Phase III Trial of AMX0035 for Amyotrophic Lateral Sclerosis Treatment

Study Overview
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Brief Summary
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The Phoenix Trial is a randomized double blind placebo controlled Phase III trial to evaluate the safety and efficacy of AMX0035 for treatment of ALS

Detailed Description
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AMX0035 is a combination therapy designed to reduce neuronal death through blockade of key cellular death pathways originating in the mitochondria and endoplasmic reticulum (ER). This clinical trial is designed to demonstrate that treatment is safe, tolerable, and able to slow decline in function as measured by the ALSFRS-R and survival over 48 week. The trial will also assess the effects of AMX0035 on slow vital capacity, quality of life and plasma biomarkers of ALS.

Official Title
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A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial to Evaluate the Safety and Efficacy of AMX0035 Versus Placebo for 48-week Treatment of Adult Patients With Amyotrophic Lateral Sclerosis (ALS)

Conditions
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Amyotrophic Lateral Sclerosis

Intervention / Treatment
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* Other: Placebo
* Drug: AMX0035


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, at least 18 years of age Diagnosis of ALS (definite or clinically probable) Time since onset of first symptom of ALS should be <24 months prior to randomization; If the participant is to be treated with riluzole and/or edaravone during the course of the trial, then treatment with riluzole and/or edaravone was, at the time of the screening visit, started and maintained at a stable regimen for at least 14 days for riluzole and/or for a full treatment cycle for edaravone; Capable of providing informed consent Capable and willing to follow trial procedures including visits to the trial clinic and visit requirements; Women of child bearing potential (e.g. not post-menopausal for at least one year or surgically sterile) must agree to use adequate birth control for the duration of the study and 3 months after last dose of study drug. Women must not be planning to become pregnant for the duration of the study and 3 months after last dose of study drug Men must agree to practice contraception for the duration of the study and 3 months after last dose of study drug. Men must not plan to father a child or provide for sperm donation for the duration of the study and 3 months after last dose of study drug Exclusion Criteria: Presence of tracheostomy or permanent assisted ventilation(PAV) Slow Vital Capacity (SVC) less than 55% History of known allergy to phenyl butyrate or bile salts Abnormal liver function defined as bilirubin levels and/or aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 5 times the upper limit of the normal (obtained within 12 weeks from first dose) Renal insufficiency as defined by eGFR <60 mL/min/1.73m^2 (obtained within 12 weeks from first dose) Pregnant women (confirmed by a pregnancy test within 7 days of first dose) or women currently breastfeeding Current severe biliary disease which may result in the Investigator medical judgement in biliary obstruction including for example active cholecystitis, primary biliary cirrhosis, sclerosing cholangitis, gallbladder cancer, gangrene of the gallbladder, abscess of the gallbladder History of Class III/IV heart failure (per New York Heart Association - NYHA) Participant under severe salt restriction where the added salt intake due to treatment would put the participant at risk, in the Investigator clinical judgment Presence of unstable psychiatric disease, cognitive impairment, dementia or substance abuse that would impair ability of the participant to provide informed consent, according to Investigator judgment Clinically significant unstable medical condition (other than ALS) (e.g., cardiovascular instability, systemic infection, untreated thyroid dysfunction, severe laboratory test anomaly or clinically significant electrocardiogram [ECG] changes) that would pose a risk to the participant if he/she were to participate in the trial, according to Investigator judgment Previous treatment for ALS with cellular therapies or gene therapies Currently enrolled in another trial involving use of an investigational therapy Previous treatment with PB or taurursodiol within 30 days from Screening Implantation of Diaphragm Pacing System (DPS) Currently or previously treated within the last 30 days or planned exposure to any prohibited medications listed in Section 6.8 of the protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo administered by mouth or via feeding tube for 48 weeks: once daily for first 3 weeks and then twice daily for remainder of study if participant tolerating | Other: Placebo<br>* Matching Placebo Comparator<br>|
| Experimental: AMX0035<br>Placebo administered by mouth or via feeding tube for 48 weeks: once daily for first 3 weeks and then twice daily for remainder of study if participant tolerating | Drug: AMX0035<br>* Proprietary formulation of taurursodiol and sodium phenylbutyrate<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Slope Change And Survival | Change in slope of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) over treatment duration. The ALSFRS-R consists of 12 items across 4 subdomains of function (bulbar, fine motor, gross motor, and breathing) with each item scored on a scale from 0 (total loss of function) to 4 (no loss of function). Total scores range from 0 to 48, with higher scores indicating better function. | 48 weeks | 
| Number of Participants With Adverse Events | Comparison Between Groups of Number of Participants With Adverse Events Until Planned Completion | 48 weeks | 
| Number of Participants in Each Group Able to Remain on Study Drug Until Planned Discontinuation | A comparison o0f the number of participants in each group able to remain on study drug until planned discontinuation between groups | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Decline in Slow Vital Capacity (SVC) | Respiratory muscle function will be assessed according to slow vital capacity (SVC). SVC is measured in an upright position for at least three trials per assessment. SVC volumes will be standardized to the percentage of predicted normal value based on age, sex, and height. | 48 weeks | 
| Participant Quality of Life (QOL) | QOL will be measured using the 40-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) patient-reported outcome (PRO) | 48 weeks | 
| Decline in King's and MiToS Stages | The decline in King's and MiToS (Milano-Torino staging) will be derived from ALSFRS-R data | 48 weeks | 
| Ventilation Free Survival | The composite outcome is defined as death, a death-equivalent event (tracheostomy), or hospitalization, whichever occurs first | 48 weeks | 
| Participant Health Status | Participant health status will be measured using the EQ-5D descriptive system and the EQ visual analogue scale [EQ VAS] patient reported outcomes questionnaire | 48 weeks | 
| Assess Long-Term Survival | Long-Term Survival will be obtained by monitoring of all-cause mortality | 3 years |