Clinical trial NCT02110706
Conditions: Myasthenia Gravis
Keywords: Myasthenia Gravis Rituximab SNOMED code 31839002
Sponsor: Yale University
Start date: 2014-05-01; Completion date: 2018-05-01
Enrollment: 52 participants; Allocation: RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The specific primary objective of this study is to determine whether rituximab is a safe and beneficial therapeutic for Myasthenia Gravis (MG) that warrants further study in a phase III efficacy trial.

Detailed description:
Investigators plan on conducting a multicenter randomized, double-blind, placebo controlled Phase II clinical trial utilizing a futility design. The study would include acetylcholine receptor (AChR) antibody positive generalized MG subjects. This study also presents a unique opportunity to study both drug and disease mechanisms because unlike many other autoimmune diseases in which rituximab has been used, MG affords the investigation of antigen-specific components that participate in the immunopathology of the disease, namely autoantibodies, autoantibody-producing B cells, and antigen-specific T cells. This work will further our understanding of MG immunopathology and it represents the first step toward gaining a more complete understanding of the immune mechanisms underlying treatment of MG with rituximab leading to new ways to treat the disease.

The specific aim of this study is to determine whether rituximab is a safe and effective treatment for subjects with MG.

The SNOMED code for MG is 31839002.

Arms: arm 1: The placebo group will receive a vehicle control infusion arm 2: Intervention (rituximab): The treatment group will receive a total of two cycles of rituximab separated by 6 months. Each cycle is defined as one infusion (375mg/m2 IV) per week for four consecutive weeks
Interventions: intervention 1: Rituximab intervention 2: Placebo
Intervention descriptions: intervention 1: Intervention (rituximab): The treatment group will receive a total of two cycles of rituximab separated by 6 months. Each cycle is defined as one infusion (375mg/m2 IV) per week for four consecutive weeks intervention 2: The placebo group will receive a vehicle control infusion

Protocol documents:
Prot_000.pdf: 
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FULL PROTOCOL TITLE 
 
B Cell Targeted Treatment In Myasthenia Gravis: A Phase II Trial of Rituximab In 
Myasthenia Gravis  
 
 
Protocol Version: V11.0 
 
 
Protocol Date: (07/05/2017) 
 
 
SHORT PROTOCOL TITLE 
 
BeatMG: Rituximab in Myasthenia Gravis 
 
 
 
Protocol Principal Investigator (PPI): 
 
Richard J. Nowak, MD, MS 
Yale University School of Medicine 
 
 
Co-Investigators (alphabetically): 
 
Richard J. Barohn, MD 
University of Kansas Medical Center 
 
Mazen M. Dimachkie, MD 
University of Kansas Medical Center 
 
Jonathan M. Goldstein, MD 
Hospital for Special Surgery/Weill Cornell Medical College 
 
David A. Hafler, MD 
Yale University School of Medicine 
 
Kevin C. O’Connor, PhD 
Yale University School of Medicine 
 
 
 
 
 
 
 
 


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Supported by: 
The National Institute of Neurological Disorders and Stroke (NINDS) 
 
NeuroNEXT Grant Award: 1U01NS084495-01A1 
Central Coordination Center (CCC): U01NS77179-01 
Data Coordination Center (DCC): U01NS077352  
 
Study Intervention Provided by: 
 
Genentech/Roche Pharmaceuticals 
 
 
Sponsor of IND/IDE: 
Exempt IND # 116878 
Jonathan M. Goldstein, MD 
 
 
 
The information contained herein is confidential and proprietary in nature, and will not be 
disclosed to any third party without written approval of authorized designee.  This document may 
be disclosed to the appropriate institutional review boards or to duly authorized representatives 
of the US Food and Drug Administration or a national regulatory authority under the condition that 
they maintain confidentiality. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
OVERVIEW STUDY SCHEMA ................................................................................................. 14 
STUDY OBJECTIVES ................................................................................................................. 15 
1.1 
Primary Objectives........................................................................................................ 15 
1.2 
Secondary Objectives.................................................................................................... 16 
2 
BACKGROUND .................................................................................................................. 17 
2.1 
Rationale ....................................................................................................................... 17 
2.2 
Supporting Data ............................................................................................................ 19 
3 
STUDY DESIGN.................................................................................................................. 21 
4 
SELECTION AND ENROLLMENT OF SUBJECTS ......................................................... 24 
4.1 
Inclusion Criteria .......................................................................................................... 24 
4.2 
Exclusion Criteria ......................................................................................................... 25 
4.3 
Subject Withdrawal Criteria ......................................................................................... 26 
4.4 
Study Enrollment Procedures ....................................................................................... 26 
4.4.1 Subject Recruitment and Retention .......................................................................... 27 
4.4.2 Screening Logs.......................................................................................................... 27 
4.4.3 Informed Consent...................................................................................................... 27 
4.4.4 Subject Prednisone Diary .......................................................................................... 27 
4.4.5 Randomization/Treatment Assignment .................................................................... 28 
5 
STUDY INTERVENTIONS/STUDY MEDICATION/STUDY DRUG OR DEVICE ....... 28 
5.1 
Study Medications/Interventions, Administration, and Duration ................................. 28 
5.2 
Handling of Study Medications/Interventions .............................................................. 29 
5.2.1 Preparation of Rituximab for Administration ........................................................... 30 
5.2.2 Vital Sign Collection and Infusion Monitoring ........................................................ 31 
5.2.3 Local Labs Prior to Infusion ..................................................................................... 31 
5.3 
Study Drug Accountability ........................................................................................... 31 
5.4 
Concomitant Interventions ............................................................................................ 32 
5.5 
Subject compliance ....................................................................................................... 32 
6 
CLINICAL AND LABORATORY EVALUATIONS/STUDY PROCEDURES ............... 32 
6.1 
Schedule of Activities (SOA) – on-intervention period (Screening – Week 52) ......... 33 
6.2 
Schedule of Activities (SOA) – optional off-intervention period (Weeks 72 and 96) . 34 
6.3 
Study Staffing ............................................................................................................... 35 
6.4 
Timing of Study Activities............................................................................................ 35 
6.4.1 Screening Evaluations and Procedures ..................................................................... 35 
6.4.2 Baseline Visit Evaluations and Procedures............................................................... 37 
6.4.3 Infusion Visits ........................................................................................................... 37 
6.4.4 Clinical Study Visits ................................................................................................. 39 
6.4.5 Optional Observational Off-Intervention Follow-up Visits:..................................... 39 
6.4.6 Outcome Evaluations ................................................................................................ 40 
6.4.7 Laboratory Testing .................................................................................................... 41 
6.4.8 Prednisone Dose Adjustments .................................................................................. 42 
6.4.9 Physical Exam ........................................................................................................... 45 
6.4.10 
Study Medication/Intervention Discontinuation Evaluations/Procedures ............ 45 
6.4.11 
Off-Intervention Evaluations .............................................................................. 466 
6.4.12 
Unscheduled Visits ............................................................................................... 47 


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6.4.13 
Final On-Study Evaluations ................................................................................ 477 
6.4.14 
Pregnancy ............................................................................................................ 477 
6.5 
SPECIAL INSTRUCTIONS AND DEFINITIONS OF EVALUATIONS.................. 48 
6.5.1 Informed Consent...................................................................................................... 48 
6.5.2 Protocol Violations ................................................................................................. 488 
6.5.3 Documentation of Myasthenia Gravis .................................................................... 488 
6.5.4 Medical History ...................................................................................................... 488 
6.5.5 Treatment History ..................................................................................................... 49 
6.5.6 Concomitant Medications/Treatments ...................................................................... 49 
6.5.7 Immunization during B Cell Depletion..................................................................... 49 
6.5.8 Protocol Amendments and Study Termination ......................................................... 50 
6.5.9 Clinical Assessments ................................................................................................ 50 
6.5.10 
Laboratory Evaluations ......................................................................................... 50 
6.5.11 
Pharmacokinetic Studies ..................................................................................... 511 
6.5.12 
Subject Adherence Assessments ......................................................................... 511 
6.5.13 
Biomarker/Mechanistic Studies ............................................................................ 52 
7 
MANAGEMENT OF ADVERSE EVENTS ........................................................................ 52 
8 
CRITERIA FOR INTERVENTION DISCONTINUATION ............................................... 53 
9 
STATISTICAL CONSIDERATIONS................................................................................ 533 
9.1 
General Design Issues ................................................................................................. 533 
9.2 
Outcomes ...................................................................................................................... 55 
9.2.1 Primary Outcome (including definition) ................................................................... 55 
9.2.2 Secondary Outcome(s) .............................................................................................. 55 
9.2.3 Exploratory Outcomes ............................................................................................ 555 
9.3 
Sample Size and Accrual ............................................................................................ 566 
9.4 
Data Monitoring ............................................................................................................ 57 
9.5 
Statistical Analysis Plan .............................................................................................. 588 
10 DATA COLLECTION, SITE MONITORING, AND ADVERSE EXPERIENCE 
REPORTING .............................................................................................................................. 611 
10.1 
Data Management ......................................................................................................... 61 
10.1.1 
Registration ......................................................................................................... 622 
10.1.2 
Data Entry ........................................................................................................... 622 
10.2 
Role of Data Management .......................................................................................... 622 
10.3 
Quality Assurance ....................................................................................................... 633 
10.3.1 
Development of Monitoring Plan ....................................................................... 633 
10.3.2 
Site Monitoring Visits ......................................................................................... 633 
10.3.3 
Laboratory Data Flow ......................................................................................... 644 
10.4 
Adverse Event Reporting ............................................................................................ 644 
10.4.1 
Definitions of Adverse Events, Suspected Adverse Drug Reactions & Serious 
Adverse Events ................................................................................................................... 666 
10.4.2 
Assessment and Recording of Adverse Events ................................................... 688 
11 HUMAN SUBJECTS ......................................................................................................... 711 
11.1 
Central Institutional Review Board (CIRB) Review and Informed Consent ............. 711 
11.2 
Subject Confidentiality ............................................................................................... 711 
11.3 
Study Modification/Discontinuation ........................................................................... 711 


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12 PUBLICATION OF RESEARCH FINDINGS .................................................................... 71 
13 REFERENCES ..................................................................................................................... 73 
SAFETY REPORTING FAX COVER SHEET ........................................................................... 77 
GENENTECH SUPPORTED RESEARCH ................................................................................. 77 


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INVESTIGATOR AGREEMENT 
 
I have read the foregoing protocol V11.0 07/05/2017 and agree to conduct the study as described 
herein. 
By signing the protocol, the Investigator agrees to keep all information provided by the 
NeuroNEXT Network in strict confidence and to request the same from his/her staff and the 
Institutional Review Board. Study documents provided by the NeuroNEXT Network will be stored 
appropriately to ensure their confidentiality. The Investigator should not disclose such information 
to others without authorization, except to the extent necessary to conduct the study.  
 
 
 
 
 
 
__________________________________ 
_______________________ 
Investigator Signature 
Date 
 
__________________________________ 
Print Investigator’s Name 


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SIGNATURE PAGE 
Study Number:  
NeuroNEXT Grant Award: 1U01NS084495-01A1 
Central Coordination Center (CCC): U01NS77179-01 
Data Coordination Center (DCC): U01NS077352 
 
Principal Investigator Approval: 
 
 Signature:                                                                                   Date: 
 Name:  
Richard J. Nowak, MD 
 
 
 
 
NeuroNEXT Clinical Coordinating Center Approval: 
 
Signature:                                                                                   Date: 
 Name: 
Merit Cudkowicz, MD 
 
 
 
NeuroNEXT Data Coordinating Center Approval: 
 
Signature:                                                                                   Date: 
Name: 
Christopher Coffey, PhD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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LIST OF ACRONYMS, ABBREVIATIONS, AND DEFINITIONS OF TERMS  
Ab 
 
 
Antibody 
AChR  
 
Acetylcholine Receptor 
AChR+  
 
Acetylcholine Receptor Antibody Positive  
AE 
 
 
Adverse Event 
AZA 
 
 
Azathioprine 
CCC 
 
 
Clinical Coordination Center 
CDE 
 
 
Common Data Elements 
CFR 
 
 
Code of Federal Regulations 
CIRB   
 
Central Institutional Review Board 
CMSU 
Clinical Materials Services Unit at the University of Rochester Medical 
Center 
CRF 
 
 
Case report form 
CS 
 
 
Clinically Significant 
CSS PI 
 
Clinical Study Site PI 
CTCAE 
 
Common Terminology Criteria for Adverse Events  
DCC 
 
 
Data Coordination Center 
DM 
 
 
Data Management 
DSMB  
 
Data Safety Monitoring Board 
eCRF  
 
Electronic Case Report Form 
EDC 
 
 
Electronic data capture 
FDA      
 
Food and Drug Administration 
FVC 
 
 
Forced Vital Capacity  
GCP 
 
 
Good Clinical Practice 
HIPAA  
 
Health Insurance Portability and Accountability Act 
ICH 
 
 
International Conference on Harmonization  
IMM 
 
 
Independent Medical Monitor 
IVIg 
 
 
Intravenous Immunoglobulin  
IST 
 
 
Investigator Sponsored Trial 
IRB 
 
 
Institutional Review Board  
MedDRA 
 
Medical Dictionary for Regulatory Activities 
MG 
 
 
Myasthenia Gravis 
MG-ADL 
 
Myasthenia Gravis Activity of Daily Living  
MGC  
 
Myasthenia Gravis Composite 
 
 
MGFA  
 
Myasthenia Gravis Foundation of America 
MG-QOL 
 
Myasthenia Gravis Quality of Life  
MMF  
 
Mycophenolate Mofetil 
MS 
 
 
Multiple Sclerosis 
MuSK  
 
Muscle Specific Kinase 
MuSK+ 
 
Muscle Specific Kinase Antibody Positive  
MTX 
 
 
Methotrexate 
NCI 
 
 
National Cancer Institute 
NHL 
 
 
Non-Hodgkin’s Lymphoma 
NIAID  
 
National Institute of Allergy and Infectious Diseases 
NINDS  
 
National Institute of Neurological Disorders and Stroke 
NSAIDs 
 
Non-steroidal anti-inflammatory drugs 
PIS 
 
 
Post-intervention Status 
PLEX  
 
Plasma Exchange 
PML 
 
 
Progressive Multifocal Leukoencephalopathy 


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PPI 
 
 
Protocol Principal Investigator 
PSC 
 
 
Protocol Steering Committee 
QMG  
 
Quantitative Myasthenia Gravis  
RA 
 
 
Rheumatoid Arthritis 
SAE 
 
 
Serious adverse event 
SLE 
 
 
Systemic Lupus Erythematosus 
SOA   
 
Schedule of Activities 
URMC  
 
University of Rochester Medical Center 


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SYNOPSIS 
 
Myasthenia gravis (MG) is an autoimmune disorder of neuromuscular transmission with an 
estimated annual incidence of about 1-2 per 100,000 and prevalence as high as 20-50 per 
100,000.1 Treatment consists of symptomatic therapy with acetylcholinesterase inhibitors and 
immunotherapy such as corticosteroids, azathioprine, cyclosporine, plasma exchange (PLEX) 
and intravenous immunoglobulin (IVIg).1-3 Despite current therapies a subset of subjects remain 
medically refractory or have intolerable medication adverse effects.  There is need for another 
agent in the management of MG as there are few effective drugs for these patients.  Safe, well-
tolerated, efficacious and steroid-sparing therapeutics are needed.   
 
Several recent studies4-6, including two performed by our group 7,8, have demonstrated the 
benefits of B cell depletion rituximab treatment in MG subjects. We completed a small 
retrospective study to evaluate B cell targeted therapy in medically refractory generalized MG 7,8. 
In this analysis we showed that rituximab led to a sustained clinical improvement in parallel to a 
reduction or discontinuation of other immunotherapies.   
 
We now plan on conducting a multicenter randomized, double-blind, placebo controlled Phase II 
clinical trial utilizing a futility design. The study would include acetylcholine receptor (AChR) 
antibody positive generalized MG subjects. This study also presents a unique opportunity to study 
both drug and disease mechanisms because unlike many other autoimmune diseases in which 
rituximab has been used, MG affords the investigation of antigen-specific components that 
participate in the immunopathology of the disease, namely autoantibodies, autoantibody-
producing B cells, and antigen-specific T cells. This work will further our understanding of MG 
immunopathology and it represents the first step toward gaining a more complete understanding 
of the immune mechanisms underlying treatment of MG with rituximab leading to new ways to 
treat the disease. 
 
The specific aim of this study is to determine whether rituximab is a safe and effective treatment 
for subjects with MG.  Although not part of the current protocol, we believe that adding 
exploratory mechanistic studies to the protocol would be important in order to identify 
biomarkers that can potentially be used in future MG clinical trials as well as exploring whether 
B cell therapy is effective in MG.  With this in mind, the investigators have received funding in 
full support of an exploratory mechanistic study with extended follow-up through the National 
Institute of Allergy and Infectious Diseases (NIAID). In addition, NINDS has awarded funding in 
support of the extended clinical follow-up visits.  
 
Study Title 
 
Full Title: B Cell Targeted Treatment in Myasthenia Gravis: A Phase II Trial of Rituximab In 
Myasthenia Gravis  
 
Short Title: BeatMG: Rituximab in Myasthenia Gravis  
 
Objectives  
 
The specific primary objective of this study is to determine whether rituximab is a safe and 
beneficial therapeutic for MG that warrants further study in a phase III efficacy trial. The primary 
clinical endpoint will be the steroid sparing effect of rituximab. Our retrospective study showed 
that rituximab treatment had a measurable and significant effect on conventional 


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immunosuppression, specifically demonstrating an unmistakable prednisone dose reduction7.  
Importantly, steroid-reduction was recently demonstrated to be a practical outcome measure in a 
MG trial by an independent group9. Also in 2012, the Task Force on MG Study Design of the 
Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America (MGFA) 
recommended steroid-sparing effect as a clinical outcome measure10. Our first primary outcome 
measure is the percent of subjects achieving ≥ 75% mean daily prednisone dose reduction in the 
4 weeks prior to week 52 and with clinical improvement or no worsening of symptoms.  Our 
second primary outcome is safety and will be assessed by examining the frequency of study-
related adverse experiences between the treatment and placebo groups. 
 
Design and Outcomes 
 
We plan a multicenter randomized, double-blind, placebo controlled Phase II clinical trial 
evaluating the safety and steroid-sparing effect of rituximab in MG. The study will include 50 
AChR antibody positive generalized MG subjects.  We plan to enroll 25 subjects in a treatment 
group and 25 subjects in a control placebo group.  
 
Primary Outcomes:  
1. Steroid Sparing Effect:  Percent of subjects that achieve a ≥ 75% reduction in mean daily 
prednisone dose in the 4 weeks prior to week 52 and with clinical improvement or no 
significant worsening of symptoms (≤ 2 point increase in MG composite score) as 
compared to the 4-week period prior to randomization and initiation of treatment.  
2. Safety 
 
Secondary Outcomes: 
1. Evaluate whether there is a trend toward clinical benefit as measured by MG-specific clinical 
outcome scales used as endpoints in prior clinical trials.  We will determine if rituximab can 
significantly improve the scores of the following MG-specific clinical outcome measures:   
a.   Myasthenia Gravis Composite (MGC) score 
b. Quantitative Myasthenia Gravis (QMG) score 
 
Interventions and Duration 
 
Intervention (rituximab): The treatment group will receive a total of two cycles of rituximab 
separated by 6 months. Each cycle is defined as one infusion (375mg/m2 IV) per week for four 
consecutive weeks. As such, cycle 1 will be administered weeks 0-3 and cycle 2 will be given 
weeks 24-27. The placebo group will receive a vehicle control infusion.  A predetermined steroid 
taper schedule for both treatment (rituximab) and placebo groups will be utilized. In each subject, 
the prednisone dose will be gradually reduced based on the steroid taper schedule beginning at 
week 8. The dose will only be reduced after confirming clinical improvement or stable symptoms 
based on the MGC score (≤ 2 point increase). 
 
Duration: We set a study period of 52 weeks based on the delayed benefits observed following 
rituximab treatment and in the setting of utilizing a two-cycle protocol. The extended time points 
are needed as normalization of B cell counts typically takes 12+ months following B cell depletion 
treatment.  In order to assess safety in the B cell recovery period as well as assess the long-term 
durability of response, there are two additional optional observational off study-intervention time 
points (weeks 72 and 96). The subjects will be treated per medical standard of care during this 
period.   
 


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Evaluations: Subjects will have clinical evaluations at baseline and then every 4 weeks thereafter 
(week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52).  Clinical evaluations will be completed by a 
blinded evaluator. The dose of prednisone will be recorded by each subject daily and collected at 
each scheduled assessment. Post-intervention status (PIS) will be assessed by measuring MGFA 
class, MGC, QMG, MG-ADL and MG-QOL scores. Adverse effects will be monitored to assess 
safety and tolerability in this subject population per the NINDS Guidelines for Data and Safety 
Monitoring in Clinical Trials. A limited clinical assessment per standard of care will be completed 
during the optional off study-intervention follow-up period at weeks 72 and 96.   
 
Blinding 
This is a double-blind clinical trial.  All study subjects and Clinical Study Staff will be blinded to 
treatment assignment.  The Clinical Study Site Investigator is responsible reviewing all adverse 
events and adjusting subjects’ prednisone dose based on the Myasthenia Gravis Composite 
(MGC) score without knowing whether a subject has received drug or placebo.  The clinical 
evaluators who determine the secondary outcome measures, Myasthenia Gravis Composite 
(MGC) and Quantitative Myasthenia Gravis (QMG), are blinded to treatment assignment and 
clinical adverse event information.  Site Pharmacists will be the only staff who have access to 
treatment information.   
 
Sample Size and Population 
 
Sample Size: 50 
 
Population: Generalized AChR Antibody Positive (AChR+) Myasthenia Gravis 
 
Randomization will be performed through an interactive website, and will be stratified based on 
the steroid dose at baseline: moderate dose prednisone (15-35 mg/day) and high dose 
prednisone (>35 mg/day) as well as their treatment at baseline, prednisone only versus 
prednisone plus another immunosuppressive therapy (IST). Subjects will be assigned a study ID 
at the time of enrollment.  The study ID includes the identification of the center and a unique 
subject ID.  The DCC will generate a randomization table for each of the strata using a permuted 
block design with random block sizes. 
 
Inclusion Criteria: 
 
1. Subjects 21 to 90 years old 
2. Subjects must have generalized MG, defined as MGFA clinical classification grades 
2 (mild), 3 (moderate), or 4 (severe, but not intubated) at the time of 
screening/randomization. 
3. Elevated AChR antibody titer  
4. Subject’s signs and symptoms should not be better explained by another disease 
process. 
5. Subjects must be on a stable standard immunosuppressive regimen: 
a. Prednisone only: Prednisone dose must be at least 15mg/day (or the equivalent 
on alternate days), and the dose of prednisone must have been stable for at least 
4 weeks (28 days) prior to the baseline visit. 
b. Prednisone plus another immunosuppressive therapy (IST). Immunosuppressive 
therapies other than prednisone, specifically azathioprine, mycophenolate 


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mofetil, cyclosporine, tacrolimus or methotrexate, are permitted, but the dose 
must have been stable for at least 6 months prior to the baseline visit.  
(Note: The prednisone dose must be stable as defined in the prednisone only 
group. The IST dose must remain stable throughout the course of the study). 
6. Subjects must be willing to complete the study and return for follow-up visits. 
7. No history of thymoma, tumor, infection, or interstitial lung disease on chest CT, MRI, 
or chest x-ray. Note: Chest x-ray will be completed at screening to look of interstitial 
lung disease.  A chest CT or MRI to evaluate for thymoma must be completed as 
part of prescreening.  
8. Able and willing to give written informed consent and comply with the requirements 
of the study protocol. 
9. Subjects must be able to give written informed consent before participating in this 
study. A copy of the signed consent must be kept in the subject’s medical record. 
10. Men and women of reproductive potential must agree to use an acceptable method 
of birth control during treatment and for twelve months (1 year) after completion of 
treatment. 
 
Exclusion Criteria: 
 
1. A history of chronic degenerative, psychiatric, or neurologic disorder other than MG 
that can produce weakness or fatigue. 
2. Other major chronic or debilitating illnesses within six months prior to study entry. 
3. Female subjects who are premenopausal and are:  
(a) pregnant on the basis of a serum pregnancy test,  
(b) breast-feeding, or  
(c) not using an effective method of double barrier (1 hormonal plus 1 barrier method 
or 2 simultaneous barrier methods) or birth control (birth control pills, male condom, 
female condom, intrauterine device, Norplant, tubal ligation, or other sterilization 
procedures). 
4. Altered levels of consciousness, dementia, or abnormal mental status. 
5. Thymectomy in the previous six months. 
6. Subjects who have been medicated with immunosuppressive drugs not listed in 
inclusion #5 within the last 8 weeks (56 days) prior to the baseline visit 
7. Subjects who have been medicated with an immunosuppressive agent such as 
azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus or methotrexate, that 
is withdrawn within 8 weeks (56 days) of the Baseline Visit.  
8. Subjects who have received IVIg or PLEX treatment within the last 4 weeks (28 
days) prior to the baseline visit.   
9. Unstable dose or a stable dose of > 480 mg/day of pyridostigmine in 2 weeks prior to 
screening visit. 
10. Daily use of non-steroidal anti-inflammatory drugs (NSAIDs). 
11. History of renal or hepatic insufficiency or elevated liver enzymes (AST or ALT >2.5 x 
Upper Limit of Normal). 
12. History of bone marrow hypoplasia, leucopenia, thrombocytopenia, significant 
anemia, clinical or laboratory evidence of immunodeficiency syndromes, that are not 
transient events or side effects related to a clinical procedure (i.e. plasmapheresis) 
and within one year of screening. 
13. Forced Vital Capacity (FVC) <50% of percent predicted.  
14. ANC < 1.5 x 103 cells/microliter  


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15. Hemoglobin:  < 8.0 gm/dL  
16. Platelets:  < 100,000/mm 
17. Positive Hepatitis B or C serology (Hep B surface antigen and Hep C antibody)  
18. History of positive HIV (HIV conducted during screening if applicable) 
19. Treatment with any investigational agent within 4 weeks of screening or 5 half-lives 
of the investigational drug (whichever is longer) 
20. Receipt of a live vaccine within 4 weeks prior to randomization 
21. Previous treatment with rituximab (MabThera® / Rituxan®) 
22. Previous treatment with natalizumab (Tysabri®) 
23. History of severe allergic or anaphylactic reactions to humanized or murine 
monoclonal antibodies 
24. History of recurrent significant infection or history of recurrent bacterial infections 
25. Known active bacterial, viral fungal mycobacterial, or other infection (including 
tuberculosis or atypical mycobacterial disease, but excluding fungal infections of nail 
beds) or any major episode of infection requiring hospitalization or treatment with IV 
antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to 
screening 
26. Unstable steroid dose in the past 4 weeks (28 days) 
27. Lack of peripheral venous access 
28. History of drug, alcohol, or chemical abuse within 6 months prior to screening 
29. Concomitant malignancies or previous malignancies, with the exception of 
adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ 
of the cervix or prostate. 
30. History of psychiatric disorder that would interfere with normal participation in this 
protocol  
31. Significant cardiac or pulmonary disease (including obstructive pulmonary disease) 
32. Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the interpretation 
of the results or render the subject at high risk from treatment complications. 
33. Subjects that do not record daily prednisone doses for at least 28 days before the 
Baseline visit, or subjects whose prednisone dose varies by ≥6mg/day on average. 
34. Prednisone dose of more than 100 mg/day (or 200 mg over a two day period). 
 
OVERVIEW STUDY SCHEMA 
 
A randomized, double-blind, placebo controlled clinical trial schematic is shown below. A total of 
50 AChR+ MG subjects will be enrolled (25 in a treatment arm and 25 in a placebo arm). The 
subjects will be evaluated every 4 weeks for 52 weeks after initial treatment along with two 
additional optional observational off study-intervention time points at weeks 72 and 96. 
 


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STUDY OBJECTIVES 
1.1 
Primary Objectives 
 
Several recent studies 4-6, including two performed by our group 7,8, have demonstrated the 
benefits of B cell depletion rituximab treatment in MG subjects. We completed a small 
retrospective study to evaluate B cell targeted therapy in medically refractory generalized MG 7,8. 
In this analysis we showed that rituximab led to a sustained clinical improvement in parallel to a 
reduction or discontinuation of corticosteroid therapy and plasma exchange treatments. We 
observed a prednisone dose reduction by a mean of 65%, 86% and 94% after one, two and three 
cycles of rituximab, respectively (Figure 1). 
 
The specific primary aim of this study is to determine whether rituximab is a safe and beneficial 
therapeutic for MG that warrants further study in a phase III efficacy trial. The primary clinical 
endpoint will be the steroid sparing effect of rituximab (mean daily prednisone dose in the last 4 
weeks of the study). Our retrospective 
study showed that rituximab treatment 
had a measurable and significant effect 
on conventional immunosuppression, 
specifically 
demonstrating 
an 
unmistakable 
prednisone 
dose 
reduction. Importantly, steroid-reduction 
was recently demonstrated to be a 
practical outcome measure in a MG trial 
by an independent group 9. Also in 2012, 
the Task Force on MG Study Design of 
the Medical Scientific Advisory Board of 
the Myasthenia Gravis Foundation of 
America 
(MGFA) 
recommended 
steroid-sparing effect as a clinical 
outcome measure 10.  
 
Primary Outcome 1. Our first primary outcome measure is the percent of subjects that achieve a 
≥ 75% reduction in mean daily prednisone dose in the 4 weeks prior to week 52 and with clinical 
improvement or no significant worsening of symptoms (≤ 2 point increase in MG Composite score) 
 
 
Figure 
1. 
Effect 
of 
rituximab 
on 
conventional 
immunosuppression. Prednisone dose reduction following 
treatment with cycles 1 through 3 of rituximab. The mean dose 
reduction of the MG subject cohort (n=14) following each cycle 
of treatment was calculated as reduction of baseline dose given 
prior to treatment 


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as compared to the 4 week period prior to randomization and initiation of treatment. Statistical 
considerations, including futility design, will be further discussed in section 9. 
 
Primary Outcome 2.  Our second primary outcome is safety and will be assessed by examining 
the frequency of study-related adverse experiences in the two groups (treatment vs. placebo).   
 
1.2 
Secondary Objectives 
 
The main secondary objective is to evaluate whether there is a trend toward clinical benefit as 
measured by MG-specific clinical outcome scales.  If successful, measures studied would lay the 
groundwork toward optimizing the design of a subsequent phase III efficacy trial of rituximab in 
MG.   
 
Secondary Outcomes.  Our secondary outcomes will focus on whether there is a trend toward 
clinical benefit as measured by MG-specific clinical outcome scales used as endpoints in prior 
clinical trials.  We will determine if rituximab can significantly improve the scores of the following 
MG-specific clinical outcome measures:  (1) Myasthenia Gravis Composite score (MGC).  (2) 
Quantitative Myasthenia Gravis score (QMG).10 11-13 These studied measures would lay the 
groundwork toward optimizing the design of a subsequent phase III efficacy trial of rituximab in 
MG.   
 
Additional exploratory clinical outcomes will be investigated to monitor effectiveness as well as 
evaluate other endpoints that would be useful in optimizing future MG trial designs as well as a 
Phase III rituximab trial.   
 
Clinical Exploratory Outcomes. 
We will determine if rituximab can significantly improve the scores of the following outcome 
measures: (1) MG-Activities of Daily Living (MG-ADL).14 (2) MG-Quality of Life (MG-QOL).15  
 
Other previously used measures of steroid-sparing effect will be assessed: (1) Mean daily 
prednisone dose at each scheduled assessment (every 4 weeks). (2) A delayed start of the area 
under the dose-time curve (AUDTC), starting at week 8. (3) Percentage of subjects achieving a ≥ 
50% mean daily prednisone dose reduction with maintenance of minimal or no symptoms in 4 
weeks prior to week 52. (4) Body Mass Index (Screening Visit and weeks 24 and 52).  (5) HbA1C 
(Screening Visit and week 52). 
 
MG flare rate (failure of therapy) will be assessed by: (1) Number of rescue treatments (PLEX or 
IVIg). (2) Number of times prednisone dose needed to be increased. (3) Frequency of a ≥ 3-point 
increase in the MGC score.  
 
Additionally, there will be two optional observational off study-intervention time points (weeks 72 
and 96) The primary focus will be to assess B cell recovery/repopulation as a safety measure.  
Specifically, we will examine: (1) Percentage of subjects achieving normal B cell counts at week 
72 and 96.  (2) Percentage of achieving baseline B cell counts at week 72 and 96. (3) Percent B 
cell recovery to normal or baseline levels.  In addition, the long-term durability of response will 
also be assessed.  Specifically, we will examine: (1) Percentage of subjects achieving a sustained 
≥ 75% mean daily prednisone dose reduction. (2) Percentage of subjects achieving a ≥ 50% mean 
daily prednisone dose reduction. (3) Prednisone AUDTC (if applicable). (4) Clinical status as 


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measured by MGFA Class, MGC, MG-QOL and MG-ADL scores. (5) Number of rescue 
treatments (PLEX or IVIg). 
 
Biomarker/Mechanistic Exploratory Outcomes. 
The biomarker or mechanistic studies are focused on identifying how treatment modifies the 
immunopathology of MG. We will study changes in the antigen specific components of the MG 
immune system. We have developed/adapted immunoassays so that we can examine 
autoantibodies, B cells and T cells. The principal mechanistic outcome will be the decrease in titer 
of circulating AChR autoantibodies within an individual. Other exploratory mechanism-based 
outcomes include determining how rituximab modifies antigen-specific B cell frequency, the B cell 
repertoire, B cell activating factor (BAFF) levels and whether rituximab modifies antigen-specific 
T cell frequency and phenotype. Measurements will be performed prior to and during B cell 
depletion and through repopulation of the B cell compartment, which will be of particular interest 
in terms of assessing the durability of the treatment.  Blood will be collected for mechanistic 
studies at the Baseline Visit, and at weeks 24, 52, 72 and 96. 
 
2 
BACKGROUND  
2.1 
Rationale 
 
Overview. Myasthenia gravis (MG) is an autoimmune disorder of neuromuscular transmission 
with an estimated annual incidence of about 1-2 per 100,000 and prevalence as high as 20-50 
per 100,000.1, 16  Treatment consists of symptomatic therapy with acetylcholinesterase inhibitors 
and immunotherapy such as corticosteroids, azathioprine, cyclosporine, plasma exchange 
(PLEX) and intravenous immunoglobulin (IVIg).1-3 Despite current therapies a subset of subjects 
remain medically refractory or have intolerable medication adverse effects. 
 
Project Rationale. Autoreactive B cells play an important role in the immunopathogenesis of MG 
and as such would seem to be appropriate for targeted drug therapy investigation.17 Recent 
examples from other autoimmune disorders such as rheumatoid arthritis (RA), systemic lupus 
erythematosus (SLE) and multiple sclerosis (MS), which also frequently have poor response to 
current conventional therapy and frequent relapses or refractory disease, have suggested benefit 
with B cell directed therapies.18-21 B cell depletion may therefore be a beneficial therapeutic goal 
in certain autoimmune diseases based on this experience22 and may potentially translate into a 
new treatment strategy for MG, particularly in those subjects who have failed and are resistant to 
other medical therapies.     
 
Rituximab is the only B cell directed biologic approved for use clinically.  It is a chimeric 
monoclonal antibody that targets the CD20 antigen found on B lymphocytes and modulates B cell 
activation.  CD20 is a 33-kDa protein expressed by all mature B cells, but not on pre-B or 
differentiated plasma cells.  Rituximab has been used as part of the standard therapy for non-
Hodgkin’s lymphoma (NHL) as well as a number of autoimmune diseases.18,23,24, Interest in its 
use for MG began after Gajra and coworkers reported a subject with both lymphoma and MG who 
responded favorably to rituximab.25 Since that time several groups, including our own, have 
observed the benefits of rituximab in autoimmune MG subjects.4-8,26-33 It is, however, unclear what 
changes in the cellular and molecular immune system are associated with the clinical 
improvement. 
 


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The observed positive effect of rituximab in subjects with MG, based largely on anecdotal reports, 
is promising and suggests that further investigation of this agent in MG is warranted (refer to 
Table 1).34 The rationale for the current proposal is to follow our pilot retrospective study with a 
prospective study to more carefully assess the safety, tolerability and identify biomarkers in this 
subject population as well as determine whether it is beneficial therapeutic, employing a futility 
trial design, that warrants further study in a phase 3 efficacy trial.7,8,35  In addition, we will initiate 
an examination of the changes in the cellular immune system that are associated with the clinical 
improvement to further define the immune mechanisms associated with treatment by measuring 
immune components, which participate in the pathology of MG, prior to and after immunotherapy.  
This work is significant because it addresses an important and intractable immune-mediated 
problem involving the neuromuscular junction as well as helps further our understanding of the 
immunopathology of MG.   It also represents, for the first time in MG, the application of targeted 
therapy.  The study of immunologic biomarkers will help elucidate potentially important differences 
in subjects that are responders and non-responders to B cell directed therapy.   This may give 
insight into further development of individual subject tailored therapies in the future.    
 
Table 1: Key Reports of Rituximab in Myasthenia Gravis (adapted from Ibrahim et al.)34 
 
Study 
Year 
Subject 
number 
Controll
ed 
Grade of 
Evidenc
e 
Dose of rituximab 
Outcomes 
Illa et al 
 
2008 
6 
No 
D 
375 mg/m2 every 
week for four 
consecutive weeks  
Improvement of clinical and 
laboratory parameters, 
especially in the 3 MuSK+ 
cases 
Lindberg et 
al 
2010 
5 
No 
D 
375 mg/m2 every 
week for four 
consecutive weeks, 
retreatment with 
1000 mg  weekly x2 
Slow but remarkable 
reduction in MG symptoms. 
Maddison et 
al 
2010 
12 
No 
C 
375 mg/m2 every 
week for four 
consecutive weeks 
8 improved,4 subject did not 
have significant benefit  
Tandan et al 
Stieglbauer 
et al 
Lebrun et al 
 
 
Nelson et al 
 
2010 
2009 
 
2009 
 
 
2009 
10 
3 
 
6 
 
 
3 
No 
No 
 
No 
 
 
No 
 
C 
D 
 
D 
 
 
D 
Ongoing pilot study 
Guided by the total 
count of peripheral B 
lymphocytes 
375 mg/m2 every 
week for four weeks 
then 2-monthly dose 
of 375 mg/m2 
375 mg/m2 every 
week for four 
consecutive weeks, 
one subject received 
only one dose  
Ongoing pilot study 
Improved 
 
3 MuSK+, 1 AChR+ and 2 
double seronegative 
improved 
 
3 MG cases with thymoma 
responded with stabilization 
and reductions in 
immunosuppressive 
medications 
Kundi et al   
2010 
3 
No 
D 
1 gram (750mg/m2) 
repeated twice 
1 MuSK+, 1 AchR+ and 1 
double seronegative 
improved 
Nowak et al 
2011 
14 
No  
C 
375 mg/m2 every 
week for four, 
repeated every 6 mo 
6 AChR+ and 8 MuSK+ 
subjects showed clinical 


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Study 
Year 
Subject 
number 
Controll
ed 
Grade of 
Evidenc
e 
Dose of rituximab 
Outcomes 
improvement and significant 
steroid dose reduction 
 
Blum et al 
2011 
14 
No 
C 
1 gram in 2 divided 
doses  
11 subjects clinically 
improved and 12 were able 
to reduce other 
immunotherapies 
 
Diaz-Manera 
et al 
2012 
17 
No 
C 
375 mg/m2 every 
week for 4 weeks, 
then monthly x 2 
months 
6/6 MuSK+ subjects 
achieved remission or 
minimal manifestation 
status; 10/11 AChR+ 
subjects improved with 6/10 
subjects needing reinfusion 
6-34 mo after 1st dose.  
 
 
There is a paucity of proven steroid-sparing agents in the management of MG.  The most 
convincing steroid-sparing agent is azathioprine (AZA) with some recent evidence supporting 
methotrexate (MTX).36,37 The current mycophenolate mofetil (MMF) and tacrolimus data are not 
very strong but are suggestive of some benefit.9,38  There is need for another agent in the 
management of MG as there are few effective drugs, as well as a subset of subjects that are 
medically refractory or drug-resistant to standard therapies. Safe, well-tolerated, efficacious and 
steroid-sparing therapeutics are needed.   
Protocol Rationale. A standard protocol for rituximab infusion in MG has not been established.  
Therefore, the non-Hodgkin’s Lymphoma (NHL) treatment protocol was adopted which consists 
of weekly infusions at 375 mg/m2.   One cycle is defined as 1 infusion per week for 4 consecutive 
weeks.   The interval between cycles is 6 months.  We have based our decision to use a two-
cycle regimen, instead of a single cycle approach, on the following evidence. A recently published 
European series evaluating the long-term effects of rituximab following one cycle did show clinical 
improvement 4. While clinical improvement was achieved, an immunotherapy-free remission state 
was not. Fifteen of 17 subjects continued to remain on prednisone and/or additional 
immunotherapy. Six out 10 AChR+ subjects in this study needed to be retreated to maintain initial 
clinical benefits. We believe that an additional treatment cycle may be indicated to achieve a 
durable response in parallel to successful withdrawal/reduction of steroids and/or other chronic 
immunotherapy. Retrospective analysis of twenty MG subjects followed in our neuromuscular 
clinic has shown that only 5 of 20 subjects were immunotherapy-free after completing one cycle 
as compared to 12 of 20 following two cycles. Mean steroid dose was reduced by 65% and 86% 
following one and two cycles, respectively. This suggests that a two-cycle protocol may be more 
clinically advantageous in MG and serves as the basis for our approach.  Retrospective analysis 
of our data with the DCC also revealed that 82% of subjects who received rituximab achieved at 
least a 75% reduction in their prednisone dose at 52 weeks (95% CI: 48%-98%).  This statistical 
analysis is the basis for our primary endpoint. 
2.2 
Supporting Data 
 
The first reports on the use of rituximab in MG were in subjects treated for lymphoma.25,39 In three 
of these subjects, rituximab was administered at 375 mg/m2 weekly for four weeks, and in one, the 


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dose was 260 mg/m2 weekly for four weeks. Clinical symptoms of MG such as diplopia and muscle 
fatigability as well as pulmonary function tests showed improvement with a decrease in the serum 
AChR antibody levels. 
 
This was followed by the publication of several small and one large uncontrolled case series. In 
2008, Illa and co-workers reported treating six severe refractory MG subjects (three AChR+ and 
three MuSK+ (Muscle Specific Kinase Antibody Positive)) with rituximab at 375 mg/m2 weekly for 
four weeks.5 All six cases (five MGFA Grade IVb and one Grade V) dramatically improved clinically.  
There was a decline in serum antibody titers in both AChR+ and MuSK+ groups.  There appeared 
to be a more sustained clinical improvement in the MuSK+ group.  No severe adverse events were 
reported. 
 
Investigators in the United Kingdom reported data obtained from a nationwide survey of physicians 
treating MG.27 They identified ten subjects diagnosed with generalized MG (seven AChR+ and 
three MuSK+) and two with Lambert-Eaton myasthenic syndrome. Rituximab was administered in 
standard doses in eight cases, whereas the rest received one or two infusions at 375 mg/m2. Over 
the 4 to 48 month follow-up period, three of seven AChR+ MG cases improved on their MGFA 
post-intervention status, whereas all MuSK+ cases improved. Both Lambert-Eaton myasthenic 
syndrome cases improved but did not achieve remission. Four subjects did not have significant 
benefit from rituximab, three of which received fewer than four infusions. 
 
There are other small case series that have suggested similar efficacy of rituximab in generalized 
MG.8,29,30 Lebrun and coworkers evaluated six bedridden MG cases; one was AChR+, three had 
MuSK+, and two were double-seronegative cases.6 Rituximab was administered at 375 mg/m2 on 
Days 1, 8, 15, and 21 during the first month and then one dose every 2 months. All subjects 
responded very well to rituximab with significant clinical improvement allowing for the tapering of 
prednisone and pyridostigmine bromide. 
 
Our group has recently completed a retrospective study of fourteen subjects to evaluate B cell 
targeted therapy in medically refractory generalized MG, including both MuSK+ and AChR+ 
antibody subjects.7 Rituximab was given at a standard dose of 375 mg/m2 weekly.  Each cycle 
was defined as one infusion per week for four consecutive weeks. Interval between cycles was 
set at 6 months.  In this analysis, we showed that rituximab led to a sustained clinical improvement 
in parallel to a reduction or discontinuation of corticosteroid therapy and plasma exchange 
treatments. We observed a prednisone dose reduction by a mean of 85.7% and 93.8% after two 
and three cycles of rituximab, respectively.  AChR antibody titers significantly decreased by a 
mean of 52.1% after the second cycle (p = 0.005).  
 
A group in Europe recently published a report describing seventeen drug-resistant MG subjects 
treated with rituximab (six MuSK+ and eleven AChR+).4 After a mean post-treatment period of 31 
months, ten of the AChR+ subjects improved but six of them needed reinfusions. In contrast, all 
MuSK+ subjects achieved a remission or minimal manifestations status and no need for 
reinfusions. Consequently, in the MuSK+ group, prednisone doses were reduced (average dose 
before rituximab: 49 mg/day; at last visit: 6.5 mg/day) and other immunotherapies could be 
withdrawn. Clinical improvement was associated with a significant decrease in the antibody titers 
only in the MuSK+ subjects (mean reduction of 86.7%, p = 0.002). MuSK antibody levels were 
either negative or decreased at the last follow-up period. They concluded that rituximab has long-
lasting benefits in MuSK+ subjects and recommend rituximab as an early therapeutic option in 
this group of subjects with MG if they do not respond to steroids. AChR+ subjects also responded 
to treatment but required repeat treatment.     


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To date, approximately seventy-five cases of MG treated with rituximab have been reported.  The 
majority of subjects were observed to benefit from treatment.  In the absence of a controlled, 
prospective clinical trial and reporter bias for positive studies, it is difficult to firmly conclude that 
rituximab is an efficacious therapeutic in MG.  The evidence thus far warrants further investigation.   
 
The safety of rituximab therapy is an important concern. The most common side effect reported 
is an infusion reaction consisting mainly of fever, rigors, nausea and hypotension.  Progressive 
multifocal leukoencephalopathy (PML) is the most significant complication, however, the relative 
risk is thought to be low per a recent review40. Per this review, there have been a total of 57 PML 
cases following rituximab therapy in HIV-negative patients from 1997 to 2008.  These numbers 
are based on cases reported to the Food and Drug Administration (FDA) as well as reported in 
the medical literature. Fifty-two of the cases were patients with B-cell lymphoproliferative 
disorders and the remaining 5 cases were patients with an autoimmune disorder (i.e., SLE, 
rheumatoid arthritis, autoimmune pancytopenia).  There have been no cases of PML reported in 
MG subjects treated with rituximab.  We plan to minimize concomitant immunosuppressive 
therapies in our subjects and plan to enroll subjects who are either only on prednisone or on 
prednisone plus only one other IST.  Please refer to eligibility criteria for specific details.  These 
regimens represent real world scenarios and are also consistent with the types of patients 
included in our pilot study7.  We recommend this type of approach prior to initiating rituximab as 
combination treatments could pose a higher PML risk.   
 
Please refer to the study drug package insert for additional details.   
3 
STUDY DESIGN 
 
Clinical Trial Design. We propose a 
multicenter randomized, double-blind, 
placebo 
controlled 
clinical 
trial 
evaluating the safety and steroid-
sparing effect of rituximab in MG. The 
study would enroll AChR antibody 
positive 
generalized 
MG 
subjects 
(Figure 2). Based on sample size 
calculations we propose a study of 50 
total subjects. We expect to enroll 25 
AChR+ subjects in a treatment group 
along with 25 subjects in a control 
placebo group.  
 
Subjects. 
Subjects 
who 
are 
on 
standard of care treatment regimens 
for MG may enroll.  Each previously 
diagnosed generalized MG subject at 
time of enrollment will be expected to be on a stable fixed dose of prednisone (minimum dose of 
15 mg/day) for at least 4 weeks (28 days) with stable symptoms. Prednisone dose variation would 
be limited to less than 6 mg/day on average in the 4 weeks (28 days) prior to the start of the study 
or randomization. There will be two groups of standard of care treatment regimens and are defined 
as: 
• 
Prednisone only. 
 
Figure 2. Schematic diagram outlining trial design. A 
randomized, double-blind, placebo controlled clinical trial is shown. 
A total of 50 AChR+ subjects would be enrolled (25 in a treatment 
arm and 25 in a placebo arm). The subjects will be evaluated every 
4 weeks for 52 weeks after initial treatment.  There are two 
additional optional time points at weeks 72 and 96 in order to follow 
B cell recovery and long-term durability of response. 
 


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• 
Prednisone plus another IST.  The prednisone dose must be as defined above and the 
subject must be on a stable dose for at least 6 months prior to baseline on one of the 
following IST:  azathioprine, mycophenolate mofetile, cyclosporine, tacrolimus or 
methotrexate. 
 
Study Duration. We set a study period of 52 weeks based on the delayed benefits observed 
following rituximab treatment and in the setting of utilizing a two-cycle protocol.  
 
In order to assess the long-term durability of response, there are two additional optional 
observational off study-intervention time points (weeks 72 and 96). The subjects will be treated 
per medical standard of care during this period.  The extended time points are also needed as 
normalization of B cell counts typically takes 12+ months following B cell depletion treatment. 
 
Randomization.  Randomization will be performed through an interactive website, and will be 
stratified based on the steroid dose at baseline: moderate dose prednisone (15-35 mg/day) and 
high dose prednisone (>35 mg/day) as well as standard of care treatment regimen at the baseline 
visit (prednisone only vs. prednisone plus another IST). Subjects will be assigned a study ID at 
the time of enrollment.  The study ID includes the identification of the center and a unique subject 
ID.  The DCC will generate a randomization table for each of the strata using a permuted block 
design with random block sizes. 
 
Blinding.  This is a double-blind clinical trial.  All study subjects and Clinical Study Staff will be 
blinded to treatment assignment.  The Clinical Study Site Investigator is responsible reviewing all 
adverse events and adjusting subjects’ prednisone dose based on the Myasthenia Gravis 
Composite (MGC) score without knowing whether a subject has received drug or placebo.  The 
clinical evaluators who determine the secondary outcome measures, Myasthenia Gravis 
Composite (MGC) and Quantitative Myasthenia Gravis (QMG), are blinded to treatment 
assignment and clinical adverse event information.  Site Pharmacists will be the only staff who 
have access to treatment information.   
 
Rituximab. Treatment group will receive a total of two cycles of rituximab (375mg/m2) separated 
by 6 months. Each cycle is defined as one infusion per week for four consecutive weeks. As such, 
cycle 1 will be administered weeks 0-3 and cycle 2 will be given weeks 24-27. The placebo group 
will receive an infusion that contains only the vehicle components of the rituximab solution.   
 
Prednisone. A predetermined steroid taper schedule for both treatment (rituximab) and placebo 
groups will be utilized. In each subject, the prednisone dose will be gradually reduced based on 
the steroid taper schedule beginning at week 8. The dose will only be reduced after confirming 
clinical improvement or stable symptoms based on the MGC score (≤ 2 point increase) as 
compared to the Baseline Visit or prior study visit MGC score. If the MGC score change is ≥ 3 
points, the prednisone dose would be increased until symptoms resolved or at least stabilized to 
baseline status (baseline visit MGC score). After symptom stabilization, prednisone taper can 
again be resumed at next scheduled assessment. Subjects would continue in the study even if 
they could not taper off higher doses of steroids (40-60 mg/day) as long as their symptoms were 
controlled on that dose as this would be considered standard-of-care.  
 
Rescue Therapy. If subject symptoms significantly worsen during the course of the trial and are 
not controlled by increased steroid doses (high dose prednisone), the subject can receive PLEX 
or IVIg as a rescue therapy. PLEX and IVIg treated subjects would remain in the study and be 


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included in data analysis. The rationale for this is that these subjects would have already been up 
titrated to a high prednisone dose but failed to adequately respond. Subjects that could not be 
managed with steroids, IVIg, or PLEX and required additional immunotherapy (e.g., pulse IV 
steroids, azathioprine, etc.) would be considered treatment failures and potentially drop out of the 
study.  
  
Pyridostigmine. Subjects on pyridostigmine must be on a stable dose of ≤480 mg/day for a 
minimum of 2 weeks prior to the Screening Visit.  Subject must remain on a stable fixed dose for 
the duration of the study.  The dose cannot be changed after study entry.   
 
Note: Subjects on pyridostigmine should be instructed to hold their medication for a minimum of 
12 hours prior to the Baseline Visit and all subsequent Clinical Study Visits.   
 
Assessments. Subjects will have clinical evaluations at baseline and then every 4 weeks 
thereafter (week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52) completed by a blinded evaluator 
(refer to SOA).  Evaluations must be completed within +/- 3 days of scheduled assessment. The 
dose of prednisone will be recorded by each subject daily and collected at each scheduled 
evaluation. Post-intervention status will be assessed by measuring MGFA, MGC, QMG, MG-ADL 
and MG-QOL scores. Blood will be collected for safety, specialized and other studies at scheduled 
time points (refer to SOA table). Adverse effects will be monitored at each visit to assess safety 
and tolerability in this subject population per Genentech and DAIT’s guidelines. Please see SOA 
and Section 6.4.5 for details pertaining to assessments done at the optional off-intervention follow-
up visits at Weeks 72 and 96. 
 
Outcome Measures. We will assess both the safety and steroid-sparing effect of rituximab in MG. 
The primary clinical endpoint, steroid sparing effect, will be measured by determining the 
percentage of subjects achieving a ≥ 75% mean daily prednisone dose reduction and with clinical 
improvement or no significant worsening of symptoms in the last 4 weeks of the study (weeks 49-
52).   
 
MGC, QMG, MG-ADL and MG-QOL scales will be completed at each clinic visit and determine 
changes.    
 
Laboratory Assessments, Safety monitoring, serology testing, and specialized blood work will be 
obtained at the Screening Visit, Baseline Visit, Week 24 Visit, Week 52 visit and any Unscheduled 
Visits. All these labs will be centrally analyzed.  These include: 
• 
Standard bloods: comprehensive metabolic panel, uric acid, LDH and CBC with platelets 
and differential (Screening, Week 52 and Unscheduled).   
• 
HbA1C will be measured (Screening and Week 52). 
• 
Serology testing: HBV, HCV, HIV (Screening). 
• 
Specialized bloods:  AChR antibody titer, Total IgG, IgA and IgM levels, Flow cytometry 
to assess B cell count (Baseline, Week 24, Week 52 and Unscheduled).   
NOTE – Specialized bloods should be drawn prior to daily prednisone dose. 
• 
Mechanistic Bloods (Baseline, Week 24, Week 52 and Unscheduled). 
 
**Note** Specialized and Mechanistic Biomarker blood work will also be done at the optional off-
intervention follow-up visits at Weeks 72 and 96. For more details, please refer to section 6.4.7. 
 
 


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Infusion Labs (complete metabolic panel, uric acid, LDH and CBC with platelets and differential) 
will be collected at each infusion visit and analyzed at each institution’s local laboratory prior to 
study drug infusion.  
 
A complete listing of Laboratory Assessments is included in Section 6.3.6 
 
Optional off-intervention follow-up. A limited clinical assessment will be completed during the 
optional observational off-study intervention period at weeks 72 and 96. Evaluations for these 
visits, if the subject is willing to participate, must be completed within /+/-30 days of scheduled 
assessment. Procedures include physical exam, outcomes assessments and blood collection. 
For more details regarding what is required to be done and collected, please refer to the SOA and 
section 6.4.5. 
 
**Note** As the primary focus of the two additional optional observational time points is to 
assess B cell recovery/repopulation as a safety measure, subjects who have received treatment 
with rituximab, or have been involved with other interventions that result in Bcell depletion since 
completion of the trial (i.e. Week 52) will be excluded from the optional off-intervention follow-up 
visits. 
4 
SELECTION AND ENROLLMENT OF SUBJECTS 
4.1 
Inclusion Criteria 
 
Subject selection will be based on a diagnosis of MG and the following specific criteria: 
 
1. Subjects 21 to 90 years old 
2. Subjects must have generalized MG, defined as MGFA clinical classification grades 
2 (mild), 3 (moderate), or 4 (severe, but not intubated) at the time of 
screening/randomization. 
3.  Elevated AChR antibody titer  
4. Subject’s signs and symptoms should not be better explained by another disease 
process. 
5. Subjects must be on a stable standard immunosuppressive regimen: 
a. Prednisone only: Prednisone dose must be at least 15mg/day (or the equivalent 
on alternate days), and the dose of prednisone must have been stable for at least 
4 weeks (28 days) prior to the baseline visit. 
b. Prednisone plus another immunosuppressive therapy (IST). Immunosuppressive 
therapies other than prednisone, such as azathioprine, mycophenolate mofetil, 
cyclosporine, tacrolimus or methotrexate, are permitted, but the dose must have 
been stable for at least 6 months prior to the baseline visit.   
(Note: The prednisone dose must be stable as defined in the prednisone only 
group. The IST dose must remain stable throughout the course of the study). 
6. Subjects must be willing to complete the study and return for follow-up visits. 
7. No history of thymoma, tumor, infection, or interstitial lung disease on chest CT, MRI, 
or chest x-ray. Note: Chest x-ray will be completed at screening to look of interstitial 
lung disease.  A chest CT or MRI to evaluate for thymoma must have been 
completed as part of prescreening.   
8. Able and willing to give written informed consent and comply with the requirements 
of the study protocol. 


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9. Subjects must to able to give written informed consent before participating in this 
study. A copy of the signed consent must be kept in the subject’s medical record. 
10. Men and women of reproductive potential must agree to use an acceptable method 
of birth control during treatment and for twelve months (1 year) after completion of 
treatment. 
4.2 
Exclusion Criteria 
 
Disease Specific Exclusion Criteria 
 
1. A history of chronic degenerative, psychiatric, or neurologic disorder other than MG 
that can produce weakness or fatigue. 
2. Other major chronic or debilitating illnesses within six months prior to study entry. 
3. Female subjects who are premenopausal and are:  
(a) pregnant on the basis of a serum pregnancy test,  
(b) breast-feeding, or  
(c) not using an effective method of double barrier (1 hormonal plus 1 barrier method 
or 2 simultaneous barrier methods) or birth control (birth control pills, male condom, 
female condom, intrauterine device, Norplant, tubal ligation, or other sterilization 
procedures). 
4. Altered levels of consciousness, dementia, or abnormal mental status. 
5. Thymectomy in the previous six months. 
6. Subjects who have been medicated with immunosuppressive drugs not listed in 
inclusion #5 within the last 8 weeks (56 days) prior to the baseline visit. 
7. Subjects who have been medicated with an immunosuppressive agent such as 
azathioprine, mycophenolate mofetil, cyclosporine, tacrolimus or methotrexate, that 
is withdrawn within 8 weeks (56 days) of the Baseline Visit.  
8. Subjects who have received IVIg or PLEX treatment within the last 4 weeks (28 
days) prior to the baseline visit.   
9. Unstable dose or a stable dose of > 480 mg/day of pyridostigmine in 2 weeks prior to 
screening visit 
10. Daily use of non-steroidal anti-inflammatory drugs (NSAIDs). 
11. History of renal or hepatic insufficiency or elevated liver enzymes (AST or ALT >2.5 x 
Upper Limit of Normal). 
12. History of bone marrow hypoplasia, leucopenia, thrombocytopenia, significant 
anemia, clinical or laboratory evidence of immunodeficiency syndromes, that are not 
transient events or side effects related to a clinical procedure (i.e. plasmapheresis) 
and within one year of screening. 
13. Forced Vital Capacity (FVC) <50% of percent predicted.  
 
General Safety & Laboratory Exclusion Criteria  
 
14. ANC < 1.5 x 103  cells/microliter  
15. Hemoglobin:  < 8.0 gm/dL  
16. Platelets:  < 100,000/mm 
17. Positive Hepatitis B or C serology (Hep  B surface antigen and Hep C antibody)  
18. History of positive HIV (HIV conducted during screening if applicable) 
19. Treatment with any investigational agent within 4 weeks of screening or 5 half-lives 
of the investigational drug (whichever is longer) 


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20. Receipt of a live vaccine within 4 weeks prior to randomization 
21. Previous treatment with rituximab (MabThera® / Rituxan®) 
22. Previous treatment with natalizumab (Tysabri®) 
23. History of severe allergic or anaphylactic reactions to humanized or murine 
monoclonal antibodies 
24. History of recurrent significant infection or history of recurrent bacterial infections 
25. Known active bacterial, viral fungal mycobacterial, or other infection (including 
tuberculosis or atypical mycobacterial disease, but excluding fungal infections of nail 
beds) or any major episode of infection requiring hospitalization or treatment with IV 
antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to 
screening 
26. Unstable steroid dose in the past 4 weeks (28 days) 
27. Lack of peripheral venous access 
28. History of drug, alcohol, or chemical abuse within 6 months prior to screening 
29. Concomitant malignancies or previous malignancies, with the exception of 
adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ 
of the cervix or prostate. 
30. History of psychiatric disorder that would interfere with normal participation in this 
protocol  
31. Significant cardiac or pulmonary disease (including obstructive pulmonary disease) 
32. Any other disease, metabolic dysfunction, physical examination finding, or clinical 
laboratory finding giving reasonable suspicion of a disease or condition that 
contraindicates the use of an investigational drug or that may affect the interpretation 
of the results or render the subject at high risk from treatment complications  
33. Subjects that do not record daily prednisone doses for at least 28 days before the 
Baseline Visit, or subjects whose prednisone dose varies by ≥6mg/day on average. 
34. Prednisone dose of more than 100 mg/day (or 200 mg over a two day period). 
 
4.3 
Subject Withdrawal Criteria 
 
If subject symptoms significantly worsen during the course of the trial and are not controlled by 
increased steroid doses (high dose prednisone), the subject can receive PLEX or IVIg as a rescue 
therapy. PLEX and IVIg treated subjects would remain in the study and be included in data 
analysis. The rationale for this is that these subjects would have already been up titrated to a high 
prednisone dose but failed to adequately respond. Subjects that could not be managed with 
steroids, IVIg, or PLEX and required additional immunotherapy (e.g., pulse IV steroids, 
azathioprine, etc.) would be considered treatment failures and likely withdrawn from the study.  
 
Sample size has been determined to include a 20% subject withdrawal rate and will not replace 
subjects.   
 
Subjects that exhibit serious adverse effects will be reviewed by the safety monitoring board to 
determine if removal from the study is necessary.  
4.4 
Study Enrollment Procedures 
 
The informed consent will be obtained by study team member at the Screening Visit or up to 1 
week (7 days) prior.    


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4.4.1 Subject Recruitment and Retention  
 
Participants will be recruited from clinics at participating NeuroNEXT Network sites. Postings will 
be placed on www.neuronext.org, www.myasthenia.org, www.mda.org,  
www.ninds.nih.gov/disorders/clinical_trials,and other disease specific websites. Flyers about the 
study will be sent to community neurologists at NeuroNEXT clinical sites. Webinars will be 
conducted for participant recruitment as needed.  Interested participants will be contacted by the 
investigators or their staff and invited to participate. These recruitment strategies will include a 
mechanism by which the subjects can provide their contact information. We will use the 
NeuroNEXT Recruitment and Retention Committee to identify recruitment strategies.  If 
recruitment is slower than expected and specific enrollment targets are not reached, we plan to 
activate additional NeuroNEXT sites. 
4.4.2 Screening Logs 
 
Screening logs to document reasons for ineligibility and reasons for nonparticipation of eligible 
subjects will be stored centrally at the NeuroNEXT Data Coordination Center. 
 
Sites will be instructed to complete EDC based pre-screening logs for all pre-screened patients 
that meet the following criteria:  generalized AChR positive MG AND on prednisone. 
4.4.3 Informed Consent 
 
Written informed consent will be obtained from each study participant before any study-specific 
procedures or assessments are done and after the aims, methods, anticipated benefits, and 
potential hazards are explained. The participant’s willingness to participate in the study will be 
documented in writing in a consent form approved by the NeuroNEXT Central Institutional Review 
Board (CIRB), which will be signed by the participant with the date of that signature indicated. 
The site will keep the original consent forms and a copy will be given to the participant. It will also 
be explained to the participant that they are free to refuse entry into the study and free to withdraw 
from the study at any time without prejudice to future treatment. Written and/or oral information 
about the study in a language understandable by the participant will be given to all participants. 
 
Written informed consent will also be obtained from each study participant prior to proceeding 
with and performing all procedures at the optional Week 72 and Week 96 Visits. A separate 
consent form will be provided by the study team, which will be used to document the subject’s 
willingness to participate in the off study-intervention follow-up visits. All the requirements outlined 
above also apply to this secondary consent form and consent process. Subjects may be 
consented prior to Week 52 or at Week 72 prior to any study-related procedures being performed. 
If the Week 72 window has passed for any given subject, but they are willing to coming for Week 
96, they can be consented at Week 96 prior to any procedures being performed. 
4.4.4 Subject Prednisone Diary 
 
Subjects will be provided a daily prednisone diary at the Screening Visit.  Subjects will be 
instructed how to fill out the diaries for accurate recording of dosage for prednisone.  These will 
be collected, reviewed and information recorded at each scheduled visit, including the baseline 
visit.  Compliance with prednisone diary completion will be monitored at each visit. 
 


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Prednisone Diaries do not need to be collected at the extended follow-up visits at Weeks 72 and 
96.   
 
4.4.5 Randomization/Treatment Assignment 
 
Randomization will be performed through an interactive website, and will be stratified based on 
the steroid dose at baseline, moderate dose prednisone (15-35 mg/day) and high dose 
prednisone (>35 mg/day), as well as standard of care treatment regimen at the baseline visit.  
Subjects will be assigned a study ID at the time of enrollment.  The study ID includes the 
identification of the center and a unique subject ID.  The DCC will generate a randomization table 
for each of the strata using a permuted block design with random block sizes. 
5 
STUDY INTERVENTIONS/STUDY MEDICATION/STUDY DRUG OR DEVICE 
5.1 
Study Medications/Interventions, Administration, and Duration 
 
Genentech, Inc. will provide rituximab (Rituxan®) and matching placebo labeled for 
investigational use. The NeuroNEXT central pharmacy, the Clinical Materials Services Unit 
(CMSU) at the University of Rochester Medical Center (URMC) will create active and placebo 
study drug kits with unique identifiers not associated with the randomization ID. Each kit will 
contain 12 of the 100mg/10ml vials of the Rituxan® or matching placebo and four (4) of the 
500mg/50ml vials of the Rituxan® or matching placebo.  Each kit is good for 1 full cycle of dosing 
(4 infusions over the course of 4 weeks) of study drug assuming a maximum dose of 
800mg/weekly dose.  Each subject will receive a total of 2 full kits to allow for 2 full cycles of 
dosing. The CMSU will provide each approved site with an appropriate number of active and 
placebo kits to support subjects enrolled at the site. CMSU will prepare and dispense both study 
drug and placebo control.  The Protocol PI will ensure maintenance of complete and accurate 
records of the receipt, dispensation, and disposal or return of all study drug in accordance with 
Title 21 Code of Federal Regulations (C.F.R.), Part 312.57 and 312.62 and Genentech 
requirements. 
 
Rituximab is a highly purified, 1328–amino acid antibody with an approximate molecular mass of 
145 kD.  The chimeric mouse/human anti-CD20 antibody is a glycosylated IgG1  
immunoglobulin containing murine light and heavy chain variable regions and human 1 heavy 
chain and  light chain constant regions. 
 
Rituximab will be administered intravenously (IV) at 375mg/m2 weekly consecutively for four 
weeks and then repeated at six months. To prevent infusion-associated reactions, each subject 
will be administered premedication with 1000 mg oral acetaminophen and 50 mg oral 
diphenhydramine within 30 to 60 minutes prior to each rituximab infusion. If subject has an 
infusion related reaction, the subject will receive 100 mg methylprednisolone IV 30 minutes prior 
to the next infusion.  If the subject tolerates this infusion than methylprednisolone premedication 
would not be offered at next infusion.   Subjects will be administered rituximab by staff and at an 
infusion center experienced with this medication.  Refer to section 5.2 for additional specific 
details. 
 
The most common side effects are infusion-related symptoms, particularly with the first rituximab 
infusion.  These symptoms include flu-like symptoms, fever, chills/rigors, nausea, urticaria, 
headache, bronchospasm, angioedema, and hypotension.  Since hypotension may occur during 


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Rituximab infusion, consideration should be given to withholding antihypertensive medications 12 
hours prior to and throughout the rituximab infusion.  The decision to hold antihypertensive 
medications will be based on the discretion of local site investigator.   Angina pectoris or cardiac 
arrhythmias, such as atrial flutter or fibrillation, have occurred in subjects treated with rituximab. 
Therefore, cardiac monitoring will be performed during and after all infusions (immediate post-
infusion period) for subjects with a history of cardiac disease. In the pooled, placebo-controlled 
studies, the proportion of patients with serious cardiovascular reactions was 1.7% and 1.3% in 
the rituximab and placebo treatment groups, respectively. In rare instances, severe and fatal 
infusion-related reactions have occurred.   
 
Progressive multifocal leukoencephalopathy (PML) is the most significant potential complication, 
however, the relative risk is thought to be low in HIV negative subjects based on a recent review.40 
The incidence is < 1 per every 10,000 patients treated with rituximab.  It is reassuring that no 
cases of PML have been reported in the rituximab MG population.  We plan to minimize 
concomitant immunosuppressive therapies in our subjects and enroll subjects who are only 
receiving standard of care MG treatment regimens.  We have defined these groups as subjects 
receiving either only prednisone or prednisone plus only one IST.  Please refer to eligibility criteria 
for specific details.  These regimens represent real world scenarios and are also consistent with 
the types of patients included in our pilot study where no significant safety concerns were 
observed7. We recommend careful review of immunotherapy regimen for every subject prior to 
initiating rituximab and to limit use of rituximab treatment to the groups as defined above as 
combined treatments could pose a higher PML risk. Refer to the manufacture Investigator’s 
Brochure for additional details. Subjects who are on prednisone plus one other IST, will continue 
to have routine safety monitoring as per standard of care practices specific to that IST.  This 
monitoring will be conducted by treating the physician.    
5.2 
Handling of Study Medications/Interventions 
 
Overview.  Rituximab is formulated for IV administration as a sterile product in 9.0 mg/mL sodium 
chloride, 0.7 mg/mL polysorbate 80, 7.35 mg/mL sodium citrate dihydrate, and Sterile Water for 
Injection (pH 6.5).  Rituximab is a sterile, clear, colorless, preservative-free liquid concentrate for 
intravenous (IV) administration. Rituximab is supplied at a concentration of 10 mg/mL in either 
100 mg (10 mL) or 500 mg (50 mL) single-use vials and will be reconstituted for infusion by the 
site’s investigational drug pharmacy in 0.9%NaCl or D5W. Local pharmacists should refer to the 
Study Drug Package Insert provided to obtain guidance on the dilution of Rituximab, and follow 
the institutional policies for the specific dilution ratio.  
 
Placebo will be provided by Genentech and is a sterile product in 9.0 mg/mL sodium chloride, 
0.7 mg/mL polysorbate 80, 7.35 mg/mL sodium citrate dihydrate, and Sterile Water for Injection 
(pH 6.5).  Placebo will be reconstituted for infusion by the site’s investigational drug pharmacy or 
appropriately trained designee for IV administration as a sterile product of 0.9%NaCl or D5W.   
 
To prevent infusion-associated reactions, each subject will be administered premedication with 
1000 mg oral acetaminophen and 50 mg oral diphenhydramine within 30 to 60 minutes prior to 
each rituximab infusion. If subject has an infusion related reaction, subject will receive 100 mg 
methylprednisolone IV 30 minutes prior to the next infusion.  If subject tolerates this infusion than 
methylprednisolone premedication would not be offered at next infusion.    Premedications will be 
stored at each local pharmacy and prepared by the local pharmacist.   
 


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Storage and Stability.   No preservative is used in rituximab; therefore, the vials are intended for 
single use only.  Rituximab is biologically and chemically stable at 2C–8C (36F–46F). Do not 
use rituximab vials beyond the expiration date stamped on the drug packaging and protect the 
drug from direct sunlight. Rituximab solutions for infusion, once diluted, may be stored at 2C–
8C (36F–46F) for 24 hours and at room temperature (23C) for an additional 24 hours.  
However, since Rituximab solutions do not contain preservative, diluted solutions should be 
stored refrigerated (2C–8C).  No incompatibilities between rituximab and polyvinyl chloride or 
polyethylene bags have been observed.  A temperature monitoring log is to be maintained at all 
sites to record temperature on an at least daily basis.  
 
5.2.1 Preparation of Rituximab for Administration   
 
The dose of Rituximab should be based on the subject’s Body Surface Area (BSA), calculated 
per local institution procedures, and the amount to be infused should be calculated for a dose of 
375 mg/m2 for each infusion. For more details, please refer to the NN103 Drug Dispensing 
System Users Manual and Site Pharmacy Manual. 
   
Note: The weight recorded at Baseline Visit should be used for the first Infusion Cycle 
(Infusions1-4) and the weight recorded at Week 24 Visit should be used for the second Infusion 
Cycle (Infusions 5-8). 
 
Rituximab should be given as a slow intravenous infusion.  It should not be administered as an 
intravenous push or bolus.  Premedication as noted in Section 5.1 is required before each 
infusion. Although rituximab may be administered on an outpatient basis, subjects may be 
hospitalized for observation at the discretion of the investigator.  Irrespective, rituximab should 
be administered in a hospital environment where full resuscitation facilities are immediately 
available and under close supervision of the investigator or Safety assessor. Caution should be 
exercised when administering rituximab to subjects with a history of asthma.  Rituximab should 
only be administered by a healthcare professional with appropriate medical support to manage 
severe infusion reactions that can be fatal if they occur.   
 
Since hypotension may occur during rituximab infusion, consideration should be given to 
withholding antihypertensive medications approximately 12 hours prior to and throughout the 
rituximab infusion. This will be completed at the discretion of local site investigator.   
 
First Infusion (Infusion 1 only): Initiate infusion at a rate of 50 mg/hr.  In the absence 
of infusion toxicity, increase infusion rate by 50 mg/hr increments every 30 minutes, to a 
maximum of 400 mg/hr. 
 
Subsequent Infusions (Infusions 2-8):  Initiate infusion at a rate of 100 mg/hr.  In the 
absence of infusion toxicity, increase rate by 100 mg/hr increments at 30-minute 
intervals, to a maximum of 400 mg/hr. 
 
If a hypersensitivity (non-IgE-mediated) or an infusion reaction develops, the infusion rate 
should be reduced to half that rate, i.e. from 100 mg/h to 50 mg/h.  Subjects who experience a 
moderate to severe infusion related reaction (fever, chills, or hypotension) should have their 
infusion interrupted immediately and should receive aggressive symptomatic treatment.  The 


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infusion should not be restarted before all the symptoms have disappeared and then the 
infusion can continue at one-half the previous rate. 
 
Immediate infusion related reactions can occur with either placebo or rituximab treatment.  
 
After the end of infusion, the intravenous line should remain in situ for at least 1 hour in order to 
be able to administer drugs intravenously if necessary. If there are no adverse events during 
this period of time, the intravenous line may be removed. 
 
For further details, including further management of infusion reactions, see the Investigator 
Brochure and the Rituxan Package Insert. 
5.2.2 Vital Sign Collection and Infusion Monitoring  
 
Vital signs and monitoring for infusions reactions will be performed per standard practices of the 
local infusion center. For purposes of this study, vital signs will be measured and recorded at a 
minimum of every 15 minutes for the first hour, then every 30 minutes until completion of the 
rituximab infusion.  Pulse oximetry will be obtained at baseline and as needed for symptoms of 
dyspnea.   
 
Cardiac monitoring will be performed during and after all infusions of rituximab for subjects who 
develop clinically significant arrhythmias, or who have a history of arrhythmia or angina.  
5.2.3 Local Labs Prior to Infusion 
 
Lab panels will be drawn and analyzed locally up to 1 day prior to initiation of study drug infusion.  
Lab panels will include complete metabolic panels (including LFT and GFR calculation), uric acid, 
LDH and CBC with differential (including ANC).  These labs will be reviewed by the site 
investigator to ensure that there are no contraindications to infusion.   
5.3 
Study Drug Accountability 
 
In accordance with local regulatory requirements, the investigator, designated site staff, or head 
of the medical institution (where applicable) must document the amount of investigational product 
dispensed and/or administered to study subjects, the amount received from the central pharmacy, 
and the amount destroyed upon completion of the study. Each site investigator is responsible for 
ensuring product accountability records are maintained throughout the course of the study.  The 
designated unblinded pharmacist will keep drug inventory and accountability logs.  The inventory 
will include details of rituximab received and dispensed to subjects, batch, and ID numbers. All 
unused vials must be kept until reconciliation of delivery records with accountability logs by the 
monitor. After the monitor has performed accountability, the site will be instructed by the CCC or 
designee to either destroy the remaining study medication/device or return it to the Central 
Pharmacy or manufacturer. An accounting must be made of any drug deliberately or accidentally 
destroyed. Discrepancies between the amount of rituximab received and dispensed drug must be 
reconciled. 
 
 


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5.4 
Concomitant Interventions 
 
Subjects will be on either prednisone only or prednisone plus another IST at time of enrollment.  
Subjects who are on prednisone plus one other IST, will continue to have routine safety 
monitoring as per standard of care practices specific to that IST.  This monitoring will be 
conducted by the treating physician. The dose of IST must remain stable throughout the course 
of the study (i.e. through week 52).   Subjects who are on pyridostigmine (≤ 480 mg/day) at the 
time of enrollment must remain on a stable dose throughout the course of the study,and cannot 
be changed.  
 
These requirements are not applicable to the optional off-intervention follow-up visits. During 
this time subjects will be treated per best medical practice (standard of care) for their MG at the 
discretion of the treating physician. However, as the primary focus of the two additional optional 
observational time points is to assess B cell recovery/repopulation as a safety measure, 
subjects who have received treatment with rituximab, or have been involved with other 
interventions that result in b cell depletion since completion of the trial (i.e. Week 52) will be 
excluded from the optional off-intervention follow-up visits. 
 
For more details please refer to section 6.4.5. 
 
 
5.5 
Subject compliance 
 
Subject compliance with study intervention (rituximab) will be directly monitored at the infusion 
center.  Subjects will complete a daily prednisone dose log that will be collected and reviewed 
every 4 weeks to monitor steroid compliance during the study.  
 
6 
CLINICAL AND LABORATORY EVALUATIONS/STUDY PROCEDURES


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6.1 
Schedule of Activities (SOA) – on-intervention period (Screening – Week 52) 
Visit Windows +/- 3 days for Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52.  Cycle 1 Infusion Visits will take place weekly beginning at Week 0 through Week 3. Cycle 2 Infusion Visits will take 
place beginning at Week 24 through Week 27 (See Section 6.3.3 for timing of visits) 
 
Screening 
Visit 
Day 0 
Week 
0 
Wk 1 
Wk 2 
Wk 3 
Wk 
 4 
Wk  
8 
Wk 
12 
Wk 
16 
Wk 
20 
Wk 
24 
Wk 
24 
Wk 
25 
Wk 
26 
Wk 
27 
Wk 
28 
Wk 
32 
Wk 
36 
Wk 
40 
WK 
44 
Wk 48 
Wk 52 
Unsc
hedul
ed 
 
 (-4 - 6 wk) 
Baselin
e 
Infusio
n 1 
Infusio
n 2 
Infusio
n 3 
Infusio
n 4 
 
 
 
 
 
 
Infus
ion 5 
Infus
ion 6 
Infus
ion 7 
Infus
ion 8 
 
 
 
 
 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam  
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy 
Testinga 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Standardized 
Bloodsb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
HbA1C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Serology Testing 
(HBV,HCV, HIV) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rituximab 
Infusionsc 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Infusion Labsc 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Specialized 
Bloods d 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
Mechanistic 
Bloods 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
MGC Score 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
QMG Score 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
MG-ADL Score 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
MG-QOL Score 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Prednisone Dose 
Adjustments 
 
 
 
 
 
 
Xe 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Xg 
Daily Steroid 
Diary Information 
Xf 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
AE Review/ 
Safety 
Monitoring 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a – Serum pregnancy test at screening; urine pregnancy tests thereafter 
b – Standard bloods: Comprehensive metabolic panel, LDH, uric acid, CBC with platelets and differential 
c – Rituximab dose: 375mg/m2 IV (cycle 1: week1-4; cycle 2: week 24-27).  Infusion visit labs (comprehensive metabolic panel, LDH, uric acid, CBC with platelets and differential) performed locally  
d – Specialized Bloods: 1. AChR antibody titer (Mayo Medical Laboratory, Rochester, MN). 2. Total IgG, IgA and IgM levels.  3. IgG subclasses (1,2,3, 4) . 4. Flow Cytometry to assess B cell counts. NOTE – Specialized bloods should be drawn prior to 
daily prednisone dose. 
e – Prednisone dose may be increased at this visit per Site Investigator judgment in cases of clinical worsening.  Forced taper begins at Week 8 based on steroid taper protocol. 
f – Subjects will be instructed on how to fill out the diaries for accurate recording of dosage for prednisone only. Subjects will record their daily prednisone dose on a Daily Prednisone Diary beginning the day after the Screening Visit.  The diary will be 
recorded in the EDC starting at the Baseline Visit and every visit thereafter. 
g – Prednisone dose may be evaluated and increased at the Unscheduled Visit per Site Investigator judgment in cases of clinical worsening. Prednisone tapering should not occur at Unscheduled Visits that occur after Week 8. If the Site Investigator 
feels that it is clinically necessary to taper at the visit, the study team must be consulted and provide approval for doing so.  


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6.2 
Schedule of Activities (SOA) – optional off-intervention period (Weeks 72 and 96) 
 
Visit Windows +/-30 days for Weeks 72 and 96 
 
Wk 72 
Wk 96 
 
 
 
Informed Consenta 
X 
 
Randomization 
 
 
Demographics 
 
 
Medical Historyb 
X 
X 
Physical Exam  
X 
X 
Concomitant 
Medicationc 
X 
X 
Vital Signs 
X 
X 
Pregnancy Testing 
 
 
Standardized Bloods 
 
 
HbA1C 
 
 
Serology Testing 
(HBV,HCV, HIV) 
 
 
Rituximab Infusions 
 
 
Infusion Labs 
 
 
Specialized Bloodsd  
X 
X 
Mechanistic Bloods 
X 
X 
MGC Score 
X 
X 
QMG Score 
 
 
MG-ADL Score 
X 
X 
MG-QOL Score 
X 
X 
Prednisone Dose 
Adjustments 
 
 
Daily Steroid Diary 
Information 
 
 
AE Review/ Safety 
Monitoringe 
X 
X 
EKG 
 
 
Chest X-ray 
 
 
 
**Note** Subjects who have received treatment with rituximab, or have been involved with other 
interventions that result in B cell depletion since completion of the trial (i.e. Week 52) will be excluded 
from the optional off-intervention follow-up visits. If there’s a plan or interest by the treating physician to 
utilize rituximab clinically as part of the disease management strategy for a given subject prior to the 
Week 72 or 96 Visits, the study team should be notified and all efforts should be made to bring the 
subject in prior to receipt of rituximab in order to capture long-term follow-up data.  
 
a – Written informed consent will also be obtained from each study participant prior to proceeding with and 
performing all procedures at the optional Week 72 and Week 96 Visits. Subjects may be consented prior 
to Week 52 or at Week 72 prior to any study-related procedures being performed. 
b – Medical History will be updated at these two visits to record only any autoimmune disease(s) that the 
subject has been diagnosed with since the previous visit. 
c – MG-related medication, including prednisone dose and/or any changes if applicable will be recorded. 
Additionally, any immunosuppressive therapies and steroids taken for other diseases will also be 
recorded. 


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d – Specialized Bloods: 1. AChR antibody titer (Mayo Medical Laboratory, Rochester, MN). 2. Total IgG, 
IgA and IgM levels.  3. IgG subclasses (1,2,3, 4) . 4. Flow Cytometry to assess B cell counts. NOTE – 
Specialized bloods should be drawn prior to daily prednisone dose. 
e – At the Week 72 and 96 Visits, only those adverse events, serious and non-serious, that in the opinion 
of the Investigator are deemed related to study procedures will be reported, given that the subject has 
consented to the optional off-intervention follow-up visits. Additionally, any MG relapses requiring rescue 
therapy that have occurred since the last visit will also be recorded.  
 
6.3 
Study Staffing 
 
A blinded Clinical Evaluator will be required to perform the outcome assessments (QMG, MGC, 
MG-QOL, and MG-ADL) and attend the Investigator's Meeting for training. The Clinical Evaluator 
may be a MD, RN, PA, PT, NP, or other health professional.  This individual may not be directly 
involved in reviewing adverse events.   
 
The principal investigator or a co-investigator (considered “treating physicians”) will perform the 
following procedures: 
 
• 
Medical history  
• 
Physical examination including assigning a MGFA MG grade.   
• 
Prednisone dose adjustment beginning at week 8.   
• 
Determination of worsening of MG symptoms. 
• 
Review of adverse events and concomitant medications 
 
The study coordinator will perform the following: 
 
 
• 
Explain in detail how subjects will fill out the diaries for accurate recording of dosage for 
prednisone 
• 
Collect and review daily prednisone dose diaries  
• 
Vital signs including weight  
• 
Pregnancy test for women of childbearing potential  
 
6.4 
Timing of Study Activities 
6.4.1 Screening Evaluations and Procedures 
 
Subjects identified as a potential candidate will be appropriately consented prior to the initiation 
of any study related procedures. The signing of consent constitutes the start of the study for a 
given subject. 
 
The following will be performed during the screening visit: 
 
• 
Subjects will undergo a complete physical and neurological examination 
 
• 
Vital signs will be measured 
 
• 
Phlebotomy will be performed in order to analyze the following: 


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o Serum Pregnancy  
o Standard Labs: Comprehensive metabolic panel, uric acid, LDH and CBC with 
differential  
o HbA1C  
o Serology Testing: HBV, HCV, and HIV 
 
• 
Subjects will be provided with information about the HIV and Hepatitis testing prior to the 
blood draw.  Subjects will be referred for HIV and hepatitis post-test counseling and 
medical care at each institution if necessary. 
 
• 
A 2-view chest x-ray (posterioranterior and lateral), and EKG will be obtained to document 
baseline status.  Chest x-rays will be read by a local radiologist, and EKGs will be read 
locally by an internist/cardiologist or any qualified physician. If a cardiologist/internist is 
not available to do the read, it is recommended for the EKG to be remotely read, if 
possible based on the site’s current setup.  
 
Note: If the subject has had a chest x-ray done within 60 days prior to the Screening Visit, 
a repeat will not be required at Screening, provided that the results from the previous chest 
x-ray are available and unrevealing. The previous chest x-ray source document will be 
required.  
 
• 
Immunization status or need for the following vaccinations in advance of randomization 
will be completed:  tetanus, diphtheria, influenza, pneumococcus polysaccharide, 
Varicella, measles, mumps, rubella (MMR) and hepatitis B vaccines.   
 
Note: Any required vaccination/booster for a subject must be given at least 28 days 
(4 weeks) prior to the baseline/randomization visit.  Required immunizations should be 
determined based on a subject’s age and comorbidities and are per best medical practice 
standard.  
 
• 
MGC, MG-ADL and MG-QOL assessments will be completed. (Note: MG-QOL should be 
administered prior to other outcomes evaluations.) 
 
• 
Women of child bearing potential will be instructed to take proper precautions to avoid 
pregnancy.  
 
• 
When inclusion/exclusion criteria are met, protocol eligibility and admission information 
consisting of demographic data including age, sex, past medical history, concomitant 
medications including prednisone dose, prior AChR antibody titer history, confirmation of 
no history of thymoma on each subject will be documented.  Subjects will be instructed 
not to take pyridostigmine for at least 12 hours prior to the Baseline Visit and each follow-
up visit.   
 
Note: It is recommended that a chest CT or MRI source document (i.e. radiology report) 
be obtained to evaluate for thymoma during the prescreening process to determine 
eligibility.  
 


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• 
Subjects will be instructed to complete prednisone diaries for accurate recording of 
dosage.  These will be collected, reviewed and information recorded at the Baseline 
Visit and each scheduled visit thereafter. 
 
• 
Concomitant medications will be recorded. 
 
6.4.2 Baseline Visit Evaluations and Procedures 
 
All screening evaluations to determine eligibility will be completed within 4 to 6 weeks of 
screening visit (refer to SOA for details).  All successfully screened subjects will be randomized 
into the study within 6 weeks. 
 
The following will be performed during the baseline visit: 
 
• 
Prednisone diaries will be reviewed to ensure that subjects have maintained a stable 
prednisone dose during the 28 days before the Baseline Visit.  A stable dose is defined 
as a dose that does not vary by ≥ 6mg per day on average. 
• 
All Eligibility Criteria will be reviewed and verified by the site investigator.  The site 
investigator will sign off on the eligibility confirmation form prior to the randomization of 
any subject. 
• 
Subjects will undergo a complete physical examination 
• 
Vital signs will be measured 
• 
Urine Pregnancy Test 
• 
Phlebotomy will be performed in order to analyze the following (Note: Subjects will be 
asked to hold their usual prednisone dose on the day of the visit.): 
o Specialized bloods: AChR antibody titer, Total IgG, IgA and IgM levels, IgG 
subclasses (1,2,3, 4), and Flow Cytometry to assess B cell counts  
▪ 
NOTE – Specialized bloods should be drawn prior to daily prednisone 
dose. 
o Mechanistic bloods (immune cell analyses) 
 
• 
Outcome Assessments: MGC, QMG, MG-ADL and MG-QOL will be completed. (Note: 
MG-QOL should be administered prior to other outcomes evaluations.) 
• 
Adverse Events will be reviewed and recorded 
• 
Concomitant medications will be recorded. 
6.4.3 Infusion Visits 
 
Cycle 1 Infusion Visits will take place weekly beginning at Week 0 through Week 3. Cycle 2 
Infusion Visits will take place beginning at Week 24 through Week 27. 
 
Ideally, the timing of Infusions 2-4 would be anchored to Infusion Visit 1, such that: 
• 
Infusion 2 is 7 (+/- 1) days from Infusion 1 
• 
Infusion 3 is 14 (+/- 1) days from Infusion 1 
• 
Infusion 4 is 21 (+/- 1) days from Infusion 1 
 
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• 
Infusion 6 is 7 (+/- 1) days from Infusion 5 
• 
Infusion 7 is 14 (+/- 1) days from Infusion 5 
• 
Infusion 8 is 21 (+/- 1) days from Infusion 5 
 
Please refer to the Manual of Operations, Section X (Study Medication and Central Pharmacy) 
and the Visit Windows Report available in the EDC once the Baseline Visit is complete. 
 
Infusion 1 may take place the same day as the Baseline Visit and must take place within 3 days 
following the Baseline Visit. 
 
Infusion 5 may take place the same day as the Week 24 Visit and must take place within 3 days 
of the Week 24 Visit. 
 
If, for any reason, an infusion is held during either of the two cycles, it can be postponed up to 
one week (7 days) after the original scheduled date. 
 
• 
If the delayed infusion is administered within that one week, the subsequent infusion 
should take place within the original time window in order to resume the initial infusion 
schedule. For example, if Infusion 2 is delayed but administered < 7 days after the 
scheduled date, Infusion 3 should be administered as originally planned and not 
delayed as well.  
 
**Note** Two separate Infusions should not be scheduled on consecutive days. There 
should be a minimum of one day in between infusions.  
 
• 
If an Infusion is delayed by one week (7 days), then all subsequent infusions should be 
delayed by that same amount. For example if Infusion 2 takes place 14 days after 
Infusion 1, then Infusion 3 will take place 21 days after Infusion 1, and Infusion 4 will 
take place 28 days after Infusion 1. 
 
**Note** If the Infusion cycles are delayed, the 4th infusion must take place prior to the 
Week 4 Visit, and the 8th Infusion must take place prior to the Week 28 Visit. The visits 
may take place on the same day,  
 
• 
If an infusion is held and cannot be administered within one week (7 days) of the original 
scheduled date, then that Infusion will be skipped altogether (this will be designated as 
“missed”), and efforts should be made to administer all subsequent infusions as 
scheduled. 
 
• 
If the 1st infusion of either cycle (Infusion 1 or 5) cannot be administered as scheduled, it 
can be delayed up to one week after the original date. Subsequent infusions will be 
anchored on the new date of the first infusion and will follow the weekly window 
described above. If the first infusion of the cycle cannot be administered within one 
week of the original date, then that Infusion will be skipped altogether (this will be 
designated as “missed”), The schedule will then resume with second infusion of that 
cycle (i.e. the second infusion and all subsequent infusions will be anchored to the 
original date of the first infusion).  
 


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The study team must be notified, consulted and provide approval, should the site PI feel that an 
Infusion be held or postponed. 
 
The following will be performed during the infusion visits: 
 
• 
Urine Pregnancy Test 
• 
Infusion Labs: Complete metabolic panel, uric acid, LDH and CBC with differential 
(analyzed locally up to 1 day prior to each infusion)  
• 
Adverse Events will be reviewed and recorded 
• 
Concomitant medications will be recorded. 
• 
Study drug infusions (detailed in section 5.2) 
 
6.4.4 Clinical Study Visits 
 
Study Intervention Follow-up Visits: 
 
The allowable time window for study visits is plus or minus 3 days for Week 4, 8, 12, 16, 20, 24, 
28, 32, 36, 40, 44, 48, and 52 visits. 
 
The following will be performed during each study visit: 
 
• 
Prednisone diaries will be collected and reviewed 
o Prednisone dose will be reviewed and adjusted at Week 4 and each visit thereafter.  
The forced prednisone taper will begin at Week 8 as per steroid taper protocol. 
• 
Subjects will undergo a complete physical examination 
• 
Vital signs will be measured 
• 
Phlebotomy will be performed at week 24 and 52. 
• 
Outcome Assessments: MGC, QMG, MG-ADL and MG-QOL will be completed. (Note: 
MG-QOL should be administered prior to other outcomes evaluations.) 
• 
Adverse Events will be reviewed and recorded 
• 
Concomitant medications will be recorded. 
 
A Participation Survey will also be given to each subject at the Week 52 or last Study Visit. This 
will be a brief survey consisting of five questions. The purpose of the questionnaire will be to 
determine why the subject decided to participate in the study. The questions will ask how the 
subject initially heard of the study, why they chose to participate, and what motivated them to 
stay in the trial. This information will help to determine which recruitment and retention efforts 
were the most effective.  
 
For procedures done at Unscheduled Visits, see section 6.3.11. 
 
6.4.5 Optional Observational Off-Intervention Follow-up Visits: 
 
Weeks 72 and 96 Visits: 
 


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The allowable time window for study visits is 60days for Week 72 and 96 visits (+/-30 days).  
These two additional optional time points at weeks 72 and 96 will be done to follow B cell recovery 
and long-term durability of response. 
 
Subjects will be consented prior to the initiation of any study related procedures at these optional 
visits. Subjects will also be instructed not to take pyridostigmine for at least 12 hours prior to the 
Baseline Visit and each follow-up visit.   
 
 
The following will be performed during each study visit: 
• 
Subjects will undergo a complete physical examination 
• 
Vital signs will be measured 
• 
Phlebotomy will be performed at week 72 and 96 (please refer to the SOA and section 
6.4.7). 
• 
Outcome Assessments: MGC, MG-ADL and MG-QOL will be completed. (Note: MG-QOL 
should be administered prior to other outcomes evaluations.) 
• 
Medical history will be updated at these two visits to record only any autoimmune 
disease(s) that the subject has been diagnosed with since the previous visit. 
• 
MG-related medication, including prednisone dose and/or any changes if applicable will 
be recorded. Additionally, any immunosuppressive therapies and steroids taken for other 
diseases will also be recorded. 
• 
MG relapse requiring rescue therapy will be recorded  
• 
Adverse Events, serious and non-serious, related to study procedures per site 
investigator, will be reviewed and recorded. 
 
**Note** Subjects who have received treatment with rituximab, or have been involved with other 
interventions that result in B cell depletion since completion of the trial (i.e. Week 52) will be 
excluded from the optional off-intervention follow-up visits. If there’s a plan or interest by the 
treating physician to utilize rituximab clinically as part of the disease management strategy for a 
given subject prior to the Week 72 or 96 Visits, the study team should be notified and all efforts 
should be made to bring the subject in prior to receipt of rituximab in order to capture long-term 
follow-up data.  
 
6.4.6 Outcome Evaluations 
 
A blinded evaluator will be required to perform the outcome assessments (QMG, MGC, MG-
QOL, and MG-ADL) and attend the Investigator's Meeting for training. The Clinical Evaluator 
may be a MD, RN, PA, PT, NP, or other health professional.  This individual may not be directly 
involved in reviewing adverse events. 
 
Myasthenia Gravis Composite (MGC).   
The MGC is a new end-point that has been developed for MG.  Specific components of the 
QMG, MG-ADL, and muscle testing are combined to obtain the MGC score.  This is a brief 
assessment that takes approximately 10 minutes to complete. 
 
Quantitative Myasthenia Gravis (QMG).   
The QMG is a validated 13-item test that objectively measures ocular, bulbar, extremity 
fatigue/strength, and respiratory function (forced vital capacity). A battery of quantitative 


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functional tests is completed from which a QMG score is calculated. This assessment takes 30-
40 minutes to administer. 
 
MG-Activities of Daily Living score (MG-ADL) 
This 8 point scale assesses the subject’s ability to perform daily activities and can be performed 
in approximately 5 minutes.   
 
MG-Quality of Life (MG-QOL) score. 
The subject completes the 15-question MG-QOL questionnaire and reports the effect of MG on 
their quality of life. The MG-QOL should be administered prior to other outcomes evaluations at 
each visit. 
 
6.4.7 Laboratory Testing  
 
Safety labs will be drawn and analyzed locally the day before or at each infusion visit.  All other 
labs will be analyzed centrally and sent to CMSU with the exception of the mechanistic labs 
which will be sent to Yale University.  
 
Subjects will be instructed not to take pyridostigmine for at least 12 hours prior to the Baseline 
Visit and each follow-up visit.   
 
Subjects are asked not to take their usual prednisone dose on the day of the Baseline Visit, 
Week 24 Visit, and Week 52 Visit as well as any Unscheduled Visit 
 
Screening Visit: 
• 
Serum Pregnancy  
• 
Standard Labs: Comprehensive metabolic panel, uric acid, LDH and CBC with 
differential  
• 
HbA1C  
• 
Serology Testing: HBV, HCV, and HIV 
 
Baseline: 
• 
Urine Pregnancy (analyzed on site) 
• 
Specialized bloods: AChR antibody titer, Total IgG, IgA and IgM levels, IgG subclasses 
(1,2,3, 4), and Flow Cytometry to assess B cell counts  
• 
Mechanistic bloods (immune cell analyses) 
 
Note: Please remind subjects to hold their usual prednisone dose the day of the visit. 
 
Infusion 1-4 
• 
Urine Pregnancy (analyzed on site) 
• 
Infusion Labs: Comprehensive metabolic panel, uric acid, LDH and CBC with differential 
(analyzed locally up to 1 day prior to each infusion)  
  
Week 24 
• 
Specialized bloods: AChR antibody titer, Total IgG, IgA and IgM levels, IgG subclasses 
(1,2,3, 4), and Flow Cytometry to assess B cell counts  
• 
Mechanistic bloods (immune cell analyses) 


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Note: Please remind subjects to hold their usual prednisone dose the day of the visit. 
 
Infusion 5-8 
• 
Urine Pregnancy (analyzed on site) 
• 
Infusion Labs: Comprehensive metabolic panel, uric acid, LDH and CBC with differential 
(analyzed locally up to 1 day prior to each infusion)  
 
Week 52 
• 
Specialized bloods: AChR antibody titer, Total IgG, IgA and IgM levels, IgG subclasses 
(1,2,3, 4), and Flow Cytometry to assess B cell counts  
• 
Standard Labs: Comprehensive metabolic panel, uric acid, LDH and CBC with 
differential  
• 
HbA1C  
• 
Mechanistic bloods (immune cell analyses) 
 
Note: Please remind subjects to hold their usual prednisone dose the day of the visit. 
 
Unscheduled Visit (if applicable) 
• 
Specialized bloods: AChR antibody titer, Total IgG, IgA and IgM levels, IgG subclasses 
(1,2,3, 4), and Flow Cytometry to assess B cell counts  
• 
Standard Labs: Comprehensive metabolic panel, uric acid, LDH and CBC with 
differential  
• 
Mechanistic bloods (immune cell analyses) 
 
Note: Please remind subjects to hold their usual prednisone dose the day of the visit. 
 
Optional Observation Off-Intervention Follow-up Visits (weeks 72 and 96): 
• 
Specialized bloods: AChR antibody titer, Total IgG, IgA and IgM levels, IgG subclasses 
(1,2,3, 4), and Flow Cytometry to assess B cell counts  
• 
Mechanistic bloods (immune cell analyses) 
 
Note: Please remind subjects to hold their usual prednisone dose the day of the visit. 
 
6.4.8 Prednisone Dose Adjustments 
 
Subjects will be treated with a minimum oral prednisone dose of 15 mg/day or equivalent every 
other day until week 8.  Each subject’s prednisone dose will be evaluated at the Week 4 Visit.   
 
The prednisone dose cannot be tapered at the Week 4 Visit. It should be maintained at enrollment 
dose and only increased in cases of clinical worsening (as determined by the MGC Score) only, 
per the site investigator’s discretion.    
  
Forced Prednisone Taper 
 
A forced prednisone steroid taper will begin at the Week 8 Visit.  Dose adjustments are based on 
changes from the subject's baseline MGC score and prior study visit.  The MGC score will be 
calculated, confirmed and available during the study visit in order to make steroid dose 
adjustment. Prednisone dose will be lowered at every 4-week assessment beginning at the Week 


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8 Visit following confirmation of clinical improvement or stable symptoms based on MGC score 
(current MGC score is not more than 2 points above the Baseline Visit or prior study visit MGC 
score). 
  
Prednisone will be tapered: 
❖ If the MGC score is no more than 2 points higher than the Baseline Visit score AND 
❖ MGC score is no more than 2 points above the Prior Study Visit score 
 
For subjects taking prednisone daily, the every 4 week taper schedule will be: 
 
Daily Prednisone Dose (mg) 
Taper to Dose (mg): 
100 
90 
90 
80 
80 
70 
70 
60 
60 
50 
50 
40 
40 
30 
30 
20 
20 
15 
15 
10 
10 
7.5 
7.5 
5 
5 
3 
3 
2 
2 
1 
1 
0 
 
For subjects taking prednisone every other day, the every 4 week taper schedule will be: 
 
Every Other Day Prednisone Dose (mg) 
Taper to Dose (mg): 
200 
180 
180 
160 
160 
140 
140 
120 
120 
100 
100 
80 
80 
60 
60 
40 
40 
30 
30 
20 
20 
15 
15 
10 
10 
7.5 
7.5 
5 


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Every Other Day Prednisone Dose (mg) 
Taper to Dose (mg): 
5 
2.5 
2.5 
0 
 
Note: While typical maximum daily doses of prednisone will be 60 mg per day (or equivalent on 
alternating days), the above table details a taper schedule with rows shaded in grey if subjects 
enter the study on a higher dose.  The absolute maximum allowable prednisone dose at study 
entry is 100 mg per day (or equivalent on alternating days).    
 
As subjects may be on a dose that is slightly different than the above (i.e., 45 mg/day, 
alternating doses), the tapered dose will begin at the closest lower dose on the table and then 
follow tapering as per protocol.  Subjects taking more than 100 mg/day or 200 mg over a two 
day period will be excluded from the study.    
 
It is recommended that the Prednisone Dose Adjustment at Week 52 be done in the same 
manner as the other clinical study visits (i.e. tapered, maintained, or increased based on the 
subject’s MGC score).  However, if the site PI feels that it is in the best interest of the subject to 
deviate from the dose adjustment protocol (i.e., for safety related reasons for instance), this will 
be allowed. If the decision is to not adjust the prednisone dose per protocol at Week 52, please 
notify the study team prior to proceeding. 
 
Prednisone Dose Adjustments in Cases of Clinical Worsening  
 
If the MGC score is 3 or more points higher than the Baseline Visit score: 
❖ The taper will be stopped and prednisone will be increased per the guidelines below.   
 
If the MGC score is less than or no more than 2 points higher than the Baseline Visit score, but 
has increased 3 or more points than the MGC score at the previous Study Visit: 
❖ The taper will be stopped and prednisone dose may be either held or increased per study 
prednisone schedule. The decision to hold or increase the prednisone dose in this case is at 
the discretion of the Site Investigator. 
 
Note: The prednisone dose will be increased until symptoms are resolved or at least stabilized 
to baseline status (MGC score is the same or less than the Baseline Visit score). 
 
The following schedule will be followed for subjects with clinical worsening and who require the 
prednisone dose to be increased:  
• 
For subjects on > 15 mg daily or the equivalent for every other day dosing, it is 
recommended that the prednisone daily dose be initially increased by 20 mg. 
• 
 For subjects on ≤ 15 mg daily or the equivalent for every other day dosing, prednisone may 
be increased by 10 or 20 mg, at the physician’s discretion.  
• 
If the prednisone dose is up titrated, the maximum dose would be 60 mg/day even if the 
subject was on a higher dose at study entry.  
 
Once symptoms stabilize (MGC score is the same or less than the Baseline Visit score and not 
more than 2 points above the prior study visit), the prednisone taper can again be resumed per 
the above protocol at the next scheduled visit/assessment. 
 


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This is a forced steroid taper that is based on MGC score.  If the site investigator (treating 
physician) did not taper per protocol, this will be recorded as a protocol deviation and will be 
corrected immediately.  As this is linked with primary outcome we wanted to make the decision 
on lowering the dose as objective as possible.  A mechanism will be put in place to double check 
the MGC score calculation made at the visit and whether or not prednisone adjustment decision 
was made correctly.   
 
6.4.9 Physical Exam 
 
A physical exam will be completed at the Screening Visit, Baseline Visit, weeks 4, 8, 12, 16, 20, 
24, 28, 32, 36, 40, 44, 48 and 52 Visits, as well as the optional weeks 72 and 96 Visits.   
 
The physical exam will include assigning a MGFA clinical classification grade. The grades are 
as follows:  
Class I- Any ocular muscle weakness, may have weakness of eye closure, all other 
muscle strength is normal.  
Class II – Mild weakness affecting other than ocular muscles, may also have ocular 
muscle weakness of any severity.  
Class III – Moderate weakness affecting 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 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 by intubation, with or without mechanical ventilation, except when 
employed during routine postoperative management.   
 
6.4.10 Study Medication/Intervention Discontinuation Evaluations/Procedures 
 
Subjects will be monitored through regular physical examinations, vital signs, laboratory tests, 
and incidence and severity of adverse events. Infections will be treated symptomatically. 
Cardiovascular risk factors will be assessed prospectively by recording risk factors (e.g., family 
history, smoking history, and status).  The safety evaluations will be conducted on conventional 
safety variables, such as serious adverse events, laboratory tests, and vital sign changes. In 
particular, B cell counts, immunoglobulin levels, infusion-related reactions, and thromboses, 
infections will be carefully examined. 
 
Adverse events will be reviewed and recorded at each study visit and infusion visit.  An adverse 
event is any untoward, undesired, or unplanned event in the form of signs, symptoms, disease, 
laboratory or physiologic observations occurring in study participants.  Information on adverse 
effects of medication and on inter-current events will be determined at each visit by direct 


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questioning of the subjects, clinical examination, and laboratory tests. Tolerability will be 
determined by the ability to complete the study on the assigned experimental medication.   
 
Study Hold Rules (Safety). 
 
Individual study subjects may be withdrawn from the study medication but  continue to be followed 
for safety if subjects develop a grade 3 or more suspected toxicity as graded by the National 
Cancer Institute’s (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 
or a Serious Adverse Event (SAE) related to study medication as determined by the Independent 
Medical Monitor (IMM).  Grade 3 adverse events are severe or medically significant but not 
immediately life-threatening and may cause hospitalization or prolongation of hospitalization 
indicated.  Descriptions of CTCAE grading criteria are included in the Manual of Operations and 
SAEs are specifically defined in Section 10.4.1.2.  Subjects will be allowed to resume participation 
in the study if their suspected toxicity or adverse event (AE) resolves completely and if the 
judgment of the investigator and IMM it is safe for the subject to continue.  
 
 
Please see Section 8 for additional details regarding Criteria For Intervention Discontinuation. 
 
Please also see Package Insert and Investigator Brochure for additional safety information. 
Additional safety monitoring visits will be at the discretion of the investigator or as directed by the 
IRB and/or other regulatory authorities. 
 
Study Stopping Rules (Safety). 
 
The study will be permanently stopped and no further administration of rituximab will be given if 
the investigator, the IRB and/or DSMB and/or any other institutional or regulatory body deems it 
inappropriate for the study to resume due to the following: 
 
A significant number of enrolled subjects develop safety concerns that cannot otherwise be 
attributed to MG, infections, disease relapse or pre-existent comorbidities as deemed by theIMM.   
 
 Please also see SOA for additional safety monitoring information. Additional safety monitoring 
visits will be at the discretion of the investigator or as directed by the IRB and/or other regulatory 
authorities. 
 
 
6.4.11 Off-Intervention Evaluations 
 
In the event that a subject is unable to tolerate study drug infusions resulting in the study 
medication being withdrawn but has completed at least one infusion, and is otherwise able to 
comply with study procedures, the subject will be asked to attend all study visits per protocol.  
 
If the subject is withdrawn from the study, either for being unable to tolerate the study drug (i.e. 
unable to complete any infusions) or being unable to comply with the remaining study 
procedures, they will go on reduced follow-up. For more information regarding the reduced 
follow- up, please see Section 8 – Criteria for Intervention Discontinuation. 
 


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There are two additional off study-intervention time points (week 72 and 96) to assess durability 
of response as well as monitor B cell count normalization.  Subjects will have similar clinical 
evaluations as during the on-study drug intervention period.  Subjects will be treated per 
medical standard of care. For more details regarding these visits, please refer to the SOA and 
Section 6.4.5.    
 
6.4.12 Unscheduled Visits 
 
Subjects will be clinically evaluated at an Unscheduled Visit at the discretion of the treating 
physician for any concern of disease relapse and/or significant worsening of symptoms as well 
concern for adverse event related to study.  A standard physical exam and the MGC score 
assessments will be performed during this visit.  Prednisone diary will also be reviewed.  Blood 
work will also be performed as per SOA and primary study team recommendations.    
 
The following are recommended to be performed during Unscheduled Visits: 
• 
Prednisone diaries will be collected and reviewed 
o Prednisone dose may be evaluated and increased at the Unscheduled Visit per Site 
Investigator judgment in cases of clinical worsening. Prednisone tapering should not 
occur at Unscheduled Visits that occur after Week 8. If the Site Investigator feels 
that it is clinically necessary to taper at the visit, the study team must be consulted 
and provide approval for doing so.  
• 
Subjects will undergo a complete physical examination 
• 
Vital signs will be measured 
• 
Phlebotomy will be performed. For a complete list of recommended lab tests, please see 
Section 6.3.6. 
• 
Outcome Assessments: MGC will be completed.  
• 
Adverse Events will be reviewed and recorded 
• 
Concomitant medications will be recorded. 
 
6.4.13 Final On-Study Evaluations 
 
Final on-study visit (week 52) includes: physical exam, vital signs, blood draws, safety 
assessments and specific myasthenia gravis clinical assessments as described above.   
 
**NOTE** All subjects will have the option to return for two additional off-intervention follow-up 
visits (weeks 72 and 96) in order to monitor B cell counts along with MG clinical status. This 
portion of the trial will only include subjects that have not received rituximab or other B cell 
depleting treatments after study completion (i.e. Week 52). B cell levels typically return to normal 
levels approximately 12+ months following B cell depletion therapy.   
 
6.4.14 Pregnancy  
 
Pregnancy is an exclusion criterion.  Routine testing as described above at screening visit and 
prior to each rituximab infusion will be performed in all women of child-bearing age. Men and 
women of reproductive potential must agree to use an acceptable method of birth control during 
treatment and for twelve months (1 year) after completion of treatment. 
 
If a subject becomes pregnant within the course of the study, site staff will be asked to follow the 
subject by telephone to determine the outcome of the pregnancy. 


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6.5 
SPECIAL INSTRUCTIONS AND DEFINITIONS OF EVALUATIONS 
 
6.5.1 Informed Consent 
 
The Clinical Study Site PI (CSS PI) and all IRB approved Licensed Physician Sub-Investigators 
personnel will be able to obtain informed consent from the participant.  
 
Written informed consent will be obtained from each participant before any study-specific 
procedures or assessments are performed and after the aims, methods, anticipated benefits, and 
potential hazards are explained. The participant’s willingness to participate in the study will be 
documented in writing in a consent form, approved by the NeuroNEXT CIRB, which will be signed 
by the participant with the date of that signature indicated. The investigator will keep the original 
consent forms and copies will be given to the participants. It will also be explained to the 
participants that they are free to refuse entry into the study and free to withdraw from the study at 
any time without prejudice to future treatment. Written and/or oral information about the study in 
a language understandable by the participant will be given to all participants. HIPAA guidelines 
for confidentiality and the principles of medical ethics will be adhered to during the study. 
**NOTE** The above statement applies to the secondary consent form for the Weeks 72 and 96 
Visits as well. Subjects may be consented prior to Week 52 or at Week 72 prior to any study-
related procedures being performed. If the Week 72 window has passed for any given subject, 
but they are willing to coming for Week 96, they can be consented at Week 96 prior to any 
procedures being performed. 
6.5.2 Protocol Violations 
 
Deviations from the written protocol will be considered a protocol violation and reported to the 
medical monitor and the safety monitoring board.  
6.5.3 Documentation of Myasthenia Gravis  
 
Autoimmune myasthenia gravis will be defined as a person who has the following: 
 
1. Positive serum acetylcholine receptor (AChR) binding antibodies* in conjunction with  
2. Positive decremental response on repetitive nerve stimulation at 3 Hz, OR a clinical 
examination consistent with generalized myasthenia gravis.  
  
*Positive acetylcholine receptor binding antibodies as defined by a certified commercial 
laboratory.  The following are some common labs.    
• 
Mayo Medical Laboratories: Muscle AChR Binding Antibody >0.02 nmol/L 
• 
Quest Diagnostics:  AChR Binding Antibody ≥0.50 nmol/L 
• 
LabCorp: AChR Binding Antibodies >0.40 nmol/L 
6.5.4 Medical History 
 
A routine medical history will be obtained during the screening phase of the trial. Subjects will be 
asked about adverse events at each subsequent visit.  Medical history will be updated at the 


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optional off-intervention follow-up visits to record only any autoimmune disease(s) that the subject 
has been diagnosed with between weeks 52 and 72 and weeks 72 and 96.  
6.5.5 Treatment History 
 
All prior treatments from the time of diagnosis (a minimum of one year’s history prior to screening) 
with immune therapies (prednisone, azathioprine, mycophenolate mofetil, monoclonal antibodies, 
etc.) will be obtained from the subject source documents.  Treatment history between weeks 52 
and 72 and weeks 72 and 96 will be documented at the optional off-intervention follow-up visits. 
MG-related medication, including prednisone dose and/or any changes if applicable will be 
recorded.  
6.5.6 Concomitant Medications/Treatments 
 
All immune therapies and treatments that modulate or suppress the immune system will be 
obtained from source documents. MG-related medication (including prednisone dose and/or any 
changes if applicable) taken between weeks 52 and 72 and weeks 72 and 96 will be 
documented at the optional off-intervention follow-up visits. Any immunosuppressive therapies 
and steroids taken for other diseases will be recorded as well during these visits.  
 
**Note** Subjects who have received treatment with rituximab, or have been involved with other 
interventions that result in B cell depletion since completion of the trial (i.e. Week 52) will be 
excluded from the optional off-intervention follow-up visits.  
6.5.7 Immunization during B Cell Depletion 
 
The efficacy and safety of immunization during periods of B cell depletion have not been 
adequately studied. Subject’s vaccination record and the need for immunization will be carefully 
evaluated prior to receiving study drug.  For those who are likely to require immunization in the 
foreseeable future, such as subjects planning to travel to countries where specific immunization 
is required or subjects requiring vaccination/booster for their professional activity, any required 
vaccination/booster must be given at least 4 weeks prior to the baseline/randomization visit.  
Review of the subject’s immunization status or need for the following vaccinations in advance of 
randomization (as noted previously) will be completed: tetanus, diphtheria, influenza, 
pneumococcus polysaccharide, varicella, measles, mumps, rubella (MMR) and hepatitis B, 
vaccines. Required immunizations should be determined based on a subject’s age and 
comorbidities and are per best medical practice standard.  
 
The safety and efficacy of immunization with a live or attenuated live vaccine in B cell depleted 
subjects are not known.  For this reason, the use of live or attenuated vaccines (e.g., measles, 
mumps, rubella, oral polio vaccine, Bacillus Calmette-Guérin [BCG], typhoid, yellow fever, 
vaccinia, varicella-zoster virus (VZV) or any other vaccines not yet licensed but belonging to this 
category) is specifically excluded 28 days prior to screening through the end of the 52 week 
follow-up period or until return of B cells to within normal limits or baseline.  
 
Vaccines that do not contain live organisms (e.g., influenza, Pneumovax, tetanus) are not 
prohibited; however, vaccinations during B cell depletion may be ineffective. 


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6.5.8 Protocol Amendments and Study Termination 
All revisions and/or amendments to this protocol must be approved in writing by the Sponsor and 
the CIRB. The Investigator will not make any changes to the conduct of the study or the protocol 
without first obtaining written approval from the Sponsor and the CIRB, except where necessary 
to eliminate an apparent immediate hazard to a study subject. 
The Sponsor and NeuroNEXT Network reserve the right to discontinue the study at a clinical study 
site(s) for safety or administrative reasons at any time. Should the study be terminated and/or the 
clinical study site closed for any reason, all documentation and study medication pertaining to the 
study must be returned to the Sponsor or its representative.  
 
6.5.9 Clinical Assessments 
 
Subjects will have clinical evaluations at the Baseline Visit and then every 4 weeks thereafter 
(week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52).  Post-intervention status will be assessed 
by measuring the MGFA clinical classification grade, MGC, QMG, MG-ADL and MG-QOL scores. 
Most of these clinical evaluations will also be completed at unscheduled visits (MGC only) as well 
as at weeks 72 and 96 (all except QMG). The dose of prednisone will be recorded by each subject 
daily and collected at each scheduled evaluation.  These will be recorded on the CRFs.   
 
All appropriate MG-specific common data elements as determined by the protocol steering 
committee will be collected and recorded on CRFs.  
 
Adverse effects will be monitored to assess safety and tolerability in this subject population per 
Genentech and DAIT’s guidelines. 
6.5.10 Laboratory Evaluations 
 
The Investigator will review, sign and date all lab reports.  The investigator will indicate if out of 
range lab value is Clinically Significant “CS” or Not Clinically Significant “NCS” on the lab report.  
CTCAE version 3.0 will be used for grading events. 
 
Safety labs will be drawn and analyzed locally up to 1 day prior to each infusion visit.  All other 
labs will be analyzed centrally and sent to CMSU. 
 
Subjects will be instructed not to take pyridostigmine for at least 12 hours prior to the Baseline 
Visit and each follow-up visit, including the optional Week 72 and Week 96 Visits.   
 
Subjects are asked not to take their usual prednisone dose on the day of the Baseline Visit, 
Week 24 Visit, Week 52 Visit, as well as the optional Week 72 and Week 96 Visits. 
 
• 
Pregnancy Testing.  All women of childbearing potential will have a serum pregnancy test 
at Screening and urine pregnancy test at Baseline and all Infusion Visits (infusion visit 1, 
2, 3, 4, 5, 6, 7 and 8).  The serum pregnancy test will be analyzed centrally.  The urine 
pregnancy tests will be locally read.   
 
• 
Standard Bloods.  All subjects will have standard safety blood work completed at the 
Screening Visit and week 52.  These include: comprehensive metabolic panel, uric acid, 


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LDH and CBC with platelets and differential.  These labs will be shipped to CMSU to be 
analyzed centrally.  
 
• 
HbA1C will be checked at the Screening and Week 52 Visits. These labs will be shipped 
to CMSU to be analyzed centrally. 
 
• 
Infusion Labs. Complete metabolic panel, uric acid, LDH and CBC with differential will be 
analyzed locally up to 1 day prior to each infusion.  Site Investigators will review the lab 
results prior to the infusion.  Site Investigators may hold the rituximab infusion if the lab 
results indicate that the subject is not medically able to tolerate the infusion.   
 
• 
Serology Testing. All subjects will have hepatitis panel and HIV testing completed at the 
Screening Visit.  These labs will be shipped to CMSU to be analyzed centrally.   Subjects 
will be referred to pre-test and post-test counseling and provided with an information 
sheet. 
 
• 
Specialized Bloods.  All subjects will have specialized blood work completed at the 
Baseline Visit, Week 24, Week 52, and optional Week 72 and Week 96 Visits.  These 
include: 1. AChR antibody titer (Mayo Medical Laboratory, Rochester, MN). 2. Total IgG, 
IgA and IgM levels.  3. IgG subclasses (1, 2, 3 and 4).  4. Flow Cytometry to assess B 
cell count.  These labs will be shipped to CMSU to be analyzed centrally.    
 
• 
Biomarker/Mechanistic Blood.  The biomarker or mechanistic studies are focused on 
identifying how treatment modifies the immunopathology of MG. These blood draws will 
be completed at the Baseline Visit, Week 24, Week 52, and optional Week 72 and Week 
96 Visits. Samples will be kept at room temperature and shipped priority overnight to Dr. 
Kevin O’Connor’s Laboratory at Yale University for processing and immunologic studies.  
Deliveries must arrive within 24 hours of collection.  
 
 
Shipping Address: 
 
 
  
 
 
 
 
 
 
 
 
Refer to SOA and section 6.3.6 for additional details.   
6.5.11 Pharmacokinetic Studies 
 
Pharmacodynamics will specifically be followed by monitoring B cell depletion and repopulation.   
6.5.12 Subject Adherence Assessments 
 
Daily prednisone dose will be recorded in a diary by each subject and reviewed at each scheduled 
clinic evaluation (every 4 weeks).  Adherence to taking prednisone as well as taking correct dose 
of prednisone will be monitored.    


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6.5.13 Biomarker/Mechanistic Studies 
 
The biomarker or mechanistic studies are focused on identifying how treatment modifies the 
immunopathology of MG. We will study changes in the antigen specific components of the MG 
immune system. We have developed/adapted immunoassays so that we can examine 
autoantibodies, B cells and T cells. The principal mechanistic outcome will be the decrease in titer 
of circulating AChR autoantibodies within an individual. Other exploratory mechanism-based 
outcomes include determining how rituximab modifies antigen-specific B cell frequency, the B cell 
repertoire, B cell activating factor (BAFF) levels and whether rituximab modifies antigen-specific 
T cell frequency and phenotype. Measurements will be performed prior to and during B cell 
depletion and through repopulation of the B cell compartment, which will be of particular interest 
in terms of assessing the durability of the treatment.  Blood will be collected for mechanistic 
studies at the Baseline Visit, Week 24, Week 52 Visits, as well as the optional Week 72 and Week 
96 Visits. 
 
7 
MANAGEMENT OF ADVERSE EVENTS 
 
The most common side effects are infusion-related symptoms, particularly with the first rituximab 
infusion.  These symptoms include flu-like symptoms, fever, chills/rigors, nausea, urticaria, 
headache, bronchospasm, angioedema, and hypotension.  Since hypotension may occur during 
rituximab infusion, consideration should be given to withholding antihypertensive medications 12 
hours prior to and throughout rituximab infusion.  The decision to hold antihypertensive 
medications will be based on the discretion of local site investigator.  Angina pectoris or cardiac 
arrhythmias, such as atrial flutter and fibrillation, have occurred in subjects treated with rituximab. 
Therefore, subjects with a history of cardiac disease should be monitored closely. In rare 
instances, severe and fatal infusion-related reactions have occurred.  
 
If a hypersensitivity (non-IgE-mediated) or an infusion reaction develops, the infusion rate should 
be reduced to half that rate, i.e. from 100 mg/h to 50 mg/h.  Subjects who experience a moderate 
to severe infusion related reaction (fever, chills, or hypotension) should have their infusion 
interrupted immediately and should receive aggressive symptomatic treatment per local 
institutional policy or protocol.  The infusion should not be restarted before all the symptoms have 
disappeared and then the infusion can continue at one-half the previous rate.  If hypersensitivity 
reaction should occur, subject will receive 100 mg methylprednisolone IV 30 minutes prior to the 
next infusion. 
 
The infusion should be interrupted for severe reactions, and supportive care measures should be 
instituted as medically indicated (e.g., IV fluids, vasopressors, oxygen, bronchodilators, 
diphenhydramine, and acetaminophen).  The infusion should not be restarted until all the 
symptoms have disappeared. 
  
Pregnancy: 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study drug may 
have interfered with the effectiveness of a contraceptive medication. However, the outcome of all 
pregnancies that occur during paternal or maternal exposure to study drug (spontaneous 
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documented even after the subject has been withdrawn from the study. All reports of congenital 
abnormalities/birth defects are SAEs. Spontaneous miscarriages should also be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. All 
outcomes of pregnancy must be reported to the data safety monitor.   
 
Disease-Related Events (DREs): 
Given that variations in symptoms are an inherent part of the natural history of MG, all recorded 
information regarding MG status will be captured as outcomes data. While disease relapse or 
treatment failure is not considered an AE in our study, the DSMB will monitor the percentage of 
treatment failures in the two groups.  If the treatment failure rate reaches a level of concern, the 
DSMB has the ability to stop the trial at any point.  In the setting of a forced steroid taper, we 
expect to possibly observe an increased frequency of disease relapse, particularly in the placebo 
group.  As the forced steroid taper is guided by the MGC score, we do not expect for this to be a 
significant concern.  Relapses will be managed by increasing the prednisone dose and possibly 
offering PLEX or IVIg (rescue therapies) depending on severity.  These are standard of care 
practices.   For the purpose of this study, variation in MG symptoms will not be considered an AE 
unless the MG relapse requires hospitalization for rescue therapy. If a subject is hospitalized for 
an MG relapse, it will be reported as an SAE. 
 
8 
CRITERIA FOR INTERVENTION DISCONTINUATION 
 
See section 6.2.9 
 
Subjects that are withdrawn from the study or intervention discontinued due to an SAE will have 
reduced follow-up. This will include being followed monthly via telephone or in person for a 
minimum of 90 days or until SAE resolution, whichever comes first, after which a Termination Visit 
will be conducted. The Termination Visit will mirror the Week 52 Visit. 
• 
If the SAE is resolved within 90 days, the Termination Visit can occur earlier. 
• 
If the SAE is not resolved within 90 days, the SAE will be Resolved with Sequelae, and 
the Termination Visit occur. 
 
During the 90 day (or less) SAE follow-up period, no new AEs will be recorded. Existing AEs 
would be followed until resolution, or the Termination Visit, whichever comes first. 
 
Subjects that are withdrawn from the study or intervention discontinued due to reasons other than 
an SAE, will complete a Termination Visit only – no follow-up will be required. 
 
9 
STATISTICAL CONSIDERATIONS 
 
The NeuroNEXT Data Coordinating Center has developed a statistical analysis plan, in 
collaboration with the PPI, co-PPI, co-investigators and protocol steering committee. 
 
9.1 
General Design Issues 
 
9.1.1. Summary of Study Design 
 
A previous study conducted at Yale demonstrated that 82% of subjects who received rituximab 
achieved at least a 75% reduction in their prednisone dose at 52 weeks (95% CI: 48%-98%).  The 


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objective of the proposed study is to determine whether the large benefit observed in the prior 
Yale study can be refuted, or looks promising enough to justify a future phase III trial.  This 
objective will be accomplished using a futility design, which tests the hypothesis that subjects 
treated with rituximab will achieve at least an absolute 30% increase in the frequency of favorable 
responses.60,61  If “futility” is declared, then the results would imply that it is not cost effective to 
conduct a future phase III trial with this agent.  If “futility” is not declared, then the study would 
suggest that there could be a potentially clinically meaningful effect of rituximab which should be 
explored in a larger follow-up study. 
 
The proposed study will involve a randomized, double-blind, placebo-controlled multicenter futility 
study with 50 subjects randomized in a 1:1 manner to receive either rituximab or placebo (25 per 
group).  The primary objective of the study is to test whether rituximab is a beneficial steroid 
sparing therapeutic for myasthenia gravis subjects.  A predetermined steroid taper schedule will 
be utilized.  At the time of enrollment, each subject will be expected to be on a stable fixed dose 
of prednisone for at least 28 days (4 weeks).  Subjects assigned to the rituximab group will receive 
a total of two cycles of rituximab separated by six months.  Each cycle is defined as one infusion 
(375 mg/m2) per week for four consecutive weeks.  As such, cycle 1 will be administered at weeks 
0-3 and cycle 2 will be given during weeks 24-27.  Subjects assigned to the placebo group will 
receive similar cycles of placebo. 
 
MGFA clinical classification grade along with quantitative testing (i.e., MG-ADL score, QMG 
score, MG Composite, MG-QOL) will be assessed every four weeks.  The proposed study 
duration is 52 weeks.  In each subject, the prednisone dose will be gradually reduced based on 
the steroid taper schedule beginning at week 8 (8 weeks after starting cycle 1 of rituximab).  The 
dose will only be reduced after confirming improvement or minimal stable symptoms based on 
judgment of the examining physician and MG Composite Score.  If symptoms worsen, the 
prednisone dose would immediately be increased until the symptoms improved and/or resolved.  
In addition, subjects who worsen can receive PLEX or IVIg if the investigator decides it is 
warranted, and these subjects can remain in the study.  Prednisone taper would again be resumed 
four weeks after the subjects have improved.  The dose of prednisone will be recorded by each 
subject daily and collected at each evaluation. 
 
The primary endpoint will be a binary indicator of whether a subject achieved at least a 75% 
reduction of prednisone dose from baseline.  The endpoint will be computed by comparing the 
mean daily prednisone dose during the four-week period prior to randomization versus the four 
week period at the end of the study (weeks 49-52).  Secondary endpoints will include the MGC 
and QMG.  Other exploratory clinical endpoints will include MG-ADL, other clinical measures, 
immune markers, and safety evaluations.  There will be a treating investigator who does the dose 
adjustments and a blinded investigator who performs the blinded assessments. 
 
9.1.2. Randomization 
 
Randomization will be performed through an interactive website, and will be stratified based on 
the steroid dose at baseline [moderate (15-35 mg/day) vs. high (>35 mg/day)] and baseline 
therapy (prednisone only vs. prednisone plus another IST).  Subjects will be assigned a study ID 
at the time of enrollment.  The study ID includes the identification of the center and a unique 
subject ID.  The DCC will generate a randomization table for each of the strata using a permuted 
block design with random block sizes.  At the time of randomization, the study coordinator logs 
into the study website and enters the potential subject’s baseline prednisone dose as well as other 


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eligibility criteria.  The subject will then be randomized to one of the two treatments.  The study 
ID is added to all subsequent CRF’s and on the dispensed study medication. 
9.2 
Outcomes 
9.2.1 Primary Outcome (including definition) 
 
The specific primary aim of this study is to determine whether rituximab is a safe and shows 
sufficient promise as a steroid sparing therapeutic for MG to warrant further study in a phase III 
efficacy trial.  Refer to Section 9.5 for statistical analysis plan. 
 
Steroid Sparing Effect. The primary endpoint is the percent of subjects that achieve a ≥ 75% 
reduction in mean daily prednisone in the four weeks prior to week 52 (week 49-52) along with 
clinical improvement or no significant worsening of symptoms (≤2 point increase in MG composite 
score) as compared to the four week period prior to randomization. 
 
Safety. Safety will be assessed by examining the frequency of study-related adverse experiences 
in the two groups. 
9.2.2 Secondary Outcome(s) 
 
Our secondary objective is to evaluate whether there is a trend toward clinical benefit as 
measured by MG-specific clinical outcome scales used as endpoints in prior clinical trials.  We 
will determine if rituximab can significantly improve the scores of the following MG-specific clinical 
outcome measures:  (1) Myasthenia Gravis Composite (MGC).  (2) Quantitative Myasthenia 
Gravis (QMG).  These studied measures would lay the groundwork toward optimizing the design 
of a subsequent phase III efficacy trial of rituximab in MG.   
 
Myasthenia Gravis Composite (MGC).  The MGC is a new end-point that has been developed 
for MG.  Specific components of the QMG, MG-ADL, and manual muscle testing scales are 
combined to obtain the MGC score. 
 
Quantitative Myasthenia Gravis (QMG).  The QMG is a validated 13-item test that objectively 
measures ocular, bulbar, extremity fatigue/strength, and respiratory function.  A battery of 
quantitative functional tests are completed from which a QMG score is calculated.  
 
9.2.3 Exploratory Outcomes 
 
9.2.3.1 Clinical Exploratory Outcomes 
 
Determine if rituximab can significantly improve the scores of the following other previously 
validated MG-specific outcome measures: (1) MG-Activities of Daily Living score (MG-ADL).  (2) 
MG-Quality of Life (MG-QOL) score.  
 
Other previously used measures of steroid-sparing effect will be assessed: (1) Mean daily 
prednisone dose at each scheduled assessment (every 4 weeks). (2) A delayed start of the area 
under the dose-time curve (AUDTC), starting at week 8. (3) Percentage of subjects achieving a ≥ 
50% mean daily prednisone dose reduction with maintenance of minimal or no symptoms in 4 
weeks prior to week 52. (4) Body mass index (Screening Visit and weeks 24 and 52).  (5) HbA1C 
(Screening Visit and week 52).   


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MG flare rate (failure of therapy) will be assessed by: (1) Number of rescue treatments (PLEX or 
IVIg). (2) Number of times prednisone dose needed to be increased. (3) Frequency of a ≥ 3-point 
increase in the MGC score.  
 
The primary focus of the two observational off study-intervention time points (weeks 72 and 96) 
will be to assess B cell recovery/repopulation as a safety measure.  Specifically, we will examine: 
(1) Percentage of subjects achieving normal B cell counts at week 72 and 96.  (2) Percentage of 
achieving baseline B cell counts at week 72 and 96. (3) Percent B cell recovery to normal or 
baseline levels.  In addition, the long-term durability of response will also be assessed.  
Specifically, we will examine: (1) Percentage of subjects achieving a sustained ≥ 75% mean daily 
prednisone dose reduction. (2) Percentage of subjects achieving a ≥ 50% mean daily prednisone 
dose reduction. (3) Prednisone AUDTC (if applicable). (4) Clinical status as measured by MGFA 
Class, MGC, MG-QOL and MG-ADL scores. (5) Number of rescue treatments (PLEX or IVIg). 
9.2.3.2 Biomarker/Mechanistic Exploratory Outcomes 
 
The biomarker or mechanistic studies are focused on identifying how treatment modifies the 
immunopathology of MG. We will study changes in the antigen specific components of the MG 
immune system. We have developed/adapted immunoassays so that we can examine 
autoantibodies, B cells and T cells. The principal mechanistic outcome will be the decrease in titer 
of circulating AChR autoantibodies within an individual. Other exploratory mechanism-based 
outcomes include determining how rituximab modifies antigen-specific B cell frequency, the B cell 
repertoire, B cell activating factor (BAFF) levels and whether rituximab modifies antigen-specific 
T cell frequency and phenotype. Measurements will be performed prior to and during B cell 
depletion and through repopulation of the B cell compartment, which will be of particular interest 
in terms of assessing the durability of the treatment.  Blood will be collected for mechanistic 
studies at the Baseline Visit, Week 24. Week 52 Visits, as well as the optional Week 72 and Week 
96 Visits. 
9.3 
Sample Size and Accrual 
Below, we introduce some key notation that we use to describe the analysis plan for the 
proposed trial: 
• 
Let pP represent the true (unknown) percentage of subjects treated with placebo who will 
achieve success on the primary endpoint 
• 
Let pR represent the true (unknown) percentage of subjects treated with rituximab who 
will achieve success on the primary endpoint 
Based on a prior study completed by Sanders and coworkers in 2008 on MMF in AChR+ MG, 
38.6% of placebo treated case achieved a treatment response.38 The placebo start point was 34.1 
mg prednisone; hence, 38.6% of placebo recipients had a reduction of prednisone dose by at 
least 78%.  Also the MMF start point was 30.7 mg prednisone; therefore, 44.3% of MMF recipients 
had a reduction of prednisone dose by at least 76%.  Based on this information, we assume that 
40% of placebo recipients will achieve a 75% or greater prednisone dose reduction (pP = 0.40). 
The design of this trial was somewhat restricted due to the fact that the company that produces 
rituximab has only agreed to provide 25 doses to the investigators.  As a consequence, this 
study requires more of a sample size justification (for the sample size fixed by external factors) 
as opposed to a standard sample size calculation that determines the required sample size for a 


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fixed target power.  Using the notation above, the one-sided futility hypothesis that the treatment 
achieved the desired clinically meaningful level of interest may be stated as: 
𝐻0,𝐹: 𝑝𝑅−𝑝𝑃≥0.30     𝑣𝑠.     𝐻𝐴,𝐹: 𝑝𝑅−𝑝𝑃< 0.30. 
Therefore, rejecting the null hypothesis suggests ‘futility’ in the sense that it appears unlikely 
that conducting a future phase III clinical trial would lead to a significant effect with a magnitude 
at least as large as the specified clinically meaningful effect of interest.  If we don’t reject the null 
hypothesis, this would provide one of the “go” conditions for conducting a future phase III study.   
The table below shows the power computed across a range of assumed values for the true 
response rate in the rituximab subjects.  The calculations assume a type I error rate of 10%, pP 
= 0.40, and a conservative assumption of up to 20% missing data.  The table below 
demonstrates the benefits of using the futility design.  When the true success rate for rituximab 
is near or below the true success rate for placebo, the study will declare “futility” with high 
probability.  Likewise, when the true success rate for rituximab is well above the true success 
rate for placebo, the study has a very low chance of incorrectly declaring “futility”.  Given the 
sample size limitations mentioned above, we feel that this provides a reasonable chance of 
having a successful study – where “success” is defined as answering the main question of 
interest regarding whether there is clear evidence to rule out an effect of rituximab in this 
population, or to provide enough evidence to justify a larger trial in the future.  
 
Rituximab 
Rate (pR) 
 
30% 
 
35% 
 
40% 
 
45% 
 
50% 
 
55% 
 
60% 
 
65% 
 
70% 
 
75% 
 
80% 
 
85% 
 
90% 
Pr(Futility) 
92% 
84% 
74% 
63% 
50% 
37% 
25% 
16% 
10% 
4% 
2% 
1% 
<1% 
 
9.4 
Data Monitoring 
 
All aspects of the study will be monitored by qualified individuals designated by the sponsor.  
Monitoring will be conducted according to Good Clinical Practice and applicable government 
regulations.  The investigator agrees to allow monitors access to the clinical supplies, dispensing 
and storage areas, and to the clinical files of the study subjects, and, if requested, agrees to assist 
the monitors. 
 
Safety monitoring will include careful assessment and appropriate reporting of adverse events.  
Medical monitoring will include contemporaneous assessment of serious adverse events. 
 
The monitoring of subject safety and data quality will follow the NINDS Guidelines for Data and 
Safety Monitoring in Clinical Trials.  A Data and Safety Monitoring Board (DSMB) appointed by 
the NIH/NINDS will meet at six-month intervals (or as determined by the NINDS) to review partially 
unblinded study data provided by the study statistician.  This committee will monitor rates of 
adverse events and endpoints in the trial and will monitor the performance of the trial. The 
frequency and format of DSMB meetings, reports, and guidelines for interim analysis will be 
agreed upon prior to study subject enrollment. 
 
The Protocol PI will appoint an Independent Medical Monitor (IMM) to review all adverse events, 
in a blinded fashion, on a periodic basis. In addition, the IMM will review all events that meet the 
regulatory definition of a Serious Adverse Event, upon receipt of notification via the Electronic 
Data Capture (EDC) system.    


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An adverse event (AE) is any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with a 
study, use of a drug product or device whether or not considered related to the drug product or 
device.  FDA, Office of Human Research Protection (OHRP), and NeuroNEXT CIRB requirements 
for reporting AEs will be followed. Subjects will be monitored for AEs from the time they sign 
consent until the Week 52 Visit. If a new AE is discovered at the Week 52 Visit, it will be followed 
until resolution or for a minimum of 30 days, whichever comes first. The IMM/DSMB will review 
cumulative AEs; the frequency of this review will be determined by the IMM/DSMB in conjunction 
with the Protocol PI. 
All SAEs must be followed until resolution, or until the Week 52 Visit, whichever comes first. If 
the SAE is still ongoing at Week 52, it will be Resolved with Sequelae.  
• 
SAEs that are discovered less the 90 days prior to the Week 52 Visit will be followed 
until resolution or for a minimum of 90 days, whichever comes first, even if it is past the 
Week 52 Visit. A repeat Termination Visit does not need to occur. 
• 
If a new SAE is discovered at the Week 52 Visit, it must be followed until resolution, or for a 
minimum of 90 days, whichever comes first. 
• 
For SAEs that result in study treatment discontinuation and a limited follow-up period, please 
refer to Section 8 – Criteria for Intervention Discontinuation.  
 
At the Week 72 and 96 Visits, only those adverse events, serious and non-serious, that in the 
opinion of the Investigator are deemed related to study procedures will be reported, given that 
the subject has consented to the optional off-intervention follow-up visits. Additionally, any MG 
relapses requiring rescue therapy that have occurred since the last visit will also be recorded.  
 
Each Clinical Study Site Investigator and research team (co-Investigators, research nurse, clinical trial 
coordinator) are responsible for identifying and reporting AEs and determining the relationship of the 
event to the study drug/study procedures.  Aggregate reports blinded by treatment group, detailed by 
severity, attribution (expected or unexpected), and relationship to the study drug/study procedures, 
will be available from the DCC for review by the IMM. A separate report detailing protocol 
compliance will also be available monthly from the DCC for review by the Protocol PI, who will 
provide feedback to individual sites as needed. The Protocol Steering Committee (PSC) will 
advise the Protocol PI as to whether the protocol or informed consent document requires 
revision based on these reports.  
 
9.5 
Statistical Analysis Plan 
 
9.5.1. Primary Hypotheses 
Primary Futility Hypothesis: Subjects treated with rituximab will have at least a 30% 
absolute increase in the frequency of achieving at least a 75% reduction in mean daily 
prednisone dose with maintenance of minimal or no symptoms. 
The primary futility hypothesis being tested in this trial is that subjects treated with rituximab will 
achieve at least an absolute 30% increase in the frequency of favorable responses.  Assuming a 
placebo response rate of 40% (as in the original sample size calculations), this corresponds to an 
odds ratio of 3.5.  Therefore, the primary futility hypothesis will be assessed using a logistic 
regression model, adjusted for the two stratification variables, to estimate the log-odds of primary 
endpoint success in each group.  The logistic regression model used for these purposes is stated 
here: 
 


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𝑙𝑜𝑔𝑖𝑡(𝑌𝑖) = 𝛽0 + 𝛽1𝑋𝑑𝑜𝑠𝑒+ 𝛽2𝑋𝐼𝑆𝑇,𝑖+ 𝛽3𝑋𝑅𝑀𝐵,𝑖 
where  
• 
Yi represents the binary variable indicating whether or not the ith subject met the primary 
outcome requirement of a 75% or greater reduction in prednisone dose  
• 
Xdose,i is an indicator variable for prednisone dose at baseline (=0 if moderate, =1 if high)  
• 
XIST,i is an indicator variable for whether the subject was receiving prednisone plus IST at 
baseline (=0 if prednisone alone, =1 if prednisone plus IST)  
• 
XRMB,i is an indicator variable for whether the ith subject was randomized to the Rituximab 
group 
Correspondingly, the primary futility hypothesis of interest can be assessed by performing the 
following hypothesis test: 
𝐻0,𝐹: log (𝛽3) ≥3.5     𝑣𝑠.     𝐻𝐴,𝐹: log (𝛽3) < 3.5. 
Therefore, rejecting the null hypothesis suggests ‘futility’ in the sense that it appears unlikely that 
conducting a future phase III clinical trial would lead to a significant effect with a magnitude at 
least as large as the specified clinically meaningful effect of interest.  If we don’t reject the null 
hypothesis, this would provide justification for proceeding to examine the superiority hypothesis.   
Due to randomization, it is unlikely that important covariates will be imbalanced in this study.  
However, given the small sample size, this cannot be dismissed.  We will assess for important 
baseline imbalances, and if any imbalances exist, we will adjust for these additional covariates in 
the logistic regression model. 
 
Primary Safety Hypothesis: There will be no increase in adverse experiences for the 
rituximab-treated vs. placebo subjects. 
The second primary hypothesis will involve a comparison of the safety profiles of rituximab vs. 
placebo.  As described elsewhere, general assessments of safety will occur throughout the trial 
in conjunction with the medical safety monitor.  This specific hypothesis will be assessed in two 
ways.  First, the percentage of subjects who experience a study-related AE, overall and by body 
system, will be compared across the two groups using standard chi-square tests.  Then, the rates 
of study-related AE’s across the two groups will be compared using a Poisson regression model. 
 
9.5.2. Secondary Hypotheses 
 
Secondary Hypothesis #1: Rituximab-treated subjects will have clinically significant 
improvement in their Myasthenia Gravis Composite (MGC) scores at the end of the 52 week 
treatment period. 
The first secondary hypothesis assesses the change in Myasthenia Gravis Composite (MGC) 
scores at the end of the 52 week study period.  The outcome will be defined as the change from 
baseline to week 52 in the MGC.  This hypothesis will be assessed using a linear regression 
model, adjusted for baseline MGC score.  For example, the following model will be fit to these 
data: 
 
𝑌𝑖= 𝛽0 + 𝛽1𝑋𝑑𝑜𝑠𝑒+ 𝛽2𝑋𝐼𝑆𝑇,𝑖+ 𝛽3𝑋𝑀𝐺𝐶,𝑖+ 𝛽3𝑋𝑅𝑀𝐵,𝑖 
where  
• 
Yi represents the change from baseline in the MGC score for the ith subject  
• 
Xdose,i is an indicator variable for prednisone dose at baseline (=0 if moderate, =1 if high)  


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• 
XIST,i is an indicator variable for whether the subject was receiving prednisone plus IST at 
baseline (=0 if prednisone alone, =1 if prednisone plus IST)  
• 
XMGC,i is the baseline MGC score for the ith subject  
• 
XRMB,i is an indicator variable for whether the ith subject was randomized to the Rituximab 
group 
Correspondingly, the secondary hypothesis of interest can be assessed by performing a test of: 
H0: β4 = 0 vs. HA: β4 ≠ 0. 
As above, should important treatment imbalances occur across treatment groups with respect to 
covariates of interest, the model will be adjusted to control for these additional covariates. 
 
Secondary Hypothesis #2: Rituximab-treated subjects will have clinically significant 
improvement in their Quantitative Myasthenia Gravis (QMG) scores at the end of the 52 
week treatment period. 
 
The second secondary hypothesis assesses the change in Quantitative Myasthenia Gravis 
(QMG) scores over the course of the 52 week study period.  Because the only difference between 
this and the first secondary hypothesis is the choice of outcome, the analysis will proceed in the 
same manner described above for the first secondary hypothesis. 
 
Secondary Hypothesis #3: Rituximab subjects will have complete B-cell recovery by the 
end of the 96 week assessment period. 
 
The third secondary hypothesis will assess the rate of B-cell recovery among subjects treated 
with rituximab during the study.  The rate of B-cell recovery will be assessed by quantifying the 
percentage of subjects who: 1) return to their individual baseline level of B-cells, and 2) return to 
either the individual baseline level of B-cells or the lower limit of ‘normal’ based on the central 
lab (whichever is lower).  Point estimates, and 95% confidence intervals, will be computed for 
the rate of B-cell recovery at both 72 & 96 weeks.  If rates are high, as expected, exact methods 
for the computation of confidence intervals will be utilized.  We expect the upper limit of the 
confidence intervals to include the value 100% - which would support a high rate of B-cell 
recovery in this population.  Any subject who receives open-label rituximab treatment after 
Week 52 would be excluded from this analysis as well as from the extended follow-up study.  
 
9.5.3. Exploratory Analyses  
  
Additional exploratory clinical outcomes will be investigated to monitor effectiveness as well as 
evaluate other endpoints that would be useful in optimizing future MG trial designs as well as a 
Phase III rituximab trial.  We will assess whether rituximab can improve the scores on the MG-
Activities of Daily Living (MG-ADL) and MG-Quality of Life (MG-QOL) scales.  We will also 
assess other measures of steroid-sparing effect: 1. Mean daily prednisone dose in the 4 weeks 
prior to week 52. 2. Mean daily prednisone dose in the 8 weeks prior to week 52. 3. Percentage 
of subjects achieving a ≥ 50% mean daily prednisone dose reduction with maintenance of 
minimal or no symptoms in 4 weeks prior to week 52. 4. Mean daily prednisone dose at each 
scheduled assessment (every 4 weeks). 5. A delayed start of the area under the dose-time 
curve (AUDTC), started at week 8.  Failure of therapy (or MG flare rate) will be assessed by 
examining the number of rescue treatments (PLEX or IVIg), number of times prednisone dose 
needed to be increased, and the frequency of a ≥ 3 point increase in the MGC score. In addition 
we will review the following predictable steroid related effects between the two groups: 1) 


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HbA1C (screening and week 52); 2) BMI (screening, week 24 and week 52).  A formal statistical 
analysis plan for these outcomes will be prepared and approved prior to final data lock by the 
protocol steering committee.  Finally, we assess B cell recovery/repopulation as a safety 
measure at the optional observational off study-intervention time points (weeks 72 and 96) 
along with MG clinical status during off study-intervention. A formal statistical analysis plan for 
these outcomes will be prepared and approved prior to final data lock by the protocol steering 
committee. Refer to Section 9.2.3.1.  
 
9.5.4. Impact of Missing Data 
 
The primary analysis will follow the intent-to-treat (ITT) paradigm.  All enrolled subjects must be 
included in the primary ITT analysis, and will be analyzed in the treatment group to which they 
were initially randomized.  As such, it will be critically important to minimize the occurrence of 
missing data.  Obviously, the optimal strategy for dealing with missing data is to make every effort 
to obtain complete data during the conduct of the study.  Our team of data managers and protocol 
coordinators will work diligently and use a variety of methods in order to minimize the percentage 
of missing data in this trial.  Nevertheless, there is likely to be a small percentage of missing data.  
For the primary analysis, we will take a conservative approach.  If the mean prednisone dose is 
not known during weeks 49-52, then that subject will be considered to not have achieved a 75% 
dose reduction (i.e., they will be counted as a failure).  In order to further assess the potential 
dependence of the results of the primary analysis of these missing values, a series of sensitivity 
analyses will be conducted, including: 
• 
A Multiple Imputation Approach: This multiple imputation approach will be implemented 
using a model based on the prednisone dose at baseline and all observed time points for 
subjects throughout the study.  We will use five separate implementations of this 
approach, and will average the parameters across the five imputations for the final 
analysis. 
• 
Using Only Observed Data (No Imputation) 
• 
Using a Last Observation Carried Forward Approach 
• 
Worst-case scenario: Assume all missing subjects in the rituximab group did not achieve 
a dose reduction and all missing subjects in the placebo group did achieve a dose 
reduction 
• 
Best-case scenario: Assume all missing subjects in the rituximab group did achieve a dose 
reduction and all missing subjects in the placebo group did not achieve a dose reduction. 
 
 
10 DATA COLLECTION, SITE MONITORING, AND ADVERSE EXPERIENCE REPORTING 
10.1 Data Management 
 
Site personnel will collect, transcribe, correct, and transmit the data onto source documents, 
CRFs, and other forms used to report, track and record clinical research data.  The DCC will 
monitor clinical sites to ensure compliance with data management requirements and Good 
Clinical Practices. The DCC is responsible for developing, testing, and managing clinical data 
management activities, as required, at the study sites, the CCC, and at the DCC. 
 


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The general NINDS Common Data Elements (CDE) will be used to construct data collection 
forms. All study data will be collected via systems created in collaboration with the DCC and will 
comply with all applicable guidelines regarding subject confidentiality and data integrity. 
10.1.1 Registration 
 
Registration of participants on this protocol will employ an interactive data system in which the 
clinical study site will attest to the participant’s eligibility as per protocol criteria and obtain 
appropriate informed consent. NeuroNEXT CIRB approval for the protocol must be on file at the 
DCC before accrual can occur from the clinical study site. 
 
The DCC will use a system of coded identifiers to protect participant confidentiality.  When the 
participant is registered to participate in the study using the DCC-provided web-based registration, 
the system will assign a participant ID number. The unique ID code will include a protocol ID, a 
site ID, and a unique participant ID.  To confirm the correct participant ID, the data entry system 
will require a second entry of the unique participant ID and compare for consistency.  In this 
fashion, no personal identifiers would be accessible to the DCC and the data will be collected on 
the correctly identified subject.  
10.1.2 Data Entry 
 
Data entry will occur at the enrolling clinical study sites. Data quality assurance and analyses will 
be performed by the DCC.  The DCC, located at the University of Iowa, will coordinate all data 
and statistical services for the study, as well as on-site monitoring for all participating clinical study 
sites. 
 
Data collection for this study will be accomplished with online electronic case report forms.  Using 
encrypted communication links, online forms will be developed that contain the requisite data 
fields.   
 
10.2 Role of Data Management 
 
Data Management (DM) is the development, execution and supervision of plans, policies, 
programs, and practices that control, protect, deliver, and enhance the value of data and 
information assets. 
 
All data will be managed in compliance with NeuroNEXT policies, and applicable Sponsor and 
regulatory requirements. The DCC will instruct site personnel to collect, transcribe, correct, and 
transmit the data onto source documents, CRFs, and other forms used to report, track and record 
clinical research data.  The DCC will monitor clinical sites to ensure compliance with data 
management requirements and Good Clinical Practices. The DCC is responsible for developing, 
testing, and managing clinical data management activities, as required, at the clinical study sites 
(CSS), the CCC, and at the DCC. 
 
The DCC is responsible for all aspects of clinical data management, and for properly instructing 
key study personnel (including the CCC, the CSS, and DCC staff) on how to collect, transcribe, 
correct and transmit the data onto CRFs or other data collection forms and logs. 
 


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The DCC is responsible for establishing procedures to ensure that clinical data management 
activities occur as required at the CCC, the CSS, and at the DCC. 
10.3 Quality Assurance 
By signing this protocol, the Sponsor and Investigator agree to be responsible for implementing 
and maintaining quality control and quality assurance systems with written standard operating 
procedures (SOPs) to ensure that studies are conducted and data are generated, documented, 
and reported in compliance with the protocol, accepted standards of GCP, and all applicable 
federal, state, and local laws, rules and regulations relating to the conduct of the clinical study. 
10.3.1 Development of Monitoring Plan 
Onsite monitoring visits will be conducted by DCC monitors according to a pre-defined Monitoring 
Plan.  The monitoring plan will detail the frequency of on-site visits, the study data to be monitored, 
the review of any regulatory files, drug and supplies accountability (if applicable), documentation 
of the on-site visit, and the resolution process for data errors that are discovered during the visits.   
All participating clinical study sites will be monitored at least once after a study initiation visit and 
all sites will have a close-out visit for each protocol.  One on-site monitoring visit is anticipated for 
each clinical study site per year.  All subjects will be monitored for inclusion and exclusion criteria, 
informed consent procedures, and adverse events.  A certain percentage of data is also 
monitored/ source data verified against the data entered into the study database.  The monitoring 
plan will include flexibility to revise the frequency of visits or data monitored depending on clinical 
study site or study related issues. 
 
 
10.3.2 Site Monitoring Visits 
 
On-site monitoring visits will be conducted by DCC monitors according to a pre-defined monitoring 
plan for each protocol.  The goal of on-site monitoring is to analyze (review) the data as it is 
collected, to check the validity and integrity of the data, to verify source documentation, to ensure 
protection of human subjects, and to ensure protocol compliance with federal regulations.  During 
the monitoring visit, the monitor assesses the overall status of the study, staff, and facilities to 
determine whether the study is being conducted per protocol and in compliance with regulatory 
requirements.  The monitor also conducts a CRF review that includes checks of all adverse event 
documentation, verifies the presence of all critical correspondence and records related to 
investigational products and clinical supplies (if applicable), and determines if protocol violations 
have occurred and are documented properly.  After the monitoring visit, the monitor documents 
the results of the monitoring visit and completes a post-visit monitoring letter that conveys any 
issues discovered during the visit and the need for data corrections, if appropriate.  Drug and 
supplies accountability may also be monitored during the site visit.  The DCC will work closely 
with the CCC to monitor and document drug distribution from the manufacturers to the clinical 
study sites (CSS).  Each CSS will be provided with a drug accountability log which will be reviewed 
by the DCC monitors and reconciled with distribution logs. At the study closeout visit, the monitors 
confirm that appropriate data have been reviewed, source documentation has been verified, and 
all required documents are present in the Study Regulatory File. 


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10.3.3 Laboratory Data Flow 
Specialized bloods. The DCC will provide laboratories with online forms and/or electronic data 
exchange mechanisms - depending on their capabilities and needs - to enter, update and obtain 
relevant data. When biologic sample has been obtained, the clinical study site study coordinator 
will send the sample (participant ID, site ID, and protocol ID numbers will be used) to the University 
of Rochester central laboratory). Results will be sent via a secure system to University of 
Rochester laboratory with no individual-identifying information on the report. The laboratory will 
electronically communicate the test results to the respective clinical study sites in a secure 
manner.  The laboratory will also transfer test results electronically to the DCC. 
Safety Monitoring Labs. The safety monitoring labs will be performed at specific visits as part of 
routine care.  The DCC will provide online forms and/or electronic data exchange mechanisms - 
depending on their capabilities and needs - to enter, update and obtain the results from these 
tests.  Results that meet criteria for adverse experience reporting, including study drug 
discontinuation will be reported in accordance with guidelines noted below.    
 
Biomarker/Mechanistic Blood. When biologic sample has been obtained, the clinical study site 
study coordinator will send the sample (participant ID, site ID, and protocol ID numbers will be 
used) to Dr. Kevin O’Connor’s Laboratory at Yale University.  Samples will be kept at room 
temperature and shipped priority overnight for processing and immunologic studies.  Deliveries 
must arrive within 24 hours of collection. 
10.4 Adverse Event Reporting 
 
The adverse event (AE) definitions and reporting procedures provided in this protocol comply with 
all applicable United States FDA regulations and International Conference on Harmonization 
(ICH) guidelines.  The Site Investigator will carefully monitor each subject throughout the study 
for possible adverse events.  All AEs will be documented on CRFs designed specifically for this 
purpose.  It is important to report all AEs, especially those that result in permanent discontinuation 
of the investigational product being studied, whether serious or non-serious. 
 
All SAEs must be followed until resolution, or until the Week 52 Visit, whichever comes first. If 
the SAE is still ongoing at Week 52, it will be Resolved with Sequelae.  
• 
SAEs that are discovered less the 90 days prior to the Week 52 Visit will be followed 
until resolution or for a minimum of 90 days, whichever comes first, even if it is past the 
Week 52 Visit. A repeat Termination Visit does not need to occur. 
• 
If a new SAE is discovered at the Week 52 Visit, it must be followed until resolution, or 
for a minimum of 90 days, whichever comes first. 
• 
For SAEs that result in study treatment discontinuation and a limited follow-up period, 
please refer to Section 8 – Criteria for Intervention Discontinuation.  
 
At the Week 72 and 96 Visits, only those adverse events, serious and non-serious, that in the 
opinion of the Investigator are deemed related to study procedures will be reported, given that 
the subject has consented to the optional off-intervention follow-up visits. Additionally any MG 
relapses requiring rescue therapy that have occurred since the last visit will also be recorded.  
Each clinical study site’s Principal Investigator and research team are responsible for identifying 
adverse events and reporting them through the DCC Online Adverse Event Reporting System.  


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Investigators are also responsible for complying with NeuroNEXT CIRB’s reporting requirements 
for all safety reports.  Copies of each report and documentation of IRB notification and receipt will 
be kept in the investigator’s study file.  
On-line Adverse Event Reporting System  
 
Upon entry of a serious adverse event by a site investigator, the DCC Online Adverse Event 
Reporting System will immediately notify the Independent Medical Monitor (IMM).   
 
• Within 24 hours (of learning of the event), investigators must report any Serious Adverse Event 
(SAE). Investigators must report all other AEs within 5 working days/7 calendar days (of 
learning of the event). 
 
Serious adverse events: The site investigator determines causality (definitely not related, probably 
not related, possibly related, probably related, definitely related) of the adverse event. The IMM 
will review the SAE report.  The IMM may request further information if necessary.  The Online 
Adverse Event Reporting System maintains audit trails and stores data (and data updated) and 
communication related to any adverse event in the study.  The IMM may determine that the 
Serious Adverse Event requires expedited reporting to the FDA.  The DCC will prepare a 
Medwatch safety report for submission to the FDA and to Genentech.  If warranted, the IMM will 
notify the DSMB chair.  The DSMB may suggest changes to the protocol or consent form to the 
Study Chair as a consequence of adverse events.  
 
Non-serious adverse events: Non-serious adverse events that are reported to or observed by the 
investigator or a member of his or her research team will be submitted to the DCC in a timely 
fashion (within 5 working days/7 calendar days). The events will be presented in tabular form and 
given to the IMM on a quarterly basis or as requested. Local site investigators are also required 
to fulfill all reporting requirements of their local institutions. 
 
For the purposes of this study, before randomization, only those adverse events, serious and non-
serious, that in the opinion of the Investigator are deemed related to study procedures will be 
reported.  After randomization, all adverse events will be reported. 
 
The DCC will prepare aggregate reports of all adverse events (serious/not serious, 
expected/unexpected and relationship to study drug) for the IMM and the DSMB on a quarterly 
basis or as requested. In addition, all adverse events will be coded using the MedDRA system. A 
separate report detailing protocol compliance will also be available from the DCC for DSMB and/or 
site review monthly or as requested. The research team will then evaluate whether the protocol 
or informed consent document requires revision based on the reports.  
 
IND Annual Reports 
In accordance with the regulation 21 CFR § 312.32, the Sponsor-Investigator would be required 
within 60 days of the anniversary date that the IND went into effect to submit a brief report of the 
progress of the investigation.  This study has Exempt IND status and as such there are no 
required annual IND reports to the FDA.   The section below details additional reporting 
requirements.   
 
Safety Reporting Requirements for IND Exempt Studies 
 


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For Investigator Sponsored IND Exempt Studies, there are some reporting requirements for the 
FDA in accordance with the guidance set forth in 21 CFR 314.80. 
 
Postmarketing 15-Day “Alert Report”: 
 
The Sponsor-Investigator is required to notify the FDA of any fatal or life-threatening adverse 
event that is unexpected and assessed by the investigator to be possibly related to the use of 
Rituximab. An unexpected adverse event is one that is not already described in the Investigator 
Brochure.
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
     
 
 
     
 
 
 
10.4.1 Definitions of Adverse Events, Suspected Adverse Drug Reactions & Serious 
Adverse Events 
10.4.1.1 Adverse Event and Suspected Adverse Drug Reactions 
 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  
 
Adverse drug reactions (ADR) are all noxious and unintended responses to a medicinal product 
related to any dose.  The phrase “responses to a medicinal product” means that a causal 
relationship between a medicinal product and an adverse event is at least a reasonable possibility, 
i.e., the relationship cannot be ruled out.  Therefore, a subset of AEs can be classified as 
suspected ADRs, if there is a causal relationship to the medicinal product. 
 
Examples of adverse events include: new conditions, worsening of pre-existing conditions, 
clinically significant abnormal physical examination signs (i.e. skin rash, peripheral edema, etc), 


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or clinically significant abnormal test results (i.e. lab values or vital signs), with the exception of 
outcome measure results, which are not being recorded as adverse events in this trial (they are 
being collected, but analyzed separately). Stable chronic conditions (i.e., diabetes, arthritis) that 
are present prior to the start of the study and do not worsen during the trial are NOT considered 
adverse events. Chronic conditions that occur more frequently (for intermittent conditions) or with 
greater severity, would be considered as worsened and therefore would be recorded as adverse 
events. 
 
Adverse events are generally detected in two ways: 
 
 
Clinical  symptoms reported by the subject or signs detected on examination. 
Ancillary Tests  abnormalities of vital signs, laboratory tests, and other diagnostic procedures 
(other than the outcome measures: the results of which are not being captured as AEs). 
 
If discernible at the time of completing the AE log, a specific disease or syndrome rather than 
individual associated signs and symptoms should be identified by the Site Investigator and 
recorded on the AE log.  However, if an observed or reported sign, symptom, or clinically 
significant laboratory anomaly is not considered by the Site Investigator to be a component of a 
specific disease or syndrome, then it should be recorded as a separate AE on the AE log.  
Clinically significant laboratory abnormalities, such as those that require intervention, are those 
that are identified as such by the Site Investigator. 
 
An unexpected adverse event is any adverse event, the specificity or severity of which is not 
consistent with the current Investigators Brochure or package insert or described in the protocol.  
An unexpected, suspected adverse drug reaction is any unexpected adverse event that, in the 
opinion of the Site Investigator or Sponsor, there is a reasonable possibility that the investigational 
product caused the event. 
10.4.1.2 Serious Adverse Events 
 
A SAE is defined as an adverse event that meets any of the following criteria: 
 
1. Results in death. 
2. Is life threatening: that is, poses an immediate risk of death as the event occurred. 
a. This serious criterion applies if the study subject, in the view of the Site Investigator or 
Sponsor, is at immediate risk of death from the AE as it occurs.  It does not apply if an 
AE hypothetically might have caused death if it were more severe. 
3. Requires inpatient hospitalization or prolongation of existing hospitalization. 
a. Hospitalization for an elective procedure (including elective PEG tube/g-tube/feeding 
tube placement) or a routinely scheduled treatment is not an SAE by this criterion 
because an elective or scheduled “procedure” or a “treatment” is not an untoward 
medical occurrence. 
4. Results in persistent or significant disability or incapacity. 
a. This serious criterion applies if the “disability” caused by the reported AE results in a 
substantial disruption of the subject’s ability to carry out normal life functions. 
5. Results in congenital anomaly or birth defect in the offspring of the subject (whether the 
subject is male or female).   
6. Necessitates medical or surgical intervention to preclude permanent impairment of a body 
function or permanent damage to a body structure. 


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7. Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may also be considered SAEs when, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition.  Examples of such medical events include 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
 
An inpatient hospital admission in the absence of a precipitating, treatment-emergent, clinical 
adverse event may meet criteria for "seriousness" but is not an adverse experience, and will 
therefore, not be considered an SAE.  An example of this would include a social admission 
(subject admitted for other reasons than medical, e.g., lives far from the hospital, has no place to 
sleep). 
 
A serious, suspected adverse drug reaction is an SAE that, in the opinion of the Site Investigator 
or Sponsor, suggests a reasonable possibility that the investigational product caused the event. 
 
The Site Investigator is responsible for classifying adverse events as serious or non-serious. 
10.4.1.3 Pregnancy 
 
If a female subject becomes pregnant while receiving investigational therapy or within 90 days 
after the last dose of study drug, a report should be completed and expeditiously submitted to 
the Genentech, Inc. Follow-up to obtain the outcome of the pregnancy should also occur. 
Abortion, whether accidental, therapeutic, or spontaneous, should always be classified as 
serious, and expeditiously reported as an SAE. Similarly, any congenital anomaly/birth defect in 
a child born to a female subject exposed to the {study drug} should be reported as an SAE. 
 
10.4.1.4  AEs of Special Interest (AESIs) 
 
AEs of Special Interest are defined as a potential safety problem, identified as a result of safety 
monitoring of the Product  
  
The Rituxan Events of Special Interest are: NONE 
10.4.2  Assessment and Recording of Adverse Events 
 
This study will utilize the CTCAE version 4.0 coding system for adverse event recording.  Adverse 
events reported using CTCAE will be recoded into MedDRA terms by the DCC. 
 
Assessment of Adverse Events 
At each visit (including telephone interviews), the subject will be asked “Have you had any 
problems or symptoms since your last visit?” in order to determine the occurrence of adverse 
events. If the subject reports an adverse event, the Investigator will determine: 
 
1. Type of event 
2. Date of onset and resolution (duration) 
3. Severity (mild, moderate, severe) 
4. Seriousness (does the event meet the above definition for an SAE) 
5. Causality, relation to investigational product and disease 


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6. Action taken regarding investigational product 
7. Outcome 
 
Relatedness of Adverse Event to Investigational Product 
 
The relationship of the AE to the investigational product should be specified by the Site 
Investigator, using the following definitions: 
 
1. Not Related: Concomitant illness, accident or event with no reasonable association with 
treatment. 
2. Unlikely: The reaction has little or no temporal sequence from administration of the 
investigational product, and/or a more likely alternative etiology exists. 
3. Possibly Related: The reaction follows a reasonably temporal sequence from administration of 
the investigational product and follows a known response pattern to the suspected 
investigational product; the reaction could have been produced by the investigational product 
or could have been produced by the subject’s clinical state or by other modes of therapy 
administered to the subject. (suspected ADR) 
4. Probably Related: The reaction follows a reasonably temporal sequence from administration 
of investigational product; is confirmed by discontinuation of the investigational product or by 
re-challenge; and cannot be reasonably explained by the known characteristics of the subject’s 
clinical state. (suspected ADR) 
5. Definitely Related: The reaction follows a reasonable temporal sequence from administration 
of investigational product; that follows a known or expected response pattern to the 
investigational product; and that is confirmed by improvement on stopping or reducing the 
dosage of the investigational product, and reappearance of the reaction on repeated exposure. 
(suspected ADR) 
 
Recording of Adverse Events 
 
All clinical adverse events are recorded in the AE Log in the subject’s study binder. The site should 
fill out the AE Log and enter the AE information into the online Adverse Event Reporting System 
within 5 working days/7 calendar days of the site learning of a new AE or receiving an update on 
an existing AE.   
 
Please Note: SAEs must be reported to the NeuroNEXT Data Coordinating Center within 24 hours 
of the site learning of the SAE.  
 
All SAEs must be followed until resolution, or until the Week 52 Visit, whichever comes first. If 
the SAE is still ongoing at Week 52, it will be Resolved with Sequelae.  
• 
SAEs that are discovered less the 90 days prior to the Week 52 Visit will be followed 
until resolution or for a minimum of 90 days, whichever comes first, even if it is past the 
Week 52 Visit. A repeat Termination Visit does not need to occur. 
• 
If a new SAE is discovered at the Week 52 Visit, it must be followed until resolution, or 
for a minimum of 90 days, whichever comes first. 
• 
For SAEs that result in study treatment discontinuation and a limited follow-up period, 
please refer to Section 8 – Criteria for Intervention Discontinuation.  
 


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Entries on the AE Log (and into the online Adverse Event Reporting System) will include the 
following: name and severity of the event, the date of onset, the date of resolution, relationship to 
investigational product, action taken, and primary outcome of event. 
 
Adverse Events and Serious Adverse Events - Reportable Events 
 
The following are considered reportable events and must be reported to the NeuroNEXT Data 
Coordinating Center within 24 hours of the site being notified of the event.  
 
• 
All events that meet the above criteria for Serious Adverse Events (SAEs) 
 
All occurrences of SAEs must be reported within 24 hours of discovery of the event.   All other 
AEs must be reported within 5 working days/7 calendar days of discovery of the event. 
 
Adverse Event Data Management System (AEDAMS) 
 
Upon entry of a serious adverse event by a clinical site, the DCC Online Adverse Event Reporting 
System will immediately notify the IMM. If warranted, the IMM will notify the DSMB chair.  
 
Serious adverse events: The site investigator determines causality (definitely not related, probably 
not related, possibly related, probably related, definitely related) of the adverse event. The IMM 
will review the SAE report.  The IMM may request further information if necessary.  The DSMB 
may suggest changes to the protocol or consent form to the Project PI as a consequence of 
adverse events. The Online Adverse Event Reporting System maintains audit trails and stores 
data (and data updated) and communication related to any adverse event in the study.  
 
Non-serious adverse events: Non-serious adverse events that are reported to or observed by the 
investigator or a member of his research team will be submitted to the DCC within 5 working 
days/7 calendar days. The events will be presented in tabular form and given to the IMM on a 
monthly basis or as requested. Local site investigators are also required to fulfill all reporting 
requirements of their local institutions. 
 
The DCC will prepare aggregate reports of all adverse events (serious/not serious and expected, 
unexpected) for the DSMB.  
 
10.4.2.1 Reconciliation 
 
The Sponsor agrees to conduct reconciliation for the product. Genentech and the Sponsor will 
agree to the reconciliation periodicity and format, but agree at minimum to exchange monthly 
line listings of cases received by the other party. If discrepancies are identified, the Sponsor and 
Genentech will cooperate in resolving the discrepancies. The responsible individuals for each 
party shall handle the matter on a case-by-case basis until satisfactory resolution. 
 
10.4.2.2 Study Close Out 
 
Any study report submitted to the FDA by the Sponsor-Investigator should be copied to 
Genentech. This includes all IND annual reports and the Clinical Study Report (final study 
report). Additionally, any literature articles that are a result of the study should be sent to 


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Genentech. Copies of such reports should be mailed to the assigned Clinical Operations contact 
for the study: 
 
 
11 HUMAN SUBJECTS 
Documented approval from the NeuroNEXT CIRB will be obtained for all participating centers 
prior to clinical trial start, according to ICH GCP, local laws, regulations and organization. When 
necessary, an extension, amendment or renewal of the CIRB approval must be obtained. 
Evidence of training in responsible conduct of research shall be on file for each CSS PI and co-
investigator. 
11.1 Central Institutional Review Board (CIRB) Review and Informed Consent 
 
This protocol and the informed consent document (Appendix A) and any subsequent 
modifications will be reviewed and approved by the NeuroNEXT CIRB responsible for oversight 
of the study.  A signed consent form, approved by the NeuroNEXT CIRB, will be obtained from 
the subject.   For subjects who cannot provide consent for themselves, such as those below the 
legal age, a parent, legal guardian, or person with power of attorney, must sign the consent form; 
additionally, the subject's assent must also be obtained if he or she is able to understand the 
nature, significance, and risks associated with the study.  The consent form will describe the 
purpose of the study, the procedures to be followed, and the risks and benefits of participation.  A 
copy of the consent form will be given to the subject, parent, or legal guardian, and this fact will 
be documented in the subject’s record. 
 
11.2 Subject Confidentiality 
 
All laboratory specimens, evaluation forms, reports, video recordings, and other records that leave 
the clinical study site will be identified only by the study specific Subject Identification Number 
(SID) to maintain subject confidentiality.  All records will be kept in a locked file cabinet.  All 
computer entry and networking programs will be done using study specific SIDs only.  Clinical 
information will not be released without written permission of the subject, except as necessary for 
monitoring by CIRB, the FDA, the NINDS, the OHRP, the sponsor, or the sponsor’s designee. 
 
11.3 Study Modification/Discontinuation 
 
The study may be modified or discontinued at any time by the CIRB, the NINDS, the sponsor, the 
OHRP, the FDA, or other government agencies as part of their duties to ensure that research 
subjects are protected. 
 
12 PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by the policies of the NeuroNEXT Network 
and procedures developed by the NeuroNEXT Data Sharing and Publication Committee.  Any 
presentation, abstract, or manuscript will be made available for review by the sponsor and the 
NINDS prior to submission.  A copy of proposed publications or presentations should be submitted 
to Genentech a minimum of 2 months in advance.  
 


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Appendix 1 
 
 
 
 
SAFETY REPORTING FAX COVER SHEET 
GENENTECH SUPPORTED RESEARCH 
AE / SAE FAX No: (650) 225-4682 
Alternate Fax No: (650) 225-5288 
 
Genentech Study Number 
 
Principal Investigator 
 
Site Name 
 
Reporter name 
 
Reporter Telephone # 
 
Reporter Fax # 
 
 
 
Initial Report Date 
[DD] / [MON] / [YY] 
Follow-up Report Date 
[DD] / [MON] / [YY] 
Subject Initials 
(Enter a dash if patient has no 
middle name) 
[ ] - [ ] - [ ] 
 
SAE or Safety Reporting questions, contact Genentech Safety: (888) 835-2555 
 
PLEASE PLACE MEDWATCH REPORT or SAFETY REPORT BEHIND THIS COVER SHEET 
 

SAP_001.pdf: 
1 
 
         
                        
 
 
 
NN103 
 
Statistical Analysis Plan 
 
B Cell Targeted Treatment in Myasthenia 
Gravis: A Phase II Trial of Rituximab in 
Myasthenia Gravis 
 
Richard J. Nowak, MD, MS 
Yale University School of Medicine  
Protocol Principal Investigator 
 
Christopher S. Coffey, PhD 
University of Iowa Data Coordinating Center 
Principal Investigator 
 
Merit E. Cudkowicz, MD 
Massachusetts General Hospital Clinical Coordinating Center 
Principal Investigator 
 
 
VERSION 1.0 
November 17, 2017 
 
        
 
 
 
 


2 
 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
NN103 
[BEAT MG: B Cell Targeted Treatment in Myasthenia Gravis: A Phase II Trial of Rituximab in 
Myasthenia Gravis] 
 
 
Principal Investigator Approval 
 
 
 
Signature: ____________________________________ Date: __________________ 
Name: 
 
Richard J. Nowak, MD, MS 
 
 
NeuroNEXT Clinical Coordinating Center Approval 
 
 
 
Signature: ____________________________________ Date: __________________ 
Name: 
 
Merit Cudkowicz, MD 
 
 
NeuroNEXT Data Coordinating Center Approval 
 
 
 
Signature: ____________________________________ Date: ___________________ 
Name: 
 
Christopher S. Coffey, PhD 
 


3 
 
PREFACE 
This Statistical Analysis Plan (SAP) describes the planned analyses for the NeuroNEXT NN103 
(BEAT MG) study [National Institute of Neurological Disorders and Stroke (NINDS) grant # 
U01NS084495]. The planned analyses identified in this SAP are intended to support the completion 
of the Final Study Report (FSR) and will be included in regulatory submissions and/or future 
manuscripts. All final, planned analyses identified in this SAP will be performed only after the last 
randomized subject has completed the full 52 week study period. Once all week 52 data have been 
cleaned and verified, a “locked” version of the data will be used for reporting the final study results. 
Key statistics and study results will be made available to the Protocol Principal Investigator (PPI) 
following database lock and prior to completion of the final FSR. It is important to recognize that this 
SAP only applies to the primary 52 week study. Additional exploratory analyses added to the protocol 
as part of the extended follow-up study will be reported separately.  
1. STUDY DESIGN 
A previous study conducted at Yale demonstrated that 82% of subjects who received rituximab 
achieved at least a 75% reduction in their prednisone dose at 52 weeks (95% CI: 48%-98%). This 
study follows up on that finding with a multicenter randomized, double-blind, placebo controlled phase 
II clinical trial evaluating the safety and steroid-sparing effect of rituximab in MG utilizing a futility 
design. The specific primary objective of this study is to determine whether rituximab is a safe and 
beneficial therapeutic for MG that warrants further study in a phase III efficacy trial. The primary 
clinical endpoint will be the steroid sparing effect of rituximab, and the primary objective will be 
accomplished using a futility design which tests the hypothesis that subjects treated with rituximab will 
achieve at least an absolute 30% increase in the frequency of favorable responses (Levin, 2012). If 
“futility” is declared, then the results would imply that it is not cost effective to conduct a future phase 
III trial with this agent. If “futility” is not declared, then the study would suggest that there could be a 
potentially clinically meaningful effect of rituximab which should be explored in a larger, phase III 
follow-up study. 
The study will enroll 50 AChR antibody positive generalized MG subjects, with subjects randomized in 
a 1:1 manner to receive either rituximab or placebo (25 per group). Each previously diagnosed 
generalized MG subject will be expected to be on a stable dose of prednisone (minimum dose of 15 
mg/day) for at least 4 weeks (28 days) with stable symptoms at the time of enrollment. There will be 
two groups of standard of care treatment regimens allowed into the study: 
 Prednisone Only 
 Prednisone + Another IST: The subject must be on a stable dose for at least 6 months prior to 
baseline on one of the following IST: azathioprine, mycophenolate mofetil, cyclosporine, 
tacrolimus, or methotrexate 
Subjects on pyridostigmine must be on a stable dose of ≤ 480 mg/day for a minimum of 2 weeks prior 
to the Screening Visit. Subjects must remain on a stable fixed dose for the duration of the study. The 
dose cannot be changed after study entry. 
For the main study, subjects will be followed for 52 weeks. The study period of 52 weeks was chosen 
based on the delayed benefits observed following rituximab treatment, and in the setting of utilizing a 
two-cycle protocol. In order to assess safety in the B cell recovery period, as well as assess the long-
term durability of response, there are two additional optional observational off study-intervention time 
points (weeks 72 & 96 – extended study follow-up). 
The treatment group will receive a total of two cycles of rituximab (375mg/m2 IV) separated by 6 
months. Each cycle is defined as one infusion per week for four consecutive weeks. As such, cycle 1 


4 
 
will be administered weeks 0-3 and cycle 2 will be given at weeks 24-27. The placebo group will 
receive an infusion that contains only the vehicle components of the rituximab solution. 
A predetermined, forced steroid taper schedule for both treatment (rituximab) and placebo groups will 
begin at the week 8 visit. At every 4-week assessment thereafter, the MGC score will be calculated, 
confirmed, and available during the study visit in order to make the steroid dose adjustment. 
Prednisone dose will be lowered following confirmation of clinical improvement or stable symptoms 
based on the MGS score (current MGC score is ≤ 2 points above the baseline visit or MGC score at 
the prior study visit). If the MGC score change is ≥ 3 points above the baseline visit score, the taper 
will be stopped the prednisone dose increased until symptoms resolve or are at least are stabilized to 
baseline status (baseline visit MGC score). If the MGC score is ≤ 2 points above the baseline visit 
score, but has increased ≥ 3 points from the MGC score at the previous study visit, the taper will be 
stopped and prednisone dose will either be held or increased (at the discretion of the Site 
Investigator). Once symptoms stabilize (MGC score is the same or less than the baseline visit score 
and ≤ 2 points above the prior study visit), the prednisone taper can again be resumed at the next 
scheduled assessment. If the Site Investigator does not taper per protocol, this will be recorded as a 
protocol deviation and will be corrected immediately. As this is linked with primary outcome, we 
wanted to make the decision on lowering the dose as objective as possible. A mechanism will be put 
in place to double check the MGC score calculation made at the visit, and whether or not the 
prednisone adjustment was made correctly. The dose of prednisone taken will be record by each 
subject daily and collected at each evaluation. 
Subjects will have clinical evaluations at baseline and then every 4 weeks thereafter (week 4, 8, 12, 
16, 20, 24, 28, 32, 36, 40, 44, 48, 52). Clinical evaluations will be completed by a blinded evaluator. 
The dose of prednisone will be recorded by each subject daily and collected at each scheduled 
assessment. Post-intervention status will be assessed by measuring MGFA class, Myasthenia Gravis 
Composite (MGC), Quantitative Myasthenia Gravis (QMG), MG-Activities of Daily Living (MG-ADL), 
and MG-Quality of Life (MG-QOL) scores. Blood will be collected for safety, specialized and other 
studies at scheduled time points. Adverse effects will be monitored at each visit to assess safety and 
tolerability in this subject population per the NINDS Guidelines for Data and Safety Monitoring in 
Clinical Trials and Genentech guidelines. 
If subject symptoms significantly worsen during the course of the trial and are not controlled by 
increased steroid doses (high dose prednisone), the subject can receive PLEX or IVIg as a rescue 
therapy. Subjects that could not be managed with steroids, IVIg, or PLEX and required additional 
immunotherapy (e.g. pulse IV steroids, azathioprine, etc.) would be considered treatment failures and 
likely withdrawn from the study. 
1.1. Primary Outcomes 
Primary Objective 1 – Steroid Sparing Effect: Percent of subjects that achieve a ≥75% 
reduction in mean daily prednisone dose in the 4 weeks prior to week 52 and with clinical 
improvement or no significant worsening of symptoms (≤ 2 point increase in MG composite 
score) as compared to the 4-week period prior to randomization and initiation of treatment. 
Primary Objective 2 - Safety: Percentage of subjects with treatment-related adverse events. 
1.2. Major Secondary Objective 
The main secondary objective is to evaluate whether there is a trend towards clinical benefit at the 
end of the 52 week treatment period, as measured by MG-specific clinical outcome scales used as 
endpoints in prior clinical trials: 
(1) Myasthenia Gravis Composite (MGC) Score  
(2) Quantitative Myasthenia Gravis (QMG) Score  


5 
 
The clinical evaluators who determine the MGC & QMG will be blinded to treatment assignment. If 
successful, measures studied would lay the groundwork toward optimizing the design of a 
subsequent phase III efficacy trial of rituximab in MG. 
2. PRIMARY ENDPOINTS 
2.1. Prednisone Reduction 
The first primary outcome measure for this study is the percent of subjects achieving a ≥ 75% mean 
daily prednisone reduction in the four weeks prior to week 52 (week 49-52) along with clinical 
improvement or no significant worsening of symptoms (≤2 point increase in MG composite score), as 
compared to the four week period prior to randomization. The primary endpoint will be a binary indicator 
of whether the subject achieved the definition above. The prednisone-sparing aspect of the endpoint 
will be computed by comparing the mean daily prednisone dose (per the protocol defined taper) during 
the four week period prior to randomization versus the four week period at the end of the study (weeks 
49-52). For subjects that had their prednisone dose changed after the week 48 visit, or who missed 
their week 48 visit, the primary endpoint will be determined by comparing the prednisone dose reported 
at baseline to the last prednisone dose recorded prior to the week 52 visit. The MGC aspect of the 
endpoint will be computed by comparing the MGC obtained at baseline to the MGC obtained at the 
week 52 visit. For the primary analysis, we will take a conservative approach and impute an outcome 
of “failure” for any subject that either terminates the study early, for whom the prednisone dose in the 
last 4 weeks is unknown, or for whom the week 52 MGC score is missing. 
2.2. Safety 
The second primary outcome will assess the safety profiles of rituximab vs. placebo. Primary interest 
involves an examination: 
 Treatment-related adverse events (AEs) 
 Treatment-related serious adverse events (SAEs) 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or 
not considered drug related. Examples of AEs include new conditions, worsening of pre-existing 
conditions, clinically significant abnormal physical examination signs (i.e. skin rash, peripheral edema, 
etc), or clinically significant abnormal test results (i.e. lab values or vital signs). Stable chronic 
conditions (i.e. diabetes, arthritis) that are present prior to the start of the study and do not worsen 
during the trial are NOT considered AEs. Chronic conditions that occur more frequently (for 
intermittent conditions) or with greater severity, would be considered as worsened and therefore 
would be recorded as AEs. 
AEs are generally detected in two ways: 
 Clinical → Symptoms reported by the subject or signs detected on examination 
 Ancillary Tests → Abnormalities of vital signs, laboratory tests, and other diagnostic 
procedures 
All AEs should be reported within 5 working days / 7 calendar days of the site learning of a new AE. 
Similar timelines apply for reporting upon receipt of any updates for previously reported AEs. If 
discernible at the time of reporting, a specific disease or syndrome rather than individual associated 
signs and symptoms should be identified by the Site Investigator and recorded as an AE. However, if 
an observed or reported sign, symptom, or clinically specific disease or syndrome, then it should be 
recorded as a separate AE. Clinically significant laboratory abnormalities, such as those that require 
intervention, are those that are identified by the Site Investigator. 


6 
 
The study will utilize the CTCAE version 4.0 coding system for AE recording. AEs reported using 
CTCAE will be recoded into MedDRA terms by the DCC. 
For the purposes of this study, a treatment-related AE (also referred to as an Adverse Drug Reaction) 
is defined as any noxious or unintended response to a medicinal product related to any dose. The 
phrase “responses to a medicinal product” means that a causal relationship between a medicinal 
product and an AE is at least a reasonable possibility, i.e., the relationship cannot be ruled out. 
Therefore, a subset of AEs can be classified as treatment related if there is thought to be a causal 
relationship to Rituximab. At the time of reporting, the relationship of the AE to the investigational 
product should be specified by the Site Investigator using the following definitions: 
 Definitely Related: The reaction follows a reasonable temporal sequence from administration of 
investigational product; that follows a known or expected response pattern to the investigational 
product; and that is confirmed by improvement on stopping or reducing the dosage of the 
investigational product, and reappearance of the reaction on repeated exposure (suspected 
treatment related AE or ADR) 
 Probably Related: The reaction follows a reasonably temporal sequence from administration of 
investigational product; is confirmed by discontinuation of the investigational product or by re-
challenge; and cannot be reasonably explained by the known characteristics of the subject’s 
clinical state (suspected treatment related AE or ADR) 
 Possibly Related: The reaction follows a reasonably temporal sequence from administration of 
the investigational product and follows a known response pattern to the suspected 
investigational product; the reaction could have been produced by the investigational product or 
could have been produced by the subject’s clinical state or by other modes of therapy 
administered to the subject (suspected treatment related AE or ADR) 
 Unlikely to be Related: The reaction has little or no temporal sequence from administration of 
the investigational product, and/or a more likely alternative etiology exists 
 Not Related: Concomitant illness, accident, or event with no reasonable association with 
treatment 
As this is a double-blind study, the causality assessment should be made under the assumption that 
the subject is receiving active study medication. If considering unblinding, this assessment should be 
made prior to unblinding to avoid bias. 
An AE is considered serious if it meets one or more of the following criteria: 
 Results in death 
 Is life-threatening (i.e., poses an immediate risk of death as the event occurred) 
 Requires inpatient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability or incapacity 
 Results in a congenital anomaly or birth defect in the offspring of the subject (whether the subject 
is male or female) 
 Necessitates medical or surgical intervention to preclude permanent impairment of a body 
function or permanent damage to the body structure 
 Important medical events that may not result in death, are not life-threatening, or do not require 
hospitalization may also be considered SAEs when, based on appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed above. Examples of such medical events include blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 


7 
 
An inpatient hospital admission in the absence of a precipitating, treatment-emergent, clinical AE may 
meet criteria for “seriousness” but is not an adverse experience, and will therefore not be considered 
an SAE. An example of this would include a social admission (subject admitted for reasons other than 
medical, e.g. lives far from the hospital, has no place to sleep). The Site Investigator is responsible for 
initially classifying AEs as serious or non-serious. SAEs must be reported using the OEARS within 24 
hours of the site learning of the SAE. 
Dr. Michael Shy will serve as the Medical Safety Monitor (MSM) for this trial. Dr. Shy will work closely 
with the DCC, and will use the online AE reporting system to review all SAEs in near real time and 
evaluate them to identify the need for timely intervention. For any reported SAEs, an automatic email 
will be sent to Dr. Shy to prompt a review of the event for determination of whether the event meets the 
criteria for an SAE and, if so, whether the SAE is unanticipated and/or related to study drug. An 
unexpected SAE is any SAE for which the specificity or severity is not consistent with the current 
Investigators Brochure or package insert described in the protocol. An unexpected and treatment-
related SAE is an unexpected SAE that, in the opinion of the MSM, has a reasonable possibility that 
the investigational product caused the event. With the assistance of the coordinators at the DCC, Dr. 
Shy has the option of requesting additional information about any SAE. He will complete a form for 
each review, and this information will be entered into the online data entry system. 
Thus, in summary, the determination of whether an AE or SAE is treatment-related (at least possibly 
related to treatment) differs. Because the MSM only reviews SAEs in real-time, the determination of 
whether or not a non-serious AE is considered treatment-related will be made at the site level. However, 
for SAEs, the MSM determination of whether or not an SAE is treatment-related will take precedent 
over the classification at the site level.  
3. MAJOR SECONDARY ENDPOINTS 
3.1. Myasthenia Gravis Composite Score (MGC) 
The Myasthenia Gravis Composite (MGC) score is a validated, patient- and physician-reported 10-
item assessment tool for evaluating the symptoms and signs of MG. Physician assessment includes 
evaluation for ptosis (upward gaze), double vision on lateral gaze, eye closure, neck flexion or 
extension, should abduction, and hip flexion. Patient assessment includes self-report of impact 
(normal, mild, moderate, or severe) and is additionally weighted for clinical significance. Total score 
ranges from 0 to 50, with higher scores indicating a greater impact of MG on functional activities. A 
three point change is considered clinical meaningful. This brief assessment takes approximately 10 
minutes to complete (Burns et al, 2008; Burns et al, 2010; Burns, 2012; Sadjadi et al, 2012). 
3.2. Quantitative Myasthenia Gravis Score (QMG) 
The QMG score is a validated, physician-reported 13-item disease-severity assessment tool. It 
evaluates muscle strength based on quantitative testing of sentinel muscle groups: ocular (two items), 
facial (one item), bulbar (two items), gross motor (six items), axial (one item), and respiratory (one 
item). Each item is graded on a scale of 0 to 3, with 3 being the most severe. Total score ranges from 
0 to 39, with higher scores representing greater disease burden. A 3-point improvement in total score 
considered a clinically meaningful improvement. This assessment takes 30-40 minutes to complete, 
and is the most widely used tool in MG trials (Barohn et al, 1998). 
4. ENROLLMENT & RANDOMIZATION 
Subjects who meet the eligibility criteria and have given their consent will be randomized to one of the 
2 treatment arms. Randomization will be performed through an interactive website, and will be 
stratified based on the steroid dose at baseline [moderate dose prednisone (15-35 mg/day) vs. high 
dose prednisone (>35 mg/day)] and treatment regimen at the baseline visit [prednisone only vs. 


8 
 
prednisone plus another immunosuppressive therapy (IST)]. Subjects will be assigned a study ID at 
the time of enrollment. The study ID includes the identification of the clinical study site and a unique 
subject ID. The DCC will generate a randomization table for each of the strata using a permuted block 
design with random block sizes. 
5. PRELIMINARY TABLULATIONS 
All subjects who provide informed consent will be accounted for in this study. Regularly generated 
enrollment reports will describe: 
 Number of subjects consented, eligible, and randomized by site 
 Ongoing study status of all randomized subjects 
 Reasons for ineligibility 
 Protocol deviations 
 Early study terminations 
The data set will also be summarized by treatment group with respect to important confounders. The 
distributions of categorical variables will be tabulated by treatment group and overall. Continuous 
variables will be summarized as mean, median, standard deviation, minimum, and maximum by 
treatment group and overall. Variables to be collected will include:  
 Gender 
 Race 
 Ethnicity 
 Age 
 Baseline Prednisone Dose (mg/day) 
 Baseline Myasthenia Gravis Composite Score (MGC) 
 Baseline Quantitative Myasthenia Gravis Score (QMG) 
 Baseline MG-Activities of Daily Living Score 
 Baseline MG-Quality of Life Score (MG-QOL) 
 Baseline MGFA Clinical Classification Grade 
 Hand Preference 
 Thymectomy Results 
6. ANALYSIS POPULATIONS 
Due to the exploratory nature of this study, all analyses to address the primary and major secondary 
objectives will be conducted at the 0.10 significance level. All analyses will be implemented using an 
intent-to-treat approach. Any subject who received a random treatment assignment will be included in 
all analyses. 
7. PRIMARY EFFICACY ANALYSES 
7.1 Primary Futility Hypothesis: Subjects treated with rituximab will have at least a 30% absolute 
increase in the frequency of achieving at least a 75% reduction in mean daily prednisone dose 
with maintenance of minimal or no symptoms. 
The primary futility hypothesis being tested in this trial is that subjects treated with rituximab will achieve 
at least an absolute 30% increase in the frequency of favorable responses. Assuming a placebo 
response rate of 40% (as in the original sample size calculations – see section 9), this corresponds to 


9 
 
an odds ratio of 3.5. Therefore, the primary futility hypothesis will be assessed using a logistic 
regression model, adjusted for the two stratification variables, to estimate the log-odds of primary 
endpoint success in each group. The logistic regression model used for these purposes is stated here: 
logit(Yi) = β0 + β1X1i + β2X2i + β3X3i  
where  
 Yi represents the binary variable indicating whether or not the ith subject met the primary 
outcome requirement of a 75% or greater reduction in prednisone dose, with no significant 
worsening of symptoms (≤2 point increase in MG composite score at baseline) 
 X1i is an indicator variable for prednisone dose at baseline (=0 if moderate, =1 if high)  
 X2i is an indicator variable for treatment status at baseline (=0 if prednisone alone, =1 if 
prednisone plus IST)  
 X3i is an indicator variable for whether the ith subject was randomized to the Rituximab group 
(=0 if placebo, =1 if rituximab) 
Correspondingly, the primary futility hypothesis of interest can be assessed by performing the following 
hypothesis test: 
H0: exp(β3) ≥ 3.5 vs. HA: exp(β3) < 3.5 
Results will be summarized in the following tables (number and percent of primary endpoint success 
are displayed in Table 7.1; Odds ratios and confidence intervals are displayed in Table 6.2). 
Table 7.1: Number and Percent of Primary Endpoint Success 
Treatment Group 
Number in each 
group 
Number and 
Percent of 
Success 
Number and 
Percent of Failure 
Number missing 
Rituximab 
xx 
xx (xx%) 
xx (xx%) 
xx 
Placebo 
xx 
xx (xx%) 
xx (xx%) 
xx 
Table 7.2: Odds-ratios of Primary Endpoint Success 
Comparison 
Odds-ratio 
(1-sided 90% CI) 
p-value 
Rituximab vs. Placebo 
xx.x (xx.x, xx.x) 
x.xx 
Rejecting the null hypothesis suggests ‘futility’ in the sense that it appears unlikely that conducting a 
future phase III clinical trial would lead to a significant effect with a magnitude at least as large as the 
specified clinically meaningful effect of interest. If we don’t reject the null hypothesis, this would provide 
justification for proceeding to examine the superiority hypothesis, with the magnitude of the estimate 
and confidence intervals surrounding β3 providing information helpful for planning the future phase III 
trial. 
Due to randomization, it is unlikely that important covariates will be imbalanced in this study. However, 
given the small sample size, this cannot be dismissed. We will assess for important baseline 
imbalances, and if any imbalances exist, we will conduct sensitivity analyses to examine the impact on 
the results when the relevant covariate(s) are added to the logistic regression model. 
7.2 Primary Safety Hypothesis: There will be no increase in adverse experiences for the rituximab-
treated vs. placebo subjects. 
As described elsewhere, general assessments of safety will occur throughout the trial in conjunction 
with the medical safety monitor. The primary assessment of safety will compare the percentage of 
subjects in each group with: 


10 
 
 Treatment-related adverse events (AEs) 
 Treatment-related serious adverse events (SAEs) 
This hypothesis will be assessed in two ways. First, the percentage of subjects who experience any 
treatment-related AE or SAE (overall and by MedDRA system organ class) in each group will be 
compared using a Fisher’s exact test. If the null hypothesis is rejected, with a greater frequency 
observed in the rituximab group, we will conclude that rituximab was associated with a significantly 
greater frequency of treatment-related AEs. If the hypothesis is not rejected, we will conclude that the 
study does not provide sufficient evidence to conclude that rituximab was associated with a 
significantly greater frequency of treatment-related AEs. If there are significant differences between 
groups within any specific SOC, then additional tests will compare differences across groups for 
specific MedDRA preferred terms in order to further explore the cause of observed differences. 
In addition to the comparison of percentages in the manner described above, the rates of treatment-
related AEs in each group will be compared using the following Poisson regression model: 
log ൬ܻ௜
ܶ௜
൰ൌߚ଴൅ߚଵݔଵ௜൅߳௜ 
where 
 Yi represents the number of treatment related AEs experienced by the ݅௧௛ subject. 
 Ti represents the number of days between the date of randomization and the date of last 
follow-up for the ith subject. 
 x1i = 1 if ith subject was randomized to rituximab, and 0 if the subject was randomized to 
placebo group 
 ߳௜ is random error for the ݅௧௛ subject 
To determine if the rate of treatment related AEs differ across treatment group we will test the 
following hypothesis: 
Ho: β1 = 0 vs. HA: β1 ≠ 0 
If the null hypothesis is rejected, the direction of β1 will indicate the direction of the observed effect. 
Values of β1 > 0 indicate an increased rate of treatment-related AEs associated with the rituximab 
group, while values of β1 < 0 indicate a decreased rate of treatment-related AEs associated with the 
rituximab group. 
Treatment-related SAEs will be analyzed in the same manner described above. Additional safety 
analyses will assess all treatment-emergent AEs, treatment-emergent SAEs, unanticipated SAEs, 
and treatment-related & unanticipated SAEs in a similar manner. 
8. IMPACT OF MISSING DATA 
The primary analysis will follow the intent-to-treat (ITT) paradigm. All enrolled subjects must be 
included in the primary ITT analysis, and will be analyzed in the treatment group to which they were 
initially randomized. As such, it will be critically important to minimize the occurrence of missing data. 
Obviously, the optimal strategy for dealing with missing data is to make every effort to obtain 
complete data during the conduct of the study. Our team of data managers and protocol coordinators 
will work diligently and use a variety of methods in order to minimize the percentage of missing data 
in this trial. Nevertheless, there is likely to be a small percentage of missing data. As specified above, 
we will take a conservative approach for the primary analysis and impute an outcome of “failure” for 
any subject that either terminates the study early, for whom the prednisone dose in the last 4 weeks 
is unknown, or for whom the week 52 MGC score is missing. We then propose a series of sensitivity 


11 
 
analyses to further assess the potential dependence of the results of the primary analysis on these 
missing values. This sensitivity analysis will employ multiple methods: 
 Using Only Observed Data: Use only subjects who completed the study, for whom the 
prednisone dose in the last 4 weeks was known, and for whom the week 52 MGC score is 
known. 
 Tolerability/Imputation: For all additional sensitivity analyses, all subjects who terminated 
from the study due to an AE or had clinical worsening (an MGC score >2 above baseline) at 
the time of termination will be considered “failures”. For remaining subjects with missing data 
due to other reasons (lost to follow-up, discontinuation for reasons other than AE, etc.), 
outcomes will be imputed using a variety of methods 
o Last Observation Carried Forward: Last known prednisone dose status at the time of 
termination will be carried forward and used for the endpoint determination for these 
subjects 
o Multiple Imputation: For simplicity, we assume subjects requiring imputation will not 
have had clinical worsening had they stayed in the study. Thus, the imputation is 
focused solely on the missing prednisone dose information. To implement this multiple 
imputation model, we will impute week 52 prednisone dose data using a multiple 
imputation model based on the prednisone dose strata and treatment status at baseline, 
as well as prednisone dose data computed at each intermediate time point for all 
subjects with observed data. Imputed values will be derived using the MCMC method 
with multiple chains, adequate burn-in iterations, and a non-informative prior 
distribution. Once the imputed prednisone dose data have been obtained, the binary 
outcome variable will be generated for all subjects and fit using the same model 
described in section 6.1. We will conduct five separate iterations, and the mean of the 
parameter estimates from the five imputed data sets will be used as the estimate for the 
final analysis. Variances for the primary parameter estimate will be estimated using 
standard formulas as a function of within imputation and between imputation variable 
(Little & Rubin, 2002). 
o Best-case scenario: Assume all subjects missing prednisone dose information during 
the last 4 weeks, or missing a week 52 MGC score, in the rituximab group are 
“successes” (did achieve ≥ 75% dose reduction); Assume all subjects missing 
prednisone dose information during the least 4 weeks, or missing a week 52 MGC 
score, in the placebo group are “failures” (did not achieve ≥ 75% dose reduction).  
o Worst-case scenario: Assume all subjects missing prednisone dose information during 
the last 4 weeks, or missing a week 52 MGC score, in the rituximab group are “failures” 
(did not achieve ≥ 75% dose reduction); Assume all subjects missing prednisone dose 
information during the last 4 weeks, or missing a week 52 MGC score, in the placebo 
group are “successes” (did achieve ≥ 75% dose reduction) 
Results will be reported from both the primary analysis and all sensitivity analyses in order to inform 
how robust the overall trend observed in the study is to the missing data. For example, if the final 
analysis suggests a non-futile study, future researchers might be more comfortable proceeding to a 
phase III study if that finding of non-futility is also supported by the majority of the sensitivity analyses. 
On other hand, if a primary finding of non-futility is not supported by the sensitivity analyses, further 
exploration of the data might be needed prior to embarking on a future phase III trial. These results 
will be displayed in the following table:  


12 
 
Table 8.1: Number and Percent of Subjects Meeting Primary Endpoint w/ Odds Ratios & One-Sided 90% CIs 
Imputation Method 
 
Reduction in mean daily prednisone dose 
≥ 75% 
 
 
 
Odds Ratios 
(1-Sided 90% CI) 
Rituximab vs. Placebo 
Rituximab 
N (%) 
Placebo 
N (%) 
Primary 
xx (xx.x%) 
xx (xx.x%) 
x.xx (x.xx, x.xx) 
Observed 
xx (xx.x%) 
xx (xx.x%) 
x.xx (x.xx, x.xx) 
Last Observation Carried Forward 
xx (xx.x%) 
xx (xx.x%) 
x.xx (x.xx, x.xx) 
Multiple Imputation 
xx (xx.x%) 
xx (xx.x%) 
x.xx (x.xx, x.xx) 
Best Case 
xx (xx.x%) 
xx (xx.x%) 
x.xx (x.xx, x.xx) 
Worst Case 
xx (xx.x%) 
xx (xx.x%) 
x.xx (x.xx, x.xx) 
9. MAJOR SECONDARY ANALYSES 
The secondary objective of the study is to evaluate whether there is a trend towards clinical benefit as 
measured by MG-specific clinical outcome scales used as endpoints in prior clinical trials. 
Specifically, we will determine if rituximab can significantly improve the scores of the following MG-
specific clinical outcome measures: 1) Myasthenia Gravis Composite (MGC), and 2) Quantitative 
Myasthenia Gravis (QMG). These studies measures would lay the groundwork towards optimizing the 
design of a subsequent phase III efficacy trial of rituximab in MG. 
9.1. Major Secondary Objective #1 – Myasthenia Gravis Composite: Rituximab-treated subjects 
will have clinically significant improvement in their Myasthenia Gravis Composite (MGC) scores at 
the end of the 52 week treatment period. 
The first secondary hypothesis assesses the change in MGC scores at the end of the 52 week study 
period. This objective will be assessed longitudinally comparing the final score at the end of the study 
to the score obtained at baseline. The outcome will be defined as the change from baseline to week 
52 in the MGC. This hypothesis will be assessed using a linear regression model, adjusted for 
baseline MGC score. For example, the following model will be fit to these data: 
 
Yi = β0 + β1X1i + β2X2i + β3X3i + β4X4i 
 
where 
 Yi represents the change from baseline in the MGC score for the ith subject 
 X1i is an indicator variable for prednisone dose at baseline (=0 if moderate, =1 if high) 
 X2i is an indicator variable for baseline treatment (=0 if prednisone alone, =1 if prednisone plus 
IST)  
 X3i is the baseline MGC score for the ith subject 
 X4i is an indicator variable for whether the ith subject was randomized to the Rituximab group 
(=0 if placebo, =1 if rituximab) 
Correspondingly, the secondary hypothesis of interest can be assessed by performing the following 
test: 
H0: β4 = 0 vs. HA: β4 ≠ 0. 
 
 
 
 


13 
 
The results will be displayed in the following table 
Table 9.1: Change in MGC Scores from Baseline to 52 Weeks  
MGC Score 
Rituximab 
Placebo 
Model Adjusted 
Difference (90% CI) 
(52 week – baseline) 
Mean (SD) 
Min. – Max 
Missing 
 
xx (xx) 
xx – xx 
xx 
 
xx (xx) 
xx – xx 
xx 
 
xx.x (xx.x, xx.x) 
 
9.2. Major Secondary Objective #2 – Quantitative Myasthenia Gravis: Rituximab-treated subjects 
will have clinically significant improvement in their Quantitative Myasthenia Gravis (QMG) scores at 
the end of the 52 week treatment period. 
The second secondary hypothesis assesses the change in QMG scores over the course of the 52 
week study period. Because the only difference between this and the first secondary hypothesis is the 
choice of outcome, the analysis will proceed in the same manner described above for the first 
secondary hypothesis. 
9.3. Exploratory Analyses 
A number of additional exploratory analyses are also planned to monitor effectiveness as well as 
evaluate other endpoints that may be useful in optimizing future MG trial designs, but will not be 
included as part of the FSR. These additional analyses may include, but are not limited to: 
 Other Previously Validated MG-specific outcome measures 
o MG-Activities of Daily Living (MG-ADL) – This 8 point scale assesses the subject’s 
ability to perform daily activities (Wolfe et al, 1999). 
o MG-Quality of Life (MG-QOL) – The subject completes a 15-question questionnaire 
and reports the effect of MG on their quality of life (Burns et al, 2008). 
 Other Previously Used Measures of Steroid-Sparing Effect: 
o Mean daily prednisone dose at each scheduled assessment (every 4 weeks) 
o A delayed start of the area under the dose-time curve (AUDTC), starting at week 8 
o Percentage of subjects achieving a ≥ 50% mean daily prednisone reduction with 
maintenance of minimal or no symptoms in 4 weeks prior to week 52 
o Body mass index (screening visit and weeks 24 & 52) 
o HbA1C (screening visit and week 52) 
 MG Flare Rate (Failure of Therapy) 
o Percentage of subjects requiring rescue treatments (PLEX or IVIg) 
o Percentage of subjects requiring prednisone dose increase 
o Rate of subjects requiring prednisone dose increase 
o Percentage of subjects with a ≥ 3 point increase in the MGC score 
Additional exploratory analyses will be conducted as part of the extended follow-up study. The 
primary focus of the two observational off study-intervention time points (weeks 72 & 96) will be to 
assess B cell recovery/repopulation as a safety measure. Specifically, we will examine: (1) 
Percentage of subjects achieving normal B cell counts at weeks 72 & 96; and (2) Percentage of 
subjects returning to at least baseline (pre-treatment) B cell counts at weeks 72 & 96.  


14 
 
10. SAMPLE SIZE JUSTIFICATION 
Below, we introduce some key notation that we use to describe the analysis plan for the proposed 
trial: 
 Let pP represent the true (unknown) percentage of subjects treated with placebo who will 
achieve success on the primary endpoint 
 Let pR represent the true (unknown) percentage of subjects treated with rituximab who will 
achieve success on the primary endpoint 
Based on a prior study completed by Sanders et al (2008) on MMF in AChR+ MG, 38.6% of placebo 
treated case achieved a treatment response. The placebo start point was 34.1 mg prednisone; hence, 
38.6% of placebo recipients had a reduction of prednisone dose by at least 78%. Also the MMF start 
point was 30.7 mg prednisone; therefore, 44.3% of MMF recipients had a reduction of prednisone 
dose by at least 76%. Based on this information, we assume that 40% of placebo recipients will 
achieve a 75% or greater prednisone dose reduction (pP = 0.40). 
The design of this trial was somewhat restricted due to the fact that the company that produces 
rituximab only agreed to provide 25 doses to the investigators. As a consequence, this study required 
more of a sample size justification (for the sample size fixed by external factors) as opposed to a 
standard sample size calculation that determines the required sample size for a fixed target power. 
Using the notation above, the one-sided futility hypothesis that the treatment achieved the desired 
clinically meaningful level of interest may be stated as: 
H0: pR - pP ≥ 0.30 vs. HA: pR - pP < 0.30 
Therefore, rejecting the null hypothesis suggests ‘futility’ in the sense that it appears unlikely that 
conducting a future phase III clinical trial would lead to a significant effect with a magnitude at least as 
large as the specified clinically meaningful effect of interest. If we don’t reject the null hypothesis, this 
would provide one of the “go” conditions for conducting a future phase III study.  
The table below shows the power computed across a range of assumed values for the true response 
rate in the rituximab subjects. The calculations assume a type I error rate of 10%, pP = 0.40, and a 
conservative assumption of up to 20% missing data. The table below demonstrates the benefits of 
using the futility design. When the true success rate for rituximab is near or below the true success 
rate for placebo, the study will declare “futility” with high probability. Likewise, when the true success 
rate for rituximab is well above the true success rate for placebo, the study has a very low chance of 
incorrectly declaring “futility”. Given the sample size limitations mentioned above, we feel that this 
provides a reasonable chance of having a successful study – where “success” is defined as 
answering the main question of interest regarding whether there is clear evidence to rule out an effect 
of rituximab in this population, or to provide enough evidence to justify a larger trial in the future. 
Table 10.1: Power of Futility Test as a Function of True Rituximab Rate  
Rituximab 
Rate (pR)  
30%  
35%  
40%  
45%  
50%  
55%  
60%  
65%  
70%  
75%  
80%  
85%  
90%  
Pr (Futility)  
92%  
84%  
74%  
63%  
50%  
37%  
25%  
16%  
10%  
4%  
2%  
1%  
<1%  
11. SAFETY MONITORING 
The monitoring of subject safety and data quality will follow the NINDS Guidelines for Data and Safety 
Monitoring in Clinical Trials. Subjects will be monitored through regular physical examinations, vital 
signs, laboratory tests, and incidence and severity of adverse events. Infections will be treated 
symptomatically. Cardiovascular risk factors will be assessed prospectively by recording risk factors 
(e.g. family history, smoking history, and status). Additional safety evaluations will be conducted on 
conventional safety variables, such as adverse events, laboratory tests, and vital sign changes. In 


15 
 
addition, B cell counts, immunoglobulin levels, infusion-related reactions, and thromboses infections 
will be carefully examined. Tolerability will be determined by the ability to complete the study on the 
assigned experimental medication. 
11.1. Adverse Experience Reporting 
The adverse event (AE) definitions and reporting procedures for this study comply with all applicable 
United States FDA regulations and International Conference on Harmonization (ICH) guidelines. 
Adverse events will be reviewed and recorded at each study visit and infusion visit. Information on 
AEs of medication and on inter-current events will be determined at each visit by direct questioning of 
the subjects, clinical examination, and laboratory tests. The Site Investigator will carefully monitor 
each subject throughout the study for possible AEs. All AEs will be documented on CRFs designed 
specifically for this purpose. It is important to report all AEs, especially those that result in permanent 
discontinuation of the investigational product being studied, whether serious or non-serious. 
Subjects will be monitored for AEs from the time they sign consent until the Week 52 visit. All SAEs 
must be followed until resolution, or until the Week 52 Visit, whichever comes first. If the SAE is still 
ongoing at Week 52, it will be Resolved with Sequelae. 
 SAEs that are discovered less the 90 days prior to the Week 52 Visit will be followed until 
resolution or for a minimum of 90 days, whichever comes first, even if it is past the Week 52 
Visit. A repeat Termination Visit does not need to occur. 
 If a new SAE is discovered at the Week 52 Visit, it must be followed until resolution, or for a 
minimum of 90 days, whichever comes first. 
 Subjects that are withdrawn from the study or have intervention discontinued due to an SAE 
will have reduced follow-up. This will include being followed monthly via telephone or in person 
for a minimum of 90 days or until SAE resolution, whichever comes first, after which a 
Termination Visit will be conducted. The Termination visit will mirror the Week 52 Visit. 
o If the SAE is resolved within 90 days, the Termination Visit can occur earlier. 
o If the SAE is not resolved within 90 days, the SAE will be Resolved with Sequelae, and 
the Termination Visit will occur 
During the 90 day (or less) SAE follow-up period, no new AEs will be recorded. Existing AEs 
will be followed until resolution, or the Termination Visit, whichever comes first. 
During the optional week 72 & 96 visits, only those AEs that in the opinion of the investigator are 
deemed related to study procedures will be reported. 
Each Clinical Study Site Investigator and research team (co-investigators, research nurse, clinical trial 
coordinator) are responsible for identifying AEs, reporting them through the DCC Online Adverse 
Event Reporting System (OEARS), and determining the relationship of the AE to the study drug/study 
procedures (as described in section 2.2). Investigators are also responsible for complying with the 
NeuroNEXT Central IRB (CIRB) reporting requirements for all safety reports. Copies of each report 
and documentation of IRB notification and receipt will be kept in the investigator’s study file. 
For the purposes of this study, before randomization only those AEs (serious and non-serious) that, in 
the opinion of the investigator, are deemed related to study procedures will be reported. Non-serious 
adverse events that are reported to or observed by the investigator or a member of their research 
team will be submitted to the DCC in a timely fashion (within 5 working days / 7 calendar days). 
Investigators must report any SAE within 24 hours of learning of the event. Upon entry of an SAE by 
a site investigator, the DCC Online Adverse Event Reporting System (OEARS) will immediately notify 
the Medical Safety Monitor (MSM). The MSM will review the SAE report, and may request further 
information if necessary. The OEARS maintains audit trails and stores data and communication 
related to the review of any AE reported in the study. The MSM may determine that the SAE requires 


16 
 
expedited reporting to the FDA. For example, the Sponsor-Investigator are required to notify the FDA 
of any fatal or life-threatening AE that is unexpected and assessed by the MSM to be at least possibly 
related to the use of Rituximab. If expedited reporting is required, the DCC will prepare a MedWatch 
safety report for submission to the FDA and Genentech. If warranted, the MSM will notify the DSMB 
chair. The DSMB may suggest changes to the protocol or consent form to the PPI as a consequence 
of SAEs. 
11.2 Medical Safety Monitor 
As previously indicated, Dr. Michael Shy will serve as the MSM for this trial. In addition to performing 
real-time reviews of all SAEs (as described in section 2.2), Dr. Shy will also receive quarterly 
tabulations, by blinded treatment group, of all AEs/SAEs for the purpose of determining if any safety 
trends exist that may raise concerns. Aggregate reports, blinded by treatment group, will be provided 
by severity, attribution (anticipated or unanticipated), and relationship to study treatment. The 
percentage of subjects who experience any AE will be compared by body system across the two 
groups. The additional questions related to whether the AE/SAE is related to treatment and/or 
unanticipated will be used to subset these into a series of additional tables. The quarterly review will 
identify any disconcerting discrepancy in the frequency of any AE/SAE between the two groups. 
11.3 Data and Safety Monitoring Board 
A Data and Safety Monitoring Board (DSMB), appointed by the NIH/NINDS, will meet at 
approximately six-month intervals (or as determined by the NINDS) to review partially unblinded study 
data provided by the study statistician. The DSMB will periodically review and evaluate the 
accumulated data for participant safety, adverse events, study conduct, and study progress. The 
DSMB may suggest changes to the protocol or consent form to the Study Chair as a consequence of 
AEs. The DSMB may also make recommendations to NINDS concerning continuation, modification, 
or termination of the study. The frequency and format of DSMB meetings, reports, and guidelines for 
interim analysis will be agreed upon prior to study subject enrollment. 
11.4 Study Hold Rules (Safety) 
Individual study subjects may be withdrawn from the study medication, but continue to be followed for 
safety, if subjects develop a grade 3 or more suspected toxicity as graded by the National Cancer 
Institute’s (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 or an SAE 
related to study medication as determined by the MSM. Grade 3 adverse events are severe or 
medically significant, but not immediately life-threatening and may cause hospitalization or 
prolongation of hospitalization indicated. Descriptions of CTCAE grading criteria are included in the 
Manual of Operations and SAEs are specifically defined in section 2.2. Subjects will be allowed to 
resume participation in the study if their suspected toxicity or AE resolves completely, and in the 
judgement of the investigator and MSM it is safe for the subject to continue. 
12. INTERIM STOPPING RULES 
The study will be permanently stopped, and no further administration of rituximab will be given, if the 
investigator, CIRB, DSMB, and/or any other institutional or regulatory body deems it inappropriate for 
the study to resume due to a significant number of randomized subjects developing safety concerns 
that cannot otherwise be attributed to MG, infections, disease relapse, or pre-existent comorbidities 
as deemed by the MSM. 
 
 


17 
 
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