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AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS) (CENTAUR)

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ClinicalTrials.gov Identifier: NCT03127514
Recruitment Status : Completed
First Posted : April 25, 2017
Results First Posted : August 11, 2021
Last Update Posted : August 11, 2021
Sponsor:
Collaborators:
ALS Finding a Cure
ALS Association
Northeast ALS Consortium
Neurological Clinical Research Institute at Massachusetts General Hospital
Leandro P. Rizzuto Foundation
Information provided by (Responsible Party):
Amylyx Pharmaceuticals Inc.

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Amyotrophic Lateral Sclerosis Motor Neuron Disease Neuromuscular Diseases Neurodegenerative Diseases Spinal Cord Diseases TDP-43 Proteinopathies Nervous System Diseases Central Nervous System Diseases Drug: AMX0035 Other: Placebo Phase 2

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 137 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : June 22, 2017
Actual Primary Completion Date : September 25, 2019
Actual Study Completion Date : November 24, 2019


Arm Intervention/treatment
Placebo Comparator: Placebo
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
Matching Placebo Comparator

Experimental: AMX0035
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
AMX0035
Other Name: Proprietary formulation of taurursodiol and sodium phenylbutyrate




Primary Outcome Measures :
  1. Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Slope Change [ Time Frame: 24 Weeks ]
    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.

  2. Number of Participants With Adverse Events [ Time Frame: 24 Weeks ]
    Comparison Between Groups of Number of Participants With Adverse Events Until Planned Completion

  3. Number of Participants in Each Group Able to Remain on Study Drug Until Planned Discontinuation [ Time Frame: 24 weeks ]
    A comparison of the number of participants in each group able to remain on study drug until planned discontinuation between groups


Secondary Outcome Measures :
  1. Accurate Testing of Limb Isometric Strength (ATLIS) Total Score Change [ Time Frame: 24 Weeks ]
    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.

  2. Change in Plasma Levels of Phosphorylated Axonal Neurofilament H Subunit (pNF-H) [ Time Frame: 24 Weeks ]
    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

  3. Rate of Decline in Slow Vital Capacity (SVC) [ Time Frame: 24 Weeks ]
    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.

  4. Death, Tracheostomy, and Hospitalization [ Time Frame: 24 Weeks ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  1. Male or female, aged 18-80 years of age
  2. Sporadic or familial ALS diagnosed as definite as defined by the World Federation of Neurology revised El Escorial criteria
  3. Less than or equal to 18 months since ALS symptom onset
  4. Capable of providing informed consent and following trial procedures
  5. Slow Vital Capacity (SVC) >60% of predicted value for gender, height, and age at the Screening Visit
  6. 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.
  7. 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
  8. 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:

  1. Presence of tracheostomy
  2. 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
  3. History of known allergy to PB or bile salts
  4. Abnormal liver function defined as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 times the upper limit of the normal
  5. Renal insufficiency as defined by a serum creatinine > 1.5 times the upper limit of normal
  6. Poorly controlled arterial hypertension (systolic blood pressure (SBP)>160mmHg or diastolic blood pressure (DBP)>100mmHg) at the Screening Visit
  7. Pregnant women or women currently breastfeeding
  8. History of cholecystectomy
  9. 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.
  10. History of Class III/IV heart failure (per New York Heart Association - NYHA)
  11. Severe pancreatic or intestinal disorders that may alter the enterohepatic circulation and absorption of TUDCA including biliary infections, pancreatitis and ileal resection
  12. 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
  13. Clinically significant unstable medical condition (other than ALS) that would pose a risk to the subject if they were to participate in the study
  14. Active participation in an ALS clinical trial evaluating a small molecule within 30 days of the Screening Visit
  15. 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.
  16. Implantation of Diaphragm Pacing System (DPS)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03127514


Locations
Show Show 25 study locations
Sponsors and Collaborators
Amylyx Pharmaceuticals Inc.
ALS Finding a Cure
ALS Association
Northeast ALS Consortium
Neurological Clinical Research Institute at Massachusetts General Hospital
Leandro P. Rizzuto Foundation
Investigators
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Study Director: Patrick Yeramian, MD Amylyx Pharmaceuticals Inc.
Principal Investigator: Sabrina Paganoni, MD Massachusetts General Hospital
  Study Documents (Full-Text)

Documents provided by Amylyx Pharmaceuticals Inc.:
Study Protocol  [PDF] January 11, 2019
Statistical Analysis Plan  [PDF] October 9, 2019

Additional Information:
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Amylyx Pharmaceuticals Inc.
ClinicalTrials.gov Identifier: NCT03127514    
Other Study ID Numbers: AMX-3500
First Posted: April 25, 2017    Key Record Dates
Results First Posted: August 11, 2021
Last Update Posted: August 11, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Amylyx Pharmaceuticals, Inc., is in the process of developing a formal data sharing plan; requests for future data sharing can be sent to medinfo@amylyx.com

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Amylyx Pharmaceuticals Inc.:
Randomized
Double-blind
Placebo-controlled
Amyotrophic Lateral Sclerosis
Sodium Phenylbutyrate
Tauroursodeoxycholic Acid
Additional relevant MeSH terms:
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Amyotrophic Lateral Sclerosis
Motor Neuron Disease
Nervous System Diseases
Neuromuscular Diseases
Neurodegenerative Diseases
Central Nervous System Diseases
Spinal Cord Diseases
TDP-43 Proteinopathies
Sclerosis
Pathologic Processes
Proteostasis Deficiencies
Metabolic Diseases
4-phenylbutyric acid
Antineoplastic Agents