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)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Lupin Atlantis Holdings S.A.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Phenomena and Processes [G] - Musculoskeletal and Neural Physiological Phenomena [G11]

Trial duration

3 Sep 2025 → ongoing

Decision date (initial)

2025-02-14

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

LUPIN ATLANTIS HOLDINGS SA

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To compare the safety of mexiletine PR vs mexiletine IR for the symptomatic treatment of myotonia in adult patients with non-dystrophic myotonias (myotonia congenita (MC), paramyotonia congenita (PC) and sodium channel myotonia (SCM)).

Secondary objectives 3

1. To assess the efficacy of mexiletine PR vs mexiletine IR on patient-reported outcomes
2. To assess the efficacy of mexiletine PR vs mexiletine IR on functional capacity outcome measures
3. To assess a new clinical myotonia rating scale (CMRS) to evaluate myotonia severity

Conditions and MedDRA coding

Non-Dystrophic Myotonias (NDM)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Non-dystrophic myotonias including myotonia congenita (MC), paramyotonia congenita (PC) and sodium channel myotonia (SCM) confirmed genetically;
2. Male or non-pregnant female ≥16 years and older at screening;
3. Body Mass Index (BMI) of 18.5 kg/m2 to 30 kg/m2, and weight ≥45 kg;
4. 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 7 days after last dose of study drug;
5. No significant cardiac abnormalities as determined by a cardiologistincludingcardiologist including electrocardiogram (ECG) and echocardiogram not older than 3 months prior to study entry;
6. Participants with myotonic symptoms severe enough to justify treatment;
7. 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);

Exclusion criteria 15

1. Are pregnant or lactating;
2. 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;
3. 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);
4. Known allergy to mexiletine or any of the excipients or any local anesthetics;
5. Participation in another interventional clinical study during the last 3 months or 5 half-lives of the investigational medicinal product, whichever is longer;
6. Wheelchair-bound or bedridden;
7. Any cardiac safety-associated condition including any of the following criteria detected by screening cardiac evaluations including 24-hour Holter monitoring, ECG, echocardiogram and clinical evaluations (see protocol Section 5.3 for a detailed list).
8. 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;
9. Severe renal impairment (glomerular filtration rate (GFR) < 30 mL/min);
10. Medical conditions which could interfere with muscle function such as infections, trauma, fractures, or planned surgery;
11. Medical conditions that could affect hand functioning including but not limited to rheumatoid arthritis, Dupuytren's contracture, hand deformity, etc.;
12. Severe arthritis or medical condition (other than NDM) that would significantly impact ambulation;
13. 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;
14. 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.
15. Current smokers (within one month of the screening visit) (eg, cigarettes, cigars, vape/e-cigarette products, etc.);

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Incidence of treatment emergent Adverse Events (TEAEs), treatment-related TEAEs, serious AEs, AEs of Special Interest (AESIs), and patient discontinuation rate between mexiletine PR and mexiletine IR after 12 weeks of treatment.

Secondary endpoints 7

1. Video-recording of hand opening time (VHOT)
2. Individualized Neuromuscular Quality of Life Questionnaire (INQoL)
3. Myotonia Behavior Scale (MBS)
4. Timed “Up & Go” (TUG) Test
5. Visual Analog Scale (VAS) for myotonia/stiffness
6. Clinical Global Impression (CGI) – Efficacy
7. Clinical Global Impression (CGI) – Tolerability Index

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Lupin Atlantis Holdings S.A.

Sponsor organisation

Lupin Atlantis Holdings S.A.

Address

Landis + Gyr-Strasse 1

City

Zug

Postcode

6300

Country

Switzerland

Scientific contact point

Organisation

Lupin Atlantis Holdings S.A.

Contact name

Alla Zozulya Weidenfeller

Public contact point

Organisation

Lupin Atlantis Holdings S.A.

Contact name

Alla Zozulya Weidenfeller

Third parties 10

Locations

4 EU/EEA countries · 6 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 53 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications