William David

BACKGROUND: Mutations in SOD1 cause 13% of familial amyotrophic lateral sclerosis. In the SOD1 Gly93Ala rat model of amyotrophic lateral sclerosis, the antisense oligonucleotide ISIS 333611 delivered to CSF decreased SOD1 mRNA and protein concentrations in spinal cord tissue and prolonged survival. We aimed to assess the safety, tolerability, and pharmacokinetics of ISIS 333611 after intrathecal administration in patients with SOD1-related familial amyotrophic lateral sclerosis. METHODS: In this randomised, placebo-controlled, phase 1 trial, we delivered ISIS 333611 by intrathecal infusion using an external pump over 11·5 h at increasing doses (0·15 mg, 0·50 mg, 1·50 mg, 3·00 mg) to four cohorts of eight patients with SOD1-positive amyotrophic lateral sclerosis (six patients assigned to ISIS 333611, two to placebo in each cohort). We did the randomisation with a web-based system, assigning patients in blocks of four. Patients and investigators were masked to treatment assignment. Participants were allowed to re-enrol in subsequent cohorts. Our primary objective was to assess the safety and tolerability of ISIS 333611. Assessments were done during infusion and over 28 days after infusion. This study was registered with Clinicaltrials.gov, number NCT01041222. FINDINGS: Seven of eight (88%) patients in the placebo group versus 20 of 24 (83%) in the ISIS 333611 group had adverse events. The most common events were post-lumbar puncture syndrome (3/8 [38%] vs 8/24 [33%]), back pain (4/8 [50%] vs 4/24 [17%]), and nausea (0/8 [0%] vs 3/24 [13%]). We recorded no dose-limiting toxic effects or any safety or tolerability concerns related to ISIS 333611. No serious adverse events occurred in patients given ISIS 333611. Re-enrolment and re-treatment were also well tolerated. INTERPRETATION: This trial is the first clinical study of intrathecal delivery of an antisense oligonucleotide. ISIS 333611 was well tolerated when administered as an intrathecal infusion. Antisense oligonucleotides delivered to the CNS might be a feasible treatment for neurological disorders. FUNDING: The ALS Association, Muscular Dystrophy Association, Isis Pharmaceuticals.

OBJECTIVE: 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.

OBJECTIVE: amyotrophic lateral sclerosis (ALS). METHODS: -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. CLINICALTRIALSGOV 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.

OBJECTIVE: To determine the steroid-sparing effect of methotrexate (MTX) in patients with symptomatic generalized myasthenia gravis (MG). METHODS: We performed a 12-month multicenter, randomized, double-blind, placebo-controlled trial of MTX 20 mg orally every week vs placebo in 50 acetylcholine receptor antibody-positive patients with MG between April 2009 and August 2014. The primary outcome measure was the prednisone area under the dose-time curve (AUDTC) from months 4 to 12. Secondary outcome measures included 12-month changes of the Quantitative Myasthenia Gravis Score, the Myasthenia Gravis Composite Score, Manual Muscle Testing, the Myasthenia Gravis Quality of Life, and the Myasthenia Gravis Activities of Daily Living. RESULTS: Fifty-eight patients were screened and 50 enrolled. MTX did not reduce the month 4-12 prednisone AUDTC when compared to placebo (difference MTX - placebo: -488.0 mg, 95% confidence interval -2,443.4 to 1,467.3, p = 0.26); however, the average daily prednisone dose decreased in both groups. MTX did not improve secondary measures of MG compared to placebo over 12 months. Eight participants withdrew during the course of the study (1 MTX, 7 placebo). There were no serious MTX-related adverse events. The most common adverse event was nonspecific pain (19%). CONCLUSIONS: We found no steroid-sparing benefit of MTX in MG over 12 months of treatment, despite being well-tolerated. This study demonstrates the challenges of conducting clinical trials in MG, including difficulties with recruitment, participants improving on prednisone alone, and the need for a better understanding of outcome measure variability for future clinical trials. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with generalized MG MTX does not significantly reduce the prednisone AUDTC over 12 months of therapy.

BACKGROUND: There is no generally accepted instrument for measuring quality of life (QOL) in patients with ALS. Current instruments are either too heavily weighted toward strength and physical function or useful for the evaluation of individuals but of less utility in assessing large samples. OBJECTIVE: To develop and evaluate the psychometric properties of an ALS-specific QOL instrument (the ALSSQOL) that would reflect overall QOL as assessed by the patient and would be valid and reliable across large samples. METHODS: The ALSSQOL is based on the McGill Quality of Life Questionnaire (MQOL), modified by changes in format and by adding questions on religiousness and spirituality, items derived from interviews with ALS patients, and items identified from open-ended questions administered during the MQOL. The psychometric properties of the ALSSQOL were assessed by a prospective multicenter study in which participants completed the ALSSQOL, other instruments measuring overall QOL, and instruments assessing religiousness, spirituality, and psychological distress. RESULTS: A 59-item ALSSQOL was developed; 342 patients evaluated its psychometric properties. Completion time averaged 15 minutes. Forty-six items loaded on six factors. The ALSSQOL demonstrated concurrent, convergent, and discriminant validity for the overall instrument and convergent validity for its subscales. Analysis of individual items permitted insight into variables of clinical importance. CONCLUSIONS: This new ALS-specific quality of life instrument is a practical tool for the assessment of overall quality of life in individuals with ALS and appears to be valid and useful across large samples. Validation studies of a shortened version are now under way.