Myasthenia Gravis
Conditions
Keywords
Myasthenia Gravis, Rituximab, SNOMED code 31839002
Brief summary
The specific primary objective of this study is to determine whether rituximab is a safe and beneficial therapeutic for Myasthenia Gravis (MG) that warrants further study in a phase III efficacy trial.
Detailed description
Investigators plan on conducting a multicenter randomized, double-blind, placebo controlled Phase II clinical trial utilizing a futility design. The study would include acetylcholine receptor (AChR) antibody positive generalized MG subjects. This study also presents a unique opportunity to study both drug and disease mechanisms because unlike many other autoimmune diseases in which rituximab has been used, MG affords the investigation of antigen-specific components that participate in the immunopathology of the disease, namely autoantibodies, autoantibody-producing B cells, and antigen-specific T cells. This work will further our understanding of MG immunopathology and it represents the first step toward gaining a more complete understanding of the immune mechanisms underlying treatment of MG with rituximab leading to new ways to treat the disease. The specific aim of this study is to determine whether rituximab is a safe and effective treatment for subjects with MG. The SNOMED code for MG is 31839002.
Interventions
DRUGRituximab
Intervention (rituximab): The treatment group will receive a total of two cycles of rituximab separated by 6 months. Each cycle is defined as one infusion (375mg/m2 IV) per week for four consecutive weeks
DRUGPlacebo
The placebo group will receive a vehicle control infusion
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 90 Years
Healthy volunteers
No
Inclusion criteria
1. Subjects 21 to 90 years old 2. Subjects must have generalized MG, defined as MGFA clinical classification grades 2 (mild), 3 (moderate), or 4 (severe, but not intubated) at the time of screening/randomization. 3. Elevated AChR antibody titer 4. Subject's signs and symptoms should not be better explained by another disease process. 5. Subjects must be on a stable standard immunosuppressive regimen: 1. Prednisone only: Prednisone dose must be at least 15mg/day (or the equivalent on alternate days), and the dose of prednisone must have been stable for at least 4 weeks (28 days) prior to the baseline visit. 2. Prednisone plus another immunosuppressive therapy (IST). Immunosuppressive therapies other than prednisone, specifically azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus or methotrexate, are permitted, but the dose must have been stable for at least 6 months prior to the baseline visit. (Note: The prednisone dose must be stable as defined in the prednisone only group. The IST dose must remain stable throughout the course of the study). 6. Subjects must be willing to complete the study and return for follow-up visits. 7. No history of thymoma, tumor, infection, or interstitial lung disease on chest CT, MRI, or chest x-ray. Note: Chest x-ray will be completed at screening to look of interstitial lung disease. A chest CT or MRI to evaluate for thymoma must be completed as part of prescreening. 8. Able and willing to give written informed consent and comply with the requirements of the study protocol. 9. Subjects must be able to give written informed consent before participating in this study. A copy of the signed consent must be kept in the subject's medical record. 10. Men and women of reproductive potential must agree to use an acceptable method of birth control during treatment and for twelve months (1 year) after completion of treatment.
Exclusion criteria
1. A history of chronic degenerative, psychiatric, or neurologic disorder other than MG that can produce weakness or fatigue. 2. Other major chronic or debilitating illnesses within six months prior to study entry. 3. Female subjects who are premenopausal and are: 1. pregnant on the basis of a serum pregnancy test, 2. breast-feeding, or 3. not using an effective method of double barrier (1 hormonal plus 1 barrier method or 2 simultaneous barrier methods) or birth control (birth control pills, male condom, female condom, intrauterine device, Norplant, tubal ligation, or other sterilization procedures). 4. Altered levels of consciousness, dementia, or abnormal mental status. 5. Thymectomy in the previous six months. 6. Subjects who have been medicated with immunosuppressive drugs not listed in inclusion #5 within the last 8 weeks (56 days) prior to the baseline visit 7. Subjects who have been medicated with an immunosuppressive agent such as azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus or methotrexate, that is withdrawn within 8 weeks (56 days) of the Baseline Visit. 8. Subjects who have received IVIg or PLEX treatment within the last 4 weeks (28 days) prior to the baseline visit. 9. Unstable dose or a stable dose of \> 480 mg/day of pyridostigmine in 2 weeks prior to screening visit. 10. Daily use of non-steroidal anti-inflammatory drugs (NSAIDs). 11. History of renal or hepatic insufficiency or elevated liver enzymes (AST or ALT \>2.5 x Upper Limit of Normal). 12. History of bone marrow hypoplasia, leucopenia, thrombocytopenia, significant anemia, clinical or laboratory evidence of immunodeficiency syndromes. 13. Forced Vital Capacity (FVC) \<50% of percent predicted. General Safety & Laboratory
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Steroid Sparing Effect | 4 weeks prior baseline and 4 weeks prior to week 52 | Percent of subjects that achieve a ≥ 75% reduction in mean daily prednisone dose in the 4 weeks prior to week 52 and have clinical improvement or no significant worsening of symptoms (≤ 2 point increase in MGC score) as compared to 4-week period prior to randomization and initiation of treatment. |
| Safety:Percentage of Study Participants With Treatment-related Adverse Experiences | 52 weeks | Evaluate treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Myasthenia Gravis Composite (MGC) Scores From Baseline to Week 52 | baseline and 52 weeks | Evaluate whether there is a trend towards clinical benefit at end of 52 week treatment period, as measured by mean change in the MGC score, an MG-specific clinical outcomes scale used as endpoint in prior MG clinical trials. The Myasthenia Gravis Composite (MGC) scale consists of test items from the MG-ADL (Myasthenia Gravis Activities of Daily Living) scale and the QMG (Quantitative Myasthenia Gravis Scale) that measure symptoms and signs of MG, with weighted response options. The minimum score is 0, and the maximum score is 50. Higher scores correlate with clinical worsening of the disease. |
| Change in Quantitative Myasthenia Gravis(QMG) Scores From Baseline to Week 52 | baseline and 52 weeks | Evaluate whether there is a trend towards clinical benefit at end of 52 week treatment period, as measured by the mean change in the QMG score - a specific clinical outcome scale used as endpoint in prior MG clinical trials. The Quantitative Myasthenia Gravis Score (QMG) is a commonly used objective outcome measure in myasthenia gravis (MG) comprising 13 items, each with a possible score from 0 to 3, and a maximum possible of 39 points, where a higher score indicates more severe disease. |
Countries
United States
Participant flow
Pre-assignment details
68 study participants were consented and assessed for eligibility. 14 participants were ineligible. 2 participants declined. 52 study participants were randomized.
Participants by arm
| Arm | Count |
|---|---|
| Rituximab \- Treatment group received two cycles of rituximab (375mg/m2 iv), separated by 6 months. Each cycle defined as one infusion per week for four consecutive weeks. For the main study, participants were followed for 52 weeks. Study participants had clinical evaluations performed by a blinded evaluator at baseline and every 4 weeks thereafter. | 25 |
| Placebo \- Placebo group received infusion containing only vehicle components of rituximab solution. Infusion was done in 2 cycles, separated by 6 months. Each cycle defined as one infusion per week for four consecutive weeks. For the main study, participants were followed for 52 weeks. Study participants had clinical evaluations performed by a blinded evaluator at baseline and every 4 weeks thereafter. | 27 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 3 |
| Overall Study | Patients who didn't receive 2nd infusion | 3 | 1 |
Baseline characteristics
| Characteristic | Rituximab | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 53.2 years STANDARD_DEVIATION 17.5 | 56.8 years STANDARD_DEVIATION 17 | 55.1 years STANDARD_DEVIATION 17.1 |
| Baseline MG-Activities of Daily Living Score | 5.8 units on a scale STANDARD_DEVIATION 3.6 | 4.0 units on a scale STANDARD_DEVIATION 3.4 | 4.9 units on a scale STANDARD_DEVIATION 3.6 |
| Baseline MGFA Clinical Classification Grade Class I | 0 Participants | 1 Participants | 1 Participants |
| Baseline MGFA Clinical Classification Grade Class II | 15 Participants | 16 Participants | 31 Participants |
| Baseline MGFA Clinical Classification Grade Class III | 9 Participants | 9 Participants | 18 Participants |
| Baseline MGFA Clinical Classification Grade Class IV | 1 Participants | 1 Participants | 2 Participants |
| Baseline MG-Quality of Life (MG-QOL) score | 22.7 units on a scale STANDARD_DEVIATION 14.1 | 17.7 units on a scale STANDARD_DEVIATION 10.6 | 20.1 units on a scale STANDARD_DEVIATION 12.5 |
| Baseline Myasthenia Gravis Composite (MGC) | 11.1 units on a scale STANDARD_DEVIATION 6.1 | 8.5 units on a scale STANDARD_DEVIATION 4 | 9.8 units on a scale STANDARD_DEVIATION 5.2 |
| Baseline Prednisone Dose | 23 mg/day STANDARD_DEVIATION 11.2 | 21.3 mg/day STANDARD_DEVIATION 8.3 | 22.1 mg/day STANDARD_DEVIATION 9.7 |
| Baseline Quantitative Myasthenia Gravis (QMG) | 11.0 units on a scale STANDARD_DEVIATION 5.1 | 9.2 units on a scale STANDARD_DEVIATION 3.9 | 10.1 units on a scale STANDARD_DEVIATION 4.5 |
| Race/Ethnicity, Customized Race and ethnicity African American | 2 Participants | 9 Participants | 11 Participants |
| Race/Ethnicity, Customized Race and ethnicity Asian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race and ethnicity Hispanic | 3 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Race and ethnicity Non-Hispanic white | 20 Participants | 15 Participants | 35 Participants |
| Sex: Female, Male Female | 11 Participants | 12 Participants | 23 Participants |
| Sex: Female, Male Male | 14 Participants | 15 Participants | 29 Participants |
| Thymectomy | 8 Participants | 4 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 27 |
| other Total, other adverse events | 25 / 25 | 26 / 27 |
| serious Total, serious adverse events | 9 / 25 | 14 / 27 |
Outcome results
Primary
Safety:Percentage of Study Participants With Treatment-related Adverse Experiences
Evaluate treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: 52 weeks
Population: Intention to treat participants
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Rituximab | Safety:Percentage of Study Participants With Treatment-related Adverse Experiences | % of participants with treatment related AEs | 19 Participants |
| Rituximab | Safety:Percentage of Study Participants With Treatment-related Adverse Experiences | % participants with treatment related SAEs | 6 Participants |
| Placebo | Safety:Percentage of Study Participants With Treatment-related Adverse Experiences | % of participants with treatment related AEs | 22 Participants |
| Placebo | Safety:Percentage of Study Participants With Treatment-related Adverse Experiences | % participants with treatment related SAEs | 8 Participants |
Comparison: % of study participants with treatment related AEsp-value: 0.6390% CI: [0.23, 2.21]t-test, 2 sided
Comparison: % study participants with treatment related SAEsp-value: 0.6590% CI: [0.27, 2.11]t-test, 2 sided
Primary
Steroid Sparing Effect
Percent of subjects that achieve a ≥ 75% reduction in mean daily prednisone dose in the 4 weeks prior to week 52 and have clinical improvement or no significant worsening of symptoms (≤ 2 point increase in MGC score) as compared to 4-week period prior to randomization and initiation of treatment.
Time frame: 4 weeks prior baseline and 4 weeks prior to week 52
Population: Intention to treat participants
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rituximab | Steroid Sparing Effect | 15 Participants |
| Placebo | Steroid Sparing Effect | 15 Participants |
Comparison: This futility design tests the following hypothesis:~H0: Rituximab improves outcome by at least 30% compared to placebo (pR - pP ≥ 0.30 - not futile) versus HA: Rituximab does not improve outcome by at least 30% compared to placebo (pR - pP \< 0.30 - futile)p-value: 0.03Regression, Logistic
Secondary
Change in Myasthenia Gravis Composite (MGC) Scores From Baseline to Week 52
Evaluate whether there is a trend towards clinical benefit at end of 52 week treatment period, as measured by mean change in the MGC score, an MG-specific clinical outcomes scale used as endpoint in prior MG clinical trials. The Myasthenia Gravis Composite (MGC) scale consists of test items from the MG-ADL (Myasthenia Gravis Activities of Daily Living) scale and the QMG (Quantitative Myasthenia Gravis Scale) that measure symptoms and signs of MG, with weighted response options. The minimum score is 0, and the maximum score is 50. Higher scores correlate with clinical worsening of the disease.
Time frame: baseline and 52 weeks
Population: Intention to treat participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rituximab | Change in Myasthenia Gravis Composite (MGC) Scores From Baseline to Week 52 | -5.7 score on a scale | Standard Deviation 7.26 |
| Placebo | Change in Myasthenia Gravis Composite (MGC) Scores From Baseline to Week 52 | -4.0 score on a scale | Standard Deviation 4.1 |
Comparison: This objective was assessed longitudinally by comparing the final score at the end of the study to the score obtained at baseline. The outcome was defined as the change from baseline to week 52 in the MGC. This hypothesis was assessed using a linear regression model, adjusted for differences in baseline MGC scores.p-value: 0.93Regression, Linear
Secondary
Change in Quantitative Myasthenia Gravis(QMG) Scores From Baseline to Week 52
Evaluate whether there is a trend towards clinical benefit at end of 52 week treatment period, as measured by the mean change in the QMG score - a specific clinical outcome scale used as endpoint in prior MG clinical trials. The Quantitative Myasthenia Gravis Score (QMG) is a commonly used objective outcome measure in myasthenia gravis (MG) comprising 13 items, each with a possible score from 0 to 3, and a maximum possible of 39 points, where a higher score indicates more severe disease.
Time frame: baseline and 52 weeks
Population: Intention to treat participants
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rituximab | Change in Quantitative Myasthenia Gravis(QMG) Scores From Baseline to Week 52 | -3.95 score on a scale | Standard Deviation 5.43 |
| Placebo | Change in Quantitative Myasthenia Gravis(QMG) Scores From Baseline to Week 52 | -1.70 score on a scale | Standard Deviation 3.91 |
Comparison: This objective was assessed longitudinally by comparing the final score at the end of the study to the score obtained at baseline. The outcome was defined as the change from baseline to week 52 in the QMG. This hypothesis was assessed using a linear regression model, adjusted for differences in baseline QMG scores.p-value: 0.39Regression, Linear