Open Label Study in Adolescents and Children With Myotonic Disorders

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Brief Title

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

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).
    

Study Phase

Phase 3

Study Type

Interventional


Primary Outcome

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

Secondary Outcome

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

Condition

Myotonic Dystrophy

Intervention

Mexiletine

Study Arms / Comparison Groups

 Cohort 1 and 2
Description:  7 patients aged 12 to < 18 years , inclusive in cohort-1 7 patients aged 6 to < 12 years, inclusive in cohort-2

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

14

Start Date

September 3, 2021

Completion Date

March 1, 2024

Primary Completion Date

January 2, 2024

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.
      

Gender

All

Ages

6 Years - 18 Years

Accepts Healthy Volunteers

No

Contacts

Christine Barnérias, MD, 443-447-4534, [email protected]

Location Countries

France

Location Countries

France

Administrative Informations


NCT ID

NCT04624750

Organization ID

MEX-NM-301


Responsible Party

Sponsor

Study Sponsor

Lupin Ltd.


Study Sponsor

Christine Barnérias, MD, Principal Investigator, Hopital universitaire Necker-Enfants Malades


Verification Date

September 2021