An Open-Label, Randomized, Cross-Over Study to Investigate the Efficacy and Safety of Mexiletine PR compared to Mexiletine IR in Patients with Non-Dystrophic Myotonias (ACHILLES study)

This is a multicenter, open-label, randomized, cross-over study intended to evaluate the efficacy and the safety of mexiletine PR (QD) vs mexiletine IR (TID) in patients with non-dystrophic myotonias including myotonia congenita (MC), paramyotonia congenita (PC) and sodium channel myotonia (SCM). The study will consist of a 4-week screening period followed by two 12-week treatment periods. Eligible patients will be randomized to receive mexiletine PR or mexiletine IR for 12 weeks. After a wash out period of at least 7 days the patients will receive the opposite treatment for 12 weeks.

A total of 24 patients are planned to be enrolled (with a target enrollment of 12 naïve to previous mexiletine treatment and 12 previously treated with mexiletine).

Safety assessments include patient- and physician-reported adverse event reporting, electrocardiogram (ECG), standard clinical laboratory evaluations, physical examinations, and vital signs. Efficacy assessments include patient-reported outcomes (PROs) and functional capacity outcome measures.

Inclusion Criteria

1. Ability to comprehend and willingness to sign an informed consent (ICF) or ICF of the parent(s)/legal guardian and written assent from the patient (if patient < 18 years of age);
2. Non-dystrophic myotonias including myotonia congenita (MC), paramyotonia congenita (PC) and sodium channel myotonia (SCM) confirmed genetically;
3. Male or non-pregnant female ≥16 years and older at screening;
4. Body Mass Index (BMI) of 18.5 kg/m2 to 30 kg/m2, and weight ≥45 kg;
5. Female patients of childbearing potential must be using a highly effective form of birth control for the duration of the study and for at least 30 days after last dose of study drug. Male patients must use birth control for the duration of the study and for at least 30 days after last dose of study drug;
6. No significant cardiac abnormalities as determined by a cardiologist including electrocardiogram (ECG) and echocardiogram not older than 3 months prior to study entry;
7. Participants with myotonic symptoms severe enough to justify treatment (in the opinion of the study investigator);
8. Presence of clinical handgrip myotonia (delayed relaxation of grip of ≥ 3 second using a stopwatch) at screening (naïve patients only) and on Day 1 (pre-dose) (patients naïve and previously treated with mexiletine).

Exclusion Criteria

1. Are pregnant or lactating;
2. Have any one of the following medical conditions: uncontrolled diabetes mellitus, cancer other than skin cancer less than five years previously (e.g., basal-cell carcinoma (BCC) and squamous-cell carcinoma (SCC) of skin allowed), multiple sclerosis, seizure disorders, or other serious medical illness or has any other condition, which in the opinion of the Investigator, precludes the participant's participation in the study or the participant is unlikely to comply with the protocol-defined procedures and therefore is unlikely to complete the study;
3. Severe renal impairment (glomerular filtration rate (GFR) < 30 mL/min);
4. Medical conditions which could interfere with muscle function such as infections, trauma, fractures, or planned surgery;
5. Medical conditions that could affect hand functioning including but not limited to rheumatoid arthritis, Dupuytren's contracture, hand deformity, etc.;
6. Severe arthritis or medical condition (other than NDM) that would significantly impact ambulation;
7. Severe hepatic impairment or preexisting elevated liver function tests > 3 times the upper limit of normal (ULN) at screening (alanine transaminase (ALT)/aspartate transaminase (AST), gamma-glutamyl transferase (GGT)) and/or any abnormal chemistry, hematology or urine lab considered clinically significant by the investigator;
8. Serum potassium values < 3.5 mmol/L or > 5.0 mmol/L or serum magnesium values < 1.7 mg/dL. Electrolytic imbalance such as hypocalcaemia, hypercalcaemia, hypokalaemia, hyperkalaemia or hypomagnesaemia may increase the proarrhythmic effects of mexiletine. Electrolyte imbalances need to be corrected before administering mexiletine and will be monitored throughout treatment.
9. Intake of any other anti-myotonic treatment within 4 weeks prior to baseline (Day 1) or 5 half-lives, whichever is longer (e.g., metformin, propafenone, flecainide, lamotrigine, carbamazepine or any other channel-blocker/anticonvulsive drugs;
10. Use of any concomitant medications that could increase the cardiac risk or increases the risk of adverse reactions (see Section 6.8 for a complete list of prohibited concomitant medications);
11. Known allergy to mexiletine or any of the excipients or any local anesthetics;
12. Participation in another interventional clinical study during the last 3 months or 5 half-lives of the investigational medicinal product, whichever is longer;
13. Wheelchair-bound or bedridden;
14. Any cardiac safety-associated condition including any of the following criteria detected by screening cardiac evaluations including ECG, echocardiogram and clinical evaluations (see protocol Section 5.3 for a detailed list);
15. Current smokers (within one month of the screening visit) (eg, cigarettes, cigars, vape/e-cigarette products, etc.);
16. Subgroup 'mexiletine-naïve': patients with previous treatment with mexiletine are excluded. Subgroup 'previous mexiletine treatment': patients with treatment with mexiletine within 1 week prior to baseline (Day 1) are excluded

Study drug (mexiletine PR or mexiletine IR) will be started as a 167 mg once a day (QD) treatment regimen. The dose will be titrated up at Week 1 to 333 mg and at Week 2 to a maximum dose of 500 mg. All dose escalations will be done with safety ECG assessments using portable ECG device. Study drug should be taken at the beginning of the meal at approximately the same time of the day every day, preferably in the morning for Mexiletine PR or Mexiletine IR QD. Mexiletine IR twice a day (BID) should be taken in the morning and afternoon and Mexiletine IR TID should be taken in the morning, afternoon, and evening.