Clinical trial NCT02950155
Conditions: Generalized Myasthenia Gravis
Sponsor: Fredrik Piehl
Start date: 2016-10-16; Completion date: 2022-01-31
Enrollment: 47 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 1: A single infusion at a dose of 500 mg of Mabthera/Rituximab. arm 2: A single infusion with sodium chloride solution.
Interventions: intervention 1: Rituximab intervention 2: Sodium Chloride solution
Intervention descriptions: intervention 1: A single infusion at a dose of 500 mg Mabthera/Rituximab. intervention 2: A single infusion of Placebo/Sham.

Protocol documents:
Prot_SAP_000.pdf: 
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The RINOMAX Study 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED MULTICENTER STUDY EVALUATING THE SAFETY 
AND EFFICACY OF RITUXIMAB (Mabthera®) IN PATIENTS WITH NEW ONSET GENERALIZED MYASTHENIA 
GRAVIS. 
 
 
 
 
 
Product: 
Mabthera® 
 
Substance: 
Rituximab 
 
EudraCT-number: 
2015-005749-30 
 
Sponsor: 
Karolinska Institutet 
Department of Clinical Neuroscience 
171 77 Stockholm 
 
 
Sponsor’s representative 
and coordinating 
investigator: 
Fredrik Piehl 
Neuroimmunology Unit. Dept Clinical Neuroscience. 
Karolinska Institutet 
CMM L8:4 Karolinska University Hospital (Solna) 
S171 76 Stockholm 
 
 
 
 
 


 
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Table of Contents 
 
1 
SUMMARY ................................................................................................................................................ 5 
2 
ABBREVIATIONS ........................................................................................................................................ 8 
3 
ADMINISTRATIVE INFORMATION .............................................................................................................. 9 
3.1 SPONSOR AND COORDINATING INVESTIGATOR ............................................................................................................ 9 
3.2 STUDY CENTERS AND PARTICIPATING INVESTIGATORS ................................................................................................... 9 
3.3 NEUROPHYSIOLOGIST  ......................................................................................................................................... 11 
3.4 BIOSTATISTICIAN ................................................................................................................................................ 11 
3.5 MONITORING .................................................................................................................................................... 11 
4 
SIGNATURES ........................................................................................................................................... 12 
5 
BACKGROUND ......................................................................................................................................... 13 
5.1 
BACKGRUND AND RATIONALE ........................................................................................................................ 13 
6 
STUDY QUESTIONS .................................................................................................................................. 14 
6.1 
PRIMARY QUESTION ..................................................................................................................................... 14 
6.2 
SECONDARY QUESTIONS ............................................................................................................................... 14 
6.3 
TERTIARY AND EXPLORATIVE QUESTIONS .......................................................................................................... 14 
7 
ENDPOINTS ............................................................................................................................................. 14 
7.1 
PRIMARY ENDPOINT ..................................................................................................................................... 14 
7.2 
SECONDARY ENDPOINTS ............................................................................................................................... 14 
7.3 
TERTIARY AND EXPLORATIVE ENDPOINTS .......................................................................................................... 14 
8 
DESIGN .................................................................................................................................................... 15 
8.1 
STUDY DESIGN ............................................................................................................................................ 15 
8.2 
SCREENING PERIOD ...................................................................................................................................... 15 
8.3 
RANDOMIZATION ........................................................................................................................................ 15 
8.4 
TREATMENT, BASELINE (WEEK 0) .................................................................................................................... 16 
8.5 
EVALUATION, OBSERVATION PERIOD (24 WEEKS) .............................................................................................. 17 
8.6 
FOLLOW UP PERIOD (WEEKS 25-48) ............................................................................................................... 17 
8.7 
STUDY END ................................................................................................................................................ 18 
9 
STUDY PARTICIPANTS ............................................................................................................................. 19 
9.1 
INCLUSION CRITERIA ..................................................................................................................................... 19 
9.2 
EXCLUSION CRITERIA  ................................................................................................................................... 19 
9.3 
CRITERIA FOR DISCONTINUING PARTICIPATION ................................................................................................... 20 
9.4 
SCREENING LOG .......................................................................................................................................... 20 
9.5 
STUDY PERSONELL ....................................................................................................................................... 20 
10 
STUDY DRUG ........................................................................................................................................... 20 
10.1 
STUDY DRUG .............................................................................................................................................. 20 
10.2 
DESCRIPTION OF STUDY DRUG ....................................................................................................................... 20 
10.3 
PLACEBO ................................................................................................................................................... 21 
10.4 
PACKAGING, LABELING AND HANDLING OF STUDY DRUG  ..................................................................................... 21 
10.5 
RANDOMIZATION  ....................................................................................................................................... 21 
10.6 
BLINDING AND EMERGENCY CODE BREAKING ..................................................................................................... 21 
10.7 
PERMITTED / NOT PERMITTED TREATMENTS IN DIFFERENT STUDY PHASES ............................................................... 21 


 
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10.8 
CLINICAL WORSENING, RESCUE TREATMENTS .................................................................................................... 22 
10.9 
STUDY DRUG DOCUMENTATION, ACCOUNTABILITY ............................................................................................. 23 
10.10 TREATMENT AFTER STUDY END ....................................................................................................................... 23 
11 
ASSESSMENT OF SAFETY AND EFFICACY .................................................................................................. 23 
11.1 
BLOOD SAMPLES ......................................................................................................................................... 23 
11.2 
QUANTITATIVE MYASTHENIA GRAVIS SCALE, QMG ........................................................................................... 23 
11.3 
MYASTHENIA GRAVIS ACTIVITIES OF DAILY LIFE SCALE, MG-ADL .......................................................................... 23 
11.4 
EUROQOL 5-DIMENSIONS QUALITY OF LIFE, EQ5D ............................................................................................ 23 
11.5 
QUALITY OF LIFE IN MYASTHENIA GRAVIS, MG-QOL15 ...................................................................................... 24 
11.6 
NEUROPHYSIOLOGY ..................................................................................................................................... 24 
11.7 
ADVERSE EVENT, AE AND SERIOUS ADVERSE EVENT, SAE. ................................................................................. 24 
12 
MANAGMENT OF ADVERSE EVENTS ........................................................................................................ 25 
12.1 
DEFINITIONS .............................................................................................................................................. 25 
12.2 
ASSESSEMENT OF ADVERSE EVENTS ................................................................................................................. 25 
12.3 
METHODS FOR DETECTION OF ADVERSE EVENTS ................................................................................................ 25 
12.4 
REPORTING OF ADVERSE EVENTS  .................................................................................................................... 26 
12.5 
FOLLOW UP OF ADVERSE EVENTS  ................................................................................................................... 26 
12.6 
ANNNUAL SAFETY REPORTING (DEVELOPMENT SAFETY UPDATE REPORT, DSUR) .................................................... 26 
13 
STATISTICS, DATA HANDLING AND ARCHIVING ....................................................................................... 27 
13.1 
DECIDING ON NUMBER OF STUDY SUBJECTS ...................................................................................................... 27 
13.2 
STATISTICAL ANALYSES.................................................................................................................................. 27 
13.3 
DATA HANDLING AND CASE REPORT FORMS, CRF ............................................................................................. 27 
13.4 
DATA PROCESSING ....................................................................................................................................... 28 
13.5 
ARCHIVING ................................................................................................................................................ 28 
14 
QUALITY CONTROL .................................................................................................................................. 28 
14.1 
SOURCE DATA............................................................................................................................................. 28 
14.2 
MONITORING ............................................................................................................................................. 28 
14.3 
ACCESS TO SOURCE DATA .............................................................................................................................. 28 
15 
ETHICS ..................................................................................................................................................... 28 
15.1 
ETHICS REVIEW BOARD AND MEDICAL PRODUCTS AGENCY  ................................................................................... 28 
15.2 
ETHICAL CONDITIONS FOR THE STUDY .............................................................................................................. 28 
15.3 
RISK BENEFIT ASSESSEMENT ........................................................................................................................... 29 
15.4 
COLLECTION OF INFORMED CONSENT .............................................................................................................. 29 
16 
INSURANCE ............................................................................................................................................. 30 
17 
FUNDING ................................................................................................................................................. 30 
18 
PUBLICATION OF RESULTS ....................................................................................................................... 30 
19 
REFERENCES ............................................................................................................................................ 31 
20 
ANNEX 1, FLOW CHART ........................................................................................................................... 32 
21 
ANNEX 2, MGFA CLASSIFICATION ............................................................................................................ 33 
22 
ANNEX 3, STUDY DRUG INFUSION/OBSERVATION .................................................................................. 34 
23 
ANNEX 4, QMG ....................................................................................................................................... 36 
24 
ANNEX 5, MG-QOL15 ............................................................................................................................ 388 
 


 
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ANNEX 6, MG-ADL ................................................................................................................................. 399 
26 
ANNEX 7, EQ5D ....................................................................................................................................... 40 
 
 


 
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Summary 
PROTOCOL IDENTITY AND STUDY OBJECTIVE 
EudraCT-number: 
2015-005749-30 
Protocol number 
2015-00887 
Protocol title: 
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). 
Study objective  
To evaluate the safety and efficacy of 
rituximab (Mabthera) in the treatment of 
patients with recent onset MG.  
STUDY DRUG 
Product:  
 
Mabthera (Rituximab) 
Pharmaceutical formula: 
Concentrate for infusion, solution 
Dose 
500 mg  
Mode of administration: 
Intravenous 
METODOLOGY 
 
Study design: 
Randomized, double-blind, placebo-controlled 
multicenter study  
Primary question: 
Is rituximab more effective than placebo at 
achieving minimal clinical MG symptoms 
without the need for higher doses of oral 
corticosteroids or rescue treatments at 16 
weeks post-treatment? 
Primary endpoint: 
Proportion of patients with QMG score ≤ 4 
and a daily dose of Prednisolone of ≤ 10mg 
and no rescue treatment at 16 weeks after 
study start  
STUDY POPULATION 
 
Study subjects: 
Patients with new onset generalized 
myasthenia gravis (MG) 
Study size:  
N=47 
Inclusion criteria 
1. Patients with oculobulbar, bulbar or 
generalized MG ≥ 18 years of age and ≤ 12 
months after onset of generalized symptoms 
or neurophysiological detection of generalized 
disease. 
2. The diagnosis of MG should be made by the 
following tests: 
Clinical neurological status with motor 
symptoms compatible with MG and ≥ 2 of the 
following: 
a Positive serological test for anti-
acetylcholine receptor antibodies (AChR), 
and/or 
b. For MG typical findings on neuro-
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transmission by single fiber electromyography 
(SFEMG) and / or repetitive nerve stimulation 
(RNS), 
and/or 
c. Positive anticholinesterase test, e.g. 
edrophonium chloride test or improvement of 
MG symptoms with oral cholinesterase 
inhibitors at the discretion of the treating 
physician. 
3. MGFA clinical classification 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 given written informed 
consent. 
7. Patients must be able and willing to follow 
all study procedures. 
 
Exclusion criteria 
Weakness affecting only ocular or periocular 
muscles (MGFA class I). 
2. MG crisis at screening (MGFA class V) 
3. Thymectomy already performed. To avoid 
difficulties in evaluating the effect of the study 
drug, thymectomy, in cases where it is 
deemed indicated, should be planned for the 
follow-up period, i.e. only after the first 24 
weeks. 
4. Strong suspicion of thymoma and where 
thymectomy according to the treating 
physician should be performed within 24 
weeks. 
5. Active cancer, unless adequately treated 
6. Pregnancy or breast-feeding. 
7. Any ongoing acute or chronic viral or 
systemic bacterial infection including HIV and 
latent hepatitis B, which is clinically significant 
in the opinion of the study physician, and 
which has not been treated with appropriate 
antibiotic / antiviral drugs. 
8. Severe heart failure (New York Heart 
Association Class IV) or severe uncontrolled 
heart disease 
9. Previous use of immunosuppressive drugs 
including rituximab, azathioprine, ciclosporin 
and MMF. The use of Prednisolone at a dose 
of ≤40mg / d within 3 months and IVIG and 
PLEX 12 months from the screening date does 
not constitute an exclusion criterion. Note 
that this does not apply to treatment with 
immunosuppressive drugs / corticosteroids 
(excluding rituximab) for indications other 
than MG, provided that> 12 months have 
elapsed since the end of treatment. 
10. Hypersensitivity to the active substance,  
to murine proteins or to any of the other 
excipients in the study medicinal product 
11. Participation in any other clinical drug 
study or exposure to any other study drug, 


 
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study product or study procedures within 30 
days before screening. 
12. Any medical condition which, in the 
opinion of the study physician, may interfere 
with the patient's participation in the study, 
poses any additional risk to the patient, or 
which complicates the assessment of the 
patients. 
13. Vaccination within 4 weeks before 
inclusion 
 
TIDSPLAN 
 
Study period: 
Q4 2016 – Q1 2021  
Recruitment period: 
Q4 2016 – Q1 2020  
 
 


 
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Abbreviations 
 
Förkortning 
Förklaring 
AE 
Adverse Event 
APL 
Apotek Produktion & Laboratorier AB  
CMM  
Center for Molecular Medicine  
DSUR 
Development Safety Update Report 
EQ5D 
EuroQol 5-dimensions  
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
IV 
Intravenous  
IVIG 
Intravenous immunoglobulines  
KI 
Karolinska Institutet  
MG 
Myasthenia gravis 
MGFA 
Myasthenia Gravis Foundation of America 
MG-QOL 15 
Quality of life - myasthenia gravis 
MMF 
Mycophenolate mofetil (Cellcept) 
RNS 
Repetitive nerve stimulation   
SAE 
Serious Adverse Event 
SUSAR 
Suspected Unexpected Serious Adverse Event  
QMG 
Quantitative Myasthenia Gravis scale  


 
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3 
Administrative information 
3.1 Sponsor and coordinating investigator 
Sponsor:  
 
Karolinska Institutet 
Department of Clinical Neuroscience 
171 77 Stockholm 
Sponsor´s representative/ 
coordinating investigator 
Fredrik Piehl, Neuroimmunology Unit. Dept Clinical Neuroscience 
 
 
CMM L8:4 Karolinska University Hospital (Solna) 
 
 
S171 76 Stockholm 
 
Telephone:  
 
+46 8 51779840 or +46-736718101 
Fax:  
 
+46 8 51773757 
E-mail: 
 
fredrik.piehl@ki.se 
 
3.2 Participating study centers   
3.2.1 Karolinska University Hospital 
3.2.1.1 Karolinska University Hospital, Solna 
Neurology Clinic 
171 76 Stockholm 
Principal investigator: 
Fredrik Piehl 
 
fredrik.piehl@ki.se  
Co-investigator:  
Albert Hietala  
hietala@mac.com 
 
3.2.1.2 Karolinska University Hospital, Huddinge 
Neurology Clinic  
141 86 Stockholm 
Principal investigator:  
Rayomand Press 
Rayomand.press@karolinska.se 
Co-investigators:  
Ivan Kmezic 
 
ivan.kmezic@gmail.com 
Katharina Fink  
katharina.fink@karolinska.se 
Kristin Samuelsson 
kristin.samuelsson@karolinska.se 
 
3.2.2 Akademic hospital Uppsala  
Neurology Clinic  
Akademiska sjukhuset 
751 85 Uppsala  
Principal investigato 
Ingela Nygren  
ingela.nygren@akademiska.se 
Co-investigator 
Anna Rostedt Punga 
annarostedtpunga@gmail.com 
Amalia Feresiadou 
feresiadouamalia@gmail.com 
 
 
 


 
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3.2.3 Central hospital Karlstad 
Neurology Clinic  
Centralsjukhuset 
Rosenborgsgatan 2 
651 85 Karlstad 
Principal investigator 
Rune Johansson 
Rune.Johansson@liv.se 
Co-investigator 
Oskar Wickberg  
oskar.wickberg@liv.se 
 
3.2.4 University Hospital Linköping 
Neurology Clinic 
Universitetssjukhuset i Linköping 
581 85 Linköping 
Principal investigator 
Fredrik Lundin  
fredrik.lundin@regionostergotland.se 
Co-investigator 
Irene Håkansson 
irene.hakansson@regionostergotland.se 
 
3.2.5 Sahlgrenska University Hospital 
Neurology Clinic  
Sahlgrenska Universitetssjukhuset 
413 46 Göteborg  
Principal investigator 
Daniel Jons 
 
daniel.jons@vgregion.se 
Co-investigator 
Christopher Lindberg 
christopher.lindberg@vgregion.se 
 
3.2.6 Norrland´s University Hospital 
Neurology Clinic 
Norrlands Universitetssjukhus 
901 85 Umeå 
Principal investigator 
Peter Sundström 
peter.sundstrom@umu.se 
Co-investigator 
Mattias Vågberg  
mattias.vagberg@umu.se 
 
3.2.7 Örebro University Hospital 
Neurology Clinic 
Universitetssjukhuset Örebro  
701 85 Örebro 
Principal investigator 
Martin Gunnarsson  
martin.gunnarsson@regionorebrolan.se 
Co-investigator 
Anna Wittrin  
 
anna.wittrin@regionorebrolan.se 
 
 


 
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 3.2.8 Östersund´s Hospital  
Östersunds sjukhus 
Neurologmottagningen 
831 83 Östersund 
Principal investigato 
Pierre De Flon   
pierre.deflon@regionjh.se 
 3.2.9 Ryhov´s Regional Hospital  
Neurology Section  
Department of Medicine 
Länssjukhuset Ryhov 
551 85 Jönköping 
Principal investigato 
Anna Budzianowska 
anna.budzianowska@rjl.se 
Co-investigator  
Jonas Lind 
 
jonas.lind@rlj.se 
 
            3.2.10 Skåne´s University Hospital 
Neurology Clinic  
Skånes Universitetssjukhus 
Jan Waldenströms gata 19 
222 41 Lund 
Principal investigato 
Andreea Ilianca                            andreea.ilianca@skane.se 
Co-investigator 
Fredrik Buchwald 
fredrik.buchwald@skane.se 
3.3 Neurophysiologist 
Anna Rostedt Punga 
annarostedtpunga@gmail.com 
Neurophysiology Clinic  
Akademiska sjukhuset 
751 85 Uppsala 
  
3.4 Biostatistician 
Thomas Frisell  
thomas.frisell@ki.se 
Department of Medicine 
Karolinska Institutet 
171 76 Stockholm 
 
3.5 Monitoring 
Karolinska Trial Alliance,  
kta@karolinska.se 
KTA Support  
Norra Stationsgatan 67 
171 76 Stockholm 


 
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4 
Signature page 
 
 
Sponsor/ 
coordinating investigator 
Fredrik Piehl 
Karolinska Institutet 
Department of Clinical Neuroscience 
Stockholm 
 
 
 
Signature
Date
 
 
 
 
 
 
 
Investigator 
Name, title 
Clinic 
Hospital 
 
 
 


 
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5 
Background 
5.1 Background and rationale 
Myasthenia gravis (MG) is a relatively rare autoimmune disease of the neuromuscular junction, caused by a 
defective neuromuscular transmission, which results from autoantibodies that bind to proteins involved in 
signaling at the neuromuscular synapse. MG is characterized by weakness and fatigue in skeletal muscles and 
occurs at all ages, but mainly among young adult women and in people of both sexes over 60 years. About 2,500 
people in Sweden have the disease according to a recent epidemiological study1. 
The disease has a large variation in severity, where in more severe cases you need intensive care for a shorter or 
longer periods of time. Traditionally, MG is treated with purely symptom-relieving drugs and immunomodulatory / 
suppressive drugs. Pure symptom-relieving cholinesterase inhibitors can be sufficient in milder cases, but 
immunosuppressive agents must often be used to avoid persistent symptoms, which can be life-threatening as a 
result of failing respiratory functions. 
MG is traditionally treated with high doses of corticosteroids (Prednisolone up to 60 mg / day) over a longer 
periods of time, which carries significant risks of side effects. Since the 1970s, therefore, oral immunosuppressive 
drugs have also been used as corticosteroid-sparing agents. This group includes azathioprine (Imurel), cyclosporine 
(Sandimmun) and mycophenolate (Cellcept). None of these drugs have the indication MG and the onset of effect is 
usually delayed. 
In the largest randomized study to date in MG, in which 176 patients with persistent symptoms were randomized 
1: 1 to mycophenolate or placebo, the active arm showed no significant improvement over placebo over 6 months 
on the primary endpoint; the proportion of patients with minimal symptoms and a daily dose of prednisolone ≤ 10 
mg per day (44% in active arm versus 39% in placebo)2. In another study, 80 patients with mild to moderate 
generalized AChR-positive MG and a daily dose of 20 mg Prednisolone were randomized to MMF and placebo, 
respectively, and followed for 12 weeks with MMF. The primary efficacy parameter was change in the quantitative 
MG (QMG) scale3, which did not differ significantly between the study arms (p = 0.71)4. These study results show 
that a significant proportion of MG patients continue to have generalized weakness involving limb weakness and 
bulbar symptoms (difficulty chewing, swallowing, speaking, and breathing) despite adequate dosing of 
immunosuppressive therapy. There is thus a great need to test newer treatment algorithms, which may include 
more effective biological drugs. 
Several minor observational studies have shown that rituximab, an anti-CD20 monoclonal antibody that eliminates 
B cells, may have beneficial effects in treatment-refractory MG. There are currently a couple of randomized drug 
trials with rituximab using a haematological treatment protocol with repeated dosing of the drug for several weeks, 
with a total dose of over 2,000 mg. At Karolinska University Hospital, in recent years, more than 30 patients with 
MG, both refractory and new-onset patients, have been treated with rituximab, with a single infusion of 500 mg 
with good results and without serious side effects. In some cases, the treatment has been repeated after 6-12 
months. An interesting observation is that the effect of the treatment seems to come much earlier than traditional 
immunosuppressive drugs, which leads to a reduced risk of hospitalizations and exposure to unnecessarily high 
cortisone doses. These experiences warrant further investigation of the efficacy and safety of rituximab in newly-
diagnosed MG patients with moderate-to-severe disease and a low-dose protocol. The same dose (500 mg) is used 
by us for multiple sclerosis, where we currently have about 500 patients under treatment at Karolinska University 
Hospital. 
The aim of the current study is to study the effect of rituximab compared to placebo in the treatment of newly 
debuted MG of at least moderate severity and with a risk of deterioration, i.e. subjects for whom prednisolone 
administration, repeated doses of IVIG or the addition of immunosuppressive medication may be indicated. 
 


 
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6 
Study questions 
6.1 Primary question 
Is rituximab more effective than placebo at achieving minimal clinical MG symptoms without the need for higher 
doses of oral corticosteroids or rescue treatments at 16 weeks post-treatment? 
6.2 Secondary questions 
Is rituximab more effective than placebo at achieving improvement in standardized muscle fatigue testing at 24 
weeks post-treatment? 
Is rituximab more effective than placebo at achieving an improvement in the ability to perform activities of daily 
living at 16 weeks after treatment? 
Is rituximab more effective than placebo at achieving an improvement in perceived quality of life at 16 weeks post-
treatment? 
6.3 Tertiary and explorative questions 
Is rituximab more effective than placebo at achieving improvement in standardized muscular fatigue tests at 16, 36 
and 48 weeks after treatment? 
Is rituximab more effective than placebo at achieving differences in the ability to perform activities of daily living at 
24, 36 and 48 weeks after treatment? 
Is rituximab more effective than placebo at achieving an improvement in perceived quality of life at 24, 36 and 48 
weeks after treatment? 
Is rituximab more effective than placebo at achieving normalization of repetitive nerve stimulation at 24 weeks 
post-treatment? 
To study the safety and effect of rituximab on the need for care in the treatment of MG 
To study drug antibodies and immunological markers 6 months after treatment 
 
7 
Endpoints 
7.1 Primary endpoint 
Proportion of patients with QMG score ≤ 4 and a daily dose of Prednisolone of ≤ 10mg and no rescue treatment at 
16 weeks after study start 
7.2 Secondary endpoints 
QMG scores at 24 weeks after treatment 
MG-ADL scores at 16 weeks after treatment 
MG-QOL scores at 16 weeks after treatment 
7.3 Tertiary and explorative endpoints 
Proportion of patients with QMG score ≤ 4 and a daily prednisolone dose ≤ 10mg and no rescue treatment at 24 
weeks after treatment 
QMG scores at 16, 36 and 48 weeks after treatment 
MG-ADL scores at 24, 36 and 48 weeks after treatment 
EQ5D scores at 16, 24, 36 and 48 weeks after treatment 
MG-QOL scores at 24, 36 and 48 weeks after treatment 
Hospital admissions 
Rescue treatments 
Adverse events 
Autoantibody levels 24 weeks after treatment 
Blood samples for exploratory immunological analyses at baseline, 16 and 24 weeks after treatment 
 


 
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8 
Design 
8.1 Study design 
The study is a randomized, double-blind, parallel group, placebo-controlled multicenter study aimed at evaluating 
the safety and efficacy of rituximab (Mabthera) in the treatment of patients with new-onset MG. The study is 
expected to be carried out at 10 -15 centers in Sweden. In the study, approximately 50 individuals will be 
randomized 1: 1 to one of two treatment arms, (1) rituximab or (2) placebo infusion (NaCl). 
Possible study participants are informed orally and in writing about the study during in- or outpatient care at the 
respective neurology clinic and can, after signed consent, be included in the study. No study-related measures can 
be carried out before the consent is signed. 
8.2 Screening period 
If the patient agrees to participate in the study, the following examinations are performed: 
• Review of medical history and current medication 
• Somatic status: including general condition (blood pressure, heart rate, body temperature), age, sex, height, 
weight and disease activity. 
• Evaluation of muscle strength, QMG. If the patient has <6 in QMG, the evaluation must be repeated after at least 
6 hours since last dose of cholinesterase inhibitors 
Repetitive neurophysiology, RNS, for study subjects with a neurophysiology clinic in the hospital. See section 11.6, 
Neurophysiology 
• Questionnaire regarding quality of life, EQ5D and MG-QoL15 
• Ability to perform daily activities, MG-ADL. 
• Blood tests: CBC incl. differential, Na, K, Creatinine, Asat, Alat, CRP, Glucose, hepatitis B screening, total IgG. 
• Pregnancy test if the patient is a woman of childbearing age. 
All women of childbearing potential are instructed to use effective contraception throughout the study after 
receiving the study drug. One of the following counts as an effective contraceptive: 
* Combined hormonal contraceptives (estrogen and progestin) that inhibit ovulation 
 -oral, intravaginal, or transdermal 
* Progesterone -hormonal contraceptives that inhibit ovulation 
-oral, injectable, or implantable 
* Spiral 
* Bilateral fallopian tube occlusion 
* Vasectomized partner 
* Sexual abstinence, to refrain from heterosexual intercourse throughout the study.  
8.3 Randomization  
If all inclusion and exclusion criteria are met, the patient will be contacted to agree on a time for study drug 
administration. Apotek Produktion & Laboratorier, APL, is then contacted for randomization and ordering of study 
drug. 
The study drug is delivered to the centers in ready-made infusion bags with refrigerated transport and temperature 
log by World Courier. The study drug is stored after delivery from APL in a refrigerator (+ 2-8 ◦C) until 
administration. 
In addition to the study drug, study participants may receive other immunosuppressive treatment according to 
what is listed in the protocol under section 10.7, Permitted / non-permitted treatment at different times. 


 
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8.4 Study drug administration, baseline (V.0) 
Study drug administration is carried out at a ward or outpatient clinic, depending on whether the patient is 
hospitalized or policlinic. 
Inclusion and exclusion criteria are reconciled and QMG, MG-ADL, MG-QOL15, EQ5D are performed and somatic 
status is checked.  
Note that QMG testing should be performed ≥12 hours after last dose of cholinesterase inhibitors. 
To reduce the risk of allergic reactions, 1,000 mg paracetamol (Alvedon), 50 mg prednisone (Deltison) and 10 mg 
Cetirizine are administered at least 45 minutes before the infusion. Blood pressure, pulse and temp are checked 
before starting the infusion. 
Important: Before starting the infusion, take a serum tube for exploratory immunological analysis.  
The blood sample is sent to the sample management Karolinska University Hospital Solna, attach study-specific 
consultant referral. 
 
Study drug is administered as an intravenous infusion (2 mg rituximab / ml, total 500 mg or placebo) with 
increasing infusion rate for a total of about 150 minutes by the nurse in charge of the infusion with the physician in 
charge of the infusion as support. See Appendix 3, Mabthera Infusion Monitoring. 
Speed of Infusion 
0-30 min 
50ml/h 
30-60 
100ml/h 
60-90 min 
150ml/h 
90 min - 
200ml/h 
 
In case of allergic reactions, the infusion is stopped temporarily and if necessary, 0.5 - 1 mg clemastine (Tavegyl) iv 
and / or 100 mg hydrocortisone (Solu-Cortef) can be administered intravenously. If the symptoms subside, the 
infusion can be restarted at the initial drip rate. In case of more severe reactions affecting systemic condition or 
with circulatory effects, the infusion should be stopped permanently. 
The patient is monitored throughout the infusion and blood pressure, pulse and temperature are checked again 
after the end of the administration. The patient is then observed for another 60 minutes. 
Important: before returning home, make sure the patient has: 
• Current contact information 
• Informed to contact new / aggravated symptoms urgently, no later than 48 hours. 
• Received instructions on medication with Prednisolone schedule if it has been deemed indicated 
The prednisolone schedule listed below may, if Prednisolone has not already been started on a purely clinical 
indication, be initiated immediately after the screening visit, or alternatively the day after administration of study 
drugs, if cortisone treatment is judged clinically indicated by the treating physician: 
Starting dose 40 mg / day, with tapering of 5 mg / week until discontinuation. 
For patients already on Prednisolone before screening, the pre-screening dose may be increased to 40 mg / day 
with subsequent tapering according to the above schedule. 
To reduce the risk of study endpoints being affected by another MG-specific treatment, such treatment should be 
given after randomization in accordance with section 10.7, Permitted / non-permitted treatment at different times. 
If the cortisone dose can not be reduced due to persistent or worsening clinical symptoms, you may first choose to 
increase the dose of Prednisolone and make a new plan for phasing out or, secondly, to give rescue treatment with 
IvIg or PLEX. 
Immunosuppressive therapy (azathioprine, ciclosporin, MMF, methotrexate) can be started if indicated from 12 
weeks after randomization. Pulse cures with cortisone should not be given after randomization. In cases where the 
study physician for medical reasons considers that the above treatments are insufficient or inappropriate, other 
treatment may also be considered, including rituximab. The patient will then be classified as a non-responder in 
the primary outcome measure and censored in the secondary outcome measures. 


 
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8.5 Evaluation, observation period (24 weeks) 
After the single administration of study drug, the effect is followed up according to the following schedule: 
• Telephone contact with the study nurse after 2 weeks (+/- 2 days): checking for side effects, verifying 
current medication and Prednisolone dose. 
• Return visit after 4 weeks (+/- 2 days): checking for side effects, verifying current drugs and Prednisolone 
dose, QMG, MG-ADL, MG-QoL15, EQ5D and somatic status. 
Note that QMG testing should be performed 12 hours after the last dose of cholinesterase inhibitors and 
preferably at the same time of day throughout all testing sessions. 
• Telephone contact with a nurse after 8 weeks (+/- 4 days): checking for side effects, verifying current 
medication and Prednisolone dose. 
• Telephone contact with a nurse after 12 weeks (+/- 4 days): checking for side effects, verifying current drugs 
and Prednisolone dose. 
• Return visit after 16 weeks (+/- 21 days): checking for side effects, verifying current drugs and Prednisolone 
dose, QMG, MG-ADL, MG-QoL15, EQ5D and somatic status. 
Note that QMG testing should be performed 12 hours after the last dose of cholinesterase inhibitors. 
Important: a serum tube for exploratory immunological analyzes is taken and sent to the sample management 
Karolinska University Hospital Solna, attach study-specific consultant referral. 
• Telephone contact with a nurse after 20 weeks (+/- 7 days): checking for side effects, verifying current drugs 
and Prednisolone dose. 
• Return visit after 24 weeks (+/- 21 days): checking for side effects, verifying current drugs and Prednisolone 
dose, QMG, MG-ADL, MG-QoL15, EQ5D and somatic status. 
Note that QMG testing should be performed 12 hours after the last ingestion of cholinesterase inhibitors. 
Important: a serum tube for exploratory immunological analyzes is taken and sent to the sample management 
Karolinska University Hospital Solna, attach study-specific consultant referral. 
At the centers that have a neurophysiology clinic at the hospital, a repetitive nerve stimulation will be 
performed in connection with the return visit or in close proximity to the visit, see section 11.6 
Neurophysiology.  
8.6 Follow up period (25-48 weeks) 
After a 24-week evaluation phase, the study moves to an open-label follow-up phase, where restrictions on 
other MG-specific therapies, including rituximab, no longer exist. 
To provide information on the possible effects of the study drug in the longer term, two follow-up return 
visits are included: 
• Return visit after 36 weeks (+/- 21 days): checking for side effects, verifying current drugs and Prednisolone 
dose, QMG, MG-ADL, MG-QoL15, EQ5D and somatic status. 
Note that QMG testing should be performed 12 hours after the last ingestion of cholinesterase inhibitors. 
• Return visit after 48 weeks (+/- 21 days): checking for side effects, verifying current drugs and Prednisolone 
dose, QMG, MG-ADL, MG-QoL15, EQ5D and somatic status. 
Note that QMG testing should be performed 12 hours after the last dose of cholinesterase inhibitors. 
See Section 20, Appendix 1 for flow chart 
8.7 Study end 
The study ends when the last patient has completed the last follow-up. 
The study may be terminated prematurely if it turns out that the treatment causes a large number of undesirable 
serious events or if patient recruitment cannot be fulfilled within a reasonable time limit. 


 
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Decisions on early termination of studies are made by the sponsor / coordinating investigator. 
When the study is completed, the Ethical Review Board and the Medical Products Agency will be informed of this in 
accordance with set time limits. 


 
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9 
Study participants 
9.1 Inclusion criteria 
1. Patients with oculobulbar, bulbar or generalized MG ≥ 18 years of age and ≤ 12 months after onset of 
generalized symptoms or neurophysiological detection of generalized disease. 
2. The diagnosis of MG should be made by the following tests: 
Clinical neurological status with motor symptoms compatible with MG and ≥ 2 of the following: 
a Positive serological test for anti-acetylcholine receptor antibodies (AChR), 
and/or 
b. For MG typical findings on neuro-physiological testing of neuromuscular transmission by single fiber 
electromyography (SFEMG) and / or repetitive nerve stimulation (RNS), 
and/or 
c. Positive anticholinesterase test, e.g. edrophonium chloride test or improvement of MG symptoms with oral 
cholinesterase inhibitors at the discretion of the treating physician. 
3. MGFA clinical classification 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 given written informed consent. 
7. Patients must be able and willing to follow all study procedures. 
9.2 Exclusion criteria 
1. Weakness affecting only ocular or periocular muscles (MGFA class I). 
2. MG crisis at screening (MGFA class V). 
3. Thymectomy already performed. To avoid difficulties in evaluating the effect of the study drug, thymectomy, in 
cases where it is deemed indicated, should be planned for the follow-up period, i.e. only after the first 24 weeks. 
4. Strong suspicion of thymoma and where thymectomy according to the treating physician should be performed 
within 24 weeks. 
5. Activecancer, unless adequately treated. 
6. Pregnancy or breast-feeding. 
7. Any ongoing acute or chronic viral or systemic bacterial infection including HIV, latent hepatitis B, which is 
clinically significant in the opinion of the study physician, and which has not been treated with appropriate 
antibiotic / antiviral drugs. 
8. Severe heart failure (New York Heart Association Class IV) or severe uncontrolled heart disease 
9. Previous use of immunosuppressive drugs including rituximab, azathioprine, ciclosporin and MMF. The use of 
Prednisolone at a dose of ≤40mg / d within 3 months and IVIG and PLEX 12 months from the screening date does 
not constitute an exclusion criterion. Please also note that this does not apply to treatment with 
immunosuppressive drugs / corticosteroids (excluding rituximab) for indications other than MG, provided that > 12 
months have elapsed since the end of treatment. 
10. Hypersensitivity to the active substance, to murine proteins or to any of the other excipients in the study 
medicinal product 
11. Participation in any other clinical drug study or exposure to any other study drug, study product or study 
procedures within 30 days before screening. 
12. Any medical condition which, in the opinion of the study physician, may interfere with the patient's 
participation in the study, poses any additional risk to the patient, or which complicates the assessment of the 
patients. 


 
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13. Vaccination within 4 weeks before inclusion. 
 
9.3 Criteria for discontinuing participation 
The patient can at any time during the course of the study interrupt his / her participation in the study without 
explaining the reason for this in more detail. The reason why the patient cancels his participation should, if 
possible, be registered. Data collected up to and including the cessation of study participation will be used in the 
final analysis of the study. 
The examiner may also interrupt the patient's continued participation in the study; 
- between the time of inclusion and the administration of study drugs if new data emerges that may pose risks 
during rituximab treatment, such as the detection of active hepatitis B infection, cancer or other factors that mean 
that inclusion and exclusion criteria are no longer met. 
- after administration of study drugs: as the study involves only one administration of study drugs, continued 
participation will only be discontinued if the treating physician considers that continued participation in follow-up 
controls would in any way have negative consequences for the subject's mental or physical well-being. 
Patients who have been included in the study but have not received study medication before discontinuation of 
participation, can be replaced with a new participant. Patients who have received study drugs are not substituted 
by additional participants. 
The sponsor reserves the right to terminate the study prematurely based on scientific, administrative and / or 
ethical reasons. The study may be terminated prematurely if it turns out that the treatment causes a large number 
of undesirable serious events or if patient recruitment cannot be fulfilled within a reasonable time limit. Decisions 
on early termination are made by the sponsor / coordinating investigator.  
9.4 Screening log 
Patients evaluated for possible participation in the study are noted on a screening log at each center. Possible 
participants are only identified with initials, no personal data may be documented.  
9.5 Study personell 
The principal investigator at each center is responsible for conducting the study at the center. If study-specific tasks 
are delegated, it must be documented in writing to which persons and which study-specific tasks have been 
delegated.  
10 Study drug  
10.1 Study drug 
Mabthera® 500 mg concentrate for infusion, solution 
Active substance: Rituximab 
ATC-kod: L01XC02 
10.2 Description of study drug 
Rituximab is a genetically engineered chimeric mouse / human monoclonal antibody consisting of a glycosylated 
immunoglobulin with human IgG1 constant regions and murine variable regions of the light and heavy chains. The 
antibody is produced by mammalian (Chinese hamster ovary) cell suspension culture and purified by affinity 
chromatography and ion exchange, as well as specific viral inactivation and purification steps. 
According to the SmPC, Rituximab has been shown to have high specificity for the CD20 antigen on B cells. Toxicity 
studies in cynomolgus monkeys have not shown any other effects other than the expected pharmacological 
elimination of B cells in peripheral blood and lymphatic tissue. 
Toxicity studies have been performed with cynomolgus monkeys at doses up to 100 mg / kg (treatment on 
gestational day 20-50) and showed no evidence of fetal toxicity caused by rituximab. In contrast, pharmacologically 
dose-dependent low levels of B cells in the lymphoid organs were observed in the fetus, which remained 
postnatally and was followed by a decrease in IgG levels in the newborn animals affected. The number of B cells 
returned to normal in these animals within 6 months after birth and did not affect the response to vaccination. 
Standard tests to examine mutagenicity have not been performed as such tests are not relevant for this molecule. 
No long-term animal studies have been performed to determine the carcinogenicity of rituximab. 
Specific studies to determine the effect of rituximab on fertility have not been performed. In general toxicity 
studies in cynomolgus monkeys, no adverse effects on male or female reproductive organs were observed.  


 
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10.3 Placebo 
Sodium Chloride, solution for infusion, 9 mg/ml 
Active substance: Sodium Chloride 
ATC-kod: B05BB01 
 
10.4 Packaging, labeling and handling of study drug 
Study drugs (rituximab / placebo) are prepared and labeled at APL. 
Mabthera (500 mg / 50 ml vial) is mixed in 250 ml NaCl infusion bags. 50 ml of NaCl is aspirated, 50 ml of Mabthera 
(500 mg) is added to a strength of 2 mg / ml. For placebo, use 250 ml NaCl in the corresponding infusion bags. 
Study drugs are labeled with the date and time of preparation and the date and time of the latest time for use. The 
maximum shelf life of the study drug is 36 hours according to APL's guidelines. 
The study drug is delivered in ready-made infusion bags to the centers during refrigerated transport and 
temperature log by World Courier. In most cases, delivery will take place within 24 hours. 
10.5 Randomization 
Study staff at the center contact APL for randomization or contact the study coordinator / study coordinating 
research nurse at Karolinska for help with randomization via APL. 
10.6 Blinding and emergency code breeaking 
The study is double-blind and labeling of study drugs (rituximab / placebo) is done by APL. 
APL sends a code envelope for the patient in question in connection with sending the study drug to the center. The 
code envelopes must be stored in a safe place at the center and only opened when information about the given 
treatment (rituximab / placebo) is deemed necessary for the continued care of the patient. The integrity/status of 
envelopes will be checked at study center closure. 
10.7 Permitted/Not permitted treatments in different study phases 
Before screening 
I] Permitted: Corticosteroids: Oral - Prednisolone ≤40mg / d within 3 months before screening. 
IVIG: Within 12 months before screening 
PLEX: Within 12 months before screening 
Cholinesterase inhibitors: no restrictions on pre-screening use. 
II] Not permitted: Immunosuppressants: Rituximab, azathioprine, cyclosporine, MMF, methotrexate or other 
immunosuppressants for the treatment of MG. Treatment (excluding rituximab) discontinued> 12 months ago 
for another indication is permitted 
Methylprednisolone pulse 
 
After screening, until randomization 
I] Permitted: A stable dose of cholinesterase inhibitor and Prednisolone according to standard schedule if 
clinically indicated and PLEX and IVIG according to clinical routine. 
II] Not permitted: Immunosuppressants: Rituximab, azathioprine, cyclosporine, MMF, methotrexate or other 
immunosuppressants. 
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After randomization, until week 8 
I] Permitted: Prednisolone: For patients taking Prednisolone, the predetermined schedule of 8 weeks of 
tapering applies, i.e. 40mg / d, with a reduction of 5mg / v to discontinuation. 
Extension of the tapering schedule in clinically clearly unstable patients, but with the aim of 
reach a maximum dose of 10mg / day from week 9. 
Cholinesterase inhibitors: No restrictions. 
IVIG / PLEX: No restrictions. 
II] Not permitted: Immunosuppressants: Rituximab, azathioprine, cyclosporine, MMF, methotrexate or other 
immune suppressants. 
Methylprednisolone pulse 
After randomization, week 9-24 
I] Permitted: Prednisolone: Max dose 10mg / day 
Cholinesterase inhibitors: No restrictions. 
Immunosuppressants: azathioprine, cyclosporine, MMF or methotrexate may be initiated if clinically 
indicated; 
Azathioprine: azathioprine, up to 2.5 mg / kg / day divided into one or two doses 
Ciclosporin: up to 3mg / kg / day divided into two doses 
Methotrexate: up to 20mg / week 
II] Not permitted: Immunosuppressants: Rituximab or another immunosuppressant. 
IVIG / PLEX 
Methylprednisolone pulse 
After randomization, week 25-48 
I] Permitted: Prednisolone: No restrictions. 
Methylprednisolone: No restrictions. 
Cholinesterase inhibitors: No restrictions. 
Immunosuppressants: No restrictions. 
 
10.8 Clinical worsening, rescue treatments  
In case of persistent or worsening MG symptoms, rescue treatment should be considered. 
Primarily prolonging or reintroducing Prednisolone up to 40mg / d with a new phasing-out schedule; reduction 
5mg / week to discontinuation (total treatment time 8 weeks) 
Secondarily: 
IVIg: total dose 1g / kg, spread over 2-3 days, alternatively 
PLEX: A plasma volume is exchanged 3-5 times over 10-14 days 
For more info about the above immunomodulatory therapies and the respective degree of evidence at MG, please 
see the National MG care program at www.snema.se (tab "Documents") 
NOTE! Any newly initiated MG immunotherapy (excluding azathioprine, methotrexate and ciclosporin) or dose 
increase of Prednisolone> 10 mg / d during weeks 9-24 will by definition be considered rescue treatment. This also 
includes rituximab. 


 
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10.9 Study drug documentation, accountability 
The investigator is responsible for the study drugs that are received, administered, or destroyed at the center being 
registered on the intended documents by delegated staff. 
When administering study drugs, this is documented with information such as who gave the drug, patient, date, 
and time. 
10.10 Treatment after study end 
After the end of the study, the patient will be treated according to a clinical assessment by the treating physician. 
 
11 Assessement of safety and efficacy 
11.1 Blood samples  
Blood samples for analysis of CBC including diff., Na, K, Creatinine, Asat, Alat, CRP, Glucose, hepatitis B screening 
and total IgG are taken at screening and analyzed at the local laboratory at each hospital. 
Blood samples for analysis of drug antibodies and markers of disease activity, such as acetylcholine receptor 
antibodies, are taken in the study for evaluation of tertiary issue / exploratory analyzes in the study. 
Analysis of autoantibodies is performed at Clinical Immunology / Transfusion Medicine, Karolinska University 
Laboratory after completion of the study. 
Antibody antibodies and samples for exploratory analyzes will be sent to the Center for Molecular Medicine (CMM) 
at Karolinska Institutet (KI). 
In total, a blood volume of about 50 ml is drawn from the patient during the study. 
11.2 Quantitative Myastenia Gravis scale, QMG 
The QMG scale is used in the study to evaluate primary, secondary, and tertiary study objectives. 
The scale is used for quantitative evaluation of MG status and will be carried out by testers who have not 
participated in the administration of the study drug. The scale consists of 13 domains that are scored 0-3 as well as 
information about MGFA and subjective health status. 
Evaluations on the scale take about 20-30 minutes to complete and are carried out during visits to the center.  
11.3 Myasthenia gravis activities of daily life scale, MG-ADL 
The MG-ADL scale is used in the study to evaluate secondary and tertiary study objectives. 
The scale consists of eight items such as speech, swallowing, double vision, and mobility where the patient himself 
estimates activities in daily life on a three-point scale. 
Filling in the form takes about 5 -10 minutes and is carried out by the patient during a visit to the center together 
with the research nurse.  
11.4 EuroQol 5-dimensions quality of life, EQ5D 
The EQ5D health survey is used in the study to evaluate tertiary study objectives. 
EQ5D is an instrument for measuring health and has been developed by EuroQol Group. The form contains a part 
with 5 items where the patient classifies his health, such as mobility, main activities, pain / discomfort, and a part 
with a scale where the patient estimates his current state of health based on the criteria best to worst imaginable. 
Filling in the form takes about 5 -10 minutes and is carried out by the patient during a visit to the center together 
with the research nurse.  


 
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11.5 Quality of life in myasthenia gravis, MG-QOL15 
MG-QOL15 is used in the study for evaluation of secondary and tertiary study objectives. 
MG-QOL15 is a short form for evaluation for certain aspects of quality of life associated with myasthenia gravis. 
The form consists of 15 items, such as frustration over the condition, difficulty eating, difficulty speaking, difficulty 
walking, etc. The patient himself estimates his function on a five-point scale based on criteria from not at all to very 
much based on how the statements are true during the last 4 weeks. 
Filling in the form takes about 5 -10 minutes and is carried out by the patient during a visit to the center together 
with the research nurse. 
 
11.6 Neurophysiology 
Repetitive nerve stimulation (RNS) is performed at baseline and after 24 weeks for centers where 
neurophysiology is located locally. 
Surface electrodes are applied to a muscle, the muscle nerve is stimulated with a series of electric shocks at rest, 
after maximum activation of the muscle, 1 min and 3 min after activation and the amplitude is measured. 
RNS is performed in the proximal arm muscle (deltoid) and facial muscle (nasalis) and measures disturbed 
neuromuscular transmission by measuring decrements. 
The patient should not take cholinesterase inhibitors within 12 hours before the examination. 
• RNS procedure: 
o Low-frequency nerve stimulation (3 Hz) 10 times at rest 
o Muscle activation 20 seconds and then again 3 Hz stimulation 10 times 
o 1 minute after activation again low-frequency nerve stimulation (3 Hz) 10 times 
o 3 minutes after activation again low-frequency nerve stimulation (3 Hz) 10 times 
• Measurement parameters: 
o% amplitude decrement (reduction) between 1st and 4th muscle response (compound motor action 
potential; CMAP) 
o% area decrement between 1st and 4th CMAP 
o CMAP amplitude in absolute numbers at rest (mV) 
The examination is performed at a neurophysiological lab at each hospital. Patients admitted to centers that do 
not have a neurophysiological lab in the hospital do not need to do this test. 
11.7 Adverse Event, AE and Serious Adverse Event, SAE. 
Follow-up regarding AE and SAE will be carried out during the telephone follow-ups and all physical visits that the 
patient carries out at the center. 
The patient is informed at the start of the study to contact the center if new or worsening symptoms should arise. 
If symptoms worsen significantly, or if the patient experiences an MG crisis (difficulty breathing), the patient should 
inform the physician and make an evaluation visit as soon as possible or no later than 48 hours after the onset of 
symptoms. Treatment of the patient then takes place in accordance with standard care for the patient's clinic or 
hospital. 


 
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12 Management of adverse events 
As a reference safety information for assessing whether an adverse event is expected or not, Mabthera SmPC / 
SmPC will be used.  
12.1 Definitions 
12.1.1 Adverse events (AE) 
Any adverse medical event or deterioration of an existing medical condition, whether related to treatment or not. 
12.1.2 Serious adverse events (SAE) 
Any accidental medical event occurring at any dose: 
• results in death 
• is life threatening 
• causes hospital stay or extended hospital stay (see also section 12.5 regarding hospitalization for MG 
relapses) 
• results in permanent or temporary disability 
• results in a congenital injury / malformation 
• a medically important event that involves danger to the patient or that could have resulted in any of the 
above if not taken care of  
12.1.3 Suspected, unexpected, serious adverse events (SUSAR) 
A reaction / event that is unexpected, serious, suspected to be caused by the treatment and that has not been 
described before. 
12.2 Assessement of adverse events 
12.2.1 Assessement of seriousness 
Any adverse medical event should be classified by the examiner as mild, moderate, or severe. 
Mild: The event does not affect the person's normal life. 
Moderate: The event causes deterioration of function but does not affect health. The event causes discomfort 
and / or discomfort / obstacles. 
Severe: The event causes impairment of function or ability to work or poses a health risk to the person. 
12.2.2 Assessement of causality 
Related / probably related: Clinical event, including abnormal laboratory analyzes, which occur within a 
reasonable time after administration of the intervention / study product. It is unlikely that the event can be 
attributed to the underlying disease or other drugs. 
Possibly related: Clinical event, including laboratory analyzes, occurring within a reasonable time after 
administration of the intervention / study product. The event can also be explained by the underlying disease 
or other drugs. 
Not related: Clinical event, including abnormal laboratory analyzes, which may be temporarily related to the 
administration of the intervention / study product. The event is unlikely to be related to the intervention / 
study product and may better be explained by other drugs or underlying disease. 
12.3 Methods for detection of adverse events 
At the start of the study, the patient is informed to contact the center in the event of new or worsening symptoms. 
During telephone follow-ups and return visits that the patient carries out at the clinic, the patient will also be asked 
if any unwanted medical events have occurred since the last time. 


 
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12.4 Reporting of adverse events 
12.4.1 Reporting of adverse events (AE) 
All adverse medical events are noted in a special AE form, where the severity is assessed as severe or non-serious. 
12.4.2 Reporting of serious adverse events (SAE) 
Serious adverse events should be reported to the sponsor on a special SAE form within 24 hours of the study 
center becoming aware of the SAE. 
Follow-up information describing the outcome and management of SAE should be reported as soon as that 
information is available. The original report must be inserted in the investigator binder. 
12.4.3 Reporting of suspected, unexpected, serious adverse events (SUSAR) 
The sponsor is responsible for all relevant information about suspicious, unforeseen, serious adverse reactions 
being registered and reported to the EudraVigilance database. 
SUSARs that are fatal or life-threatening are reported to the EudraVigilance database as soon as possible and no 
later than 7 days after the occurrence has become known to the sponsor. Relevant follow-up information must 
then be submitted within a further 8 days. Other SUSARs are reported as soon as possible and no later than within 
15 days after they have come to the sponsor's notice. 
Information about SUSAR that occurs during the study will be compiled by the sponsor and sent out to the principal 
examiner at all participating centers quarterly in the form of a CIOMS form.  
 
12.5 Follow up of adverse events 
Adverse Event, AE 
AE that occurs after the study drug has been administered until the visit week 48 will be documented, summarized, 
and analyzed in the study. If treatment is needed, this is done in accordance with the protocol and based on the 
medical assessment of the treating physician. 
AE that is judged to be caused by the underlying disease or previously known diseases will not be registered as AE 
in the study. Should the underlying disease worsen during the study, this may be considered an AE. 
AEs will be followed up until they are “resolved” or until the patient's participation in the study is completed. 
Serious Adverse Event, SAE 
SAE that arises from the start of administration of study drugs until the patient ends his / her participation in the 
study will be documented and reported, as well as summarized and analyzed after the study. 
Planned hospitalization / surgery for illness or condition that the patient had before the start of the study will not 
be registered as SAE. 
Note that hospitalization that is primarily caused by exacerbated MG symptoms (MG crisis) should not be 
considered SAE. If the deterioration and hospitalization are secondary to, for example, pneumonia, the event must 
be reported as SAE. 
SAEs will be followed up until they are “resolved” or until the patient's participation in the study is completed. 
12.6 Annual safety reporting (Development Safety Update Report, DSUR)  
During the study, an annual safety report (DSUR) will be sent to the Medical Products Agency and the Regional 
Ethics Review Board. 
The report contains a summary of the SAEs and SUSARs that have occurred, a summary assessment of the safety of 
the patients included in the study and information on the benefit-risk assessment has changed since the study was 
approved. 


 
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13 Statistics, data handling and archiving 
13.1 Deciding on number of study subjects 
Based on results reported in Sanders DB et al.2, our own experience, and a shorter phasing out of cortisone than 
used in most protocols, it is estimated that ≤40% in the placebo group achieve the primary endpoint of a daily 
Prednisolone dose ≤10mg with QMG ≤ 4. With 25 patients in each arm, the power will be 0.85 with an alpha = 0.05 
for a two-sided test of 80% reaching the primary endpoint of the active arm. 
[Note, due to slow recruitment the funder of the study, the Swedish MRC, requested a revised power calculation. 
March 15th 2018 the following text was submitted, which was approved May 25th 2018: 
“The study regards a study drug being administered on only one occasion, with determination of main endpoints at 
4 and 6 months, respectively. Possible drop-outs are therefore limited to study participants actively interrupting 
the study, including the follow-up visits that the protocol stipulates, or that dies before these visits. Of a total of 23 
included study participants, none have interrupted. One study participant died due to a medical condition not 
considered directly related to the study medication. A revised power calculation with the same input variables 
(without loss) shows that with the same number of patents in each treatment arm: 20 per arm (N = 40), power = 
81%; 22.5 per arm (N = 45), power = 85%; 25 per arm (N = 50), power = 89%. Based on interim results, it is 
therefore reasonable to expect a dropout rate <5%. In order to maintain a power of at least 80% and a certain 
margin for any minor imbalance in the randomization, n≥45 is needed.” The power calculation provided in the 
paper is based on this revised calculation.] 
13.2 Analysis plan  
Differences in the primary endpoint will be tested on an intention-to-treat basis using Fisher's exact test. As a 
secondary analysis, the primary endpoint will also be analyzed with log-binomial regression, adjusted for any 
observed baseline differences that have occurred despite randomization. 
Patients who have received disease-modulating MG treatment as indicated in section 10.7 as "Not allowed" after 
randomization and before the assessment visit at 16 weeks will be counted as non-responders. 
In addition to the primary efficacy variable, a few secondary outcome measures of particular clinical relevance 
have been selected to reduce the risk of false-positive findings. Differences in the change of these continuous 
measures will be tested with the Mann-Whitney U-test. P-values will be adjusted with Bonferroni correction for 
these three tests. To estimate 95% confidence intervals around the difference, linear regression with robust 
standard errors will be used, without adjustment for the number of tests. Patients who have received disease-
modulating MG therapy as indicated in section 10.7 as "Not allowed" after randomization and before the 
assessment visits at 16 and 24 weeks will be censored from the time these treatments were administered. 
Other measures are tertiary or exploratory. 
A challenge in clinical trials is the management of dropouts, which risks introducing a selection error if response 
data are only available to the patients who remain in the study. As this study only involves study drug 
administration at baseline, we expect that the drop-out rate, and thus the need for imputation for those who have 
left the study, will be limited. If the dropout rate is higher than 10%, imputation will be performed, partly with 
multiple imputation with explicit modeling of the treatment outcome as a function of baseline variables (age, 
gender, disease activity), partly through so-called "last observation carried forward", where values for patients who 
left the study are replaced with their most recently observed value. However, it is very important to emphasize the 
importance of including complete study data on as many subjects as possible. 
13.3 Data handling and Case Report Forms, CRF 
Data collected in the study are registered by the study staff in paper CRF (source document), where certain 
information is also entered in specially modified pages in the Swedish MG register (MGreg). This concerns rating 
scales, dates of follow-up visits, cortisone dose, possible side effects and any need for other MG-specific therapy 
(rescue treatments). This part of MGreg belongs to the decision support and not the quality register part of MGreg. 
MGreg is located on the same platform as the other sub-registries in the Swedish Neuroregister and is accessed in 
the usual way by logging in from a computer with an Internet connection. For patients who give consent to 
registration in the MGreg quality registry part, results from the assessment scales are also transferred to this part. 
However, the study does not require the consent of the quality registry section. 
Patient data is collected according to the protocol and registered continuously in paper CRF (source documents), 
with duplication of certain information in MGreg CRF. For each contact occasion, there is a page with the necessary 


 
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information to fill in. When extracting data from MGreg (the decision support part), the patient's name and social 
security number are deleted, so that only the patient number in MGreg remains. This number is thus the link to the 
person's name and social security number and is available only to the investigators and nurses who work locally at 
the patient's clinic and people who work with quality assurance of the study. All withdrawals from the registry are 
logged. 
Information entered in MGreg is locally available to each investigator even after the end of the study. 
All blood samples leaving the hospital will also be marked with this patient number only. No unauthorized person 
will have access to the code key. 
Collected data originates in source documents at the clinic such as lab reports and other test results and results. 
13.4 Data processing 
Data processing and statistical analysis will be carried out by the coordinating investigator in collaboration with 
biostatisticians at the Department of Medicine, Karolinska University Hospital Solna. A compilation of study data is 
distributed to participating investigators when the study is completed. 
Data processing can begin after the last patient has completed the last visit in the study. 
13.5 Archiving 
Data collected during the study will be archived for at least 10 years after the study is completed.  
14 Quality control 
14.1 Source data 
Source data in the study are the patient's medical record, paper CRF for all contact sessions, questionnaires / 
assessment scales as well as transcripts such as analysis answers and lab lists. 
At each center, a source data document will be drawn up specifying what is the source data for the center. 
14.2 Monitoring 
To ensure that the study is conducted according to the protocol, that data is collected, documented, and reported 
in accordance with ICH-GCP (Good Clinical Practice) and current ethical and regulatory requirements, the study will 
be monitored by an external party before the study begins, during the study and after that the study has been 
completed. 
The monitoring also aims to ensure that the subject's rights, safety, and well-being are met and that the data in the 
CRF are filled in, correct and in accordance with the source data. 
14.3 Access to source data 
Study monitors can gain access to medical records and source data after a confidentiality agreement has been 
signed by the medical record manager at the clinic and monitor. The accuracy of data entered in MGreg will be 
checked against source documents. 
15 Ethics 
15.1 Ethical review board and Medical Products Agency 
The sponsor / coordinating investigator is responsible for ensuring that the application for approval for the 
implementation of the study is obtained from the Regional Ethics Review Board and the Medical Products Agency. 
Additions to or significant changes to the protocol can be made after the application for an addition / amendment 
has been approved by the Regional Ethics Review Board and / or the Medical Products Agency.  
15.2 Ethical conditions for the study 
The study will be conducted in accordance with the protocol and the latest version of the Declaration of Helsinki, 
ICH-GCP and other applicable ethical and regulatory laws, rules, and requirements. 
Patients are informed orally and in writing about the study and are informed that participation in the study is 
completely voluntary and that participation can be interrupted at any time, regardless of the reason, without this 
affecting the patient's future treatment in any way. 
The patient is informed that the data collected until the interruption will be analyzed. 


 
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Data collected during the study are coded so that no individual can be distinguished. 
15.3 Benefit risk assessement  
During the study, blood samples will be taken and an intravenous catheter inserted for the administration of study 
drugs. For most patients, the placement of intravenous catheters and needle punctures for blood sampling is well 
tolerated. In rare situations, however, they can cause bleeding, bruising, swelling, coagulation in the vein, leakage 
of medication or solution into the surrounding tissues, and possibly infection at the site of insertion of the needle 
or catheter. Sampling and insertion of an intravenous catheter will be performed according to clinical practice by 
staff with extensive experience in this field. 
As with all medicines, rituximab can cause side effects, although well tolerated compared to other biological 
medicines. The side effects of rituximab are usually mild or moderate. The investigator will discuss possible side 
effects with the patient and explain the risks and benefits of rituximab before treatment. Because rituximab is 
being studied in MG patients, not all possible side effects are known. 
Very common side effects (affects at least 1 in 10 patients) include fever, itching, redness of the skin, nausea, 
headache. 
Common side effects (affects 1 or more in 100 patients and less than 10 in 100 patients) include: reduced platelet 
count, abdominal pain, constipation, vomiting, diarrhea, stomach discomfort after meals, nausea, chest discomfort, 
chills, infusion-related reaction, anaphylactic reaction, edema, fever, tiredness, weakness, cold sores, cold, viral 
infection, stomach flu, bronchitis, severe infection, muscle aches, back and neck pain, pain in limbs and joints, 
muscle cramps, dizziness, disturbances in taste, tingling of the body, vertigo, high blood pressure, difficulty or pain 
when urinating, spontaneous erection, upper respiratory tract infection, pneumonia, urinary tract infection, joint 
infection, cough, irritation or pain in the throat, nasal congestion, itchy skin, rash, hair loss, and dry skin . 
In addition, serious infections, sepsis, and infusion reactions have been reported in patients receiving rituximab 
and these are identified safety hazards. 
Patients receiving rituximab will have a weakened immune system, which may affect the patient's ability to fight 
viral and bacterial infections. Patients treated with rituximab have an increased risk of worsening certain chronic 
infections, such as hepatitis B. 
Based on what has been described above, the risks that study participation entails are considered acceptable given 
that the study population includes patients with new-onset moderate to severe MG (moderate to severe effects on 
ADL), which is a condition that risks deteriorating further if immunomodulatory treatment is not instituted, in turn 
involving other types of risks such as osteoporosis, poor blood sugar control and other side effects of cortisone. 
The patient's condition may improve, remain the same, or worsen during the study. If the study and possibly other 
studies with rituximab in MG are positive, this may lead to benefit for other patients, as clinical evidence for 
efficacy with this drug is then substantiated. It is worth mentioning that today there is a complete lack of approved 
treatments for MG and that clinical practice is based entirely on proven experience. We believe that this will affect 
national practice for the treatment of MG. 
15.4 Procedure for collection of informed consent 
The responsible investigator or other delegated co- investigator first informs the patient orally about the study 
structure, purpose, examinations, risks and discomforts, as well as alternative treatments and provides the written 
patient information and consent form to the patient. The information is provided during inpatient stay or during an 
outpatient visit at the investigator's clinic. The patient is informed that participation in the study is completely 
voluntary and that he / she can interrupt his / her participation in the study at any time and without specifying the 
reason. The patient is informed that data collected until interruption will be analyzed in the study. 
The responsible investigator can delegate to the study nurse to provide parts of the oral information on their own, 
such as how the administration of study drugs is done and routine for telephone follow-ups. 
The patient is given the opportunity to read the patient information in peace and quiet and think through their 
decision well before deciding. If the patient, after reading the information, is interested in participating in the 
study, he / she is given the opportunity to meet the examiner and is then given the opportunity to ask further 
questions and have them answered.  


 
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Consent to participation in the study, after information and time to reflection, is given by the patient personally 
providing written consent to participate. The investigator who provided information about the study also signs and 
dates the consent form. The signed original of the consent form is kept at each clinic and the patient receives a 
copy of patient information including the consent form. The investigator documents in the patient's medical record 
that the person agrees to participate in the study. No examinations within the framework of the study may be 
carried out before the patient has given his or her written consent. 
16 Insurance 
During the study, the study participants are covered by the regular insurance covering medical care in Sweden.  
17 Funding  
The study is funded by the Swedish Research Council via a framework grant for clinical treatment research 
18 Publication of results 
The results from the study will be compiled in a summary clinical study report within one year after the end of the 
study. The report is distributed in accordance with current European guidelines. 
The study results will be published in scientific journals and / or presented at international meetings and 
conferences. 


 
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19 References 
1.  
Fang F, Sveinsson O, Thormar G, Granqvist M, Askling J, Lundberg IE, et al.  
 
The autoimmune spectrum of myasthenia gravis: a Swedish population-based study.  
 
J Intern Med. 2014. 
2. 
Sanders DB, Hart IK, Mantegazza R, Shukla SS, Siddiqi ZA, De Baets MH, et al.  
 
An international, phase III, randomized trial of mycophenolate mofetil in myasthenia gravis. 
 
Neurology. 2008;71(6):400-6. 
3. 
Bedlack RS, Simel DL, Bosworth H, Samsa G, Tucker-Lipscomb B, Sanders DB.  
 
Quantitative myasthenia gravis score: assessment of responsiveness and longitudinal validity. 
 
Neurology. 2005;64(11):1968-70. 
4. 
Group MS. 
 
A trial of mycophenolate mofetil with prednisone as initial immunotherapy in myasthenia gravis. 
 
Neurology. 2008;71(6):394-9. 
5. 
Wolfe GI, Herbelin L, Nations SP, Foster B, Bryan WW, Barohn RJ. 
 
Myasthenia gravis activities of daily living profile. 
 
Neurology. 1999;52(7):1487-9. 
6. 
Muppidi S, Wolfe GI, Conaway M, Burns TM, Mg C, Mg-Qol15 Study G. 
 
MG-ADL: still a relevant outcome measure. 
 
Muscle Nerve. 2011;44(5):727-31. 
 


 
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20 Annex 1, Study flow chart 
 
Screening 
 
Baseline 
(week 0) 
Week 2  
(+/- 2 days) 
Phone 
Week 4  
(+/- 2 days) 
Visit 
Week 8  
(+/- 4 days) 
Phone 
Week 12  
(+/- 4 days) 
Phone 
Week 16  
(+/- 21 days) 
Visit 
Week 20  
(+/- 21 days) 
Phone 
Week 24  
(+/- 21 days) 
Visit 
Week 36  
(+/- 21 days) 
Visit 
Week 48  
(+/- 21 days) 
Visit 
Informed consent 
X 
 
 
 
 
 
Inclusion-/exclusion criteria 
X 
X 
 
 
 
 
MGFA (class II-IV) 
X 
X 
 
 
 
 
 
 
Medical history 
20.1.1.1.1.1.1.1
 
 
 
 
 
 
 
 
 
 
Physical exam 
X1 
X 
 
X 
 
 
X 
 
X 
X
X
Concomitant medication2 
20.1.1.1.1.1.1.2
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood tests 
20.1.1.1.1.1.1.3
3
X8 
 
 
 
 
X11 
 
X11 
Pregnancy test4 
20.1.1.1.1.1.1.4
 
 
 
 
 
 
 
 
QMG 
X 
X 
 
X 
 
 
X 
 
X 
X
X
Repetitive neurophysiology, RNS 5  
X 
 
 
 
 
 
X11
Randomisation 
X 
 
 
 
 
 
EQ5D6 
X 
X 
 
X 
 
 
X 
 
X 
X 
X 
MG-QoL156 
X 
X 
 
X 
 
 
X 
 
X 
X 
X 
MG-ADL7   
X 
X 
 
X 
 
 
X 
 
X 
X 
X 
Study drug8,9, 10 
 
X 
 
 
 
 
 
 
 
Prednisolone dose  
 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
AE/SAE (continuous) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 Previous and current diseases, concomitant medications, blood pressure, heart rate, body temperature, age, sex, height, weight and disease activity. 2To be updated at all visits. 3 Haematology 
including differential count, electrolytes, creatinine, liver enzymes C-reactive protein, glucose, hepatitis B screening, total immunoglobulin G levels. 4 Fertile women. 5 Optional. No 
cholinesterase inhibitors within 12 hours before examination. 6 Myasthenia Gravis-Quality of Life. 7 Myasthenia Gravis-Activities of Daily Living. 8 Serum sample to be collected before 
administration of study drug.  
9 1 000 mg paracetamol, 50 mg prednisolone and 10 mg Cetirizine ≥ 45 min before administration of study drug. 10 Heart rate, blood pressure and body temperature to be recorded before and 
after administration of study drug.11 At or close to visit 


 
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21 Annex 2, MGFA classification 
 
MGFA clinical classification 
 
Class I: Any ocular muscle weakness; may have weakness of eye closure. Strength of all the other muscles 
is normal. 
 
Class II: Mild weakness affecting muscles other than ocular muscles; may also have ocular muscle 
weakness of any severity. 
 
IIa. Predominantly affecting limb, axial muscles, or both. May also have lesser involvement of 
oropharyngeal muscles. 
 
IIb. Predominantly affecting oropharyngeal, respiratory muscles, or both. May also have lesser or equal 
involvement of limb, axial muscles, or both. 
 
Class III: Moderate weakness affecting muscles other than ocular muscles; may also have ocular muscle 
weakness of any severity. 
 
IIIa. Predominantly affecting limb, axial muscles, or both. May also have lesser involvement of 
oropharyngeal muscles. 
 
IIIb. Predominantly affecting oropharyngeal, respiratory muscles, or both. May also have lesser or equal 
involvement of limb, axial muscles, or both. 
 
Class IV: Severe weakness affecting muscles other than ocular muscles; may also have ocular muscle 
weakness of any severity. 
 
IVa. Predominantly affecting limb, axial muscles, or both. May also have lesser involvement of 
oropharyngeal muscles. 
 
IVb. Predominantly affecting oropharyngeal, respiratory muscles, or both. May also have lesser or equal 
involvement of limb, axial muscles, or both. 
 
Class V: Defined as intubation, with or without mechanical ventilation, except when employed during 
routine postoperative management. The use of a feeding tube without intubation places the patient in class 
IVb. 
 
 
 
 


 
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22 Annex 3, Study drug infusion/observation 
 
 
Mabthera/Placebo infusion observation 
 
Date: ___________________________ 
Pre-medication 45-60 min before start of infusion: 
T. Deltison 50 mg, 1 st 
Subject no: ____________________________ 
T. Alvedon 500 mg, 2 st        Admin (time): _________ 
T. Cetirizin 10 mg, 1 st 
Initials: ____________________ 
 
 
Study physician: _________________________ 
 
 
Time: 
Temp:  
Blood 
pressure: 
Pulse: 
Notes/Signature 
Before start: 
 
 
 
 
 
 
 


 
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Start of  
infusion. 
Time: 
End of  
infusion. 
Time: 
Time: 
Infusion-
speed: 
Blood 
pressure: 
Pulse: 
Notes/Signature  
(infusion reactions) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Time: 
Temp: 
Blood 
pressure: 
Pulse: 
Notes/Signature 
After infusion: 
 
 
 
 
 
 
 
First infusion (”slow drip rate”) 
0-30 min:  
50 ml/hr (100 mg/hr) 
30-60 min:  
100 ml/hr (200mg/hr) 
60-90 min:  
150 ml/hr (300mg/hr) 
90 min and after:  
200 ml/hr (400 mg/hr) 
 
Blood pressure is checked before the start of the infusion and after the end of the infusion. 
Observe the patient during the ongoing infusion and check blood pressure and reduce the infusion rate if 
the patient experiences side effects. 
 


 
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23 Annex 4, QMG  
Test Item 
None  
Mild 
Moderate Severe 
                                            Score points 
0 
1 
2 
3 
Double vision on upwards gaze (sec) 
120 
91-119 
11-90 
<11 
Ptosis on upwards gaze (sec) 
120 
91-119 
11-90 
<11 
Facial muscles 
Normal lid 
closure 
Complete,  
some 
resistance 
Complete, 
without 
resistance  
Incomplete
Swallowing a cup of water 
Normal 
Minimal 
coughing 
Severe 
coughing 
Cannot 
swallow 
Speech, dysarthria at counting from 1 to 100 
100 
41-99 
5-40 
<5 
Lifting right arm over the head (counts) 
degrees sitting), seconds  
40 
25-39 
10-24 
<10 
Or right arm streched forward (sec) 
degrees sitting), seconds  
180 
60-179 
10-59 
<10 
Lifting left arm over the head (counts) 
degrees sitting), seconds  
40 
25-39 
10-24 
<10 
Or left arm streched forward (sec) 
degrees sitting), seconds  
180 
60-179 
10-59 
<10 
PEF adjusted for age/sex/height (see PEF ref 
values) 
>75% 
51-75% 
26-50% 
<26% 
Finger extenstion right (counts) 
degrees sitting), seconds  
70 
40-69 
10-39 
<10 
Finger extenstion left (counts) 
degrees sitting), seconds  
70 
40-69 
10-39 
<10 
Lifting head in supine position (counts) 
degrees sitting), seconds  
30 
15-29 
5-14 
<5 
Raising right leg in supine position (counts) 
degrees sitting), seconds  
35 
21-34 
10-20 
<10 
Or raising right leg in supine position 45 
degrees (sec) 
degrees sitting), seconds  
60 
40-59 
15-39 
<15 
Raising left leg in supine position (counts) 
degrees sitting), seconds  
35 
21-34 
10-20 
<10 
Or raising left leg in supine position 45 
degrees (sec) 
60 
40-59 
15-39 
<15 
 


 
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Reference values for adjusting PEF values according to age, sex and height 
 
 
 


 
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24 Annex 5, MG-QoL15  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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25 Annex 6, MG-ADL 
 
 
Grade 
Domain
0 
1 
2 
3 
1 Talking 
Normal Intermittent slurring or 
nasal speech 
Constant slurring or 
nasal, but can be 
understood 
Difficult to understand 
speech 
2 Chewing 
Normal Fatigue with solid food 
Fatigue with soft food 
Gastric tube 
3 Swallowing 
Normal Rare episode of choking 
Frequent choking 
necessitating changes 
in diet 
Gastric tube 
4 Breathing 
Normal Shortness of breath with 
exertion 
Shortness of breath at 
rest 
Ventilator dependence 
5
Impaired ability to 
brush teeth or comb 
hair 
None 
Extra effort, but no rest 
periods needed 
Rest periods needed 
Cannot do one of these 
functions 
6 Impaired ability to 
get up from a chair 
None 
Mild, sometimes uses 
arms 
Moderate, always uses 
arms 
Severe, requires 
assistance 
7 Double vision 
None 
Occurs, but not daily 
Daily, but not constant Constant 
8 Eyelid droop 
None 
Occurs, but not daily 
Daily, but not constant 
Constant 
Add items 1-8 for total MG-ADL score


 
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26 Annex 7, EQ5D 
 


 
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