Stride Velocity 95th Centile Detects Decline in Ambulatory Function Over Shorter Intervals than the 6-Minute Walk Test or North Star Ambulatory Assessment in Duchenne Muscular Dystrophy.
[en] [en] BACKGROUND: Stride Velocity 95th Centile (SV95C) is the first wearable device-derived clinical outcome assessment (COA) to receive European Medicines Agency (EMA) qualification as a primary endpoint in ambulant patients with Duchenne muscular dystrophy (DMD) aged ≥4 years.
OBJECTIVE: To compare SV95C-in its first-ever clinical trial application as a secondary endpoint-with established motor function COAs used in the trial (Four-Stair Climb [4SC] velocity, North Star Ambulatory Assessment [NSAA], and Six-Minute Walk Distance [6MWD]).
METHODS: SV95C was a secondary endpoint in a subset (n = 47) of participants in the SPITFIRE/WN40227 trial of taldefgrobep alfa, which was discontinued due to lack of clinical benefit. Participants in the ≤48-week SV95C sub-study were 6-11 years old and received corticosteroids for ≥6 months pre-treatment. Pearson correlations were used to compare SV95C with the other COAs. Responsiveness and changes over time were respectively assessed via standardized response means (SRMs) based on absolute changes and mixed models for repeated measures.
RESULTS: SV95C change at Week 24 was -0.07 m/s, with limited variability (standard deviation: 0.16, n = 27). The SRM for SV95C indicated moderate responsiveness to clinical change at the earliest timepoint (Week 12, n = 46), while those of the other COAs did not indicate moderate responsiveness until Week 36 (6MWD, n = 33) or Week 48 (4SC velocity, n = 20; NSAA total score, n = 20). Baseline correlations between SV95C and other COAs were strong (r = 0.611-0.695). Correlations between SV95C change from baseline to Week 48 and changes in other COAs were moderate to strong (r = 0.443-0.678).∥.
CONCLUSIONS: Overall, SV95C demonstrated sensitivity to ambulatory decline over short intervals, low variability, and correlation with established COAs. Although the negative trial precluded demonstration of SV95C's sensitivity to drug effect, these findings support the continued use of SV95C in DMD clinical trials.
Disciplines :
Pediatrics
Author, co-author :
Rabbia, Michael; Genentech Inc., 1 DNA Way, South San Francisco, CA, USA
Staunton, Hannah; Roche Products Ltd, Hexagon Place, Shire Park, 6 Falcon Way, Welwyn Garden City, UK
Veenstra, Klaas; F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
Eggenspieler, Damien; SYSNAV, 72 Rue Emile Loubet, Vernon, France
Annoussamy, Mélanie; SYSNAV, 72 Rue Emile Loubet, Vernon, France
Servais, Laurent ; Université de Liège - ULiège > Département des sciences cliniques ; MDUK Oxford Neuromuscular Centre and NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK
Strijbos, Paul; F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, Basel, Switzerland
Language :
English
Title :
Stride Velocity 95th Centile Detects Decline in Ambulatory Function Over Shorter Intervals than the 6-Minute Walk Test or North Star Ambulatory Assessment in Duchenne Muscular Dystrophy.
Michael Rabbia is an employee and shareholder of Genentech, Inc., a member of the Roche Group. Hannah Staunton is an employee and shareholder of Roche Products Ltd. Maitea Guridi Ormazabal, Klaas Veenstra, and Paul Strijbos are employees and shareholders of F. Hoffmann-La Roche Ltd. Damien Eggenspieler and M\u00E9lanie Annoussamy are employees of SYSNAV, a company that collaborated with The Institute of Myology to create ActiMyo. Laurent Servais reports grants and personal fees from Sysnav, F. Hoffmann-La Roche Ltd, AveXis, Biogen, and Dynacure and personal fees from Cytokinetics, Audentes, Santhera, Sarepta Therapeutics, Affinia, Pfizer, REGENXBIO, Lupin Pharmaceuticals, and FibroGen outside the submitted work. He is co-inventor of a patent developed on ActiMyo data, with no personal financial return.
Falzarano MS, Scotton C, Passarelli C, Ferlini A. Duchenne Muscular Dystrophy: From Diagnosis to Therapy. Molecules. 2015;20(10):18168-84. doi: 10.3390/molecules201018168.
Verhaart IEC, Aartsma-Rus A. Therapeutic developments for Duchenne muscular dystrophy. Nat Rev Neurol. 2019;15(7):373-86. doi: 10.1038/s41582-019-0203-3.
Ryder S, Leadley RM, Armstrong N, Westwood M, de Kock S, Butt T, et al. The burden, epidemiology, costs and treatment for Duchenne muscular dystrophy: An evidence review. Orphanet J Rare Dis. 2017;12(1):79. doi: 10.1186/s13023-017-0631-3.
Markati T, Oskoui M, Farrar MA, Duong T, Goemans N, Servais L. Emerging therapies for Duchenne muscular dystrophy. Lancet Neurol. 2022;21(9):814-29. doi: 10.1016/S1474-4422(22)00125-9.
Markati T, De Waele L, Schara-Schmidt U, Servais L. Lessons Learned from Discontinued Clinical Developments in Duchenne Muscular Dystrophy. Front Pharmacol. 2021;12:735912. doi: 10.3389/fphar.2021.735912.
McDonald CM, Henricson EK, Han JJ, Abresch RT, Nicorici A, Atkinson L, et al. The 6-minute walk test in Duchenne/Becker muscular dystrophy: Longitudinal observations. Muscle Nerve. 2010;42(6):966-74. doi: 10.1002/mus.21808.
McDonald CM, Henricson EK, Han JJ, Abresch RT, Nicorici A, Elfring GL, et al. The 6-minutewalk test as a new outcome measure in Duchenne muscular dystrophy. Muscle Nerve. 2010;41(4):500-10. doi: 10.1002/mus.21544.
Scott E, Eagle M, Mayhew A, Freeman J, Main M, Sheehan J, et al. Development of a functional assessment scale for ambulatory boys with Duchenne muscular dystrophy. Physiother Res Int. 2012;17(2):101-9. doi: 10.1002/pri.520.
Servais L, Yen K, Guridi M, Lukawy J, Vissiere D, Strijbos P. Stride Velocity 95th Centile: Insights into Gaining Regulatory Qualification of the First Wearable-Derived Digital Endpoint for use in Duchenne Muscular Dystrophy Trials. J Neuromuscul Dis. 2021. doi: 10.3233/JND-210743.
European Medicines Agency. Qualification Opinion for Stride velocity 95th centile as primary endpoint in studies in ambulatory Duchenne Muscular Dystrophy studies; 2023. Available from: https://www.ema.europa.eu/en/documents/ scientific-guideline/qualification-opinion-stride-velocity-9 5th-centile-primary-endpoint-studies-ambulatory-duchenn e en.pdf
Servais L, Eggenspieler D, Poleur M, Grelet M, Muntoni F, Strijbos P, et al. First regulatory qualification of a digital primary endpoint to measure treatment efficacy in DMD. Nat Med. 2023;29(10):2391-2. 10.1038/s41591-023-02459-5.
US Food and Drug Administration. DDT COA #000103: ActiMyo® ; 2020. Available from: https://www.fda.gov/ drugs/clinical-outcome-assessment-coa-qualification-prog ram/ddt-coa-000103-actimyor
European Medicines Agency. Guideline on the clinical investigation of medicinal products for the treatment of Duchenne and Becker muscular dystrophy; 2015. Available from: https://www.ema.europa.eu/en/documents/scientificguideline/ guideline-clinical-investigation-medicinal-produ cts-treatment-duchenne-becker-muscular-dystrophy en.pdf
Servais L, Camino E, Clement A, McDonald CM, Lukawy J, Lowes LP, Eggenspieler D, Cerreta F, Strijbos P. First Regulatory Qualification of a Novel Digital Endpoint in Duchenne Muscular Dystrophy: A Multi-Stakeholder Perspective on the Impact for Patients and for Drug Development in Neuromuscular Diseases. Digital Biomarkers. 2021;5(2):183-90. doi: https://doi.org/10.1159/000517411
Annoussamy M, Seferian AM, Daron A, Pereon Y, Cances C, Vuillerot C, et al. Natural history of Type 2 and 3 spinal muscular atrophy: 2-year NatHis-SMA study. Ann Clin Transl Neurol. 2021;8(2):359-73. doi: 10.1002/acn3. 51281.
Gidaro T, Gasnier E, Annoussamy M, Vissing J, Attarian S, Mozaffar T, et al. Home-based gait analysis as an exploratory endpoint during a multicenter phase 1 trial in limb girdle muscular dystrophy type R2 and facioscapulohumeral muscular dystrophy. Muscle Nerve. 2022;65(2):237-42. doi: 10.1002/mus.27446.
Poleur M, Ulinici A, Daron A, Schneider O, Farra FD, Demonceau M, et al. Normative data on spontaneous stride velocity, stride length, and walking activity in a non-controlled environment. Orphanet J Rare Dis. 2021;16(1):318. doi: 10.1186/s13023-021-01956-5.
Muntoni F, Byrne BJ, McMillan HJ, Ryan MM, Wong BL, Dukart J, et al. The clinical development of taldefgrobep alfa: An anti-myostatin adnectin for the treatment of Duchenne muscular dystrophy. PLOS One. Manuscript submitted.
Lilien C, Gasnier E, GidaroT, Seferian A, Grelet M,Vissiere D, et al. Home-Based Monitor for Gait and Activity Analysis. J Vis Exp. 2019(150). doi: 10.3791/59668.
Goemans N, Wong B, Van den Hauwe M, Signorovitch J, Sajeev G, Cox D, et al. Prognostic factors for changes in the timed 4-stair climb in patients with Duchenne muscular dystrophy, and implications for measuring drug efficacy: A multi-institutional collaboration. PLoS One. 2020;15(6):e0232870. doi: 10.1371/journal.pone. 0232870.
Mercuri E, Coratti G, Messina S, Ricotti V, Baranello G, D'Amico A, et al. Revised North Star Ambulatory Assessment for Young Boys with Duchenne Muscular Dystrophy. PLoS One. 2016;11(8):e0160195. doi: 10.1371/journal.pone.0160195.
Chetta A, Zanini A, Pisi G, Aiello M, Tzani P, Neri M, et al. Reference values for the 6-min walk test in healthy subjects 20-50 years old. Respir Med. 2006;100(9):1573-8. doi: 10.1016/j.rmed.2006.01.001.
Middel B, van Sonderen E. Statistical significant change versus relevant or important change in (quasi) experimental design: Some conceptual and methodological problems in estimating magnitude of intervention-related change in health services research. Int J Integr Care. 2002;2:e15. doi: 10.5334/ijic.65.
Husted JA, Cook RJ, Farewell VT, Gladman DD. Methods for assessing responsiveness: A critical review and recommendations. J Clin Epidemiol. 2000;53(5):459-68. doi: 10.1016/s0895-4356(99)00206-1.
Lenth R. Least-Squares Means: The R Package lsmeans. Journal of Statistical Software. 2016;69(1):1-33. doi: 10.18637/jss.v069.i01.
Correlation and regression: BMJ Publishing Group Ltd; 2022. Available from: https://www.bmj.com/aboutbmj/ resources-readers/publications/statistics-squareone/ 11-correlation-and-regression
Syde digital endpoint platform for mobility assessment; 2023. Available from: https://healthcare.sysnav.com/sydedigital- platform-2/
Dang UJ, Ziemba M, Clemens PR, Hathout Y, Conklin LS, Investigators CV, et al. Serum biomarkers associated with baseline clinical severity in young steroid-naive Duchenne muscular dystrophy boys. Hum Mol Genet. 2020;29(15):2481-95. 10.1093/hmg/ddaa132.
Audhya I, Rogula B, Szabo SM, Feeny D, Bolatova T, Gooch K. Exploring the relationship between North Star Ambulatory Assessment and Health Utilities Index scores in Duchenne muscular dystrophy. Health Qual Life Outcomes. 2023;21(1):76. 10.1186/s12955-023-02160-8.
Annoussamy M, Eggenspieler D, Strijbos P, Rabbia M, Tricot A, Vissiere D, et al. EP.323Wearable technology allows faster and more accurate detection of functional changes in Duchenne muscular dystrophy than traditional hospitalbased tests. Neuromuscular Disorders. 2021;31:S148. doi: https://doi.org/10.1016/j.nmd.2021.07.348
European Medicines Agency. Qualification opinion on stride velocity 95th centile as a secondary endpoint in Duchenne Muscular Dystrophy measured by a valid and suitable wearable device; 2019. Available from: https:// www.ema.europa.eu/en/documents/scientific-guideline/qu alification-opinion-stride-velocity-95th-centile-secondaryendpoint- duchenne-muscular-dystrophy en.pdf
Coon CD, Cook KF.Moving from significance to real-world meaning: Methods for interpreting change in clinical outcome assessment scores. Qual Life Res. 2018;27(1):33-40. doi: 10.1007/s11136-017-1616-3.
McDonald CM, Henricson EK, Abresch RT, Florence J, Eagle M, Gappmaier E, et al. The 6-minute walk test and other clinical endpoints in duchenne muscular dystrophy: Reliability, concurrent validity, and minimal clinically important differences from a multicenter study. Muscle Nerve. 2013;48(3):357-68. doi: 10.1002/mus.23905.
Wong B, Signorovitch J, Staunton H, Ong R, Rabbia M, Sajeev G, et al. Estimating clinically meaningful change thresholds in the North StarAmbulatory Assessment (NSAA) and Four-Stair Climb (4SC) in Duchenne muscular dystrophy (DMD). 2019.
Muntoni F, Signorovitch J, Sajeev G, Done N, Yao Z, Goemans N, et al. EP.125 Minimal detectable changes in functional measures in Duchenne muscular dystrophy (DMD): A study of multiple centers, networks and trial arms. Neuromuscul Disord. 2021;31. doi: https://doi.org/10.1016/j.nmd.2021.07.150
Ayyar Gupta V, Pitchforth JM, Domingos J, Ridout D, Iodice M, Rye C, et al. Determining minimal clinically important differences in the North Star Ambulatory Assessment (NSAA) for patients with Duchenne muscular dystrophy. PLoS One. 2023;18(4):e0283669. doi: 10.1371/journal.pone.0283669.
Miller NF, Alfano LN, Iammarino MA, Connolly AM, Moore-Clingenpeel M, Powers BR, et al. Natural History of Steroid-Treated Young Boys With Duchenne Muscular Dystrophy Using the NSAA, 100m, and Timed Functional Tests. Pediatr Neurol. 2020;113:15-20. doi: 10.1016/j.pediatrneurol.2020.08.013.
Duong T, Canbek J, Birkmeier M, Nelson L, Siener C, Fernandez-Fernandez A, et al. The Minimal Clinical Important Difference (MCID) in Annual Rate of Change of Timed Function Tests in Boys with DMD. J Neuromuscul Dis. 2021;8(6):939-48. doi: 10.3233/JND-210646.
Haberkamp M, Moseley J, Athanasiou D, de Andres- Trelles F, Elferink A, Rosa MM, et al. European regulators' views on a wearable-derived performance measurement of ambulation for Duchenne muscular dystrophy regulatory trials. Neuromuscul Disord. 2019;29(7):514-6. doi: 10.1016/j.nmd.2019.06.003.
Guglieri M, Clemens PR, Perlman SJ, Smith EC, Horrocks I, Finkel RS, et al. Efficacy and Safety of Vamorolone vs Placebo and Prednisone Among Boys With Duchenne Muscular Dystrophy: A Randomized Clinical Trial. JAMA Neurol. 2022;79(10):1005-14. 10.1001/jamaneurol. 2022.2480.
Emery N, Strachan K, Kulshrestha R, Kuiper JH, Willis T. Evaluating the Feasibility and Reliability of Remotely Delivering and Scoring the North Star Ambulatory Assessment in Ambulant Patients with Duchenne Muscular Dystrophy. Children (Basel). 2022;9(5):728. 10.3390/children9050728.
Sarepta Therapeutics Announces Topline Results from EMBARK, a Global Pivotal Study of ELEVIDYS Gene Therapy for Duchenne Muscular Dystrophy. [press release]. 2023.
McDonald CM, Henricson EK, Abresch RT, Duong T, Joyce NC, Hu F, et al. Long-term effects of glucocorticoids on function, quality of life, and survival in patients with Duchenne muscular dystrophy: A prospective cohort study. Lancet. 2018;391(10119):451-61. 10.1016/S0140- 6736(17)32160-8.
