Conditions: Sickle Cell Disease (SCD)
Keywords: Sickle cell disease Sickle cell disorder SCD Sickle cell anemia Hemoglobin SC disease Sickling disorder due to hemoglobin S Vaso-occlusive crisis VOC P-selectin Crizanlizumab SEG101
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 140
Healthy volunteers: no

Brief summary:
Sickle cell disease (SCD) is a genetic blood disorder. Crizanlizumab is indicated to reduce the frequency of vaso-occlusive crises (VOCs) in patients with SCD aged 16 years and older.

The purpose of this local Phase IV study was to evaluate the safety of crizanlizumab specifically in Indian patients with SCD aged 16 years or older with a history of VOC leading to healthcare visit.

Detailed description:
Sickle cell disease (SCD) is a genetic blood disorder, caused by a mutation in the β-globin gene, which early on progresses into a systemic disease. Vaso-occlusion is a hallmark of SCD and can lead to serious acute and chronic complications.

The purpose of this local Phase IV study was to evaluate the safety of crizanlizumab specifically in Indian patients with SCD aged 16 years or older with a history of VOC leading to healthcare visit.

The study was open label and single armed. 140 patients were treated with crizanlizumab for approximately one year at a dose of 5 mg/kg in addition to receiving standard of care.

The primary objective was to assess frequency, severity and causality of serious adverse events (SAEs) during the treatment period. Secondary objective was to assess overall safety and tolerability of crizanlizumab.

Arms:
arm 1: Participants received Crizanlizumab at a dose of 5.0 mg/kg, and standard of care.

Interventions: intervention 1: crizanlizumab
Intervention descriptions: intervention 1: Crizanlizumab 5.0 mg/kg i.v. initial dose on Week 1 Day 1, second dose on Week 3 Day 1. Subsequently, Day 1 of every 4 weeks until Week 51, in addition of standard of care.

Protocol document:
Prot_000.pdf: 


 
 
 
Appendix 16.1.1 
Protocol and protocol amendments 
 
History of changes 
Version  
Summary of changes 
1.0 
Original version 
1 
Protocols and protocol amendments 
Table 1-1 
List of protocols, protocol amendments and post text supplements 
 
Document 
Effective Date 
Original Protocol 
27-Jul-2020 
 
 
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Clinical Trial Protocol (Version No. 00)
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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................9
Protocol summary..............................................................................................................11
1
Introduction .......................................................................................................................14
1.1
Background............................................................................................................14
1.1.1
Overview of disease pathogenesis, epidemiology and current 
treatment................................................................................................14
1.1.2
Introduction to investigational treatment ..............................................16
1.2
Purpose ..................................................................................................................16
1.2.1
Study rationale and purpose..................................................................17
2
Objectives and endpoints...................................................................................................17
3
Study design ......................................................................................................................17
4
Rationale............................................................................................................................18
4.1
Rationale for study design .....................................................................................18
4.2
Rationale for dose/regimen and duration of treatment ..........................................19
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................19
4.4
Purpose and timing of interim analyses/design adaptations..................................19
4.5
Risks and benefits..................................................................................................19
5
Study Population ...............................................................................................................22
5.1
Inclusion criteria ....................................................................................................22
5.2
Exclusion criteria...................................................................................................23
6
Treatment...........................................................................................................................24
6.1
Study treatment......................................................................................................24
6.1.1
Investigational and control drugs..........................................................24
6.1.2
Additional study treatments ..................................................................25
6.1.3
Treatment arms/group ...........................................................................25
6.1.4
Guidelines for continuation of treatment ..............................................25
6.1.5
Treatment duration................................................................................25
6.2
Other treatment(s)..................................................................................................25
6.2.1
Concomitant therapy.............................................................................25
6.2.2
Prohibited medication ...........................................................................27
6.3
Participant numbering, treatment assignment, randomization ..............................27
 
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6.3.1
Participant numbering...........................................................................27
6.3.2
Treatment assignment, randomization ..................................................27
6.4
Treatment blinding.................................................................................................27
6.5
Dose escalation and dose modification..................................................................27
6.5.1
Dose modifications................................................................................28
6.5.2
Follow-up for toxicities.........................................................................32
6.6
Additional treatment guidance...............................................................................33
6.6.1
Treatment compliance...........................................................................33
6.7
Preparation and dispensation.................................................................................33
6.7.1
Handling of study treatment and additional treatment..........................34
6.7.2
Instruction for prescribing and taking study treatment .........................34
7
Informed consent procedures ............................................................................................34
8
Visit schedule and assessments .........................................................................................35
8.1
Screening ...............................................................................................................40
8.1.1
Eligibility screening ..............................................................................40
8.1.2
Information to be collected on screening failures.................................40
8.2
Participant demographics/other baseline characteristics .......................................41
8.3
Efficacy..................................................................................................................41
8.4
Safety.....................................................................................................................41
8.4.1
Laboratory evaluations..........................................................................42
8.4.2
Electrocardiogram (ECG) .....................................................................43
8.4.3
Pregnancy and assessments of fertility .................................................44
8.5
Additional assessments..........................................................................................44
8.5.1
Pharmacokinetics ..................................................................................44
8.5.2
Sickle cell  VOC event..........................................................................45
9
Study discontinuation and completion ..............................................................................46
9.1
Discontinuation and completion............................................................................46
9.1.1
Study treatment discontinuation and study discontinuation..................46
9.1.2
Withdrawal of informed consent...........................................................47
9.1.3
Lost to follow-up...................................................................................47
9.1.4
Early study termination by the sponsor.................................................48
9.2
Study completion and post-study treatment ..........................................................48
10 Safety monitoring and reporting........................................................................................48
10.1
Definition of adverse events and reporting requirements......................................49
10.1.1
Adverse events ......................................................................................49
10.1.2
Serious adverse events ..........................................................................50
 
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10.1.3
SAE reporting........................................................................................51
10.1.4
Pregnancy reporting ..............................................................................52
10.1.5
Reporting of study treatment errors including misuse/abuse................52
10.2
Additional Safety Monitoring................................................................................53
10.2.1
Liver safety monitoring.........................................................................53
10.2.2
Renal safety monitoring........................................................................53
10.3
Protocol Exempt AEs & SAEs ..............................................................................53
11 Data Collection and Database management......................................................................54
11.1
Data collection.......................................................................................................54
11.2
Database management and quality control............................................................54
11.3
Site monitoring ......................................................................................................54
12 Data analysis and statistical methods ................................................................................55
12.1
Analysis sets ..........................................................................................................55
12.2
Participant demographics and other baseline characteristics.................................55
12.3
Treatments .............................................................................................................56
12.4
Analysis of the primary endpoint(s)/estimand(s) ..................................................56
12.4.1
Definition of primary endpoint(s)/estimand(s) .....................................56
12.4.2
Statistical model, hypothesis, and method of analysis..........................56
12.5
Analysis of secondary endpoints/estimands..........................................................56
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................56
12.5.2
Safety endpoints....................................................................................57
12.6
Analysis of exploratory endpoints.........................................................................58
12.7
Interim analyses.....................................................................................................58
12.8
Sample size calculation..........................................................................................59
12.8.1
Primary endpoint(s)...............................................................................59
13 Ethical considerations and administrative procedures ......................................................59
13.1
Regulatory and ethical compliance........................................................................59
13.2
Responsibilities of the investigator and IRB/IEC..................................................59
13.3
Publication of study protocol and results...............................................................60
13.4
Quality Control and Quality Assurance.................................................................60
14 Protocol adherence ............................................................................................................60
14.1
Protocol amendments.............................................................................................61
15 References .........................................................................................................................62
16 Appendices ........................................................................................................................64
 
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List of tables
Table 2-1
Objectives and related endpoints ..........................................................17
Table 6-1
Investigational and control drug............................................................25
Table 6-2
Criteria for dose interruption and re-initiation of crizanlizumab 
treatment for adverse drug reactions.....................................................29
Table 8-1
Assessment Schedule ............................................................................37
Table 8-2
Assessment & Specifications................................................................41
Table 8-3
Clinical laboratory parameters collection plan .....................................43
Table 8-4
ECG collection plan..............................................................................43
Table 8-5
Pharmacokinetic and Immunogenicity blood collection log.................45
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................53
Table 12-1
Confidence intervals (95%) for different proportions of SAE..............59
List of figures
Figure 3-1
Study design..........................................................................................18
 
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Clinical Trial Protocol (Version No. 00)
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List of abbreviations
ACS
Acute Chest Syndrome
ADA
Anti-drug antibody
ADR
Adverse drug reaction
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
APC
Acute Pain Crisis
APTT
Activated partial thromboplastin time
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC 
Area Under Curve
BUN
Blood Urea Nitrogen
CDS
Core Data Sheet
CFR
Code of Federal Regulation
CI
Confidence Interval
CK
Creatinine Kinase
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CMO&PS 
Chief Medical Office and Patient Safety
CMV
Cytomegalovirus
CO
Country Organization
COVID-19
Coronavirus disease of 2019
CRA
Clinical Research Associate
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CTC
Common Terminology Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DCGI
Drug Controller General of India
DDE
Direct Data Entry
DILI
Drug-Induced Liver Injury
DNA
Deoxyribonucleic acid
EBV
Epstein-Barr virus
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic Data Capture
EDTA
Ethylenediaminetetraacetic acid
EMA 
European Medicines agency
EOS
End of Study
EOT
End of Treatment
eSource
Electronic Source
 
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FAS
Full Analysis Set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
h
Hour
Hb
Hemoglobin
HbC
Hemoglobin C
HBcAb 
Hepatitis B core Antibody
HbS
Hemoglobin S
HbS/β0 or
HbS/β+
Hemoglobin S with β0-thalassemia or β+-thalassemia
HBsAb 
Hepatitis B surface antibody
HBsAg
Hepatitis B surface antigen
HbSS
Homozygous hemoglobin S
HBV
Hepatitis B Virus
hCG
Human chorionic gonadotropin
HCV
Hepatitis C Virus
HDL
High Density Lipoproteins
HIV
Human immunodeficiency virus
HPLC
High performance liquid chromatography
HSV
Herpes simplex virus
HU/HC
hydroxyurea/hydroxycarbamide
i.v.
intravenous
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IG
Immunogenicity
IN
Investigator Notification
INR
International Normalized Ratio
IRB
Institutional Review Board
IRR
Infusion-related reaction
IRT
Interactive Response Technology
LDH
lactate dehydrogenase
LDL
low density lipoproteins
LFT
Liver function test 
LLN
lower limit of normal
mAb
monoclonal antibody
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
 
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MedDRA
Medical dictionary for regulatory activities 
mg
milligram(s)
mL
milliliter(s)
NCI
National Cancer Institute
NSAID
nonsteroidal anti-inflammatory drug
OTC
Over the counter
PCR
Polymerase chain reaction
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PSGL-1
P-selectin glycoprotein ligand-1
PT
prothrombin time
PTT
Partial thromboplastin time
QMS 
Quality Management System
QoL
Quality of Life
QTcF
QT interval corrected by Fridericia’s formula
R Value
ALT/ALP x ULN
RBC
red blood cell(s)
SAE
Serious Adverse Event
SCD
Sickle Cell Disease
SCT
Sickle cell trait
SD
standard deviation
SEG101
Novartis humanized anti-P-selectin monoclonal antibody variant
SelG1
Reprixys humanized anti-P-selectin monoclonal antibody variant
SOP
standard operating procedures
SUSAR
Suspected Unexpected Serious Adverse Reaction
TBIL
Total Bilirubin
ULN
upper limit of normal
US
United States
USD
United States dollar
USPI
US Package Insert
VOC
Vaso-occlusive crisis
WHO
World Health Organization 
WoC
Withdrawal of Consent
 
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Glossary of terms
Additional 
treatment
Medicinal products that may be used during the clinical trial as described in 
the protocol, but not as an investigational medicinal product (e.g. any 
background therapy)
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study participant 
Dosage
Dose of the study treatment given to the participant 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
End of the clinical 
trial
The end of the clinical trial is defined as the last visit of the last participant or 
at a later point in time as defined by the protocol
Enrollment
Point/time of participant entry into the study at which screening was completed 
successfully and participant is ready to receive first dose
eSource (DDE)
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications 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
Investigational 
drug/ treatment
The drug whose properties are being tested in the study. Investigational 
treatment does not include other treatments (i.e HU/HC and L-glutamine) 
administered as concomitant background therapy allowed by the protocol 
when used within approved indication/dosage.
Medication 
number
A unique identifier on the label of medication kits
Other treatment
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy)
Participant
A trial participant (can be a healthy volunteer or a patient)
Participant number
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant and 
should be used to identify the participant throughout the study for all data 
collected, sample labels, etc.
Patient
An individual with the condition of interest for the study
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and will 
be used in clinical trial database setup and eventually in analysis
Personal data
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data includes 
participant identifier information, study information and biological samples.
Premature 
participant 
withdrawal
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned
Screen Failure
A participant who did not meet one or more criteria that were required for 
participation in the study
 
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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
Start of the clinical 
trial
The start of the clinical trial is defined as the signature of the informed consent 
by the first participant or as defined as per protocol
Study treatment
Any drug or combination of drugs or intervention 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 participant permanently stops taking any of the study drug(s) prior to 
the defined study treatment completion date (if any) for any reason; may or 
may not also be the point/time of study discontinuation 
Treatment 
arm/group 
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts.
Treatment of 
interest
The treatment of interest and, as appropriate, the alternative treatment to 
which comparison will be made. These might be individual interventions, 
combinations of interventions administered concurrently, e.g. as add-on to 
standard of care, or might consist of an overall regimen involving a complex 
sequence of interventions. This is the treatment of interest used in describing 
the related clinical question of interest, which might or might not be the same 
as the study treatment.
Variable (or 
endpoint)
The variable (or endpoint) to be obtained for each participant that is required 
to address the clinical question. The specification of the variable might include 
whether the participant experiences an intercurrent event.
Withdrawal of 
study consent 
(WoC)
Withdrawal of consent from the study occurs only when a participant 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
CSEG101A2403
Full Title
An Indian multi-centric Phase IV study to assess the safety of Crizanlizumab with 
or without hydroxyurea therapy in sickle cell disease patients with vaso-occlusive 
crises
Brief title
Study of safety of crizanlizumab in Indian patients with sickle cell disease
Sponsor and 
Clinical Phase
Novartis
Phase IV
Investigation 
type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this study is to evaluate the safety of crizanlizumab in Indian 
patients with sickle cell disease aged 16 years or older with history of vaso-
occlusive crisis to in accordance with permission no. IMP/BIO/20/000026 to 
import and market crizanlizumab by the Drug Controller General of India (DCGI) 
and the requirement to conduct a local Phase IV safety study
Primary 
Objective(s) 
The primary objective of this study is to assess the serious adverse events of 
crizanlizumab in Indian patients with sickle cell disease
Secondary 
Objectives
The secondary objective of this study is to assess the overall safety and 
tolerability of crizanlizumab in Indian patients with sickle cell disease
Study design
This is a Phase IV non-randomized, open label, single-arm, interventional, 
multicenter study to evaluate the safety of crizanlizumab at a dose of 5.0 mg/kg 
in addition to standard of care for 12 months, in patients with sickle cell disease 
and a history of vaso-occlusive crisis leading to healthcare visit 
Study 
population
This study will enroll 140 participants with confirmed diagnosis of sickle cell 
disease who have had a history of vaso-occlusive crisis leading to a healthcare 
visit
The participants will be 16 years or older, who may or may not be receiving 
hydroxyurea/hydroxycarbamide for treatment
Key Inclusion 
criteria

Signed informed consent must be obtained prior to participation in the study

Male or female participants aged 16 years and older on the day of signing 
informed consent

Confirmed diagnosis of sickle cell disease by hemoglobin electrophoresis or 
high performance liquid chromatography

Concomitant sickle cell therapy with hydroxyurea/hydroxycarbamide is 
permitted

History of vaso-occlusive crisis leading to healthcare visit prior to screening 
visit as determined by medical history and investigator assessment

Participants must meet the following central laboratory values at the 
screening visit: 
 
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
Absolute Neutrophil Count ≥1.0 x 109/L

Platelet count ≥75 x 109/L

Hemoglobin: for adults (Hb) ≥4.0 g/dL and for adolescents (Hb) ≥5.5 
g/dL

Glomerular filtration rate ≥ 45 mL/min/1.73 m2 using CKD-EPI formula

Direct (conjugated) bilirubin < 2.0 x ULN

Alanine Aminotransferase (ALT) < 3.0 x ULN

ECOG Performance Status ≤2 for adults and Karnofsky Performance Scale 
≥ 50% for adolescents
Key Exclusion 
criteria

Contraindication or hypersensitivity to any drug or metabolites from similar 
class as study drug or to any excipients of the study drug formulation. 
History of severe hypersensitivity reaction to other monoclonal antibodies, 
which in the opinion of the investigator may pose an increased risk of serious 
infusion reaction

participant has received crizanlizumab and/or other P-selectin inhibitor prior 
to the study or plans to receive it during the duration of the study.

Concurrent severe and/or uncontrolled medical conditions which, in the 
opinion of the Investigator, could cause unacceptable safety risks or 
compromise participation in the study

Participant has documented immunogenicity to a prior biological drug

Participants who are on active treatment with Voxelotor, other investigational 
drug or other monoclonal antibody, or intend to initiate the same during the 
course of the trial

Pregnant females or females who have given birth within the past 90 days or 
who are breastfeeding, and women of child-bearing potential unless they are 
using effective methods of contraception during dosing and for 15 weeks 
after stopping treatment

Clinically significant bleeding disorder

Positive test for hepatitis C ribonucleic acid (HCV RNA).

Malignant disease

participant has significant active infection (i.e. HIV, hepatitis B , COVID-19 
infections) or immune deficiency (including chronic use of 
immunosuppressive drugs)
Study 
treatment
Crizanlizumab (SEG101) at 5.0 mg/kg dose
Treatment of 
interest
Not applicable
Efficacy 
assessments
Not applicable
Key safety 
assessments

Monitoring of adverse events and serious adverse events

Vital signs

Hematology, chemistry, coagulation and urinalysis

Electrocardiograms at relevant time points

Immunogenicity: measurement of anti-drug antibodies (ADA) to 
crizanlizumab
 
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Additional 
assessments 

Pharmacokinetic parameters

Vaso-occlusive events 
Data analysis
This is a descriptive study and no hypothesis testing will be conducted
However the primary endpoint which is the proportion of patients reporting a 
serious adverse event over the treatment period, will be presented with a 2-sided 
95% confidence interval
Key words
Sickle cell disease, crizanlizumab, safety, vaso-occlusive crisis
 
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1
Introduction
1.1
Background
1.1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Sickle cell disease (SCD) is a genetic blood disorder, caused by a single missense mutation 
(Glu6Val) in the β-globin gene, which early on progresses into a systemic disease. Vaso-
occlusion is the hallmark of SCD and can lead to serious acute and chronic complications. 
Vascular dysfunction, inflammation, and P-selectin mediated cell-to-cell and cell-to-
endothelium adhesion play an important role in the pathophysiology of SCD. Vaso-occlusive 
crisis (VOC) is the most common clinical manifestation of SCD. Every VOC increases 
morbidity and can result in organ damage/failure and/or death (Ballas et al 2010, 
Brousseau et al 2010, Powars et al 2005). Additionally, VOCs lead to significant health care 
utilization and are the most common cause of emergency room visits and hospital admissions 
in SCD patients, with total medical costs exceeding 1.1 billion USD annually (Kauf et al 2009).
SCD is the most common single gene disorder in African Americans, affecting approximately 
1 in 375-600 people of African ancestry (Nietert et al 2002). Sickle cell conditions are also 
common among people of Mediterranean countries, Africa, Middle East, India, Caribbean and 
parts of South and Central America. In India, existing prevalence data suggest that there may 
be 18 million subjects with sickle cell trait (SCT) and 1.4 million SCD patients among the tribal 
population (Saxena et al 2017).
The most frequent and typically most severe form is homozygous HbSS (sickle cell anemia) 
(α2 βs2, HbS). Other forms of SCD include compound heterozygous conditions, such as 
hemoglobin C (HbC) with HbS (HbSC), HbS with β-thalassemia (HbS/β0-thalassemia or 
HbS/β+-thalassemia), and HbS with other variants (Ware et al 2017). Clinical signs appear 
within the first 6 months of life, but there is considerable variability in severity 
(Gill et al 1995) resulting from genetic and environmental factors. Patients describe acute pain 
crises (APCs) and chronic pain clearly as the most debilitating effects on their lives, affecting 
them physically and emotionally. Fatigue and cognitive effects also emerge as other debilitating 
effects. In addition, organ-damage and long-term complications have also a severe effect on 
them. As a result of these complications, patients often have reduced quality of life (QoL), 
significant anxiety, depression, and short-life expectancy (Kanter and Kruse-Jarres 2013).
Current treatment:
Stem cell bone transplantation remains the only curative modality for SCD patients. However, a 
limited number of patients are eligible, and substantial concerns remain about transplant-related 
mortality and long-term toxicities, including infertility (Ware et al 2017).
Blood transfusions are commonly used as a single transfusion to ameliorate acute, even life-
threatening complications, and/or as chronic transfusions to prevent long-term complications 
most frequently related to stroke prevention.
 
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Vaso-occlusive crises are typically treated symptomatically with pain management and with 
other supportive care (Bender, MA 1993, Rees et al 2010). Severe pain is often treated with 
opioids but their use is controversial due to the risk of opioid-related adverse events.
Preventive 
treatments 
to 
reduce 
the 
number 
of 
VOCs 
are 
limited. 
Hydroxyurea/hydroxycarbamide (HU/HC) is approved to reduce the frequency of painful crises 
and the need for transfusions in SCD patients aged 2 and older with a history of recurrent, 
moderate-to-severe painful crises. HU/HC presents several limitations, including significant 
toxicities, need for blood monitoring, leading to poor patient compliance. HU/HC is cytotoxic, 
myelosuppressive 
and 
teratogenic, 
potentially 
carcinogenic, 
impacts 
fertility 
(Charache et al 1995, Pászty et al 1997, Sicklos-USPI 2017, Droxia-USPI 2012), and has a 
number of contraindications/special warnings and precautions for use.
Crizanlizumab has been approved by the US FDA on 15-Nov-2019, to reduce the frequency of 
VOCs in adult and pediatric patients aged 16 years and older with SCD. As of 14-July-2020, 
approval has been granted in 8 countries including India.
Other therapies, approved by the US FDA but not in India:

L-glutamine (Endari™) was approved by the FDA in July-2017 to reduce acute 
complications associated with SCD in patients aged ≥5 years old. The mechanism of action 
of the amino acid L-glutamine in treating SCD is not fully understood. L-glutamine 
decreases oxidative state in red blood cells (RBCs). Oxidative stress phenomena are 
involved in the pathophysiology of SCD. Sickled RBCs are more susceptible to oxidative 
damage than normal RBCs, which may contribute to the chronic hemolysis and vaso-
occlusive events associated with SCD. 

Voxelotor is a novel hemoglobin S (HbS) polymerization inhibitor for the treatment of SCD 
approved by the FDA in November-2019. Voxelotor regulates the affinity of Hb for oxygen, 
resulting in a decrease in the concentration of deoxygenated sickle hemoglobin which forms 
polymers.
Despite the use of HU/HC, transfusions, and/or L glutamine patients with SCD may still 
experience VOC. Therefore, SCD is a life-threatening disease with severe morbidities and 
represents a major unmet medical need.
1.1.1.1
Role of P-selectin in VOC
The recognition that adherence of leukocytes, platelets and sickled RBC to blood vessel 
endothelium and to each other have a primary role in VOC led to further research into the 
selectins, which mediate the first steps in the recruitment of leukocytes to specific tissues. P-
selectin is the best characterized of the selectins and binding specificity and affinity to its 
physiological ligand P-selectin glycoprotein ligand-1 (PSGL-1) is well-documented 
(McEver 2004, Mehta et al 1998).
Extensive data suggests a pivotal role for P-selectin in the pathophysiology of SCD 
(Matsui et al 2001). Using mice engineered or altered to express human hemoglobin S (sickle 
cell hemoglobin) investigators have demonstrated P-selectin mediates cell-cell and cell-
endothelium interactions between the endothelium and sickled RBC, leukocytes, and platelets. 
All of these interactions have been implicated in SCD vaso-occlusion. Further, blockade or 
 
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genetic absence of P-selectin decreases or eliminates these interactions and vaso-occlusion. 
Taken together, these studies establish P-selectin as a key mediator of vaso-occlusion in SCD.
1.1.2
Introduction to investigational treatment
1.1.2.1
Overview of crizanlizumab (SEG101)
Crizanlizumab is a selective humanized monoclonal antibody (mAb) that binds to P-selectin 
with high affinity, blocking its interaction with its ligands, including PSGL-1. Extensive pre-
clinical data have established P-selectin as a key mediator of VOC in SCD 
(Matsui et al 2001) and suggest that its blockade could eliminate or reduce VOC.
The compound was previously developed by Reprixys Pharmaceuticals Corporation under the 
investigational drug code SelG1. Novartis acquired the company on 18-Nov-2016, and is now 
the drug developer and sponsor for crizanlizumab, under the investigational drug code, SEG101. 
First global approval for crizanlizumab for SCD treatment has been obtained from the US FDA 
on 15-Nov-2019.
[Crizanlizumab Investigator's Brochure] provides detailed information related to toxicology, 
nonclinical pharmacology, drug properties and preclinical data.
1.1.2.2
Clinical experience
As of the safety cut-off date of the last [Crizanlizumab Investigator's Brochure] (31-Mar-2020), 
523 subjects, including 95 healthy volunteers, have been enrolled into crizanlizumab clinical 
program, 
including 
two 
Reprixys–sponsored 
studies 
with 
Reprixys–manufactured 
crizanlizumab SelG1, and six Novartis-sponsored studies (one completed and five ongoing) 
with Novartis manufactured crizanlizumab SEG101.
Crizanlizumab was received by 23 patients, as a part of Managed access program 
([CSEG101A2001M]) and by 1 patient, as a part of a post-study drug supply product program 
following completion of previous Phase II ([CSEG101A2201] – SUSTAIN).
In SUSTAIN study, the treatment of SCD patients with crizanlizumab at 5.0 mg/kg showed 
positive clinical activity as demonstrated by a statistically significant and clinically relevant 
decrease in the annual VOC rate compared with placebo and it was also found to be well 
tolerated.
The substantial efficacy and acceptable safety of crizanlizumab demonstrate an overall 
favorable benefit-risk profile and warrant further clinical development in SCD.
1.2
Purpose
The purpose of this study is to evaluate the safety of crizanlizumab in Indian SCD patients aged 
16 years or older with history of VOC in accordance with permission no. IMP/BIO/20/000026 
to import and market crizanlizumab by the Drug Controller General of India (DCGI) and the 
requirement to conduct a local Phase IV safety study.
 
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1.2.1
Study rationale and purpose
Globally, SCD is a neglected chronic disorder of increasing health importance with estimates 
suggesting India to have the second highest burden of disease (Hockham et al 2018).
Based on the data from the SUSTAIN study ([CSEG101A2201]), marketing authorization for 
crizanlizumab in India and other countries has been obtained.
However, the SUSTAIN study did not include Indian patients and the ongoing crizanlizumab 
global clinical trials include relatively small numbers of Indian patients.
This phase IV multi-center study will be conducted in India to evaluate the safety of 
crizanlizumab at a dose of 5 mg/kg in patients with SCD and history of VOC leading to 
healthcare visit. 
2
Objectives and endpoints
Objectives and related endpoints are described in Table 2-1 below.
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

To assess the serious adverse 
events (SAEs) of crizanlizumab 
in Indian patients with SCD

Frequency, severity and causality of SAEs during the 
treatment period
Secondary objective(s)
Endpoint(s) for secondary objective(s)

To assess the overall safety and 
tolerability of crizanlizumab in 
Indian patients with SCD

Frequency, severity and causality of treatment emergent 
adverse events (including Adverse Events of Special 
Interest (AESI)), as well as labs, vital signs, ECGs and 
immunogenicity
3
Study design
This is a Phase IV open label, single-arm, interventional, multicenter study to evaluate safety 
of crizanlizumab at a dose of 5.0 mg/kg in addition to standard of care in Indian patients with 
SCD and a history of VOC leading to healthcare visit.
The study will include 140 participants aged 16 years and older with confirmed diagnosis of 
SCD (all genotypes are eligible) who have had a history of VOC leading to a healthcare visit 
prior to screening visit. Participants may receive HU/HC, L-glutamine (Endari™) or 
erythropoietin-stimulating agents as treatment/concomitant medication for SCD before and 
during the study. 
The enrollment period for this study is expected to be approximately 24 months.
Screening
Within 35 days before enrollment, written informed consent, according to local guidelines, will 
be signed by the participants, and prior to any study related screening procedures are performed. 
All screening evaluations must be performed during the screening period.
 
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Treatment
An Interactive Response Technology (IRT) system will be used to confirm eligibility, enroll 
the participant and dispense the uniquely numbered treatment packages.
Participants will receive crizanlizumab 5.0 mg/kg via intravenous (i.v.) infusion on Week 1 Day 
1, followed by a second dose 14 days later (Week 3 Day 1), and then every 4 weeks. Participants 
will receive crizanlizumab for approximately 12 months (until week 51) in the trial or until 
unacceptable toxicity, death, are lost to follow-up or discontinued from crizanlizumab for any 
other reasons at the discretion of the investigator or the participant.
Following study treatment discontinuation, participants will perform an end of treatment visit.
Post-treatment follow-up
After the end of treatment visit, all participants will be followed up for safety up to 105 days 
(15 weeks) after the last infusion of investigational study drug. In case the participant switches 
to non-study crizanlizumab within this period, all the assessments are still performed as per the 
Table 8-1 and crizanlizumab obtained from other sources as study drug supply will be recorded 
as concomitant medication. 
For participants who in the opinion of the investigator are still deriving clinical benefit from 
crizanlizumab, every effort will be made to continue provision of crizanlizumab via a roll over 
trial or other available options at the time.
The end of the study (EOS) will occur when all the patients have either completed or 
discontinued the study treatment and/or the 105 days follow-up period. The final analysis will 
occur at the EOS. All available data from all patients up to the trial end and will be analyzed 
and summarized in a final CSR.
Figure 3-1
Study design
4
Rationale
4.1
Rationale for study design
This is a multicenter phase IV study that will be conducted in India to assess the safety of 
crizanlizumab with or without HU/HC in SCD patients with vaso-occlusive crises.
This is a descriptive study and no hypothesis testing will be conducted, but rather is designed 
to assess safety of crizanlizumab at the 5 mg/kg dose in Indian SCD patients (Section 12.8.1). 
 
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4.2
Rationale for dose/regimen and duration of treatment
Participants will receive crizanlizumab at the approved dose of 5.0 mg/kg by i.v. infusion over 
30 minutes. Dose number 2 is administered as a loading dose 2 weeks following the first dose 
to rapidly achieve steady-state serum concentrations. This is followed by repeated 
administration of the same dose every 4-weeks ± 7 days (until week 51, see Section 6.1.5) to 
ensure that steady-state serum concentrations of crizanlizumab are maintained to provide a 
consistent blockade of P-selectin throughout the study.
The treatment period will be approximately 12 months, in line with the pivotal study SUSTAIN.
The eligibility criteria and the design of this study will enable assessment of the safety of 
crizanlizumab in patients representative of current SCD clinical practice and management in 
India.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Not applicable.
4.4
Purpose and timing of interim analyses/design adaptations
There is no planned interim analysis before the conduct of the primary analysis.
4.5
Risks and benefits
Results from the randomized, placebo-controlled SUSTAIN study in SCD patients (aged 16 
years and older, any genotype) established the efficacy of crizanlizumab 5 mg/kg compared to 
placebo by showing a statistically significant and clinically meaningful reduction of the annual 
rate of VOC leading to healthcare visit. In addition, a more than a two-fold increase in the 
number of patients who remained completely free of VOC leading to healthcare visit during the 
study, and a three-fold increase in the median time to first VOC leading to healthcare was 
observed.
Pooled safety data from the SUSTAIN and [CSEG101A2202] studies in patients treated with 
crizanlizumab 5 mg/kg (n=111 patients, Oct-2019 cut-off) showed that crizanlizumab is 
generally associated with a favorable safety profile. Adverse drug reactions (ADRs) were 
nausea (16.2%), back pain (15.3%), arthralgia (14.4%), pyrexia (14.4%), abdominal pain 
(9.0%), diarrhea (8.1%), pruritus (7.2%), vomiting (5.4%), myalgia (4.5%), musculoskeletal 
chest pain (4.5%), oropharyngeal pain (3.6%), infusion site reaction (2.7%), and infusion-
related reaction (1.8%). 
In addition, in the randomized SUSTAIN study the overall frequency of AEs, SAEs and AEs 
leading to treatment discontinuation was similar among patients treated with crizanlizumab 5 
mg/kg and placebo. Use of crizanlizumab in combination with HU/HC did not result in any 
meaningful differences in the safety profile.
Based on class effects, pre-/clinical findings, the mechanism of action of crizanlizumab, 
identified and potential risks include the following:
 
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Infusion-related reactions (IRRs)
Administration of mAbs can be associated with IRRs. A focused search for potentially “severe” 
IRRs (i.e. indicative of hypersensitivity/anaphylaxis or cytokine-release syndrome) identified 2 
(1.8%) patients treated with crizanlizumab 5 mg/kg in the pooled data set; the reported term 
was infusion-related reaction, none of which was serious. Severe IRRs including cases requiring 
hospitalization have been described in ongoing clinical trials and the post-marketing setting.
Additionally, a broad search for IRRs using an extensive list of potential signs and symptoms 
related to infusion reactions, and occurring within 24 hours of the infusion, identified 28.8% of 
patients in the safety pool with at least one event. Most of these events were reported in 1 or 2 
patients only, except for nausea (9.0%), headache (8.1%), arthralgia and back pain (4.5%), and 
fatigue and myalgia (2.7%). None of these events were grade 3 or grade 4 in severity. In the 
SUSTAIN study, IRRs using this broader search were more frequent in the 5 mg/kg arm 
(34.8%) compared to the placebo arm (21.0%). Except for nausea, none of the events were 
reported with an absolute differences of more than 5% in the crizanlizumab 5 mg/kg vs. the 
placebo arm.
Immunogenicity
Administration of mAb can be associated with immunogenicity (IG), including development of 
anti-drug antibodies (ADA) or hypersensitivity following treatment with crizanlizumab (see 
above).
In clinical studies, treatment-emergent ADAs were transiently detected in 1 patient among the 
111 patients who received crizanlizumab 5 mg/kg (0.9%). There was no evidence of an altered 
pharmacokinetic/pharmacodynamic (PK/PD) or safety profile with ADA development. 
Immunogenicity (IG) and development of ADA will be monitored during the study.
Infections
Based on the mechanism of action and physiological role of P-selectin, crizanlizumab could 
potentially be associated with an increased infection risk.
Infection-related AEs (based on all preferred terms included in the system organ class 
“Infections”) were reported in 43.2% patients in the safety pool. The most frequently reported 
infections were urinary tract infection (9.9%), upper respiratory tract infections (8.1%), 
pneumonia and sinusitis (4 patients each, 3.6%). Most infections were low in severity (grade 1 
or 2). In the randomized SUSTAIN study, the frequency of infection-related AEs was similar 
across the arms: 53.0% in the crizanlizumab 5 mg/kg and 53.2% in the placebo arm. In addition, 
there was no difference between the arms in the incidence of neutropenia or increased white 
blood cell counts.
In summary, no increased frequency or severity of infections has been observed in clinical 
studies with crizanlizumab so far, suggesting that crizanlizumab has no clinically relevant effect 
to induce or complicate infections in SCD patients. However, investigators are advised to 
monitor patients for signs/symptoms of infections.
Effect on hemostasis
Considering the mode of action of crizanlizumab and physiological role of P-selectin, a 
potential effect on the hemostatic system was evaluated by searching for AEs related to 
 
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hemorrhage, abnormal laboratory parameters of the hemostatic system, or thrombosis. In the 
safety pool, a search for hemorrhagic events identified 13 (11.7%) patients, mostly related to 
abnormal laboratory findings. Except for prolonged prothrombin time (PT) reported in 3 (2.7%) 
patients, these events were reported in 1 or 2 patients only. None were grade 4 or led to study 
withdrawal, and none were considered treatment related as per investigator assessment. The 
only grade 3 event was decreased hemoglobin, consistent with hemolysis and the underlying 
disease. 
In Study [CSEG101A2201], hemorrhagic events were reported in 11 (16.7%) patients in the 5 
mg/kg and 8 (12.9%) patients in the placebo arm, mostly related to laboratory abnormalities. 
Of note, 1 event (intracranial hemorrhage) reported in the 2.5 mg/kg arm was considered serious 
(grade 4, hospitalization) and led to study drug discontinuation. Cerebrovascular accidents, 
including hemorrhagic stroke, are known complication and leading cause of death in patients 
with SCD.
In summary, bleeding events were rare, with the majority of the observed AEs being abnormal 
laboratory parameters on single occasions. The available data do not suggest an adverse effect 
of crizanlizumab on hemostasis. Nevertheless, participants should be monitored for 
signs/symptoms of bleeding; additionally, hematology and coagulation parameters will be 
regularly assessed during the study. 
A separate search for potential AEs related to thrombosis did not further identify any patients 
with AEs related to thrombosis in the 5 mg/kg pooled data, suggesting that crizanlizumab does 
not have a relevant pro-aggregant or pro-thrombotic effect.
Laboratory test interference with automated platelet counts
Laboratory interference with automated platelet counts (platelet clumping) has been observed 
in patients treated with crizanlizumab in clinical studies, in particular when tubes containing 
EDTA (ethylenediaminetetraacetic acid) were used. This may lead to unevaluable or falsely 
decreased platelet counts. Current clinical and pre-clinical data suggest this is an ex vivo effect 
that is EDTA- and time-dependent, without indication of platelet clumping, true reduction in 
circulating platelets or pro-aggregant effect in vivo.
To mitigate the potential for this laboratory test interference, it is recommended to run 
respective test as soon as possible (within 4 hours of blood collection) or use citrate tubes. When 
needed, platelet counts can be estimated via a peripheral blood smear. Additional details are 
provided in Section 8.4.1 of protocol and the [CSEG101A2403 laboratory manual].
QT prolongation and hepatic safety
Based on the data generated to date, crizanlizumab does not have a clinically relevant effect on 
QT interval, and there no evidence for severe or drug-induced hepatotoxicity.
Pregnancy and lactation
The potential risk to pregnant women is unknown, and there are no adequate and well-controlled 
studies in pregnant women to inform the associated risk. Animal reproduction studies in 
cynomolgus monkeys have not shown embryofetal toxicity or risk of increased fetal 
abnormalities with i.v. administration of crizanlizumab during gestation at doses up to 50 mg/kg 
(approximately 16 times the human clinical exposure based on AUC in patients with SCD at 5 
 
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mg/kg once every 4 weeks). There was a numerical increase in fetal losses, the cause of which 
is unclear and may be related to development of antibodies against crizanlizumab in monkeys. 
No maternal toxicity was observed.
Pregnant or breastfeeding women as well as those of childbearing potential (unless using 
effective contraception) will not be allowed to participate in the study. Please refer to the 
Eligibility criteria of the protocol for details.
Appropriate eligibility criteria and stopping rules are included in this protocol. Recommended 
guidelines for prophylactic or supportive management of study-drug induced adverse events are 
provided in Section 6.2 . The risk to participants in this trial may be minimized by compliance 
with the eligibility criteria and study procedures and close clinical monitoring. If deemed 
clinically necessary, participants optionally could be kept in the hospital for 24 hours following 
an investigational treatment dose. 
There may be unforeseen risks with crizanlizumab, which could be serious. 
Please refer to the latest version of the [Crizanlizumab Investigator's Brochure] for the most 
recent information on the efficacy and safety.
5
Study Population
CSEG101A2403 will enroll 140 participants with confirmed diagnosis of SCD of any genotype 
who have had a history of VOC leading to a healthcare visit. No replacement will be done for 
participants that discontinue early. The study will include participants aged 16 years or older, 
who may or may not be receiving HU/HC for SCD.
The investigator or designee must ensure that only participants who meet all of the following 
inclusion and none of the exclusion criteria are offered treatment and are entered in the study.
5.1
Inclusion criteria
1. Signed informed consent must be obtained prior to participation in the study. 
2. Male or female participants aged 16 years and older on the day of signing informed 
consent.
3. Confirmed diagnosis of SCD by hemoglobin electrophoresis or high performance liquid 
chromatography (HPLC) [performed locally]. All SCD genotypes are eligible, genotyping 
is not required for study entry.
4. Concomitant sickle cell therapy with HU/HC is permitted.
5. History of VOC leading to healthcare visit prior to screening visit as determined by 
medical history and investigator assessment.
6. Participants must meet the following central laboratory values at the screening visit:

Absolute Neutrophil Count ≥1.0 x 109/L

Platelet count ≥75 x 109/L

Hemoglobin: for adults (Hb) ≥4.0 g/dL and for adolescents (Hb) ≥5.5 g/dL

Glomerular filtration rate ≥ 45 mL/min/1.73 m2 using CKD-EPI formula

Direct (conjugated) bilirubin < 2.0 x ULN
 
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
Alanine Aminotransferase (ALT) < 3.0 x ULN
7. ECOG performance status ≤2 for adults and Karnofsky Performance Scale ≥ 50% for 
adolescents.
5.2
Exclusion criteria
1. Contraindication or hypersensitivity to any drug or metabolites from similar class as study 
drug or to any excipients of the study drug formulation. History of severe hypersensitivity 
reaction to other monoclonal antibodies, which in the opinion of the investigator may pose 
an increased risk of serious infusion reaction.
2. Participant has received crizanlizumab and/or other P-selectin inhibitor prior to the study 
or plans to receive it during the duration of the study.
3. Concurrent severe and/or uncontrolled medical conditions which, in the opinion of the 
Investigator, could cause unacceptable safety risks or compromise participation in the 
study.
4. Any condition which, in the opinion of the investigator, is likely to interfere with the 
successful collection of the measurements required for the study.
5. Participant has documented immunogenicity to a prior biological drug.
6. Participants who are on active treatment with Voxelotor, other investigational drug or 
other monoclonal antibody, or intend to initiate the same during the course of the trial.
7. Pregnant females or females who have given birth within the past 90 days prior screening 
or who are breastfeeding.
8. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant unless they are using highly effective methods of contraception during 
dosing and for 15 weeks after stopping treatment.
Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant. 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 before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment

Male sterilization (at least 6 months prior to screening).  For female participants on 
study the vasectomized male partner should be the sole partner for that participant

Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception. In case of use of oral 
contraception women should have been stable on the same pill for a minimum of 3 
months before taking study treatment. If local regulations deviate from the 
contraception methods listed above to prevent pregnancy, local regulations apply and 
will be described in the Informed Consent Form (ICF)
 
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Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal 
ligation at least six weeks ago. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment is she considered not of child bearing potential.
9. Clinically significant bleeding disorder.
10. Participant with active HIV infection (detectable viral load).
11. Participant with active Hepatitis B infection (HBsAg positive) will be excluded. Note: 
Participant with antecedent but not active Hepatitis B (i.e. anti-HBc positive, HBsAg and 
HBV-DNA negative) are eligible.
12. Positive test for hepatitis C ribonucleic acid (HCV RNA). Note: Participant in whom HCV 
infection resolved spontaneously (positive HCV antibodies without detectable HCV-
RNA) or those that achieved a sustained virological response after antiviral treatment and 
show absence of detectable HCV RNA ≥ 6 months (with the use of IFN-free regimes) or ≥ 
12 months (with the use of IFN-based regimes) after cessation of antiviral treatment are 
eligible.
13. Malignant disease. Exceptions to this exclusion include the following: malignancies that 
were treated curatively and have not recurred within 3 years prior to study treatment; 
completely resected basal cell and squamous cell skin cancers and any completely 
resected carcinoma in situ.
14. Participant has significant active infection or immune deficiency (including chronic use of 
immunosuppressive drugs).
6
Treatment
6.1
Study treatment
The sponsor will supply the investigational product crizanlizumab (SEG101) as an open label 
medication. Investigational treatment will be administered by i.v. infusion on Week 1 Day 1, 
followed by a second dose 14 days later (Week 3 Day 1), and then administration will take place 
every 4 weeks until week 51.
6.1.1
Investigational and control drugs
Crizanlizumab (SEG101) is supplied in individual single use glass vials each containing 10.0 
mL of concentrate for solution for infusion. The crizanlizumab formulation is supplied at a 
concentration of 10 mg/mL.
On infusion day, the pharmacist or designated personnel will prepare an individual dose of 
crizanlizumab to study participants (as assigned by the IRT system) diluted in 0.9% saline 
sodium chloride solution or 5% dextrose infusion bags. Refer to the [CSEG101A2403 
Pharmacy Manual] for further instructions on dose regimen and dose preparation.
Study drug will be administered over 30 minutes by i.v. infusion.
 
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Table 6-1
Investigational and control drug
Investigational Drug
Pharmaceutical 
Dosage Form and 
Route of 
Administration
Dose
Frequency and/or 
regimen
Crizanlizumab 
(SEG101) 10mg/ml
Concentrate for 
solution for i.v. 
infusion
5.0 mg/kg
Week 1 Day 1, Week 3 
Day 1, and Day 1 of 
every 4-weeks cycle 
until Week 51 Day 1
There is no control drug in this single-arm open label trial.
6.1.2
Additional study treatments
No other study treatment beyond crizanlizumab is included in this trial.
6.1.3
Treatment arms/group
This is a single-arm study where all participants will receive crizanlizumab (SEG101) at the 
dose of 5.0 mg/kg.
6.1.4
Guidelines for continuation of treatment
For guidelines for continuation of treatment, refer to Section 6.5.1 and Section 6.5.2.
Participants who permanently discontinued the study for any reason should follow the protocol 
safety assessments as scheduled. After discontinuing study treatment, further treatment is left 
to the physician’s discretion.
6.1.5
Treatment duration
The total duration of treatment in the study for each participant is planned to be approximately 
12 months (a total of 51 weeks).
Participants may be permanently discontinued due to unacceptable toxicity, death, lost to 
follow-up or discontinued from the study treatment for any other reasons at the discretion of the 
investigator or the participant.
Every effort will be made to supply crizanlizumab after the end of the trial to participants who 
may benefit from continued treatment as per the Investigator’s opinion.
6.2
Other treatment(s)
6.2.1
Concomitant therapy
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant joined the study must be recorded on the 
appropriate Case Report Forms (CRF).
In general, the use of any concomitant medication/therapies deemed necessary for the care of 
the participant is permitted, except as specifically prohibited (see Section 6.2.2).
 
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The participant must be told to notify the investigational site about any new medications he/she 
takes within 30 days prior to initial dosing until the completion of end of study (EOS) visit 
(through 105 days after the last dose of study treatment). All medications (including prescription 
drugs, herbal medications/supplements, over the counter (OTC) medication, dietary and vitamin 
supplements) and significant non-drug therapies (including physical therapy and blood 
transfusions) taken or administered within the timeframe defined in the entry criteria until 
completion of the EOS visit must be listed on the Prior and Concomitant Medications and 
Surgical and Medical Procedures page of the CRF.
Concomitant sickle cell therapy with HU/HC is permitted. However, for participants who are 
receiving, or for whom the investigator is considering to initiate, treatment with HU/HC, it is 
recommended that HU/HC treatment has been initiated at least 3 months prior to study entry.
Erythropoietin-stimulating agents are also permitted to manage chronic symptomatic anemia. 
L-glutamine oral powder (EndariTM) is also permitted without restriction. Please refer to 
Section 6.2.1.1 for over-the counter forms of L-glutamine.
Aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs) and prophylactic doses of 
anticoagulants are permitted as per local guidance, while other anti-platelets agents or 
anticoagulants at doses targeting therapeutic levels should be used with caution (refer to 
Section 6.2.1.1).
All approved forms of analgesia for pain are permitted per standard of care. Other approved 
medications for supportive care (antiemetics, anxiolytics, hypnotics, antihistamines) are 
permitted, including marinol (dronabinol, tetrahydrocannabinol).
There is no restriction on administration of inactivated vaccines during this trial.
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
Although EndariTM, the FDA-approved version of L-glutamine, is permitted, other over-the-
counter forms of L-glutamine are discouraged, as are other natural and herbal remedies (e.g., 
EvenFlo and/or products containing dang gui, ligustrum root, ginseng root, white peony, 
corydalis, salvia, copodonosis, poria, jujbe, angelica sinensis, lovage) due to the unproven 
efficacy and variable quality and composition of these products. Vitamin and mineral 
supplements (e.g. fish oil, folic acid, L-arginine, L-citrulline, magnesium, riboflavin, vitamin 
C, vitamin D, vitamin E, and Zinc) are also permitted, though caution is advised when taking 
amounts exceeding 100% of the recommended daily allowance.
Anti-platelets agents or anticoagulants at therapeutic doses should be used with caution due to 
a potential effect of P-selectin inhibition on coagulation and platelet clumping.
Avoid any live vaccines against infectious diseases within 4 weeks prior to the first dose of 
investigational treatment. There is no restriction on the administration of inactivated vaccines 
during the study.
Infusion-related reactions have been reported in patients treated with crizanlizumab. 
Prophylactic pre-medication is permitted, and sites should follow local practice or guidelines 
for administration of monoclonal antibodies; pre-medications may be adjusted based on clinical 
presentation as deemed appropriate (e.g. for pain management). Steroids should be used 
with caution in SCD patients (Brandow et al 2020).
 
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If a participant experiences a grade 3 or grade 4 infusion related reaction, study drug must be 
discontinued (see Table 6-2).
In the event that a major surgery becomes necessary, it is recommended to hold crizanlizumab 
for at least 4 weeks prior to the procedure, and then restarted once the patient has fully recovered, 
at the investigator discretion.
6.2.2
Prohibited medication
The use of voxelotor is prohibited during the study.
The use of other investigational drugs is prohibited during the study. In addition, the 
administration of monoclonal antibodies other than the investigational treatment is prohibited, 
due to the theoretical potential for cross-reactivity and/or overlapping toxicities with other 
monoclonal antibodies. If voxelotor, other investigational agents or other monoclonal 
antibodies have been used in the past, they must have been discontinued at least 30 days (or 5 
half-lives of that agent, whichever is greater) prior to the Screening visit.
6.3
Participant numbering, treatment assignment, randomization
6.3.1
Participant numbering
Each participant is identified in the study by a participant Number (participant No.), that is 
assigned when the participant is registered for screening and is retained for the participant 
throughout his/her participation in the trial. A new participant No. will be assigned if the 
participant is re-screened.
The participant No. consists of the Center Number (Center No.) (as assigned by Novartis to the 
investigative site) with a sequential participant number suffixed to it, so that each participant is 
numbered uniquely across the entire database. Upon signing a new informed consent form, the 
participant is assigned to the next sequential participant No. available.
6.3.2
Treatment assignment, randomization
No randomization will be performed in this study.
All participants who fulfill all inclusion/exclusion criteria will be assigned to be treated with 
crizanlizumab. The IRT system will assign the study medication kits to be dispensed at each 
participant visit.
6.4
Treatment blinding
Treatment will be open to participants, investigator staff, persons performing the assessments, 
and the Clinical Trial Team (CTT).
6.5
Dose escalation and dose modification
Investigational drug dose escalation is not permitted.
For dose interruption please refer to Section 6.5.1.
 
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6.5.1
Dose modifications
For participants who do not tolerate the protocol-specified dosing schedule, dose interruptions 
are either recommended or mandated (see Table 6-2). Dose reductions are not allowed.
If drug-induced toxicities are present, participants are required to be closely monitored. 
Subsequently, a decision to continue or discontinue the participant from the study would have 
to be determined.
These dose interruption guidelines are summarized in the table below. Deviations from 
mandatory dose interruptions are not allowed. Furthermore, permanent treatment 
discontinuation is mandatory for specific events as indicated in the table below.
These dose interruptions must be recorded in the Study Treatment CRF.
Every effort should be made to maintain the participant on the protocol-defined dosing schedule. 
In case of dose delay for any reason, the dose should be given as soon as possible. If that infusion 
visit occurs within ±7 days of a protocol-scheduled visit, then the dose and all required 
assessments will be assigned to the nearest protocol-scheduled visit. However, if that infusion 
visit does not fall within ±7 days of a protocol-scheduled visit, the dose and corresponding 
assessments will be documented as an unscheduled visit. At that point, every effort should be 
made to bring the participant’s infusions back onto the protocol-defined schedule (within the 
±7 day window).
In the event that a major surgery becomes necessary, it is recommended to hold crizanlizumab 
for at least 4 weeks prior to the procedure, and then restarted once the patient has fully recovered, 
at the investigator discretion.
It is recommended that trial participants with confirmed active COVID-19 or presenting with 
symptoms indicative of COVID-19 such as fever, cough, difficulty breathing, sore throat or 
feeling unwell should interrupt study treatment until the trial participant has fully recovered; in 
case of suspected COVID-19, testing for COVID-19 is recommended as per local 
guidance/practice. For confirmed participants, re-testing is encouraged if signs or symptoms 
indicative of COVID-19 newly develop or persist. Participants with suspected infection who 
tested negative, may continue study treatment.
In case of trial participants who have been exposed to someone infected by COVID-19 and in 
self-quarantine, administration of the study treatment should be delayed until the trial 
participant completes the quarantine and remains asymptomatic and/or COVID-19 has been 
ruled out.
 
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Table 6-2
Criteria for dose interruption and re-initiation of crizanlizumab 
treatment for adverse drug reactions.
Dose modifications for crizanlizumab
Worst toxicity
CTCAEa Grade (CTCAE version 5) during a 
cycle of therapy
Investigations (Hematologic)
Neutropenia (ANC)
Grade 1 (ANC < LLN - 1500/mm3) and 
Grade 2 (ANC < 1500 - 1000/mm3)
Recommendation: continue study treatment.
Grade 3 (ANC < 1000 - 500/mm3)
Mandatory: interrupt dose until resolved to ≤ Grade 
2 or next dose scheduled. If abnormality persists, 
permanently discontinue study treatment.
Grade 4 (ANC < 500/mm3)
Mandatory: permanently discontinue study 
treatment.
Febrile neutropenia (ANC < 1.0 x 109/L, fever 
≥ 38.3°C)
Mandatory: interrupt dose until resolved or next 
dose schedule. If abnormality persists, permanently 
discontinue study treatment.
Thrombocytopenia
Grade 1 (PLT < LLN - 75,000/mm3) and 
Grade 2 (PLT < 75,000 - 50,000/mm3)
Recommendation: continue study treatment.
Grade 3 (PLT < 50,000 - 25,000/mm3)
Recommendation: interrupt dose until resolved to ≤ 
Grade 2 or next dose scheduled. If abnormality 
persists, permanently discontinue study treatment.
Grade 4 (PLT < 25,000/mm3)
Mandatory: interrupt dose until resolved to ≤ Grade 
2 or next dose scheduled. If abnormality persists, 
permanently discontinue study treatment.
Investigations (Hepatic)
Isolated Direct Bilirubin
Grade 1
>ULN - 1.5 x ULN if baseline was normal;
> 1.0 - 1.5 x baseline if baseline was abnormal
Recommendation: continue study treatment.
Grade 2 and 3
(>1.5 - 10.0 x ULN if baseline was normal;
>1.5 - 10.0 x baseline if baseline was 
abnormal)
Recommendation: interrupt study treatment. Monitor 
LFTsb weekly, or more frequently if clinically
indicated, until resolved to ≤ 1.5 x ULN or baseline.
Monitor for hemolysis.
If resolved to ≤ Grade 1 or baseline, then continue 
study treatment.
Grade 4
(>10.0 x ULN if baseline was normal;
Mandatory: permanently discontinue study 
treatment.
 
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>10.0 x baseline if baseline was abnormal)
Isolated ALT elevation
Grade 1 (> ULN - 3.0 x ULN if baseline was 
normal; 1.5 -3.0 x baseline if baseline was 
abnormal)
Recommendation: continue study treatment.
Grade 2 (> 3.0 - 5.0 x ULN if baseline was 
normal; > 3.0 - 5.0 x baseline if baseline was 
abnormal)
Recommendation: continue study treatment. Repeat 
LFTsb as soon as possible, preferably within
48-72 hours from awareness of the abnormal results; 
if abnormal lab values are confirmed
upon the repeat test, then monitor LFTs -b weekly, or 
more frequently if clinically indicated, until
resolved to ≤ 3.0 x ULN or baseline. If resolved, then 
continue with next dose scheduled.
If 
abnormalities 
persist 
>2 
weeks, 
refer 
to 
Section 6.5.2.1 for additional follow-up evaluations 
as applicable.
Grade 3 (> 5.0 - 20.0 x ULN if baseline was 
normal; >5.0 – 20.0 x baseline if baseline 
was abnormal)
Recommendation: interrupt dose. Repeat LFTsb as 
soon as possible, preferably within 48-72
hours from awareness of the abnormal results; 
monitor LFTsb weekly, or more frequently if
clinically indicated, until resolved to ≤ 3.0 x ULN.
If resolved, to ≤ 3.0 x ULN or baseline, then continue 
study treatment.
Grade 4 (> 20.0 x ULN if baseline was 
normal; > 20.0 x baseline if baseline was 
abnormal)
Mandatory: permanently discontinue study 
treatment.
Combined elevations of ALT and bilirubin (direct (conjugated))

For participants with normal baseline 
ALT and direct bilirubin value: ALT >3.0 
x ULN combined with direct bilirubin >2.0 
x ULN
OR

For participants with elevated baseline 
ALT or direct bilirubin value: ALT>2x 
baseline AND > 2.0 x baseline direct 
bilirubin
Mandatory: interrupt study treatment.
Repeat LFTs as soon as possible, preferably within 
48-72 hours from awareness of the abnormal
results, follow-up for symptoms and initiate workup 
for competing etiologies.
Then with weekly monitoring of LFTsb, or more 
frequently if clinically indicated, until
ALT and direct bilirubin have resolved to ≤ Grade 1 
or baseline or stabilization over 4 weeks.
Study drug may be restarted only if another etiology 
has been identified and liver enzymes have returned 
to ≤Grade 1 or baseline.
If DILI (drug-induced liver injury) is confirmed, 
permanently discontinue study treatment.
Refer to Section 6.5.2.1 for additional follow-up 
evaluations as applicable.
 
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Infections
Grades 1 and 2 
Recommendation: continue study treatment
Grade 3
Mandatory: interrupt dose until resolved. If resolved, 
then continue with next dose scheduled.
Grade 4
Mandatory: permanently discontinue study 
treatment.
Infusion-related reactions (IRR)
Grade 1
Mild transient reaction; infusion interruption 
not indicated; intervention not indicated
Recommendation:

Continue study treatment and increase 
monitoring of vital signs as medically indicated 
until the paticipant is deemed medically stable 
in the opinion of the investigator.

Consider slowing infusion rate.
Grade 2
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(e.g., antihistamines, NSAIDS, opioids, i.v. 
fluids); prophylactic medications indicated for 
<=24 hrs
Recommendation:

Interrupt infusion and increase monitoring of 
vital signs as medically indicated until the 
participant is deemed medically stable in the 
opinion of the investigator.

Administer appropriate medical therapy (e.g. 
analgesics such as paracetamol/acetaminophen 
or NSAIDs and anti-histamines) as per local 
institutional guidelines and clinical presentation.

Steroids should be used with caution unless 
clinically indicated (e.g. management of 
hypersensitivity/anaphylaxis) 
(Brandow et al 2020).

If symptoms resolve, restart infusion per 
investigator discretion at a slower rate (50% 
rate or slower) under continuous observation. 
Ensure a minimum of 1 hour observation period 
prior to restarting the infusion.

Administer premedication before restarting 
(e.g.analgesics such as 
paracetamol/acetaminophen or NSAIDs and 
anti-histamines within 1 hour prior to dosing) if 
not done already to manage the event, as per 
local institutional guidelines for prophylaxis of 
infusion related reactions, including subsequent 
infusions.

In case of recurring infusion reactions despite 
premedication and prolonged infusion, consider 
discontinuation of study treatment.
Grade 3 and 4
Mandatory:

Permanently discontinue study treatment and 
initiate appropriate medical care.
 
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Prolonged (e.g., not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical sequelae; 
Life-threatening consequences; urgent 
intervention indicated
General Note: Decision for dosing is made on prior lab results. If lab results found to be abnormal, 
repeat (unscheduled) labs should be performed at least 1 week prior to scheduled dose in order to 
have results to show resolution of the abnormality before the scheduled dose is given
a Common Terminology Criteria for Adverse Events (CTCAE Version 5)
b Core Liver Function Tests (LFTs) consist of ALT, AST, GGT, LDH, total bilirubin (fractionated [direct 
and indirect]) ALP, albumin and creatinine kinase (CK).
6.5.2
Follow-up for toxicities
Participants whose treatment is interrupted or permanently discontinued due to an adverse event 
or clinically significant laboratory value, must be followed up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts such as ophthalmologist, endocrinologist, 
dermatologist, psychiatrists etc. should be consulted as deemed necessary. All participants must 
be followed up for adverse events and serious adverse events for 105 days following the last 
doses of crizanlizumab.
6.5.2.1
Follow up on potential drug-induced liver injury (DILI) cases
Participants with an elevation of transaminases in combination with an increase of total bilirubin 
(TBIL) and a normal ALP may be indicative of potentially severe DILI, and should be 
considered as clinically important events and assessed appropriately to establish the diagnosis. 
The required clinical information, as detailed below, should be sought to obtain the medical 
diagnosis of the most likely cause of the observed laboratory abnormalities.
NOTE: Patients with SCD tend to have elevated transaminases, especially AST, and indirect 
bilirubin due to the hemolytic nature of this condition. Hence, ONLY ALT and Direct BIL will 
be required in this criteria.
Participants meeting the following criteria will require further follow-up as outlined below:

For participants with normal ALT and Direct BIL value at baseline: ALT > 3.0 x 
ULN combined with Direct BIL > 2.0 x ULN

For participants with elevated ALT or Direct BIL value at baseline: ALT > 2.0 x 
baseline AND Direct BIL > 2.0 x baseline

For participants with normal ALT at baseline: ALT > 5.0 x ULN for more than 2 
weeks

For participants with elevated ALT at baseline: ALT >3.0 x baseline for more than 
2 weeks
 
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For these participants, repeat LFTs as soon as possible, preferably within 48-72 hours. 
Participants should be closely monitored and workup for competing etiologies initiated 
including hemolysis or cholestasis, defined as ALP elevation > 2.0 x ULN with R value < 2.
Note: (The R value is calculated by dividing the ALT by the ALP (alkaline phosphatase), using 
multiples of the ULN for both values. It denotes whether the relative pattern of ALT and/or ALP 
elevation is due to cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver 
injury).
In the absence of an alternative explanation, these participants should be immediately 
discontinued from study treatment. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions as described below:
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, 
direct and indirect bilirubin, GGT, LDH, prothrombin time (PT)/INR and alkaline 
phosphatase.
2. A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, and history of any pre-existing 
liver conditions or risk factors, should be collected.
3. Further local testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. 
biliary tract) may be warranted.
4. Additional local testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist.
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, and thus, meet the definition of SAE and should be reported as SAE using the term 
“potential drug-induced liver injury." All events should be followed up with the outcome clearly 
documented.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
Compliance will be assessed by administration of the study treatment under the supervision of 
the investigator or his/her designee. This information must be captured in the source document 
and in the Drug Accountability Form.
6.7
Preparation and dispensation
Each study site will be supplied with investigational treatment in packaging as described in the 
Pharmacy Manual. A unique medication number is printed on the study medication label. 
Crizanlizumab solution will be prepared by a pharmacist or designated personnel appropriately 
qualified and trained in the preparation procedure in accordance with the [CSEG101A2403 
Pharmacy Manual].
 
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Participants should be closely observed for potential infusion-related reactions including rigors, 
chills, wheezing, flushing, pruritus, rash, hypotension, hypoxemia, and fever, and vital signs 
monitored more frequently if clinical indicated, in accordance with the Pharmacy Manual. The 
same applies for the subsequent infusions, if medically indicated. If a participant experiences 
an IRR (see Table 6-2), he/she may receive pre-medication on subsequent dosing days as per 
institutional standard of care, at the discretion of the treating physician. Please refer to 
Section 6.2.1.1 regarding use of corticosteroids.
If a participant experiences a Grade 3 or 4 IRR, the participant will discontinue investigational 
treatment. Please refer to Table 6-2.
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the [Crizanlizumab Investigator's Brochure] .
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis CO Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements in India. 
They will include storage conditions for the study treatment but no information about the 
participant except for the medication number.
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial.
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the 
investigator folder at each site.
6.7.1.2
Handling of additional treatment
Not applicable.
6.7.2
Instruction for prescribing and taking study treatment
All kits of study treatment assigned by the IRT will be recorded in the IRT system.
7
Informed consent procedures
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
 
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possible given his/her understanding. If the participant is capable of doing so, he/she must 
indicate agreement by personally signing and dating the written informed consent document.
Informed consent 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 participant 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 Investigator's Brochure (IB) (and/or CDS for marketed drugs). This information 
will be included in the participant informed consent and should be discussed with the 
participant 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 (IN) or an aggregate safety finding. New 
information might require an update to the informed consent and then must be discussed with 
the participant.
The following informed consents are included in this study:

Main study consent, which also included: 

A subsection that requires a separate signature for the ‘Optional Consent for 
Additional Research’ to allow future research on data/samples collected during this 
study

Main study consent for parent/legal guardian to give consent for their child

Model participant information and adolescent assent for16 and17 years old participants to 
express their understanding of the purpose of this study and what will happen if their 
parent(s)/legal guardian(s) give their consent for their participation in this study

Pregnancy Outcomes Reporting Consent for female participants
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 forms must be provided to Novartis after IRB/IEC 
approval.
8
Visit schedule and assessments
Table 8-1 lists all assessments and indicates with an "X" (for data captured in the database) or 
"S" (for data documented in medical files) the visits at which they are performed.
All data obtained from these assessments must be supported in the participant’s source 
documentation.
No CRF will be used as a source document.
 
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Allowed visit windows are specified as follows:
Screening assessments, apart from those listed below, must occur within 35 days prior to the 
enrollment as per Table 8-1.
There is a ± 7 day visit window permitted for every dosing visit (with a minimum of 21 days to 
be respected between 2 doses following Week 3 Day 1), except Week 3 Day 1 where a visit 
window of ±3 days is allowed (and dose is given within 14±3 days of Week 1 Day 1 dose).
Participants who discontinue the study for any reason should be scheduled for a visit as soon as 
possible (within 7 days of the last dose of the discontinued study treatment), at which time all 
of the assessments listed for visit End of Treatment (EOT) will be performed.
All participants will be followed in the mandatory safety follow-up period which includes safety 
assessments at 105 days after the Week 51 Day 1 visit, or, if the participant discontinued the 
study early, at 105 days after the last dose of the discontinued study treatment. A + 7 days for 
the end of follow-up period (last infusion + 105 days) is allowed.
Every effort should be made to follow the schedule outlined in Table 8-1.
 
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Table 8-1
Assessment Schedule
Period Screening
Treatment
End of Treatment (EOT)
Follow Up Phase
Visit Name
Screening
Week 1 Day 1
Week 3 Day 1
Week 7 Day 1
Week 11 Day 1
Week 15 Day 1
Week 19 Day 1
Week 23 Day 1
Week 27 Day 1
Week 31 Day 1
Week 35 Day 1
Week 39 Day 1
Week 43 Day 1
Week 47 Day 1
Week 51 Day 1
EOT
Safety Follow Up (EOS)
Days
-35 to -1
1
15
43
71
99
127
155
183
211
239
267
295
323
351 Within 7days of last dose
105 days after last dose
Informed consent
X
IRT Registration
X
X
X
IRT Enrollment1
X
Study Disposition
X
X
X
Demography
X
Inclusion / Exclusion 
criteria
X
ECOG/Karnofsky 
performance status
X
Medical History
X
Sickle Cell – VOC 
History
X
Sickle Cell –
Reasons for Non-
Administration of 
HU/HC2
X
Hepatitis screen
X
HIV screen
X
COVID-19 testing3
X
if required
Physical 
Examination
S
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Period Screening
Treatment
End of Treatment (EOT)
Follow Up Phase
Visit Name
Screening
Week 1 Day 1
Week 3 Day 1
Week 7 Day 1
Week 11 Day 1
Week 15 Day 1
Week 19 Day 1
Week 23 Day 1
Week 27 Day 1
Week 31 Day 1
Week 35 Day 1
Week 39 Day 1
Week 43 Day 1
Week 47 Day 1
Week 51 Day 1
EOT
Safety Follow Up (EOS)
Days
-35 to -1
1
15
43
71
99
127
155
183
211
239
267
295
323
351 Within 7days of last dose
105 days after last dose
Abbreviated physical 
examination
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body Height
X
X4
Body Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
Clinical Chemistry
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
Pregnancy Test 
(serum)
S
S
S
Urine Pregnancy 
Test
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Immunogenicity
X
X
X
X
X
X
X
Pharmacokinetics
X
X
X
X
X
X
X
Electrocardiogram 
(ECG)
X
X
X
Sickle cell – VOC 
event
X
Continuous
Prior/concomitant 
medications
X
Continuous
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Period Screening
Treatment
End of Treatment (EOT)
Follow Up Phase
Visit Name
Screening
Week 1 Day 1
Week 3 Day 1
Week 7 Day 1
Week 11 Day 1
Week 15 Day 1
Week 19 Day 1
Week 23 Day 1
Week 27 Day 1
Week 31 Day 1
Week 35 Day 1
Week 39 Day 1
Week 43 Day 1
Week 47 Day 1
Week 51 Day 1
EOT
Safety Follow Up (EOS)
Days
-35 to -1
1
15
43
71
99
127
155
183
211
239
267
295
323
351 Within 7days of last dose
105 days after last dose
Concomitant non-
drug 
therapies/procedures
X
Continuous
Adverse Events5
X
Continuous
Serious Adverse 
Events
X
Continuous
Study drug 
administration
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only
1 IRT enrollment call to be performed at Week 1 Day 1 so that the patient can start receiving medication
2 Prior treatment with HU/HC and reason why treatment has been interrupted will be collected at Screening
3 COVID-19 testing will be performed at screening and during scheduled visit as per investigator's discretion or if the patient presents symptoms
4 At EOT, height will only be assessed in adolescent patients
5 Including Adverse Events of Special Interest
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8.1
Screening
After signing the study ICF, the screening assessments will be done within 1 to 35 days prior 
to Week 1 Day 1 (see Table 8-1 for list of assessments to be performed). The investigator will 
obtain consent / assent of participants and/or parents according to local procedures.
Re-screening of participants is only allowed once per participant if the participant was not 
enrolled in the treatment period before. In this case a new participant Number will be assigned 
via IRT and the participant will be identified with this new number for the rest of his/her 
participation in the study. If participant has been enrolled and treated, re-screening of participant 
is not allowed.
In case rescreening occurs, all evaluations re-assessed should meet the eligibility criteria. A new 
informed consent form must be signed only if there is an interruption in the participant’s 
eligibility evaluation and the investigator chooses to re-screen the participant following screen 
failure. If a new informed consent form is signed, AEs and medical history will be assessed 
relative to the new informed consent date. Assessments from the initial screening can be used 
for re-screening if they fall within the screening window of 35 days before the first dose.
If the results from the central laboratory are partial or unavailable at time of the first infusion, 
local re-sampling is allowed from Day -14 on. Specifically, for platelet count test, local re-
sampling is allowed at any time in case of clumping or other issues reported from the central 
laboratory.
For laboratory evaluations used to determine eligibility, a repeated evaluation within the 
screening window is permitted for screening results out of the defined range before screen 
failing the participant. If the repeated laboratory result meets the criteria, that result may be used 
to determine eligibility. If the repeated laboratory result does not meet the criteria, the 
participant will be considered a screen failure. For details of assessments, see Table 8-1.
8.1.1
Eligibility screening
Following IRT registration for screening, participant eligibility will be evaluated once all 
screening procedures are completed. The eligibility evaluation 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
Participants who sign an informed consent form and subsequently found to be ineligible will be 
considered a screen failure. The reason for screen failure should be entered on the applicable 
Case Report Form. The demographic information, informed consent, and Inclusion/Exclusion 
pages must also be completed for screen failure participants. No other data will be entered into 
the clinical database for participants who are screen failures, unless the participant experienced 
a serious adverse event during the screening period (see SAE section for reporting details).
Participants who sign an informed consent and are considered eligible but fail to be started on 
treatment for any reason will be considered an early terminator. The reason for early termination 
should be captured on the appropriate disposition CRF.
 
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8.2
Participant demographics/other baseline characteristics
Participant demographic characteristics, which include age, gender, self-identified race and 
ethnicity, will be collected. 
Background medical information, including Sickle Cell and VOC History, prior use of HU/HC 
and reason for discontinuation (as applicable), ECG, ECOG/Karnofsky performance status, 
relevant and current medical history will also be collected.
Other baseline characteristics and assessments performed at screening for eligibility are detailed 
in Table 8-1.
8.3
Efficacy
Efficacy is not measured in this safety study.
8.4
Safety
Safety will be monitored by assessing physical examinations, vital signs, ECG, laboratory 
assessments including hematology, chemistry, coagulation, urinalysis, immunogenicity as well 
as by evaluation of adverse events as collected per schedule on Table 8-1.
For details on AE collection and reporting, refer to Section 10.1.1.
Table 8-2
Assessment & Specifications
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. If indicated based on medical history 
and/or symptoms, rectal, external genitalia, breast, and pelvic exams 
will be performed. A complete physical examination will be performed 
only at Screening.
An abbreviated (short) physical exam will be performed at all remaining 
visits and includes the examination of general appearance and vital 
signs, as needed based on observed signs or reported symptoms.
Significant findings that were present prior to the signing of informed 
consent must be included in the Medical History page on the 
participant’s electronic Case Report Form (eCRF). Significant new 
findings that begin or worsen after informed consent must be recorded 
on the Adverse Event page of the participant’s eCRF.
Vital signs
Vital signs include blood pressure (supine position preferred when 
ECG is collected), pulse measurement, respiratory rate and body 
temperature. Vital sign will be performed at screening, at all visits for 
which there is a scheduled investigational treatment infusion, at EOT 
and also at Follow up visit (last infusion + 105 days).
Height and weight
Height will be measured at screening both in adults and adolescents 
and end of treatment for adolescents only. Body weight (in indoor 
clothing, but without shoes) will be measured at screening, at all 
visits for which there is a scheduled investigational treatment infusion 
(for dosing) and at end of treatment visit.
 
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8.4.1
Laboratory evaluations
Clinical laboratory analyses are to be performed centrally, unless otherwise mentioned in the 
schedule of assessments or in Table 8-3. Novartis must be provided with a copy of the central 
laboratory’s certification, and a tabulation of the normal ranges and units of each parameter 
collected in the eCRF. Any changes regarding normal ranges and units for laboratory values 
assessed during the study must be reported via an updated tabulation indicating the new 
effective date.
If at any time a participant has laboratory parameters obtained from a different (local) laboratory, 
Novartis must be provided with a copy of the certification and a tabulation of the normal ranges 
and units for this laboratory.
The investigator is responsible for reviewing all laboratory reports for participants in the study 
and evaluating any abnormalities for clinical significance.
For assessment of participants’ eligibility to the study, laboratory results from the central 
laboratory will be used. If the results from the central laboratory are partial or unavailable at 
time of the first infusion, local re-sampling from Day -14 is allowed.
Specifically, for platelet count test, local re-sampling is allowed at any time in case of clumping 
(see Section 4.5) or other issues reported from the central laboratory. In such a case, eligibility 
may be based on the results from the local laboratory.
The results of the local laboratory will need to be recorded in the local lab eCRF if local tests 
are performed during the scheduled visits (or in the unscheduled local lab eCRF if performed 
during unscheduled visit).
Unscheduled local laboratory assessments may be performed if medically indicated to 
document a (potential) AE or when the treating physician cannot wait for central laboratory 
results for decision making. In this particular situation, if possible, the blood sample obtained 
at the same time point should be submitted to the central laboratory for analysis in parallel with 
local analysis.
The results of the local laboratory will be recorded in the eCRF if any the following criteria are 
met:
• A treatment decision was made based on the local results, or
• There are no concomitant central results available, or
• Local lab results document an AE not reported by the central lab, or
• Local lab results document an AE where the severity is worse than the one reported by the 
central lab, or
• Eligibility had to be based on the local lab results due to pending/missing central lab results.
At any time during the study up to safety follow-up, abnormal laboratory parameters which are 
clinically relevant and require an action to be taken with study treatment (e.g., require dose 
modification and/or interruption of study treatment, lead to clinical symptoms or signs, or 
require therapeutic intervention), whether specifically requested in the protocol or not, will be 
 
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recorded on the AE eCRF page. The severity of laboratory data will be graded using the CTCAE 
version 5. Additional analyses are left to the discretion of the investigator.
Table 8-3
Clinical laboratory parameters collection plan
Test Category*
Test Name**
Hematology
Hematocrit, Hemoglobin, MCH, MCHC, MCV, Reticulocytes (%), Platelets**, 
Red blood cells, White blood cells, RBC Morphology, Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands, Other (absolute 
value preferred, %s are acceptable)
Chemistry
Albumin, Alkaline phosphatase, ALT, AST, Gamma-glutamyl-transferase 
(GGT), Lactate dehydrogenase (LDH), Bicarbonate, Calcium, Magnesium, 
Phosphorus, Chloride, Sodium, Potassium, Creatinine, Creatine kinase, Direct 
Bilirubin, Indirect Bilirubin, Total Bilirubin, Blood Urea Nitrogen (BUN) or 
Urea***, Uric Acid, Glucose (fasting)
At Screening only and when medically indicated: Total Cholesterol, LDL, HDL, 
Total Protein, Triglycerides; Glucose in fasting state.
Urinalysis
Macroscopic Panel (Dipstick) will be done locally: Color, Bilirubin, Blood, 
Glucose, Ketones, Leukocytes esterase, Nitrite, pH, Protein, albumin, Specific 
Gravity, Urobilinogen
Microscopic Panel: Red Blood Cells, White Blood Cells, Casts, Crystals, 
Bacteria, Epithelial cells performed, if a positive dipstick
Coagulation
Prothrombin time (PT), International normalized ratio [INR]), Partial 
thromboplastin time (PTT), Activated partial thromboplastin time (APTT)
Hepatitis markers
HBV-DNA, HBsAg, HBsAb, HBcAb, HCV RNA-PCR (At Screening only)
Additional tests
HIV Ab (at Screening only), COVID-19 testing (PCR)****
Pregnancy Test
Serum pregnancy test (at Screening, EOT and follow-up visit only), urine 
pregnancy test (before each infusion) will be done locally.
* At the discretion of the Investigator, safety laboratory tests can be performed locally before dosing 
(i.e, the day before or on the same dosing day).
**Local clinical laboratory collection only where specified. For platelet count test, local re-sampling is 
allowed at any time in case of clumping or other issues reported from the central laboratory.
*** Either BUN or Urea test to be performed. It will be defined in the Laboratory manual.
**** During the COVID-19 pandemic, if a participant experiences symptoms indicative of COVID-19 
infection, viral testing for COVID-19 is recommended as per local guidance/practice.
8.4.2
Electrocardiogram (ECG)
Standard 12-lead ECGs will be performed (in the supine position) after the patient has been 
resting for at least 5 min (10 min resting period preferred) prior to each time point indicated in 
Table 8-4. Electrocardiogram assessments will be locally conducted as outlined. The preferred 
sequence of cardiovascular data collection during study visits is ECG collection first, followed 
by vital signs, and blood sampling.
Table 8-4
ECG collection plan
Visit
Time
ECG Type
Screening (Day -35 to Day -1)
Anytime
Triplicate 12 Lead
 
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Visit
Time
ECG Type
Week 51 Day 1 (Last Infusion 
Visit)
Pre-dose (before infusion)
Triplicate 12 Lead
Safety Follow Up Visit
Anytime
Triplicate 12 Lead
Unscheduled with clinically 
significant finding
Anytime
Triplicate 12 Lead
Additional, unscheduled ECGs may be done at the discretion of the investigator at any time 
during the study as clinically indicated. Unscheduled ECGs with clinically significant findings 
should be collected in triplicate. The mean result of the ECG analysis will be entered into the 
study database and used for AE reporting.
Clinically significant ECG abnormalities present at screening should be reported on the Medical 
History eCRF page. New or worsened clinically significant findings occurring after informed 
consent must be recorded on the Adverse Events eCRF page.
8.4.3
Pregnancy and assessments of fertility
All female participants of childbearing potential and premenopausal who are not surgically 
sterile must perform serum hCG pregnancy testing at screening in order to confirm study 
eligibility. Additional pregnancy testing might be performed per local requirements.
Serum pregnancy testing is required at screening, at the EOT visit, and at the follow up visit. 
During the study, urine pregnancy testing will be performed locally prior to each dosing. A 
positive urine pregnancy test needs to be confirmed with a serum hCG test. If confirmed, the 
participant must be discontinued from study treatment and the pregnancy reported to Novartis 
within 24 hour (see Section 10.1.4).
Local pregnancy test and associated results will not be collected on eCRF.
Assessment of fertility: 
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child-
bearing potential must also be available as source documentation in the following cases:
1. Surgical bilateral oophorectomy without a hysterectomy
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile.
In the absence of the above medical documentation, FSH testing is required of any female 
participant regardless of reported reproductive/menopausal status at screening/baseline.
8.5
Additional assessments
8.5.1
Pharmacokinetics
Immunogenicity (IG) samples will be collected along with pre-dose (Ctrough) pharmacokinetic 
(PK) samples at the visits defined in the assessment schedule (Table 8-1). PK data is collected 
to support the evaluation of IG results.
 
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Follow instructions outlined in the [CSEG101A2403 Laboratory Manual] regarding sample 
collection, numbering, processing and shipment.
The number of samples/blood draws collected will not exceed those stated in the protocol.
8.5.1.1
Pharmacokinetics and Immunogenicity blood collection and handling
At specified time points described in Table 8-5, blood samples will be taken by either direct 
venipuncture or through an indwelling cannula or port.
Each serum sample should be labeled with the appropriate study, center, and participant 
numbers, as well as the sequential PK/IG samples and PK/IG collection number with a unique 
sample number. The actual collection date and time of each sample will be entered on the PK/IG 
blood collection eCRF pages.
Refer to the [CSEG101A2403 Laboratory Manual] for detailed instructions for the collection, 
handling, and shipment of IG and PK samples.
Table 8-5
Pharmacokinetic and Immunogenicity blood collection log
Week / Day 
Scheduled 
Time Point
Dose 
reference ID
PK Sample 
No
IG Sample 
No
Sample 
Volume 
Week 1 Day 1
Pre-dose
1
1
101
5.0 mL
Week 3 Day 1
Pre-dose
2
2
102
5.0 mL
Week 15 Day 1
Pre-dose
3
3
103
5.0 mL
Week 27 Day 1
Pre-dose
4
4
104
5.0 mL
Week 39 Day 1
Pre-dose
5
5
105
5.0 mL
Week 51 Day 1
Pre-dose
6
6
106
5.0 mL
Safety Follow Upa
-
601
7
107
5.0 mL
Unscheduledb
-
-
1001+
2001+
5.0 mL
Total
35 mL
Pre-dose is within 24 hours before dose administration
a the actual date and time of administration of the previous dose of study medication should also be 
recorded with Dose Reference ID 1 for 601
b unscheduled samples may be obtained as appropriate to support safety assessment
8.5.2
Sickle cell  VOC event
VOC is defined as a pain crisis (acute onset of pain for which there is no other medically 
determined explanation other than vaso-occlusion) which requires therapy with oral or 
parenteral opioids or parenteral NSAID. Acute chest syndrome (ACS), priapism and hepatic or 
splenic sequestration and as per investigator's discretion will be considered VOC in this study.
Only VOC leading to healthcare visit will be collected and this is defined as a VOC with any 
visit to a medical facility such as an emergency room, hospital and/or office visit, which 
includes pain management of that VOC in situ.
VOCs occurring within 7 days following the documented resolution of a crisis event will be 
counted as part of the prior crisis, and the date for end of VOC will subsequently be revised.
 
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In certain cases, due to the anatomic location and/or characteristics of the event, the investigator 
may consider it as new VOC, in which case it will be reported as separate event in the eCRF.
Associated conditions in SCD (e.g., intermittent or chronic pain due to ankle/leg ulcers, aseptic 
necrosis of bone or gout) should not be considered a VOC event. Similarly, complications such 
as pulmonary, cardiac, or renal failure are not themselves to be considered crises. If such events 
precipitate VOC, the event will be documented separately.
For each visit to a medical facility for a pain episode thought to be a VOC, the following 
information must be documented in the eCRF: diagnostic evaluation for the episode, participant 
treatment, duration of the crisis, and outcome. For participants who are treated at medical 
facilities other than the study site, summary documents will need to be obtained.
If a participant experiences a VOC surrounding a protocol-scheduled visit day, and the 
participant presents for this visit, it will be counted as a VOC that led to a healthcare visit 
(provided the event meets the criteria for VOC discussed above).
During COVID-19 pandemic, if a participant experiences a VOC and other subtypes of VOC 
event such as hepatic/splenic, priapism and especially acute chest syndrome, testing for 
COVID-19 is recommended as per local guidance/practice.
9
Study discontinuation and completion
9.1
Discontinuation and completion
9.1.1
Study treatment discontinuation and study discontinuation
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of study 
treatment and record this information.
Participants who discontinue study treatment or who decide they do not wish to participate in 
the study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see withdraw of informed consent section). When possible, they should return 
for the follow up visit. If they fail to return for the follow up visit for unknown reasons, every 
effort (e.g. telephone, e-mail, letter) should be made to contact the participant/pre-designated 
contact as specified in the lost to follow-up section. This contact should preferably be done 
according to the study visit schedule.
The investigator must discontinue study treatment for a given participant if he/she believes that 
continuation would be detrimental to the participant’s well-being.
In addition to mandatory discontinuation reasons for study treatment listed in 
Section 6.5section_6_5_1, study treatment must also be discontinued under the following 
circumstances:

Pregnancy

Lactation

Participant/Guardian decision

Unsatisfactory therapeutic effect as per Investigator decision
 
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
Grade 4 AE and dose interruptions of investigational treatment due to toxicity (see 
Section 6.5section_6_5_1)

Use of prohibited medication (see Section 6.2.2)

Any situation in which study participation might result in a safety risk to the participant
Following the treatment discontinuation, participants will perform an End of Treatment visit. 
Permanent treatment discontinuation is mandatory for specific events indicated as indicated in 
Table 6-2. All participants must be followed up for adverse events and serious adverse events 
for 105 days following the last dose of crizanlizumab.
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment.
9.1.2
Withdrawal of informed consent
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant:

Does not want to participate in the study anymore,
and

Does not want any further visits or assessments
and

Does not want any further study related contacts
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw his/her consent and 
record this information.
Where consent to the use of personal and coded data is not required, participant therefore cannot 
withdraw consent. They still retain the right to object to the further use of personal data.
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 participant are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study discontinuation. A final 
evaluation at the time of the participant’s study discontinuation should be made as detailed in 
the assessment table.
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation.
9.1.3
Lost to follow-up
For participants 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 participant, e.g. dates of 
 
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telephone calls, registered letters, etc. A participant should not be considered as lost to follow-
up until due diligence has been completed or until the end of the study.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time.
Reasons for early termination could be the following:

Unexpected, significant, or unacceptable safety risk to participants enrolled in the study

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 participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a prematurely withdrawn participant. 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 participant’s interests. The investigator or sponsor depending on 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 participant 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 treated participants should have a safety follow-up visit conducted 105 days (15 weeks) 
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. Documentation of attempts to contact the participant should be recorded in the 
source documentation.
Novartis will make every effort to supply crizanlizumab (SEG101) to participants who may 
benefit from continued treatment as per the Investigator’s opinion; safety will be monitored and 
reported to Health Authorities per regulatory requirements.
10
Safety monitoring and reporting
During the COVID-19 pandemic that limits or prevents on-site study visits regular phone calls 
will occur for safety monitoring and discussion of the participant´s health status until the 
participant can again visit the site. This telephone contact should preferably be done according 
to the study visit schedule, or more frequently if needed.
 
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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 clinical 
investigation participant 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 participant and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments.
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2)
1. The Common Terminology Criteria (CTC) AE grade (version 5). Adverse events will be 
assessed and graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.
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 participant.
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 (not recovered/not resolved, recovered/resolved, recovered/resolved with 
sequelae, recovering/resolving, fatal, unknown)
 
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If the event worsens the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a 
lower grade is determined a new entry for this event should be reported in the CRF noting the 
start date when the event improved from having been Grade 3 or Grade 4.
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 105 days following the last dose of 
study treatment.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (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
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease.
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 participant 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
 
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
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 participant’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 participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above
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 participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
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 (please refer to the ICH-
E2D Guidelines).
All new 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
SAE reporting
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 105 days following the last administration of study 
treatment 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 participant has provided informed consent until the time the participant 
is deemed a Screen Failure must be reported to Novartis.
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 
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.
 
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Follow-up information is submitted in the same way as the original SAE Report and should 
describe whether the event has resolved or continues, if and how it was treated, and whether the 
participant continued or withdrew from study participation
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the 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.
Any SAEs experienced after the 105 day safety follow-up period should only be reported to 
Novartis Safety if the investigator suspects a causal relationship to study treatment.
Section 10.3 describes protocol exempted AEs and SAEs.
10.1.4
Pregnancy reporting
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
trial participant must be asked to read and sign pregnancy consent form to allow the Study 
Doctor ask about her pregnancy. To ensure participant 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.
If the pregnancy results in a live birth, the baby will have regular check-ups and the Study 
Doctor will need to know the outcomes of these check-ups until one year after the baby was 
due to be born.
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 crizanlizumab 
(SEG101) any pregnancy outcome. Any SAE experienced during pregnancy must be reported.
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, participant 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.
 
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Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF 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 within 24 hours of 
Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
CRF (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 and SAE definition and reporting requirements, please see the 
respective sections (Section 10.1.1 and Section 10.1.2).
10.2
Additional Safety Monitoring
10.2.1
Liver safety monitoring
Refer to Section 6.5.2.1 Follow-up on potential drug-induced liver injury (DILI) cases.
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF.
10.2.2
Renal safety monitoring
Not applicable.
10.3
Protocol Exempt AEs & SAEs
Protocol Exempt AEs & SAEs are implemented in the SEG101 program. VOCs must be 
reported on the VOC page in the eCRF. AEs and SAEs involving VOCs SHOULD NOT be 
reported as AEs or SAEs for the purpose of this study. These events will not be considered as 
SAEs in regards to reporting requirements. Procedures which are directly related to the VOC, 
e.g. ventilation of a participant with acute chest syndrome are considered part of the VOC and 
will not be reported as AE/SAEs but entered in the eCRF-page "concomitant non-drug 
therapies/procedures". Additional events or complications which are not VOCs itself will be 
reported as AE/SAEs. Details will be given in the eCRF-completion guidance.
In case that new information arises which changes the diagnosis of a VOC, i.e. gives another 
medically determined explanation than vaso-occlusion in the opinion of the investigator, the 
event has to be reported according to the rules of Section 10.1 and must be reported to Novartis 
within 24 hours of learning of the new information.
The events in Section 8.5.2 are the VOCs that will not be reported as AEs/SAEs. However, in 
case a VOC event is suspected to be related to study treatment, and/or resulting in a fatal 
outcome, it will be reported also as AE/SAE in addition to the VOC eCRF page.
 
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11
Data Collection and Database management
11.1
Data collection
All data captured for this study will have an external originating source (either written or 
electronic) with the CRF not being considered as source.
Designated investigator staff will enter the data required by the protocol into the 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 Electronic Data 
Capture (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 data by 
the investigator staff.
The investigator/designee is responsible for assuring that the data 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 participant 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 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical (ATC) classification system. Medical history/current medical conditions 
and adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) terminology.
Dates of screenings, enrollment, screen failures and study completion, as well as data about all 
study treatment (s) dispensed to the participant and all dosage changes will be tracked using an 
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.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after that time can only 
be made after written agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource DDE or 
 
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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 participant 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 participant 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 
participant's file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant).
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 
participants will be disclosed.
12
Data analysis and statistical methods
The primary safety analyses will be conducted on all patient data at the time the trial ends (see 
Section 9.2 for the definition of study completion).
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
Full Analysis set:
The Full Analysis Set (FAS) comprises all participants to whom study treatment has been 
assigned and who received at least one dose of study treatment.
Safety Set:
The Safety Set includes all participants who received at least one dose of study treatment. 
12.2
Participant demographics and other baseline characteristics
Demographic and other baseline data will be listed and summarized descriptively for the FAS.
 
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Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. For selected parameters, 
25th and 75th percentiles will also be presented.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term.
The number of VOCs leading to healthcare visit will be summarized descriptively.
12.3
Treatments
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented.
The duration of exposure in weeks to crizanlizumab as well as the dose intensity (computed as 
the ratio of actual cumulative dose received and actual duration of exposure) and the relative 
dose intensity (computed as the ratio of dose intensity and planned dose intensity) will be 
summarized by means of descriptive statistics using the safety set.
The 
number 
of 
participants 
with 
dose 
adjustments (interruption, 
or 
permanent 
discontinuation) and the reasons will be summarized and all dosing data will be listed.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the ATC classification system.
12.4
Analysis of the primary endpoint(s)/estimand(s)
12.4.1
Definition of primary endpoint(s)/estimand(s)
The primary endpoint is the frequency, severity and causality of SAEs over the treatment period.
12.4.2
Statistical model, hypothesis, and method of analysis
The number and proportion of patients with at least one SAE will be presented along with the 
2-sided 95% confidence interval (CI). SAEs will be summarized by number and percentage of 
participants having at least one SAE in each primary system organ class (SOC) and for each 
preferred term. SAE's will be summarized by relationship, leading to treatment discontinuation, 
leading to dose interruption and leading to fatal outcome.
12.5
Analysis of secondary endpoints/estimands
The secondary endpoint is the frequency, severity and causality of AEs as well as the assessment 
of labs, vital signs, ECGs and immunogenicity.
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
Not applicable.
 
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12.5.2
Safety endpoints
Safety assessments will consist of monitoring and recording all AEs, based on CTCAE v5.0. It 
will also include regular monitoring of laboratory assessments including hematology and 
clinical chemistry, urinalysis, coagulation, measurement of vital signs, ECG evaluation and 
physical examination.
For all safety analyses, the safety set will be used.
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 addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. 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).
The overall observation period will be divided into three mutually exclusive segments:
1. Pre-treatment period: from day of participant’s informed consent to the day before first 
dose of study medication
2. On-treatment period: from day of first dose of study medication to 105 days after last dose 
of study medication
3. Post-treatment period: starting at day 105+1 after last dose of study medication
Adverse events
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs.
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment.
Serious adverse events, non-serious adverse events and adverse events of special 
interest (AESI) during the on-treatment period will be tabulated.
All deaths (on-treatment and post-treatment) will be summarized.
All AEs, deaths, and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged.
Clinical laboratory evaluations
Grading of laboratory values will be assigned programmatically as per NCI CTCAE
version 5.0. The calculation of CTCAE grades will be based on the observed laboratory values 
only, clinical assessments will not be taken into account.
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used.
For laboratory tests where grades are not defined by CTCAE version 5.0, results will be 
categorized as low/normal/high based on laboratory normal ranges.
 
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The following listings/summaries will be generated separately for hematology, biochemistry, 
urinalysis (macroscopic only), coagulation tests:

Listing of all laboratory data with values flagged to show the corresponding 
CTCAE version 5.0 grades if applicable and the classifications relative to the laboratory 
normal ranges
For laboratory tests where grades are defined by CTCAE version 5.0:

Worst post-baseline CTCAE grade (regardless of the baseline status). Each participant 
will be counted only once for the worst grade observed post-baseline.

Shift tables using CTCAE version 5.0 grades to compare baseline to the worst on-
treatment value
For laboratory tests where grades are not defined by CTCAE version 5.0:

Shift tables using the low/normal/high/ (low and high)classification to compare baseline to 
the worst on-treatment value.
In addition to the above mentioned tables and listings, other exploratory analyses, for example, 
figures plotting time course of raw or change in laboratory tests over time or box plots might 
be specified in the analysis plan.
Specific analyses to assess the impact of the liver function tests will be performed and described 
in the analysis plan.
Vital signs
All vital signs data will be listed by patient and visit/time and if ranges are available, 
abnormalities will be flagged. Summary statistics will be provided by treatment and visit/time.
12-Lead ECG
12-lead ECGs including PR, QRS, QT, QTcF, and RR intervals will be obtained from 12-lead 
ECGs for each patient during the study. ECG data will be read and interpreted locally.
All ECG data will be listed by patient and visit/time, abnormalities will be flagged. Summary 
statistics will be provided by treatment and visit/time.
Immunogenicity and Pharmacokinetics
All immunogenicity results and pre-dose PK will be listed by participant and visit/time.
12.6
Analysis of exploratory endpoints
Not applicable.
12.7
Interim analyses
No interim analysis is planned for this trial.
 
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12.8
Sample size calculation
12.8.1
Primary endpoint(s)
This is a descriptive study and no hypothesis testing will be conducted. However the primary 
endpoint which is the proportion of patients reporting an SAE over the treatment period, will 
be presented with a 2-sided 95% CI.
In the SUSTAIN study ([CSEG101A2201]), the proportion of patients reporting at least one 
SAE over the treatment period on Crizanlizumab 5mg/kg was 26%.
Assuming the percentage of patients with at least one serious adverse event in this study in India 
should be approximately in the range of values previously observed, the half width of the 
confidence interval is calculated for potential observed proportions of 15, 25 and 35%.
With a sample size of 140 patients, the half-width of the confidence interval would vary from 
+/-5.9 to +/-7.9 if the proportion of patients with SAEs remains between 15 and 35%. This 
precision is considered appropriate to estimate with enough reliably the safety profile of 
crizanlizumab in India. The sample size calculation is done in EAST version 6.4.
Table 12-1
Confidence intervals (95%) for different proportions of SAE
Sample Size
Assumed 
proportion of SAE
Half width of 95% 
2-sided CI
Lower 95% 2-
sided CI
Upper 95% 2-
sided CI
140
0.15
0.059
0.091
0.209
140
0.25
0.072
0.178
0.322
140
0.35
0.079
0.271
0.429
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, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to patients. Prior to study start, 
the investigator is required to sign a protocol signature page confirming his/her agreement to 
conduct the study in accordance with these documents and all of the instructions and procedures 
found in this protocol and to give access to all relevant data and records to Novartis monitors, 
auditors, Novartis Quality Assurance representatives, designated agents of Novartis, IRBs/IECs, 
and regulatory authorities as required. If an inspection of the clinical site is requested by a 
 
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Clinical Trial Protocol (Version No. 00)
Protocol No. CSEG101A2403
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 patient 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 participants 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 participant 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 participant 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
References
References are available upon request.
(2012) Droxia-USPI p. 33. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/016295s041s042lbl.pdf.
(2017) Sicklos-USPI p. 25. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208843s000lbl.pdf.
Ballas SK, Bauserman RL, McCarthy WF, et al (2010) Hydroxyurea and acute painful crises 
in sickle cell anemia: effects on hospital length of stay and opioid utilization during 
hospitalization, outpatient acute care contacts, and at home. J Pain Symptom Manage; 
40(6)870-82.
Bender, MA (1993) Sickle Cell Disease.
Brandow AM, Carroll CP, Creary S, et al (2020) American Society of Hematology 2020 
guidelines for sickle cell disease: management of acute and chronic pain. Blood Adv; 4(12) 
2656-701.
Brousseau DC, Owens PL, Mosso AL, et al (2010) Acute care utilization and 
rehospitalizations for sickle cell disease. JAMA; 303(13):1288-94.
Charache S, Terrin ML, Moore RD, et al (1995) Effect of hydroxyurea on the frequency of 
painful crises in sickle cell anemia. N Engl J Med; 332(20):1317-22.
Gill FM, Sleeper LA, Weiner SJ, et al (1995) Clinical events in the first decade in a cohort of 
infants with sickle cell disease. Blood; 86(2):776-83.
Hockham C, Bhatt S, Colah R, et al (2018) The spatial epidemiology of sickle-cell anaemia in 
India. Sci Rep; 8:17685.
Kanter J, Kruse-Jarres R (2013) Management of sickle cell disease from childhood through 
adulthood. Blood Rev; 27:279-87.
Kauf TL, Coates TD, Huazhi L, et al (2009) The cost of health care for children and adults 
with sickle cell disease. Am. J. Hematol; 84:323-7.
Matsui NM, Borsig L, Rosen SD, et al (2001) P-selectin mediates the adhesion of sickle 
erythrocytes to the endothelium. Blood; 98(6):1955-62.
McEver RP (2004) Interactions of selectins with PSGL-1 and other ligands. Ernst Schering 
Res. Found. Workshop p. 137-47.
Mehta P, Cummings RD, McEver RP (1998) Affinity and kinetic analysis of P-selectin 
binding to P-selectin glycoprotein ligand-1 J Biol Chem; 273(49):32506-13.
Nietert PJ, Silverstein MD, Abboud MR (2002) Sickle cell anaemia: epidemiology and cost of 
illness. Pharmacoeconomics; 20(6):357-66.
 
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Powars DR, Chan LS, Hiti A, et al (2005) Outcome of sickle cell anemia: a 4-decade 
observational study of 1056 patients. Medicine; 84:363-76.
Pászty C, Brion CM, Manci E, et al (1997) Transgenic knockout mice with exclusively human 
sickle hemoglobin and sickle cell disease. Science; 278:876-8.
Rees DC, Williams TN, Gladwin MT (2010) Sickle-cell disease. Lancet; 376:2018-31.
Saxena D, Yasobant S, Golechha M (2017) Situational Analysis of Sickle Cell Disease in 
Gujarat, India. Indian J Community Med; 42(4):218-21
Ware RE, de Montalembert M, Tshilolo L, et al (2017) Sickle cell disease. Lancet; 390:311-
23.
 
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16
Appendices
Not applicable.
 
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SAP_001.pdf: 




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Document History – Changes compared to previous final version of SAP 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
11-
Mar-
2021 
Prior 
to 
FPFV 
N/A - First version 
NA 
22-
Feb-
2024 
Prior 
to 
DBL 
Summary table was added to the 
description of planned analyses 
Section 2.8.4.3 
The analyses for PK were added to the 
section 
Section 2.10 
Imputation rules for end dates were 
updated 
Section 5.1.2 
Title of Table 5-1 was updated to 
reflect the fact that assessment dates 
for LB, EG, VS should not be imputed 
Imputation logic for time (AE only) was 
added 
Appendix, Table 
5-1
Details on which laboratory data will 
be displayed in the outputs were added 
Section 2.8.3 
Details on which baseline laboratory 
data will be displayed in the outputs 
were added 
Section 2.1.1 
The mentioned CTC grading document 
has been changed to the latest version 
Section 5.3 
CTC grading document has been 
updated to the latest version 
Reference 
20-
May-
2024 
After 
DBL 
Typo is corrected 
Section 2.4.1 


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Table of contents 
Table of contents ................................................................................................................. 3 
1 
Introduction ......................................................................................................................... 6 
1.1 
Study design............................................................................................................. 6 
1.2 
Study objectives and endpoints ............................................................................... 6 
2 
Statistical methods ............................................................................................................... 7 
2.1 
Data analysis general information ........................................................................... 7 
2.1.1 
General definitions .................................................................................. 8 
2.2 
Analysis sets .......................................................................................................... 10 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 10 
2.3.1 
Patient disposition ................................................................................. 10 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 11 
2.4.1 
Study treatment / compliance ................................................................ 11 
2.4.2 
Prior, concomitant and post therapies ................................................... 13 
2.5 
Analysis of the primary objective .......................................................................... 13 
2.5.1 
Primary endpoint ................................................................................... 14 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 14 
2.5.3 
Handling of missing values/ discontinuations....................................... 14 
2.6 
Analysis of the key secondary objective ............................................................... 14 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 14 
2.8 
Safety analyses ....................................................................................................... 14 
2.8.1 
Adverse events (AEs) ............................................................................ 14 
2.8.2 
Deaths .................................................................................................... 15 
2.8.3 
Laboratory data ..................................................................................... 15 
2.8.4 
Other safety data ................................................................................... 17 
2.9 
Pharmacokinetic endpoints .................................................................................... 20 
2.10 
PD and PK/PD analyses......................................................................................... 20 
2.11 
Patient-reported outcomes ..................................................................................... 20 
2.12 
Biomarkers ............................................................................................................. 20 
2.13 
Other Exploratory analyses .................................................................................... 20 
2.14 
Interim analysis ...................................................................................................... 20 
3 
Sample size calculation ..................................................................................................... 20 
3.1 
Primary analysis ..................................................................................................... 20 
4 
Change to protocol specified analyses .............................................................................. 21 
5 
Appendix ........................................................................................................................... 21 


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5.1 
Imputation rules ..................................................................................................... 21 
5.1.1 
Study drug ............................................................................................. 21 
5.1.2 
AE, ConMeds and safety assessment date imputation .......................... 21 
5.2 
AEs coding/grading ............................................................................................... 23 
5.3 
Laboratory parameters derivations ........................................................................ 23 
6 
Reference ........................................................................................................................... 24 


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List of abbreviations 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Classification 
CSR 
Clinical Study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
DAR 
Dose administration record 
DBILI 
Direct bilirubin 
DI 
Dose intensity 
DILI 
Drug induced liver injury 
DRL 
Drug Reference  Listing 
EOS 
End of study 
FAS 
Full Analysis Set 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
HGLT 
High level group terms 
HLT 
High level terms 
HU/HC 
Hydroxyurea/Hydroxycarbamide 
i.v 
intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
NMQ 
Novartis MedDRA queries 
PK 
Pharmacokinetics 
PT 
Preferred Term 
RDI 
Relative dose intensity 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SCD 
Sickle cell disease 
SD 
Standard deviation 
SMQ 
Standardized MedDRA Queries 
SOC 
System Organ Class 
TBL 
Total bilirubin 
ULN 
Upper limit of normal 
VOC 
Vaso-occulsive crisis 
WHO 
World Health Organization 


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1 
Introduction 
This statistical analysis plan (SAP) describes all planned analyses for the Clinical Study Report 
(CSR) of study CSEG101A2403, a phase IV, open label safety study in sickle cell disease 
(SCD) subjects with vaso-occulsive crisis (VOC). 
The content of this SAP is based on protocol CSEG101A2403 v00. All decisions regarding 
final analysis, as defined in the SAP document, have been made prior to database lock of the 
study data. 
1.1 
Study design 
This is a Phase IV open label, single-arm, interventional, multicenter study to evaluate safety 
of crizanlizumab at a dose of 5.0 mg/kg in addition to standard of care in Indian patients with 
SCD and a history of VOC leading to healthcare visit. 
 
The study will include 140 participants aged 16 years and older with confirmed diagnosis of 
SCD (all genotypes are eligible) who have had a history of VOC leading to a healthcare visit 
prior to screening visit. Participants may receive HU/HC, L-glutamine (Endari™) or 
erythropoietin-stimulating agents as treatment/concomitant medication for SCD before and 
during the study. 
 
Participants will receive crizanlizumab 5.0 mg/kg via intravenous (i.v.) infusion on Week 1 
Day 1, followed by a second dose 14 days later (Week 3 Day 1), and then every 4 weeks. 
Participants will receive crizanlizumab for approximately 12 months (until week 51) in the 
trial or until unacceptable toxicity, death, are lost to follow-up or discontinued from 
crizanlizumab for any other reasons at the discretion of the investigator or the participant.  
 
Following study treatment discontinuation, participants will perform an end of treatment visit. 
After the end of treatment visit, all participants will be followed up for safety up to 105 days 
(15 weeks) after the last infusion of investigational study drug. 
 
The end of the study (EOS) will occur when all the patients have either completed or 
discontinued the study treatment and/or the 105 days follow-up period.  
1.2 
Study objectives and endpoints 
Objective 
Endpoint 
Analysis 
Primary 
 
Refer to Section 2.5 
To assess the serious adverse 
events (SAEs) of crizanlizumab 
in Indian patients with SCD 
Frequency, severity and causality of 
SAEs during the treatment period 
 
Secondary 
 
 
To assess the overall safety 
and tolerability of crizanlizumab 
in Indian patients with SCD 
Frequency, severity and causality of 
treatment emergent adverse events 
(including Adverse Events of Special 
Interest (AESI)), as well as labs, vital 
signs, ECGs and immunogenicity 
 
Refer to Section 2.7 


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2 
Statistical methods 
2.1 
Data analysis general information 
All analysis will be performed by Novartis and/or a designated CRO. SAS version 9.4 or later 
software will be used to perform all data analyses and to generate tables, figures and listings. 
Data included in the analysis 
All statistical analyses will be performed using all data collected in the database. All data with 
an assessment date or event start date (e.g. vital sign assessment date or start date of an adverse 
event) will be included in the analysis. Any data collected beyond the cut-off date will not be 
included in the analysis and will not be used for any derivations. 
General analysis conventions 
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small number of patients enrolled at each center, no center effect 
will be assessed.  
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency 
tables; a missing category will be included as applicable. Percentages will be calculated using 
the number of patients in the relevant population or subgroup as the denominator. 
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate 
descriptive statistics (i.e. mean, standard deviation, median, minimum, and maximum). 
For PK parameters, CV%, geometric mean, and geometric CV% will be presented in addition 
to the previously mentioned summary statistics. 
Coefficient of variation (CV) (%) is calculated as follows:  
100*(Standard deviation (SD)/arithmetic mean). 
Geometric CV (%) is calculated as follows: 
sqrt (exp (variance for log transformed data)-1)*100. 
Unscheduled assessments 
The following points summarize the rules for unscheduled assessments: 
• Baseline: All unscheduled assessments before the first dose should be included for 
consideration when calculating the baseline value.   
• In summary tables by visit, unscheduled assessments should not be included unless they 
qualify as baseline. 
• In shift and abnormality tables, all unscheduled assessments are included. 
Unscheduled assessments will be reported with the scheduled assessments in the listings. 


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2.1.1 
General definitions  
Investigational drug and study treatment 
Both investigational drug and study treatment refer to crizanlizumab. The term investigational 
treatment may also be referred to as study treatment which is used throughout this document.   
Date of first administration of investigational drug 
The date of first administration of investigational drug is defined as the first date when a non-
zero dose of investigational drug is administered and recorded on the Dosage Administration 
Record (DAR) (e)CRF. The date of first administration of study drug will also be referred as 
start of investigational drug. 
Date of last administration of investigational drug 
The date of last administration of investigational drug is defined as is the last date when a 
nonzero dose of investigational drug is administered and recorded on DAR eCRF. The date of 
last administration of investigational drug will also be referred as end of investigational drug. 
Date of first administration of study treatment  
The date of first administration of study treatment is derived as the first date when a nonzero 
dose of study treatment was administered as per the DAR CRF. The date of first administration 
of study treatment will also be referred as start of study treatment. 
The date of first administration of study treatment is the same as the date of first administration 
of investigational drug.   
Date of last administration of study treatment  
The date of last administration of study treatment is defined as the last date when a nonzero 
dose of study treatment was administered as per DAR (e)CRF.  
The date of last administration of study treatment is the same as the date of last administration 
of investigational drug.  
Study day 
The study day, describes the day of the event or assessment date, relative to the reference start 
date.  
The study day is defined as: 
 •   The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date + 1 if event is on or after the reference start date; 
• The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date if event precedes the reference start date. 
The reference date for all assessments (safety, PK etc) is the start of study treatment.  


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Time unit 
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration 
is reported in months, duration in days will be divided by 30.4375.  If duration is  reported in 
years, duration in days will be divided by 365.25. 
Baseline 
For safety evaluations, the last available assessment on or before the date of start of study 
treatment is defined as “baseline” assessment.  
In case time of assessment and time of treatment start is captured (e.g. pre-dose ECG), the last 
available assessment before the treatment start date/time is used for baseline.  
For safety parameters (e.g ECGs or vital signs), where study requires multiple replicates per 
time point, the average of theses measurements would be calculated for baseline (if not already 
available in the database). 
For those lab parameters collected only in the local laboratories as per protocol, the last 
available assessment on or before the start date of study treatment from the local laboratories 
will be considered as baseline in the tables and figures.  
For all other lab parameters, the last available assessment on or before the start date of study 
treatment from the central laboratories will be considered as baseline in the tables and figures. 
If patients have no value as defined above, the baseline result will be missing in the tables and 
figures.  
Listings will display all available baseline patient data, regardless if they were collected from 
local or central laboratories.  
On-treatment assessment/event and observation periods  
For adverse event reporting the overall observation period will be divided into three mutually 
exclusive segments:  
1. pre-treatment period: from day of patient’s informed consent to the day/time before 
first administration of study treatment 
2. on-treatment period: from date/time of first administration of study treatment to 105 
days after date of last actual administration of any study treatment included 
3. post-treatment period: starting at day 106 after last administration of study treatment. 
Notes: 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.    
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 addition, a separate summary for death including on treatment and post 
treatment deaths will be provided.  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).   


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However, all safety data (including those from the post-treatment period) will be listed and 
those collected during the pre-treatment and post-treatment period will be flagged. 
2.2 
Analysis sets 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned 
and who received one dose of study treatment.  
Safety Set 
The Safety Set includes all participants who received at least one dose of study treatment. 
Withdrawal of Informed Consent 
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis.  The date on which a patient 
withdraws full consent is recorded in the eCRF.   
2.3 
Patient disposition, demographics and other baseline 
characteristics 
The Full Analysis Set (FAS) will be used for all baseline and demographic summaries and 
listings unless otherwise specified.  
Basic demographic and background data 
All demographic and baseline disease characteristics data will be summarized and listed. 
Categorical data (e.g. gender, race, ethnicity) will be summarized by frequency counts and 
percentages; the number and percentage of patients with missing data will be provided. 
Continuous data (e.g. age, weight, height) will be summarized by descriptive statistics (N, 
mean, median, standard deviation, minimum and maximum).   
Medical history 
Medical history and ongoing conditions entered on (e)CRF will be summarized and listed. The 
summaries will be presented by primary system organ class (SOC) and preferred term (PT). 
Medical history and current medical conditions will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) terminology. The MedDRA version used for reporting will 
be specified in the CSR and as a footnote in the applicable tables/listings. 
Other 
All data collected at baseline will be listed. 
2.3.1 
Patient disposition 
Enrollment by center will be summarized for all screened patients using the FAS. The number 
(%) of enrolled patients included in the FAS will be presented. The number (%) of screened 
and not-treated patients and the reasons for screening failure will also be displayed. The number 


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(%) of patients in the FAS who are still on treatment, who discontinued the study phases and 
the reason for discontinuation will be presented. 
The following summaries will be provided (with % based on the total number of FAS patients): 
• Number (%) of patients who are still on-treatment (based on the ‘Treatment 
Disposition’ page not completed);  
• Number (%) of patients who discontinued the study treatment phase (based on the 
‘Treatment Disposition’ page)  
• Primary reason for study treatment phase discontinuation (based on the ‘Treatment 
Disposition’ page) 
• Number (%) of patients who have entered the post-treatment follow-up (based on 
the ‘Treatment Disposition’ page); 
• Number (%) of patients who have discontinued from the post-treatment follow-up 
(based on the Post-treatment follow-up Disposition page); 
• Reasons for discontinuation from the post-treatment follow-up (based on Post-
treatment follow-up Disposition page); 
In addition, disposition of patients with their relationship to the COVID-19 status will be 
summarized. 
Protocol deviations 
The number (%) of patients in the FAS with any protocol deviation will be tabulated by 
deviation category (as specified in the study edit checks specification) for the FAS. In addition, 
COVID-19 related protocol deviations and issues with potential impact on quality will be 
summarized. 
All protocol deviations will be listed. 
Analysis sets 
The number (%) of patients in each analysis set (defined in Section 2.2) will be summarized. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
Duration of exposure, actual cumulative dose, dose intensity (DI) and relative dose intensity 
(RDI) will be summarized. Duration of exposure will be categorized into time intervals; 
frequency counts and percentages will be presented for the number (%) of subjects in each 
interval. The number (%) of subjects who have dose reductions or interruptions, and the reasons, 
will be summarized.  
Subject level listings of all doses administered on treatment along with dose change reasons 
will be produced.   
The safety set will be used for all summaries and listings of study treatment.  


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Duration of exposure to study treatment 
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to the investigational drug: 
Duration of exposure to study treatment (weeks) = ((last date of exposure to study treatment) – 
(date of first administration of study treatment) + 1)/7.  
The last date of exposure to study treatment is the earliest of the last date of treatment + 27 
days, the date of death (if the participant died). 
Summary of duration of exposure of study treatment in appropriate time units will include 
categorical summaries and continuous summaries (i.e. mean, standard deviation etc.) using 
appropriate units of time. 
Cumulative dose 
Cumulative dose of a study treatment is defined as the total dose given during the study 
treatment exposure and will be summarized.  
The planned cumulative dose for a study treatment component refers to the total planned dose 
as per the protocol up to the last date of investigational drug administration.  
The actual cumulative dose  refers to the total actual dose administered, over the duration for 
which the subject is on the study treatment as documented in the Dose Administration eCRF.  
For patients who did not take any drug the cumulative dose is by definition equal to zero. 
Dose intensity and relative dose intensity 
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows:  
DI (mg/kg/28days) = (Actual Cumulative dose (mg/kg) / Duration of exposure to study 
treatment (weeks))*4. 
For patients who did not take any drug the DI is by definition equal to zero.  
Planned dose intensity (PDI) is defined as follows: 
PDI (mg/kg/28days) = (Planned Cumulative dose (mg/kg) / Duration of exposure (weeks))*4. 
Relative dose intensity (RDI) is defined as follows: 
RDI = DI (mg/kg/28days)  / PDI (mg/kg).   
DI and RDI will be summarized. 
Dose reductions, interruptions 
The number of subjects who have dose reductions or interruptions, and the reasons, will be 
summarized. In addition, their relationship to the COVID-19 status will be summarized. 
‘Dose change’, and ‘Dose interrupted’ fields from the Dosage Administration CRF pages 
(DAR) will be used to determine the dose change and dose interruptions respectively. 


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The corresponding fields ‘Reason for dose change/dose interrupted’ will be used to summarize 
the reasons. 
A dose change is either ‘partial dose administered’  or ‘dosing error’ where actual dose 
administered/total daily dose is different from the prescribed dose. 
Reduction: A dose change where the actual dose administered is lower than the calculated dose 
amount based on the prescribed dose. Therefore any dose change to correct a dosing error will 
not be considered a dose reduction.  Only dose change is collected in the CRF, number of 
reductions will be derived programmatically  based on the change and the  direction of the 
change. 
Interruption: A dose interruption occurred when a dose could not be administered within 7 
days of the scheduled day of infusion, as per protocol. If a dose was temporarily stopped during 
infusion, it should not be considered as a dose interruption. Duration of a dose interruption is 
calculated as the time between the scheduled date of infusion and the actual date of infusion 
after the interruption. 
2.4.2 
Prior, concomitant and post therapies 
Concomitant medications 
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a patient coinciding with the study treatment 
period. Concomitant therapy include medications (other than study drugs) starting on or after 
the start date of study treatment or medications starting prior to the start date of study treatment 
and continuing after the start date of study treatment.  
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Reference Listing (DRL) dictionary that employs the WHO Anatomical Therapeutic Chemical 
(ATC) classification system and summarized by lowest ATC class and preferred term using 
frequency counts and percentages. Surgical and medical procedures will be coded using 
MedDRA and summarized by SOC and preferred term. These summaries will include: 
1. Medications starting on or after the start of study  treatment but no later than 105 days 
after start of last dose of study  treatment and 
2. Medications starting prior to start of study treatment and continuing after the start of 
study treatment. 
All concomitant therapies will be listed. Any concomitant therapies starting and ending prior 
to the start of study treatment or starting more than 105 days after the last date of study 
treatment will be flagged in the listing. The safety set will be used for all concomitant 
medication tables and listings. 
2.5 
Analysis of the primary objective 
The primary objective is to assess the serious adverse events (SAEs) of crizanlizumab in 
Indian patients with SCD. 


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2.5.1 
Primary endpoint 
The primary end point is the frequency, severity and causality of SAEs during the treatment 
period. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
The number and proportion of patients with at least one SAE will be presented along with the 
2-sided 95% confidence interval (CI). SAEs will be summarized by number and percentage of 
participants having at least one SAE in each primary system organ class (SOC) and for each 
preferred term. SAE's will be summarized by relationship, leading to treatment 
discontinuation, leading to dose interruption and leading to fatal outcome. 
2.5.3 
Handling of missing values/ discontinuations 
Not applicable. 
2.6 
Analysis of the key secondary objective 
Not applicable 
2.7 
Analysis of secondary efficacy objective(s) 
Not applicable 
2.8 
Safety analyses 
All safety analyses will be based on the Safety set unless otherwise specified. Safety summaries 
include only on-treatment assessments; safety listings include all assessments with those more 
than 105 days after last study treatment flagged. 
2.8.1 
Adverse events (AEs) 
AE summaries will include all AEs occurring during on treatment period. All AEs collected in 
the AE (e)CRF page will be listed along with the information collected on those AEs e.g. AE 
relationship to study drug, AE outcome etc. AEs with start date outside of on-treatment period 
will be flagged in the listings. 
AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT) 
using MedDRA coding. A subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event. 
AE with missing CTCAE grade will be included in the ‘All grades’ column of the summary 
tables. 
In AE summaries, the primary system organ class will be presented alphabetically and the PTs 
will be sorted within primary SOC in descending frequency. The sort order for the PT will be 
based on their frequency. 
The following AE summaries will be produced: overview of AEs and deaths, AEs by SOC and 
PT, summarized by relationship, seriousness, leading to treatment discontinuation, leading to 


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dose interruption/adjustment and leading to fatal outcome. In addition, a summary of  SAEs 
with number of occurrences will be produced (an occurrence is defined as >1 day between start 
and prior end date of record of same preferred term).   
Adverse events identified in the Novartis MedDRA Query (NMQ) topic of “COVID-19 
diagnosis, manifestations, risks and complications including death” will be summarized and 
listed. Summaries for these AEs will be provided by different classification levels defined 
within this topic COVID-19 topic, as well as by PT within each level. 
2.8.1.1 
Adverse events of special interest / grouping of AEs 
Data analysis of AESIs 
An AESI is a grouping of AEs that are of scientific and medical concern specific to compound 
crizanlizumab. These groupings are defined using MedDRA terms, SMQs (standardized 
MedDRA queries), HGLTs (high level group terms), HLT (high level terms) and PTs (preferred 
terms). Customized SMQs (Novartis MedDRA queries, NMQ) may also be used. A NMQ is a 
customized group of search terms which defines a medical concept for which there is no official 
SMQ available or the available SMQ does not completely fit the need. It may include a 
combination of single terms and/or an existing SMQ, narrow or broad. For each specified AESI, 
number and percentage of participants with at least one event of the AESI occurring during on 
treatment period will be summarized. The list of AESI to be taken into account for SEG101 
trials is documented in the eCRS for the project. The most up to date version of the eCRS 
available at the time of a DB lock for an analysis will be used to define on which AESIs the 
analysis will be conducted. 
Summaries of these AESIs will be provided (specifying grade, SAE, relationship, leading to 
treatment discontinuation, leading to dose interruption, hospitalization, death etc.). If sufficient 
number of events occurred, analysis of time to first occurrence will be applied.  
A listing of all grouping levels down to the MedDRA preferred terms used to define each AESI 
will be generated.  
2.8.2 
Deaths 
Separate summaries for on-treatment and all deaths (including post-treatment death)  will be 
produced by treatment arm, SOC and PT.  
All deaths  will be listed, post treatment deaths will be flagged. A separate listing of deaths prior 
to starting treatment will be provided for all screened subjects. 
The death summaries cover subjects from the Safety Set. 
2.8.3 
Laboratory data 
If the data are available from both central and local laboratories, only central lab results will be 
reported in the tables and figures for consistency. For those lab parameters collected only in the 
local laboratories as per protocol, the data from the local laboratories will be reported in the 
tables and figures. Listings will contain all available patient data from both local and central 
laboratories.  


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The summaries will include all assessments available for the lab parameter collected no later 
than 105 days after the last study treatment administration date (see Section 2.1.1). 
The following summaries will be produced for hematology and biochemistry laboratory data 
(by laboratory parameter): 
• Worst post-baseline CTC grade (regardless of the baseline status). Each subject will be 
counted only for the worst grade observed post-baseline. 
• Shift tables using CTC grades to compare baseline to the worst on-treatment  value  
• For laboratory tests where CTC grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment  value. 
The following listings will be produced for the laboratory data: 
• Listings of all laboratory data, with CTC grades and classification relative to the 
laboratory normal range. Lab data collected during the post-treatment period will be 
flagged.   
• Listing of all CTC grade 3 or 4 laboratory toxicities 
Liver function parameters 
Liver function parameters of interest are total bilirubin (TBL), Alanine aminotransferase (ALT), 
Aspartate aminotransferase (AST) and alkaline phosphatase (ALP). The number (%) of 
participants with worst post-baseline values as per Novartis Liver Toxicity guidelines will be 
summarized in addition to the baseline values. 
Shift tables using ALT, AST and TBL will be generated, respectively. Evaluation of drug 
induced serious hepatotoxicity (eDISH) plot will be produced. A similar plot of direct bilirubin 
(DBILI) vs. ALT will also be generated. Individual participant plots will be produced for 
participants with potential severe drug induced liver injury (DILI) as defined below. Individual 
participant reticulocyte count plots, and a plot of PT-INR and albumin over time will also be 
produced for the same participants. A corresponding listing of participants with potential severe 
DILI will be generated. 
The following summaries will be produced based on peak post-baseline values for each 
parameter during on-treatment period (i.e. not necessarily concurrent assessments for 
combinations of parameters): 
• ALT or AST > 3xULN (upper limit of normal) 
• ALT or AST > 5xULN 
• ALT or AST > 8xULN 
• ALT or AST > 10xULN 
• ALT or AST > 20xULN 
• TBL > 2xULN 
• TBL > 3xULN 
• DBILI > 2xULN 


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• DBILI > 3xULN 
For participants with AST and ALT ≤ ULN at baseline: 
• Elevated ALT or AST (*) & TBL > 2xULN 
• Elevated ALT or AST (*) & TBL > 2xULN & ALP < 2xULN  (potential Hy’s law) 
• Elevated ALT or AST (*) & TBL > 2xULN & ALP ≥ 2xULN 
• Elevated ALT (*) & DBILI  > 2xULN & ALP < 2xULN (potential severe DILI)    
For participants with AST or ALT > ULN at baseline (Bsl): 
• Elevated ALT or AST (*) & TBL (> 2xBsl and 2xULN) 
• Elevated ALT or AST (*) & TBL (> 2xBsl and 2xULN) & ALP < 2xULN  (potential 
Hy’s law) 
• Elevated ALT or AST (*) & TBL (> 2xBsl and 2xULN) & ALP ≥ 2xULN 
• Elevated ALT (*) & DBILI (> 2x Bsl and 2xULN) & ALP < 2xULN (potential severe 
DILI)       
(*) Elevated ALT or AST is defined as: >3xULN if ≤ ULN at baseline, or (> 3xBsl or 8xULN) 
if > ULN at baseline. 
Other Laboratory parameters 
Hematuria (defined as urinalysis RBC of 6-8/HPF or more), glycosuria (defined as urine 
glucose of 1+ or more), and proteinuria (defined as urine protein of 1+ or more) will be 
evaluated using shift tables to compare baseline to the worst on-treatment  value. 
2.8.4 
Other safety data 
2.8.4.1 
ECG  
Data handling 
In case the study requires ECG replicates at any assessment, the average of the ECG parameters 
at that assessment should be used in the analyses. 
Data analysis 
12-lead ECGs including PR, QRS, QT, QTcF, RR and HR intervals will be obtained locally for 
each subject during the study. ECG data will be read and interpreted locally.  
The number and percentage of subjects with notable ECG values will be presented.  
• QT, QTcF 
- 
New value of > 450 and ≤ 480 ms 
- 
New value of > 480 and ≤ 500 ms 
- 
New value of > 500 ms 
- 
Increase from Baseline of > 30 ms to ≤  60ms 


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- 
Increase from Baseline of > 60 ms 
• HR 
- 
Increase from baseline >25% and to a value > 100 bpm 
- 
Decrease from baseline >25% and to a value < 50 bpm 
• PR 
- 
Increase from baseline >25% and  to a value > 200 ms 
- 
New value of > 200 ms 
• QRS 
- 
Increase from baseline >25% and  to a value > 120 ms 
- 
New value of > 120 ms 
• RR 
- 
Increase from baseline >25% and to a value > 1200 ms 
- 
Decrease from baseline >25% and to a value < 600 ms 
A listing of all ECG assessments will be produced and notable values will be flagged. In the 
listing, the assessments collected during the post-treatment period will be flagged. 
2.8.4.2 
Vital signs 
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: height (cm), weight (kg), body temperature (°C), pulse 
rate (beats per minute), respiratory rate (breaths per minute), systolic and diastolic blood 
pressure (mmHg). 
Data handling 
Vital signs collected on treatment will be summarized. Values measured during the post-
treatment period will be flagged in the listings. 
Data analysis 
For analysis of vital signs the clinically notable vital sign criteria are provided in Table 2-1 
below. 
Table 2-1 
Clinically notable changes in vital signs 
Vital sign 
(unit) 
Criteria 
< 18 years at 
screening and < 18 
years at time of 
assessment 
< 18 years at 
screening and ≥ 18 
years at time of 
assessment 
≥ 18 years at 
screening 
Systolic 
blood 
pressure 
(mmHg) 
High 
≥ 95th percentile of the 
age and height group1 
≥ 180 with increase from 
updated baseline5 of 
≥20 
≥180 with increase 
from baseline of 
≥20 
Low 
≤ 5th percentile of the 
age and height group1 
≤ 90 with decrease from 
updated baseline5 of 
≥20  
≤90 with decrease 
from baseline of 
≥20 
 


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Vital sign 
(unit) 
Criteria 
< 18 years at 
screening and < 18 
years at time of 
assessment 
< 18 years at 
screening and ≥ 18 
years at time of 
assessment 
≥ 18 years at 
screening 
Diastolic 
blood 
pressure 
(mmHg) 
High 
≥ 95th percentile of the 
age and height group1 
≥ 105 with increase from 
updated baseline4 of 
≥15 
≥105 with increase 
from baseline of 
≥15 
Low 
≤ 5th percentile of the 
age and height group1 
≤ 50 with decrease from 
updated baseline4 of 
≥15 
≤50 with decrease 
from baseline of 
≥15 
Pulse rate 
(bpm) 
High 
≥15 years: >92 
 
≥120 with increase from 
updated baseline4 of 
≥15 
≥100 with increase 
from baseline of 
>25% 
Low 
≥15 years: <58 
≤50 with decrease from 
updated baseline4 of 
≥15 
≤50 with decrease 
from baseline of  
>25% 
 
Weight (kg) 
High 
increase from baseline 
of ≥2 BMI-for-age 
percentile categories3 
increase from updated 
baseline4 of ≥10% 
increase >10% 
from baseline 
Low 
decrease from baseline 
of ≥2 BMI-for-age 
percentile categories3 
decrease from updated 
baseline4 of ≥10% 
decrease >10% 
from baseline 
Respiratory 
rate (breath 
per 
minute)2,5, 6 
High 
≥15 years: >20 
 
≥30 
≥30 
 
Low 
≥15 years: <13 
 
≤10 
≤10 
 
 
 
 
 
Oral body 
temperatur
e (°C) 
High 
≥38.4 
≥39.1 
≥39.1 
 
Low 
≤35.0 
≤35.0 
≤35.0 
bpm=beats per minute; NHLBI= National Heart, Lung, and Blood Institute;  
1 Blood pressure percentiles are calculated for each blood pressure record using the method described in 
Appendix B of the following reference: The Fourth Report on Diagnosis, Evaluation and Treatment of High 
Blood Pressure in Children and Adolescents. Pediatrics 2004; 114; 555. 
2 Fleming S, 2011 
3 BMI-for-age percentiles categories (P3, P5, P10, P25, P50, P75, P85, P90, P95, P97) are obtained from the 
WHO Growth Charts; 
4 Updated baseline is the last value collected before the 18th birthday. 
5 Eldridge L, 2014;  
6 Kou .R, 2009. 
 
The number and percentage of subjects with notable vital sign values (high/low) will be 
presented.          


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A listing of all vital sign assessments will be produced by treatment arm and notable values will 
be flagged. In the listing, the assessments collected outside of on-treatment period will be 
flagged.  
2.8.4.3 
Immunogenicity 
Immunogenicity will be characterized descriptively tabulating ADA prevalence at baseline 
and ADA incidence on-treatment. 
All immunogenicity results and pre-dose PK will be listed by participant and visit/time, and 
summarized by visit and schedule time point in a table. 
2.8.4.4 
VOC 
In this study, there is no efficacy endpoint, objective or analysis planned. Information about 
VOCs leading to HC visit is however collected to allow individual patient review and 
description. All information about VOCs leading to HC visit on treatment will thus be listed.  
2.9 
Pharmacokinetic endpoints   
Not applicable  
2.10 
PD and PK/PD analyses 
PK concentration data for crizanlizumab will be listed as well as summarized by visit and 
schedule time point in a table.   
2.11 
Patient-reported outcomes 
Not applicable 
2.12 
Biomarkers 
Not applicable 
2.13 
Other Exploratory analyses 
Not applicable  
2.14 
Interim analysis 
Not applicable 
3 
Sample size calculation 
3.1 
Primary analysis 
This is a descriptive study and no hypothesis testing will be conducted. However the primary 
endpoint which is the proportion of patients reporting an SAE over the treatment period, will 
be presented with a 2-sided 95% CI. 


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In the SUSTAIN study ([CSEG101A2201]), the proportion of patients reporting at least one 
SAE over the treatment period on Crizanlizumab 5mg/kg was 26%. 
Assuming the percentage of patients with at least one serious adverse event in this study in  
India should be approximately in the range of values previously observed, the half width of  the 
confidence interval is calculated for potential observed proportions of 15, 25 and 35%. With a 
sample size of 140 patients, the half-width of the confidence interval would vary from +/-5.9 to 
+/-7.9 if the proportion of patients with SAEs remains between 15 and 35%. This precision is 
considered appropriate to estimate with enough reliably the safety profile of crizanlizumab in 
India. The sample size calculation is done in EAST version 6.4. 
 
Table 12-1 Confidence intervals (95%) for different proportions of SAE 
Sample Size 
Assumed 
proportion of SAE 
Half width of 95% 
2-sided CI 
Lower 95% 2-
sided CI 
Upper 95% 2-
sided CI 
140 
0.15 
0.059 
0.091 
0.209 
140 
0.25 
0.072 
0.178 
0.322 
140 
0.35 
0.079 
0.271 
0.429 
 
4 
Change to protocol specified analyses 
No change from protocol specified analyses was made. 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
Missing dates for study drug administration should be queried and will not be imputed. 
5.1.2 
AE, ConMeds and safety assessment date imputation 
Table 5-1 
Imputation of start dates (AE, CM)  
Missing 
Element 
Rule 
day, month, 
and year 
• No imputation will be done for completely missing dates 
day, month 
• If available year = year of study treatment start date then  
o If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date = 01JanYYYY  
o Else set start date = study treatment start date.  
• If available year > year of study treatment start date then 01JanYYYY 
• If available year < year of study treatment start date then 01JulYYYY 


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Missing 
Element 
Rule 
day 
• If available month and year = month and year of study treatment start 
date then  
o If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date= 01MONYYYY.  
o Else set start date = study treatment start date. 
• If available month and year > month and year of study treatment start 
date then 01MONYYYY   
• If available month and year < month year of study treatment start date 
then 15MONYYYY   
time (for AE 
only) 
• If AE available day, month and year = day, month and year of study 
treatment start date then 
o If AE stop date/time contains a full date/time (time, day, month 
and year) and AE stop date/time is earlier than study treatment 
start date/time then set start date/time = DDMONYYYY:00:01.  
o If Infusion related reaction = “Yes” and “when did the Infusion 
related reaction start” = “During the infusion” then set start 
date/time = study treatment start date/time  
o If Infusion related reaction = “Yes” and “when did the Infusion 
related reaction start” = “Within 24 hours after the infusion” 
then set start date/time = study treatment infusion end date/time 
+01 min of that day of AE 
o Else set start time = study treatment start time 
• Otherwise if day, month and year < day, month and year of study 
treatment start date or if day, month and year > day, month and year of 
study treatment start date  do not impute the AE start time and leave it 
blank 
Table 5-2 
Imputation of end dates (AE, CM)  
Missing 
Element 
Rule  
(*=last treatment date plus 105 days not > (death date, cut-off date, 
withdrawal of consent date)) 
day, month, 
and year 
• 
Completely missing end dates (incl. ongoing events) will be imputed 
by the end date of the on-treatment period* only if start date ≤ end date 
of the on-treatment period 
day, month 
• 
If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period *  
If start date > end date of the on-treatment period, set end date = 
31DecYYYY 
day 
• 
If partial end date contains month and year, set end date = earliest of 
last day of the month or end date of the on-treatment period* 
If start date > end date of the on-treatment period, set end date = last 
day of the month 


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Any AEs and ConMeds with partial/missing dates will be displayed as such in the data listings. 
Any AEs and ConMeds which are continuing will be shown as ‘ongoing’ rather than the end 
date provided.  
5.1.2.1 
Other imputations 
5.2 
AEs coding/grading 
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. 
Note: The latest available MedDRA version at the time of the analyses should be used. The 
MedDRA version used should be specified in the footnote of relevant tables.   
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0.  
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding 
to mild, moderate, severe, life threatening, and death. This grading system inherently places a 
value on the importance of an event, although there is not necessarily proportionality among 
grades (a grade 2 is not necessarily twice as bad as a grade 1).  
5.3 
Laboratory parameters derivations 
Grade categorization of lab values will be assigned programmatically as per Novartis Internal 
Guidance on CTC Grading of Lab Parameters version 1.0. The calculation of CTCAE grades 
will be based on the observed laboratory values only, clinical assessments will not be taken into 
account. The criteria to assign CTCAE grades are given in Novartis internal criteria for CTCAE 
grading of laboratory parameters. The latest available version of the document at the time of 
analysis will be used. For laboratory tests where grades are not defined by CTCAE v5.0, results 
will be graded by the low/normal/high classifications based on laboratory normal ranges. 
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 will not be used. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labelled by direction, e.g., sodium will be summarized 
as hyponatremia and hypernatremia. 
Imputation Rules   
CTC grading for blood differentials is based on absolute values. However,  this data may not 
be reported as absolute counts but rather as percentage of WBC.  
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X.   
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential 


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xxx count = (WBC count) * (xxx %value / 100) 
Further derivation of laboratory parameters might be required for CTCAE grading. For 
instance, corrected calcium can be derived using the reported total calcium value and albumin 
at the same assessment using the following formula: 
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4] 
In order to apply the above formula, albumin values in g/L will be converted to g/dL by  
multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 
0.2495. For calculation of laboratory CTC grades 0 and 1, the normal range for  derived 
corrected calcium is set to the same limits (in mg/dL) as for calcium. 
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium will be assigned as described above for grading 
6 
Reference 
Novartis internal CTC grading document: 
Internal Guidance on 
CTC Grading of Lab Pa 
Novartis Internal Guidance on CTC Grading of Lab Parameters, Version Number: 1.0. Effective 
Date: 27-Nov-2023  
Smith B, Vandenhende FR, DeSante KA, Farid NA, Welch PA, Callaghan JT and Forgue ST . 
Confidence Interval Criteria for Assessment of Dose Proportionality. Pharmaceutical 
Research, 17(10), 1278-83 (2000)..