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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).
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Rituximab | Experimental | A single infusion at a dose of 500 mg of Mabthera/Rituximab. |
|
| Sodium Chloride solution | Sham Comparator | A single infusion with sodium chloride solution. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Rituximab | Drug | A single infusion at a dose of 500 mg Mabthera/Rituximab. |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 16 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
Inclusion Criteria:
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.
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.
MGFA Class II to IV at screening.
Quantitative MG score ≥ 6 at screening
Women of childbearing potential must have a negative pregnancy test.
Patients must have provided written informed consent.
Patients must be able and willing to comply with all study procedures.
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Fredrik Piehl, Professor | Dept Clinical Neuroscience Karolinska Institutet, Neuroimmunology Unit | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Karolinska University Hospital | Stockholm | Solna | 171 76 | Sweden |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36121672 | Derived | Piehl F, Eriksson-Dufva A, Budzianowska A, Feresiadou A, Hansson W, Hietala MA, Hakansson I, Johansson R, Jons D, Kmezic I, Lindberg C, Lindh J, Lundin F, Nygren I, Punga AR, Press R, Samuelsson K, Sundstrom P, Wickberg O, Brauner S, Frisell T. Efficacy and Safety of Rituximab for New-Onset Generalized Myasthenia Gravis: The RINOMAX Randomized Clinical Trial. JAMA Neurol. 2022 Nov 1;79(11):1105-1112. doi: 10.1001/jamaneurol.2022.2887. |
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All included participants received study drug
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | Rituximab | A single intravenous infusion at a dose of 500 mg of Mabthera/Rituximab in Sodium Chloride solution. |
| FG001 | Placebo | A single intravenous infusion with sodium chloride solution in infusion bag matched to active treatment. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Rituximab | A single infusion at a dose of 500 mg of Mabthera/Rituximab in Sodium Chloride solution. |
| BG001 | Sodium Chloride Solution | A single infusion with sodium chloride solution in infusion bag matched to active treatment. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Missing data, rituximab=1, placebo=1 | Posted | Count of Participants | Participants | 16 weeks |
|
48 weeks, i.e. time from baseline to last follow up.
The definitions described in clinicaltrials.gov are used with no exception. Information on potential adverse events was collected at each study visit (n=5) and telephone follow-ups (n=4).
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Rituximab | A single infusion at a dose of 500 mg of Mabthera/Rituximab in Sodium Chloride solution. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anemia | Blood and lymphatic system disorders | SNOMED CT | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Rash | Skin and subcutaneous tissue disorders | SNOMED CT | Systematic Assessment |
Imbalances in some baseline characteristics, with a lower age, higher AChR antibody titres, a lower proportion treated with prednisolone, and a greater proportion with MGFA class III disease among those randomized to placebo compared with rituximab. On the other hand, late onset MG has been associated with worse disease, and one subject in the active arm suffered a condition (ALS) that effectively excluded the possibility to evaluate a treatment effect.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Prof. Fredrik Piehl | Karolinska Institutet | +46 736718101 | fredrik.piehl@ki.se |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Apr 26, 2021 | Aug 2, 2024 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D009157 | Myasthenia Gravis |
| ID | Term |
|---|---|
| D020361 | Paraneoplastic Syndromes, Nervous System |
| D009423 | Nervous System Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
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| ID | Term |
|---|---|
| D000069283 | Rituximab |
| D012965 | Sodium Chloride |
| ID | Term |
|---|---|
| D058846 | Antibodies, Monoclonal, Murine-Derived |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
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| Sodium Chloride solution | Drug | A single infusion of Placebo/Sham. |
|
|
| 24 weeks |
| 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. | 16 weeks |
| 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. . | 16 weeks |
| 24 weeks |
| 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 | 16, 36 and 48 weeks |
| 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 | 24, 36 and 48 weeks |
| 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 | 16, 24, 36 and 48 weeks |
| 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 | 24, 36 and 48 weeks |
| 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. | 24 weeks |
| 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). | 8 - 24 weeks |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Body mass index | Mean | Standard Deviation | kg/m^2 |
|
| Concentration of acetylcholine receptor antibodies | Mean | Standard Deviation | nmol/L |
|
| Time since onset of generalized symptoms of myasthenia gravis | Mean | Standard Deviation | days |
|
| Ocular symptoms prior to generalized symptoms of myasthenia gravis | Number | participants |
|
| Quantitative Myasthenia Gravis score | The Quantitative Myasthenia Gravis (QMG) score is a physician rated disease activity score which ranges from 0 (minimum) to 39 (maximum) units on the scale. Lower score indicates better outcome. | Mean | Standard Deviation | units on a scale |
|
| Myasthenia Gravis Quality of Life questionnaire score | The Myasthenia Gravis Quality of Life (MG-QoL) questionnaire is a patient rated quality of life score which ranges from 0 (minimum) to 60 (maximum) units on the scale. Lower score indicates better outcome. | Mean | Standard Deviation | units on a scale |
|
| Myasthenia Gravis Activities of Daily Living score | The Myasthenia Gravis Activities of Daily Living (MG-ADL) scale is a patient rated disease activity score which ranges from 0 (minimum) to 24 (maximum) units on the scale. Lower score indicates better outcome. | Mean | Standard Deviation | units on a scale |
|
| Prednisolone | Number of patients treated with oral Prednisolone at baseline. | Count of Participants | Participants |
|
| Dose of Prednisolone (mg/day) | Average daily dose Prednisolone for the above indicated patients treated with oral Prednisolone at baseline. | Average daily dose of Prednisolone for patients treated at baseline. | Mean | Standard Deviation | mg/day |
|
| Intravenous immunoglobulins prior to baseline | Number of patients treated with intravenous immunoglobulins (IVIG) within three months prior to baseline. | Count of Participants | Participants |
|
| Plasmapheresis prior to baseline | Number of patients treated with Plasmapheresis (PLEX) within three months prior to baseline. | Count of Participants | Participants |
|
| Early-onset myasthenia gravis | Subgroup defined as anti-AChR+ and age <50 years at onset | Count of Participants | Participants |
|
| OG001 |
| Sodium Chloride Solution |
A single infusion with sodium chloride solution in infusion bag matched to active treatment. |
|
|
|
| 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. | censured patients, rituximab=2, placebo=9 | Posted | Mean | Standard Deviation | change in score points | 24 weeks |
|
|
|
|
| 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. | censured patients, rituximab=3, placebo=7 | Posted | Mean | Standard Deviation | change in score points | 16 weeks |
|
|
|
|
| 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. . | censured patients, rituximab=3, placebo=7 | Posted | Mean | Standard Deviation | change in score points | 16 weeks |
|
|
|
|
| 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. | missing data, rituximab=0, placebo=1 | Posted | Count of Participants | Participants | 24 weeks |
|
|
|
|
| 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 | Not Posted | 16, 36 and 48 weeks | Participants |
| 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 | Not Posted | 24, 36 and 48 weeks | Participants |
| 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 | Not Posted | 16, 24, 36 and 48 weeks | Participants |
| 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 | Not Posted | 24, 36 and 48 weeks | Participants |
| 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. | Posted | Number | hospital adminssions | 24 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). | Posted | Number | events | 8 - 24 weeks |
|
|
|
| 1 |
| 25 |
| 5 |
| 25 |
| 21 |
| 25 |
| EG001 | Sodium Chloride Solution | A single infusion with sodium chloride solution in infusion bag matched to active treatment. | 0 | 22 | 4 | 22 | 17 | 22 |
| Pneumonia | Infections and infestations | SNOMED CT | Systematic Assessment |
|
| Septicaemia | Infections and infestations | SNOMED CT | Systematic Assessment |
|
| Nausea | Nervous system disorders | SNOMED CT | Systematic Assessment |
|
| Ileus | Gastrointestinal disorders | SNOMED CT | Systematic Assessment |
|
| Chest pain | Cardiac disorders | SNOMED CT | Systematic Assessment |
|
| Asystole | Cardiac disorders | SNOMED CT | Systematic Assessment |
|
| Vertebral compression fracture | Musculoskeletal and connective tissue disorders | SNOMED CT | Systematic Assessment |
|
| Syncope | Cardiac disorders | SNOMED CT | Systematic Assessment |
|
| Thymoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | SNOMED CT | Systematic Assessment |
|
| Allergic reaction | Skin and subcutaneous tissue disorders | SNOMED CT | Systematic Assessment |
|
| Dry mouth | Gastrointestinal disorders | SNOMED CT | Systematic Assessment |
|
| Arrythmia | Cardiac disorders | SNOMED CT | Systematic Assessment |
|
| Upper respiratory infection | Infections and infestations | SNOMED CT | Systematic Assessment |
|
| Conjunctivitis | Eye disorders | SNOMED CT | Systematic Assessment |
|
| Fever of unknown cause | Infections and infestations | SNOMED CT | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | SNOMED CT | Systematic Assessment |
|
| Diarrhea | Gastrointestinal disorders | SNOMED CT | Systematic Assessment |
|
| Rectal bleeding | Gastrointestinal disorders | SNOMED CT | Systematic Assessment |
|
| Fatigue | General disorders | SNOMED CT | Systematic Assessment |
|
| Anemia | Blood and lymphatic system disorders | SNOMED CT | Systematic Assessment |
|
| Muscle cramps | Musculoskeletal and connective tissue disorders | SNOMED CT | Systematic Assessment |
|
| Vertigo | Ear and labyrinth disorders | SNOMED CT | Systematic Assessment |
|
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | SNOMED CT | Systematic Assessment |
|
| Urine leaks | Renal and urinary disorders | SNOMED CT | Systematic Assessment |
|
| Kidney stone | Renal and urinary disorders | SNOMED CT | Systematic Assessment |
|
| Urinary tract infection | Renal and urinary disorders | SNOMED CT | Systematic Assessment |
|
| Bite from animal (dog) | Injury, poisoning and procedural complications | SNOMED CT | Systematic Assessment |
|
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| D010257 | Paraneoplastic Syndromes |
| D020274 | Autoimmune Diseases of the Nervous System |
| D009422 | Nervous System Diseases |
| D019636 | Neurodegenerative Diseases |
| D020511 | Neuromuscular Junction Diseases |
| D009468 | Neuromuscular Diseases |
| D001327 | Autoimmune Diseases |
| D007154 | Immune System Diseases |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |