Myasthenia Gravis
Conditions
Keywords
Myasthenia Gravis
Brief summary
Randomized, double-blind, placebo-controlled, Phase 3, parallel-group study with optional open-label extension.
Detailed description
This study is a phase 3, randomized, double-blind, placebo-controlled study, to be conducted at approximately 120 study sites. Approximately 230 participants (188 acetylcholine receptor antibody positive \[AChR-Ab+\] and 42 muscle-specific tyrosine kinase antibody positive \[MuSK-Ab+\]) will be enrolled. Participants with Myasthenia Gravis (MG) who are positive for anti-AChR or anti-MuSK antibodies will be enrolled and analyzed. Patients who do not have anti-AChR or anti-MuSK antibodies will not be enrolled. Patients with Myasthenia Gravis Foundation of America (MGFA) classification II, III, or IV disease, Myasthenia Gravis Activities of Daily Living (MG-ADL) score at screening and randomization between 6 and 10 with \> 50% of this score attributed to non-ocular items, or an MG-ADL score \>=11, Quantitative Myasthenia Gravis (QMG) score \>= 11 at the time of screening and randomization, and use of a corticosteroid and/or non-steroidal immunosuppressant will be included in the study. All subjects who complete the randomized controlled period (RCP) will have the option to enroll in a 3-year (156 weeks) open-label period. Study acquired from Horizon in 2023.
Interventions
DRUGinebilizumab
Participants will receive IV inebilizumab
DRUGIV Placebo
Participants will receive IV placebo matched to inebilizumab
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
This is a double-blind study in which the IV inebilizumab and the IV placebo are matching in appearance.
Intervention model description
A Randomized, Double-blind, Multicenter, Placebo-controlled Phase 3 Study with Open-label Period
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of MG with anti-AChR or anti-MuSK antibody. 2. MGFA Clinical Classification Class II, III, or IV. 3. MG-ADL score of 6 or greater at screening and at randomization with \> 50% of this score attributed to non-ocular items. 4. QMG score of 11 or greater. 5. Participants must be on: 1. Corticosteroids only, with no dose increase within 4 weeks prior to randomization, or 2. One allowed non-steroidal immunosuppressive therapy (IST), with continuous use for at least 6 months prior to randomization and no dose increase within 4 months prior to randomization, or 3. Combination of (1) corticosteroids with no dose increase within 4 weeks prior to randomization and (2) one allowed non-steroidal IST with continuous use for at least 6 months prior to randomization and no dose increase within 4 months prior to randomization. Allowed ISTs, alone or in combination with corticosteroids, are azathioprine, mycophenolate mofetil, and mycophenolic acid.
Exclusion criteria
1. Receipt of the following medications within the 4 weeks prior to Day 1: 1. Cyclosporine (except eye drops) 2. Tacrolimus (except topical) 3. Methotrexate 2. Current use of: 1. Corticosteroids (Prednisone \> 40 milligram (mg)/day or \> 80 mg over a 2-day period (or equivalent dose of other corticosteroids). 2. Acetylcholinesterase inhibitors (pyridostigmine) \> 480 mg/day) or unstable dose in the 2 weeks prior to Day 1. 3. Azathioprine \> 3 mg/kilogram (kg)/day 4. Mycophenolate mofetil \> 3 grams/day or mycophenolic acid \> 1440 mg/day 5. Any IST, alone or in combination with corticosteroids, except for azathioprine, mycophenolate mofetil, and mycophenolic acid.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline at Week 26 in Myasthenia Gravis Activities of Daily Living (MG-ADL) Score in the Overall Study Population | Baseline and Week 26 | MG-ADL score is an 8-item questionnaire that focuses on relevant symptoms and functional performance of activities of daily living over the previous 7 days. The MG-ADL score assesses 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. Each response is graded 0 (normal) to 3 (most severe). The range of total MG-ADL scores is 0-24. A higher score represents more severe disease Outcome measure is reported for the overall population. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Quantitative Myasthenia Gravis (QMG) Score at Week 26 in the Overall Study Population | Baseline and Week 26 | The QMG score is a validated outcome comprised of 13 items: ocular (2 items), facial (1 item), bulbar (2 items), gross motor (6 items), axial (1 item), and respiratory (1 item). Each item has a possible score of between 0 and 3 points. The total score range is 0-39 points, with higher score indicating more severe disease. Outcome measure is reported for the overall population. |
| Change From Baseline at Week 26 in MG-ADL Score in Anti-AChR-Ab+ and Anti-MuSK-Ab+ Populations | Baseline and Week 26 | MG-ADL score is an 8-item questionnaire that focuses on relevant symptoms and functional performance of activities of daily living over the previous 7 days. The MG-ADL score assesses 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. Each response is graded 0 (normal) to 3 (most severe). The range of total MG-ADL scores is 0-24. A higher score represents more severe disease. Outcome measure is reported for the Anti-AChR-Ab+ and Anti-MuSK-Ab+ populations. |
| Change From Baseline in QMG Score at Week 26 in Anti-AChR-Ab+ and Anti-MuSK-Ab+ Populations | Baseline and Week 26 | The QMG score is a validated outcome comprised of 13 items: ocular (2 items), facial (1 item), bulbar (2 items), gross motor (6 items), axial (1 item), and respiratory (1 item). Each item has a possible score of between 0 and 3 points. The total score range is 0-39 points, with higher score indicating more severe disease. Outcome measure is reported for the Anti-AChR-Ab+ and Anti-MuSK-Ab+ populations. |
| Percentage of Participants With Both ≥ 3-point Improvement in MG-ADL Score at Week 26 and no Use of Rescue Therapy Between Day 28 and Week 26 in the Overall Study Population | Up to Week 26 | MG-ADL score is an 8-item questionnaire that focuses on relevant symptoms and functional performance of activities of daily living over the previous 7 days. The MG-ADL score assesses 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. Each response is graded 0 (normal) to 3 (most severe). The range of total MG-ADL scores is 0-24. A higher score represents more severe disease. The protocol-allowed rescue therapy options included intravenous immunoglobulin (IVIg) and therapeutic plasma exchange (PLEX). Outcome measure is reported for the overall population. |
| Percentage of Participants With Both ≥ 3-point Improvement in MG-ADL Score at Week 26 and no Use of Rescue Therapy Between Day 28 and Week 26 in Anti-AChR-Ab+ and Anti-MuSK-Ab+ Populations | Up to Week 26 | MG-ADL score is an 8-item questionnaire that focuses on relevant symptoms and functional performance of activities of daily living over the previous 7 days. The MG-ADL score assesses 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. Each response is graded 0 (normal) to 3 (most severe). The range of total MG-ADL scores is 0-24. A higher score represents more severe disease. The protocol-allowed rescue therapy options included IVIg and PLEX. Outcome measure is reported in Anti-AChR-Ab+ and Anti-MuSK-Ab+ populations. |
| Percentage of Participants With Both ≥ 3-point Improvement in MG-ADL Score at Week 52 and no Use of Rescue Therapy Between Day 28 and Week 52 in Anti-AChR-Ab+ Population | Up to Week 52 | MG-ADL score is an 8-item questionnaire that focuses on relevant symptoms and functional performance of activities of daily living over the previous 7 days. The MG-ADL score assesses 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. Each response is graded 0 (normal) to 3 (most severe). The range of total MG-ADL scores is 0-24. A higher score represents more severe disease. The protocol-allowed rescue therapy options included IVIg and PLEX. Outcome measure is reported for the Anti-AChR-Ab+ population. |
| Change From Baseline in MG-ADL Score at Week 52 in the Anti-AChR-Ab+ Population | Baseline and Week 52 | MG-ADL score is an 8-item questionnaire that focuses on relevant symptoms and functional performance of activities of daily living over the previous 7 days. The MG-ADL score assesses 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. Each response is graded 0 (normal) to 3 (most severe). The range of total MG-ADL scores is 0-24. A higher score represents more severe disease. Outcome measure is reported for the Anti-AChR-Ab+ population. |
| Change From Baseline in QMG Score at Week 52 in the Anti-AChR-Ab+ Population | Baseline and Week 52 | The QMG score is a validated outcome comprised of 13 items: ocular (2 items), facial (1 item), bulbar (2 items), gross motor (6 items), axial (1 item), and respiratory (1 item). Each item has a possible score of between 0 and 3 points. The total score range is 0-39 points, with higher score indicating more severe disease. Outcome measure is reported for the Anti-AChR-Ab+ population. |
| Change From Baseline in Myasthenia Gravis Composite (MGC) Score at Week 26 in the Overall Study Population | Baseline and Week 26 | The MGC score consists of test items from MG-ADL score and the QMG score, with weighted response options. Scores range from 0-50, with higher scores indicating worse disease manifestations. Outcome measure is reported for the overall population. |
| Change From Baseline in MGC Score at Week 26 in Anti-AChR-Ab+ and Anti-MuSK-Ab+ Populations | Baseline and Week 26 | The MGC score consists of test items from MG-ADL score and the QMG score, with weighted response options. Scores range from 0-50, with higher scores indicating worse disease manifestations. Outcome measure is reported for the Anti-AChR-Ab+ and Anti-MuSK-Ab+ populations. |
| Change From Baseline in MGC Score at Week 52 in Anti-AChR-Ab+ Population | Baseline and Week 52 | The MGC score consists of test items from MG-ADL score and the QMG score, with weighted response options. Scores range from 0-50, with higher scores indicating worse disease manifestations. Outcome measure is reported for the Anti-AChR-Ab+ population. |
| Change From Baseline in Myasthenia Gravis Quality of Life-15, Revised (MGQOL-15r) Score at Week 26 in the Overall Study Population | Baseline and Week 26 | MGQOL-15r score is a validated, patient-scored instrument, which measures the impact of MG on health-related quality of life (HRQoL). The 15 items in the questionnaire evaluate mobility (9 items), symptoms (3 items), general contentment (1 item), and emotional well-being (2 items) domains. Each item is rated on a 3-point scale ranging from 0 ("not at all") to 2 ("very much") based on their experience "over the past few weeks." Items scores are summed to generate a total score ranging from 0-45, with higher score indicating worse HRQoL. Outcome measure is reported for the overall population. |
| Change From Baseline in MGQOL-15r Score at Week 26 in Anti-AChR-Ab+ and Anti-MuSK-Ab+ Populations | Baseline and Week 26 | MGQOL-15r score is a validated, patient-scored instrument, which measures the impact of MG on health-related quality of life (HRQoL). The 15 items in the questionnaire evaluate mobility (9 items), symptoms (3 items), general contentment (1 item), and emotional well-being (2 items) domains. Each item is rated on a 3-point scale ranging from 0 ("not at all") to 2 ("very much") based on their experience "over the past few weeks." Items scores are summed to generate a total score ranging from 0-45, with higher score indicating worse HRQoL. Outcome measure is reported in Anti-AChR-Ab+ and Anti-MuSK-Ab+ populations. |
| Change From Baseline in MGQOL-15r Score at Week 52 in Anti-AChR-Ab+ Population | Baseline and Week 52 | MGQOL-15r score is a validated, patient-scored instrument, which measures the impact of MG on health-related quality of life (HRQoL). The 15 items in the questionnaire evaluate mobility (9 items), symptoms (3 items), general contentment (1 item), and emotional well-being (2 items) domains. Each item is rated on a 3-point scale ranging from 0 ("not at all") to 2 ("very much") based on their experience "over the past few weeks." Items scores are summed to generate a total score ranging from 0-45, with higher score indicating worse HRQoL. Outcome Measure is reported for the Anti-AChR-Ab+ population. |
| Percentage of Participants With Patient Global Impression of Change (PGIC) Scores at Week 26 in the Overall Study Population | Week 26 | The self-report measure PGIC reflects a participant's belief about the efficacy of treatment. PGIC is a 7 point scale depicting a participant's rating of overall improvement. Participant rate their change as "very much improved", "much improved", "minimally improved", "no change", "minimally worse", "much worse", or "very much worse", Outcome measure is reported for the overall population. |
| Percentage of Participants With PGIC Scores at Week 26 in Anti-AChR-Ab+ and Anti-MuSK-Ab+ Populations | Week 26 | The self-report measure PGIC reflects a participant's belief about the efficacy of treatment. PGIC is a 7 point scale depicting a participant's rating of overall improvement. Participants rate their change as "very much improved", "much improved", "minimally improved", "no change", "minimally worse", "much worse", or "very much worse". Outcome measure is reported for the Anti-AChR-Ab+ and Anti-MuSK-Ab+ populations. |
| Percentage of Participants With PGIC Scores at Week 52 in Anti-AChR-Ab+ Population | Week 52 | The self-report measure PGIC score reflects a participant's belief about the efficacy of treatment. PGIC is a 7 point scale depicting a participant's rating of overall improvement. participants rate their change as "very much improved", "much improved", "minimally improved", "no change", "minimally worse", "much worse", or "very much worse". Outcome measure is reported for the Anti-AChR-Ab+ population. |
| Percentage of Participants Experiencing Exacerbation by Week 26 in the Overall Study Population | Up to Week 26 | An exacerbation was defined as one of the following: * Use of protocol defined rescue therapy, or * Myasthenic crisis, defined as worsening of myasthenic weakness requiring intubation or non-invasive ventilation to avoid intubation, except when these measures are employed during routine postoperative management, or * Significant symptomatic worsening to a score of 3 or a 2-point worsening from baseline on any one of the individual MG-ADL items other than double vision or eyelid droop. Outcome measure is reported for the overall population. |
| Percentage of Participants Experiencing Exacerbation by Week 26 in Anti-AChR-Ab+ and Anti-MuSK-Ab+ Populations | Up to Week 26 | An exacerbation was defined as one of the following: * Use of protocol defined rescue therapy, or * Myasthenic crisis, defined as worsening of myasthenic weakness requiring intubation or non-invasive ventilation to avoid intubation, except when these measures are employed during routine postoperative management, or * Significant symptomatic worsening to a score of 3 or a 2-point worsening from baseline on any one of the individual MG-ADL items other than double vision or eyelid droop. Outcome measure is reported for the Anti-AChR-Ab+ and Anti-MuSK-Ab+ populations. |
| Percentage of Participants Experiencing Exacerbation by Week 52 in Anti-AChR-Ab+ Population | Up to Week 52 | An exacerbation was defined as one of the following: * Use of protocol defined rescue therapy, or * Myasthenic crisis, defined as worsening of myasthenic weakness requiring intubation or non-invasive ventilation to avoid intubation, except when these measures are employed during routine postoperative management, or * Significant symptomatic worsening to a score of 3 or a 2-point worsening from baseline on any one of the individual MG-ADL items other than double vision or eyelid droop. Outcome measure is reported for the Anti-AChR-Ab+ population. |
| Percentage of Participants Achieving Minimal Symptom Expression (MSE) at Week 26 | From Day 28 to Week 26 | MSE was defined as MG-ADL= 0 or 1. Outcome measure is reported for the Anti-AChR-Ab+ and Anti-MuSK+ populations. |
| Percentage of Participants With Steroid Tapered to ≤ 5 mg/Day Steroid at Week 26 in the Overall Study Population | Week 26 | Outcome measure is reported for the overall population. |
| Percentage of Participants With Steroid Tapered to ≤ 5 mg/Day Steroid at Week 26 in Anti-AChR-Ab+ and Anti-MuSK-Ab+ Populations | Week 26 | Outcome measure is reported in Anti-AChR-Ab+ and Anti-MuSK-Ab+ populations. |
| Percentage of Participants With Steroid Tapered to ≤ 5 mg/Day Steroid at Week 52 in Anti-AChR-Ab+ Population | Week 52 | Outcome measure is reported for the Anti-AChR-Ab+ population. |
| Percentage of Participants Who Achieved ≥ 50% Steroid Reduction at Week 26 in the Overall Study Population | Week 26 | Outcome measure is reported for the overall population. |
| Percentage of Participants Who Achieved ≥ 50% Steroid Reduction at Week 26 in the Anti-AChR-Ab+ and Anti-MuSK-Ab+ Populations | Week 26 | Outcome measure is reported for the Anti-AChR-Ab+ and Anti-MuSK-Ab+ populations. |
| Percentage of Participants Who Achieved ≥ 50% Steroid Reduction at Week 52 in the Anti-AChR-Ab+ Population | Week 52 | Outcome measure is reported for the Anti-AChR-Ab+ population. |
| Percentage of Participants Experiencing Treatment Emergent Adverse Events (TEAEs), AE of Special Interest (AESIs) and Serious TEAEs (SAEs). | For RCP AE reporting: from Day 1 to the end of RCP or cutoff date (up to 65.4 weeks) | An AE is any untoward medical occurrence associated with the use of the IP, whether or not it is considered related. Clinically significant changes from baseline in clinical laboratory results, vital signs and ECGs were also reported as AEs. An AESI is an event of medical interest specific to the understanding of the IP and which may require close monitoring and collection of additional information. A SAE is considered "serious" if it results in any of the following outcomes: * Death; * A life-threatening AE. An event is considered "life-threatening" if its occurrence places the patient or subject at immediate risk of death; * Inpatient hospitalization or prolongation of existing hospitalization; * A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; * A congenital anomaly/birth defect; * May require medical or surgical intervention to prevent one of the outcomes listed in this definition. |
| Percentage of Participants With Anti-drug Antibodies (ADA) by Week 26 in the Overall Study Population | From Baseline to Week 26 | Treatment emergent ADA were defined as ADA positive post-baseline only or boosted pre-existing ADA titer. Outcome measure is reported for the overall population. |
| Percentage of Participants With ADA by Week 26 in Anti-AChR-Ab+ and Anti-MuSK-Ab+ Populations | From Baseline to Week 26 | Treatment emergent ADA were defined as ADA positive post-baseline only or boosted pre-existing ADA titer. Outcome measure is reported in Anti-AChR-Ab+ and Anti-MuSK-Ab+ populations. |
| Percentage of Participants With ADA by Week 52 in Anti-AChR-Ab+ Population | From Baseline to Week 52 | Treatment emergent ADA were defined as ADA positive post-baseline only or boosted pre-existing ADA titer. Outcome measure is reported for the Anti-AChR-Ab+ population. |
| Time to Maximum Serum Concentration (Tmax) of Inebilizumab in Anti-AChR-Ab+ and Anti-MuSK-Ab+ Populations | Days 1 and 15 for Anti-MuSK-Ab+ population; Days 1, 15 and 183 (Week 26) for Anti-AChR-Ab+ population | On inebilizumab dosing days, inebilizumab pharmacokinetic (PK) serum samples were collected pre-dose and approximately 15 minutes (± 5 minutes) after completion of the IP infusion. Outcome measure is reported for the Anti-AChR-Ab+ and Anti-MuSK-Ab+ populations. |
| Maximum Observed Serum Concentration (Cmax) of Inebilizumab in Anti-AChR-Ab+ and Anti-MuSK-Ab+ Populations | Days 1 and 15 for Anti-MuSK-Ab+ population; Days 1, 15 and 183 (Week 26) for Anti-AChR-Ab+ population | On inebilizumab dosing days, inebilizumab PK serum samples were collected pre-dose and approximately 15 minutes (± 5 minutes) after completion of the IP infusion. Outcome measure is reported for the Anti-AChR-Ab+ and Anti-MuSK-Ab+ populations. |
| Percentage of Participants With no Use of Rescue Therapy Between Day 28 and Week 52 in Anti-AChR-Ab+ Population | Up to Week 52 | The protocol-allowed rescue therapy options included corticosteroids, IVIg and PLEX. Outcome measure is reported for the Anti-AChR-Ab+ population. |
| Area Under the Serum Concentration Time Curve of the Dosing Interval (AUC0-14d) of Inebilizumab | Days 1 and 15 for Anti-MuSK-Ab+ population; Days 1, 15 and 183 (Week 26) for Anti-AChR-Ab+ population | On inebilizumab dosing days, inebilizumab PK serum samples were collected pre-dose and approximately 15 minutes (± 5 minutes) after completion of the IP infusion. Outcome measure is reported for the Anti-AChR-Ab+ and Anti-MuSK-Ab+ populations. |
Countries
Argentina, Belarus, Brazil, Canada, China, Denmark, France, Germany, India, Italy, Japan, Poland, Russia, South Korea, Spain, Taiwan, Turkey (Türkiye), Ukraine, United States
Contacts
STUDY_DIRECTORMD
Amgen
Participant flow
Recruitment details
A total of 238 participants were enrolled in 18 countries, from 15 October 2020. This study is ongoing. Data cut-off date for primary analysis was 28 May 2024.
Pre-assignment details
The study consisted of a Randomized Controlled Period (RCP) which lasted 52 weeks for the anti-AChR-Ab+ population and 26 weeks for the anti-MuSK-Ab+ population and an optional Open-label Period (OLP) of the duration of 3 years. This study also has a 2-year safety follow up period. The primary analysis was conducted when the last participants had the opportunity to complete Week 26 visit.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 3 Participants |
| Age, Categorical Between 18 and 65 years | 200 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 86 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants |
| Race/Ethnicity, Customized Asian | 40 Participants |
| Race/Ethnicity, Customized Black or African American | 5 Participants |
| Race/Ethnicity, Customized Moore than one race | 0 Participants |
| Race/Ethnicity, Customized Other | 2 Participants |
| Race/Ethnicity, Customized Unknown or not reported | 2 Participants |
| Race/Ethnicity, Customized White | 126 Participants |
| Sex: Female, Male Female | 145 Participants |
| Sex: Female, Male Male | 46 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 119 | 1 / 119 | 1 / 178 |
| other Total, other adverse events | 47 / 119 | 53 / 119 | 40 / 178 |
| serious Total, serious adverse events | 16 / 119 | 10 / 119 | 14 / 178 |
Outcome results
None listed