Clinical trial NCT04624750: Open Label Study in Adolescents and Children With Myotonic Disorders
Official title: An Open-label, Non-Comparative Study to Evaluate the Steady-State Pharmacokinetics, Safety, and Efficacy of Mexiletine in Adolescents and Children With Myotonic Disorders
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Myotonic Dystrophy
Lead sponsor: Lupin Ltd.
Sponsor class: INDUSTRY
First posted: 2020-11-12
Enrollment: 12
Sex: ALL
Minimum age (years): 6
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: 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).
Primary purpose: TREATMENT

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.

Detailed description: 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.

Patients who meet the eligibility criteria will be enrolled stepwise, sequentially in 2 cohorts by age groups.

Cohort 1 - Adolescents aged 12 to \<18 years, will be enrolled first. If no safety concerns are observed (based on data evaluation by the Data Safety Monitoring Board \[DSMB\]), and the dose for the age group 6 to \<12 years is confirmed by PK model, enrolment for Cohort 2 will begin.

Cohort 2 - Children aged 6 to \<12 years, will be enrolled. The overall treatment duration for each cohort will be approximately 56 days (8 weeks): a dose titration phase of 4 weeks and the maintenance phase of 4 weeks. The overall study duration would be approximately 22 months.

Dose titration phase: In this phase, patients will receive mexiletine starting at an age appropriate dose (as evaluated by the investigator and based on body weight) at a frequency of once a day. Dose will be up-titrated every 14 days based on tolerability of mexiletine up to a maximum of three-times a day as assessed by investigator.

Maintenance phase: During the maintenance phase, patients will continue to receive mexiletine at the best-tolerated dose from the titration phase for further 4 weeks. Following completion, all participants will be offered follow-up in PIP Study 7 (MEX-NM-303) (EudraCT: 2019-003758-97).

Eligibility criteria: Inclusion Criteria:

1. Male or female patients aged ≥ 6 and \< 18 years who are able to comply with the study requirements
2. A genetically confirmed diagnosis of NDM or DM (DM1or DM2)
3. Presence of clinical symptoms of myotonia (hand grip myotonia, myotonia in the leg muscles, any other myotonia symptoms)
4. 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)
5. No history of any significant liver disorder
6. Patients receiving mexiletine treatment agree to stop treatment at least 7 days prior to initiation of treatment with Namuscla
7. Patients receiving other antimyotonic treatment agree to stop treatment for at least 7 times the half-life of respective drug
8. 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.
9. 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.
10. Patients able to provide assent to study participation and a parent or legal guardian to sign the written informed consent prior to study entry.

Exclusion Criteria:

1. Any contra-indication to mexiletine as listed in the Namuscla Summary of Product Characteristics (SmPC):

   1. Hypersensitivity to the active substance, or to any of the excipients
   2. Hypersensitivity to any local anaesthetic
   3. Ventricular tachyarrhythmia
   4. 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),
   5. QT interval \> 450ms
   6. Myocardial infarction (acute or past), or abnormal Q-waves
   7. Symptomatic coronary artery disease
   8. Heart failure with ejection fraction \<50%
   9. Atrial tachyarrhythmia, fibrillation or flutter
   10. 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.
   11. Co-administration with medicinal products with narrow therapeutic index
2. Any other neurological or psychiatric condition that might affect the study assessments
3. 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
4. Strong inducer or inhibitor of CYP2D6 or CYP1A2 within 7 days prior to study drug administration
5. Any concurrent illness, or medications which could affect the muscle function
6. Seizure disorder, diabetes mellitus requiring treatment by insulin
7. Pregnant or breastfeeding
8. Concurrent participation in any other clinical trial.

Primary outcomes:
measure: Number and frequency of adverse events (AEs)/serious adverse events (SAEs)
timeFrame: Baseline to Day 56
measure: Incidence of adverse events of special interest (AESI)
timeFrame: Baseline to Day 56
measure: Changes in ECG assessments from baseline
timeFrame: Baseline to Day 56
measure: Efficacy of Namuscla treatment on the clinical outcomes based on the following functional evaluation mean change in Visual Analogue Scale (VAS) for muscle stiffness.
timeFrame: Baseline to Day 56
measure: 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
timeFrame: Baseline to Day 56
Secondary outcomes:
measure: Mean change in VAS score for muscle pain, weakness and fatigue
timeFrame: Baseline - Day 56
measure: Clinical myotonia assessment for mean change in time to open the eyes
timeFrame: Baseline - Day 56
measure: Clinical myotonia assessment of clinical change in flexor myotonia
timeFrame: Baseline - Day 56
measure: Clinical myotonia assessment of mean change in time to perform Timed-up and go (TUG) test
timeFrame: Baseline - Day 56
measure: Mean change in health-related quality-of-life as measured by the Paediatric Quality of Life (PedsQL) score
timeFrame: Baseline - Day 56
measure: Clinical Global Impression (CGI) scores (efficacy and tolerability) evaluated by the patient
timeFrame: Baseline - Day 56
measure: Mean change in Myotonia Behaviour Scale (MBS) scores
timeFrame: Baseline - Day 56
measure: Changes in clinical laboratory values for laboratory safety assessments - Potassium
timeFrame: Baseline - Day 56
measure: Acceptability of the capsule formulation with respect to the swallowability.
timeFrame: Baseline - Day 56
measure: Palatability of alternative administration
timeFrame: Baseline - Day 56
measure: Changes in clinical laboratory values from baseline to Day 56 for laboratory safety assessments - Changes in Magnesium values
timeFrame: Baseline - Day 56
measure: Changes in clinical laboratory values from baseline to Day 56 for laboratory safety assessments - Changes in Sodium values
timeFrame: Baseline - Day 56
measure: Changes in clinical laboratory values from baseline to Day 56 for laboratory safety assessments - Changes in Calcium values
timeFrame: Baseline - Day 56
measure: Changes in clinical laboratory values from baseline to Day 56 for laboratory safety assessments - Changes in Chloride values
timeFrame: Baseline - Day 56
measure: Mean change in Faces scale for muscle pain, weakness and fatigue
timeFrame: Baseline - Day 56
Other outcomes:
Locations:
city: Paris
country: France
facility: Hôpital Necker-Enfants-Malades
Study officials:
affiliation: Hopital universitaire Necker-Enfants Malades
name: Christine Barnérias, MD
role: PRINCIPAL_INVESTIGATOR
References: