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Hyperkalemic periodic paralysis (HyperPP) is a rare neurological channelopathy caused by gain-of-function mutations in the skeletal muscle sodium channel gene (SCN4A) that disrupts sarcolemmal membrane excitability. Clinically, HyperPP is characterised by episodic muscle weakness attacks with associated rise in serum potassium and a degree of myotonia. Attacks are triggered by exercise, stress, potassium-rich food and a fasting state.
Therapy of periodic paralysis typically consists of avoiding triggers and the use of prophylactic carbonic anhydrase inhibitors. Although these drugs have shown their efficacy in randomised controlled trials (RCTs), many patients oppose a daily drug intake and side effects are frequently experienced.1
Alternatively, salbutamol has been used as an attack treatment in HyperPP, presumably because catecholamines stimulate the cellular uptake of potassium.2 Still, only a few patients with HyperPP are being treated with salbutamol and the large heterogeneity in individual treatment responses makes it difficult to predict who will benefit from the treatment. We report the results from an N-of-1 trial that compared salbutamol aerosol versus placebo treatment to test whether salbutamol aerosol treatment alone, without prophylactic treatment, reduces weakness attack characteristics to a clinically meaningful degree in a single patient with HyperPP.
A randomised, placebo-controlled, double-blind, single patient, multiple cross-over trial (ie, N-of-1 trial) with two (block-randomised) treatment sets: each consisting of a 2-week treatment period of salbutamol and placebo aerosol treatment. The patient (see online supplemental file 1) preferred attack treatment over daily prophylactic treatment with acetazolamide (for baseline data see online supplemental file 2, online supplemental efigure 1). We performed an N-of-1 trial because we had no experience with salbutamol treatment in HyperPP and trial evidence on the abortive effect of salbutamol in an out-of-hospital setting was lacking.
The patient was instructed to use blinded study inhalators (online supplemental efigure 2) according to the instructions from …
Contributors GJvdW, BGMvE and BCS obtained funding for the study and designed the study with input of ECM, JR, CGJS, RW, BvV, HG, RCG and JS. BCS is the primary investigator and responsible for data collection. BvV is responsible for the randomisation process and production of blinded study medication. HMG and BCS are responsible for the data analysis. CGJS and BCS are responsible for the EMG measurements. JR, CGJS and BGMvE supervised BCS during the study. BCS wrote the first draft of the manuscript. All authors have read, critically revised and approved the final version of the manuscript.
Funding This study is funded by ZonMw, The Netherlands Organisation for Health Research and Development (ZonMw project number, 152002029). The funder had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.The first author (BCS) and trial statistician (HG) had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Several authors of this publication (BSC, CGJS, RW, BGMvE and JR) are members of the European Reference Network for Neuromuscular Diseases (EURO-NMD).
Competing interests Dr RG reports grants (during the conduct of the study) from NIH, The Muscular dystrophy association and The Parent Project for Muscular dystrophy, and, personal fees from Strongbridge Pharmaceuticals, Sarepta Pharmaceuticals, Marathon Pharmaceuticals, Stealth Pharmaceuticals, outside the submitted work; Dr JS reports grants from NINDS, grants from FSH Society, personal fees from Acceleron, personal fees from Sarepta, personal fees from Fulcrum, personal fees from PTC, personal fees from Dyne Therapeutics, outside the submitted work; Dr BGMvE reports grants from European Union’s Horizon 2020 research and innovation programme (Murab), grants from European FP7 programme (OPTIMISTIC), grants from Association Francaise contre les Myopathies, grants from Global FSH, grants from The Netherlands Organisation for Health Research and Development (ZonMw), grants from Prinses Beatrix Spierfonds, grants from Stiching Spieren voor Spieren, grants from Dutch FSHD Foundation, grants from Netherlands Organisation for Scientific Research (NWO), personal fees from Fulcrum, outside the submitted work. All other authors declare that they have no financial or non-financial competing interests.
Provenance and peer review Not commissioned; externally peer reviewed.
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