Generalized Myasthenia Gravis
Conditions
Brief summary
The primary purpose of this study is to evaluate the safety and efficacy of ravulizumab for the treatment of participants with generalized myasthenia gravis (gMG).
Interventions
BIOLOGICALRavulizumab
Concentrated sterile, preservative-free aqueous solution (10 milligrams \[mg\]/milliliter \[mL\]) in single-use, 30-mL vial for intravenous (IV) infusion. Single loading dose on Day 1, followed by regular maintenance dosing beginning on Day 15, based on weight.
DRUGPlacebo
Matching, sterile, preservative-free aqueous solution in single-use, 30-mL vial for IV infusion. Single loading dose on Day 1, followed by regular maintenance dosing beginning on Day 15, based on weight.
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
All investigative site personnel, sponsor staff, sponsor designees, staff directly associated with the conduct of the study, and all participants will be blinded to treatment assignments.
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
1. Diagnosed with Myasthenia Gravis at least 6 months (180 days) prior to the date of the Screening Visit as confirmed by specific criteria. 2. Myasthenia Gravis Foundation of America Clinical Classification Class II to IV at screening. 3. MG-ADL profile must be ≥ 6 at screening and randomization (Day 1). 4. Vaccinated against meningococcal infections within 3 years prior to, or at the time of, initiating study drug to reduce the risk of meningococcal infection (N meningitidis).
Exclusion criteria
Medical Conditions 1. Any active or untreated thymoma. History of thymic carcinoma or thymic malignancy unless deemed cured by adequate treatment with no evidence of recurrence for ≥ 5 years before screening. 2. History of thymectomy within the 12 months prior to screening. 3. History of N meningitidis infection. 4. Use of the following within the time period specified below: * IV immunoglobulin within 4 weeks of randomization * Use of plasma exchange within 4 weeks of randomization * Use of rituximab within 6 months of screening 5. Participants who have received previous treatment with complement inhibitors (for example, eculizumab).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline In Myasthenia Gravis-Activities Of Daily Living (MG-ADL) Total Score At Week 26 | Baseline, Week 26 | The MG-ADL is an 8-point questionnaire that focused on relevant symptoms and functional performance of activities of daily living in participants with MG. The 8 items of the MGADL questionnaire were derived from symptom-based components of the original 13-item QMG scale to assess disability secondary to ocular (2 items), bulbar (3 items), respiratory (1 item), and gross motor or limb (2 items) impairment related to effects from MG. In this functional status instrument, each response was graded 0 (normal) to 3 (most severe). The range of total MG-ADL score was 0 to 24. A decrease in score indicated improvement. Estimates were based on Mixed Effect Repeated Measures (MMRM) that included treatment group, stratification factor region, and MG-ADL total score at baseline, study visit, and study visit by treatment group interaction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline In The Quantitative Myasthenia Gravis (QMG) Total Score At Week 26 | Baseline, Week 26 | The QMG scoring system consisted of 13 items: ocular (2 items), facial (1 item), bulbar (2 items), gross motor (6 items), axial (1 item), and respiratory (1 item); each graded 0 to 3, with 3 being the most severe. The range of total QMG score is 0 to 39. The QMG scoring system was considered to be an objective evaluation of therapy for MG and was based on quantitative testing of sentinel muscle groups. A decrease in score indicated improvement. Estimates were based on MMRM that included treatment group, stratification factor region, and QMG total score at baseline, study visit, and study visit by treatment group interaction. |
| Percentage of Participants With a Quantitative Myasthenia Gravis (QMG) Total Score Reduction of at Least 5 Points At Week 26 | Week 26 | The QMG scoring system consisted of 13 items: ocular (2 items), facial (1 item), bulbar (2 items), gross motor (6 items), axial (1 item), and respiratory (1 item); each graded 0 to 3, with 3 being the most severe. The range of total QMG score is 0 to 39. A decrease in score indicated improvement. Percentage of participants with a ≥5-point reduction in the QMG total score are reported. Estimates were based on a generalized linear mixed model (GLMM) that included treatment group, stratification factor region and QMG total score at baseline, study visit and study visit by treatment group interaction. |
| Change From Baseline In the Revised 15 Component Myasthenia Gravis Quality of Life (MG-QOL15r) At Week 26 | Baseline, Week 26 | The revised Myasthenia Gravis Qualify of Life 15-item scale (MG-QOL15r) is a health-related QoL evaluative instrument specific to participants with MG. The MG-QOL15r was designed to provide information about participants' perception of impairment and disability, determine the degree to which disease manifestations are tolerated, and to be administered and interpreted easily. Each item was graded on a scale of 0 to 2, with 2 being the most severe. The range of MG-QOL15r score is 0 to 30. Higher scores indicated greater extent of and dissatisfaction with MG-related dysfunction. Estimates are based on MMRM that included treatment group, stratification factor region and MG-QOL15r score at baseline, study visit and study visit by treatment group interaction. |
| Change From Baseline in Neurological Quality of Life (Neuro-QoL) Fatigue Score at Week 26 | Baseline, Week 26 | The Neuro-QOL Fatigue is a reliable and validated brief 19-item survey of fatigue, completed by the participant. Each items was rated on a scale of 1 to 5, with 5 being the most severe. The range of total score is 19 to 95. Higher scores indicated greater fatigue and greater impact of MG on activities. Estimates were based on MMRM that included treatment group, stratification factor region and Neuro-QoL Fatigue score at baseline, study visit, and study visit by treatment group interaction. |
| Percentage of Participants With a Myasthenia Gravis Activities of Daily Living (MG-ADL) Total Score Reduction of at Least 3 Points At Week 26 | Week 26 | The MG-ADL is an 8-point questionnaire that focused on relevant symptoms and functional performance of activities of daily living in participants with MG. The 8 items of the MGADL questionnaire were derived from symptom-based components of the original 13-item QMG scale to assess disability secondary to ocular (2 items), bulbar (3 items), respiratory (1 item), and gross motor or limb (2 items) impairment related to effects from MG. In this functional status instrument, each response was graded 0 (normal) to 3 (most severe). The range of total MG-ADL score was 0 to 24. A decrease in score indicated improvement. Percentage of participants with a ≥3-point reduction in the MG-ADL total score are reported. Estimates were based on a GLMM that included treatment group, stratification factor region and MG-ADL total score at baseline, study visit and study visit by treatment group interaction. |
Countries
Austria, Canada, Czechia, Denmark, France, Germany, Israel, Italy, Japan, Netherlands, Portugal, South Korea, Spain, Switzerland, United States
Participant flow
Pre-assignment details
Participants were randomized 1:1 to either the ravulizumab or placebo group during the Randomized-Controlled Period. Following the placebo-controlled part of the study, participants were transitioned to the ongoing Open-Label Extension Period to receive treatment with ravulizumab.
Participants by arm
| Arm | Count |
|---|---|
| Ravulizumab Participants received a weight-based single loading dose (2400 to 3000 mg) of ravulizumab IV on Day 1, followed by regular maintenance IV weight-based doses (3000 to 3600 mg) of ravulizumab beginning on Day 15 q8w during the 26-week Randomized-Controlled Period of the study. After the randomized-controlled part of the study, participants were transitioned to the ongoing open-label extension period to receive treatment with ravulizumab IV for up to 2 years. | 86 |
| Placebo Participants received a weight-based single loading dose of placebo IV on Day 1, followed by regular maintenance IV weight-based doses of placebo beginning on Day 15 q8w, during the 26-week Randomized-Controlled Period of the study. After the randomized-controlled part of the study, participants were transitioned to the ongoing open-label extension period to receive treatment with ravulizumab IV for up to 2 years. | 89 |
| Total | 175 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Open- Label Extension Period | Death | 3 | 3 |
| Open- Label Extension Period | Participants who transitioned to alternative treatment by the Investigator when the study closed | 3 | 5 |
| Open- Label Extension Period | Physician Decision | 5 | 3 |
| Open- Label Extension Period | Withdrawal by Subject | 7 | 9 |
| Randomized-Controlled Period | Adverse Event | 0 | 2 |
| Randomized-Controlled Period | Death | 2 | 0 |
| Randomized-Controlled Period | Noncompliance | 1 | 0 |
| Randomized-Controlled Period | Physician Decision | 1 | 2 |
| Randomized-Controlled Period | Protocol Violation | 1 | 0 |
| Randomized-Controlled Period | Sponsor Decision | 0 | 1 |
| Randomized-Controlled Period | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | Ravulizumab |
|---|---|---|---|
| Age, Continuous | 53.3 years STANDARD_DEVIATION 16.05 | 55.6 years STANDARD_DEVIATION 15.14 | 58.0 years STANDARD_DEVIATION 13.82 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 7 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 78 Participants | 157 Participants | 79 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 11 Participants | 5 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 16 Participants | 31 Participants | 15 Participants |
| Race/Ethnicity, Customized Black or African American | 4 Participants | 6 Participants | 2 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 6 Participants | 8 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 61 Participants | 128 Participants | 67 Participants |
| Sex: Female, Male Female | 45 Participants | 89 Participants | 44 Participants |
| Sex: Female, Male Male | 44 Participants | 86 Participants | 42 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 | 2 / 86 | 0 / 89 | 3 / 83 | 3 / 78 |
| other Total, other adverse events | 77 / 86 | 75 / 89 | 79 / 83 | 77 / 78 |
| serious Total, serious adverse events | 20 / 86 | 14 / 89 | 32 / 83 | 24 / 78 |
Outcome results
Primary
Change From Baseline In Myasthenia Gravis-Activities Of Daily Living (MG-ADL) Total Score At Week 26
The MG-ADL is an 8-point questionnaire that focused on relevant symptoms and functional performance of activities of daily living in participants with MG. The 8 items of the MGADL questionnaire were derived from symptom-based components of the original 13-item QMG scale to assess disability secondary to ocular (2 items), bulbar (3 items), respiratory (1 item), and gross motor or limb (2 items) impairment related to effects from MG. In this functional status instrument, each response was graded 0 (normal) to 3 (most severe). The range of total MG-ADL score was 0 to 24. A decrease in score indicated improvement. Estimates were based on Mixed Effect Repeated Measures (MMRM) that included treatment group, stratification factor region, and MG-ADL total score at baseline, study visit, and study visit by treatment group interaction.
Time frame: Baseline, Week 26
Population: Full Analysis Set: All randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ravulizumab | Change From Baseline In Myasthenia Gravis-Activities Of Daily Living (MG-ADL) Total Score At Week 26 | -3.1 units on a scale | Standard Error 0.38 |
| Placebo | Change From Baseline In Myasthenia Gravis-Activities Of Daily Living (MG-ADL) Total Score At Week 26 | -1.4 units on a scale | Standard Error 0.37 |
p-value: =0.000995% CI: [-2.6, -0.7]MMRM
Secondary
Change From Baseline in Neurological Quality of Life (Neuro-QoL) Fatigue Score at Week 26
The Neuro-QOL Fatigue is a reliable and validated brief 19-item survey of fatigue, completed by the participant. Each items was rated on a scale of 1 to 5, with 5 being the most severe. The range of total score is 19 to 95. Higher scores indicated greater fatigue and greater impact of MG on activities. Estimates were based on MMRM that included treatment group, stratification factor region and Neuro-QoL Fatigue score at baseline, study visit, and study visit by treatment group interaction.
Time frame: Baseline, Week 26
Population: Full Analysis Set: All randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ravulizumab | Change From Baseline in Neurological Quality of Life (Neuro-QoL) Fatigue Score at Week 26 | -7.0 units on a scale | Standard Error 1.92 |
| Placebo | Change From Baseline in Neurological Quality of Life (Neuro-QoL) Fatigue Score at Week 26 | -4.8 units on a scale | Standard Error 1.87 |
Secondary
Change From Baseline In The Quantitative Myasthenia Gravis (QMG) Total Score At Week 26
The QMG scoring system consisted of 13 items: ocular (2 items), facial (1 item), bulbar (2 items), gross motor (6 items), axial (1 item), and respiratory (1 item); each graded 0 to 3, with 3 being the most severe. The range of total QMG score is 0 to 39. The QMG scoring system was considered to be an objective evaluation of therapy for MG and was based on quantitative testing of sentinel muscle groups. A decrease in score indicated improvement. Estimates were based on MMRM that included treatment group, stratification factor region, and QMG total score at baseline, study visit, and study visit by treatment group interaction.
Time frame: Baseline, Week 26
Population: Full Analysis Set: All randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ravulizumab | Change From Baseline In The Quantitative Myasthenia Gravis (QMG) Total Score At Week 26 | -2.8 units on a scale | Standard Error 0.46 |
| Placebo | Change From Baseline In The Quantitative Myasthenia Gravis (QMG) Total Score At Week 26 | -0.8 units on a scale | Standard Error 0.45 |
Secondary
Change From Baseline In the Revised 15 Component Myasthenia Gravis Quality of Life (MG-QOL15r) At Week 26
The revised Myasthenia Gravis Qualify of Life 15-item scale (MG-QOL15r) is a health-related QoL evaluative instrument specific to participants with MG. The MG-QOL15r was designed to provide information about participants' perception of impairment and disability, determine the degree to which disease manifestations are tolerated, and to be administered and interpreted easily. Each item was graded on a scale of 0 to 2, with 2 being the most severe. The range of MG-QOL15r score is 0 to 30. Higher scores indicated greater extent of and dissatisfaction with MG-related dysfunction. Estimates are based on MMRM that included treatment group, stratification factor region and MG-QOL15r score at baseline, study visit and study visit by treatment group interaction.
Time frame: Baseline, Week 26
Population: Full Analysis Set: All randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ravulizumab | Change From Baseline In the Revised 15 Component Myasthenia Gravis Quality of Life (MG-QOL15r) At Week 26 | -3.3 score on a scale | Standard Error 0.71 |
| Placebo | Change From Baseline In the Revised 15 Component Myasthenia Gravis Quality of Life (MG-QOL15r) At Week 26 | -1.6 score on a scale | Standard Error 0.7 |
Secondary
Percentage of Participants With a Myasthenia Gravis Activities of Daily Living (MG-ADL) Total Score Reduction of at Least 3 Points At Week 26
The MG-ADL is an 8-point questionnaire that focused on relevant symptoms and functional performance of activities of daily living in participants with MG. The 8 items of the MGADL questionnaire were derived from symptom-based components of the original 13-item QMG scale to assess disability secondary to ocular (2 items), bulbar (3 items), respiratory (1 item), and gross motor or limb (2 items) impairment related to effects from MG. In this functional status instrument, each response was graded 0 (normal) to 3 (most severe). The range of total MG-ADL score was 0 to 24. A decrease in score indicated improvement. Percentage of participants with a ≥3-point reduction in the MG-ADL total score are reported. Estimates were based on a GLMM that included treatment group, stratification factor region and MG-ADL total score at baseline, study visit and study visit by treatment group interaction.
Time frame: Week 26
Population: Full Analysis Set: All randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ravulizumab | Percentage of Participants With a Myasthenia Gravis Activities of Daily Living (MG-ADL) Total Score Reduction of at Least 3 Points At Week 26 | 56.7 percentage of participants |
| Placebo | Percentage of Participants With a Myasthenia Gravis Activities of Daily Living (MG-ADL) Total Score Reduction of at Least 3 Points At Week 26 | 34.1 percentage of participants |
Secondary
Percentage of Participants With a Quantitative Myasthenia Gravis (QMG) Total Score Reduction of at Least 5 Points At Week 26
The QMG scoring system consisted of 13 items: ocular (2 items), facial (1 item), bulbar (2 items), gross motor (6 items), axial (1 item), and respiratory (1 item); each graded 0 to 3, with 3 being the most severe. The range of total QMG score is 0 to 39. A decrease in score indicated improvement. Percentage of participants with a ≥5-point reduction in the QMG total score are reported. Estimates were based on a generalized linear mixed model (GLMM) that included treatment group, stratification factor region and QMG total score at baseline, study visit and study visit by treatment group interaction.
Time frame: Week 26
Population: Full Analysis Set: All randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ravulizumab | Percentage of Participants With a Quantitative Myasthenia Gravis (QMG) Total Score Reduction of at Least 5 Points At Week 26 | 30.0 percentage of participants |
| Placebo | Percentage of Participants With a Quantitative Myasthenia Gravis (QMG) Total Score Reduction of at Least 5 Points At Week 26 | 11.3 percentage of participants |