J. Mayhew

A Randomized Study of Alglucosidase Alfa in Late-Onset Pompe's Disease

BACKGROUND Pompes disease is a metabolic myopathy caused by a deficiency of acid alpha glucosidase (GAA), an enzyme that degrades lysosomal glycogen. Late-onset Pompes disease is characterized by progressive muscle weakness and loss of respiratory function, leading to early death. We conducted a randomized, placebo-controlled trial of alglucosidase alfa, a recombinant human GAA, for the treatment of late-onset Pompes disease. METHODS Ninety patients who were 8 years of age or older, ambulatory, and free of invasive ventilation were randomly assigned to receive biweekly intravenous alglucosidase alfa (20 mg per kilogram of body weight) or placebo for 78 weeks at eight centers in the United States and Europe. The two primary end points were distance walked during a 6-minute walk test and percentage of predicted forced vital capacity (FVC). RESULTS At 78 weeks, the estimated mean changes from baseline in the primary end points favored alglucosidase alfa (an increase of 28.1+/-13.1 m on the 6-minute walk test and an absolute increase of 3.4+/-1.2 percentage points in FVC; P=0.03 and P=0.006, respectively). Similar proportions of patients in the two groups had adverse events, serious adverse events, and infusion-associated reactions; events that occurred only in patients who received the active study drug included anaphylactic reactions and infusion-associated reactions of urticaria, flushing, hyperhidrosis, chest discomfort, vomiting, and increased blood pressure (each of which occurred in 5 to 8% of the patients). CONCLUSIONS In this study population, treatment with alglucosidase alfa was associated with improved walking distance and stabilization of pulmonary function over an 18-month period. (ClinicalTrials.gov number, NCT00158600.)

Clinical features of late-onset Pompe disease: a prospective cohort study.

The objective of this 12‐month study was to describe the clinical features of late‐onset Pompe disease and identify appropriate outcome measures for use in clinical trials. Assessments included quantitative muscle testing (QMT), functional activities (FAA), 6‐min walk test (6MWT), and pulmonary function testing (PFT). Percent predicted values indicated quantifiable upper and lower extremity weakness, impaired walking ability, and respiratory muscle weakness. Significant declines in arm and leg strength and pulmonary function were observed during the study period. The outcome measures were demonstrated to be safe and reliable. Symptom duration was identified as the best predictor of the extent of skeletal and respiratory muscle weakness. Muscle Nerve 38: 1236–1245, 2008

Reliable surrogate outcome measures in multicenter clinical trials of Duchenne muscular dystrophy

We studied the reliability of a series of endpoints in an evaluation of subjects with Duchenne muscular dystrophy (DMD). The endpoints included quantitative muscle tests (QMTs), timed function tests, forced vital capacity (FVC), and manual muscle tests (MMT). Thirty‐one ambulatory subjects with DMD (mean age 8.9 years; range 5–16 years) were evaluated at eight sites by 15 newly trained evaluators as a test of interrater reliability of outcome measures. Both total QMT score [intraclass correlation coefficient (ICC) 0.96] and individual QMT assessments (ICC 0.85–0.96) were highly reliable. Forced vital capacity and all timed function tests were also highly reliable (ICC 0.97–0.99). MMT was the least reliable assessment method (ICC 0.61). These data suggest that primary surrogate outcome measures in large multicenter clinical trials in DMD should use QMT, FVC, or time function tests to obtain maximum power and greatest sensitivity. Muscle Nerve, 2006

CINRG randomized controlled trial of creatine and glutamine in Duchenne muscular dystrophy

We tested the efficacy and safety of glutamine (0.6gm/kg/day) and creatine (5gm/day) in 50 ambulant boys with Duchenne muscular dystrophy in a 6‐month, double‐blind, placebo‐controlled clinical trial. Drug efficacy was tested by measuring muscle strength manually (34 muscle groups) and quantitatively (10 muscle groups). Timed functional tests, functional parameters, and pulmonary function tests were secondary outcome measures. Although there was no statistically significant effect of either therapy based on manual and quantitative measurements of muscle strength, a disease‐modifying effect of creatine in older Duchenne muscular dystrophy and creatine and glutamine in younger Duchenne muscular dystrophy cannot be excluded. Creatine and glutamine were well tolerated. Ann Neurol 2005;58:151–155

Randomized, blinded trial of weekend vs daily prednisone in Duchenne muscular dystrophy

Objective: To perform a double-blind, randomized study comparing efficacy and safety of daily and weekend prednisone in boys with Duchenne muscular dystrophy (DMD). Methods: A total of 64 boys with DMD who were between 4 and 10 years of age were randomized at 1 of 12 centers of the Cooperative International Neuromuscular Research Group. Efficacy and safety of 2 prednisone schedules (daily 0.75 mg/kg/day and weekend 10 mg/kg/wk) were evaluated over 12 months. Results: Equivalence was met for weekend and daily dosing of prednisone for the primary outcomes of quantitative muscle testing (QMT) arm score and QMT leg score. Secondary strength scores for QMT elbow flexors also showed equivalence between the 2 treatment groups. Overall side effect profiles of height and weight, bone density, cataract formation, blood pressure, and behavior, analyzed at 12 months, did not differ between weekend and daily dosing of prednisone. Conclusions: Weekend dosing of prednisone is equally beneficial to the standard daily dosing of prednisone. Analysis of side effect profiles demonstrated overall tolerability of both dosing regimens. Classification of evidence: This study provides Class I evidence that weekend prednisone dosing is as safe and effective as daily prednisone in preserving muscle strength and preventing body mass index increases in boys with DMD over a 12-month period.

CINRG pilot trial of coenzyme Q10 in steroid-treated duchenne muscular dystrophy†

Introduction: Corticosteroid treatment slows disease progression and is the standard of care for Duchenne muscular dystrophy (DMD). Coenzyme Q10 (CoQ10) is a potent antioxidant that may improve function in dystrophin‐deficient muscle. Methods: We performed an open‐label, “add‐on” pilot study of CoQ10 in thirteen 5–10‐year‐old DMD patients on steroids. The primary outcome measure was the total quantitative muscle testing (QMT) score. Results: Twelve of 16 children (mean age 8.03 ± 1.64 years) completed the trial. Target serum levels of CoQ10 (≥2.5 μg/ml) were shown to be subject‐ and administration‐dependent. Nine of 12 subjects showed an increase in total QMT score. Overall, CoQ10 treatment resulted in an 8.5% increase in muscle strength (P = 0.03). Conclusions: Addition of CoQ10 to prednisone therapy in DMD patients resulted in an increase in muscle strength. These results warrant a larger, controlled trial of CoQ10 in DMD. Muscle Nerve, 2011

A randomized, placebo-controlled trial of creatine in children with spinal muscular atrophy

Objective: To determine whether oral creatine produces positive changes in any of 4 outcomes in children with spinal muscular atrophy (SMA). Methods: The authors conducted a randomized, double-blind, placebo-controlled trial on 55 patients aged 2-18 years with SMA. Patients aged younger than 5 years received 2 g/day of creatine/placebo for 6 months. Patients aged 5 years and older received 5 g/day. The primary outcome measure was the Gross Motor Function Measure (GMFM). Secondary outcome measures were Quantitative Muscle Testing (QMT), Parent Questionnaire for the PedsQL™ Neuromuscular Module (QOL), and Pulmonary Function Tests (PFT). Results: Forty of the 55 patients completed the protocol. There was no significant difference in the 4 outcome measures between creatine and placebo groups. Conclusions: Under the experimental conditions of our study, creatine supplementation for 6 months did not improve motor function, muscle strength, pulmonary function, or quality of life in children with SMA,

Pentoxifylline as a rescue treatment for DMD: A randomized double-blind clinical trial

Objective: To determine whether pentoxifylline (PTX) slows the decline of muscle strength and function in ambulatory boys with Duchenne muscular dystrophy (DMD). Methods: This was a multicenter, randomized, double-blinded, controlled trial comparing 12 months of daily treatment with PTX or placebo in corticosteroid-treated boys with DMD using a slow-release PTX formulation (∼20 mg/kg/day). The primary outcome was the change in mean total quantitative muscle testing (QMT) score. Secondary outcomes included changes in QMT subscales, manual muscle strength, pulmonary function, and timed function tests. Outcomes were compared using Student t tests and a linear mixed-effects model. Adverse events (AEs) were compared using the Fisher exact test. Results: A total of 64 boys with DMD with a mean age of 9.9 ± 2.9 years were randomly assigned to PTX or placebo in 11 participating Cooperative International Neuromuscular Research Group centers. There was no significant difference between PTX and the placebo group in total QMT scores (p = 0.14) or in most of the secondary outcomes after a 12-month treatment. The use of PTX was associated with mild to moderate gastrointestinal or hematologic AEs. Conclusion: The addition of PTX to corticosteroid-treated boys with DMD at a moderate to late ambulatory stage of disease did not improve or halt the deterioration of muscle strength and function over a 12-month study period. Classification of evidence: This study provides Class I evidence that treatment with PTX does not prevent deterioration in muscle function or strength in corticosteroid-treated boys with DMD.

Liquid formulation of pentoxifylline is a poorly tolerated treatment for duchenne dystrophy.

Introduction: In this study we performed an open‐label, pilot study of an orally administered liquid formulation of immediate‐release pentoxifylline (PTX) on patients with Duchenne muscular dystrophy (DMD). Treatment efficacy, safety, and tolerability were assessed. Methods: The tolerability and safety of PTX and measures of muscle strength and function were evaluated during 12 months of treatment. Results: Seventeen boys with DMD, between 4 and 8 years of age, were enrolled at one of five Cooperative International Neuromuscular Research Group (CINRG) centers. Only 9 were able to complete the 12‐month PTX treatment phase; the primary reason for discontinuation was adverse events. Intolerable gastrointestinal side effects were experienced by 65% of participants. Two participants had severe leukopenia that resolved with medication withdrawal. Conclusions: Open‐label treatment with a liquid formulation of immediate‐release PTX resulted in a high incidence of adverse events in boys with DMD. Poor tolerability of this PTX formulation precluded adequate assessment of efficacy. Muscle Nerve, 2011

P.3.1 GNE myopathy functional activity scale (GNEM-FAS): Development of a disease-specific instrument for measuring function and independence

GNE myopathy or hereditary inclusion body myopathy (HIBM) is an autosomal recessive myopathy presenting with distal leg weakness in early adulthood. Progressive weakness results in greater dependence and disability over time. A disease-specific measurement of functional activity is needed to better understand the burden of illness, inform the design of clinical studies and optimize care. After clinical interview of patients, a 25-item questionnaire was developed to assess ability and independence in three domains: mobility, upper extremity (UE) use and self-care. Each item was rated from 0 to 4 with higher scores representing better function. Total scores range from 0 to 100; subscale scores range from 0 to 40 for Mobility, 0–32 for UE and 0–28 for Self-Care. The GNE Myopathy Functional Activity Scale (GNEM-FAS) was administered to 47 ambulatory subjects enrolled in a Phase 2 study of extended release sialic acid. Physical therapists completed the GNEM-FAS based on clinical observation and subject interview. Scores were compared to performance on volitional measures of strength and function, as well as scores on the Inclusion Body Myositis Functional Rating Scale (IBMFRS), a validated instrument for myositis. The mean GNEM-FAS total score was 69 out of 100 (23–94). Mobility subscores averaged 50%, UE, 81% and Self-Care, 82% of the maximum possible. Higher Mobility scores were associated with greater lower extremity strength ( r =0.83) and longer 6MWT distances ( r =0.83). A moderate association was seen between the UE domain scores and UE strength ( r =0.66). Self-care domain scores and the stair climb time were negatively related ( r =−0.68). There was a strong correlation between GNEM-FAS total scores and IBMFRS scores ( r =0.94). Mobility was limited more than UE or self-care function in this cohort of ambulatory subjects with GNE myopathy. Repeat administration in treated and untreated patients with varying degrees of severity is underway to further validate the instrument.