Once-daily mexiletine PR versus three-times-daily mexiletine IR for non-dystrophic myotonias

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 study will test whether a once-daily prolonged-release mexiletine works as well and is as safe as the standard immediate-release mexiletine taken three times a day for people with genetically confirmed non-dystrophic myotonias.

Quick facts

• Phase: Phase 3
• Study type: Interventional
• Enrollment: 24 (estimated)
• Ages: 16 Years and up
• Sex: All
• Sponsor: Lupin Ltd. (Industry-sponsored)
• Locations: 1 site (Leuven)
• Trial ID: NCT07097701 on ClinicalTrials.gov

What this trial studies

This is an open-label, randomized, cross-over Phase 3 study enrolling about 24 patients with genetically confirmed non-dystrophic myotonias (MC, PC, SCM). Participants will be randomized to receive either mexiletine PR once daily or mexiletine IR three times daily for 12 weeks, followed by at least a 7-day washout and then the alternate formulation for another 12 weeks. Safety monitoring includes ECGs, labs, vital signs and adverse event reporting while efficacy will be measured with patient-reported outcomes and functional capacity tests. The planned cohort includes both patients naïve to mexiletine and those previously treated with mexiletine.

Who should consider this trial

Good fit: Ideal candidates are people aged 16 or older with genetically confirmed non-dystrophic myotonia (MC, PC, or SCM), BMI 18.5–30 kg/m2 and weight ≥45 kg without significant cardiac abnormalities and willing to use required contraception during the study.

Not a fit: Patients who are pregnant, have dystrophic forms of myotonia, significant cardiac disease, do not meet BMI/weight criteria, or lack genetic confirmation are unlikely to benefit from participating in this comparison.

Why it matters

Potential benefit: If successful, the once-daily mexiletine PR could offer similar symptom control with simpler dosing and potentially improved convenience and adherence.

How similar studies have performed: Immediate-release mexiletine has established benefit for non-dystrophic myotonia, while prolonged-release formulations have more limited published data and are being tested for comparable efficacy and safety.

Eligibility criteria

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

Where this trial is running

Leuven

• Universitair Ziekenhuis Leuven"UZ Leuven Gasthuisberg Campus Herestraat 49 Leuven, 3000" — Leuven, Belgium (Recruiting)

Study contacts

• Study coordinator: Nikki Adetoro

Conditions Myotonia