
description BACKGROUND AND OBJECTIVES: Clinical trials of genotype-targeted treatments in Duchenne muscular dystrophy (DMD) traditionally compare treated patients with untreated patients with the same DMD genotype class. This avoids confounding of drug efficacy by genotype effects but also shrinks the pool of eligible controls, increasing challenges for trial enrollment in this already rare disease. To evaluate the suitability of genotypically unmatched controls in DMD, we quantified effects of genotype class on 1-year changes in motor function endpoints used in clinical trials. METHODS: More than 1,600 patient-years of follow-up (>700 patients) were studied from 6 real-world/natural history data sources (UZ Leuven, PRO-DMD-01 shared by CureDuchenne, iMDEX, North Star UK, Cincinnati Children's Hospital Medical Center, and the DMD Italian Group), with genotypes classified as amenable to skipping exons 44, 45, 51, or 53, or other skippable, nonsense, and other mutations. Associations between genotype class and 1-year changes in North Star Ambulatory Assessment total score (ΔNSAA) and in 10-m walk/run velocity (Δ10MWR) were studied in each data source with and without adjustment for baseline prognostic factors. RESULTS: The studied genotype classes accounted for approximately 2% of variation in ΔNSAA outcomes after 12 months, whereas other prognostic factors explained >30% of variation in large data sources. Based on a meta-analysis across all data sources, pooled effect estimates for the studied skip-amenable mutation classes were all small in magnitude (<2 units in ΔNSAA total score in 1-year follow up), smaller than clinically important differences in NSAA, and were precisely estimated with standard errors <1 unit after adjusting for nongenotypic prognostic factors. DISCUSSION: These findings suggest the viability of trial designs incorporating genotypically mixed or unmatched controls for up to 12 months in duration for motor function outcomes, which would ease recruitment challenges and reduce numbers of patients assigned to placebos. Such trial designs, including multigenotype platform trials and hybrid designs, should ensure baseline balance between treatment and control groups for the most important prognostic factors, while accounting for small remaining genotype effects quantified in this study.
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spelling pubmed-101031112023-04-15 DMD Genotypes and Motor Function in Duchenne Muscular Dystrophy: A Multi-institution Meta-analysis With Implications for Clinical Trials Muntoni, Francesco Signorovitch, James Sajeev, Gautam Lane, Henry Jenkins, Madeline Dieye, Ibrahima Ward, Susan J. McDonald, Craig Goemans, Nathalie Niks, Erik H. Wong, Brenda Servais, Laurent Straub, Volker Guglieri, Michela de Groot, Imelda J.M. Chesshyre, Mary Tian, Cuixia Manzur, Adnan Y. Mercuri, Eugenio Aartsma-Rus, Annemieke Neurology Research Article BACKGROUND AND OBJECTIVES: Clinical trials of genotype-targeted treatments in Duchenne muscular dystrophy (DMD) traditionally compare treated patients with untreated patients with the same DMD genotype class. This avoids confounding of drug efficacy by genotype effects but also shrinks the pool of eligible controls, increasing challenges for trial enrollment in this already rare disease. To evaluate the suitability of genotypically unmatched controls in DMD, we quantified effects of genotype class on 1-year changes in motor function endpoints used in clinical trials. METHODS: More than 1,600 patient-years of follow-up (>700 patients) were studied from 6 real-world/natural history data sources (UZ Leuven, PRO-DMD-01 shared by CureDuchenne, iMDEX, North Star UK, Cincinnati Children's Hospital Medical Center, and the DMD Italian Group), with genotypes classified as amenable to skipping exons 44, 45, 51, or 53, or other skippable, nonsense, and other mutations. Associations between genotype class and 1-year changes in North Star Ambulatory Assessment total score (ΔNSAA) and in 10-m walk/run velocity (Δ10MWR) were studied in each data source with and without adjustment for baseline prognostic factors. RESULTS: The studied genotype classes accounted for approximately 2% of variation in ΔNSAA outcomes after 12 months, whereas other prognostic factors explained >30% of variation in large data sources. Based on a meta-analysis across all data sources, pooled effect estimates for the studied skip-amenable mutation classes were all small in magnitude (<2 units in ΔNSAA total score in 1-year follow up), smaller than clinically important differences in NSAA, and were precisely estimated with standard errors <1 unit after adjusting for nongenotypic prognostic factors. DISCUSSION: These findings suggest the viability of trial designs incorporating genotypically mixed or unmatched controls for up to 12 months in duration for motor function outcomes, which would ease recruitment challenges and reduce numbers of patients assigned to placebos. Such trial designs, including multigenotype platform trials and hybrid designs, should ensure baseline balance between treatment and control groups for the most important prognostic factors, while accounting for small remaining genotype effects quantified in this study. Lippincott Williams & Wilkins 2023-04-11 /pmc/articles/PMC10103111/ /pubmed/36725339 http://dx.doi.org/10.1212/WNL.0000000000201626 Text en Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
spellingShingle Research Article
Muntoni, Francesco
Signorovitch, James
Sajeev, Gautam
Lane, Henry
Jenkins, Madeline
Dieye, Ibrahima
Ward, Susan J.
McDonald, Craig
Goemans, Nathalie
Niks, Erik H.
Wong, Brenda
Servais, Laurent
Straub, Volker
Guglieri, Michela
de Groot, Imelda J.M.
Chesshyre, Mary
Tian, Cuixia
Manzur, Adnan Y.
Mercuri, Eugenio
Aartsma-Rus, Annemieke
DMD Genotypes and Motor Function in Duchenne Muscular Dystrophy: A Multi-institution Meta-analysis With Implications for Clinical Trials
title DMD Genotypes and Motor Function in Duchenne Muscular Dystrophy: A Multi-institution Meta-analysis With Implications for Clinical Trials
title_full DMD Genotypes and Motor Function in Duchenne Muscular Dystrophy: A Multi-institution Meta-analysis With Implications for Clinical Trials
title_fullStr DMD Genotypes and Motor Function in Duchenne Muscular Dystrophy: A Multi-institution Meta-analysis With Implications for Clinical Trials
title_full_unstemmed DMD Genotypes and Motor Function in Duchenne Muscular Dystrophy: A Multi-institution Meta-analysis With Implications for Clinical Trials
title_short DMD Genotypes and Motor Function in Duchenne Muscular Dystrophy: A Multi-institution Meta-analysis With Implications for Clinical Trials
title_sort dmd genotypes and motor function in duchenne muscular dystrophy: a multi-institution meta-analysis with implications for clinical trials
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10103111/
https://www.ncbi.nlm.nih.gov/pubmed/36725339
http://dx.doi.org/10.1212/WNL.0000000000201626
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