Conditions: Myasthenia Gravis, Generalized
Keywords: CFZ533, Myasthenia Gravis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 44
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate safety, tolerability, pharmacokinetics/pharmacodynamics and efficacy of CFZ533 as an add-on therapy to standard of care in patients with moderate to severe myasthenia gravis (MG).

Detailed description:

Arms:
arm 1: CFZ533 arm 2: Placebo

Interventions: intervention 1: Placebo intervention 2: CFZ533
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
CFZ533
Clinical Trial Protocol CCFZ533X2204
A multi-center, randomized, double-blind, 
placebo-controlled, parallel group study to preliminarily 
evaluate the safety, tolerability, pharmacokinetics and 
efficacy of CFZ533 in patients with moderate to 
severe myasthenia gravis
Document type:
Amended Protocol Version
EUDRACT number:
2015-000097-35
Version number:
v03 Clean (incorporating amendment 3)
Development phase:
IIa
Release date:
19-May-2016
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Personal Data


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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct.
Notification of serious adverse events
Refer to Section 9.2 of the protocol for definitions and reporting requirements for Serious 
Adverse Events (within 24 hours after awareness of the SAE to the local Novartis Drug Safety 
and Epidemiology Department and notify the Clinical Trial Leader.). 
Contact information is listed in the SOM. 


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Table of contents
Site Operations Manual (SOM)...........................................................................................2
Notification of serious adverse events.................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................6
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Pharmacokinetic definitions and symbols.........................................................................10
Protocol synopsis...............................................................................................................16
1
Introduction .......................................................................................................................20
1.1
Background............................................................................................................20
1.2
Study purpose ........................................................................................................26
2
Study objectives.................................................................................................................26
2.1
Primary objective(s)...............................................................................................26
2.2
Secondary objective(s)...........................................................................................27
3
Investigational plan ...........................................................................................................28
3.1
Study design...........................................................................................................28
3.2
Rationale for study design .....................................................................................29
3.3
Rationale for dose/regimen, duration of treatment................................................30
3.4
Rationale for choice of comparator .......................................................................31
3.6
Risks and benefits..................................................................................................32
4
Population..........................................................................................................................33
4.1
Inclusion criteria ....................................................................................................34
4.2
Exclusion criteria...................................................................................................35
5
Restrictions for Study Subjects .........................................................................................37
5.1
Contraception requirements...................................................................................37
5.2
Prohibited treatments.............................................................................................37
5.3
Dietary restrictions and smoking...........................................................................38
5.4
General restrictions................................................................................................38
6
Treatment...........................................................................................................................38
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6.1
Study treatment......................................................................................................38
6.1.1
Investigational treatment.......................................................................38
6.2
Treatment arms ......................................................................................................39
6.3
Permitted dose adjustments and interruptions of study treatment.........................39
6.4
Treatment assignment............................................................................................39
6.5
Treatment blinding.................................................................................................40
6.6
Emergency breaking of assigned treatment code ..................................................40
6.7
Treatment exposure and compliance .....................................................................40
6.8
Recommended treatment of adverse events ..........................................................41
6.9
Rescue medication.................................................................................................41
6.10
Concomitant treatment...........................................................................................41
7
Discontinuation and study completion ..............................................................................43
7.1
Discontinuation of study treatment........................................................................43
7.2
Study completion and post-study treatment ..........................................................43
7.2.1
Lost to follow-up...................................................................................44
7.3
Withdrawal of consent...........................................................................................44
7.4
Study stopping rules ..............................................................................................44
7.5
Early study termination..........................................................................................45
8
Procedures and assessments ..............................................................................................46
8.1
Informed consent procedures.................................................................................49
8.2
Subject demographics/other baseline characteristics.............................................49
8.3
Efficacy / Pharmacodynamics ...............................................................................50
8.3.1
Quantitative Myasthenia Gravis (QMG) score .....................................50
8.3.2
Myasthenia Gravis Composite (MGC) score........................................50
8.3.3
Quality of Life questionnaires...............................................................51
8.4.1
Physical examination ............................................................................51
8.4.2
Vital signs..............................................................................................52
8.4.3
Height and weight .................................................................................52
8.4.4
Laboratory evaluations..........................................................................52
8.4.5
Electrocardiogram (ECG) .....................................................................53
8.4.6
Pregnancy and assessments of fertility .................................................54
8.4.7
Other safety evaluations........................................................................54
8.5
Pharmacokinetics...................................................................................................55
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9
Safety monitoring ..............................................................................................................57
9.1
Adverse events.......................................................................................................57
9.2
Serious adverse event reporting.............................................................................59
9.2.1
Definition of SAE .................................................................................59
9.2.2
SAE reporting........................................................................................60
9.3
Liver safety monitoring .........................................................................................61
9.4
Renal safety monitoring.........................................................................................63
9.5
Pregnancy reporting...............................................................................................64
9.6
Early phase safety monitoring ...............................................................................64
10 Data review and database management.............................................................................65
10.1
Site monitoring ......................................................................................................65
10.2
Data collection.......................................................................................................65
10.3
Data Monitoring Committee..................................................................................66
10.4
Adjudication Committee........................................................................................66
11 Data analysis......................................................................................................................66
11.1
Analysis sets ..........................................................................................................67
11.2
Subject demographics and other baseline characteristics......................................67
11.3
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance)............................................................................................................67
11.4
Analysis of the primary variable(s) .......................................................................67
11.4.1
Variable(s).............................................................................................67
11.4.2
Statistical model, hypothesis, and method of analysis..........................67
11.4.3
Handling of missing values/censoring/discontinuations.......................68
11.4.4
Supportive analyses...............................................................................68
11.5
Analysis of secondary and exploratory variables ..................................................68
11.5.1
Efficacy / Pharmacodynamics...............................................................68
11.5.2
Safety.....................................................................................................70
11.5.3
Pharmacokinetics ..................................................................................70
11.6
Sample size calculation..........................................................................................72
11.7
Power for analysis of key secondary variables......................................................73
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12 Ethical considerations........................................................................................................74
12.1
Regulatory and ethical compliance........................................................................74
12.2
Responsibilities of the investigator and IRB/IEC..................................................74
12.3
Publication of study protocol and results...............................................................75
13 Protocol adherence ............................................................................................................75
13.1
Protocol Amendments ...........................................................................................75
14 References .........................................................................................................................76
Table 5-1
Prohibited treatments ............................................................................37
Table 6-1
Predefined tapering scheme ..................................................................42
Table 8-1
Assessment Schedule ............................................................................47
Table 9-1
Liver Event and Laboratory Trigger Definitions ..................................62
Table 9-2
Follow Up Requirements for Liver Events and Laboratory Triggers...62
Table 9-3
Specific Renal Alert Criteria and Actions.............................................64
List of figures
Figure 3-1
Study Design .........................................................................................29
Figure 11-1
Operating characteristics for the planned interim and final analyses ...73
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List of abbreviations
AChR
Acetylcholine Receptors
ADA
Anti-drug antibodies
ADCC
Antibody dependent cell mediated cytotoxicity
AE
adverse event
ALT
alanine aminotransferase
ALP
alkaline phosphatase
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BMI
Body Mass Index
BUN
blood urea nitrogen
CD-ROM
compact disc – read only memory
CDC
Complement dependent cytotoxicity
CFR
Code of Federal Regulation
CI
cholinesterase inhibitor
CI
confidence interval
CK
creatinine kinase
CRF
Case Report/Record Form (paper or electronic)
CRP
C-Reactive Protein
CTL
Clinical trial leader
CO2
carbon dioxide
CRO
Contract Research Organization
CSR
Clinical Study Report
CV
coefficient of variation
EC
Ethics committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
ELISA
Enzyme-linked immunosorbent assay
DLTs
dose limiting toxicities
FAS
full analysis set
FDA
Food and Drug Administration
AChR
Acetylcholine Receptors


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GCP
Good Clinical Practice
GLP
Good Laboratory Practice
γ-GT
Gamma-glutamyl transferase
h
hour
HIV
human immunodeficiency virus
IA
Interim Analysis
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IgG
Immunoglobulin G 
IgM
Immunoglobulin M 
IN
Investigator Notification
i.v. or IV
Intravenous
IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
intrauterine device
IUS
intrauterine system
KLH
keyhole limpet hemocyanin
LFT
Liver function test
LDH
lactate dehydrogenase
LLOQ
lower limit of quantification
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
MG
Myasthenia gravis
MG-ADL
Myasthenia Gravis Activities of Daily Living Scale 
MGC
Myasthenia Gravis Composite 
MG QOL-15
Myasthenia Gravis Quality of Life
ml
milliliter
MM
minimal manifestation
MMF
Mycophenolate mofetil
MPA
Mycophenolic acid
MuSK 
Muscle Specific Kinase
MuSK 
Muscle Specific Kinase
MPA
Mycophenolic acid


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nACHR
nicotinic acetylcholine receptor
NHP
non-human primate
NOAEL
No observed adverse effect level
PA
posteroanterior
PBMC
peripheral blood mononuclear cell
PD
pharmacodynamic(s)
PoC
Proof of Concept
PK
pharmacokinetic(s)
PT
prothrombin time
PTT
partial thromboplastin time
QMG
Quantitative Mysthenia Gravis
RA
Rheumatoid Arthritis
RBC
red blood cell(s)
REB
Research Ethics Board
SAE
serious adverse event
s.c. or SC
subcutaneous
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SD
standard deviation
solCD40
soluble CD40
SOM
site operations manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
total bilirubin
TE
thromboembolic events
TEG
thromboelastography
totCD40
total CD40 (free CD40 and bound CD40)
TTx
tetanus toxoid
ULN
upper limit of normal
ULOQ
upper limit of quantification
WBC
white blood cell(s)
wk
week
WHO
World Health Organization
totCD40
total CD40 (free CD40 and bound CD40)


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Pharmacokinetic definitions and symbols
AUCtau
The area under the plasma concentration-time curve from time zero to the 
end of the dosing interval tau [μg x day / mL]
AUCtau,ss
The area under the plasma concentration-time curve from time zero to the 
end of the dosing interval tau, at steady state [μg x day / mL]
Cav,ss
The average steady state plasma concentration during multiple dosing [μg / 
mL]
Cmax
The observed maximum plasma concentration following drug administration 
[μg / mL]
Cmax,ss
The observed maximum plasma concentration following drug administration 
at steady state [μg / mL]
Cmin,ss
The lowest plasma concentration observed during a dosing interval at steady 
state [μg / mL]
Tmax
The time to reach the maximum concentration after drug administration [day]


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Protocol synopsis
Protocol number
CCFZ533X2204
Title
A multi-center, randomized, double-blind, placebo-controlled, parallel group 
study to preliminarily evaluate the safety, tolerability, pharmacokinetics and 
efficacy of CFZ533 in patients with moderate to severe myasthenia gravis
Brief title
Safety, tolerability, pharmacokinetics and efficacy of CFZ533 in moderate to 
severe myasthenia gravis patients.
Sponsor and Clinical 
Phase
Novartis 
Phase IIa
Intervention type
Drug 
Study type
Interventional 
Purpose and rationale
This study is designed to preliminarily evaluate safety, tolerability, 
pharmacokinetics/pharmacodynamics and efficacy of CFZ533 as an add-on 
therapy to standard of care in patients with moderate to severe myasthenia 
gravis (MG). 
The results of this study will provide preliminary data to evaluate a further 
development of CFZ533 in the treatment of myasthenia gravis.
Primary Objective(s)
To evaluate the safety and tolerability of CFZ533 as an add-on therapy to 
standard of care in moderate to severe MG patients.
To evaluate the efficacy of IV CFZ533 as an add-on therapy to standard of 
care in patients with moderate to severe MG after 24 weeks of treatment. 
Secondary Objectives
To evaluate the efficacy of CFZ533 throughout the 24 weeks treatment period
and the decay in efficacy throughout the 24 weeks follow-up period.
To evaluate changes in patient’s quality of life (QOL) throughout 24 weeks 
the treatment period.
To evaluate the pharmacokinetics of CFZ533
To evaluate the pharmacodynamics of CFZ533
To assess immunogenicity of CFZ533
Study design
This is a randomized, double-blind, placebo controlled, non-confirmatory 
study in MG patients administered IV CFZ533 over a 24 weeks treatment 
period followed by other 24 weeks safety follow-up period.
Population
A total of approximately 44 male and female patients aged 18-85 (inclusive) 
years will be randomized in this study.
Inclusion criteria
Key inclusion criteria are listed:
Diagnosis of MG class IIa to IVa inclusive (Myasthenia Gravis Foundation of 
America Clinical Classification).
Quantitative Myasthenia Gravis (QMG) score of 10 or greater. If the QMG 
score is < 15 no more than 4 points may be derived from items 1 or 2 (ocular 
motility disturbance and ptosis).
Presence of acetylcholine receptor (AChR) or Muscle Specific Kinase (MuSK) 
autoantibodies based on medical history and confirmed by autoantibodies 
diagnostic test performed at screening.


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Inclusion criteria
(cont’d)
Only one immunosuppressant or immunomodulatory drug at a stable dose is 
allowed during the study (i) azathioprine and mycophenolate mofetil must be 
stable for at least 4 months prior to randomization (ii) cyclosporine must be 
stable for at least 3 months prior to randomization. 
If the patient is on oral corticosteroids, methotrexate or tacrolimus at 
screening, the dose must be stable for at least 1 month prior to 
randomization. 
If the patient is on cholinesterase inhibitors at screening, the dose must be 
stable for at least 2 weeks prior to randomization. 
Women of child-bearing potential, defined as all women physiologically 
capable of becoming pregnant, may be included in the study if they are using 
highly effective methods of contraception during the study and for 12 weeks
after study treatment. 
Exclusion criteria
Key exclusion criteria are listed:
MGFA grade I, IVb, or V disease.
Documented presence of unresected thymoma.
Patients having undergone thymectomy or thymo thymectomy (resection of 
thymoma) within 6 months of screening. 
Patients having received any of the following treatments prior to 
randomization:
IVIg or plasma exchange within 8 weeks; 
oral or IV cyclosphosphamide treatment within 3 months;
IV corticosteroid bolus (dose higher than 1 mg/kg) within 3 months;
belimumab within 6 months. For patients who received belimumab earlier, B 
cell count should be within normal range; 
rituximab within 12 months. For patients who received rituximab earlier, B cell 
count should be within normal range;
any other biologic or an investigational drug within 1 month or five times the 
half-life, whichever is longer.
Live vaccines within 4 weeks of study drug infusion.
Patients who are at significant risk for TE as judged by the investigator or 
have any one of the following:
History of either thrombosis or 3 or more spontaneous abortions with or 
without the presence of anti-cardiolipin autoantibodies;
Presence of prolonged partial thromboplastin time (PTT).
Investigational 
and 
reference therapy
CFZ533 10 mg/kg IV infusion 
CFZ533 matching placebo IV infusion 


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Efficacy/PD 
assessments
Efficacy assessments:
Quantitative Myasthenia Gravis (QMG) Score
Myasthenia Gravis Composite (MGC) Score
Quality of life questionnaires: MG-ADL and MG QOL-15
Pharmacodynamics assessments: 
Safety assessments
Physical examination
AEs 
Vital signs 
ECGs
Hematology, blood chemistry, urinalysis
Data analysis
Analysis methods
The primary efficacy variable is the change from baseline in QMG score after 
24 weeks of treatment (at week 25 visit). The changes from baseline in QMG 
scores during the treatment period will be analyzed using a Bayesian model 
for repeated measurements. The model may investigate effects for treatment 
(CFZ533 or placebo), time (visit week), baseline QMG score, treatment by 
time and baseline by time interactions. 
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Data analysis (cont’d)
The target efficacy will be reached if at the end of the study, there is at least 
90% probability that the difference between CFZ533 and placebo is ≥ 0 and 
50% probability that the difference between CFZ533 and placebo is ≥ 3.
The MGC composite is a key secondary endpoint. The changes from 
baseline in QMG scores at each visit of the treatment period (weeks 5, 9, 13, 
17, 21 and 25) will be analyzed using a Bayesian model for repeated 
measurements.
Key words
CFZ533, Myasthenia Gravis 


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1
Introduction
1.1
Background
Acquired myasthenia gravis (MG) is an autoimmune disease that leads to fluctuating muscle 
weakness and fatigue. In the most common cases, muscle weakness is caused by circulating 
antibodies that bind to acetylcholine receptors at the postsynaptic neuromuscular junction, 
inhibiting the excitatory effects of the neurotransmitter acetylcholine.
The disease incidence is 3-30 cases per million per year and rising, most likely as a result of 
increased awareness. The prevalence of MG in the USA is estimated to be between 100 and 
150 per million (Trouth et al 2012). In MG, muscle weakness ﬂuctuates with activity, and 
periods of rest offer only a temporary reprieve. The muscles that control eye and eyelid 
movement are particularly susceptible to weakness, but other muscles for chewing, talking, 
and swallowing are frequently involved. Patients may initially present with purely ocular MG, 
but this usually progresses to more severe, generalized disease with involvement of bulbar, 
axial, limb, and/or respiratory muscles (Trouth et al 2012).  It is important to distinguish MG 
from congenital myasthenic syndromes that can present with similar symptoms but are due to 
genetically determined defects in neuromuscular junction proteins, and do not respond to 
immunosuppressive treatments. 
In MG, the autoantibodies most commonly act against the nicotinic acetylcholine receptor 
(nAChR), the receptor at the motor end plate for the neurotransmitter acetylcholine that 
stimulates muscular contractions. A minority of antibodies has
specificity for the 
acetylcholine binding site and thereby directly impairs the ability of acetylcholine to bind to 
receptors. Others lead to the loss of functional receptors, either by complement fixation and 
focal lysis of the endplate region, or by inducing the muscle cell to eliminate the receptors 
through endocytosis (Ha and Richmond 2014).
MG is treated medically with acetylcholinesterase inhibitors or immunosuppressants, and in 
selected cases, thymectomy. There is a high medical need in MG, and the disease can be 
life-threatening. In myasthenic crisis, patients can develop acute respiratory failure, due to 
paralysis of the respiratory muscles. 
 
 
 
The use of corticosteroids and other immunomodulatory drugs (e.g., azathioprine, 
cyclosporine, and mycophenolate mofetil) have proven beneﬁcial for some patients in the 
management of this disorder; however, the majority of the MG patients develop an increased 
risk of infections and other long-term complications (Mehndiratta et al 2014), therefore there 
is a medical need for new treatments.
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Several lines of evidence suggest that inhibition of the CD40-CD154 co-stimulation pathway 
can be beneficial for the treatment of MG. In the majority of MG patients (85%), the 
production of pathogenic antibodies targeting muscle acetylcholine receptors (anti-AChR 
antibodies) is T cell dependent (Meriggioli and Sanders 2009). Most of these patients have 
thymic pathology usually in the form of hyperplasia, characterized by a hyper-proliferative 
thymus and ectopic germinal center formation with an activated B cell signature, including 
prominent CD40-CD154 signaling (Le Panse et al 2006). 
 
Risks and benefits of treatment with 
CFZ533 are outlined in Section 3.6
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1.2
Study purpose
This 
study 
is 
designed
to 
preliminarily 
evaluate 
safety, 
tolerability, 
pharmacokinetics/pharmacodynamics and efficacy of CFZ533 as an add-on therapy to 
standard of care in patients with moderate to severe myasthenia gravis (MG). 
The results of this study will provide preliminary data to evaluate a further development of 
CFZ533 in the treatment of MG. 
2
Study objectives
2.1
Primary objective(s)
Objective(s)
Endpoint(s)
To evaluate the safety and tolerability of IV
CFZ533 as an add-on therapy to standard of 
care in patients with moderate to severe MG 
throughout the study
!
AEs / SAEs
!
Vital signs and body measurements
!
ECGs
!
Hematology, blood chemistry, urinalysis.
To evaluate the efficacy of IV CFZ533 as an 
add-on therapy to standard of care in patients 
with moderate to severe MG
!
Mean change from baseline in the QMG 
Score for Disease Severity after 24 weeks
of treatment (primary endpoint).
!
Mean changes from baseline in the MGC 
Score for Disease Severity after 24 weeks
of treatment.
!
Proportions of patients requiring rescue 
therapy (i.e. IV immunoglobulins or 
plasma exchange).
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2.2
Secondary objective(s)
Objective(s)
Endpoint(s)
To evaluate the efficacy of IV CFZ533 using 
relevant MG related outcome measures
throughout the 24 weeks treatment period
To evaluate the decay in efficacy of IV 
CFZ533 using relevant MG related outcome 
measures throughout the 24 weeks follow-up 
period
!
Mean Change from baseline in QMG 
Score and MGC Score.
!
Proportion of patients with improvement 
by ≥ 3 points in QMG score.
!
Proportion of patients with worsening by 
≥ 3 points in QMG score.
!
Proportion of patients intolerant to steroid 
taper.
!
Proportion of patients who discontinued 
due to inefficacy or worsening.
To evaluate changes in patient’s quality of 
life (QOL) throughout the 24 weeks treatment 
period
Mean change from baseline in the MG-ADL
and MG QOL-15.
To evaluate the PK of 2-hour IV infusion of 
CFZ533 at 10 mg/kg administered q4w for 6 
doses
Free CFZ533 in plasma
To evaluate the PD of CFZ533 (CD40 
saturation on B cells, extent/duration of target 
engagement)
Free CD40 on B cells, total CD40 on B cells 
and total soluble CD40 in plasma 
To assess immunogenicity in CFZ533-treated 
patients and in placebo-treated patients (pre-
existing anti-drug antibodies).
Quantitative analysis of anti-CFZ533 
antibodies in plasma
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3
Investigational plan
3.1
Study design
This is a randomized double-blind,
placebo controlled, non-confirmatory study to
preliminarily evaluate the safety, tolerability, PK/PD, and efficacy of IV CFZ533 
administered every four weeks (q4w) over a 24 week treatment period in patients with 
moderate to severe MG. The investigational drug or placebo will be administered in addition 
to standard of care therapy for MG.
Patients should remain on their standard of care therapies and the dose should be maintained 
at a constant level during the study (Section 4.1 and Section 6.10). For patients that are 
receiving corticosteroids at baseline, a predefined steroid tapering will be allowed after 
achievement of minimal manifestations (MM) state (Jaretzki et al 2000). 
Patients on cholinesterase inhibitors (CI) should remain on stable doses throughout the study, 
but CIs should not be taken for at least 12 hours prior to QMG and MG composite testing at 
each visit, in order to reduce fluctuations in performance on functional tests due to the
temporary symptomatic effects associated with CI use.
For each patient, there will be two screening visits. Most of the screening assessments are 
done during Screening Visit 1 (Day -28 to Day -8), while Screening Visit 2 (Day -7 to Day -3)
is performed to collect a blood sample to allow laboratory results (chemistry, hematology, and 
pregnancy test, if applicable) to be available prior to randomization on Day 1. All laboratory 
results, including the MG autoantibodies diagnostic test performed at screening, must be 
available prior to dosing (Day 1-Visit 3) and meet eligibility criteria. Once continued 
eligibility is confirmed, patients will be assigned a randomization number at Day 1 and 
receive CFZ533 or placebo via a 2-hour intravenous infusion. Patients will be dosed every 
four weeks (q4w) according to their randomization for a total of 6 doses on Day 1 ± 2 
(Week 1), Day 29 ± 2 (Week 5), Day 57 ± 2 (Week 9), Day 85 ± 2 (Week 13), Day 113 ± 2 
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(Week 17) and Day 141 ± 2 (Week 21). The treatment period (24 weeks) will be followed by 
a safety follow-up period of other 24 weeks. The duration of the entire study including 
screening will be approximately 52 weeks.
An overview of the study design is given in Figure 3-1:
Figure 3-1
Study Design
All infusions will take place at the investigative site in a suitable facility. Patients will remain 
at the clinic for at least 2 hours after the end of the infusion. The investigator will discharge 
the patient following satisfactory monitoring of safety parameters.
Safety assessments will include physical examinations, ECGs, vital signs, standard clinical 
laboratory evaluations, hematology, blood chemistry and urinalysis. Adverse Events (AEs) 
will be monitored throughout the study duration with special interest to infections. PK/PD 
and biomarkers will be evaluated during the study.
Details of the study procedures and samplings are provided in the Assessment Schedule
(Table 8-1).
3.2
Rationale for study design
In this study, a randomized, double-blind approach will be used to eliminate potential bias on
safety and clinical efficacy data. Patients will be randomized to IV CFZ533 or IV placebo in a 
1:1 ratio. 
Placebo will be used as comparator to provide objective evidence of safety and efficacy data 
from patients exposed to the experimental therapy. Use of placebo will be in addition to 
standard of care therapy so as not to leave patients without established treatment. 
For patients that are receiving corticosteroids at baseline, a predefined steroid tapering 
(Table 6-1)
will be allowed after achievement of minimal manifestations state 
(Jaretzki et al 2000). The steroid tapering is instituted to follow the common medical practice 
in MG to minimize steroid exposure and to mirror standard of care. The proportion of patients 
who are intolerant to steroid taper in the CFZ533 vs the placebo arm will be a secondary 
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This study will use the Quantitative Myasthenia Gravis score (QMG) and MG Composite 
score (MGC) as key efficacy outcome measures. Both the scores are established and validated 
efficacy measure in MG trials (Jaretzki et al 2000, Howard et al 2013, Burns et al 2010) and 
therefore assumed sufficiently sensitive to provide preliminary evidence for efficacy after 
24 weeks of treatment. This timeframe is consistent with previous trials of MG therapeutics in 
similar target populations (Howard et al 2013, Muscle Study Group 2008).
3.3
Rationale for dose/regimen, duration of treatment
Safety and tolerability confirmed in humans: A Phase 1 study (CCFZ533X2101), testing 
single ascending doses (0.03 to 10 mg/kg) of CFZ533 IV and 3 mg/kg SC, is currently 
ongoing. Safety and tolerability data are presented in Section 1.1.1.3 Based on clinical 
experience so far, the 10 mg/kg IV q4w dosing regimen is anticipated to be safe and tolerable 
in MG patients.
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3.4
Rationale for choice of comparator
In this study, placebo will be used as comparator to provide objective evidence of safety and 
efficacy data from patients exposed to the experimental therapy. Patients should remain on 
their standard of care therapies and dose maintained at a constant level during the study 
(Section 6.10).
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3.6
Risks and benefits
It is not known if there could be a benefit to patients from treatment with CFZ533 . 
 
The risk to subjects in this trial will be 
minimized by adherence to the inclusion/exclusion criteria, close clinical monitoring, and 
targeted monitoring/follow-up visit safety assessments.
Hypersensitivity or infusion reactions can manifest with itching, flushing, headache, 
nausea/vomiting, hypotension, urticaria, bronchospasm, or angioedema. No such events were 
found in the Phase 1 study with CFZ533. In this study, CFZ533 will be admi nistered as a 
2-hour infusion where such hypersensitivity reactions can still occur. Subjects will be 
monitored up to 4 hours after the end of the infusion at each visit.
Subjects treated with CFZ533 may be at an increased risk of infection. 
 
 
Administration of CFZ533 is 
expected to result in immunosuppression, with a decreased capacity to mount a response to 
novel immunogens requiring T cell-dependent B cell activation (potentially including 
bacterial, viral, fungal and parasitic origin) when full receptor occupancy has been achieved.
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In addition, subjects will have adequate preformed antibody to maintain protective humoral 
response for extended periods of time (months). Subjects enrolled in this study will be
carefully monitored for signs and symptoms of an infection.
Although not expected in this clinical study, the investigator will monitor for signs, symptoms 
and laboratory results consistent with clinically significant inflammation as well as for 
changes in renal function and signs of acute kidney injury as per local practice.
There has been no evidence that CFZ533 has an effect on clinical coagulation parameters, and 
no evidence from preclinical or clinical studies that CFZ533 presents an increased risk of 
thromboembolic events (TE).
 
 Nevertheless, standard coagulation 
parameters and TEs will be carefully monitored throughout the study.
The overall risk-benefit supports further investigation in patients with autoimmune diseases 
such as MG patients. However, there may be unknown risks of CFZ533 which may be serious 
and unforeseen.
A maximum of approximately 600 mL of blood is planned to be collected over a period of 
52 weeks (including screening, treatment and follow up period) from each subject as part of 
the study. Additional samples for monitoring of any safety findings would be in addition to 
this. This is not considered to be a risk for this population.
4
Population
A total of approximately 44 subjects will be enrolled in the study and randomized. At least 
36 subjects are expected to complete the study.
Subject selection is to be established by checking all eligibility criteria at screening (Visit 1)
and before randomization (Visit 3). A relevant record (e.g. checklist) of the eligibility criteria 
must be stored with the source documentation at the study site. No additional criteria should 
be applied by the investigator, in order that the study population will be representative of all 
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eligible subjects. Deviation from any entry criterion excludes a subject from enrollment into 
the study.
4.1
Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1. Able to provide signed informed consent.
2. 18-85 year old male or female patients.
3. Body mass index of 18-40 kg/m2.
4. Diagnosis of MG class IIa to IVa inclusive (Myasthenia Gravis Foundation of America 
Clinical Classification).
5. Quantitative Myasthenia Gravis (QMG) score of 10 or greater. If the QMG score is < 15,
no more than 4 points may be derived from items 1 or 2 (ocular motility disturbance and 
ptosis).
6. Presence of acetylcholine receptor (AChR) or Muscle Specific Kinase (MuSK) 
autoantibodies based on medical history and confirmed by autoantibodies diagnostic test 
performed at screening.
7. Only one immunosuppressant or immunomodulatory drug at a stable dose is allowed 
during the study (i) azathioprine and mycophenolate mofetil must be stable for at least 4
months prior to randomization (ii) cyclosporine must be stable for at least 3 months prior 
to randomization. 
8. If the patient is on oral corticosteroids, methotrexate or tacrolimus at screening, the dose 
must be stable for at least 1 month prior to randomization. 
9. If the patient is on cholinesterase inhibitors at screening, the dose must be stable for at 
least 2 weeks prior to randomization.
10. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, may be included in the study if they are using highly effective 
methods of contraception during the study and for 12 weeks after study treatment. 
11. Highly effective contraception methods include: 
!
Total abstinence (when this is in line with the preferred and usual lifestyle of the
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation
methods) and withdrawal are not acceptable methods of contraception.
!
Female sterilization (have had surgical bilateral oophorectomy with or without
hysterectomy) or tubal ligation at least six weeks before taking study treatment,
confirmed by medical documentation. In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment.
!
Male sterilization (at least 6 months prior to screening, with the appropriate post-
vasectomy documentation of the absence of sperm in the ejaculate). For female subjects on 
the study the vasectomized male partner should be the sole partner for that subject.


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!
Combination of any two of the following (a+b or a+c, or b+c):
a.
Use of oral, injected or implanted hormonal methods of contraception or
other forms of hormonal contraception that have comparable efficacy (failure 
rate <1%), e.g. hormone vaginal ring or transdermal hormone contraception.
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS).
c. Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps). For UK: with spermicidal 
foam/gel/film/cream/vaginal/suppository
!
In case of use of oral contraception, women should have been stable on the same pill 
for a minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. 
In the case of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of child bearing 
potential.
4.2
Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study. 
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
1. MGFA grade I, IVb, or V disease.
2. Documented presence of unresected thymoma.
3. Patients having undergone thymectomy or thymothymectomy (resection of thymoma) 
within 6 months of screening. 
4. Patients having received any of the following treatments prior to randomization:
!
IVIg or plasma exchange within 8 weeks;
!
oral or IV cyclosphosphamide treatment within 3 months;
!
IV corticosteroid bolus (dose higher than 1 mg/kg) within 3 months;
!
belimumab within 6 months. For patients who received belimumab earlier, B cell 
count should be within normal range;
!
rituximab within 12 months. For patients who received rituximab earlier, B cell count 
should be within normal range;
!
any other biologic or an investigational drug within 1 month or five times the half-
life, whichever is longer.
5. Live vaccines within 4 weeks prior to randomization.
6. History of tumor, infection, or interstitial lung disease on chest CT, MRI, or CXR. 
7. History of malignancy within 3 years prior to screening, with the exception of basal cell or 
squamous cell carcinoma of the skin or in situ carcinoma of the cervix.


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8. History or presence of any medically significant cardiac condition which according to the 
investigator may jeopardize the patient in case of participation in the study including 
ischemic heart disease, congestive heart failure or cardiomyopathy, myocardial infarction 
or stroke.
9. Sitting vital signs outside of the following ranges at baseline: oral temperature: 
35.0 - 37.5°C, systolic blood pressure: 90 - 145 mmHg, diastolic blood pressure: 
50 - 90 mmHg, pulse rate 50 - 100 bpm.
10. Patients who are at significant risk for thromboembolic events as judged by the 
investigator or have any one of the following:
!
History of either thrombosis or 3 or more spontaneous abortions with or without the
presence of anti-cardiolipin autoantibodies;
!
Presence of prolonged partial thromboplastin time (PTT).
11. Pancreatic injury or pancreatitis as indicated by abnormal signs or symptoms of 
pancreatitis or clinically significant elevations in amylase or lipase at screening.
12. Have had signs or symptoms of a clinically significant systemic viral, bacterial or fungal 
infection within 30 days prior to randomization.
13. Any significant concurrent medical condition such as pulmonary, renal or liver disease 
that, in the opinion of the principal Investigator, could affect the patient's ability to tolerate 
or complete the study.
14. Evidence of active or latent tuberculosis as assessed by quantiferon testing at screening 
(PPD is not recommended as immunosuppression may result in false negative result).
15. Positive serology for HIV antibodies, hepatitis B surface antigen or hepatitis C antibodies 
(confirmed by an appropriate licensed test) at screening.
16. Any of the following abnormal laboratory values at screening:
!
total white blood cell count (WBC) outside the range of 1,500-15,000/mm3
(1.5-15.0 x 109/L)
!
total white blood cell count (WBC) outside the range of 1,500-20,000/mm3
(1.5-20.0 x 109/L), only for patients taking corticosteroids
!
platelets <100,000/mm3 (<100 x 109/L)
!
Hgb <8.0 g/dL
!
lymphocyte count <500/mm3 (<0.5 X 109 / L)
!
neutrophil count <1500/mm3 (<1.5 X 109 / L)
17. Hypoalbuminemia (serum albumin of less than 2.0 g/dL) at screening.
18. Clinical evidence of liver disease or liver injury or any of the following hepatic conditions:
!
known history of alcohol abuse, chronic liver or biliary disease 
!
conjugated bilirubin greater than the upper limit of normal (ULN)
!
alkaline phosphatase (ALP) greater than 2 x ULN
!
AST (SGOT), ALT (SGPT) greater than 2 x ULN
!
gamma-glutamyl-transferase (γ -GT) greater than 2 x ULN


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19. History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such
abuse as indicated by the laboratory assays conducted during screening.
20. Have donated blood or experienced a loss of blood >500 mL within 4 weeks of study drug 
infusion.
21. Allergy to murine or human antibodies.
22. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a
female after conception and until the termination of gestation, confirmed by a positive
hCG laboratory test.
5
Restrictions for Study Subjects
Subjects must be informed and reminded of the restrictions reported in the following 
paragraphs.
5.1
Contraception requirements
Please refer to inclusion criteria (Section 4.1) for details of contraception requirements for the 
study. In consideration of the patient population and overall risk benefit profile, women of 
childbearing potential must utilize highly effective contraception to avoid becoming pregnant 
while receiving CFZ533 and for 12 weeks after the last dose or until data from the 
reproductive toxicity studies suggest otherwise.
5.2
Prohibited treatments
Use of the treatments in Table 5-1 is not allowed during the study and until at least four weeks 
after the last administration of study drug. 
In case of rescue therapy (IVIg or plasma exchange), study treatment should be interrupted 
but patient can remain in the study for the safety follow-up period or at least complete the 
End of Study (EoS) visit (Visit 777) assessments.
If any other prohibited treatment is given during the course of the trial, patients should be 
discontinued from the study and complete EoS visit (Visit 777) assessments as per 
Assessment Schedule (Table 8-1).
Table 5-1
Prohibited treatments
Medication
Wash-out
Action to be taken
IVIg or plasma exchange
8 weeks prior to randomisation
Investigational treatment
discontinued, but patient can 
remain in the study for the safety 
follow-up period
Oral or IV cyclosphosphamide;
IV corticosteroid bolus (dose higher
than 1 mg/kg)
3 months prior to randomisation
Patient’s discontinuation and EoS 
assessments to be undertaken
Belimumab
6 months prior to randomisation
Patient’s discontinuation and EoS 
assessments to be undertaken
Rituximab 
12 months prior to randomisation
Patient’s discontinuation and EoS 
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Medication
Wash-out
Action to be taken
Any other biologic or an 
investigational drug
1 month or five times the half-life, 
whichever is longer prior to 
randomisation
Patient’s discontinuation and EoS 
assessments to be undertaken
Live vaccination
4 weeks prior to randomisation
Patient’s discontinuation and EoS 
assessments to be undertaken
Please, refer to Section 6.10 for standard of care treatment instructions (e.g. corticosteroids, 
immunosuppressants and cholinesterase inhibitors) and other concomitant treatments.
5.3
Dietary restrictions and smoking
Subjects will maintain their usual diet and life habits during the entire study.
5.4
General restrictions
No general restrictions are required in this study.
6
Treatment
6.1
Study treatment
6.1.1
Investigational treatment
The investigational drug (CFZ533) and placebo will be prepared by Novartis and supplied to 
the Investigative site as open-label bulk medication. CFZ533 will be provided as lyophilisate 
in vial (150 mg) and the placebo as liquid in vials. 
To maintain the blind, the investigational treatments will be prepared by an unblinded 
pharmacist/designee and the investigational treatment will only be administered by blinded 
study personnel to patient treatment allocation.
Instructions for infusion preparation, storage and handling of CFZ533 vials and placebo are 
described in the Pharmacy Manual, provided as a separate document. Once the active or 
placebo will be diluted there will be no possibility to differentiate the two solutions for 
injection. 
Study drugs must be received at the study site by a designated person, handled and stored 
safely and properly, and kept in a secure location to which only the Investigator and 
designated staff have access. 
Upon receipt, the study drugs should be stored according to the instructions specified on the
drug labels. Storage conditions must be adequately monitored and appropriate temperature
logs maintained as source data. Appropriate documentation of the subject specific dispensing 
process must be maintained.
Medication labels will be in the local language, will comply with the legal requirements of
each country, and will include storage conditions for the drug but no information about the
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All drug supplies are to be used only for this protocol and not for any other purpose. 
Unless specifically instructed by Novartis, the Investigator must not destroy any drug labels, 
or any partly used or unused drug supply. Only after receiving a written authorization by 
Novartis, the Investigator/designee will send all the unused and partly used drug supplies as 
well as the empty containers to the address provided at the time of authorization for 
destruction.
6.2
Treatment arms
Subjects will be assigned to CFZ533 or matching placebo according to a 1:1 randomization 
scheme, as follows:
!
CFZ533 10 mg/kg IV infusion every 28 days (q4w), for a treatment duration of 24 weeks
(6 doses).
!
CFZ533 matching placebo IV infusion every 28 days (q4w), for a treatment duration of 
24 weeks (6 doses).
Both infusions (drug and vehicle) will be at matched volumes, constant rates, and given over 
2 hours. In case of any adverse event please refer to Section 6.8 treatment of adverse events.
6.3
Permitted dose adjustments and interruptions of study treatment
Study drug dose adjustments or interruptions are not permitted. In case of an AE or for any 
reason (e.g., non-compliance, operational hurdle) resulting in a deviation from the required 
dosing scheme, agreement with Novartis will be necessary to decide whether the subject can 
continue or needs to be discontinued from the study.
6.4
Treatment assignment
Prior to dosing, eligible patients will be randomized via an IRT system to one of the two 
treatment arms. Randomization numbers will be generated in ascending, sequential order by a 
validated IRT system.
The site personnel (e.g. PI or delegate or unblinded pharmacist) will log into the IRT system 
to randomize the patient. The IRT will then assign a randomization number to the patient and 
will indicate to the unblinded site personnel the treatment to be assigned to the patient.
The screening number will be maintained as unique identifier for each patient throughout the 
study and will be entered into the CRF (details in the SOM).The randomization numbers will 
be generated using the following procedure to ensure that treatment assignment is unbiased 
and concealed from patients and from the blinded site staff. A patient randomization list will 
be produced by a Contract research Organisation (CRO) using a validated system that 
automates the random assignment of treatment arms.
The patient randomization list will be reviewed and approved by a member of the Novartis 
randomization office. After approval the randomization list will be integrated into the IRT 
system. 
Patients will not be replaced.


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6.5
Treatment blinding
This is a double blind study: subjects, investigators performing the assessments and data 
analysts will remain blind to the identity of study treatments according to the specifications 
provided in Appendix 3 of the SOM. Randomization data are kept strictly confidential, and 
are accessible only to authorized personnel, until unblinding of the trial.
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, schedule of administration, appearance, taste and odor.  
The bioanalyst will request a copy of the randomization to facilitate analysis of the 
samples.The bioanalyst will provide the sample data to the team under blinded conditions. 
The bioanalyst will keep this information confidential until IA or final clinical database lock.
The DMC will receive unblinded data as described in the DMC charter.
Otherwise, unblinding will only occur in the case of patient emergencies (Section 6.6), at the 
time of the IA and  the conclusion of the study.
6.6
Emergency breaking of assigned treatment code
Emergency unblinding should only be undertaken when it is essential to treat the subject 
safely and efficaciously. Most often, study treatment discontinuation and knowledge of the 
possible treatment assignments are sufficient to treat a study subject who presents with an 
emergency condition. Emergency unblinding of a patient is managed via the IRT system. 
Study site personnel will be trained on the Emergency Unblinding Procedure in IRT prior to
study start. The unblinded treatment code should not be recorded on the CRF.
The investigator must also immediately inform the Novartis local monitor that a patient has 
been unblinded. Unblinded patients will be discontinued from the study. 
If appropriate, the investigator will inform the subject how to contact his/her trained backup in 
cases of emergency when he/she is unavailable.
An assessment will be done by the appropriate site personnel and the Sponsor after an 
emergency unblinding to assess whether or not study drug should be discontinued for a given 
subject and, if applicable, whether the subject can continue into the next trial phase.
6.7
Treatment exposure and compliance
Compliance with treatment administration will be collected in the eCRF. Exposure to CFZ533 
will be measured by appropriate PK parameters as detailed in Section 8.5.
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6.8
Recommended treatment of adverse events
Parenteral administration of monoclonal antibodies can be associated with acute, severe
reactions (occurring within the first few hours post dose) secondary to hypersensitivity, 
immunogenicity, or ADCC-mediated cell depletion. 
In this study, CFZ533 will be administered as a 2-hour infusion.  No systemic infusion 
reactions
have been noted with CFZ533 in healthy volunteers
or RA patients 
(Study CCFZ533X2101); however, investigators should be aware of the possibility and be 
prepared to treat such events.
In case of any signs of an acute reaction, clinical treatment will be provided as determined by 
the treating physician on a case-by-case basis and depending on the severity, using 
symptomatic treatment, antihistamines,
NSAIDs, acetaminophen, intravenous fluids, 
corticosteroids, or adrenaline. Patients will be monitored at the site for at least 6 hours post 
dose or longer at the discretion of the Investigator to ensure adequate safety monitoring.
For the management of allergic reaction, anaphylaxis and cytokine release, it is recommended 
to follow the guidelines by the National Cancer Institute Common Toxicity Criteria 
(NCI-CTCAE/v4.03, Reference http://evs.nci.nih.gov/ftp1/CTCAE/About.html).
Medication used to treat AEs must be recorded on the Concomitant medications/Significant 
non-drug therapies CRF.
6.9
Rescue medication
Rescue therapy (IVIg or plasma exchange) is instituted due to worsening of myasthenic 
weakness that in the opinion of the treating physician requires immediate therapy.  
This usually involves acute worsening of oropharyngeal or respiratory function so that 
compromise of the airway or ventilator function is judged to be imminent.
In case of rescue therapy, study treatment should be discontinued but the patient can remain in 
the study or for the safety follow-up period or at least complete the EoS visit (Visit 777) 
assessments.
Use of rescue medication must be recorded on the Concomitant medications/Significant 
non-drug therapies CRF after start of study drug.
6.10
Concomitant treatment
Patients should remain on their standard of care therapies (if not prohibited) and dose should 
be maintained stable, unless changes are judged to be necessary based on history and clinical 
examination after discussion between the investigator and Novartis.


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Corticosteroid
If the patient is on oral corticosteroids, methotrexate or tacrolimus at screening the dose must 
be stable for at least 1 month prior to randomization. 
For patients that are receiving corticosteroids, a predefined steroid tapering (Table 6-1) will be 
allowed after achievement of MM state (Jaretzki et al 2000). In patients whose disease 
substantially worsens after tapering, the previous steroid dose will be reinstituted, and no 
further dose reduction will be attempted in the study. 
Table 6-1
Predefined tapering scheme
Baseline daily 
dose (x)*
Week 13
Week 17
Week 21
After Week 25
x ≤10 mg
No change
No change
 by 2.5 mg
As needed #
10 < x ≤20mg
No change
 by 2.5 mg
 by 2.5 mg
As needed #
x > 20 mg
 by 5 mg
 by 5 mg
 by 2.5 mg
As needed #
* Or equivalent alternate day dose
# According to usual standard of care
 Decrease
Immunosuppressant or immunomodulatory drugs
In addition to corticosteroids, only one immunosuppressant or immunomodulatory drug at a 
stable dose is allowed during the study. Azathioprine and mycophenolate mofetil must be at a 
stable dose for at least 4 months prior to randomization. Cyclosporin should be at a stable 
dose for at least 3 months prior to randomization.
Cholinesterase inhibitors
Patients on cholinesterase inhibitors must be on a stable dose for at least 2 weeks prior to 
randomization.
Cholinesterase inhibitors will be held at least 12 hours prior to QMG and MGC testing at 
each study visit. It may be necessary for patients to remain overnight at the study site for 
observation during this time, if the investigator deems it necessary.
Other concomitant medications
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the 
timeframe defined in the entry criteria prior to the start of the study and during the study, must 
be recorded on the Concomitant medications/Significant non-drug therapies section of the 
CRF. Medication entries should be specific to trade name, the single dose and unit, the
frequency and route of administration, the start and discontinuation date and the reason for 
therapy.


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7
Discontinuation and study completion
7.1
Discontinuation of study treatment
Patients may voluntarily discontinue the study treatment for any reason at any time.  
The Investigator should discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would be detrimental to the subject’s well-being.
!
Study treatment must be discontinued and patients followed up for safety, 
if possible, if the following occur:
!
In case of non-detectable AChR or MuSK autoantibodies for patients enrolled prior to 
this amendment. 
!
Significant increase in MG disease activity requiring treatment outside of a clinical 
trial setting. 
!
Worsening of MG with severe oropharyngeal or respiratory weakness (MGFA class 
IVb or V). 
!
Rescue medication use (IVIg or plasma exchange).
!
Pregnancy.
!
Severe or life threatening infusion reaction.
!
Major worsening of renal function (e.g. >40% increase from baseline creatinine level).
!
Acute infection as a severe AE as judged by the investigator.
!
Major elevations (>4.0 x ULN) in amylase or lipase or any abnormal signs or 
symptoms suggesting pancreatic injury.
!
Significant changes in standard coagulation parameters, including prothrombin time 
(PT), activated partial thromboplastin time (aPTT) suggesting an increased risk for 
hypercoagulability or any sign or symptom of a TE.
!
Any other AE or complication where continued dosing of the patient is considered to 
be placing them at excess risk.
!
Patient withdraws consent (when patient must also be withdrawn from the study).
Patients who are withdrawn from the study for any reason will not be replaced. 
Study patients who discontinue participation for any reason or who decide they do not wish to 
participate in the study further should not be considered withdrawn from the study unless they 
withdraw their consent (see Section 7.3). Where possible, they should return for their EoS 
visit assessments (Visit 777). If they fail to return for these assessments for unknown reasons, 
every effort (e.g. telephone, e-mail, letter) should be made to contact them as specified in
Section 7.2.1 Any unresolved AEs will be followed by the investigator until resolution.
7.2
Study completion and post-study treatment
Each subject will be required to complete the study in its entirety and thereafter no further 
study treatment will be made available to them. Study completion is defined as when the last 
subject completes the EoS visit (Visit 777), and any assessments associated with this visit 
have been documented and followed-up appropriately by the Investigator. 


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After study participation, the patients will continue to be treated by his/her general 
practitioner according to the local standard clinical management related to the underlying 
disease. The investigator must provide follow-up medical care for all subjects who are 
prematurely withdrawn from the study, or must refer them for appropriate ongoing care.
7.2.1
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of 
telephone calls, registered letters, etc. A subject should not be formally considered lost to 
follow-up until his/her scheduled EoS visit would have occurred.
7.3
Withdrawal of consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time.
Withdrawal of consent occurs only when a subject does not want to participate in the study 
anymore, does not want any further visits or assessments or study related contact and does not 
allow analysis of already obtained biologic material.
If a subject withdraws consent, the investigator must make every effort to determine the 
primary reason for this decision and record this information. Study treatment must be 
discontinued and no further assessments conducted. All biological material that has not been 
analyzed at the time of withdrawal must not be used. Further attempts to contact the subject 
are not allowed unless safety findings require communicating or follow-up.
7.4
Study stopping rules
As a guidance, dose limiting toxicities (DLTs) will be assessed according to the standardized 
toxicity grading scale.
The study will be placed on hold with no further dosing pending full safety review if any of 
the following criteria are met:
!
One (1) patient with CFZ533-related death.
!
Three (3) or more patients presenting with a serious adverse event that is related to 
CFZ533.
!
One (1) patient presenting with CFZ533-related cytokine release syndrome.
!
One (1) patient presenting with a CFZ533-related thromboembolic events that is at least of
moderate severity.
!
More than one (1) patient with a severe allergic reaction within the first 5 treated subjects 
or an incidence of >20% thereafter.
!
Any treatment-related, severe adverse event considered drug related by the Investigator 
with the following exceptions:
!
Events not requiring treatment, and diagnostic procedures involving elective or non-
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!
Disease Specific Events that are due to the patients underlying MG diagnosis,
!
AEs/SAEs unrelated to the experimental compound as determined by the Investigator 
or Novartis.
!
Two (2) or more patients presenting with:
!
Acute severe exacerbation of MG symptoms requiring hospitalization for treatment.
!
Progressive renal insufficiency or acute kidney injury defined as a moderate increase 
in serum creatinine (1.5 X ULN) in the setting of euvolemia at any time during the 
study related to CFZ53.
!
Emergent hypogammaglobulinemia defined as a reduction in total serum IgG or IgM 
concentration by 50% or more from baseline.
!
Severe systemic infection or opportunistic infection that requires treatment, e.g., 
sepsis, urosepsis, mycoses, pneumonia.
!
Clinically significant (according to the Investigator), study drug-related persisting changes 
from baseline in vital signs, ECGs, or relevant persistent changes in laboratory parameters
(not due to existing co-morbidities), in more than one (1) patient within the first 5 treated 
patients or an incidence of >20% thereafter.
!
Other clinically significant changes or effects in the opinion of the Investigator or Sponsor 
that are deemed unsafe to continue dosing.
All blinded safety data, including disease specific events, will be evaluated by the Sponsor 
and Investigator on an ongoing basis and at scheduled meetings. The study may be put on 
hold pending further data analysis, if the principal investigator or the Sponsor considers that 
the number and/or severity of AEs justify discontinuation of the study.
In addition, a DMC will be instituted (see Section 10.3) with the aim to review safety data 
regularly (and efficacy data, if required) as outlined in their charter and at ad hoc meetings. 
The DMC can recommend stopping the entire trial if it is considered unsafe or unethical to 
continue administering CFZ533.
7.5
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
subjects should be seen as soon as possible and treated as a prematurely withdrawn subject
and complete their EoS visit assessments as per Assessment Schedule (Table 8-1).
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the subject’s interests.
The investigator will be responsible for informing IRBs/IECs of the early termination of the 
trial.


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8
Procedures and assessments
Visits should be scheduled within the allowed visit/assessment window as specified in the 
Assessment Schedule (Table 8-1). 
PK samples should be taken at the time points as specified in the Assessment Schedule. When 
other assessments are scheduled to be performed at the same time-point, these will be taken 
after the PK samples.
The preferred sequence of data collection during study visits is safety, ECG, followed by vital 
signs and blood sampling.


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Table 8-1
Assessment Schedule
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Assessment Schedule (cont’d)
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8.1
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
If incapable of doing so, in cases where the subject’s representative gives consent, the subject 
should be informed about the study to the extent possible given his/her understanding. If the 
subject is capable of doing so, he/she should indicate assent by personally signing and dating 
the written informed consent document or a separate assent form.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
should be documented in the subject source documents.
The date of signing of informed consent (and withdrawal, if later withdrawn) should be 
documented in the CRF.
Novartis will provide to investigators a proposed informed consent form that complies with 
the ICH GCP guideline and regulatory requirements and is considered appropriate for this 
study. Any changes to the proposed consent form suggested by the investigator must be 
agreed to by Novartis before submission to the IRB/IEC.
In the event that Novartis wants to perform testing on the samples that are not described in 
this protocol, additional Institutional Review Board and/or Ethics Committee approval will be 
obtained.
8.2
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data to be collected on all subjects include: 
date of birth, age, sex, race, predominant ethnicity.
Relevant medical history/current medical conditions data includes data prior to signature of 
informed consent. Where possible, diagnoses and not symptoms should be recorded.
The date of original diagnosis of Myasthenia Gravis and the MG class will be recorded in the 
CRF. 
Medical history of MG and the autoantibodies diagnostic test results (performed at V1) will 
be maintained/recorded in the source data.
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Hepatitis screen, HIV screen
All subjects will be screened for Hepatitis B surface antigen (HBsAg). Screening for Hepatitis 
C will be based on HCV antibodies.
Evaluation for HIV seropositivity will be performed, and if positive, confirmation by a second 
technique available at the laboratory site, e.g., Western blot. Appropriate subject counseling 
will be made available by the Investigator in the event of a positive finding. Notification of 
state and federal authorities, as required by law, will be the responsibility of the Investigator.
Results will be available as source data and will not be recorded within the eCRF.
Alcohol test, Drug screen
Subjects will be tested for substances of abuse (e.g., alcohol, amphetamines, barbiturates, 
benzodiazepines, cannabinoids, cocaine, and opiates).
Results will be available as source data and will not be recorded within the eCRF.
8.3
Efficacy / Pharmacodynamics
Exploratory efficacy and PD assessments are described in this section. Assessments will be 
performed and samples collected at the visits/timepoint(s) defined in the Assessment Schedule
(Table 8-1).
8.3.1
Quantitative Myasthenia Gravis (QMG) score
The Quantitative Myasthenia Gravis (QMG) score is an established and validated measure of 
disease severity used in MG trials (Jaretzki et al 2000). This scoring system is based on 
quantitative testing of sentinel muscle groups by means of a 4 point scale ranging from 0
(no symptoms) to 3 (severe symptoms). 
The scale measures ocular, bulbar, respiratory, and limb function, grading each finding, and 
the total score ranges from 0 (no myasthenic findings) to 39 (maximal myasthenic deficits). 
Its reliability and longitudinal validity have been demonstrated in several studies 
(Sharshar et al 2000, Bedlack et al 2005).  It has been used as the primary outcome measure in 
several recent randomized trials in MG (Zinman et al 2007,
Barth et al 2011,
the Muscle Study Group 2008).
8.3.2
Myasthenia Gravis Composite (MGC) score
The MG Composite score (MGC) is another key efficacy outcome measure. It is reliable and 
demonstrates concurrent and longitudinal construct validity in the MG practice care setting 
(Burns et al 2010). The MGC scale covers 10 important functional domains most frequently 
involved in patients with MG. The proportion of bulbar and respiratory items reflect the 
clinical importance of these domains in the disease, and are appropriately weighted. 
The assessment of each of the 10 test items provides immediate insight into the status of that 
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8.3.3
Quality of Life questionnaires
The MG-QOL15 is a 15-item survey, completed by the patient that is designed to assess some 
aspects of quality of life related to MG (Burns et al 2011). 
The MG-ADL is an 8-item survey to assess functional performance of daily activities that are 
sometimes impaired by MG (Muppidi et al 2011).
Patients will be asked to complete a paper copy of the questionnaires in their local language. 
The printed copy will serve as source data and the subject’s responses will be transcribed into 
the eCRF.
Further details can be found in the SOM.
8.4
Safety
Safety assessments are specified below and in the Assessment Schedule (Table 8-1).
8.4.1
Physical examination
The Physical examination will include the following:
!
Eyelid closure
!
Extra-ocular movements
!
Facial strength
!
Palatal elevation
!
Tongue protrusion
!
Jaw closure
!
Neck flexion/extension
!
Strength in upper and lower extremities (proximal and distal muscles)
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8.4.2
Vital signs
!
Body temperature
!
Blood pressure (BP)/ Pulse rate 
If vital signs are out-of-range at baseline, the Investigator may obtain two additional readings, 
so that a total of up to three consecutive assessments are made, with the subject seated quietly 
for approximately five minutes preceding each repeat assessment. 
At least the last reading at baseline must be within the ranges provided above in order for the 
subject to qualify.
8.4.3
Height and weight
!
Height
!
Body weight
!
Body mass index (BMI) will be calculated (Body weight (kg) / [Height (m)]2)
8.4.4
Laboratory evaluations
In the case where a laboratory assessment that is listed in the inclusion/exclusion criteria is 
outside of a protocol-specified range at screening (Visit 1 or 2), the assessment may be 
repeated once prior to randomization. If the repeat value remains outside of protocol-specified 
ranges, the subject is excluded from the study.
In the case where a laboratory range is outside the reference range for the laboratory at 
screening or baseline, a decision regarding whether the result is of clinical significance or not 
shall be made by the Investigator and shall be based, in part, upon the nature and degree of the 
observed abnormality. The assessment may be repeated once prior to randomization.
In all cases, the Investigator must document in the source documents, the clinical 
considerations (i.e., result was/was not clinically significant and/or medically relevant) in 
allowing or disallowing the subject to continue in the study. 
Clinically relevant deviations of laboratory test results occurring during or at completion of 
the study must be reported and discussed with Novartis personnel. The results should be 
evaluated for criteria defining an adverse event and reported as such if the criteria are met. 
Repeated evaluations are mandatory until normalization of the result(s) or until the change is 
no longer clinically relevant. In case of doubt, Novartis personnel should again be contacted.
The blood sample for hematology and clinical chemistry should be taken in fasting conditions.
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential 
(e.g., neutrophils, basophils, eosinophils, monocytes, lymphocytes, including reticulocyte 
counts) and platelet count will be measured.


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Clinical chemistry
Albumin, alkaline phosphatase, total bilirubin, bicarbonate/CO2, calcium, cholesterol, 
chloride, creatinine, CK, γ-GT, glucose, LDH, inorganic phosphorus, lipase, amylase, 
magnesium, potassium, total protein, AST, ALT, sodium, triglycerides, urea/BUN and uric 
acid, free Hbg and haptoglobin. If the total bilirubin concentration is increased above 
1.5 times the upper limit of normal, direct and indirect reacting bilirubin should be 
differentiated. 
Prothrombin time (PT/INR), activated partial thromboplastin time (aPTT) and C-Reactive 
Protein (CRP) will be measured.
Urinalysis
A midstream urine sample (approximately 30 mL) will be obtained, in order to avoid 
contamination with epithelial cells and sediments, and allow proper assessments.
A semi-quantitative “dipstick” evaluation for the following parameters will be performed: 
specific gravity, pH, glucose, protein, bilirubin, ketones, nitrite, leukocytes and blood.
If the dipstick result is positive for protein, nitrite, leucocytes or blood, the sample will be sent 
for microscopic analysis of WBC, RBC and casts.
Serum IgG and IGM
Serum total immunoglobulin G (IgG) and M (IgM) will be assessed in the study.
8.4.5
Electrocardiogram (ECG)
ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable baseline. 
The Fridericia QT correction formula (QTcF) should be used for clinical decisions.
Single 12 lead ECGs are collected. The original ECGs, appropriately signed, should be 
collected and archived at the study site.
Each ECG tracing should be labeled with study number, subject initials, subject number, date 
and time, be appropriately signed and dated to confirm review and filed in the study site 
source documents. For any ECGs with subject safety concerns, two additional ECGs should 
be performed to confirm the safety finding. Clinically significant ECG findings prior to 
dosing with investigational treatment must be discussed with the Sponsor.
Clinically significant abnormalities should be recorded on the relevant section of the medical 
history/Current medical conditions if known prior to informed consent signature or in the AE 
eCRF page (if the abnormality is detected after informed consent signature).


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The following data will be collected in the eCRF: 
!
date and time of ECG
!
heart rate
!
PR interval
!
QT uncorrected
!
QTcF
!
QRS duration
8.4.6
Pregnancy and assessments of fertility
Pregnancy 
tests
are 
required 
of 
all 
female 
subjects 
regardless 
of 
reported 
reproductive/menopausal status.
Serum pregnancy tests will be performed at the screening visits and at the end of the study.
The result of this test must be received before the subject may be dosed. At all other times 
urine pregnancy tests will be performed.
If a urine pregnancy test is performed and is found to be positive, this will require immediate 
performing a serum β-hCG. If positive, the Sponsor and Investigator will decide if 
discontinuation from the trial is required or whether study assessments can continue without 
compromising the patient’s safety.
In case the subject will be aware of pregnancy anytime during the study, the subject should 
contact the investigator immediately.
8.4.7
Other safety evaluations
All occurrences of infections must be carefully monitored by the investigator. Significant 
findings, which meet the definition of infection, must be recorded in the eCRF.
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8.5
Pharmacokinetics
PK blood samples will be collected from all patients, at baseline and during the treatment and 
follow-up periods at the timepoints defined in the Assessment Schedule (Table 8-1).
Untreated samples (placebo-treated patients) will not be analyzed unless a safety issue 
suggests otherwise or there is clinical suspicion of treatment group misclassification.
For standard PK abbreviations and definitions see the list provided at the beginning of this 
protocol.
The following PK parameters will be determined using the actual recorded sampling times 
and non-compartmental method(s) with Phoenix WinNonlin (Version 6.2 or higher): Cmax, 
Cmax,ss, Cmin,ss, Tmax, AUCtau, AUCtau,ss and Cav,ss from the plasma concentration-time 
data.
The linear trapezoidal rule will be used for AUC calculation.
A SOM accompanies this protocol, providing operational details for study conduct (incl. 
subject numbering, blood log with sample numbers). Further details on sample collection, 
processing and shipment will be provided in the Central Lab Manual. The detailed methods of 
analysis and data will be provided in the Bioanalytical Data Report.
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9
Safety monitoring
9.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study. Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The occurrence of adverse events should be sought by non-directive questioning of the subject 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the subject during or between visits or through physical examination, laboratory test, or 
other assessments.
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:
!
they induce clinical signs or symptoms, 
!
they are considered clinically significant, 
!
they require therapy. 
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events. Alert ranges for liver related events are included in 
Section 9.3. 
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Adverse events must be recorded on the Adverse Events CRF for subjects that pass screening 
and enter into the study. The adverse events should be reported according to the signs, 
symptoms or diagnosis associated with them, and accompanied by the following information:
1. the severity grade:
!
mild: usually transient in nature and generally not interfering with normal activities
!
moderate: sufficiently discomforting to interfere with normal activities
!
severe: prevents normal activities
2. its relationship to the study treatment (no/yes), or
investigational treatment (no/yes), or other study treatment (non-investigational) (no/yes), 
or both or indistinguishable,
3. its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved should be reported.
4. whether it constitutes a serious adverse event (SAE). See Section 9.2 for definition of SAE
5. action taken regarding study treatment.
All adverse events should be treated appropriately. Treatment may include one or more of the 
following: 
!
no action taken (i.e. further observation only) 
!
study treatment dosage adjusted/temporarily interrupted 
!
study treatment permanently discontinued due to this adverse event 
!
concomitant medication given 
!
non-drug therapy given 
!
subject hospitalized/subject’s hospitalization prolonged
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if 
necessary) of any changes in severity, the suspected relationship to the study drug, the 
interventions required to treat it, and the outcome.
Information about common side effects already known about the investigational drug can be 
found in the Investigator Brochure (IB) or will be communicated between IB updates in the 
form of Investigator Notifications. This information will be included in the subject informed 
consent and should be discussed with the subject during the study as needed.
The investigator should also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes 
might reasonably be related to study treatment. This information should be recorded in the 
investigator’s source documents, however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.


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9.2
Serious adverse event reporting
9.2.1
Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s) which meets any one of the 
following criteria:
!
is fatal or life-threatening 
!
results in persistent or significant disability/incapacity
!
constitutes a congenital anomaly/birth defect
!
requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:
a. routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
b. elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since the start of study drug
c. treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
d. social reasons and respite care in the absence of any deterioration in the patient’s 
general condition
!
is medically significant, i.e. defined as an event that jeopardizes the subject or may require 
medical or surgical intervention.
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if more severe.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse.
All AEs (serious and non-serious) are captured on the CRF, SAEs also require individual 
reporting to DS&E as per Section 9.2.2.


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9.2.2
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis within 24 hours of learning of its occurrence as described below. Any SAEs 
experienced after this should only be reported to Novartis if the investigator suspects a causal 
relationship to study treatment. 
Recurrent episodes, complications, or progression of the initial SAE must be reported as 
follow-up to the original episode, regardless of when the event occurs. This report must be 
submitted within 24 hours of the investigator receiving the follow-up information. An SAE 
that is considered completely unrelated to a previously reported one should be reported 
separately as a new event.
Information about all SAEs (either initial or follow up information) is collected and recorded 
on the paper Serious Adverse Event Report Form. The investigator must assess the 
relationship to each specific component of study treatment (if study treatment consists of 
several drugs) complete the SAE Report Form in English, and send the completed, signed 
form by fax within 24 hours after awareness of the SAE to the local Novartis Drug Safety and 
Epidemiology Department, notifying the Clinical Trial Leader. Contact information is listed 
in the SOM.
The original copy of the SAE Report Form and the fax confirmation sheet must be kept with 
the source documentation at the study site. Follow-up information should be provided using a 
new paper SAE Report Form stating that this is a follow-up to a previously reported SAE.
Follow- up information provided should describe whether the event has resolved or continues, 
if and how it was treated, whether the treatment code was broken or not and whether the 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the investigational treatment a Drug Safety 
and Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same 
investigational treatment that this SAE has been reported. Suspected Unexpected Serious 
Adverse Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with EU Guidance 2011/C 172/01 or as per national 
regulatory requirements in participating countries.


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9.3
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study:
!
Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter
!
Liver events, which will require close observation, follow-up monitoring and completion 
of the standard base liver CRF pages
Please refer to Table 9-1 and Table 9-2 for complete definitions of liver laboratory triggers 
and liver events. 
Every liver laboratory trigger or liver event should be followed up by the investigator or 
designated personal at the trial site, as summarized below and detailed in in Table 9-2.
For the liver laboratory trigger:
!
Repeating the LFT within the next week to confirm elevation.
These LFT repeats should be performed using the central laboratory if possible. If this is not 
possible, then the repeats can be performed at a local laboratory to monitor the safety of the 
patient. Repeats laboratory should then be performed at central laboratory as soon as possible. 
If a liver event is subsequently reported, any local LFTs previously conducted that are 
associated with this event should be reported on the Liver CRF pages.
!
If the elevation is confirmed, close observation of the patient will be initiated, including 
consideration of treatment interruption if deemed appropriate.
For the liver events:
!
Repeating the LFT to confirm elevation as appropriate
!
Discontinuation of the investigational drug (refer to Section 7.1, if appropriate) 
!
Hospitalization of the subject if appropriate
!
A causality assessment of the liver event via exclusion of alternative causes (e.g. disease, 
co-medications)
!
An investigation of the liver event which needs to be followed until resolution. 
These investigations can include serology tests, imaging and pathology assessments, 
hepatologist’s consultancy, based on investigator’s discretion. All follow-up information, and 
the procedures performed should be recorded as appropriate in the CRF, including the liver 
event overview CRF pages.


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Table 9-1
Liver Event and Laboratory Trigger Definitions
Definition/ threshold
Liver laboratory triggers
3 x ULN < ALT / AST ∀5 x ULN
1.5 x ULN < TBL ∀2 x ULN
Liver events
ALT or AST > 5 × ULN
ALP > 2 × ULN (in the absence of known bone pathology)
TBL > 2 × ULN (in the absence of known Gilbert syndrome)
ALT or AST > 3 × ULN and INR > 1.5 
Potential Hy’s Law cases (defined as ALT or AST > 3 × ULN and TBL > 
2 × ULN [mainly conjugated fraction] without notable increase in ALP 
to > 2 × ULN)
Any clinical event of jaundice (or equivalent term)
ALT or AST > 3 × ULN accompanied by (general) malaise, fatigue, 
abdominal pain, nausea, or vomiting, or rash with eosinophilia
Any adverse event potentially indicative of a liver toxicity* 
Table 9-2
Follow Up Requirements for Liver Events and Laboratory Triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law 
casea
Discontinue the study drug immediately
Hospitalize, if clinically appropriate
Establish causality
Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion)
ALT or AST
> 8 × ULN
Discontinue the study drug immediately
Hospitalize if clinically appropriate
Establish causality
Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion)
> 3 × ULN and 
INR > 1.5
Discontinue the study drug immediately
Hospitalize, if clinically appropriate
Establish causality
Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion)
> 5 to ≤ 8 × ULN
Repeat LFT within 48 hours
If elevation persists, continue follow-up 
monitoring
If elevation persists for more than 2 
weeks, discontinue the study drug
Establish causality
Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion)
> 3 × ULN 
accompanied by 
symptomsb
Discontinue the study drug immediately
Hospitalize if clinically appropriate
Establish causality
Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion)
> 3 to ≤ 5 × ULN 
(patient is 
asymptomatic)
Repeat LFT within the next week
If elevation is confirmed, initiate close 
observation of the patient
Investigator discretion
Monitor LFT within 1 to 4 weeks 


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Criteria
Actions required
Follow-up monitoring
ALP (isolated)
> 2 × ULN (in the 
absence of known 
bone pathology)
Repeat LFT within 48 hours
If elevation persists, establish causality
Complete liver CRF
Investigator discretion
Monitor LFT within 1 to 4 weeks or 
at next visit
TBL (isolated)
> 2 × ULN (in the 
absence of known 
Gilbert syndrome)
Repeat LFT within 48 hours
If elevation persists, discontinue the study 
drug immediately
Hospitalize if clinically appropriate
Establish causality
Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion)
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin)
> 1.5 to ≤ 2 × ULN
(patient is 
asymptomatic)
Repeat LFT within the next week
If elevation is confirmed, initiate close 
observation of the patient 
Investigator discretion
Monitor LFT within 1 to 4 weeks or 
at next visit
Jaundice
Discontinue the study drug immediately
Hospitalize the patient
Establish causality
Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, ALP 
and γGT until resolutionc (frequency 
at investigator discretion)
Any AE potentially 
indicative of a liver 
toxicity*
Consider study drug interruption or 
discontinuation 
Hospitalization if clinically appropriate
Establish causality
Complete liver CRF
Investigator discretion
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms
aElevated ALT/AST > 3 × ULN and TBL > 2 × ULN but without notable increase in ALP to > 2 × ULN
b(General) malaise, fatigue, abdominal pain, nausea, or vomiting, or rash with eosinophilia 
c Resolution is defined as an outcome of one of the following: (1) return to baseline values, (2) stable values at 
three subsequent monitoring visits at least 2 weeks apart, (3) remain at elevated level after a maximum of 6 
months, (4) liver transplantation, and (5) death.
9.4
Renal safety monitoring
Renal events are defined as one of the following:
!
confirmed (after ≥ 24h) increase in serum creatinine of ≥ 25% compared to baseline 
during normal hydration status
!
new onset (≥1+) proteinuria, hematuria or glucosuria; or as a
!
doubling in the urinary albumin-creatinine ratio (ACR) or urinary protein-creatinine ratio 
(PCR) (if applicable).
The following two categories of abnormalities/adverse events have to be considered during 
the course of the study:
!
serum creatinine triggers that will require follow up and repeat assessments of the 
abnormal laboratory parameter 
!
urine dipstick triggers that will require follow up and repeat assessments of the abnormal 
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Table 9-3
Specific Renal Alert Criteria and Actions
Renal Event
Actions
Serum creatinine increase
25 – 49% compared to baseline
Confirm 25% increase after 24-48h 
Follow up within 2-5 days
Serum creatinine increase  # 50 % 
compared to baseline
Follow up within 24-48h if possible
Consider drug interruption 
Consider patient hospitalization /specialized treatment
Albumin- or Protein-creatinine ratio 
increase ≥ 2-fold
Albumin-creatinine ratio (ACR) ≥ 30 mg/g 
or ≥ 3 mg/mmol;
New dipstick proteinuria ≥ 1+
Protein-creatinine ratio (PCR )≥ 150 mg/g 
or >15 mg/mmol
Confirm value after 24-48h
Perform urine microscopy
Consider drug interruption / discontinuation 
New dipstick glucosuria ≥ 1+ not due to 
diabetes
Blood glucose (fasting)
Perform serum creatinine, ACR 
New dipstick hematuria not due to trauma
Urine sediment microscopy
Perform serum creatinine, ACR 
Document contributing factors: co-medication, other co-morbid conditions, and additional diagnostic 
procedures performed in the CRF
Monitor patient regularly (frequency at investigator’s discretion) until one of the following:
Event resolution: (sCr within 10% of baseline or protein-creatinine ratio within 50% of baseline) 
Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio 
stabilization at a new level with ±50% variability over last 6 months.
9.5
Pregnancy reporting
To ensure patient safety, each pregnancy in a subject on study drug must be reported to 
Novartis within 24 hours of learning of its occurrence. The pregnancy should be followed up 
to determine outcome, including spontaneous or voluntary termination, details of the birth, 
and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications. The study drug must be discontinued and the patient should be 
discontinued. Discontinued pregnant women will complete the EoS visit (Visit 777) 
assessments as described in the Assessment Schedule (Table 8-1).
Pregnancy must be recorded on a Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the Novartis study drug of any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on an SAE Report Form.
9.6
Early phase safety monitoring
The Investigator will monitor adverse events in an ongoing manner and inform the Sponsor of 
any clinically relevant observations. Any required safety reviews will be made jointly 
between medically qualified personnel representing the
Sponsor and Investigator. 
Such evaluations may occur verbally, but the outcome and key discussion points will be 


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summarized in writing (e-mail) and made available to both Sponsor and all Investigator(s). 
Criteria pertaining to stopping the study/treatment or adapting the study design are presented 
above.
When two or more clinical site(s) are participating in the clinical study, the Sponsor will 
advise the Investigator(s) at all sites in writing (e-mail and by telephone if possible) of any 
new, clinically relevant safety information reported from another site during the conduct of 
the study in a timely manner.
10
Data review and database management
10.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. 
During the study, Novartis employs several methods of ensuring protocol and GCP 
compliance and the quality/integrity of the sites’ data. The monitor will visit the site to check 
the completeness of subject records, the accuracy of entries on the CRFs, the adherence to the 
protocol and to GCP, the progress of enrollment, and to ensure that study drug is being stored, 
dispensed, and accounted for according to specifications. Key study personnel must be 
available to assist the monitor during these visits.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject's file. The investigator must also keep the original informed consent form signed by 
the subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the eligibility criteria, documentation of 
SAEs, and the recording of data that will be used for all primary and safety variables. 
Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. No information in source documents about 
the identity of the subjects will be disclosed.
10.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (CRF) using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies and, 
by generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to the CRO working on behalf of Novartis. The Investigator must certify 
that the data entered into the Electronic CRF are complete and accurate. After database lock, 
the investigator will receive a CD-ROM or paper copies of the subject data for archiving at 
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All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
The CRO working on behalf of Novartis reviews the data entered into the eCRFs by 
investigational staff for completeness and accuracy and instruct the site personnel to make any 
required corrections or additions. Queries are sent to the investigational site using an 
electronic data query. Designated investigator site staff are required to respond to the query 
and confirm or correct the data. If the electronic query system is not used, a paper Data Query 
Form will be faxed to the site. Site personnel will complete and sign the faxed copy and fax it 
back to the CRO working on behalf of Novartis who will make the correction to the database.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results sent electronically to the 
designated CRO.
At the conclusion of a non-IRT study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies to Novartis.
The occurrence of any protocol deviations will be determined. After these actions have been 
completed and the database has been declared to be complete and accurate, it will be locked 
and the treatment codes will be unblinded and made available for data analysis. Any changes 
to the database after that time can only be made by joint written agreement between the 
Global Head of Clinical Information Sciences and the Clinical Franchise Head.
10.3
Data Monitoring Committee
A Data Monitoring Committee (DMC) will be instituted. The DMC will be responsible for 
reviewing the safety results from the interim and final analyses, as well as overseeing the 
safety data accruing in the trial at regular intervals. It is expected that the DMC will consist of 
a myasthenia gravis specialist, a neurologist, an immunologist and a statistician.
Details of the working procedures of the DMC are described in the DMC Charter.
10.4
Adjudication Committee
Not required.
11
Data analysis
Analysis of the data will be under the direction of Novartis personnel. Full statistical details 
will be presented in the Reporting and Analysis Plan (RAP), which will be finalized prior to 
database lock.


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11.1
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The full analysis set (FAS) will include all patients who received any study drug.
The safety analysis set will include patients who received any study drug.
The PD analysis set will include all patients who received any study drug and with no 
protocol deviations with relevant impact on efficacy data.
The PK analysis set will include patients with available PK data and no protocol deviations 
with relevant impact on PK data.
Patients with non-detectable AChR or MuSK autoantibodies will be excluded from the PD 
and PK analysis sets.
11.2
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and 
subject. Summary statistics will be provided by treatment group.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and subject.
11.3
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)
Data for study drug administration, rescue medication and concomitant therapies will be listed 
by treatment group and subject.
11.4
Analysis of the primary variable(s)
The primary objectives of this study are to preliminarily evaluate the safety, tolerability and 
efficacy of IV CFZ533 in moderate to severe Myasthenia Gravis patients after 24 weeks of 
treatment as an add-on therapy to standard of care as compared to placebo.
11.4.1
Variable(s)
The safety variables and analysis are detailed in Section 11.5.2.
The primary efficacy variable is the change from baseline in QMG score after 24 weeks of 
treatment (at week 25 visit). The baseline value will be the predose assessment on Day 1. It is 
assumed that the change from baseline in QMG score is normally distributed.
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11.4.3
Handling of missing values/censoring/discontinuations
No imputation of missing data for dropouts will be done. 
 
11.4.4
Supportive analyses
In order to assess the robustness of the results, the primary analysis will be repeated on the 
FAS.
In addition, the changes from baseline in QMG scores at each visit of the treatment period 
(weeks 5, 9, 13, 17, 21 and 25) will be analyzed using a mixed effect model for repeated 
measurements. The model may investigate effects for treatment (CFZ533 or placebo), time 
(visit week), baseline QMG score, treatment by time and baseline by time interactions. 
An unstructured covariance matrix may be used to model the correlations between the 
measurements in the same subject. In case of convergence issues, the covariance matrix that 
best fit the data will be chosen. The estimated treatment differences at each visit will be 
provided with 90% CI and 2-sided p-values.
Other potentially influent factors such as sex, age at onset of the disease, makers of baseline 
severity of the disease or prednisone dose may be explored.
11.5
Analysis of secondary and exploratory variables
11.5.1
Efficacy / Pharmacodynamics
The MGC composite is a key secondary endpoint. The changes from baseline in QMG scores 
at each visit of the treatment period (weeks 5, 9, 13, 17, 21 and 25) will be analyzed using a 
Bayesian model for repeated measurements. The model may investigate effects for treatment 
(CFZ533 or placebo), time (visit week), baseline QMG score, treatment by time and baseline 
by time interactions.  An unstructured covariance matrix may be used to model the 
correlations between the measurements in the same subject. In case of convergence issues, the 
covariance matrix that best fit the data will be chosen. The estimated treatment differences at 
each visit will be provided with 90% CI and 2-sided p-values.
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Other secondary efficacy variables include:
!
proportions of patients requiring rescue therapy (i.e. IV immunoglobulins or plasma 
exchange)
!
mean change from baseline in QMG Score and MGC Score at all visits
!
proportion of patients with improvement by ≥ 3 points in QMG score
!
proportion of patients with worsening by ≥ 3 points in QMG score
!
proportion of patients intolerant to steroid taper
!
proportion of patients who discontinued due to inefficacy or worsening
!
Mean change in the Myasthenia Gravis Activities of Daily Living Scales (MG-ADL, 
MG QOL-15).
The changes from baseline in MG-ADL and MG QOL-15 at each visit until week 25 will be 
analyzed using the main mixed model as described above for MGC.
The proportions of patients requiring rescue therapy between Week 1 and Week 25 (i.e. IV 
immunoglobulins or plasma exchange) will be described. Time to first rescue therapy will be 
described using Kaplan-Meier curves and compared between CFZ533 and placebo using the log-
rank test. In case of dropouts, the data will be censored at the last visit before or at Week 25.
The proportion of patients with improvement by ≥ 3 points in QMG score at Week 25, the 
proportion of patients with worsening by ≥ 3 points in QMG score at week 25, the proportion 
of patients intolerant to steroid taper and the proportion of patients who discontinued due to 
inefficacy or worsening before week 25 will be analyzed via logistic regression with treatment 
as a factor compared between CFZ533. Additional covariates such as sex, gender, age at onset 
of MG, QMG score at baseline will be explored. Odds ratios together with 90% CI and 
p-values will be provided for comparisons of CFZ533 versus placebo utilizing the logistic 
regression model fitted.
The statistical analysis for exploratory efficacy and PD variables will be described in the RAP.
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11.5.2
Safety
Vital signs
All vital signs data will be listed by treatment, subject, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment, subject and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment, subject, and visit/time and if normal ranges are 
available abnormalities will be flagged. Summary statistics will be provided by treatment and 
visit/time.
Adverse events
All information obtained on adverse events will be displayed by treatment and subject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A subject with multiple adverse events 
within a body system is only counted once towards the total of this body system.
11.5.3
Pharmacokinetics
Free CFZ533 plasma concentration data will be listed by treatment, subject, and 
visit/sampling time point. Descriptive summary statistics will be provided by treatment and 
visit/sampling time point, including the frequency (n, %) of concentrations below the LLOQ. 
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. An exception to this is Tmax where median, 
minimum and maximum will be presented. Concentrations below LLOQ will be treated as 
zero in summary statistics and will not be considered for PK parameter calculations. 
A geometric mean will not be reported if the dataset includes zero values. PK parameters will 
be calculated as described in Section 8.5 and will be listed by treatment and subject.
Population modeling of PK data using compartmental, non-linear or mechanistic approaches 
(i.e. together with PD endpoints), may be performed as appropriate, and will be reported in a 
separate, standalone modeling and simulation report. During modeling activities, the broad 
principles outlined in the FDA Guidance for Industry: Population PK, will be followed.
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11.6
Sample size calculation
The sample size is based on the primary efficacy endpoint and the primary analysis described 
in Section 11.4.2
A sample size of 36 evaluable patients (18 on CFZ533, 18 on placebo) was determined, 
assuming a SD of 5.5 (Zinman et al 2007) for the QMG endpoint. To account for 
approximately 20% anticipated dropouts, 44 patients will be randomized in this study (22 on 
CFZ533 and 22 on placebo). 
To account for potential discontinuations due to non-detectable AChR or MuSK 
autoantibodies, the sample size might be increased to compensate the discontinued 
seronegative patients.The operating characteristics of this design are shown on Figure 11-1
below. The probability of reaching the target efficacy (success) at final analysis is about 8% if 
CFZ533 is equal to placebo, and it is >80% if the true difference between CFZ533 and 
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placebo is ≥ 4.5. At the planned IA the probability of success is 42% if the true difference 
between CFZ533 and placebo is ≥ 4.5 and the probability of stopping for futility is 5% if 
CFZ533 is equal to placebo. This sample size was considered adequate to preliminarily 
evaluate the efficacy of CFZ533 in the treatment of myasthenia gravis. 
Figure 11-1
Operating characteristics for the planned interim and final analyses
Figure 11-1 shows the operating characteristics curves for the planned interim and final analyses. 
The horizontal axis shows the difference CFZ533 minus placebo in mean QMG change from baseline
(from 0 to 6). The vertical axis displays the probabilities (i) success (target efficacy, green curves)), 
(ii) futility (red curves), and (iii) indeterminate (neither success nor futility achieved (yellow curves).
11.7
Power for analysis of key secondary variables
MGC score is a key secondary variable. It ranges from 0 to 53, with a SD of 6.6. The change 
form baseline is assumed to be normally distributed. With 36 patients, the study will have 
more than 80% power to detect a difference of 4.7 between CFZ533 and placebo mean change 
from baseline using a 1-sided t-test at 10% significance level.
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12
Ethical considerations
12.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 
21, and Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid 
down in the Declaration of Helsinki.
12.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution should obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g. advertisements) and any other written information to be provided to subjects. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
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agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
For multi-center trials, a Coordinating Investigator will be selected by Novartis around the 
time of Last Patient Last Visit to be a reviewer and signatory for the clinical study report.
12.3
Publication of study protocol and results
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this trial will be either submitted for publication 
and/or posted in a publicly accessible database of clinical trial results.
13
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances should an 
investigator collect additional data or conduct any additional procedures for any research 
related purpose involving any investigational drugs.
Investigators must apply due diligence to avoid protocol deviations. If the investigator feels a 
protocol deviation would improve the conduct of the study this must be considered a protocol 
amendment, and unless such an amendment is agreed upon by Novartis and approved by the 
IRB/IEC/REB it cannot be implemented. All significant protocol deviations will be recorded 
and reported in the CSR.
13.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are intended to eliminate an apparent immediate hazard to subjects 
may be implemented, provided the Health Authorities and the reviewing IRB/IEC are 
subsequently notified by protocol amendment.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the CTL 
should be informed and (serious) adverse event reporting requirements (Section 9) followed 
as appropriate.


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14
References
Available upon request
Barth D, Nabavi M, Ng E, et al. (2011) Comparison of IVIG and PLEX in patients with 
myasthenia gravis. Neurology. 76:2017-2023.
Bedlack RS, Simmel D, Bosworth H, et al. (2005) Quantitative myasthenia gravis score: 
assessment of responsiveness and longitudinal validity. Neurology. 64:1968-1970.
Burns TM, Conaway M, Sanders DB et al (2010) The MG Composite: A valid and reliable 
outcome measure for myasthenia gravis. Neurology 4;74(18):1434-40. 
Burns TM, Grouse CK, Wolfe GI et al. (2011) The MG-QOL15 for following the health-
related quality of life of patients with myasthenia gravis. Muscle Nerve; 43(1):14-8. 
Ha JC, Richman DP (2014) Myasthenia gravis and related disorders: Pathology and molecular 
pathogenesis. Biochimica et Biophysica Acta 1852: 651-657
Howard JF, Barohn RJ, Cutter GR et al. (2013) A randomized, double-blind, placebo-
controlled phase II study of eculizumab in patients with refractory generalized myasthenia 
gravis; Muscle Nerve; 48(1):76-84.
Jaretzki A, Barohn RJ, Ernstoff RM et al. (2000) Myasthenia gravis: recommendations for 
clinical research standards. Task Force of the Medical Scientific Advisory Board of the 
Myasthenia Gravis Foundation of America. Ann Thorac Surg. 70(1):327-34.
Le Panse R, Cizeron-Clairac G, Bismuth J (2006) Microarrays reveal distinct gene signatures 
in the thymus of seropositive and seronegative myasthenia gravis patients and the role of CC 
chemokine ligand 21 in thymic hyperplasia.  J Immunol; 177(11):7868-79.
Mehndiratta MM, Pandey S, Kuntzer T. (2014) Acetylcholinesterase inhibitor treatment for 
myasthenia gravis. Cochrane Database of Systematic Reviews. vol:10: 1361-6137
Meriggioli MN, Sanders DB (2009) Autoimmune myasthenia gravis: emerging clinical and 
biological heterogeneity. Lancet Neurol. 8(5): 475-490.
Muppidi S, Wolfe GI, Conaway M, et al. (2011) MG-ADL: still a relevant outcome measure. 
Muscle Nerve. 44(5):727-31. 
Muscle Study Group (2008) A trial of mycophenolate mofetil with prednisone as initial 
immunotherapy in myasthenia gravis. Neurology. 71(6):394-9.
Sharshar T, Chevret S, Mazighi M, et al. (2000) Validity and reliability of two muscle 
strength scores commonly used as endpoints in assessing treatment of myasthenia gravis. J 
Neurol. 247:286-290. 
Trouth AJ, Dabi A, Solieman N, et al. (2012) Myasthenia gravis: a review. Autoimmune Dis. 
2012:874680.
Zinman L, Ng E, Bril V. (2007) IV immunoglobulin in patients with myasthenia gravis: a 
randomized controlled trial. Neurology. 68:837-841.

SAP_001.pdf: 
Biostatistics & Statistical Programming /
Novartis Institutes for BioMedical Research
CFZ533
Study CCFZ533X2204
A multi-center, randomized, double-blind, 
placebo-controlled, parallel group study to preliminarily 
evaluate the safety, tolerability, pharmacokinetics and 
efficacy of CFZ533 in patients with moderate to 
severe myasthenia gravis
RAP Module 3: Detailed Statistical Methodology
Document type:
Amendment 1 RAP Module 3: Detailed Statistical Methodology
Document status:
Final
Release date
18 November 2016
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Personal Data


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CCFZ533X2204
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................3
1
Introduction to RAP documentation....................................................................................5
1.1
Scope........................................................................................................................5
1.2
Changes to RAP documentation (M3).....................................................................5
2
Study objectives and design ................................................................................................6
2.1
Study objectives.......................................................................................................6
2.1.1
Primary objectives...................................................................................6
2.1.2
Secondary objectives...............................................................................6
2.2
Study design and treatment......................................................................................7
3
First interpretable results (FIR) ...........................................................................................8
5
Statistical methods: Analysis sets........................................................................................9
6
Statistical methods for Pharmacokinetic (PK) parameters................................................10
6.1.1
Variables ...............................................................................................10
6.1.3
Statistical model, assumptions and hypotheses.....................................11
6.1.4
Model checking procedures ..................................................................11
6.1.5
Graphical presentation of results...........................................................11
7
Statistical methods for Pharmacodynamic (PD) parameters .............................................11
7.1
Primary objective...................................................................................................11
7.1.1
Variables ...............................................................................................11
7.1.2
Descriptive analyses..............................................................................11
7.1.4
Graphical presentation of results...........................................................12
7.1.5
Handling of missing values/censoring/discontinuations.......................12
7.2
Secondary objectives .............................................................................................13
7.2.1
Variables ...............................................................................................13
7.2.2
Descriptive analyses..............................................................................13
7.2.3
Statistical model, assumptions and hypotheses.....................................14
7.2.4
Model checking procedures ..................................................................14
7.2.5
Graphical presentation of results...........................................................14
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8
Statistical methods for safety and tolerability data............................................................15
8.1.1
Variables ...............................................................................................15
8.1.2
Descriptive analyses..............................................................................15
8.1.3
Graphical presentation of results...........................................................16
9
Statistical methods for Biomarker data .............................................................................17
10 Reference list.....................................................................................................................17
List of tables
Table 5-1
Protocol deviation codes and analysis sets .............................................................9
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1
Introduction to RAP documentation
1.1
Scope
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CCFZ533X2204”.
Module 3 (M3) provides the description of the statistical methodology used to analyze the 
data, Module 7 (M7) details the presentation of the data, including shells of summary tables, 
figures and listings, and Module 8 (M8) contains programming specifications e.g. for derived 
variables and derived datasets, to support the creation of CSR outputs.
1.2
Changes to RAP documentation (M3)
Refer to corresponding guidances and NIBR RAP Addendum template for detailed 
information on the requirements of documenting changes to RAP documentation.
For the statistical methodology (M3), any major changes to the statistical methodology 
should be reflected in the RAP M3 documentation via version control (M3 amendment) (new 
document version to be approved by the trial team as the original module).
Such major changes could include (but are not limited to):

change in statistical methodology

substantial change in (derivation of) main endpoint

substantial change in study design (e.g. protocol amendment introducing new multiple-
dose cohorts in a so far single-dose trial)
Such changes may also require a protocol amendment to ensure consistency. In addition they 
need to be mentioned (high-level) in the CSR (section for changes to planned analysis).
Minor changes to the RAP M3 documentation can be captured e.g. by a study note to file / 
note in RAP Addendum or within the CSR itself. 
 
 Corrections of typographical errors or modification 
of spelling (from English to American, for example) do not need to be incorporated into the 
RAP M3 documentation.
Analyses and outputs related to additional exploratory ad-hoc requests used for reporting are 
regarded minor changes and should be documented in the RAP addendum (no RAP 
amendment necessary). 
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2
Study objectives and design 
2.1
Study objectives
2.1.1
Primary objectives

To evaluate the safety and tolerability of IV CFZ533 as an add-on therapy to standard 
of care in patients with moderate to severe Myasthenia gravis (MG) throughout the 
study

To evaluate the efficacy of IV CFZ533 as an add-on therapy to standard of care in 
patients with moderate to severe MG
2.1.2
Secondary objectives 

To evaluate the efficacy of IV CFZ533 using relevant MG related outcome measures 
throughout the 24 weeks treatment period

To evaluate the decay in efficacy of IV CFZ533 using relevant MG related outcome 
measures throughout the 24 weeks follow-up period

To evaluate changes in patient’s quality of life (QOL) throughout the 24 weeks 
treatment period

To evaluate the PK of 2-hour IV infusion of CFZ533 at 10 mg/kg administered q4w 
for 6 doses (endpoint: free CFZ533 in plasma)

To evaluate the PD of CFZ533 (CD40 saturation on B cells, extent/duration of target 
engagement (endpoints: free CD40 on B cells, total CD40 on B cells, and total soluble 
CD40 in plasma)

To assess immunogenicity in CFZ533-treated patients and in placebo-treated patients 
(pre-existing anti-drug antibodies)
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2.2
Study design and treatment
This is a randomized double-blind, placebo controlled, non-confirmatory study to 
preliminarily evaluate the safety, tolerability, PK/PD, and efficacy of IV CFZ533 
administered every four weeks (q4w) over a 24 week treatment period in patients with 
moderate to severe MG. The investigational drug or placebo will be administered in addition 
to standard of care therapy for MG.
Patients should remain on their standard of care therapies and the dose should be maintained 
at a constant level during the study. For patients that are receiving corticosteroids at baseline, 
a predefined steroid tapering will be allowed after achievement of minimal manifestations 
(MM) state (Jaretzki et al 2000).
Patients on cholinesterase inhibitors (CI) should remain on stable doses throughout the study, 
but CIs should not be taken for at least 12 hours prior to QMG and MG composite testing at 
each visit, in order to reduce fluctuations in performance on functional tests due to the 
temporary symptomatic effects associated with CI use.
For each patient, there will be two screening visits. Most of the screening assessments are 
done during Screening Visit 1 (Day -28 to Day -8), while Screening Visit 2 (Day -7 to Day -3) 
is performed to collect a blood sample to allow laboratory results (chemistry, hematology, and 
pregnancy test, if applicable) to be available prior to randomization on Day 1. All laboratory 
results must be available prior to dosing (Day 1-Visit 3) and meet eligibility criteria. Once 
continued eligibility is confirmed, patients will be assigned a randomization number at Day 1 
and receive CFZ533 or placebo via a 2-hour intravenous infusion. Patients will be dosed 
every four weeks (q4w) according to their randomization for a total of 6 doses on Day 1 ± 2 
(Week 1), Day 29 ± 2 (Week 5), Day 57 ± 2 (Week 9), Day 85 ± 2 (Week 13), Day 113 ± 2 
(Week 17) and Day 141 ± 2 (Week 21). The treatment period (24 weeks) will be followed by 
a safety follow-up period of other 24 weeks. The duration of the entire study including 
screening will be approximately 52 weeks.
An overview of the study design is given in Figure 2-1.
Figure 2-1
Study design


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3
First interpretable results (FIR)
First interpretable results (FIR) will be provided for this trial.
The study FIR template (mock slides) can be found in CREDI in the study RAP folder.
The template shows the analysis / results to be presented in the FIR. Study outputs required to 
be created at the time of the FIR will be highlighted in RAP Module 7 and marked as “Key” 
in the M9.1 Tracking sheet output list. 
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5
Statistical methods: Analysis sets
For subjects for which the actual treatment received does not match the randomized treatment 
the treatment actually received will be used for the analysis.
The full analysis set (FAS) will include all patients who received any study drug.
The safety analysis set will include patients who received any study drug.
The PD analysis set will include all patients who received any study drug and with no 
protocol deviations with relevant impact on efficacy data.
The PK analysis set will include patients with available PK data and no protocol deviations 
with relevant impact on PK data.
The analysis sets and protocol deviation codes are related as follows:
Table 5-1
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from all (safety) analysis in case of these 
PDs: 
Exclude subject completely 
from all (safety) analysis 
sets
I##
ICF not obtained
I##
ICF was signed after the other screening 
procedure; ICF wrong version was obtained.
E##
xxxxxxx
Subjects are excluded from PK analysis in case of these PDs: 
Exclude subject from PK 
analysis set 
I06
Deviation from inclusion criterion 6.
YES
E##
xxxxxxx
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Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from PD analysis in case of these PDs:
Exclude subject from PD 
analysis set
I06
Deviation from inclusion criterion 6.
YES
E##
xxxxxxx
Subjects are excluded from PK and PD analysis in case of these 
PDs:
Exclude subject from PK and 
PD analysis sets
I06
Deviation from inclusion criterion 6.
YES
E##
xxxxxxx
Subjects are excluded from PD analysis at the impacted visit in
case of these PDs:
Exclude subject from PD 
analysis set at the impacted 
visit
M02
Use of Cholinesterase inhibitors less than 12 
hours prior to QMG and MGC testing.
YES
If updates to this table are needed, an amendment to RAP M3 needs to be implemented prior 
to DBL.
6
Statistical methods for Pharmacokinetic (PK) parameters
6.1.1
Variables 
The following PK parameters will be determined, if data permit, using the actual recorded 
sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 6.2 or 
higher): Cmax, Cmax,ss, Cmin,ss, Tmax, AUCtau, AUCtau,ss and Cav,ss from the plasma 
concentration-time data.
In the zz.xpt file in GPSII (merge file), PK concentration (free CFZ533 in plasma) will be 
expressed in unit ‘microg/mL’ (in addition to ‘nanog/mL’), and time will be expressed in unit 
‘day’ (in addition to ‘hours’). Two variables for the elapsed time will be provided: (i) elapsed 
time since first dose, and (ii) elapsed time since last dose.
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6.1.3
Statistical model, assumptions and hypotheses
Not applicable.
6.1.4
Model checking procedures
Not applicable.
6.1.5
Graphical presentation of results
Arithmetic mean (SD) and geometric mean (95% CI) plasma concentration data will be 
plotted across time.
Overlaying individual plasma concentration-time profiles will be generated.
7
Statistical methods for Pharmacodynamic (PD) parameters
7.1
Primary objective
The primary objectives of this study are to preliminarily evaluate the safety, tolerability and 
efficacy of IV CFZ533 in moderate to severe Myasthenia Gravis patients after 24 weeks of 
treatment as an add-on therapy to standard of care as compared to placebo.
7.1.1
Variables 
The primary efficacy variable is the change from baseline in QMG score after 24 weeks of 
treatment (at Week 25 visit). The baseline value will be the predose assessment on Day 1. It is 
assumed that the change from baseline in QMG score is normally distributed.
The analysis of safety and tolerability is descriptive and detailed below in Section 8.
7.1.2
Descriptive analyses
Descriptive summary statistics will be provided by treatment and visit/sampling time point. 
Summary statistics will include mean, SD, median, minimum and maximum. 
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7.1.4
Graphical presentation of results
Arithmetic mean (±SD) of QMG score and change from baseline in QMG score will be 
plotted across time. 
The posterior probability distribution from the Bayesian analysis will be plotted at Week 25.
7.1.5
Handling of missing values/censoring/discontinuations
No imputation of missing data dropouts or any other reason will be done. The main analysis 
model will include all data of all patients in the PD analysis set, including dropouts.
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7.2
Secondary objectives
7.2.1
Variables 
Secondary efficacy/pharmacodynamic variables include:

change from baseline in MGC score after 24 weeks of treatment (at Week 25 visit)

proportion of patients requiring rescue therapy (i.e. IV immunoglobulins or plasma 
exchange).

mean change from baseline in QMG Score and MGC Score at all visits

proportion of patients with improvement by ≥ 3 points in QMG score

proportion of patients with worsening by ≥ 3 points in QMG score

proportion of patients intolerant to steroid taper (i.e the proportion of patients that will 
require to reinstitute their previous steroid dose)

proportion of patients who discontinued due to inefficacy or worsening

Mean change in the Myasthenia Gravis Activities of Daily Living Scales (MG-ADL, 
MG QOL-15).

Free and total CD40 on B cells (peripheral blood)

Total soluble CD40 in plasma.
The baseline value for all secondary variables will be the predose assessment on Day 1.
An improvement is a reduction in QMG score and worsening is an increase in QMG score.
7.2.2
Descriptive analyses
Descriptive summary statistics of efficacy data will be provided by treatment and 
visit/sampling time point. Summary statistics will include mean, SD, median, minimum and 
maximum.
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7.2.3
Statistical model, assumptions and hypotheses
The changes from baseline in MGC scores at each visit of the treatment period (weeks 5, 9, 13, 
17, 21 and 25) will be analyzed using a mixed effect model for repeated measurements. The 
model may investigate effects for treatment (CFZ533 or placebo), time (visit week), baseline 
MGC score, treatment by time and baseline by time interactions. An unstructured covariance 
matrix may be used to model the correlations between the measurements in the same subject. 
In case of convergence issues, the covariance matrix that best fit the data will be chosen. The 
estimated treatment differences at each visit will be provided with 90% CI and 2-sided p-
values.
Other potentially influent factors such as sex, age at onset of the disease, makers of baseline 
severity of the disease or prednisone dose may be explored.
The changes from baseline in MG-ADL and MG QOL-15 at each visit until Week 25 will be 
analyzed using the main mixed model as described above for MGC.
The proportions of patients requiring rescue therapy between Week 1 and Week 25 (i.e. IV 
immunoglobulins or plasma exchange) will be summarized. Time to first rescue therapy will 
be described using Kaplan-Meier curves and compared between CFZ533 and placebo using 
the logrank test. In case of dropouts, the data will be censored at the last visit before or at 
Week 25.
The changes from baseline in MGC score at Week 25 will be analyzed using the Bayesian 
model described above. 
The proportion of patients with improvement by ≥ 3 points in QMG score at Week 25, the 
proportion of patients with worsening by ≥ 3 points in QMG score at Week 25, the proportion 
of patients intolerant to steroid taper and the proportion of patients who discontinued due to 
inefficacy or worsening before Week 25 will be analyzed via logistic regression with 
treatment as a factor (and baseline value as a covariate if relevant) compared between CFZ533
and placebo. Additional covariates such as sex, gender, age at onset of MG, QMG score at 
baseline will be explored. Odds ratios together with 90% CI and p-values will be provided for 
comparisons of CFZ533 versus placebo utilizing the logistic regression model fitted.
7.2.4
Model checking procedures
In case of convergence issues, the covariance matrix that best fit the data will be chosen.
Diagnostic plots will be provided.
7.2.5
Graphical presentation of results
Arithmetic mean (±SD) of secondary variables (MGC, MG-ADL, MG QOL-15, CD40 on B 
cells and total soluble CD40 in plasma) and their change from baseline will be plotted across 
time. 
The proportion of patients requiring rescue therapy, the proportion of patients with 
improvement by ≥ 3 points in QMG score, the proportion of patients with worsening by ≥ 3 
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points in QMG score, the proportion of patients intolerant to steroid taper and the proportion 
of patients who discontinued due to inefficacy or worsening will be shown via bar charts. 
8
Statistical methods for safety and tolerability data
8.1.1
Variables 
Adverse events, serious adverse events (SAEs), vital signs (blood pressure, pulse rate, body 
temperature), ECG intervals, laboratory measurements, immunogenicity, as well as subject 
demographics, baseline characteristics, and treatment information.
8.1.2
Descriptive analyses
All safety analyses will be performed on the safety analysis set; patients will be analyzed as 
treated.
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Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment group and 
subject. Summary statistics will be provided by treatment group.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and subject.
Treatment
Data for study drug administration, rescue medication and concomitant therapies will be listed 
by treatment group and subject.
Vital signs
All vital signs data will be listed by treatment, subject, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time.
ECG evaluations
All ECG data will be listed by treatment, subject and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by treatment, subject, and visit/time and if normal ranges are 
available abnormalities will be flagged. A separate listing is provided presenting all 
parameters in a subject with any abnormal values. Summary statistics will be provided by 
treatment and visit/time.
Adverse events
All information obtained on adverse events will be displayed by treatment and subject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A subject with multiple adverse events 
within a body system is only counted once towards the total of this body system and treatment.
Serum total immunoglobulin G (IgG) and M (IgM) 
Serum total IgG and IgM and percentage change from baseline will be listed by subject and 
visit/time. No descriptive summary statistics will be provided.
Immunogenicity
All immunogenicity results will be listed by subject and visit/time. No descriptive summary 
statistics will be provided.
8.1.3
Graphical presentation of results
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
created.


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Statistical methods for Biomarker data
All biomarker data (except for hypothesis-free platforms) will be listed by treatment, subject, 
and visit/time. Summary statistics for each variable (absolute and change from baseline) will 
be provided by treatment and visit/time.
In the summary tables, the frequency (n, %) of values below the LLOQ and above the ULOQ, 
respectively, will be included.
In case of censored values (values below the LLOQ and/or values above the ULOQ), the 
summary statistics (arithmetic mean, SD, geometric mean and CV% of geometric mean) will 
be calculated as the maximum likelihood estimates using a parametric model for data that can 
be right censored and left censored assuming the data being normally or log-normally 
distributed.
Concomitant immunosuppressive therapies trough levels
Plasma/blood concentrations for mycophenolic acid (MPA), azathioprine metabolite(s) or 
cyclosporine will be listed by treatment, subject, and visit/sampling time point. No descriptive 
summary statistics will be provided.
10
Reference list
Jaretzki A, Barohn RJ, Ernstoff RM et al. (2000) Myasthenia gravis: recommendations for 
clinical research standards. Task Force of the Medical Scientific Advisory Board of the 
Myasthenia Gravis Foundation of America. Ann Thorac Surg. 70(1):327-34.
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