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Amifampridine phosphate in the treatment of muscle-specific kinase myasthenia gravis: a phase IIb, randomized, double-blind, placebo-controlled, double crossover study.

ABSTRACT: Objective:The aim of this study is to determine the safety and the efficacy of amifampridine phosphate in muscle-specific kinase antibody-positive myasthenia gravis, in a 1:1 randomized, double-blind, placebo-controlled, switchback, double crossover study. Methods:Eligible patients had muscle-specific kinase myasthenia gravis, >18 years of age, and Myasthenia Gravis Foundation of America class II-IV with a score of ?9 on Myasthenia Gravis Composite scale. After the run-in phase, during which amifampridine phosphate was titrated to a tolerable and effective dosage, patients were randomized to receive placebo-amifampridine-placebo sequence or amifampridine-placebo-amifampridine sequence daily for 7?days. Then, patients switched treatment arms twice, for a total of 21?days of double-blind treatment. Safety was determined by serial assessments of adverse events/serious adverse events, physical examinations, and clinical and laboratory tests. The co-primary outcome measures included changes from baseline of Quantitative Myasthenia Gravis score and Myasthenia Gravis-specific Activities of Daily Living Profile score. The secondary outcome measures comprised changes from baseline of Myasthenia Gravis Composite score, Myasthenia Gravis Quality of Life scale-15 questions, Fatigue Severity Scale, and Carlo Besta Neurological Institute-Myasthenia Gravis scale. Statistical analyses were assessed using a switchback model for three-period, two-treatment crossover design. Results:A total of 10 patients were screened, enrolled, and treated. Transient paresthesias (60%) were the only amifampridine phosphate-related adverse events reported. Four patients were randomized to receive placebo-amifampridine-placebo sequence and three patients to receive amifampridine-placebo-amifampridine sequence. The co-primary objectives were statistically met (Quantitative Myasthenia Gravis score: p?=?0.0003 and Myasthenia Gravis-specific Activities of Daily Living Profile score: p?=?0.0006), as well as all the secondary endpoints (Myasthenia Gravis Composite score: p?

SUBMITTER: Bonanno S

PROVIDER: S-EPMC6299310 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Amifampridine phosphate in the treatment of muscle-specific kinase myasthenia gravis: a phase IIb, randomized, double-blind, placebo-controlled, double crossover study.

Bonanno Silvia S Pasanisi Maria Barbara MB Frangiamore Rita R Maggi Lorenzo L Antozzi Carlo C Andreetta Francesca F Campanella Angela A Brenna Greta G Cottini Lorenzo L Mantegazza Renato R

SAGE open medicine 20181217

<h4>Objective</h4>The aim of this study is to determine the safety and the efficacy of amifampridine phosphate in muscle-specific kinase antibody-positive myasthenia gravis, in a 1:1 randomized, double-blind, placebo-controlled, switchback, double crossover study.<h4>Methods</h4>Eligible patients had muscle-specific kinase myasthenia gravis, >18 years of age, and Myasthenia Gravis Foundation of America class II-IV with a score of ⩾9 on Myasthenia Gravis Composite scale. After the run-in phase, d ...[more]

PMID: 30574306

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Project description:BACKGROUND:To determine the efficacy of low-dose, immediate-release tacrolimus in patients with myasthenia gravis (MG) with inadequate response to glucocorticoid therapy in a randomized, double-blind, placebo-controlled study. METHODS:Eligible patients had inadequate response to glucocorticoids (GCs) after ?6 weeks of treatment with prednisone ?0.75 mg/kg/day or 60-100 mg/day. Patients were randomized to receive 3 mg tacrolimus or placebo daily (orally) for 24 weeks. Concomitant glucocorticoids and pyridostigmine were allowed. Patients continued GC therapy from weeks 1-4; from week 5, the dose was decreased at the discretion of the investigator. The primary efficacy outcome measure was a reduction, relative to baseline, in quantitative myasthenia gravis (QMG) score assessed using a generalized linear model; supportive analyses used alternative models. RESULTS:Of 138 patients screened, 83 [tacrolimus (n = 45); placebo (n = 38)] were enrolled and treated. The change in adjusted mean QMG score from baseline to week 24 was -4.9 for tacrolimus and -3.3 for placebo (least squares mean difference: -1.7, 95% confidence interval: -3.5, -0.1; p = 0.067). A post-hoc analysis demonstrated a statistically significant difference for QMG score reduction of ?4 points in the tacrolimus group (68.2%) versus the placebo group (44.7%; p = 0.044). Adverse event profiles were similar between treatment groups. CONCLUSIONS:Tacrolimus 3 mg treatment for patients with MG and inadequate response to GCs did not demonstrate a statistically significant improvement in the primary endpoint versus placebo over 24 weeks; however, a post-hoc analysis demonstrated a statistically significant difference for QMG score reduction of ?4 points in the tacrolimus group versus the placebo group. This study was limited by the low number of patients, the absence of testing for acetylcholine receptor antibody and the absence of stratification by disease duration (which led to a disparity between the two groups). ClinicalTrials.gov identifier: NCT01325571.

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Dataset Information

Amifampridine phosphate in the treatment of muscle-specific kinase myasthenia gravis: a phase IIb, randomized, double-blind, placebo-controlled, double crossover study.

Publications

Amifampridine phosphate in the treatment of muscle-specific kinase myasthenia gravis: a phase IIb, randomized, double-blind, placebo-controlled, double crossover study.

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