Open Label Study in Adolescents and Children With Myotonic Disorders

NCT04624750 | Completed Phase 3 DMC

• 1 other identifier: MEX-NM-301
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open-label, multi-centre, single arm, interventional study to describe the steady-state PK, safety, and efficacy of mexiletine in paediatric patients (6 to \<18 years of age) with myotonic disorders.

Conditions

Myotonic Dystrophy

Outcome Measures

Primary Outcomes (5)

• Number and frequency of adverse events (AEs)/serious adverse events (SAEs)

  Number and frequency of adverse events (AEs)/serious adverse events (SAEs), throughout the study while on treatment with Namuscla

  Baseline to Day 56

• Incidence of adverse events of special interest (AESI)

  Incidence of adverse events of special interest (AESI)

  Baseline to Day 56

• Changes in ECG assessments from baseline

  On resting ECG any alteration will be noted: * Mild ECG abnormalities: PR interval ≥200 ms and QRS duration ≥100 ms * Severe ECG abnormalities: PR interval ≥240 ms, QRS duration ≥120 ms, second or third degree AV block and a rhythm other than sinus

  Baseline to Day 56

• Efficacy of Namuscla treatment on the clinical outcomes based on the following functional evaluation mean change in Visual Analogue Scale (VAS) for muscle stiffness.

  Mean change in Visual Analogue Scale (VAS) for muscle stiffness. The VAS is constructed as an absolute measure, with a 10 cm straight horizontal line having the endpoints "no stiffness at all" and "stiffness as worst possible". The patient's responses will be scored on the line to the nearest millimetre (a 100-point scale). (myotonia severity).

  Baseline to Day 56

• Efficacy of Namuscla treatment on the clinical outcomes(change from baseline to Days 14, 28, 42 and 56, respectively) based on the following functional evaluation

  The score of handgrip myotonia as quantitatively measured using a commercially available grip dynamometer and computerised capture system. In standardised conditions (i.e. in a room at controlled temperature, after a definite period of rest), maximum voluntary contractions following forced right hand grip will be recorded and the time to relax from 90% to 5% of maximal force will be determined using automated analysis software

  Baseline to Day 56

Secondary Outcomes (15)

• Mean change in VAS score for muscle pain, weakness and fatigue

  Baseline - Day 56

• Clinical myotonia assessment for mean change in time to open the eyes

  Baseline - Day 56

• Clinical myotonia assessment of clinical change in flexor myotonia

  Baseline - Day 56

• Clinical myotonia assessment of mean change in time to perform Timed-up and go (TUG) test

  Baseline - Day 56

• Mean change in health-related quality-of-life as measured by the Paediatric Quality of Life (PedsQL) score

  Baseline - Day 56

Study Arms (1)

Cohort 1 and 2

OTHER

7 patients aged 12 to \< 18 years , inclusive in cohort-1 7 patients aged 6 to \< 12 years, inclusive in cohort-2

Drug: Mexiletine

Interventions

Mexiletine DRUG

Patients will be enrolled sequentially into 2 cohorts. Cohort 1 - (patients aged 12 to \< 18 years): approximately 8 weeks - 4 weeks of dose titration period + 4 weeks of maintenance period. Cohort 2 - (patients aged 6 to \< 12 years,): approximately 8 weeks - 4 weeks of dose titration period + 4 weeks of maintenance period. Enrolment for Cohort 2 will begin after initial safety assessment of patients in Cohort 1 by the DSMB and no safety concerns are observed. The dose level for cohort 2 will be confirmed by PK modelling study.

Also known as: Namuscla ™

Cohort 1 and 2

Eligibility Criteria

• Age: 6 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Male or female patients aged ≥ 6 and \< 18 years who are able to comply with the study requirements
• A genetically confirmed diagnosis of NDM or DM (DM1or DM2)
• Presence of clinical symptoms of myotonia (hand grip myotonia, myotonia in the leg muscles, any other myotonia symptoms)
• No significant cardiac abnormalities as determined by a cardiologist's assessment of the ECG and echocardiogram performed within 3 months prior to enrolment in the study. (If not done within 3 months before trial, electrocardiogram (ECG) and echocardiogram assessments will be performed at screening)
• No history of any significant liver disorder
• Patients receiving mexiletine treatment agree to stop treatment at least 7 days prior to initiation of treatment with Namuscla
• Patients receiving other antimyotonic treatment agree to stop treatment for at least 7 times the half-life of respective drug
• Laboratory investigations for haematology, biochemistry, and urinalysis at screening are within the normal range, or showing no clinically relevant abnormal values, as judged by the Investigator.
• Female patients of childbearing potential must be using an acceptable form of birth control as determined by the Investigator (e.g., oral contraception, implantable, injectable/transdermal hormonal contraception, intrauterine device (IUD), barrier methods), tubal ligation or are practicing abstinence.
• Patients able to provide assent to study participation and a parent or legal guardian to sign the written informed consent prior to study entry.

You may not qualify if:

• Any contra-indication to mexiletine as listed in the Namuscla Summary of Product Characteristics (SmPC):
• Hypersensitivity to the active substance, or to any of the excipients
• Hypersensitivity to any local anaesthetic
• Ventricular tachyarrhythmia
• Complete heart block (i.e., third-degree atrioventricular block) or any heart block susceptible to evolve to complete heart block (first-degree atrioventricular block with markedly prolonged PR interval (≥ 200 ms) and/or wide QRS complex (≥ 120 ms), second-degree atrioventricular block, bundle branch block, bifascicular and trifascicular block),
• QT interval \> 450ms
• Myocardial infarction (acute or past), or abnormal Q-waves
• Symptomatic coronary artery disease
• Heart failure with ejection fraction \<50%
• Atrial tachyarrhythmia, fibrillation or flutter
• Sinus node dysfunction (including sinus rate \< 50 bpm)
• Co-administration with medicinal products inducing torsades de pointes (class Ia, Ic, III antiarrhythmics): Co-administration of mexiletine and antiarrhythmics inducing torsades de pointesclass Ia: quinidine, procainamide, disopyramide, ajmaline; class Ic: encainide, flecainide, propafenone, moricizine; class III: amiodarone, sotalol, ibutilide, dofetilide, dronedarone, vernakalant) increases the risk of potentially lethal torsades de pointes.
• Co-administration with medicinal products with narrow therapeutic index
• Any other neurological or psychiatric condition that might affect the study assessments
• Any clinically significant illness, laboratory findings, ECG, or other clinical symptoms, which in the opinion of the Investigator could affect the patient's optimal participation in the study

Sponsors & Collaborators

• Lupin Ltd.: lead

Study Sites (1)

Hôpital Necker-Enfants-Malades

Paris, France

Location

MeSH Terms

Conditions

Myotonic Dystrophy

Interventions

Mexiletine

Condition Hierarchy (Ancestors)

Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Myotonic Disorders; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Propylamines; Amines; Organic Chemicals; Phenyl Ethers; Phenols; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons

Study Officials

• Christine Barnérias, MD

  Hopital universitaire Necker-Enfants Malades

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: This is an open-label, multi-centre, single arm, interventional, study to evaluate the safety, steady-state PK, and efficacy of mexiletine for the treatment of myotonia in paediatric population aged 6 to \< 18 years. The study comprises a screening period of 30 days, a dose-titration period of 4 weeks, and a maintenance period of 4 weeks. After last visit, all patients will be offered follow-up in clinical study MEX-NM-303 (PIP Study 7).

Study Record Dates

• First Submitted: October 20, 2020
• First Posted: November 12, 2020
• Study Start: September 3, 2021
• Primary Completion: June 14, 2024
• Study Completion: August 8, 2024
• Last Updated: November 25, 2024

Record last verified: 2024-11

Locations

FR (1)