A Phase III, Multicenter, Randomized, Double-blind Study to Assess Efficacy and Safety of Two Doses of Crizanlizumab Versus Placebo, With or Without Hydroxyurea/ Hydroxycarbamide Therapy, in Adolescent and Adult Sickle Cell Disease Patients With Vaso-Occlusive Crises (STAND)
Phase: PHASE3
Conditions: Sickle Cell Disease (SCD)
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development 
SEG101 
Clinical Trial Protocol CSEG101A2301/ NCT03814746 
A phase III, Multicenter, Randomized, Double-blind Study to 
Assess Efficacy and Safety of Two Doses of Crizanlizumab 
versus placebo, with or without Hydroxyurea/ 
Hydroxycarbamide Therapy, in Adolescent and Adult Sickle 
Cell Disease Patients with Vaso-Occlusive Crises (STAND) 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2017-001746-10 
Version number: 
05 Clean (Protocol Amendment) 
Clinical Trial Phase: 
III 
Release date: 
05-Mar-2021 (content final)
Property of Novartis  
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.0 (31-Jan-2020) 

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Table of contents 
 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 11 
Amendment 5 (05-Mar-2021) ........................................................................................... 14 
Summary of previous amendments ................................................................................... 17 
Amendment 4 (04-Nov-2020) ........................................................................................... 17 
Amendment 3 (28-Jul-2020) ............................................................................................. 18 
Amendment 2 (02-Jun-2020) ............................................................................................ 23 
Amendment 1 (12-Feb-2020) ............................................................................................ 23 
Protocol summary .............................................................................................................. 31 
1 
Introduction ....................................................................................................................... 35 
1.1 
Background ............................................................................................................ 35 
1.1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment ................................................................................................ 35 
1.1.2 
Introduction to investigational treatment .............................................. 36 
1.2 
Purpose .................................................................................................................. 39 
1.2.1 
Study rationale and purpose .................................................................. 39 
2 
Objectives and endpoints ................................................................................................... 39 
3 
Study design ...................................................................................................................... 41 
4 
Rationale ............................................................................................................................ 43 
4.1 
Rationale for study design ..................................................................................... 43 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 43 
4.3 
Rationale for choice of control drugs (comparator/placebo) ................................. 43 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 44 
4.5 
Risks and benefits .................................................................................................. 44 
4.6 
Rationale for Public Health Emergency mitigation procedures ............................ 47 
5 
Study Population ............................................................................................................... 47 
5.1 
Inclusion criteria .................................................................................................... 47 
5.2 
Exclusion criteria ................................................................................................... 48 
6 
Treatment ........................................................................................................................... 50 
6.1 
Study treatment ...................................................................................................... 50 
6.1.1 
Investigational and control drugs .......................................................... 50 
6.1.2 
Additional study treatments .................................................................. 51 
6.1.3 
Treatment arms/group ........................................................................... 51 

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6.1.4 
Guidelines for continuation of treatment .............................................. 51 
6.1.5 
Treatment duration ................................................................................ 51 
6.2 
Other treatment(s) .................................................................................................. 52 
6.2.1 
Concomitant therapy ............................................................................. 52 
6.2.2 
Prohibited medication ........................................................................... 53 
6.3 
Participant numbering, treatment assignment, randomization .............................. 54 
6.3.1 
Participant numbering ........................................................................... 54 
6.3.2 
Treatment assignment, randomization .................................................. 54 
6.4 
Treatment blinding ................................................................................................ 54 
6.5 
Dose escalation and dose modification.................................................................. 56 
6.5.1 
Dose modifications ................................................................................ 56 
6.5.2 
Follow-up for toxicities ......................................................................... 60 
6.6 
Additional treatment guidance ............................................................................... 61 
6.6.1 
Treatment compliance ........................................................................... 61 
6.6.2 
Emergency breaking of assigned treatment code .................................. 61 
6.7 
Preparation and dispensation ................................................................................. 62 
6.7.1 
Handling of study treatment and additional treatment .......................... 62 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 62 
7 
Informed consent procedures ............................................................................................ 62 
8 
Visit schedule and assessments ......................................................................................... 64 
8.1 
Screening ............................................................................................................... 77 
8.1.1 
Eligibility screening .............................................................................. 77 
8.1.2 
Information to be collected on screening failures ................................. 77 
8.2 
Participant demographics/other baseline characteristics ....................................... 77 
8.3 
Efficacy .................................................................................................................. 78 
8.3.1 
Efficacy assessment .............................................................................. 78 
8.3.2 
Appropriateness of efficacy assessments .............................................. 81 
8.4 
Safety ..................................................................................................................... 81 
8.4.1 
Laboratory evaluations .......................................................................... 82 
8.4.2 
Electrocardiogram (ECG) ..................................................................... 84 
8.4.3 
Pregnancy and assessments of fertility ................................................. 85 
8.5 
Additional assessments .......................................................................................... 85 
8.5.1 
Clinical Outcome Assessments (COAs) ............................................... 85 
8.5.2 
Pharmacokinetics .................................................................................. 88 
 91 
 
 92 

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8.6 
Participant Off-site research nursing visits ............................................................ 93 
8.7 
Eligibility criteria for participants who switch from placebo to crizanlizumab 
after primary analysis ............................................................................................ 95 
9 
Study discontinuation and completion .............................................................................. 95 
9.1 
Discontinuation and completion ............................................................................ 95 
9.1.1 
Study treatment discontinuation and study discontinuation.................. 95 
9.1.2 
Withdrawal of informed consent ........................................................... 97 
9.1.3 
Lost to follow-up ................................................................................... 97 
9.1.4 
Early study termination by the sponsor ................................................. 97 
9.2 
Study completion and post-study treatment .......................................................... 98 
10 Safety monitoring and reporting ........................................................................................ 98 
10.1 
Definition of adverse events and reporting requirements ...................................... 99 
10.1.1 
Adverse events ...................................................................................... 99 
10.1.2 
Serious adverse events ........................................................................ 100 
10.1.3 
SAE reporting...................................................................................... 101 
10.1.4 
Pregnancy reporting ............................................................................ 102 
10.1.5 
Reporting of study treatment errors including misuse/abuse .............. 102 
10.2 
Additional Safety Monitoring .............................................................................. 103 
10.2.1 
Liver safety monitoring ....................................................................... 103 
10.2.2 
Data Monitoring Committee ............................................................... 103 
10.2.3 
Steering Committee ............................................................................. 103 
10.2.4 
Adjudication committee ...................................................................... 104 
10.3 
Protocol Exempt AEs & SAEs ............................................................................ 104 
11 Data Collection and Database management .................................................................... 104 
11.1 
Data collection ..................................................................................................... 104 
11.2 
Database management and quality control .......................................................... 105 
11.3 
Site monitoring .................................................................................................... 105 
12 Data analysis and statistical methods .............................................................................. 106 
12.1 
Analysis sets ........................................................................................................ 107 
12.2 
Participant demographics and other baseline characteristics ............................... 107 
12.3 
Treatments ........................................................................................................... 108 
12.4 
Analysis of the primary endpoint(s) .................................................................... 108 
12.4.1 
Definition of primary endpoint(s) ....................................................... 108 
12.4.2 
Statistical model, hypothesis, and method of analysis ........................ 108 
12.4.3 
Handling of missing values/censoring/discontinuations ..................... 109 
12.4.4 
Sensitivity and Supportive analyses .................................................... 110 

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12.5 
Analysis of secondary endpoints ......................................................................... 110 
12.5.1 
Efficacy endpoint(s) ............................................................................ 111 
12.5.2 
Safety endpoints .................................................................................. 113 
12.5.3 
Pharmacokinetics ................................................................................ 115 
12.5.4 
Pharmacodynamics ............................................................................. 116 
116 
12.7 
Interim analyses ................................................................................................... 119 
12.8 
Sample size calculation........................................................................................ 119 
12.8.1 
Primary endpoint(s) ............................................................................. 119 
12.8.2 
Secondary endpoint(s) ......................................................................... 119 
13 Ethical considerations and administrative procedures .................................................... 120 
13.1 
Regulatory and ethical compliance ...................................................................... 120 
13.2 
Responsibilities of the investigator and IRB/IEC ................................................ 120 
13.3 
Publication of study protocol and results............................................................. 120 
13.4 
Quality Control and Quality Assurance ............................................................... 120 
13.5 
Participant Engagement ....................................................................................... 121 
14 Protocol adherence .......................................................................................................... 121 
14.1 
Protocol Amendments ......................................................................................... 121 
15 References (available upon request) ................................................................................ 123 
16 Appendices ...................................................................................................................... 125 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 39 
Table 6-1 
Dose and treatment schedule ................................................................. 51 
Table 6-2 
Blinding levels ...................................................................................... 55 
Table 6-3 
Criteria for dose interruption and re-initiation of investigational 
treatment due to adverse drug reactions ................................................ 57 
Table 8-1 
Assessment schedule ............................................................................. 66 
Table 8-2 
VOC or other APC Assessment Collection Plan .................................. 80 
Table 8-3 
Assessments & Specifications............................................................... 81 
Table 8-4 
Central Clinical laboratory parameters collection plan ......................... 83 
Table 8-5 
ECG collection plan .............................................................................. 84 
Table 8-6 
Pharmacokinetics, pharmacodynamics, and immunogenicity blood 
collection log ......................................................................................... 88 
91 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ....................................................................................... 103 

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Table 12-1 
Intersection hypotheses and local significance levels ......................... 111 
Table 12-2 
Non-compartmental pharmacokinetic parameters .............................. 115 
List of figures 
Figure 3-1 
Study design .......................................................................................... 43 
 

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List of abbreviations 
Ab 
antibody 
AC 
Adjudication Committee 
ACR 
albumin creatinine ratio 
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 transaminase 
ANC 
absolute neutrophil count 
APC 
Acute Pain Crisis 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under curve 
AUC0-t 
area under the concentration-time curve to a defined point of time 
AUCinf (AUC0-∞) 
area under the concentration-time curve extrapolated to infinity 
AUClast 
area under the curve calculated to the last measurable concentration point 
AV 
Atrioventricular 
BIL 
Bilirubin 
BUN 
Blood Urea Nitrogen 
C3a 
Complement component 3a 
C5a 
Complement component 5a 
CFR 
Code of Federal Regulation 
CI 
confidence interval 
CKD 
chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
Maximum concentration 
CMO & PS 
Central Monitoring Operations & Patient Safety 
CMV 
Cytomegalovirus 
COVID-19 
Coronavirus disease of 2019 
CPO 
Country Pharma Organization 
CRA 
Clinical Research Associate 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CRP 
C-Reactive Protein 
CSR 
clinical study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
DAR 
dose administration record 
DDE 
direct data entry 
DILI 
drug-induced liver injury 

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DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
EBV 
Epstein-Barr virus 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
Electronic Data Capture 
EDTA 
ethylenediamine tetraacetic acid 
e.g. 
for example 
ELISA 
Enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
EOT 
end of treatment 
ER 
emergency room 
eSAE 
Electronic Serious Adverse Event 
 
 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FWER 
family-wise type I error rate 
GCP 
Good Clinical Practice 
GFR 
glomerular filtration rate 
GGT 
gamma-glutamyl transferase 
h 
Hour 
HA 
Health Authority 
Hb 
Hemoglobin 
HbF 
fetal hemoglobin 
HBcAb 
hepatitis B core antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV-DNA  
hepatitis B virus - deoxyribonucleic acid 
hCG 
human chorionic gonadotrophin 
HCV 
hepatitis C 
HCVAb 
hepatitis C virus antibody 
HDL 
high density lipoproteins 
HIV 
human immunodeficiency virus 
HIV Ab 
human immunodeficiency virus antibody 
HPLC 
high performance liquid chromatography 
HR 
hazard ratio 
HSV 
herpes simplex virus 
HU/HC 
hydroxyurea/hydroxycarbamide 
IB 
Investigator Brochure 
 
 
ICF 
Informed consent form 

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ICH 
International Council for Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
IG 
Immunogenicity 
IL 
Interleukin 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IRT 
Interactive Response Technology 
IUD 
intrauterine device 
IUS 
intrauterine system 
IV 
Intravenous 
LDL 
low density lipoproteins 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
LLN 
lower limit of normal 
LLOQ 
lower limit of quantification 
LPT 
low platelet count 
LVEF 
left ventricular ejection fraction 
mAb 
monoclonal antibody 
MedDRA 
Medical dictionary for regulatory activities 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
mg 
milligram(s) 
 
 
mL 
milliliter(s) 
mPAP 
mean pulmonary arterial pressure 
NCA 
non-compartmental analysis 
NCI 
National Cancer Institute 
NSAID 
nonsteroidal anti-inflammatory drug 
ORN 
Off-site Research Nurse 
OTC 
over the counter 
PAP 
pulmonary arterial pressure 
PAS 
pharmacokinetic analysis set 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic(s) 
PDS 
pharmacodynamics analysis set 
 
 
 
 
PK 
pharmacokinetic(s) 
PopPK 
population pharmacokinetic 
PROs 
patient reported outcomes 
Psel-Ig 
P-selectin coupled to Ig 
PSGL-1 
P-selectin glycoprotein ligand-1 

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PT 
prothrombin time 
q4w 
every 4 weeks 
QMS 
Quality Management System 
quality of life 
QTcF 
Fridericia's Correction Formula 
R Value 
ALT/ALP in x ULN 
RBC 
red blood cell(s) 
RNA 
ribonucleic acid 
ROW 
rest of the world 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Steering Committee 
 
SCD 
Sickle Cell Disease 
SD 
standard deviation 
SEG101 
Novartis humanized anti-P-selectin monoclonal antibody variant 
SelG1 
Reprixys humanized anti-P-selectin monoclonal antibody variant 
SOP 
standard operating procedure(s) 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
T1/2 
half-life during a dose interval (time) 
 
 
TBIL 
total bilirubin 
TEAE 
Treatment-emergent adverse events 
TBV 
Total Blood Volume 
TFQ 
Trial Feedback Questionnaire 
Tmax 
time to reach maximum concentration 
TNF-a 
tumor necrosis factor alpha 
TRV 
tricuspid regurgitant jet velocity 
ULN 
upper limit of normal 
US 
United States 
USD 
United States dollar 
 
 
VOC 
vaso-occlusive crisis 
Vwf 
von Willebrand factor 
Wk 
week(s) 
WHO 
World Health Organization 
 

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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  
Clinical Outcome 
Assessment 
(COA) 
A measure that describes or reflects how a participant feels, functions, 
or survives 
Clinical Trial Team 
A group of people responsible for the planning, execution and reporting 
of all clinical trial activities. Examples of team members include the 
Study Lead, Medical Monitor, Trial Statistician etc. 
Coded Data 
Personal Data which has been de-identified by the investigative center 
team by replacing personal identifiers with a code 
Control drug 
A study drug (active or placebo) used as a comparator to reduce 
assessment bias, preserve blinding of investigational drug, assess 
internal study validity, and/or evaluate comparative effects of the 
investigational drug 
Discontinuation from 
study 
Point/time when the participant permanently stops receiving the study 
treatment and further protocol required assessments or follow-up, for 
any reason. No specific request is made to stop the use of their 
samples or data. 
Discontinuation from 
study 
treatment 
Point/time when the participant permanently stops receiving the study 
treatment for any reason (prior to the planned completion of study drug 
administration, if any). Participant agrees to the other protocol required 
assessments including follow-up. No specific request is made to stop 
the use of their samples or data. 
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 source 
data/documents used at the point of care 
Enrollment 
Point/time of participant entry into the study at which informed consent 
must be obtained  
Investigational treatment 
The investigational drug whose properties are being tested in the study 
as well as their associated treatment control (placebo). Investigational 
treatment does not include other treatments (p.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 
Off-site 
Describes trial activities that are performed at remote location by 
an off-site healthcare professional, such as procedures performed at 
the participant's home 
Off-site healthcare 
Professional 
A qualified healthcare professional, such as include those used 
in the study e.g. Nurse, Phlebotomist, Physician, who performs 

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(OHP) 
  
certain protocol procedures for the participant in an off-site 
location such as a participant's home. 
 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study 
(i.e. concomitant or rescue therapy) 
Part  
A sub-division of a study used to evaluate specific objectives or contain 
different populations. For example, one study could contain a single 
dose part and a multiple dose part, or a part in participants with 
established disease and in those with newly-diagnosed disease 
Patient  
An individual with the condition of interest for the study 
Participant 
A trial participant (patient). "Participant" terminology is used in the 
protocol whereas term "Subject" is used in data collection 
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-Reported 
Outcome 
(PRO) 
A measurement based on a report that comes directly from the patient 
about the status of a participant's health condition without amendment 
or interpretation of the patient's report by a clinician or anyone else 
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 
Randomization 
The process of assigning trial participants to investigational drug or 
control/comparator drug using an element of chance to determine the 
assignments in order to reduce bias. 
Randomization number 
A unique identifier assigned to each randomized participant 
Re-screening 
If a participant fails the initial screening and is considered as a 
Screen Failure, he/she can be invited once for a new Screening visit 
after medical judgment and as specified by the protocol 
Remote 
Describes any trial activities performed at a location that is not the 
investigative site where the investigator will conduct the trial, but is for 
example a home or another appropriate location 
Screen Failure 
A participant who did not meet one or more criteria that were required 
for participation in the study 
Study Completion 
Point/time at which the participant came in for a final evaluation visit or 
when study drug was discontinued whichever is later 
Source Data/Document 
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a dataset, 
a spreadsheet or even hard-coded data, such as paper or eSource 

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Study treatment 
Any investigational treatment administered to the participant as part of 
the required study procedures  
Tele-visit 
Procedures or communications conducted using technology such as 
telephone or video-conference, whereby the participant is not at the 
investigative site where the investigator will conduct the trial 
Study treatment 
interruption 
Dose administration that cannot be made as per protocol and the 
infusion is fully skipped 
Treatment arm/group  
A treatment arm/group defines the dose and regimen or the 
combination, and may consist of 1 or more cohorts. 
Withdrawal of study 
consent (WoC) / 
Opposition to use data / 
biological samples 
Withdrawal of consent from the study occurs only when the participant 
explicitly requests to stop use of their data and biological samples 
(opposition to use data and biological samples) AND no longer wishes 
to receive study treatment AND does not agree to further protocol 
required assessments. This request should be in writing (depending on 
local regulations) and recorded in the source documentation. 
Opposition to use data/biological samples occurs in the countries where 
collection and processing of personal data is justified by a different 
legal reason than consent  
 
 
 

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Amendment 5 (05-Mar-2021) 
Amendment rationale 
At the time of this amendment, 186 participants have been enrolled into the study. 
 
The primary purpose of this amendment is: 
- to specify that, as per HA feedback and EMA guideline (2017) for trial related blood loss in 
the adolescent population, the volume of blood to be taken in adolescents with body weight ≤ 
45kg, will not exceed 1% of the total blood volume (TBV) per single time and will be no more 
than 3% of TBV in a 4 weeks period. Consequently, hematology/biochemistry, PK, 
pharmacogenomic 
 parameters and/or the time points at which they are collected 
are adapted  
- to clarify that participants continuing crizanlizumab upon completion of their EOT visit via 
commercial supply or post-trial access (e.g. enrollment in a Novartis post-trial access program 
to provide continued study treatment), do not have to complete the 105 days post-treatment 
follow-up. Exception will be made if treatment discontinuation occurred before end of week 
52, the monthly phone calls up to 1 year after first treatment will be required. If the participant 
will continue crizanlizumab beyond the EOT visit, via commercial supply or post-trial access, 
the assessments requested at EOT visit will have to be performed prior to next crizanlizumab 
infusion. For participants discontinuing from study treatment prior to completion of W259D1 
visit and continuing under crizanlizumab outside the study, and for all participants completing 
the W259D1 visit whether they continue on crizanlizumab outside the study or not, EOT visit 
should be completed 28 days +/-7 days from the last dose  
- to provide with the mitigation plan during ongoing or future Public  Health  emergency  as  
declared  by  Local  or  Regional  authorities  i.e. pandemic,  epidemic  or  natural  disaster 
 
 
 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
• 
The following Sections and Tables, as per the per HA feedback and EMA guideline 
(2017) for trial related blood loss in the adolescent population to ensure that the volume of blood 
to be taken in adolescents with body weight ≤ 45kg will not exceed 1% of the total blood volume 
(TBV) per single time and will be no more than 3% of TBV in a 4 weeks period, are updated: 
-Table 8-1: W15D2 visit is added. The collection of Hematology, Chemistry and Coagulation 
samples for adolescents with body weight ≤ 25kg is transferred from W15D1 to W15D2  
-Table 8-1 COVID-19 Ab samples for adolescents with body weight ≤ 25kg should be collected 
separately from safety samples at Screening visit and collection should stop after W23D1  
-Table 8-1 Pharmacogenetic sample collection: removed for adolescents with body weight ≤ 
45kg 

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-Table 8-6: collection of W1D1 PD 2h sample number 102, W16D1 PD sample number 113, 
W18D1 PD sample number 115 and W19D1 IG sample number 204 is removed for adolescents 
with weight ≤ 25 kg 
 
 
 
Pharmacogenetic sample collection is removed for adolescents with body 
weight ≤ 45kg 
• 
The following Sections and Tables, in order to clarify that participants continuing 
crizanlizumab upon completion of their EOT visit via commercial supply or post-trial access 
(e.g. enrollment in a Novartis post-trial access program to provide continued study treatment), 
do not have to complete the post-treatment follow-up, are updated: Table 2-1; Section 3 Study 
design and Post-Treatment Follow-up; Section 6.2.1 (in addition, safety follow up visit is 
replaced with last protocol visit); Section 6.5.2; Section 8; Table 8-1; Table 8-3; Section 9.1.1; 
Section 9.2; Section 10.1.1 and Section 10.1.3  
• 
Table 8-1 and Section 9.1.1, to clarify that EOT visit should be completed 28 days +/-7 
days from the last dose, is updated 
• 
The following sections, to clarify that if the participant will continue crizanlizumab 
beyond the EOT visit, via commercial supply or post-trial access, the assessments requested at 
EOT visit will have to be performed prior to next crizanlizumab infusion, are updated: Table 
8.1; section 8 and 9.1.1 
• 
Updates to align with the latest Novartis Global Clinical Trial Protocol Template v4.0 
(15-Feb-2021) are in following Tables and Sections: Glossary of Terms, Exclusion criteria 8, 
Table 6-2; Sections 6.4; 9.1.1; 9.1.2; 9.1.3 and 13-5 
 
The rest of updated Sections and Tables are listed below: 
• 
Section 1.1.2.1: update of the approval status in the US and worldwide  
• 
Section 4-6: addition of the new section “Rationale for Public Health Emergency 
mitigation procedures”, as per global template 
• 
Section 6.2.1: since the current safety profile did not show safety concerns, clarification 
that anti-platelets agents or anticoagulants at doses targeting therapeutic levels should be used 
with caution  
• 
Section 6.2.1.1: clarification that anti-platelets agents or anticoagulants at therapeutic 
doses should be used with caution due to a potential effect of P-selectin inhibition on hemostasis 
• 
Table 6-3: clarification that in case of Grade 2 IRR the interruption of infusion should 
be “temporary”  
• 
Section 8: addition, as per global template,  of alternative methods of providing 
continuing care if on-study visits are limited or prevented during a  Public  Health  emergency  
as  declared  by  Local  or  Regional  authorities 

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• 
Table 8-1: addition of IRR testing and instruction that IRR eCRF page should be 
completed if infusion related reaction is reported as such in the AE eCRF page 
• 
Section 8.1, 8.4.1 and Tables 8-1 and 8-4: clarification that, local sampling for platelet 
count test will be performed throughout the trial for adolescents with body weight > 45kg and 
adults 
• 
Table 8-6: PK sample number 15 and footnote “c” for pre-dose samples at EOT visit are 
removed 
• 
Section 8.6: additional information added to bring more clarity to Off-site research 
nursing visits  
• 
Section 10: as per global template, replacement of COVID 19 pandemic with “ during  
a  Public  Health  emergency  as  declared  by  Local  or  Regional  authorities  i.e. pandemic,  
epidemic  or  natural  disaster “ . In addition, the word will is replaced with can, “it is safe” is 
added to read: ...regular phone or virtual calls can occur for safety monitoring and discussion 
of the participant´s health status until it is safe the participant visit the site again. 
• 
Section 12.5.2: Clarification added regarding the definition of the on-treatment and post-
treatment periods 
• 
Section References: reference “Ethical considerations for clinical trials on medicinal 
products conducted with minors, 2017” is added  
Various administrative and spelling corrections made throughout the protocol. 
 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.   
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
 
 
 
 

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Summary of previous amendments 
 
Amendment 4 (04-Nov-2020) 
Amendment rationale 
At the time of this amendment, 120 participants have been enrolled into the study. 
The primary purpose of this amendment is: 
1. In order to allow adequate opportunity for enrollment into each of the four strata (the four 
possible combinations of the stratification factors), and avoid over-representation of any 
individual stratum, a capping of 90 adult participants per stratum will be implemented.  
 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
• Section 3: Clarification added that a cap of 90 adult participants (adults defined as ≥ 18 
years) will be implemented into any individual stratum. 
• Section 4.5: the following language was added to summarize data on IRR and pain events, 
“In summary, current data suggest that administration of crizanlizumab can be commonly 
associated with infusion related reactions, including pain events, some of which can be 
severe and/or require hospitalization.” 
• Section 5 Study Population: the following language was added to create a cap on adult 
participants into each stratum: A capping of 90 adult participants per stratum will be 
implemented (Section 3).  
• Section 6.4 Treatment Blinding: the word “unblinded” has been added for clarity. 
• Section 7 Informed Consent Procedures: administrative changes for spacing issues. 
• Section 8.1 Screening: the following text has been removed, “the 28 day screen period does 
not apply to the informed consent process.”  This sentence may be misinterpreted as 
screening starts the moment informed consent is fully signed. 
• Table 8-1: Included immunoglobulins to the analysis of IRRs.  Immunoglobulin added to 
footnote 24. 
• Section 8.3.1 Efficacy Assessment: The following text was added: “as defined below” for 
clarity. 
• Section 8.4.2 Electrocardiogram (ECG): the following duplicative text was removed for 
clarity, “ECG assessments will be conducted as outlined.” 
 

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• Table 8-6: Administrative updates to add dose reference ID to the follow-up PK and align 
sample numbers for footnote c. 
• Various administrative and spelling corrections made throughout the protocol. 
 
 
Amendment 3 (28-Jul-2020)  
Amendment rationale  
At the time of this amendment, 88 participants have been enrolled into the study.  
The primary purpose of this amendment is described below: 
 
1. To introduce a new definition of acute pain crises (APCs) leading to healthcare visit; to 
define and collect data of those acute events leading to healthcare visit that do not meet 
the definition of VOC in terms of analgesic used per protocol. As a result, APCs leading 
to healthcare visit will also be reviewed and evaluated by an Adjudication Committee 
(AC). 
2. To supplement the data collected on prior use of hydroxyurea/hydroxycarbamide 
(HU/HC) by adding reason for discontinuation as part of participant demographics as 
requested by the European Medicine Agency (EMA). 
3. To provide additional guidance on how to manage infusion-related reactions (IRRs), e.g. 
with regard to  
• use of pre-medication as prophylaxis  
• caution in the use of steroids  
• slowing/reduction of infusion rate  
4. To update blood sample collection based on current data that suggest that administration 
of crizanlizumab can be associated with IRRs, including pain events, some of which can 
be severe and/or require hospitalization. In order to better characterize these IRRs, blood 
samples will be collected pre-dose and post-dose at different time points and analyzed for 
cytokines, complement analytes and tryptase. 
5. To update the risks and benefits of treatment with crizanlizumab to reflect the most recent 
available clinical data described in the latest edition of the Investigator’s Brochure 
(Edition 10, released on 12-May-2020). 
6. To provide guidance on the option of having certain protocol procedures performed at an 
off-site location by a qualified Research Nurse.  
• The existing protocol language that allows off-site Research Nursing visits to occur 
after one year of treatment has been further defined. Investigators can only offer this 
option to their participants if they meet certain eligibility criteria, if local regulations 
allow, and if the investigator, the participant, the parent(s)/legal guardian(s) (if 
applicable), and Novartis agree. 

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7. To add blood sample collection to allow for testing for COVID-19, in light of the COVID-
19 pandemic and potential interaction with efficacy and safety assessments. 
• Language is included to address COVID-19-related changes to trial conduct and allow 
some flexibility when needed. Recommendations for handling of study treatment in 
case of active or suspected COVID-19 infection are added. 
8. To remove pharmacodynamics (PD) sample collection beyond week 51 since there was no 
time-dependent PD observed in previous SEG101 studies. Since PD data up to week 51 is 
obtained when possible in other SEG101 studies, a similar period is implemented for this 
study. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
 
• Throughout: Reference to “subject” or “patient” replaced with “participant” when 
referring to trial participant, to align with the latest Novartis Global Clinical Trial Protocol 
Template v3.0 (31-Jan-2020) 
• Throughout: Use of acronym “APC” to reference “acute pain crises” 
• Throughout: Typographical and grammatical errors addressed 
• List of abbreviations: Updated by adding new abbreviations used across the protocol 
• Glossary of terms: Updated to align with the last latest Novartis Global Clinical Trial 
Protocol Template v3.0 (31-Jan-2020) and include all terms referenced in the protocol 
• Protocol Summary: Updated in alignment with the modifications made in the protocol 
sections  
 
• Figure 3-1: Updated to correct grammatical errors, and references of “patient” or “subject” 
to “participant” 
• Section 4.5: Added language regarding the potential risks of hemorrhages, infections, 
IRRs and immunogenicity in line with the latest edition of the Investigator’s Brochure 
(Edition 10, released on 12-May-2020).  
• Section 5: Aligned wording with protocol summary, specifying SCD patients who are not 
planning to initiate HU/HC or L-glutamine during the first year of investigational 
treatment can participate in this study 
• Section 5.1 and 5.2: Suffix “a” added to the numbers of inclusion/exclusion criteria that 
had been changed with Protocol Amendment 1 (unintentionally omitted in Amendment 1) 
• Section 5.2: Exclusion criterion #8 clarification added for contraception methods per local 
regulations 
• Section 6.2.1.1: Added that prophylactic pre-medication is permitted and steroids should 
be used with caution for acute pain management in SCD patients 
• Section 6.3.1:  Additional information included for participants who are re-screened  

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• Section 6.5.1:  Recommendations added for handling of study treatment in case of active 
or suspected COVID-19 infection 
• Table 6-3:   
• Throughout:  for consistency, instances of “maintain dose level” updated to “continue 
study treatment”; and instances of “discontinue the subject from the study” updated to 
“discontinue study treatment” 
• Isolated ALT Elevation:  language updated to align across the studies of the clinical 
program 
• Combined elevations of ALT and bilirubin:  language updated and reference to “in the 
absence of cholestasis” removed to align across the studies of the clinical program 
• Infusion-related reactions:  criteria updated to provide further guidance 
• Footnote c deleted as a result of removing “in the absence of cholestasis” 
• Section 6.5.2: Added that in case of a grade 3 or 4 IRR, additional blood samples will be 
collected 
• Section 6.5.2.1:   
• Clarified that clinical information should be sought to obtain the medical diagnosis of 
the most likely cause of the observed laboratory abnormalities for drug-induced liver 
injury 
• Reference to “in the absence of cholestasis” removed to align across the studies of the 
clinical program 
• Section 7:  Included the title and description of all informed consent documents which are 
utilized for the study to align with the latest Novartis Global Clinical Trial Protocol 
Template v3.0 (31-Jan-2020) 
• Section 8:   
• Added “virtual contact” as a means for communication between the site staff and 
participant (or designee) 
• +/- 10 days visit window for the Follow-up in case of treatment discontinuation before 
end of Week 52 has been updated from treatment interruption 
• Table 8-1:  
• Removed “Cycle” header and 0.5h and 2h post-dose time points as these are not 
needed 
• Added assessment “Optional Informed Consent Form for Off-site Research Nursing 
Visits” 
• Added assessment “COVID-19 testing” and corresponding footnote 23 
 
 
• Removed Prior/concomitant medications - HU/HC - L-glutamine as this line was 
redundant 
• Added Week information for End of Treatment visit and Monthly Follow Up 
•  Footnote 17 reworded for clarity, referring to APCs separately from the categories of 
VOCs  

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• Footnote 22 reworded for clarity, referring to APCs separately from the categories of 
VOCs  
• Section 8.2:  Updated to specify that prior use of HU/HC and reason for discontinuation 
will be collected as part of participant demographics 
• Section 8.3.1:   
• Added clarification and additional information for definition of other APCs managed 
at home and those leading to healthcare visit 
• Removed wording which states that APCs managed at home (reported >24 hours) and 
entered in the CRF will not be counted as an APC 
• Removed reference to study participation card which is not required globally 
• Modified text to state that grouping of VOC and APC events which occur within 7 
days of preceding event be based on clinical presentation and/or location  
• Recommendations added for COVID-19 testing if participant experiences a 
VOC/APC 
• Table 8-4: Added “COVID-19 Ab” under the Additional Tests category, as well as 
corresponding footnote 
• Table 8-5:  Added footnote c to provide instructions for ECG collection when steady-state 
is not achieved at Week 15 Day 1 
• Section 8.5.2.1 updated to clarify that serum samples are to be frozen and kept at -70°C in 
an upright position until shipment and analysis 
• Table 8-6 
• Removed PD sample collections beyond week 51 to align across the studies of the 
clinical program 
• Added PK sample collection at Follow-up (Last Infusion +105 days) to align with IG 
sampling  
• Clarified 2hr PK/PD sampling requirements in footnote g 
• Section 8.5.3:   
• Added that in case a participant has a grade 3 or grade 4 IRR, an additional sample 
should be collected 
 
 
 
 
 
 
  
• Added Section 8.6 on “Participant Off-site research nursing visits” to provide more 
information on what the requirements are in order to offer Off-site research nursing visits 
to participants 

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• Section 9:  Section headings aligned with the latest Novartis Global Clinical Trial Protocol 
Template v3.0 (31-Jan-2020)  
• Section 9.1.1:   
• Added APCs to data being collected during follow-up phone calls for participants 
who discontinue treatment during the first year 
• Further guidance provided for contacting the IRT in case of treatment discontinuation  
• Further guidance provided for cases in which treatment is discontinued because the 
treatment code has been broken 
• Section 9.1.2:  Wording aligned with the latest Novartis Global Clinical Trial Protocol 
Template v3.0 (31-Jan-2020) 
• Section 10:  Language added to cover COVID-19 pandemic and maintenance of 
virtual/phone contacts with the participants for safety monitoring and discussion on 
participant’s health in case on-sites visits cannot be performed 
• Section 10.1.2:  Added reference to the ICH-E2D Guidelines for “medically significant” 
events  
• Section 10.1.4:  Additional wording added to align with the latest Novartis Global Clinical 
Trial Protocol Template v3.0 (31-Jan-2020) and clarify that in case of pregnancy, study 
treatment must be stopped and pregnancy consent form read and signed by the participant 
• Section 10.2.2:  DMC assessment criteria corrected to remove “critical efficacy variables” 
• Section 10.2.4:  Added APCs leading to healthcare visit as a criteria for review and 
confirmation by the Adjudication Committee 
• Section 10.3: Clarification that VOC/APC events suspected to be related to study 
treatment, and/or resulting in a fatal outcome, will be reported as AE/SAE in addition to 
the VOC/acute pain crisis eCRF page 
• Section 11.2:   
• Included additional data points which are tracked in IRT to align with the latest 
Novartis Global Clinical Trial Protocol Template v3.0 (31-Jan-2020) 
 
  
 
• Section 12.4.1:  Clarified VOCs “leading to healthcare visit” will be reviewed and 
confirmed by an Adjudication committee 
• Section 12.5.1: Removed the reference to Pharmacodynamic in the section heading, as PD 
is discussed in Section 12.5.4 
 

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IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
Amendment 2 (02-Jun-2020)  
Amendment rationale  
At the time of this amendment, 81 patients have been enrolled in the study. 
Amendment 2 is required to implement specific feedback received from the Medicines & 
Healthcare products Regulatory Agency (MHRA) upon review of the Amendment 1 dated 12-
Feb-2020.   
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
• Table 6-3 and Section 6.7:  Initial protocol wording reinstated for Grade 3 infusion-related 
reactions. Recommendation updated from temporary interruption of study treatment to 
permanent discontinuation of study treatment. Change mandated by MHRA. 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
Amendment 1 (12-Feb-2020) 
At the time of this amendment, 46 patients have been enrolled in the study. 
The primary purpose of this amendment is described below: 
1. To clarify in the objectives, endpoints and statistical analysis section: 
• The annual rate of all VOCs (leading to healthcare visit and treated at home) will also 
be evaluated as a long term objective on the entire study period (on top of the key 
secondary endpoint focusing on the first year of treatment) 

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• VOCs managed at home will not only be analyzed as part of the key secondary 
endpoint, but also as part of a stand-alone secondary endpoint on annualized rate of 
VOCs managed at home.  
• The secondary objective originally called “number of days with VOCs leading to 
healthcare visit” was renamed into “duration of VOC leading to healthcare visit”, as it 
is a clearer name, in line with how this endpoints was actually defined in the original 
protocol Section 12.5. 
2. To clarify definition and duration of the different VOCs as well as the definition of other 
acute pain crises (APCs) managed at home.  
In addition, to minimize potential confounding effect with investigational treatment on efficacy 
endpoints, requirements for the use of approved therapies to treat SCD prior to study entry have 
been clarified in the inclusion criteria #5.  
Updated safety information, consistent with the Investigator’s Brochure Edition 9 (released on 
17-May-2019), has been added. 
Sections related to the study treatment preparation, dispensation, accountability and timing have 
been updated. Some details have been removed and reference to the Pharmacy Manual has been 
added instead. 
It has been clarified that local laboratory re-sampling for platelet count is allowed at any time 
in case of clumping or other issues reported from the central laboratory. 
Exclusion criteria #12 has been revised to exclude hospitalizations within 7 days prior to Week 
1 Day 1 dosing instead of prior to screening for consistency with updated inclusion criteria #4. 
Exclusion criteria #22 ‘Received prior treatment with crizanlizumab or other selectin targeting 
agent’ has been added as required by the HA as well as the prohibition to use approved 
crizanlizumab or other selectin targeting agents during the entire study duration. 
The Assessment Schedule has been updated to remove assessments that are no longer needed 
according to known safety profile of crizanlizumab. Other assessments have been entered and 
changes in format have been made for consistency with the CRF and Database (refer to changes 
to Table 8-1 described below). 
The ECG collection plan has been updated to remove several ECG measures no longer needed 
since no effect of crizanlizumab on QT was identified.  
PRO related sections have been updated to align with the new template text provided by PRO 
Center of Excellence at Novartis. 
The number of consecutive doses to reach steady state sampling has been updated to 3 as 
confirmed by latest data. 
The statistical section has been updated in line with the endpoints clarifications mentioned 
above and the final SAP. 
Other minor corrections are also applied throughout the protocol. 
Changes to the Protocol 

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Changes to specific sections of the protocol are shown in track changes version of the protocol 
using strike through red font for deletions and red underline for insertions 
• Throughout: typographical and grammatical errors addressed  
• List of abbreviations: EOS (end of study) removed as not applicable to the study. HA 
(Health Authority) and mPAP (mean pulmonary arterial pressure) were added. 
• Glossary of terms: “Cycles” removed as not applicable to the study, “Study treatment 
interruption” included to align with infusion page in the EDC system and “Subject” 
definition updated 
• Protocol Summary: updated in alignment to the protocol sections updated  
• Section 1.1: Including Oxbryta (voxelotorTM) as  approved by US FDA on 25-Nov-2019 for 
SCD treatment in adults and pediatric patients 12 years of age and older 
• Section 1.1.2.1: Including first global approval for crizanlizumab obtained from the US 
FDA on 15-Nov-2019 
• Table 2-1:  
o Clarifying that annualized rate of all VOCs leading to healthcare visit and treated at 
home is also part of efficacy objective over the entire study period 
o “Number of days with VOC” renamed to “duration of VOC leading to healthcare 
visit” as per definitions provided in Section 12.5.1 and in line with feedback received 
from scientific advice. 
o Secondary objective added: “To assess the annualized rate of VOCs managed at 
home in each group” 
• Section 3:  
o Clarifying that HU/HC and/or L-glutamine medicinal products may be received by 
the subjects as standard of care only if approved by local HA  
o Sentences “Once eligibility criteria have been confirmed to Novartis via the 
eligibility checklist, the subject will be randomized and will receive investigational 
treatment” and “A subject eligibility checklist will be embedded into the IRT 
enrolment process” removed as not applicable per current process 
o Infusion time removed and reference to pharmacist manual made instead  
• Section 5: Population description updated according to changes in Section 5.1 
• Section 5.1 
o Revised inclusion criterion #4 to reflect that 1) prior VOC leading to healthcare visit 
must resolve at least 7 days prior to Week 1 Day 1 and 2) clarify that acute chest 
syndrome, priapism and hepatic or splenic sequestration are to be considered VOC 
in this study 
o Revised inclusion criterion #5 to 1) clarify that HU/HC and/or L-glutamine that may 
be received by the patients as standard of care must be medicinal products approved 
by local HA and must have been taken for at least 6 months and at a stable dose for 
at least 3 months and 2) clarify that, in case of HU/HC and/or L-glutamine intake, 
patients must have evidence of insufficient control of acute pain, such as at least one 
VOC leading to healthcare visit while on HU/HC or L-Glutamine treatment and 3) 
clarify that patients who have not been receiving any standard of care medication 

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(HU/HC, L-glutamine, and/or erythropoietin stimulating agent) must not have 
received it for at least 6 months prior to screening. The same changes have been 
implemented across the document when applicable 
o Revised inclusion criterion #6 to 1) clarify that central laboratory values used to 
determine patients eligibility must be met prior to Week 1 Day 1 visit and 2) include 
the possibility to use local laboratory values to confirm eligibility as per section 8.4.1 
• Section 5.2  
o Revised exclusion criterion #12 to exclude hospitalizations within 7 days prior to 
Week 1 Day 1 dosing instead of prior to screening 
o Revised exclusion criterion #19 to remove resting QTcF parameter as crizanlizumab 
has no QT liability 
o Exclusion criterion #22 added to clarify that prior treatment with crizanlizumab or 
other selectin targeting agent and use of approved crizanlizumab is prohibited 
• Section 6.1.1: modified as per updated Pharmacy Manual. Some information related to the 
study drug preparation, dispensation and timing has been removed. Reference to the 
Pharmacy Manual has been added 
• Table 6-1: modified as per updated Pharmacy Manual 
• Section 6.2.1:  
o Details for treatment with erythropoietin-stimulating agents to manage chronic 
symptomatic anemia added 
o Updated to reflect that EOS visit is not applicable to this study and it was replaced 
with the safety follow-up visit. 
o Updated to clarify that L-glutamine to be used as concomitant treatment has to be 
local HA approved medicinal product 
o Updated to clarify the concomitant use is permitted provided that the subject has 
been prescribed HU/HC or L-glutamine consistently over at least the 6 months and 
at a stable dose for at least 3 months prior to the  screening visit 
• Section 6.2.1.1: modified to clarify that the use of other forms of L-Glutamine not approved 
by local HA must be collected in the eCRF and to add instructions for crizanlizumab 
treatment in case a major surgery becomes necessary 
• Section 6.2.2: clarifying that 1) prior treatment with crizanlizumab is not allowed as well as 
use of approved crizanlizumab during the entire study duration (both double-blind and 
open-label periods) and 2) new treatments to treat SCD and or to prevent/reduce VOCs are 
not permitted during the study except for those specifically mentioned in Sections 6.2.1 and 
6.2.1.1 
• Section 6.4: details about unblinding process in case of emergency situations has been added 
• Table 6-2: Blinding levels and roles corrected as per current process 
• Table 6-3:  
o Neutropenia (ANC) units updated to International System units  
o Criteria for body temperature in febrile neutropenia changed from ≥38.5 C to ≥ 38.3 
C 
o Range for grade 1 to grade 4 isolated direct bilirubin has been clarified 

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o Updated recommendation to continue study treatment for grade 1 infusion related 
reactions 
o For grade 3 infusion reaction, recommendation is updated from permanent 
discontinuation of study treatment to temporary interruption of study treatment 
o Foot note has been deleted regarding recommendation to continue study treatment 
at Investigator’s discretion if total bilirubin > 3.0 × ULN is only due to indirect 
component 
• Section 6.5.2.1: 
o Modified definition of potential DILI to include normal ALP along with elevation 
of transaminases and increase in TBIL 
o Criteria for subjects with normal ALT and Direct BIL value at baseline modified to 
include that the subjects should be without evidence of cholestasis 
o Text modified to reflect that LFTs will be repeated for certain defined criteria 
preferably within 48-72 hours 
• Section 6.7: crizanlizumab and/or placebo solution preparation instructions updated to refer 
to the updated Pharmacy Manual 
• Section 6.7.1.1:  Information about the study drug accountability has been removed and 
reference to the Pharmacy Manual has been added 
• Section 8: clarifying that a minimum of 21 days between 2 doses must be respected.  
• Table 8-1 
o Treatment duration limited to week 259 for consistency with 4-week interval from 
week 15 
o Prior/concomitant medications assessments for anticoagulants, hydroxyurea/ 
hydroxycarbamide, L-glutamine and erythropoietin stimulating agent added for 
consistency with EDC system  
o Update to include that ECG shall not be performed on post dose week 1 day 1 and 
clarified to reflect that ECG will be performed on week 23, week 47 and then every 
12 months 
o Clarifying that cardiac imaging can be performed before first dosing if not done 
within the last 12 weeks prior to start of study drug 
o Clarifying that pharmacogenetic samples can be collected at any time during the 
study. Note: The term ‘pharmacogenomic’ was updated to ‘pharmacogenetic’ across 
the document as more appropriate  
o Alcohol test and drug screen removed as crizanlizumab is not metabolized in the 
liver and drugs that are substrates, inhibitors or inducers of CYP450 are not expected 
to affect the PK of crizanlizumab 
o Optional TFQ assessment added as missed in previous Protocol version. Footnote 
#19 added to refer to Section 8.5.1 
o Headers for End of Treatment and Post-treatment follow-up Periods and respective 
visit names corrected for consistency with EDC system 

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o Footnote #20 added to clarify that eligibility criteria listed in Section 8.6 must be 
met by subjects switching from placebo to crizanlizumab after completion of 
primary analysis 
o Footnote #21 added to inform that, for treatment visits following Week 1 Day 1 visit, 
patient’s body weight at previous visit can be used to prepare the infusion in 
advanced in order to avoid delays in administering the investigational treatment. If 
more than 5% of difference between body weight at previous and current visits is 
identified, infusion will be re-prepared according to patient’s body weight at the 
time of every particular visit.    
o Footnote #22 added to clarify type of VOCs to be collected as medical history of 
VOC  
• Section 8.1: Updated per current IRT process in case of re-screening. For platelet count test, 
it has been clarified that local re-sampling is allowed at any time in case of clumping or 
other issues reported from the central laboratory.  
• Section 8.1.1: “The investigator site will then register the subject in the IRT system to obtain 
the treatment number” has been removed as not applicable per current process 
• Section 8.3.1  
o “Uncomplicated pain crisis” updated to “Uncomplicated VOC” for consistency  
o Resolution of an uncomplicated VOC has been clarified  
o Definition and/or duration of Acute Chest Syndrome, priapism, hepatic 
sequestration and splenic sequestration has been updated to add clarity. 
o Clarifying that visit to a medical facility  for collection of analgesic prescription is 
allowed 
o Definition of VOC leading to healthcare visit and VOC managed at home have been 
updated 
o Definition of ‘Other acute pain crises (APCs) managed at home’ not meeting VOC 
conditions and of interest in the study has been clarified 
o Clarifying that subjects should contact the Investigator within 24 hours when they 
believe they are experiencing a VOC or other APC that they can manage at home.  
o Clarifying that VOCs/ other APCs occurring within 7 days following the 
documented resolution of a crisis event will be counted as part of the prior crisis.  
• Section 8.4.1: Removal of alcohol test and drug screen from laboratory evaluations to be 
performed, allowance of local re-sampling at any time for platelet count test in case of 
clumping or other issues reported from the central laboratory and clarification of how to 
document the results of the local laboratory in the EDC system  
• Table 8-4: Clarifying that glucose sample can be taken non-fasting. RBC morphology, 
blood alcohol screen and urine drug screen removed 
• Clarifying that safety laboratory tests can be performed locally before dosing at the 
discretion of the investigator.  
• Table 8-5:  
o ECG collection plan re-designed for clarity 

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o ECG measures at Week 1 Day 1 (2h post dose) and at 105 days safety follow-up 
visit removed from collection plan 
o Clarifying that unscheduled ECG with clinically significant findings should be 
collected in triplicate and sent for central review 
o Footnote ‘b’ added to clarify time points for post dose ECG measures 
• Section 8.4.2.1: parameters to be assessed by Echocardiogram are re-defined: PAP replaced 
with mPAP 
• Section 8.5.1:  
 
 
o Information about the structure, completion and review of subject questionnaires has 
been added 
o Instructions to follow when entry in the diary has been missed are updated 
 
 
o Time points for TFQ collection have been added 
o Collection instructions for spontaneous information about AEs removed as not 
applicable.  
• Table 8-6:  
o Clarifying that Follow up IG sample refers to last infusion + 105 days 
o Number of consecutive doses given to reach steady state sampling updated from 4 
to 3 
o Foot note ‘g’ has been added to clarify when the 0.5 hr  PK sample is to be collected  
 
• Section 8-6: Clarifying that local laboratory re-sampling is allowed as described in section 
8.4.1 
• Section 9.1.1: “Unsatisfactory therapeutic event” and “Emergency unblinding before 
Primary Analysis, as described in section 6.6.2” added as reasons for discontinuation of 
study treatment 
• Section 10.1.1: list of outcomes to be recorded in the eCRF updated to include 
recovering/resolving AEs 
• Section 12.1: Conditions for evaluable PK profile in the definition of PAS1 corrected per 
consistency with updated Table 8-6. The term “Primary” for PK parameter removed as not 
applicable per analysis planned. 
• Section 12.3: “permanent discontinuation” removed as not collected in the CRF  
• Section 12.4.2: definition of the treatment effect of interest for prohibited medications 
clarified in line with section 6.2.2 
• Section 12.4.4:  

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o definition of the treatment effect of interest for prohibited medications clarified in 
line with section 6.2.2. 
o definition of the age subgroup changed considering number of subjects ≥ 65 years 
expected to be low 
• Section 12.5: changes made for consistency with updated Objectives section 
• Section 12.5.1: Details for closure principle provided for clarity. Other changes made for 
consistency with updated Objectives section and to clarify that in the analysis, VOC leading 
to healthcare visit referred to VOC assessed by Adjudication Committee and VOC managed 
at home referred to VOC reported in the CRF. 
• Section 12.5.3: Individual plots of concentration-time profile and pre-dose concentrations 
removed considering the high number of subjects. Geometric mean replaced by median in 
the concentration.-time profiles over time and pre-dose concentrations over time plots given 
the distribution of the PK observations 
• Section 12.5.4: Individual plots of PD-time profile removed considering the high number 
of subjects and geometric mean replaced by median in the PD-time profiles over time plots 
given the distribution of the PD observations 
• Section 15: Oxbryta-USPI (2019) reference was added 
 IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment 
 

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Protocol summary 
Protocol number 
CSEG101A2301 
Title 
A Phase III, Multicenter, Randomized, Double-blind Study to Assess Efficacy and 
Safety of Two Doses of Crizanlizumab versus placebo, with or without 
Hydroxyurea/ Hydroxycarbamide Therapy, in Adolescent and Adult Sickle Cell 
Disease Patients with Vaso-Occlusive Crises (STAND) 
Brief title 
Study of two doses of crizanlizumab versus placebo in adolescent and adult sickle 
cell disease patients 
Sponsor and Clinical 
Phase 
Novartis 
Phase III 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
Pre-clinical data have established P-selectin as a key mediator of vaso-occlusion in 
SCD and suggest that its blockade could eliminate or reduce VOCs.  
The A2201 study (SUSTAIN) compared the mean trough percentage P-selectin 
inhibition obtained with crizanlizumab following administration of 2.5 mg/kg dose 
and 5.0 mg/kg dose and suggested that the degree of clinical benefit may be 
correlated with achieving a certain level of P-selectin inhibition. 
Since trough concentration is highly correlated with % P-selectin inhibition, 7.5 
mg/kg is the proposed dose to achieve higher % P-selectin inhibition in SCD 
patients. 
The purpose of this study is to compare the efficacy and safety of 2 doses of 
crizanlizumab (5.0 mg/kg and 7.5 mg/kg) versus placebo in adolescent and adult 
SCD patients with history of VOC leading to healthcare visit.  
Primary Objective(s) 
and Key Secondary 
Objective(s) 
Primary Objective: 
• 
To compare the efficacy of 7.5 mg/kg of crizanlizumab versus placebo on the 
annualized rate of VOC leading to healthcare visit, in addition to standard of 
care 
• 
To compare the efficacy of 5.0 mg/kg of crizanlizumab versus placebo on the 
annualized rate of VOC leading to healthcare visit, in addition to standard of 
care 
Key Secondary Objective: 
• 
To compare the efficacy of 7.5 mg/kg versus placebo on the annualized rate of 
all VOCs (managed at home + leading to healthcare visit) 
• 
To compare the efficacy of 5.0 mg/kg versus placebo on the annualized rate of 
all VOCs (managed at home + leading to healthcare visit) 
Secondary 
Objective(s) 
• 
To assess the annualized rate of VOCs managed at home in each group 
• 
To assess the time to first and second VOC leading to healthcare visit in each 
group  
• 
To assess rate of participants free from VOC leading to healthcare visit in each 
group  
• 
To assess the duration of VOC leading to healthcare visit in each group  
• 
Healthcare resource utilization (visits to clinic, Emergency room (ER) and 
hospitalizations) in each group  
• 
To assess SCD-related renal damage in each group  
• 
To characterize the pharmacokinetic (PK) profile of crizanlizumab at 5.0 and 
7.5 mg/kg 
• 
To characterize the pharmacodynamic (PD) (P-selectin inhibition) of 
crizanlizumab at 5.0 and 7.5 mg/kg 
• 
To assess efficacy, safety and immunogenicity of crizanlizumab over the study 
period (taking into account potential treatment switch after primary analysis) 
Study Design 
Phase 3, randomized, placebo-controlled, double-blind study comparing 2 doses of 
crizanlizumab (5.0 mg/kg and 7.5 mg/kg) versus placebo in addition to standard of 

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care that patients might be taking at the time of study start in adolescent and adult 
SCD patients with history of VOC leading to healthcare visit. 
240 participants will be randomized in a 1:1:1 ratio to either 5.0 mg/kg or 7.5 mg/kg 
of crizanlizumab or placebo. Central randomization will be stratified by concomitant 
HU/HC usage (yes/no) and baseline rate of VOCs leading to healthcare visit in 12 
months prior to Screening (2 to 4 vs ≥ 5 VOCs). 
Following conduct of the primary analysis (once all randomized participants have 
reached 1 year of investigational treatment or discontinued within year 1), 
unblinding and change to an alternative dose or switch to crizanlizumab will be 
permitted for each individual participant, based on primary study results and 
investigator's assessment of sub-optimal efficacy vs. apparent therapy-related 
toxicity. Participants will receive open label investigational drug for the remaining 
period of treatment. It is planned to observe participants for five years on 
investigational treatment; earlier termination of the study can be considered. 
Study Population 
SCD patients aged 12 years and older (including at least 48 adolescents) who 
experienced at least 2 VOCs leading to healthcare visit in the 12 months prior to 
screening visit, and who are not planning to initiate HU/HC or L-glutamine (local HA 
approved medicinal product) during the first year of investigational treatment. 
Patients who have been taking HU/HC or L-glutamine for at least 6 months and a 
stable dose for at least 3 months and plan to continue taking at the same dose and 
schedule until the patient has reached one year of investigational treatment will be 
permitted. 
Key Inclusion criteria 
1. 
Written informed consent must be obtained prior to any screening 
procedures 
2. 
Male or female patients aged 12 years and older on the day of signing 
informed consent. Adolescents include patients aged 12 to 17 years old 
and adults ≥ 18 years  
3. 
Confirmed diagnosis of SCD by Hb electrophoresis or high performance 
liquid chromatography (HPLC) (performed locally). All SCD genotypes 
are eligible, genotyping is not required for study entry. 
4. 
Experienced at least 2 VOCs leading to healthcare visit within the 12 
months prior to screening visit as determined by medical history. Prior 
VOC leading to healthcare visit must resolve at least 7 days prior to 
Week 1 Day 1 and must include:  
a. 
Pain crisis defined as an acute onset of pain for which there is no 
other medically determined explanation other than vaso – occlusion 
(refer to Section 8.3.1 for details on VOC definition),    
b. 
which requires a visit to a medical facility and/or healthcare 
professional 
c. 
and receipt of oral/parenteral opioids or parenteral nonsteroidal anti-
inflammatory drug (NSAID) analgesics 
Acute chest syndrome (ACS), priapism and hepatic or splenic 
sequestration will be considered VOC in this study.  
5. 
If receiving HU/HC or L-glutamine (local HA approved medicinal product), 
must have been receiving the drug for at least 6 months and at stable 
dose for at least 3 months prior to Screening visit and plan to continue 
taking it at the same dose and schedule until the participant has reached 
one year of study treatment. Patients must have evidence of insufficient 
control of acute pain, such as at least one VOC leading to healthcare visit 
while on HU/HC or L-Glutamine treatment. 
If receiving erythropoietin stimulating agent must have been receiving the 
drug for at least 6 months prior to screening visit and plan to continue 
taking the drug to maintain stable Hb levels at least until the participant 
has reached one year of study treatment  
Patients who have not been receiving any of these drugs (HU/HC, L-
glutamine, and/or erythropoietin stimulating agent) must not have 
received it for at least 6 months prior to screening. 

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6. 
Patients must meet the following central laboratory values prior to Week1 
Day 1. In case of re-sampling needed, local laboratory values are 
allowed. Refer to Section 8.4.1 for further details 
• 
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 in adults, and Schwartz formula in adolescents 
• 
Direct (conjugated) bilirubin < 2.0 x ULN 
• 
Alanine transaminase (ALT) < 3.0 x ULN 
7. 
ECOG performance status ≤ 2.0 for adults and Karnofsky ≥ 50% for 
adolescents 
Key Exclusion criteria 
1. 
History of stem cell transplant. 
2. 
Participating in a chronic transfusion program (pre-planned series of 
transfusions for prophylactic purposes) and/or planning on undergoing an 
exchange transfusion during the duration of the study; episodic transfusion in 
response to worsened anemia or VOC is permitted. 
3. 
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. 
4. 
Received active treatment on another investigational trial within 30 days (or 5 
half-lives of that agent, whichever is greater) prior to Screening visit or plans to 
participate in another investigational drug trial. 
5. 
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. 
6. 
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. 
7. 
History or current diagnosis of ECG abnormalities indicating significant risk of 
safety such as:  
• 
Concomitant clinically significant cardiac arrhythmias (e.g ventricular 
tachycardia), and clinically significant second or third degree AV block 
without a pacemaker 
• 
History of familial long QT syndrome or know family history of Torsades de 
Pointes 
8. 
Not able to understand and to comply with study instructions and requirements. 
9. 
Received prior treatment with crizanlizumab or other selectin targeting agent.  
Study treatment 
Crizanlizumab (SEG101) at 5.0 mg/kg 
Crizanlizumab (SEG101) at 7.5 mg/kg 
Placebo 
Efficacy assessments 
• 
VOC events leading to healthcare visit 
• 
VOC events managed at home 
• 
Hospitalizations, clinic and ER visits (both overall and VOC-related) 
• 
Albuminuria and albumin creatinine ratio (ACR) 
 
 
• 
Echocardiograph 
• 
Other acute pain crises (APCs)  
Key safety 
assessments 
• 
Monitoring of AEs/SAEs 
• 
Vital signs 

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• 
Hematology, chemistry, coagulation and urinalysis 
• 
Growth and sexual maturity assessment in adolescents (Tanner stage) 
• 
ECGs at relevant time points 
• 
Immunogenicity: measurement of anti-drug antibodies (ADA) to crizanlizumab 
Other assessments 
• 
PK parameters 
• 
PD parameter (%P-selectin inhibition) 
 
 
 
 
 
• 
Pharmacogenetic 
Data analysis 
The primary efficacy endpoint, annualized rate of VOC leading to healthcare visit 
over the first year post-randomization, will be analyzed based on the data from the 
Full Analysis Set (FAS) according to the treatment arm and the stratification factors 
participants were randomized to. 
A negative binomial regression model with treatment and randomization 
stratification factors as covariates will be used for analysis, with the logarithm of 
observation time as offset. The hypotheses will be tested using the Wald test 
statistic within the generalized linear model assuming a negative binomial 
distribution. The estimates of annualized VOC rates between treatment groups and 
their 95% confidence intervals will be provided.  
The key secondary endpoint, the annualized rate of all VOCs leading to healthcare 
visit and treated at home over the first year post randomization, will be analyzed 
using the same method used in the primary endpoint.  
To control the overall family-wise type I error rate (FWER) an appropriate 
multiplicity adjustment procedure using a closed testing strategy will be applied to 
the analyses of the primary and key secondary endpoints for the 2 doses 
comparisons to placebo. The key secondary endpoint of a given dose will be tested 
only if the difference in the primary endpoint for the same dose is statistically 
significant. 
The primary analysis will be conducted once all randomized participants have 
reached one year of investigational treatment or discontinued within year 1. 
Key words 
Sickle cell disease, crizanlizumab, adolescents, vaso-occlusive crisis, adults 

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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. The most frequent and typically most severe 
form is homozygous HbSS (sickle cell anemia) (α2 βs2, HbS). Other forms of sickle cell disease 
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 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.  
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. 

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Preventive treatments to reduce the number of VOCs are limited. 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 2017, and has a number of contraindications/special 
warnings and precautions for use.  
L-glutamine (Endari™) is approved in the United States to reduce the acute complications of 
SCD in adult and pediatric patients 5 years and older and Oxbryta (voxelotorTM) has been 
approved by FDA since 25 Nov 2019 for the treatment of sickle cell disease (SCD) in adult and 
pediatric patients 12 years of age and older. 
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 red blood cells (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 
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. Crizanlizumab was first approved in the US on 15-Nov-2019 and is now approved in 
more than 40 countries for the prevention/reduction of VOCs in adults and pediatric patients 

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aged 16 years and older with SCD.. The crizanlizumab IB provides detailed information related 
to toxicology, nonclinical pharmacology, drug properties and preclinical data. 
1.1.2.2 
Clinical experience 
Phase I Clinical Study (Reprixys study code: [Se1G1-00003]; Novartis study 
code: [CSEG101A2101]) 
Throughout this description of CSEG101A2101, the study drug is denoted as crizanlizumab 
and refers to SelG1. 
The objectives of this study were to evaluate the safety, PK, PD, and immunogenicity of IV 
administered crizanlizumab versus placebo in 27 healthy participants at ascending dose levels 
(0.2, 0.5, 1.0, 5.0 mg/kg and 8.0 mg/kg).  
At this dose levels, mean half-life (T1/2) values increased in a dose-dependent manner. 
The exposure to crizanlizumab (mean Cmax, AUC0-t, and AUC0-∞) increased in a greater than 
proportional manner over the dose range of 0.2 to 8.0 mg/kg. For participants receiving a single 
dose of crizanlizumab at 5.0 mg/kg, P-selectin inhibition was complete for at least 28 days with 
a mean crizanlizumab concentration on Day 28 of 19.9 ± 3.8 μg/mL. 
There were no infection-related AEs, changes in coagulation parameters, increased bleeding 
tendencies, or notable treatment-related changes in peripheral blood immunophenotyping. The 
immunogenicity data indicated that no specific antibody (Ab) response to crizanlizumab 
occurred in any participants receiving up to 2 doses of crizanlizumab. 
Phase II Clinical Study (SUSTAIN study; Reprixys study code: [Se1G1-00005]; 
Novartis study code: [CSEG101A2201]) 
Throughout this description of SUSTAIN, the study drug is denoted as crizanlizumab and refers 
to SelG1. 
The objective of this pivotal, randomized, placebo-controlled study was to assess the safety and 
efficacy of crizanlizumab with or without HU/HC therapy in SCD patients with a history of 
VOC leading to a healthcare visit. A total of 198 SCD patients aged 16-65 years (inclusive), 
with any SCD genotype, a history of crisis within the previous 12 months, and either with a 
steady dose of HU/HC or not taking HU/HC, were randomized 1:1:1 to crizanlizumab 5.0 
mg/kg, crizanlizumab 2.5 mg/kg or placebo.  
The median annual rate of VOC leading to a healthcare visit was 45.3% lower with 5 mg/kg 
crizanlizumab than with placebo (Hodges-Lehmann, median absolute difference of -1.01 versus 
placebo, 95% confidence interval (CI) [-2.00, 0.00]). The difference between the 5 mg/kg arm 
and placebo arm was statistically significant (Wilcoxon rank sum test, p= 0.010). The median 
annual rate of uncomplicated crises and median number of days hospitalized, were 62.9% and 
41.8% lower in the 5.0 mg/kg than in the placebo group, respectively. Crizanlizumab also 
delayed the time to onset of first and second VOC, and consistent benefit was further observed 
in a number of clinically relevant subgroups for the primary endpoint.  
Crizanlizumab was generally well tolerated with similar incidence of treatment-emergent 
adverse events (TEAEs) across the three groups, and overall low incidence of discontinuations 

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due to TEAEs (<5%). The proportion of participants experiencing SAEs was 25.8% at 5.0 
mg/kg, 32.8% at 2.5 mg/kg and 27.4% in the placebo group. There were 5 deaths during the 
study (2 at 5.0 mg/kg, 1 at 2.5 mg/kg and 2 in the placebo group), and none was deemed to be 
treatment-related. Please refer to IB for further information. 
Overall, 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. 
All completed clinical studies described above were performed by Reprixys Pharmaceuticals 
Corporation. These studies were conducted using monoclonal antibodies produced in Invitrogen 
CHO-S cells (SelG1). To ensure supply of future clinical studies as well as commercial demand, 
Novartis has optimized the production of crizanlizumab. SEG101 will be used in future 
clinical/toxicological studies and as a commercial product.  
Phase I Clinical Study (Novartis study code: [CSEG101A2102]) 
The primary objective of this study was to evaluate the PK and PD (% P-selectin inhibition) 
comparability of crizanlizumab (SEG101 (test) and SelG1 (reference)) following a single IV 
infusion of 5.0 mg/kg in 61 healthy participants. This study also included an exploratory 
analysis with 7 healthy participants treated at 7.5 mg/kg of SEG101, in order to characterize its 
PK and PD at a higher dose for potential assessment in future studies. Comparable Cmax and 
PD were observed between SEG101 and SelG1. The areas under the curve (AUCinf and 
AUClast) for SEG101 were 28% greater than SelG1, and the half-lives were similar with 
parallel concentrations-time profiles and the difference in AUC is not expected to affect the 
efficacy. Crizanlizumab PK with SEG101 exhibited less variability as compared to SelG1. 
Treatment with SEG101 and SelG1 was safe (i.e., no death and grade 3/4 AEs) and well 
tolerated with a similar safety profile. SEG101 at 7.5 mg/kg showed no apparent safety concern 
with 62% greater AUC (AUCinf) than 5.0 mg/kg. 
Phase II Clinical Study (Novartis study code: [CSEG101A2202]) 
A Phase 2, multicenter, open-label Study in adolescent and adult SCD patients with VOC 
leading to healthcare visit is ongoing to characterize PK and PD (P-selectin inhibition) of 
crizanlizumab at 5.0 mg/kg. This study also includes an exploratory cohort to characterize PK 
and PD of crizanlizumab at 7.5 mg/kg. 
Phase II Clinical Study (Novartis study code: [CSEG101B2201]) - Pediatric 
study 
A Phase 2, multicenter, open-label study to confirm and establish appropriate dosing, and to 
evaluate the PK and safety of crizanlizumab, with or without HU/HC in pediatric SCD patients 
(6 months <18 years old) with a history of at least one VOC leading to healthcare visit in the 
prior 12 months is ongoing. Three groups will be sequentially enrolled with PK/PD and safety 
assessments: 12 to <18 years, 6 to <12 years, and 2 to <6 years. Once the appropriate dose is 
confirmed in participants aged 2 to <6 years, participants aged 6 to <24 months can be enrolled.  

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1.2 
Purpose 
The purpose of this study is to compare the efficacy and safety of 2 doses of crizanlizumab (5.0 
mg/kg and 7.5 mg/kg) versus placebo in adolescent and adult SCD patients with history of VOC 
leading to healthcare visit.  
1.2.1 
Study rationale and purpose 
Extensive pre-clinical data have established P-selectin as a key mediator of vaso-occlusion in 
SCD and suggest that its blockade could eliminate or reduce VOCs Matsui et al 2001.  
In the SUSTAIN study, the mean trough percentage P-selectin inhibition obtained with 
crizanlizumab at 4 weeks post-dose (from Week 6 to Week 50) ranged from 24% to 40% 
following administration of 2.5 mg/kg dose and from 64% to 76% following administration of 
5.0 mg/kg dose, which suggests that the degree of clinical benefit may be correlated with 
achieving a certain level of P-selectin inhibition. 
Adolescents and adults with SCD share the same etiology, genetic variability and 
pathophysiology, causing a comparable range of clinical manifestations and prognostic factors 
and lead to a similar treatment approach for the disease. Like adults, adolescents experience 
both acute and chronic pain, and the prevalence of complications, such as pulmonary 
hypertension and kidney dysfunction, begin to increase at this age compared to younger ages. 
The rate of VOCs is similar to adults (20% of adolescents experience 1-3 VOCs per year 
compared to 21% in adults aged 30-39 years old) Platt et al 1991. In addition, adolescents and 
young adults have the highest rates of hospitalizations, partially attributable to the progress of 
the disease and often turbulent transition from pediatric to adult care. Based on the above, the 
benefits and risks of crizanlizumab in adolescents are expected to be similar to the adult 
population. 
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To compare the efficacy of 7.5 
mg/kg of crizanlizumab versus 
placebo on the annualized rate of 
VOC leading to healthcare visit, in 
addition to standard of care 
• 
To compare the efficacy of 5.0 
mg/kg of crizanlizumab versus 
placebo on the annualized rate of 
VOC leading to healthcare visit, in 
addition to standard of care 
• 
Annualized rate of VOC events leading to healthcare 
visit in each treatment group over the first year post-
randomization 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
Key secondary objective: 
To compare the efficacy of 7.5 
mg/kg versus placebo on the 
• 
Annualized rate of all VOCs leading to healthcare 
visit and treated at home (based on documentation 

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Objective(s) 
Endpoint(s) 
annualized rate of all VOCs 
(managed at home + leading to 
healthcare visit)  
To compare the efficacy of 5.0 
mg/kg versus placebo on the 
annualized rate of all VOCs 
(managed at home + leading to 
healthcare visit) 
• 
To assess the annualized rate of 
VOCs managed at home in each 
group 
by health care provider following contact with 
participant) over the first year post randomization 
 
 
 
 
• 
Annualized rate of VOCs managed at home over the 
first year post randomization 
• 
To assess the  duration of VOCs 
leading to healthcare visit in each 
group 
• 
Duration of VOCs leading to healthcare visit over the 
first year post randomization 
• 
To assess rate of participants free 
from VOC leading to healthcare visit 
in each group  
• 
Number and percentage of participants free from 
VOCs leading to healthcare visit in each group over 
the first year post randomization 
• 
To assess the time to first and 
second VOC leading to healthcare 
visit in each group 
• 
The time to first and second VOC calculated 
respectively as the time from date of randomization 
until the first and the second VOC leading to 
healthcare visit over the first year post randomization 
• 
Healthcare resource utilization 
(visits to clinic, Emergency room 
(ER) and hospitalizations) in each 
group versus placebo 
• 
Annualized rate of visits to clinic, Emergency room 
(ER) and hospitalizations, both overall and VOC-
related over the first year post randomization 
• 
To assess SCD-related renal 
damage in each group  
• 
Evolution of albuminuria and ACR over the first year 
post randomization 
• 
To characterize the pharmacokinetic 
(PK) profile of crizanlizumab at 5.0 
and 7.5 mg/kg  
• 
PK parameters after the first and fifth dose (e.g., 
AUC, Cmax, Tmax,  half-life) 
• 
To characterize the 
pharmacodynamic (PD) (P-selectin 
inhibition) of crizanlizumab at 5.0 
and 7.5 mg/kg  
• 
PD parameter (P-selectin inhibition) after the first 
and fifth dose 
• 
To assess efficacy, safety and 
immunogenicity of crizanlizumab 
over the study period  (taking into 
account potential treatment switch 
after primary analysis) 
• 
Annualized rate of VOCs leading to healthcare visit 
• 
Annualized rate of all VOCs leading to healthcare 
visit and treated at home 
• 
Annualized rate of VOCs managed at home 
• 
Number, seriousness, severity, and causality 
assessments of treatment-emergent adverse events, 
including infections (serious, non-serious and 
opportunistic infections) and other safety data as 
considered appropriate 
• 
Absolute change from baseline in hemoglobin 
• 
Growth and sexual maturity assessment in 
adolescents (Tanner stage) 
• 
Immunogenicity: measurement of anti-drug 
antibodies (ADA) to crizanlizumab 

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3 
Study design 
This is a multicenter, randomized, double-blinded, parallel-group Phase 3 study in which two 
doses of crizanlizumab, 5.0 mg/kg and 7.5 mg/kg, will be compared to placebo in addition to 
standard of care in adolescent and adult SCD patients with history of VOC leading to healthcare 
visit. 
The study will include participants aged 12 years and older with confirmed diagnosis of SCD 
(all genotypes are eligible) who have experienced at least 2 VOCs leading to healthcare visit in 
the 12 months prior to screening visit. Participants may receive HU/HC and/or L-glutamine 
(local HA approved medicinal product) as a standard of care, as indicated in Section 6.2.1. 
240 participants, including a minimum of 48 adolescents, will be randomized in a 1:1:1 ratio to 
either 5.0 mg/kg or 7.5 mg/kg of crizanlizumab or placebo. Central randomization will be 
stratified by concomitant HU/HC usage (yes/no) and baseline rate of VOCs leading to 
healthcare visit in 12 months prior to screening visit (2-4 vs ≥ 5 VOCs). In order to allow 
adequate opportunity for enrollment into each of the four strata (the four possible combinations 
of the stratification factors), a capping of 90 adult participants per stratum will be implemented. 

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Following randomization, participants will receive their first dose of investigational treatment 
(crizanlizumab or placebo) via IV administration on Week 1 Day 1, followed by a second dose 
14 days later (Week 3 Day 1), and then investigational treatment administration will take place 
every 4 weeks for a total on-study treatment period of up to 5 years. Following conduct of the 
primary analysis, once all randomized participants have reached one year of investigational 
treatment or discontinued within year one, unblinding and change from placebo to 
crizanlizumab or to an alternative dose of crizanlizumab will be permitted for each individual 
participant. See Section 6.1.5.2 for further information. It is planned to observe participants for 
5 years on investigational treatment, however early termination of the study could be 
considered. Participants will continue on study until 105 days after discontinuing drug or until 
receiving crizanlizumab commercially or through a different study or drug access program. The 
participants continuing crizanlizumab upon completion of their EOT visit via commercial 
supply or post-trial access (e.g. enrollment in a Novartis post-trial access program to provide 
continued study treatment), do not have to complete the post-treatment follow-up.  
Screening  
Within 28 days before randomization, 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 from day 
-28 to day -1. 
Treatment 
An Interactive Response Technology (IRT) system will be used to confirm eligibility, 
randomize the participant and dispense the uniquely numbered treatment package.  
Participants will receive investigational treatment by IV infusion on Week 1 Day 1, Week 3 
Day 1, and then on Day 1 of every 4-week cycle. Refer to the Pharmacy Manual for instructions 
on preparation and dispensation of the investigational treatment. 
Safety will be monitored as outlined in Section 8.4. Participants will receive investigational 
treatment for 5 years or until unacceptable toxicity, death, are lost to follow-up or discontinued 
from the investigational treatment for any other reasons at the discretion of the investigator or 
the participant. 
Following the treatment discontinuation, participants will perform an End of Treatment visit. 
Post-treatment follow-up  
 All participants will remain in the study until completion of the 105 day safety follow-up visit, 
except the participants continuing crizanlizumab via commercial supply or post-trial access 
(e.g. enrollment in a Novartis post-trial access program to provide continued study treatment) 
upon completion of their EOT visit.  

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Figure 3-1 
Study design 
 
4 
Rationale 
4.1 
Rationale for study design 
This placebo-controlled randomized double-blind study is designed to confirm efficacy and 
safety of crizanlizumab 5mg/kg dose and assess safety and efficacy of a higher dose (7.5mg/kg). 
4.2 
Rationale for dose/regimen and duration of treatment 
The doses chosen for the SUSTAIN study (see Section 1.1.2.2 for further details) were based 
on P-selectin inhibition of SelG1 evaluated in healthy participants, as well as the acceptable 
safety experience observed in the Phase I study [CSEG101A2101]. The Phase I study 
[CSEG101A2101] showed that a single dose of SelG1 at 5.0 mg/kg and two doses of 8.0 mg/kg 
at a 2-week interval, respectively, maintained complete (100%) P-selectin inhibition at least for 
28 days. Subsequently, in another Phase I study [CSEG101A2102] with healthy participants, 
the PD comparability between SEG101 and SelG1 was demonstrated with complete P-selectin 
inhibition, while the SEG101 exposure (Cmax and AUC) was greater at 7.5 mg/kg than 5 mg/kg 
with similar safety profiles. The Phase II study with SCD participants, or SUSTAIN study 
showed dose-dependent P-selectin inhibition and efficacy at the doses of 2.5 mg/kg and 5.0 
mg/kg of crizanlizumab, indicating that a dose higher than 5.0 mg/kg may potentially achieve 
greater P-selectin inhibition and/or efficacy in SCD participants. Adult and pediatric 
SCD patients are known to have the similar soluble P-selectin concentration at the identified 
range (42.5 to 268 ng/mL in adult patients (Kanavaki 2012, Blann 2008, Al Najjar et al Najjaret 
2017); 29.7 to 370 ng/mL in pediatric patients (Hatzipantelis 2013, Colombatti 2013, Krishnan 
2010, Setty 2012). Therefore, crizanlizumab at the dose of 7.5 mg/kg may potentially lead to 
greater P-selectin inhibition and/or efficacy in SCD patients. 
4.3 
Rationale for choice of control drugs (comparator/placebo) 
This study will compare 2 doses of crizanlizumab versus placebo: 5.0 mg/kg which has shown 
efficacy in reducing the number of VOCs in SCD patients at the age of 16 years and over, and 
a higher dose (7.5 mg/kg). The placebo will be used as a comparator to provide objective 

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evidence of clinical efficacy, and safety data generated from participants exposed to the 
experimental drug. 
Participants will continue on standard of care, including HU/HC and/or L-glutamine, as 
established prior to study entry, thereby justifying potential treatment for placebo. Please refer 
to Section 6.2.1 for details. 
4.4 
Purpose and timing of interim analyses/design adaptations 
There is no planned interim efficacy 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, 31-Mar-2019 cutoff) 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:  
Infusion-related reactions (IRRs)  
Administration of monoclonal antibodies (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. However, severe IRRs including cases requiring hospitalization have been 
described in ongoing clinical trials and in 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 

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fatigue and myalgia (2.7%). 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%). However, 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. In summary, current data suggest that 
administration of crizanlizumab can be associated with IRRs, including pain events, some of 
which can be severe and/or require hospitalization. 
Immunogenicity  
Administration of mAb can be associated with immunogenicity, including development of anti-
drug antibodies (ADA) or hypersensitivity following treatment with crizanlizumab). 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 
PK/PD or safety profile with ADA development.  
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, 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 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; participants further should have 
received standard age-appropriate care for SCD, including penicillin prophylaxis and 
immunizations.  
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 hemorrhage, abnormal laboratory parameters. 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 SUSTAIN study, 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 

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(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.  
A separate search for potential AEs related to thrombosis did further not identify any patients 
with AEs related to thrombosis in the 5 mg/kg pooled data, suggesting that crizanlizumab does 
not have relevant a pro-aggregant or pro-thrombotic effect. 
Laboratory test interference with automated platelet counts  
Interference with automated platelet counts (platelet clumping) has been observed in patients 
treated with crizanlizumab in clinical studies, in particular when tubes containing 
ethylenediamine tetraacetic acid (EDTA) 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.  
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 IV 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 
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.  
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 6.2.1.1. 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 also to the latest version of the Investigator Brochure for the most recent 
information on the efficacy and safety of crizanlizumab.  

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4.6 
Rationale for Public Health Emergency mitigation procedures 
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, mitigation procedures to ensure participant safety and trial integrity 
are listed in relevant sections. Notification of the Public health emergency should be discussed 
with Novartis prior to implementation of mitigation procedures, and permitted/approved by 
Local or Regional Health Authorities and Ethics Committees as appropriate. 
5 
Study Population 
SCD patients aged 12 years and older (including a minimum of 48 adolescents) who 
experienced at least 2 VOCs leading to healthcare visit in the 12 months prior to screening visit, 
and who are not planning to initiate HU/HC or L-glutamine during the first year of 
investigational treatment. Patients who have been taking HU/HC or L-glutamine (local HA 
approved medicinal product) for at least 6 months at a stable dose for at least 3 months and plan 
to continue taking at the same dose and schedule until the participant has reached one year of 
investigational treatment will be permitted. Participants must have evidence of insufficient 
control of acute pain, such as at least one VOC leading to healthcare visit while on HU/HC or 
L-Glutamine treatment. See Section 6.2.1 Concomitant therapy for further details. A capping 
of 90 adult participants per stratum will be implemented (Section 3). 
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment and are entered in the study. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Written informed consent must be obtained prior to any screening procedures 
2. Male or female patients aged 12 years and older on the day of signing informed consent. 
Adolescent include patients aged 12 to 17 years old and adults ≥ 18 years  
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 
4a. Experienced at least 2 VOCs leading to healthcare visit within the 12 months prior to 
screening visit as determined by medical history. Prior VOC leading to healthcare visit 
must resolve at least 7 days prior to Week 1 Day 1 and must include:  
a. Pain crisis defined as an acute onset of pain for which there is no other medically 
determined explanation other than vaso-occlusion (refer to Section 8.3.1 for details on 
VOC definition)  
b. which requires a visit to a medical facility and/or healthcare professional 
c. and receipt of oral/parenteral opioids or parenteral nonsteroidal anti-inflammatory 
drug (NSAID) analgesics 
Acute chest syndrome (ACS), priapism and hepatic or splenic sequestration will be 
considered VOC in this study (refer to Section 8.3.1 for further definition). 
5. If receiving HU/HC or L-glutamine (local HA approved medicinal product), must have 
been receiving the drug for at least 6 months and at a stable dose for at least 3 months 

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prior to Screening visit and plan to continue taking it at the same dose and schedule until 
the participant has reached one year of study treatment. Patients who have not been 
receiving such drug must not have received it for at least 6 months prior to Screening visit 
to be included. Patients must have evidence of insufficient control of acute pain, such as at 
least one VOC leading to healthcare visit while on HU/HC or L-Glutamine treatment. If 
receiving erythropoietin stimulating agent, must have been receiving the drug for at least 6 
months prior to Screening visit and plan to continue taking the treatment to maintain 
stable Hb levels at least  until the participant has reached one year of study treatment. See 
Section 6.2.1 Concomitant therapy for further details. 
Patients who have not been receiving HU/HC, L-glutamine, and/or erythropoietin 
stimulating agent must not have received it for at least 6 months prior to screening visit. 
6. Patients must meet the following central laboratory values prior to Week 1 Day 1. In case 
of re-sampling needed, local laboratory values are allowed. Refer to Section 8.4.1 for 
further details: 
• 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 in adults, 
and Shwartz formula in adolescents 
• Direct (conjugated) bilirubin < 2.0 x ULN 
• Alanine transaminase (ALT) < 3.0 x ULN 
7. ECOG performance status ≤ 2.0 for adults and Karnofsky ≥ 50% for adolescents 
8. Received standard age-appropriate care for SCD, including an up-to-date record of 
immunizations, as per local requirements 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. History of stem cell transplant 
2. Received blood products within 30 days prior to Week 1 Day 1 dosing 
3. Participating in a chronic transfusion program (pre-planned series of transfusions for 
prophylactic purposes) and/or planning on undergoing an exchange transfusion and/or 
plasmapheresis during the duration of the study; episodic transfusion in response to 
worsened anemia or VOC is permitted 
4. 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 
5. Use of therapeutic anticoagulation or antiplatelet therapy (other than aspirin or NSAIDs) 
within the 10 days prior to Week 1 Day 1 dosing. Note: Prophylactic anticoagulant dose is 
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6. Received active treatment on another investigational trial within 30 days (or 5 half-lives of 
that agent, whichever is greater) prior to Screening visit or plans to participate in another 
investigational drug trial 
7. Pregnant females or females who have given birth within the past 90 days 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 
patient. 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 bilateral 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). The vasectomized male 
partner should be the sole partner for that patient 
• 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 ICF 
9. Any documented history of a clinical stroke or intracranial hemorrhage, or an 
uninvestigated neurologic finding within the past 12 months before screening visit. Silent 
infarct only present on imaging is not excluded 
10. Clinically significant bleeding disorder 
11. Planning to undergo a major surgical procedure during the duration of the study 
12a. Hospitalized within 7 days prior to Week 1 Day 1 dosing 
13. Patient with active HIV infection (detectable viral load) 
14. Patients with active Hepatitis B infection (HBsAg positive)  
Note: Patients with antecedent but no active Hepatitis B (i.e. anti-HBc positive, HBsAg 
and HBV-DNA negative) are eligible 
15. Positive test for hepatitis C ribonucleic acid (HCV RNA) 
Note: Patients 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 

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16. 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 
17. 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 
18. Any condition which, in the opinion of the investigator, is likely to interfere with the 
successful collection of the measurements required for the study 
19a. History or current diagnosis of ECG abnormalities indicating significant risk of safety 
such as:  
• 
Concomitant clinically significant cardiac arrhythmias (e.g ventricular tachycardia), 
and clinically significant second or third degree AV block without a pacemaker 
• 
History of familial long QT syndrome or know family history of Torsades de Pointes 
20. Not able to understand and to comply with study instructions and requirements 
21. Acute vaso-occlusive crisis ending within 7 days prior to Week 1 Day 1 dosing  
22. Received prior treatment with crizanlizumab or other selectin targeting agent 
6 
Treatment 
6.1 
Study treatment 
Crizanlizumab (SEG101) and placebo are supplied as concentrate for solution for infusion. The 
investigational drug is crizanlizumab (SEG101). 
Following conduct of the primary analysis (once all randomized participants have reached one 
year of investigational treatment or discontinued within year 1), unblinding and change to an 
alternative dose or active treatment will be permitted for each individual participant, based on 
primary study results and investigator's assessment of sub-optimal efficacy vs. apparent 
therapy-related toxicity. Participants will receive open label crizanlizumab for the remaining 
period of treatment. Refer to Section 6.1.5 and Section 8.7 for further details. It is planned to 
observe participants for five years on investigational treatment; earlier termination of the study 
can be considered. 
6.1.1 
Investigational and control drugs 
Crizanlizumab (SEG101) is supplied in individual 10 mL glass vials each containing 10.0 mL 
of concentrate for solution for infusion, and placebo in individual 10 mL glass vials containing 
10.0 mL of solution.  
On infusion day, an unblinded pharmacist or unblinded designated personnel will prepare an 
individual dose of crizanlizumab or placebo for study participants (as assigned by the IRT 
system) diluted in 0.9% saline sodium chloride solution or 5% dextrose infusion bags. Refer to 
the Pharmacy Manual for further instructions on dose regimen and dose preparation. 
See Table 6-1 for dose and treatment schedule. 

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Table 6-1 
Dose and treatment schedule 
Study treatments 
Pharmaceutical form 
and route of 
administration 
Dose 
Frequency and/or 
Regimen 
Crizanlizumab 
(SEG101) 
Concentrate for 
solution for infusion 
IV use 
5mg/kg or 7.5mg/kg 
Week 1 Day 1, Week 3 
Day 1, and Day 1 of 
every 4-week cycle 
Placebo 
Concentrate for 
solution for infusion 
IV use 
0.5mL/kg 
(no active substance) 
Week 1 Day 1, Week 3 
Day 1, and Day 1 of 
every 4-week cycle 
6.1.2 
Additional study treatments 
No additional treatment beyond investigational drug and control drug are included in this trial. 
6.1.3 
Treatment arms/group 
Not applicable. 
6.1.4 
Guidelines for continuation of treatment 
Not applicable. 
6.1.5 
Treatment duration 
The total duration of treatment in the study for each participant is planned to be up to 5 years. 
Participants may be permanently discontinued due to unacceptable toxicity, death, lost to 
follow-up or discontinued from the investigational treatment for any other reasons at the 
discretion of the investigator or the participant. 
Participants who may benefit from continued investigational drug as per investigator's opinion 
may receive post-trial access treatment after trial completion, as indicated in Section 9.2. 
6.1.5.1 
Treatment beyond disease progression 
Not applicable. 
6.1.5.2 
Treatment beyond primary analysis 
Following conduct of the primary analysis, once all randomized participants have reached one 
year of investigational treatment or discontinued within year one, unblinding and change from 
placebo to crizanlizumab or alternative dose of crizanlizumab (5.0mg/kg or 7.5mg/kg) will be 
permitted for each individual participant. 
All participants randomized to placebo will be switched to crizanlizumab. Prior to commencing 
treatment with crizanlizumab, these participants must meet the eligibility criteria as indicated 
in Section 8.7. 
Decision of the dose of crizanlizumab (either 5.0 mg/kg or 7.5 mg/kg) for ALL participants will 
be based on primary study results and investigator's assessment of sub-optimal efficacy vs 
apparent therapy-related toxicity.  

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6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
In general, the use of any concomitant medication/therapies deemed necessary for the care of 
the participant is permitted, except as specifically prohibited. The participant must notify the 
study site about any new medications he/she takes within 30 days prior to initial dosing until 
the safety follow-up visit (through 105 days after the last dose of investigational treatment). The 
participants continuing crizanlizumab via commercial supply or post-trial access (e.g. 
enrollment in a Novartis post-trial access program to provide continued study treatment), upon 
completion of their EOT visit, do not have to complete the 105 days post-treatment follow-up. 
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 last protocol visit must be listed on the Prior 
and Concomitant medications, Surgical and Medical Procedures or Transfusion page of the 
eCRF. Each concomitant drug must be individually assessed against all exclusion 
criteria/prohibited medication. If in doubt, the investigator should contact the Novartis medical 
monitor before randomizing a participant or allowing a new medication to be started. If the 
participant is already randomized, contact Novartis medical monitor to determine if the 
participant should continue participation in the study. Concomitant preventive treatment for 
VOC with HU/HC or L-glutamine (local HA approved medicinal product) are permitted, as per 
local guidelines provided the participant has been prescribed HU/HC or L-glutamine 
consistently over at least the 6 months and at a stable dose for at least 3 months prior to the 
screening visit. The dosing should not be altered or terminated, other than for safety reasons or 
for weight adjustments until the participant has reached one year of investigational treatment. 
If a physician deems it medically necessary to terminate, or alter HU/HC treatment or L-
glutamine during the first year of investigational treatment, changes should not lead by default 
to discontinuation of the trial; however, the Novartis medical monitor must be notified.  
Erythropoietin-stimulating agents are also permitted to manage chronic symptomatic anemia 
provided the participant has been prescribed erythropoietin-stimulating agents consistently for 
6 months prior to the screening visit. The dosing should not be altered or terminated, other than 
for safety reasons or to maintain hemoglobin level until the participant has reached one year of 
investigational treatment. Aspirin, NSAIDs and prophylactic doses (as per local guidelines) of 
anticoagulants are permitted. 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 
analgesics for pain are permitted as per standard of care. Other approved medications for 
supportive care (antiemetics, anxiolytics, hypnotics, antihistamines) are permitted, including 
Marinol. 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
Although transfusion of blood components is permitted, it is unclear how such transfusions will 
impact the PK/PD of crizanlizumab, so investigators are encouraged to obtain PK and PD 
samples before and after each transfusion session when possible. It should also be considered 
that the administration of products containing immunoglobulins (plasma, IVIG, anti-globulins) 

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may also impact the efficacy of crizanlizumab, and optional PK and PD testing may also be 
performed prior to and following administration of such therapies. Although EndariTM, the HA-
approved version of L-glutamine is permitted as outlined above, 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 the unproven efficacy and variable 
quality and composition of these products. If other forms of L-Glutamine not approved by local 
HA are used, the treatment information will be collected in the eCRF. 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.  
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 and guidelines 
for administration of monoclonal antibodies; pre-medications may be adjusted based on clinical 
presentation as deemed appropriate (e.g. for pain management). If a participant experiences a 
grade 3 or grade 4 IRR, study drug will be discontinued. Please refer to Table 6-3 for further 
guidance on management of IRRs.  
Steroids should be used with caution in SCD patients. For participants presenting acute pain 
related to SCD, the 2020 guideline from the American Society of Hematology suggests against 
corticosteroids for acute pain management (Brandow et al 2020). 
Anti-platelets agents or anticoagulants at therapeutic doses should be used with caution due to 
a potential effect of P-selectin inhibition on hemostasis. 
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 participant has fully 
recovered, at the investigator discretion. 
6.2.2 
Prohibited medication 
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 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. Participants that have received prior treatment 
with crizanlizumab are not allowed to enroll in this study. Use of approved crizanlizumab or 
other selectin targeting agents is prohibited during the entire study duration, both during the 
double blind and open label periods.  New treatments to treat SCD and or to prevent/reduce 
VOCs are not permitted (except as outlined above) during the study.  

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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 first enrolled for screening and is retained as the primary 
identifier for the participant throughout his/her entire participation in the trial. A new Participant 
No. will be assigned at every subsequent enrollment if the participant is re-screened. The 
Participant No. consists of the Center Number (Center No.) (as assigned by Novartis to the 
study site) with a sequential number suffixed to it, so that each participant ’s participation is 
numbered uniquely across the entire database. Upon signing the informed consent form, the 
participant is assigned to the next sequential Participant No. available. 
A new ICF will need to be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed. 
6.3.2 
Treatment assignment, randomization 
At visit “Week 1” all eligible participants will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms. The investigator or his/her delegate will 
complete the participant randomization form in IRT after confirming that the participant fulfills 
all the inclusion/exclusion criteria. The IRT will assign a randomization number to the 
participant, which will be used to link the participants to a treatment arm and will specify a 
unique medication number for the first package of study treatment to be dispensed to the 
participant. The randomization numbers will be generated using the following procedure to 
ensure that treatment assignment is unbiased and concealed from participants and investigator 
staff. A participant randomization list will be produced by the IRT provider using a validated 
system that automates the random assignment of participant numbers to randomization 
numbers. These randomization numbers are linked to the different treatment arms, which in 
turn are linked to medication numbers. A separate medication list will be produced by or under 
the responsibility of Novartis Drug Supply Management using a validated system that 
automates the random assignment of medication numbers to packs containing the study 
treatment. 
240 SCD participants will be randomized in a 1:1:1 ratio to either 5.0 mg/kg of crizanlizumab, 
7.5 mg/kg of crizanlizumab or placebo. Central randomization will be stratified by HU/HC 
usage (yes/no) and baseline rate of VOCs leading to healthcare visit within 12 months prior to 
Screening visit (2-4 vs ≥ 5 VOCs). The randomization scheme for participants will be reviewed 
and approved by a member of the Randomization Office. 
6.4 
Treatment blinding 
Participant, investigator staff, individuals performing the assessments, and Novartis study team 
(except for some selected roles indicated in Table 6-2) will remain blind to the identity of the 
investigational treatment from the time of randomization until the database lock for the primary 
analysis. An unblinded pharmacist or delegate will be responsible for the compounding of 
individual doses for study participants. 

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Unblinding will occur in the case of participant emergencies, after the primary analysis and 
following a treatment discontinuation if needed to ensure adequate treatment of the participant, 
under the oversight of Novartis. Unblinding a single participant at site for safety reasons 
(necessary for participant management) will occur via an emergency system in place at the site. 
As a result the participant should be discontinued from the study treatment. The randomization 
codes associated with participants from whom PK samples are taken will be disclosed to PK 
analysts who will keep PK results confidential until data base lock. Data with unblinding 
potential, such as Pharmacokinetics, Pharmacodynamics, 
 and dosing  collected 
after the randomization visit, will be kept blind until the database lock for the primary analysis. 
It is the Investigator’s responsibility to maintain the blind at the clinic site. In the case of an 
SAE or treatment discontinuation if needed to ensure adequate treatment where the Investigator 
deems identification of the study drug necessary, the Investigator or delegate can perform un-
blinding through IRT. In addition, the unblinded pharmacist or delegate can also provide 
emergency disclosure of unblinding information at the site to the Investigator. This method of 
unblinding should only be used in emergency situations when such information might affect the 
course of participant treatment. In this case, the unblinding will also need to be performed 
retrospectively in IRT. The circumstances surrounding the breaking of the blinding code will 
require documentation. The Investigator should determine and document “causality” prior to 
unblinding the study drug. Please refer to Table 6-2 for details on data which will be assessed 
by independent committees in a blinded fashion.  
Table 6-2 
Blinding levels 
  
Randomization 
list generated 
Treatment 
allocation & 
dosing 
Safety event 
(single 
participant 
unblinding) 
Safety review 
Participants 
B 
B 
UI 
B 
Site staff 
B 
B 
UI 
B 
Novartis CTT 
B 
B 
UI 
B 
Randomization 
Office  
UI 
UI 
UI 
UI 
Unblinded 
pharmacist 
UI 
UI 
NA 
NA 
Unblinded sponsor 
staff 
(examples: Clinical 
Trial Supply 
Manager, 
Independent 
Statistician, 
Independent 
Programmer, 
Independent Data 
Manager, 
Independent 
Clinical Reviewer, 
External 
Development 
UI 
UI 
NA 
UI  

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Randomization 
list generated 
Treatment 
allocation & 
dosing 
Safety event 
(single 
participant 
unblinding) 
Safety review 
Operations Supplier 
Lead, Unblinded 
CRA) 
Data Monitoring 
Committee 
UI 
UI 
NA 
UI 
UI= Allowed to be unblinded on individual participant level; B= Remains blinded; NA= Not applicable 
6.5 
Dose escalation and dose modification 
6.5.1 
Dose modifications 
If a participant does not tolerate the protocol-specified dosing schedule, dose interruptions are 
either recommended or mandated. Dose reductions are not allowed. 
If a participant experiences drug-induced toxicities, the participant should be closely monitored 
and a decision to continue or discontinue the participant from the study should be made at the 
next dose scheduled. 
These dose interruptions are summarized in Table 6-3. Deviations to mandatory dose 
interruptions are not allowed. Permanent treatment discontinuation is mandatory for specific 
events as indicated in Table 6-3. 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). If a participant misses 2 consecutive doses during 
the first year of treatment due to an ADR, the participant should be discontinued from study 
treatment. Participants with grade 4 ADR will be permanently discontinued from study 
treatment. Dose interruptions must be recorded on the Dosage Administration Record eCRF. 
It is recommended that trial participants with confirmed active Coronavirus disease of 2019 
(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 6-3 
Criteria for dose interruption and re-initiation of investigational 
treatment due to adverse drug reactions 
Dose interruption and re-initiation of investigational treatment 
Worst toxicity 
CTCAEa Grade (CTCAE version 5) during a 
cycle of therapy 
  
Investigations (Hematologic) 
Neutropenia (ANC) 
Grade 1 (ANC < LLN - 1.5 x 109/L) and Grade 2 
(ANC < 1.5 x 109/L – 1.0 x 109/L ) 
Recommendation:  continue study treatment.  
Grade 3 (ANC < 1.0 x 109/L – 0.5 x 109/L) 
Mandatory: Interrupt dose until resolved to ≤ 
Grade 2 or next dose scheduled. If abnormality 
persists, 
permanently 
discontinue 
study 
treatment. 
Grade 4 (ANC < 0.5 x 109/L) 
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 (LPT < LLN - 75,000/mm3) and Grade 2 
(LPT < 75,000 - 50,000/mm3) 
Recommendation: continue study treatment. 
Grade 3 (LPT < 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 (LPT < 25,000/mm3) 
Mandatory: 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; >10.0 x baseline if baseline was 
abnormal)  
 
Mandatory: Permanently discontinue study 
treatment.  
Isolated ALT elevation 

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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 
LFTsb 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 abnormality persists >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 
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 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) confirmed, 
permanently discontinue study treatment. 
Refer to Section 6.5.2.1 for additional follow-up 
evaluations as applicable. 
Infections 
Grade 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 
Grade 1 
Recommendation:  

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Mild transient reaction; infusion interruption not 
indicated; intervention not indicated   
Continue 
study 
treatment 
and 
increase 
monitoring of vital signs as medically indicated 
until the participant is deemed medically stable in 
the opinion of the investigator. 
Consider slowing the infusion rate. 
Grade 2 
  
Therapy or infusion interruption indicated but 
responds promptly to symptomatic treatment 
(e.g., antihistamines, NSAIDS, opioids, IV 
fluids); prophylactic medications indicated for 
≤24 hours   
 
Recommendation: 
Temporarily 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, 
including at subsequent infusions. 
In case of recurring IRRs despite premedication 
and prolonged infusion, discontinue study 
treatment. 
 
Grade 3 and 4  
 
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  
Mandatory: 
Permanently discontinue study treatment and 
initiate appropriate medical care. 
Collect blood sample immediately after onset of 
the AE for further characterization of the IRR 
(Section 8.5.3) 
General Note: Decision for dosing is made on prior lab results, not those from labs performed on the day of 
infusion. 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 Toxicity Criteria for Adverse Events (CTCAE Version 5) 
b Core LFTs consist of ALT, AST, GGT, total bilirubin (fractionated [direct and indirect], LDH, albumin, creatinine 
kinase and ALP. 
 
 

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6.5.2 
Follow-up for toxicities 
In case of a grade 3 or 4 IRR, additional blood samples will be collected as outlined in Table 6-
3 and Section 8.5.3. These blood samples should be collected as soon as possible after the start 
of the event. 
Participants whose investigational treatment is interrupted or permanently discontinued due to 
an adverse event 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 
(e.g. 
ophthalmologist, 
endocrinologist, 
dermatologist, 
psychiatrists) 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 
investigational treatment. The participants continuing crizanlizumab via commercial supply or 
post-trial access (e.g. enrollment in a Novartis post-trial access program to provide continued 
study treatment), upon completion of their EOT visit, do not have to complete the post-treatment 
follow-up.  
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 
BIL 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 
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). 

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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, 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. Obtain PK sample, as close as possible to last dose of study drug. 
5. 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 investigational 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. 
6.6.2 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
participant safely. Most often, investigational treatment discontinuation and knowledge of the 
possible treatment assignments are sufficient to treat a participant who presents with an 
emergency condition. Emergency treatment code breaks are performed using the IRT. When 
the investigator contacts the system to break a treatment code for a participant, he/she must 
provide the requested participant identifying information and confirm the necessity to break the 
treatment code for the participant. The investigator will then receive details of the 
investigational treatment for the specified participant and a fax or email confirming this 
information. The system will automatically inform the Novartis monitor for the site and the 
study team that the code has been broken. 
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide: 
• protocol number 

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• name (if available) 
• participant number 
In addition, oral and written information to the participant must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time. 
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 and/or placebo solution will be prepared by an unblinded pharmacist or 
unblinded designated personnel appropriately qualified and trained in the preparation procedure 
in accordance with the Pharmacy Manual. 
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, he/she may receive pre-medication on subsequent dosing days as per institutional 
standard of care, at the discretion of the treating physician.  
If a participant experiences a Grade 3 or 4 IRR, the participant will discontinue investigational 
treatment. Please refer to Table 6-3 for further guidance on management of IRRs. 
6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
Investigational treatment must be received by the unblinded pharmacist or delegate at the study 
site, handled and stored safely and properly and kept in a secured location. Upon receipt, all 
investigational treatment must be stored according to the instructions specified on the labels 
and in the IB. Clinical supplies are to be dispensed only in accordance with the protocol and 
Pharmacy Manual. Technical complaints are to be reported to the respective Novartis CPO 
Quality Assurance. 
Refer to the Pharmacy Manual for further details on study drug accountability. 
6.7.1.2 
Handling of additional treatment 
Not applicable. 
6.7.2 
Instruction for prescribing and taking study treatment 
All kits of investigational 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 written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 

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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 
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 IB. 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 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 includes: 
• 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 parents / legal guardians to give consent for their child 
• Model Participant Information and Adolescent Assent 12-17 years old for adolescents to 
express their understanding of the purpose of this study and what will happen to them if 
their parent(s)/legal guardian(s) give their consent for their participation in this study 
• As applicable, Pregnancy Outcomes Reporting Consent for female participants  
• Optional Off-site Research Nursing Consent to have study procedures performed at an off-
site location 
• Optional Off-site Research Nursing Consent for parents / legal guardians to give consent 
for their child to have study procedures performed at an off-site location 
• Optional Adolescent Assent 12-17 years old for adolescents to express their understanding 
of the purpose of Off-site Research Nursing and what it means for them if their 
parent(s)/legal guardian(s) give their consent to have study procedures performed at an 
off-site location 
 
 
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 

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to participate in the study they must adhere to the contraception requirement for the duration of 
the study. If there is any question that the participant will not reliably comply, then they should 
not be entered in the study. 
The study includes an optional pharmacogenetics component which requires a separate 
signature if the participant agrees to participate. It is required as part of this protocol that the 
Investigator presents this option to the subjects, as permitted by local governing regulations. 
The process for obtaining consent should be exactly the same as described above for the main 
informed consent. Declining to participate in this optional assessment will in no way affect the 
participant’s ability to participate in the main research study. 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
The participant might be asked to complete an optional questionnaire to provide feedback on 
their clinical trial experience. 
8 
Visit schedule and assessments 
The assessment schedule Table 8-1 lists all of the assessments and indicates with an “X” and 
“S”, the visits when they are performed. All data obtained from these assessments must be 
supported in the subject’s source documentation. 
Subjects should be seen for all visits/assessments as outlined in the assessment schedule (Table 
8-1) and as allowed per specified visit window. Missed or rescheduled visits should not lead to 
automatic discontinuation. Participants who prematurely discontinue the study for any reason 
should be scheduled for a visit as soon as possible, at which time all of the assessments listed 
for the final visit will be performed. At this final visit, all dispensed investigational treatment 
should be reconciled, and the adverse event and concomitant medications recorded on the 
eCRF. 
As  per  Section  4.6 ,  during  a  Public  Health  emergency  as  declared  by  Local  or  Regional  
authorities i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study visits, 
alternative methods of providing continuing care may be implemented by the investigator as 
the  situation  dictates. If allowed by local Health Authority and depending on operational 
capabilities  phone calls, virtual contacts (e.g. tele consult) or  visits by site staff  to the 
participant’s home, can replace on-site study visits, for the duration of the disruption until it is 
safe for the participant to visit the site again. This telephone/virtual contact/visits to 
participant’s home should preferably be done according to the study visit schedule. 
Allowed visit windows are specified as follows: 
• Screening assessments must occur within 28 days prior to the randomization 
• A +/- 3 days for the visit on Day 15 (Week 3 Day 1) 
• A +/- 7 days for every dosing visit (occurring every 4 weeks) from Week 7 through Week 
259 (Final Dose) with a minimum of 21 days to be respected between 2 doses. 
• A +/- 1 day for 336 hour post dose PK time point 
• A +/- 5 days for the Phone call last infusion + 30 days  
• A +/- 10 days for the Phone call last infusion + 60 days  

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• A + 7 days for the end of follow-up phase (last infusion + 105 days) is allowed. The 
participants continuing crizanlizumab upon completion of their EOT visit via commercial 
supply or post-trial access (e.g. enrollment in a Novartis post-trial access program to 
provide continued study treatment), do not have to complete post-treatment follow-up. 
Exception will be made if treatment discontinuation occurred before end of week 52, the 
monthly phone calls up to 1 year after first treatment will be required.  If the participant 
will continue crizanlizumab beyond the EOT visit, via commercial supply or post-trial 
access, the assessments requested at EOT visit will have to be performed prior to next 
crizanlizumab infusion 
• A +/- 10 days for the Follow-up in case of treatment discontinuation before end of Week 
52  
 

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Table 8-1 
Assessment schedule 
Period Screeni
ng 
 
Treatment 
Visit Name Screeni
ng 
Week 1 
Day 1 
Week 3 
Day 1 
Week 7 
Day 1 
Week 11 
Day 1 
Week 15 Day 1 
Week 15 
Day 2 
every 4 weeks from week 19 to week 2591, 20 
Days -28 to -1 
1 to 1 
15 
43 
71 
99 
 
127 to 1820 
Weeks -4 to -1 
1 
3 
7 
11 
15 
 
19 to 259 
Time 
- 
pre-dose 
 
pre-dose pre-dose pre-dose pre-dose 
 
post-
dose 
2h 
 
- 
Study drug administration 
  
X 
X 
X 
X 
X 
  
 
X 
Informed consent 
X 
  
  
  
  
  
  
 
  
Optional 
pharmacogenetic 
informed consent 
X 
  
  
  
  
  
  
 
  
Optional informed 
consent for Off-site 
Research Nursing Visits 
 
 
 
 
 
 
 
 
After W51 if patient is considered eligible for Off-Site 
Research Nursing visits1 
Demography 
X 
  
  
  
  
   
  
 
  
Inclusion / Exclusion 
criteria 
X 
  
  
  
  
  
  
 
  
Confirmed diagnosis of 
SCD 
X2 
  
  
  
  
  
  
 
  
Medical history/current 
medical conditions 
X 
 
  
  
  
  
  
 
  
Sickle Cell – Vaso- 
Occlusive Crisis history22 
X 
 
  
  
  
  
  
 
  
Smoking history 
X 
  
  
  
  
  
  
 
  
Randomization 
  
X 
  
  
  
  
  
 
  
Physical Examination 
S 
  
  
  
  
  
  
 
  
Abbreviated physical 
exam 
  
S 
S 
S 
S 
S 
  
 
S 

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Period Screeni
ng 
 
Treatment 
Visit Name Screeni
ng 
Week 1 
Day 1 
Week 3 
Day 1 
Week 7 
Day 1 
Week 11 
Day 1 
Week 15 Day 1 
Week 15 
Day 2 
every 4 weeks from week 19 to week 2591, 20 
Days -28 to -1 
1 to 1 
15 
43 
71 
99 
 
127 to 1820 
Weeks -4 to -1 
1 
3 
7 
11 
15 
 
19 to 259 
Time 
- 
pre-dose 
 
pre-dose pre-dose pre-dose pre-dose 
 
post-
dose 
2h 
 
- 
Body Height18 
X 
Annually 
Body Weight21 
X 
X 
X 
X 
X 
X 
  
 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
  
 
X 
Hematology4,28 
X 
X3 
X 
X 
X 
X28 
  
 
X 
Platelets (local) 4,34 
X 
X 
X 
X 
X 
X 
 
 
X 
Hematology for 
adolescents ≤ 25kg28 
 
 
 
 
 
 
 
X 
 
Urinalysis4 
X 
X3 
X 
X 
X 
X 
  
 
X 
Pregnancy Test (serum) 
X 
   
  
  
  
  
  
 
  
Urine pregnancy test25 
  
S 
S 
S 
S 
S 
  
 
S 
Hepatitis and HIV Screen 
X 
  
  
  
  
  
  
 
  
COVID-19 Ab testing23,27  
X33 
 
 
 
 
 
 
 
Week 27 Day 127, Week 51 Day 1, then annually  
VOC Event5 
  
Continuous 
Chest X-ray 
X6 
If clinically indicated 
Hospitalization 
  
Continuous 
Prior/concomitant 
medications 
X 
Continuous 
Prior/concomitant 
medications – Analgesic 
X 
Continuous 
Prior/concomitant 
medications – 
Anticoagulants 
X 
Continuous 

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Period Screeni
ng 
 
Treatment 
Visit Name Screeni
ng 
Week 1 
Day 1 
Week 3 
Day 1 
Week 7 
Day 1 
Week 11 
Day 1 
Week 15 Day 1 
Week 15 
Day 2 
every 4 weeks from week 19 to week 2591, 20 
Days -28 to -1 
1 to 1 
15 
43 
71 
99 
 
127 to 1820 
Weeks -4 to -1 
1 
3 
7 
11 
15 
 
19 to 259 
Time 
- 
pre-dose 
 
pre-dose pre-dose pre-dose pre-dose 
 
post-
dose 
2h 
 
- 
Prior/concomitant 
medications – 
Hydroxyurea/ 
Hydroxycarbamide 
X 
Continuous 
Prior/concomitant 
medications – L-
Glutamine 
X 
Continuous 
Prior/concomitant 
medications – 
Erythropoietin stimulating 
agent 
X 
Continuous 
Concomitant non-drug 
therapies/procedures 
X 
Continuous 
RBC transfusion 
X 
Continuous 
Electrocardiogram 
(ECG)7 
X 
X 
  
 
  
X 
X 
 
Week 23 Day 1, Week 47 Day 1 and then every 12 
months7 
Cardiac imaging (ECHO) 
X8 
Annually 
Adverse events/Serious 
adverse events 
X 
Continuous 
IRR32 
 
Continuous 
Pharmacokinetics9 
See Table 8-6 
Pharmacodynamics9 
See Table 8-6  
Immunogenicity9 
See Table 8-6  

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Period Screeni
ng 
 
Treatment 
Visit Name Screeni
ng 
Week 1 
Day 1 
Week 3 
Day 1 
Week 7 
Day 1 
Week 11 
Day 1 
Week 15 Day 1 
Week 15 
Day 2 
every 4 weeks from week 19 to week 2591, 20 
Days -28 to -1 
1 to 1 
15 
43 
71 
99 
 
127 to 1820 
Weeks -4 to -1 
1 
3 
7 
11 
15 
 
19 to 259 
Time 
- 
pre-dose 
 
pre-dose pre-dose pre-dose pre-dose 
 
post-
dose 
2h 
 
- 
Pharmacogenetic sample 
collection10,31 
  
X10 
  
  
  
  
  
 
  
Alcohol history 
X 
  
  
  
  
  
  
 
  
Fetal Hemoglobin 
  
X 
  
  
  
  
  
 
Week 27 Day 1, every 3 months during the first year 
and then, every 6 months  
Disposition 
X 
  
  
  
  
  
  
 
  
Chemistry4,29 
X 
X3 
X 
X 
X 
X29 
  
 
X 
Chemistry for 
adolescents ≤ 25kg29 
 
 
 
 
 
 
 
X 
 
Coagulation4,30 
X 
X3 
X 
X 
X 
X30 
  
 
X 
Coagulation for 
adolescents ≤ 25kg30 
 
 
 
 
 
 
 
X 
 

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Period Screeni
ng 
 
Treatment 
Visit Name Screeni
ng 
Week 1 
Day 1 
Week 3 
Day 1 
Week 7 
Day 1 
Week 11 
Day 1 
Week 15 Day 1 
Week 15 
Day 2 
every 4 weeks from week 19 to week 2591, 20 
Days -28 to -1 
1 to 1 
15 
43 
71 
99 
 
127 to 1820 
Weeks -4 to -1 
1 
3 
7 
11 
15 
 
19 to 259 
Time 
- 
pre-dose 
 
pre-dose pre-dose pre-dose pre-dose 
 
post-
dose 
2h 
 
- 
Growth and sexual 
maturation assessment in 
adolescent 
  
X 
Annually 
ECOG/ Karnofsky 
performance status 
X 
  
  
  
  
  
  
 
  
Trial Feedback 
Questionnaire (TFQ), 
optional19  
 
X 
 
 
 
X 
 
 
 

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Period End of Treatment (EOT)26 
Post-treatment follow-up26 
Visit Name End of Treatment (EOT) 
30 Days Safety  
Follow-Up 
(Phone call) 
60 Day Safety  
Follow-Up 
(Phone call) 
105 Days Safety 
Follow-up 
Monthly Follow Up 1 to 
Monthly Follow Up 9 
(phone calls) 17  
Days 
Within 7 days of last 
infusion 
Last infusion + 30 
days 
Last infusion + 60 days 
Last infusion + 
105 days 
Monthly  
Weeks 
260 
264 
268 
275 
N/A 
Time (post-dose) 
- 
- 
- 
- 
- 
Study drug administration 
  
  
  
  
  
Informed consent 
  
  
  
  
  
Optional pharmacogenetic 
informed consent 
  
  
  
  
  
Demography 
  
  
  
  
  
Inclusion / Exclusion criteria 
  
  
  
  
  
Confirmed diagnosis of SCD 
  
  
  
  
  
Medical history/current medical 
conditions 
  
  
  
  
  
Sickle Cell – Vaso- Occlusive 
Crisis history 
  
  
  
  
  
Smoking history 
  
  
  
  
  
Randomization 
  
  
  
  
  
Physical Examination 
S 
  
  
  
  
abbreviated physical exam 
  
  
  
  
  
Body Height 
X 
  
  
  
  
Body Weight21 
X 
  
  
  
  
Vital Signs 
X 
  
  
X 
  
Hematology 
X 
  
  
X 
  
Platelets (local)34 
X 
 
 
X 
 
Urinalysis 
X 
  
  
X 
  

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Period End of Treatment (EOT)26 
Post-treatment follow-up26 
Visit Name End of Treatment (EOT) 
30 Days Safety  
Follow-Up 
(Phone call) 
60 Day Safety  
Follow-Up 
(Phone call) 
105 Days Safety 
Follow-up 
Monthly Follow Up 1 to 
Monthly Follow Up 9 
(phone calls) 17  
Days 
Within 7 days of last 
infusion 
Last infusion + 30 
days 
Last infusion + 60 days 
Last infusion + 
105 days 
Monthly  
Weeks 
260 
264 
268 
275 
N/A 
Time (post-dose) 
- 
- 
- 
- 
- 
Pregnancy Test (serum) 
X 
  
  
X 
  
Urine pregnancy test 
  
  
  
  
  
Hepatitis and HIV Screen 
  
  
  
  
  
COVID-19 Ab testing23,27 
X 
 
 
 
 
VOC Event5 
Continuous 
X 
X 
X 
X 
Chest X-ray 
If clinically indicated 
  
  
If clinically indicated 
  
Hospitalization 
Continuous 
X 
X 
X 
X 
Prior/concomitant medications 
Continuous 
  
  
X 
  
Prior/concomitant medications – 
Analgesic 
Continuous 
X 
X 
X 
X 
Prior/concomitant medications – 
Anticoagulants 
Continuous 
X 
X 
X 
X 
Prior/concomitant medications – 
Hydroxyurea/ Hydroxycarbamide 
Continuous 
X 
X 
X 
X 
Prior/concomitant medications – 
L-Glutamine 
Continuous 
X 
X 
X 
X 
Prior/concomitant medications – 
Erythropoietin stimulating agent 
Continuous 
X 
X 
X 
X 
Concomitant non-drug 
therapies/procedures 
Continuous 
  
  
X 
  
RBC transfusion 
Continuous 
X 
X 
X 
X 
Electrocardiogram (ECG) 
X 
  
  
 
  
Cardiac imaging (ECHO) 
  
  
  
  
  

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Period End of Treatment (EOT)26 
Post-treatment follow-up26 
Visit Name End of Treatment (EOT) 
30 Days Safety  
Follow-Up 
(Phone call) 
60 Day Safety  
Follow-Up 
(Phone call) 
105 Days Safety 
Follow-up 
Monthly Follow Up 1 to 
Monthly Follow Up 9 
(phone calls) 17  
Days 
Within 7 days of last 
infusion 
Last infusion + 30 
days 
Last infusion + 60 days 
Last infusion + 
105 days 
Monthly  
Weeks 
260 
264 
268 
275 
N/A 
Time (post-dose) 
- 
- 
- 
- 
- 
Adverse events/Serious adverse 
events 
Continuous 
  
  
X 
  
Pharmacokinetics9 
See Table 8-6 
Pharmacodynamics9 
See Table 8-6  
Immunogenicity9 
See Table 8-6  
Pharmacogenetic sample 
collection10 
  
  
  
  
  
Alcohol history 
  
  
  
  
  
Fetal Hemoglobin 
X 
  
  
  
  
Disposition 
X 
  
  
X 
X 
Chemistry 
X 
  
  
X 
  
Coagulation 
X 
  
  
X 
  
Growth and sexual maturation 
assessment in adolescent 
X 
  
  
  
  
ECOG/ Karnofsky performance 
status 
  
  
  
  
  

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Period End of Treatment (EOT)26 
Post-treatment follow-up26 
Visit Name End of Treatment (EOT) 
30 Days Safety  
Follow-Up 
(Phone call) 
60 Day Safety  
Follow-Up 
(Phone call) 
105 Days Safety 
Follow-up 
Monthly Follow Up 1 to 
Monthly Follow Up 9 
(phone calls) 17  
Days 
Within 7 days of last 
infusion 
Last infusion + 30 
days 
Last infusion + 60 days 
Last infusion + 
105 days 
Monthly  
Weeks 
260 
264 
268 
275 
N/A 
Time (post-dose) 
- 
- 
- 
- 
- 
Trial Feedback Questionnaire 
(TFQ), optional19 
 
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 After first year of treatment, participant visits to the study site might be replaced by off-site visits by a qualified Research Nurse as per Section 8.6 if local settings and 
Novartis allow it.  
2 Confirmed diagnosis of SCD at Screening by hemoglobin electrophoresis or high performance liquid chromatography (HPLC) (performed locally) 
3 Not to be repeated on Day 1 if screening assessment took place within 72 hours  
4 Prior to every dose during year 1, prior to dosing every 3 months during year 2, prior to dosing every 6 months from year 3 to end of treatment 
5 Other APCs leading to healthcare visit and managed at home will also be collected  
6 Within 3 months of Week 1 Day 1 dosing 
7 as per Table 8-5 
8 Assessment to be done before first dosing if not done within the last 12 weeks prior to start of study drug 
9 At specified time points, blood samples will be collected from the arm opposite from the investigational drug infusion into serum separator tubes. All blood samples will 
be taken by either direct venipuncture or an indwelling cannula inserted in a forearm vein. The total blood volume (combining the volume needed for PK, PK, and 
Immunogenicity) is collected into a single serum separation tube. 
10 Whole blood will be collected for the Pharmacogenetic sample at any time during the study upon the participant's informed consent for this specific analysis purpose. 
Refer to Table 8-7 
11 Samples to be collected also at time of VOCs, if possible. Refer to Table 8-7 
 
  
 
 
. 
16 Assessment to be done as part of the abbreviated physical examination and then at the End of Treatment and at the Follow-up visit. Refer to Section 8.5.4.1 

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17 Follow-up in case of treatment discontinuation before end of week 52: Monthly phone calls up to 1 year after first treatment to follow-up and monitor VOCs/APCs 
leading to healthcare visit in participants who discontinued treatment during first year of treatment  (including participants who continue crizanlizumab outside the study). 
18 Refer to Table 8-3 
19 Refer to Section 8.5.1 
20 After completion of primary analysis, participants randomized to placebo will be switched to crizanlizumab. Check Section 8.7 for eligibility criteria to be met prior to 
commencing treatment. 
21 Body weight measure is to be collected at every treatment visit so that the correct treatment dose is calculated before preparing the infusion. For treatment visits 
following Week 1 Day 1 visit, in order to avoid potential delays in the administration of the investigational treatment, infusion can be prepared in advance by using the 
participant’s body weight collected at the previous treatment visit.  
In all cases, body weight must be verified before dosing the participant and, if more than 5% of difference in body weight (between previous and current visit) is identified, 
infusion will be re-prepared using the participant’s body weight collected at the current visit.  
22 Medical history of VOC includes those VOCs leading to healthcare visit (uncomplicated VOC, acute chest syndrome, priapism, hepatic and splenic sequestration 
events) and APCs leading to healthcare visit that the participant experienced within the 12 months prior to screening visit and also those VOCs/APCs leading to 
healthcare visit experienced during the screening phase ending 7 days prior to Week 1 Day 1 dosing. 
23  Additional samples to be collected according to Section 8.3.1. Samples will be collected so long as COVID-19 infections remain active within respective local 
geographic environment. Upon agreement between sponsor and local investigator, or once the participant is vaccinated (upon availability), the sample collection and 
testing may be stopped.  
 
 
 
In case a patient has a grade 3 or 4 AE that is a suspected IRR, the sample should be collected as soon as possible after the start of the AE 
25 If urine pregnancy test is positive a serum pregnancy test must be performed (refer to Section 8.4.3).  
26The participants continuing crizanlizumab upon completion of their EOT visit, via commercial supply or post-trial access (e.g. enrollment in a Novartis post-trial access 
program to provide continued study treatment), upon completion of EOT visit, do not have to complete the post-treatment follow-up. Exception will be made if treatment 
discontinuation occurred before end of week 52, the monthly phone calls up to 1 year after first treatment will be required. If the participant will continue crizanlizumab 
beyond the EOT visit, via commercial supply or post-trial access, the assessments requested at EOT visit will have to be performed prior to next crizanlizumab infusion. 
For participants discontinuing from study treatment prior to completion of W259D1 visit and continuing under crizanlizumab outside the study, and for all participants 
completing the W259D1 visit whether they continue on crizanlizumab outside the study or not, EOT visit should be completed 28 days +/-7 days from last dose  
27 Samples for COVID-19 Ab testing should not be collected after W23D1 for adolescents with body weight ≤ 25kg 
28 Hematology samples at W15D1 should not be collected for adolescents with body weight ≤ 25kg. They are instead collected at W15D2 
29 Chemistry samples at W15D1 should not be collected for adolescents with body weight ≤ 25kg. They are instead collected at W15D2 
30 Coagulation samples at W15D1 should not be collected for adolescents with body weight ≤ 25kg. They are instead collected at W15D2 
31 Blood sample for Pharmacogenetic testing should not be collected for adolescents with body weight ≤ 45kg 
32 Certain adverse events reported in the AE/SAE eCRF as Infusion Related Reactions will require the IRR eCRF to be completed 
33 At SCR visit, samples for COVID-19 Ab testing should not be collected on the same day when Hematology, Chemistry, Coagulation and Hepatitis/HIV samples are 
collected for adolescents with body weight ≤ 25kg 
34 Local sampling for platelet assessment will be performed throughout the trial for adolescents with body weight > 45kg and adults 

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8.1 
Screening 
After signing the study ICF, the screening assessments will be done within 1 to 28 days prior 
to Week 1 Day 1. Re-screening of participants is only allowed if the participant was not 
randomized and treated previously. In case of re-screening, site should enter this participant as 
a new participant in IRT via the Rescreen form, where the original participant No. must be 
added. If participant has been randomized and treated, re-screening of participant is not allowed. 
In case re-screening 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. 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 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 sampling will be performed throughout 
the trial for adolescents with body weight >45kg and adults. 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 screening failure. An 
additional genetic informed consent will be available to the participant for optional participation 
in the pharmacogenetics part of the trial. 
8.1.1 
Eligibility screening 
The investigator is responsible to ensure only participants who meet all inclusion and do not 
meet any exclusion criteria are included in the study. An eligibility question will be included 
on the Randomization Form available 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 but fail to be randomized for any reason will be 
considered a screen failure. The reason for not starting treatment will be entered on the 
screening phase disposition page. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for screen failure 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 phase (see Section 10.1.3 
for SAE reporting details). If the participant fails to be randomized, the IRT must be notified 
within 2 days of the screen fail that the participant was not randomized. 
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 diagnosis of Sickle Cell 
Disease and Vaso–Occlusive Crisis History, prior use of HU/HC and reason for discontinuation 
(as applicable), ECG, ECOG/Karnofsky performance status, relevant and current medical 
conditions and alcohol and smoking history will also be collected. 

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8.3 
Efficacy 
8.3.1 
Efficacy assessment 
Definitions 
Vaso-occlusive crisis (VOC) 
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 as defined below will be considered VOC in this study.  
For purposes of this study, the following detailed definitions will be used to identify each 
subtype of VOC event: 
1. Uncomplicated VOC is defined as an acute episode of pain with no known cause for pain 
other than a vaso-occlusive event, and requiring treatment with a parenteral or oral opioid 
or other parenteral NSAIDs, but is NOT classified as an ACS, hepatic sequestration, splenic 
sequestration or priapism.  
Resolution of the uncomplicated VOC:  
• An uncomplicated VOC will end once the acute pain has resolved and the pain 
medications given to manage the acute episode of pain have been discontinued. 
• In participants with residual pain after an uncomplicated VOC, the uncomplicated 
VOC will end once the acute pain has resolved such that residual pain becomes 
chronic, and the current pain medication regimen is used to manage the residual 
chronic pain. 
• For participants with chronic pain prior to onset of an uncomplicated VOC, the 
uncomplicated VOC will end once the participant discontinues the pain medication 
given to manage the uncomplicated VOC and returns back to baseline in terms of prior 
pain and  pain medication regimen.  
2. Acute Chest Syndrome (ACS) is defined on the basis of the finding of a new pulmonary 
infiltrate involving at least one complete lung segment that was consistent with alveolar 
consolidation, but excluding atelectasis (as indicated by chest X-ray). At least one of the 
following additional signs or symptoms needs to be present as well: chest pain, a 
temperature of more than 38.5°C, tachypnea, hypoxia, wheezing or cough.  
ACS will end when the participant is no longer hospitalized (unless for reason other than 
the ACS episode) and none of the additional signs or symptoms above are present. 
3. Priapism is defined as an unwanted or painful penile erection lasting at least 30 minutes. 
The end of an acute priapism event will be when the unwanted erection has resolved for at 
least 2 hours. 
4. Hepatic sequestration is defined on the basis of findings of right upper quadrant pain, an 
enlarged liver, and an acute decrease in hemoglobin concentration (e.g. a decrease in 
hemoglobin of ~ 2 g/dL).  
Acute hepatic sequestration will end when right upper quadrant pain has returned to baseline 
(pre-event) levels and hemoglobin has been stable for 24 hrs. 

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5. Splenic sequestration is defined on the basis of findings of left upper quadrant pain, an 
enlarged spleen, and an acute decrease in hemoglobin concentration (e.g., a decrease in 
hemoglobin of ~ 2 g/dL).  
Acute splenic sequestration will end when left upper quadrant pain has returned to baseline 
(pre-event) levels and hemoglobin has been stable for 24 hrs. 
 
VOCs as defined above, can be managed at home or by a healthcare visit.  
• VOC leading to healthcare visit 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.  
• VOC managed at home is defined as a VOC with no visit to any medical facility 
and/or healthcare professional to receive treatment for VOC. Healthcare contacts for 
medical advice or collection of analgesic prescription in a medical facility are allowed. 
Participants should contact the Investigator (or surrogate from the site) within 24 
hours when they believe they are experiencing a VOC that they can manage at home, 
both for treatment guidance and for accurate information to collect in the VOC eCRF 
page. 
Other acute pain crises (APCs) 
In addition to VOCs as defined above, other APCs are of interest in this study.  Other APC is 
defined as an acute episode of pain with no known cause for pain other than vaso-occlusion, 
and requiring treatment with analgesics other than opioids or parenteral NSAIDs. 
- 
 Other APC leading to healthcare visit is defined as an APC with any visit to a medical 
facility such as an emergency room, hospital and/or office visit, which includes pain 
management of that APC in situ.  
- 
 Other APC managed at home is defined as an other APC with no visit to any medical 
facility and/or healthcare professional to receive treatment for APC 
Resolution of other APCs will match the definition of resolution of uncomplicated 
VOCs (see above). A participant experiencing other APCs managed at home should 
contact the investigator within 24h, as indicated for VOCs managed at home (see 
above).   
VOCs or other APCs that start within 7 days of the end of the preceding crisis event and which 
are considered a recurrence or continuation of the same event (e.g. based on clinical presentation 
and/or location) should be reported together with the preceding event as a single event. In such 
a case, the start and end date of this single event will be revised accordingly to cover its full 
duration.  
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 or other APC event. Similarly, 
complications such as pulmonary, cardiac, or renal failure are not themselves to be considered 
crises. If such events precipitate VOC or other APC, the event will be documented separately. 

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For each visit to a medical facility for a pain episode thought to be a VOC or other APC, the 
following information must be documented in the eCRF: diagnostic evaluation for the episode, 
participant treatment, route of administration and management, course, duration of the crisis, 
and outcome. For participants who are treated at medical facilities other than the study site, 
summary documents (e.g. ER or hospital discharge summaries) will need to be obtained.  
If a participant experiences a VOC/ other APC 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/other APC 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.  
VOC/APC leading to healthcare visit will be reviewed and determined by an Adjudication 
Committee (AC) comprised of independent hematologists as defined in the AC Charter. 
Chest X-ray 
Chest X- ray must be conducted within 3 months prior to Week 1 Day 1. Chest X- ray must be 
repeated during the study in case of suspected ACS and reported as unscheduled assessment in 
eCRF. 
Transfusions:  
Participants participating in a chronic transfusion program (pre-planned series of transfusions 
for prophylactic purposes) are not eligible. Episodic transfusion in response to worsened anemia 
or vaso-occlusive crisis is permitted and investigators are encouraged to obtain PK/PD samples 
before and after the simple or exchange transfusion is administered. 
For participants who discontinued investigational treatment during the first year, phone calls 
will be scheduled monthly after treatment discontinuation to collect data over VOC/APC 
leading to healthcare visit up to one year following the first treatment administration. Sufficient 
data should be collected by the investigator to allow adjudication of these VOCs/APCs leading 
to healthcare visit as for any other VOC/APC occurring during the study. 
Table 8-2 
VOC or other APC Assessment Collection Plan 
Procedure / Assessment 
collection plan 
Screening/Baseline 
During Treatment/Follow-up 
Chest X-Ray1 
Mandated 
If clinically indicated 
VOC or other APC information 
Mandated 
Mandated, when VOC or other 
APC occurs 
Concomitant medication - 
Analgesics 
If clinically indicated 
Mandated, when VOC or other 
APC occurs 
Healthcare resource utilization 
details 
If clinically indicated 
Mandated, when VOC or other 
APC occurs 
Transfusion 
If clinically indicated 
If clinically indicated 

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Procedure / Assessment 
collection plan 
Screening/Baseline 
During Treatment/Follow-up 
Pharmacokinetic, 
Pharmacodynamic and 
Immunogenicity samples 
Not Applicable 
Optional at onset and 
resolution of VOC, fever or 
suspected infection. Optional 
before and after transfusion 
1 Within 3 months of Week 1 Day 1 dosing 
8.3.2 
Appropriateness of efficacy assessments 
The primary endpoint of annualized rate of VOC leading to healthcare visit is an established 
surrogate efficacy endpoint used for regulatory approvals. However, there is no homogeneous 
definition of VOC. 
The definition of VOC leading to healthcare visit used in the present study is the same to the 
SUSTAIN study in order to have comparable results. 
8.4 
Safety 
Safety will be monitored by assessing physical examinations, vital signs, ECG, laboratory 
assessments including hematology, chemistry, coagulation, urinalysis, immunogenicity and as 
well as collecting of the adverse events at every visit. 
For details on AE collection and reporting, refer to Section 10.1.1. 
Table 8-3 
Assessments & 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 at Screening and within 7 days 
following last infusion. An abbreviated (short) physical exam will include the 
examination of general appearance and vital signs, as well as additional 
components of the physical exam 
 as 
needed based on observed signs or reported symptoms. A short physical 
exam will be performed at all visits for which there is a scheduled 
investigational treatment infusion. Significant findings that were present 
prior to the signing of informed consent must be included in the Medical 
History page on the participant’s 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 sign 
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). The participants continuing crizanlizumab 
upon completion of their EOT visit via commercial supply or post-trial 
access (e.g. commercial drug or enrollment in a Novartis post-trial access 
program to provide continued study treatment), do not have to complete the 
post-treatment follow-up.  

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Assessment 
Specification 
Body height and body 
weight 
Height will be measured at screening in adults and adolescents, then 
annually and at end of treatment visit, only for adolescents. 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. 
Growth and sexual 
maturation in 
adolescents 
Pubertal stage according to Tanner staging will be scored at Week 1 Day 
1, at the end of first year of treatment (week 51 Day 1), every year and at 
End of Treatment visit. 
8.4.1 
Laboratory evaluations 
Clinical laboratory analyses (hematology, chemistry, urinalysis, coagulation, hepatitis and HIV 
markers, COVID-19 Ab testing, serum pregnancy test and fetal hemoglobin) are to be 
performed centrally, unless otherwise mentioned in the schedule of assessments. Novartis must 
be provided with a copy of the central laboratory’s certification (if applicable), 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. Additionally, if at any time a participant 
has laboratory parameters obtained from a different (outside) laboratory, Novartis must be 
provided with a copy of the certification and a tabulation of the normal ranges and units for this 
laboratory as well. 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, only 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 sampling will be performed throughout the trial for adolescents with body 
weight >45kg and adults.. In such a case, eligibility may be based on the results from the local 
laboratory and a copy of the local lab normal ranges must be provided. 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, 

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or require therapeutic intervention), whether specifically requested in the protocol or not, 
will be recorded on the AE eCRF page. The severity of laboratory data will be graded using 
the Common Terminology Criteria for Adverse events (CTCAE) version 5. Additional 
analyses are left to the discretion of the investigator. 
 
Table 8-4 
Central Clinical laboratory parameters collection plan 
Test Category (***) 
*Test Name 
Hematology 
Hematocrit, 
Hemoglobin, 
MCH, 
MCHC, 
MCV, 
Reticulocytes 
(%), 
Platelets*****, Red blood cells, White blood cells, 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, Total Cholesterol, LDL, HDL, 
Total Protein, Triglycerides, Blood Urea Nitrogen (BUN) or Urea (**), Uric Acid, 
Amylase, Lipase, Glucose (non-fasting), estimated glomerular filtration rate 
(eGFR).  
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 
Albumin/Creatinine Ratio Microalbumin 
Coagulation 
PT, International normalized ratio [INR], Activated partial thromboplastin time 
(APTT) 
Hepatitis markers 
HBV-DNA, HBsAg, HBsAb, HBcAb, HCV RNA-PCR, HCV Ab (at Screening 
only) 
Additional tests 
HIV Ab (at Screening only), Fetal hemoglobin, and COVID-19**** Ab 
(including but not limited to) 
Pregnancy Test 
Serum pregnancy test (at Screening, EOT and follow-up visit only), urine 
pregnancy test (before each infusion) will be done locally. 
* Local clinical laboratory collection only where specified 
** Either BUN or Urea test to be performed. It will be defined in the Laboratory manual. 
*** At the discretion of the Investigator, safety laboratory tests can be performed locally before dosing 
(i.e, the day before or even on the same dosing day), even if not required per Protocol 
****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. Please refer to 
lab manual for sample volume requirements and collection times for Ab testing 
*****Local sampling for platelets count test will be performed throughout the trial for adults and 
adolescents with body weight >45kg 
8.4.1.1 
Fetal Hemoglobin 
HbF by HPLC will be performed at the central lab to screen for hemoglobin variants in whole 
blood including HbA, HbS, HbC, HbF, and HbA2. 
Samples will be collected at Week 1 Day 1, Week 27 Day 1, every 3 months during the first 
year and then, every 6 months and at the end of treatment. 

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8.4.2 
Electrocardiogram (ECG) 
Standard 12-lead ECGs will be performed (in the supine position) after the participant has been 
resting for at least 5 min (10 min resting period preferred) prior to each time point indicated in 
Table 8-5.  
Table 8-5 
ECG collection plan 
Visit 
 Timea, b 
ECG Type 
Screening (Day -28 to Day -1) 
Anytime 
Single 12-Lead (local ECG) 
Week 1 Day 1 
Pre-dose (before infusion) 
Triplicate 12 Lead (central ECG) 
Week 15 Day 1c 
Pre-dose (before infusion) 
Single 12-Lead (central ECG) 
Week 15 Day 1c 
2h post-dose (± 5 min) 
Single 12 Lead (central ECG) 
Week 23 Day 1 (6 months) 
Pre-dose (before infusion) 
Single 12-Lead (local ECG) 
Week 47 Day 1 (12 months) 
Pre-dose(before infusion) 
Single 12-Lead (local ECG) 
Every 12 months (until 5 
years) 
Pre-dose (before infusion) 
Single 12-Lead (local ECG) 
End of Treatment 
Anytime  
Single 12-Lead (local ECG) 
Unscheduled with clinically 
significant findings 
Anytime 
Triplicate 12-Lead (central ECG) 
a The exact date and time of dosing must be recorded on the appropriate eCRF. Interpretation of the 
tracing must be made by a qualified physician and documented on the ECG eCRF page. Each ECG 
tracing should be labeled with the study number, participant initials (where regulations permit), 
participant number, date, and kept in the source documents at the study site. Additional, unscheduled 
ECGs may be repeated 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 and sent 
for central review. The mean result of the central 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. 
b All post dose ECG time points are to be calculated based on the start time of the infusion.  
c At week 15 Day 1, 2h post-dose measure is planned for steady-state.  If steady-state is not achieved 
at week 15 Day 1, then ECG should be shifted to correlate with steady-state PK/PD sampling visit and 
submitted for central review.  Week 15 Day 1 pre-dose ECG should still be performed at the 
designated visit regardless of steady-state. 
8.4.2.1 
Cardiac imaging - Echocardiogram 
Cardiac imaging will be performed by Echocardiogram (ECHO) in order to assess the left 
ventricular ejection fraction (LVEF) and mean pulmonary arterial pressure (mPAP), as 
estimated from the tricuspid regurgitation jet velocity (TRV) if assessable, or otherwise by other 
formula (per institutional preference). This assessment will be performed locally, interpreted 
by site personnel as per Table 8-1 and documented on the eCRF page containing information 
on LVEF, TRV, (estimated) mPAP and an overall assessment in case abnormal findings. 
Each echocardiography must be kept in the source documents at the study site. Clinically 
significant Echo abnormalities present at screening when the participant signed informed 
consent should be reported on the Medical History eCRF page. 

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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 pre-menopause 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 if requested by local requirements. 
Serum pregnancy testing is required at screening, at the EOT visit and at the end of the follow 
up visit. During the study, urine pregnancy testing will be performed locally prior to each 
dosing. The positive urine test needs to be confirmed with serum test. If positive, the participant 
must be discontinued from study treatment. 
Local pregnancy test and associated results will not be collected on eCRF. 
8.5 
Additional assessments 

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Trial Feedback Questionnaire (TFQ) 
This trial will include an option for participants to complete an anonymized questionnaire, ‘Trial 
Feedback Questionnaire’ at Week 1 Day 1, Week 15 Day 1 and EOT. The intention of this 
questionnaire is to collect participant feedback on their clinical trial experience. Individual 
participant level responses will NOT be reviewed by investigators. Novartis will use these 
responses to understand where improvements can be made in the clinical trial process. This 
questionnaire DOES NOT collect data about the participant's disease, symptoms, treatment 
effect or adverse events, and therefore would not be trial data.  

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8.5.2 
Pharmacokinetics 
Serial blood samples will be collected from all participants to assess PK/PD/IG of 
crizanlizumab. Non-compartmental PK and PD parameters will be derived from each individual 
serum concentration- or inhibition-time profile using appropriate methods and software. Refer 
to Section 12.5.3 for a table of PK parameters that will be derived. Additionally, when possible 
and appropriate, PK/PD/IG samples should be collected at the time of onset and resolution of 
VOC event, fever, or suspected infection and at the time of transfusion (prior to and ≥ 24 hours 
after each of the listed events). 
8.5.2.1 
Pharmacokinetics, pharmacodynamics, and immunogenicity blood 
collection and handling 
At specified time points described in Table 8-6, blood samples will be taken by either direct 
venipuncture or an indwelling cannula inserted in a forearm vein. 
For PK/PD/IG samples, blood draws will be collected into serum separator tubes (without 
anticoagulant) and allowed to clot for 30 minutes (undisturbed) at room temperature. The tubes 
will be centrifuged for 10 minutes at approximately 3000 x g in order to separate serum. Each 
serum sample will be aliquoted and transferred into freezer-proof polypropylene screw-cap 
tubes (2 tubes for PK, 2 tubes for PD, and 3 tubes for IG at each specified time points, at least 
0.5 mL serum in each tube). The serum tubes will be frozen within 90 minutes of venipuncture 
and kept at -70ºC in an upright position until shipment and analysis. 
Each serum samples should be labeled with the appropriate study, center, and participant 
numbers, as well as the sequential PK/PD/IG samples and PK/PD/IG collection number with a 
unique sample number. The actual collection date and time of each sample will be entered on 
the PK/PD/IG blood collection eCRF pages. On days and time points where blood PK/PD/IG 
samples are to be drawn, the PK samples must be drawn first. The exact date and time of dosing, 
as well as the date and actual time of blood sampling must be recorded on the appropriate eCRF. 
Sampling problems will be noted in the relevant field of eCRF. 
Refer to the [CSEG101A2301 Laboratory Manual] for detailed instructions for the collection, 
handling, and shipment of PK/PD/IG samples. 
Table 8-6 
Pharmacokinetics, pharmacodynamics, and immunogenicity blood 
collection log 
Week 
Day 
Scheduled 
time point 
following 
initiation 
of 
infusiona 
PK collection 
number/Dose 
reference ID 
PK 
Sample 
No 
PD 
sample 
Nob 
IG 
sample 
No 
Sample 
volume 
(mL) 
1 
1 
Pre-dose 
1 
-- 
1 
101 
201 
7.5 
1 
1 
0.5hg (± 10 
min; end of 
infusion) 
1 
-- 
2 
-- 
-- 
2.5 
1 
1 
2h (± 30 
min) 
1 
-- 
3 
102h 
-- 
5 

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Week 
Day 
Scheduled 
time point 
following 
initiation 
of 
infusiona 
PK collection 
number/Dose 
reference ID 
PK 
Sample 
No 
PD 
sample 
Nob 
IG 
sample 
No 
Sample 
volume 
(mL) 
1 
1 
4h (± 
30 min) 
1 
-- 
4 
-- 
-- 
2.5 
1 
2 
24h (± 2h) 
1 
-- 
5 
103 
-- 
5 
1 
4 
72h (± 2h) 
1 
-- 
6 
104 
-- 
5 
2 
1 
168h (± 
24h) 
1 
-- 
7 
105 
-- 
5 
3 
1 
Pre-dosee 
2 
101c 
8 
106 
202 
7.5 
7 
1 
Pre-dosee  
3 
201c 
9 
107 
-- 
5 
11 
1 
Pre-dosee  
4 
301c 
10 
108 
-- 
5 
15d 
1 
Pre-dosee 
5 
401c 
11 
109 
203 
7.5 
15d 
1 
0.5hg (± 10  
min; end of 
infusion) 
5 
-- 
12 
-- 
-- 
2.5 
15d 
1 
2h (± 30 
min) 
5 
-- 
13 
110 
-- 
5 
15d 
1 
4h (± 
30 min) 
5 
-- 
14 
-- 
-- 
2.5 
15d 
2 
24h (± 2h) 
5 
-- 
15 
111 
-- 
5 
15d 
4 
72h (± 2h) 
5 
-- 
16 
112 
-- 
5 
16d 
1 
168h (± 
24h) 
5 
-- 
17 
113h 
-- 
5 
17d 
1 
336h (± 
24h) 
5 
-- 
18 
114 
-- 
5 
18d 
1 
504h (± 
24h) 
5 
-- 
19 
115h 
-- 
5 
19d 
1 
Pre-dosee 
6 
501c 
20 
116 
204h 
7.5 
23 
1 
Pre-dosee 
7 
601c 
21 
117 
-- 
5 
27 
1 
Pre-dosee 
8 
701c 
22 
118 
205 
7.5 
51 
1 
Pre-dosee 
9 
801c 
23 
119 
206 
7.5 
75 
1 
Pre-dosee 
10 
901c 
24 
-- 
207 
5 
99 
1 
Pre-dosee 
11 
1001c 
25 
-- 
208 
5 
147 
1 
Pre-dosee 
12 
1101c 
26 
-- 
209 
5 
195 
1 
Pre-dosee 
13 
1201c 
27 
-- 
210 
5 
243 
1 
Pre-dosee 
14 
1301c 
28 
-- 
211 
5 
End of 
Treatment 
(EOT) 
1 
-- 
 
1401 
29 
-- 
212 
5 
Follow up 
1 
 
-- 
-- 
1501 
30 
-- 
213 
5 

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Week 
Day 
Scheduled 
time point 
following 
initiation 
of 
infusiona 
PK collection 
number/Dose 
reference ID 
PK 
Sample 
No 
PD 
sample 
Nob 
IG 
sample 
No 
Sample 
volume 
(mL) 
(Last 
infusion + 
105 days) 
Unscheduled 
Samplef 
Anytime 
-- 
-- 
-- 
1001+ 
2001+ 
3001+ 
7.5 
a Scheduled PK/PD/IG time points are relative to the start of infusion of crizanlizumab. All blood 
samples are to be collected from the arm opposite from the investigational drug infusion. On days and 
time points where blood PK/PD/IG samples are to be drawn, the PK samples must be drawn first. 
b PD: P-selectin inhibition 
c For any PK pre-dose samples (sample numbers 8-11, 20-29), the actual date and time of 
administration of the previous dose of study medication (therapy) should also be recorded with 
appropriate Dose reference IDs as indicated in the above table. 
d Sampling to occur at steady-state (week 15). If dose is interrupted (missed dose) or an infusion is 
delayed beyond the visit day before week 15, the steady-state sampling will occur after the dose has 
been resumed and at least 3 consecutive infusions have been given without interruption. 
e Within 24 hours before dose administration 
f Including at onset and resolution of VOC event, fever, or suspected infection and at the time of 
transfusion (prior to and ≥ 24 hours after each of the listed events), if feasible. 
g The 0.5h sample is intended for collection at end of typical 0.5h infusion. In the instance that infusion 
time is prolonged beyond 0.5h (for example if infusion is completed at 1h, then 0.5h sample will not be 
collected and end of infusion sample will be collected at 1h, if the end of the infusion is within 
collection window of 2h PK/PD sample then collection of 2h PK/PD sample is not required). Maximum 
allowed infusion time to allow PK/PD profile sampling is 2h, beyond which PK/PD sampling for profile 
purpose will not proceed. However, despite the delay in infusion, if the full dose is administered at the 
visit day then multiple dose PK/PD profile sampling may occur at week 15. In this case, pre-dose 
PK/PD sampling at weeks 3, 7 or 11 will still need to be collected.  
h W1D1 PD 2h sample number 102, W16D1 PD sample number 113, W18D1 PD 
sample number 115, W19D1 IG sample number 204 should not be collected for adolescents with 
weight  ≤ 25 kg. The blood volume for adolescent with body ≤ 25 kg is is aligned with EMA guideline 
2017 
8.5.2.2 
Analytical method 
The crizanlizumab PK assay is a target capture ELISA to determine the concentration of 
crizanlizumab remaining in serum samples. Concentrations below the lower limit of 
quantification (LLOQ) will be reported as 0.00 μg/mL and missing samples will be labeled 
accordingly. 
A pharmacodynamic (PD) marker of crizanlizumab is the ex vivo P-selectin inhibition measured 
by a surface plasmon resonance assay using human serum samples. Crizanlizumab in serum 
samples binds to spiked Psel-Ig (P-selectin coupled to Ig) and inhibits is binding to a PSGL1 
peptide. 
Immunogenicity determination will be performed using a bridging immunoassay format 
validated for immunogenicity screening in human serum samples. 
Details of each analytical method will be given in bioanalytical data reports. 

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8.6 
Participant Off-site research nursing visits 
At the investigator’s direction and based on benefit-risk considerations of the participant’s 
clinical condition, qualifying participants may be offered the option to have certain clinical trial 
procedures according to Table 8-1 performed at an off-site location. The off-site location is not 
a site location where the investigator will conduct the trial and where source data will be 
maintained, but is for example the participant’s home or another safe location. Suitability for 
the off-site location will be assessed by the Off-site Research Nurse (ORN) and ultimately 
decided by the investigator.  
These off-site visits will involve a qualified ORN who will visit the participant to perform study 
procedures according to Table 8-1 under delegation of the investigator. The investigator will 
retain accountability for participant oversight and all medical decisions (i.e. protocol specified 
medical procedures, AE/SAE assessment and reporting, changes in medication, etc.). The 
rationale for the optional off-site visits is to unburden the participant by reducing the number 
of times they are required to travel the study site. 
The off-site visits will be offered in certain countries and sites as determined by Novartis. Off-
site visits may replace on-site visits if Novartis, investigator and local regulations and 
conditions allow.   
Procedures can be conducted in an off-site location after one year on treatment if agreed 
between investigator, participant, and Novartis. Off-site visits may only occur if they can be 
done without affecting the wellbeing of the participant during the study and with the same level 
of scientific integrity as assessments conducted on-site.  
The following conditions must be met for infusion of investigational treatment to occur at an 
off-site location: 
• The participant must have completed one year of treatment on-site (up to and including 
week 51 day 1). 
• At least the last 3 consecutive infusion visits must have occurred on-site without any 
AE Grade 3 or higher (possibly related to study treatment) or Grade 2 IRR and/or any 
concurrent medical conditions which, in the opinion of the investigator, could cause 
unacceptable safety risks. 
o Where a participant has begun off-site visits and an AE Grade 3 or higher 
(possibly related to study treatment) or Grade 2 IRR and/or any concurrent 
medical conditions which, in the opinion of the investigator, could cause 
unacceptable safety risks occurs, the participant must resume the on-site visits 
until the above condition is met 
o Where a participant switches from placebo to crizanlizumab following conduct 
of the primary analysis and unblinding of the study, the participant must 
resume/continue the on-site visits until the above condition is met for the 
treatment with crizanlizumab  
• The investigator must consider that emergency services are adequately accessible to the 
participant within a reasonable timeframe in order to treat any potential SAEs during 
the Off-site Research Nursing visit. 

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The participants are under no obligation to participate in off-site visits, as they can decide to 
continue with on-site visits at the study site. Participants that the investigator identifies as 
suitable as per the Off-site Study Operational Manual and who may benefit from off-site visits 
must provide consent in the optional Off-site Research Nursing Informed Consent. 
Participants have the right to revert to attend all, or specific, study visits on-site at the study site 
at any time. The investigator and Novartis also have the right to revert all, or specified, study 
visits to be performed on-site at the study site instead of off-site.  
Some on-site visits are expected when the investigator (or delegated study physician) needs to 
physically see the participant or study procedures can only be performed on-site. It is 
recommended that on-site visits occur every 3rd month during the participants second year of 
study treatment, and every 6th month during the participants 3rd, 4th and 5th years of study 
treatment when sample collection is scheduled. The on-site visit schedule will be determined in 
discussion between the participant, investigator, and Novartis.  
The information if a visit was conducted at an off-site location must be recorded on the visit 
date eCRF.  
The off-site visits will use a third-party vendor centrally sourced by Novartis that can provide 
qualified research nurses to perform study assessments. Investigator-delegated activities 
performed by the ORN will be under the oversight of the investigator who will be responsible 
to confirm that the ORN is adequately qualified and trained. The investigational treatment will 
be compounded according to the Pharmacy Manual. Shipping of investigational treatment will 
be under controlled conditions to be received by the qualified ORN for administration to the 
participant. The ORN will be blinded according to Section 6.4.  
Where off-site visits are offered to participants and if allowed by local regulations, Novartis-
may offer an approved third party Telemedicine platform to investigators, ORNs and 
participants to support the management and communication of the off-site research activities. 
The use of the platform is recommended for off-site visits as the provided software interface 
allows the investigator/delegate to connect securely via video call with the ORN and the 
participant during the off-site visit, if agreed by the participant. In addition, both site personnel 
and ORN can securely upload electronic copies of helpful information to facilitate the planning 
and conduct of the off-site visits. Site personnel may also share, where locally applicable, 
IRB/IEC/HA-approved educational materials with participants through the digital application, 
if agreed by the participant and the investigator. As ensuring data privacy and security is 
essential, the selected telemedicine platform uses measures such as data encryption, access 
controls and audit trails to ensure integrity, reliability and security of data flow.  
More details of the off-site research nursing and telemedicine processes are  outlined in a 
separate Off-site Study Operational Manual that will be provided to the sites participating in 
the off-site research nursing visits. 

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8.7 
 Eligibility criteria for participants who switch from placebo to 
crizanlizumab after primary analysis 
After completion of primary analysis (see Section 6.1.5.2), all participants randomized to 
placebo will be switched to crizanlizumab. Prior to commencing treatment with crizanlizumab, 
these participants must meet the following eligibility criteria: 
• ECOG performance status ≤ 2.0 for adults and Karnofsky ≥ 50% for adolescents 
• Participants must meet the following central laboratory values. In case of re-sampling 
needed, local laboratory values are allowed. Refer to Section 8.4.1 for further details: 
• 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 in adults, 
and Schwartz formula in adolescents  
• Direct (conjugated) bilirubin < 2.0 x ULN 
• Alanine transaminase (ALT) < 3.0 x ULN 
• Participants with concurrent severe and/or uncontrolled medical conditions which, in the 
opinion of the Investigator, could cause unacceptable safety risks must not initiate 
crizanlizumab. 
If the participant has not undergone these specific lab assessments 14 days prior to commencing 
treatment with crizanlizumab, they must be completed via an unscheduled visit in order to 
ensure the participant meets the eligibility criteria.  NOTE: An additional visit to allow the 
loading dose at a 2 week interval after the initiation of crizanlizumab must take place. 
Additional, unscheduled lab assessments can be performed at the discretion of the investigator 
as clinically indicated. 
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. 

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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 6.5.1, 
study treatment must also be discontinued under the following circumstances: 
• Pregnancy 
• Lactation 
• Participant/Guardian decision 
• Unsatisfactory therapeutic effect 
• Grade 4 AE and dose interruptions of investigational treatment due to toxicity (see Section 
6.5) 
• Use of prohibited medication (see Section 6.2.2) 
• Emergency unblinding before Primary Analysis, as described in Section 6.6.2 
• Any other protocol deviation that results in a significant risk to the participant’s safety 
• Other reason for earlier termination may include but are not limited to: 
• Decision based on recommendations from applicable board(s) after review of safety 
• Discontinuation of study drug development 
For participants who discontinue treatment during the first year (including participants who 
continue crizanlizumab outside the study), phone calls will be scheduled monthly after 
treatment discontinuation to collect data over VOCs/APCs leading to healthcare visit up to one 
year following the first treatment administration. Sufficient data (as specified in the adjudication 
charter) will be collected by the investigator to allow adjudication of these VOCs/APCs as any 
other VOC/APC occurring during the study. 
Following the treatment discontinuation, participants will perform an End of Treatment visit. If 
a participant misses 2 consecutive doses due to an ADR during the first year of treatment, the 
participant should be discontinued. Permanent treatment discontinuation is mandatory for 
specific events indicated as indicated in Table 6-3. All participants must be followed up for 
adverse events and serious adverse events for 105 days following the last doses of 
crizanlizumab. The participants continuing crizanlizumab upon completion of their EOT visit 
via commercial supply or post-trial access (e.g. enrollment in a Novartis post-trial access 
program to provide continued study treatment), do not have to complete post-treatment follow-
up.  If the participant will continue crizanlizumab beyond the EOT visit, via commercial supply 
or post-trial access, the assessments requested at EOT visit will have to be performed prior to 
next crizanlizumab infusion. For participants discontinuing from study treatment prior to 
completion of W259D1 visit and continuing under crizanlizumab outside the study, and for all 
participants completing the W259D1 visit whether they continue on crizanlizumab outside the 
study or not, EOT visit should be completed 28 days +/-7 days from the last dose. 
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code section. 

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9.1.2 
Withdrawal of informed consent 
Withdrawal of consent/opposition to use data/biological samples occurs when a participant: 
• 
Explicitly requests to stop use of their biological samples and/or data (opposition to use 
participant’s data and biological samples) and  
• 
No longer wishes to receive study treatment and  
• 
Does not want any further visits or assessments (including further study-related 
contacts). 
This request should be in writing (depending on local regulations) and recorded in the source 
documentation. 
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 their consent 
/opposition to use data/biological samples and record this information. 
Where consent to the use of Personal and Coded data is not required in a certain country's legal 
framework, the participant therefore cannot withdraw consent. However, they still retain the 
right to object to the further collection  or use of their 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. 
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/opposition to use data/biological samples should be made as detailed in the assessment 
table (refer to Section 8). 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation, including processing of biological samples that has already 
started at time of consent withdrawal/opposition. No new Personal Data (including biological 
samples) will be collected following withdrawal of consent/opposition. 
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 consent/oppose to the use of their data/biological 
samples, the investigator must show "due diligence" by documenting in the source documents 
steps taken to contact the participant, e.g. dates of telephone calls, registered letters, etc. A 
participant should not be considered as lost to follow-up until due diligence has been completed. 
9.1.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the participant welfare and safety. Should early termination be 
necessary, participants must be seen as soon as possible (provide instruction for contacting the 

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participant, when the participant should stop taking drug, when the participant should come for 
a final visit) 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 the local regulation will be responsible for informing IRBs/IECs of the early termination of 
the trial. 
9.2 
Study completion and post-study treatment 
Study completion is defined as when the last 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. 
The study will be completed when all the randomized participants have either completed or 
discontinued the study treatment and/or the 105 days follow-up period. The participants 
continuing crizanlizumab upon completion of their EOT visit via commercial supply or post-
trial access (e.g. enrollment in a Novartis post-trial access program to provide continued study 
treatment), do not have to complete post-treatment follow-up. Exception will be made if 
treatment discontinuation occurred before end of week 52, the monthly phone calls up to 1 year 
after first treatment will be required. 
The final analysis will occur when the study is completed. All available data from all 
participants up to the trial end will be analyzed and summarized in a final CSR. 
Novartis will provide crizanlizumab to participants who may benefit from continued 
treatment as per the Investigator's opinion after study completion until the earliest occurrence 
of the following:  
• Crizanlizumab is commercially available and reimbursed in the participant's country for 
this participant population, and participants are eligible to be prescribed the commercial 
drug 
• Another clinical study becomes available that can continue to provide crizanlizumab in 
this participant population and ongoing participants are eligible to be transferred to that 
clinical study 
• Participant is no longer deriving benefit per the investigator's evaluation. 
Safety will be monitored and reported to Health Authorities per regulatory requirements. 
10 
Safety monitoring and reporting 
As per  Section  4.6,  during  a  Public  Health  emergency  as  declared  by  Local  or  Regional  
authorities  i.e. pandemic,  epidemic  or  natural  disaster that limits or prevents on-site study 
visits, regular phone or virtual calls can occur  for safety monitoring and discussion of the 
participant´s health status until it is safe the participant to  visit the site again. This 
telephone/virtual 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 participant 
or 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 in the Adverse Events eCRF 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 Toxicity 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 the assessment 
of causality will usually be ‘Not suspected’. The rationale for this guidance is that the 
symptoms of a lack of efficacy are not caused by the trial drug, they happen in spite of its 
administration and/or a lack of efficacy 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, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown) 
If the event worsens, it should be reported a second time in the eCRF 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 

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in the eCRF 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. The participants continuing crizanlizumab upon completion of their EOT visit 
via commercial supply or post-trial access (e.g. enrollment in a Novartis post-trial access 
program to provide continued study treatment), do not have to complete post-treatment follow-
up.  
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 participants 
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 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  

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• 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. The 
participants continuing crizanlizumab upon completion of their EOT visit via commercial 
supply or post-trial access (e.g. enrollment in a Novartis post-trial access program to provide 
continued study treatment), do not have to complete post-treatment follow-up. SAEs occurring 
after the participant has provided informed consent until the time the participant is deemed a 
screen failure must be reported to Novartis.  
Information about all SAEs is collected and recorded on the electronic Serious Adverse Event 
Report Form; all applicable sections of the form must be completed in order to provide a 
clinically thorough report. The investigator must assess and record the relationship of each SAE 
to the study treatment, complete the eSAE Report Form in English, and submit the completed 
form within 24 hours to Novartis. Detailed instructions regarding the submission process and 
requirements are to be found in the investigator folder provided to each site. 
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 

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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. 
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, whether the 
blind was broken or not, 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 (EC) in accordance with EU Guidance 
2011/C172/01 or as per national regulatory requirements in participating countries. 
Any SAEs experienced after the 105 day period following the last administration of study 
treatment should only be reported to Novartis Safety if the investigator suspects a causal 
relationship to study treatment. The participants continuing crizanlizumab upon completion of 
their EOT visit via commercial supply or post-trial access (e.g. enrollment in a Novartis post-
trial access program to provide continued study treatment), do not have to complete post-
treatment follow-up.  
10.1.4 
Pregnancy reporting 
Pregnancies 
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. 
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 study treatment and 
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 
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Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the dose administration record (DAR) eCRF irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an SAE. Misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an AE/SAE 
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 Dose 
Administration (DAR) 
eCRF (Yes/No) 
Document in AE 
eCRF 
Complete eSAE 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. 
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 the procedures performed must be recorded as appropriate in the 
eCRF. 
10.2.2 
Data Monitoring Committee 
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will assess at defined intervals the progress 
of a clinical trial, safety data and recommend to Novartis whether to continue, modify, or 
terminate a trial. 
The DMC will consist of clinicians specialized in sickle cell disease and a biostatistician. 
Details of the role of the DMC will be described in the DMC charter. 
10.2.3 
Steering Committee 
The steering committee (SC) will be established comprising investigators participating in the 
clinical trial and Novartis representatives from the Clinical Trial Team. The SC will ensure 
transparent management of the study according to the protocol. The SC will review protocol 
amendments as appropriate. Together with the clinical trial team, the SC will also develop 

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recommendations for publications of study results including authorship rules. The details of the 
role of the Steering Committee will be defined in the Steering Committee charter. 
10.2.4 
Adjudication committee 
All VOCs/APCs leading to healthcare visit will be reviewed and confirmed by an Adjudication 
Committee. The AC will be comprised of independent hematologists specialized in the 
treatment of SCD, to ensure consistency across study sites and to allow for an unbiased endpoint 
assessment. 
All personnel involved in the adjudication process will remain blinded to participant 
information and treatment allocation. Specific details regarding the adjudication and endpoint 
definitions will be described in the AC charter. 
Case-by-case results of the adjudications will not be communicated to the sites. Consistency 
between investigator assessment and AC assessment of the VOC will be reviewed on an 
ongoing basis. Additional guidance may be provided to investigator in case of inconsistencies. 
10.3 
Protocol Exempt AEs & SAEs 
Protocol Exempt AEs & SAEs are implemented in the SEG101 program. VOCs and other APC 
must be reported on the VOC/other APC page in the eCRF. As VOCs and other APCs are 
considered endpoints for the purpose of evaluation of efficacy, AEs and SAEs involving VOCs 
or other APCs 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 8.3 are the VOCs and other APCs that will not be reported as AEs/SAEs. 
In case a VOC/APC event is suspected to be related to study treatment, and/or resulting in a 
fatal outcome, it will be reported as AE/SAE in addition to the VOC/acute pain 
crisis eCRF page.  
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 eCRF not being considered as source. 

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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 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 (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the 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 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, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment (s) dispensed to the participant and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis at specific timelines. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study primary analysis or upon request of 
Novartis. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 
available for data analysis/moved to restricted area to be accessed by independent programmer 
and statistician before the primary analysis. 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 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 

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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 eCRFs 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 eCRFs 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 
For this study, there are two main analyses: the primary analysis and the study completion 
analysis. 
The cut-off date for primary efficacy and safety analyses will be defined as the date where all 
randomized participants have reached one-year of treatment or discontinued within year 1. 
After the primary analysis, there will be no formal comparison of 7.5 mg/kg and 5.0 mg/kg 
respectively versus placebo since dose change or treatment change is allowed. However, the 
long term efficacy and safety after year 1 will be evaluated through efficacy and safety 
assessments by group (5.0 mg/kg only, 7.5 mg/kg only, placebo only, at least one dose 
escalation in the group with starting dose of 5.0 mg/kg, at least one dose reduction in the group 
with starting dose of 7.5 mg/kg, treatment change to 5.0 mg/kg in the group with starting 
treatment of placebo, treatment change to 7.5 mg/kg in the group with starting treatment of 
placebo). Periods defined based on pre- and post- switch of treatment/dose will be considered 
for the analyses. The analyses after the primary analysis will be descriptive and exploratory. 
The analysis will be performed when the study is complete. Hence, it is referred to as the "study 
completion analysis." 
In addition to the two main analyses, safety DMC analyses will also be performed prior to the 
primary analysis. 
The following sections will focus on the primary analysis. 

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Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
12.1 
Analysis sets 
The Full Analysis Set (FAS) comprises all participants to whom study treatment has been 
assigned by randomization. According to the intent to treat principle, participants will be 
analyzed according to the treatment and strata, they have been assigned to during the 
randomization procedure. 
The Safety Set includes all participants who received at least one dose of study treatment. 
Participants will be analyzed according to the study treatment received, where treatment 
received is defined as the randomized treatment if the participant took at least one dose of that 
treatment or the first treatment received if the randomized treatment was never received. 
The Pharmacokinetic analysis set 1 (PAS1) includes all participants who provide at least one 
evaluable PK profile. A profile is considered evaluable if all of the following conditions are 
satisfied: 
• participant receives the planned treatment of 5.0 mg/kg or 7.5 mg/kg before single dose PK 
profile or 3 consecutive doses of the planned treatment before the multiple dose PK profile  
• participant provides at least one PK parameter 
• participant does not have any transfusion of blood product in the last 4 weeks before the 
first PK sample of the full PK profile, or during the full PK profile 
The Pharmacokinetic analysis set 2 (PAS2) includes all participants who receive at least one 
planned treatment of 5.0 mg/kg or 7.5 mg/kg and provide at least one corresponding evaluable 
PK concentration. 
The pharmacodynamics analysis set 1 (PDS1) includes all participants who provide at least one 
evaluable PD profile. A profile is considered evaluable if all of the following conditions are 
satisfied: 
• participant receives the planned treatment of 5.0 mg/kg or 7.5 mg/kg before single dose PD 
profile or 3 consecutive doses of the planned treatment before the multiple dose PD profile 
• participants provides at least one PD-AUC (single dose or multiple dose) parameter 
• participant does not have any transfusion of blood product in the last 4 weeks before the 
first PD sample of the full PD profile, or during the full PD profile 
The pharmacodynamics analysis set 2 (PDS2) includes all participants who receive at least one 
planned treatment of 5.0 mg/kg or 7.5 mg/kg and provide at least one corresponding evaluable 
PD assessment. 
12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for the FAS. 
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. 

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Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, by treatment group. 
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 to investigational treatment (in months) 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. 
The number of participants with dose adjustments (interruption,) and the reasons will be 
summarized by treatment group 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 Anatomical Therapeutic 
Chemical (ATC) classification system and by treatment group. 
12.4 
Analysis of the primary endpoint(s) 
The primary objective is to compare the efficacy of 7.5 mg/kg and 5.0 mg/kg of crizanlizumab 
respectively versus placebo (in addition to standard of care) for preventing VOCs leading to 
healthcare visits over the first year post randomization in SCD patients 12 years and older at 
the time of study entry. The primary analysis cut-off date will be defined as the date by which 
all randomized participants have reached one-year of investigational treatment or discontinued 
within Year 1. 
12.4.1 
Definition of primary endpoint(s) 
The primary endpoint is the annualized rate of VOC events leading to healthcare visit in each 
treatment group over the first year post randomization. The annualized rate of VOC is the 
number of VOCs multiplied by 365 and divided by the number of days in the observation 
period. VOCs leading to healthcare visit will be reviewed and confirmed by an AC comprised 
of independent hematologists. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The scientific objective guiding the primary analysis is to estimate the treatment effect of 
crizanlizumab compared to placebo, for the target population on the annualized rate of VOC 
leading to healthcare visit. The treatment effect of interest shall be defined as: 
• on treatment over one year 
• without initiation or discontinuation of HU/HC or L-Glutamine (or other therapies to treat 
SCD and or to prevent/reduce VOCs such as voxelotor and erythropoietin) over the first 
year post randomization 
• and regardless of intake of analgesic (including opioids) or ad hoc transfusions 
administered temporarily 

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The primary efficacy endpoint, annualized rate of VOC leading to healthcare visit, will be 
analyzed based on the data from the FAS according to the treatment arm and the stratification 
factors participants were randomized to. In line with the treatment effect of interest, the primary 
observation period will include only data before study treatment discontinuation and before 
initiation or discontinuation of HU/HC or L-Glutamine (or other therapies to treat SCD and or 
to prevent/reduce VOCs such as voxelotor and erythropoietin); while data after intake of 
analgesic (including opioids) or ad hoc transfusions administered temporarily until one year 
post randomization, will be included. 
More details will be provided in a standalone document, defining the estimands. 
A negative binomial regression model with treatment and randomization stratification factors 
as covariates will be used for analysis, with the logarithm of observation time as offset. The 
estimates of annualized VOC rates between treatment groups and their 95% confidence 
intervals will be provided. 
To control the overall family-wise type I error rate (FWER) an appropriate multiplicity 
adjustment procedure using a closed testing strategy will be applied to the analyses of the 
primary and key secondary endpoints for the 2 doses comparisons to placebo. This strategy to 
preserve the overall FWER at α = 5% (two-sided) is described in Section 12.5.1. 
Pairwise comparison of the 7.5 mg/kg and 5.0 mg/kg crizanlizumab annualized rate of VOC 
leading to healthcare visit will be performed against the placebo. The following hypotheses will 
be tested: 
The primary statistical null hypotheses are: 
• H0(7.5 mg/kg): there is no difference between crizanlizumab 7.5 mg/kg and placebo groups 
with respect to the annualized rate of VOCs leading to healthcare visit over the first year 
post randomization 
• H0(5.0 mg/kg): there is no difference between crizanlizumab 5.0 mg/kg and placebo groups 
with respect to the annualized rate of VOCs leading to healthcare visit over the first year 
post randomization 
These hypotheses will be tested using the Wald test statistic within generalized linear model 
assuming a negative binomial distribution and will compare 7.5 mg/kg and 5.0 mg/kg 
crizanlizumab versus placebo at the appropriate α-level adjusted considering multiple testing 
(as described in Section 12.5.1).  
12.4.3 
Handling of missing values/censoring/discontinuations 
By using as primary endpoint the annualized rate of VOCs leading to healthcare visit, the 
intrinsic assumption is that the frequency of VOCs before treatment discontinuation would have 
been observed also for the entire first year of treatment. Supportive analyses are exploring 
different assumptions to handle missing data (Section 12.4.4). 

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12.4.4 
Sensitivity and Supportive analyses 
Supportive analyses 
For the supportive analysis 1, the treatment effect regardless of treatment discontinuation, 
initiation or discontinuation of HU/HC or L-Glutamine (or other therapies to treat SCD and or 
to prevent/reduce VOCs such as voxelotor and erythropoietin) during year 1 is of interest. 
Consequently, data collected after these events and before the end of year 1 will be included. 
For the supportive analysis 2, different imputation methods will be used for different reasons 
for treatment discontinuation and other events mentioned above.  For the supportive analysis 3, 
all the VOCs collected until the primary analysis cut-off and before treatment discontinuation 
and initiation or discontinuation of HU/HC or L-Glutamine (or other therapies to treat SCD and 
or to prevent/reduce VOCs such as voxelotor and erythropoietin) will be included. Details of 
the supportive analyses will be provided in a standalone estimand document. 
The same analyses as for the primary analysis will be repeated for the supportive analyses.  
The time to treatment discontinuation and the time to initiation or discontinuation of HU/HC or 
L-Glutamine (or other treatments to treat SCD and or to prevent/reduce VOCs such as voxelotor 
and erythropoietin) will be summarized using Kaplan-Meier methods. 
Some subgroup analyses of the primary efficacy endpoint are planned by the following 
subgroups, if there is enough participants in each category allowing such analysis: 
• Categorized Crisis (VOC) History: 2-4 and ≥ 5 
• HU/HC Use: YES and NO 
• Genotype: HbSS and HbSβ+ /HbSC/HbSβ0 /Other 
• Gender: Male and Female 
• Ethnicity: the subgroups of ethnicity will be defined in the SAP 
• Age: 12-<18, ≥18 years 
• Race: the subgroups of race will be defined in the SAP 
12.5 
Analysis of secondary endpoints 
The key secondary objective is to assess the annualized rate of all VOCs (managed at home + 
leading to healthcare visit) over the first year post randomization. Other secondary objectives 
over the first year post randomization include annualized rate of VOCs managed at home, rate 
of participants free from VOC leading to healthcare visit, time for first and second VOC leading 
to healthcare visit, duration of VOC leading to healthcare visit, healthcare resource utilization 
(visits to clinic, ER, hospitalizations), SCD-related renal damage and PK and PD (P-selectin 
inhibition). Another set of secondary objectives will evaluate the long-term efficacy, safety and 
immunogenicity of crizanlizumab not only over the first year post randomization but over the 
entire study period. 
Secondary efficacy endpoints will be analyzed using the FAS. For all safety analyses the safety 
set will be used. 

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12.5.1 
Efficacy endpoint(s) 
The key secondary efficacy endpoint is the annualized rate of all VOCs (managed at home + 
leading to healthcare visit) over the first year post randomization. VOCs managed at home 
reported in the eCRF and VOCs leading to healthcare visit assessed by AC will be considered. 
The analysis method used in the primary endpoint will be utilized for the key secondary 
endpoint. 
To ensure control of FWER of α = 5% (two-sided), the closed testing procedure will account 
for testing the primary (H1 for 7.5 mg/kg vs. Placebo and H2 for 5.0 mg/kg vs. Placebo) and 
key secondary endpoints (H3 for 7.5 mg/kg vs. Placebo and H4 for 5.0 mg/kg vs. Placebo) for 
each of the 2 doses comparisons to placebo, being a total of 4 hypotheses: 
• H1 for the primary endpoint comparison between 7.5 mg/kg and Placebo 
• H2 for the primary endpoint comparison between 5.0 mg/kg and Placebo 
• H3 for the key secondary endpoint comparison between 7.5 mg/kg and Placebo 
• H4 for the key secondary endpoint comparison between 5.0 mg/kg and Placebo 
Any intersection hypothesis will be tested by either a Dunnett-test or a Bonferroni-test 
(depending on whether the correlation is known or not) or a single test as described in Table 
12-1. All intersections which contain H1 and H2 (including the global hypothesis that all 4 
hypotheses are true) will be tested by the Dunnett test of H1 and H2. All intersections which 
contain (H1 and H4) or (H2 and H3) will be tested by the Bonferroni-test splitting alpha between 
H1 and H4 or H2 and H3, respectively. All intersections which contain H3 and H4 will be tested 
by the Dunnett test. All other tests will use full level alpha test. As per the closure principle, a 
given hypothesis Hi (with i=1, 2, 3, 4) will be rejected if all intersections it is in, are also 
rejected. In other words, the adjusted p-value will be the maximum of the p-values from all 
intersection tests in which Hi is included. The key secondary endpoint of a given dose will be 
tested only if the difference in the primary endpoint for the same dose is statistically significant. 
Table 12-1 
Intersection hypotheses and local significance levels 
Intersection 
hypotheses 
Test 
H1 
H2 
H3 
H4 
H1∩H2∩H3∩H
4 
Dunnett 
α* 
α* 
0 
0 
H1∩H2∩H3 
Dunnett 
α* 
α* 
0 
- 
H1∩H2∩H4 
Dunnett 
α* 
α* 
- 
0 
H1∩H2 
Dunnett 
α* 
α* 
- 
- 
H1∩H3∩H4 
Bonferroni 
splitting alpha 
α/2 
- 
0 
α/2 
H1∩H3 
Full level 
α 
- 
0 
- 
H1∩H4 
Bonferroni 
splitting alpha 
α/2 
- 
- 
α/2 
H1 
Full level 
α 
- 
- 
- 
H2∩H3∩H4 
Bonferroni 
splitting alpha 
- 
α/2 
α/2 
0 

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Intersection 
hypotheses 
Test 
H1 
H2 
H3 
H4 
H2∩H3 
Bonferroni 
splitting alpha 
- 
α/2 
α/2 
- 
H2∩H4 
Full level 
- 
α 
- 
0 
H2 
Full level 
- 
α 
- 
- 
H3∩H4 
Dunnett 
- 
- 
α* 
α* 
H3 
Full level 
- 
- 
α 
- 
H4 
Full level 
- 
- 
- 
α 
*adjusted alpha using Dunnett’s procedure 
For all other secondary endpoints described below, estimates and confidence intervals will be 
presented, but no formal statistical testing will be conducted. 
The same analyses as for the primary endpoint will be repeated for each subtype of VOC 
event  (uncomplicated VOC, acute chest syndrome, hepatic sequestration, splenic sequestration 
and priapism) leading to healthcare visit as per AC and for the annualized rate of VOC managed 
at home as reported in the eCRF. 
The number of participants free from VOC leading to healthcare visit as per AC will be 
presented. 
The time to first occurrence of VOC leading to healthcare visit will be summarized by treatment 
using Kaplan-Meier methods. Median time, 25th and 75th percentiles along with 95% 
confidence interval will be summarized and Kaplan-Meier plots will be generated. A stratified 
Cox regression analysis will be used to estimate the hazard ratio (HR), along with 95% 
confidence interval. The time to first occurrence of VOC leading to healthcare visit will be 
defined as the time from the date of randomization to the date of the first occurrence of the VOC 
as per AC. In the absence of a VOC leading to healthcare visit, participants will be censored at 
the time of the end of the primary observation period. 
The same analyses will be repeated for the time to second VOC leading to healthcare visit. The 
time to second occurrence of VOC leading to healthcare visit will be defined as the time from 
date of randomization to the date of the second occurrence of VOC leading to healthcare visit 
as per AC. In the absence of two VOCs leading to healthcare visit, the participant will be 
censored at the time of the end of the primary observation period. 
The mean duration of VOC leading to healthcare visit in days (defined as end date of the VOC 
per AC - start date of the VOC per AC + 1) will be described by treatment arm. 
The same analyses as for the primary endpoint will be repeated for the annualized rate of clinic, 
hospitalizations and ER visits (both overall and VOC-related) and for the annualized rate of 
days of clinic/ER/hospitalization (both total and VOC-related). 
SCD-related renal damage 
Renal function tests will be analyzed similarly to the laboratory data and as described in 
Section 12.5.2. In addition change from baseline will be presented. 

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Long-term efficacy 
The annualized rate of VOCs (leading to healthcare visit, managed at home and all) after 5 years 
of treatment post randomization will be summarized descriptively by groups in the FAS. The 
number and percentage of participants free from VOC leading to healthcare visit will be 
presented. Summaries will be provided for the corresponding annualized rate of VOC overall 
and per year and for the corresponding change from baseline. 
12.5.2 
Safety endpoints 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group.  
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 (or until EOT date for participants continuing crizanlizumab 
after their EOT via commercial supply or post-trial access program). 
3. Post-treatment period: starting at day 106 after last dose of study medication (or after 
EOT date for participants continuing crizanlizumab after their EOT via commercial 
supply or a post-trial access program). 
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). 
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), including infections, 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. 

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Clinical laboratory evaluations 
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5. 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 v5, results will be categorized as 
low/normal/high based on laboratory normal ranges. 
The following listings/summaries will be generated separately for hematology, biochemistry 
and urinalysis (macroscopic only) tests: 
• Listing of all laboratory data with values flagged to show the corresponding CTCAE v5 
grades if applicable and the classifications relative to the laboratory normal ranges 
For laboratory tests where grades are defined by CTCAE v5: 
• 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 v5 grades to compare baseline to the worst on-treatment value 
For laboratory tests where grades are not defined by CTCAE v5: 
• Shift tables using the low/normal/high/ (low and high) classification to compare baseline to 
the worst on-treatment value. 
Microscopic urinalyses tests will be provided in listings only. 
For hemoglobin parameter, summary and box plot of the absolute change from baseline over 
time will be provided. 
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in other laboratory tests over time or box plots 
might be specified in the analysis plan. 
Specific analyses to assess the impact of the renal (as part of efficacy) and liver function tests 
will be performed and described in the analysis plan. 
Immunogenicity 
Immunogenicity will be characterized descriptively tabulating ADAprevalence at baseline and 
ADA incidence on-treatment. 
Other safety evaluations 
Vital signs 
All vital signs data will be listed by treatment group, participant, and visit/time and if ranges 
are available, abnormalities will be flagged. Summary statistics will be provided by treatment 
and visit/time. 
Growth and sexual maturation 

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Data on growth and sexual maturation (Tanner stage) will be tabulated and listed for 
adolescents. 
12-lead ECG 
12-lead ECGs including PR, QRS, QT, QTcF and HR intervals will be obtained centrally or 
locally for each participant during the study. ECG data will be read and interpreted centrally or 
locally. 
All ECG data will be listed by treatment group, participant and visit/time, abnormalities will be 
flagged. Summary statistics will be provided by treatment and visit/time. 
12.5.3 
Pharmacokinetics 
Biofluid concentrations will be expressed in mass per volume units. All concentrations below 
the limit of quantitation or missing data will be reported as such in the concentration data 
listings. Concentrations below the limit of quantitation will be treated as zero in summary 
statistics. 
The inter-participant variations and CV% will be presented for the PK parameters. The point 
estimate and the corresponding two-sided 90% confidence interval (CI) for the mean of the log-
transformed PK parameters after single dose and multiple doses will be derived respectively in 
each treatment group. The point estimate and CI will be anti-log transformed to obtain the point 
estimate and the 90% confidence interval for the geometric mean on the original scale. 
The descriptive statistics (n, mean, CV%, standard deviation (SD), median, geometric mean, 
geometric CV%, minimum and maximum) will be presented for all PK parameters defined in 
Table 12-1 except Tmax, where only n, median, minimum and maximum will be presented 
since it is generally evaluated by a nonparametric method. Zero concentrations will not be 
included in the geometric mean calculation. The descriptive statistics will also be presented by 
the dose and age groups (adolescents and adults).  
The PAS1 for 5.0 mg/kg and 7.5 mg/kg treatment groups will be used for all PK analyses 
described above. 
Table 12-2 
Non-compartmental pharmacokinetic parameters 
AUCd15 
The AUC from time zero to the last measurable concentration sampling time (tlast) 
(mass x time x volume-1) after single dose 
AUCtau 
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x 
time x volume-1) 
Cmax 
The maximum (peak) observed serum drug concentration after dose administration 
(mass x volume-1) 
Tmax 
The time to reach maximum (peak) serum drug concentration after dose 
administration (time) 
Lambda_z  
Smallest (slowest) disposition (hybrid) rate constant (time-1) 
T1/2 
The half-life during a dose interval (time) 
Descriptive statistics for crizanlizumab concentration will be presented at each scheduled 
timepoint. 

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In addition, the mean (+/- SD) and median concentration-time profiles over time will be 
displayed graphically on the linear and semi-log view. 
All individual PK parameters and PK concentration data for crizanlizumab will be listed. 
In addition, the mean (+/- SD) and median pre-dose concentrations over time will be displayed 
graphically on the linear and semi-log view. 
The PAS2 for 5.0 mg/kg and 7.5 mg/kg treatment groups will be used for these PK analyses. 
Crizanlizumab concentrations may be integrated into a population pharmacokinetic model. 
Details of the analysis methods will be developed in an independent modeling analysis plan and 
will be documented in a separate report document. 
12.5.4 
Pharmacodynamics 
PD-AUCd15 and PD-AUCd29 will be derived from the P-selectin inhibition data of week 1 and 
week 15, respectively. The point estimate and the corresponding two-sided 90% CI for the mean 
of the log-transformed PD-AUC after single dose and multiple doses will also be provided by 
treatment group. The point estimate and CI will be anti-log transformed to obtain the point 
estimate and the 90% confidence interval for the geometric mean on the original scale. 
The descriptive statistics will also be presented by the dose and age groups (adolescents and 
adults). 
The PDS1 for 5.0 mg/kg and 7.5 mg/kg treatment groups will be used for all PD analyses 
described above. 
Descriptive statistics for PD inhibition will be presented at each scheduled timepoint. 
In addition, the mean (+/- SD) and median PD-time profiles over time will be displayed 
graphically on the linear and semi-log view. 
All individual PD parameters and PD data will be listed. 
In addition, the mean (+/- SD) and median pre-dose inhibition over time will be displayed 
graphically on the linear and semi-log view. 
The PDS2 for 5.0 mg/kg and 7.5 mg/kg treatment groups will be used for these PD analyses. 

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12.7 
Interim analyses 
Not applicable. 
12.8 
Sample size calculation 
12.8.1 
Primary endpoint(s) 
The sample size calculation is based on the primary variable annualized rate of VOCs leading 
to healthcare visit over the first year post randomization. The hypotheses to be tested and details 
of the testing strategy are described in  Section 12.4.2 and Section 12.5.1. 
Based on available data from SUSTAIN study, the mean VOC rate was 3.74 in placebo group 
and the ratio of VOC rate between 5.0 mg/kg and placebo was 0.65 (both estimates from a 
negative binomial regression with treatment, HU/HC use, and VOC rate in 12 months prior to 
screening (2-4 vs ≥5-10 VOC) as covariates). 
Assuming a true treatment difference between crizanlizumab (7.5 mg/kg and 5.0 mg/kg) and 
placebo in the annualized rate of VOC of 35% over the first year of treatment, a sample size of 
240 participants provides 90% power that the primary analysis will be statistically significant 
at the two-sided 5% significance level. This calculation assumes 1:1:1 randomization ratio and 
a dispersion parameter of 0.5 for all treatment groups. These calculations were made using 
power calculation based on normal approximation and Dunnett's adjustment and software SAS 
(9.4). 
12.8.2 
Secondary endpoint(s) 
To assess the number of pediatric participants evaluable for PK trial simulations, following the 
recommendations from Wang et al (2012) for pediatric participants, have been performed and 
revealed a need of 16 participants with evaluable PK per dose group based on an expected 
interparticipant coefficient of variability for NCA AUC CV% (AUClast)= 59.89%, a need of 
27 participants across dose groups based on the expected variability of popPK parameters, and 
27 participants per dose group to achieve a precision of 20% for the 90% confidence interval of 
PK AUC assuming an estimated standard deviation of 0.554 for the log-transformed 
NCA AUC. 
Given the uncertainties around the expected NCA AUC in pediatric participants, more weight 
is given to the popPK approach suggesting an overall need of 27 adolescent participants across 
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Assuming 27 participants evaluated for PD the precision for the PD-AUC is expected to be 
sufficiently high (11.5%). 
Assuming a drop-out rate of 20% and a 1:1:1 randomization to placebo:5mg/kg:7.5mg/kg dose 
group, 48 adolescents need to be randomized. 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC, Art. 3 Par. 2 of the Directive 
2005/28/EC and US Code of Federal Regulations Title 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 participants. 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 Clinical Quality Assurance representatives, designated agents of 
Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site 
is requested by a regulatory authority, the investigator must inform Novartis immediately that 
this request has been made. 
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 participant last 
visits) 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 (SOP) as well as applicable global/local GCP regulations and ICH 
Guidelines. 

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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. 
13.5 
Participant Engagement 
The following participant engagement initiatives are included in this study and will be provided, 
as available, for distribution to study participants at the timepoints indicated. If compliance is 
impacted by cultural norms or local laws and regulations, sites may discuss modifications to 
these requirements with Novartis/Sponsor. 
• Thank You letter 
• Plain language trial summary - after CSR publication 
• Individual study results - after CSR publication 
• Trial Feedback Questionnaires (TFQ) - end of trial 
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. 
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 

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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 (available upon request) 
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Krishnan et al (2010) Increased levels of the inflammatory biomarker C-reactive protein at 
baseline are associated with childhood sickle cell vasocclusive crises. 
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Platt OS, Thorington BD, Brambilla DJ, et al (1991) Pain in sickle cell disease. Rates and risk 
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Rees DC, Williams TN, Gladwin MT (2010) Sickle-cell disease. Lancet p. 2018-31. 
Setty et al (2012) Tissue factor-positive monocytes in children with sickle cell disease: 
correlation with biomarkers of haemolysis. 
 
Wang Y, Jadhav PR, Lala M, et al (2012) Clarification on precision criteria to derive sample 
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16 
Appendices 
Not applicable.