Amyotrophic Lateral Sclerosis, Motor Neuron Disease, Neuromuscular Diseases, Neurodegenerative Diseases, Spinal Cord Diseases, TDP-43 Proteinopathies, Nervous System Diseases, Central Nervous System Diseases
Conditions
Keywords
Randomized, Double-blind, Placebo-controlled, Amyotrophic Lateral Sclerosis, Sodium Phenylbutyrate, Tauroursodeoxycholic Acid
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.
Interventions
DRUGAMX0035
AMX0035
OTHERPlacebo
Matching Placebo Comparator
Sponsors
ALS Finding a Cure
ALS Association
Northeast ALS Consortium
Neurological Clinical Research Institute at Massachusetts General Hospital
Leandro P. Rizzuto Foundation
Amylyx Pharmaceuticals Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion 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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Slope Change | 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. |
| Number of Participants With Adverse Events | 24 Weeks | 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 | 24 weeks | A comparison of the number of participants in each group able to remain on study drug until planned discontinuation between groups |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Accurate Testing of Limb Isometric Strength (ATLIS) Total Score Change | 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. |
| Death, Tracheostomy, and Hospitalization | 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. |
| Change in Plasma Levels of Phosphorylated Axonal Neurofilament H Subunit (pNF-H) | 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 |
| Rate of Decline in Slow Vital Capacity (SVC) | 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. |
Countries
United States
Participant flow
Recruitment details
Adults with sporadic or familial ALS were enrolled at 25 centers of the Northeast Amyotrophic Lateral Sclerosis Consortium (NEALS) in the United States from June 2017 through September 2019.
Participants by arm
| Arm | Count |
|---|---|
| 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
Placebo: Matching Placebo Comparator | 48 |
| 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
AMX0035: AMX0035 | 87 |
| Total | 135 |
Baseline characteristics
| Characteristic | Placebo | AMX0035 | Total |
|---|---|---|---|
| Age, Continuous | 57.3 years STANDARD_DEVIATION 7.6 | 57.6 years STANDARD_DEVIATION 10.4 | 57.5 years STANDARD_DEVIATION 9.5 |
| Bulbar Onset | 10 Participants | 26 Participants | 36 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 46 Participants | 82 Participants | 128 Participants |
| Sex: Female, Male Female | 16 Participants | 26 Participants | 42 Participants |
| Sex: Female, Male Male | 32 Participants | 61 Participants | 93 Participants |
| Time Since ALS Symptom Onset | 13.6 months STANDARD_DEVIATION 3.6 | 13.5 months STANDARD_DEVIATION 3.8 | 13.5 months STANDARD_DEVIATION 3.8 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 48 | 5 / 89 |
| other Total, other adverse events | 46 / 48 | 86 / 89 |
| serious Total, serious adverse events | 9 / 48 | 11 / 89 |
Outcome results
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.
Time frame: 24 Weeks
Population: mITT population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Slope Change | -1.66 Change in ALSFRS-R Total Score Per Month | Standard Error 0.16 |
| AMX0035 | Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Slope Change | -1.24 Change in ALSFRS-R Total Score Per Month | Standard Error 0.12 |
p-value: 0.03Mixed Models Analysis
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
Time frame: 24 weeks
Population: mITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants in Each Group Able to Remain on Study Drug Until Planned Discontinuation | 38 Participants |
| AMX0035 | Number of Participants in Each Group Able to Remain on Study Drug Until Planned Discontinuation | 61 Participants |
Primary
Number of Participants With Adverse Events
Comparison Between Groups of Number of Participants With Adverse Events Until Planned Completion
Time frame: 24 Weeks
Population: ITT population
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Adverse Events | 46 Participants |
| AMX0035 | Number of Participants With Adverse Events | 86 Participants |
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.
Time frame: 24 Weeks
Population: mITT population (1 participant in the placebo group and 3 in the AMX0035 group did not have complete muscle strength data and are not included in this analysis population)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Accurate Testing of Limb Isometric Strength (ATLIS) Total Score Change | -3.54 % of Predicted Normal Change Per Month | Standard Error 0.26 |
| AMX0035 | Accurate Testing of Limb Isometric Strength (ATLIS) Total Score Change | -3.03 % of Predicted Normal Change Per Month | Standard Error 0.19 |
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
Time frame: 24 Weeks
Population: mITT population (1 participant in the placebo group and 3 in the AMX0035 group did not have sample analyzed and are not included in this analysis population)
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Plasma Levels of Phosphorylated Axonal Neurofilament H Subunit (pNF-H) | -2.34 pg/ml Per Month | Standard Error 4.19 |
| AMX0035 | Change in Plasma Levels of Phosphorylated Axonal Neurofilament H Subunit (pNF-H) | 3.58 pg/ml Per Month | Standard Error 3.19 |
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.
Time frame: 24 Weeks
Population: mITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Death, Tracheostomy, and Hospitalization | 17 events |
| AMX0035 | Death, Tracheostomy, and Hospitalization | 18 events |
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.
Time frame: 24 Weeks
Population: mITT population
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Rate of Decline in Slow Vital Capacity (SVC) | -4.03 % of Predicted Normal Change Per Month | Standard Error 0.42 |
| AMX0035 | Rate of Decline in Slow Vital Capacity (SVC) | -3.10 % of Predicted Normal Change Per Month | Standard Error 0.31 |