AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS)

Amyotrophic Lateral Sclerosis Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03127514
• Other study ID #: AMX-3500
• Status: Completed
• Phase: Phase 2
• Start date: June 22, 2017
• Est. completion date: November 24, 2019

Study information

• Verified date: May 2024
• Source: Amylyx Pharmaceuticals Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 137
• Est. completion date: November 24, 2019
• Est. primary completion date: September 25, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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)

Related Conditions & MeSH terms

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

Intervention

Drug:
• AMX0035
AMX0035

Other:
• Placebo
Matching Placebo Comparator

Locations

Country	Name	City	State
United States	University of Michigan Medical Center	Ann Arbor	Michigan
United States	Emory University Hospital	Atlanta	Georgia
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	The Ohio State University Wexner Medical Center	Columbus	Ohio
United States	Texas Neurology, P.A.	Dallas	Texas
United States	University of Florida Medical Center	Gainesville	Florida
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	University of Kentucky Medical Center	Lexington	Kentucky
United States	Neurology Associates P.C.	Lincoln	Nebraska
United States	Hennepin County Medical Center	Minneapolis	Minnesota
United States	Ochsner Neuroscience Institute	New Orleans	Louisiana
United States	Mount Sinai Beth Israel	New York	New York
United States	UC Irvine Medical Center	Orange	California
United States	Temple University Hospital	Philadelphia	Pennsylvania
United States	The Penn Comprehensive ALS Center	Philadelphia	Pennsylvania
United States	Barrow Neurological Institute	Phoenix	Arizona
United States	Oregon Health & Science University	Portland	Oregon
United States	Washington University Medical Center	Saint Louis	Missouri
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	Forbes Norris MDA/ALS Research Center - California Pacific Medical Center	San Francisco	California
United States	ALS Center at the Swedish Neuroscience Institute	Seattle	Washington
United States	Carol and Frank Morsini Center for Advanced Health Care - University of South Florida	Tampa	Florida
United States	Wake Forest Baptist Medical Center	Winston-Salem	North Carolina
United States	University of Massachusetts Memorial Medical Center	Worcester	Massachusetts

Sponsors (6)

Lead Sponsor	Collaborator
Amylyx Pharmaceuticals Inc.	ALS Association, ALS Finding a Cure, Leandro P. Rizzuto Foundation, Neurological Clinical Research Institute at Massachusetts General Hospital, Northeast ALS Consortium

Country where clinical trial is conducted

United States, 

References & Publications (2)

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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Number of Participants With Adverse Events	Comparison Between Groups of Number of Participants With Adverse Events Until Planned Completion	24 Weeks
Primary	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	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   TUDCA in patients with ALS