Clinical trial NCT04129528
Conditions: Type 1 Diabetes Mellitus
Keywords: T1DM
Sponsor: Novartis Pharmaceuticals
Start date: 2019-11-08; Completion date: 2024-06-04
Enrollment: 44 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study was a Phase 2, multicounty, multicenter, non-confirmatory, investigator- and subject masked, randomized, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics, and efficacy of CFZ533 on preservation of residual pancreatic β-cell function in new onset T1DM in pediatric and young adult subjects.

Detailed description:

Arms: arm 1: Randomized in a 2:1 ratio: 2 Active / 1 Placebo arm 2: Similar in appearance to active study drug
Interventions: intervention 1: CFZ533 intervention 2: Placebo
Intervention descriptions: intervention 1: First dose is administered via intravenous infusion, subsequent doses are administered subcutaneously. intervention 2: Placebo for active drug

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development
CFZ533 (Iscalimab)
Clinical Trial Protocol CCFZ533X2207 / NCT04129528
Investigator- and subject-blinded, randomized, 
placebo-controlled study to evaluate safety, tolerability, 
pharmacokinetics and efficacy of CFZ533 in pediatric and 
young adults with new onset type 1 diabetes mellitus 
(T1DM)
Document type:
Amended Protocol Version
EUDRACT number:
2018-004553-25
Version number:
v06 (Clean)
Clinical Trial Phase:
II
Release date:
03-Apr-2023
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study procedures. Note: The SOM will not be a part of the Clinical Study Report.


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Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................7
List of figures ......................................................................................................................7
List of abbreviations............................................................................................................8
Glossary of terms...............................................................................................................11
Protocol summary..............................................................................................................30
1
Introduction .......................................................................................................................34
1.1
Background............................................................................................................34
1.2
Purpose ..................................................................................................................39
2
Objectives and endpoints...................................................................................................39
3
Study design ......................................................................................................................40
3.1
Off-site procedures ................................................................................................43
3.1.1
Responsibility of Investigators..............................................................43
3.1.2
Responsibility of off-site healthcare professional (OHPs)....................44
3.1.3
Telemedicine.........................................................................................44
3.1.4
Data flow...............................................................................................44
4
Rationale............................................................................................................................45
4.1
Rationale for study design .....................................................................................45
4.1.1
Rationale for choice of background therapy.........................................47
4.2
Rationale for dose/regimen and duration of treatment ..........................................47
4.2.1
Rationale for treatment duration and subsequent follow up without 
continued treatment...............................................................................55
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................55
4.3.1
Rationale for diabetes-specific endpoints .............................................55
4.4
Purpose and timing of interim analyses/design adaptations..................................56
4.5
Risks and benefits..................................................................................................56
4.5.1
Blood sample volume............................................................................63
4.6
Rationale for Public Health Emergency mitigation procedures ............................64
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5
Population..........................................................................................................................64
5.1
Inclusion criteria ....................................................................................................64
5.2
Exclusion criteria...................................................................................................65
6
Treatment...........................................................................................................................68
6.1
Study treatment......................................................................................................68
6.1.1
Investigational and control drugs..........................................................69
6.1.2
Additional study treatments ..................................................................69
6.1.3
Treatment arms/group ...........................................................................70
6.2
Other treatment(s)..................................................................................................70
6.2.1
Concomitant therapy.............................................................................70
6.2.2
Prohibited medication ...........................................................................70
6.2.3
Rescue medication ................................................................................70
6.2.4
Restriction for study subjects................................................................71
6.3
Subject numbering, treatment assignment, randomization....................................71
6.3.1
Subject numbering ................................................................................71
6.3.2
Treatment assignment, randomization ..................................................72
6.4
Treatment blinding.................................................................................................72
6.5
Dose escalation and dose modification..................................................................74
6.6
Additional treatment guidance...............................................................................75
6.6.1
Treatment compliance...........................................................................75
6.6.2
Recommended treatment of adverse events..........................................75
6.6.3
Emergency breaking of assigned treatment code..................................75
6.7
Preparation and dispensation.................................................................................76
7
Informed consent procedures ............................................................................................77
8
Visit schedule and assessments .........................................................................................78
8.1
Screening ...............................................................................................................86
8.1.1
Eligibility screening ..............................................................................86
8.1.2
Information to be collected on screening failures.................................86
8.2
Subject demographics/other baseline characteristics.............................................86
8.2.1
Mixed Meal Tolerance Test (MMTT) for glucose and stimulated 
C-peptide...............................................................................................89
8.2.2
Insulin requirements and glycemic control...........................................89
8.2.4
Appropriateness of efficacy assessments..............................................90
8.3
Safety.....................................................................................................................90
8.3.1
Hypoglycemic events............................................................................91
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8.3.2
Laboratory evaluations..........................................................................93
8.3.3
Electrocardiogram (ECG) .....................................................................95
8.3.4
Pregnancy..............................................................................................95
8.3.5
Appropriateness of safety measurements..............................................96
8.4
Additional assessments..........................................................................................96
9
Study discontinuation and completion ............................................................................100
9.1
Discontinuation....................................................................................................100
9.1.1
Discontinuation of study treatment .....................................................100
9.1.2
Withdrawal of informed consent and exercise of participants’ data 
privacy rights.......................................................................................102
9.1.3
Lost to follow-up.................................................................................102
9.1.4
Study stopping rules............................................................................103
9.1.5
Early study termination by the sponsor...............................................103
9.2
Study completion and post-study treatment ........................................................104
10 Safety monitoring and reporting......................................................................................104
10.1
Definition of adverse events and reporting requirements....................................104
10.1.1
Adverse events ....................................................................................104
10.1.2
Serious adverse events ........................................................................106
10.1.3
Serious Adverse Event (SAE) reporting .............................................107
10.1.4
Pregnancy reporting ............................................................................108
10.1.5
Reporting of study treatment errors including misuse/abuse..............108
10.2
Additional Safety Monitoring..............................................................................109
10.2.1
Viral safety monitoring .......................................................................109
10.2.2
Liver safety monitoring.......................................................................110
10.2.3
Renal safety monitoring......................................................................111
10.2.4
Data Monitoring Committee ...............................................................111
11 Data Collection and Database management....................................................................111
11.1
Data collection.....................................................................................................111
11.2
Database management and quality control..........................................................112
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11.3
Site monitoring ....................................................................................................113
12 Data analysis and statistical methods ..............................................................................113
12.1
Analysis sets ........................................................................................................113
12.2
Subject demographics and other baseline characteristics....................................114
12.3
Treatments ...........................................................................................................114
12.4
Analysis of the primary endpoint(s) ....................................................................114
12.4.1
Definition of primary endpoint(s).......................................................114
12.4.2
Statistical model, hypothesis, and method of analysis........................114
12.4.3
Handling of missing values/censoring/discontinuations.....................115
12.4.4
Sensitivity and supportive analyses ....................................................115
12.5
Analysis of secondary endpoints .........................................................................116
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)..................................116
12.5.2
Pharmacokinetics ................................................................................116
12.5.3
Biomarkers..........................................................................................117
12.5.4
PK/PD relationships............................................................................117
12.7
Interim analyses...................................................................................................118
12.8
Sample size calculation........................................................................................119
12.8.1
Primary endpoint(s).............................................................................119
13 Ethical considerations and administrative procedures ....................................................119
13.1
Regulatory and ethical compliance......................................................................119
13.2
Responsibilities of the investigator and IRB/IEC................................................119
13.3
Publication of study protocol and results.............................................................120
13.4
Quality Control and Quality Assurance...............................................................120
14 Protocol adherence ..........................................................................................................120
14.1
Protocol Amendments .........................................................................................121
15 References .......................................................................................................................122
16 Appendices ......................................................................................................................128
16.1
Appendix 1: Liver event and Laboratory trigger Definitions and Follow-up 
Requirements.......................................................................................................128
16.2
Appendix 2: Specific Renal Alert Criteria and Actions and Event Follow-up....131
16.3
Appendix 3: General Guidance on Select Virus - Cytomegalovirus, Epstein-
Barr virus, and coronavirus SARS-CoV-2 ..........................................................132
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16.3.1
Cytomegalovirus .................................................................................132
16.3.2
Epstein-Barr virus ...............................................................................133
16.3.3
SARS-CoV-2 virus of COVID-19 disease..........................................134
16.4
Appendix 4: European Medical Agency Guidance for Trial Related Blood 
Loss......................................................................................................................135
List of tables
Table 2-1
Objectives and related endpoints ..........................................................39
Table 6-1
Overview of study medication (CFZ533/Placebo) ...............................69
Table 6-2
Prohibited medication ...........................................................................70
Table 6-3
Blinding Levels.....................................................................................74
Table 8-1
Assessment Schedule ............................................................................79
Table 8-2
Safety assessments ................................................................................91
Table 8-3
Recording and classification of hypoglycemia as reported in the 
Study Diary ...........................................................................................92
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .......................................................................................109
Table 16-1
Liver Event and Laboratory Trigger Definitions ................................128
Table 16-2
Follow Up Requirements for Liver Events and Laboratory Triggers.129
Table 16-3
Specific Renal Alert Criteria and Actions...........................................131
Table 16-4
Total blood volume, 1 percent and 3 percent of total blood volume 
by weight assuming 85mL per kg total blood volume:.......................135
List of figures
Figure 1-1
Immune-mediated mechanisms in type 1 diabetes................................35
Figure 1-2
Putative role of the CD40-CD154 co-stimulatory pathway in type 1 
diabetes..................................................................................................38
Figure 3-1
Study Design .........................................................................................43
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List of abbreviations
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
AST
Aspartate aminotransferase
BMI
Body Mass Index
BUN
Blood urea nitrogen
BW
Body weight
C-SSRS
Columbia Suicide Severity Rating Scale
CD-ROM
Compact disc – read only memory
CDS
Core Data Sheet (for marketed drugs)
CFR
U.S. Code of Federal Regulations
CK
Creatinine kinase
CMO&PS
Chief Medical Office & Patient Safety
CMV
Cytomegalovirus
CO2
Carbon dioxide
COVID-19
Coronavirus disease 2019
CQA
Clinical Quality Assurance
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CTC
Common Toxicity Criteria
CV
Coefficient of variation
DDC
Direct Data Capture
DMC
Data Monitoring Committee
EBV
Epstein-Barr virus
ECG
Electrocardiogram
EDC
Electronic Data Capture
ELISA
Enzyme-linked immunosorbent assay
eSAE
Electronic Serious Adverse Event
eSource
Electronic Source
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
h
Hour
HbA1c
Glycated hemoglobin
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HSV
Herpes Simplex Virus
ICF
Informed Consent Form


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ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IgM
Immunoglobulin M
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
Intravenous
Kg
Kilogram
LADA
Latent autoimmune diabetes of the adult
LDH
Lactate dehydrogenase
LFT
Liver function test
LLN
Lower limit of normal
LLOQ
Lower limit of quantification
mAb
Monoclonal Antibody
MABEL
Minimum anticipated biological effect level
MedDRA
Medical dictionary for regulatory activities
mg
Milligram(s)
mL
Milliliter(s)
MMTT
Mixed Meal Tolerance Test
MODY
Maturity-onset diabetes of the young
MRSD
maximum recommended starting dose
NCDS
Novartis Clinical Data Standards
NOVDD
Novartis Data Dictionary
PA
Posteroanterior
PBMC
Peripheral blood mononuclear cell
PC
Personal computer
PCR
Polymerase chain reaction
PCR
Protein-creatinine ratio* as 1 abbreviation is common for 2 meanings these are clarified 
in text
PD
Pharmacodynamic(s)
PIP
Pediatric investigation plan
PK
Pharmacokinetic(s)
PSD
Premature subject discontinuation
PT
Prothrombin time
RBC
Red blood cell(s)
RDC
Remote Data Capture
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2
SAE
Serious adverse event
SC 
Subcutaneous
sCR
Serum creatinine
SD
Standard deviation
SOM
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SUSAR
Suspected Unexpected Serious Adverse Reactions
T1DM
Type 1 Diabetes Mellitus
TBL
Total bilirubin
TD
Study Treatment Discontinuation
Tfh
Follicular helper T cells
TP
Therapeutic protein
ULN
Upper limit of normal
ULQ
Upper limit of quantification
WBC
White blood cell(s)
WHO
World Health Organization
WoC
Withdrawal of Consent


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Glossary of terms
Assessment
A procedure used to generate data required by the study.
Cohort
A specific group of subjects fulfilling certain criteria.
Control drug
Any drug(s) (an active drug or an inactive drug, such as a placebo) which is 
used as a comparator to the investigational drug being tested in the trial.
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day).
Electronic Data 
Capture (EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical study data 
using data collection systems, such as Web-based applications, interactive 
voice response systems and clinical laboratory interfaces.
EDC includes the use of Electronic Case Report Forms (eCRFs) which are 
used to capture data transcribed from paper source forms used at the point of 
care.
Enrollment
Point/time of subject entry into the study at which informed consent must be 
obtained (i.e. prior to starting any of the procedures described in the protocol).
eSource
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource combines source documents and 
case report forms (eCRFs) into one application, allowing for the real time 
collection of clinical trial information to sponsors and other oversight 
authorities, as appropriate.
Hybrid Trial Design
Flexible model incorporating both on-site (traditional site based) and off-site 
(decentralized) elements within the same study design
Investigational drug
The study drug whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and Directive 2001/20/EC and is 
synonymous with “investigational new drug,” "Investigational Medicinal 
Product," or “test substance”.
Medication pack 
number
A unique identifier on the label of each drug package in studies that dispense 
study treatment using an IRT system.
Off-site
Describes trial activities that are performed at remote location by an off-site 
healthcare professional, such as procedures performed at the subject's home.
Off-site Healthcare 
Professional (OHP)
A qualified healthcare professional, such as a nurse, who performs certain 
protocol procedures for the subject in an off-site location such as a subject's 
home.
Part
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study are: a single 
dose part and a multiple dose part, or a part in subjects with established 
disease and in those with newly-diagnosed disease.
Subject
An individual with the condition of interest
Personal data
Subject information collected by the Investigator that is transferred to Novartis 
for the purpose of the clinical trial. This data includes subject identifier 
information, study information and biological samples.
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding to a 
specific treatment arm assignment.
Screen Failure
A subject who is screened but is not treated or randomized.
Source 
Data/Document
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource.


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Study treatment
Any drug or combination of drugs administered to the study participants as part 
of the required study procedures; includes investigational drug(s), control(s) or 
background therapy.
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the defined 
study treatment completion date.
Subject
A trial participant (can be a healthy volunteer or a subject).
Subject number
A unique number assigned to each subject upon signing the informed consent. 
This number is the definitive, unique identifier for the subject and should be 
used to identify the subject throughout the study for all data collected, sample 
labels, etc.
SUSAR
Serious, Unexpected and Suspected Adverse Reaction.
Telemedicine
Electronic information and telecommunications technologies (both video-
based and audio-only) to facilitate the delivery of health care and health related 
education where subject and health care provider (HCP) are not in the same 
location.
Treatment number
A unique identifier assigned in non-randomized studies to each dosed subject, 
corresponding to a specific treatment arm.
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being tested in 
the study.
Withdrawal of 
consent (WoC)
Withdrawal of consent from the study occurs only when a subject does not want to 
participate in the study any longer and does not allow any further collection of personal 
data.


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Protocol summary
Protocol number
CCFZ533X2207
Full Title
Investigator- and subject-blinded, randomized, placebo-controlled study to 
evaluate safety, tolerability, pharmacokinetics and efficacy trial of CFZ533 in 
pediatric and young adult subjects with new onset type 1 diabetes (T1DM).
Brief title
Study of safety and efficacy of CFZ533 in type 1 diabetes pediatric and 
young adult subjects.
Sponsor and 
Clinical Phase
Novartis
Phase II
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this study is to enable the development of CFZ533 in new 
onset T1DM and to inform the design of subsequent confirmatory studies.
Primary Objective(s)

To evaluate safety and tolerability of CFZ533 in new onset T1DM by 
assessing adverse events (AEs) and standard safety labs.

To evaluate the treatment effect of CFZ533 on pancreatic beta cell 
function in new onset T1DM after 52 weeks, by assessing stimulated 
C-peptide AUC by mixed meal tolerance test (MMTT).
Secondary 
Objectives

To evaluate the pharmacokinetics (PK) of CFZ533 in new onset T1DM 
by measuring free CFZ533 plasma concentrations at baseline, during 
treatment and follow up period.

To evaluate the treatment effect of CFZ533 on full remission by HbA1c 
≤6.5% (48 mmol/mol) and no exogenous insulin use, or partial remission 
by insulin dose adjusted HbA1c (IDAA1c) ≤9.0 or HbA1c < 7.0% 
(53 mmol/mol) with total daily insulin dose of <0.5 units /kg /day, at week 
52 in new onset T1DM.

To evaluate durability of effects after washout of CFZ533 on pancreatic 
beta cell function by assessing stimulated C-peptide AUC by MMTT at 
week 72 in subjects with new-onset T1DM.
Study design
CCFZ533X2207 is a Phase 2, non-confirmatory, investigator- and subject-
blinded, randomized, placebo-controlled study to evaluate the safety, 
tolerability, pharmacokinetics, and efficacy of CFZ533 on preservation of 
residual pancreatic β-cell function in new onset T1DM in pediatric and young 
adult subjects.
The study is planned for 44 subjects randomized and assuming ~18% 
dropout rate, 36 subjects for primary efficacy (at 52 weeks) and safety 
endpoints (at 72 weeks). 
Eligible subjects will be enrolled and randomized to active or placebo in a 
2:1 ratio, stratified by age at first screening visit (≥18 to 21 years, followed 
by ≥12 to <18 years).
The study timeline includes a screening period of approximately 8 weeks, a 
baseline period of 2 weeks, a treatment period of 52 weeks and a follow-up 
period following last dose of CFZ533 of 20 weeks. 
This study will be the first study to evaluate CFZ533 in a pediatric population 
in any indication. Thus, enrollment will be staggered to evaluate safety and 


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tolerability on a rolling basis and enable gradual enrollment of younger age 
and lower weight groups.
The PK profile of CFZ533 will be evaluated throughout the study (Month 3, 
6 and 9). Dosage adjustments may be introduced based on emerging PK 
data. The current assumptions considered allometric scaling based on body 
weight. The PK assumptions will be confirmed using population PK 
modelling.
Sequential enrollment by age and body weight (BW) categories include:

Cohort 1: age ≥15 to ≤21 years (older adolescents to young adults), body 
weight ≥40 kg to ≤125 kg.

Cohort 2: age ≥12 to ≤21 years (adolescents to young adults), body 
weight ≥30 kg to ≤125 kg.
Before opening a subsequent cohort, safety and tolerability data from at least 
6 subjects in Cohort 1 must be reviewed and deemed safe to proceed by the 
Sponsor and Lead Investigator.
Population
The study population will be comprised of newly diagnosed T1DM pediatric 
and young adult subjects.
Forty-four subjects between the ages of 12 and 21 (inclusive) will be enrolled 
and randomized in the study in sequential order as outlined in the study 
design.
Key Inclusion 
criteria

Newly diagnosed auto immune T1DM confirmed by at least one positive 
auto antibody: glutamic acid decarboxylase (anti-GAD), protein tyrosine 
phosphatase-like protein (anti-IA-2); zinc transporter 8 (anti-ZnT8); islet 
cell (cytoplasmic) (anti-ICA).

Peak stimulated C-peptide levels ≥ 0.2 nmol/L (0.6 ng/mL) following 
standard liquid MMTT within one month prior to randomization.

Study participants are to complete all recommended inactivated (killed) 
immunizations at least 2 weeks prior and attenuated (live) immunizations 
at least 8 weeks in accordance with local immunization guidelines and 
prior to first dose with study drug.

Able to receive the intravenous (IV) loading dose of CFZ533 within 56 
days of diagnosis (which may be extended to 100 days in the event a 
screening assessment needs to be confirmed or for vaccine 
administration).
Key Exclusion 
criteria

Diabetes forms other than autoimmune T1DM such as maturity-onset 
diabetes of the young (MODY), latent autoimmune diabetes of the adult 
(LADA), acquired diabetes (secondary to medications or surgery), type 
2 diabetes.

Diabetic ketoacidosis within 2 weeks of the baseline MMTT test.

History of polyglandular autoimmune disease, Addison’s disease, 
pernicious anemia, celiac sprue.

History of immunodeficiency disorders, such as HyperIgM syndrome; history 
of recurrent infections suggestive of immune deficiency disorders.

Major dental work within 8 days prior to CFZ533 intravenous loading 
dose; febrile illness within 48 hours prior to first dose.

Use of other investigational drugs or use of immunosuppressive agents 
at the time of enrollment, or within 5 half-lives of enrollment, or until the 


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expected pharmacology effect has returned to baseline, whichever is 
longer; or longer if required by local regulations.

Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV). A positive 
HBV surface antigen (HBsAg) test, or if standard local practice, a 
positive HBV core antigen test, excludes a subject. Subjects with a 
positive HCV antibody test should have HCV RNA levels measured. 
Subjects with positive (detectable) HCV RNA should be excluded

Evidence of Epstein-Barr Virus (EBV), Cytomegalovirus (CMV), Herpes 
simplex virus (HSV), or coronavirus SARS-CoV-2 by viral load above 
laboratory threshold or only positive IgM serology in the absence of 
positive IgG, suggestive of active or recent infection.

Any of the following abnormal laboratory values at screening: 

total white blood cell count (WBC) outside the range of 1,500-
15,000/mm3 (1.5-15.0 x 109/L).

neutrophil count (<1500/mm3) (<1.5 X 109 / L).

lymphocyte count <500/mm3 (<0.5 X 109 / L).

hemoglobin (Hgb) <8.0 g/dL.

platelets <100,000/mm3 (<100 x 109/L).
Study treatment
Subjects will be assigned to one of the 2 treatment arms in a ratio of 2:1, 
CFZ533 or matching placebo, stratified by age at first screening visit (≥18 to 
21 years and ≥12 to <18 years).
For the single intravenous (IV) loading dose, all subjects receive the same 
dose: CFZ533 30 mg/kg IV on Study Day 1.
For the subcutaneous (SC) maintenance regimen, a fixed CFZ533 dose by 
body weight (BW) category will be administered every week from Day 8 
(Week 1) up to Week 51 (last dose). Last dose is administered at 
 
and the end of the treatment assessment will be performed at Week 52.

BW category II (≥30 to <50 kg): 195 mg (1 injection of 1.3 mL) SC 
weekly.

BW category III (≥ 50 kg): 300 mg (1 injection of 2 mL, or 2 injections of 
1 mL) SC weekly.
*note earlier versions of the protocol included body weight in the 20 to 
30 kg range, which would have been in a Body weight Category I. This 
lower body weight category is no longer included and explains the 
nomenclature of weight categories II and III only.
Efficacy 
assessments

C-peptide during MMTT.
Pharmacodynamic 
assessments

Soluble CD40 (sCD40) concentrations in plasma (target biology and 
target engagement in whole blood) at baseline, during treatment and 
follow-up period.
Pharmacokinetic 
assessments

CFZ533 concentrations in plasma (at baseline, during treatment and 
follow up period).
Key safety 
assessments

AE and serious adverse events (SAEs).

Vital signs, height and weight.

Physical exam.

Tanner staging (only for subjects aged 12-17 years, inclusive).
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
Hematology.

Chemistry.

Urinalysis.

Thyroid function tests.

Viral load and serology.

Lymphocyte class T cells, B cells, and NK cells (TBNK).

ECG evaluation.

Pregnancy and assessments of fertility.
Other assessments
Data analysis
Primary efficacy analysis will be conducted based on all randomized
subjects reaching the Week 52 visit or discontinued early. 
For all analyses, subjects will be analyzed according to the study 
treatment(s) received.
The safety analysis set will include all subjects that received any study 
treatment.
The PK analysis set will include all subjects with at least one available valid 
CFZ533 concentration measurement, who received any study drug and with 
no protocol deviations that impact PK data.
The PD analysis set will include all subjects with available PD data and 
without major protocol deviations that affect the PD outcome.
Key words
Type 1 diabetes mellitus (T1DM), pediatric, juvenile
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1
Introduction
1.1
Background
Type 1 diabetes is a life-threatening autoimmune disease with no cure.
Insulin replacement is life-saving and treats the symptoms of type 1 diabetes mellitus (T1DM) 
but does not alter disease progression. Around 132,600 children and adolescents develop T1DM 
each year worldwide (Cho et al 2018) and prevalence is rising, with an estimated 3% increase per 
year. The number of children with T1DM in Europe is projected to triple between 2010 and 2050 
(Imperatore et al 2012). New onset T1DM can occur at any age but peak incidence occurs between 
the ages of 5 and 15 years. Life expectancy is reduced by 12 years on average compared to the general 
population (Secrest et al 2010). Long-term micro and macrovascular complications continue to 
be burden for T1DM patients, their families, and for society (Secrest et al 2010).
Pediatric compared to adults patients are at increased risk for acute complications of T1DM, 
diabetic ketoacidosis and severe hypoglycemia (a side effect of insulin); and for death from 
these complications (Wherrett et al 2015). Pediatric patients are also at higher risk for 
neurocognitive changes due to chronic hyperglycemia and severe hypoglycemia 
(Wherrett et al 2015). Transformative therapies are urgently needed to improve clinical 
outcomes for children with T1DM.
Glycemic control is the most important factor for reducing the long-term microvascular 
complications in T1DM of retinopathy, nephropathy, and neuropathy as shown in the landmark 
Diabetes Control and Complications Trial (DCCT) (Diabetes Control and Complications Trial 
Research Group 1994, Steffes et al 2003). Yet, despite technological and clinical advances in 
the standard of care of T1DM, the majority of patients and particularly pediatric patients are not 
meeting glycemic targets. The mean glycated hemoglobin (HbA1c) level in adolescents was 
9.0% (75 mmol/mol), well above guideline driven target for youth <7.5% (<58 mmol/mol) and 
close to levels in the 1980’s (Miller et al 2015). T1DM patients with residual β-cell function, as 
measured by stimulated C-peptide > 0.2 nmol/L, achieve better glycemic control, are protected 
from severe hypoglycemia with insulin therapy (62% reduction), and have a 79% lower risk for 
progression of retinopathy and long-term complications (Diabetes Control and Complications 
Trial Research Group 1994; Steffes et al 2003). Therefore, therapies preserving residual β-cell 
function have potential to improve glycemic control and avoid serious short and long 
complications associated with T1DM.
T1DM disease onset and progression over the first year are markedly more aggressive in 
pediatric versus adult patients. Pediatric patients with new onset T1DM present with lower 
residual β-cell function at disease onset and a more rapid decline in remaining β-cell function 
over the first year when compared to adults. At 1 year of T1DM, pediatric patients lose about 
50% of residual beta cell function while adults lose about 15% (Greenbaum et al 2012). 
Pediatric patients with new onset T1DM have more severe insulitis (inflammation of the 
pancreatic β-cells) with increased infiltration of B lymphocytes, including aggressive CD20+ 
B lymphocytes in pancreatic islets. Yet pediatric patients with new onset T1DM appear to be 
more responsive to immune modulatory interventions such as rituximab and teplizumab in 
randomized control trials (Woittiez and Roep 2015). Collectively, these observations support a 


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different pathobiology and disease kinetics between adults and pediatrics, such that 
interventions in one age group may not translate to the other in clinical trials.
Overview of auto-immune mechanisms in type 1 diabetes
T1DM develops when pathogenic autoreactive immune cells invade the pancreatic islets, and 
damage insulin producing in β-cells (Katsarou et al 2017) (Figure 1-1). Insulitis is a hallmark 
of aggressive disease and has higher prevalence in pediatric patients (Leete et al 2016). 
T1DM is generally considered a T lymphocyte-mediated autoimmune disease as islet 
autoantibodies are currently the best available biomarker for autoimmunity and disease risk, but 
are not considered pathogenic. These antibodies are produced by autoreactive B cells, in which 
activation is largely dependent on the function of follicular B helper T cells (also known as 
follicular helper T cells or Tfh) and thus the role of B lymphocytes in T1DM disease 
pathogenesis is being increasingly recognized (Bottazzo et al 1983). This is partly due to the 
efficacy of rituximab, an anti-CD20 antibody that broadly depletes B lymphocytes, in delaying 
disease progression in patients with new onset T1DM (Pescovitz et al 2014). One course of 
rituximab reduced circulating Tfh cells in T1DM with disease duration of < 2 years, p< 0.01 
(Xu et al 2013), Islet antigen reactive B lymphocytes act as antigen-presenting cells (APC), 
which prime and activate diabetogenic CD4+ T effector and CD8+ T lymphocytes. 
Pediatric patients with new onset T1DM or autoantibody-positive at-risk children with impaired 
glucose tolerance have multiple features indicative of an aggressive auto-immune process 
including (1) a higher frequency of activated Tfh lymphocytes compared to controls, Tfh being 
critical activators of autoreactive B lymphocytes; (2) multiple auto-antibody specificities 
(markers of beta-cell autoimmunity) and elevated IFNγ (marker of inflammation) compared to 
adults with T1DM; and (3) evidence of insulitis with increased B lymphocyte infiltrates and 
increased numbers of CD20+ B lymphocytes in the pancreas, all hallmarks of aggressive 
inflammation (Viisanen et al 2017, Leete et al 2016). Overall these observations implicate an 
important role of auto-reactive pathogenic B lymphocytes in the pathophysiology of aggressive 
T1DM.
Figure 1-1
Immune-mediated mechanisms in type 1 diabetes
From Katsarou et al 2017.


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Role of the CD40 Pathway in type 1 diabetes
CD40 is a transmembrane glycoprotein in the tumor necrosis factor receptor superfamily 
expressed by immune and non-immune cells. CD154, the ligand for CD40 (also known as 
CD40L) is also widely expressed (Peters et al 2009). CD40-CD154 interactions mediate 
T-dependent B cell responses and is important for priming and activation of CD4+ autoreactive 
T lymphocytes and CD8+ cytolytic T lymphocyte. Aberrant expression of MHC class II 
molecules on endocrine tissue may contribute to the initiation of autoimmune disease.
CD40 is upregulated upon antigen presenting cell (APC) activation, and the interaction between 
CD40+ APCs such as B lymphocytes with naïve T lymphocytes induces the production of 
CD154 on the surface of these lymphocytes. CD40 signaling may also function at the level of 
T cell selection in the thymus, and enhance production of pro-inflammatory cytokines which 
can further influence T cell differentiation into active Th17 cells (Iezzi et al 2009). Thus, CD40 
plays a pathogenic role in T1DM, and disrupting CD40-CD154 interactions or activity may be 
an effective autoimmune therapeutic strategy for this disorder.
Non-clinical data strongly support a role for the CD40-CD154 costimulatory pathway in 
defective tolerance in autoreactive T lymphocytes, development of insulitis and diabetes 
(Price et al 2014). The non-obese diabetic (NOD) mouse, a model of spontaneous autoimmune 
diabetes, shows functional tertiary lymphoid structures with ectopic germinal centers (GC) in 
early pancreatic lesions during progression from peri- to intrainsulitis (Astorri et al 2010). 
Data in the NOD mouse supports a causative and functional role of the CD40-CD154 pathway 
in disease pathogenesis including:

CD40-CD154 is necessary for the initiation of insulitis and diabetes in the NOD mouse 
(Balasa et al 1997).

NOD mice deficient for CD154 (CD154-KO/NOD) do not develop insulitis or diabetes 
(Eshima et al 2003).

CD 40+CD4+T lymphocytes from the NOD are highly pathogenic and readily transfer 
progressive insulitis and diabetes (Wagner 2017).

Blockade of CD40 at different stages of disease delayed disease progression, prevent 
hyperglycemia and reverse new-onset diabetes (Vaitaitis et al 2014, Vaitaitis et al 2017).

Blockade of CD154 restores dendritic cell-mediated induction of tolerance in autoreactive 
CD4+ T lymphocytes (Price et al 2014). 

In the RIP-CD154 transgenic model, β cell-specific expression of CD154 mediates immune 
activation, 
insulitis, 
and 
diabetes 
on
a 
non-diabetes-prone 
background 
(Haase and Markholst 2007).

Transient blockade of BAFF, a B lymphocyte survival and maturation factor provides 
protection against early and late stage T1DM in NOD mice by enriching in B lymphocytes 
that suppress T cell proliferation (Wang et al 2017).
In summary, non-clinical data provides compelling evidence that multiple CD40+ immune cell 
types contribute to insulitis and pathogenesis of T1DM.
Clinical data in patients with T1DM also support a role for the CD40-CD154 costimulatory 
pathway disease pathogenesis (Figure 1-2). Pediatric patients with new onset T1DM have 2-fold 


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elevated levels of soluble CD40 (sCD40) (Chatzigeorgiou et al 2010b). T1DM patients with 
disease duration from diagnosis between 1 and 6 months exhibit the highest levels of sCD40. 
Elevated levels of sCD40 levels in pediatric patients with new onset T1DM are positively 
associated with HbA1c, hyperglycemia, and inflammatory markers, CRP, IL-6 and MMP-9 
(Chatzigeorgiou et al 2010b, Chatzigeorgiou et al 2010a). Although there are no data for sCD40 
in adults with T1DM, for those with disease duration over 1 year and with no complications, 
circulating CD154 concentrations are increased compared to age- and sex-matched healthy 
controls (Devaraj et al 2006). Together these observations point to a role for the CD40-CD154 
pathway in T1DM in general and in pediatric new onset T1DM that could respond to an 
intervention with an anti-CD40 monoclonal antibody like CFZ533.
Mechanistically, CD40-CD154 interactions may contribute to autoimmune T1DM by the 
priming of autoreactive T cells via activated diabetogenic B lymphocytes in target tissue, e.g.
pancreas and pancreatic lymph nodes. Human pancreatic β-cells express functional CD40 
receptors that release inflammatory cytokines and chemokines upon activation with CD154, 
which could contribute to insulitis in new onset T1DM (Klein et al 2005).
Collectively these data indicate a complex role for the CD40-CD154 pathway and pathogenic 
B-T lymphocyte interactions in the pathogenesis of T1DM, justifying the evaluation with CD40 
blockade with CFZ533, an anti-CD40 antibody, in new-onset T1DM patients. It is therefore 
hypothesized that blockade of CD40-CD154 activation with CFZ533 in patients with new-onset 
T1DM could halt the immune-mediated β-cell destruction and the insulitis leading to 
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Figure 1-2
Putative role of the CD40-CD154 co-stimulatory pathway in type 1 
diabetes
A Schematic diagram of the complex role of CD40-CD154 in various aspects of T1DM pathophysiology 
(Adapted from Christie 2016). B, Circulating follicular T helper cells are significantly elevated in patients 
with recent onset T1DM (duration < 2 years) (Xu et al 2013). C, CD40 is expressed in human pancreatic 
β-cells (Klein et al 2005). D, A single treatment course of rituximab (green bar) in patients with new onset 
T1DM delays disease progression (Pescovitz et al 2014).
CFZ533 (iscalimab) - a CD40 blocking antibody for type 1 diabetes
CFZ533 (iscalimab) is a fully human, immunoglobulin G1 (IgG1) anti-CD40 antibody that 
blocks recombinant(r) CD154-induced CD40 signaling and which does not cause depletion of 
CD40 expressing cell types (i.e. Fc-silent). 
The CFZ533 clinical development program consists of completed studies in both healthy 
volunteers (HVs) and patients. CFZ533 is in clinical development for autoimmune diseases 
(AID). Additional information can be found in the Investigator’s Brochure (IB).
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1.2
Purpose
The purpose of this study is to enable the development of CFZ533 in new onset T1DM and to 
provide clinical data for the design of subsequent confirmatory studies.
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To evaluate effects of CFZ533 on 
pancreatic beta cell function in subjects 
with new-onset T1DM.

Stimulated C-peptide AUC by mixed meal tolerance 
test (MMTT) after 52 weeks of treatment.

To evaluate the safety and tolerability 
of CFZ533 in subjects with new onset 
T1DM.

Adverse events, safety labs.
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To evaluate the pharmacokinetics (PK) 
of CFZ533 in subjects with new onset 
T1DM.

CFZ533 plasma concentrations at baseline, during 
treatment (Cmax, Tmax after IV administration, and 
Ctroughs after SC administration) and follow-up 
period.

To evaluate durability of effects after 
washout of CFZ533 on pancreatic beta 
cell function in subjects with new-onset 
T1DM.

Stimulated C-peptide AUC by MMTT at 20 weeks
from last dose.

To evaluate the treatment effect of 
CFZ533 
on 
remission 
or 
partial 
remission in subjects with new onset 
T1DM.

Not requiring exogenous insulin therapy with HbA1c 
<6.5% (remission) or Insulin dose adjusted HbA1c 
(IDAA1c ≤9.0) or HbA1c < 7.0% (53 mmol/mol) and 
total daily insulin dose <0.5 units per kg per day at 
52 weeks (partial remission).
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3
Study design
CCFZ533X2207 is a Phase 2, non-confirmatory, investigator- and subject-blinded, randomized, 
placebo-controlled study to evaluate the safety, tolerability, PK, and efficacy of CFZ533 
compared to placebo on preservation of residual pancreatic β-cell function in new onset T1DM 
pediatric and young adult subjects.
Newly diagnosed T1DM patients are identified based on American Diabetes Association 
diagnostic criteria and National Institute for Health and Care Excellence (NICE) 
(Johnston 2004), and the presence of at least one diabetes-related autoantibody as specified in 
Section 5. Enrollment in the trial should occur no less than two weeks and within 56 days 
(8 weeks) from the time of diagnosis and first study drug administration, however this 56 day 
interval may be extended to 100 days in the event a screening assessment needs to be confirmed 
or vaccination is required prior to initiation of the study drug (see Sections on Risks Section 4.5 
and Screening procedures Section 8.1). Enrollment will be based on both screening and baseline 
results. The screening and baseline visit(s) may be conducted over 1 or more than one visit 
depending on the subject’s body weight and World Health Organization (Howie 2011) and 
European Medicines Agency (EMA) recommendations for trial related phlebotomy limits (see 
Site Operations Manual - SOM for more details).
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Forty-four subjects aged 12-21 years with weight between 30 to ≤125 kg, will be enrolled. 
Two sequential study cohorts (based on age at first screening visit) are planned.
Cohorts are based on descending order of age and weight groups (Figure 3-1).
Sequential enrollment by age and body weight (BW) categories include:

Cohort 1: age ≥15 to ≤21 years (older adolescents to young adults), body weight ≥40 kg to
≤125 kg.

Cohort 2: age ≥12 to ≤21 years (adolescents to young adults), body weight ≥30 kg to ≤125 kg.
The screening and baseline periods continue until the first dose of CFZ533 or placebo is 
administered. Screening and baseline assessments may be conducted over one, two, or more 
visits but must provide adequate time for subjects and their guardians to consider the risks and 
benefits and trial burden, adhere to safe phlebotomy limits based on subject weight, and have 
sufficient time for laboratory reporting of all inclusion/exclusion criteria and safety measures 
prior to administration of the study drug.
After a screening and baseline period
subjects eligible for a cohort open for enrollment will be randomized 
to receive either CFZ533 or placebo (2:1 ratio, stratified by age at first screening visit ≥18 to 
21 years and ≥12 to <18 years) for one year, in addition to background standard of care with 
intensive insulin therapy, 
. In case of screening being extended, some screening procedures 
may need to be repeated, please refer to Site Operations Manual (SOM) for more information.
The treatment includes an initial loading dose of CFZ533 (administered at a dose of 30 mg/kg 
via a peripheral intravenous (IV) line 
 on Day 1; all subjects 
receive the same dose in mg/kg) or matching placebo. All subjects will be observed for at least 
one hour following IV infusion to monitor for any untoward infusion-related adverse reaction. 
All subsequent doses of CFZ533 (or matching placebo), from Day 8 
 are administered on a weekly basis by subcutaneous (SC) injections at a 
dose which is based on body weight (details in Section 4.2). The last dose of the study drug is 
administered 
, and the end of the treatment assessment will be performed at 
Week 52.
A standardized liquid MMTT to assess β-cell function using C-peptide will be performed at 
baseline, Week 12, 24, 36, 52, and 72 (end of study), during the course of the study, as described 
in Section 8.2.1. The following diabetes-related endpoints will also be monitored during the 
study: HbA1c, 
 and diabetic ketoacidosis and hypoglycemic events. A study 
diary must be provided to subjects to report daily dose of insulin administration and glucose 
values 
, whenever possible and for a period of 
at least approximately 3-10 days. At the baseline visit (prior to first dose), 
 and instructed to start collecting data 
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3 to 10 days before the administration of first dose of study drug, with data collection intervals 
at:

screening or baseline (prior to first dose),

after receiving first dose of study drug,

every 3 months (Weeks 12, 24, 36, and 52 or early drug discontinuation) during the first
year of treatment,

and Week 72 during follow-up, or early termination.

Any subject enrolled in the study under an earlier version of the protocol which had longer
follow up and who is beyond Week 72 when Clinical Study Protocol Amendment 6 is
approved, will have an end of study visit at the next scheduled visit.
Glycemic measures and insulin dosage may be obtained from device records (i.e. meter and 
 glucose and insulin pump downloads for insulin 
dosing) if available. Date and time of study drug dosing will also be captured in a study diary.
Safety assessments will include height, weight, vital signs, physical examination, ECGs, 
standard clinical laboratory evaluations of hematology, blood chemistry, urinalysis, viral load 
and serology, adverse events and serious adverse events. Additional safety assessments for 
children and adolescents include: Tanner stage, growth velocity, and serial bone ages. Blood 
samples will also be taken for inflammatory 
 biomarkers at various time points 
during the study, as indicated in the Assessment Schedule, Table 8-1.
Subjects must be instructed to use their own insulin as this is part of standard of care and not 
part of the study. Insulin management including dose adjustments will be made by the subject's 
care provider according to local guidelines and individualized glycemic targets.
Minimum safety monitoring for each subject will be performed at least 
 post-last dose 
of CFZ533 or placebo, a time when pharmacodynamic response is anticipated to have returned 
to the subject’s baseline. However, subjects will be followed until week 72, 20 weeks post dose, 
to assess safety and effects on pancreatic β-cell function after stopping the investigational drug.
Reviews of safety and pharmacokinetic (PK) data will be jointly completed by the Sponsor 
(limited unblinding) and Lead Investigator (blinded) (see Section 6.5 and Section 12.7). The 
safety evaluation will include all SAEs and AEs, laboratory evaluations, and ECGs. Cohort 
expansion will be based on the following:

To open Cohort 2: At least 
 (aged 15 to ≤21 years) of Cohort 1 treated with
CFZ533 or placebo 
 along with the safety data for all subjects enrolled up to that
point, must be reviewed and deemed satisfactory jointly by the sponsor and Lead
Investigator.  Assessment of  subjects in this cohort, as opposed to 
 in other cohorts, is 
because existing safety data is more robust for subjects in this age and weight range 
population.
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Figure 3-1
Study Design
3.1
Off-site procedures
A hybrid trial design is planned for this study incorporating a flexible model of both on-site and 
off-site (remote from clinic, also known as remote or decentralized) visits. The off-site 
procedures will be utilized in certain countries and sites as determined by Novartis based on 
national and local regulations. Subjects have the option of participating in one or more off-site 
visits, based on national and local regulations, investigator discretion, and subject preference. 
Specific clinical trial procedures that may be performed at an off-site location are defined in 
Section 8.
One or more of the following elements may be implemented to support off-site visits where 
allowed by national and local regulations:

Telemedicine.

Off-site healthcare professionals (OHP).

Direct-to-patient shipment of study supplies.

Direct-to-patient shipment of study treatment (refer to Section 6).

Electronic Source (eSource) Direct Data Capture (DDC) (refer to Section 3.1.4).
3.1.1
Responsibility of Investigators
Procedures that are performed off-site remain under the oversight of the investigator, who 
retains accountability for the conduct of all safety and efficacy assessments delegated to an 
OHP. This includes ensuring the following (including, but not limited to):

Identification, management and reporting of adverse events and serious adverse events (AEs
and SAEs) are performed in accordance with the protocol and applicable regulations.

Thorough review and approval of the qualifications and experience of the OHP, including
an interview where requested, prior to delegating responsibilities to the assigned OHP.
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
Source data collected off-site are reviewed and evaluated in a timely manner.

The investigator or delegate is available to be contacted by the off-site healthcare 
professionals if any issues or concerns are noted during an off-site visit.

Where relevant, the Investigator or delegate will be present via telemedicine for a portion 
of the off-site visit to support the physical examination.
3.1.2
Responsibility of off-site healthcare professional (OHPs)
The OHPs must have the required qualifications, training, and experience to conduct off-site 
assessments. The OHP are responsible to conduct delegated assessments and collect relevant 
data at off-site visits in accordance with the clinical trial protocol, International Conference for 
Harmonization (ICH) Good Clinical Practice (GCP) guidelines, and national and local 
regulations and guidelines.
The OHP will be provided by a third-party vendor sourced by Novartis. Where a site wishes to 
use OHP that are not provided by Novartis this must be agreed with Novartis before use.
Any issues or safety concerns identified by the OHP will be promptly communicated to the 
investigator or delegate according to a pre-defined communication plan.
3.1.3
Telemedicine
The sponsor has qualified and contracted a third-party vendor to provide telemedicine platform 
technology for this study. The selected platform is a validated system complying with relevant 
ICH E6 GCP guidelines. Trial subjects can interact with site personnel using online 
communication tools built into the platform, enabling the following capabilities:

Secure videoconferencing which allows the subject, OHP, and site personnel to be 
connected.

eSource Direct Data Capture (DDC) (see Section 3.1.4).
3.1.4
Data flow
Investigators will have continuous, near real time access to all subject records in the eSource 
Direct Data Capture (DDC) platform, with the ability to add, edit, review and sign forms within 
subject records.
The OHPs will enter data at off-site visits into electronic source documentation forms contained 
in an eSource DDC platform, which has been validated for use in clinical research. Where paper 
source documentation exists, images of documentation will be uploaded electronically into the 
same platform as certified copies, and the original documentation will then be sent to the trial 
site for review and retention.
Data contained in the platform are available to site and sponsor staff based on role-based access 
and permissions, and will be stored in a robust and secure cloud-based back-end environment. 
Only sponsor staff who are responsible for field monitoring activities will have access to the 
source data, which may include some personally identifiable information, consistent with the 
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Relevant data in the eSource DDC platform may be manually transcribed by site staff into the 
study electronic data capture (EDC) system. Alternatively, the platform allows for configuration 
that enables data to be automatically exported into the study EDC system.
Certified copies of data in the eSource DDC platform will be provided to investigator and/or 
site personnel, and promptly and regularly uploaded into the subject’s medical records, 
according to local guidelines.
The platform maintains a secure, GCP-compliant audit trail and uses measures such as 
encryption and access controls to ensure that data privacy and security is maintained. Additional 
details will be contained in a separate Off-Site Study Operational Manual.
4
Rationale
4.1
Rationale for study design
The study employs staggered inclusion of subject cohorts by age and body weight in order to 
facilitate enrollment of younger subjects in a gradual manner based on emerging safety and 
tolerability in previous cohorts.
Cohorts are designed according to a descending age range (for the lower age limit). Lower age 
cut-offs per cohort are selected based on International Council for Harmonization of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) Topic E11 2001 approximate stages 
of development: Age 15-21 years late adolescent to young adult; and age 12 to <18 years 
adolescent. Body weight thresholds are based on anticipated weight boundaries for age
(CDC 2001), noting that permitted weight ranges may impact age of each cohort.
The first cohort will be used to evaluate safety as lower age and weight subjects are exposed in 
the second cohort. 
 of exposure per age and body-weight cohort will be required 
before a decision to open the next cohort can be made. 
 considered long enough 
to observe any potential acute/immediate effects (infusion site reactions, allergic reactions, 
delayed type hypersensitivity reactions, etc.) and mid-term effects. Effects which may occur at 
a later point will be monitored throughout the study at any point in time and for all cohorts. 
Dosing by body weight categories for the subcutaneous doses (lower body weight receive a 
lower fixed dose) is justified to provide similar exposures throughout the body weight range 
(see Section 4.2).
Age: Age range of 12 to 21 years. Cohorts advance from Cohort 1 of young adult to late 
adolescents (ages ≥15 to ≤21 years) to Cohort 2, comprised of young adult through adolescents 
(ages ≥12 to ≤21 years). The age range enables enrollment of young adult and adolescent 
subjects in whom new onset T1DM frequently occurs.
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The upper age limit of 21 years is selected because the severity of T1DM at diagnosis and 
T1DM progression in new onset T1DM up to this age are reported to be similar to that of 
adolescents (Hao et al 2016).
The lower age limit of 12 years is selected because the disease is more aggressive in children
and adolescents, and they may be more likely to respond to treatment (Greenbaum et al 2012, 
Woittiez and Roep 2015). In addition, 12 years of age provides ample time for immune system 
development and maturation, and vaccinations, which both occur generally by the approximate 
age of 6 years:

The immune system is considered fully competent by age 6 years for T lymphocyte sub-
sets (for e.g. CD4+, CD8+) and B lymphocyte subsets (for e.g. absolute counts, percentages 
of naive, isotype switched, and non-isotype switched memory B cells (Shearer et al 2003, 
Simon et al 2015, Huck et al 2009). Immunoglobulin levels, especially IgM and IgG plateau 
by age 6-8 years (Thomas 2012).

Childhood immunization schedules are largely completed by age 6 years for primary and 
major booster immunizations consistent with maturation of the immune system.
Investigator- and subject- blind design: avoids bias in treatment allocation, causality 
assessment, and reporting of adverse events. Limited unblinding of the lead investigator (e.g. at 
safety reviews) could improve the accuracy of safety-related decisions. Novartis will have 
limited unblinding so as to enable rapid, accurate and effective safety evaluation, and because 
this trial is non-confirmatory.
Placebo control: CFZ533 treatment and placebo will be administered on top of standard of 
care. First, placebo control is justified as there is no available active comparator for disease 
modification in T1DM. Second, placebo control provides a comparison group for 
safety/tolerability and pharmacodynamic endpoints. Concomitant medication and devices to 
treat the underlying disease diabetes (e.g. insulin, pen or pump) will be allowed in the active 
and placebo groups. Placebo comparator is required to understand the rate of progression of the 
underlying disease in the study cohort meeting specific inclusion/exclusion criteria and to 
distinguish treatment-related adverse events from underlying disease or study procedures.
Parallel two arm design: Allows for valid treatment group comparison between active and 
placebo. As new onset disease is required, sequential trial designs would be ineffective.
Randomization: Decreases the chance of an imbalance in subject characteristics (for example 
age, BMI, or duration of T1DM) between treatment groups, as there may be differences in 
pancreatic β-cell function at presentation of T1DM, rate of decline of residual β-cell function 
early after diagnosis, and severity of autoimmunity at different ages.
Treatment allocation 2:1 (2 active, 1 placebo) enables evaluation of safety of CFZ533 
(first-in-pediatrics) and assessment of the risk-benefit of CFZ533 in pediatric subjects with new 
onset T1DM, optimizing exposure to obtain safety data for CFZ533 and minimizing exposure 
to placebo with attendant study burden.
Treatment duration: One year of treatment is required to be able to differentiate potential drug 
effect on reduction in β-cell function (slowing of the decline) from the natural disease 
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Follow-up duration: Subjects will be followed 
 from the last dose 
of study drug to ensure health during drug pharmacokinetic and pharmacodynamic elimination.
Follow-up observation 
from the last dose of study drug permits 
assessment of the elimination of CFZ533 down to plasma levels that are expected to have no 
pharmacodynamic (PD) effects in tissues, and safety monitoring. Up to 20 weeks of follow-up 
is planned (with last dose of CFZ533 or placebo administered 
), which permits 
monitoring of durability of effect on the primary endpoint of β-cell preservation, approximately 
20 weeks post treatment.
4.1.1
Rationale for choice of background therapy
Subjects with T1DM require insulin therapy to avoid the life-threatening complication of 
diabetic ketoacidosis. Multiple insulin preparations are available with differing half-lives and 
dosing schedules may vary to cover daily basal and meal-related insulin requirements. 
Insulin may be administered by multiple daily injection or continuous subcutaneous insulin 
infusion via insulin pump. Therapeutic approaches to achieve individualized glycemic targets 
will be permitted with adjustment in order to achieve to local, provider, and subject goals. 
CFZ533 or placebo will be administered in the setting of good medical care.
4.2
Rationale for dose/regimen and duration of treatment
Overview of dose rationale: The CFZ533 dosing approach is in line with the allometric scaling 
assumptions and is predicted to ensure consistency of exposure and consequently comparable 
immunosuppression in a broad population of treated pediatric T1DM patients independent of 
body weight.  Allometric scaling, based on a power law relationship between body weight and 
pharmacokinetic parameters, is widely used to predict pharmacokinetics of monoclonal 
antibodies; the emerging CFZ533 pharmacokinetic data from adult populations are in line with 
these allometric assumptions and body weight appears to be a good predictor of plasma 
pharmacokinetics of CFZ533.
The dosing regimen in this trial includes an initial intravenous loading dose to fully saturate the 
CD40 binding sites followed by a body weight adjusted subcutaneous maintenance dose 
. The recommended body weight-adjustments aim to provide 
consistent plasma exposures for all treated young adult and pediatric subjects in this study 
(Figure 4-1).
While the maintenance subcutaneous doses are adjusted based on three predefined body weight 
categories, the initial intravenous loading dose (mg) is individualized based on the body weight 
of the individual subject. All subjects in the study will receive the weight based intravenous 
loading dose of 30 mg/kg. For example, the total intravenous loading dose for a hypothetical 
70 kg subject will be 2100 mg (30 mg/kg x 70 kg) while a lighter subject with body weight of 
30 kg will receive a lower total intravenous loading dose of 900 mg (30 mg/kg x 30 kg).
Dose rationale: The dosing rationale for CFZ533 in new onset T1DM subjects is based on 
exposure, safety and tolerability data from trials with CFZ533 in:

Kidney transplant (kidney Tx; Study CCFZ533X2201-Part 2),

Primary Sjögren's Syndrome (pSS; Study CCFZ533X2203),

Graves' disease (GD; Study CCFZ533X2205),
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
Myasthenia gravis (MG; Study CCFZ533X2204),

Rheumatoid arthritis (RA) subjects (first in human Study CCFZ533X2101),
and based on efficacy data in kidney transplant, Primary Sjögren's Syndrome, and Graves' 
disease.
The CFZ533 dosing regimen includes,

A body weight-adjusted intravenous (IV) loading dose of 30 mg/kg on Day 1 for all subjects
in the trial, followed by

A weight-tiered fixed subcutaneous (SC) dose administered weekly from Day 8 (Week 1)
to 
 (last dose), which is based on the following body weight categories,

Body weight Category II* (≥30 to <50 kg): 195 mg (1 injection of 1.3 mL),

Body weight Category III* (≥ 50 kg to ≤125 kg): 300 mg (1 injection of 2 mL or
2 injections of 1 mL).
*note earlier versions of the protocol included body weight in the 20 to 30 kg range,
which would have been in a Body weight Category I. This lower body weight
category is no longer included and explains the nomenclature of weight categories II
and III only.
The CFZ533 IV loading dose will be administered at the Investigator site.
The CFZ533 SC weekly dose (195 or 300 mg) will be defined based on the body weight of the 
subject recorded every 3 months at site visits on Day 1, Day 85/Week 12, Day 169/Week 24, 
Day 253/Week 36 and Day 337/Week 48 to account for body weight gain or loss during the 
treatment period. Last dose is administered 
 and the end of the treatment assessment 
will be performed at Week 52. CFZ533 Weekly SC doses may be administered at home or at 
Investigator site. Every effort should be made to respect the weekly schedule and the protocol 
specified visits. Compensatory doses must be administered at the discretion of the Investigator, 
on-site only, and not at an off-site visit. See Section 6.1 for instructions when a dose of the 
investigational drug is delayed or missed, and when a dose is considered compensatory.
Body weight Categories (II, and III) differ from Cohort age based anticipated weights, but are 
designed to maintain comparable exposure across the weight ranges anticipated in the trial. 
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Rationale for the intravenous (IV) loading dose on Day 1
The CFZ533 30 mg/kg IV loading dose on Day 1 is predicted:

To rapidly saturate CD40 receptors in target tissues (i.e. pancreatic lymph nodes) and 
minimize the CD40-mediated elimination of CFZ533 in conditions early after diagnosis 
where the aggressiveness of the disease (including insulitis, B- and T-lymphocytes 
infiltration in pancreatic islets, active ectopic germinal centers) is greatest and likely to be 
associated with high tissue CD40 expression,

To rapidly block the aggressive autoimmune destruction of residual β-cells, insulitis and 
local infiltration of pathogenic auto reactive B lymphocytes.
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CD40 expression in new onset T1DM patients
Patients with autoimmune diseases (including T1DM) generally present with increased CD40 
expression in target tissues and elevated serum/plasma soluble CD40 (sCD40; shed receptors) 
levels.
In T1DM patients, data on tissue CD40 levels, distribution and turnover in the pancreas and 
pancreatic lymph nodes are not available. As well, the quantitative relationship between plasma 
sCD40 and tissue CD40 levels is unknown. Nevertheless, elevated plasma sCD40 levels are 
assumed to reflect elevated expression of CD40 in target tissues.
In Chatzigeorgiou et al (2010a),

Pediatric T1DM patients had significantly higher plasma sCD40 levels (93 pg/mL) 
compared to healthy controls (66 pg/mL), which were associated with elevated plasma 
interleukin-6 (IL-6), matrix metalloproteinase-9 (MMP-9) and CRP levels.

Urine sCD40 levels were also elevated in T1DM compared to healthy controls: 335 pg/mL 
and 150 pg/mL, respectively, suggesting that the elevated plasma levels of sCD40 in these 
patients reflect increased CD40 production rather than diminished kidney excretion.

Upregulation of cellular CD40 (peripheral blood mononuclear cells) was also observed 
and was positively correlated with plasma sCD40, IL-6, CRP as well as hemoglobin A1c 
(HbA1c).

Plasma and peripheral blood mononuclear cell (PBMC) CD40 levels appear to be elevated 
in pediatric patients with T1DM, and positively correlate with inflammation.
In Chatzigeorgiou et al (2010b), plasma CD40 concentrations were also significantly higher in 
diabetic patients than in healthy controls (about 110 pg/mL vs. 55 pg/mL) and correlated 
positively with HbA1c. Moreover, for patients with disease duration < 1 month, 1-6 months, 
or > 6 months, plasma CD40 was about 75, 190 and 88 pg/mL, respectively.
Achieving saturating and efficacious conditions in pancreatic islets at start of treatment (dosing 
to be within 56 days of diagnosis which may extend to within 100 days of diagnosis in the event 
a screening assessment needs to be confirmed or vaccination administered) through an IV 
loading dose is critical for an effective immune intervention to preserve residual β-cell function.
Saturation of CD40 receptors in inflamed tissues
The CFZ533 30 mg/kg IV loading dose is further justified considering that CFZ533 is subject 
to CD40-mediated drug disposition (or target mediated drug disposition - TMDD; a process in 
which a significant proportion of the drug (relative to dose) is bound to CD40 receptors and 
affects CFZ533 clearance).
The extent of TMDD is dictated by the level of CD40 receptors in tissues and the level of 
saturation of these receptors. Elevated CD40 expression may be associated with a high 
elimination rate of CFZ533 and loss of target engagement in target tissues if CD40 is not fully 
saturated.
The loading regimen is expected to provide full CD40-CD154 pathway blockade at start of 
treatment.
 
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Failure to saturate CD40 receptors in conditions where CD40 expression in tissues is 
significantly enhanced can translate in clinical efficacy failure.
This was demonstrated with a competitor anti-CD40 antibody ASKP1240 (bleselumab; 
Goldwater et al 2013).
Bleselumab was investigated in kidney transplant (Tx) subjects (Phase 2 trial; 
Harland et al 2017) and in transplanted monkeys (Ma et al 2014).
In the Phase 2 trial with bleselumab, most of the rejections in the calcineurin inhibitor-free arm 
occurred before Day 60. 
CFZ533 exposures after the 30 mg/kg IV loading dose
The CFZ533 30 mg/kg IV loading dose is expected to reach exposures (including a median 
Cmax of about 826 μg/mL) which correspond to doses and regimens which have been used in 
Rheumatoid arthritis (RA) and kidney transplant patients.
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Rationale for the subcutaneous (SC) maintenance regimen
As opposed to the body weight (BW)-adjusted approach for the IV loading dose, the weekly 
SC maintenance regimen which starts on Day 8/Week 1 up to the last dose on 
, is based 
on a fixed SC dose selected according to the following two body weight categories,

Body weight Category II (30 to <50 kg): 195 mg SC weekly.

Body weight Category III (≥ 50 kg to ≤125 kg): 300 mg SC weekly.
Assuming a fixed dosing strategy, body weight categories were created to maintain similar 
exposure levels for all subjects across the body weight range in this study. This is justified based 
on the anticipated effect of body weight on the clearance of CFZ533. If the same fixed dose 
would have been applied across the body weight range in this study, lower body weight subjects 
would have been overexposed. This is typical for a monoclonal antibody like CFZ533 and 
consistent with allometric principles where a fixed dose strategy is used (Wang et al 2009, 
Wang and Prueksaritanont 2010).
Two body weight categories are proposed (30 to < 50 kg and ≥ 50 kg to ≤125 kg). This is 
justified to ensure similar between subject variability within each category and based on similar 
fold-exposure differences between each boundary within a body weight category
 
The selected body-weight adjusted maintenance CFZ533 doses of 195 and 300 mg SC weekly
for the two body weight categories of pediatric T1DM patients, are expected to provide steady-
state exposures comparable with the CFZ533 maintenance doses of 600 mg SC every other 
week in adults. Maintenance doses of CFZ533 up to 600 mg SC every other week are being 
evaluated across multiple indications as potential future dosing regimens, which may provide 
the optimal risk-benefit in adult patients treated with CFZ533. This maintenance dosing 
regimen is being used specifically in the ongoing dose-range finding studies in adult Sjögren’s 
Syndrome (CCFZ533B2201) and de-novo kidney transplant patients (CCFZ533A2201) and to 
date, has not been associated with any major safety concerns. To date, approximately 
50 de-novo kidney transplant patients have been continuously treated at least one year with 
CFZ533 600 mg SC every other week.
Weekly as opposed to every other week dosing is being used in this pediatric trial for reduced 
variability in drug levels, and allows for the reduction of injection volumes, which may increase 
the comfort of administration and treatment compliance in youth.
In body-weight Category III (≥50 kg body weight) CFZ533 300 mg SC weekly will lead to the 
predicted typical steady-state trough CFZ533 plasma concentration (Ctrough, ss) 
 
. Similar CFZ533 
plasma steady state (ss) Ctrough values are predicted for Category II (body weight 30 to 
< 50 kg) with CFZ533 195 mg SC weekly.
Predicted CFZ533 plasma Ctrough, ss values in T1DM were already evaluated in ongoing or 
completed clinical studies with CFZ533 in Primary Sjögren's Syndrome, kidney transplant, 
Graves’ disease and Myasthenia gravis patients, where they were overall safe and well tolerated. 
Predicted CFZ533 plasma Ctrough, ss values for T1DM patients/subjects in body weight 
Category III (similar Ctrough,ss are predicted for Category II) are compared to observed trough 
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concentrations for CFZ533 in previous clinical trials
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Previous experience with the 300 mg weekly SC regimen
The CFZ5533 300 mg weekly SC regimen for T1DM patients with body weight ≥ 50 kg 
(Category III) has recently been evaluated in Primary Sjögren's Syndrome patients from Study 
CCFZ533X2203-Cohort 3 (N=25; after an IV loading dose or after a SC loading regimen).
The predicted steady state median CFZ533 trough concentration 
 for T1DM 
patients/subjects in Category III is:

similar to the mean trough level observed in Primary Sjögren's Syndrome subjects in Study 
CCFZ533X2203-Cohort 2 
 and
Similar steady state trough plasma concentrations of CFZ533 are predicted for Category II (195 
mg SC weekly) and III (300 mg SC weekly).
Efficacy
Predicted plasma CFZ533 exposures in T1DM patients/subjects are within observed exposures 
demonstrated to be efficacious in Primary Sjögren's Syndrome and kidney transplant subjects.
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4.2.1
Rationale for treatment duration and subsequent follow up without
continued treatment
Type 1 diabetes is characterized by progressive loss of pancreatic β-cell function. No 
acceleration in loss is anticipated after discontinuing CFZ533. It is possible that there may be 
prolonged protection from loss in β-cell function for some time after stopping CFZ533. Whether 
prolonged protection may occur is being evaluated during the post-treatment follow up period
of the trial.
The treatment period with CFZ533 in this study is one year.  This is the amount of time generally 
considered to be the minimum interval necessary to demonstrate a clear preservation of 
pancreatic β-cell function in the active treatment group compared to the placebo assigned group 
(Ehlers 2016). Subjects will be followed for an additional 20 weeks post treatment period (up 
to week 72) to establish the durability of the effect off-treatment. This will potentially inform 
recommendations for duration of CFZ533 use in clinical care following drug approval.
No treatment beyond 12 months is anticipated at this time.  If the drug is effective, then it is 
important to understand the durability of response to inform future clinical use (i.e. to address 
for what duration of time should the drug be prescribed and when should treatment be 
discontinued). This important information will be obtained in this study, when both efficacy 
and safety of prolonged exposure is uncertain.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Placebo is used as control since there are no approved therapies for disease modification in 
T1DM.
4.3.1
Rationale for diabetes-specific endpoints
C-peptide is a direct measure of beta cell function and sustained C-peptide values reflect 
preservation of function.  In diabetes, preservation of beta cell function is disease modifying. 
The primary trial endpoint of stimulated C-peptide (area under the curve following MMTT) is 
aligned with both US and EU regulatory guidance for the determination of the preservation of 
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beta cell function, recognizing that Health Authorities will require additional clinically 
meaningful co-primary or secondary endpoints at the time of registration.
Secondary 
 endpoints in this study will help establish the clinical value of 
preservation of pancreatic beta cell function.  These additional measures include:

Diabetes remission or partial remission including not requiring exogenous insulin therapy
with HbA1c <6.5% (remission) or insulin dose adjusted HbA1c (IDAA1c ≤9.0) or HbA1c
< 7.0% (53 mmol/mol) and total daily insulin dose <0.5 units per kg per day at 52 weeks
(partial remission),

HbA1c,

Episodes of severe hypoglycemia,

Episodes of diabetic ketoacidosis,

Fasting glucose, 2 hour glucose after mixed meal tolerance test,
4.4
Purpose and timing of interim analyses/design adaptations
4.5
Risks and benefits
Type 1 diabetes is characterized by progressive loss of pancreatic β-cell function. No 
acceleration in loss is anticipated after discontinuing CFZ533. It is possible that there may be 
prolonged protection from loss in β-cell function after stopping CFZ533. Whether prolonged 
protection may occur is being evaluated during the post-treatment follow up period of the trial.
It is hoped that treatment with CFZ533 will provide a new therapeutic approach to treat or 
prevent T1DM. There is no established benefit to individual study participants although it is 
possible that individuals with T1DM participating in the trial who receive CFZ533 will benefit 
from preserved β-cell function.
Overall, CFZ533 has been safe and well tolerated in clinical trials to date. The available data in 
subjects in the CFZ533 development program 
 
 as reported in the Investigator Brochure 
Edition 12,
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Clinical safety risks with CFZ533 include:

Class (biologic)-related risks: hypersensitivity reactions, anaphylactic reactions and
immunogenicity.

Pediatric-specific safety considerations: immaturity of the immune system, growth,
puberty, blood volume.

Study related risks: venipuncture, injection site reactions.
The safety profile of CFZ533 should be viewed separately for transplant and autoimmune 
(non-transplant) indications. Kidney transplant is a more severe and complex indication due in 
part to background immune suppressive therapy per standard of care. Adverse events leading 
to discontinuation are reported in the transplant trials and not in autoimmune diseases (AID) 
trials.
Key differences include that 
the subjects in the CCFZ533X2207 trial:
1. will not be receiving concomitant immunosuppressive therapy,
2. will be excluded for leukopenia/lymphopenia,
3. will be screened for CMV viral status at study entry, and
4. will be monitored at weeks 16, 32 and 48 for seroconversion (with additional monitoring
added in the Protocol V02 amendment).
Potential infection risk
CD40 is important for the development of protective immune responses against a broad range 
of external pathogens, bacterial, viral, fungal and parasitic in origin. Blockade of CD40 with 
CFZ533 may impair the immune response to new pathogens but should not affect the 
preexisting humoral immunity which is expected to provide adequate protection from infections 
to known pathogens. Once CFZ533 concentrations fall below levels associated with full 
receptor occupancy, the drug undergoes target mediated drug clearance and the immune system 
recovers.
There are specific infection risk challenges in the pediatric population (Allen 2016). 
The potentially immunocompromised child may be at a greater risk of acquiring specific 
infections compared to their adult counterparts. Several reasons may contribute to this increased 
infection risk. Multiple infections are more prevalent in younger age groups, such as respiratory 
viral diseases including respiratory syncytial virus illness (Hall et al 2009), such that infection 
risk is related to their age group regardless of immune competence. Children have increased 
likelihood of primary infections as they are still developing their immune repertoire. For 
example, adult organ transplant recipients are more likely to be partially immune to some 
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infections, such as CMV and EBV, whereas their pediatric counterparts are not. Primary 
infections typically are associated with more severe illnesses because of no preexisting host 
immunity.
Compared with adults, young children are less likely to have received their full series of 
vaccines and generally tend to be at a greater risk of vaccine-preventable diseases after the onset 
of immunosuppression. For this reason this study will not enroll children under the age of 
6 years, where most primary vaccine series have been administered.
The immune system is mature by age 6 years (Thomas 2012), and immunosuppression is not 
anticipated to be different across age groups included in this study.
Infections are reported separately for non-transplant studies (healthy volunteers, Rheumatoid 
arthritis subjects, autoimmune diseases (AID) indications), and for the kidney transplant study 
where background immune suppressive therapy is universally present as standard of care 
therapy.
T1DM patients are not immunosuppressed and the data generated to date in healthy volunteers, 
and in patients with no or minimal immunosuppression, such as Primary Sjögren's Syndrome 
are likely to be more relevant: such data also do not suggest an increased infection risk. 
However, as data are limited, no definitive conclusions can be made and infection remains an 
important risk for CFZ533 and will be mitigated in the proposed trial.
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In autoimmune diseases under investigation, to date, 
which can be seen in hyperimmunoglobulin M syndrome, a rare 
disorder of CD154 (CD40 ligand (CD40L)) deficiency characterized by defective class-switch 
recombination (CSR), resulting in normal or increased levels of serum IgM associated with 
deficiency of immunoglobulin G (IgG), immunoglobulin A (IgA), and immunoglobulin E (IgE) 
and poor antibody function.
Potential risk associated with SARS-CoV-2 (COVID-19)
Novartis is committed to supporting the safety and well-being of our study participants, 
investigators, and site staff.  All local regulations and site requirements must be applied in the 
countries that are affected by the COVID-19 pandemic. Having T1DM does not make patients 
more susceptible to contracting COVID-19, but the disease may be more severe in patients with 
diabetes than in those without (CDC 2020). This is largely driven by obesity and type 2 diabetes 
and there is no current evidence that younger individuals with type 1 diabetes are at increased 
risk for more severe disease (CDC 2020). 
SARS-CoV-2 Vaccination 
Study subjects are not specifically mandated to receive COVID-19 vaccination prior to study 
entry. However, subjects must complete all locally recommended immunizations, including 
COVID-19 vaccinations where applicable, prior to first dose with study drug and in accordance 
with local immunization guidelines. Killed/inactive vaccines must be administered at least 
2 weeks prior to first dose with study drug.  Currently, there are no live, attenuated COVID-19 
vaccinations available, but this may be subject to change if new vaccine types are developed. 
Investigators must be sure to check locally approved vaccine types. Immunization with a live, 
attenuated vaccine must be completed at least 8 weeks prior to the first dose. Administration of 
live, attenuated vaccines during treatment is prohibited and should be avoided while receiving 
CFZ533 (iscalimab) and for at least 
 thereafter. 
Vaccination during treatment with CFZ533 (iscalimab) prior to clearance of CFZ533 
(iscalimab) from the body is anticipated to result in an insufficient immune response (i.e. non-
protective antibody titers). Reduced or absent immunization effectiveness may be expected for 
both live (attenuated) and killed (inactivated) vaccines.
SARS-CoV-2 Testing
Subjects will be tested for SARS-CoV-2, the virus causing COVID-19 disease prior to receiving 
the study drug. Those with active viral load or evidence of recent infection based on serologic 
testing (IgM positive, IgG negative) will not be dosed.  Retesting is permitted for viral clearance 
and seroconversion for subjects who have remained asymptomatic or whose symptoms have 
resolved. It is important for investigators to follow local guidelines for reporting of positive 
cases. It is also important to recognize that subjects who were not previously infected can be 
exposed and develop COVID-19 despite previously normal testing. Repeat testing or consult 
with infectious disease specialist may be warranted. Subjects must be advised to continue social 
and personal hygiene to reduce infection risk according to local guidance, and to report any 
signs and symptoms of infection to the Site Investigator immediately. As the COVID-19 
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situation evolves, investigators must use their best judgement to minimize risk to subjects 
during the conduct of the study.
Impaired vaccination effectiveness and related-infection risk
Overview: The ability to mount primary and secondary T-cell-dependent antibody responses 
(TDAR) is expected to be affected by CFZ533. However, the memory B-cell repertoire should 
remain intact and protective. Antibody concentrations in the blood and existing immune 
memory are not impacted by CFZ533 in non-clinical and in vivo studies.  Pre-formed immunity 
to pathogens and vaccines (circulating antibody titers and plasma cells) is not expected to be 
affected by exposure to CFZ533. Finally, the effect of CFZ533 on the immune system is 
reversible; once CFZ533 is cleared, the capability to generate humoral immune responses is 
restored.
Blockade of CD40 receptors by CFZ533 impairs T-lymphocyte dependent antibody responses 
(TDAR) to vaccines. CFZ533 plasma concentrations above 
 were associated in non-
human primates with complete suppression of germinal center development, and prevented 
recall antibody responses after Keyhole Limpet Hemocyanin (KLH) vaccinations. 
Upon elimination of CFZ533 a normal memory antibody response could be mounted in all 
animals (more details in the Investigator Brochure). In healthy volunteers a single dose of 3 
mg/kg (IV or SC) of CFZ533 transiently suppressed anti-KLH responses to the first KLH 
immunization at CFZ533 concentrations corresponding to full receptor occupancy (RO) in 
whole blood (RO; ≥90%) for about 3-4 weeks. Anti-KLH primary responses were detected in 
all subjects as CFZ533 concentration and accompanying receptor occupancy declined. All 
subjects were able to mount recall responses to a second KLH immunization (administered after 
loss of RO; details in the IB).
CFZ533 is non-depleting of cells that express CD40, including memory B lymphocytes, which 
supports rapid functional recovery of immune responses as the compound is being cleared. 
CFZ533 is not expected to affect plasma cells as they are not believed to express functional 
CD40 receptors.
The ability to mount a T lymphocyte-dependent primary and memory immune response to 
vaccines and pathogens is expected to be impaired in subjects with plasma CFZ533 
concentrations 
. The risk to subjects of vaccination ineffectiveness while exposed 
to CFZ533 is mitigated by eligibility requirements of up-to-date immunizations (per local 
guidelines) and confirmation of protective serology prior to initial dosing with CFZ533. 
Mitigation plans for the infection risks to subjects during exposure to CFZ533 was covered 
previously. Once CFZ533 is cleared, subjects are expected to mount normal primary and 
secondary immune responses to vaccines and pathogens as CD40 receptor blockade is released.
Pre-formed immunity to pathogens and vaccines (circulating antibody titers and plasma cells) 
is not expected to be affected by exposure to CFZ533. Plasma cells are long lived and confer 
long-lasting immune protection to subjects, for example at least 10 years for tetanus toxoid and 
potentially even longer for measles. Thus, subjects with pre-formed immunity are expected to 
retain protection against pathogens during exposure to CFZ533.
There is always a risk of infection with new pathogens that have not been previously 
encountered and for pathogens against which there are no available or commonly used vaccines 
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in the first world countries where this study will be conducted. Such examples include cholera 
and typhoid fever for which vaccines are not standard in these countries. Subjects enrolled in 
the study must be advised against traveling to areas with endemic diseases that they are not 
vaccinated against, particularly because preventive travel vaccines will not work during 
exposure to CFZ533. Immunization with live attenuated vaccines is prohibited for eight weeks 
prior to first dose administration of study drug (Rubin et al 2014) until 
 following the 
last dose.
Potential risk of thrombotic events
The risk of thrombotic events with CFZ533 is considered minimal.
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renders an association between CFZ533 and the thrombotic events highly 
unlikely (Andrassy et al 2004). Finally, thrombosis rates for CFZ533 should be considered 
versus the rate seen with standard of care in renal transplant trials.
Overall, while anti-CD154 antibodies are clearly associated with a high risk for thrombophilia, 
both preclinical and clinical data from an extensive Phase 2 clinical program across healthy 
subjects and patients across different indications have not indicated an associated risk with 
CFZ533.
Lymphoproliferative risk
A hypothetical risk for lymphoproliferative disorders for some subjects under strong 
immunosuppression cannot be excluded for CFZ533.
 
Additional safety considerations for CFZ533 in a pediatric population
Immune system maturation in pediatrics: The immune system, adaptive and innate, is 
deemed functionally competent at 6 years of age, and comparable to that of adults. Thus, this 
study enrolls pediatric subjects anticipated to have a mature immune system.
CD40 and bone growth: There is no indication of an effect of the CD40-CD154 pathway on 
linear bone growth. 
CD40 and puberty: There is no known role or involvement of the CD40 pathway in puberty.
In general, the risk in this trial will be managed and minimized by appropriate eligibility criteria, 
specific dose selection criteria and stopping rules.
The risk to subjects in this trial will be minimized by compliance with the eligibility criteria 
and study procedures, as well as close clinical monitoring, stopping rules, and periodic safety 
reviews by the clinical team, the PI and in addition by an independent DMC. This is a first in 
pediatric study and information on safety of CFZ533 in this age group is not yet available 
indicating the potential for unknown risks.
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Females of child bearing potential (e.g. menstruating) must be informed that taking the study 
treatment 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 
requirements outlined in the exclusion criteria. If there is any question that the subject will not 
reliably comply, they should not be entered or continue in the study.  
Male contraception is not required based on the low distribution of IgG monoclonal antibodies 
into the semen and low exposure to the female partner and potential fetus (Moffat et al 2014; 
Morris et al 2014).
Potential risks and benefits related to off-site visits
Subjects are not anticipated to be exposed to greater risks when participating in off-site
assessments. OHPs will perform assessments according to the same processes and instructions 
defined in the protocol and study manuals for on-site visits wherever possible, thus data 
integrity is also expected to be comparable to on-site assessments. Safety management in an
off-site setting will adhere to the same quality standards as for the traditional on-site model, and 
remains under the responsibility of the Investigator (refer to Section 3.1.1). Furthermore, all 
subject data is treated with the strictest confidence to align with the requirements of local 
guidelines (i.e. General Data Protection Regulation and Health Insurance Portability and 
Accountability Act). Off-site procedures minimize burden on subjects and parent/caregiver, and 
offer them increased flexibility to participate in the study from a convenient off-site location 
(as described in Section 3 and defined in Section 8). This has the potential to broaden access to 
clinical trials for both subjects and parent/caregiver and the investigators. The hybrid approach 
will allow subjects to maintain contact with the Investigator, both face-to-face during on-site 
clinic visits, and through the telemedicine platform during off-site visits.
The scope of off-site procedures was determined based on a thorough operational feasibility 
review of the assessment schedule to assure comparability with on-site assessments, together 
with consideration of patient safety and investigator feedback. Off-site procedures will only be 
conducted where approved by the Health Authority and Ethic Committee.
4.5.1
Blood sample volume
Recognizing the pediatric population under study, and following recommended by the World 
Health Organization (Howie 2011) and European Medical Agency (EMA) for trial related blood 
volume in pediatric populations, total blood volume per single time point is less than 1% of a 
subject’s total blood volume at a single time point, and the total blood volume will not exceed 
3% of a subject’s total blood volume and in a 4 week period. In Cohorts 1 and 2 subjects have 
body weight ≥30 kg, and total blood volume will not exceed EMA recommendations for trial 
related blood volume (see Appendix 4). 
In addition, screening visit may be organized over two separate visits to adhere to safe 
phlebotomy limits. Likewise for larger subjects, screening and baseline visits may be combined. 
Additional samples may be required for safety monitoring.
Timings of blood sample collection are outlined in the assessment schedule.
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A summary blood log is provided in the Site Operations Manual . Instructions for all sample 
collection, processing, storage and shipment information is also available in the Site Operations 
Manual and central laboratory manual.
See the Section 8.4.6 on the potential use of residual samples.
4.6
Rationale for Public Health Emergency mitigation procedures
In addition to the planned off-site procedures, in the event of a Public Health emergency as 
declared by Local or Regional authorities i.e., pandemic, epidemic or natural disaster, additional 
mitigation procedures to ensure subject safety and trial integrity may be implemented. If 
allowable by a local Health Authority and depending on operational capabilities, phone calls, 
virtual contacts (e.g. telephone assisted consult) or additional visits by OHPs to the subject’s 
home, can replace on-site study visits (in addition to the already planned off-site visits), for the 
duration of the disruption until it is safe for the subject to visit the site again.
Notification of the Public Health emergency should be discussed with Novartis prior to 
implementation of mitigation procedures and permitted/approved by Local or Regional Health 
Authorities and Ethics Committees as appropriate.
5
Population
The investigator must ensure that all subjects being considered for the study meet the following 
eligibility criteria. Subject
selection is to be established by checking through all 
inclusion/exclusion criteria at screening and again prior to dosing as appropriate. A relevant 
record (e.g. checklist) must be stored with the source documentation at the study site. Deviation 
from any entry criterion excludes a subject from enrollment into the study.
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Written informed consent, and if needed assent from the child on the trial, must be 
obtained before any assessment is performed.
2. Males and females aged between 12 and 21 years (inclusive, and enrolled in stages) at 
screening.
3. Body weight range from 30 to 125 kg (inclusive).
4. Evidence of one or more type 1 diabetes autoantibody(ies) against: glutamic acid 
decarboxylase (anti-GAD), protein tyrosine, phosphatase-like protein (anti-IA-2); zinc 
transporter 8 (anti-ZnT8); islet cell (cytoplasmic) (anti-ICA) at screening or baseline in the 
central laboratory OR historical clinical record of one or more of the T1DM diabetes 
autoantibodies. As part of the historical record insulin autoantibodies (IAA) may have 
been used as part of the autoantibody panel but the blood sample must have been obtained 
prior to or within one week of starting exogenous insulin treatment.
5. Able to receive first dose of study drug within 56 days of diagnosis of T1DM (which may 
be extended to within 100 days of diagnosis in the event a screening assessment needs to 
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6. Peak stimulated C-peptide levels ≥0.2 nmol/L (0.6 ng/mL) following standard liquid 
mixed meal tolerance test (MMTT), to be conducted when the subject is metabolically 
stable, at least 2 weeks from diagnosis and within 56 days prior to randomization (or 
within 100 days of diagnosis in the event a screening assessment needs to be confirmed or 
vaccine is required).
7. Study participants are to complete all recommended immunizations with live, attenuated 
vaccine at least eight weeks prior and killed, inactivated vaccine at least two weeks prior 
to first dose with study drug and in accordance with local immunization guidelines. In the 
event a subject has not had all vaccinations recommended according to local guidance, the 
screening period may be extended beyond 56 days to allow these vaccinations to be 
administered, but first dose of study drug must be administered within 100 days of 
diagnosis of T1DM (see Sections on Risks Section 4.5 and Screening procedures
Section 8.1).
8. Must be willing to comply with the standard of care for diabetes management.
9. A negative pregnancy test at screening is required for all sexually mature female subjects 
prior to participation in the study.
10. Subject and/or guardian must be able to communicate well with the investigator, to 
understand and comply with the requirements of the study.
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.
1. Diabetes forms other than auto immune type 1 such as maturity-onset diabetes of the young 
(MODY), latent autoimmune diabetes of the adult (LADA), acquired diabetes (secondary 
to medications or surgery), type 2 diabetes by judgement of the investigator.
2. Diabetic ketoacidosis within 2 weeks of the baseline MMTT test.
3. Polyglandular auto immune disease, Addison’s disease, pernicious anemia, celiac sprue. 
Note: Investigators are not mandated to test for Celiac disease (also known as Sprue). 
Subjects suspected of having Celiac disease should be tested for the presence of disease, as 
part of good medical care, as treatment would differ. Treated, stable Hashimoto’s thyroiditis 
is not exclusionary.
4. Any of the following abnormal laboratory values at screening:

total white blood cell count (WBC) outside the range of 1,500-15,000/mm3 (1.5-15.0 x 
109/L)

neutrophil count (<1500/mm3) (<1.5 X 109 / L)

lymphocyte count <500/mm3 (<0.5 X 109 / L)

hemoglobin (Hgb) <8.0 g/dL

platelets <100,000/mm3 (<100 x 109/L)
5. History of immunodeficiency disorders, such as HyperIgM syndrome; history of recurrent 
infections suggestive of immunodeficiency disorders.
6. History of or active coagulation disorder with increased thromboembolic risk; a PTT and 
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7. Tuberculosis infection assessed by positive QuantiFERON TB-Gold test (QFT) at 
screening. Subjects with a positive QFT test may participate in the study if further work up 
(according to local practice/guidelines) establishes conclusively that the subject has no 
evidence of active tuberculosis. If presence of latent tuberculosis is established, then anti 
tuberculosis treatment must have been initiated and maintained according to local country 
guidelines.
8. Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV). A positive HBV surface 
antigen (HBsAg) test, at screening, excludes a subject. Subjects with a positive HCV 
antibody test should have HCV RNA levels measured. Subjects with positive (detectable) 
HCV RNA should be excluded.
9. Positive human immune virus HIV test (ELISA and Western Blot) at screening. 
10. Evidence of EBV, CMV, HSV, and/or SARS-CoV-2 infection by viral load above 
laboratory upper limit of normal or only positive IgM serology in the absence of positive 
IgG at screening. Rescreening is permitted in persistently asymptomatic or post-
symptomatic subjects, but study drug must be able to be administered within 100 days of 
diagnosis of T1DM and viral load must be negative and IgG titers positive.
11. Major dental work (e.g. tooth extractions or dental surgery with access to dental pulp) within 
8 days of first dose; febrile illness within 48 hrs of first dose.
12. Use of other investigational drugs or use of immunosuppressive agents at the time of 
enrollment, or within 5 half-lives of enrollment, or until the expected PD effect has returned 
to baseline, whichever is longer; or longer if required by local regulations.
13. History of multiple and recurring allergies or allergy to the investigational 
compound/compound class being used in this study. Multiple and recurring allergies refer 
to known allergies to the investigational compound, to immunoglobulin based therapies, or 
to multiple drug classes. Dust mites, hay fever, and similar environmental allergies are not 
exclusionary.
14. History of severe hypersensitivity reaction or anaphylaxis to biological agents, e.g. human 
monoclonal antibody.
15. History of malignancy of any organ system (other than localized basal cell carcinoma of the 
skin), treated or untreated, within 5 years of screening, regardless of whether there is 
evidence of local recurrence or metastases.
16. Active serious psychiatric disorders (diagnosed or treated by a psychiatrist), such as eating 
disorders and psychosis or history thereof.
17. Any complicating medical issues or clinically abnormal laboratory results that may cause 
an increased safety risk to the subject as judged by the investigator.
18. Ongoing, and up to 2 weeks prior to screening, use of medications that may affect glucose 
control (e.g, systemic steroids, thiazides, beta blockers). A short course of oral steroids < 
10 days if medically required is permissible with sponsor notification.
19. History of drug abuse, nicotine or harmful alcohol use within 12 months prior to first dose, 
or evidence (as determined by the investigators) of such abuse at screening. For example, 
harmful alcohol use in adults is defined as five or more drinks per day for 5 or more days in 
the past 30 days. Harmful alcohol use by adolescents (age 13-18 years) is to be determined 
by the investigator, based on local culture and laws. Harmful cannabinoid use is difficult to 


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define universally and the determination of abuse will be made by the Investigator based on 
local culture and law.
20. Taking medications prohibited by the protocol (see Section 6.2.2 (Prohibited treatment) or 
Table 6-2 Prohibited medication).
21. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test.
22. Women of child-bearing potential, defined as all women, who are sexually active, 
physiologically capable of becoming pregnant (e.g. menstruating), unless they are using 
highly effective methods of contraception during dosing and for 14 weeks (Section 4.2) 
after stopping the investigational drug. Highly effective contraception methods include:

Total abstinence from heterosexual intercourse (when this is in line with the preferred 
and usual lifestyle of the subject). Periodic abstinence (e.g. calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods 
of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks prior to first 
dose. In case of oophorectomy alone, only when the reproductive status of the woman 
has been confirmed by follow up hormone level assessment.

Male sterilization in the sexual partner of female study participant (at least 6 months 
prior to screening). For female subjects on the study the vasectomized male partner 
should be the sole partner for that subject.

Use of oral (estrogen and progesterone), 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 be stable on the same pill for a 
minimum of 3 months prior to first dose.
If local regulations deviate from the contraception methods listed above and require more 
extensive measures to prevent pregnancy, local regulations apply and will be described in the 
Informed Consent Form (ICF).

Refer to Section 8.3.4 (Pregnancy).
No additional exclusions may be applied by the investigator, in order to ensure that the study 
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6
Treatment
6.1
Study treatment
Dosing of the study drug, CFZ533 (iscalimab) or placebo, will be based on body weight (details 
in Section 4.2).
Study drug dosage will be adjusted based on bodyweight recorded at Day 1 and then every 
3 months during site visits (Section 4.2) to account for body weight gain or loss during the 
treatment period.
The first dose of study drug will be administered in clinic intravenously (IV) on study Day 1 
and two subcutaneous (SC) dose will be administered under observation at a scheduled visit on 
Every effort should be made to respect the weekly dosing schedule regardless of whether dosing 
is planned in clinic, off-site, or at home by subject or guardian in order to maintain target plasma 
CFZ533 exposure levels, and ensure complete CD40-CD154 pathway blockade in target 
tissues, and permit assessment of drug safety and potential efficacy. A ± 3 days window may 
be applied to the study drug SC administrations (regardless of whether dosing is planned in 
clinic, off-site, or at home by subject or guardian). In all cases the original visit and dosing 
schedule should be maintained, so that the visits and doses must continue to be administered as 
per the original schedule, and the administration schedule should not be recalculated from the 
time of the last dosing. For example, if the subject’s usual dosing day is Wednesday, but a visit 
is planned for Friday, the dose would be administered at the time of the Friday visit (on-site or 
off-site), but the next dose administration would continue on the following Wednesdays as 
originally planned.
One delayed dose or missed dose: Every effort should be made to administer the study drug 
dose within the ± 3 days intended window. However, in case of exceptional medical or 
operational need, or unintentional omission (i.e. forgotten dose) study drug administration may 
be delayed by a maximum of 6 days before it is considered a missed dose (i.e. if subject’s dosing 
day is Wednesday the late dose may be administered up to and including Tuesday, but a dose 
is considered missed on the day the next scheduled dose is due).
Compensatory dosing: Administration of a compensatory dose aims to minimize the impact of 
missed doses. In case of a missed in-home CFZ533 or placebo SC administration (
 
), the subject should contact the Investigator to plan the administration of a 
compensatory SC dose at the Investigator site. In case of one missed dose, an additional 
compensatory SC dose, same as the SC maintenance dose used for the individual subject may 
be administered at Investigator site together with the scheduled SC dose administration (i.e. 
two doses administered simultaneously, the compensatory dose and the next scheduled dose). 
In this case, an individual subject in body weight Category III may receive a cumulative dose 
up to 600 mg SC per occasion (up to two x 300 mg SC). The compensatory dose will enable 
the subject to rapidly re-establish the steady-state exposures and consequently reduce the 
overall variability associated with the missed dose. Since the compensatory dose may be 
administered only in case of a previously missed dose it is not expected to be associated with 
risk of over-exposure and exposures will not exceed the steady-state exposure expected with 
CCI
Thereafter, weekly subcutaneous (SC) doses may be 
administered at home or at Investigator site (see Assessment Schedule Table 8-1).
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the full compliance to the recommended treatment regimen. Additionally, administration of two 
x 2 mL 300 mg SC injections at one occasion is routinely used in ongoing trials with CFZ533 
in adult populations and up to date it does not appear to be associated with lower tolerability or 
an increased risk of hypersensitivity reactions.
Compensatory doses can be administered only at the Investigator site and cannot be 
administered during an off-site or in-home SC administration by the OHP or the 
subject/guardian. If the subject cannot present to the site within the week of the missed dose, 
the site should contact Novartis for further guidance on consideration of a missed dose or 
administration of a later compensatory dose.
Delayed or missed consecutive dosing: In case of an exceptional medical or operational need, 
or in case a second consecutive dose administration has been delayed or missed, the investigator 
must contact the Sponsor immediately to discuss if the subject can remain on treatment or be 
permanently discontinued from randomized study treatment and managed as per local practice. 
Two consecutive doses can be missed no more than once within 
Missing 
 will drop systemic drug levels below concentrations which 
can be expected to provide clinical efficacy. Subjects who have missed 
 
 will need to discontinue treatment permanently.
Details on the requirements for storage and management of study treatment, and instructions to 
be followed for subject numbering, prescribing/dispensing and taking study treatment are 
outlined in the Site Operations Manual.
6.1.1
Investigational and control drugs
Table 6-1
Overview of study medication (CFZ533/Placebo)
Investigational/ 
Control Drug
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Packaging
Sponsor 
(global)
CFZ533 
150 mg/mL
Concentrate/solution 
for injection and for 
Infusion;
Intravenous and 
subcutaneous
Double blind 
subject packs; 
Type I glass vials
Novartis 
CFZ533 matching 
Placebo 
0 mg/mL
Concentrate/solution 
for injection and for 
Infusion;
Intravenous and 
subcutaneous
Double blind 
subject packs; 
Type I glass vials
Novartis 
6.1.2
Additional study treatments
There are no additional study treatments to CFZ533 or placebo. All subjects should continue 
on background intensive insulin therapy per standard of care to optimize glycemic control (see 
Section 4.1.1).
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6.1.3
Treatment arms/group
Two parallel treatment arms CFZ533 or matching placebo receiving one IV loading dose of 
study drug on Day 1, followed by 
 SC maintenance doses 
 (see dose section in Section 4.2).
6.2
Other treatment(s)
6.2.1
Concomitant therapy
Insulin therapy, contraceptive measures as described in exclusion criterion number 22, per 
standard of care is allowed.
All medications administered after a subject is enrolled into the study must be recorded in the 
concomitant medications / significant non-drug therapies.
Each concomitant medication must be individually assessed against all exclusion criteria and 
all prohibited medications. If in doubt the investigator should contact the Novartis medical 
monitor before randomizing a subject or allowing a new medication to be started. If the subject 
is already enrolled, contact the Novartis medical monitor to determine if the subject should
continue participation in the study.
6.2.2
Prohibited medication
Use of the treatments displayed in the below table are not allowed during the prohibited period 
stated in Table 6-2.
Table 6-2
Prohibited medication
Medication
Prohibition period
Action taken
Immune suppressive therapy
Screening until 
 after 
last dose of study drug
Discontinue dosing with study 
drug
Attenuated "live" vaccine
Eight weeks prior to first dose 
administration of study drug 
until 
after last dose of 
study drug
Discontinue dosing with study 
drug, monitor closely for signs 
and symptoms of infection, 
initiate anti-infective therapy 
per standard of care
Killed, inactivated vaccine
At least two weeks prior to first 
dose with study drug
Delay first dose of study drug, 
however first administration 
must be within 100 days of 
diagnosis of T1DM
Oral corticosteroids except for 
< 10 day treatment e.g. asthma 
exacerbation*
Screening until 
 after 
last dose of study drug
Adjust background insulin dose 
to correct hyperglycemia
*Topical or inhaled corticosteroids may be permitted, for example for treatment of mild stable
asthma, when doses are not anticipated to have systemic effects of adrenal suppression
6.2.3
Rescue medication
There is no specific rescue medication for CFZ533.
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Infections should be treated promptly with anti-infective therapies and symptomatic treatment 
as per standard of care. Refer to Protocol Section 10.2.1 for guidance on viral safety monitoring.
In addition, depending on clinical severity of an infection and response to anti-infective 
treatment, stopping of CFZ533 treatment should be considered by the Investigator.
Plasmapheresis may be used as needed in case of severe infection not responding to standard 
of care anti-infective therapy, should the need arise to clear CFZ533 quickly.
Anaphylactic and hypersensitivity reactions should be treated per standard of care.
Glucagon may be used as needed per T1DM standard of care for the treatment of hypoglycemia.
6.2.4
Restriction for study subjects
For the duration of the study, the subjects should be informed and reminded of the restrictions 
outlined in this section.
6.2.4.1
Dietary restrictions and smoking
Subjects should comply with a diabetic diet per standard of care.
On visits where the mixed meal tolerance test (MMTT) is scheduled, subjects should comply 
with an overnight fast for 8-10 hours and until the MMTT is completed. A standard mixed meal 
will be provided by the site and subjects must consume the entire contents of this meal. No food 
other than the mixed meal should be given for the duration of the test. Water intake is allowed.
Smoking should be discouraged and is not permitted during MMTT.
6.2.4.2
Other restrictions
Subjects should be advised against travelling to an area of the world with endemic disease, (e.g., 
tuberculosis, dengue, Chagas disease, etc.) for which they have not been vaccinated or no 
vaccine exists due to potential effects of CFZ533 to limit immune response to new infectious 
pathogens. Notably, subjects treated with CFZ533 can mount recall immune responses after the 
drug has been eliminated.
Subjects need to be informed that vaccinations under treatment with CFZ533 most likely will 
not mount an adequate immune response and therefore will not be protective. This information 
is also contained in the informed consent form.
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
The subject number assigned to a subject at screening remains the unique identifier for the 
subject throughout the study. For information on subject numbering, please see ‘Subject 
numbering’ section in the Site Operations Manual.


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6.3.2
Treatment assignment, randomization
Subject’s eligibility is assessed at the Screening and baseline visits. If no change in status occurs 
subjects will be randomized at the Day 1 visit, and treatment will be assigned via the IRT system 
used for randomization of eligible subjects and for distribution and assignment of the study 
medication. Eligible subjects will be assigned to a treatment arm (see Site Operations Manual 
for details).
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff.
A randomization list will be produced by the IRT provider using a validated system that 
automates the assignment of subject numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list will be produced by or under the responsibility of Novartis 
Drug Supply Management using a validated system that automates the random assignment of 
medication numbers to packs containing the investigational drug(s).
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office.
Follow the details outlined in the Site Operations Manual (SOM) regarding the process and 
timing of treatment assignment and randomization of subjects.
6.4
Treatment blinding
This is a subject and investigator-blinded study. Subjects and investigators will remain blinded 
to study treatment throughout the study, except where indicated below. The identity of the 
treatments will be concealed by the use of study drugs that are all identical in packaging, 
labeling, schedule of administration, appearance, and odor.
Site staff
Site staff (including study investigator and study nurse), will be blinded to study treatment 
throughout the study.
Unblinding a single subject at site for safety reasons (necessary for subject management) will 
occur via an emergency system in place at the site (see Section 6.6.3).
Drug product will be supplied as double-blind subject kits and treatment allocation will be 
determined by IRT system. 
Sponsor staff or delegate
The following unblinded sponsor roles are required for this study: Unblinded sample analysts 
for PK, PD (sCD40) and IG.
The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office), to facilitate analysis of the samples. The sample analysts will provide 
the sample data to the study team under blinded conditions unless otherwise allowed.


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All unblinded personnel will otherwise keep randomization lists and data or information that 
could unblind other study team members confidential and secure except as described above.
Following final database lock all roles may be considered unblinded.
Subjects, investigator staff, persons performing the assessments, and CTT will remain blind to 
the identity of the treatment from the time of randomization until database lock, using the 
following methods: 
(1) Randomization data are kept strictly confidential until the time of unblinding, and will not 
be accessible by anyone else involved in the study with a few exceptions, eg: PK analyst.
(2) The identity of the treatments will be concealed by the use of the use of study treatment 
that are all identical in packaging, labeling, schedule of administration, appearance and 
odor.
The randomization codes associated with subjects from whom PK samples are analyzed will be 
disclosed to PK analysts who will keep PK results confidential until data base lock. Unblinding 
will occur in the case of subject emergencies and at the conclusion of the study. 
 
Drug product will be supplied in double blinded kits, so no unblinded site personnel is required 
for this study. Study staff or site pharmacist will receive a medication code after entering 
eligible subject into IRT system. Sample data may be provided to the independent 
committee/analysis team, under unblinded conditions.
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Table 6-3
Blinding Levels
Role
Randomization 
list generated
Treatment 
allocation 
& dosing
Safety 
event 
(single 
subject 
unblinded)
Cohort 
progression
Subjects
B
B
UI
B
Site staff (including 
OHP)
B
B
UI
B
Unblinded site staff 
e.g. pharmacy staff
Not applicable
Drug Supply and 
Randomization 
Office
UI
UI
UI
UI
Unblinded sponsor 
staff e.g. for drug re-
supply, PK 
bioanalyst, 
biomarker analyst
B
UI
UI
UI
Statistician/statistical 
programmer
B
B
UI
UI
Independent 
committees (e.g. 
DMC, internal stats 
analysis team) 
 
B
B
UI
UI
Sponsor Trial team
B
B
UI
UI
All other sponsor 
staff not identified 
above (project team, 
management & 
decision boards, 
support functions)
B
B
UI
B
B Remains Blinded
UI Allowed to be unblinded on individual subject level
6.5
Dose escalation and dose modification
Data to be reviewed for moving between Cohorts include all adverse events, 
and safety laboratory values.
The sponsor (limited unblinding) and lead investigator (blinded) will perform a joint review of 
safety data to assess the nature of adverse events, laboratory abnormalities, and decide upon 
study continuation with the next subject cohort.
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To open enrollment into Cohort 2, 
 treatment 
must be reviewed for safety and tolerability and assessed as satisfactory to proceed to the next 
cohort. 
6.6
Additional treatment guidance
6.6.1
Treatment compliance
After the intravenous loading dose at Day 1 (administered at the Investigator site), two 
subcutaneous (SC) doses will be administered under observation at a scheduled visit on 
 in order to provide instruction on correct study drug 
administration to the subject/caregiver. The subsequent subcutaneous doses of the study drug 
(
) may be administered at home or at Investigator 
site, or when applicable during the off-site visit by the OHP. Last dose is administered at 
 and the end of the treatment assessment will be performed at Week 52.
The investigator must promote compliance by instructing the subject/guardian (or trained 
designee) to take the study treatment exactly as prescribed and by stating that compliance 
(weekly dose schedule) is necessary for the subject’s safety and the validity of the study. 
The subject/guardian must also be instructed to contact the investigator if he/she is unable for 
any reason to take the study treatment as prescribed. Compliance will be assessed by the 
investigator and/or study personnel at each visit using vial counts and information provided by 
the subject/guardian. This information should be captured in the source document at each visit. 
All study treatment dispensed and returned must be recorded in the Drug Accountability Log.
6.6.2
Recommended treatment of adverse events
This is a first in indication trial in type 1 diabetes and a first in pediatrics trial for CFZ533. 
Infections should be treated promptly with anti-infective therapies and palliative treatment as 
per standard of care. Refer to Risk/Benefit section (Section 4.5) in this document and in the 
Investigator Brochure.
Medication used to treat AEs must be recorded on the Concomitant Medications/Significant 
non-drug therapies CRF.
6.6.3
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a subject, he/she must provide the 
requested subject identifying information and confirm the necessity to break the treatment code 
for the subject. The investigator will then receive details of the investigational drug treatment 
for the specified subject and a fax or email confirming this information. The system will 
automatically inform the Novartis monitor for the site and the study team that the code has been 
broken.
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It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency. The investigator will provide:

protocol number

subject number
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that unblinding 
can be performed at any time. A subject can continue to be monitored in the study after an 
emergency break but cannot continue dosing with study drug.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under the 
investigational and control drugs section (Section 6.1.1).
A unique medication number is printed on the study medication label.
Investigator staff will identify the study medication kits to dispense to the subject by contacting 
the IRT and obtaining the medication number(s). The study medication has a two-part label 
(base plus tear-off label), immediately before dispensing the medication kit to the subject, site 
personnel will detach the outer part of the label from the packaging and affix it to the source 
document.
CFZ533 will be administered to the subject via the following route of administration: IV for the 
loading dose on Day 1, and subcutaneous injections for the weekly maintenance regimen 
(
). The IV loading dose will be done at the site on Day 1, and the first and the 
second subcutaneous (SC) dose will be administered under observation at a scheduled visit on 
. Thereafter, weekly subcutaneous (SC) doses may be 
administered at home or at Investigator site, or when applicable during the off-site visit by the 
OHP. SC maintenance doses may be administered at home, by subject or caregiver after 
training, if the subject or caregiver feels comfortable administering SC injections. See the Site 
Operations Manual and Pharmacy Manual for further details.
Where delivery of investigational medicinal product (IMP) directly to a subject's secure off-site 
location (e.g. home) is permitted by national and local governing regulations, then dispatch of 
study medication from the site to the subject may be performed under the accountability of the 
Investigator. The provisioning of supply will be for a maximum of 
 doses to last till 
the next follow-up visit. In this case, regular contacts (approximately every 4 weeks or more 
frequently if needed) will occur between the site and the subject for instructional purposes, 
safety monitoring, and discussion of the subject's health status until the subject's next visit to 
the study site.
The treatment for off-site administration will be handled and shipped in line with the pharmacy 
manual and required procedures for shipping.
Off-site treatment administration compliance will be assessed by the OHP and information 
provided to the Investigator and/or study personnel.
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7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent/assent.
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent/assent document.
Informed consent/assent must be obtained before conducting any study-specific procedures 
(e.g. all of the procedures described in the protocol). The process of obtaining informed consent 
must be documented in the subject source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the IB. This information will be included in the subject informed consent/assent and 
should be discussed with the subject during the study as needed. Any new information regarding 
the safety profile of the investigational drug that is identified between IB updates will be 
communicated as appropriate, for example, via an investigator notification or an aggregate 
safety finding. New information might require an update to the informed consent/assent and 
then must be discussed with the subject.
Women of child-bearing potential must be informed that taking the study treatment 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 requirements.
A copy of the approved version of all consent/assent forms must be provided to 
Novartis/sponsor after IRB/IEC approval.
Subjects receiving CFZ533 therapy who will be travelling to an area of the world with endemic 
disease, e.g., tuberculosis, dengue, Chagas disease, etc. for which they have not been vaccinated 
or no vaccine exists should be informed of a potential increased infection risks. Of note, subjects 
treated with CFZ533 can mount recall immune responses after the drug has been eliminated.
Subjects might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience. Refer to the Site Operations Manual for a complete list of ICFs 
included in this study.
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The study includes the option for the subject to have certain study procedures performed off-
site by an OHP instead of at the study site, for which a signature on a separate consent form is 
required if the subject agrees. It is required as part of this protocol that the Investigator presents 
this option to the subject, when permitted by national and local governing regulations and 
deemed appropriate by the Investigator. The process for obtaining consent should be exactly 
the same as described above for the main informed consent.
8
Visit schedule and assessments
Assessment schedule lists all of the assessments and indicates with an “X” the visits when 
assessments are performed. All data obtained from these assessments must be supported in the 
subject’s source documentation.
Subjects should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation. Subjects who prematurely discontinue study dosing should be 
encouraged to continue in study, off drug. Those who prematurely fully withdraw consent or 
discontinue the study for any reason should be scheduled for the end of treatment visit as soon 
as possible, at which time all of the assessments listed for the final visit will be performed. At 
this final visit, all dispensed investigational product should be reconciled, and the adverse event 
and concomitant medications recorded on the CRF.
Specification and timing of each assessment are detailed in the protocol.


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Table 8-1
Assessment Schedule
Period
Screening1
Treatment
Visit Name
Screening
Baseline
Day 
12
Wk   
1
Wk 
23
Wk  
43
Wk  
83
Wk 
12
Wk 
163
Wk 
203
Wk 
24
Wk 
283
Wk 
323
Wk 
36
Wk 
403
Wk 
443
Wk 
483
Wk 52
or 
EOT20
Days
-56 to -14
-14 to -1
1
8
±3
15
±3
29
±3
57
±3
85
±3
113
±3
141
±3
169
±3
197
±3
225
±3
253
±3
281
±3
309
±3
337
±3
365
±3
Informed consent
X
Demography
X
Inclusion / Exclusion 
criteria
X
X
X
Medical history/current 
medical conditions
X
X
Alcohol Test, Drug 
Screen, and Cotinine 
Test
X
Insulin dose and other 
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug 
Administration (iv/sc) 
AT SITE
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vaccine administration
S
Study diary
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination 4
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Tanner staging 
(subjects 12-17 only) 21
X
X
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Period
Screening1
Treatment
Visit Name
Screening
Baseline
Day 
12
Wk   
1
Wk 
23
Wk  
43
Wk  
83
Wk 
12
Wk 
163
Wk 
203
Wk 
24
Wk 
283
Wk 
323
Wk 
36
Wk 
403
Wk 
443
Wk 
483
Wk 52
or 
EOT20
Days
-56 to -14
-14 to -1
1
8
±3
15
±3
29
±3
57
±3
85
±3
113
±3
141
±3
169
±3
197
±3
225
±3
253
±3
281
±3
309
±3
337
±3
365
±3
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body Height
X
X
X
X
X
X
Body Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogram 
(ECG)
X
X
X
X
Bone age5
X
X
MMTT Glucose and C-
peptide6
X
X
X
X
X
Urinalysis7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation 
parameters 
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HbA1C
X
X
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy8
S
S
S
S
S
S
S
S
S
s
S
S
S
S
S
S
Thyroid function tests
X
X
X
HLA
X
Diabetes 
Autoantibodies
X
X
X
X
Serology
for vaccines9
X
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Period
Screening1
Treatment
Visit Name
Screening
Baseline
Day 
12
Wk   
1
Wk 
23
Wk  
43
Wk  
83
Wk 
12
Wk 
163
Wk 
203
Wk 
24
Wk 
283
Wk 
323
Wk 
36
Wk 
403
Wk 
443
Wk 
483
Wk 52
or 
EOT20
Days
-56 to -14
-14 to -1
1
8
±3
15
±3
29
±3
57
±3
85
±3
113
±3
141
±3
169
±3
197
±3
225
±3
253
±3
281
±3
309
±3
337
±3
365
±3
Viral load/serology for 
CMV, EBV10
X
X
X
X
X
X
X
X
X
X
X
X
X
Viral Load HSV
X
Viral serology for HSV
X
X
X
X
Viral load for SARS-
CoV-2 11
X
Serology for SARS-
CoV-2 11
X
X
X
X
X
Hepatitis and HIV 
screen
X
Tuberculosis test
X
Immunoglobulin 
X
X
X
X
X
X
PK blood collection13
X14
X
X
X
X
X
X
X
X
X
X
X
X
X
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Period
Screening1
Treatment
Visit Name
Screening
Baseline
Day 
12
Wk   
1
Wk 
23
Wk  
43
Wk  
83
Wk 
12
Wk 
163
Wk 
203
Wk 
24
Wk 
283
Wk 
323
Wk 
36
Wk 
403
Wk 
443
Wk 
483
Wk 52
or 
EOT20
Days
-56 to -14
-14 to -1
1
8
±3
15
±3
29
±3
57
±3
85
±3
113
±3
141
±3
169
±3
197
±3
225
±3
253
±3
281
±3
309
±3
337
±3
365
±3
Adverse Events
X
X
X
X 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study completion 
information
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Period
Follow-up Period
Visit Name
Wk 563
Wk 603
Wk 643
Wk 683
Wk 72
End of Study
Days
393
±7
421
±7
449
±7
477
±7
505
±7
Informed consent
Genetic consent
Demography
Inclusion / Exclusion criteria
Medical history/current medical conditions
Alcohol Test, Drug Screen, and Cotinine Test
Concomitant medications
X
X
X
X
X
Study Drug Administration (iv/sc) AT SITE
Vaccine administration
Study diary
X
X
X
X
X
Physical Examination4
S
S
S
S
S
Tanner staging (subjects 12-17 only)
Vital Signs
X
X
X
X
X
Body Height
Body Weight
X
X
X
X
X
Electrocardiogram (ECG)
X
Bone age5
MMTT Glucose and C-peptide6
X
Urinalysis7
X
X
X
Coagulation parameters 
Hematology
X
X
X
X
HbA1C
X
X
Clinical Chemistry
X
X
X
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Period
Follow-up Period
Visit Name
Wk 563
Wk 603
Wk 643
Wk 683
Wk 72
End of Study
Days
393
±7
421
±7
449
±7
477
±7
505
±7
Pregnancy8
S
S
S
S
Thyroid function tests
HLA
Diabetes Autoantibodies
X
X
Serology for vaccines9
Viral Load/serology for EBV, HSV, CMV10
X
Hepatitis and HIV screen
Tuberculosis test
Immunoglobulin
X
X
PK blood collection13
X
X
X
X
X
Adverse Events
X
X
X
X
X
Study completion information
X
“S” denotes source data only.
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1 The screening and baseline evaluations continue until the first dose of study drug is administered. Investigators should note that the turnaround time for screening and 
baseline laboratory assessments range from 4 to 21 business days and visits should be planned to ensure reporting of inclusionary and safety labs. Turnaround times of 
laboratory measures are provided in the SOM under section 1.2. Study months equal 28 days or 4 weeks. Screening and Baseline evaluations may be done over one or 
more visits. World Health Organization and European Medicine Agency recommendations for trial related blood volume will not be exceeded. All inclusion/exclusion 
assessments must be resolved and reviewed prior to CFZ533 administration.
2 First dose of CFZ533 is to be administered as early as possible following diagnosis of T1DM and within a 56 day interval from the time of diagnosis, however the interval 
from diagnosis to first study drug administration may be extended to 100 days in the event a screening assessment needs to be confirmed or vaccination is required.
3 This visit may be performed in clinic or scheduled as an off-site visit at an off-site location as allowed by local laws and regulations
4Abbreviated Physical exam can be done after day 1 visit. Exam of the thyroid must be included in all physical exams.
5 Bone age assessments will be performed on all subjects aged 12-17 at screening. Assessments at subsequent visits will only be performed if bone age is < 17 years
6 Glucose and C-peptide will be done in serum, at the time of MMTT, 6 timepoints.
7 Including the assessment of creatinine, and C-peptide concentration in urine.
8 Urine pregnancy tests will be used at all visits indicated, for subjects of child-bearing age (at the discretion of the investigator). Serum testing can be done for 
confirmation at the discretion of the investigator.
9 Vaccination records will be required at screening. If documentation is not available for any reason, serology for missing vaccine’s documentation will be performed prior 
to inclusion.
10Viral load and/or serology can be assessed at additional times at the discretion of the investigator. For subjects with evidence of an active CMV infection based on viral 
load measurement, increase the frequency of serial polymerase chain reaction (PCR) to detect CMV DNA and clinical monitoring for early signs of CMV end organ 
disease, to at least weekly frequency until resolution of the viral infection.
11SARS-CoV-2 is the virus associated with COVID-19 virology is performed by nasopharyngeal swab and serology is run at baseline and saved for later analysis during 
treatment. This sample may be used for additional infectious testing, if warranted.
12 
13 Unless otherwise stated, blood samples are taken pre-dose (within 1 hour before dosing) on dosing visits at site
14 Two blood samples are taken:  (i) at pre-dose (within 1 hour before dosing) and (ii) at about 90 minutes AFTER the start of the IV infusion (duration of the infusion is 
about 30 minutes).
15
16
17
18
19
20 Subjects that discontinue treatment or stop both treatment and study early are to complete subsequent end of treatment visit as soon as possible, if they are willing to 
do so. 
21 Tanner staging assessments will not be performed at subsequent visits after the subject has reached Tanner stage 5 (fully mature).
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8.1
Screening
Rescreening is allowed once, after subject has failed screening. Rescreening must be done to 
permit initial dosing within 100 days of diagnosis to meet inclusion criterion. The earliest 
dosing possible is preferred to protect remaining pancreatic beta cell function. Subjects deemed 
eligible for rescreening will be re-consented and a new subject ID will be assigned.
Information on re-screening is outlined in the Site Operations Manual. However, rescreening 
must be discussed and agreed with the sponsor on case by case basis.
8.1.1
Eligibility screening
Following registering in the IRT for screening, subject eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT system. 
Please refer and comply with detailed guidelines in the IRT manual.
8.1.2
Information to be collected on screening failures
Subjects who sign an informed consent but fail to be started on treatment for any reason will be 
considered a screen failure. The reason for not being started on treatment will be entered on the 
screening phase disposition page. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for screen failure subjects. No other data 
will be entered into the clinical database for subjects who are screen failures, unless the subject 
experienced a serious adverse event during the screening phase (see Section 10.1.3 for reporting 
details). If the subject fails to be randomized, the IRT must be notified within 2 days of the 
screen fail that the subject was not randomized.
8.2
Subject demographics/other baseline characteristics

Subject Demographics: Subject demographic and baseline characteristic data to be
collected on all subjects include: date of birth, sex, race, predominant ethnicity.

Relevant Medical History/Current Medical Conditions: A diagnosis of T1DM will be
confirmed by the presence of at least one diabetes-related autoantibody. A MMTT will also
be conducted at baseline to confirm a stimulated C-peptide level ≥0.2 nmol/L.
Where possible, diagnoses and not symptoms will be recorded. Family history of T1DM
will also be included (grandparents, or parents, or siblings, or relatives diagnosed with
T1DM). Other relevant medical history and current medical conditions will be recorded on
the in the eCRF until the start of the study drug. Any event or change in the subject’s
condition or health status occurring prior to the initial study drug administration will be
reported in the Relevant medical history/Current medical conditions section of the eCRF.

Diabetes autoantibodies: Blood samples will be collected to measure the following
markers of immune destruction of beta-cells: autoantibodies to glutamic acid decarboxylase
(anti-GAD65), autoantibodies to protein tyrosine phosphatase-like protein (anti-IA-2),
autoantibodies to islet cell (cytoplasmic) (ICA), autoantibodies to zinc transporter 8
(anti-ZnT8).  The presence of one or more of the T1DM diabetes autoantibodies from the
historical clinical record may also be used for inclusion. As part of the historical record
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blood sample must have been obtained prior to or within one week of starting exogenous 
insulin treatment for this to be used for eligibility.

HLA profiling: A blood sample will be collected for HLA profiling in order to characterize
the subject population. Specifically to T1DM disease, linkage for class II genes encoding
HLA-DR and HLA-DQ genes, and high resolution genotyping for DRB1, DQA1 and DQB1
will be carried out. Sample handling and shipping instructions will be provided in the
Laboratory Manual.

Hepatitis screen, HIV screen: All subjects will be screened for Hepatitis B surface antigen
(HBsAg). Screening for Hepatitis C will be based on HCV antibodies. Evaluation for HIV
seropositivity will be performed, and, if positive, confirmation by a second technique
available at the laboratory site, e.g., Western blot. If required, appropriate counseling will
be made available by the Investigator in the event of a positive finding. Notification of state
and federal authorities, as required by law, will be the responsibility of the Investigator.
Results will be available as source data and will not be recorded within the eCRF.

Screening for SARS-CoV-2: All subjects will be screened for the coronavirus
SARS-CoV-2, the virus causing the COVID-19 disease. Nasopharyngeal swab and blood
samples will be taken at screening to assess viral load and serology (IgM and IgG),
respectively for recent or past exposure. Rescreening for SARS-CoV-2 is permitted in
persistently asymptomatic or post-symptomatic subjects, but first dose of study drug must
be able to be administered within 100 days of diagnosis of T1DM and viral load must be
negative and IgG titer positive. Serum will be stored for subsequent analysis. Subjects who
have clinical signs and laboratory evidence of active infection with SARS-CoV-2 will not
receive first dose of study drug until resolution of the active infection. When vaccination
becomes available per local and National guidance, study subjects are to complete all
recommended immunizations prior to first dose with study drug and in accordance with
local immunization guidelines (See Section 5.1, Inclusion Criteria). This includes
emergency authorization vaccine use. During the time of emergency use authorization of
SARS-CoV-2 vaccine eligible subjects who have not received vaccination per local
guidance or who have negative titers, may be encouraged to receive or be re-vaccinated
during screening. However, as with all vaccines (Section 6.2.2), study drug must not be
administered within eight weeks of live (attenuated) vaccine or within two weeks of
inactivated vaccine (Rubin et al 2014). The screening window may be extended to permit
these vaccinations if required, but the goal is to start the study drug as soon after diagnosis
of T1DM as possible and the first dose of study drug must be administered within 100 days
of diagnosis of T1DM. Notification of state and federal authorities, as required by law, of
positive SARS-CoV-2 testing will be the responsibility of the Investigator.

Tuberculosis test: Subjects will be tested for tuberculosis at screening using the
Quantiferon Gold™ blood test.

Screening for CMV, EBV, and HSV: Subjects will be monitored for infection with CMV,
EBV, and HSV during the study. Blood samples will be taken at screening to assess viral
load and serology (IgM and IgG) for recent or past exposure. During treatment and follow
up, blood samples will be collected for viral load and/or serology to monitor for new
exposure or viral reactivation. Samples at additional times may be assessed if clinically
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CMV, EBV or HSV will not receive additional study drug administrations until resolution 
of the active infection. Subjects who have not received vaccination per local guidance or 
who have negative titers, may receive or be re-vaccinated during screening. Study drug must 
not be administered within eight weeks of live (attenuated) vaccine or within two weeks of 
inactivated vaccine (Rubin et al 2014). The screening window may be extended to permit 
these vaccinations if required, but the goal is to start the study drug as soon after diagnosis 
of T1DM as possible and the first dose of study drug must be administered within 100 days 
of diagnosis of T1DM.

Alcohol test, Nicotine and Drug screen: Subjects will be tested for substances of abuse
(e.g., alcohol, amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, cotinine
and opiates). Age range is applied according to exclusion criterion number 18. Results will be
available as Source data and will not be recorded within the case report form (CRF).

Date and time of study drug dosing will also be captured in study diary.
Glycemic measures and insulin dosage may be obtained from device records (i.e. meter 
 
 downloads of glucose and insulin pump downloads for insulin 
dosing) if available. Glycemic measures, insulin dosage and hypoglycemic events will be 
entered in CRFs as per CRF Completion Guidance documents. 
Date and time of study drug dosing will also be captured in a study diary.

Efficacy and pharmacodynamic assessments
All blood samples will be taken by either direct venipuncture or an indwelling cannula inserted 
in a vein. Local anesthetic, such as Emla® cream or similar, is permitted if approved by local 
and National Health Authorities.
Details of sample processing, handling, storage and shipment will be described in a separate 
laboratory manual.
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Study diary: A study diary must be provided to subjects to report insulin dose 
administration, 
, and 
hypoglycemic events. Glycemic measures and insulin dosage may be obtained from device 
records (i.e. meter 
 downloads of glucose and insulin pump 
downloads for insulin dosing) if available. The study diary can be provided at screening or 
baseline, but data capture will start at baseline to ensure values prior to first dose.
At every visit, subjects will report their daily dose of insulin administration for the three full 
days prior to the visit, along with daily glucose values
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Samples will be given a unique sample number (as listed in the Blood Log in Site Operations 
Manual - SOM). The actual sample collection date and time will be entered on the appropriate 
CRF. The detailed methods and analysis will be described in Bioanalytical Data Reports.
Measures are described in the next sections.
8.2.1
Mixed Meal Tolerance Test (MMTT) for glucose and stimulated C-
peptide
The mixed meal tolerance test (MMTT) has appropriate sensitivity to detect residual insulin 
secretion and beta cell function. In the MMTT, following an 8-10 hour overnight fast, a weight-
based liquid meal provided as 6 mL/kg (maximum 360 mL) of mixed meal (Ensure Plus, 
Abbott , see Site Operations Manual), ingested over 5 min with timed blood samples for glucose 
and C-peptide determination obtained 10 min prior to ingestion (t = −10), at baseline (t = 0), 
and at 15, 30, 60, 90, and 120 min after consumption of the liquid meal (Leighton et al 2017). 
The time collections for post load samples are based on the start time of the mixed meal.
Blood sample collection will allow measurement of area under the curve (AUC0-2 hr) and peak 
C-peptide values. MMTT will be collected at baseline, at Weeks 12, 24, 36 and 52 on treatment, 
and at Week 72 (End of study) visit. The primary efficacy endpoint is the treatment effect on 
stimulated C-peptide AUC0-2 hrs by mixed meal tolerance test (MMTT) at Week 52 (12 months). 
Detailed instructions for subjects regarding fasting requirements are summarized in Site 
Operations Manual. 
Proportion of subjects with detectable C-peptide, rate of decline from baseline C peptide; time 
to undetectable C peptide will be assessed. A timed urine for C-peptide:creatinine ratio will also 
be assessed as a measure of beta cell function.
8.2.2
Insulin requirements and glycemic control
A key secondary analysis will be to assess partial remission following CFZ533 compared to 
placebo.
HbA1c is measured as indicated in the Assessment Schedule (Table 8-1).
Total daily dose of insulin is reported as total daily units of insulin (adding short and long acting 
preparations) adjusted per body weight (unit/Kg/24 h). This information will be recorded at the 
site for at least 3 days and up to 7 days prior to each visit, as available (See Site Operations 
Manual). The average of total daily units of insulin per day (at each visit) will be calculated.
The Insulin Dose Adjusted HbA1c (IDAA1c) is a validated measure to determine beta cell 
reserve in subjects with T1DM. IDAA1c values ≤9.0 correspond to a predicted stimulated 
C-peptide >300 pmol/L. The formula for IDAA1c is defined as follows: HbA1c (%) + [4× 
insulin dose (units/kg/24 h)] (Andersen et al 2014). If HbA1c is stated in mmol/mol, it can be 
converted to percent by the following formula: HbA1c % = (HbA1c mmol/mol × 0.0915) + 
2.15).
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8.2.4
Appropriateness of efficacy assessments

The mixed-meal tolerance test (MMTT) is a standardized, reproducible measure of beta cell 
function with C-peptide measures to evaluate endogenous residual beta cell function in 
T1DM in the setting of exogenously administered insulin (Leighton et al 2017).

HbA1c is the standard clinical measure of average glycemia. National Glycohemoglobin 
Standardization Program (NGSP) methodology will be used.
8.3
Safety
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to the AE section (see Section 10.1.1).
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Table 8-2
Safety assessments
Assessment
Specification
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, extremities, vascular, and 
neurological. Tanner staging will include examination of external genitalia, 
breast and pubic hair.
A short physical exam will include the examination of general appearance, 
vital signs (blood pressure [SBP and DBP] and pulse), thyroid, skin for 
injection sites. A short physical exam will be at all visits starting from 
screening visit except where a complete physical examination is required.
Information for all physical examinations must be included in the source 
documentation at the study site. Clinically relevant findings that are 
present prior to signing informed consent must be included in the Medical 
History part of the CRF. Significant findings made after first administration 
of investigational drug which meet the definition of an Adverse Event must 
be recorded on the Adverse Event section of the CRF.
Vital signs
Vital signs include temperature, BP and pulse measurements.
For all visits: After the subject has been sitting for five minutes, with back 
supported and both feet placed on the floor, systolic and diastolic blood 
pressure will be measured once using an automated validated device and 
with an appropriately sized cuff including for pediatric use. A single repeat 
measurement for systolic and diastolic BP can be performed as needed 
to verify the first measurement and as per the PI's judgment.
Height and weight
Height in centimeters (cm and to the nearest 0.1 cm, without shoes and 
with the use of a calibrated equipment for subjects < age 18 years) and 
body weight (to the nearest 0.1 kilogram (kg) in indoor clothing and without 
shoes) will be measured.
The methods, assessment, specification, and recording for each assessment will be detailed in 
the Study Operation Manual.
8.3.1
Hypoglycemic events
The American Diabetes Association (ADA) has proposed a definition of hypoglycemia as an 
event accompanied by a measured plasma glucose concentration ≤3.9 mmol/L (70 mg/dL) 
based on the observed threshold for glucose counter-regulation activation in a non-diabetic 
population with a lower threshold of 3.9 mmol/L (70 mg/dL) as the definition of clinically 
relevant glucose levels (Workgroup on Hypoglycemia, American Diabetes Association 2005; 
Seaquist et al 2013).
While standardized reporting of hypoglycemia is desirable, it has been argued that defining
hypoglycemia at a glucose level ≤3.9 mmol/L (70 mg/dL) may lead to considerable 
overestimation of the frequency of clinically relevant hypoglycemia. In a study report with a 
large cohort of patients it was shown that a threshold level of 3.1 mmol/L (56 mg/dL) would 
provide a more accurate estimate of the frequency (Swinnen et al 2009) Continuous glucose 
monitor (Dexcom) alert and alarm thresholds are set at 54 mg/dL (3.0 mmol/L) and so this 
proposed cut-off value will be used in the current study to define hypoglycemia events.


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Severe hypoglycemia is an event requiring assistance of another person to actively administer 
carbohydrates, glucagon, or take other corrective actions.
Hypoglycemic data will be classified as defined in Table 8-3. Glycemic thresholds above and 
below 54 mg/dL (3.0 mmol/L) indicate different degrees of urgency for clinical action: 
Hypoglycemia with glucose 54 to 69 mg/dL (3.0 to 3.9 mmol/L, often referred to as Level 1 
hypoglycemia), is an alert threshold, independent of any acute symptoms, and healthcare 
professionals and people with diabetes should monitor time spent in this range of hypoglycemia. 
Hypoglycemia with a glucose level of below 54 mg/dL (3.0 mmol/L, often referred to as Level 
2 hypoglycemia), with or without symptoms, is considered clinically significant in that it may 
trigger counterregulatory responses, cause cognitive impairment leading to severe 
hypoglycemia, and therefore requires immediate attention.
While hypoglycemic adverse events will follow the classification in Table 8-3, adverse events 
other than hypoglycemia will follow standard grading mild, moderate, or severe 
(Section 10.1.1) grading system.
Hypoglycemia events will be recorded in the study diary which will be reviewed and discussed 
with the subject at each visit. Hypoglycemia may also be assessed via 
 
 data review performed by the investigator, but asymptomatic events do not need to 
be entered as adverse events when additional treatments are not required.
 
 
The investigator will record 
these events according to the table below under actions taken:
Table 8-3
Recording and classification of hypoglycemia as reported in the Study 
Diary
Severity 
Symptoms
Plasma 
Glucose1
Action Taken
Classification2
Subject able to 
initiate self-
treatment if 
necessary
Symptoms 
suggestive of 
hypoglycemia
≥ 3.0 mmol/L
(54 mg/dL)
Complete the Adverse Event 
and Hypoglycemia forms of the 
eCRF
Pseudo or possible 
symptomatic 
hypoglycemia
(other causes of 
symptoms 
reasonably excluded)
Symptoms 
suggestive of 
hypoglycemia
≤ 3.0 mmol/L
(54 mg/dL)
Complete the Adverse Event 
and Hypoglycemia forms of the 
eCRF
Documented 
Symptomatic 
Hypoglycemia
Symptoms 
suggestive of 
hypoglycemia 
Not taken
Complete the Adverse Event 
and Hypoglycemia forms in the 
eCRF
Probable 
Hypoglycemia
Asymptomatic
≤ 3.0 mmol/L
(54 mg/dL)
Enter on Hypoglycemia form 
unless detected on CGM3 (i.e. 
enter if detected by fingerstick)
Confirm glucose value(s) in the 
study diary, unless detected on 
CGM.
Asymptomatic 
Hypoglycemia
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Severity 
Symptoms
Plasma 
Glucose1
Action Taken
Classification2
Subject is 
unable to 
initiate self-
treatment and 
requires third 
party 
assistance or 
hospitalization
Symptoms 
suggestive of 
hypoglycemia 
< 3.0 mmol/L
(54 mg/dL)
Enter symptom(s) and glucose 
value(s) in the Adverse Event 
and Hypoglycemia forms of the 
eCRF.
Severe 
Hypoglycemia
Symptoms 
suggestive of 
hypoglycemia
Not taken
Enter symptom(s) in the 
Adverse Event and 
Hypoglycemia forms of the 
eCRF
Suspected Severe 
Hypoglycemia
1. A plasma glucose level of 3.0 mmol/L (54 mg/dL) corresponds to a whole blood glucose (glucometer 
data) of about 2.7 mmol/L (49 mg/dL), noting plasma glucose values are about 11% higher than those 
of whole blood when the hematocrit is normal.
2. The classification of adverse events as hypoglycemic events should be adjudicated by the clinical 
Investigator.
3. Low glucose values that are asymptomatic 
 do 
not need to be entered into the Hypoglycemia form. If the subject is not using CGM and the low glucose 
value is detected by alternate means (i.e. fingerstick or serum/plasma) then the asymptomatic 
hypoglycemic event should be captured on the Hypoglycemia form.
8.3.2
Laboratory evaluations
In the case where a laboratory range is not specified by the protocol, but is outside the reference 
range for the center or study central laboratory assays at screening, a decision regarding whether 
the result is of clinical significance or not shall be made by the Investigator and shall be based, 
in part, upon the nature and degree of the observed abnormality. The assessment may be 
repeated once (for the purpose of inclusion) and in any case, prior to enrollment/randomization, 
to rule out laboratory error.
In all cases, the Investigator must document in the source documents, the clinical considerations 
(i.e., result was/was not clinically significant and/or medically relevant) in allowing or 
disallowing the subject to continue in the study. Clinically relevant deviations of laboratory test 
results occurring during or at completion of the study must be reported and discussed with 
Novartis personnel. The results should be evaluated for criteria defining an adverse event and 
reported as such if the criteria are met. Repeated evaluations are mandatory until normalization 
of the result(s) or until the change is no longer clinically relevant. In case of doubt, Novartis 
personnel should again be contacted.
For off-site visits (described in Section 3.1), samples will be collected, processed and shipped 
from the off-site location to the Central Laboratory for analysis in line with instructions 
contained in the study laboratory manual.
8.3.2.1
Clinical Chemistry, including coagulation parameters
Sodium, potassium, creatinine, BUN/urea, uric acid, chloride, albumin, calcium, alkaline 
phosphatase, total bilirubin, bicarbonate/HCO3, LDH, GGT, AST, ALT, CK, glucose, total 
cholesterol, HDL-C, LDL-C, triglycerides, Prothrombin Time (PT)/ International Normalized 
Ratio (INR), activated partial thromboplastin time (aPTT).
If the total bilirubin concentration is increased above 1.5 times the upper limit of normal, direct 
and indirect reacting bilirubin should be differentiated.
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HbA1c and 
will be collected during the trial as per the Assessment 
Schedule (Table 8-1).
8.3.2.2
Hematology
Hemoglobin, hematocrit, red blood cell count, white blood cell count with differential, and 
platelet count will be measured.
8.3.2.3
Urinalysis
A midstream urine sample (approx. 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, leukocytes, creatinine, and blood, microalbumin. If the 
dipstick result is positive for protein leucocytes and/or blood, the sample will be sent for 
microscopic analysis of WBC, RBC and casts.
8.3.2.4
Endocrinology
Thyroid function tests: TSH and total T4.
8.3.2.5
Viral Monitoring
CMV and EBV viral load and serology (IgM and IgG) will be obtained at screening and monthly 
following dosing during the treatment period. SARS-CoV-19 viral load and serology (IgM and 
IgG) will be obtained at screening. Serum will be banked for subsequent evaluation as needed, 
for clinical assessment or when testing sensitivity/specificity are better understood. This banked 
specimen may be analyzed for additional infectious agents if warranted.
HSV viral load and serology (IgM and IgG) will be obtained at screening and serology will be 
assessed at week 16, 32 and 48 following dosing. This will provide surveillance for new 
exposure, seroconversion, and potential reactivation of viral infections.
8.3.2.6
Tanner staging (subjects 12 to 17 years only)
For subjects aged between 12 and 17 at visits as indicated in the Assessment Schedule, pubertal 
assessment will be carried out using the Tanner scale. While the details of the assessment will 
remain with the source document, the outcome of the evaluation (scale values 1 through 5) will 
be recorded in the eCRFs. Subjects who have reached sexual maturity, Tanner stage 5, do not 
need to have continued assessments.
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8.3.3
Electrocardiogram (ECG)
A standard 12 lead ECG will be performed. Interpretation of the tracing must be made by a 
qualified physician and documented on the ECG section of the eCRF. Each ECG tracing should 
be labeled with the

study number

subject/ initials

subject/ number

date and kept in the source documents at the study site. 
Only clinically significant abnormalities should be reported on this page. Clinically significant 
abnormalities should also be recorded on the relevant medical history/Current medical 
conditions eCRF page. Clinically significant findings must be discussed with the sponsor. 
Original ECG tracings, appropriately signed, will be archived at study site. The CRF will 
contain:

date and time of ECG

heart rate

PR interval

QT and QTcF interval

RR interval

QRS duration
8.3.4
Pregnancy 
Females of child-bearing potential are defined as all females physiologically capable of 
becoming pregnant. This includes female pediatric subjects who are menarchal or who become 
menarchal during the study. Urine pregnancy test will be performed for all females of child-
bearing potential according to the schedule in Table 8-1. Serum pregnancy tests can be 
performed for positive urine tests and at the discretion of the site investigator. All menarchal 
girls and their guardian/caregiver should be informed about the potential risks of pregnancy and 
the need to prevent pregnancy during the study.
Pediatric subjects: In case of puberty and sexual activity, adolescents and when appropriate 
children will be informed about the need for preventing any pregnancy, testing for pregnancy 
and the management of the test results, including whether they will be shared with the 
guardian/caregiver. They should be counseled in a sensitive manner about abstinence (which 
should be promoted) and other forms of birth control. Their need, request and rights for privacy 
during the counseling process should be respected. Building a trusting relationship is important. 
These discussions with the subject and her guardian/caregiver are therefore best performed by 
investigators familiar with the pediatric subject and her family and should be guided by 
requirements of the local regulatory authorities. These discussions should take into account the 
socio-economic, cultural factors and religious beliefs of the adolescent participant and her 
family. The investigator should also discuss the management of the pregnancy test results with 
the subject and her guardian/caregiver. The privacy of the subject should be considered in 
accordance with the local law and ethics. Additional pregnancy tests may be performed at the 


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investigator’s discretion during the study. Subjects becoming pregnant must be discontinued 
from study drug. However, a subject may choose to remain in the study should she become 
pregnant, and be followed according to the protocol-defined study visits.
Pharmacokinetic (PK) and pharmacodynamic (PD) studies show CFZ533 is cleared from the 
body and immune responses have normalized 
post dose, and women are advised 
not to become pregnant until the PK/PD responses are eliminated. However, in the case that a 
subject becomes pregnant at any time during the trial, 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 to inform on fetal and early growth and developmental health. After 
consent is provided, the pregnancy reporting will occur up to one year after the estimated date 
of delivery or the pregnancy has ended in the absence of a live birth.
8.3.5
Appropriateness of safety measurements
The majority of safety assessments in this study are standard for this type of study (i.e., AE 
monitoring, standard laboratory safety assessments, vital signs, ECGs and physical 
examinations).
Additional specific clinical laboratory assessments are included to exclude any active infection 
before treating the subject with study drug, which based on the pharmacology of CFZ533 could 
potentially put the subject at risk.
8.4
Additional assessments
Additional assessments are described below.
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9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration, and can be initiated by either the subject, the investigator, 
or the Sponsor.
The investigator must discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being.
Study treatment must be discontinued under the following circumstances:

Subject/guardian decision

Informed consent/assent is withdrawn

Pregnancy

Use of prohibited treatment as per recommendations in the prohibited treatment section 
(see Section 6.2.2)

Any situation in which study participation might result in a safety risk to the subject

Following emergency unblinding
Subjects may voluntarily discontinue the study for any reason at any time.
Missing 
 will drop systemic drug levels below concentrations which 
can be expected to provide clinical efficacy. Subjects should therefore not miss more than 
2 subsequent doses of study drug in 
. Similarly, 2 consecutive doses cannot be missed 
more than once within a 
 period as this would also drop systemic levels below 
concentrations which can be expected to provide clinical efficacy. Subjects who have missed 3 
or more doses in 
 or have missed 2 consecutive doses more than once within 
 
will need to discontinue treatment permanently. The site should contact Novartis for further 
guidance if multiple compensatory doses are required.
Site Investigators should discontinue or temporarily suspend study treatment for any given 
subject if, on balance, they believe that continuation would be detrimental to the subject’s well-
being. Site Investigators should contact Novartis prior to resuming study drug that was 
discontinued or temporarily suspended for safety reasons. The DMC may be involved in the 
decision to resume dosing.
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Study treatment must be discontinued and medical treatment must be started per standard of 
care where needed at the site Investigator’s discretion under the following circumstances:

Infusion reactions/anaphylaxis reactions to CFZ533.

Recurrent systemic or severe infections. Recurrent local candidiasis, e.g. genital that is 
responsive to topical standard of care treatment and is deemed related to inadequate 
glycemic control is exempt.

Severe infections. Resumption of dosing may be considered once the course of 
anti-infective therapy is completed and the infection is documented as cleared, so long as 3 
or more doses have not been missed. For COVID-19, clearance of infection in order to 
resume treatment during the study requires resolution of symptoms and absence of 
infectious virus / viral replication from a respiratory specimen.

Neutropenia with an absolute neutrophil count (ANC) < 0.5 x10(9)/L until resolution 
defined as an ANC > 1x10(9)/L on 2 separate occasions.

Severe and symptomatic hypogammaglobulinemia, e.g. IgG levels lower than 400 mg/dL 
necessitating replacement therapy with gamma globulins.
Resumption of dosing for subjects in whom study treatment was temporarily suspended must 
be decided based on the site Investigator’s judgement, in consultation with the Sponsor and the 
DMC on a case-by case basis.
If permanent discontinuation of study treatment occurs, the investigator should make a 
reasonable effort to understand the primary reason for the subject’s premature discontinuation 
of study treatment and record this information.
Subjects 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/assent (see Section 9.1.2 withdraw of informed consent section). Where possible, 
they should return for the assessments indicated in the assessment schedule. If they fail to return 
for these assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should 
be made to contact the subject/pre-designated contact as specified in the lost to follow-up 
section (see Section 9.1.3). This contact should preferably be done according to the study visit 
schedule.
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. 
This telephone contact should preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:

new / concomitant treatments

Adverse Events/Serious Adverse Events
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment.
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
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9.1.1.1
Replacement policy
Subjects who were randomized, but not dosed may be replaced. 
9.1.2
Withdrawal of informed consent and exercise of participants’ data 
privacy rights
Withdrawal of consent/opposition to use of data and/or biological samples occurs in countries 
where the legal justification to collect and process the data is consent and when a subject:

Explicitly requests to stop use of their data
and

No longer wishes to receive study treatment
and

Does not want any further visits or assessments (including further study-related contacts)
This request should be as per local regulations (e.g. in writing) and recorded in the source 
documentation.
Withdrawal of consent impacts ability to further contact the participant, collect follow-up data 
(e.g. to respond to data queries) and potentially other country-specific restrictions.  It is 
therefore very important to ensure accurate recording of withdrawal vs. discontinuation based 
on the protocol definitions of these terms.
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw their consent/exercise 
data privacy rights and record this information. The Investigator shall clearly document if the 
subject has withdrawn his/her consent for the use of data in addition to a study discontinuation.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.If the subject agrees, a final evaluation at the time of the subject’s 
withdrawal of consent/exercise data privacy rights should be made as detailed in the assessment 
table (Table 8-1).
Further details on withdrawal of consent or the exercise of subjects’ data privacy rights are 
included in the corresponding informed consent form.
9.1.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
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9.1.4
Study stopping rules
The Sponsor, the DMC and Lead Investigator will continually review and ad hoc as needed, 
adverse events and laboratory findings throughout the study, including the number and/or 
severity of adverse events, cumulative cases of clinically significant adverse events, severe 
adverse events, clinically significant laboratory changes, except those that are reasonably 
suspected to be due to extraneous causes.
As a result of the safety review, study recruitment or the study (a part/ or cohort of the study) 
may be placed on hold pending further safety analysis if Novartis, the DMC, and Lead 
Investigator, considers that the cumulative number and/or severity of AEs or other clinically 
significant changes are deemed unsafe to continue recruitment or dosing. Novartis and the Lead 
Investigator must jointly evaluate the relationship between an adverse event and CFZ533, and 
decide whether to resume enrollment, or to stop one cohort, all dosing, or to terminate the study 
prematurely.
Study recruitment will be stopped, pending a full safety review, if any of the following criteria 
are met:

At least 2 of the 6 (for Cohort 1) or 3 of the 10 (for Cohort 2) subjects in the same cohort 
experience a CFZ533-related AE (CTCAE grade 3 or higher) in the first month of treatment.

Three (3) or more subjects with recurrent and severe systemic infections (CTCAE grade 3) 
per cohort in the first month of treatment, or more than 50% of all treated subjects at any 
point in time.

One (1) or more subjects with a severe allergic reaction (CTCAE grade 3 or higher) to study 
drug in the first five (5) treated subjects or an incidence of > 20 % thereafter.

One (1) or more subjects with cytokine release syndrome.

The sponsor unilaterally requests it.

The DMC recommends it.
If one of the above stopping rules is met, the Competent Authorities and Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) will be informed of the temporary halt of 
study via a Substantial Amendment in accord with local regulations. The study may resume 
following the safety review, if the Sponsor and DMC, and Lead Investigator agree it is safe to 
proceed and after approval to restart the study is obtained from the Competent Authorities and 
IRB/IECs.
Cohort stopping rules are described in the above study stopping criteria list.
Individual stopping rules are listed in the Section 9.1.1.
9.1.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time.
Reasons for early termination:

Unexpected, significant, or unacceptable safety risk assessment of participating to subjects 
enrolled in the study, practical reasons (including slow enrollment), or for regulatory or 
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
Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data.

Discontinuation of study drug development.
In taking the decision to terminate, Novartis will always consider the subject welfare and safety. 
Should early termination be necessary, subjects must be seen as soon as possible (provide 
instruction for contacting the subject, when the subject should stop taking drug, when the 
subject should come for a final visit) and treated as a prematurely withdrawn subject. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the subject’s interests. The investigator 
or sponsor depending on the local regulation will be responsible for informing IRBs/IECs of 
the early termination of the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last subject finishes their Study Completion 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.
All randomized and/or treated subjects will be followed up for an additional 20 weeks period.
During the 20 week follow up period, safety monitoring will continue as described in the 
assessments table, Table 8-1.
All randomized and/or treated subjects who do not continue study visits after receiving 
treatment should have a safety follow-up call conducted a minimum of 
 after last 
administration of study treatment. The information collected is kept as source documentation. 
All SAEs reported during this time period must be reported as described in Section 10.1.3 and 
the Site Operations Manual. Documentation of attempts to contact the subject should be 
recorded in the source documentation.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g., 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 investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
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The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments.
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them. Severe hypoglycemia is an event requiring assistance of another 
person to actively administer carbohydrates, glucagon, or take other corrective actions.
Definitions of hypoglycemia are provided in Section 8.3.1 and Table 8-3. All other adverse 
events reported in the CRF should be accompanied by the following information (as far as 
possible) (if the event is serious refer to Section 10.1.2):
1. The severity grade

mild: usually transient in nature and generally not interfering with normal activities.

moderate: sufficiently discomforting to interfere with normal activities.

severe: prevents normal activities.
2. its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected’. The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single subject.
3. its duration (start and end dates) or if the event is ongoing, an outcome of not recovered/not 
resolved must be reported.
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met.
5. action taken regarding with study treatment.

All adverse events must be treated appropriately. Treatment may include one or more 
of the following:

Dose not changed

Drug interrupted/withdrawn
6. its outcome, 
a. not recovered/not resolved;
b. recovered/resolved;
c. recovering/resolving,
d. recovered/resolved with sequelae;
e. fatal; or unknown.
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
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Adverse event monitoring should be continued until end of study visit.
Information about adverse drug reactions for the investigational drug can be found in the IB.
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
Follow the instructions found in the Site Operations Manual for data capture methodology 
regarding AE collection for subjects that fail screening.
10.1.2
Serious adverse events
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:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

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

elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

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

is medically significant, e.g. defined as an event that jeopardizes the subject or may require 
medical or surgical intervention to prevent one of the outcomes listed above

Hypoglycemia which requires the assistance of another person to treat must be reported as 
an SAE.
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 subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 


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considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse.
All 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.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.
10.1.3
Serious Adverse Event (SAE) reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until last study visit must be reported to Novartis safety within 
24 hours of learning of its occurrence. Detailed instructions regarding the submission process 
and requirements are to be found in the investigator folder provided to each site.
SAEs occurring after the subject has provided informed consent until the time the subject is 
deemed a Screen Failure must be reported to Novartis.
Randomized subject's SAEs will be collected between time subject signs ICF until subject has 
discontinued or stopped study participation, or until 
 after last treatment.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, and under no circumstances later than within 24 hours of 
the investigator receiving the follow-up information. An SAE occurring at a different time 
interval or otherwise considered completely unrelated to a previously reported one must be 
reported separately as a new event.
If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is 
thought to be related to the study treatment, a CMO & PS 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 study 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.
Adverse events and serious adverse events (AE and SAE) will continue to be collected after the 
 post dosing interval, but will generally not be attributed to CFZ533 as 
pharmacodynamics effects of the drug are anticipated to be back to baseline. These events may 
help elucidate potential benefits of preserved pancreatic beta-cell function.
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10.1.4
Pregnancy reporting
To ensure subject safety, each pregnancy occurring after signing the informed consent 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.
After consent for pregnancy monitoring, the pregnancy reporting will occur up to one year after 
the estimated date of delivery.
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the CFZ533 treatment 
and any pregnancy outcome. Any SAE experienced during pregnancy must be reported.
The study drug must be discontinued, though the subject may choose to remain in the study, if 
she wishes to do so. If the subject chooses to remain in the study, all assessments that are 
considered as a risk during pregnancy must not be performed. The subject may continue all 
other protocol assessments. Pregnancy must be recorded on a Drug Exposure in 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 the SAE Report Form.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dose administration record) eCRF irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an SAE. Misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an AE/SAE 
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Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dose 
Administration (DAR) 
eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE (see Section 10.1.1) and SAE definition (see Section 10.1.2) and 
reporting requirements (see Section 10.1.3), please see the respective sections.
10.2
Additional Safety Monitoring
10.2.1
Viral safety monitoring
Subjects are anticipated to retain immune memory for antigens to which they were previously 
exposed, but not mount a humoral immune response and memory for neo-antigens. Combined 
immunotherapy is expected to increase the risk for infection. Thus no additional 
immunosuppressive agents are permitted in this study.
See Section 16.3 for general guidance information on CMV and EBV.
At screening, identify and exclude subjects with evidence of active CMV, EBV, HSV 1 and 2, 
or SARS-CoV-2 infection based on baseline viral load (determined via polymerase chain 
reaction (PCR)) or positive IgM serology in the absence of positive IgG.
At screening, identify subjects at risk for CMV, EBV, HSV, or SARS-CoV-2 primary infection 
or reactivation based on baseline IgG serology (negative or positive IgG serology, respectively). 
Rescreening for SARS-CoV-2 is permitted in persistently asymptomatic or post-symptomatic 
subjects, but study drug must be able to be administered within 100 days of diagnosis of T1DM 
and viral load must be negative and IgG titers positive.
During the study identify subjects with CMV or EBV reactivation or primary infections with 
serial PCR to detect virus DNA in addition to serology at least at monthly intervals, or when 
the clinical presentation suggests possible CMV or EBV infection. During the study monitor 
for HSV seroconversion quarterly (weeks 16, 32, and 48).
During the study, for subjects with evidence of an active CMV infection based on viral load 
measurement, increase the frequency of serial PCR to detect CMV DNA and clinical monitoring 
for early signs of CMV end organ disease, to at least weekly frequency until resolution of the 
viral infection. Consider consultation with an infectious disease expert.
During the study, for subjects with confirmed or probable cytomegalovirus disease, consider 
stopping study drug and consider initiating appropriate anti-cytomegalovirus therapy (or other 
anti-viral therapy as appropriate) in consultation with an infectious disease expert.
For subjects with potential infectious symptoms during the trial, but without laboratory 
confirmation of CMV or EBV infection, consider age- and country-appropriate infectious 
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virology, and/or serology, and initiating appropriate targeted anti-viral or anti-bacterial 
therapies as indicated in consult with an infectious disease expert. Additional viral infection 
should be considered and viral load/ titer assessed as serology/ immunoglobulin response may 
be diminished.
For subjects with potential infectious COVID-19 symptoms during the trial repeat virology
(PCR) to detect SARS-CoV-2 RNA, serologic evaluation, and clinical monitoring for early 
signs of end organ disease and initiating appropriate targeted anti-viral or anti-bacterial 
therapies as indicated in consult with an infectious disease expert may be warranted.
10.2.2
Liver safety monitoring
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed.
The following two categories of abnormalities / adverse events have to be considered during 
the course of the study (irrespective of whether classified/reported as AE/SAE):

Liver laboratory triggers, which will require repeated assessments of the abnormal 
laboratory parameter

Liver events, which will require close observation, follow-up monitoring and completion of 
the standard base liver CRF pages
Please refer to Section 16.1 for complete definitions of liver laboratory triggers and liver events.
Every liver event defined in Section 16.1 should be followed up by the investigator or 
designated personnel at the trial site, as summarized below. Additional details on actions 
required in case of liver events are outlined in Section 16.1. Repeat liver chemistry tests (ALT, 
AST, TBL, PT/INR, ALP and GGT) to confirm elevation.

These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at a local 
laboratory to monitor the safety of the subject. If a liver event is subsequently reported, any 
local liver chemistry tests previously conducted that are associated with this event should 
have results reported on the unplanned local laboratory CRF.

If the initial elevation is confirmed, close observation of the subject will be initiated, 
including consideration of treatment interruption if deemed appropriate.

Discontinuation of the investigational drug (refer to the Section 9.1.1 Discontinuation of 
study treatment section), if appropriate

Hospitalization of the subject if appropriate

Causality assessment of the liver event

Thorough follow-up of the liver event should include 

These investigations can include based on investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, history of concomitant 
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
Recent European Association for the Study of the Liver (EASL) guidelines support 
consideration of liver biopsy for patients with hepatotoxicity grade ≥3 to assess the 
pattern of damage and severity of the liver injury (Andrade et al 2019). 
Site investigators may consider consult with hepatologist and liver biopsy in cases with 
hepatotoxicity grade ≥3.
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF.
Refer to the Site Operations Manual for additional details.
10.2.3
Renal safety monitoring
The following two categories of abnormal renal laboratory values have to be considered during 
the course of the study:

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).
Every renal laboratory trigger or renal event as defined in Table 16-3 should be followed up by 
the investigator or designated personnel at the trial site as summarized in Section 16.2.
Refer to the Site Operations Manual for additional details.
10.2.4
Data Monitoring Committee
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will assess at defined intervals the progress 
of a clinical trial, safety data, and critical efficacy variables and recommend to the sponsor 
whether to continue, modify or terminate a trial.
Specific details regarding composition, responsibilities, data monitoring and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate charter that is established between the sponsor and the DMC.
11
Data Collection and Database management
11.1
Data collection
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
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The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate.
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
11.2
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior 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.
Randomization codes and data about all study treatment(s) dispensed to the subject and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines.
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis.  Any changes to the database after that time can only be made after 
written agreement by Novartis development management.
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11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis or 
delegated Contract Research Organization (CRO) representative will review the protocol and 
data capture requirements (i.e. eSource DDE or eCRFs) 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 field monitor will visit the site to check the 
completeness of subject records, the accuracy of data capture / data entry, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. Continuous remote 
monitoring of each site’s data may be performed by a centralized Novartis/CRA organization. 
Additionally, a central analytics organization may analyze data & identify risks & trends for 
site operational parameters, and provide reports to Novartis clinical teams to assist with trial 
oversight.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. 
Additional checks of the consistency of the source data with the CRFs are performed according 
to the study-specific monitoring plan. No information in source documents about the identity 
of the subjects will be disclosed.
12
Data analysis and statistical methods
Primary safety and efficacy analysis will be conducted based on all randomized subjects having
completed treatment, either having reached the Week 52 visit or discontinued early. All 
participants should be followed for at least
 following last dose administered to assess 
safety during drug wash-out.
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
For all analyses, subjects will be analyzed according to the study treatment(s) received.
The safety analysis set will include all subjects that received any study treatment.
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The PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that impact on PK data.
The PD analysis set will include all subjects with available PD data and no protocol deviations 
with relevant impact on PD data.
12.2
Subject demographics and other baseline characteristics
All data for background and demographic variables will be summarized by treatment group and 
subject. Summary statistics will be provided by treatment group. Additional summary statistics 
may be generated by treatment group and age group.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment group and subject.
12.3
Treatments
Data for study drug administration and concomitant therapies will be listed by treatment group 
(CFZ533 or placebo) and subject.
12.4
Analysis of the primary endpoint(s)
The primary objectives of this study are (1) to evaluate the safety and tolerability of CFZ533 in 
subjects with new onset T1DM and (2) to evaluate the effects of CFZ533 on pancreatic β-cell 
function in subjects with new onset T1DM.
12.4.1
Definition of primary endpoint(s)
All safety data, including laboratory measurements, vital signs, adverse events, and ECGs are 
considered primary endpoints for the first primary objective.
Stimulated C-peptide AUC by mixed meal tolerance test (MMTT) after 52 weeks, normalized 
by the duration of measurements, is the primary endpoint for the second primary objective. 
This endpoint is derived from the blood samples taken for C-peptide determination over the 
course of 2 hours. The AUC will be logarithmically transformed prior to analysis.
12.4.2
Statistical model, hypothesis, and method of analysis
Safety

Vital signs
All vital signs data will be listed by treatment, subject, and visit/time and if ranges are available 
abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics will be 
provided by treatment and visit/time.

ECG evaluations
All ECG data will be listed by treatment, subject and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit/time.


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
Clinical laboratory evaluations
All laboratory data will be listed by treatment, subject, and visit/time and if normal ranges are 
available abnormalities will be flagged. A separate listing is provided presenting all parameters 
in a subject with any abnormal values. Summary statistics will be provided by treatment and 
visit/time.

Adverse events
All information obtained on adverse events will be displayed by treatment and subject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A subject with multiple adverse events 
within a body system is only counted once towards the total of this body system and treatment.
The number and percentage of subjects with adverse events by maximum severity of adverse 
events will be tabulated by body system and preferred term with a breakdown by treatment.
The number and percentage of subjects with adverse events classified as related to study drug 
will be tabulated by body system and preferred term with a breakdown by treatment.
Stimulated C-peptide AUC
Stimulated C-peptide AUC by the standard MMTT, normalized by the duration of 
measurements, will be analyzed with a mixed model repeated measures analysis and the primary 
objective will be examined with the results of this analysis at the 52 week time point. The natural 
log of the AUC will be the dependent variable in this analysis. Independent variables will 
include age, treatment, visit, and the treatment by visit interaction. The natural log of the 
baseline AUC will be used as a covariate and subject will be used as a random effect. 
Least square geometric mean and geometric mean ratio to baseline of each treatment, the ratio 
of CFZ533 to placebo, the 80% confidence interval of the ratio, and the one-sided p-value of 
treatment benefit will be presented for each time point.
12.4.3
Handling of missing values/censoring/discontinuations
Safety and efficacy data at key time points will not be imputed for the primary analysis. 
Data from subjects who discontinue study treatment will be excluded, from the date of study 
drug discontinuation from the primary efficacy analysis. The primary analysis based on mixed 
model repeated measurements for Stimulated C-peptide AUC measurements at various visits is 
valid under the assumption that the missing data are missing at random (MAR).
12.4.4
Sensitivity and supportive analyses
Sensitivity analyses may be considered if a substantial proportion of subjects (e.g. more than 
15%) discontinue from study treatment. Multiple imputation models may be used to assess the 
robustness of the missing at random assumption of the primary analysis.
Additional analyses including all subjects regardless of their adherence to treatment will be 
performed. Further details of these analyses will be specified in the SAP.
Subgroup analyses of primary safety and efficacy data may be conducted by age group, race, 
gender, and the weight group.


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12.5
Analysis of secondary endpoints
The secondary objectives of this study are (1) to evaluate the pharmacokinetics of CFZ533 in 
subjects with new onset T1D, (2) to evaluate the treatment effect of CFZ533 on full or partial 
remission, and (3) to evaluate durability effects of CFZ533 over time on pancreatic beta cell 
function.
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
Data for the secondary variables (i.e. total daily dose of insulin, insulin-dose adjusted HbA1c) 
will be descriptively summarized for each treatment group and each time point 
(where applicable).
Full remission will be defined by HbA1c ≤6.5% (48 mmol/mol) and no exogenous insulin use, 
at 52 weeks (1 year).  Two validated criteria will be used to assess partial remission including 
proportion of subjects with (1) Insulin Dose Adjusted HbA1c (IDAA1c) ≤ 9.0 
(Mortensen et al 2009) and (2) HbA1c < 7.0% (53 mmol/mol) and total daily insulin dose 
<0.5 units per kg per day (Couper and Donaghue 2009). Stimulated C-peptide AUC by MMTT 
at Week 72 will be analyzed in the same manner as the primary objective. The baseline*visit 
interaction term may also be considered for this model due to the follow-up.
The proportion of subjects with detectable C-peptide, rate of decline from baseline C-peptide, 
and time to undetectable C-peptide will be descriptively summarized with estimates and 
confidence intervals for each treatment group and each time point (where applicable).
12.5.2
Pharmacokinetics
Blood samples for CFZ533 concentrations in plasma will be collected from all subjects (to 
protect blinding), at selected time points as defined in the Assessment Schedule (Table 8-1). 
Analysis will be performed in samples collected from CFZ533-treated subjects only.
CFZ533 plasma concentration data will be listed by subject, and visit/sampling time point. 
Descriptive summary statistics will be provided by visit/sampling time point, 
 
. Summary statistics will include mean 
(arithmetic and geometric), SD, CV (arithmetic and geometric), median, minimum and 
maximum. 
 
The following PK parameters will be determined: Ctrough, Ctrough,ss (steady state) and Cmax, 
Tmax (after IV loading only) will be directly derived from the bioanalytical data in tables and 
listings. Additional PK parameters may be determined if data permit.
Pharmacokinetic parameters will be listed by subject. Descriptive summary statistics will 
include mean (arithmetic and geometric), SD, and CV (arithmetic and geometric), median, 
minimum and maximum. An exception to this is Tmax where median, minimum and maximum 
will be presented.
Parameters like clearance, volume of distribution, or half-life will not be derived using non-
compartmental analysis (NCA). The pharmacokinetics of CFZ533 is non-linear and 
characterized by target-mediated disposition where CD40 binding by CFZ533 is leading to 
CFZ533 elimination (this includes receptor-mediated endocytosis by the membrane bound 
CD40, and subsequent metabolism of the CFZ533-CD40 complexes). The NCA approach is 
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not appropriate due to violations of the assumptions that the disposition of the drug is linear, 
and that the elimination is from sites that are in rapid equilibrium with blood.
12.5.3
Biomarkers
See Section 12.6.1.
12.5.4
PK/PD relationships
The relationship between PK, PD, efficacy or biomarker endpoints may be explored 
graphically.
Modeling of PK data using a population approach may be performed as appropriate and will be 
reported if necessary in a separate, standalone modeling and simulation report.
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12.7
Interim analyses
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12.8
Sample size calculation
12.8.1
Primary endpoint(s)
The sample size calculation is based on the primary endpoint of stimulated C-peptide AUC by 
the standard MMTT.
In Greenbaum (2012) the average baseline stimulated C-peptide AUC by MMTT is 
approximately 0.7 pmol*hr/mL. They show a linear decline in untreated subjects resulting in 
an average AUC of 0.4 pmol*hr/mL at one year. It is assumed that a clinically significant 
prevention of decline would occur if the rate of decline was one half (50%) of that of untreated 
subjects. Thus, a clinically relative improvement due to treatment would occur if the AUC at 
1-year was 37.5% larger for treatment than placebo (0.55/0.4 = 1.375). Starting with 44 subjects 
and accounting for ~18% dropout rate, a total of 36 subjects randomized in a 2:1 ratio (stratified 
by age at first screening visit: ≥18 to 21 years, ≥12 to <18 years) between CFZ533 and placebo 
provides 55% power to detect an improvement over placebo using a one-sided alpha=0.1 test 
when the true ratio of treatment to placebo is 1.375 (Note: if the rate of decline in treatment vs 
placebo is instead 75% less, corresponding to a ratio of 1.56, the power is 75%). This calculation 
assumes a coefficient of variation of 70% for the AUC; the standard deviation of log (AUC) 
was derived from the relationship between the CV and variance parameter for the lognormal 
distribution. This assumption was the result of the observed CV% of 5 TrialNet studies in 
T1DM subjects (Bundy et al 2016).
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed 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 CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
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requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last subject last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
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 and health authorities, where required, it cannot be implemented.


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14.1
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 required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.


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15
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16
Appendices
16.1
Appendix 1: Liver event and Laboratory trigger Definitions and 
Follow-up Requirements
Table 16-1
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*
*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
TBL: total bilirubin; ULN: upper limit of normal
Recent European Association for the Study of the Liver (EASL) guidelines support consideration of 
liver biopsy for patients with hepatotoxicity grade ≥3 to assess the pattern of damage and severity of 
the liver injury (Andrade et al 2019). Site investigators may consider consult with hepatologist and liver 
biopsy in cases with hepatotoxicity grade ≥3.


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Table 16-2
Follow Up Requirements for Liver Events and Laboratory Triggers
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law casea

Discontinue the study 
treatment 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 
treatment 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 
treatment 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 
treatment 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 (subject is 
asymptomatic)

Repeat LFT within the next 
week

If elevation is confirmed, 
initiate close observation of 
the subject
Investigator discretion
Monitor LFT within 1 to 4 
weeks


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Criteria
Actions required
Follow-up monitoring
ALP (isolated)
> 2 × ULN (in the absence of 
known bone pathology)

Repeat LFT within 48 
hours

If elevation persists, 
establish causality

Complete liver CRF
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
TBL (isolated)
> 2 × ULN (in the absence of 
known Gilbert syndrome)

Repeat LFT within 48 
hours

If elevation persists, 
discontinue the study drug 
immediately

Hospitalize if clinically 
appropriate

Establish causality

Complete liver CRF
ALT, AST, TBL, Alb, PT/INR, 
ALP and γGT until resolutionc
(frequency at investigator 
discretion)
Test for hemolysis (e.g., 
reticulocytes, haptoglobin, 
unconjugated [indirect] 
bilirubin)
> 1.5 to ≤ 2 × ULN (subject is 
asymptomatic)

Repeat LFT within the next 
week

If elevation is confirmed, 
initiate close observation of 
the subject
Investigator discretion
Monitor LFT within 1 to 4 
weeks or at next visit
Jaundice

Discontinue the study 
treatment immediately

Hospitalize the subject

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 treatment 
interruption or 
discontinuation

Hospitalization if clinically 
appropriate

Establish causality

Complete liver CRF
Investigator discretion
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.
Recent European Association for the Study of the Liver (EASL) guidelines support consideration of 
liver biopsy for patients with hepatotoxicity grade ≥3 to assess the pattern of damage and severity of 
the liver injury (Andrade 2019). Site investigators may consider consult with hepatologist and liver 
biopsy in cases with hepatotoxicity grade ≥3.


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16.2
Appendix 2: Specific Renal Alert Criteria and Actions and Event 
Follow-up
Table 16-3
Specific Renal Alert Criteria and Actions
Serum Event
Serum creatinine increase
25 – 49% compared to baseline
Confirm 25% increase after 24-48h
Follow up within 2-5 days
Acute Kidney Injury: Serum creatinine increase ³ 
50% compared to baseline
Follow up within 24-48h if possible
Consider study treatment interruption
Consider subject hospitalization /specialized
treatment
Urine Event
New dipstick proteinuria ≥1+
Albumin- or Protein-creatinine ratio increase ≥2-
fold
Albumin-creatinine ratio (ACR) ≥30 mg/g or ≥3 
mg/mmol;
Protein-creatinine ratio (PCR )≥150 mg/g or >15 
mg/mmol
Confirm value after 24-48h
Perform urine microscopy
Consider study treatment interruption / or 
discontinuation
New dipstick glycosuria ≥1+ not due to diabetes
Blood glucose (fasting)
Perform serum creatinine, ACR
New dipstick hematuria ≥1+ not due to trauma
Urine sediment microscopy
Perform serum creatinine, ACR
For all renal events:
Document contributing factors in the CRF: co-medication, other co-morbid conditions, and additional 
diagnostic procedures performed
Monitor subject regularly (frequency at investigator’s discretion) until either:
Event resolution: sCr within 10% of baseline or protein-creatinine ratio within 50% of baseline, or
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.


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16.3
Appendix 3: General Guidance on Select Virus -
Cytomegalovirus, Epstein-Barr virus, and coronavirus SARS-
CoV-2
There are specific infection risk challenges in the pediatric population (Allen 2016). 
The potentially immunocompromised child may be at a greater risk of acquiring specific 
infections compared to their adult counterparts, as multiple infections are more prevalent in 
younger age groups, such as respiratory viral diseases including respiratory syncytial virus 
illness (Hall et al 2009), such that infection risk is related to their age group regardless of 
immune competence; and children have increased likelihood of primary infections as they are 
still developing their immune repertoire and may lack preexisting host immunity. Thus children 
may experience more severe illnesses and poorer outcomes compared to adults, and consulting 
with local experts for diagnosing and managing infections in the potentially immunosuppressed 
patient may be warranted (Drgona et al 2018; Dropulic and Lederman 2016).
16.3.1
Cytomegalovirus
Positive serology for cytomegalovirus is approximately 30% at the age of 6 years and 
approximately 60% by young adulthood in a western country (Lanzieri et al 2015; 
Zuhair et al 2019), an approximate doubling of the rates of seropositivity for cytomegalovirus 
from new exposure over the enrollment age range of this trial.
Acquired cytomegalovirus infection in healthy children and adolescents is most often 
asymptomatic. However, approximately 10 percent of acquired cytomegalovirus infections 
produce symptoms. Cytomegalovirus can cause a mononucleosis–like syndrome; the most 
common manifestations are fever, fatigue, pharyngitis, adenopathy (especially cervical 
adenopathy), and hepatitis. Headache, abdominal pain with diarrhea, arthralgias, and rash also 
may occur. Laboratory abnormalities include lymphocytosis or lymphopenia with 
thrombocytopenia and elevated transaminases. The heterophile antibody titers or monospot 
tests will be negative.
Unusual manifestations or complications of acquired cytomegalovirus infections in healthy 
individuals include rare reports of pneumonitis, myopericarditis, hemolytic anemia, viral 
hemophagocytic syndrome, granulomatous hepatitis, Guillain-Barré syndrome,
and 
meningoencephalitis (American Academy of Pediatrics 2015; Demmler-Harrison 2018). 
Cytomegalovirus disease is defined according to published criteria (Ljungman et al 2017) as 
described below.
a. ACTIVE CYTOMEGALOVIRUS infection is defined as a detectable cytomegalovirus 
viral load in the absence of signs or symptoms attributable to cytomegalovirus. 
Active cytomegalovirus infection can be the result of cytomegalovirus reactivation or 
primary cytomegalovirus infection.
b. PROVEN DISEASE: For pneumonia, central nervous system (CNS) disease, 
gastrointestinal disease, hepatitis, nephritis, cystitis, myocarditis, pancreatitis, and disease 
in other organs, definite tissue-invasive disease requires the correct clinical syndrome 
combined with the detection of cytomegalovirus in tissue samples (or in bronchoalveolar 
lavage fluid for pneumonia) by virus isolation, immunohistochemical analysis, in situ


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hybridization, or conventional histologic features. Detection of cytomegalovirus by PCR 
alone is not sufficient.

Cytomegalovirus viral syndrome requires fever (oral temperature >38°C) for two or 
more days within a 4-day period, neutropenia or thrombocytopenia, and the detection 
of cytomegalovirus in the blood by culture or the detection of antigen, DNA, or RNA. 
Human herpes virus -6 (HHV-6) infection needs to be excluded.

For central nervous system (CNS) disease, detection of cytomegalovirus in 
cerebrospinal fluid (CSF) samples by culture or PCR is sufficient.

For retinitis, typical cytomegalovirus lesions must be confirmed by an ophthalmologist; 
detection of cytomegalovirus is not required.
c. PROBABLE DISEASE requires the correct clinical syndrome but the detection of 
cytomegalovirus cannot be confirmed as outlined above.
16.3.2
Epstein-Barr virus
Epstein-Barr virus (EBV) is a widely disseminated herpesvirus spread by close contact between 
susceptible persons and asymptomatic EBV shedders. Most primary EBV infections are 
asymptomatic or subclinical (Demmler-Harrison 2018).
EBV is the primary agent of infectious mononucleosis. Infectious mononucleosis usually begins 
with malaise, headache, and low-grade fever before onset of more specific signs of the infection, 
such as pharyngitis and cervical lymph node enlargement. Patients usually have a peripheral 
blood lymphocytosis, with atypical lymphocytes. Splenic rupture is a rare but potentially life-
threatening complication of infectious mononucleosis and may be the first symptom that brings 
the patient to medical attention.
Antiviral therapy, such as acyclovir, may reduce EBV transmission, but may not impact latent 
infection. EBV has been associated with the development of B cell lymphoma, T cell 
lymphoma, Hodgkin lymphoma, and nasopharyngeal carcinoma.


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16.3.3
SARS-CoV-2 virus of COVID-19 disease
SARS-CoV-2 is a member of the coronavirus family which is responsible for the COVID-19 
disease. Having T1DM does not make patients more susceptible to contracting COVID-19. 
Although patients with diabetes have higher morbidity from COVID-19 in general, this 
epidemiologic finding is largely driven from the substantial contribution of data from patients 
with type 2 diabetes mellitus (T2DM). There is no evidence to date this is the case for pediatric 
T1DM (https://www.cdc.gov/mmwr, 6th April, 2020). Testing for SARS-CoV-2 virology and 
serology is performed prior to the first dose of study drug. Serum specimens are banked for 
testing at later times, and not assayed immediately given current uncertainties on sensitivity and 
specificity. 
Subjects should be reminded to follow local appropriate hygienic preventive guidance to avoid 
contracting COVID-19. In subjects who are suspected to have COVID-19 additional testing 
may be warranted during the trial including virology (PCR) to detect SARS-CoV-2 RNA, 
serologic evaluation, and clinical monitoring for early signs of end organ disease. Appropriate 
targeted anti-viral or anti-bacterial therapies should be initiated as indicated in consult with an 
infectious disease expert.
If CFZ533/placebo administration is withheld for COVID-19, clearance of COVID19 infection 
in order to resume treatment during the study includes resolution of symptoms and absence of 
infectious virus / viral replication from a respiratory specimen.


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16.4
Appendix 4: European Medical Agency Guidance for Trial 
Related Blood Loss 
European Medicines Agency (EMA) recommendations for trial related blood volume 
(including any losses in the maneuver) in pediatric populations are that no more than 3% of 
total blood volume should be taken during a four week period and not more than 1% of total 
blood volume at a single time-point. At a total blood volume estimated at 80 to 90 mL per 
kilogram (kg) body weight, this equates to 2.4 mL to 2.7 mL blood per kg body weight during 
a four week period, or 0.8 mL to 0.9 mL blood per kg at any one time. 
These recommended volumes must not be exceeded for any patient. Please use the information 
below to ensure that the recommended volumes are adhered to:
Table 16-4
Total blood volume, 1 percent and 3 percent of total blood volume by 
weight assuming 85mL per kg total blood volume:
Weight (Kg)
Total Blood Volume (mL)
1% Blood Volume (mL)*
3% Blood Volume (mL)*
5
425
4
12
10
850
8
24
15
1275
12
36
20
1700
17
51
25
2125
21
63
30
2550
25
75
35
2975
29
87
40
3400
34
102
45
3825
38
114
50
4250
42
126
55
4675
46
138
60
5100
51
103
65
5525
55
165
70
5950
59
177
75
6375
63
186
80
6800
68
204

SAP_001.pdf: 
Clinical Development 
CFZ533 (Iscalimab) 
Clinical Trial Protocol CCFZ533X2207  / NCT04129528
Investigator- and subject-blinded, randomized, placebo-
controlled study to evaluate safety, tolerability, 
pharmacokinetics and efficacy of CFZ533 in pediatric and 
young adults with new onset type 1 diabetes mellitus 
(T1DM) 
Statistical Analysis Plan (SAP) 
Document type: 
SAP Documentation 
Document status: 
Final 2.0  
Release date: 
27-Jun-2024
Number of pages: 
25 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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SAP V2.0 
 
CCFZ533X2207 
 
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Table of contents 
Table of contents ................................................................................................................. 3 
List of tables ........................................................................................................................ 4 
List of figures ...................................................................................................................... 4 
1 
Introduction ......................................................................................................................... 5 
1.1 
Scope of document .................................................................................................. 5 
1.2 
Study reference documentation ............................................................................... 5 
1.3 
Study objectives ....................................................................................................... 5 
1.3.1 
Primary objective(s) ................................................................................ 5 
1.3.2 
Secondary objective(s) ............................................................................ 5 
1.4 
Study design and treatment ...................................................................................... 6 
2 
First interpretable results (FIR) and interim analysis report ............................................... 7 
3 
Interim analyses ................................................................................................................... 8 
4 
Statistical methods ............................................................................................................... 8 
4.1 
Data analysis general information ........................................................................... 8 
4.1.1 
General definitions .................................................................................. 8 
4.2 
Analysis sets ............................................................................................................ 8 
4.2.1 
Withdrawal of Informed Consent .......................................................... 10 
5 
Statistical methods for Pharmacokinetic (PK) parameters ................................................ 10 
5.1 
Variables ................................................................................................................ 10 
5.2 
Descriptive analyses .............................................................................................. 10 
6 
Statistical methods for Efficacy ......................................................................................... 11 
6.1 
Primary objective ................................................................................................... 11 
6.1.1 
Variables ............................................................................................... 11 
6.1.2 
Descriptive analyses .............................................................................. 11 
6.1.3 
Statistical model, assumptions and hypotheses ..................................... 12 
6.2 
Secondary objectives ............................................................................................. 13 
6.2.1 
Variables ............................................................................................... 13 
6.2.2 
Descriptive analyses .............................................................................. 13 
6.2.3 
Statistical model, assumptions and hypotheses ..................................... 14 
7 
Statistical methods for safety and tolerability data ............................................................ 18 
7.1 
Variables ................................................................................................................ 18 
7.2 
Descriptive analyses .............................................................................................. 18 
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7.3 
Graphical presentation ........................................................................................... 21 
8 
Pharmacokinetic / pharmacodynamic relationships .......................................................... 21 
10 Reference list ..................................................................................................................... 25 
List of tables 
Table 4-1 
Protocol deviation codes and analysis sets.............................................. 9 
List of figures 
Figure 1-1 
Study design ............................................................................................ 7 
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CCFZ533X2207 
 
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 “CCFZ533X2207”. 
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol. 
Tables, Figures, Listings (TFL) details the presentation of the data, including shells of summary 
tables, figures and listings, and Programming Datasets Specification (PDS) contains 
programming specifications e.g. for derived variables and derived datasets, to support the 
creation of CSR outputs. 
1.2 
Study reference documentation 
Final study protocol (version v06) is available at the time of finalization of Statistical Analysis 
Plan. 
1.3 
Study objectives 
1.3.1 
Primary objective(s) 
Primary objective(s) 
Endpoints related to primary objectives 
• To evaluate effects of CFZ533 on pancreatic beta 
cell function in subjects with new-onset T1DM. 
• Stimulated C-peptide AUC by mixed meal 
tolerance test (MMTT) after 52 weeks of 
treatment. 
• To evaluate the safety and tolerability of CFZ533 
in subjects with new onset T1DM. 
• Adverse events, safety labs. 
1.3.2 
Secondary objective(s) 
Secondary objective(s) 
Endpoints related to secondary objectives 
• To evaluate the pharmacokinetics (PK) of 
CFZ533 in subjects with new onset T1DM. 
• CFZ533 plasma concentrations at baseline, 
during treatment (Cmax, Tmax after IV 
administration, and Ctroughs after SC 
administration) and follow-up period. 
• To evaluate durability of effects of CFZ533 on 
pancreatic beta cell function in subjects with new-
onset T1DM. 
• Stimulated C-peptide AUC by MMTT at 20 weeks 
from last dose. 
• To evaluate the treatment effect of CFZ533 on 
remission or partial remission in subjects with 
new onset T1DM. 
• Not requiring exogenous insulin therapy with 
HbA1c <6.5% (remission) or Insulin dose 
adjusted HbA1c (IDAA1c ≤9.0) or HbA1c < 7.0% 
(53 mmol/mol) and total daily insulin dose <0.5 
units per kg per day at 52 weeks (partial 
remission). 


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1.4 
Study design and treatment 
CCFZ533X2207 is a Phase 2, non-confirmatory, investigator- and subject-blinded, randomized, 
placebo-controlled study to evaluate the safety, tolerability, PK, and efficacy of CFZ533 
compared to placebo on preservation of residual pancreatic β-cell function in new onset T1DM 
pediatric and young adult subjects.  
Forty-four subjects aged 12-21 years with weight between 30 to ≤125kg will be enrolled. Two 
sequential study cohorts (based on age and body weight at screening visit) are planned.  
Cohort expansion safety data (adverse events and safety lab) review will initially be based on 
pooled data at first. Aggregate data by treatment group (i.e. CFZ533 or Placebo) or specific 
subject(s)’ treatment information can be requested if such information is needed as part of the 
crucial information in safety evaluation.  
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Figure 1-1 
Study design 
2 
First interpretable results (FIR) and interim analysis report 
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3 
Interim analyses 
4 
Statistical methods 
4.1 
Data analysis general information 
Unless otherwise specified: categorical data will be presented as frequencies (n) and 
percentages. Continuous data will be presented as n, mean, standard deviation (SD), median, 
minimum, and maximum.  
4.1.1 
General definitions 
On-treatment assessment/event  
The overall observation period will be divided into three mutually exclusive segments: 
1. pre-treatment period: from day of subject’s informed consent to before date of first
administration of study treatment
2. on-treatment period: from date of first administration of study treatment to 98 days after
date of last administration of study treatment (including start and stop date)
3. post-treatment period: starting at day 98+1 after last administration of study treatment.
Note: If dates are incomplete in a way that clear assignment to pre-, on-, post-treatment period 
cannot be made, then the respective data will be assigned to the on-treatment period.  
4.2 
Analysis sets 
For subjects whose actual treatment received does not match the randomized treatment, the 
treatment actually received will be used for the analysis, except for analyses using the Full 
analysis set. 
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The Per-protocol analysis set includes subjects compliant with the protocol and is characterized 
by the following criteria: 
1. Subject received at least 9 months of the randomized treatment,
a. Within those 9 months, subject received at least 75% of the planned doses.
2. Subject does not have any major protocol violations (See Table 4-1)
The Full analysis set includes all subjects to whom study treatment has been assigned by 
randomization. According to the intent-to-treat principle, subjects will be analyzed according 
to the treatment they have been assigned to during the randomization procedure.  
The safety analysis set will include all subjects that received any study drug. 
The PK (Pharmacokinetics) analysis set will include all subjects 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 (Pharmacodynamic) analysis set will include all subjects who received any study drug 
with at least a baseline or one post-baseline PD assessment. 
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 PP analysis set in case of these PDs: 
Exclude subject from PP 
analysis set 
Inc04 
Deviation from inclusion criterion 4-Evidence of one or more 
T1D autoantibody(ies): anti-GAD, protein tyrosine, anti-IA-2, 
anti-ZnT8 and anti-ICA. 
Inc06 
Deviation from Inc06-Peak stimulated C-peptide≥0.2 nmol/L 
after standard liquid MMTT when subject is metabolically 
stable, at least 2 weeks from diagnosis and within 56 days 
prior to randomization. 
Exc01 
Any other diabetes present except auto immune type 1, by 
judgement of the investigator. 
Exc18 
Ongoing, and up to 2 weeks prior to screening, use of 
medications that may affect glucose control (e.g., systemic 
steroids, thiazides, beta blockers).  
Subjects are excluded from PP and PK analysis set in case of these PDs: 
Exclude subject from PP 
and PK analysis sets 
Exc20 
Taking medications prohibited by the protocol 
Subjects are excluded from PP analysis set in case of these PDs: 
Exclude subject from PP 
analysis sets 
OTH01  
  Subject potentially unblinded 
Exclude only data after 
the date of unblinding 
OTH02 
Inv or Site Staff- Unblinded 
Exclude only data after 
the date of unblinding 
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to 
DBL. 


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4.2.1 
Withdrawal of Informed Consent 
Any data collected in the clinical database after a subject withdraws informed consent from 
ALL further participation in the trial (meaning all criteria are checked on the eCRF), will not 
be included in the analysis. The date on which a subject withdraws full consent is recorded in 
the eCRF. 
5 
Statistical methods for Pharmacokinetic (PK) parameters 
All subjects within the PK analysis set will be included in the PK data analysis. 
5.1 
Variables  
Free CFZ533 concentration in plasma 
For each PK sample, the actual recorded sampling time will be captured (CRF). The actual 
elapsed time since the first dose (with reference to the Dose Reference ID series #1; see Table 
8-1 Blood sampling log in the Site Operations Manual) and since the specified dose (with
reference to the Dose Reference ID series #2 in Table 8-1 in the SOM) will be calculated.
PK parameters 
The following PK parameters will be determined and reported: Ctrough, Ctrough,ss (steady 
state) and Cmax (.defined as concentration at the end of infusion 1.5 hr after start of infusion). 
They will be directly derived from the bioanalytical data in tables and listings. 
Additional PK parameters (independent Novartis analysis) may be determined if data permit. A 
dose-independent, model-based analysis considering both IV and SC PK data may be performed 
as appropriate and will be reported in a separate, standalone modeling and simulation report. 
During modeling of PK data, the broad principles outlined in the FDA Guidance for Industry: 
Population Pharmacokinetics, will be followed. 
5.2 
Descriptive analyses 
All statistical summaries and plots will be produced by body weight category: ≥30 to <50 kg, 
≥50 to ≤125 kg and overall. 
CFZ533 plasma concentrations will be listed by treatment, subject, and visit/sampling time 
point. Descriptive summary statistics will be provided by treatment and visit/sampling time 
point, 
Pharmacokinetic parameters will be listed by treatment and subject and summarized by 
treatment and visit. Summary statistics will include mean (arithmetic and geometric), SD, CV 
(arithmetic and geometric), median, minimum and maximum.  
Arithmetic mean (SD) plasma concentration by time will be plotted on linear-linear and log-
linear scale (all treatment groups in the same graph). 
Overlaying individual plasma concentration by time profile will be plotted (one graph per 
treatment group, all subjects in the same graph) on linear-linear and log-linear scale. 
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Individual plasma concentration by time profile, by subject will be plotted on linear-linear and 
log-linear scale. 
6 
Statistical methods for Efficacy 
All efficacy analyses will be performed on the full analysis set (FAS). 
In case of dose adjustment occurring during the study, subjects will be analyzed under first 
doses received, censoring any observations post dose adjustment (if any) in statistical models 
and descriptive summaries. 
6.1 
Primary objective 
The primary objective is to evaluate effects of CFZ533 on pancreatic beta cell function in 
subjects with new-onset T1DM. 
6.1.1 
Variables 
Normalized stimulated C-peptide AUC, defined by stimulated C-peptide AUC0-2 hrs by mixed 
meal tolerance test (MMTT) after 52 weeks, divided by the actual duration of measurements, is 
the primary analysis variable. This variable is derived from the blood samples taken for C-
peptide determination over the course of 2 hours: at baseline (average of t = -10 and t = 0 C-
peptide values), and at 15, 30, 60, 90, and 120 min after completing consumption of the liquid 
meal. AUC will be calculated by linear trapezoid rule under the stimulated C-peptide 
concentration curve. At a minimum the baseline and 120 min (first and last) concentrations 
must be available to compute the AUC. Under linear trapezoid rule, if there are concentration 
missing for time points between first and last observed time point during the 2 hours window, 
this part of area under the curve will be covered by the trapezoid constructed by the closest 
neighboring time points with concentration values. 
Actual time between each concentration measurement will be used during the 
calculation. If the total duration of measurement is >120 minutes, the trapezoid will be truncated 
at 120 minutes. 
Baseline stimulated C-peptide AUC will be derived from the last set of C-peptide values 
collected before the start of study treatment. 
6.1.2 
Descriptive analyses 
Normalized stimulated C-peptide AUC (Weeks 12, 24, 36 and 52 on treatment and  Week 72), 
its change and percent change from baseline will be listed by treatment, subject and visit. 
Summary statistics will be provided for raw value, change and percent from baseline by 
treatment and visit/time and will include mean (arithmetic), SD, CV (arithmetic), median, 
minimum and maximum. In addition, geometric mean/CV will be provided for raw value. 
6.1.2.1 
Graphical presentation of results 
Geometric mean (80% CI) of normalized stimulated C-peptide AUC and ratio to baseline will 
be plotted by visit and treatment. Spaghetti plots of normalized stimulated C-peptide AUC and 
percent change from baseline of all individuals will be given by treatment. 
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6.1.3 
Statistical model, assumptions and hypotheses 
The primary statistical analysis will be done using the Full analysis set (treatment policy 
estimand). As a secondary analysis, the model will be run using the Per Protocol set 
(hypothetical strategy estimand). For both analyses, all data collected for subjects in the 
respective analysis sets will be used in the model (e.g. including data after study drug 
discontinuation). Stimulated C-peptide AUC by the standard MMTT, normalized by the 
duration of measurements, will be analyzed with a mixed model repeated measures (MMRM) 
analysis. The natural log of the AUC (Weeks 12, 24, 36 and 52 on treatment) will be the 
dependent variable in this analysis. Independent variables will include age group (≥12 to <18, 
≥18 to 21) treatment, visit, and the treatment by visit interaction. 
The natural log of the baseline AUC will be used as a covariate and subject will be used as a 
random effect. Back transformation (exponential) will be used to obtain the least square 
geometric mean of each treatment, the ratio of CFZ533 to placebo, the 80% confidence interval 
of the ratio, and the one-sided p-value of treatment benefit for each time point. The model-based 
estimated fixed effects and p-values will be presented, along with the overall treatment effect. 
Note 1: Any C-peptide AUC collected at a post-baseline unscheduled visit will be assigned to 
the closest scheduled visit for the model-based analysis; in the case of a tie it will be assigned 
to the previous visit (e.g. unscheduled collected at Week 30 will be assigned to Visit 24 for the 
model-based analysis). If a C-peptide AUC is already available at the scheduled visit, the 
average of the scheduled and unscheduled visit AUC will be used in the model. 
Note 2: Week 52 C-peptide AUC which was not actually collected 365 +-15 days after the first 
dose (i.e. due to it being the EOT assessment for early treatment discontinuation) will not be 
used for the model-based analysis as a Week 52 assessment, but will be assigned to the closest 
visit. 
6.1.3.1 
Model checking procedures 
Handling of missing values/censoring/discontinuations 
The primary analysis will be based on all subjects in FAS analysis dataset. There will be no 
imputation for the primary analysis based on mixed model repeated measurements (MMRM) 
for stimulated C-peptide AUC measurements at various visits, which is valid under the 
assumption that the missing data are missing at random (MAR). 
6.1.3.2 
Graphical presentation of results 
Model estimated treatment geometric means and ratio between treatment and their 80% CI will 
be plotted over time, by visit. 
6.1.3.3 
Sensitivity analyses 
If there are reasonable evidence that data may be missing not at random (MNAR), for example 
there are subjects discontinued study due to lack of efficacy or worsening of disease, alternative 
statistical model such as pattern mixture models may be used to evaluate the robustness of the 
primary analysis results.  


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6.2 
Secondary objectives 
The secondary objectives of this study are to evaluate the treatment effect of CFZ533 on full or 
partial remission, and to evaluate durability effects of CFZ533 over time on pancreatic beta cell 
function. 
6.2.1 
Variables  
• Normalized stimulated C-peptide AUC0-2 hrs by MMTT at Week 72. 
• Average of Total daily dose of insulin 
Total daily dose of insulin for a given day is the total daily units of insulin (adding insulin 
pump total basal units per day, insulin pump total bolus units per day and total units 
insulin injection (syringe) units per day) adjusted per body weight (unit/Kg/24 h). This 
information will be recorded at the site for at least 3 days and up to 7 days prior to each 
visit, as available (See Site Operations Manual). The average of total daily units of insulin 
per day (at each visit) will be calculated. 
• Insulin-dose adjusted HbA1c (IDAA1c) (Andersen et al 2014). 
IDAA1C = HbA1C (percent) + 4 × [insulin dose (units per kg per day)]. 
If HbA1c is stated in mmol/mol, it can be converted to percent by the following formula: 
HbA1c % = (HbA1c mmol/mol × 0.0915) + 2.15). 
• Remission at 52 weeks defined by meeting any of the below criteria:  
• Full remission defined by HbA1c ≤6.5% (48 mmol/mol) and no exogenous insulin 
use at 52 weeks.  
• Partial remission defined by Insulin Dose Adjusted HbA1c (IDAA1c) ≤ 9.0 
(Mortensen et al 2009)  
• Partial remission defined by HbA1c < 7.0% (53 mmol/mol) and total daily insulin 
dose <0.5 units per kg per day (Couper and Donaghue 2009).  
• The proportion of subjects with detectable C-peptide and time to undetectable C peptide. 
Undetectable C-peptide is defined as all timed values on the MMTT below the LLOQ. 
• The proportion of subjects with Peak C-peptide ≥0.2 pmol/mL and time to Peak C-peptide 
<0.2 pmol/mL (or below LLOQ) 
• Rate of decline from baseline C-peptide 
A linear mixed model regression of the log transformed stimulated C-peptide AUC, 
including baseline assessment, on time expressed in years (time = 1 at Week 52 and 0 at 
baseline) will be performed. The mixed model will include treatment effect, time by 
treatment interaction with time as continuous variable and subject as random effect. The 
estimates of the yearly rate of decline by treatment and their 80% confidence intervals will 
be obtained after back transformation (exponential) of the estimates of the slopes. 
6.2.2 
Descriptive analyses 
• For stimulated C-peptide AUC by MMTT at Week 72, total daily dose of insulin, 
insulin-dose adjusted HbA1c, their change and percent from baseline will be 
summarized by descriptive statistics for each treatment group and each time point 
(where applicable). 


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• The proportion of subjects with remission and each of the three components (full 
remission and two different criteria for partial remission) and subjects with detectable 
C-peptide will be descriptively summarized for each treatment group and each time 
point and overall study period. 
• Time to undetectable C peptide will be analyzed by Kaplan-Meier methods by treatment 
group. Estimates of median time to undetectable C peptide and proportion of subjects 
with detectable C-peptide and their confidence intervals for each treatment group and 
each time point (where applicable) will be produced. Time to Peak C-peptide<0.2 
pmol/mL (or below LLOQ) and proportion of subjects with C-peptide ≥0.2 pmol/mL 
will be analyzed similarly. 
6.2.2.1 
Graphical presentation of results 
Model-based geometric mean (80% CI) of stimulated C-peptide AUC by MMTT will be plotted 
by treatment and time point. 
Arithmetic mean (80% CI) of insulin-dose adjusted HbA1c and total daily dose of insulin will 
be plotted by treatment and time point. 
Graphical presentation of Kaplan-Meier estimate of proportion of subjects with detectable C-
peptide will be plotted by treatment. 
6.2.3 
Statistical model, assumptions and hypotheses 
Normalized stimulated C-peptide AUC by MMTT at Week 72 will be analyzed in the same 
manner (and using the same model) as the primary objective. C-peptide AUC at all time points 
up to and including Week 72 will be included. The baseline by visit interaction term may also 
be considered for this model. 
6.2.3.1 
Model checking procedures 
Model checking procedures for stimulated C-peptide AUC by MMTT at Week 72 will be the 
same as for primary analysis, refer to Section 6.1.3.1. 
6.2.3.2 
Graphical presentation of results 
Model estimated treatment geometric means for stimulated C-peptide AUC by MMTT at Week 
72 and ratio between treatment and their 80% CI will be plotted over time, by visit. 
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7 
Statistical methods for safety and tolerability data 
All subjects within the Safety set will be included in the safety data analysis. Safety outputs will 
be produced by treatment.  
7.1 
Variables 
Safety variables include adverse events, vital signs (blood pressure [SBP and DBP] and pulse), 
height and weight, ECG intervals, laboratory measurements (hematology, clinical chemistry, 
urinalysis, coagulation panel, virology and viral serology for SARS-CoV-2, CMV, EBV, and 
HSV), as well as subject demographics, baseline characteristics, and treatment information. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In particular, summary tables for adverse events (AEs) will summarize 
only on-treatment events, with a start date during the on-treatment period (treatment-emergent 
AEs).  
For all safety data listings (e.g. ECG, lab, vital signs, AEs), data collected during the post-
treatment period will be flagged. 
7.2 
Descriptive analyses 
Subject demographics and other baseline characteristics 
• All data for background (Growth z score, puberty, bone age, tanner stage, HLA) and 
demographic variables will be listed by treatment group and subject. Summary statistics 
will be provided by treatment group. Growth Z-scores include z-score (SDS) for height, 
weight and BMI. 
Note: HLA data for each allele will be captured in separate columns in the database. For the 
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analysis, the data should be combined into one record. For example: 
Format in database (with a dummy example): 
HLA-DRB1 Allele 1 
DRB1*03:01 
HLA-DQB1 Allele 1 
DQB1*02:01 
HLA-DQA1 Allele 1 
DQA1*03:01 
HLA-DRB1 Allele 2 
DRB1*04:01 
HLA-DQB1 Allele 2 
DQB1*03:02 
HLA-DQA1 Allele 2 
DQA1*05:01 
Format transposed for the analysis: 
HLA-DRB1 
Allele 1 
HLA-DRB1 
Allele 2 
HLA-DQA1 
Allele 1 
HLA-DQA1 
Allele 2 
HLA-DQB1 
Allele 1 
HLA-DQB1 
Allele 2 
DRB1*03:01 
DRB1*04:01 
DQA1*03:01 
DQA1*05:01 
DQB1*02:01 
DQB1*03:02 
Type 1 diabetes risk associated with HLA haplotypes at baseline will be summarized by 
treatment with frequency counts and percentages. 
Haplotypes associated with T1D are listed in the table (Atkinson and all 2001) below. 
Type 1 diabetes risk associated with HLA-DR and HLA-DQ haplotypes 
Risk 
HLA 
HLA DRB1 
HLA DQA1 
HLA DQB1 
High risk 
0401 
0301 
0302 
 
0402 
0301 
0302 
 
0405 
0301 
0302 
0301 
0501 
0201 
Moderate risk 
0801 
0401 
0402 
0101 
0101 
0501 
0901 
0301 
0303 
Weak or moderate 
0401 
0301 
0301 
protection 
0403 
0301 
0302 
0701 
0201 
0201 
1101 
0501 
0301 
Strong protection 
1501 
0102 
0602 
 
1401 
0101 
0503 
0701 
0201 
0303 


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Relevant medical history including diabetic ketoacidosis at time of diagnosis of T1DM, current 
medical conditions, any other relevant baseline information will be listed by treatment group 
and subject. 
Treatment 
Data for study drug administration and concomitant therapies will be listed by treatment group 
and subject. 
Vital signs 
All vital signs data will be listed by treatment, subject, and visit/time and if ranges are available 
abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics will be 
provided by treatment and visit/time. For height, weight and BMI using SDS (z-score) summary 
statistics for change from baseline by treatment at Week 52 and Week 72 may be provided if 
enough data allows, otherwise percentiles will be listed. 
ECG evaluations 
All ECG data will be listed by treatment, subject and visit/time, abnormalities will be flagged. 
Summary statistics will be provided by treatment and visit/time. 
Clinical laboratory evaluations 
Listing of all laboratory parameters will be provided in subjects with abnormal values. 
Summary statistics will be provided by treatment and visit/time. Shift table will be provided. 
Adverse events 
All information obtained on adverse events will be displayed by treatment and subject. 
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. A subject with multiple adverse events 
within a body system is only counted once towards the total of this body system and treatment. 
Similar information will also be presented by preferred term.  
The number and percentage of subjects with adverse events by maximum severity of adverse 
events will be tabulated by body system and preferred term with a breakdown by treatment. 
The number and percentage of subjects with adverse events classified as related to study drug 
will be tabulated by body system and preferred term with a breakdown by treatment. Similar 
analysis will be performed for serious adverse events, and adverse events leading to treatment 
discontinuation. 
ClinicalTrials.gov and EudraCT 
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 
5% and on treatment emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set population 
and prepared internally by Novartis. 


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If for a same subject, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
• a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE 
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non-SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.  
7.3 
Graphical presentation  
Boxplots to visualize trends in longitudinal safety data (vitals, ECG, lab parameter) will be 
created. 
8 
Pharmacokinetic / pharmacodynamic relationships 
The relationship between PK, PD, efficacy or biomarker endpoints may be explored 
graphically. 
Modeling of PK/PD data using a population approach may be performed as appropriate and 
will be reported if necessary in a separate, standalone modeling and simulation report. 
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10 
Reference list 
Akirav, E. M., Lebastchi, J., Galvan, E. M., Henegariu, O., Akirav, M., Ablamunits, V., Lizardi, 
P.M., Herold, K. C. (2011). Detection of β cell death in diabetes using differentially methylated 
circulating DNA. Proceedings of the National Academy of Sciences of the United States of 
America, 108(47), 19018–19023. doi:10.1073/pnas.1111008108  
Andersen ML, Hougaard P, Pörksen S, et al. (2014) Partial Remission Definition: Validation 
based on the insulin dose-adjusted HbA1c (IDAA1C) in 129 Danish Children with New-Onset 
Type 1 Diabetes. Pediatr Diabetes (15): 469-476. 
Couper J, Donaghue KC (2009) Phases of diabetes in children and adolescents. 
Pediatr Diabetes. 13-6. 
Mortensen HB, Hougaard P, Swift P, et al (2009) New definition for the partial remission period 
in children and adolescents with type 1 diabetes. Diabetes Care. 1384-90. 
Atkinson MA, Eisenbarth GS. Type 1 diabetes: new perspectives on disease pathogenesis and 
treatment. Lancet. 2001 Jul 21;358(9277) 
Forbes S, Oram RA, Smith A, et al. Validation of the BETA-2 score: an improved tool to 
estimate beta cell function after clinical islet transplantation using a single fasting blood sample 
(2016). American Journal of Transplantation. 16: 2704-2713.