23 research outputs found
Suitability of external controls for drug evaluation in Duchenne muscular dystrophy
OBJECTIVE: To evaluate the suitability of real-world data (RWD) and natural history data (NHD) for use as external controls in drug evaluations for ambulatory Duchenne muscular dystrophy (DMD). METHODS: The consistency of changes in the 6-minute walk distance (Î6MWD) was assessed across multiple clinical trial placebo arms and sources of NHD/RWD. Six placebo arms reporting 48-week Î6MWD were identified via literature review and represented 4 sets of inclusion/exclusion criteria (n = 383 patients in total). Five sources of RWD/NHD were contributed by Universitaire Ziekenhuizen Leuven, DMD Italian Group, The Cooperative International Neuromuscular Research Group, ImagingDMD, and the PRO-DMD-01 study (n = 430 patients, in total). Mean Î6MWD was compared between each placebo arm and RWD/NHD source after subjecting the latter to the inclusion/exclusion criteria of the trial for baseline age, ambulatory function, and steroid use. Baseline covariate adjustment was investigated in a subset of patients with available data. RESULTS: Analyses included âŒ1,200 patient-years of follow-up. Differences in mean Î6MWD between trial placebo arms and RWD/NHD cohorts ranged from -19.4 m (i.e., better outcomes in RWD/NHD) to 19.5 m (i.e., worse outcomes in RWD/NHD) and were not statistically significant before or after covariate adjustment. CONCLUSIONS: We found that Î6MWD was consistent between placebo arms and RWD/NHD subjected to equivalent inclusion/exclusion criteria. No evidence for systematic bias was detected. These findings are encouraging for the use of RWD/NHD to augment, or possibly replace, placebo controls in DMD trials. Multi-institution collaboration through the Collaborative Trajectory Analysis Project rendered this study feasible
Longitudinal ophthalmic findings in a child with Helsmoortel-Van der Aa Syndrome
Purpose: We present the first detailed ophthalmic description of a child with Helsmoortel-Van der Aa Syndrome (HVDAS), including longitudinal follow-up and analysis. Observations: After extensive workup, a young child with poor visual behavior, hypotonic cerebral palsy, intellectual disability, and global developmental delay was found to have a heterozygous de novo mutation in the ADNP gene and diagnosed with HVDAS. Ophthalmic findings were remarkable for progressive nystagmus, macular pigment mottling, mild foveal hypoplasia with abnormal macular laminations, persistent rod dysfunction with electronegative waveform, and progressive cone degeneration. Conclusions and importance: Patients with HVDAS are known to have abnormal visual behavior due to refractive or cortical impairment. However, we present the first description, to our knowledge, of an association with retinal mal-development and degeneration. Thus, patients with HVDAS should be referred for ophthalmic genetics evaluation, and HVDAS should be on the differential diagnosis for young children with global developmental delay who present with nystagmus, rod and cone dysfunction with electronegative waveform, and relative lack of severe structural degeneration on optical coherence tomography. Keywords: Helsmoortel-Van der Aa Syndrome, HVDAS, Activity-dependent neuroprotective protein, ADNP, Nystagmus, Retinal degeneration, Electronegative waveform, Optical coherence tomograph
Magnetic resonance imaging and spectroscopy assessment of lower extremity skeletal muscles in boys with Duchenne muscular dystrophy: a multicenter cross sectional study.
IntroductionDuchenne muscular dystrophy (DMD) is an X-linked recessive disorder that results in functional deficits. However, these functional declines are often not able to be quantified in clinical trials for DMD until after age 7. In this study, we hypothesized that (1)H2O T2 derived using (1)H-MRS and MRI-T2 will be sensitive to muscle involvement at a young age (5-7 years) consistent with increased inflammation and muscle damage in a large cohort of DMD subjects compared to controls.MethodsMR data were acquired from 123 boys with DMD (ages 5-14 years; mean 8.6 SD 2.2 years) and 31 healthy controls (age 9.7 SD 2.3 years) using 3-Tesla MRI instruments at three institutions (University of Florida, Oregon Health & Science University, and Children's Hospital of Philadelphia). T2-weighted multi-slice spin echo (SE) axial images and single voxel 1H-MRS were acquired from the lower leg and thigh to measure lipid fraction and (1)H2O T2.ResultsMRI-T2, (1)H2O T2, and lipid fraction were greater (pDiscussionOverall, MR measures of T2 and lipid fraction revealed differences between DMD and Controls. Furthermore, MRI-T2 was greater in the older age group compared to the young age group, which was associated with higher lipid fractions. Overall, MR measures of T2 and lipid fraction show excellent sensitivity to DMD disease pathologies and potential therapeutic interventions in DMD, even in the younger boys
Skeletal muscle magnetic resonance biomarkers correlate with function and sentinel events in Duchenne muscular dystrophy.
OBJECTIVE:To provide evidence for quantitative magnetic resonance (qMR) biomarkers in Duchenne muscular dystrophy by investigating the relationship between qMR measures of lower extremity muscle pathology and functional endpoints in a large ambulatory cohort using a multicenter study design. METHODS:MR spectroscopy and quantitative imaging were implemented to measure intramuscular fat fraction and the transverse magnetization relaxation time constant (T2) in lower extremity muscles of 136 participants with Duchenne muscular dystrophy. Measures were collected at 554 visits over 48 months at one of three imaging sites. Fat fraction was measured in the soleus and vastus lateralis using MR spectroscopy, while T2 was assessed using MRI in eight lower extremity muscles. Ambulatory function was measured using the 10m walk/run, climb four stairs, supine to stand, and six minute walk tests. RESULTS:Significant correlations were found between all qMR and functional measures. Vastus lateralis qMR measures correlated most strongly to functional endpoints (|Ï| = 0.68-0.78), although measures in other rapidly progressing muscles including the biceps femoris (|Ï| = 0.63-0.73) and peroneals (|Ï| = 0.59-0.72) also showed strong correlations. Quantitative MR biomarkers were excellent indicators of loss of functional ability and correlated with qualitative measures of function. A VL FF of 0.40 was an approximate lower threshold of muscle pathology associated with loss of ambulation. DISCUSSION:Lower extremity qMR biomarkers have a robust relationship to clinically meaningful measures of ambulatory function in Duchenne muscular dystrophy. These results provide strong supporting evidence for qMR biomarkers and set the stage for their potential use as surrogate outcomes in clinical trials
Use of Skeletal Muscle MRI in Diagnosis and Monitoring Disease Progression in Duchenne Muscular Dystrophy
Scatterplot displaying the relationship between <sup>1</sup>H<sub>2</sub>O T<sub>2</sub> and lipid/(lipid+water) in the soleus of controls and boys with DMD.
<p>Red dotted lines denote 95% confidence interval of MRS <sup>1</sup>H<sub>2</sub>O T<sub>2</sub> in controls (A). In those with low lipid/(lipid+water) levels (i.e., less than 5%), the <sup>1</sup>H<sub>2</sub>O T<sub>2</sub> was longer in DMD (nâ=â34) than controls (nâ=â29) (B). * denotes significantly different (<0.05) than controls. Bars represent mean (SEM).</p
Subject demographics of Duchenne muscular dystrophy (DMD) and unaffected control boys.
<p>Subject demographics of Duchenne muscular dystrophy (DMD) and unaffected control boys.</p
Comparison of tibialis anterior (TA), tibialis posterior (TP), peroneus brevis and longus (Per), and medial gastrocnemius (MG) of the lower leg (A) and the gracilis (Gra) and biceps femoris long head (BFLH) of the thigh (B).
<p>In all muscles and age groups DMD was greater than controls, except in Gra in the 5â6.9 and 7â8.9 age groups. # indicates differences (<0.05) among age groups in DMD. No significant differences were observed among control age groups. Bars represent mean (SEM).</p
Activation of serum/glucocorticoidâinduced kinase 1 (SGK1) is important to maintain skeletal muscle homeostasis and prevent atrophy
Example upper leg axial spin echo (SE) images (TE 60 ms) with single voxel <sup>1</sup>H-MRS spectra (TE 108 ms) from the vastus lateralis of a control and boys with DMD at different ages.
<p>Example upper leg axial spin echo (SE) images (TE 60 ms) with single voxel <sup>1</sup>H-MRS spectra (TE 108 ms) from the vastus lateralis of a control and boys with DMD at different ages.</p