Amyotrophic Lateral Sclerosis, ALS
Conditions
Brief summary
This extension study, in which all participants received active treatment (AMX0035), was designed to assess the longer-term safety and therapeutic potential of AMX0035 for participants who have completed the Main Study (AMX3500, also known as CENTAUR).
Detailed description
The Centaur Open Label Extension Study (CENTAUR-OLE) is an extension study for patients with ALS who participated in the CENTAUR study (Study AMX3500). During the OLE, all participants received active treatment (AMX0035), and the investigators, evaluators, and participants remained blinded to the randomized treatment assigned at the beginning of the double-blind main study. The study was designed to assess the longer term safety and therapeutic potential of AMX0035.
Interventions
DRUGAMX0035
Combination therapy of PB and TURSO
Sponsors
Massachusetts General Hospital
Amylyx Pharmaceuticals Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is an open-label extension study to CENTAUR (AMX3500)
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
1. Completion of all visits in the randomized, double blind AMX3500 study. Participants who received tracheostomy or permanent assisted ventilation (PAV) during the course of the main study could enroll in the OLE if they completed all visits in the main study. 2. Must enroll in the OLE within 28 days of the Week 24 visit of the main study. 3. Signed informed consent to enter the OLE phase.
Exclusion criteria
1. Discontinued study drug prematurely in the double-blind phase of the study for reasons other than tracheostomy or PAV. 2. Exposure to or anticipated requirement for any disallowed medication listed in the protocol. 3. Any ongoing adverse events that in the opinion of the Site Investigator are clear contraindications to the study drug. 4. Unstable cardiac or other life-threatening disease emergent during the randomized, double blind study 5. Any major medical condition that in the opinion of the Site Investigator would interfere with the study and place the subject at increased risk.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | From the Baseline Visit in the OLE study through Week 132 or the Early Discontinuation (Final Safety) Visit for each participant (for up to approximately 132 weeks) | Number of participants with TEAEs from baseline in the OLE study through the last participant's last visit in the OLE |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Survival - Time to Death | From date of first dose in the Main Study (each participant's Baseline Visit) through up to approximately 42 months (approximately 182 weeks) | Median survival in months |
| Composite of Time to Hospitalization, Death or Death Equivalent | From date of first dose in the Main Study (each participant's Baseline Visit) through up to approximately 42 months (approximately 182 weeks) | The composite endpoint of time to hospitalization, death or death equivalent was defined as hospitalization, death, tracheostomy or PAV. PAV is defined as more than 22 hours daily of non-invasive mechanical ventilation for more than 1 week (7 days). |
| Accurate Testing of Limb Isometric Strength (ATLIS) Change in Slope - Upper Extremities | From baseline in the Main Study through Week 24 of the OLE (48 weeks overall) | Comparison of the difference in change in slope of Accurate Testing of Limb Isometric Strength (ATLIS) upper extremity score from the Main Study baseline through Week 48 of the open-label extension (OLE) between the 2 treatment groups: those randomized to AMX0035 in the Main Study and those randomized to Placebo in the main study (all participants in the OLE received AMX0035). The ATLIS device measures isometric strength in 6 upper extremity muscle groups. Raw values were standardized to percent predicted normal values for strength based on sex, age, weight, and height. |
| Amyotrophic Lateral Sclerosis Rating Scale Revised Total Score (ALSFRS-R) Change in Slope | From baseline in the Main Study through Week 24 of the OLE (48 weeks overall) | Comparison of the difference in change in slope of Amyotrophic Lateral Sclerosis Rating Scale Revised (ALSFRS-R) total score from the Main Study baseline through Week 48 of the open-label extension (OLE) between the 2 treatment groups: those randomized to AMX0035 in the Main Study and those randomized to Placebo in the main study (all participants in the OLE received AMX0035). The slope is measured as a change in score divided by a change in time. 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. |
| Slow Vital Capacity Change in Slope | From baseline in the Main Study through Week 24 of the OLE (48 weeks overall) | Comparison of the difference in change in slope of Slow Vital Capacity (SVC) from the Main Study baseline through Week 48 of the open-label extension (OLE) between the 2 treatment groups: those randomized to AMX0035 in the Main Study and those randomized to Placebo in the main study (all participants in the OLE received AMX0035). SVC volumes were standardized to predicted percent normalized values for respiratory muscle function based on age, sex, and height. |
| Accurate Testing of Limb Isometric Strength (ATLIS) Total Score Change in Slope | From Baseline in the Main Study through Week 24 in the OLE (48 weeks overall) | Comparison of the difference in change in slope of Accurate Testing of Limb Isometric Strength (ATLIS) total score from the Main Study baseline through Week 48 of the open-label extension (OLE) between the 2 treatment groups: those randomized to AMX0035 in the Main Study and those randomized to Placebo in the main study (all participants in the OLE received AMX0035). The ATLIS device measures isometric strength in 6 upper and 6 lower extremity muscle groups. Raw values were standardized to percent predicted normal values for strength based on sex, age, weight, and height. |
| Accurate Testing of Limb Isometric Strength (ATLIS) Change in Slope - Lower Extremities | From baseline in the Main Study through Week 24 of the OLE (48 weeks overall) | Comparison of the difference in change in slope of Accurate Testing of Limb Isometric Strength (ATLIS) lower extremity score from the Main Study baseline through Week 48 of the open-label extension (OLE) between the 2 treatment groups: those randomized to AMX0035 in the Main Study and those randomized to Placebo in the main study (all participants in the OLE received AMX0035). The ATLIS device measures isometric strength in 6 lower extremity muscle groups. Raw values were standardized to percent predicted normal values for strength based on sex, age, weight, and height. |
Countries
United States
Participant flow
Recruitment details
Participants who completed the 24-week double-blind main study (Study AMX3500) on treatment were eligible to enter into the OLE.
Pre-assignment details
To maintain the study blind, participants who entered the OLE initiated dosing in the OLE with 2 sachets of AMX0035 daily (ie, participants who switched from placebo to AMX0035 were not titrated using a starting dose of 1 sachet daily for the first 3 weeks, which was the starting dosing in the Main Study AMX3500).
Participants by arm
| Arm | Count |
|---|---|
| Placebo in Main Study-AMX0035 in OLE AMX0035 twice daily--a combination of Sodium Phenylbutyrate (PB) and Taurursodiol (TURSO) | 34 |
| AMX0035 in Main Study-AMX0035 in OLE AMX0035 twice daily--a combination of Sodium Phenylbutyrate (PB) and Taurursodiol (TURSO) | 56 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 19 |
| Overall Study | Lost to Follow-up | 3 |
| Overall Study | Physician Decision | 4 |
| Overall Study | Study Sponsor | 11 |
| Overall Study | Withdrawal by Subject | 51 |
Baseline characteristics
| Characteristic | Placebo in Main Study-AMX0035 in OLE | Total | AMX0035 in Main Study-AMX0035 in OLE |
|---|---|---|---|
| Accurate Test of Limb Isometric Strength (ATLIS) lower extremity score | 51.89 percent of predicted normal values STANDARD_DEVIATION 25.22 | 50.72 percent of predicted normal values STANDARD_DEVIATION 23.45 | 49.98 percent of predicted normal values STANDARD_DEVIATION 22.52 |
| Accurate Test of Limb Isometric Strength (ATLIS) total score | 43.21 percent of predicted normal values STANDARD_DEVIATION 23.2 | 41.12 percent of predicted normal values STANDARD_DEVIATION 23.4 | 39.82 percent of predicted normal values STANDARD_DEVIATION 23.69 |
| Accurate Test of Limb Isometric Strength (ATLIS) upper extremity score | 43.29 percent of predicted normal values STANDARD_DEVIATION 23.24 | 41.21 percent of predicted normal values STANDARD_DEVIATION 23.45 | 39.91 percent of predicted normal values STANDARD_DEVIATION 23.74 |
| Age, Continuous | 58.5 years STANDARD_DEVIATION 7.41 | 58.0 years STANDARD_DEVIATION 9.22 | 57.8 years STANDARD_DEVIATION 10.22 |
| ALS Functional Rating Scale - Revised (ALSFRS-R) total score | 29.8 scores on a scale STANDARD_DEVIATION 9.36 | 30.3 scores on a scale STANDARD_DEVIATION 8.74 | 30.6 scores on a scale STANDARD_DEVIATION 8.42 |
| Body Mass Index | 27.1 kg/m^2 STANDARD_DEVIATION 6.5 | 26.9 kg/m^2 STANDARD_DEVIATION 5.4 | 26.8 kg/m^2 STANDARD_DEVIATION 4.67 |
| Del-FS: Rate of disease progression prior to entering the study | 1.03 ScaleScore/Months post-symptom onset STANDARD_DEVIATION 0.73 | 0.96 ScaleScore/Months post-symptom onset STANDARD_DEVIATION 0.57 | 0.92 ScaleScore/Months post-symptom onset STANDARD_DEVIATION 0.46 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 5 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants | 85 Participants | 52 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 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 | 33 Participants | 85 Participants | 52 Participants |
| Sex: Female, Male Female | 10 Participants | 23 Participants | 13 Participants |
| Sex: Female, Male Male | 24 Participants | 67 Participants | 43 Participants |
| Slow vital capacity (SVC) - % Predicted | 72.7 percent of predicted STANDARD_DEVIATION 21.22 | 71.7 percent of predicted STANDARD_DEVIATION 22.34 | 71.2 percent of predicted STANDARD_DEVIATION 23.12 |
| Time since ALS diagnosis | 11.9 months STANDARD_DEVIATION 3.54 | 11.8 months STANDARD_DEVIATION 3.69 | 11.7 months STANDARD_DEVIATION 3.8 |
| Time since onset of ALS symptoms | 19.2 months STANDARD_DEVIATION 3.72 | 19.3 months STANDARD_DEVIATION 4.07 | 19.4 months STANDARD_DEVIATION 4.29 |
| Use of either edaravone or riluzole at or prior to study entry | 28 Participants | 73 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 19 / 90 |
| other Total, other adverse events | 81 / 90 |
| serious Total, serious adverse events | 31 / 90 |
Outcome results
Primary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Number of participants with TEAEs from baseline in the OLE study through the last participant's last visit in the OLE
Time frame: From the Baseline Visit in the OLE study through Week 132 or the Early Discontinuation (Final Safety) Visit for each participant (for up to approximately 132 weeks)
Population: Safety Population, which included all participants who received at least 1 dose of study medication in the OLE.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AMX0035 in OLE | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 81 Participants |
Secondary
Accurate Testing of Limb Isometric Strength (ATLIS) Change in Slope - Lower Extremities
Comparison of the difference in change in slope of Accurate Testing of Limb Isometric Strength (ATLIS) lower extremity score from the Main Study baseline through Week 48 of the open-label extension (OLE) between the 2 treatment groups: those randomized to AMX0035 in the Main Study and those randomized to Placebo in the main study (all participants in the OLE received AMX0035). The ATLIS device measures isometric strength in 6 lower extremity muscle groups. Raw values were standardized to percent predicted normal values for strength based on sex, age, weight, and height.
Time frame: From baseline in the Main Study through Week 24 of the OLE (48 weeks overall)
Population: mITT Population. Participants from the Main Study who did not enter the OLE were included in this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AMX0035 in OLE | Accurate Testing of Limb Isometric Strength (ATLIS) Change in Slope - Lower Extremities | 20.48 % of Predicted Normal Change per Month | Standard Error 3.653 |
| Randomized to AMX0035 in Main Study and Did or Did Not Participate in OLE | Accurate Testing of Limb Isometric Strength (ATLIS) Change in Slope - Lower Extremities | 25.24 % of Predicted Normal Change per Month | Standard Error 2.893 |
p-value: 0.226195% CI: [-2.95, 12.47]Mixed Models Analysis
Secondary
Accurate Testing of Limb Isometric Strength (ATLIS) Change in Slope - Upper Extremities
Comparison of the difference in change in slope of Accurate Testing of Limb Isometric Strength (ATLIS) upper extremity score from the Main Study baseline through Week 48 of the open-label extension (OLE) between the 2 treatment groups: those randomized to AMX0035 in the Main Study and those randomized to Placebo in the main study (all participants in the OLE received AMX0035). The ATLIS device measures isometric strength in 6 upper extremity muscle groups. Raw values were standardized to percent predicted normal values for strength based on sex, age, weight, and height.
Time frame: From baseline in the Main Study through Week 24 of the OLE (48 weeks overall)
Population: mITT Population. Participants from the Main Study who did not enter the OLE were included in this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AMX0035 in OLE | Accurate Testing of Limb Isometric Strength (ATLIS) Change in Slope - Upper Extremities | 12.06 % of Predicted Normal Change per Month | Standard Error 3.283 |
| Randomized to AMX0035 in Main Study and Did or Did Not Participate in OLE | Accurate Testing of Limb Isometric Strength (ATLIS) Change in Slope - Upper Extremities | 19.83 % of Predicted Normal Change per Month | Standard Error 2.591 |
p-value: 0.029195% CI: [0.8, 14.75]Mixed Models Analysis
Secondary
Accurate Testing of Limb Isometric Strength (ATLIS) Total Score Change in Slope
Comparison of the difference in change in slope of Accurate Testing of Limb Isometric Strength (ATLIS) total score from the Main Study baseline through Week 48 of the open-label extension (OLE) between the 2 treatment groups: those randomized to AMX0035 in the Main Study and those randomized to Placebo in the main study (all participants in the OLE received AMX0035). The ATLIS device measures isometric strength in 6 upper and 6 lower extremity muscle groups. Raw values were standardized to percent predicted normal values for strength based on sex, age, weight, and height.
Time frame: From Baseline in the Main Study through Week 24 in the OLE (48 weeks overall)
Population: mITT Population. Participants from the Main Study who did not enter the OLE were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AMX0035 in OLE | Accurate Testing of Limb Isometric Strength (ATLIS) Total Score Change in Slope | 16.65 % of Predicted normal change per month | Standard Error 2.973 |
| Randomized to AMX0035 in Main Study and Did or Did Not Participate in OLE | Accurate Testing of Limb Isometric Strength (ATLIS) Total Score Change in Slope | 22.84 % of Predicted normal change per month | Standard Error 2.371 |
p-value: 0.0503Mixed Models Analysis
Secondary
Amyotrophic Lateral Sclerosis Rating Scale Revised Total Score (ALSFRS-R) Change in Slope
Comparison of the difference in change in slope of Amyotrophic Lateral Sclerosis Rating Scale Revised (ALSFRS-R) total score from the Main Study baseline through Week 48 of the open-label extension (OLE) between the 2 treatment groups: those randomized to AMX0035 in the Main Study and those randomized to Placebo in the main study (all participants in the OLE received AMX0035). The slope is measured as a change in score divided by a change in time. 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: From baseline in the Main Study through Week 24 of the OLE (48 weeks overall)
Population: mITT Population. Participants from the Main Study who did not enter the OLE were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AMX0035 in OLE | Amyotrophic Lateral Sclerosis Rating Scale Revised Total Score (ALSFRS-R) Change in Slope | 17.38 Change in ALSFRS-R Total Score per Month | Standard Error 1.545 |
| Randomized to AMX0035 in Main Study and Did or Did Not Participate in OLE | Amyotrophic Lateral Sclerosis Rating Scale Revised Total Score (ALSFRS-R) Change in Slope | 21.61 Change in ALSFRS-R Total Score per Month | Standard Error 1.178 |
Comparison: Participants who did not enter the open-label extension (OLE) were included in this analysis.p-value: 0.023995% CI: [0.56, 7.9]Mixed Models Analysis
Secondary
Composite of Time to Hospitalization, Death or Death Equivalent
The composite endpoint of time to hospitalization, death or death equivalent was defined as hospitalization, death, tracheostomy or PAV. PAV is defined as more than 22 hours daily of non-invasive mechanical ventilation for more than 1 week (7 days).
Time frame: From date of first dose in the Main Study (each participant's Baseline Visit) through up to approximately 42 months (approximately 182 weeks)
Population: ITT population. Participants from the Main Study who did not enter the OLE were included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AMX0035 in OLE | Composite of Time to Hospitalization, Death or Death Equivalent | 10.0 Months |
| Randomized to AMX0035 in Main Study and Did or Did Not Participate in OLE | Composite of Time to Hospitalization, Death or Death Equivalent | 14.8 Months |
p-value: 0.030895% CI: [0.403, 0.957]Hazard Ratio
Secondary
Slow Vital Capacity Change in Slope
Comparison of the difference in change in slope of Slow Vital Capacity (SVC) from the Main Study baseline through Week 48 of the open-label extension (OLE) between the 2 treatment groups: those randomized to AMX0035 in the Main Study and those randomized to Placebo in the main study (all participants in the OLE received AMX0035). SVC volumes were standardized to predicted percent normalized values for respiratory muscle function based on age, sex, and height.
Time frame: From baseline in the Main Study through Week 24 of the OLE (48 weeks overall)
Population: mITT Population. Participants from the Main Study who did not enroll in the OLE were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| AMX0035 in OLE | Slow Vital Capacity Change in Slope | 37.85 % of Predicted Normal Change per Month | Standard Error 4.427 |
| Randomized to AMX0035 in Main Study and Did or Did Not Participate in OLE | Slow Vital Capacity Change in Slope | 48.52 % of Predicted Normal Change per Month | Standard Error 3.356 |
p-value: 0.037295% CI: [0.63, 20.69]Mixed Models Analysis
Secondary
Survival - Time to Death
Median survival in months
Time frame: From date of first dose in the Main Study (each participant's Baseline Visit) through up to approximately 42 months (approximately 182 weeks)
Population: ITT Population. Participants from the Main Study who did not enter the OLE were included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| AMX0035 in OLE | Survival - Time to Death | 18.7 Months |
| Randomized to AMX0035 in Main Study and Did or Did Not Participate in OLE | Survival - Time to Death | 23.5 Months |
Comparison: Cox Proportional Hazards analysisp-value: 0.047595% CI: [0.416, 0.995]Hazard ratio