Mexiletine in Sporadic Amyotrophic Lateral Sclerosis (Mexiletine-2)

• ClinicalTrials.gov Identifier: NCT02781454
• Recruitment Status: Completed
• First Posted: May 24, 2016
• Results First Posted: December 5, 2019
• Last Update Posted: December 5, 2019
• Sponsor: University of Washington
• Collaborator: Massachusetts General Hospital
• Information provided by (Responsible Party): Michael D Weiss, University of Washington

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Sporadic Amyotrophic Lateral Sclerosis
• Interventions: Drug: Mexiletine; Drug: Placebo
• Enrollment: 20

Participant Flow

Recruitment Details	Subjects were enrolled at 9 Northeast ALS Consortium (NEALS) centers in the US. These NEALS centers were academic clinical research centers with established practices where sporadic ALS (sALS) patients are regularly seen and treated.
Pre-assignment Details	Within 21 days prior to treatment assignment, patients were screened for eligibility based on inclusion/exclusion criteria. Failure to meet any of these criteria at the time of this screening would result in exclusion from the study, and these patients would not be assigned to a treatment group.

Arm/Group Title	Mexiletine, 300 Milligrams	Mexiletine, 600 Milligrams	Placebo
Arm/Group Description	Mexiletine, 300 milligrams by mouth per day for 4 weeks. Mexiletine	Mexiletine, 600 milligrams by mouth per day for 4 weeks. Mexiletine	Placebo, by mouth per day for 4 weeks. Placebo
Period Title: Overall Study
Started	8	6	6
Completed	8	6	5
Not Completed	0	0	1

Baseline Characteristics

Arm/Group Title		Mexiletine, 300 Milligrams	Mexiletine, 600 Milligrams	Placebo	Total
Arm/Group Description		Mexiletine, 300 milligrams by mouth per day for 4 weeks. Mexiletine	Mexiletine, 600 milligrams by mouth per day for 4 weeks. Mexiletine	Placebo, by mouth per day for 4 weeks. Placebo	Total of all reporting groups
Overall Number of Baseline Participants		8	6	6	20
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	8 participants	6 participants	6 participants	20 participants
		58.5 (10.8)	60.5 (14.1)	52.0 (11.3)	57.2 (11.9)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	8 participants	6 participants	6 participants	20 participants
	Female	3 37.5%	2 33.3%	1 16.7%	6 30.0%
	Male	5 62.5%	4 66.7%	5 83.3%	14 70.0%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	8 participants	6 participants	6 participants	20 participants
	Hispanic or Latino	0 0.0%	1 16.7%	0 0.0%	1 5.0%
	Not Hispanic or Latino	8 100.0%	5 83.3%	6 100.0%	19 95.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	8 participants	6 participants	6 participants	20 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	White	8 100.0%	6 100.0%	6 100.0%	20 100.0%
	More than one race	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants
United States	Number Analyzed	8 participants	6 participants	6 participants	20 participants
		8 100.0%	6 100.0%	6 100.0%	20 100.0%
El Escorial Diagnosis [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	8 participants	6 participants	6 participants	20 participants
	Possible	1 12.5%	0 0.0%	3 50.0%	4 20.0%
	Prob Lab Supported	5 62.5%	5 83.3%	2 33.3%	12 60.0%
	Probable	2 25.0%	0 0.0%	1 16.7%	3 15.0%
	Definite	0 0.0%	1 16.7%	0 0.0%	1 5.0%
		[1] Measure Description: Participants were classified according to the El Escorial World Federation of Neurology Criteria for the Diagnosis of ALS (Brooks J Neurol Sci 1994) based on the extent of ALS disease signs and symptoms consistent with neurodegeneration of upper and lower motor neurons

Outcome Measures

1. Primary Outcome

Title	Change in Resting Motor Threshold
Description	The resting motor threshold (RMT) assessed from single pulse transcranial magnetic stimulation (TMS) measurements made before treatment, after 4 weeks of treatment, and then again after a 4 week washout, was used as the primary pharmacodynamic marker of cortical hyperexcitability. RMT is the stimulus intensity required to produce and maintain a 0.2 mV peak-to-peak motor evoked potential of the abductor pollicis brevis muscle by TMS. A smaller RMT is thought to suggest greater neuronal excitability.
Time Frame	Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 and from Week 4 to Week 8 reported

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mexiletine, 300 Milligrams	Mexiletine, 600 Milligrams	Placebo
Arm/Group Description:	Mexiletine, 300 milligrams by mouth per day for 4 weeks. Mexiletine	Mexiletine, 600 milligrams by mouth per day for 4 weeks. Mexiletine	Placebo, by mouth per day for 4 weeks. Placebo
Overall Number of Participants Analyzed	8	6	6
Least Squares Mean (Standard Error); Unit of Measure: percentage of maximum stimulus output
change from baseline to week 4	-2.430 (2.323)	0.805 (2.207)	4.746 (2.185)
change from week 4 to week 8	1.465 (2.357)	-0.284 (2.169)	-2.908 (2.247)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mexiletine, 300 Milligrams, Mexiletine, 600 Milligrams, Placebo
	Comments	Comparison of active (300 and 600 mg) vs placebo for change from baseline to week 4
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.039
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	linear contrast active vs placebo
	Estimated Value	-5.558
	Confidence Interval	(2-Sided) 95%; -10.80 to -0.315
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Effect on Short-interval Intracortical Inhibition
Description	Short-interval intracortical inhibition (SICI) is a measure of neuronal excitability measured by dual pulse TMS with a conditioned (80% of RMT) and test pulses (120% of RMT) to generate a stable MEP amplitude of 0.2 mV, averaged over interstimulus intervals of 1-7 ms. It is thought to reflect refractory cortical axons and subsequent resynchronization of cortico-cortical and corticomotoneuronal volleys or activation of non-GABAergic cortical inhibitory circuits (initial phase) and synaptic neurotransmission through GABAA receptors (second phase). The value for SICI thought to be maximally sensitive for detecting in changes in ALS subjects compared to controls is is derived by measuring the motor evoked potential amplitude (MEP) at an interstimulus interval of 3 ms (ISI 3 ms) and normalizing to the MEP amplitude at 120% of the resting motor threshold (MEP 120% RMT). A reduction in SICI reflecting greater excitability would generate a larger ratio of MEP ISI 3 ms/MEP 120% RMT.
Time Frame	Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mexiletine, 300 Milligrams	Mexiletine, 600 Milligrams	Placebo
Arm/Group Description:	Mexiletine, 300 milligrams by mouth per day for 4 weeks. Mexiletine	Mexiletine, 600 milligrams by mouth per day for 4 weeks. Mexiletine	Placebo, by mouth per day for 4 weeks. Placebo
Overall Number of Participants Analyzed	8	6	6
Geometric Least Squares Mean (95% Confidence Interval); Unit of Measure: unitless ratio MEP ISI 3 ms/MEP 120% RMT
	0.655; (0.437 to 0.983)	0.886; (0.608 to 1.291)	0.961; (0.634 to 1.459)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mexiletine, 300 Milligrams, Mexiletine, 600 Milligrams, Placebo
	Comments	Comparison of active (300 and 600 mg) vs placebo ratio of week 4 to week 0
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.332
	Comments	linear contrast active vs placebo
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	linear contrast active vs placebo
	Estimated Value	0.792
	Confidence Interval	(2-Sided) 95%; 0.484 to 1.296
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Change in Motor Evoked Potential Amplitude
Description	The motor evoked potential (MEP) amplitude is taken from single pulse transcranial magnetic stimulation (TMS) and reflects the density of corticomotoneuronal projections onto motor neurons and is affected by cortical hyperexcitability early in ALS where it is thought to be larger than age-matched controls and axonal degeneration later in the disease when it decreases in amplitude. The MEP is most reliable in assessing cortical motor neuronal preservation and excitability when normalized to the peak compound nerve action potential (CMAP) amplitude which reflects the integrity of peripheral motor nerve axons. It is also normalized here to 120% of the RMT to derive a ratio of MEP at 120% RMT/peak CMAP.
Time Frame	Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported

Outcome Measure Data

Analysis Population Description

MEP at 120% RMT/peak CMAP

Arm/Group Title	Mexiletine, 300 Milligrams	Mexiletine, 600 Milligrams	Placebo
Arm/Group Description:	Mexiletine, 300 milligrams by mouth per day for 4 weeks. Mexiletine	Mexiletine, 600 milligrams by mouth per day for 4 weeks. Mexiletine	Placebo, by mouth per day for 4 weeks. Placebo
Overall Number of Participants Analyzed	8	6	6
Geometric Least Squares Mean (95% Confidence Interval); Unit of Measure: unitless ratio of ms/ms
	0.589; (0.315 to 1.102)	0.490; (0.249 to 0.965)	1.308; (0.695 to 2.462)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mexiletine, 300 Milligrams, Mexiletine, 600 Milligrams, Placebo
	Comments	Comparison of active (300 and 600 mg) vs placebo ratio of week 4 to week 0
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.013
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	linear contrast active vs placebo
	Estimated Value	0.411
	Confidence Interval	(2-Sided) 95%; 0.208 to 0.810
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Effect on Cortical Silent Period
Description	The cortical silent period (CSP) is recorded with single pulse TMS as a duration from the onset of the MEP response to resumption of voluntary electromyography activity with the patient performing a voluntary contraction, set to 30% of maximal voluntary contraction. A shorter CSP compared to controls would reflect greater excitability.
Time Frame	Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mexiletine, 300 Milligrams	Mexiletine, 600 Milligrams	Placebo
Arm/Group Description:	Mexiletine, 300 milligrams by mouth per day for 4 weeks. Mexiletine	Mexiletine, 600 milligrams by mouth per day for 4 weeks. Mexiletine	Placebo, by mouth per day for 4 weeks. Placebo
Overall Number of Participants Analyzed	8	6	6
Least Squares Mean (95% Confidence Interval); Unit of Measure: milliseconds
	3.937; (-31.75 to 39.624)	4.823; (-29.76 to 39.408)	4.037; (-30.84 to 38.911)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mexiletine, 300 Milligrams, Mexiletine, 600 Milligrams, Placebo
	Comments	Comparison of active (300 and 600 mg) vs placebo for change from baseline to week 4
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.986
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	linear contrast active vs placebo
	Estimated Value	0.343
	Confidence Interval	(2-Sided) 95%; -41.36 to 42.042
	Estimation Comments	[Not Specified]

5. Secondary Outcome

Title	Effect on Strength Duration Time Constant
Description	The strength duration time constant (SDTC) is used in threshold tracking nerve axonal excitability studies and is interpreted as a measure of axonal excitability that is dependent upon the biophysical properties of the axonal membrane at the node of Ranvier, especially persistent sodium current. It is derived from the relationship between stimulus duration and intensity. A higher SDTC would reflect greater excitability of motor nerve axons.
Time Frame	Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported

Outcome Measure Data

Analysis Population Description

strength duration time constant

Arm/Group Title	Mexiletine, 300 Milligrams	Mexiletine, 600 Milligrams	Placebo
Arm/Group Description:	Mexiletine, 300 milligrams by mouth per day for 4 weeks. Mexiletine	Mexiletine, 600 milligrams by mouth per day for 4 weeks. Mexiletine	Placebo, by mouth per day for 4 weeks. Placebo
Overall Number of Participants Analyzed	8	6	6
Geometric Least Squares Mean (95% Confidence Interval); Unit of Measure: milliseconds
	0.895; (0.802 to 0.998)	0.966; (0.848 to 1.099)	0.935; (0.837 to 1.045)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mexiletine, 300 Milligrams, Mexiletine, 600 Milligrams, Placebo
	Comments	Comparison of active (300 and 600 mg) vs placebo ratio of week 4 to week 0
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.915
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	linear contrast active vs placebo
	Estimated Value	0.994
	Confidence Interval	(2-Sided) 95%; 0.876 to 1.126
	Estimation Comments	[Not Specified]

6. Secondary Outcome

Title	Effect on Depolarizing Threshold Electrotonus (90-100 ms)
Description	Depolarizing threshold electrotonus (90-100 ms) (TEd 90-100 ms) is used in threshold tracking nerve axonal excitability studies in which long-lasting subthreshold depolarizing currents are generated, measured at 90-100 ms following the stimulus. This measure is associated with a decrease in the membrane excitability threshold due to opening of potassium channels on the axonal membrane. Intrinsic changes in axonal excitability properties, such as thought to occur in ALS, could possibly alter this measure, presumably by decreasing TEd 90-100 ms more substantially than normal.
Time Frame	Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mexiletine, 300 Milligrams	Mexiletine, 600 Milligrams	Placebo
Arm/Group Description:	Mexiletine, 300 milligrams by mouth per day for 4 weeks. Mexiletine	Mexiletine, 600 milligrams by mouth per day for 4 weeks. Mexiletine	Placebo, by mouth per day for 4 weeks. Placebo
Overall Number of Participants Analyzed	8	6	6
Least Squares Mean (95% Confidence Interval); Unit of Measure: percentage of threshold depolarization
	-0.140; (-4.925 to 4.645)	4.005; (-1.375 to 9.384)	0.844; (-3.735 to 5.423)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mexiletine, 300 Milligrams, Mexiletine, 600 Milligrams, Placebo
	Comments	Comparison of active (300 and 600 mg) vs placebo for change from baseline to week 4
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.694
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	linear contrast active vs placebo
	Estimated Value	1.089
	Confidence Interval	(2-Sided) 95%; -4.609 to 6.786
	Estimation Comments	[Not Specified]

7. Secondary Outcome

Title	Effect on Hyperpolarizing Threshold Electrotonus (90-100 ms)
Description	Hyperpolarizing threshold electrotonus (90-100 ms) (TEh 90-100 ms) is used in threshold tracking nerve axonal excitability studies in which long-lasting subthreshold hyperpolarizing currents are generated, measured at 90-100 ms following the stimulus. This measure is associated with an increase in the membrane excitability threshold due to closure of potassium channels causing increased resistance of the internodal axonal membrane. Intrinsic changes in axonal excitability properties, such as thought to occur in ALS, could possibly alter this measure.
Time Frame	Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mexiletine, 300 Milligrams	Mexiletine, 600 Milligrams	Placebo
Arm/Group Description:	Mexiletine, 300 milligrams by mouth per day for 4 weeks. Mexiletine	Mexiletine, 600 milligrams by mouth per day for 4 weeks. Mexiletine	Placebo, by mouth per day for 4 weeks. Placebo
Overall Number of Participants Analyzed	8	6	6
Least Squares Mean (95% Confidence Interval); Unit of Measure: percentage threshold hyperpolarization
	-10.184; (-21.57 to 1.204)	2.230; (-10.52 to 14.979)	-4.219; (-15.00 to 6.562)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mexiletine, 300 Milligrams, Mexiletine, 600 Milligrams, Placebo
	Comments	Comparison of active (300 and 600 mg) vs placebo for change from baseline to week 4
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.969
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	linear contrast active vs placebo
	Estimated Value	0.242
	Confidence Interval	(2-Sided) 95%; -12.64 to 13.126
	Estimation Comments	[Not Specified]

8. Secondary Outcome

Title	Effect on Superexcitability
Description	Superexcitability is a component of recovery cycle analysis assessing motor axonal excitability, employing threshold tracking nerve conduction study. It is a depolarizing afterpotential measured following a single supramaximal stimulus followed by a second smaller stimulus of variable intensity and reflects passive depolarization of the internodal axon.
Time Frame	Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mexiletine, 300 Milligrams	Mexiletine, 600 Milligrams	Placebo
Arm/Group Description:	Mexiletine, 300 milligrams by mouth per day for 4 weeks. Mexiletine	Mexiletine, 600 milligrams by mouth per day for 4 weeks. Mexiletine	Placebo, by mouth per day for 4 weeks. Placebo
Overall Number of Participants Analyzed	8	6	6
Least Squares Mean (95% Confidence Interval); Unit of Measure: percentage of threshold change
	2.234; (-2.129 to 6.597)	1.511; (-3.391 to 6.413)	-0.724; (-4.974 to 3.526)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mexiletine, 300 Milligrams, Mexiletine, 600 Milligrams, Placebo
	Comments	Comparison of active (300 and 600 mg) vs placebo for change from baseline to week 4
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.323
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	linear contrast active vs placebo
	Estimated Value	2.597
	Confidence Interval	(2-Sided) 95%; -2.772 to 7.966
	Estimation Comments	[Not Specified]

9. Secondary Outcome

Title	Effect on Subexcitability
Description	Subexcitability is a component of recovery cycle analysis assessing motor axonal excitability, employing threshold tracking nerve conduction study. It is a late hyperpolarizing after potential measured following a single supramaximal stimulus followed by a second smaller stimulus of variable intensity and is related to the very slow turn-off of slow potassium channels.
Time Frame	Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mexiletine, 300 Milligrams	Mexiletine, 600 Milligrams	Placebo
Arm/Group Description:	Mexiletine, 300 milligrams by mouth per day for 4 weeks. Mexiletine	Mexiletine, 600 milligrams by mouth per day for 4 weeks. Mexiletine	Placebo, by mouth per day for 4 weeks. Placebo
Overall Number of Participants Analyzed	8	6	6
Least Squares Mean (95% Confidence Interval); Unit of Measure: percentage of threshold change
	-2.563; (-5.706 to 0.581)	-0.575; (-4.178 to 3.027)	0.448; (-3.001 to 3.897)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mexiletine, 300 Milligrams, Mexiletine, 600 Milligrams, Placebo
	Comments	Comparison of active (300 and 600 mg) vs placebo for change from baseline to week 4
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.273
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	linear contrast active vs placebo
	Estimated Value	-2.017
	Confidence Interval	(2-Sided) 95%; -5.767 to 1.733
	Estimation Comments	[Not Specified]

10. Secondary Outcome

Title	Effect on Frequency of Muscle Cramps
Description	Will be assessed using a daily muscle cramps diary tabulated weekly beginning at Baseline.
Time Frame	Accessed at Screening, Baseline, Week 4, and Week 8; comparisons of treatments at Weeks 3-4 reported

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mexiletine, 300 Milligrams	Mexiletine, 600 Milligrams	Placebo
Arm/Group Description:	Mexiletine, 300 milligrams by mouth per day for 4 weeks. Mexiletine	Mexiletine, 600 milligrams by mouth per day for 4 weeks. Mexiletine	Placebo, by mouth per day for 4 weeks. Placebo
Overall Number of Participants Analyzed	8	6	6
Geometric Least Squares Mean (95% Confidence Interval); Unit of Measure: muscle cramps/week
	3.430; (1.152 to 10.210)	1.987; (0.686 to 5.755)	3.774; (0.687 to 20.740)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mexiletine, 300 Milligrams, Mexiletine, 600 Milligrams, Placebo
	Comments	Comparison of active (300 and 600 mg) vs placebo
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.713
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	linear contrast active vs placebo
	Estimated Value	0.708
	Confidence Interval	(2-Sided) 95%; 0.111 to 4.535
	Estimation Comments	[Not Specified]

11. Secondary Outcome

Title	Effect on Frequency of Fasciculations (Muscle Twitching)
Description	Will be assessed using a daily fasciculations diary tabulated as a percentage of days from weeks 3-4.
Time Frame	Accessed at Screening, Baseline, Week 4, and Week 8; comparisons of treatments at Weeks 3-4 reported

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mexiletine, 300 Milligrams	Mexiletine, 600 Milligrams	Placebo
Arm/Group Description:	Mexiletine, 300 milligrams by mouth per day for 4 weeks. Mexiletine	Mexiletine, 600 milligrams by mouth per day for 4 weeks. Mexiletine	Placebo, by mouth per day for 4 weeks. Placebo
Overall Number of Participants Analyzed	8	6	6
Median (Inter-Quartile Range); Unit of Measure: percentage of days with fasciculations
	100; (83.3 to 100)	100; (100 to 100)	100; (100 to 100)

12. Other Pre-specified Outcome

Title	Change in the Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised
Description	The Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) is an instrument for evaluating the functional status of patients with ALS that includes functions related to speech, swallowing, salivation, fine motor control, gross motor function, and respiration. The score is the sum of 12 items (range 0 to 48) with higher scores reflecting better function.
Time Frame	Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mexiletine, 300 Milligrams	Mexiletine, 600 Milligrams	Placebo
Arm/Group Description:	Mexiletine, 300 milligrams by mouth per day for 4 weeks. Mexiletine	Mexiletine, 600 milligrams by mouth per day for 4 weeks. Mexiletine	Placebo, by mouth per day for 4 weeks. Placebo
Overall Number of Participants Analyzed	8	6	6
Least Squares Mean (95% Confidence Interval); Unit of Measure: score on a scale
	-1.414; (-2.554 to -0.274)	-1.038; (-2.352 to 0.276)	-0.827; (-2.141 to 0.487)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mexiletine, 300 Milligrams, Mexiletine, 600 Milligrams, Placebo
	Comments	Comparison of active (300 and 600 mg) vs placebo for change from baseline to week 4
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.601
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	linear contrast active vs placebo
	Estimated Value	-0.399
	Confidence Interval	(2-Sided) 95%; -1.966 to 1.169
	Estimation Comments	[Not Specified]

13. Other Pre-specified Outcome

Title	Change in Slow Vital Capacity
Description	Measure of decline in respiratory muscle strength
Time Frame	Accessed at Screening, Baseline, Week 4, and Week 8; change from Baseline to Week 4 reported

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Mexiletine, 300 Milligrams	Mexiletine, 600 Milligrams	Placebo
Arm/Group Description:	Mexiletine, 300 milligrams by mouth per day for 4 weeks. Mexiletine	Mexiletine, 600 milligrams by mouth per day for 4 weeks. Mexiletine	Placebo, by mouth per day for 4 weeks. Placebo
Overall Number of Participants Analyzed	8	6	6
Least Squares Mean (95% Confidence Interval); Unit of Measure: maximum percent predicted
	-0.532; (-4.425 to 3.361)	-6.918; (-11.370 to -2.461)	-0.991; (-5.450 to 3.467)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Mexiletine, 300 Milligrams, Mexiletine, 600 Milligrams, Placebo
	Comments	Comparison of active (300 and 600 mg) vs placebo for change from baseline to week 4
	Type of Statistical Test	Superiority
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.285
	Comments	[Not Specified]
	Method	Mixed Models Analysis
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	linear contrast active vs placebo
	Estimated Value	-2.734
	Confidence Interval	(2-Sided) 95%; -7.938 to 2.471
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	8 weeks
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Mexiletine, 300 Milligrams		Mexiletine, 600 Milligrams		Placebo
Arm/Group Description	Mexiletine, 300 milligrams by mouth per day for 4 weeks. Mexiletine		Mexiletine, 600 milligrams by mouth per day for 4 weeks. Mexiletine		Placebo, by mouth per day for 4 weeks. Placebo
All-Cause Mortality
	Mexiletine, 300 Milligrams		Mexiletine, 600 Milligrams		Placebo
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	0/8 (0.00%)		0/6 (0.00%)		0/6 (0.00%)
Serious Adverse Events
	Mexiletine, 300 Milligrams		Mexiletine, 600 Milligrams		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0.00%)		0/6 (0.00%)		1/6 (16.67%)
Vascular disorders
Deep vein thrombosis *	0/8 (0.00%)	0	0/6 (0.00%)	0	1/6 (16.67%)	1
* Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Mexiletine, 300 Milligrams		Mexiletine, 600 Milligrams		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/8 (62.50%)		5/6 (83.33%)		5/6 (83.33%)
Ear and labyrinth disorders
Inner ear signs and symptoms *	0/8 (0.00%)	0	1/6 (16.67%)	1	0/6 (0.00%)	0
Gastrointestinal disorders
Dental pain and sensation disorders *	1/8 (12.50%)	1	0/6 (0.00%)	0	0/6 (0.00%)	0
Diarrhoea (excl infective) *	0/8 (0.00%)	0	1/6 (16.67%)	1	0/6 (0.00%)	0
Dyspeptic signs and symptoms *	1/8 (12.50%)	1	0/6 (0.00%)	0	0/6 (0.00%)	0
Gastrointestinal atonic and hypomotility disorders NEC *	0/8 (0.00%)	0	2/6 (33.33%)	2	3/6 (50.00%)	3
Nausea and vomiting symptoms *	0/8 (0.00%)	0	2/6 (33.33%)	2	1/6 (16.67%)	1
Oral dryness and saliva altered *	0/8 (0.00%)	0	1/6 (16.67%)	1	0/6 (0.00%)	0
Oral soft tissue pain and paraesthesia *	1/8 (12.50%)	1	0/6 (0.00%)	0	0/6 (0.00%)	0
General disorders
General signs and symptoms NEC *	0/8 (0.00%)	0	1/6 (16.67%)	1	0/6 (0.00%)	0
Implant and catheter site reactions *	1/8 (12.50%)	1	0/6 (0.00%)	0	0/6 (0.00%)	0
Oedema NEC *	1/8 (12.50%)	1	0/6 (0.00%)	0	0/6 (0.00%)	0
Asthenic *	0/8 (0.00%)	0	1/6 (16.67%)	1	0/6 (0.00%)	0
Infections and infestations
Lower respiratory tract and lung infections *	0/8 (0.00%)	0	1/6 (16.67%)	1	0/6 (0.00%)	0
Injury, poisoning and procedural complications
Non-site specific injuries NEC *	0/8 (0.00%)	0	2/6 (33.33%)	2	0/6 (0.00%)	0
Musculoskeletal and connective tissue disorders
Muscle pains *	0/8 (0.00%)	0	1/6 (16.67%)	1	0/6 (0.00%)	0
Muscle related signs and symptoms NEC *	1/8 (12.50%)	2	0/6 (0.00%)	0	0/6 (0.00%)	0
Musculoskeletal and connective tissue signs and symptoms NEC *	0/8 (0.00%)	0	1/6 (16.67%)	1	0/6 (0.00%)	0
Nervous system disorders
Headaches NEC *	1/8 (12.50%)	1	2/6 (33.33%)	2	0/6 (0.00%)	0
Neurological signs and symptoms NEC *	2/8 (25.00%)	2	1/6 (16.67%)	1	1/6 (16.67%)	1
Speech and language abnormalities *	0/8 (0.00%)	0	1/6 (16.67%)	1	0/6 (0.00%)	0
Tremor (excl congenital) *	0/8 (0.00%)	0	1/6 (16.67%)	1	0/6 (0.00%)	0
Psychiatric disorders
Disturbances in initiating and maintaining sleep *	0/8 (0.00%)	0	0/6 (0.00%)	0	1/6 (16.67%)	1
Renal and urinary disorders
Bladder and urethral symptoms *	0/8 (0.00%)	0	1/6 (16.67%)	1	0/6 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Breathing abnormalities *	1/8 (12.50%)	1	0/6 (0.00%)	0	0/6 (0.00%)	0
Upper respiratory tract signs and symptoms *	1/8 (12.50%)	1	0/6 (0.00%)	0	0/6 (0.00%)	0
Skin and subcutaneous tissue disorders
Erythemas *	2/8 (25.00%)	5	1/6 (16.67%)	3	2/6 (33.33%)	8
Rashes, eruptions and exanthems NEC *	1/8 (12.50%)	1	0/6 (0.00%)	0	0/6 (0.00%)	0
Vascular disorders
Peripheral embolism and thrombosis *	0/8 (0.00%)	0	1/6 (16.67%)	1	0/6 (0.00%)	0
* Indicates events were collected by non-systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Dr. Michael D. Weiss
• Organization: University of Washington
• Phone: 206-598-7688
• EMail: mdweiss@uw.edu

• Responsible Party: Michael D Weiss, University of Washington
• ClinicalTrials.gov Identifier: NCT02781454
• Other Study ID Numbers: MX-ALS-002
• First Submitted: May 10, 2016
• First Posted: May 24, 2016
• Results First Submitted: October 6, 2019
• Results First Posted: December 5, 2019
• Last Update Posted: December 5, 2019