Protocol for a phase II, monocentre, double-blind, placebo-controlled, cross-over trial to assess efficacy of pyridostigmine in patients with spinal muscular atrophy types 2-4 (SPACE trial)

Marloes Stam, Renske I Wadman, Camiel A Wijngaarde, Bart Bartels, Fay-Lynn Asselman, Louise A M Otto, H Stephan Goedee, Laura E Habets, Janke F de Groot, Marja A G C Schoenmakers, Inge Cuppen, Leonard H van den Berg, W Ludo van der Pol, Marloes Stam, Renske I Wadman, Camiel A Wijngaarde, Bart Bartels, Fay-Lynn Asselman, Louise A M Otto, H Stephan Goedee, Laura E Habets, Janke F de Groot, Marja A G C Schoenmakers, Inge Cuppen, Leonard H van den Berg, W Ludo van der Pol

Abstract

Introduction: Hereditary proximal spinal muscular atrophy (SMA) is caused by homozygous loss of function of the survival motor neuron 1 gene. The main characteristic of SMA is degeneration of alpha motor neurons in the anterior horn of the spinal cord, but recent studies in animal models and patients have shown additional anatomical abnormalities and dysfunction of the neuromuscular junction (NMJ). NMJ dysfunction could contribute to symptoms of weakness and fatigability in patients with SMA. We hypothesise that pyridostigmine, an acetylcholinesterase inhibitor that improves neuromuscular transmission, could improve NMJ function and thereby muscle strength and fatigability in patients with SMA.

Methods and analysis: We designed a monocentre, placebo-controlled, double-blind cross-over trial with pyridostigmine and placebo to investigate the effect and efficacy of pyridostigmine on muscle strength and fatigability in patients with genetically confirmed SMA. We aim to include 45 patients with SMA types 2-4, aged 12 years and older in the Netherlands. Participants receive 8 weeks of treatment with pyridostigmine and 8 weeks of treatment with placebo in a random order separated by a washout period of 1 week. Treatment allocation is double blinded. Treatment dose will gradually be increased from 2 mg/kg/day to the maximum dose of 6 mg/kg/day in four daily doses, in the first week of each treatment period. The primary outcome measures are a change in the Motor Function Measure and repeated nine-hole peg test before and after treatment. Secondary outcome measures are changes in recently developed endurance tests, that is, the endurance shuttle nine-hole peg test, the endurance shuttle box and block test and the endurance shuttle walk test, muscle strength, level of daily functioning, quality of and activity in life, perceived fatigue and fatigability, presence of decrement on repetitive nerve stimulation and adverse events.

Ethics and dissemination: The protocol is approved by the local medical ethical review committee at the University Medical Center Utrecht and by the national Central Committee on Research Involving Human Subjects. Findings will be shared with the academic and medical community, funding and patient organisations in order to contribute to optimisation of medical care and quality of life for patients with SMA.

Trial registration number: NCT02941328.

Keywords: cross-over; fatigability; neuromuscular junction; pyridostigmine; sma; spinal muscular atrophy.

Conflict of interest statement

Competing interests: BB serves on scientific advisory board for Roche Hoffman-La Roche, Zurich. LHvdB serves on the scientific advisory boards for the Prinses Beatrix Spierfonds, Thierry Latran Foundation, Biogen Idec and Cytokinetics; received an educational grant from Baxter International; serves on the editorial board of Amyotrophic Lateral Sclerosis and the Journal of Neurology, Neurosurgery and Psychiatry and receives research support from the Prinses Beatrix Fonds, Netherlands ALS Foundation, The European Community’s Health Seventh Framework Programme (grant agreement no 259867), The Netherlands Organisation for Health Research and Development (Vici Scheme, JPND (SOPHIA, STRENGTH)). WLvdP serves on the scientific advisory boards of Biogen and Avexis and the LMI070 data monitoring committee of Novartis and receives research support from the Prinses Beatrix Spierfonds, Netherlands ALS Foundation and Stichting Spieren voor Spieren.

© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Flow chart of the study protocol visit 1 has to take place 5–14 days after the baseline visit. Visit 2 has to take place 7–9 weeks after visit 1. The washout period consists of at least 7 days up to a maximum of 14 days. Visit 3 is planned at the end of the washout period. Visit 4 has to take place 7–9 weeks after visit 3. There is no physical close out visit. Participants are instructed to contact the study team if any events occur in the first week after last intake of study medication. V, visit.

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