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

Primary Purpose

Amyotrophic Lateral Sclerosis, Motor Neuron Disease, Neuromuscular Diseases

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
AMX0035
Placebo
Sponsored by
Amylyx Pharmaceuticals Inc.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Amyotrophic Lateral Sclerosis focused on measuring Randomized, Double-blind, Placebo-controlled, Amyotrophic Lateral Sclerosis, Sodium Phenylbutyrate, Tauroursodeoxycholic Acid

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • Barrow Neurological Institute
  • UC Irvine Medical Center
  • Forbes Norris MDA/ALS Research Center - California Pacific Medical Center
  • University of Florida Medical Center
  • Carol and Frank Morsini Center for Advanced Health Care - University of South Florida
  • Emory University Hospital
  • University of Iowa Hospitals and Clinics
  • University of Kentucky Medical Center
  • Ochsner Neuroscience Institute
  • Johns Hopkins Hospital
  • Massachusetts General Hospital
  • University of Massachusetts Memorial Medical Center
  • University of Michigan Medical Center
  • Hennepin County Medical Center
  • Washington University Medical Center
  • Neurology Associates P.C.
  • Mount Sinai Beth Israel
  • Wake Forest Baptist Medical Center
  • The Ohio State University Wexner Medical Center
  • Oregon Health & Science University
  • The Penn Comprehensive ALS Center
  • Temple University Hospital
  • Texas Neurology, P.A.
  • University of Texas Health Science Center at San Antonio
  • ALS Center at the Swedish Neuroscience Institute

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Experimental

Arm Label

Placebo

AMX0035

Arm Description

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

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

Outcomes

Primary Outcome Measures

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.
Number of Participants With Adverse Events
Comparison Between Groups of Number of Participants With Adverse Events Until Planned Completion
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

Secondary Outcome Measures

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.
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
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.
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.

Full Information

First Posted
April 12, 2017
Last Updated
July 20, 2021
Sponsor
Amylyx Pharmaceuticals Inc.
Collaborators
ALS Finding a Cure, ALS Association, Northeast ALS Consortium, Neurological Clinical Research Institute at Massachusetts General Hospital, Leandro P. Rizzuto Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT03127514
Brief Title
AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS)
Acronym
CENTAUR
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
Study Type
Interventional

2. Study Status

Record Verification Date
July 2021
Overall Recruitment Status
Completed
Study Start Date
June 22, 2017 (Actual)
Primary Completion Date
September 25, 2019 (Actual)
Study Completion Date
November 24, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Amylyx Pharmaceuticals Inc.
Collaborators
ALS Finding a Cure, ALS Association, Northeast ALS Consortium, Neurological Clinical Research Institute at Massachusetts General Hospital, Leandro P. Rizzuto Foundation

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Amyotrophic Lateral Sclerosis, Motor Neuron Disease, Neuromuscular Diseases, Neurodegenerative Diseases, Spinal Cord Diseases, TDP-43 Proteinopathies, Nervous System Diseases, Central Nervous System Diseases
Keywords
Randomized, Double-blind, Placebo-controlled, Amyotrophic Lateral Sclerosis, Sodium Phenylbutyrate, Tauroursodeoxycholic Acid

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
137 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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
Arm Title
AMX0035
Arm Type
Experimental
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
AMX0035
Other Intervention Name(s)
Proprietary formulation of taurursodiol and sodium phenylbutyrate
Intervention Description
AMX0035
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Matching Placebo Comparator
Primary Outcome Measure Information:
Title
Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Slope Change
Description
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.
Time Frame
24 Weeks
Title
Number of Participants With Adverse Events
Description
Comparison Between Groups of Number of Participants With Adverse Events Until Planned Completion
Time Frame
24 Weeks
Title
Number of Participants in Each Group Able to Remain on Study Drug Until Planned Discontinuation
Description
A comparison of the number of participants in each group able to remain on study drug until planned discontinuation between groups
Time Frame
24 weeks
Secondary Outcome Measure Information:
Title
Accurate Testing of Limb Isometric Strength (ATLIS) Total Score Change
Description
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.
Time Frame
24 Weeks
Title
Change in Plasma Levels of Phosphorylated Axonal Neurofilament H Subunit (pNF-H)
Description
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
Time Frame
24 Weeks
Title
Rate of Decline in Slow Vital Capacity (SVC)
Description
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.
Time Frame
24 Weeks
Title
Death, Tracheostomy, and Hospitalization
Description
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.
Time Frame
24 Weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Patrick Yeramian, MD
Organizational Affiliation
Amylyx Pharmaceuticals Inc.
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Sabrina Paganoni, MD
Organizational Affiliation
Massachusetts General Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Barrow Neurological Institute
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85013
Country
United States
Facility Name
UC Irvine Medical Center
City
Orange
State/Province
California
ZIP/Postal Code
92868
Country
United States
Facility Name
Forbes Norris MDA/ALS Research Center - California Pacific Medical Center
City
San Francisco
State/Province
California
ZIP/Postal Code
94114
Country
United States
Facility Name
University of Florida Medical Center
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610
Country
United States
Facility Name
Carol and Frank Morsini Center for Advanced Health Care - University of South Florida
City
Tampa
State/Province
Florida
ZIP/Postal Code
33612
Country
United States
Facility Name
Emory University Hospital
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
University of Iowa Hospitals and Clinics
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
Facility Name
University of Kentucky Medical Center
City
Lexington
State/Province
Kentucky
ZIP/Postal Code
40536
Country
United States
Facility Name
Ochsner Neuroscience Institute
City
New Orleans
State/Province
Louisiana
ZIP/Postal Code
70121
Country
United States
Facility Name
Johns Hopkins Hospital
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
University of Massachusetts Memorial Medical Center
City
Worcester
State/Province
Massachusetts
ZIP/Postal Code
01655
Country
United States
Facility Name
University of Michigan Medical Center
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Hennepin County Medical Center
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55415
Country
United States
Facility Name
Washington University Medical Center
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Neurology Associates P.C.
City
Lincoln
State/Province
Nebraska
ZIP/Postal Code
68506
Country
United States
Facility Name
Mount Sinai Beth Israel
City
New York
State/Province
New York
ZIP/Postal Code
10003
Country
United States
Facility Name
Wake Forest Baptist Medical Center
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157
Country
United States
Facility Name
The Ohio State University Wexner Medical Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43221
Country
United States
Facility Name
Oregon Health & Science University
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239
Country
United States
Facility Name
The Penn Comprehensive ALS Center
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19107
Country
United States
Facility Name
Temple University Hospital
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19140
Country
United States
Facility Name
Texas Neurology, P.A.
City
Dallas
State/Province
Texas
ZIP/Postal Code
75214
Country
United States
Facility Name
University of Texas Health Science Center at San Antonio
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Facility Name
ALS Center at the Swedish Neuroscience Institute
City
Seattle
State/Province
Washington
ZIP/Postal Code
98122
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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
Citations:
PubMed Identifier
25664595
Citation
Elia AE, Lalli S, Monsurro MR, Sagnelli A, Taiello AC, Reggiori B, La Bella V, Tedeschi G, Albanese A. Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis. Eur J Neurol. 2016 Jan;23(1):45-52. doi: 10.1111/ene.12664. Epub 2015 Feb 9. Erratum In: Eur J Neurol. 2017 Apr;24(4):659.
Results Reference
background
PubMed Identifier
18688762
Citation
Cudkowicz ME, Andres PL, Macdonald SA, Bedlack RS, Choudry R, Brown RH Jr, Zhang H, Schoenfeld DA, Shefner J, Matson S, Matson WR, Ferrante RJ; Northeast ALS and National VA ALS Research Consortiums. Phase 2 study of sodium phenylbutyrate in ALS. Amyotroph Lateral Scler. 2009 Apr;10(2):99-106. doi: 10.1080/17482960802320487.
Results Reference
background
PubMed Identifier
35577511
Citation
Paganoni S, Hendrix S, Dickson SP, Knowlton N, Berry JD, Elliott MA, Maiser S, Karam C, Caress JB, Owegi MA, Quick A, Wymer J, Goutman SA, Heitzman D, Heiman-Patterson TD, Jackson C, Quinn C, Rothstein JD, Kasarskis EJ, Katz J, Jenkins L, Ladha SS, Miller TM, Scelsa SN, Vu TH, Fournier C, Johnson KM, Swenson A, Goyal N, Pattee GL, Babu S, Chase M, Dagostino D, Hall M, Kittle G, Eydinov M, Ostrow J, Pothier L, Randall R, Shefner JM, Sherman AV, Tustison E, Vigneswaran P, Yu H, Cohen J, Klee J, Tanzi R, Gilbert W, Yeramian P, Cudkowicz M. Effect of sodium phenylbutyrate/taurursodiol on tracheostomy/ventilation-free survival and hospitalisation in amyotrophic lateral sclerosis: long-term results from the CENTAUR trial. J Neurol Neurosurg Psychiatry. 2022 May 16;93(8):871-5. doi: 10.1136/jnnp-2022-329024. Online ahead of print.
Results Reference
derived
PubMed Identifier
32877582
Citation
Paganoni S, Macklin EA, Hendrix S, Berry JD, Elliott MA, Maiser S, Karam C, Caress JB, Owegi MA, Quick A, Wymer J, Goutman SA, Heitzman D, Heiman-Patterson T, Jackson CE, Quinn C, Rothstein JD, Kasarskis EJ, Katz J, Jenkins L, Ladha S, Miller TM, Scelsa SN, Vu TH, Fournier CN, Glass JD, Johnson KM, Swenson A, Goyal NA, Pattee GL, Andres PL, Babu S, Chase M, Dagostino D, Dickson SP, Ellison N, Hall M, Hendrix K, Kittle G, McGovern M, Ostrow J, Pothier L, Randall R, Shefner JM, Sherman AV, Tustison E, Vigneswaran P, Walker J, Yu H, Chan J, Wittes J, Cohen J, Klee J, Leslie K, Tanzi RE, Gilbert W, Yeramian PD, Schoenfeld D, Cudkowicz ME. Trial of Sodium Phenylbutyrate-Taurursodiol for Amyotrophic Lateral Sclerosis. N Engl J Med. 2020 Sep 3;383(10):919-930. doi: 10.1056/NEJMoa1916945.
Results Reference
derived
Links:
URL
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5024041/
Description
TUDCA in patients with ALS

Learn more about this trial

AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS)

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