Marleen van den Hauwe

Idebenone as a novel, therapeutic approach for Duchenne muscular dystrophy: Results from a 12 month, double-blind, randomized placebo-controlled trial

Early mortality in Duchenne muscular dystrophy (DMD) is related to cardiac and respiratory complications. A phase IIa double-blind randomized placebo-controlled clinical trial was conducted to investigate the tolerability and efficacy of idebenone therapy in children with DMD. Twenty-one DMD patients (aged 8-16 years) were randomly assigned to daily treatment with 450 mg idebenone (Catena®) (n=13) or placebo (n=8) for 12 months. All subjects completed the study and idebenone was safe and well tolerated. Idebenone treatment resulted in a trend (p=0.067) to increase peak systolic radial strain in the left ventricular inferolateral wall, the region of the heart that is earliest and most severely affected in DMD. A significant respiratory treatment effect on peak expiratory flow was observed (p=0.039 for PEF and p=0.042 for PEF percent predicted). Limitations of this study were the small sample size, and a skewed age distribution between treatment groups. Data from this study provided the basis for the planning of a confirmatory study.

Long-Term Efficacy, Safety, and Pharmacokinetics of Drisapersen in Duchenne Muscular Dystrophy: Results from an Open-Label Extension Study

Background Drisapersen induces exon 51 skipping during dystrophin pre-mRNA splicing and allows synthesis of partially functional dystrophin in Duchenne muscular dystrophy (DMD) patients with amenable mutations. Methods This 188-week open-label extension of the dose-escalation study assessed the long-term efficacy, safety, and pharmacokinetics of drisapersen (PRO051/GSK2402968), 6 mg/kg subcutaneously, in 12 DMD subjects. Dosing was once weekly for 72 weeks. All subjects had a planned treatment interruption (weeks 73–80), followed by intermittent dosing (weeks 81–188). Results Subjects received a median (range) total dose of 5.93 (5.10 to 6.02) mg/kg drisapersen. After 177 weeks (last efficacy assessment), median (mean [SD]) six-minute walk distance (6MWD) improved by 8 (-24.5 [161]) meters for the 10 subjects able to complete the 6MWD at baseline (mean age [SD]: 9.5 [1.9] years). These statistics include 2 subjects unable to complete the test at later visits and who scored “zero”. When only the 8 ambulant subjects at week 177 were taken into account, a median (mean [SD]) increase of 64 (33 [121]) meters in 6MWD was observed. Of 7 subjects walking ≥330 m at extension baseline, 5 walked farther at week 177. Of 3 subjects walking <330 m, 2 lost ambulation, while 1 declined overall but walked farther at some visits. Over the 188 weeks, the most common adverse events were injection-site reactions, raised urinary α1-microglobulin and proteinuria. Dystrophin expression was detected in all muscle biopsies obtained at week 68 or 72. Conclusion Drisapersen was generally well tolerated over 188 weeks. Possible renal effects, thrombocytopenia and injection-site reactions warrant continued monitoring. Improvements in the 6MWD at 12 weeks were sustained after 3.4 years of dosing for most patients. For a small, uncontrolled study, the outcomes are encouraging, as natural history studies would anticipate a decline of over 100 meters over a 3-year period in a comparable cohort. Trial Registration ClinicalTrials.gov NCT01910649

Ambulatory capacity and disease progression as measured by the 6-minute-walk-distance in Duchenne muscular dystrophy subjects on daily corticosteroids

In order to understand contemporary natural history of Duchenne muscular dystrophy (DMD), we report 6-minute walk distance (6MWD) and its change over time from a large single centre population of corticosteroid treated DMD boys. Sixty-five boys on daily corticosteroid treatment were identified with a mean (SD) age of 9.5 (2.3) years at first observation. 6MWD was described for 1year age groupings. In addition, changes in 6MWD at 1, 1.5 and 2years (±12weeks) of follow-up were evaluated. The same evaluations were applied to 6MWD data converted to percent predicted values based on the Geiger equation. 6MWD showed an increase from age group 4.5-5.5years to age group 6.5-7.5years, followed by a decline, which became precipitous from 12.5years onwards. From 15.5years, all boys were unable to perform the 6-min test. Changes in 6MWD demonstrated a mean (median, SD) decline of -43 (-14, 90) m at 1year (N=25, mean baseline age 9.5years), -64 (-56, 99) m at 1.5years (N=18, mean baseline age 9.6years), -125 (-106, 139) m at 2years (N=14, mean baseline age 10.0years). Conversion to percent predicted values showed the same pattern of evolution.This study provides data on the ambulatory capacity and its changes over time in a homogenous cohort of 65 DMD boys on daily corticosteroids. The variability, the age-related aspects and the slope of decline of the 6MWD should be considered in the design and interpretation of therapeutic trials in ambulant DMD patients.

Six-Minute Walk Test: Reference Values and Prediction Equation in Healthy Boys Aged 5 to12 Years

OBJECTIVE This study aimed to (1) generate normative data in healthy boys aged 5–12 years for the six-minute walk test (6MWT), an outcome measure currently used in clinical trials in Duchenne muscular dystrophy (DMD), (2) to describe the relation with anthropometric variables and myometry, and (3) to compare our data with published equations. METHODS The 6MWT was conducted in 442 boys according to a standardized protocol, as currently used in clinical trials in DMD. Maximal voluntary isometric contractions for knee flexion and extension were recorded with a hand-held myometer. RESULTS The 6MWD increased significantly with age, from 478.0±44.1 m at age 5, to 650.0±76.8 m at age 12, with the steepest increase between 5 and 8 years. Age- and height related percentile curves of the 6MWD were developed. Correlations with anthropometric variables were fair to good (age r = 0.60, height r = 0.57, weight r = 0.44). Myometric variables (knee flexors and extensors) showed correlations of 0.46 and 0.50 respectively. When dividing into two age categories (5–8 years, 9–12 years), these magnitudes of correlations only applied to the younger age group. Additionally, predicted values were calculated according to available reference equations (Geiger and Ben Saad), indicating an overestimation by those equations. Finally, the Geiger equation was refitted to our population. CONCLUSION The percentile curves according to age and height provide a useful tool in the assessment of ambulatory capacity in boys aged 5 to 12 years. Significant correlations with anthropometric variables and myometry were only found in the 5–8 years age group. The Geiger prediction equation, currently used to assess ambulatory capacity in DMD was refitted to obtain a more accurate prediction model based on a large sample with a homogenous distribution across the age categories 5 to 12 years and applying the methodology as currently used in clinical trials in DMD.

Effects of glucocorticoids and idebenone on respiratory function in patients with duchenne muscular dystrophy

In Duchenne muscular dystrophy (DMD) progressive weakness of respiratory muscles leads to a restrictive pulmonary syndrome that contributes to early morbidity and mortality. Currently no curative treatment exists for DMD. In a Phase II randomized placebo‐controlled study (DELPHI) in 21 DMD boys at age 8–16 years, idebenone (450 mg/d) showed trends of efficacy for cardiac and respiratory endpoints. Since the DELPHI study population comprised both glucocorticoid‐naïve subjects and glucocorticoid‐users, we now report a post‐hoc analysis investigating the effects of glucocorticoids and idebenone on markers of respiratory weakness, particularly peak expiratory flow (PEF) percent predicted (PEF%p). Baseline values of PEF%p correlated well with the percent predicted values for maximal inspiratory mouth pressure (MIP%p), forced vital capacity (FVC%p), and forced expired volume in 1 sec (FEV1%p). Baseline PEF%p and FVC%p were significantly higher in patients on concomitant glucocorticoids compared to glucocorticoid‐naïve patients. In the latter subgroup, idebenone caused a 8.0 ± 12.1% improvement in PEF%p, whilst patients on placebo declined by −12.3 ± 17.9% (P < 0.05) in the course of the 12 month study. In patients receiving concomitant glucocorticoids, PEF%p remained stable (−0.4 ± 14.6%) in the idebenone group compared to a decline by −6.2 ± 12.4% (P = 0.24) in the placebo group. Idebenone showed a trend for efficacy on FVC%p only in glucocorticoid‐naïve patients. Because of the study limitations, these data are exploratory and preclude any firm conclusions. In conclusion, PEF appears to be a sensitive respiratory function parameter that could be a valid and clinically relevant endpoint in intervention studies in DMD. In DELPHI the effect size of idebenone on PEF%p was significantly larger in steroid‐naive patients, possibly indicating a maximum treatment effect reached by steroids or steroid‐mediated suppression of idebenones effects. The impact of standard care glucocorticoids on respiratory function will have to be considered in the planning of future interventional trials in DMD. Pediatr Pulmonol. 2013; 48:912–920.

Patterns of disease progression in type 2 and 3 SMA: Implications for clinical trials

Highlights • The paper reports for the first time patterns of progression in type 2 and 3 SMA.• Different trajectories can be identified in ambulant and non-ambulant patients.• Age appears to be an important factor in determining trajectories of progression.

Gait Assessment in Children With Duchenne Muscular Dystrophy During Long-Distance Walking:

The aim of this study was to investigate the alteration of the gait pattern in 25 children with Duchenne muscular dystrophy, using body-worn inertial sensors during a long walking distance. Normalized spatiotemporal gait parameters and their variability were extracted from the angular velocity of the shanks; the smoothness of the trunk movement was assessed based on the spectral entropy of the acceleration norm. As compared to healthy children, patients with Duchenne muscular dystrophy showed significantly lower stride velocity and a less smooth trunk movement. When the group of patients was divided into mild and moderate based on the Motor Function Measure, the authors noticed significantly higher values both for cadence and stride velocity, as well as improved trunk smoothness in the mild versus moderate group. The potential of such parameters to distinguish between different disease states opens new perspectives for the objective assessment of efficacy of the new therapies associated with Duchenne muscular dystrophy.

Test–retest reliability and developmental evolution of the 6-min walk test in Caucasian boys aged 5–12 years

The 6-min walk test (6MWT) assesses functional capacity and has been used as outcome measure in therapeutic studies in childhood neuromuscular disorders. The objectives were to evaluate test-retest reliability of the 6MWT and to generate normative data for healthy boys aged 5-12 years. Ninety boys (mean age 8 years 10 months) were recruited over four age subcategories (5-6, 7-8, 9-10, 11-12 years). Mean 6MWT distance and velocity (±standard deviation) for the total group were 555.5±93 m and 92.6±16.6 m/min. The 6MWT distance increased significantly with age. Test-retest reliability (mean interval 12 days) was very high for the total group (ICC>0.95) and for all age subcategories (ICC>0.80) a moderately high reliability (ICC>0.75) was found from 3 min onwards for each age subcategory. There was a mean difference of 5.2 m between test and retest without systematic bias. The standard error of measurement and smallest detectable difference were 20.7 and 57.4 m, respectively. These findings demonstrate the reliability of the 6MWT in young children, underscore its evolution with age, and indicate that a shorter version of the test is also reliable.

Individualized Prediction of Changes in 6-Minute Walk Distance for Patients with Duchenne Muscular Dystrophy

Background Deficits in ambulatory function progress at heterogeneous rates among individuals with Duchenne muscular dystrophy (DMD). The resulting inherent variability in ambulatory outcomes has complicated the design of drug efficacy trials and clouded the interpretation of trial results. We developed a prediction model for 1-year change in the six minute walk distance (6MWD) among DMD patients, and compared its predictive value to that of commonly used prognostic factors (age, baseline 6MWD, and steroid use). Methods Natural history data were collected from DMD patients at routine follow up visits approximately every 6 months over the course of 2–5 years. Assessments included ambulatory function and steroid use. The annualized change in 6MWD (Δ6MWD) was studied between all pairs of visits separated by 8–16 months. Prediction models were developed using multivariable regression for repeated measures, and evaluated using cross-validation. Results Among n = 191 follow-up intervals (n = 39 boys), mean starting age was 9.4 years, mean starting 6MWD was 351.8 meters, and 75% had received steroids for at least one year. Over the subsequent 8–16 months, mean Δ6MWD was -37.0 meters with a standard deviation (SD) of 93.7 meters. Predictions based on a composite of age, baseline 6MWD, and steroid use explained 28% of variation in Δ6MWD (R2 = 0.28, residual SD = 79.4 meters). A broadened prognostic model, adding timed 10-meter walk/run, 4-stair climb, and rise from supine, as well as height and weight, significantly improved prediction, explaining 59% of variation in Δ6MWD after cross-validation (R2 = 0.59, residual SD = 59.7 meters). Conclusions A prognostic model incorporating timed function tests significantly improved prediction of 1-year changes in 6MWD. Explained variation was more than doubled compared to predictions based only on age, baseline 6MWD, and steroid use. There is significant potential for composite prognostic models to inform DMD clinical trials and clinical practice.

Gait deviations in Duchenne muscular dystrophy—Part 1. A systematic review

BACKGROUND Although prolonged ambulation is considered important in children with Duchenne muscular dystrophy (DMD), articles describing gait deviations in DMD are scarce. RESEARCH QUESTION Therefore, our research questions were the following: 1) what are the most consistently reported spatiotemporal-, kinematic-, kinetic-, and muscle activity deviations in children with DMD in literature, 2) what is the quality of the studies describing these deviations, and 3) is there need for further research? METHODS We conducted a systematic literature search for studies published before the end of June 2017 in six online databases. We created a data extraction form to define information on materials and methods and on the analyzed gait parameters for each paper included in the review. If enough information was available, we calculated standardized mean differences (SMDs). RESULTS The search yielded nine articles, but generalizability was poor. Seventy-nine parameters were analyzed by seven research groups, but they only agreed on a decrease in walking speed (minimal SMD: 1.26), stride length (1.83), step length (1.80), dorsiflexion during swing (1.43), maximal power generation at the hip (0.92), maximal knee extension torque (0.99), maximal dorsiflexion torque (-1.30), and maximal power generation at the ankle (0.92), and an increased knee range of motion (-0.82) in DMD. SIGNIFICANCE In order to keep children with DMD ambulant as long as possible, a clear understanding of their pathological gait pattern is necessary. However, gait deviations in DMD appear not well defined. Previous studies appear to be of an exploratory nature while using predefined gait parameters to assess an undirected null hypothesis. This made them prone to regional focus bias, thereby increasing the chance of a type I error. Therefore, further research is required to define the altered gait pattern in children with DMD.