An Open-Label, Randomized, Cross-Over Study to Investigate the Efficacy and Safety of Mexiletine PR Compared to Mexiletine IR

Официальное название

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)

Обзор

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)

Подробное описание

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.

Вмешательства

• Препарат Granular powder in unit dose foil-lined sachet Mexiletine (PR)
  Mexiletine (PR)
• Препарат Oral Capsule Mexiletine (IR)
  Mexiletine (IR)

Первичные конечные точки

• To compare the safety of mexiletine PR vs mexiletine IR by incidence of treatment emergent Adverse Events (TEAEs), treatment-related TEAEs, serious AEs, and patient discontinuation rate between mexiletine PR and mexiletine IR after 12 weeks of treatment. [Срок оценки: Baseline to week 24]
• To compare the safety of mexiletine PR vs mexiletine IR by mean change from baseline in QTc intervals by12-lead in ECG [Срок оценки: Baseline to week 24]
• To compare the safety of mexiletine PR vs mexiletine IR by mean change from baseline in PR intervals by12-lead in ECG [Срок оценки: Baseline to week 24]
• To compare the safety of mexiletine PR vs mexiletine IR by mean change from baseline in QRS intervals by12-lead in ECG [Срок оценки: Baseline to week 24]
• To compare the safety of mexiletine PR vs mexiletine IR by mean change from baseline by average minimum heart rate by12-lead in ECG [Срок оценки: Baseline to week 24]
• To compare the safety of mexiletine PR vs mexiletine IR by performing physical examiniations [Срок оценки: Baseline to week 24]
• To compare the safety of mexiletine PR vs mexiletine IR by assessing vital signs [Срок оценки: Baseline to week 24]
• To compare the safety of mexiletine PR vs mexiletine IR by performing standard clinical laboratory evaluations [Срок оценки: Baseline to week 24]

Вторичные конечные точки (12)

• Mean change in handgrip relaxation time [Срок оценки: Baseline to week 24]
• Mean change in health-related quality of life [Срок оценки: Baseline to week 24]
• Mean change in MBS scores [Срок оценки: Baseline to week 24]
• Mean change in time to perform Timed-up and go (TUG) test [Срок оценки: Baseline to week 24]
• Mean change in VAS [Срок оценки: Baseline to week 24]
• Mean change in Clinical Global Impression (CGI) - Efficacy Scale [Срок оценки: Baseline to week 24]
• Mean change in Clinical Global Impression (CGI) - Tolerability Index Scale [Срок оценки: Baseline to week 24]
• Mean change in time to perform the 10-meter Walk Test [Срок оценки: Baseline to week 24]
• Mean change in Gastrointestinal function: The Gastroesophageal Reflux Disease-Health Related Quality of Life (GERD-HRQoL) [Срок оценки: Baseline to week 24]
• Mean change in CMRS Scale [Срок оценки: Baseline to week 24]
• Mean change Swallowing function [Срок оценки: Baseline to week 24]
• Preference between the two study treatments [Срок оценки: Baseline to week 24]

Критерии участия

Критерии включения

• 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);
• Non-dystrophic myotonias including myotonia congenita (MC), paramyotonia congenita (PC) and sodium channel myotonia (SCM) confirmed genetically;
• Male or non-pregnant female ≥16 years and older at screening;
• Body Mass Index (BMI) of 18.5 kg/m2 to 30 kg/m2, and weight ≥45 kg;
• 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;
• No significant cardiac abnormalities as determined by a cardiologist including electrocardiogram (ECG) and echocardiogram not older than 3 months prior to study entry;
• Participants with myotonic symptoms severe enough to justify treatment (in the opinion of the study investigator);
• 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).

Критерии исключения

• Are pregnant or lactating;
• 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;
• Severe renal impairment (glomerular filtration rate (GFR) < 30 mL/min);
• Medical conditions which could interfere with muscle function such as infections, trauma, fractures, or planned surgery;
• Medical conditions that could affect hand functioning including but not limited to rheumatoid arthritis, Dupuytren's contracture, hand deformity, etc.;
• Severe arthritis or medical condition (other than NDM) that would significantly impact ambulation;
• 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;
• 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.
• 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;
• 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);
• Known allergy to mexiletine or any of the excipients or any local anesthetics;
• Participation in another interventional clinical study during the last 3 months or 5 half-lives of the investigational medicinal product, whichever is longer;
• Wheelchair-bound or bedridden;
• 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);
• Current smokers (within one month of the screening visit) (eg, cigarettes, cigars, vape/e-cigarette products, etc.);
• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Перекрёстный дизайн

Маскирование

Простое слепое

Основная цель

Лечение

Центры проведения

Бельгия · 1 центр

• Universitair Ziekenhuis Leuven"UZ Leuven Gasthuisberg Campus Herestraat 49 Leuven, 3000" — Leuven

Идентификаторы

NCT: NCT07097701 · MEX-NDM-301

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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