Safety and Biomarker Study of EPI-589 in Participants With Amyotrophic Lateral Sclerosis (ALS)

Study Overview
=================
Brief Summary
-----------------
This is an open label study with 30-day run in phase to establish baseline parameters, 90-day treatment phase, and a 90-day withdrawal phase to determine long-term effects, duration of treatment response, and potential effects of EPI-589 therapy on known trajectory.

Official Title
-----------------
A Phase 2A Safety and Biomarker Study of EPI-589 in Subjects With Amyotrophic Lateral Sclerosis

Conditions
-----------------
Amyotrophic Lateral Sclerosis

Intervention / Treatment
-----------------
* Drug: EPI-589


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of possible, probable, laboratory supported probable, or definite ALS by E1 Escorial Criteria Forced vital capacity (FVC) ≥ 70% of predicted Weakness onset within 3 years Agreement to use contraception if within reproductive years Willingness and ability to comply with study procedures Stable regimen of dietary supplements and /or riluzole for at least 30 days prior to enrollment Abstention from use of other investigative or non-approved drugs Participants must be able to swallow 0.375 * 0.700 inch tablets Exclusion Criteria: Allergy to EPI-589 Use of ventilation Participation in other intervention studies Diagnosis of any other neurologic disease Malignancy within the past 2 years History of stroke History of brain surgery Hepatic insufficiency with liver function tests (LFTs) greater than 3 times upper limit of normal (ULN) Renal insufficiency requiring dialysis End stage cardiac failure Participation in a trial of a device, drug, or other therapy for ALS within 3 months of screening or during the trial

Ages Eligible for Study
-----------------
Minimum Age: 21 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EPI-589<br>Participants will receive EPI-589 500 milligrams (mg) (2 tablets of 250 mg each) twice daily (BID) for 3 months, unless discontinued for safety or tolerability issues. | Drug: EPI-589<br>* An immediate release film-coated table at a 250 mg dosage strength will be administered per dose and schedule specified in arm.<br>* Other names: (R)-troloxamide quinone;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Drug-Related Serious Adverse Events (SAEs) | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'. | Baseline (Day 0) to Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Concentration Versus Time Curve From Time 0 to 12 Hours (AUC0-12) |  | Pre-dose (0 hour), 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose at Month 1 and 3 | 
| Maximum Observed Plasma Concentration (Cmax) |  | Pre-dose (0 hour), 0.5, 1, 2, 4, 6, 8, and 12 hours post-dose at Month 1 and 3 | 
| Change From Baseline in ALSFRS-R Total Score at Month 6 | ALSFRS-R is a quickly administered (5 minutes) ordinal rating scale that assesses participant's capability and independence in 12 functional activities. All 12 activities, 6 bulbar-respiratory functions, 3 upper extremity functions (writing, cutting food, and dressing), 2 lower-extremity functions (walking and climbing), and 1 other function (turning in bed), are relevant in ALS. Each activity was recorded to the closest approximation from a list of 5 choices, scored 0-4, with the total score ranging from 48 (normal function) to 0 (unable to attempt the task). | Baseline, Month 6 | 
| Change From Baseline in Vital Capacity at Month 6 | Vital capacity is the maximum amount of air a participant can expel from the lungs after a maximum inhalation. | Baseline, Month 6 | 
| Change From Baseline in MIP at Month 6 | MIP is a measure of the strength of inspiratory muscles, primarily the diaphragm, and allows for the assessment of ventilatory failure, restrictive lung disease, and respiratory muscle strength. | Baseline, Month 6 | 
| Change From Baseline in Respiratory Rate at Month 6 | Respiratory rate is the rate at which breathing occurs. | Baseline, Month 6 | 
| Change From Baseline in Heart Rate at Month 6 | The heart rate measures the number of times the heart beats per minute. | Baseline, Month 6 | 
| Change From Baseline in SpO2 at Month 6 | SpO2, also known as oxygen saturation, is a measure of the amount of oxygen-carrying hemoglobin in the blood relative to the amount of hemoglobin not carrying oxygen. | Baseline, Month 6 | 
| Change From Baseline in ETCO2 at Month 6 | ETCO2 is the amount of CO2 in exhaled air, which assesses ventilation. | Baseline, Month 6 | 
| Failure to Thrive: Number of Participants With Weight Loss of More Than 5 Percent (%) From Baseline at Month 6 | The failure to thrive as measured by body weight was defined as weight loss of more than 5% from baseline | Baseline, Month 6 | 
| Change From Baseline in Average Solid Swallowing Time and Water Swallowing Time at Month 6 | Participants were observed and timed swallowing water as well as solid foods in accordance with a standardized protocol. | Baseline, Month 6 | 
| Change From Baseline in Muscle Function at Month 6, as Assessed by Handheld Dynamometry Parameters (Grip Strength, Shoulder Flexion, Knee Extension, Hip Flexion, Elbow Flexion, Elbow Extension, and Ankle Dorsi Flexion) | The strength of designated muscle groups was measured using handheld dynamometry. | Baseline, Month 6 | 
| Change From Baseline in Number of Words Participant Read at Month 6 | The participant performed tasks in which speech was assessed through a perceptual assessment of overall intelligibility, vocal quality, and other factors by a speech language pathologist. | Baseline, Month 6 | 
| Change From Baseline in Time Spent in Reading at Month 6 | The participant performed tasks in which speech was assessed through a perceptual assessment of overall intelligibility, vocal quality, and other factors by a speech language pathologist. | Baseline, Month 6 | 
| Change From Baseline in Number of Words Per Minute Read at Month 6 | The participant performed tasks in which speech was assessed through a perceptual assessment of overall intelligibility, vocal quality, and other factors by a speech language pathologist. | Baseline, Month 6 | 
| Number of Participants With Normal Loudness, Normal Nasality, and Normal Intelligibility | The participant performed tasks in which speech was assessed through a perceptual assessment of overall intelligibility, vocal quality, and other factors by a speech language pathologist. | Month 6 | 
| Level of Disease-Related Biomarker (Glutathione) in Plasma | Glutathione lowest limit of quantification (LLOQ) = 0.089 micromoles (uM) and upper limit of quantification (ULOQ) = 13.916 uM in plasma. | Baseline up to Month 6 | 
| Level of Disease-Related Biomarker (Glutathione) in Cerebrospinal Fluid (CSF) | Glutathione LLOQ = 0.002 uM and ULOQ = 0.35 uM in CSF. | Baseline up to Month 3 | 
| Level of Disease-Related Biomarker (Glutathione) in Urine | Glutathione LLOQ = 0.01 uM, and ULOQ = 1.39 uM in urine. | Baseline up to Month 6 |