Importance:Corticosteroids improve strength and function in boys with Duchenne muscular dystrophy. However, there is uncertainty regarding the optimum regimen and dosage. Objective:To compare efficacy and adverse effects of the 3 most frequently prescribed corticosteroid regimens in boys with Duchenne muscular dystrophy. Design, Setting, and Participants:Double-blind, parallel-group randomized clinical trial including 196 boys aged 4 to 7 years with Duchenne muscular dystrophy who had not previously been treated with corticosteroids; enrollment occurred between January 30, 2013, and September 17, 2016, at 32 clinic sites in 5 countries. The boys were assessed for 3 years (last participant visit on October 16, 2019). Interventions:Participants were randomized to daily prednisone (0.75 mg/kg) (n = 65), daily deflazacort (0.90 mg/kg) (n = 65), or intermittent prednisone (0.75 mg/kg for 10 days on and then 10 days off) (n = 66). Main Outcomes and Measures:The global primary outcome comprised 3 end points: rise from the floor velocity (in rise/seconds), forced vital capacity (in liters), and participant or parent global satisfaction with treatment measured by the Treatment Satisfaction Questionnaire for Medication (TSQM; score range, 0 to 100), each averaged across all study visits after baseline. Pairwise group comparisons used a Bonferroni-adjusted significance level of .017. Results:Among the 196 boys randomized (mean age, 5.8 years [SD, 1.0 years]), 164 (84%) completed the trial. Both daily prednisone and daily deflazacort were more effective than intermittent prednisone for the primary outcome (P < .001 for daily prednisone vs intermittent prednisone using a global test; P = .017 for daily deflazacort vs intermittent prednisone using a global test) and the daily regimens did not differ significantly (P = .38 for daily prednisone vs daily deflazacort using a global test). The between-group differences were principally attributable to rise from the floor velocity (0.06 rise/s [98.3% CI, 0.03 to 0.08 rise/s] for daily prednisone vs intermittent prednisone [P = .003]; 0.06 rise/s [98.3% CI, 0.03 to 0.09 rise/s] for daily deflazacort vs intermittent prednisone [P = .017]; and -0.004 rise/s [98.3% CI, -0.03 to 0.02 rise/s] for daily prednisone vs daily deflazacort [P = .75]). The pairwise comparisons for forced vital capacity and TSQM global satisfaction subscale score were not statistically significant. The most common adverse events were abnormal behavior (22 [34%] in the daily prednisone group, 25 [38%] in the daily deflazacort group, and 24 [36%] in the intermittent prednisone group), upper respiratory tract infection (24 [37%], 19 [29%], and 24 [36%], respectively), and vomiting (19 [29%], 17 [26%], and 15 [23%]). Conclusions and Relevance:Among patients with Duchenne muscular dystrophy, treatment with daily prednisone or daily deflazacort, compared with intermittent prednisone alternating 10 days on and 10 days off, resulted in significant improvement over 3 years in a composite outcome comprising measures of motor function, pulmonary function, and satisfaction with treatment; there was no significant difference between the 2 daily corticosteroid regimens. The findings support the use of a daily corticosteroid regimen over the intermittent prednisone regimen tested in this study as initial treatment for boys with Duchenne muscular dystrophy. Trial Registration:ClinicalTrials.gov Identifier: NCT01603407.

Trials in rare diseases have many challenges, among which are the need to set up multiple sites in different countries to achieve recruitment targets and the divergent landscape of clinical trial regulations in those countries. Over the past years, there have been initiatives to facilitate the process of international study set-up, but the fruits of these deliberations require time to be operationally in place. FOR-DMD (Finding the Optimum Steroid Regimen for Duchenne Muscular Dystrophy) is an academic-led clinical trial which aims to find the optimum steroid regimen for Duchenne muscular dystrophy, funded by the National Institutes of Health (NIH) for 5 years (July 2010 to June 2015), anticipating that all sites (40 across the USA, Canada, the UK, Germany and Italy) would be open to recruitment from July 2011. However, study start-up was significantly delayed and recruitment did not start until January 2013.

Despite corticosteroids being the only treatment documented to improve strength and function in boys with Duchenne muscular dystrophy (DMD) corticosteroid prescription is inconsistent and in some countries, corticosteroids are not prescribed. We are conducting a clinical trial that (1) compares the 3 most frequently prescribed corticosteroid regimes; (2) standardizes treatment of DMD complications; and (3) standardizes prevention of corticosteroid side effects. Investigators at 38 sites in 5 countries plan to recruit 300 boys aged 4-7 who are randomly assigned to one of three regimens: daily prednisone; daily deflazacort; or intermittent prednisone (10days on/10days off). Boys are followed for a minimum of 3years to assess the relative effectiveness and adverse event profiles of the different regimens. The primary outcome is a 3-dimensional variable consisting of log-transformed time to rise from the floor, forced vital capacity, and subject/parent satisfaction with treatment, each averaged over all post-baseline visits. The study protocol includes evidence- and consensus-based treatment of DMD complications and of corticosteroid side effects. This study seeks to establish a standard corticosteroid regimen for DMD. Since all new interventions for DMD are being developed as add-on therapies to corticosteroids, defining the optimum regimen is of importance for all new treatments.

Objective: Report the results of pivotal trials investigating the short- and long-term effects of dichlorphenamide on attack frequency and quality of life (QoL) in hypokalemic and hyperkalemic periodic paralysis (PP). Background: PP is a muscle channelopathy causing acute flaccid paralysis and long-term progressive weakness. Dichlorphenamide recently became the first US Food and Drug Administration-approved treatment for primary hypokalemic and hyperkalemic PP. Design/Methods: Two multicenter randomized, double-blind, placebo-controlled, parallel-group trials following identical protocols lasting 9 weeks, followed by a 1-year open-label extension in which all subjects received dichlorphenamide. The primary outcome was the average number of weekly attacks over the final 8 weeks of the double-blind phase. Results: Forty-four hypokalemic and 21 hyperkalemic subjects participated. Median attack rate in the double-blind phase was lower in subjects treated with dichlorphenamide than in subjects treated with placebo (hypokalemic, 0.3 vs 2.4, P=0.02; hyperkalemic, 0.9 vs 4.8, P=0.08). Severity-weighted attack rate was also lower in dichlorphenamide-treated subjects relative to placebo-treated subjects (hypokalemic, 0.6 vs 5.7, P=0.02; hyperkalemic, 1.0 vs 5.8, P=0.03). Furthermore, the physical component summary score of the Short Form-36 assessment was improved in hypokalemic subjects treated with dichlorphenamide compared with subjects treated with placebo (treatment effect=7.29, 95[percnt] confidence interval 2.26, 12.32, P=0.006). Benefit was maintained during the 1-year extension. Dichlorphenamide had no significant effect on interattack muscle strength during the double-blind phase. The most common adverse events were paresthesia (47[percnt] dichlorphenamide vs 14[percnt] placebo) and confusion (19[percnt] dichlorphenamide vs 7[percnt] placebo). Three subjects, all receiving dichlorphenamide (2 hyperkalemic and 1 hypokalemic), withdrew from the double-blind phase because of adverse events. Conclusions: Dichlorphenamide was well tolerated with few safety-related withdrawals; hypokalemic subjects demonstrated improved attack frequency, severity, and QoL. Treatment effects on attack rates appeared consistent in both trials but, partly due to small sample size, were inconclusive for hyperkalemic patients.

Objective: To determine the short-term and long-term effects of dichlorphenamide (DCP) on attack frequency and quality of life in hyperkalemic (HYP) and hypokalemic (HOP) periodic paralysis. Methods: Two multicenter randomized, double-blind, placebo-controlled trials lasted 9 weeks (Class I evidence), followed by a 1-year extension phase in which all participants received DCP. Forty-four HOP and 21 HYP participants participated. The primary outcome variable was the average number of attacks per week over the final 8 weeks of the double-blind phase. Results: The median attack rate was lower in HOP participants on DCP than in participants on placebo (0.3 vs 2.4, p = 0.02). The 9-week mean change in the Physical Component Summary score of the Short Form–36 was also better in HOP participants receiving DCP (treatment effect = 7.29 points, 95% confidence interval 2.26 to 12.32, p = 0.006). The median attack rate was also lower in HYP participants on DCP (0.9 vs 4.8) than in participants on placebo, but the difference in median attack rate was not significant (p = 0.10). There were no significant effects of DCP on muscle strength or muscle mass in either trial. The most common adverse events in both trials were paresthesia (47% DCP vs 14% placebo, both trials combined) and confusion (19% DCP vs 7% placebo, both trials combined). Conclusions: DCP is effective in reducing the attack frequency, is safe, and improves quality of life in HOP periodic paralysis. Classification of evidence: These studies provide Class I evidence that DCP significantly reduces attack frequency in HOP but lacked the precision to support either efficacy or lack of efficacy of DCP in HYP.

ABSTRACTIntroduction: We have developed a rare disease center in China. Methods: In this study we analyzed how patients with periodic paralysis accessed centers in China vs. in the USA and UK. Results: A total of 116 patients with periodic paralysis were evaluated in Beijing and Hangzhou (2003–2012). These patients traveled long distances for outpatient specialist care without an appointment or physician referral. In contrast, at the University of Rochester in the USA, >90% of patients were referred from physicians throughout the country by identifying physician expertise or by referrals from a patient advocacy group. In the UK, a single center, supported by the National Health Service, provides assessment/genetic testing for all UK patients. Conclusions: Rare disease centers in China require: (1) establishing a center for clinical characterization of the disease (e.g., periodic paralysis); (2) establishing a genetic diagnostic platform; (3) placing the center at a major city hospital; and (4) facilitating patient access through internet websites. Muscle Nerve 49: 171–174, 2014

Introduction: In 2004, a Cochrane Review and AAN practice parameter concluded that prednisone 0.75 mg/kg/day is of short-term efficacy in Duchenne muscular dystrophy (DMD). Subsequent efforts to standardize care for DMD indicated wide variation in corticosteroid use. Methods: We surveyed physicians who follow patients with DMD, including: (1) clinics in the TREAT-NMD (Translational Research in EuropeAssessment and Treatment of Neuromuscular Diseases) network (predominantly Europe) and (2) U.S. MDA clinic directors. We also documented the co-administered corticosteroids in a trial of a putative treatment (ataluren) for DMD. Results: Of 105 Treat-NMD clinicians, corticosteroids were not used in 10 clinics, and 29 different regimens were usedthe most frequent 0.75 mg/kg/day prednisone (61 centers); 10 days on/10 days off (36 centers); 0.9 mg/kg/day deflazacort (32 centers); and 5 mg/kg/day on weekends (10 centers). Similar diversity was identified in MDA clinics and in the ataluren trial. Conclusions: Variability in corticosteroid use suggests uncertainty about risks/benefits of corticosteroid regimens for DMD. Muscle Nerve, 2013

Background and Objective An assessment of clinically important change is useful in interpreting clinical trial outcomes. The 4-point Ashworth Scale (AS) is a widely accepted measure of muscle tone, and the 9-point Physician Global Assessment Score (PGAS) is a global measure of post-treatment change as evaluated by the physician. The quantitative relationship between AS and PGAS has not previously been described in spasticity. Methods Data from three clinical trials of botulinum toxin type A (BOTOX; Allergan, Irvine, CA) in poststroke spasticity were analyzed ( n = 442). Mean change from baseline in AS score was plotted as a function of PGAS and correlations were calculated. Receiver–operator curve (ROC) analyses with the wrist flexor AS change from baseline as the independent variable and PGAS as the dependent variable were performed using the following criteria: PGAS of ≥1 (mild improvement or better) and PGAS of ≥2 (moderate improvement or better). Results In pooled data, the Pearson's correlation coefficient r between the change in wrist Ashworth Score and the PGAS was −0.44 ( p = 0, t = −26.5). Pearson correlations by individual study were also statistically significant. By ROC analysis, a PGAS of ≥1 was associated with 33% reduction of wrist AS and a PGAS of ≥2 was associated with approximately 50% reduction. In a well-powered phase 3 study, the Pearson's correlation coefficient was even higher ( r = −0.76, p = 0, t = −28.5). Conclusions Changes in disease-specific scales that correlate significantly with changes in physician global assessments are considered clinically meaningful. In clinical trials of chronic spasticity, we found that 33% and 50% changes in the Ashworth Scale scores correlate with 1-point or 2-point changes in PGAS. This is similar to findings from pooled chronic pain studies, in which 30% and 50% changes on the pain numeric rating scale were considered clinically important (Farrar et al., Pain 2001;94:149–158). Study supported by Allergan, Irvine, CA.

Satisfaction with treatment has become a useful outcome measure in oncologic studies, in which severe side effects must be balanced with tumor regression to determine if the treatment is of overall benefit to a patient. The use of corticosteroids in Duchenne muscular dystrophy (DMD) poses a similar dilemma: Does the improvement in strength outweigh the inevitable side effects and need for life-long medication? We are planning an international, randomized, double-blind trial in 300 DMD boys aged 4 to 7 years to compare three corticosteroid regimens with respect to function and patient–parent satisfaction over a 3- to 5-year follow-up period. Global treatment satisfaction will be measured by the Treatment Satisfaction Questionnaire for Medication (TSQM), which is a patient-centered assessment of satisfaction with treatment that is particularly relevant to a noncurative therapy applied in a chronic disease. The hypothesis is that a patient–parent satisfaction measure as a component of the primary outcome variable can yield firm evidence for changing practice and developing a standard of care. The questionnaire is designed to be completed by the individual with the chronic disease. Because the DMD boys are too young to complete the form, parents will serve as proxies, answering the questionnaire as they think their sons would. The TSQM has been validated only in adults with chronic disease, and only with the patient as responder. We asked 50 parents to complete the questionnaire from the perspective of their DMD sons taking corticosteroids. Parents also provided the son's age, walking ability, medications, and a rating of ease in completing the TSQM from the son's perspective. The results show that the parents felt that they could easily report on behalf of the sons. Associations between TSQM responses and demographic information (e.g., age, ambulatory status) will be analyzed for a future report. Sponsored in part by the National Institute of Neurological Disorders and Stroke, National Institutes of Health.

Neurologic channelopathies are rare, inherited paroxysmal disorders of muscle (e.g., the periodic paralyses and nondystrophic myotonias) and brain (e.g., episodic ataxias, idiopathic epilepsies, and familial hemiplegic migraine). Mutation is necessary but not sufficient for phenotypic expression and there are no simple phenotype-genotype relationships. Attacks may be spontaneous or triggered, with affected individuals often asymptomatic and neurologic ally normal between attacks. Performance of daily activities may be affected by the unpredictable nature; often late-onset degenerative changes cause permanent disability; for example, muscle atrophy and fixed weakness in periodic paralysis and cerebellar atrophy and progressive ataxia in the episodic ataxias. Currently, the natural history of these disorders is being defined. Clearly, the established methodologies for randomized controlled clinical trials are not feasible for rare diseases and innovative trial design is essential. There is a requirement for clinically relevant outcome measures for episodic disorders. Increasing our knowledge of the pathophysiology will help in targeting and designing rational therapeutic approaches. We will use the current understanding of the neurological channelopathies to illustrate some of the opportunities, challenges, and strategies in bringing safe and effective treatments to patients. There are reasons for optimism that new partnerships between clinical investigators, government, patient advocacy groups, and industry will prevent symptoms and progression of the neurological channelopathies.

Objective: To determine the major reasons for the treatment of upper limb spasticity in post-stroke patients among the leading three specialties that evaluate and manage these patients.Methods: 523 physicians were contacted to participate in an Internet-based survey.A total of 50 neurologists, 50 physiatrists (PM&Rs) and 300 primary care physicians (PCPs) fulfilled eligibility criteria and completed the survey.Physician demographics and patient population characteristics pertaining to post-stroke spasticity were collected.Results: The average number of adult stroke patients evaluated per month was 23.8 for neurologists, 17.9 for PM&Rs, and 38.6 for PCPs.Approximately half of these patients had spasticity in the upper and/or lower limb (10.3, 10.0, and 12.5, respectively).A majority of the upper limb spasticity patients presented with a clenched fist.The main treatment goals in this population were: relief of pain/discomfort and improved access to the palm for hygiene purposes (passive function goals) or to improve the ability to grasp and hold objects (active function goals).Conclusions: Physicians interviewed in this survey evaluate and treat a significant number of poststroke spasticity patients who suffer from passive and active functional consequences.Symptoms of hand pain/discomfort and inability to access palm for hygiene purposes (passive function symptoms) or inability to use hand for grasping/holding (active function symptoms) were the major reasons cited for treatment.Allergan, Inc. (Irvine, CA), retained Beta Research Corporation, a market research firm (Syosset, NY).Beta Research programmed and hosted the survey, produced the data tabulations, and prepared the analysis.

Pigs raised under free-range conditions are expected to experience a higher level of animal welfare than conventionally raised pigs. However, free-range conditions may challenge prevention and treatment of diseases. In order to identify disease problems associated with raising conditions, this study compared slaughter lesions in pigs from conventional indoor, conventional free-range and organic free-range production systems. The study used data from 1,096,756 pigs slaughtered at one Danish abattoir from 1 January 2013 to 31 December 2015. Associations between production system and lesions at slaughter were tested in statistical models taking year, season and herd of origin into account.Both conventional free-range and organic free-range production systems were associated with increased population averaged odd ratios (ORPA) for several lesions compared with conventional indoor systems. Pigs raised in conventional free-range and organic free-range production systems had higher odds for white liver-spots (ORPA, 5–7), tail lesions (ORPA, 3–4), arthritis (ORPA, 3), skin lesions (ORPA, 3), bone fractures (ORPA, 2), septicaemia (ORPA, 1.1–1.5) and abscesses (ORPA, 1.1–1.3) at slaughter. Pairwise comparisons of the two free-range production systems did not reveal statistically significant differences (P > 0.05). In all three production systems, airway infection was the most prevalent disease complex. In contrast to previous studies, this study did not find any association between airway infection and type of production (P > 0.05). Three lesions (leg swellings (ORPA, 0.4–0.5), hernia (ORPA, 0.7–0.8) and hoof abscess (ORPA, 0.7–0.9)) had lower ORs in conventional free-range and organic free-range production compared with conventional indoor production. There was a marked herd effect (intraclass correlation coefficients 21–35%) on the occurrence of white liver-spots, tail lesions, skin lesions and airway infections. These results suggest possibilities for herd-level management interventions of the problems studied.