Generalized Myasthenia Gravis
Conditions
Brief summary
A randomized, double-blind, placebo-controlled multicenter study evaluating the safety and efficacy of Rituximab (Mabthera®) in patients with new onset generalized myasthenia gravis (MG).
Detailed description
Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction caused by auto-antibodies. MG is characterized by weakness in skeletal muscles and occurs in all ages, but mostly among young adult women and in people of both sexes over the age of 60 years. The disease has a wide variation in severity, where in milder cases only symptom-relieving choline esterase blockers may be sufficient. In many cases, however, immunomodulatory drugs are required. Traditionally MG has been treated with high doses of corticosteroids over longer time periods, which causes significant risks of side effects. Therefore, since several decades, oral immunosuppressive drugs have been used in order to reduce the need for steroids. This group includes azathioprine, cyclosporine and mycophenolate. However, none of these drugs has been approved for use in MG and the effect is usually delayed. There is thus a great need to develop newer treatment algorithms for MG, for example including more effective biological drugs. Several small observational studies have shown that rituximab, an anti-CD20 monoclonal antibody that eliminate B cells, can have good effects in treatment refractory MG. The aim of the present study is to study the effect of rituximab compared to placebo in the treatment of new onset MG of moderate to severe symptomatology.
Interventions
DRUGRituximab
A single infusion at a dose of 500 mg Mabthera/Rituximab.
A single infusion of Placebo/Sham.
Sponsors
Fredrik Piehl
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients with oculobulbar, bulbar or generalized MG ≥ 18 years of age and with onset of generalized symptoms or neurophysiological detection of generalized disease not more than 12 months ago. 2. The diagnosis of MG should be determined with the following: Clinical neurological status with motor symptoms consistent with MG and at least two of the following: a positive serologic test for anti-acetylcholine receptor antibody (AChR) and/or b. typical MG findings on neurophysiological testing of neuromuscular transmission with single fiber electromyography (SFEMG) and / or repetitive nerve stimulation (RNS), and / or c. Positive anti-choline esterase-test, e.g. edrophoniumchloride or improvement of MG symptoms with oral cholinesterase inhibitors as judged by the treating physician. 3. MGFA Class II to IV at screening. 4. Quantitative MG score ≥ 6 at screening 5. Women of childbearing potential must have a negative pregnancy test. 6. Patients must have provided written informed consent. 7. Patients must be able and willing to comply with all study procedures.
Exclusion criteria
1. Weakness only affecting ocular or periocular muscles (MGFA Class I). 2. MG crisis at screening (MGFA Class V) 3. Thymectomy already carried out. In order to avoid difficulties to evaluate the effect of the study drug, thymectomy, where it is indicated, should be scheduled to the follow-up period, ie after the first 24 weeks. 4. Strong suspicion of thymoma, where thymectomy as judged by the treating physician should be done within 24 weeks. 5. Active malignancy, if not adequately treated 6. Pregnancy or breast-feeding. 7. Ongoing acute or chronic viral or systemic bacterial infections including HIV, latent hepatitis B, which is clinically significant, according to the study doctor's opinion and not treated with appropriate antibiotic / antiviral drugs. 8. Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease 9. Previous use of immunosuppressive drugs, including rituximab, except prednisolone at a dose of up to 40mg daily for less than 3 months. This does not apply to treatment with immunosuppressive drugs / corticosteroids (except rituximab) for other indications than MG, provided at least 12 months have passed since treatment was terminated. 10. Suspected hypersensitivity to the study drug 11. Participation in another trial of study drug within 30 days prior to screening. 12. Any medical condition which, according to the study physician's opinion, may interfere with the patient's participation in the study, poses additional risks for the patient, or that complicate the assessment of patients. 13. Vaccination within 4 weeks before inclusion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Quantitative MG Score (QMG) Score ≤ 4 and a Daily Prednisolon Dose of ≤ 10mg at 16 Weeks After Administration of Study Drug/Placebo. | 16 weeks | The Quantitative Myasthenia Gravis (QMG) score is a physician rated disease activity score that ranges from 0 to 39, where lower indicates better outcome. QMG was measured at 16 weeks under standardized conditions with at least 12 hours since last intake of choline esterase inhibitors. Patients meeting the primary outcome had a QMG score of 4 or less whilst also requiring a daily oral Prednisolone dose of 10 mg or less. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in QMG Score From Week 0 to Week 24 After Administration of Study Drug/Placebo. | 24 weeks | The Quantitative Myasthenia Gravis (QMG) score is a physician rated disease activity score that ranges from 0 to 39, where lower indicates better outcome. QMG was measured under standardized conditions with at least 12 hours since last intake of choline esterase inhibitors. Change in QMG scores between the two time points was compared between groups. |
| Change in Myasthenia Gravis Activities of Daily Living (MG-ADL) Score From Week 0 to Week 16 After Administration of Study Drug/Placebo | 16 weeks | The Myasthenia Gravis Activities of Daily Living (MG-ADL) score is a patient rated disease activity score that ranges from 0 to 24, where lower indicates better outcome. MG-ADL was assessed at 16 weeks under standardized conditions with at least 12 hours since last intake of choline esterase inhibitors. Change in MG-ADL scores between the two time points was compared between groups. |
| Change in Myasthenia Gravis Quality of Life (QoL) Score From Week 0 to Week 16 After Administration of Study Drug/Placebo. | 16 weeks | The Myasthenia Quality of Life (QoL) score is a patient rated quality of life score that ranges from 0 to 60, where lower indicates better outcome. Change in MG-QoL scores between the two time points was compared between groups. . |
Other
| Measure | Time frame | Description |
|---|---|---|
| MG-QoL Score at 24, 36 and 48 Weeks After Administration of Study Drug/Placebo | 24, 36 and 48 weeks | MG-QoL is a patient-reported outcome measured under standardized conditions with at least 12 hours since last intake of choline esterase inhibitors |
| Percentage of Patients With Quantitative MG Ascore (QMG) Score ≤ 4 and a Daily Prednisolon Dose of ≤ 10mg at 24 Weeks After Administration of Study Drug/Placebo. | 24 weeks | The Quantitative Myasthenia Gravis (QMG) score is a physician rated disease activity score that ranges from 0 to 39, where lower indicates better outcome. QMG was measured at 24 weeks under standardized conditions with at least 12 hours since last intake of choline esterase inhibitors. Patients meeting the primary outcome had a QMG score of 4 or less whilst also requiring a daily oral Prednisolone dose of 10 mg or less. |
| Rescue Treatments During Week 8 to 24 After Administration of Study Drug/Placebo | 8 - 24 weeks | The number of events when rescue treatment was given during week 8-24 of the study. Rescue treatments were defined as i.v immunoglobulins, plasma exchange, high dose corticosteroids and biologics (rituximab, tocilizumab). |
| Number of Hospital Admissions for MG Worsening During Week 0 to 24 After Administration of Study Drug/Placebo | 24 weeks | The total number of hospital admissions for MG worsening during week 0 to 24 of the study. |
| QMG Scores at 16, 36 and 48 Weeks After Administration of Study Drug/Placebo. | 16, 36 and 48 weeks | QMG is measured under standardized conditions with at least 12 hours since last intake of choline esterase inhibitors |
| MG-activities of Daily Living (ADL) Score at 24, 36 and 48 Weeks After Administration of Study Drug/Placebo | 24, 36 and 48 weeks | MG-ADL is a patient-reported outcome measured under standardized conditions with at least 12 hours since last intake of choline esterase inhibitors |
| EQ5D Score at 16, 24, 36 and 48 Weeks After Administration of Study Drug/Placebo | 16, 24, 36 and 48 weeks | The EQ5D scale is a generic QoL score measured under standardized conditions with at least 12 hours since last intake of choline e |
Countries
Sweden
Participant flow
Recruitment details
Between October 16th, 2016, and March 2nd, 2020, 87 potentially eligible patients were screened at 7 Swedish neurology clinics (5 university hospitals, 2 regional hospitals). 47 fulfilled inclusion and exclusion criteria and provided informed consent to participation.
Pre-assignment details
All included participants received study drug
Participants by arm
| Arm | Count |
|---|---|
| Rituximab A single infusion at a dose of 500 mg of Mabthera/Rituximab in Sodium Chloride solution. | 25 |
| Sodium Chloride Solution A single infusion with sodium chloride solution in infusion bag matched to active treatment. | 22 |
| Total | 47 |
Baseline characteristics
| Characteristic | Rituximab | Sodium Chloride Solution | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 10 Participants | 8 Participants | 18 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 14 Participants | 29 Participants |
| Age, Continuous | 67.4 years STANDARD_DEVIATION 13.4 | 58.0 years STANDARD_DEVIATION 18.6 | 63.0 years STANDARD_DEVIATION 16.6 |
| Body mass index | 27.5 kg/m^2 STANDARD_DEVIATION 3.7 | 27.6 kg/m^2 STANDARD_DEVIATION 5.7 | 27.5 kg/m^2 STANDARD_DEVIATION 4.7 |
| Concentration of acetylcholine receptor antibodies | 22.7 nmol/L STANDARD_DEVIATION 19.3 | 70.7 nmol/L STANDARD_DEVIATION 117 | 46.7 nmol/L STANDARD_DEVIATION 86.5 |
| Dose of Prednisolone (mg/day) | 22.5 mg/day STANDARD_DEVIATION 10.8 | 20.8 mg/day STANDARD_DEVIATION 9 | 21.8 mg/day STANDARD_DEVIATION 9.9 |
| Early-onset myasthenia gravis | 2 Participants | 7 Participants | 9 Participants |
| Intravenous immunoglobulins prior to baseline | 8 Participants | 8 Participants | 16 Participants |
| Myasthenia Gravis Activities of Daily Living score | 5.1 units on a scale STANDARD_DEVIATION 3.2 | 4.5 units on a scale STANDARD_DEVIATION 2.7 | 4.9 units on a scale STANDARD_DEVIATION 2.9 |
| Myasthenia Gravis Quality of Life questionnaire score | 20.1 units on a scale STANDARD_DEVIATION 11 | 22.2 units on a scale STANDARD_DEVIATION 12.8 | 21.1 units on a scale STANDARD_DEVIATION 11.8 |
| Ocular symptoms prior to generalized symptoms of myasthenia gravis | 4 participants | 2 participants | 6 participants |
| Plasmapheresis prior to baseline | 1 Participants | 0 Participants | 1 Participants |
| Prednisolone | 16 Participants | 12 Participants | 28 Participants |
| Quantitative Myasthenia Gravis score | 9.4 units on a scale STANDARD_DEVIATION 4.5 | 9.3 units on a scale STANDARD_DEVIATION 4.5 | 9.4 units on a scale STANDARD_DEVIATION 4.4 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Region of Enrollment Sweden | 25 participants | 22 participants | 47 participants |
| Sex: Female, Male Female | 7 Participants | 7 Participants | 14 Participants |
| Sex: Female, Male Male | 18 Participants | 15 Participants | 33 Participants |
| Time since onset of generalized symptoms of myasthenia gravis | 132.4 days STANDARD_DEVIATION 91.5 | 143.0 days STANDARD_DEVIATION 93.3 | 137.4 days STANDARD_DEVIATION 91.5 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 25 | 0 / 22 |
| other Total, other adverse events | 21 / 25 | 17 / 22 |
| serious Total, serious adverse events | 5 / 25 | 4 / 22 |
Outcome results
Primary
Percentage of Patients With Quantitative MG Score (QMG) Score ≤ 4 and a Daily Prednisolon Dose of ≤ 10mg at 16 Weeks After Administration of Study Drug/Placebo.
The Quantitative Myasthenia Gravis (QMG) score is a physician rated disease activity score that ranges from 0 to 39, where lower indicates better outcome. QMG was measured at 16 weeks under standardized conditions with at least 12 hours since last intake of choline esterase inhibitors. Patients meeting the primary outcome had a QMG score of 4 or less whilst also requiring a daily oral Prednisolone dose of 10 mg or less.
Time frame: 16 weeks
Population: Missing data, rituximab=1, placebo=1
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rituximab | Percentage of Patients With Quantitative MG Score (QMG) Score ≤ 4 and a Daily Prednisolon Dose of ≤ 10mg at 16 Weeks After Administration of Study Drug/Placebo. | 17 Participants |
| Sodium Chloride Solution | Percentage of Patients With Quantitative MG Score (QMG) Score ≤ 4 and a Daily Prednisolon Dose of ≤ 10mg at 16 Weeks After Administration of Study Drug/Placebo. | 6 Participants |
Comparison: The primary end-point was analyzed as an intention-to-treat analysis, with Fisher's exact test of the difference in proportion, with α=0·05 to indicate statistically significant differencep-value: 0.00795% CI: [1.2, 5.11]Fisher Exact
Secondary
Change in Myasthenia Gravis Activities of Daily Living (MG-ADL) Score From Week 0 to Week 16 After Administration of Study Drug/Placebo
The Myasthenia Gravis Activities of Daily Living (MG-ADL) score is a patient rated disease activity score that ranges from 0 to 24, where lower indicates better outcome. MG-ADL was assessed at 16 weeks under standardized conditions with at least 12 hours since last intake of choline esterase inhibitors. Change in MG-ADL scores between the two time points was compared between groups.
Time frame: 16 weeks
Population: censured patients, rituximab=3, placebo=7
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rituximab | Change in Myasthenia Gravis Activities of Daily Living (MG-ADL) Score From Week 0 to Week 16 After Administration of Study Drug/Placebo | -1.7 change in score points | Standard Deviation 2.5 |
| Sodium Chloride Solution | Change in Myasthenia Gravis Activities of Daily Living (MG-ADL) Score From Week 0 to Week 16 After Administration of Study Drug/Placebo | -0.5 change in score points | Standard Deviation 3.6 |
Comparison: Subjects receiving rescue treatment before evaluation being censored (per-protocol analysis)p-value: 0.3495% CI: [-3.3, 0.8]Wilcoxon (Mann-Whitney)
Secondary
Change in Myasthenia Gravis Quality of Life (QoL) Score From Week 0 to Week 16 After Administration of Study Drug/Placebo.
The Myasthenia Quality of Life (QoL) score is a patient rated quality of life score that ranges from 0 to 60, where lower indicates better outcome. Change in MG-QoL scores between the two time points was compared between groups. .
Time frame: 16 weeks
Population: censured patients, rituximab=3, placebo=7
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rituximab | Change in Myasthenia Gravis Quality of Life (QoL) Score From Week 0 to Week 16 After Administration of Study Drug/Placebo. | -9.2 change in score points | Standard Deviation 9.2 |
| Sodium Chloride Solution | Change in Myasthenia Gravis Quality of Life (QoL) Score From Week 0 to Week 16 After Administration of Study Drug/Placebo. | -7.0 change in score points | Standard Deviation 9.3 |
Comparison: Subjects receiving rescue treatment before evaluation being censored (per-protocol analysis)p-value: 0.4795% CI: [-8.2, 3.8]Wilcoxon (Mann-Whitney)
Secondary
Change in QMG Score From Week 0 to Week 24 After Administration of Study Drug/Placebo.
The Quantitative Myasthenia Gravis (QMG) score is a physician rated disease activity score that ranges from 0 to 39, where lower indicates better outcome. QMG was measured under standardized conditions with at least 12 hours since last intake of choline esterase inhibitors. Change in QMG scores between the two time points was compared between groups.
Time frame: 24 weeks
Population: censured patients, rituximab=2, placebo=9
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rituximab | Change in QMG Score From Week 0 to Week 24 After Administration of Study Drug/Placebo. | -6.9 change in score points | Standard Deviation 5.6 |
| Sodium Chloride Solution | Change in QMG Score From Week 0 to Week 24 After Administration of Study Drug/Placebo. | -5.8 change in score points | Standard Deviation 4.6 |
Comparison: Subjects receiving rescue treatment before evaluation being censored (per-protocol analysis)p-value: 0.7995% CI: [-4.4, 2.1]Wilcoxon (Mann-Whitney)
Other Pre-specified
EQ5D Score at 16, 24, 36 and 48 Weeks After Administration of Study Drug/Placebo
The EQ5D scale is a generic QoL score measured under standardized conditions with at least 12 hours since last intake of choline e
Time frame: 16, 24, 36 and 48 weeks
Other Pre-specified
MG-activities of Daily Living (ADL) Score at 24, 36 and 48 Weeks After Administration of Study Drug/Placebo
MG-ADL is a patient-reported outcome measured under standardized conditions with at least 12 hours since last intake of choline esterase inhibitors
Time frame: 24, 36 and 48 weeks
Other Pre-specified
MG-QoL Score at 24, 36 and 48 Weeks After Administration of Study Drug/Placebo
MG-QoL is a patient-reported outcome measured under standardized conditions with at least 12 hours since last intake of choline esterase inhibitors
Time frame: 24, 36 and 48 weeks
Other Pre-specified
Number of Hospital Admissions for MG Worsening During Week 0 to 24 After Administration of Study Drug/Placebo
The total number of hospital admissions for MG worsening during week 0 to 24 of the study.
Time frame: 24 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab | Number of Hospital Admissions for MG Worsening During Week 0 to 24 After Administration of Study Drug/Placebo | 0 hospital adminssions |
| Sodium Chloride Solution | Number of Hospital Admissions for MG Worsening During Week 0 to 24 After Administration of Study Drug/Placebo | 3 hospital adminssions |
Other Pre-specified
Percentage of Patients With Quantitative MG Ascore (QMG) Score ≤ 4 and a Daily Prednisolon Dose of ≤ 10mg at 24 Weeks After Administration of Study Drug/Placebo.
The Quantitative Myasthenia Gravis (QMG) score is a physician rated disease activity score that ranges from 0 to 39, where lower indicates better outcome. QMG was measured at 24 weeks under standardized conditions with at least 12 hours since last intake of choline esterase inhibitors. Patients meeting the primary outcome had a QMG score of 4 or less whilst also requiring a daily oral Prednisolone dose of 10 mg or less.
Time frame: 24 weeks
Population: missing data, rituximab=0, placebo=1
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rituximab | Percentage of Patients With Quantitative MG Ascore (QMG) Score ≤ 4 and a Daily Prednisolon Dose of ≤ 10mg at 24 Weeks After Administration of Study Drug/Placebo. | 18 Participants |
| Sodium Chloride Solution | Percentage of Patients With Quantitative MG Ascore (QMG) Score ≤ 4 and a Daily Prednisolon Dose of ≤ 10mg at 24 Weeks After Administration of Study Drug/Placebo. | 8 Participants |
p-value: 0.03695% CI: [1.04, 3.44]Fisher Exact
Other Pre-specified
QMG Scores at 16, 36 and 48 Weeks After Administration of Study Drug/Placebo.
QMG is measured under standardized conditions with at least 12 hours since last intake of choline esterase inhibitors
Time frame: 16, 36 and 48 weeks
Other Pre-specified
Rescue Treatments During Week 8 to 24 After Administration of Study Drug/Placebo
The number of events when rescue treatment was given during week 8-24 of the study. Rescue treatments were defined as i.v immunoglobulins, plasma exchange, high dose corticosteroids and biologics (rituximab, tocilizumab).
Time frame: 8 - 24 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rituximab | Rescue Treatments During Week 8 to 24 After Administration of Study Drug/Placebo | 1 events |
| Sodium Chloride Solution | Rescue Treatments During Week 8 to 24 After Administration of Study Drug/Placebo | 8 events |