Sporadic Amyotrophic Lateral Sclerosis
Conditions
Keywords
SALS, Mexiletine, Safety
Brief summary
The purpose of this research is to find out if mexiletine is safe and effective in people with Amyotrophic Lateral Sclerosis (ALS). In this trial, participants will be taking either 300 milligrams per day of mexiletine, 900 milligrams per day of mexiletine or placebo (non-active study drug). The safety and efficacy of these doses will be compared to see if one dose is better than the other.
Detailed description
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting primarily motor neurons, for which treatment designed to slow or arrest progression remains lacking. Mexiletine is a use-dependent sodium channel blocker that has been FDA-approved for decades for the treatment of cardiac arrhythmias and more recently to treat neuropathic pain in diabetic polyneuropathy. Mexiletine has been shown also to be protective of neurons following spinal cord, head injury, and cerebral ischemia, largely by blocking excitotoxicity. Based on previous studies, mexiletine appears to penetrate into the central nervous system at concentrations sufficient to confer significant protection. Recent unpublished studies in the laboratory of Dr. Robert Brown at the University of Massachusetts have also demonstrated that mexiletine ingestion in mice genetically engineered to express high levels of mutant cytosolic copper-zinc superoxide dismutase-1 (SOD1) transgene prolongs survival in these animals. As mexiletine already has FDA-approval as an anti-arrhythmic agent, much is known about the pharmacology and safety of this drug in non-ALS patients. We anticipate that by excluding subjects with a known history of cardiac disease and with the known neuroprotectant properties of this medication, mexiletine is a good choice for further study in an ALS clinical trial.
Interventions
DRUGPlacebo
DRUGMexiletine
Sponsors
University of Washington
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Sporadic Amyotrophic Lateral Sclerosis (SALS) diagnosed as possible, laboratory-supported probable, probable, or definite ALS as defined by revised El Escorial criteria. * Age 18 years or older. * Disease duration ≤ 36 months from ALS symptom onset. * Capable of providing informed consent and following trial procedures. * Subjects must not have taken riluzole for at least 30 days or be on a 50 milligrams twice daily dose of riluzole for at least 60 days prior to randomization (riluzole-naïve subjects are permitted in the study). * Subjects must not have taken medication for muscle cramping such as cyclobenzaprine, baclofen, carisoprodol, or methocarbamol, for at least 30 days prior to randomization or be on a stable dose for at least 60 days prior to randomization. * Geographic accessibility to the site. * Women must not become pregnant for the duration of the study and must be willing to use two contraceptive therapies and have a negative pregnancy test throughout the course of the study. * Slow vital capacity (SVC) measure greater than or equal to 50% of predicted for gender, height, and age at the screening visit. * Subjects medically able to undergo lumbar puncture (LP) as determined by the investigator (for example, no bleeding disorder, allergy to local anesthetics, a skin infection at or near the LP site, or evidence of high intracranial pressure). * Must be able to swallow capsules throughout the course of the study, according to Principal Investigator (PI) judgment. * Must have a caregiver assist with dispensing the study drug.
Exclusion criteria
* Invasive ventilator dependence, such as tracheostomy. * Creatinine level greater than 1.5 milligram/deciliter. * Serum glutamic oxaloacetic transaminase or (aspartate transaminase) / serum glutamic pyruvic transaminase (alanine aminotransferase) greater than 3 times the upper limit of normal at screening. * History of known sensitivity or intolerability to mexiletine or lidocaine. * Any history of either substance abuse within the past year, unstable psychiatric disease, cognitive impairment, or dementia. * Clinically significant conduction abnormalities on electrocardiogram or a known history of cardiac arrhythmia. * Known history of epilepsy. * Known history of congestive heart failure (CHF) or history of myocardial infarction within the past 24 months. * Use of mexiletine for 60 days prior to Baseline Visit. * Exposure to any other experimental agent (off-label use or investigational) including high dose creatine (greater than 10 grams a day) within 30 days prior to Baseline Visit. * Use of amiodarone, flecainide, duloxetine, tizanidine, or clozapine. * Pregnant women or women currently breastfeeding. * Placement of Diaphragm Pacing System (DPS) device less than 60 days prior to Baseline Visit. * Planned DPS device implantation after Baseline Visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants That Discontinued Study Drug | Screening, Baseline Visit Pre-Dose and Post-Dose, Weeks 2, 6, and 12, and at the Final Safety Visit, if a subject discontinues study drug early. Adverse Events will be assessed via telephone Weeks 1, 10, and 16. | Information on adverse effects of mexiletine will be determined at each visit by direct questioning of the subjects, clinical examination, review of concomitant medications, vital signs and laboratory test results. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Trough Plasma Concentration (Cmin) of Mexiletine | Week 6 Visit (pre-dose, hours 1, 2, 3, and 6 post-dose on Week 6) | Subjects will have blood drawn to assess mexiletine concentrations for pharmacokinetics (PK) at the Week 6 Visit. |
| Peak Plasma Concentration (Cmax) of Mexiletine | Week 6 Visit (pre-dose, hours 1, 2, 3, and 6 post-dose on Week 6) | Subjects will have blood drawn to assess mexiletine concentrations for pharmacokinetics (PK) at the Week 6 Visit. |
| Area Under the Concentration Time Curve (AUC) of Mexiletine in Plasma. | Week 6 Visit (up to 6 hours post dose) | Subjects will have blood drawn to assess mexiletine concentrations for pharmacokinetics (PK) at the Week 6 Visit. |
| Mean Cerebrospinal Fluid (CSF)/Plasma Ratio | Week 6 Visit (up to 6 hours post dose) | The concentrations of Mexiletine were measured in cerebrospinal fluid (CSF) and plasma. |
| Mean Weekly Cramp Frequency | Week 3-12, post titration of study medication | — |
| Mean Pain Severity | Weeks 3-12, post titration of study medication | At the Baseline Visit, subjects will be asked to recount the maximum intensity experienced with a muscle cramp in the previous 24 hours and the maximum intensity experienced with a muscle cramp in the previous 30 days. The visual analog scale (VAS) will be used to measures pain associated with muscle cramping. It will be used to measure muscle cramp intensity in this study. The scale rating is from 0-10; 0 equals no symptoms, 10 equals most severe symptoms. Subject will be provided with a muscle cramp diary to record muscle cramp intensity at home, daily. |
| Mean Pain Severity - Ratios for Comparisons of Doses for Weeks 3-12 | Week 3-12, post titration of study medication | — |
| Maximal Pain Severity | Weeks 3-12, post titration of study medication | At the Baseline Visit, subjects will be asked to recount the maximum intensity experienced with a muscle cramp in the previous 24 hours and the maximum intensity experienced with a muscle cramp in the previous 30 days. The visual analog scale (VAS) will be used to measures pain associated with muscle cramping. It will be used to measure muscle cramp intensity in this study. The scale rating is from 0-10; 0 equals no symptoms, 10 equals most severe symptoms. Subject will be provided with a muscle cramp diary to record muscle cramp intensity at home, daily. |
| Cramp Frequency - Ratios for Comparisons of Doses for Weeks 3-12 | Week 3-12, post titration of study medication | — |
| Maximal Pain Severity - Ratios for Comparisons of Doses for Weeks 3-12 | Week 3-12, post titration of study medication | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in ALS Functional Rating Scale- Revised (ALSFRS-R) Score | Week 0, Week 2, Week 6, Week 12 (or Early Termination Date), and Week 16 | The ALSFRS-R is a quickly administered (5 minutes) ordinal rating scale (ratings 0-4) used to determine subjects' assessment of their capability and independence in 12 functional activities. All 12 activities are relevant in ALS. Initial validity was established by documenting that in ALS patients, change in ALSFRS-R scores correlated with change in strength over time, was closely associated with quality of life measures, and predicted survival. |
| Change in Slow Vital Capacity (SVC) Score | Week 0, Week 6, and Week 12 (or Early Termination Date) | The vital capacity (VC) (percent of predicted normal) will be determined, using the slow VC method. The SVC can be measured using conventional spirometers that have had a calibration check prior to subject testing. A printout from the spirometer of all SVC trials will be retained. |
Countries
United States
Participant flow
Recruitment details
The first subject in the study was enrolled July 23, 2013. Subjects were recruited and seen at Amyotrophic Lateral Sclerosis (ALS) clinics at 10 sites across the United States (U.S.).
Pre-assignment details
Seventy-five (75) subjects signed the consent form and were considered enrolled in the study. Fifteen (15) subjects did not meet eligibility criteria and were considered screen failures. Sixty (60) subjects were randomized to one of three treatment arms. One (1) subject was randomized to the 900mg group but never started study drug.
Participants by arm
| Arm | Count |
|---|---|
| Mexiletine, 300 Milligrams Mexiletine, 300 milligrams by mouth per day for 12 weeks.
Mexiletine | 20 |
| Mexiletine, 900 Milligrams Mexiletine, 900 milligrams by mouth per day for 12 weeks.
Mexiletine | 19 |
| Placebo Placebo, by mouth per day for 12 weeks.
Placebo | 20 |
| Total | 59 |
Baseline characteristics
| Characteristic | Mexiletine, 900 Milligrams | Placebo | Mexiletine, 300 Milligrams | Total |
|---|---|---|---|---|
| Age, Continuous | 58.0 years STANDARD_DEVIATION 10.7 | 57.0 years STANDARD_DEVIATION 7 | 59.2 years STANDARD_DEVIATION 7.1 | 58.0 years STANDARD_DEVIATION 8.3 |
| ALSFRS-R Total Score | 33.6 units on a scale STANDARD_DEVIATION 6.7 | 34.9 units on a scale STANDARD_DEVIATION 5.5 | 36.3 units on a scale STANDARD_DEVIATION 7.8 | 35.0 units on a scale STANDARD_DEVIATION 6.7 |
| Baseline Cramps in Previous 24 hours | 1.68 Number of Cramps STANDARD_DEVIATION 1.63 | 2.15 Number of Cramps STANDARD_DEVIATION 2.13 | 1.97 Number of Cramps STANDARD_DEVIATION 3.06 | 1.94 Number of Cramps STANDARD_DEVIATION 2.31 |
| Baseline Cramps in Previous 30 Days | 29.1 Number of Cramps STANDARD_DEVIATION 43.9 | 46.2 Number of Cramps STANDARD_DEVIATION 55.9 | 52.9 Number of Cramps STANDARD_DEVIATION 91 | 42.8 Number of Cramps STANDARD_DEVIATION 66.1 |
| Body Mass Index (BMI) (kg/m^2) | 27.3 kilograms (kg)/meter squared (m^2) STANDARD_DEVIATION 4.1 | 27.1 kilograms (kg)/meter squared (m^2) STANDARD_DEVIATION 3.3 | 28.1 kilograms (kg)/meter squared (m^2) STANDARD_DEVIATION 5.1 | 27.5 kilograms (kg)/meter squared (m^2) STANDARD_DEVIATION 4.2 |
| Maximum Cramp Pain in Previous 24 hours | 2.32 units on a scale STANDARD_DEVIATION 2.11 | 2.55 units on a scale STANDARD_DEVIATION 2.78 | 1.75 units on a scale STANDARD_DEVIATION 2.24 | 2.20 units on a scale STANDARD_DEVIATION 2.38 |
| Maximum Cramp Pain in Previous 30 Days | 3.37 units on a scale STANDARD_DEVIATION 2.36 | 3.35 units on a scale STANDARD_DEVIATION 2.7 | 3.00 units on a scale STANDARD_DEVIATION 2.38 | 3.24 units on a scale STANDARD_DEVIATION 2.45 |
| Months Since Diagnosis | 8.9 Months STANDARD_DEVIATION 8.2 | 7.3 Months STANDARD_DEVIATION 5.9 | 8.6 Months STANDARD_DEVIATION 7.7 | 8.3 Months STANDARD_DEVIATION 7.2 |
| Months Since Symptom Onset | 18.6 Months STANDARD_DEVIATION 9.2 | 17.5 Months STANDARD_DEVIATION 8.3 | 21.0 Months STANDARD_DEVIATION 10.3 | 19.0 Months STANDARD_DEVIATION 9.3 |
| Race/Ethnicity, Customized Asian | 0 participants | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Caucasian | 19 participants | 20 participants | 19 participants | 58 participants |
| Region of Enrollment United States | 19 participants | 20 participants | 20 participants | 59 participants |
| Sex: Female, Male Female | 7 Participants | 10 Participants | 6 Participants | 23 Participants |
| Sex: Female, Male Male | 12 Participants | 10 Participants | 14 Participants | 36 Participants |
| Slow Vital Capacity (Max % predicted) | 86.2 Max %-predicted STANDARD_DEVIATION 23.7 | 83.7 Max %-predicted STANDARD_DEVIATION 22.6 | 86.7 Max %-predicted STANDARD_DEVIATION 19.1 | 85.6 Max %-predicted STANDARD_DEVIATION 21.5 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 17 / 20 | 19 / 19 | 18 / 20 |
| serious Total, serious adverse events | 0 / 20 | 1 / 19 | 2 / 20 |
Outcome results
Primary
Percentage of Participants That Discontinued Study Drug
Information on adverse effects of mexiletine will be determined at each visit by direct questioning of the subjects, clinical examination, review of concomitant medications, vital signs and laboratory test results.
Time frame: Screening, Baseline Visit Pre-Dose and Post-Dose, Weeks 2, 6, and 12, and at the Final Safety Visit, if a subject discontinues study drug early. Adverse Events will be assessed via telephone Weeks 1, 10, and 16.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Mexiletine, 300 Milligrams | Percentage of Participants That Discontinued Study Drug | 5 percentage of participants |
| Mexiletine, 900 Milligrams | Percentage of Participants That Discontinued Study Drug | 32 percentage of participants |
| Placebo | Percentage of Participants That Discontinued Study Drug | 5 percentage of participants |
Secondary
Area Under the Concentration Time Curve (AUC) of Mexiletine in Plasma.
Subjects will have blood drawn to assess mexiletine concentrations for pharmacokinetics (PK) at the Week 6 Visit.
Time frame: Week 6 Visit (up to 6 hours post dose)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mexiletine, 300 Milligrams | Area Under the Concentration Time Curve (AUC) of Mexiletine in Plasma. | 2.34 µg*hr/mL | Standard Deviation 1.08 |
| Mexiletine, 900 Milligrams | Area Under the Concentration Time Curve (AUC) of Mexiletine in Plasma. | 6.24 µg*hr/mL | Standard Deviation 3.18 |
| Placebo | Area Under the Concentration Time Curve (AUC) of Mexiletine in Plasma. | 0 µg*hr/mL | Standard Deviation 0 |
Secondary
Cramp Frequency - Ratios for Comparisons of Doses for Weeks 3-12
Time frame: Week 3-12, post titration of study medication
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Mexiletine, 300 Milligrams | Cramp Frequency - Ratios for Comparisons of Doses for Weeks 3-12 | All Subjects n=20,19 | 0.313 ratio |
| Mexiletine, 300 Milligrams | Cramp Frequency - Ratios for Comparisons of Doses for Weeks 3-12 | 10+cramps previous 30 days at Baseline n=20,19 | 0.222 ratio |
| Mexiletine, 900 Milligrams | Cramp Frequency - Ratios for Comparisons of Doses for Weeks 3-12 | All Subjects n=20,19 | 0.158 ratio |
| Mexiletine, 900 Milligrams | Cramp Frequency - Ratios for Comparisons of Doses for Weeks 3-12 | 10+cramps previous 30 days at Baseline n=20,19 | 0.069 ratio |
Secondary
Maximal Pain Severity
At the Baseline Visit, subjects will be asked to recount the maximum intensity experienced with a muscle cramp in the previous 24 hours and the maximum intensity experienced with a muscle cramp in the previous 30 days. The visual analog scale (VAS) will be used to measures pain associated with muscle cramping. It will be used to measure muscle cramp intensity in this study. The scale rating is from 0-10; 0 equals no symptoms, 10 equals most severe symptoms. Subject will be provided with a muscle cramp diary to record muscle cramp intensity at home, daily.
Time frame: Weeks 3-12, post titration of study medication
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Mexiletine, 300 Milligrams | Maximal Pain Severity | All Subjects n=20,19,20 | 0.738 units on a scale |
| Mexiletine, 300 Milligrams | Maximal Pain Severity | 10+cramps previous 30 days at Baseline n=20,19,20 | 1.348 units on a scale |
| Mexiletine, 900 Milligrams | Maximal Pain Severity | All Subjects n=20,19,20 | 0.340 units on a scale |
| Mexiletine, 900 Milligrams | Maximal Pain Severity | 10+cramps previous 30 days at Baseline n=20,19,20 | 0.572 units on a scale |
| Placebo | Maximal Pain Severity | All Subjects n=20,19,20 | 0.939 units on a scale |
| Placebo | Maximal Pain Severity | 10+cramps previous 30 days at Baseline n=20,19,20 | 2.033 units on a scale |
Secondary
Maximal Pain Severity - Ratios for Comparisons of Doses for Weeks 3-12
Time frame: Week 3-12, post titration of study medication
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Mexiletine, 300 Milligrams | Maximal Pain Severity - Ratios for Comparisons of Doses for Weeks 3-12 | 10+cramps previous 30 days at Baseline n=20,19 | 0.663 ratio |
| Mexiletine, 300 Milligrams | Maximal Pain Severity - Ratios for Comparisons of Doses for Weeks 3-12 | All Subjects n=20,19 | 0.785 ratio |
| Mexiletine, 900 Milligrams | Maximal Pain Severity - Ratios for Comparisons of Doses for Weeks 3-12 | 10+cramps previous 30 days at Baseline n=20,19 | 0.281 ratio |
| Mexiletine, 900 Milligrams | Maximal Pain Severity - Ratios for Comparisons of Doses for Weeks 3-12 | All Subjects n=20,19 | 0.361 ratio |
Secondary
Mean Cerebrospinal Fluid (CSF)/Plasma Ratio
The concentrations of Mexiletine were measured in cerebrospinal fluid (CSF) and plasma.
Time frame: Week 6 Visit (up to 6 hours post dose)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mexiletine, 300 Milligrams | Mean Cerebrospinal Fluid (CSF)/Plasma Ratio | 0.38 ratio | Standard Deviation 0.15 |
| Mexiletine, 900 Milligrams | Mean Cerebrospinal Fluid (CSF)/Plasma Ratio | 0.46 ratio | Standard Deviation 0.2 |
| Placebo | Mean Cerebrospinal Fluid (CSF)/Plasma Ratio | 0 ratio | Standard Deviation 0 |
Secondary
Mean Pain Severity
At the Baseline Visit, subjects will be asked to recount the maximum intensity experienced with a muscle cramp in the previous 24 hours and the maximum intensity experienced with a muscle cramp in the previous 30 days. The visual analog scale (VAS) will be used to measures pain associated with muscle cramping. It will be used to measure muscle cramp intensity in this study. The scale rating is from 0-10; 0 equals no symptoms, 10 equals most severe symptoms. Subject will be provided with a muscle cramp diary to record muscle cramp intensity at home, daily.
Time frame: Weeks 3-12, post titration of study medication
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Mexiletine, 300 Milligrams | Mean Pain Severity | All Subjects n=20,19,20 | 0.241 units on a scale |
| Mexiletine, 300 Milligrams | Mean Pain Severity | 10+cramps previous 30 days at Baseline n=20,19,20 | 0.467 units on a scale |
| Mexiletine, 900 Milligrams | Mean Pain Severity | All Subjects n=20,19,20 | 0.136 units on a scale |
| Mexiletine, 900 Milligrams | Mean Pain Severity | 10+cramps previous 30 days at Baseline n=20,19,20 | 0.201 units on a scale |
| Placebo | Mean Pain Severity | All Subjects n=20,19,20 | 0.536 units on a scale |
| Placebo | Mean Pain Severity | 10+cramps previous 30 days at Baseline n=20,19,20 | 1.248 units on a scale |
Secondary
Mean Pain Severity - Ratios for Comparisons of Doses for Weeks 3-12
Time frame: Week 3-12, post titration of study medication
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Mexiletine, 300 Milligrams | Mean Pain Severity - Ratios for Comparisons of Doses for Weeks 3-12 | All Subjects n=20,19 | 0.450 ratio |
| Mexiletine, 300 Milligrams | Mean Pain Severity - Ratios for Comparisons of Doses for Weeks 3-12 | 10+cramps previous 30 days at Baseline n=20,19 | 0.374 ratio |
| Mexiletine, 900 Milligrams | Mean Pain Severity - Ratios for Comparisons of Doses for Weeks 3-12 | All Subjects n=20,19 | 0.254 ratio |
| Mexiletine, 900 Milligrams | Mean Pain Severity - Ratios for Comparisons of Doses for Weeks 3-12 | 10+cramps previous 30 days at Baseline n=20,19 | 0.161 ratio |
Secondary
Mean Weekly Cramp Frequency
Time frame: Week 3-12, post titration of study medication
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Mexiletine, 300 Milligrams | Mean Weekly Cramp Frequency | All Subjects n=20,19,20 | 0.785 cramps/week |
| Mexiletine, 300 Milligrams | Mean Weekly Cramp Frequency | 10+cramps previous 30 days at Baseline n=20,19,20 | 1.898 cramps/week |
| Mexiletine, 900 Milligrams | Mean Weekly Cramp Frequency | All Subjects n=20,19,20 | 0.231 cramps/week |
| Mexiletine, 900 Milligrams | Mean Weekly Cramp Frequency | 10+cramps previous 30 days at Baseline n=20,19,20 | 0.595 cramps/week |
| Placebo | Mean Weekly Cramp Frequency | All Subjects n=20,19,20 | 2.505 cramps/week |
| Placebo | Mean Weekly Cramp Frequency | 10+cramps previous 30 days at Baseline n=20,19,20 | 8.563 cramps/week |
Secondary
Peak Plasma Concentration (Cmax) of Mexiletine
Subjects will have blood drawn to assess mexiletine concentrations for pharmacokinetics (PK) at the Week 6 Visit.
Time frame: Week 6 Visit (pre-dose, hours 1, 2, 3, and 6 post-dose on Week 6)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mexiletine, 300 Milligrams | Peak Plasma Concentration (Cmax) of Mexiletine | 0.41 pg/mL | Standard Deviation 0.19 |
| Mexiletine, 900 Milligrams | Peak Plasma Concentration (Cmax) of Mexiletine | 1.27 pg/mL | Standard Deviation 0.67 |
| Placebo | Peak Plasma Concentration (Cmax) of Mexiletine | 0 pg/mL | Standard Deviation 0 |
Secondary
Trough Plasma Concentration (Cmin) of Mexiletine
Subjects will have blood drawn to assess mexiletine concentrations for pharmacokinetics (PK) at the Week 6 Visit.
Time frame: Week 6 Visit (pre-dose, hours 1, 2, 3, and 6 post-dose on Week 6)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Mexiletine, 300 Milligrams | Trough Plasma Concentration (Cmin) of Mexiletine | 0.23 pg/mL | Standard Deviation 0.15 |
| Mexiletine, 900 Milligrams | Trough Plasma Concentration (Cmin) of Mexiletine | 0.68 pg/mL | Standard Deviation 0.38 |
| Placebo | Trough Plasma Concentration (Cmin) of Mexiletine | 0 pg/mL | Standard Deviation 0 |
Other Pre-specified
Change in ALS Functional Rating Scale- Revised (ALSFRS-R) Score
The ALSFRS-R is a quickly administered (5 minutes) ordinal rating scale (ratings 0-4) used to determine subjects' assessment of their capability and independence in 12 functional activities. All 12 activities are relevant in ALS. Initial validity was established by documenting that in ALS patients, change in ALSFRS-R scores correlated with change in strength over time, was closely associated with quality of life measures, and predicted survival.
Time frame: Week 0, Week 2, Week 6, Week 12 (or Early Termination Date), and Week 16
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Mexiletine, 300 Milligrams | Change in ALS Functional Rating Scale- Revised (ALSFRS-R) Score | Week 12 n=20,19,20 | 33.33 scores on a scale |
| Mexiletine, 300 Milligrams | Change in ALS Functional Rating Scale- Revised (ALSFRS-R) Score | Week 6 n=20,19,20 | 35.72 scores on a scale |
| Mexiletine, 300 Milligrams | Change in ALS Functional Rating Scale- Revised (ALSFRS-R) Score | Week 0 n=20,19,20 | 35.21 scores on a scale |
| Mexiletine, 300 Milligrams | Change in ALS Functional Rating Scale- Revised (ALSFRS-R) Score | Week 2 n=20,19,20 | 35.14 scores on a scale |
| Mexiletine, 300 Milligrams | Change in ALS Functional Rating Scale- Revised (ALSFRS-R) Score | Week 16 n=20,19,20 | 32.44 scores on a scale |
| Mexiletine, 900 Milligrams | Change in ALS Functional Rating Scale- Revised (ALSFRS-R) Score | Week 6 n=20,19,20 | 33.08 scores on a scale |
| Mexiletine, 900 Milligrams | Change in ALS Functional Rating Scale- Revised (ALSFRS-R) Score | Week 0 n=20,19,20 | 35.21 scores on a scale |
| Mexiletine, 900 Milligrams | Change in ALS Functional Rating Scale- Revised (ALSFRS-R) Score | Week 2 n=20,19,20 | 34.58 scores on a scale |
| Mexiletine, 900 Milligrams | Change in ALS Functional Rating Scale- Revised (ALSFRS-R) Score | Week 12 n=20,19,20 | 31.85 scores on a scale |
| Mexiletine, 900 Milligrams | Change in ALS Functional Rating Scale- Revised (ALSFRS-R) Score | Week 16 n=20,19,20 | 31.94 scores on a scale |
| Placebo | Change in ALS Functional Rating Scale- Revised (ALSFRS-R) Score | Week 16 n=20,19,20 | 32.96 scores on a scale |
| Placebo | Change in ALS Functional Rating Scale- Revised (ALSFRS-R) Score | Week 12 n=20,19,20 | 33.48 scores on a scale |
| Placebo | Change in ALS Functional Rating Scale- Revised (ALSFRS-R) Score | Week 0 n=20,19,20 | 35.21 scores on a scale |
| Placebo | Change in ALS Functional Rating Scale- Revised (ALSFRS-R) Score | Week 6 n=20,19,20 | 34.25 scores on a scale |
| Placebo | Change in ALS Functional Rating Scale- Revised (ALSFRS-R) Score | Week 2 n=20,19,20 | 35.47 scores on a scale |
p-value: 0.56195% CI: [-1.03, 0.56]Random slopes model
p-value: 0.66295% CI: [-1.04, 0.66]Random slopes model
Other Pre-specified
Change in Slow Vital Capacity (SVC) Score
The vital capacity (VC) (percent of predicted normal) will be determined, using the slow VC method. The SVC can be measured using conventional spirometers that have had a calibration check prior to subject testing. A printout from the spirometer of all SVC trials will be retained.
Time frame: Week 0, Week 6, and Week 12 (or Early Termination Date)
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Mexiletine, 300 Milligrams | Change in Slow Vital Capacity (SVC) Score | Week 6 n=20,19,20 | 86.51 percent of predicted normal |
| Mexiletine, 300 Milligrams | Change in Slow Vital Capacity (SVC) Score | Week 0 n=20,19,20 | 87.74 percent of predicted normal |
| Mexiletine, 300 Milligrams | Change in Slow Vital Capacity (SVC) Score | Week 12 n=20,19,20 | 83.98 percent of predicted normal |
| Mexiletine, 900 Milligrams | Change in Slow Vital Capacity (SVC) Score | Week 6 n=20,19,20 | 82.92 percent of predicted normal |
| Mexiletine, 900 Milligrams | Change in Slow Vital Capacity (SVC) Score | Week 0 n=20,19,20 | 87.74 percent of predicted normal |
| Mexiletine, 900 Milligrams | Change in Slow Vital Capacity (SVC) Score | Week 12 n=20,19,20 | 77.18 percent of predicted normal |
| Placebo | Change in Slow Vital Capacity (SVC) Score | Week 0 n=20,19,20 | 87.74 percent of predicted normal |
| Placebo | Change in Slow Vital Capacity (SVC) Score | Week 12 n=20,19,20 | 79.58 percent of predicted normal |
| Placebo | Change in Slow Vital Capacity (SVC) Score | Week 6 n=20,19,20 | 84.79 percent of predicted normal |
p-value: 0.17895% CI: [-0.8, 4.22]Random slopes model
p-value: 0.5195% CI: [-3.8, 1.91]Random slopes model