AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS)

Study Overview
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Brief Summary
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The CENTAUR trial was a 2:1 (active:placebo) randomized, double-blind, placebo-controlled Phase II trial to evaluate the safety and efficacy of AMX0035 for the 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. The trial will also assess the effects of AMX0035 on muscle strength, vital capacity, and biomarkers of ALS including markers of neuronal death and neuroinflammation.

Official Title
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Evaluation of the Safety, Tolerability, Efficacy and Activity of AMX0035, a Fixed Combination of Phenylbutyrate (PB) and Tauroursodeoxycholic Acid (TUDCA), for the Treatment of ALS

Conditions
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Amyotrophic Lateral Sclerosis, Motor Neuron Disease, Neuromuscular Diseases, Neurodegenerative Diseases, Spinal Cord Diseases, TDP-43 Proteinopathies, Nervous System Diseases, Central Nervous System Diseases

Intervention / Treatment
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* Drug: AMX0035
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Male or female, aged 18-80 years of age Sporadic or familial ALS diagnosed as definite as defined by the World Federation of Neurology revised El Escorial criteria Less than or equal to 18 months since ALS symptom onset Capable of providing informed consent and following trial procedures Slow Vital Capacity (SVC) >60% of predicted value for gender, height, and age at the Screening Visit Subjects must either not take riluzole or be on a stable dose of riluzole for at least 30 days prior to the Screening Visit. Riluzole-naïve subjects are permitted in the study. 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 Key Exclusion Criteria: Presence of tracheostomy Exposure to PB, Taurursodiol or UDCA within 3 months prior to the Screening Visit or planning to use these medications during the course of the study History of known allergy to PB or bile salts Abnormal liver function defined as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 times the upper limit of the normal Renal insufficiency as defined by a serum creatinine > 1.5 times the upper limit of normal Poorly controlled arterial hypertension (systolic blood pressure (SBP)>160mmHg or diastolic blood pressure (DBP)>100mmHg) at the Screening Visit Pregnant women or women currently breastfeeding History of cholecystectomy Biliary disease which impedes biliary flow including active cholecystitis, primary biliary cirrhosis, sclerosing cholangitis, gallbladder cancer, gallbladder polyps, gangrene of the gallbladder, abscess of the gallbladder. History of Class III/IV heart failure (per New York Heart Association - NYHA) Severe pancreatic or intestinal disorders that may alter the enterohepatic circulation and absorption of TUDCA including biliary infections, pancreatitis and ileal resection The presence of unstable psychiatric disease, cognitive impairment, dementia or substance abuse that would impair ability of the subject to provide informed consent, according to Site Investigator judgment Clinically significant unstable medical condition (other than ALS) that would pose a risk to the subject if they were to participate in the study Active participation in an ALS clinical trial evaluating a small molecule within 30 days of the Screening Visit Exposure at any time to any biologic under investigation for the treatment of subjects with ALS (off-label use or investigational) including cell therapies, gene therapies, and monoclonal antibodies. Implantation of Diaphragm Pacing System (DPS)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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 24 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>AMX0035 administered by mouth or via feeding tube for 24 weeks: once daily for first 3 weeks and then twice daily for remainder of study if participant tolerating | Drug: AMX0035<br>* AMX0035<br>* Other names: Proprietary formulation of taurursodiol and sodium phenylbutyrate;|

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 | 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. | 24 Weeks | 
| Number of Participants With Adverse Events | Comparison Between Groups of Number of Participants With Adverse Events Until Planned Completion | 24 Weeks | 
| Number of Participants in Each Group Able to Remain on Study Drug Until Planned Discontinuation | A comparison of the number of participants in each group able to remain on study drug until planned discontinuation between groups | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Accurate Testing of Limb Isometric Strength (ATLIS) Total Score Change | The ATLIS device assess the isometric muscle strength of six upper-limb and six lower-limb muscle groups. At least two trials are performed for each muscle group to assess change in rate of decline of isometric muscle strength over treatment duration. Values are standardized to the percentage of predicted normal strength based on sex, age, weight, and height. Results are presented as percent of predicted normal. | 24 Weeks | 
| Change in Plasma Levels of Phosphorylated Axonal Neurofilament H Subunit (pNF-H) | Neuronal degeneration releases phosphorylated axonal neurofilament H subunit (pNF-H) into the cerebrospinal fluid and subsequently the blood and is thought to be a potential biomarker of motor neuron degeneration; elevated plasma levels of pNF-H are presumed to correlate with neuronal injury. Change in levels of plasma pNF-H were measured from baseline to week 24 | 24 Weeks | 
| Rate of Decline in Slow Vital Capacity (SVC) | Respiratory muscle function was assessed according to slow vital capacity (SVC). SVC was measured in an upright position for at least three trials per assessment. SVC volumes were standardized to the percentage of predicted normal value based on age, sex, and height. | 24 Weeks | 
| Death, Tracheostomy, and Hospitalization | The composite outcome was defined as death, a death-equivalent event (which consisted of only tracheostomy in one participant in this trial), or hospitalization, whichever occurred first; there were no instances of permanent ventilation delivered by noninvasive means in the study. | 24 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Randomized, Double-blind, Placebo-controlled, Amyotrophic Lateral Sclerosis, Sodium Phenylbutyrate, Tauroursodeoxycholic Acid