Myasthenia Gravis, Generalized
Conditions
Brief summary
The RAISE study is a multicenter, randomized, double-blind, placebo controlled study to confirm the efficacy, safety, and tolerability of zilucoplan in subjects with generalized Myasthenia Gravis. Subjects will be randomized in a 1:1 ratio to receive daily SC doses of 0.3 mg/kg zilucoplan or placebo for 12 weeks.
Interventions
Daily subcutaneous (SC) injection
DRUGPlacebo
Daily subcutaneous (SC) injection
Sponsors
Ra 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 74 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of gMG \[Myasthenia Gravis Foundation of America (MGFA) Class II-IV\] at Screening * Positive serology for acetylcholine receptor (AChR) autoantibodies * MG-ADL Score of ≥ 6 at Screening and Baseline * QMG score ≥ 12 at Screening and Baseline * No change in corticosteroid dose for at least 30 days prior to Baseline or anticipated to occur during the 12-week Treatment Period * No change in immunosuppressive therapy, including dose, for at least 30 days prior to Baseline or anticipated to occur during the 12-week Treatment Period
Exclusion criteria
* Thymectomy within 12 months prior to Baseline or scheduled to occur during the 12 week Treatment Period * History of meningococcal disease * Current or recent systemic infection within 2 weeks prior to Baseline or injection requiring intravenous (IV) antibiotics within 4 weeks prior to Baseline
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline (CFB) to Week 12 in Myasthenia Gravis-Activities of Daily Living (MG-ADL) Total Score | From Baseline to End of Treatment (Week 12) | The MG-ADL is an 8-item patient-reported outcome measure assessing MG symptoms and their effects on daily activities. Each item in the scale scored 0 to 3 (0=None, 3=severe disease) point scale. The total score was the sum of all individual item scores and ranged from 0 to 24. Higher scores indicated more severe disability due to MG. A decrease from Baseline score indicated improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 in the Myasthenia Gravis Composite (MGC) Scale Total Score | From Baseline to End of Treatment (Week 12) | The total MGC score was sum of responses to 10 individual items : 1. Ptosis upward gaze (0 to 3), 2. Double vision on lateral gaze, left or right (0, to 4), 3. Eye closure (0 to 2), 4. Talking (0 to 6), 5. Chewing (0 to 6), 6. Swallowing \[0 to 6\], 7. Breathing (0 to 9), 8. Neck flexion or extension (0 to 4), 9. Shoulder abduction (0 to 5), 10. Hip flexion (0 to 5). The higher score for each item indicated severity. The total score ranged 0 to 50 with higher score indicative of severe disease activity). A decrease from Baseline score showed improvement. |
| Change From Baseline to Week 12 in the Myasthenia Gravis - Quality of Life Revised (MG-QoL15r) Scale Total Score | From Baseline to End of Treatment (Week 12) | The MG-QoL15r is a 15-item patient-reported outcome measure designed to assess quality of life in patients with MG. Each item in the scale scored on a 0 to 2-point scale (0=Not much at all, 1=Somewhat, 2=Very much). The total score was the sum of the 15 individual item scores, ranging from 0 to 30. Higher scores indicated more severe impact of the disease on aspects of the patient's life. A decrease from Baseline score indicated improvement. |
| Time to First Receipt of Rescue Therapy Over the 12-week Treatment Period | From Baseline to End of Treatment (Week 12) | Time to first receipt of rescue therapy over the 12-week treatment period (in days) was defined as the date of first rescue therapy use minus date of first Investigational Medicinal Product (IMP) + 1. |
| Change From Baseline to Week 12 in the Quantitative Myasthenia Gravis (QMG) Total Score | From Baseline to End of Treatment (Week 12) | The QMG is a standardized and validated quantitative strength scoring system that was developed specifically for MG. The scale consisted of 13 items. Each item in the scale scored on a 0 to 3-point scale, ranging from 0 (no weakness) to 3 (severe weakness), summing up to the overall score range from 0 to 39. Higher scores indicated more severe impairment. A decrease from Baseline score indicated improvement. |
| Percentage of Participants Achieving a ≥ 3-point Reduction in MG-ADL Score at Week 12 Without Rescue Therapy | End of Treatment (Week 12) | Percentage of participants achieving a ≥ 3-point reduction in MG-ADL Score at Week 12 without rescue therapy were reported. The MG-ADL is an 8-item patient-reported outcome measure assessing MG symptoms and their effects on daily activities. Each item in the scale scored on a 0 to 3 (0=None, 3=severe disease) point scale. The total score was the sum of all individual item scores and ranged from 0 to 24. Higher scores indicated more severe disability due to MG. Any participant with an event of death, myasthenic crisis or rescue therapy was considered as non-responders. Any other missing data was imputed using the MAR assumption. |
| Percentage of Participants Achieving a ≥5-point Reduction in QMG Score Without Rescue Therapy at Week 12 | End of Treatment (Week 12) | Percentage of participants achieving a ≥5-point reduction in QMG Score without rescue therapy at Week 12 were reported. The QMG is a standardized and validated quantitative strength scoring system that was developed specifically for MG. The scale consisted of 13 items. Each item in the scale scored on a 0 to 3-point scale, ranging from 0 (no weakness) to 3 (severe weakness), summing up to the overall score range from 0 to 39. Higher scores indicated more severe impairment. Any participant with an event of death, myasthenic crisis or rescue therapy was considered as non-responders. Any other missing data was imputed using the MAR assumption. |
| Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | From Baseline (Day 1) to Safety Follow-up visit (19 Weeks [12 weeks Treatment Period plus up to 7 weeks Follow-up]) | A TEAE is defined as an AE starting on or after the time of first administration of IMP and up to and including 40 days after the final dose (or last contact depending on which occurs first). Adverse events starting before the date of the first administration of IMP were not considered TEAEs. |
| Percentage of Participants Achieving Minimal Symptom Expression (MSE) at Week 12 Without Rescue Therapy | End of Treatment (Week 12) | Percentage of Participants achieving MSE was defined as achieving a MG-ADL value of a 0 (No MG symptoms) or 1 (Mild MG symptoms) at Week 12 and not having taken rescue therapy. Any participant with an event of death, myasthenic crisis or rescue therapy was considered as non-responders. Any other missing data was imputed using the missing at Random (MAR) assumption. |
Countries
Canada, France, Germany, Italy, Japan, Norway, Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
The study started to enroll participants in September 2019 and concluded in December 2021.
Pre-assignment details
The Participant flow refers to the Randomized Set.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants self-administered zilucoplan (RA101495) matching placebo as subcutaneous (SC) injection during 12-week Treatment Period. | 88 |
| Zilucoplan 0.3 mg/kg Participants self-administered zilucoplan (RA101495) 0.3 milligrams/kilogram/day (mg/kg/day) SC injection during 12-week Treatment Period. | 86 |
| Total | 174 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Placebo | Zilucoplan 0.3 mg/kg | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 26 Participants | 22 Participants | 48 Participants |
| Age, Categorical Between 18 and 65 years | 62 Participants | 64 Participants | 126 Participants |
| Age, Continuous | 53.3 years STANDARD_DEVIATION 15.7 | 52.6 years STANDARD_DEVIATION 14.6 | 53.0 years STANDARD_DEVIATION 15.1 |
| Race/Ethnicity, Customized American Indian/Alaska native | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 14 Participants | 7 Participants | 21 Participants |
| Race/Ethnicity, Customized Black | 7 Participants | 6 Participants | 13 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 5 Participants | 7 Participants | 12 Participants |
| Race/Ethnicity, Customized Missing | 4 Participants | 7 Participants | 11 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 79 Participants | 72 Participants | 151 Participants |
| Race/Ethnicity, Customized Other/Mixed | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 62 Participants | 66 Participants | 128 Participants |
| Sex: Female, Male Female | 47 Participants | 52 Participants | 99 Participants |
| Sex: Female, Male Male | 41 Participants | 34 Participants | 75 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 88 | 1 / 86 |
| other Total, other adverse events | 34 / 88 | 41 / 86 |
| serious Total, serious adverse events | 13 / 88 | 11 / 86 |
Outcome results
Primary
Change From Baseline (CFB) to Week 12 in Myasthenia Gravis-Activities of Daily Living (MG-ADL) Total Score
The MG-ADL is an 8-item patient-reported outcome measure assessing MG symptoms and their effects on daily activities. Each item in the scale scored 0 to 3 (0=None, 3=severe disease) point scale. The total score was the sum of all individual item scores and ranged from 0 to 24. Higher scores indicated more severe disability due to MG. A decrease from Baseline score indicated improvement.
Time frame: From Baseline to End of Treatment (Week 12)
Population: The modified Intention-to-Treat (mITT) population included all randomized participants who received at least 1 dose of study drug and had at least 1 post-dosing MG-ADL score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline (CFB) to Week 12 in Myasthenia Gravis-Activities of Daily Living (MG-ADL) Total Score | -2.30 score on a scale |
| Zilucoplan 0.3 mg/kg | Change From Baseline (CFB) to Week 12 in Myasthenia Gravis-Activities of Daily Living (MG-ADL) Total Score | -4.39 score on a scale |
p-value: <0.00195% CI: [-3.24, -0.95]MMRM ANCOVA
Secondary
Change From Baseline to Week 12 in the Myasthenia Gravis Composite (MGC) Scale Total Score
The total MGC score was sum of responses to 10 individual items : 1. Ptosis upward gaze (0 to 3), 2. Double vision on lateral gaze, left or right (0, to 4), 3. Eye closure (0 to 2), 4. Talking (0 to 6), 5. Chewing (0 to 6), 6. Swallowing \[0 to 6\], 7. Breathing (0 to 9), 8. Neck flexion or extension (0 to 4), 9. Shoulder abduction (0 to 5), 10. Hip flexion (0 to 5). The higher score for each item indicated severity. The total score ranged 0 to 50 with higher score indicative of severe disease activity). A decrease from Baseline score showed improvement.
Time frame: From Baseline to End of Treatment (Week 12)
Population: The modified Intention-to-Treat (mITT) population included all randomized participants who received at least 1 dose of study drug and had at least 1 post-dosing MG-ADL score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline to Week 12 in the Myasthenia Gravis Composite (MGC) Scale Total Score | -5.42 score on a scale |
| Zilucoplan 0.3 mg/kg | Change From Baseline to Week 12 in the Myasthenia Gravis Composite (MGC) Scale Total Score | -8.62 score on a scale |
p-value: 0.002395% CI: [-5.24, -1.16]MMRM ANCOVA
Secondary
Change From Baseline to Week 12 in the Myasthenia Gravis - Quality of Life Revised (MG-QoL15r) Scale Total Score
The MG-QoL15r is a 15-item patient-reported outcome measure designed to assess quality of life in patients with MG. Each item in the scale scored on a 0 to 2-point scale (0=Not much at all, 1=Somewhat, 2=Very much). The total score was the sum of the 15 individual item scores, ranging from 0 to 30. Higher scores indicated more severe impact of the disease on aspects of the patient's life. A decrease from Baseline score indicated improvement.
Time frame: From Baseline to End of Treatment (Week 12)
Population: The modified Intention-to-Treat (mITT) population included all randomized participants who received at least 1 dose of study drug and had at least 1 post-dosing MG-ADL score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline to Week 12 in the Myasthenia Gravis - Quality of Life Revised (MG-QoL15r) Scale Total Score | -3.16 score on a scale |
| Zilucoplan 0.3 mg/kg | Change From Baseline to Week 12 in the Myasthenia Gravis - Quality of Life Revised (MG-QoL15r) Scale Total Score | -5.65 score on a scale |
p-value: 0.012895% CI: [-4.45, -0.54]MMRM ANCOVA
Secondary
Change From Baseline to Week 12 in the Quantitative Myasthenia Gravis (QMG) Total Score
The QMG is a standardized and validated quantitative strength scoring system that was developed specifically for MG. The scale consisted of 13 items. Each item in the scale scored on a 0 to 3-point scale, ranging from 0 (no weakness) to 3 (severe weakness), summing up to the overall score range from 0 to 39. Higher scores indicated more severe impairment. A decrease from Baseline score indicated improvement.
Time frame: From Baseline to End of Treatment (Week 12)
Population: The modified Intention-to-Treat (mITT) population included all randomized participants who received at least 1 dose of study drug and had at least 1 post-dosing MG-ADL score.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline to Week 12 in the Quantitative Myasthenia Gravis (QMG) Total Score | -3.25 score on a scale |
| Zilucoplan 0.3 mg/kg | Change From Baseline to Week 12 in the Quantitative Myasthenia Gravis (QMG) Total Score | -6.19 score on a scale |
p-value: <0.00195% CI: [-4.39, -1.49]MMRM ANCOVA
Secondary
Percentage of Participants Achieving a ≥ 3-point Reduction in MG-ADL Score at Week 12 Without Rescue Therapy
Percentage of participants achieving a ≥ 3-point reduction in MG-ADL Score at Week 12 without rescue therapy were reported. The MG-ADL is an 8-item patient-reported outcome measure assessing MG symptoms and their effects on daily activities. Each item in the scale scored on a 0 to 3 (0=None, 3=severe disease) point scale. The total score was the sum of all individual item scores and ranged from 0 to 24. Higher scores indicated more severe disability due to MG. Any participant with an event of death, myasthenic crisis or rescue therapy was considered as non-responders. Any other missing data was imputed using the MAR assumption.
Time frame: End of Treatment (Week 12)
Population: The mITT population included randomized participants who received at least 1 dose of study drug and had at least 1 post-dosing MG-ADL score.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Achieving a ≥ 3-point Reduction in MG-ADL Score at Week 12 Without Rescue Therapy | 46.1 percentage of participants |
| Zilucoplan 0.3 mg/kg | Percentage of Participants Achieving a ≥ 3-point Reduction in MG-ADL Score at Week 12 Without Rescue Therapy | 73.1 percentage of participants |
p-value: <0.00195% CI: [1.662, 6.101]Regression, Logistic
Secondary
Percentage of Participants Achieving a ≥5-point Reduction in QMG Score Without Rescue Therapy at Week 12
Percentage of participants achieving a ≥5-point reduction in QMG Score without rescue therapy at Week 12 were reported. The QMG is a standardized and validated quantitative strength scoring system that was developed specifically for MG. The scale consisted of 13 items. Each item in the scale scored on a 0 to 3-point scale, ranging from 0 (no weakness) to 3 (severe weakness), summing up to the overall score range from 0 to 39. Higher scores indicated more severe impairment. Any participant with an event of death, myasthenic crisis or rescue therapy was considered as non-responders. Any other missing data was imputed using the MAR assumption.
Time frame: End of Treatment (Week 12)
Population: The mITT population included randomized participants who received at least 1 dose of study drug and had at least 1 post-dosing MG-ADL score.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Achieving a ≥5-point Reduction in QMG Score Without Rescue Therapy at Week 12 | 33.0 percentage of participants |
| Zilucoplan 0.3 mg/kg | Percentage of Participants Achieving a ≥5-point Reduction in QMG Score Without Rescue Therapy at Week 12 | 58.0 percentage of participants |
p-value: 0.001295% CI: [1.518, 5.409]Regression, Logistic
Secondary
Percentage of Participants Achieving Minimal Symptom Expression (MSE) at Week 12 Without Rescue Therapy
Percentage of Participants achieving MSE was defined as achieving a MG-ADL value of a 0 (No MG symptoms) or 1 (Mild MG symptoms) at Week 12 and not having taken rescue therapy. Any participant with an event of death, myasthenic crisis or rescue therapy was considered as non-responders. Any other missing data was imputed using the missing at Random (MAR) assumption.
Time frame: End of Treatment (Week 12)
Population: The mITT population included randomized participants who received at least 1 dose of study drug and had at least 1 post-dosing MG-ADL score.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants Achieving Minimal Symptom Expression (MSE) at Week 12 Without Rescue Therapy | 5.8 percentage of participants |
| Zilucoplan 0.3 mg/kg | Percentage of Participants Achieving Minimal Symptom Expression (MSE) at Week 12 Without Rescue Therapy | 14.0 percentage of participants |
p-value: 0.088595% CI: [0.866, 7.86]Regression, Logistic
Secondary
Percentage of Participants With Treatment-emergent Adverse Events (TEAEs)
A TEAE is defined as an AE starting on or after the time of first administration of IMP and up to and including 40 days after the final dose (or last contact depending on which occurs first). Adverse events starting before the date of the first administration of IMP were not considered TEAEs.
Time frame: From Baseline (Day 1) to Safety Follow-up visit (19 Weeks [12 weeks Treatment Period plus up to 7 weeks Follow-up])
Population: The Safety Set (SS) included all participants who received at least 1 dose of study drug based on the actual study treatment received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | 70.5 percentage of participants |
| Zilucoplan 0.3 mg/kg | Percentage of Participants With Treatment-emergent Adverse Events (TEAEs) | 76.7 percentage of participants |
Secondary
Time to First Receipt of Rescue Therapy Over the 12-week Treatment Period
Time to first receipt of rescue therapy over the 12-week treatment period (in days) was defined as the date of first rescue therapy use minus date of first Investigational Medicinal Product (IMP) + 1.
Time frame: From Baseline to End of Treatment (Week 12)
Population: The modified Intention-to-Treat (mITT) population included all randomized participants who received at least 1 dose of study drug and had at least 1 post-dosing MG-ADL score.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time to First Receipt of Rescue Therapy Over the 12-week Treatment Period | NA Days |
| Zilucoplan 0.3 mg/kg | Time to First Receipt of Rescue Therapy Over the 12-week Treatment Period | NA Days |