Generalized Myasthenia Gravis, Myasthenia Gravis
Conditions
Keywords
ALXN2050, gMG
Brief summary
This study will evaluate the efficacy and safety of ALXN2050 (120 milligrams \[mg\], 180 mg) in participants with generalized myasthenia gravis (gMG). Safety will be monitored throughout the study.
Detailed description
The study consists of a blinded 8-week Primary Evaluation Period (PEP) and a blinded 26-week Extended Treatment Period (ETP). After completion of 34 weeks of treatment, participants will enter an Open-label Extension (OLE) Period for up to 1.5 years.
Interventions
DRUGALXN2050
Oral tablet.
DRUGPlacebo
Oral tablet.
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Masking of treatment allocation will be observed until at least Week 34.
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosed with MG at least 3 months (90 days) prior to the date of the Screening Visit. Confirmation of MG must be made via the following: 1. Positive serologic test for anti AChR antibodies at the Screening Visit, and 2. Abnormal neuromuscular transmission demonstrated by single fiber electromyography or repetitive nerve stimulation, or 3. Positive response to an AChEI test (eg, edrophonium chloride test), or 4. Improvement of signs or symptoms related to MG during treatment with an oral AChEI, as determined by the treating physician * Myasthenia Gravis Foundation of America Clinical Classification Class II to IV at the Screening Visit. * MG-ADL total score must be ≥ 5 (with at least 50% of the score attributed to non-ocular elements) at the Screening Visit and at randomization (Day 1). * Participants receiving treatment with protocol-specified immunosuppressive therapies, corticosteroids, or acetylcholinesterase inhibitors must have been receiving treatment and on a stable dose prior to the date of the Screening Visit, with no changes to the regimen expected during screening, the PEP, and/or the ETP.
Exclusion criteria
* Estimated glomerular filtration rate ≤ 30 milliliters/minute/1.73 squared meters during Screening calculated by Chronic Kidney Disease Epidemiology Collaboration. * History of thymectomy, thymomectomy, or any other thymic surgery within 12 months prior to the Screening Visit. * Any untreated thymic malignancy, carcinoma, or thymoma. Participants with a history of treated thymic malignancy or carcinoma are eligible for enrollment if they meet pre-specified conditions outlined in the protocol. * Clinical features consistent with Clinical Deterioration at the time of the Screening Visit or at any time during the Screening Period prior to randomization (Day 1). * Use of the following within the time periods specified below: 1. Intravenous immunoglobulin G or subcutaneous immunoglobulin within the 4 weeks (28 days) prior to the Screening Visit. 2. Use of tacrolimus or cyclosporine within the 4 weeks (28 days) prior to the Screening Visit.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Of Participants With a Myasthenia Gravis Activities of Daily Living (MG-ADL) Total Score Reduction Of ≥ 2 Points In Any 4 Consecutive Weeks During The First 8 Weeks And Who Did Not Receive Rescue Therapy | Baseline through Week 8 | The MG-ADL profile is an 8-item participant-reported scale that focuses on relevant symptoms and functional performance of ADL in participants with MG. The 8 items of the MG-ADL 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 of MG. Each response is graded 0 (normal) to 3 (most severe). The MG-ADL total score was calculated as the sum of the scores of the 8 items and ranges from 0 to 24, with higher scores indicating worse function. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline In Quantitative Myasthenia Gravis (QMG) Total Score At Week 8 | Baseline, Week 8 | The QMG Score for Disease Severity is an objective evaluation of therapy for MG and is based on quantitative testing of sentinel muscle groups. The QMG instrument consists 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 QMG total score was calculated as the sum of the scores of the 13 items and ranges from 0 to 39, with higher scores indicating more severe disease. Baseline score at each timepoint as the response variable, treatment group, study visit, and treatment-by-study visit interaction as fixed categorical effects, and baseline QMG total score as a covariate were used to calculate the least square (LS) mean and the standard error. |
| Change From Baseline In MG-ADL Total Score At Week 8 | Baseline, Week 8 | The MG-ADL profile is an 8-item participant-reported scale that focuses on relevant symptoms and functional performance of ADL in participants with MG. The 8 items of the MG-ADL 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 of MG. Each response is graded 0 (normal) to 3 (most severe). The MG-ADL total score was calculated as the sum of the scores of the 8 items and ranges from 0 to 24, with higher scores indicating worse function. Baseline score at each timepoint as the response variable, treatment group, study visit, and treatment-by-study visit interaction as fixed categorical effects, and baseline MG-ADL total score as a covariate were used to calculate the LS mean and the standard error. |
| Change From Baseline In Quality Of Life In Neurological Disorders (Neuro-QoL) Fatigue Score At Week 8 | Baseline, Week 8 | The Neuro-QoL Fatigue questionnaire is a reliable and validated brief 19-item survey of fatigue, completed by the participant. Each item is scored on a scale of 1-5, with 1 indicating never and 5 indicating sometimes. The Neuro-QoL Fatigue score was calculated as the sum of the scores of the 19 items and ranges from 19-95, with higher scores indicating greater fatigue and greater impact of MG on activities. Baseline score at each timepoint as the response variable, treatment group, study visit, and treatment-by-study visit interaction as fixed categorical effects, and baseline Neuro-QoL Fatigue score as a covariate were used to calculate the LS mean and the standard error. |
Countries
Canada, Germany, Italy, Serbia, South Korea, Spain, Taiwan, United States
Participant flow
Recruitment details
This study did not meet its primary efficacy endpoint and was early terminated by the Sponsor.
Participants by arm
| Arm | Count |
|---|---|
| Group 1: ALXN2050 180 mg BID Participants received 180 mg ALXN2050 BID during all 3 study periods (primary evaluation, extended treatment, open-label extension). | 28 |
| Group 2: ALXN2050 120 mg BID Participants received 120 mg ALXN2050 BID during all 3 study periods (primary evaluation, extended treatment, open-label extension). | 14 |
| Group 3: Placebo/ALXN2050 Participants received placebo BID during the primary evaluation period, followed by re-randomization to Group 3a and Group 3b, after which they received ALXN2050 180 mg BID and ALXN205 120 mg BID, respectively, during the extended treatment period and open-label extension period. | 28 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Extended Treatment | Clinical Deterioration | 1 | 1 | 0 | 0 | 0 |
| Extended Treatment | Lack of Efficacy | 3 | 0 | 0 | 0 | 0 |
| Extended Treatment | Physician Decision | 0 | 1 | 0 | 0 | 0 |
| Extended Treatment | Study Terminated by Sponsor | 6 | 3 | 0 | 3 | 2 |
| Extended Treatment | Withdrawal by Subject | 1 | 3 | 0 | 2 | 2 |
| Open-label Extension | Adverse Event | 1 | 0 | 0 | 0 | 1 |
| Open-label Extension | Death | 0 | 0 | 0 | 1 | 0 |
| Open-label Extension | Lack of Efficacy | 1 | 2 | 0 | 0 | 0 |
| Open-label Extension | Lost to Follow-up | 1 | 0 | 0 | 0 | 0 |
| Open-label Extension | Pregnancy | 0 | 0 | 0 | 0 | 1 |
| Open-label Extension | Study Terminated by Sponsor | 13 | 4 | 0 | 7 | 7 |
| Primary Evaluation | Physician Decision | 1 | 0 | 0 | 0 | 0 |
| Primary Evaluation | Withdrawal by Subject | 0 | 0 | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Group 1: ALXN2050 180 mg BID | Group 2: ALXN2050 120 mg BID | Group 3: Placebo/ALXN2050 | Total |
|---|---|---|---|---|
| Age, Continuous | 49.0 years STANDARD_DEVIATION 15.55 | 55.9 years STANDARD_DEVIATION 13.02 | 58.2 years STANDARD_DEVIATION 16.45 | 54.1 years STANDARD_DEVIATION 15.82 |
| Baseline MG-ADL Total Score | 9.4 units on a scale STANDARD_DEVIATION 2.23 | 9.0 units on a scale STANDARD_DEVIATION 2.96 | 8.8 units on a scale STANDARD_DEVIATION 1.75 | 9.1 units on a scale STANDARD_DEVIATION 2.21 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 1 Participants | 1 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants | 13 Participants | 26 Participants | 63 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 4 Participants | 1 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 26 Participants | 10 Participants | 27 Participants | 63 Participants |
| Sex: Female, Male Female | 18 Participants | 10 Participants | 10 Participants | 38 Participants |
| Sex: Female, Male Male | 10 Participants | 4 Participants | 18 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 14 | 0 / 28 | 0 / 27 | 0 / 14 | 1 / 13 | 0 / 13 |
| other Total, other adverse events | 17 / 28 | 7 / 14 | 15 / 28 | 17 / 27 | 7 / 14 | 9 / 13 | 10 / 13 |
| serious Total, serious adverse events | 1 / 28 | 1 / 14 | 3 / 28 | 4 / 27 | 4 / 14 | 3 / 13 | 2 / 13 |
Outcome results
Primary
Percentage Of Participants With a Myasthenia Gravis Activities of Daily Living (MG-ADL) Total Score Reduction Of ≥ 2 Points In Any 4 Consecutive Weeks During The First 8 Weeks And Who Did Not Receive Rescue Therapy
The MG-ADL profile is an 8-item participant-reported scale that focuses on relevant symptoms and functional performance of ADL in participants with MG. The 8 items of the MG-ADL 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 of MG. Each response is graded 0 (normal) to 3 (most severe). The MG-ADL total score was calculated as the sum of the scores of the 8 items and ranges from 0 to 24, with higher scores indicating worse function.
Time frame: Baseline through Week 8
Population: Full Analysis Set: all participants who received at least 1 dose of study intervention. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: ALXN2050 180 mg BID | Percentage Of Participants With a Myasthenia Gravis Activities of Daily Living (MG-ADL) Total Score Reduction Of ≥ 2 Points In Any 4 Consecutive Weeks During The First 8 Weeks And Who Did Not Receive Rescue Therapy | 57.1 percentage of participants |
| Group 2: ALXN2050 120 mg BID | Percentage Of Participants With a Myasthenia Gravis Activities of Daily Living (MG-ADL) Total Score Reduction Of ≥ 2 Points In Any 4 Consecutive Weeks During The First 8 Weeks And Who Did Not Receive Rescue Therapy | 57.1 percentage of participants |
| Group 3: Placebo | Percentage Of Participants With a Myasthenia Gravis Activities of Daily Living (MG-ADL) Total Score Reduction Of ≥ 2 Points In Any 4 Consecutive Weeks During The First 8 Weeks And Who Did Not Receive Rescue Therapy | 64.3 percentage of participants |
p-value: 0.679790% CI: [-28.8, 15]Barnard's Unconditional Exact Test
p-value: 0.734190% CI: [-34.8, 19.3]Barnard's Unconditional Exact Test
Secondary
Change From Baseline In MG-ADL Total Score At Week 8
The MG-ADL profile is an 8-item participant-reported scale that focuses on relevant symptoms and functional performance of ADL in participants with MG. The 8 items of the MG-ADL 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 of MG. Each response is graded 0 (normal) to 3 (most severe). The MG-ADL total score was calculated as the sum of the scores of the 8 items and ranges from 0 to 24, with higher scores indicating worse function. Baseline score at each timepoint as the response variable, treatment group, study visit, and treatment-by-study visit interaction as fixed categorical effects, and baseline MG-ADL total score as a covariate were used to calculate the LS mean and the standard error.
Time frame: Baseline, Week 8
Population: Full Analysis Set: all participants who received at least 1 dose of study intervention. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: ALXN2050 180 mg BID | Change From Baseline In MG-ADL Total Score At Week 8 | -2.5 units on a scale | Standard Error 0.5 |
| Group 2: ALXN2050 120 mg BID | Change From Baseline In MG-ADL Total Score At Week 8 | -3.7 units on a scale | Standard Error 0.7 |
| Group 3: Placebo | Change From Baseline In MG-ADL Total Score At Week 8 | -3.2 units on a scale | Standard Error 0.51 |
Secondary
Change From Baseline In Quality Of Life In Neurological Disorders (Neuro-QoL) Fatigue Score At Week 8
The Neuro-QoL Fatigue questionnaire is a reliable and validated brief 19-item survey of fatigue, completed by the participant. Each item is scored on a scale of 1-5, with 1 indicating never and 5 indicating sometimes. The Neuro-QoL Fatigue score was calculated as the sum of the scores of the 19 items and ranges from 19-95, with higher scores indicating greater fatigue and greater impact of MG on activities. Baseline score at each timepoint as the response variable, treatment group, study visit, and treatment-by-study visit interaction as fixed categorical effects, and baseline Neuro-QoL Fatigue score as a covariate were used to calculate the LS mean and the standard error.
Time frame: Baseline, Week 8
Population: Full Analysis Set: all participants who received at least 1 dose of study intervention. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: ALXN2050 180 mg BID | Change From Baseline In Quality Of Life In Neurological Disorders (Neuro-QoL) Fatigue Score At Week 8 | -8.7 units on a scale | Standard Error 2.65 |
| Group 2: ALXN2050 120 mg BID | Change From Baseline In Quality Of Life In Neurological Disorders (Neuro-QoL) Fatigue Score At Week 8 | -10.1 units on a scale | Standard Error 3.77 |
| Group 3: Placebo | Change From Baseline In Quality Of Life In Neurological Disorders (Neuro-QoL) Fatigue Score At Week 8 | -8.3 units on a scale | Standard Error 2.73 |
Secondary
Change From Baseline In Quantitative Myasthenia Gravis (QMG) Total Score At Week 8
The QMG Score for Disease Severity is an objective evaluation of therapy for MG and is based on quantitative testing of sentinel muscle groups. The QMG instrument consists 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 QMG total score was calculated as the sum of the scores of the 13 items and ranges from 0 to 39, with higher scores indicating more severe disease. Baseline score at each timepoint as the response variable, treatment group, study visit, and treatment-by-study visit interaction as fixed categorical effects, and baseline QMG total score as a covariate were used to calculate the least square (LS) mean and the standard error.
Time frame: Baseline, Week 8
Population: Full Analysis Set: all participants who received at least 1 dose of study intervention. Here, Overall Number of Participants Analyzed signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Group 1: ALXN2050 180 mg BID | Change From Baseline In Quantitative Myasthenia Gravis (QMG) Total Score At Week 8 | -1.1 units on a scale | Standard Error 0.67 |
| Group 2: ALXN2050 120 mg BID | Change From Baseline In Quantitative Myasthenia Gravis (QMG) Total Score At Week 8 | -3.0 units on a scale | Standard Error 0.98 |
| Group 3: Placebo | Change From Baseline In Quantitative Myasthenia Gravis (QMG) Total Score At Week 8 | -1.4 units on a scale | Standard Error 0.68 |