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

• ClinicalTrials.gov Identifier: NCT02941328
• Recruitment Status: Completed
• First Posted: October 21, 2016
• Last Update Posted: February 5, 2018
• Sponsor: UMC Utrecht
• Information provided by (Responsible Party): Camiel Wijngaarde, UMC Utrecht

Tracking Information

• First Submitted Date: September 30, 2016
• First Posted Date: October 21, 2016
• Last Update Posted Date: February 5, 2018
• Actual Study Start Date: December 2015
• Actual Primary Completion Date: January 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 19, 2016)

• MFM (Motor Function Measurement). [ Time Frame: change over the course of 8 weeks compared to baseline ]
  D1+D2+D3 but also D1, D2, or D3 sub scores of the MFM scales will be used.
• repeated nine-hole peg test performance [ Time Frame: Change in performance (in time to complete) the test rounds over the course of 8 weeks of medication compared to baseline ]
  The time needed tot complete multiple rounds of the nine hole peg test (hence: repeated NHPT) will be recorded (visit 1) and compared to the performance on the test after 8 weeks of treatment (placebo or mestinon) (visit 2). Visit 3 will serve as the baseline measurement for the 2nd study period (again followed by 8 weeks of treatment and the final study visit (visit 4)).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 19, 2016)

• endurance nine hole peg test [ Time Frame: Change in performance after 8 weeks of therapy (placebo or mestinon). ]
  During the endurance tests, patients will perform at 75% of their maximum performance. Differences in before and after treatment results (number of rounds completed) will be analysed
• endurance box-and-block test [ Time Frame: Change in performance after 8 weeks of therapy (placebo or mestinon) ]
  During the endurance tests, patients will perform at 75% of their maximum performance. Differences in before and after treatment results (number of rounds completed) will be analysed. This test will be performed only if the patient is capable of performing it.
• endurance walk test [ Time Frame: Change in performance after 8 weeks of therapy (placebo or mestinon). ]
  During the endurance tests, patients will perform at 75% of their maximum performance. Differences in before and after treatment results (e.d. total distance travelled) will be analysed. This test will be performed only if the patient is able to walk.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: SPACE Trial: Pyridostigmine vs Placebo in SMA Types 2, 3 and 4
• Official Title: A Phase II, Mono-center, Placebo-controlled, Double-blind, Crossover Trial to Investigate Effect and Efficacy of Pyridostigmine in Dutch Patients With Spinal Muscular Atrophy Types 2, 3 and 4
• 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).

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Spinal Muscular Atrophy
• SMA
• Kugelberg-Welander Disease

Intervention

• Drug: 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)
  Other Name: Mestinon
• 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)

Study Arms

• Experimental: 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).
  Intervention: Drug: Pyridostigmine
• Placebo Comparator: 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).
  Intervention: Drug: Placebo

• Publications *: 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 1, 2018): 39
• Original Estimated Enrollment (submitted: October 19, 2016): 50
• Actual Study Completion Date: January 2018
• Actual Primary Completion Date: January 2018 (Final data collection date for primary outcome measure)

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).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Netherlands

Administrative Information

• NCT Number: NCT02941328
• Other Study ID Numbers: NL38048.041.14
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Camiel Wijngaarde, UMC Utrecht
• Original Responsible Party: Same as current
• Current Study Sponsor: UMC Utrecht
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: W.L. Van der Pol, MD, PhD; UMC Utrecht

• PRS Account: UMC Utrecht
• Verification Date: February 2018