Person: David, William
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David
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David, William
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Publication Randomized, double-blind, placebo-controlled trial of arimoclomol in rapidly progressive SOD1 ALS(Lippincott Williams & Wilkins, 2018) Benatar, Michael; Wuu, Joanne; Andersen, Peter M.; Atassi, Nazem; David, William; Cudkowicz, Merit; Schoenfeld, DavidObjective: To examine the safety and tolerability as well as the preliminary efficacy of arimoclomol, a heat shock protein co-inducer that promotes nascent protein folding, in patients with rapidly progressive SOD1 amyotrophic lateral sclerosis (ALS). Methods: This was a double-blind, placebo-controlled trial in which patients with rapidly progressive SOD1-mutant ALS were randomized 1:1 to receive arimoclomol 200 mg tid or matching placebo for up to 12 months. Study procedures were performed using a mix of in-person and remote assessments. Primary outcome was safety and tolerability. Secondary outcome was efficacy, with survival as the principal measure. Additional efficacy measures were the rates of decline of the Revised ALS Functional Rating Scale (ALSFRS-R) and percent predicted forced expiratory volume in 6 seconds (FEV6), and the Combined Assessment of Function and Survival (CAFS). Results: Thirty-eight participants were randomized. Thirty-six (19 placebo, 17 arimoclomol) were included in the prespecified intent-to-treat analysis. Apart from respiratory function, groups were generally well-balanced at baseline. Adverse events occurred infrequently, and were usually mild and deemed unlikely or not related to study drug. Adjusting for riluzole and baseline ALSFRS-R, survival favored arimoclomol with a hazard ratio of 0.77 (95% confidence interval [CI] 0.32–1.80). ALSFRS-R and FEV6 declined more slowly in the arimoclomol group, with treatment differences of 0.5 point/month (95% CI −0.63 to 1.63) and 1.24 percent predicted/month (95% CI −2.77 to 5.25), respectively, and the CAFS similarly favored arimoclomol. Conclusions: This study provides Class II evidence that arimoclomol is safe and well-tolerated at a dosage of 200 mg tid for up to 12 months. Although not powered for therapeutic effect, the consistency of results across the range of prespecified efficacy outcome measures suggests a possible therapeutic benefit of arimoclomol. Clinicaltrials.gov identifier NCT00706147. Classification of evidence This study provides Class II evidence that arimoclomol is safe and well-tolerated at a dosage of 200 mg tid for up to 12 months. The study lacked the precision to conclude, or to exclude, an important therapeutic benefit of arimoclomol.Publication Evidence-based guideline summary: Diagnosis and treatment of limb-girdle and distal dystrophies: Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular & Electrodiagnostic Medicine(Ovid Technologies (Wolters Kluwer Health), 2014) Narayanaswami, Pushpa; Weiss, Michael; Selcen, Duygu; David, William; Raynor, Elizabeth; Carter, Gregory; Wicklund, Matthew; Barohn, Richard J.; Ensrud, Erik; Griggs, R. C.; Gronseth, Gary; Amato, AnthonyObjective: To review the current evidence and make practice recommendations regarding the diagnosis and treatment of limb-girdle muscular dystrophies (LGMDs). Methods: Systematic review and practice recommendation development using the American Academy of Neurology guideline development process. Results: Most LGMDs are rare, with estimated prevalences ranging from 0.07 per 100,000 to 0.43 per 100,000. The frequency of some muscular dystrophies varies based on the ethnic background of the population studied. Some LGMD subtypes have distinguishing features, including pattern of muscle involvement, cardiac abnormalities, extramuscular involvement, and muscle biopsy findings. The few published therapeutic trials were not designed to establish clinical efficacy of any treatment. Principal recommendations: For patients with suspected muscular dystrophy, clinicians should use a clinical approach to guide genetic diagnosis based on clinical phenotype, inheritance pattern, and associated manifestations (Level B). Clinicians should refer newly diagnosed patients with an LGMD subtype and high risk of cardiac complications for cardiology evaluation even if they are asymptomatic from a cardiac standpoint (Level B). In patients with LGMD with a known high risk of respiratory failure, clinicians should obtain periodic pulmonary function testing (Level B). Clinicians should refer patients with muscular dystrophy to a clinic that has access to multiple specialties designed specifically to care for patients with neuromuscular disorders (Level B). Clinicians should not offer patients with LGMD gene therapy, myoblast transplantation, neutralizing antibody to myostatin, or growth hormone outside of a research study designed to determine efficacy and safety of the treatment (Level R). Detailed results and recommendations are available on the Neurology® Web site at Neurology.org.Publication Quality improvement in neurology: Muscular dystrophy quality measures(Ovid Technologies (Wolters Kluwer Health), 2015) Narayanaswami, Pushpa; Dubinsky, Richard; Wang, David; Gjorvad, Gina; David, William; Finder, Jonathan; Smith, Benn; Cheng, Jianguo; Shapiro, Frederic; Mellion, Michelle; Spurney, Christopher; Wolff, Jodi; England, JohnThe muscular dystrophies (MDs) are a heterogeneous group of genetically determined myopathies. Identification of underlying genetic defects has demonstrated that MDs exhibit significant phenotypic and genetic heterogeneity. One genetic mutation can lead to a variety of phenotypes while different genetic mutations can manifest similar phenotypes; therefore MDs are challenging to diagnose. A major goal of health care reform in the United States is to replace the traditional fee-for-service model with a value-based system, which incentivizes high-quality care. Quality measurement is an integral and necessary part of this process.1,2 While standardizing care of MDs can be challenging because of their heterogeneity, common themes of management, such as the maintenance of nutrition, sustaining mobility, and management of complications, are applicable to many MDs. We report a quality measurement set for the management of MDs.Publication Electrical impedance myography as a biomarker to assess ALS progression(Informa UK Limited, 2012) Rutkove, Seward; Caress, James B.; Cartwright, Michael S.; Burns, Ted M.; Warder, Judy; David, William; Goyal, Namita; Maragakis, Nicholas J.; Clawson, Lora; Benatar, Michael; Usher, Sharon; Sharma, Khema R.; Gautam, Shiva; Narayanaswami, Pushpa; Raynor, Elizabeth; Watson, Mary Lou; Shefner, Jeremy M.Electrical impedance myography (EIM), a non-invasive, electrophysiological technique, has preliminarily shown value as an ALS biomarker. Here we perform a multicenter study to further assess EIM’s potential for tracking ALS. ALS patients were enrolled across eight sites. Each subject underwent EIM, handheld dynamometry (HHD), and the ALS Functional Rating Scale-revised (ALSFRS-R) regularly. Techniques were compared by assessing the coefficient of variation (CoV) in the rate of decline and each technique’s correlation to survival. Results showed that in the 60 patients followed for one year, EIM phase measured from the most rapidly progressing muscle in each patient had a CoV in the rate of decline of 0.62, compared to HHD (0.82) and the ALSFRS-R (0.74). Restricting the measurements to the first six months gave a CoV of 0.55 for EIM, 0.93 for HHD, and 0.84 for ALSFRS-R. For both time-periods, all three measures correlated with survival. Based on these data, a six-month clinical trial designed to detect a 20% treatment effect with 80% power using EIM would require only 95 patients/arm compared to the ALSFRS-R, which would require 220 subjects/arm. In conclusion, EIM can serve as a useful ALS biomarker that offers the prospect of greatly accelerating phase 2 clinical trials.Publication Design and Initial Results of a Multi-Phase Randomized Trial of Ceftriaxone in Amyotrophic Lateral Sclerosis(Public Library of Science, 2013) Berry, James; Shefner, Jeremy M.; Conwit, Robin; Schoenfeld, David; Keroack, Myles; Felsenstein, Donna; Krivickas, Lisa; David, William; Vriesendorp, Francine; Pestronk, Alan; Caress, James B.; Katz, Jonathan; Simpson, Ericka; Rosenfeld, Jeffrey; Pascuzzi, Robert; Glass, Jonathan; Rezania, Kourosh; Rothstein, Jeffrey D.; Greenblatt, David J.; Cudkowicz, MeritObjectives: Ceftriaxone increases expression of the astrocytic glutamate transporter, EAAT2, which might protect from glutamate-mediated excitotoxicity. A trial using a novel three stage nonstop design, incorporating Phases I-III, tested ceftriaxone in ALS. Stage 1 determined the cerebrospinal fluid pharmacokinetics of ceftriaxone in subjects with ALS. Stage 2 evaluated safety and tolerability for 20-weeks. Analysis of the pharmacokinetics, tolerability, and safety was used to determine the ceftriaxone dosage for Stage 3 efficacy testing. Methods: In Stage 1, 66 subjects at ten clinical sites were enrolled and randomized equally into three study groups receiving intravenous placebo, ceftriaxone 2 grams daily or ceftriaxone 4 grams daily divided BID. Participants provided serum and cerebrospinal fluid for pharmacokinetic analysis on study day 7. Participants continued their assigned treatment in Stage 2. The Data and Safety Monitoring Board (DSMB) reviewed the data after the last participants completed 20 weeks on study drug. Results: Stage 1 analysis revealed linear pharmacokinetics, and CSF trough levels for both dosage levels exceeding the pre-specified target trough level of 1 µM (0.55 µg/mL). Tolerability (Stages 1 and 2) results showed that ceftriaxone at dosages up to 4 grams/day was well tolerated at 20 weeks. Biliary adverse events were more common with ceftriaxone but not dose-dependent and improved with ursodeoxycholic (ursodiol) therapy. Conclusions: The goals of Stages 1 and 2 of the ceftriaxone trial were successfully achieved. Based on the pre-specified decision rules, the DSMB recommended the use of ceftriaxone 4 g/d (divided BID) for Stage 3, which recently closed. Trial Registration ClinicalTrials.gov NCT00349622.