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

McDonald, Craig M.; Henricson, E.; Abresch, Richard T.; Florence, Julaine; Eagle, Michelle; Gappmaier, Eduard; Glanzman, Allan M.; Spiegel, Robert J.; Barth, Jay; Elfring, Gary L.; Reha, A.; Peltz, Stuart W.

doi:10.1002/mus.23905

Cited by 262 publications

(276 citation statements)

References 78 publications

(153 reference statements)

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“…Evaluation of 6MWT results of eteplirsen‐treated patients and historical control patients ≥7 years of age amenable to exon 51 skipping showed comparable baseline 6MWT distances that diverged through the second and third year, culminating in a 75m difference in 6MWT decline between the groups by 24 months, and a statistically significant ( p < 0.01 from both ANCOVA and Wilcoxon rank sum test) and clinically meaningful29 difference in 6MWT decline of 151m between the groups by 36 months (Fig 4A).…”

Section: Resultsmentioning

confidence: 93%

“…Selection based on these parameters is supported by recent reports indicating that the main variables impacting disease progression in ambulatory DMD patients as measured by 6MWT are age, genotype, 6MWT distance at baseline, and corticosteroid use 3, 16, 24, 25, 29. Given the data that support the effect of corticosteroid therapy on delaying disease progression in DMD,3 corticosteroid use at baseline was required for all patients in the eteplirsen‐treated as well as the control cohort.…”

Section: Discussionmentioning

confidence: 93%

“…These 2 investigator‐initiated studies are the only DMD natural history data sets that have prospectively and consistently collected 6MWT assessments for a substantial number of patients for 36 months or longer. Comparability to the eteplirsen data set is supported by equivalent requirements across the studies for genetic confirmation of DMD diagnosis, patient care according to the same international treatment guidelines for DMD,27, 28 6MWT administration following generally accepted standards,13, 29, 30 and exclusion of patients with cognitive impairment that could interfere with test adherence. Patient‐level data from the registries were pooled, and analysis was performed to evaluate impact of genotype on disease natural history as well as to compare an appropriately matched historical control group to eteplirsen‐treated patients.…”

mentioning

confidence: 99%

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Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy

Mendell

Goemans²,

Lowes

et al. 2016

Annals of Neurology

446

392

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ObjectiveTo continue evaluation of the long‐term efficacy and safety of eteplirsen, a phosphorodiamidate morpholino oligomer designed to skip DMD exon 51 in patients with Duchenne muscular dystrophy (DMD). Three‐year progression of eteplirsen‐treated patients was compared to matched historical controls (HC).MethodsAmbulatory DMD patients who were ≥7 years old and amenable to exon 51 skipping were randomized to eteplirsen (30/50mg/kg) or placebo for 24 weeks. Thereafter, all received eteplirsen on an open‐label basis. The primary functional assessment in this study was the 6‐Minute Walk Test (6MWT). Respiratory muscle function was assessed by pulmonary function testing (PFT). Longitudinal natural history data were used for comparative analysis of 6MWT performance at baseline and months 12, 24, and 36. Patients were matched to the eteplirsen group based on age, corticosteroid use, and genotype.ResultsAt 36 months, eteplirsen‐treated patients (n = 12) demonstrated a statistically significant advantage of 151m (p < 0.01) on 6MWT and experienced a lower incidence of loss of ambulation in comparison to matched HC (n = 13) amenable to exon 51 skipping. PFT results remained relatively stable in eteplirsen‐treated patients. Eteplirsen was well tolerated. Analysis of HC confirmed the previously observed change in disease trajectory at age 7 years, and more severe progression was observed in patients with mutations amenable to exon skipping than in those not amenable. The subset of patients amenable to exon 51 skipping showed a more severe disease course than those amenable to any exon skipping.InterpretationOver 3 years of follow‐up, eteplirsen‐treated patients showed a slower rate of decline in ambulation assessed by 6MWT compared to untreated matched HC. Ann Neurol 2016;79:257–271

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Section: Resultsmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 93%

mentioning

confidence: 99%

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Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy

Mendell

Goemans²,

Lowes

et al. 2016

Annals of Neurology

446

392

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“…The EE was calculated by the HR at gait and at rest, and the average velocity (V ave ) of gait in a circuit of 8 m. Other authors 15 assessed energy expenditure in patients with DMD by the values of HR and V ave obtained in the 6-minute walk test. However, no study has compared the energy expenditure during gait in patients with DMD with data from Rose et al 1 .…”

Section: Taktak and Bowkermentioning

confidence: 99%

Gait energy expenditure in children with Duchenne muscular dystrophy: case study

Souza¹,

Ferreira²,

Baptista³

et al. 2014

Fisioter. Pesqui.

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| This case study aimed to verify the model of Rose et al. 1 as a feasible to assess energy expenditure in gait of children with Duchenne muscular dystrophy (DMD). Three DMD patients aged 6, 7 and 8 years old participated of this study. It was obtained weight, height, leg length measurement (LLM), resting and gait heart rate (HR) held on as 55-meter oval circuit performed during a two-minute test at each speed. Energy expenditure was calculated using the HR. It was performed a descriptive analysis (average) and these were compared, individually, to normative data. The average gait speed of these three patients was similar to the normative data for slow speed and lower considering comfortable and fast speed. The energy expenditure to slow speed of the patients 2 and 3 was similar to the normality, and lowest for patient 1; at comfortable speed, the energy expenditure obtained for all patients was similar; at fast speed, the patients 1 and 2 presented similar to normal values, but the patient 3 presented higher energy expenditure. It was concluded that the energy expenditure evaluation using HR was easily executed in the clinical practice and it can help therapeutic choices. For patient 3, an aerobic training could be indicated and for the others, they could keep the routine assessments.

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“…On peut en distinguer trois catégo-ries : les outils fonctionnels, les biomarqueurs de fluides biologiques et l'imagerie. Les études fonctionnelles sont au premier plan, avec une variété de dispositifs et de protocoles, dont beaucoup sont optimisés pour la mesure de mouvements spécifiques, et d'autres visant plutôt à une éva-luation de l'activité globale du patient (Scott et al 2012 ;Mazzone et al 2012 ;Servais et al 2013 ;McDonald et al 2013 ;Mayhew et al 2013 ;Pane et al 2014 ;Mazzone et al 2014 ;Hogrel et al 2014 ;Decostre et al 2015 ;Lynn et al 2015 ;Seferian et al 2015a ;Seferian et al 2015b). Ces derniers outils font partie d'une nouvelle discipline en pleine expansion, l'actimétrie, et offrent un accès inédit à une éva-luation du patient dans son environnement personnel sur de longues périodes de temps.…”

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Imagerie et spectroscopie par résonance magnétique nucléaire du muscle strié squelettique

et al. 2016

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Au cours des dernières années, les traitements de nombreuses maladies neuromusculaires, jusqu'ici incurables, ont bénéficié d'importants progrès. Ce bouleversement contextuel a eu pour conséquence de stimuler le développement de nouveaux outils d'évaluation atraumatiques. Ceux-ci peuvent être classés en trois grandes catégories : les explorations fonctionnelles musculaires, les marqueurs des fluides biologiques et l'imagerie musculaire. Au sein de cette dernière, l'imagerie par résonance magnétique nucléaire (IRMN) offre un très large éventail de possibilités pour caractériser la composition, la fonction et le métabolisme du muscle strié squelettique. Aujourd'hui, trois indicateurs RMN sont couramment intégrés dans les protocoles de recherche clinique : 1) le volume musculaire ou l'aire d'une section musculaire transversale ciblée, 2) le pourcentage de graisse intramusculaire et 3) le T2 de l'eau musculaire. Ils permettent de quantifier respectivement la trophicité du muscle, les dégénérescences graisseuses chroniques et l'oedème tissulaire (ou plus généralement « l'activité de la maladie »). Un quatrième indicateur, le volume de tissu contractile est facilement dérivable des deux premiers. Les cartographies de fraction graisseuse, souvent issues de séquences Dixon, ont fait la preuve de leur utilité pour détecter de subtils changements de composition musculaire et se sont, à plusieurs reprises, révélées plus sensibles que les évaluations fonctionnelles standards. Cet indicateur sera probablement le premier parmi ceux proposés à être validé comme paramètre principal par les organismes de régulation. La diversité des contrastes obtenus par RMN permet d'explorer de nombreuses autres pistes de caractérisation du muscle squelettique et de nouveaux biomarqueurs RMN sont à attendre dans un avenir plus ou moins proche. Des séquences à TE ultra-courts (UTE), le rehaussement tardif post-injection de gadolinium et l'élastographie par RMN sont en cours d'étude pour l'évaluation de la fibrose interstitielle du muscle squelettique. De nombreuses options existent pour mesurer la perfusion et l'oxygénation du muscle par RMN. La RMN de diffusion ainsi que l'utilisation d'algorithmes d'analyse de texture pourraient apporter des informations supplémentaires sur l'organisation musculaire aux échelles respectivement microscopiques et mésoscopiques. La spectroscopie RMN du phosphore 31 P est la technique de référence pour l'évaluation atraumatique de l'énergétique musculaire pendant et après exercice. Le spectre 31 P du muscle dystrophique au repos est notablement altéré, et plusieurs de ses résonances informent sur l'intégrité de la membrane cellulaire. D'importants efforts sont consacrés à l'accélération de l'acquisition des images au travers plusieurs approches, allant de l'extraction du contenu en graisse et des cartographies T2 au départ d'une unique séquence, jusqu'à l'utilisation de scénarios d'acquisition partielle des matrices. Dans un avenir proche, une diminution spectaculaire du temps d'acquisition est attendue. Cela ren...

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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

Cited by 262 publications

References 78 publications

Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy

Longitudinal effect of eteplirsen versus historical control on ambulation in Duchenne muscular dystrophy

Gait energy expenditure in children with Duchenne muscular dystrophy: case study

Imagerie et spectroscopie par résonance magnétique nucléaire du muscle strié squelettique

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