ALS, Amyotrophic Lateral Sclerosis
Conditions
Keywords
Ravulizumab, ALXN1210, Ultomiris, Motor Neuron Disease, Amyotrophic Lateral Sclerosis, ALS
Brief summary
The purpose of the study is to assess the efficacy and safety of ravulizumab for the treatment of adult participants with ALS.
Interventions
DRUGPlacebo
Single loading dose via intravenous infusion, followed by regular maintenance dosing, based on weight.
BIOLOGICALRavulizumab
Single loading dose via intravenous infusion, followed by regular maintenance dosing, based on weight.
Sponsors
Alexion 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 No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: 1. A diagnosis of sporadic or familial ALS, defined by the El Escorial criteria (possible, laboratory-supported probable, probable, or definite ALS). 2. ALS onset ≤ 36 months from Screening. 3. Documented meningococcal vaccination not more than 3 years prior to, or at the time of, initiating study treatment. 4. Upright slow vital capacity ≥ 65% predicted at Screening. 5. If on riluzole, participant must be on a stable dose for 30 days; if on edaravone, participant must be on a stable dose for 60 days (2 cycles). 6. Body weight ≥ 40 kilograms at Screening. 7. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Key
Exclusion criteria
1. History of Neisseria meningitidis infection. 2. Human immunodeficiency virus (HIV) infection (evidenced by HIV 1 or HIV 2 antibody titer). 3. Dependence on invasive or non-invasive mechanical ventilation. 4. Previously or currently treated with a complement inhibitor. 5. Exposure to an investigational drug or device within 30 days of Screening or 5 half lives of the study drug, whichever is greater.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline In Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Total Score | Baseline, Week 50 | The ALSFRS-Revised is a validated instrument for evaluating the levels of the functional status of participants with amyotrophic lateral sclerosis (ALS) in 4 areas, including bulbar, gross motor activity, fine motor activity, and respiratory functions. The scale included 12 functional items and each item is rated on a 0 to 4 scale, with a maximum total score of 48. A higher score indicated greater retention of function. Baseline was defined as last non-missing value on or before first study drug administration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline In Percent Predicted Slow Vital Capacity | Baseline, Week 50 | Slow vital capacity measures slow and gradual expulsion of air from the lungs using a spirometer. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events, and TEAEs Leading To Study Drug Discontinuation | Baseline up to Week 156 | An adverse event (AE) was defined as any unfavorable and unintended sign (for example, including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product or procedure, whether or not considered related to the medicinal product or procedure, which occurred during the course of the clinical study. TEAEs were defined as AEs that occurred on or after the date and time of study drug administration, or those that first occurred before dosing but worsened in frequency or severity after study drug administration. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section. |
| Change From Baseline In Muscle Strength As Assessed By Handheld Dynamometry | Baseline, Week 50 | Handheld dynamometry (HHD) is a procedure for quantitative strength testing. Muscle strength testing was performed on prespecified muscles in the upper and lower extremities bilaterally and the force measurements were recorded. Force of measurement is reported in megascores (lower, upper, total). The total megascore is defined as the average of the non-missing ratios over baseline for all the muscles involved. The megascore at baseline is always 100. The range of a potential megascore can not be determined in advance. A megascore \>100 indicates more strength compared to baseline. |
| Time To Ventilator Assistance-free Survival | Up to Week 50 | Ventilation Assistance-Free Survival (VAFS) is a composite endpoint of survival and severe and irreversible respiratory decline. The use of VAFS allowed for the collection of survival data that was not impacted by survival prolongation from noninvasive or permanent ventilatory interventions which could prolong life without impacting underlying disease progression. |
| Change From Baseline in Serum Ravulizumab Concentration Over the Study Duration | Baseline, Predose at Week 50 | — |
| Change From Baseline in Serum Free Complement Component 5 (C5) Concentration Over the Study Duration | Baseline, Predose at Week 50 | — |
| Number of Participants With Positive Antidrug Antibodies (ADAs) to ALXN1210 | Week 50 | Blood samples were collected to evaluate antibody response through development of ADAs. |
| Change From Baseline In Serum Neurofilament Light Chain | Baseline, Week 50 | — |
Countries
Australia, Belgium, Canada, Denmark, France, Germany, Ireland, Israel, Italy, Japan, Netherlands, Poland, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ravulizumab Participants received a weight-based loading dose of ravulizumab on Day 1, followed by a weight-based maintenance dose on Day 15, then q8w up to Week 42 (inclusive) during the Randomized Controlled Period. Then, during the Open Label Extension Period, participants received ravulizumab, with a blinded 900 mg dose at Week 50, followed by an open-label ravulizumab maintenance dose at Week 52, then q8w for up to 106 weeks of treatment. | 255 |
| Placebo Participants received a weight-based loading dose of placebo matched to ravulizumab on Day 1, followed by a weight-based maintenance dose on Day 15, then q8w up to Week 42 (inclusive) during the Randomized Controlled Period. Then during the Open Label Extension Period, participants received ravulizumab, with a blinded loading dose at Week 50, followed by an open-label ravulizumab maintenance dose at Week 52, then q8w for up to 106 weeks of treatment. | 127 |
| Total | 382 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Open-label Extension Period | Study Terminated by Sponsor | 14 | 4 |
| Open-label Extension Period | Withdrawal by Subject | 0 | 1 |
| Randomized-Controlled Period | Adverse Event | 2 | 0 |
| Randomized-Controlled Period | Death | 12 | 5 |
| Randomized-Controlled Period | Lost to Follow-up | 1 | 0 |
| Randomized-Controlled Period | Physician Decision | 1 | 1 |
| Randomized-Controlled Period | Study Terminated by Sponsor | 194 | 99 |
| Randomized-Controlled Period | Withdrawal by Subject | 30 | 17 |
Baseline characteristics
| Characteristic | Total | Placebo | Ravulizumab |
|---|---|---|---|
| Age, Continuous | 58.4 years STANDARD_DEVIATION 10.72 | 58.0 years STANDARD_DEVIATION 11.03 | 58.6 years STANDARD_DEVIATION 10.57 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 34 Participants | 12 Participants | 22 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 310 Participants | 105 Participants | 205 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 38 Participants | 10 Participants | 28 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 34 Participants | 12 Participants | 22 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 4 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 36 Participants | 10 Participants | 26 Participants |
| Race (NIH/OMB) White | 305 Participants | 103 Participants | 202 Participants |
| Sex: Female, Male Female | 152 Participants | 58 Participants | 94 Participants |
| Sex: Female, Male Male | 230 Participants | 69 Participants | 161 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 15 / 255 | 6 / 127 | 0 / 14 | 0 / 5 |
| other Total, other adverse events | 196 / 255 | 106 / 127 | 3 / 14 | 1 / 5 |
| serious Total, serious adverse events | 41 / 255 | 24 / 127 | 2 / 14 | 0 / 5 |
Outcome results
Primary
Change From Baseline In Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Total Score
The ALSFRS-Revised is a validated instrument for evaluating the levels of the functional status of participants with amyotrophic lateral sclerosis (ALS) in 4 areas, including bulbar, gross motor activity, fine motor activity, and respiratory functions. The scale included 12 functional items and each item is rated on a 0 to 4 scale, with a maximum total score of 48. A higher score indicated greater retention of function. Baseline was defined as last non-missing value on or before first study drug administration.
Time frame: Baseline, Week 50
Population: FAS included all randomized participants who received at least 1 dose of study drug grouped by randomized treatment group. Here, Number of Participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ravulizumab | Change From Baseline In Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Total Score | -11.9 units on a scale | Standard Deviation 7.3 |
| Placebo | Change From Baseline In Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) Total Score | -10.6 units on a scale | Standard Deviation 6.05 |
Secondary
Change From Baseline In Muscle Strength As Assessed By Handheld Dynamometry
Handheld dynamometry (HHD) is a procedure for quantitative strength testing. Muscle strength testing was performed on prespecified muscles in the upper and lower extremities bilaterally and the force measurements were recorded. Force of measurement is reported in megascores (lower, upper, total). The total megascore is defined as the average of the non-missing ratios over baseline for all the muscles involved. The megascore at baseline is always 100. The range of a potential megascore can not be determined in advance. A megascore \>100 indicates more strength compared to baseline.
Time frame: Baseline, Week 50
Population: FAS included all randomized participants who received at least 1 dose of study drug grouped by randomized treatment group. Here, Number of Participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ravulizumab | Change From Baseline In Muscle Strength As Assessed By Handheld Dynamometry | -46.5 % (as the unit of megascore) | Standard Deviation 27.57 |
| Placebo | Change From Baseline In Muscle Strength As Assessed By Handheld Dynamometry | -53.4 % (as the unit of megascore) | Standard Deviation 20.28 |
Secondary
Change From Baseline In Percent Predicted Slow Vital Capacity
Slow vital capacity measures slow and gradual expulsion of air from the lungs using a spirometer.
Time frame: Baseline, Week 50
Population: FAS included all randomized participants who received at least 1 dose of study drug grouped by randomized treatment group. Here, Number of Participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ravulizumab | Change From Baseline In Percent Predicted Slow Vital Capacity | -20.9 percentage of predicted volume | Standard Deviation 19.74 |
| Placebo | Change From Baseline In Percent Predicted Slow Vital Capacity | -21.3 percentage of predicted volume | Standard Deviation 13.9 |
Secondary
Change From Baseline in Serum Free Complement Component 5 (C5) Concentration Over the Study Duration
Time frame: Baseline, Predose at Week 50
Population: Pharmacodynamic analysis set (PDAS) included all participants who received at least 1 dose of the study drug and had at least 1 postdose pharmacodynamics (PD) sample. Here, Number of Participants analyzed signifies those participants who were evaluable for this outcome measure. There were no participants with evaluable C5 data in the Placebo arm at Week 50.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ravulizumab | Change From Baseline in Serum Free Complement Component 5 (C5) Concentration Over the Study Duration | -155.2 micrograms/milliliter | Standard Deviation 24.42 |
Secondary
Change From Baseline In Serum Neurofilament Light Chain
Time frame: Baseline, Week 50
Population: FAS included all randomized participants who received at least 1 dose of study drug grouped by randomized treatment group. Here, Number of Participants analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ravulizumab | Change From Baseline In Serum Neurofilament Light Chain | 91.5 picograms/milliliter | Standard Deviation 40.4 |
| Placebo | Change From Baseline In Serum Neurofilament Light Chain | 73.1 picograms/milliliter | Standard Deviation 27.82 |
Secondary
Change From Baseline in Serum Ravulizumab Concentration Over the Study Duration
Time frame: Baseline, Predose at Week 50
Population: Pharmacokinetic Analysis Set (PKAS) included all participants who received at least 1 dose of the study drug and had at least 1 postdose pharmacokinetic (PK) sample. This endpoint was planned to be reported for Ravulizumab arm only.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Ravulizumab | Change From Baseline in Serum Ravulizumab Concentration Over the Study Duration | 634 micrograms/milliliter | Geometric Coefficient of Variation 29.1 |
Secondary
Number of Participants With Positive Antidrug Antibodies (ADAs) to ALXN1210
Blood samples were collected to evaluate antibody response through development of ADAs.
Time frame: Week 50
Population: PDAS included all participants who received at least 1 dose of the study drug and had at least 1 postdose PD sample. Here, Number of Participants analyzed signifies those participants who were evaluable at Week 50. There were no participants with evaluable C5 data in the Placebo arm at Week 50.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ravulizumab | Number of Participants With Positive Antidrug Antibodies (ADAs) to ALXN1210 | 0 Participants |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events, and TEAEs Leading To Study Drug Discontinuation
An adverse event (AE) was defined as any unfavorable and unintended sign (for example, including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product or procedure, whether or not considered related to the medicinal product or procedure, which occurred during the course of the clinical study. TEAEs were defined as AEs that occurred on or after the date and time of study drug administration, or those that first occurred before dosing but worsened in frequency or severity after study drug administration. A summary of all Serious Adverse Events and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section.
Time frame: Baseline up to Week 156
Population: Safety Set included all participants who received at least 1 dose of study drug grouped by treatment actually received (for reporting exposure and safety data).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Ravulizumab | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events, and TEAEs Leading To Study Drug Discontinuation | TEAEs | 204 Participants |
| Ravulizumab | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events, and TEAEs Leading To Study Drug Discontinuation | Treatment Emergent Serious AEs | 41 Participants |
| Ravulizumab | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events, and TEAEs Leading To Study Drug Discontinuation | TEAE Leading to Study Drug Discontinuation | 2 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events, and TEAEs Leading To Study Drug Discontinuation | Treatment Emergent Serious AEs | 24 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events, and TEAEs Leading To Study Drug Discontinuation | TEAEs | 108 Participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events, and TEAEs Leading To Study Drug Discontinuation | TEAE Leading to Study Drug Discontinuation | 0 Participants |
Secondary
Time To Ventilator Assistance-free Survival
Ventilation Assistance-Free Survival (VAFS) is a composite endpoint of survival and severe and irreversible respiratory decline. The use of VAFS allowed for the collection of survival data that was not impacted by survival prolongation from noninvasive or permanent ventilatory interventions which could prolong life without impacting underlying disease progression.
Time frame: Up to Week 50
Population: FAS included all randomized participants who received at least 1 dose of study drug grouped by randomized treatment group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ravulizumab | Time To Ventilator Assistance-free Survival | 6.05 months |
| Placebo | Time To Ventilator Assistance-free Survival | 7.69 months |