Conditions: Graves' Disease
Keywords: Graves' disease Hyperthyroidism CFZ533 TSH
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 15
Healthy volunteers: no

Brief summary:
An open label study to evaluate the safety and efficacy of CFZ533 following 12 weeks treatment in patients with Graves' disease

Detailed description:

Arms:
arm 1: CFZ533 intravenously over approximately one hour

Interventions: intervention 1: CFZ533
Intervention descriptions: intervention 1: CFZ533 intravenously over approximately one hour

Protocol document:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
CFZ533
Clinical Trial Protocol CCFZ533X2205
An open label study to evaluate the safety and efficacy of 
12 week treatment with CFZ533 in patients with 
Graves' disease
Authors:
 
Document type:
Amended Protocol Version
EUDRACT number:
2015-005564-41
Version number:
v02 (Clean)
Development phase:
II 
Release date:
18-May-2016
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Personal Data 
C


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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 Site Operations Manual. 


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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...........................................................................9
Protocol synopsis...............................................................................................................13
1
Introduction .......................................................................................................................16
1.1
Background............................................................................................................16
1.1.1
Relevant data summary.........................................................................17
1.2
Study purpose ........................................................................................................22
2
Study objectives.................................................................................................................22
2.1
Primary objective...................................................................................................22
2.2
Secondary objective...............................................................................................22
2.3
Exploratory objectives...........................................................................................22
3
Investigational plan ...........................................................................................................23
3.1
Study design...........................................................................................................23
3.2
Rationale of study design.......................................................................................25
3.3
Rationale of dose/regimen, duration of treatment .................................................26
3.4
Rationale for choice of comparator .......................................................................28
3.5
Purpose and timing of interim analyses/design adaptations..................................28
3.6
Risks and benefits..................................................................................................29
3.6.1
Potential benefit ....................................................................................29
3.6.2
Potential risks associated with CFZ533 administration and their 
mitigation ..............................................................................................29
4
Population..........................................................................................................................32
4.1
Inclusion criteria ....................................................................................................32
4.2
Exclusion criteria...................................................................................................33
5
Restrictions for study patients ...........................................................................................35
5.1
Contraception requirements...................................................................................35
5.2
Prohibited treatment...............................................................................................36
5.3
Dietary, fluid, smoking, and other restrictions ......................................................36
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6
Treatment...........................................................................................................................36
6.1
Study treatment......................................................................................................36
6.1.1
Investigational treatment.......................................................................36
6.2
Treatment arms ......................................................................................................36
6.3
Permitted dose adjustments and interruptions of study treatment.........................36
6.4
Treatment assignment............................................................................................36
6.5
Treatment blinding.................................................................................................37
6.6
Emergency breaking of assigned treatment code ..................................................37
6.7
Treatment exposure and compliance .....................................................................37
6.8
Recommended treatment of adverse events ..........................................................37
6.9
Rescue medication.................................................................................................37
6.10
Concomitant treatment...........................................................................................38
7
Discontinuation and study completion ..............................................................................38
7.1
Discontinuation of study treatment........................................................................38
7.2
Study completion and post-study treatment ..........................................................39
7.2.1
Lost to follow-up...................................................................................39
7.3
Withdrawal of consent...........................................................................................40
7.4
Study stopping rules ..............................................................................................40
7.5
Early study termination..........................................................................................41
8
Procedures and assessments ..............................................................................................42
8.1
Informed consent procedures.................................................................................45
8.2
Patient demographics/other baseline characteristics .............................................46
8.3
Pharmacodynamics................................................................................................46
8.4
Safety.....................................................................................................................47
8.4.1
Physical examination ............................................................................47
8.4.2
Vital signs..............................................................................................47
8.4.3
Height and weight .................................................................................47
8.4.4
Laboratory evaluations..........................................................................48
8.4.5
Electrocardiogram (ECG) .....................................................................49
8.4.6
Pregnancy and assessments of fertility .................................................49
8.4.7
Other safety evaluations........................................................................49
8.4.8
Immunogenicity ....................................................................................50
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8.5
Pharmacokinetics...................................................................................................50
8.6
Other assessments..................................................................................................51
9
Safety monitoring ..............................................................................................................52
9.1
Adverse events.......................................................................................................52
9.2
Serious adverse event reporting.............................................................................54
9.2.1
Definition of SAE .................................................................................54
9.2.2
SAE reporting........................................................................................55
9.3
Liver safety monitoring .........................................................................................55
9.4
Renal safety monitoring.........................................................................................58
9.5
Pregnancy reporting...............................................................................................59
9.6
Early phase safety monitoring ...............................................................................60
10 Data review and database management.............................................................................60
10.1
Site monitoring ......................................................................................................60
10.2
Data collection.......................................................................................................61
10.3
Data Monitoring Committee..................................................................................62
10.4
Adjudication Committee........................................................................................62
11 Data analysis......................................................................................................................62
11.1
Analysis sets ..........................................................................................................62
11.2
Subject demographics and other baseline characteristics......................................62
11.3
Treatments (study drug, rescue medication, other concomitant therapies, 
compliance)............................................................................................................62
11.4
Analysis of the primary variable(s) .......................................................................62
11.4.1
Variable(s).............................................................................................62
11.4.2
Statistical model, hypothesis, and method of analysis..........................63
11.4.3
Handling of missing values/censoring/discontinuations.......................63
11.4.4
Supportive analyses...............................................................................63
11.5
Analysis of secondary and exploratory variables ..................................................63
11.5.2
Safety.....................................................................................................64
11.5.3
Pharmacokinetics ..................................................................................64
11.5.4
Pharmacokinetic / pharmacodynamic interactions................................65
11.5.5
Other assessments .................................................................................65
11.6
Sample size calculation..........................................................................................65
11.7
Power for analysis of key secondary variables......................................................65
11.8
Interim analyses .....................................................................................................65
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12 Ethical considerations........................................................................................................66
12.1
Regulatory and ethical compliance........................................................................66
12.2
Responsibilities of the investigator and IRB/IEC..................................................66
12.3
Publication of study protocol and results...............................................................66
13 Protocol adherence ............................................................................................................67
13.1
Protocol Amendments ...........................................................................................67
14 References .........................................................................................................................68
List of tables
Table 5-1
Prohibited treatment..............................................................................36
Table 8-1
Assessment schedule.............................................................................42
Table 9-1
Liver event and laboratory trigger definitions ......................................56
Table 9-2
Follow up requirements for liver events and laboratory triggers..........57
Table 9-3
Specific renal alert criteria and actions .................................................59
List of figures
Figure 3-1
Study design..........................................................................................24
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List of abbreviations
AE
adverse event
ALT
alanine aminotransferase
ALP
alkaline phosphatase
AST
aspartate aminotransferase
ATD
antithyroid drug 
BMI
Body Mass Index
BUN
blood urea nitrogen
CD-ROM
compact disc – read only memory
CFR
Code of Federal Regulation
CK
creatinine kinase
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CRP
C-reactive protein
CTC
Common Toxicity Criteria
CV
coefficient of variation
EC
Ethics Committee
ECG
electrocardiogram
EDC
Electronic Data Capture
ELISA
enzyme-linked immunosorbent assay
FT3
free T3 (triiodothyronine)
FT4
free T4 (thyroxine)
FDA
Food and Drug Administration
GC
germinal center
GCP
Good Clinical Practice
GD
Graves’ disease
γ-GT
gamma-glutamyl transferase
h
hour
HIV
human immunodeficiency virus
HUVEC
human umbilical vein endothelial cells
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee


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i.v.
intravenous
IRB
Institutional Review Board
KLH
keyhole limpet hemocyanin
LFT
liver function test
LDH
lactate dehydrogenase
LLOQ
lower limit of quantification
LLN
lower limit of normal
MedDRA
Medical Dictionary for Regulatory Activities 
mg
milligram(s)
ml
milliliter(s)
NCDS
Novartis Clinical Data Standards
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PPD
purified protein derivative
RA
rheumatoid arthritis
RBC
red blood cell(s)
REB
Research Ethics Board
SAE
serious adverse event
s.c.
subcutaneous
SD
standard deviation
SOM
site operations manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
total bilirubin
TDAR
T cell-dependent antibody responses
TRAb
thyrotropin receptor auto-antibodies
TSH
thyroid stimulating hormone
TSI
thyroid stimulating immunoglobulin
ULN
upper limit of normal
ULOQ
upper limit of quantification
WBC
white blood cell(s)
WHO
World Health Organization


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Pharmacokinetic definitions and symbols
AUC0-t
The area under the plasma (or serum or blood) concentration-time curve 
from time zero to time ‘t’ where t is a defined time point after administration 
[mass x time / volume]
AUClast
The area under the plasma (or serum or blood) concentration-time curve 
from time zero to the time of the last quantifiable concentration [mass x time 
/ volume]
Cmax
The observed maximum plasma (or serum or blood) concentration following 
drug administration [mass / volume]
Cmax,ss
The observed maximum plasma (or serum or blood) concentration following 
drug administration at steady state [mass / volume]
Cmin,ss
The lowest plasma (or serum or blood) concentration observed during a 
dosing interval at steady state [mass / volume]
Tmax
The time to reach the maximum concentration after drug administration 
[time]


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Protocol No. CCFZ533X2205
 
 
 
 
 
  
 
 


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Protocol No. CCFZ533X2205
Protocol synopsis
Protocol number
CFZ533X2205
Title
An open label study to evaluate the safety and efficacy of 12 week treatment 
with CFZ533 in patients with Graves' disease
Brief title
Safety and efficacy study of CFZ533 in Graves’ disease patients
Sponsor and Clinical 
Phase
Novartis 
Phase II
Intervention type
Drug
Study type
Interventional 
Purpose and 
rationale
To explore the potential effects of CFZ533, an anti-CD40 antibody, on thyroid 
function in patients with Graves' disease to determine if CFZ533 has an 
adequate clinical profile to warrant further clinical development in the disease
Primary Objective
To assess the effects of CFZ533 on thyroid function (TSH, free T4 and total 
T3) in Graves' disease  patients after 12 weeks of treatment
Secondary Objective
To assess the safety and tolerability of CFZ533 for up to 36 weeks
Study design
This is a non-confirmatory, open-label, one treatment arm study in patients 
with Graves’ disease.
A total of approximately 15 patients will be enrolled and treated with CFZ533 
to ensure approximately 12 completers. For each patient, the study will 
consist of a screening epoch of up to 28 days, a baseline evaluation, a 12-
week treatment epoch, 24-week follow up epoch after the last dosing of 
CFZ533 on Study Day 85, and a study completion evaluation on Study Day 
253. The baseline visit can be skipped and the baseline assessments would 
be completed prior to the study treatment on Day 1 if Day 1 is scheduled 
within 7 days of the screening visit. Patients who discontinue the drug 
before having completed 4 weeks of treatment (including 4 week efficacy and 
safety evaluations) will be replaced with a newly enrolled patient.
Patients who meet the eligibility criteria at screening will be admitted to 
baseline evaluations. Eligible patients will enter the study to receive treatment 
with CFZ533 at 10 mg/kg IV infusion over approximately one hour. All IV 
infusions will take place in a monitored facility. Patients will be monitored 
closely for at least 2 hours after the completion of IV infusion, at the discretion 
of the Investigator, for vital signs and adverse events, including development 
of an injection reaction. Patients will be discharged if the investigator 
identifies no safety concerns.
Eligible patients will visit the study center in the morning of Study Days 1, 15, 
29, 57 and 85 for IV administration of CFZ533. PK/PD blood samples will be 
collected during study center visits prior to the dose and 2-hours post-dose.
Patients will return to the site periodically for follow up assessments (safety, 
PK and PD) as defined in the assessment table. The End of Study visit will 
take place on Day 253.


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Population
The study population will be comprised of male and female patients aged 18 
to 65 years old with Graves’ disease hyperthyroidism. Approximately fifteen 
patients will be enrolled with a goal of 12 patients completing the study.
Patients may be replaced if they withdraw consent or drop out of the study for 
reasons other than discontinuation by the investigator due to adverse events, 
and will be discussed on a case by case basis with the sponsor.
Key inclusion 
criteria

Male and female patients 18 to 65 years of age included.

Women of child-bearing potential must be willing to use highly 
effective methods of contraception during the study treatment epoch 
and for 12 weeks after the last study treatment. 

Graves’ hyperthyroidism  (Baskin et al 2002) , with the following labs 
measured at screening:

TSH<LLN and either FT3>ULN or FT4> ULN 
 

Patients must weigh at least 40 kg to participate in the study
Key exclusion 
criteria

History of treatment of Graves' disease with radio-iodine ablation or 
thyroidectomy and/or current treatment with anti-thyroid drugs 
(methimazole or propylthiouracil) within one week of starting the study 
treatment

History of hyperthyroidism not caused by Graves’ disease (e.g. toxic 
multinodular goiter, autonomous thyroid nodule, or acute inflammatory 
thyroiditis) and/or history or presence of thyroid storm (fever, profuse 
sweating, vomiting, diarrhea, delirium, severe weakness, seizures, 
markedly irregular heartbeat, yellow skin and eyes (jaundice), severe low 
blood pressure, and coma).  

Previous treatment with a B cell-depleting biologic agent or any other 
immune-modulatory biologic agent within 5 half-lives (experimental or 
approved).

History of recurrent clinically significant infection or of recurrent bacterial 
infections with encapsulated organisms.

History of primary or secondary immunodeficiency, including a positive 
HIV (ELISA and Western blot) test result.

History or evidence of tuberculosis by either of the following tests:

Positive PPD skin test (size of induration measured after 48-72 
hours, and a positive result is defined as an induration of ≥ 5mm or 
according to local practice/guidelines) OR

Positive QuantiFERON TB-Gold test 

Plans for immunization with a live vaccine within a 2-month period before 
enrollment or during the study period.

Treatment with immunomodulatory drugs, such as cyclosporine A, 
methotrexate, and/or cyclophosphamide within 3 months from baseline. 
Glucocorticosteroid therapy with prednisolone up to 10 mg daily is 
permitted if patients are on stable dose for more than 3 months before 
enrollment in the study.

Pregnant, breastfeeding females, and women of child bearing potential 
unless they are using highly effective contraception
Investigational and 
reference therapy

Patients will receive CFZ533 10mg/kg IV infusion on Study Days 1, 15, 
29, 57, and 85. 


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Efficacy/PD 
assessments

TSH

Free T4

Total T3
Safety assessments

Physical examinations

ECG

Vital signs (BP, HR, pulse, temperature)

Hematology

Blood chemistry

Urinalysis

Pregnancy test

Blood coagulation panel

Monitoring for AEs/SAEs 
Data analysis
One of the primary aims of this study is to assess the effects of CFZ533 on 
thyroid function, focusing on TSH, free T4 and total T3 levels, in Graves’ 
disease after 12 weeks of treatment. The effects of CFZ533 on thyroid 
function will be primarily assessed by the proportion of patients whose TSH 
levels normalize (>0.35 mU/L) after 12 weeks of treatment. Another important 
aim of this study is to assess the effects of CFZ533 on free T4 and total T3 
after 12 weeks of treatment. 
One of the main efficacy criteria is to show that the proportion of patients with 
normalization of TSH (above 0.35 mU/L) after 12 weeks of treatment with 
CFZ533 is statistically greater than 5%, according to a 1-sided exact test for 
proportions with a 10% type I error. This will be achieved if we observe at 
least 3/12 responders since in that case the lower bound of an 80% 
confidence interval for the proportion of responders will be about 10%. The 
other two main efficacy criteria are to show that the average free T4 and total 
T3 levels are significantly reduced after 12 weeks of treatment, according to a 
1-sided paired t-test with a 10% type I error.
Key words

Graves’ disease (GD), hyperthyroidism

CFZ533

CD40, CD154

TSH

T3, T4

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1
Introduction
1.1
Background
Graves’ disease (GD) is an autoimmune disorder characterized by hyperthyroidism, diffuse 
goiter, ophthalmopathy and rarely, dermopathy
(Weetman 2000). The underlying 
pathogenesis of GD is the production of autoantibodies that activate the thyroid stimulating 
hormone (TSH) receptor in the thyroid gland, leading to hyperthyroidism and asso ciated 
symptoms. GD affects ~1% of the adult population. Treatment strategies for GD include 
pharmacotherapy with anti-thyroid drugs (ATD) or thyroid ablation with radioiodine or 
surgery. Treatment with ATD does not only require long term treatment (12-18 months), but 
also careful monitoring of patients for side effects such as agranulocytosis and hepatotoxicity
(Toft and Weetman 1998; Weetman 2000). In addition, the relapse rate is very high (50-60%) 
after ATD therapy withdrawal (Izumi et al 2005; Abraham et al 2005). Thyroid ablation with 
iodine or surgery is associated with complications and results in permanent hypothyroidism 
and the need for lifetime replacement of thyroid hormone. An ideal treatment for GD would 
address the underlying auto-immune pathogenesis of the disease, and would restore normal 
thyroid function. 
The CD40-CD154 (CD154 is the CD40L) pathway is thought to play an important role in the 
pathogenesis of GD by promoting auto-reactive B cell activation, intrathyroidal germinal 
center (GC) function (Armengol et al 2001), and anti-thyrotropin receptor auto-antibodies 
(TRAb) production. Furthermore, CD40 expression is increased in the thyroid glands of 
patients with GD (Hwang et al 2009), and overexpression of CD40 in thyroid glands of 
transgenic mice increased their susceptibility 
to experimental 
autoimmune 
GD
(Huber et al 2012). Furthermore, several single nucleotide polymorphisms in CD40 displayed 
significant association with GD as well as higher persistent levels of thyroglobulin antibodies 
and thyroid peroxidase (Jacobson et al 2007, Tomer et al 2002). Collectively these data 
suggest that blockade of CD40-CD54 interactions could provide a novel therapeutic approach 
for treating patients suffering GD.
  
 
 
 
 
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1.1.1
Relevant data summary
 
 
1.1.1.1
Non-clinical data
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1.1.1.2
Teratogenicity and reproductive toxicity data
 
 
 
 
 
 
1.1.1.3
Human safety and tolerability data
 
 
 
 
 
 
 
 
 
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1.1.1.4
Human pharmacokinetic data
 
 
 
 
 
 
 
 
1.1.1.5
Human pharmacodynamic data
 
 
 
 
 
 
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1.2
Study purpose
The purpose of the study is to explore the potential effects of CFZ533, an anti-CD40 antibody, 
on thyroid function in patients with GD to determine if CFZ533 has an adequate clinical 
profile to warrant further clinical development in GD.
2
Study objectives
2.1
Primary objective
Objective
Endpoint

To assess the effects of CFZ533 on 
thyroid function in Graves' disease  (GD) 
after 12 week treatment

TSH, free T4 and total T3
2.2
Secondary objective
Objective
Endpoint

To assess the safety and tolerability of 
CFZ533 (10 mg/kg IV for 12 weeks) up 
to 36 weeks

Adverse events
 
 
 
 
 
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3
Investigational plan
3.1
Study design
This is a non-confirmatory, open-label, one treatment arm study in patients with GD.
A total of approximately 15 patients will be enrolled and treated with CFZ533 to ensure 
approximately 12 completers.  For each patient, the study will consist of a screening epoch of 
up to 28 days, a baseline evaluation, a 12-week treatment epoch, 24-week follow up epoch
after the last dosing of CFZ533 on Study Day 85, and a study completion evaluation on Study 
Day 253. Patients who discontinue the drug before having completed 4 weeks of treatment 
and 4 week efficacy and safety evaluations will be replaced with a newly enrolled patient. 
The study completion assessments (End of Study; EOS) should be completed in patients who 
discontinue the study. The study design is presented in Figure 3-1.


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Figure 3-1
Study design
Patients who meet the eligibility criteria at screening will be admitted to baseline evaluations. 
Baseline evaluations may be started from Day -7 to allow completion of assessments prior to 
the treatment on Study Day 1. All baseline safety evaluation results must be available prior to 
dosing and meeting the eligibility criteria. The baseline visit (Visit 99) can be skipped and the 
baseline assessments would be completed prior to the study treatment on Day 1 (Visit 101) if 
Day 1 is scheduled within 7 days of the screening visit (Visit 1).
Eligible patients will enter the study to receive treatment with CFZ533 at 10 mg/kg IV over 
approximately one hour on Study Day 1. Patients will be monitored closely for at least 
2 hours, at the discretion of the Investigator, after the completion of IV administration of 
CFZ533 for vital signs and adverse events, including development of an injection reaction.
Eligible patients will visit the study center in the morning of Study Days 1, 15, 29, 57 and 85 
for IV administration of CFZ533. PK/PD blood samples will be collected as defined in the 
assessment schedule in Table 8-1 and safety assessment will be conducted for 2 hour or 
longer after completion of each IV infusion, at the discretion of the Investigator. Following 
satisfactory review of safety data by the Investigator, patients will be discharged from the site 
on the same day after completion of all assessments, provided there are no safety concerns. 
Patients will return to the site periodically for the follow up assessment (safety, PK and PD) 
on Study Days 113, 141, 169, 211, and 253 as defined in the Assessment table. Days for 
follow-up visits may be slightly flexible based on the patients’ schedule. More information 
about visit windows can be found in the SOM. 
The end of study visit/assessment will occur on Study Day 253, which will include study 
completion evaluations followed by discharge from the study.
Screening 
Period
Baseline
Period
Follow-up Period
Treatment Period
Investigational Drug
Day 
1
Up to Day -28 
Day -1
Day 1 to Day 85
Day 113 to Day 253
* * *
*
*
*
Dosing on Days 1, 15, 29, 57 and 85
EOS
Follow up visits on Days 113, 141, 169 and 211


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Throughout the study, patients can remain on their standard of care therapies established prior 
to treatment with study drug, unless outlined otherwise in this protocol, provided that the 
treatments are maintained at a constant level during the study.
Safety, PK and PD assessment will be taken at various time points as defined in Table 8-1. 
Safety assessments will include physical examinations, ECGs, vital signs, standard clinical 
laboratory evaluations (hematology, blood chemistry, urinalysis, pregnancy test, blood 
coagulation), and adverse event and serious adverse event monitoring. Immunogenicity 
assessments will be performed before, during and after the treatment period.
3.2
Rationale of study design
GD is an autoimmune disorder, characterized by the presence of circulating thyrotropin 
receptor auto-antibodies (TRAb), which are thought to be responsible for the development of 
hyperthyroidism. The interaction of CD40 on B cells with CD154 on T cells plays a key role 
in the production of TRAb. Additionally, intrathyroidal GCs have been implicated in the 
pathogenesis of GD (Armengol et al 2001). CD40 blockade with CFZ533 is expected to 
reduce the production of TRAb as well as disrupt intrathyroidal GCs. The current 
pharmacotherapy with anti-thyroid drugs (ATD) for GD requires long term treatment 
(12-18 months) with high relapse rate (50-60%), at the same time, requires careful safety 
monitoring during treatment period (Burch et al 2012). There is no current pharmacotherapy 
for GD that addresses the underlying pathogenesis, and CFZ533 has the potential to be a 
novel therapy, addressing the underlying pathogenesis. 
The objective of this study is to assess the potential effects of CFZ533 on TSH, which is 
expected to be normalized 
 This will be a 
non-confirmatory, open-label, one treatment arm study in patients with GD. The rationale and 
justification for the key design elements are as follows:
Open label:  TSH level is recommended as the single best screening test for hyperthyroidism 
by the American Association of Clinical Endocrinologists (Baskin et al 2002). The primary 
PD endpoint, TSH, in patients with GD is objective in nature, and shows very little random 
fluctuation over time (Heemstra et al 2008) in the absence of treatment. Another important 
aim of this study is to assess the effects of CFZ533 on free T4 and total T3 after 12 weeks of 
treatment . An open label study is therefore considered to be sufficient for the purpose of the 
planned endpoints.
No comparator: No previous clinical experience with an anti-CD40 blocking agent in patients 
with GD exists. Given the nature of TSH as described above, the likelihood of observing a 
response to placebo is very low. Data provided in (Heemstra et al 2008) regarding the natural 
variability of TSH levels in this patient population in the absence of treatment were used t o 
predict, via simulations, the proportion of patients treated with placebo that would be 
expected to rise above 0.3 mU/L within 12 weeks simply due to random variability. 
This proportion is predicted to be less than 1%.
 
 Therefore, inclusion of a placebo arm is 
considered unnecessary.
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Patient population: Graves’ hyperthyroid patients 
 
 
 
Withholding standard of care treatment: Withholding standard of care treatment for Graves’ 
hyperthyroidism (ATD, radio-Iodine or surgery) for 12 weeks during the clinical study 
treatment period is justified for two reasons: 
1) The presence of hyperthyroidism for 12 weeks is unlikely to result in permanent 
complications, especially when patients are adequately treated with beta blockers 
(e.g., if the heart rate is controlled) 
2) A delay of 12 weeks is unlikely to impact the ultimate efficacy and safety of definitive 
treatment for Graves’ hyperthyroidism. Patients will undergo rescue therapy with the 
standard of care for Graves' hyperthyroidism if they meet the stopping criteria. 
3.3
Rationale of dose/regimen, duration of treatment
Dosing rationale
The dosing rationale for this study is determined based on the safety, preliminary PK/PD data 
from the FIH study, and preclinical pharmacology data. It is further supported by adequate 
safety multiples from preclinical toxicological studies, relevant PD effects in tissues in 
non-human primates, and recently disclosed data from ASKP1240 in kidney transplantation.
The dosing regimen of 10 mg/kg Q4W with an additional dose at Day 15 is predicted to 
maintain the trough plasma concentration of CFZ533 above 50 µg/mL, which is thought to be 
needed to ensure complete CD40 pathway blockade in target tissues (Figure 3-2). 
In the thyroid glands of patients with Graves' disease, CD40 expression is increased
(Smith et al 1999, Hwang 2009, Mysliwiec et al 2007a, Mysliwiec et al 2007b). 
The additional dose on Day 15 is needed to overcome efficient target mediated disposition 
and loss of target saturation in tissues where CD40 expression is increased.
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 In Goldwater et al 2013 ASKP1240 demonstrated similar PK properties 
as compared to CFZ533. Modeling of disclosed PK data from ASKP1240 in Transplantation 
(Harland et al 2015) characterized the biology (expression and turnover) of CD40 in 
conditions where CD40 expression is increased. From a quantitative point of view, the 
biology of CD40 in GD is not fully characterized, but literature data have confirmed an 
increase of CD40 expression in these patients. The transplant situation is thought to represent 
these conditions. 
 
 
 
 
 
 
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Data for another monoclonal antibody that blocks CD40, ASKP1240 - A recent analysis of 
the disclosed PK/efficacy data from ASKP1240 (Astellas’ anti-CD40 antibody) in solid organ 
transplantation (Harland et al 2015) indicated that efficient target mediated antibody clearance 
in tissue could result in loss of CD40 blockade and likely loss of efficacy, as a consequence of 
a significant increase of CD40 expression in target tissues.
Duration of Treatment
No previous experience with an anti-CD40 blocking agent exists in patients with GD. CFZ533 
at 10 mg/kg IV is associated with up to 10 week full receptor occupancy (RO) in patients with 
RA. Therefore, 12-week treatment with CFZ533 at 10 mg/kg Q4W with an additional dose on 
Day 15 is anticipated to result in full CD40 RO up to approximately 5 months.
 
 
 
Therefore, 12-week of treatment with CFZ533 is considered to be 
necessary and sufficient to test the hypothesis whether or not CFZ533 could be a potential 
treatment for GD. In addition, follow up duration may be extended up to 365 days (52 weeks) 
if clinically relevant efficacy was observed during the treatment period or up to 5-month of 
full CD40 RO. The clinical relevant efficacy is referring to normalization of TSH after 12 
week treatment with CFZ533. Another important endpoints are effects of CFZ533 on free T4 
and total T3 after 12 weeks of treatment. Extended follow up of a patient will be terminated 
when a standard of care rescue therapy is initiated for treating Graves' hyperthyroidism.
3.4
Rationale for choice of comparator
Not applicable.
3.5
Purpose and timing of interim analyses/design adaptations
 
 
 
 
 
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3.6
Risks and benefits
3.6.1
Potential benefit
Based on the established role of both B cells and T cells in the pathogenesis of Graves’ 
disease, CFZ533 has a potential to become a novel therapy to address the underlying 
pathogenesis. CFZ533 has never been used in patients with Graves’ disease. Therefore, no 
statement can be made of its efficacy for patients participating in this study at this stage.
3.6.2
Potential risks associated with CFZ533 administration and their 
mitigation
Currently, limited data exists regarding the use of agents that block the CD40/CD154 pathway. 
Preclinical and Phase 1 data for CFZ533 as well as data from compounds acting on the same 
pathway (i.e., CD40-CD154) have been taken into account to estimate the potential risks 
associated with CFZ533. The risks to patients in this trial will be minimized by adherence to 
the eligibility criteria, close clinical monitoring, avoidance of prohibited treatments and 
overall adherence to terms outlined in this protocol. The current IB (Section 6, Investigator 
Guidance) also provides detailed instructions regarding the risks and their mitigation.
Acute hypersensitivity
Hypersensitivity or infusion reactions can manifest with itching, flushing, headache, 
nausea/vomiting, hypotension, urticaria, bronchospasm, or angioedema. 
 
 In this study, CFZ533 will be administered as an 
intravenous infusion where such hypersensitivity reactions can still occur. Patients will be 
monitored for at least 2 hours after the completion of CFZ533 IV infusion at each visit.
Immunogenicity
 
 
 Extrapolation of immunogenicity risks from healthy subjects to Graves’ 
disease patients is unknown and blood samples will be collected during this trial to assess the 
immunogenicity.
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Infections
Subjects treated with CFZ533 may be at an increased risk of infection. CD40 ligation is linked 
to the functional activity of antigen presentation, as well as T-cell priming, B-cell 
differentiation, antibody production and immune memory. 
Administration of CFZ533 is expected to result in general immunosuppression with a 
decreased capacity to mount a response to novel immunogens, including those of bacterial, 
viral, fungal and parasitic origin when full receptor occupancy has been achieved.
Although the ability to mount a primary immune response will be affected by CFZ533, the 
memory B-cell repertoire and immune recall response should remain intact and protective. 
In addition, subjects will have adequate preformed antibody to maintain protective humoral 
response for extended periods of time (months).
 
In patients 
receiving weekly to bi-monthly administration of the parent antibody lucatumumab, the rate 
of infection was very low and similar to control, supporting these stated hypotheses.
Patients with current, active or latent infection susceptible to reactivation will be excluded 
from entry into the present clinical study.
The risk of infection may increase if CFZ533 is combined with steroids or strong 
immunosuppressive drugs. Patients who are HIV-positive or have taken immunomodulatory 
drugs, such as cyclosporine A, methotrexate, and/or cyclophosphamide within 3 months at the 
baseline will be excluded.
Patients enrolled in the current study will be monitored regularly and carefully for signs and 
symptoms which might indicate a severe infection. Patients will be informed to contact the 
study physician if they present with signs and symptoms of an infection such as fever, nausea, 
myalgia, headache, arthralgia, chills, diarrhea, stiff neck, and malaise for further assessment 
and treatment if necessary.
Lymphadenopathy
 
 
 
 
 
 
The investigator should pay special attention to lymph nodes in patients during physical 
assessments including unusual lymphadenopathy in the absence of infection.
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Lymphoproliferative disorders
 
 
 The clinician should monitor hematology regularly for changes 
consistent with a lymphoproliferative disorder.
Pregnancy
Women of child bearing potential should be informed that taking the study drug may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirement for the duration 
of the study. If there is any question that the subject will not reliably comply, they should not 
be entered in the study.
Thrombosis
It has been shown that monoclonal antibodies that bind to CD154 (CD40L), the natural ligand 
to CD40, are associated with a risk of thrombosis in both clinical studies and non-clinical 
studies in primates. Accordingly, the potential risk of thromboembolic events with CFZ533 
has been thoroughly investigated during the process of development.
 
 
 
 
 
 
 
Although the risk is hypothetical, hematologic and coagulation parameters will be regularly 
monitored in the current study. 
Systemic inflammation and potential kidney injury
 
 
 
 
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.
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Vaccination
Vaccination of patients during treatment with CFZ533 and prior to clearance of the antibody 
is likely to result in therapeutic failure (i.e., non-protective antibody titers) due to the 
pharmacologic activity of CFZ533. For patients participating in this study, all vaccinations 
should be up to date based on local guidelines. Administration of live attenuated agents will 
be prohibited in patients receiving CFZ533 treatment in this study.
There may be other unknown risks to CFZ533 which may be serious and unforeseen.
Blood samples will be collected frequently during the study either via venipuncture or cannula. 
Approximately 460 mL of blood is planned to be collected over the study duration (~36-week) 
from each patient. 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
The study population will be comprised of male and female patients 18 to 65 years of age 
with Graves’ disease hyperthyroidism.
To ensure 12 completers, a total of approximately 15 patients will be enrolled to participate in 
this study. 
The investigator must ensure that all patients being considered for the study meet the 
following eligibility criteria. No additional criteria should be applied by the investigator, in 
order to ensure that the study population will be representative of all eligible patients.
Patient selection is to be established by checking through all inclusion/exclusion criteria at 
screening and/or baseline. A relevant record (e.g. checklist) of the eligibility criteria must be 
stored with the source documentation at the study site.
Deviation from any entry criterion excludes a patient from enrollment into the study.
Replacement patients will be enrolled to replace patients who discontinue the study for 
reasons other than safety before having completed 4 weeks of treatment and 4 week efficacy 
and safety evaluations.
4.1
Inclusion criteria
Patients eligible for inclusion in this study have to fulfill all of the following criteria at 
screening:
1. Written informed consent must be obtained before any assessment is performed.
2. Male and female patients 18 to 65 years of age included.

Women of child-bearing potential must be willing to use the highly effective methods 
of contraception (definition in Exclusion criteria #24) during the study treatment 
epoch and for 12 weeks after the last study treatment. 


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3. Graves’ hyperthyroidism (Baskin et al 2002) with the following labs measured at 
screening:

TSH<LLN and either FT3>ULN or FT4> ULN 
 
4. Patients must weigh at least 40 kg to participate in the study
5. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study.
6. Patients have received up to date required vaccinations based on local guidelines.
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. Use of other investigational drugs within 5 half-lives prior to first treatment.
2. History of hypersensitivity to vaccines, the study drug or to drugs of similar chemical 
classes (e.g. IgG1-related biologic agents). 
3. History of treatment of Graves' disease with radio-iodine ablation or thyroidectomy.  
4. Current treatment with anti-thyroid drugs (methimazole or propylthiouracil) within one 
week of starting treatment. Discontinuation of ATD must not have been for the sole 
purpose of qualifying for this study; rather it should have been based on clinical 
considerations (e.g. lack of efficacy or safety/tolerability issues with ATD).
5. History of hyperthyroidism not caused by Graves’ disease (e.g. toxic multinodular goiter, 
autonomous thyroid nodule, or acute inflammatory thyroiditis).
6. History or presence of thyroid storm (fever, profuse sweating, vomiting, diarrhea, delirium, 
severe weakness, seizures, markedly irregular heartbeat, yellow skin and eyes (jaundice), 
severe low blood pressure, and coma).
7. Previous treatment with a B cell-depleting biologic agent or any other immunomodulatory 
biologic agent (experimental or approved) within 5 half-lives prior to first treatment.
8. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin), treated or untreated, within the past 5 years, regardless of whether there is 
evidence of local recurrence or metastases. 
9. Significant illness which has not resolved within two weeks prior to initial dosing.
10. History of recurrent clinically significant infection or of recurrent bacterial infections with 
encapsulated organisms, including current, active or latent infection susceptible to 
reactivation.
11. History of primary or secondary immunodeficiency, including a positive HIV (ELISA and 
Western blot) test result at screening.
12. A positive Hepatitis B surface antigen or Hepatitis C test result at screening.
13. History or evidence of tuberculosis by either of the following tests at screening:

Positive PPD skin test (size of induration measured after 48-72 hours, and a 
positive result is defined as an induration of ≥ 5mm or according to local 
practice/guidelines) OR
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
Positive QuantiFERON TB-Gold test 
14. A negative Epstein Barr virus (EBV) test (as defined in the laboratory manual) at 
screening.
15. Any of the following abnormal laboratory values at screening (may be repeated one time 
for a single outlying value):

Total white blood count (WBC) outside of the range 2.0-15.0 x 109/L

Absolute neutrophil count <1.5 x 109/L

Lymphocyte count <0.8 x 109/L

Platelets < 100 x 109/L

Hemoglobin < 9.0 g/dl
16. Severe liver disease or liver injury as indicated by abnormal liver function tests at 
screening:

Any single parameter of ALT, AST, γ-GT, must not exceed >5 x the upper limit of 
normal (ULN);

alkaline phosphatase (ALP) must not exceed >5 x the upper limit of normal (ULN);

serum total bilirubin (TBL) must not exceed >1.8 x the upper limit of normal (ULN)
except if the elevation is due to Gilbert’s syndrome.
If necessary, laboratory testing may be repeated on one occasion (as soon as possible) 
prior to randomization, to rule out any laboratory error.
17. Inability or unwillingness to undergo repeated venipuncture (e.g., because of poor 
tolerability or lack of access to veins).
18. Donation or loss of 400mL or more of blood within eight (8) weeks prior to initial dosing 
or longer, if required by local regulation.
19. Plans for immunization with a live vaccine within a 2-month period before enrollment or 
during the study period.
20. History or evidence of drug or alcohol abuse within the 6 months prior to dosing, or 
evidence of such abuse as indicated by the laboratory assays conducted during screening. 
21. Treatment with immunomodulatory drugs, such as cyclosporine A, methotrexate, and/or 
cyclophosphamide within 3 months from baseline. Glucocorticosteroid therapy with 
prednisolone up to 10 mg daily is permitted if patients are on stable dose for more than 
3 months before enrollment in the study.
22. History or presence of coronary artery disease, ventricular or atrial arrhythmias (including 
atrial fibrillation) with the exception of sinus tachycardia controlled with beta-blockers.
23. Pregnant or breast-feeding 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.
24. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 12 weeks after stopping medication. Highly effective contraception 
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
Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (i.e., calendar, ovulation, symptothermal, postovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy (with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
study treatment. 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 m prior to screening). The vasectomized male partner 
should be the sole partner for that subject

Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS) or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception
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.
25. Sexually active males must use a condom during intercourse while taking CFZ533 and 
for 12 weeks after stopping the investigational medication and should not father a child in 
this period. A condom is required to be used also by vasectomized men in order to prevent 
delivery of the drug via seminal fluid.
26. Treatment with amiodarone within 9 months of starting treatment in this study.
Note: In the case where a safety laboratory assessment at screening and initial baseline is 
outside of the range specified above, the assessment may be repeated once prior to 
randomization. If the repeat value remains outside of the specified ranges, the patient is 
excluded from the 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.
5
Restrictions for study patients
During recruitment, screening/informed consent review, and baseline visit, the patients must
be informed and reminded of the following restrictions:
5.1
Contraception requirements
Please refer to exclusion criteria (Section 4) for details of contraception requirements for the 
study. 


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5.2
Prohibited treatment
Use of the treatments displayed in the table below is NOT allowed after the start of study drug
until the end of study evaluation.
Table 5-1
Prohibited treatment
Medication
Action to be taken
Iodine (radioactive or cold)
Withdrawal may be required on a case-by-case 
basis
Methimazole
Propylthiouracil
Amiodarone
Live vaccinations
Withdrawal immediately
Patients may continue the medications that had been taken before enrolling in this study and 
may take medications that are permitted per protocol. Doses may be titrated if deemed 
necessary by their physicians. 
5.3
Dietary, fluid, smoking, and other restrictions
Patients should maintain their usual diet and life habits during the entire study.
6
Treatment
6.1
Study treatment
Details on the storage and management of study medication and instructions for prescribing 
and taking study treatment are outlined in Section 3 of the Site Operations Manual (SOM).
6.1.1
Investigational treatment
The investigational drug, CFZ533 will be available as lyophilisate in dose strength of 150 mg. 
CFZ533 will be packed and labeled under responsibility of drug supply management 
department of Novartis and will be supplied to the Investigator sites as open label bulk supply.
6.2
Treatment arms
Patients will receive CFZ533 intravenously at 10 mg/kg over approximately one hour on 
Study Day 1, Day 15, Day 29, Day 57, and Day 85.
6.3
Permitted dose adjustments and interruptions of study treatment
Study drug dose adjustments and/or interruptions are not permitted UNLESS safety finding(s)
warrant it at the discretion of the investigator (See Section 7.4).
6.4
Treatment assignment
All patients who are eligible to participate in the study will be assigned to study treatment
(see Site Operations Manual for more details). The investigator will enter the treatment 
number on the CRF.


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6.5
Treatment blinding
This is a non-confirmatory, open-label, one treatment arm study. 
 
 
6.6
Emergency breaking of assigned treatment code
Not applicable.
6.7
Treatment exposure and compliance
The IV infusion will be given at the study site, therefore, compliance is ensured. In addition, 
pharmacokinetic exposure will be measured in all patients treated with CFZ533, as detailed in 
Section 8.5.
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. 
Injection site reactions can also be noted during or after subcutaneous administration and are 
usually less severe than infusion reactions, however, may still require medical attention and 
treatment.
In this study, CFZ533 will be administered as an intravenous infusion. 
 
 
In the 
event of a hypersensitivity reaction, stop the infusion. Assess and treat for anaphylaxis, if 
indicated, and initiate supportive care per local practice. Fluids, vasopressors, corticosteroids, 
antihistamines, bronchodilators, and oxygen should be on hand.
Patients will be monitored at the site for at least 2 hours or longer after the completion of IV 
infusion at the discretion of the Investigator to ensure adequate safety monitoring. 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. 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 (CTCAE 2010).
Medication used to treat AEs must be recorded on the Concomitant medications/Significant 
non-drug therapies CRF.
6.9
Rescue medication
Patients may receive standard of care treatment for Graves’ hyperthyroidism at the discretion 
of the investigator in case of worsening of the disease. Patients will be discontinued from the 
study in this case as described in Section 7.1. Rescue medication is to be provided by the 
study center or personal physician.
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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 may be treated with any medications that are not listed as prohibited treatment, as 
standard of care for their medical conditions by their physicians. Use of beta-blockers for 
treating the symptoms of Graves’ disease during participation in this study is permitted at the 
discretion of the treating physician. Medication, amount and frequency of use must be 
recorded.
The investigator should instruct the patient to notify the study site about any new medications 
he/she takes after the start of the study drug.
Administration of acetaminophen is acceptable at the discretion of treatment physicians, but 
must be documented.
Should a patient have an incidental and limited need for a medication to be taken within the 
restricted pre-dose timeframe (e.g. acetaminophen for a headache, antibiotic prophylaxis prior 
to dental surgery, etc.), the sponsor should be advised, as administration of any concomitant 
medication may require the patient to be replaced. Decisions regarding replacements will be 
discussed with the sponsor on a case-by-case basis.
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 amount of single doses and units, the 
dosing frequency, route of administration, the start and discontinuation dates, and the medical 
reason for the therapy.
7
Discontinuation and study completion
7.1
Discontinuation of study treatment
Patients may voluntarily discontinue study treatment for any reason at any time.
The investigator must discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would be detrimental to the patient’s well-being.
Study treatment must be discontinued under the following circumstances: 

Patient withdraws consent  

Pregnancy

Grade 3 or higher allergic reaction

Acute, Grade 3 or higher infection as judged by the Investigator


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The study treatment should be discontinued if:

Clinically significant worsening of Graves' disease, eg. beta-blocker unable to control the 
symptoms of hyperthyroidism, at the discretion of the Investigator.

New onset atrial fibrillation or angina.

On balance, the investigator believes that continuation would be detrimental to the 
patient’s well-being.
Discontinuation of study treatment will be at the discretion of the Investigator, under the 
following circumstances:

Use of prohibited treatment as per Section 5.2.

Any other protocol deviation that results in a significant risk to the patient’s safety
Patients who discontinue study treatment 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 the assessments defined
in the Assessment table. 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. Patients who discontinue the drug before having completed 4 weeks of 
treatment and 4 week efficacy and safety evaluations will be replaced with a newly enrolled 
patient.
7.2
Study completion and post-study treatment
Each enrolled patient 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 patient completes their End of Study visit, and any repeat assessments associated with 
this visit have been documented and followed-up appropriately by the Investigator, or in the 
event of an early study termination decision, the date of that decision.
After the 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 patients who are prematurely 
withdrawn from the study, or must refer them to appropriate ongoing care.  
7.2.1
Lost to follow-up
For patients 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 actions taken to contact the patient (e.g. dates of 
telephone calls, registered letters, etc). A patient should not be formally considered lost to 
follow-up until his/her scheduled end of study visit would have occurred.


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7.3
Withdrawal of consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time.
Withdrawal of consent occurs only when a patient does not want to participate in the study 
anymore and does not want any further visits or assessments and does not want any further 
study related contact and does not allow analysis of already obtained biologic material.
If a patient 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 patient 
are not allowed unless safety findings require communicating or follow-up.
7.4
Study stopping rules
Following a review of the adverse event(s), a decision to permanently discontinue enrollment 
will be made jointly by the Investigator and Sponsor. The following stopping rules, based on 
potential preclinical findings, will serve as the basis for placing the study on hold or 
terminating the study.

Two (2) or more patients experience study-drug related SAEs

Three (3) or more treatment-related AE, CTCAE Grade 3 or higher.

Two (2) or more patients experience CTCAE Grade 3 or higher leukopenia (WBC <1.0 x 
109/L) 

Two (2) or more patients experience CTCAE Grade 3 or higher thrombocytopenia 
(platelets <25 x 109/L)

One (1) patient experiences cytokine release syndrome

One (1) patient has a treatment-related thromboembolic event of CTCAE Grade 3 or 
higher

Two (2) or more patients experience:

Emergent hypogammaglobinemia defined as ≥50% reduction in total serum IgG or 
IgM concentration from baseline

Severe systemic infection or opportunistic infection that requires treatment, e.g., 
sepsis, mycosis, pneumonia.

The principal investigator or the Sponsor considers that the number and/or severity of AEs 
justify discontinuation of the study.

The sponsor unilaterally requests it.


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7.5
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
patients should be seen as soon as possible and treated as a prematurely withdrawn patient. 
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 patient’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
Table 8-1
Assessment schedule
Patients should be seen for all visits on the designated day, with the assessments performed as per schedule, within the allowed 
“visit/assessment window” specified in the Site Operations Manual.
Study Phase
Screening
Baseline
Treatment
Follow-up
EOS visit
Visit Numbers1
V1
V9912
V101
V102
V103
V104
V199
V201
V202
V203
V204
V299
Study Day(s)
Up to -28 
-1
1
15
29
57
85
113
141
169
211
253
Time (post-dose)
-
-
0h9
1h9
0h9
1h9
0h9
1h9
0h9
1h9
0h9
1h9
-
-
-
-
-
Informed consent
X
Inclusion / Exclusion criteria
X
X2
Medical history/current medical 
conditions
X
Demography
X
Hepatitis and HIV Screen
X
TB Test10
X
EBV Screen
X
Alcohol Test and Drug Screen 
X
Blood Pressure and Pulse Rate
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
Body temperature
X
X
X
X
X
X
X
X
X
X
X
X
Body height
X
Body weight
X
X13
X
X
X
X
X
X
ECG evaluation
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test
X
X13
X
X
X
X
X
X
X
Dose administration
X
X
X
X
X
Blood chemistry4
X
X
X
X
X
X
X
X


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Study Phase
Screening
Baseline
Treatment
Follow-up
EOS visit
Visit Numbers1
V1
V9912
V101
V102
V103
V104
V199
V201
V202
V203
V204
V299
Study Day(s)
Up to -28 
-1
1
15
29
57
85
113
141
169
211
253
Time (post-dose)
-
-
0h9
1h9
0h9
1h9
0h9
1h9
0h9
1h9
0h9
1h9
-
-
-
-
-
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
Cytokine assessment
X
X
X
X
X
X
X
X
X
X
Coagulation Panel
X13
X
X
X
X
X
X
X
X
Concomitant therapies
as required
Serious adverse events
as required
Adverse events
as required
Immunogenicity3
X
X
X
X
X
X
Comments
as required
Study completion information
X
TSH
X
X
X
X
X
X
X
X
X
X
X
X
Total  and free T3 & T4
X
X
X
X
X
X
X
X
X
X
X
X
PK (CFZ533)9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Free & total CD40 on B cells5
X
X
X
X
X
X
X
X
Soluble CD405
X
X
X
X
X
X
X
X
Soluble CD1545
X
X
X
X
X
X
X
X
Exploratory Biomarkers in Serum6
X
X
X
X
X
X
X
X
X
X
X
 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X8
X13
X
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1 Visit structure given for internal programming purpose only
2 Only those inclusion/exclusion criteria that are specific for baseline visit
3 Immunogenecity: 0-hour sample is taken pre-dose
4
5 On days when patient is dosed, sample is taken pre-dose (0-hour)
6
7
 
9 0-hour sample (or assessment) is taken pre-dose, 1-hour sample is taken 1 hour AFTER the END of infusion
10PPD or QuantiFERON TB-gold test
 
12The baseline visit assessments can be completed on Day 1 (pre-dose) when the first dose (Day 1) is received 
within 7 days of the screening visit.
13These assessments will be completed prior to the study treatment on Day 1 (Visit 101, pre-dose) if Day 1 is 
scheduled within 7 days of the screening visit (Visit 1).
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8.1
Informed consent procedures
Eligible patients 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 patient’s representative gives consent, the patient 
should be informed about the study to the extent possible given his/her understanding. If the 
patient 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.
Novartis will review the Investigators proposed informed consent form to ensure it complies 
with the ICH GCP guideline and regulatory requirements and is considered appropriate for 
this study. Any further changes to the proposed consent form suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC.
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
 
 
 
 
 
 
 
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8.2
Patient demographics/other baseline characteristics
Patient demographic and baseline characteristic data will be collected on all patients at 
Screening (Visit 1). The following will only be assessed at the Screening Visit and not at 
subsequent visits: 

Demography

Medical History/Current medical conditions

Hepatitis and HIV Screen

Alcohol Test and Drug Screen
Relevant medical history/current medical conditions data includes data until signature of 
informed consent. Where possible, diagnoses rather than symptoms will be recorded.
Investigators have the discretion to record abnormal test findings on the medical history CRF 
whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
8.3
Pharmacodynamics
Pharmacodynamic assessments are specified below. The details for sample collection and 
assay methods will be specified in the Study Operations Manual (SOM). Samples will be 
collected and assessments will be performed at the timepoint(s) defined in the 
Assessment schedule.
In order to better characterize the PD profile, the timing of the sample collection may be 
altered based on emergent data. The number of samples/blood draws and total blood volume 
collected will not exceed those stated in the protocol. 
 
 
 
 
 
 
 
 
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8.4
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the SOM, with the Assessment Schedule detailing when each assessment is to be performed.
8.4.1
Physical examination
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
and extremities, as well as avascular and neurological examination. If indicated based on 
medical history and/or symptoms, rectal, external genitalia, breast, and/or pelvic exams may 
be performed.
Information for all physical examinations must be included in the source documentation at the 
study site and will not be recorded in the eCRF. Significant findings that are present prior to 
informed consent are included in the Relevant Medical History eCRF. Significant findings 
observed after informed consent signature which meet the definition of an Adverse Event
must be appropriately recorded on the Adverse Event eCRF.
8.4.2
Vital signs
Vital signs include body temperature, blood pressure (BP) and pulse measurements. After the 
patient has been sitting for 3 minutes, with back supported and both feet placed on the floor, 
systolic and diastolic BP will be measured using a validated device, with an appropriately 
sized cuff. In case the cuff sizes available are not large enough for the patient’s arm 
circumference, a sphygmomanometer with an appropriately sized cuff may be used.
To ensure accurate measurement of heart rate or blood pressure, the Investigator may obtain a 
total of up to three consecutive assessments, with the patient seated quietly for approximately 
five minutes preceding each repeat assessment. 
8.4.3
Height and weight

Height (cm)

Body weight (kg)

Body mass index (BMI) will be calculated (Body weight (kg) / [Height (m)]2)
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8.4.4
Laboratory evaluations
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.
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential 
(e.g., neutrophils, basophils, eosinophils, monocytes, lymphocytes) and platelet count will be 
measured.
Clinical chemistry
Sodium, potassium, creatinine, urea, uric acid, chloride, albumin, total protein, calcium, 
alkaline phosphatase, total bilirubin, LDH, GGT, AST, ALT, amylase, lipase, CK, glucose, 
total cholesterol, triglycerides. If the total bilirubin concentration is above 1.5 times the upper 
limit of normal, direct and indirect reacting bilirubin should be differentiated.
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 and/or blood sample will be sent 
for microscopic analysis of WBC, RBC and casts.
Coagulation panel
Prothrombin time (PT) and active partial thromboplastin time (aPTT) will be assessed. 
Additional parameters such as International Normalized Ratio (INR) may be estimated at the 
discretion of the Investigator.
 
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8.4.5
Electrocardiogram (ECG)
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, patient initials, patient number, date 
and time, be appropriately signed and dated to confirm review, and filed in the study site 
source documents. 
For any ECGs with patient safety concerns, two additional ECGs should be performed to 
confirm the safety finding. Clinically significant abnormalities should be recorded on the 
relevant section of the medical history/current medical conditions/AE eCRF page as 
appropriate.
The eCRF will contain:

Date and time of ECG

Heart rate

PR interval

RR

QT uncorrected

QTcF

QRS duration
8.4.6
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have pregnancy tests during the 
study. Serum pregnancy tests will be performed at screening; at all other times urine 
pregnancy tests may be used. 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). A positive 
urine pregnancy test requires immediate interruption of study drug until serum β-hCG is 
performed and found to be negative.
8.4.7
Other safety evaluations
8.4.7.1
PPD skin test or QuantiFeron test
A purified protein derivative (PPD) skin test will be performed and read at screening in order 
to evaluate the infection with tuberculosis (TB). The test dose is bioequivalent to 5 tuberculin 
units (or as according to local standard practice) of standard PPD injected intradermally into 
usually the volar surface of the forearm. The site is cleansed and the PPD extract is then 
injected into the most superficial dermal layer of the skin. If given correctly, the injection 
should raise a small wheal of about 5 mm, which resolves within 10-15 minutes.
Because the reaction (induration) will take 48-72 hours to develop, the patient must return to 
the investigators’ site within that time for a proper evaluation of the test site. This will 
determine whether the patients have had a significant reaction to the PPD test. A reaction is 


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measured in millimeters of induration (hard swelling) at the site. A PPD skin induration 
≥5 mm is interpreted as positive result.
Based on the study site’s normal practice, QuantiFeron test may replace PPD skin test at 
screening. A positive QuantiFeron test at screening will exclude the patients from the 
participation in the study.
T-SPOT or other types ELISPOT assays based on interferon-gamma release may also be used 
for tuberculosis diagnosis as per local practice.
Results will be available as source data and will not be recorded within the eCRF.
8.4.7.2
Infections
All occurrences of infections must be carefully monitored by the investigator. Significant 
findings, which meet the definition of infection, must be recorded in the Adverse Event eCRF.
8.4.8
Immunogenicity 
 
 
 
 
 
 
 
 
 
 
 
8.5
Pharmacokinetics
PK samples will be collected at the timepoints defined in the Assessment schedule.
 
 
 
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8.6
Other assessments
 
 
 
 
 
 
 
 
 
 
 
 
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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 patient 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the patient 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 
the underlying disease(s). Investigators have the responsibility for managing the safety of 
individual patient and identifying adverse events. Alert ranges for liver related events are 
included in Section 9.3.
Adverse events must be recorded on the Adverse Events CRF for patients 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:
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1. The severity grade is as follows based on CTC-AE grading:

1 mild:
usually transient in nature and generally not interfering with normal 
activities

2  moderate: sufficiently discomforting to interfere with normal activities

3  severe:
prevents normal activities

4  life threatening
CTC-AE grade 5 (death) is not used, but is collected in other CRFs (e.g. Study Completion, 
Death/Survival).
2. its relationship to the investigational treatment (no/yes), or other study treatment (non-
investigational) (no/yes), or both or indistinguishable,
3. its duration (start and end time/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 9.2.1 for the definition 
of SAE.
5. action taken regarding study treatment
All adverse events should be treated appropriately. Action 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 

patient hospitalized/patient’s hospitalization prolonged 
6. its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown)
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 patient during the study as needed.


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The investigator should also instruct each patient to report any new adverse event (beyond the 
protocol observation period) that the patient, or the patient’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 in a timely manner (see Section 9.2.2).
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:

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition (Graves’ disease)

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

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 

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 patient or may require 
medical or surgical intervention.
Life-threatening in the context of a SAE refers to a reaction in which the patient 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.


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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.
9.2.2
SAE reporting
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has 
provided informed consent and until the study completion, must be reported to Novartis 
within 24 hours of learning of its occurrence as described below. Any SAEs experienced after
the completion of the study 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.
SAEs (initial and follow-up) that are recorded electronically in the Electronic Data Capture 
system should be entered, saved and e-signed within 24 hours of awareness of the SAE or 
changes to an existing SAE. These data will automatically be submitted to Novartis Drug 
Safety & Epidemiology immediately after investigator signature or 24 hours after entry, 
whichever occurs first. Study site personnel must also inform the Clinical Trial Leader.
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 
patient 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 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.
9.3
Liver safety monitoring
To ensure patient 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 
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
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.
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 patient 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.
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 * 


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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 
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


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Criteria
Actions required
Follow-up monitoring
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 
cResolution 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 
laboratory parameter


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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 patient 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, though the patient may stay in 
the study, if she wishes to do so. All assessments that are considered as a risk during 
pregnancy must not be performed. The patient may continue all other protocol assessments. 
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.
Pregnancy outcomes must be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
All SAEs relating to suicidal behavior should be reviewed by the Safety Management Team 
or Early Project Teams.


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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 
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 patient records, the accuracy of entries on the CRFs, the adherence to the protocol and to 
Good Clinical Practice, 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 patient 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 
patient's file. The investigator must also keep the original informed consent form signed by 
the patient (a signed copy is given to the patient).
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 patients will be disclosed.


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10.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms 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 Case Report Forms are complete and accurate. 
After database lock, the investigator will receive a CD-ROM or paper copies of the patient 
data for archiving at the investigational site.
Data not requiring a separate written record will be defined in the Site Operations Manual and 
assessment schedule and can be recorded directly on the CRFs. All other data captured for this 
study will have an external originating source (either written or electronic) with the CRF not 
being considered as source.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
CRO working on behalf of Novartis review 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 is 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 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 will be sent electronically to 
Novartis (or a designated CRO).
 
 
 
 
 
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10.3
Data Monitoring Committee
Not required.
10.4
Adjudication Committee
Not required.
11
Data analysis
11.1
Analysis sets
For all analysis sets, patients will be analyzed according to the study treatment(s) received.
The safety analysis set will include all patients that received any study drug.
 
 
 
  
11.2
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by patient. 
Summary statistics will be provided.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by patient.
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 patient.
11.4
Analysis of the primary variable(s)
The primary aim of this study is to assess the effects of CFZ533 on thyroid function, focusing 
on TSH levels, total T3 and free T4 in GD after 12 weeks of treatment.
11.4.1
Variable(s)
The effects of CFZ533 on thyroid function will be primarily assessed by the proportion of 
patients whose TSH levels normalize (above 0.35 mU/L) after 12 weeks of treatment.
They will also be assessed by the difference in mean total T3 and free T4 between baseline 
and after 12 weeks of treatment.
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11.4.2
Statistical model, hypothesis, and method of analysis
One of the main efficacy criteria for this study is to show that the proportion of patients with 
normalization of TSH (above 0.35 mU/L) after 12 weeks of treatment with CFZ533 is 
statistically greater than 5%, according to a 1-sided exact test for proportions with a 10% 
type I error. This will be achieved if we observe at least 3/12 responders since in that case the 
lower bound of an 80% confidence interval for the proportion of responders will be about 
10%. The other efficacy criteria are that there is a significant reduction in average total T3 and 
free T4 after 12 weeks of treatment, according to a 1-sided paired t-test with 10% type I error
for each of these two endpoints.
11.4.3
Handling of missing values/censoring/discontinuations
Patients who discontinue after the 4 week efficacy assessment for any reason will be 
considered non-responders in the primary analysis (unless their last recorded TSH value was 
after 8 weeks of treatment and was above the lower limit of the normal range, 0.35 mU/L). 
Patients who discontinue before 4 weeks of treatment for any reason will be replaced and not 
counted for the calculation of responders. For total T3 and free T4, the last recorded value will 
be used for the change from baseline, provided it was obtained after at least 8 weeks of 
treatment. 
11.4.4
Supportive analyses
In case more than 2 discontinuations occur in this study, additional methods may be used to 
assess sensitivity of the results to different imputation techniques to deal with the missing data. 
11.5
Analysis of secondary and exploratory variables
 
 
 
 
 
 
 
 
 
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11.5.2
Safety
Vital signs
All vital signs data will be listed by patient, visit and if ranges are available, abnormalities 
(and relevant orthostatic changes) will be flagged. Summary statistics will be provided by 
visit.
ECG evaluations
All ECG data will be listed by patient and visit/time, and abnormalities will be flagged. 
Summary statistics will be provided by visit/time.
Clinical laboratory evaluations
All laboratory data will be listed by patient and visit, and if normal ranges are available, 
abnormalities will be flagged. Summary statistics will be provided by visit.
Adverse events
All information obtained on adverse events will be displayed by patient.
The number and percentage of patients with adverse events will be tabulated by body system 
and preferred term. A patient with multiple adverse events within a body system is only 
counted once towards the total of this body system.
 
11.5.3
Pharmacokinetics
 
 
 
 
 
 
 
 
 
 
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11.5.4
Pharmacokinetic / pharmacodynamic interactions
Not Applicable.
11.5.5
Other assessments
 
 
 
 
 
 
 
 
11.6
Sample size calculation
The proposed sample size for this study is 12 patients (to complete the study). 
Assuming CFZ533 is associated with 38% normalization of the TSH levels after 12 weeks of 
treatment (which is consistent with the response rate seen with Rituximab in 26 weeks in one 
small, open-label study (Heemstra et al 2008), there is around 89% power to detect a 
proportion of TSH responders significantly higher than 5% (this would be achieved with at 
least 3/12 responders), with a type I error of 10%. Additionally, this sample size provides 98% 
power to detect normalization of the total T3 (and free T4, respectively) below the upper limit 
of the normal range (2.79 nmol/L and 22.7 pmol/L, respectively). The assumed baseline levels 
are 7.2 nmol/L for total T3 and 58.55 pmol/L for free T4, which are the average values 
reported in GD patients in Andrade et al (2001). The assumed standard deviation for the 
change from baseline are 4.24 nmol/L and 34.58 pmol/L respectively.  
11.7
Power for analysis of key secondary variables
Not applicable
11.8
Interim analyses
 
 
 
 
 
 
 
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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, patient recruitment 
procedures (e.g. advertisements) and any other written information to be provided to patients. 
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 
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.
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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 patients 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 patients 
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 patient 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.
Abraham P, Avenell A, Park CM, et al (2005) A systematic review of drug therapy for 
Graves' hyperthyroidism. Eur J Endocrinol; 153(4):489-98.
Andrade VA, Gross JL, Maia AL (2001) The effect of Methimazole Pretreatment on the 
Efficacy of Radioactive Iodine Therapy in Graves’ Hyperthyroidism: One-Year Follow-Up of 
a Prospective, Randomized Study. J. Clin. Endocrinol. Metab; 86(8):3488-3493. 
Armengol M, Juan M, Lucas-Martin A, et al (2001) Thyroid Autoimmune Disease: 
Demonstration of Thyroid Antigen-Specific B Cells and Recombination-Activating Gene 
Expression in Chemokine-Containing Active Intrathyroidal Germinal Centers. Am J Pathol;
159(3):861-873.
Baskin HJ, Cobin RH, Duick DS, et al (2002) American Association of Clinical 
Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of 
hyperthyroidism and hypothyroidism. Endocr Pract; 8(6):457-69.
Burch HB, Burman KD, Cooper DS (2012) A 2011 survey of clinical practice patterns in the 
management of Graves' disease. J. Clin. Endocrinol. Metab; 97(12);4549-58.
Carella C, Mazziotti G, Sorvillo F, et al (2006) Serum Thyrotropin Receptor Antibodies 
Concentrtions in Patients with Graves’ Disease Before, at the End of Methimazole Treatment, 
and After Drug Withdrawal: Evidence That the Activity of Thyrotropin Receptor Antibody 
and/or Thyroid Response Modify During the Observation Period. Thyroid; 16(3):295–302.
CTCAE (2010) Common Terminology Criteria for Adverse Events v4.03 (Internet). 
Available from: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf (Accessed 20 November 2015).
Cordoba F, Wieczorek G, Audet M, et al (2015) A Novel, Blocking, Fc-Silent Anti-CD40 
Monoclonal Antibody Prolongs Nonhuman Primate Renal Allograft Survival in the Absence 
of B Cell Depletion. Am J Transplant; 15(11):2825-36.
Goldwater R, Keirns J, Blahunka P, et al (2013) A phase 1, randomized ascending single dose 
study of antagonist anti-human CD40 ASKP1240 in healthy subjects. Am J Transplant; 
13(4):1040-6.
Harland R, Klintmalm G, Yang H, et al (2015) ASKP1240 in De Novo Kidney Transplant 
Recipients. Am J Transplant; 15(S3):Abstract #3012.
Heemstra KA, Toes RE, Sepers J, et al (2008) Rituximab in relapsing Graves’ disease, a 
phase II study. European Journal of Endocrinology; 159(5):609-615.
Huber A, Finkelman F, Li, C, et al (2012) Genetically-driven target tissue over-expression of 
CD40: A novel mechanism in autoimmune disease. J Immunol; 189(6): 3043-53.


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Hwang C, Afifiyan N, Sand D, et al (2009) Orbital fibroblasts from patients with thyroid-
associated ophthalmopathy over-express CD40: CD154 hyper-induces IL-6, IL-8 and MCP-1. 
Invest Ophthalmol Vis Sci.; 50(5): 2262–68.
Izumi Y, Takeoka K, Amino N (2005) Usefulness of the 2nd generation assay for anti-TSH 
receptor antibodies to differentiate relapse of Graves' thyrotoxicosis from development of 
painless thyroiditis after antithyroid drug treatment for Graves' disease. Endocr J; 52(4):493-7. 
Jacobson E, Huber A, Akeno N, et al (2007) A CD40 Kozak sequence polymorphism and 
susceptibility to antibody-mediated autoimmune conditions: the role of CD40 tissue-specific 
expression. Genes and Immunity; 8(3):205-14
Kawai T, Andrews D, Colvin RB, et al (2000) Thromboembolic complications after treatment 
with monoclonal antibody against CD40 ligand. Nat Med; 6(2):114.
Mysliwiec J, Oklota M, Nikolajuk A, et al (2007a) Serum CD40/CD40L System in Graves' 
Disease and Hashimoto's Thyroiditis Related to Soluble Fas, FasL and Humoral Markers of 
Autoimmune Response. Immunological Investigations: A Journal of Molecular and Cellular 
Immunology; 36(3), 247-57.
Mysliwiec J, Waligorski D, Nikolajuk A, et al (2007b) Soluble CD40 and its ligand CD154 in 
patients with Graves’ ophthalmopathy during combined therapy with corticosteroids and 
teleradiotherapy. Advances in Medical Sciences; 52:104-8.
Smith T J, Sciaky D, Phipps R P, et al (1999) CD40 Expression in Human Thyroid Tissue: 
Evidence for Involvement of Multiple Cell Types in Autoimmune and Neoplastic Diseases. 
Thyroid; 9(8):749-55.
Toft AD, Weetman AP (1998) Screening for agranulocytosis in patients treated with 
antithyroid drugs. Clin Endocrinol (Oxf); 49(2):271. 
Tomer Y, Concepcion E, Greenberg D (2002) A C/T Single-Nucleotide Polymorphism in the 
Region of the CD40 Gene is Associated with Graves’ Disease. Thyroid;  12(12):1129-35.
Weetman AP (2000) Graves' disease. N Engl J Med; 343(17):1236-48.

SAP_001.pdf: 
 
 
 
 
Biostatistics & Statistical Programming /  
Novartis Institutes for BioMedical Research 
CCFZ533 
CCFZ533X2205 
An open label study to evaluate the safety and efficacy of 
12 week treatment with CFZ533 in patients with Graves' 
disease 
Statistical Analysis Plan (SAP) 
 
Author(s): 
 
Document type: 
SAP Documentation – NIBR  
Document status: 
Final 
Release date: 
19-June-2017 
Number of pages: 
12 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
C
Personal Data


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SAP  
 
CCFZ533X2205 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SAP  
 
CCFZ533X2205 
 
Table of contents 
Table of contents ................................................................................................................. 3 
List of tables ........................................................................................................................ 3 
1 
Introduction ......................................................................................................................... 4 
1.1 
Scope of document .................................................................................................. 4 
1.2 
Study reference documentation ............................................................................... 4 
1.3 
Study objectives ....................................................................................................... 4 
1.3.1 
Primary objective .................................................................................... 4 
1.3.2 
Secondary Objective ............................................................................... 4 
1.3.3 
Exploratory objectives ............................................................................ 4 
1.4 
Study design and treatment ...................................................................................... 4 
2 
First interpretable results (FIR) ........................................................................................... 5 
3 
Interim analyses ................................................................................................................... 5 
4 
Statistical methods: Analysis sets ........................................................................................ 6 
5 
Statistical methods for Pharmacokinetic (PK) parameters .................................................. 7 
5.1 
Variables .................................................................................................................. 7 
5.2 
Descriptive analyses ................................................................................................ 8 
5.2.1 
Graphical presentation of results ............................................................. 8 
5.2.2 
Pharmacokinetics/Pharmacodynamics relationships .............................. 8 
6 
Statistical methods for Pharmacodynamic (PD) parameters ............................................... 8 
6.1 
Primary objective ..................................................................................................... 8 
6.1.1 
Variables ................................................................................................. 8 
6.1.2 
Descriptive analyses ................................................................................ 9 
6.1.3 
Statistical model, assumptions and hypotheses ....................................... 9 
6.2 
Secondary and exploratory objectives ................................................................... 10 
6.2.1 
Variables ............................................................................................... 10 
6.2.2 
Descriptive analyses .............................................................................. 10 
7 
Statistical methods for safety and tolerability data ............................................................ 11 
7.1.1 
Variables ............................................................................................... 11 
7.1.2 
Descriptive analyses .............................................................................. 11 
7.1.3 
Graphical presentation .......................................................................... 12 
8 
Statistical methods for Biomarker data ............................................................................. 12 
 
List of tables 
Table 4-1 
Protocol deviation codes and analysis sets.............................................. 6 
 


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1 
Introduction  
1.1 
Scope of document 
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CCFZ533X2205”. 
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol. 
1.2 
Study reference documentation 
This SAP is based on protocol v01 (amended protocol) dated 16-Mar-2016. 
1.3 
Study objectives 
1.3.1 
Primary objective 
To assess the effects of CFZ533 on thyroid function in Graves' disease (GD) after 12 week 
treatment. 
1.3.2 
Secondary Objective 
To assess the safety and tolerability of CFZ533 (10 mg/kg IV for 12 weeks) up to 36 weeks. 
1.3.3 
Exploratory objectives 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.4 
Study design and treatment 
This is a non-confirmatory, open-label, one treatment arm study in patients with newly 
diagnosed GD.  
A total of approximately 15 patients will be enrolled and treated with CFZ533 to ensure 
approximately 12 completers. For each patient, the study will consist of a screening epoch of 
up to 28 days, a baseline evaluation, a 12-week treatment epoch, 24-week follow up epoch 
after the last dosing of CFZ533 on Study Day 85, and a study completion evaluation on Study 
Day 253. Patients who discontinue the drug before having completed 4 weeks of treatment 
and 4 week efficacy and safety evaluations will be replaced with a newly enrolled patient. The 
study design is presented in Figure 1-1. 
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Figure 1-1 Study design 
 
 
2 
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 TFL shells document and marked as 
“Key” in the Programming Deliverables Tracker (PDT) output list.  
3 
Interim analyses  
 
 
 
 
 
 
 
 
 
 
 
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4 
Statistical methods: Analysis sets 
For all analysis sets, patients will be analyzed according to the study treatment received. 
All patients that received study drug and with no protocol deviations with relevant impact on 
safety will be included in the safety analysis set. 
The PK analysis set will include all patients with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and experienced 
no protocol deviations with relevant impact on PK data. 
The PD analysis set will include all patients with any available PD data, who received any 
study drug and experienced no protocol deviations with relevant impact on PD data, who have 
completed at least 4 weeks of treatment with CFZ533. 
 
The analysis sets and protocol deviation codes are related as follows: 
Table 4-1 
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 
I01 
Deviation from inclusion criteria 1 (ICF not 
obtained) 
Yes 
 
No study drug taken 
Yes 
Subjects are excluded from PK analysis in case of these PDs:  
Exclude subject from PK 
analysis set  
I01 
Deviation from inclusion criteria 1 (ICF not 
obtained) 
Yes 
 
No study drug taken 
Yes 
 
 
 
Subjects are excluded from PD analysis in case of these PDs: 
Exclude subject from PD 
analysis set 
I01 
Deviation from inclusion criteria 1 (ICF not 
obtained) 
Yes 
 
No study drug taken 
Yes 
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Category    
   Deviation code 
Text description of deviation 
Data exclusion 
 
Subject took any prohibited medications 
interfering with efficacy 
Yes 
Subjects are excluded from PK and PD analysis in case of these 
PDs: 
Exclude subject from PK and 
PD analysis sets 
I01 
Deviation from inclusion criteria 1 (ICF not 
obtained) 
Yes 
 
No study drug taken 
Yes 
 
 
 
There are two categories of medications which are considered rescue medication. In order to 
identify these for programming purposes these are included in the protocol deviations dataset 
with codes of O01 and O02 (oral corticosteroids and anti-thyroid drugs) however they are not 
protocol deviations so will not be included in the protocol deviations listing, instead they will 
be included in a separate rescue medication listing.  
In PD outputs the following rules will be applied to subjects who received rescue medication 
• Data post rescue medication will be flagged in the listings with a * and a footnote 
added to explain.  
• Figures showing individual profiles will appear as red lines from the point at which the 
rescue medication was taken and a footnote added to explain.  
• In summary tables and summary figures datapoints after rescue medication will be 
excluded and a footnote added to explain. 
• In the inferential analyses datapoints after rescue medication will be excluded and a 
footnote added to explain. For the longitudinal models the model is expected to 
provide unbiased results under the assumption that the rescue medication intake can be 
considered dependent only on previously observed values (MAR – missing at 
random).   
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to 
DBL. 
5 
Statistical methods for Pharmacokinetic (PK) parameters 
5.1 
Variables  
 
  
 
 
 
 
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Cmin 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. 
The zz.xpt file in GPSII will combine PK output (free CFZ533 in plasma) as well as PD 
readouts including: free CD40 on blood B cells, total CD40 on blood B cells, total soluble 
CD40 in plasma, and total soluble CD154 in plasma. Also, for these PD readouts, two 
variables for the elapsed time will be provided (see above chapter). 
Concentrations below the LLOQ will not be considered for PK parameter calculations. 
 
5.2 
Descriptive analyses 
 
 
 
 
 
  
 
 
 
 
5.2.1 
Graphical presentation of results 
 
 
 
5.2.2 
Pharmacokinetics/Pharmacodynamics relationships 
 
  
6 
Statistical methods for Pharmacodynamic (PD) parameters 
6.1 
Primary objective 
The primary aim of this study is to assess the effects of CFZ533 on thyroid function, focusing 
on TSH levels, total T3 and free T4 in GD after 12 weeks of treatment. 
6.1.1 
Variables  
The effects of CFZ533 on thyroid function will be primarily assessed by the proportion of 
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patients whose TSH levels normalize (above 0.35 mU/L) after 12 weeks of treatment (TSH 
responders). They will also be assessed by the difference in mean total T3 and free T4 
between baseline (Day 1, predose) and after 12 weeks of treatment, and the proportion of 
patients whose total T3 or free T4  levels normalize (below ULN) after 12 weeks of treatment. 
6.1.2 
Descriptive analyses 
TSH levels will be summarized over time together with their changes from baseline. The 
frequency of TSH responders will be summarized for each timepoint. Same statistical analysis 
will be performed for the frequency of patients whose total T3 and free T4 levels normalize. 
Results will also be presented for free T3 and total T4. 
6.1.3 
Statistical model, assumptions and hypotheses 
One of the main efficacy criteria for this study is to show that the proportion of patients with 
normalization of TSH (above 0.35 mU/L) after 12 weeks of treatment with CFZ533 is 
statistically greater than 5%, according to a 1-sided exact test for proportions with a 10% 
type I error. This will be achieved if we observe at least 3/12 responders since in that case the 
lower bound of an 80% confidence interval for the proportion of responders will be about 
10%. The other efficacy criteria are that there is a significant reduction in average total T3 and 
free T4 after 12 weeks of treatment, according to a 1-sided paired t-test with 10% type I error 
for each of these two endpoints. Results will also be presented for free T3 and total T4 and at 
week 20. 
6.1.3.1 
Handling of missing values/censoring/discontinuations 
Patients who discontinue after the 4 week efficacy assessment for any reason will be 
considered non-responders in the primary analysis (unless their last recorded TSH value was 
after 8 weeks of treatment and was above the lower limit of the normal range, 0.35 mU/L). 
Patients who discontinue before 4 weeks of treatment for any reason will be replaced and not 
counted for the calculation of responders. For total T3 and free T4, the last recorded value will 
be used for the change from baseline (Day 1, predose), provided it was obtained after at least 
8 weeks of treatment. 
6.1.3.2 
Supportive analyses 
In case more than 2 discontinuations occur in this study, additional methods may be used to 
assess sensitivity of the results to different imputation techniques to deal with the missing 
data. 
Total and free T3 and T4 will be analyzed using a repeated measures model with baseline as a 
covariate and visit as the repeated effect. The difference from Day 1 at each timepoint will be 
presented along with the 80% CI and the 2 sided p-value. 
6.1.3.3 
Graphical presentation of results 
Mean (SD) TSH levels and Mean (SD) change from baseline in TSH levels will be plotted 
over time. Overlaying TSH level profiles will also be presented. Similar figures will be 
presented for total and free T3 and T4. Overlaying profiles will have separate pages for all 


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subjects, subjects that have received rescue medication and subjects that received no rescue 
with the time of the start of the rescue medication indicated on the plot. 
Bar charts of the number of TSH responders will be plotted over time. Similar bar charts will 
be plotted for the frequency of patients whose total and free T3 and T4 levels normalize.  
6.2 
Secondary and exploratory objectives 
6.2.1 
Variables  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.2.2 
Descriptive analyses 
 
  
 
 
 
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6.2.2.1 
Graphical presentation of results 
 
 
 
 
 
 
 
  
7 
Statistical methods for safety and tolerability data 
7.1.1 
Variables  
Adverse events, vital signs (blood pressure, pulse rate, body temperature), ECG intervals, 
laboratory measurements, as well as patient demographics, baseline characteristics, and 
treatment information. 
7.1.2 
Descriptive analyses 
Patient demographics and other baseline characteristics 
All data for background and demographic variables including background medication (type of 
medication and mean dose per day, with the average prednisone equivalent dose in mg 
presented for steroids) will be listed by treatment group and patient. 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 patient. 
Treatment 
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by treatment group and patient. 
Vital signs 
All vital signs data will be listed by treatment, patient, 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, patient and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit/time. 
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Clinical laboratory evaluations 
All laboratory data will be listed by treatment, patient, and visit/time and if normal ranges are 
available abnormalities will be flagged. A separate listing is provided presenting all 
parameters in a patient 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 patient. 
The number and percentage of patients with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment and repeated for adverse events that were 
suspected to be related to the study medication. A separate table will also be produced for 
adverse events of infection. A patient with multiple adverse events within a body system is 
only counted once towards the total of this body system and treatment. 
 
 
7.1.3 
Graphical presentation  
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
created. 
8 
Statistical methods for Biomarker data 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
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