Non-ambulatory Duchenne Muscular Dystrophy Patients Research Articles

"If you cannot measure it, you cannot improve it". Outcome measures in Duchenne Muscular Dystrophy: current and future perspectives.

Duchenne Muscular Dystrophy (DMD) is an X-linked recessive neuromuscular disorder primarily affecting males, caused by mutations in the dystrophin gene. The absence of dystrophin protein leads to progressive skeletal muscle degeneration. Recent advances in the therapeutic landscape underscore the need to identify appropriate outcome measures to assess treatment efficacy in ambulant and non-ambulant DMD patients, across clinical and research settings. This is essential for accurately evaluating new treatments and attributing therapeutic benefits.It is crucial to establish a robust correlation between outcome scores and disease progression patterns. This task is challenging since functional test performance may be influenced by different patient's characteristics, including the physiological evolution of the neurodevelopment together with the disease progression. While widely used DMD outcomes such as the North Star Ambulatory Assessment, the 6-Minute Walking Test, the 4 stairs climbed, and the Performance of the Upper Limb exhibit reliability and validity, their clinical significance is influenced by the wide phenotype and progression variability of the disease.We present and discuss the features (relevance, quantifiability, validity, objectivity, reliability, sensitivity, specificity, precision) of available DMD outcome measures, including new potential measures that may be provided by digital tools and artificial intelligence.

Decreased quality of life in Duchenne muscular disease patients related to functional neurological and cardiac impairment.

In this prospective study involving 37 Duchenne muscular dystrophy (DMD) patients aged 8-18 years and older, we examined the impact of neurological and cardiac factors on quality of life (QoL). Our findings revealed a negative correlation between upper limb movement and overall mobility, self-service, and usual activities. Ambulatory and non-ambulatory DMD patients showed significant differences in mobility-related parameters. Cardiac evaluations demonstrated associations between mitral annular plane systolic excursion (MAPSE) and mobility-related aspects. The PEDSQL 3.0 neuromuscular model questionnaire further highlighted age-related and movement-related correlations with QoL. The loss of ambulatory status and reduced upper limb movement were negatively associated with QoL, while upper limb movement positively correlated with septal MAPSE. However, no significant associations were found between MAPSE and anxiety/depression. These findings underscore the multifaceted impact of DMD on QoL and emphasize the importance of considering both neurological and cardiac factors in comprehensive patient care.

Longitudinal Analysis of PUL 2.0 Domains in Ambulant and Non-Ambulant Duchenne Muscular Dystrophy Patients: How do they Change in Relation to Functional Ability?

The performance of upper limb 2.0 (PUL) is widely used to assess upper limb function in DMD patients. The aim of the study was to assess 24 month PUL changes in a large cohort of DMD patients and to establish whether domains changes occur more frequently in specific functional subgroups. The PUL was performed in 311 patients who had at least one pair of assessments at 24 months, for a total of 808 paired assessments. Ambulant patients were subdivided according to the ability to walk: >350, 250-350, ≤250 meters. Non ambulant patients were subdivided according to the time since they lost ambulation: <1, 1-2, 2-5 or >5 years. At 12 months, the mean PUL 2.0 change on all the paired assessments was -1.30 (-1.51--1.05) for the total score, -0.5 (-0.66--0.39) for the shoulder domain, -0.6 (-0.74--0.5) for the elbow domain and -0.1 (-0.20--0.06) for the distal domain.At 24 months, the mean PUL 2.0 change on all the paired assessments was -2.9 (-3.29--2.60) for the total score, -1.30 (-1.47--1.09) for the shoulder domain, -1.30 (-1.45--1.11) for the elbow domain and -0.4 (-1.48--1.29) for the distal domain.Changes at 12 and 24 months were statistically significant between subgroups with different functional abilities for the total score and each domain (p < 0.001). There were different patterns of changes among the functional subgroups in the individual domains. The time of transition, including the year before and after loss of ambulation, show the peak of negative changes in PUL total scores that reflect not only loss of shoulder but also of elbow activities. These results suggest that patterns of changes should be considered at the time of designing clinical trials.

Natural history of circulating miRNAs in Duchenne disease: Association with muscle injury and metabolic parameters

This study aimed to evaluate whether the expression of circulating dystromiRs and a group of oxidative stress-related (OS-R) miRNAs is associated with muscle injury and circulating metabolic parameters in Duchenne muscular dystrophy (DMD) patients. Twenty-four DMD patients were included in this cross-sectional study. Clinical scales to evaluate muscle injury (Vignos, GMFCS, Brooke, and Medical Research Council), enzymatic muscle injury parameters (CPK, ALT, and AST), anthropometry, metabolic indicators, physical activity, serum dystromiRs (miR-1-3p, miR-133a-3p, and miR-206), and OS-R miRNAs (miR-21-5p, miR-31-5p, miR-128-3p, and miR-144-3p) levels were measured in ambulatory and non-ambulatory DMD patients. DystromiRs (except miR-1-3p) and miRNAs OS-R levels were lower (p-value <.05) in the non-ambulatory group than the ambulatory group. The expression of those miRNAs correlated with Vignos scale score (For instance, rho=-0.567, p-value <0.05 for miR-21-5p) and with other scales scores of muscle function and strength. CPK, AST, and ALT concentration correlated with expression of all miRNAs (For instance, rho=0.741, p-value <.05 between miR-206 level and AST concentration). MiR-21-5p level correlated with glucose concentration (rho=-0.369, p-value=.038), and the miR-1-3p level correlated with insulin concentration (rho=0.343, p-value=.05). Non-ambulatory DMD patients have lower circulating dystromiRs and OS-R miRNAs levels than ambulatory DMD patients. The progressive muscle injury is associated with a decrease in the expression of those miRNAs, evidencing DMD progress. These findings add new information about the natural history of DMD.

The Black Box of Technological Outcome Measures: An Example in Duchenne Muscular Dystrophy.

Background:Outcome measures for non-ambulant Duchenne muscular dystrophy (DMD) patients are limited, with only the Performance of the Upper Limb (PUL) approved as endpoint for clinical trials.Objective:We assessed four outcome measures based on devices developed for the gaming industry, aiming to overcome disadvantages of observer-dependency and motivation.Methods:Twenty-two non-ambulant DMD patients (range 8.6–24.1 years) and 14 healthy controls (HC; range 9.5–25.4 years) were studied at baseline and 16 patients at 12 months using Leap Motion to quantify wrist/hand active range of motion (aROM) and a Kinect sensor for reached volume with Ability Captured Through Interactive Video Evaluation (ACTIVE), Functional Workspace (FWS) summed distance to seven upper extremity body points, and trunk compensation (KinectTC). PUL 2.0 was performed in patients only. A stepwise approach assessed quality control, construct validity, reliability, concurrent validity, longitudinal change and patient perception.Results:Leap Motion aROM distinguished patients and HCs for supination, radial deviation and wrist flexion (range p = 0.006 to <0.001). Reliability was low and the manufacturer’s hand model did not match the sensor’s depth images. ACTIVE differed between patients and HCs (p < 0.001), correlated with PUL (rho = 0.76), and decreased over time (p = 0.030) with a standardized response mean (SRM) of –0.61. It was appraised as fun on a 10-point numeric rating scale (median 9/10). PUL decreased over time (p < 0.001) with an SRM of –1.28, and was appraised as fun (median 7/10). FWS summed distance distinguished patients and HCs (p < 0.001), but reliability in patients was insufficient. KinectTC differed between patients and HCs (p < 0.01), but correlated insufficiently with PUL (rho = –0.69).Conclusions:Only ACTIVE qualified as potential outcome measure in non-ambulant DMD patients, although the SRM was below the commonly used threshold of 0.8. Lack of insight in technological constraints due to intellectual property and software updates made the technology behind these outcome measures a kind of black box that could jeopardize long-term use in clinical development.

Muscle-MRI and Functional Levels for the Evaluation of Upper Limbs in Duchenne Muscular Dystrophy: A Critical Review of the Literature.

Many qualitative and quantitative Magnetic Resonance Imaging (MRI) techniques have been applied to evaluate muscle fat degeneration in Duchenne muscular dystrophy (DMD) subjects, but only few studies have focused on the upper limbs. We reviewed the literature in order to evaluate the association between muscle MRI findings and motor function levels in the upper limbs of DMD patients. Ten studies with upper limb muscle MRI data were available. Four explored all upper limb segments, while six explored only the forearm. Functional assessments were performed in nine of the ten studies. All of the studies showed a significant correlation between muscle MRI changes and motor function levels in both ambulant and non-ambulant DMD patients.

IMAGING: EP.336 Quantitative MRI, strength and function of the upper extremity flexor muscles in non-ambulant DMD patients: an 18 month follow-up analysis

Quantitative MRI (qMRI) of skeletal muscles is a promising method to objectively assess muscle involvement in Duchenne muscular dystrophy (DMD) and a potential outcome measure in clinical trials. qMRI data of the upper extremity (UE) muscles in non-ambulant DMD patients are limited. Therefore, we longitudinally assessed qMRI and UE functional outcome measures in this stage of the disease. 4-point Dixon MRI scans (3T) of the right upper arm, performance of the upper limb (PUL) version 2.0 and elbow flexion and grip strength were measured at baseline, 12 and 18 months follow-up.

Preserved thenar muscles in non-ambulant Duchenne muscular dystrophy patients.

BackgroundClinical trials in Duchenne muscular dystrophy (DMD) focus primarily on ambulant patients. Results cannot be extrapolated to later disease stages due to a decline in targeted muscle tissue. In non‐ambulant DMD patients, hand function is relatively preserved and crucial for daily‐life activities. We used quantitative MRI (qMRI) to establish whether the thenar muscles could be valuable to monitor treatment effects in non‐ambulant DMD patients.MethodsSeventeen non‐ambulant DMD patients (range 10.2–24.1 years) and 13 healthy controls (range 9.5–25.4 years) underwent qMRI of the right hand at 3 T at baseline. Thenar fat fraction (FF), total volume (TV), and contractile volume (CV) were determined using 4‐point Dixon, and T2water was determined using multiecho spin‐echo. Clinical assessments at baseline (n = 17) and 12 months (n = 13) included pinch strength (kg), performance of the upper limb (PUL) 2.0, DMD upper limb patient reported outcome measure (PROM), and playing a video game for 10 min using a game controller. Group differences and correlations were assessed with non‐parametric tests.ResultsTotal volume was lower in patients compared with healthy controls (6.9 cm3, 5.3–9.0 cm3 vs. 13.0 cm3, 7.6–15.8 cm3, P = 0.010). CV was also lower in patients (6.3 cm3, 4.6–8.3 cm3 vs. 11.9 cm3, 6.9–14.6 cm3, P = 0.010). FF was slightly elevated (9.7%, 7.3–11.4% vs. 7.7%, 6.6–8.4%, P = 0.043), while T2water was higher (31.5 ms, 30.0–32.6 ms vs. 28.1 ms, 27.8–29.4 ms, P < 0.001). Pinch strength and PUL decreased over 12 months (2.857 kg, 2.137–4.010 to 2.243 kg, 1.930–3.339 kg, and 29 points, 20–36 to 23 points, 17–30, both P < 0.001), while PROM did not (49 points, 36–57 to 44 points, 30–54, P = 0.041). All patients were able to play for 10 min at baseline or follow‐up, but some did not comply with the study procedures regarding this endpoint. Pinch strength correlated with TV and CV in patients (rho = 0.72 and rho = 0.68) and controls (both rho = 0.89). PUL correlated with TV, CV, and T2water (rho = 0.57, rho = 0.51, and rho = −0.59).ConclusionsLow thenar FF, increased T2water, correlation of muscle size with strength and function, and the decrease in strength and function over 1 year indicate that the thenar muscles are a valuable and quantifiable target for therapy in later stages of DMD. Further studies are needed to relate these data to the loss of a clinically meaningful milestone.

Expert recommendation: treatment of nonambulatory patients with Duchenne muscular dystrophy

HintergrundDie Muskeldystrophie Duchenne (DMD) ist die häufigste genetische neuromuskuläre Krankheit im Kindesalter, bei der es meist im Alter von 9 bis 11 Jahren zum Verlust der Gehfähigkeit kommt.Ziel der Arbeit und Material und MethodenAuf der Grundlage aktueller Leitlinien und Studien erarbeiteten neuropädiatrische und neurologische Experten im Rahmen eines von der Firma PTC Therapeutics GmbH (Frankfurt am Main, Deutschland), die die Substanz Ataluren vertreibt, gesponserten Advisory Boards Empfehlungen zur Behandlung nichtgehfähiger Patienten mit DMD mit Schwerpunkt medikamentöse Therapien von Erwachsenen.Ergebnisse und DiskussionDer Verlust der Gehfähigkeit wird in Studien sehr unterschiedlich definiert und bezieht sich u. a. auf die Rollstuhlpflicht, das selbständige Gehen ohne Hilfsmittel oder die maximale Gehstrecke. Grundlage der Therapie von Patienten mit DMD in jedem Krankheitsstadium sind supportive und symptomatische Maßnahmen, die in der Regel auch nach dem Verlust der Gehfähigkeit intensiv weitergeführt werden sollten. Zusätzlich stehen den Patienten medikamentöse Therapien mit dem Ziel der Modifikation des Krankheitsverlaufes zur Verfügung. Glukokortikoide bilden den Stützpfeiler der medikamentösen Therapie auch über den Verlust der Gehfähigkeit hinaus, dann meist in reduzierter Dosis. Für Patienten mit DMD aufgrund einer Nonsense-Mutation (nmDMD), ca. 13 % aller DMD-Patienten, steht Ataluren als potenziell dystrophinwiederherstellende, krankheitsmodifizierende Therapie zur Verfügung; klinische Daten aus dem STRIDE-Register zeigen eine verzögerte Krankheitsprogression auch nach Verlust der Gehfähigkeit. Zum Exon-Skipping liegen für erwachsene Patienten derzeit noch keine belastbaren Daten vor. Das Antioxidans Idebenon kommt bei nichtgehfähigen, jugendlichen Patienten ohne therapeutische Alternative, die nicht mit Glukokortikoiden behandelt werden können, infrage. Ataluren eignet sich zur kombinierten Behandlung mit Glukokortikoiden, eine Kombination von Idebenon und Glukokortikoiden wird derzeit in einer klinischen Studie überprüft. Eine Add-on-Therapie mit Idebenon zusätzlich zu Ataluren ist bei nichtgehfähigen nmDMD-Patienten zu erwägen. Bedingt durch die Tatsache, dass sich einige der diskutierten Therapieoptionen noch in der Phase der klinischen Prüfung befinden oder noch keine oder nur begrenzte Daten für ältere Patienten mit DMD vorliegen, handelt es sich um Expertenempfehlungen entsprechend der Evidenzklasse IV.

MUSCLE IMAGING – MRI: P.167 Last but not least: preserved thenar muscles in non-ambulant Duchenne muscular dystrophy patients

Hand function in Duchenne muscular dystrophy (DMD) is preserved relatively long, and is crucial for daily-life activities of non-ambulant patients such as operating a wheelchair. As a potential target for therapy, it is important to know to what extent intrinsic hand muscles are affected. We used quantitative MRI (qMRI) to study the relation between thenar muscle fat fraction (FF), total volume (TV), contractile volume (CV), T2 of muscle (T2water) and pinch strength. Seventeen non-ambulant DMD patients (range 10.2-24.1 years) and 13 healthy controls (HC; range 9.5-25.4 years) underwent qMRI of the right hand at 3T while positioned on their right side.

The association of hand grip strength with functional measures in non-ambulatory children with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a disease characterized by progressive loss of muscle fiber, gradually from proximal to distal. Although a few studies have investigated hand grip strength in non-ambulatory DMD patients, a lack of literature was found determining its relationship with functional capacity. The aim of this study was to determine the associations between hand grip strength and functional measures in non-ambulatory children with DMD. Hand grip strength was evaluated using a dynamometer in children with DMD. The children with DMD were evaluated with the Turkish version of the Egen Klassifikation Scale Version 2 (EK2) for global functional capacity, the Performance of Upper Limb (PUL) for upper limb functional performance and the ABILHAND-Kids for hand ability. The mean age of 38 DMD children was 12.02 ± 1.99 years. Dominant hand grip strength of the children with DMD was higher than the non-dominant hand (p < 0.05). The EK2 was 13.02 ± 5.50, PUL was 49.86 ± 14.34 and ABILHAND-Kids was 26.81 ± 7.59. Hand grip strength was found to be correlated with the EK2 (p < 0.05). It is known that measuring functional ability and strength in very weak children with DMD has been difficult and complex for therapists/clinicians in the clinical environment. Although there is a moderate correlation, hand grip strength may be used in clinical practice as a practical assessment tool to have an immediate insight into the global functional capacity in non-ambulatory DMD children.

EP.95Patient perception of outcome measures for non-ambulant Duchenne muscular dystrophy patients

Many therapeutic clinical trials are ongoing in ambulant Duchenne muscular dystrophy (DMD) patients. However, drugs proven effective in ambulant patients will have to be tested separately in non-ambulant patients. Several outcome measures for non-ambulant patients are under development. Natural history data of these measures is needed, while patients struggle to combine this type of extra visits with their daily life. We assessed patient's perception of several different outcome measures for non-ambulant DMD patients. Non-ambulant DMD patients underwent muscle MRI, peak muscle force tests using a Hand-held dynamometer and Myotools, Functional Workspace, Leap Motion and PUL 2.0 assessments of the right arm, and Active-Seated and PROM assessment of both arms. Using visual analogue scale (VAS) scores (range 0-10), all patients were asked directly after the respective assessment how much fun, annoying and tiresome they perceived it. Highest VAS scores on all three domains were correlated to PUL total score using Spearman correlation coefficients. 20 non-ambulant DMD patients (range 8.6-24.1 yrs) were included. Active-Seated scored highest on fun (median 8), followed by muscle force tests and PUL (median 7). MRI was the most annoying (median 5), while all other tests had a median score of 1 or 2. Active-Seated was the most tiresome (median 6), followed by muscle force tests (median 5), and Functional Workspace (median 4). No significant correlation with PUL total score was found for Active-Seated VAS fun and tiresome scores (ρ=-0.04, p=0.871 and ρ=-0.13, p=0.598), and MRI VAS annoying scores (ρ=-0.46, p=0.053). While Active-Seated and muscle force tests score highest on fun, they are also the most tiresome. MRI has the advantage of no motivation component, but scored highest on annoyment. To improve participation in both therapeutic and natural history studies, patient's perception of outcome measures for non-ambulant DMD patients and their respective burden need to be considered.

EP.79The impact of ventilation on non-ambulatory patients with DMD

Duchenne muscular dystrophy (DMD) is a severe progressive muscular dystrophy caused by mutations in the DMD gene, leading to the absence of a functional dystrophin protein. During disease progression patients develop respiratory decline, which leads to the need for ventilation, either non-invasive or invasive, in their late teens or early twenties. Also the ability to cough becomes more compromised during the course of the disease. This has a huge impact on daily life and is a burden for both patients and families. To get an insight into the effects of respiratory decline, use of ventilation, the burden and the areas on which it has the most impact, a survey has been held among non-ambulatory DMD patients. The survey was completed by 114 patients from 21 countries (age range: 11 to 54). On average ventilation (any form) was started around 17 years of age (n=101) and continuous ventilation around 20 years (n=49). BiPAP is most commonly used (68%). Also cough assists are frequently used (54%). Respiratory complications sometimes resulted in missing school or work days by both patients and parents. For the majority (85%) the use of ventilation led to an improvement of the quality of life by improving sleeping (77%) and reducing anxiety (58% of those who felt anxious before). For most patients (87%) it facilitated their participation in social activities to some extent. Patients on average give their life a rating of 68 on the EQ-5D scale. This is around 20 points lower than the healthy population. While in the general population a decrease in EQ-5D score is seen with ageing, the contrary is seen for DMD. Thereby the differences between the general and the DMD population diminish with age. The main conclusion of the respiratory survey is that ventilation has a major positive impact on the quality of life, both physically and socially.

P.305MRI brachialis contractile cross-sectional area is correlated strongest to elbow flexion in non-ambulant Duchenne muscular dystrophy patients

P.305MRI brachialis contractile cross-sectional area is correlated strongest to elbow flexion in non-ambulant Duchenne muscular dystrophy patients

Association Between Health-Related Quality of Life and Motor Function in Ambulant and Nonambulant Duchenne Muscular Dystrophy Patients.

This cross-sectional study assessed health-related quality of life (HRQOL) in ambulant and nonambulant patients with Duchenne muscular dystrophy, and explored the association between health-related quality of life and clinically assessed motor function. The Pediatric Quality of Life Inventory (PedsQL) Generic Core Scale and PedsQL Neuromuscular module were completed by 34 parent-child dyads. Association between PedsQL scores and overall motor abilities and the transfers and standing posture domain measured by the Motor Function Measure were examined. Child self-reported and parent proxy-reported mean PedsQL scores for children with Duchenne muscular dystrophy were lower than those for healthy children for the physical and psychosocial health-related quality of life. Fifty-six percent of patients reported clinically impaired psychosocial health-related quality of life scores. Several aspects of the generic and disease-specific health-related quality of life in patients with Duchenne muscular dystrophy were positively associated to overall motor function and transfers and standing posture domain. Associations remained stable when adjusted for age and corticosteroid use. The Motor Function Measure is clinically meaningful in the context of a patient's day-to-day life.

Eteplirsen Treatment Attenuates Respiratory Decline in Ambulatory and Non-Ambulatory Patients with Duchenne Muscular Dystrophy.

Background:Duchenne muscular dystrophy (DMD) patients experience skeletal muscle degeneration, including respiratory muscles. Respiratory decline in glucocorticoid-treated DMD patients, measured by percent predicted forced vital capacity (FVC% p), is typically 5% annually in patients aged 10 to 18 years.Objective:Evaluate the effects of eteplirsen on FVC% p annual change in 3 trials versus matched Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) controls.Methods:Eteplirsen studies 201/202 evaluated eligible ambulatory DMD patients for at least 4 years, study 204 evaluated primarily non-ambulatory DMD patients for 2 years, and ongoing study 301 is evaluating ambulatory DMD patients for 2 years (interim analysis is included). Eteplirsen-treated patients (n = 74) were amenable to exon 51 skipping and were receiving glucocorticoids. Three CINRG DNHS cohorts included: glucocorticoid-treated patients amenable to exon 51 skipping (Exon 51 CINRG DNHS; n = 20), all glucocorticoid-treated CINRG patients (All CINRG DNHS; n = 172), and all glucocorticoid-treated genotyped CINRG DNHS patients (Genotyped CINRG DNHS; n = 148). FVC% p assessments between ages 10 and <18 years were included for all patients; mixed-model analyses characterized FVC% p annual change.Results:FVC% p annual change was greater for CINRG DNHS Exon 51 controls (– 6.00) versus patients in studies 201/202, study 204, and study 301 (– 2.19, P < 0.001; – 3.66, P 0.004; and – 3.79, P 0.017, respectively). FVC% p annual change in all eteplirsen studies suggested treatment benefit compared with the Genotyped CINRG DNHS (– 5.67) and All CINRG DNHS (– 5.56) cohorts (P < 0.05, all comparisons).Conclusions:Significant, clinically meaningful attenuation of FVC%p decline was observed in eteplirsen-treated patients versus CINRG DNHS controls.

DMD CLINICAL THERAPIES II: P.125Eteplirsen treatment attenuates respiratory decline in ambulatory and non-ambulatory patients with Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) patients experience progressive degeneration of skeletal muscles including those involved in respiration. Well characterized respiratory decline in glucocorticoid-treated DMD patients includes forced vital capacity % predicted (FVC%p) decline ≥5% per year between the ages of 10 and 18 years. We evaluated eteplirsen treatment effect on FVC%p annual change in three eteplirsen clinical trials compared to well-matched natural history controls from the Cooperative International Neuromuscular Research Group (CINRG). Age-based mixed model analyses were conducted to determine FVC%p annual change (slope) for eteplirsen-treated patients and CINRG controls. Patients in the CINRG control (n=20) were amenable to exon 51 skipping, on glucocorticoids, and had FVC%p assessments between the ages of 10 and 18 years. Patients in the eteplirsen clinical trials (n=74) were amenable to exon 51 skipping, on glucocorticoids, and only FVC%p assessments between the ages of 10 to 18 years were included in the analysis. Study 201/202 was conducted over 216 weeks and enrolled ambulatory patients. Study 204 was conducted over 96 weeks and enrolled primarily non-ambulatory patients. Study 301 is an ongoing study which enrolled ambulatory patients; an interim week 96 analysis is presented. In Study 201/202 the annual change in FVC%p in (n=12) eteplirsen-treated patients was -2.19% compared to -6.00% in CINRG controls (p<0.001). In study 204 annual change in FVC%p in (n=20) eteplirsen-treated patients was -3.66% compared to -6.00% in CINRG controls (p=0.004). In an interim analysis of Study 301 annual change in FVC%p in (n=46) eteplirsen-treated patients was -3.79% compared to -6.00% in CINRG controls (p=0.017). Significant and clinically meaningful attenuation of FVC%p decline was seen in eteplirsen-treated patients compared to CINRG controls across three clinical trials in both ambulatory and non-ambulatory DMD patients.

P.455 - Outcome measures for Duchenne muscular dystrophy from ambulant to non-ambulant patients: implications for clinical trials

The need for a better understanding of Duchenne muscular dystrophy (DMD) natural history and the role of novel outcome measures and their impact in current and future clinical trials is well recognized. We aimed to assess the natural history of ambulant and non-ambulant DMD patients in an international multicentre study across 5 centres (London, Newcastle, Paris, Leiden, Nijmegen) with patients being assessed 6-monthly according to a shared protocol. Assessments included 6-minute walk distance (6MWD), North Star Ambulatory Assessment (NSAA), Performance of Upper Limb (PUL 1.2), MyoSet, respiratory function (forced vital capacity – FVC, maximum inspiratory and expiratory pressures – MEP and MIP, peak expiratory flow – PEF, peak cough flow – PCF). A subgroup performed annual whole body DEXA scans. We analysed longitudinal data for 82 patients (at recruitment 53 ambulant, mean age = 7.7 ± 2.3 years and 29 non-ambulant, mean age = 14.4 ± 1.9 years). For ambulant patients >7years old we observed a decline of 2.6 points per year in the NSAA (p < 0.001) and an increase of 1.04 seconds per year in the time to run 10 meters (p < 0.001). In non-ambulant patients, we observed a loss of 3.96 points on the PUL per year (p < 0.001) and a decrease in most of the %predicted respiratory measures (6.5% in FVC p < 0.001, 3.7% in PEF p < 0.01, 3.4% MIP p < 0.001 and 2.5% MEP p < 0.001) over the year. We observed a strong correlation between the PUL total and %predicted FVC (r = 0.73, p < 0.001) and between best MIP and moviplate (r = 0.71, p < 0.001). Patients with a lower limb lean body mass >30% were all ambulant except for 1 patient who lost ambulation less than 6 months later. This study adds to the current knowledge on DMD natural history. In particular, herein we explored the mean changes per year expected for non-ambulant patients for the different respiratory outcome measures and for functional measures that will be relevant for trials targeting this population. We also characterized the relationship between respiratory measures and upper limb function.

Establishment of a highly sensitive sandwich ELISA for the N-terminal fragment of titin in urine.

Muscle damage and loss of muscle mass are triggered by immobilization, loss of appetite, dystrophies and chronic wasting diseases. In addition, physical exercise causes muscle damage. In damaged muscle, the N-terminal and C-terminal regions of titin, a giant sarcomere protein, are cleaved by calpain-3, and the resulting fragments are excreted into the urine via glomerular filtration. Therefore, we considered titin fragments as promising candidates for reliable and non-invasive biomarkers of muscle injury. Here, we established a sandwich ELISA that can measure the titin N-terminal fragment over a biologically relevant range of concentrations, including those in urine samples from older, non-ambulatory Duchenne muscular dystrophy patients and from healthy donors under everyday life conditions and after exercise. Our results indicate that the established ELISA could be a useful tool for the screening of muscular dystrophies and also for monitoring the progression of muscle disease, evaluating the efficacy of therapeutic approaches, and investigating exercise-related sarcomeric disruption and repair processes.

Utility of skinfold thickness measurement in non-ambulatory patients with Duchenne muscular dystrophy

Nutritional disorders in Duchenne muscular dystrophy (DMD) worsen the medical condition. In particular, obesity is a serious problem that increases the risk of cardiomyopathy and affects nursing care. However, it is often difficult to evaluate body fatness in the advanced stages of DMD. Skinfold thickness measurement is a classical method to evaluate body fatness and is easily performed, even for bed-bound patients at home. We aimed to investigate the utility of skinfold thickness measurement in non-ambulatory DMD patients. Twenty-two patients with non-ambulatory, steroid-naive DMD ranging in age of 12–47 years were evaluated by body mass index (BMI), blood tests, measurement of triceps skinfold thickness (TSF), and abdominal computed tomography (CT) measurement of the areas of both subcutaneous and visceral fat. TSF showed good correlation with BMI (r = 0.80; p < 0.001), serum triglycerides (r = 0.67; p < 0.01), area of subcutaneous fat (r = 0.85; p < 0.0001), and area of visceral fat (r = 0.76; p < 0.0001). These results indicate the skinfold thickness measurement may be applicable as a screening tool in clinical practice where CT and magnetic resonance imaging assessment is often difficult in patients with advanced DMD.