Method development
Conditions
Interventions
Part A: Mexiletine (Namuscla) 333 mg of placebo
Part B: no medication
Sponsors
Centre for Human Drug Research
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: Part A 1. Signed informed consent prior to any study-mandated procedure 2. Healthy male subjects, 18 to 45 years of age, inclusive at screening. 3. Body mass index (BMI) between 18 and 30 kg/m2, inclusive at screening, and with a minimum weight of 50 kg. 4. All subjects must practice effective contraception during the study and be willing and able to continue contraception for at least 90 days after their last dose of study treatment. 5. Has the ability to communicate well with the Investigator in the Dutch language and willing to comply with the study restrictions. Part B 1. Signed informed consent prior to any study-mandated procedure 2. Male and female subjects, 18 to 69 years of age, inclusive at screening. 3. Diagnosis of generalized myasthenia gravis, MGFA class II, III or IVa, based on characteristic muscle weakness and with a positive AChR antibody test. 4. Has the ability to communicate well with the Investigator in the Dutch language and willing to comply with the study restrictions. 5. Must be able to cease the use of pyridostigmine as per study requirements, if applicable.
Exclusion criteria
Exclusion criteria: 1. Evidence of any active or chronic disease or condition that could interfere with, or for which the treatment of might interfere with, the conduct of the study, or that would pose an unacceptable risk to the subject in the opinion of the investigator (following a detailed medical history, physical examination, vital signs (systolic and diastolic blood pressure, pulse rate, body temperature) and 12-lead electrocardiogram (ECG)). Minor deviations from the normal range may be accepted, if judged by the Investigator to have no clinical relevance. 2. Clinically significant abnormalities, as judged by the investigator, in laboratory test results (including hepatic and renal panels, complete blood count, chemistry panel and urinalysis). Subjects with pre-dose findings of clinically significant changes in electrolytes should be excluded. In the case of uncertain or questionable results, tests performed during screening may be repeated before randomization to confirm eligibility or judged to be clinically irrelevant for healthy subjects. 3. Positive Hepatitis B surface antigen (HBsAg), Hepatitis C antibody (HCV Ab), or human immunodeficiency virus antibody (HIV Ab) at screening. 4. Systolic blood pressure (SBP) greater than 140 or less than 90 mm Hg, and diastolic blood pressure (DBP) greater than 90 or less than 50 mm Hg at screening. 5. Abnormal findings in the resting ECG at screening or baseline defined as: a. QTcF> 450 or 100 bpm) c. Personal or family history of congenital long QT syndrome or sudden death; d. Evidence of atrial fibrillation, atrial flutter, complete branch block, Wolf-Parkinson-White Syndrome, or cardiac pacemaker e. Ventricular tachyarrhythmia f. Atrial tachyarrhythmia, fibrillation or flutter g. 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 (* 240 ms) and/or wide QRS complex (* 120 ms), second-degree atrioventricular block, bundle branch block, bifascicular and trifascicular block), h. Sinus node dysfunction (sinus rate 3.5 sec) 6. Use of any medications (prescription or over-the-counter [OTC]), within 14 days of study drug administration, or less than 5 half-lives (whichever is longer). Exceptions are paracetamol (up to 4 g/day) and ibuprofen (up to 1g/day). Other exceptions will only be made if the rationale is clearly documented by the investigator. 7. Use of any vitamin, mineral, herbal, and dietary supplements within 7 days of study drug administration, or less than 5 half-lives (whichever is longer). Exceptions will only be made if the rationale is clearly documented by the investigator. 8. Participation in an investigational drug or device study within 3 months prior to first dosing, or for more than 4 times a year. 9. History of abuse of addictive substances (alcohol, illegal substances) or current use of more than 21 units alcohol per week, drug abuse, or regular user of sedatives, hypnotics, tranquillizers, or any other addictive agent 10. Positive test for drugs of abuse at screening or pre-dose. 11. Alcohol will not be allowed from at least 24 hours before screening or
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| At a minimum, following endpoints will be derived from the MVRC measurement. Other exploratory endpoints may be derived. Recovery cycles with 1+2+5 conditioning stimuli From MVRCs with one conditioning stimulus: - Relative refractory period in ms (RRP) - Early supernormality (ESN) - Late supernormality (LSN) From recordings with two conditioning stimuli: - Extra late supernormality due to the second conditioning stimulus (XLSN) From recordings with five conditioning stimuli: - Extra late supernormality due to 5 conditioning stimuli (5XLSN) Frequency ramp - Lat(15Hz)first; Lat(15Hz)last; Lat(30Hz)first; Lat(30Hz)last: the latency of the negative peak of the muscle action potential, expressed as a percentage of baseline latency recorded at 15Hz. Responses will be indicated with *First* and *Last*, because latency chances are different for the first and last responses in each train of action potentials. - Peak(15Hz)first; Peak(15Hz)last; Peak(30Hz)first; Peak(30Hz)last: peaks of action potential amplitudes, recorded as percentages of baseline values. - FLatMinfirst; FLatMinlast: the frequency at which the latency is minimal, determined by fitting a quadratic to each 6 adjacent points. 15-pt recovery cycles These are repeated recovery cycles in which the following endpoints are calculated every 30 seconds before, during and after 5 minutes of ischemia: - Relative refractory period - Peak supernormality | — |
Secondary
| Measure | Time frame |
|---|---|
| Part A: Bioanalysis of the PK samples will only by performed if a relevant pharmacodynamic effect is observed. In that case the following endpoints will be evaluated: 1. Plasma concentrations of mexiletine, pharmacokinetic parameters (AUClast, Cmax, tmax) of mexiletine, and the relationship between the MVRC endpoints and mexiletine plasma concentrations. | — |
Countries
Netherlands
Outcome results
None listed