to investigate the effect and efficacy of pyridostigmine on muscle strength and fatiquabillity in patients with SMA.
ID
Source
Brief title
Condition
- Neurological disorders congenital
- Neuromuscular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Main parameter is the change in the Nine- hole peg test and Motor Function
Measure before and after treatment.
Secondary outcome
Secondary outcome measures are scores on ESWT, ESBBT, MRC sumscore, scales on
daily activities (SMA-FRS, SF=36, PedsQL, PedsQL fatique, VAS, FSS and
fatiqueabililty guestionaire), CMAP and presence of decrement upon repetitive
nerve stimulation, and adverse events.
Background summary
Proximal spinal muscular atrophy (SMA) is characterized by weakness of
predominantly axial and proximal muscle groups and is caused by homozygous
deletion of the survival motor neuron 1 (SMN1)-gene. Treatment of SMA is
exclusively supportive. SMA is characterized by degeneration of alpha motor
neurons in the anterior horn of the spinal cord. 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. A
wellknown modulator and drug of neuromuscular junction dysfunction is the
acetylcholine-esterase inhibitor pyridostigmine. We hypothesize that
pyridostigmine could improve neuromuscular junction function resulting in
improved muscle strength and endurance in patients with SMA.
Study objective
to investigate the effect and efficacy of pyridostigmine on muscle strength and
fatiquabillity in patients with SMA.
Study design
Placebo- controlled, double-blind crossover trial with pyridostigmine.
Intervention
Treatment allocation is double-blind. One group receives 8 weeks of treatment
with pyridostigmine, followed by 1 week wash out and 8 weeks of treatment with
placebo. The other group start with 8 weeks of placebo, 1 week wash out and
followed by 8 weeks period of treatment with pyridostigmine. Dosages of
pyridostigmine and placebo is 2-4mg/kg per day over 4 doses per day in the
first three days. When this dose is well tolerated, the dose will be increased
to 4 times 4mg/kg a day during day 4 up till day 7. When this dose is well
tolerated, the dose will be increased to the full dose of 4 times 6mg/kg per
day after one week.
In case of unfavourable side-effects of pyridostigmine 6mg/kg per day, the
participant will stay on the highest achievable dose (2 or 4 mg/kg/day).
Study burden and risks
SMA is a disease resulting in progressive muscle weakness often in respiratory
failure.
SMA is a highly disabling disease with, in the majority of patients, a reduced
life-expectancy. There are no known treatments to cure or attenuate SMA and its
symptoms. Acetylcholine-esterase-inhibitors, including pyridostigmine, are
FDA- and CBG- approved drugs for symptomatic treatment of neuromuscular
junction dysfunction in myasthenia gravis. Pyridostigmine has few side effects,
in particular diarrhoea, nausea, increased bronchial secretion and sweating.
Patients need to undergo repetitive nerve stimulation 4 times during the 18
weeks- trial period.
Overall, the burden and risk associated with participation in the study will be
minor and justifiable.
Heidelberglaan 100
Utrecht 3584 CX
NL
Heidelberglaan 100
Utrecht 3584 CX
NL
Listed location countries
Age
Inclusion criteria
Patients with SMA will be included following the predefined criteria: 1) a clinical diagnosis of SMA type 2, 3a, 3b or 4 and a genetically confirmed homozygous SMN1 deletion 2) ability to complete visits during trial period; 3) given oral and written informed consent when >=18 years old; 4) given informed consent by the parents or legal representative in case of patients aged >=12 till 18 years old; 5) ability of performing at least 2 subsequent rounds of the Nine Hole Peg test; 6) A maximum Motor Function Measure score of 80%
Exclusion criteria
Exclusion criteria for patients are 1) known concomitant disorders of the NMJ (Lambert Eaton myasthenic syndrome, myasthenia gravis); 2) use of drugs that may alter NMJ function; 3) SMA type 1; 4) apprehension against participation in EMG; 5) inability to meet study visits; 6) mechanical gastro-intestinal, urinary or biliary obstruction; 6) 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; 7) electrocardiofysiology abnormalities known as a contraindication for pyridostigmine use; 8) pregnancy 9) allergy to bromides 10) severe bronchial astma (incase of uncertainty of diagnosis we will contact the treating pulmonologist or physician)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-004369-34-NL |
| CCMO | NL38048.041.14 |