Pivotal study to evaluate the efficacy and safety of riluzole versus mexiletine in patients with non dystrophic myotonia mutated in SCN4A orCLCN1 genes.

Phase 1

• Conditions: DM patients with mutations in SCN4A or CLCN1 gene; MedDRA version: 20.0Level: SOCClassification code 10029205Term: Nervous system disordersSystem Organ Class: 10029205 - Nervous system disorders; Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

• Registration Number: EUCTR2014-002627-10-IT
• Lead Sponsor: FONDAZIONE IRCCS ISTITUTO NEUROLOGICO CARLO BESTA

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2020-11-05
• Last Update Posted: 5 January 2021

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 58

Inclusion Criteria

- Aged at least 18 years.
- Clinical signs or symptoms of myotonia.
- Myotonic potentials on electromyography.
- Genetically confirmed NDM (patients mutated in SCN4A or CLCN1
gene).
- Written informed consent.
- Daily access to a personal computer and internet connection, for IWR
diary report.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 45
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 13

Exclusion Criteria

-Other neurological conditions that might affect the study assessments.
-Genetic confirmation of DM1 (more than 50 repeats of CTG) or DM2.
-Existing atrial flutter or fibrillation or other cardiac conduction defects, as evidenced on ECG at screening visit, including but not limited to the following conditions: malignant arrhythmia or cardiac conduction disturbances (e.g., second degree AV block, third degree AV block, or prolonged QT interval). Any cardiological controindications to mexiletine use will be excluded by a cardiologist. If required by the cardiologist, the patient will undergo heart echo scan and/or Holter ECG.
-Existing permanent pacemaker.
-Current use of any of the following antiarrhythmic medications for a cardiac disorder: flecainide acetate, encainide, disopyramide, procainamide, quinidine, propafenone, or mexiletine.
-Currently use of mexiletine for myotonia in 7 days before randomization.
-Use of medications for myotonia, such as phenytoin and flecainide acetate, within 5 days of study entry, carbamazepine within 3 days of study entry; or propafenone, procainamide, disopyramide, quinidine, and encainide within 2 days of study entry.
-Use of medications that produce myotonia, which may include fibrate acid derivatives, hydroxymethylglutaryl CoA reductase inhibitors, chloroquine, and colchicines.
-Kidney or liver disease or abnormally high levels of liver enzymes such as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT), alkaline phosphatase (AP), GGT, serum bilirubin, except for Gilbert’s Disease:
The investigator should be guided by the following criteria:
¿Any single transaminase may not exceed 3x times upper limits of normal (ULN). A single parameter elevated up to and including 3 x ULN should be re-checked as soon as possible, and in all cases, at least prior to randomization, to rule out any lab error. Normal lab values are shown in table 3.
¿AP and/or GGT may not exceed 2x times ULN. A single parameter elevated up to and including 2 x ULN should be re-checked as soon as possible, and in all cases, at least prior to randomization, to rule out any lab error.
¿If the total bilirubin (TBL) concentration is increased above 1.5x ULN, total bilirubin should be differentiated into the direct and indirect reacting bilirubin. In any case, serum bilirubin should not exceed the value of 1.6 mg/dL.
-Known heart failure or symptomatic cardiomyopathy or recent cardiac infarction (<3 months before randomization).
-Significant coagulopathy, platelet count less than 75,000/mm3, hemoglobin less than 11.0 g/dL.
-Seizure disorder.
-Currently pregnant or breastfeeding.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: - To assess the efficacy of riluzole compared to mexiletine in reducing severity of myotonia in patients affected by NDM with mutations in CLCN1 or SCN4A genes through stiffness evaluation by the Interactive Web Response diary;Secondary Objective: - To assess the safety and tolerability of riluzole in patients affected by NDM with mutations in CLCN1 or SCN4A gene<br>- To assess the efficacy of riluzole compared to mexiletine in reducing severity of myotonia in patients affected by NDM with mutations in<br>CLCN1 or SCN4A genes, assessed by other measures of functionality and also its impact on quality of life.;Primary end point(s): Patient-reported stiffness on the Interactive Web Response (IWR) diary, a variant of interactive voice response (IVR) diary. IVR system assessed symptom severity and frequency in four categories: muscle stiffness,weakness, pain, and tiredness (Statland et al., 2011).;Timepoint(s) of evaluation of this end point: 1, 5, 9, 13 weeks

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): a) Patient-reported Pain, Weakness and Tiredness on the IWR diary. b) Quantitative measure of handgrip myotonia (seconds). c) Clinical hand-grip myotonia evaluation (seconds). d) Individualized Neuromuscular Quality of Life Scale (INQoL). e) Short Form 12 (SF-12);Timepoint(s) of evaluation of this end point: a) 1, 5, 9 and 13 weeks. b, c, d, e) 6, 10 and 14 weeeks.