space trial: pyridostigmine vs placebo in sma types 2, 3 and 4

Conditions: Spinal Muscular Atrophy; SMA; Kugelberg-Welander Disease

Summary: a trial investigating the effects of pyridostigmine (mestinon) versus a placebo in a double-blind cross over trial in patients with hereditary proximal spinal muscular atrophy (sma) types 2, 3 and 4.

in this cross-over trial we will investigate the effects of pyridostigmine (mestinon) versus a placebo on fatigability in patients with hereditary proximal spinal muscular atrophy (sma) types 2, 3 and 4 (aged 12 and older) the study participants will be using a placebo during 8 weeks and mestinon during 8 weeks. both investigators and patients are blinded to the treatment allocation in both periods. patients will be randomly assigned to use placebo or mestinon first. at the end of the study, patients will have used both mestinon and a placebo during 8 weeks. in both phases (periods) of the cross over study, study medication dosage will slowly be increased to a maximum dosage of 6 mg/kg/day (spread over 4 doses daily) in order to either prevent side effects or to manage them as good as possible. this scheme allows us to assist our participants in case side effects do occur early. although we strive to have all patients on the same dosage per kg of body weight, serious side effects will obviously lead to lowering the dosage. before the start of medication use (either placebo or pyridostigmine), baseline measurements will be taken: a physical examination and data concerning both primary and secondary outcomes (mfm, mrc scores, fatigability tests, etc.) will be collected. after use a drug (mestinon/placebo) for 8 weeks these tests will be repeated, to evaluate possible medication effect. after a wash-out period of approximately 1-2 weeks the same scheme is used for the second study period (i.e. the cross-over design). unblinding follows after the entire study is completed (i.e.: last included patients finishes participation).

Eligibility criteria:
inclusion criteria: * a clinical diagnosis of sma type 2, 3a, 3b or 4 * genetically confirmed homozygous smn1 deletion * ability to complete visits during trial period; * given oral and written informed consent when ≥18 years old; * given informed consent by the parents or legal representative(s) in case of patients aged ≥12 till \<18 years old (in accordance with dutch law) * ability of performing at least 2 subsequent rounds of the nine hole peg test * a maximum total motor function measure (mfm) score of 80% (i.e.: a maximum score under 80% of the d1+d2+d3 subscores). exclusion criteria: * known concomitant disorders of the nmj (e.g. but not limited to: lambert eaton myasthenic syndrome, myasthenia gravis); * use of drugs that may alter nmj function * classic sma type 1; * apprehension against participation in emg; * inability to meet study visits; * mechanical gastro-intestinal, urinary or biliary obstruction; * clinical significant alterations of laboratory tests (electrolytes, liver function, kidney function, thyroid function or blood dysplasia) drawn within 14 days prior to start of study entry; * ecg abnormalities known as a contraindication for pyridostigmine use; * current pregnancy or breast-feeding * allergy to bromides * severe bronchial asthma (in case of uncertainty of diagnosis, we will contact treating pulmonologist or physician) * total mfm score at baseline (screening) \> 80% (i.e.: a maximum total mfm score above 80% of the d1+d2+d3 subscores).

Keywords: sma, smn1, kugelberg-welander