SPACE Trial: Pyridostigmine vs Placebo in SMA Types 2, 3 and 4

NCT ID: NCT02941328

Last Updated: 2018-02-05

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 39 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-12-31
• Study Completion Date: 2018-01-31

Brief 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.

Detailed Description

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).

Conditions

Spinal Muscular Atrophy; SMA; Kugelberg-Welander Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Pyridostigmine

(this is a cross-over trial, in which participants will receive both a placebo and pyridostigmine in different study periods. Both investigators and participants are blinded for what medication is used in what period. All patients will eventually use a placebo for 8 weeks and pyridostigmine for 8 weeks).

Group Type: EXPERIMENTAL

Pyridostigmine

Intervention Type: DRUG

Pyridostigmine, administered orally starting with 2mg/kg/day (in 4 daily doses, i.e. 0,5mg/kg/dose) and slowly increasing to a maximum dosage of 6mg/kg/day (4 daily doses of 1,5mg/kg/day)

Placebo

(this is a cross-over trial, in which participants will receive both a placebo and pyridostigmine in different study periods. Both investigators and participants are blinded for what medication is used in what period. All patients will eventually use a placebo for 8 weeks and pyridostigmine for 8 weeks).

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo administered orally starting with 2mg/kg/day (in 4 daily doses, i.e. 0,5mg/kg/dose) and slowly increasing to a maximum dosage of 6mg/kg/day (4 daily doses of 1,5mg/kg/day)

Interventions

Pyridostigmine

Pyridostigmine, administered orally starting with 2mg/kg/day (in 4 daily doses, i.e. 0,5mg/kg/dose) and slowly increasing to a maximum dosage of 6mg/kg/day (4 daily doses of 1,5mg/kg/day)

Intervention Type: DRUG

Placebo

Placebo administered orally starting with 2mg/kg/day (in 4 daily doses, i.e. 0,5mg/kg/dose) and slowly increasing to a maximum dosage of 6mg/kg/day (4 daily doses of 1,5mg/kg/day)

Intervention Type: DRUG

Other Intervention Names

Mestinon

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).

• Minimum Eligible Age: 12 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

UMC Utrecht

OTHER

Sponsor Role: lead

Responsible Party

Camiel Wijngaarde

MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

W.L. Van der Pol, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

UMC Utrecht

Locations

University Medical Center of Utrecht (UMCU)

Utrecht, , Netherlands

Countries

Netherlands

References

Stam M, Wijngaarde CA, Bartels B, Asselman FL, Otto LAM, Habets LE, van Eijk RPA, Middelkoop BM, Goedee HS, de Groot JF, Roes KCB, Schoenmakers MAGC, Nieuwenhuis EES, Cuppen I, van den Berg LH, Wadman RI, van der Pol WL. Randomized double-blind placebo-controlled crossover trial with pyridostigmine in spinal muscular atrophy types 2-4. Brain Commun. 2022 Dec 9;5(1):fcac324. doi: 10.1093/braincomms/fcac324. eCollection 2023.

Reference Type: DERIVED

PMID: 36632180 (View on PubMed)

Stam M, Wadman RI, Wijngaarde CA, Bartels B, Asselman FL, Otto LAM, Goedee HS, Habets LE, de Groot JF, Schoenmakers MAGC, Cuppen I, van den Berg LH, van der Pol WL. 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). BMJ Open. 2018 Jul 30;8(7):e019932. doi: 10.1136/bmjopen-2017-019932.

Reference Type: DERIVED

PMID: 30061431 (View on PubMed)

Other Identifiers

NL38048.041.14

Identifier Type: -

Identifier Source: org_study_id