Ephedrine as add-on therapy for patients with myasthenia gravis: protocol for a series of randomised, placebo-controlled n-of-1 trials

Abstract

IntroductionMyasthenia gravis (MG), a rare neuromuscular disease, is often initially treated using acetylcholinesterase inhibitors. Patients who do not respond adequately depend on the use of corticosteroids or other immunosuppressive medication, but these may have serious side effects. Clinical observations suggest that ephedrine can diminish, postpone or even prevent the need for immunosuppressive therapy when added to acetylcholinesterase inhibitors or low-dose prednisone. In the Netherlands, ephedrine is not licensed for MG nor is reimbursement guaranteed. MG is a rare condition, and ephedrine might be indicated only in a subset of patients. Thus, randomised controlled trials comparing large groups are difficult to conduct. We, therefore, aim to aggregate data from a small series of n-of-1 trials (also known as single patient trials) to assess the effect of ephedrine as add-on treatment for MG.Methods and analysisSingle-centre, placebo-controlled, double-blind, randomised, multiple crossover n-of-1 studies in 4 adult patients with generalised MG who show inadequate improvement on pyridostigmine and/or immunosuppressive drugs. Each n-of-1 trial has 3 cycles of two 5-day intervention periods. Treatment: 25 mg ephedrine or placebo, twice daily. Main outcome measure: Quantitative Myasthenia Gravis (QMG) test. Statistical analysis: fixed effects linear model for QMG for all patients combined. Secondary outcome measures: Clinical: effects on MG-Composite and MG-Activities of Daily Living (MG-ADL) scales; QMG at individual level; adverse events. Acceptability of trial design: number of patients eligible and enrolled; number of treatment cycles completed; patients’ and caregivers’ experiences.Ethics and disseminationThis study was approved by the Medical Ethics Committee of Leiden University Medical Center, No. P14.108. Results of the trial will be reported in a peer-reviewed publication. Regulatory stakeholders will comment on the suitability of the trial for market authorisation and reimbursement purposes.Trial registration numberThis study is registered under EudraCT number 2014-001355-23, protocol no. 40960, V.1.0, registration date 27 March 2014.

SPIRIT extension and elaboration for n-of-1 trials: SPENT 2019 checklist

“…Monte Carlo simulations were used to compute the power with three cycles (i.e., 6 measurements) per patient for 3, 4, and 5 patients, which was 0.648, 0.772 and 0.862, respectively. In light of the availability of eligible patients, time and resources, we chose a sample size of 4 patients, achieving approximately 77% power.”47…”

“…“Randomisation will be carried out for each individual n-of-1 trial by the dispensing hospital pharmacy to ensure patient and physician blinding, and will be performed in MS Excel. Ephedrine and placebo treatments will be randomised in a 1:1 ratio per cycle over the three cycles of the n-of-1 trial (e.g., AB-BA-BA).”47…”

“…“For each individual patient, QMG [quantitative myasthenia gravis test] scores, scores for secondary outcome measures, and adverse effects reported during the ephedrine and placebo periods will be described in an individual patient report. This report will be discussed by the patient and their physician during the evaluation phase of the n-of-1 trial and may be used to guide individual therapeutic decisions.”47…”

Off-Label Use in Rare Diseases: Myasthenia Gravis, Lambert-Eaton Myasthenic Syndrome and Congenital Myasthenic Syndromes

“…However, even with the concept of a rare disease there are "singular cases" [10] or "individual cases", which are considered "ultra-rare diseases" (prevalence: < 1:10,000), including, for example MuSK-positive myasthenia gravis (prevalence 0.05-0.65/100,000 [10]) or congenital myasthenic syndrome (CMS) [20]. Consequently, Vrinten et al [21] introduced the study concept of a so-called single-case trial, using ephedrine as an example of add-on therapy for MG. For medicinal products, the concept of "rare disease (orphan) designation" (formerly: orphan drug designation) was introduced by the EMA for a rare disease and its related constellations. The effect of this, for example, was that 3,4-diaminopyridine, which has been known and used for over 40 years and which according to the German New Prescription Formulary (NRF, no.…”

Off-Label-Use bei Seltenen Erkrankungen (SE): Myasthenia gravis, Lambert-Eaton myasthenisches Syndrom und kongenitale myasthenische Syndrome

“…B. die MuSK-pos-MG (Prävalenz 0,05 -0,65/100 000 [10] oder CMS [20]. Daher haben Vrinten et al [21] Langfristig ist nach den EU-Richtlinien die Einrichtung von krankheitsspezifischen "Centers of Expertise" (CoE) für solche Aufgaben vorgesehen, wie sie in Deutschland von der "Nationalen Allianz für Menschen mit Seltenen Erkrankungen" (NAMSE) auf den Weg gebracht wurde. Derzeit sollten die zertifizierten integrierten Myasthenie-Zentren (iMZ; [26]) oder spezialisierten Myasthenie-Ambulanzen angefragt werden.…”