Conditions: Sickle Cell Disease (SCD)
Keywords: SEG101 Sickle cell disease SCD crizanlizumab pediatric pharmacokinetic P-selectin Covid-19 Coronavirus disease 2019
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 117
Healthy volunteers: no

Brief summary:
The purpose of this study was to confirm and to establish appropriate dosing and to evaluate the safety in pediatric participants ages 2 to \<18 years with a history of Vaso-Occlusive Crisis (VOC) with or without Hydroxyurea/Hydroxycarbamide (HU/HC), receiving crizanlizumab for 2 years. The efficacy and safety of crizanlizumab was previously demonstrated in adults with sickle cell disease. The approach was to extrapolate from the pharmacokinetics (PK)/pharmacodynamics (PD) already established in the adult population. The study was designed as a Phase II, multicenter, open-label study.

Detailed description:
This was an open-label, single-arm study of crizanlizumab in sickle-cell disease (SCD) pediatric participants.

This study consisted of 2 parts, Part A and Part B. In Part A, the dose for 3 age groups (see groups below), was first confirmed on the basis of single and multiple dose (steady state) PK data and key safety data from an initial subgroup of participants. In Part B, safety and efficacy were collected from additional participants from 6 to \<18 years (Groups 1 and 2, only).

At least 100 participants were planned to be enrolled in the trial in total, split in 3 age groups:

* Group 1 (age 12 to \<18 years): at least 26 participants (≥8 in Part A and ≥18 in Part B),
* Group 2 (age 6 to \<12 years): at least 26 participants (≥8 in Part A and ≥18 in Part B),
* Group 3 (age 2 to \<6 years): at least 8 participants (≥8 Part A). Crizanlizumab was administered every 4 weeks with a loading dose 2 weeks after the first dosing (i.e., by i.v. infusion) on Week 1 Day 1, Week 3 Day 1, and then day 1 of every fourth week) for up to 2 years. The initial dose of crizanlizumab was 5 mg/kg dose for Group 1 and Group 2 Part A. It was later adjusted to 8.5 mg/kg for Group 2 and 3 based on final dose confirmation from emerging PK data analysis and safety considerations determined in Part A of the study.

Arms:
arm 1: SEG101 (crizanlizumab) 5 mg/kg or 8 mg/kg i.v. administered on Week 1 Day 1, Week3 Day 1 and Day 1 of every 4-week cycle for up to 2 years. The initial dose of crizanlizumab was 5 mg/kg dose for Group 1 and Group 2 Part A. It was later adjusted to 8.5 mg/kg for Group 2 and 3 based on final dose confirmation from emerging PK data analysis and safety considerations determined in Part A of the study.

Interventions: intervention 1: Crizanlizumab
Intervention descriptions: intervention 1: Crizanlizumab (SEG101) is a concentrate for solution for infusion, i.v. use. Supplied in single use 10 mL vials at a concentration of 10 mg/mL. One vial contains 100 mg of crizanlizumab.

Protocol document:
Prot_000.pdf: 
Clinical Development 
SEG101, crizanlizumab 
Clinical Protocol CSEG101B2201 / NCT03474965
A phase 2, Multicenter, Open-Label Study to Assess 
Appropriate Dosing and to Evaluate Safety of 
Crizanlizumab, with or without 
Hydroxyurea/Hydroxycarbamide, in Sequential, 
Descending Age Groups of Pediatric Sickle Cell Disease 
Patients with Vaso-Occlusive Crisis 
Document type 
Amended Protocol Version 
EUDRACT number 
2017‐001747‐12 
Version number 
06 (Clean) 
Development phase 
 II 
Document status 
Final 
Release date 
14-Mar-2024
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template version 6-Apr-2017 


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Table of contents 
Table of contents .................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ....................................................................................................................... 7 
List of abbreviations ............................................................................................................ 8 
Glossary of terms ............................................................................................................... 11 
Amendment 6 (14-Mar-2024) ............................................................................................ 13 
Amendment 5 (31-Mar-2022) ............................................................................................ 15 
Amendment 4 (30-Mar-2021) ............................................................................................ 21 
Amendment 3 (21-Jul-2020) .............................................................................................. 27 
Amendment 2 (29-Jan-2020) ............................................................................................. 35 
Amendment 1 (23-Oct-2018) ............................................................................................ 42 
Protocol summary .............................................................................................................. 45 
1 
Background ........................................................................................................................ 49 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 49 
1.2 
Introduction to investigational treatment(s) and other study treatment(s) ............. 53 
1.2.1 
Overview of crizanlizumab (SEG101) .................................................. 53 
2 
Rationale ............................................................................................................................ 57 
2.1 
Study rationale and purpose ................................................................................... 57 
2.1.1 
Current understanding of PK/PD properties of crizanlizumab .............. 58 
2.1.2 
Study design consideration .................................................................... 59 
2.2 
Rationale for the study design................................................................................ 59 
2.3 
Rationale for dose and regimen selection .............................................................. 60 
2.4 
Rationale for choice of combination ...................................................................... 60 
2.5 
Rationale for choice of comparators drugs ............................................................ 61 
2.6 
Risks and benefits .................................................................................................. 61 
2.7 
Rationale for Public Health Emergency mitigation procedures ............................. 65 
3 
Objectives and endpoints ................................................................................................... 65 
4 
Study design ....................................................................................................................... 68 
4.1 
Description of study design ................................................................................... 68 
4.2 
Timing of interim analyses and design adaptations ............................................... 71 
4.3 
Definition of end of study ...................................................................................... 71 
5 
Study Population ................................................................................................................ 72 
5.1 
Study population .................................................................................................... 72 
5.2 
Inclusion criteria .................................................................................................... 72 
5.3 
Exclusion criteria ................................................................................................... 73 


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6 
Treatment ........................................................................................................................... 75 
6.1 
Study treatment ...................................................................................................... 75 
6.1.1 
Dosing regimen ..................................................................................... 76 
6.1.2 
Ancillary treatments .............................................................................. 76 
6.1.3 
Rescue medication ................................................................................. 76 
6.1.4 
Guidelines for continuation of treatment ............................................... 76 
6.1.5 
Treatment duration ................................................................................ 77 
6.1.6 
Post trial access ..................................................................................... 77 
6.2 
Dose escalation guidelines ..................................................................................... 77 
6.3 
Dose modifications................................................................................................. 78 
6.3.1 
Dose modification and dose delay ......................................................... 78 
6.3.2 
Recommended actions and dose adjustments for QTcF 
prolongation ........................................................................................... 83 
6.3.3 
Follow-up for toxicities ......................................................................... 83 
6.4 
Concomitant medications ....................................................................................... 85 
6.4.1 
Permitted concomitant therapy .............................................................. 85 
6.4.2 
Permitted concomitant therapy requiring caution and/or action ........... 86 
6.4.3 
Prohibited concomitant therapy ............................................................. 86 
6.5 
Participant numbering, treatment assignment or randomization ............................ 87 
6.5.1 
Participant numbering ........................................................................... 87 
6.5.2 
Treatment assignment or randomization ............................................... 87 
6.5.3 
Treatment blinding ................................................................................ 87 
6.6 
Study drug preparation and dispensation ............................................................... 87 
6.6.1 
Study treatment packaging and labeling ................................................ 88 
6.6.2 
Drug supply and storage ........................................................................ 88 
6.6.3 
Study drug compliance and accountability ............................................ 89 
6.6.4 
Disposal and destruction ........................................................................ 89 
7 
Visit schedule and assessments .......................................................................................... 89 
7.1 
Study flow and visit schedule ................................................................................ 89 
7.1.1 
Molecular pre-screening ...................................................................... 101 
7.1.2 
Screening ............................................................................................. 101 
7.1.3 
Run-in period ....................................................................................... 102 
7.1.4 
Treatment period ................................................................................. 102 
7.1.5 
Discontinuation from study treatment ................................................. 103 
7.1.6 
Discontinuation from study ................................................................. 104 
7.1.7 
Withdrawal of consent/Opposition to use data/biological samples ..... 104 


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7.1.8 
Post-treatment Follow-up .................................................................... 105 
7.1.9 
Lost to follow-up ................................................................................. 106 
7.2 
Assessment types ................................................................................................. 106 
7.2.1 
Efficacy assessments ........................................................................... 106 
7.2.2 
Safety and tolerability assessments ..................................................... 109 
7.2.3 
Pharmacokinetics, pharmacodynamics, and immunogenicity ............. 117 
 
 122 
7.2.5 
Resource utilization ............................................................................. 123 
7.2.6 
Patient reported outcomes ................................................................... 123 
8 
Safety monitoring and reporting ...................................................................................... 123 
8.1 
Adverse events ..................................................................................................... 124 
8.1.1 
Definitions and reporting ..................................................................... 124 
8.1.2 
Laboratory test abnormalities .............................................................. 125 
8.1.3 
Adverse events of special interest ....................................................... 125 
8.2 
Serious adverse events ......................................................................................... 126 
8.2.1 
Definitions ........................................................................................... 126 
8.2.2 
Reporting ............................................................................................. 127 
8.3 
Protocol Exempt AEs & SAEs ............................................................................. 128 
8.4 
Emergency unblinding of treatment assignment .................................................. 128 
8.5 
Pregnancies .......................................................................................................... 129 
8.6 
Reporting of study treatment errors including misuse/abuse ............................... 129 
8.7 
Warnings and precautions .................................................................................... 129 
8.8 
Data Monitoring Committee ................................................................................ 130 
8.9 
Steering Committee ............................................................................................. 130 
9 
Data collection and management ..................................................................................... 130 
9.1 
Data confidentiality .............................................................................................. 130 
9.2 
Site monitoring ..................................................................................................... 130 
9.3 
Data collection ..................................................................................................... 131 
9.4 
Database management and quality control .......................................................... 131 
10 Statistical methods and data analysis ............................................................................... 132 
10.1 
Analysis sets ......................................................................................................... 133 
10.1.1 
Full Analysis Set .................................................................................. 133 
10.1.2 
Safety set ............................................................................................. 133 
10.1.3 
Per-Protocol set ................................................................................... 133 
10.1.4 
Dose-determining analysis set ............................................................. 133 
10.1.5 
Pharmacokinetic analysis sets ............................................................. 133 




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12 Protocol adherence ........................................................................................................... 151 
12.1 
Amendments to the protocol ................................................................................ 151 
13 References (available upon request) ................................................................................ 153 
14 Appendices ....................................................................................................................... 157 
14.1 
Appendix 1 - Karnofsky performance Status ....................................................... 157 
14.2 
Appendix 2 – The Lansky Play-Performance Status Scale Clinical 
Classification ........................................................................................................ 158 
List of tables 
Table 1-1 
Sickle Cell Disease genotypes ............................................................... 52 
Table 3-1 
Objectives and related endpoints ........................................................... 66 
Table 6-1 
Investigational and control drug ............................................................ 75 
Table 6-2 
Criteria for dose interruption and re-initiation of SEG101 treatment 
for adverse drug reactions ..................................................................... 80 
Table 6-3 
Management for drug-related toxicities ................................................ 83 
Table 6-4 
Packaging and labeling .......................................................................... 88 
Table 6-5 
Supply and storage of study treatments ................................................. 88 
Table 7-1 
Visit evaluation schedule ....................................................................... 91 
Table 7-2 
Vaso-Occlusion Crisis Assessment Collection Plan ........................... 107 
Table 7-3 
Central and Local Clinical laboratory parameters collection plan ...... 112 
Table 7-4 
ECG collection plan ............................................................................ 115 
Table 7-5 
Pharmacokinetic, pharmacodynamics and immunogenicity blood 
collection log Group 1 ......................................................................... 118 
Table 7-6 
Pharmacokinetic, pharmacodynamics and immunogenicity blood 
collection log Group 2 ......................................................................... 119 
Table 7-7 
Pharmacokinetic, pharmacodynamics and immunogenicity blood 
collection log Group 3 (2 to 6 years) ................................................... 121 
 
 123 
Table 8-1 
List of VOC Events Not Requiring AE/SAE Reporting ..................... 128 
Table 10-1 
Noncompartmental pharmacokinetic and pharmacodynamic 
parameter ............................................................................................. 141 
Table 10-2 
Probability to observe at least one AE for different incidence rates ... 146 
Table 14-1 
Karnofsky performance status scale rating (10%) criteria .................. 157 
Table 14-2 
The Lansky Play-Performance Status Scale Clinical Classification 
rating (10%) criteria ............................................................................ 158 


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List of figures 
Figure 4-1 
Study Design ......................................................................................... 71 
Figure 7-1 
Timing of study procedures ................................................................. 115 


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List of abbreviations 
 
ACS 
Acute Chest Syndrome 
ADA 
Anti-Drug Antibody 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
AUC 
Area Under the Curve 
BfArM 
Bundesinstitut für Arzneimittel und Medizinprodukte 
CFR 
Code of Federal Regulations 
CMO&PS 
Chief Medical Office and Patient Safety 
COVID-19 
Coronavirus disease 2019 
CRD 
Chronic Renal Disease 
CRF 
Case Report/Record Form; the term CRF can be applied to either EDC or Paper 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CSR addendum 
An addendum to Clinical Study Report (CSR) that captures all the additional information 
that is not included in the CSR 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTIS 
Clinical Trials Information System 
CTR 
Clinical Trial Regulation 
DCO 
Data cutoff 
DILI 
Drug-Induced Liver Injury 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ELISA 
Enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
EOT 
End of Treatment 
EU 
FAMHP 
European Union 
Federal Agency for Medicines and Health Products 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FEV1 
Forced Expiratory Volume in one second 
FMI 
Final Market Image 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GGT 
Gamma-Glutamyl Transferase 
Hb 
Hemoglobin 
HbA 
Hemoglobin A 
HbE 
Hemoglobin E 
HbF 
Fetal hemoglobin 
HbS 
Human hemoglobin S (sickle cell hemoglobin) 
HbS β 
one copy of the HbS gene plus a β-thalassemia variant (β0 or β+) 


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HbSC 
Heterozygous sickle Hemoglobin C disease (hemoglobin SC disease) 
HbSD 
one copy of the HbS gene plus an abnormal hemoglobin gene “D” 
HbSS 
homozygous sickle cell disease (hemoglobin SS disease) 
HIV 
Human immunodeficiency virus 
hr 
Hour 
HU/HC 
Hydroxyurea/Hydroxycarbamide 
i.v. 
intravenous(ly) 
IB 
Investigator Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IG 
Immunogenicity 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRR 
Infusion-related reaction 
IRT 
Interactive Response Technology 
ITT 
Intent-to-treat 
LFT 
Liver function test 
LLN 
Lower limit of normal 
LLOQ 
Lower limit of quantification 
LPLV 
Last patient last visit 
mAbs 
Monoclonal antibodies 
MCA 
Middle cerebral artery 
MCH 
Mean cell hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MDRD-GFR 
Modification of Diet in Renal Disease-Glomerular Filtration Rate 
MedDRA 
Medical dictionary for regulatory activities 
mg 
Milligram(s) 
MHRA 
Medicines & Healthcare products Regulatory Agency 
min 
Minute 
mL 
Milliliter(s) 
mPAP 
Mean pulmonary arterial pressure 
NSAIDs 
Non-steroidal anti-inflammatory drugs 
PAS 
Pharmacokinetic Analysis Set 
PD 
Pharmacodynamics 
 
 
PDS 
Pharmacodynamics Analysis Set 
PHI 
Protected Health Information 
PK 
Pharmacokinetics 
PKPDS 
Pharmacokinetic-Pharmacodynamics Analysis Set 
PopPK 
Population PK 
PSDS 
Post-study drug supply 
PSGL-1 
P-selectin glycoprotein ligand-1 
PT 
Prothrombin time 
PTA 
Post Trial Access 
QTcF 
QT interval corrected by Fridericia’s formula 


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R Value 
ALT/ALP x ULN 
RBC 
Red blood cell(s) 
REB 
Research Ethics Board 
RoW 
Rest of the World 
SAE 
Serious Adverse Event 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SCD 
Sickle Cell Disease 
SCPC 
Sickle Cell-related Pain Crises (also known as VOC leading to a healthcare visit in this 
document) 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBIL 
Total Bilirubin 
TCD 
Transcranial Doppler 
TRV 
UK 
Tricuspid regurgitation jet velocity 
United Kingdom 
US 
United States 
ULN 
Upper Limit Normal 
VES 
Visit Evaluation Schedule 
VOC 
Vaso-Occlusive Crisis 
WHO 
World Health Organization 
 


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Glossary of terms 
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 
Cohort 
A specific group of participants fulfilling certain criteria and generally treated 
at the same time 
Cycles 
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g., q28 days) 
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). 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 
Dose level 
The dose of drug given to the participant (total daily or weekly etc.) 
Electronic Data Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. EDC 
includes the use of Electronic Case Report Forms (eCRFs) which are used 
to capture data transcribed from paper source forms used at the point of 
care 
End of the clinical trial 
The end of the clinical trial is defined as the last visit of the last participant or 
at a later point in time as defined by the protocol 
Enrollment 
Point/time of participant entry into the study; the point at which informed 
consent must be obtained (i.e., prior to starting any of the procedures 
described in the protocol). The action of enrolling one or more participants 
Healthy volunteer 
A person with no known significant health problems who volunteers to be a 
study participant 
Investigational drug 
The study treatment whose properties are being tested in the study 
Medication number 
A unique identifier on the label of medication kits 
Multiple dose 
Time point (at Week 15 or later) when presumed steady state is reached 
following at least 3 full consecutive infusions following Week 3 Day 1 
(loading dose). If dose is interrupted, partially administered or delayed prior 
to Week 15, then 3 full consecutive infusions (administered within allowed 
visit window) are required to reach the steady state after the dose has been 
resumed 
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 
Participant 
A trial participant (can be a healthy volunteer or a patient). 
“Participant” terminology is used in the protocol whereas term “Subject” is 
used in data collection 
Participant Number (Patient 
No.) 
A unique identifying 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. 
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 


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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 
Re-screening 
If a participant fails the initial screening and is considered as a Screen 
Failure, he/she can be invited for a new Screening visit after medical 
judgment and as specified by the protocol 
Remotely 
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 
SEG101 
Novartis supply of crizanlizumab 
SelG1 
Reprixys Pharmaceuticals Corporation supply of crizanlizumab 
Source Data/Document 
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource 
Start of the clinical trial 
The start of the clinical trial is defined as the signature of the informed 
consent by the first participant 
Study treatment 
Any drug or combination of drugs or intervention administered to the study 
participants as part of the required study procedures; includes 
investigational drug(s), control(s) or background therapy 
Supportive treatment 
Refers to any treatment required by the exposure to a study treatment, e.g., 
premedication of vitamin supplementation and corticosteroid for pemetrexed 
disodium 
Study treatment interruption 
Dose administration that cannot be made as per protocol and the infusion is 
fully skipped 
Teleconsultation 
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 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified time points 
Withdrawal of consent / 
Opposition to use of data / 
biological samples 
Withdrawal of consent 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 6 (14-Mar-2024) 
Amendment Rationale 
At the time of this amendment, 117 participants were enrolled (at least 100 participants were 
planned as per the original protocol) in the study. It includes 50 participants in Group 1 (12-<18 
years), 53 participants in Group 2 (6-<12 years) and 14 participants in Group 3 (6 months – 6 
years). The primary purpose of this protocol amendment is to amend the study plan by not 
extending it to the cohort of Group 3 Part B. Novartis does not intend to enroll patients in Group 
3 Part B (6 months to 6 years) of the trial. The rationale for cancelling the Group 3 Part B is to 
focus on age groups where the manifestation of Sickle Cell Disease (SCD) and the feasibility 
of intervention assessment are more suitable. The original study plan required at least 8 patients 
aged 2-<6 years to evaluate and determine the age-appropriate dose. 14 patients have already 
been enrolled in Group 3 Part A (patients 2 to <6 years), that are expected to provide sufficient 
data to study the PK parameters for this age group. Study of the youngest age group (6 months 
to < 24 months) was initially planned 
 
 which has since been withdrawn in its entirety due to the revocation of the 
conditional marketing authorization of crizanlizumab in the EU and UK. Therefore, Novartis 
has decided not to study crizanlizumab for the reduction of VOCs in additional patients with 
SCD below the age of 6 years, as very young children with SCD are less likely to experience 
frequent vaso-occlusive crises (VOC) episodes compared to older children, adolescents, and 
adults. 
In addition, this amendment updates the risks and benefits of treatment with crizanlizumab to 
reflect the most recent available clinical data as described in the latest edition of the 
Investigator's Brochure (Edition 13, released on 15-May-2023). 
In this amendment, the dose and the rationale of the dose confirmed for Group 2 and Group 3, 
derived from Group 1 and Group 2 Part A pediatric data, are presented. These data were not 
available at the time of submission of the initial study. 
Further, typographical, grammatical and formatting errors have been addressed as part of this 
document. 
Changes to the protocol 
• Protocol summary, Section 2.2, Table 3-1, Section 4.1, Figure 4-1, Section 5.1, Section 
5.2, Section 7.1.4, Table 7-1, Section 7.2.2.3, Section 7.2.3.1, Table 7-7, Table 7-8 and 
Section 10, Section 10.1, Section 10.1.5, Section 10.4, Section 10.4.1, Section 10.5, 
Section 10.5.2, Section 10.8. 
• Text related to Group 3 Part B (6 to 24 months) cohort removed/updated. 
• Section 1.2.1.2 and Section 2.3 
• Details about Phase III Clinical Study (STAND – CSEG101A2301) added. 
• Section 2.6 
• Risks and Benefits updated. 
• Section 6.1, Table 6-1, Section 6.6.1, Section 6.6.3.1 
• Standard text language added for alignment with protocol Version 8 template. 


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• Section 6.3.3.1 
• Hy’s law and DILI language updated. 
 
 
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. 


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Amendment 5 (31-Mar-2022) 
Amendment Rationale 
At the time of this amendment, 77 participants were enrolled in the study. It includes 50 
participants in Group 1 (enrolled under SEG101 at 5 mg/kg dose) and 27 participants in Group 
2 Part A (13 participants enrolled under SEG101 at 5 mg/kg dose and 14 participants enrolled 
under SEG101 at 8.5 mg/kg). 
The primary purpose of this amendment is to: 
• update the options of post-trial access for participants in this trial who continue to derive 
clinical benefit from the treatment based on the Investigator’s evaluation. The post-trial 
access language was revised to reflect the options available to participants to continue 
treatment after completion of the study. This may include access to Novartis investigational 
product in a rollover protocol or provision of the Novartis investigational product in a non- 
trial setting (known as post-study drug supply [PSDS]) when no further safety or efficacy 
data are required, or any other mechanism appropriate as per the country regulations. 
• 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 
11, released on 12-May-2021). 
• align with the requirements of EU Clinical Trial Regulation (EU CTR) to accommodate the 
transfer of the study under this regulation. 
• include changes based on Health Authorities feedback: 
• update the Serious Adverse Event reporting section as per Bundesinstitut für 
Arzneimittel und Medizinprodukte (BfArM, Federal Institute for Drugs and Medical 
Devices in Germany) recommendations. 
• update of the wording used in Exclusion criterion #26 incorrectly considering bilateral 
tubal ligation as a female sterilization as per Medicines & Healthcare products 
Regulatory Agency (MHRA, United Kingdom (UK) health authority) feedback. 
• addition of the definition of childbearing potential in Section 7.2.7.6 Pregnancy and 
assessments of fertility as per MHRA (UK health authority) and FAMHP (Federal 
Agency for Medicines and Health Products, Belgium health authority) feedback. 
• update the recommendations on use of vaccines, to consider withholding administration of 
any live or live attenuated vaccines 4 weeks prior to first dose and during the study duration. 
The change was performed to provide more clarity about use of live vaccines considering 
the adverse events including potential infections. 
Further, typographical, grammatical and formatting errors have been addressed as part of this 
document. Some re-wording has been made to improve clarity in alignment with the latest 
Novartis Global Clinical Trial Protocol Template v 5.0 (released on 14-Jan-2022). 


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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 main changes made to the protocol are as follows: 
• List of abbreviations 
• List updated with new terms and deletion of unused term. 
• Section 1.1 Overview of disease Overview of disease pathogenesis, epidemiology and 
current treatment 
• Update to report accelerated approval received for OxbrytaTM (voxelotor) by US FDA 
on 17-Dec-2021 for treatment of sickle cell disease in patients aged 4 years to less than 
12 years, and the approval by EMA on 16-Feb-2022 for the treatment of hemolytic 
anemia due to SCD in adults and pediatric patients 12 years of age and older. 
• Section 2.6: Risks and benefits 
• Section aligned with Investigator’s Brochure (Edition 11, Safety cut-off date 31-Mar- 
2021 and released on 12-May-2021) to reflect updated frequency of adverse drug 
reactions and adverse events of special interest. 
• Section clarified to mention that highly effective contraception method must be used. 
• Section 4.1: Description of Study 
• Reference to new section 6.1.6 added. 
• Addition of non-trial setting as option for post-trial access to drug treatment 
• Section 4.3: Definition of end of study 
• Rewording of definition of end of study for improved clarity. 
• Post-trial access language moved to new section 6.1.6 
• Section 5.3: Exclusion criteria 
• Exclusion criterion #11 updated to clarify that silent infarcts are not excluding patients 
from the study participation. 
• Exclusion criterion #26 
• Text updated based on MHRA feedback to clarify that "bilateral tubal ligation" is 
not a form of female sterilization in alignment with the Clinical Trial Facilitation 
Group guidance document for clarification of effective contraception in clinical 
trials. 
• Text updated regarding feedback from MHRA for considering local regulations 
for appropriate methods of contraception if more stringent. 
• Text updated to specify oral hormonal method of contraception as estrogen and 
progesterone. 
• Section 6.1.5: Treatment duration 
• Reference to new section 6.1.6 added. 
• Section 6.1.6: Post trial access 
• New section added to reflect current post-trial access options to participants who 
continue to derive clinical benefit from the treatment based on the Investigator’s 


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evaluation, including a rollover protocol, provision of the Novartis investigational 
product in a non-trial setting (known as post-study drug supply [PSDS]) when no 
further safety or efficacy data are required, or any other mechanism appropriate as per 
the country regulations. 
• Section 6.4: Concomitant medications 
• Clarification that details on administration of Erythropoietin Stimulating Agent 
should be collected until at least 6 months prior to screening as aligned with inclusion 
criterion #4. 
• Section 6.4.1: Permitted concomitant therapy 
• Recommendation on vaccinations updated to consider withholding any live or live 
attenuated vaccines 4 weeks prior to first dose of the study treatment (Week 1 Day 1) 
and during study duration with decision to be taken on a case-by-case basis considering 
potential benefit/risk of vaccination. 
• Section 6.4.4: Use of Bisphosphonates (or other concomitant agents) 
• Heading and section deleted as not applicable for the study. 
• Section 6.5.1: Participant numbering 
• Update to limit re-screening to once in the study. Reconsent requirement in case of re- 
screening removed and added in Section 7.1.2.2. 
• Section 6.6.4: Disposal and destruction 
• Clarification added that study drug supply and destruction must comply with site 
processes, monitoring process and as per local regulation/guidelines. 
• Section 7.1: Study flow and visit schedule 
• Clarification made to allow replacements of certain protocol assessments (and not full 
visits on site) by telephone contacts and/or virtual contacts during a public Health 
emergency if allowed by local Health Authority, but also by national and local 
regulations. 
• Table 7-1: Visit evaluation schedule 
• Prior/concomitant medications – Erythropoietin stimulating agent added to visit 
evaluation schedule in alignment with Section 6.4.1. 
• The option of post-trial access in a non-trial setting was added to footnote k. 
• Section 7.1.2.2: Information to be collected on screening failures 
• Clarification added that data and samples collected from participants prior to screen 
failure may still be analyzed. 
• Clarification added that individuals who do not meet the criteria for participation in this 
study (screen failure) may be rescreened once. 
• Update to clarify requirement to reconsent the re-screened participant only in case re- 
screening is performed more than 28 days after initial consent, unless reconsent is 
required by local regulations. 
• Section 7.1.2.3: Participant demographics and other baseline characteristics 
• Clarification added that country-specific regulations should be considered for the 
collection of demographic and baseline characteristics in alignment with CRF. 


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• Requirements for documentation of relevant and current medical history until date of 
informed consent specified. 
• Section updated to specify that all prescription medications, over-the-counter drugs and 
significant non-drug therapies prior to the start of the study must be documented. 
• Section 7.1.8: Post-treatment Follow-up 
• The option of post-trial access in a non-trial setting was added to this section. 
• Section 7.1.9: Lost to follow-up 
• Section updated to clarify that a loss to follow-up could be considered if participant 
failed to respond to any site attempts to contact them, and not only if participant failed 
to appear for study visits. 
• Section 7.2.2.1: Physical examination 
• Section updated to mention that information for all physical examination information 
must be included in the source documentation at the study site. 
• Section 7.2.2.7.6: Pregnancy and assessments of fertility 
• Definition of female of childbearing potential added to comply with Novartis 
Pregnancy Guidelines and wider feedback on fertility from MHRA and FAMHP. 
• Table 7-5, Table 7-6, Table 7-7, Table 7-8 
• The option of post-trial access in a non-trial setting was added to the footnotes. 
• Section 7.2.4.1.1: Optional Additional Research 
• Headline and section updated to clarify the optional consent to the additional research 
on biological samples and data remaining after analysis and purpose of this additional 
research. 
• Section 8.1.1: Definitions and reporting 
• The option of post-trial access in a non-trial setting was added to this section. 
• Section updated to specify the follow-up period of detected AEs. 
• Section 8.2.1: Definitions 
• Section updated to include study treatment errors and uses outside of what is foreseen 
in the protocol in the AE/SAE reporting in alignment with EU CTR requirements. 
• Section 8.2.2: Reporting 
• SAE reporting definition updated to meet the needs of BfArM (Federal Institute for 
Drugs and Medical Devices) in Germany. 
• Deleted duplicate details referring to follow up information for SAE in the same 
section. 
• Reference to EU CTR added. 
• Section 8.3: Protocol Exempt AEs & SAEs 
• SAE reporting definition updated to meet the needs of BfArM (Federal Institute for 
Drugs and Medical Devices) in Germany. 
• Section 8.6: Reporting of study treatment errors including misuse/abuse 
• Section updated to include study treatment errors and uses outside of what is foreseen 
in the protocol in the SAE reporting in alignment with EU CTR requirements. 


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• Reference to Section 8.1.1 and Section 8.2 added which provide more information on 
AE and SAE definition and reporting requirements. 
• Table 8-2 deleted and replaced by a reference to AE/SAE definition and reporting 
requirements detailed in respective sections of the protocol. 
• Section 9.2: Site monitoring 
• Section updated to clarify that check on completeness of participant records will be 
completed by the field monitor via ongoing source data verification, not necessarily 
triggered by visit on sites. 
• Section 9.4: Database management and quality control 
• Clarification added that for EDC studies the investigator will receive a CD-ROM or 
paper copies of the participant data for archiving after the final database lock. 
• Section 10: Statistical methods and data analysis 
• Section updated to mention that additional cut-offs and analyses may be performed to 
support regulatory filings or potential Health Authority requests. 
• Table 10-1: Noncompartmental pharmacokinetic and pharmacodynamic parameter 
• Table updated to consider dosing interval for the first dose in the definition of AUCd15. 
• Section 11.1: Regulatory and ethical compliance 
• Reference to EU CTR added. 
• Section 11.2: Responsibilities of the investigator and IRB/IEC/REB 
• Section updated to clarify the requirement to get protocol amendments approved by 
relevant authorities before implementation of changes, except in case of urgent safety 
measures. 
• Investigator responsibilities are refined in this section. 
• Section 11.3: Informed consent procedures 
• Section updated to clarify Investigator (or representative) responsibilities in obtaining 
participants` informed consent. 
• Section updated to specify the medical record must include a statement that written 
informed consent was obtained before the participant was enrolled in the study and the 
date the written consent was obtained. The authorized person obtaining the informed 
consent must also sign the ICF. 
• Section updated to mention that a copy of the ICF(s) must be provided to the 
participants or their legally authorized representative. 
• Section updated to add that Informed Consent Form (ICF) provided by Novartis 
complies with 21 CFR 50, local regulations, ICHE6 Good Clinical Practice (GCP) 
guidelines and privacy and data protection requirements, where applicable. 
• Section updated to add the consent to optional additional research. 
• Clarification added that information included in Investigator Brochure should be shared 
with the participant upon obtaining consent. 
• Clarification added that Main Study Consents include a subsection that requires a 
separate signature for ‘Optional consent for activities that may be done outside of the 
study site’. 


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• New Section 11.4: Data Protection 
• New section added to specify data protection procedures. 
• Section 11.6: Publication of study protocol and results 
• Addition of publication of study results on CTIS public website (Clinical Trials 
Information System) upon transfer under EU CTR. 
• Statement added that any data analysis carried out independently by the Investigator 
should be submitted to Novartis before publication or presentation. 
• Clarification added that summary of results will be disclosed upon global Last 
Participant Last visit date. 
• Section 12: Protocol adherence 
• Section updated to clarify that no collection of additional data or conduct of additional 
procedure are allowed outside of protocol requirements or for reasons other than 
supporting the purpose of the study. In case additional data is collected accidentally, 
Investigator should notify Novartis immediately. 
• Section 12.1: Amendments to the protocol 
• Section updated to specify that any change or addition to the protocol can only be made 
in a written protocol amendment that must be approved prior to implementation. 
• Section updated to specify if amendments are required for participant safety it may be 
implemented immediately but providing relevant Health Authorities and reviewing 
IRB/EC are notified, and the safety measure is subsequently included in a protocol 
amendment. 
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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Amendment 4 (30-Mar-2021) 
At the time of this amendment, 77 participants were enrolled in the study. It includes 50 
participants in Group 1 (enrolled under SEG101 at 5 mg/kg dose) and 27 participants in Group 
2 Part A (13 participants enrolled under SEG101 at 5 mg/kg dose and 14 participants enrolled 
under SEG101 at 8.5 mg/kg). 
The primary purpose of this amendment is to update the requirement for a 105 days post- 
treatment follow-up visit for all participants. The intention of the 105 day post-treatment follow- 
up period is to capture any potential adverse events including development of anti-drug 
antibodies following discontinuation from study treatment, taking into account the half-life of 
the drug. This amendment clarifies that participants continuing crizanlizumab after their EOT 
visit, via commercial supply or post-trial access (e.g. enrollment in a Novartis roll-over protocol 
to provide continued drug treatment) will not have to perform the 105 days post-treatment 
follow-up visit in this study. 
Regarding eligibility, inclusion criterion (#4) was clarified regarding L-glutamine and 
erythropoietin stimulating agent. Several drugs are being used to treat SCD, including HU/HC, 
L-glutamine, and erythropoietin stimulating agent. The downstream effects of these drugs might 
affect the PK/PD analyses that are the primary objective of this study. Given this possibility, 
participants taking those drugs at study entry are required, at least for Part A, to maintain the 
same dose of these drugs unless it has to be changed for safety reasons or due to growth and 
periodic weight changes. In addition, exclusion criterion (#31) has been adapted to exclude 
patients with prior use of other selectin targeting agents as newer P-selectins antagonists are 
currently being tested in SCD, therefore patients who are screened in CSEG101B2201 may 
have been exposed, and may confound study objectives. 
Finally, the protocol has been updated to address ongoing or future public health emergency 
mitigation procedures such as for the current COVID-19 pandemic. No substantial additional 
risk for participants due to the SARS-CoV-2 virus and the COVID-19 pandemic has been 
identified at this time and therefore the benefit risk remains unchanged. The risk/benefit balance 
will be re-evaluated as and when required whilst the COVID-19 pandemic continues. 
Further, typographical, grammatical and formatting errors have been addressed as part of this 
document. 
Changes to the protocol 
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. 
• “safety follow-up” was replaced with “post-treatment follow-up visit” consistently 
through the protocol, because the follow-up includes safety as well as efficacy 
assessments. Accordingly, “follow-up” was replaced with “post-treatment follow-up”. 
• Updates to align with the latest Novartis Global Clinical Trial Protocol Template v4.0 
(15-Feb-2021). 


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• Glossary of terms 
• List of terms updated. 
• Section 2.6 
• “patient” was replaced by “participant”. 
• Section 2.7 
• Addition of new protocol section 2.7 to address ongoing or future Public Health 
emergency mitigation procedures. 
• Section 4.1 
• Update to the requirement to have a 105 days post-treatment follow-up visit for all 
participants, as exception is made to the participants continuing under crizanlizumab 
beyond their EOT visit. 
• Section 5.2 
• Clarification of inclusion criterion 4 regarding L-glutamine and erythropoietin 
stimulating agent. 
• Section 5.3 
• To update the exclusion criterion 31 to include selectin targeting agents. 
• For exclusion criterion 26 it was clarified that “bilateral” tubal ligation is considered a 
highly effective contraception methods. 
• Section 6.1.4 
• Update to the requirement to have a 105 days post-treatment follow-up visit for all 
participants, as exception is made to the participants continuing under crizanlizumab 
beyond their EOT visit. 
• Table 6-3 
• Clarification added for infusion-related reactions (grade 2) that infusion is 
recommended to be interrupted temporarily. 
• Section 6.4 
• Clarification added regarding notification of any new concomitant medications taken 
until completion of last visit: EOT visit or post-treatment follow-up visit. 
• Section 6.4.1 
• Clarification added regarding the dosing modification of the (HU/HC, L-glutamine and 
erythropoietin stimulating agent) permitted concomitant medication in the study. 
• Use of other anti-platelets agents or anticoagulants at therapeutic doses have been 
moved to Section 6.4.2 as concomitant medications to be used with caution. 
• Section 6.4.2 
• Paragraph added regarding cautious use of anti-platelets agents or anticoagulants due 
to potential effect of P-selectin on hemostasis. 


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• Section 6.4.3 
• Paragraph added regarding prohibition of new SCD treatments and/or treatments to 
prevent/reduce VOCs during the study and the use of selectin agents prior or during the 
study. 
• 6.6.3.2 
• Clarification added that drug accountability will be monitored by the field monitor also 
during remote monitoring visits. 
• Section 7.1 
• Wording added to address ongoing or future public health emergency mitigation 
procedures. 
• Wording added for allowed visit windows of EOT visit and 105 day post-treatment 
follow-up visit. 
• Table 7-1 
• IRR added under safety assessments. 
• Footnote added regarding allowed visit windows of EOT visit and 105 day post- 
treatment follow-up visit. 
• Footnote added regarding the requirement to get 105 days post-treatment follow-up 
visit. 
• Footnote added regarding Infusion Related Reactions (IRR) eCRF page to be 
completed in case certain AE are reported as IRR. 
• Section 7.1.5 
• Section header was updated. 
• Clarification added regarding EOT visit, and the 105 days post-treatment follow-up 
visit. 
• Withdrawal description removed as provided in Section 7.1.7. 
• Clarification added regarding data that should be collected at clinic visits or via 
telephone/email contacts after discontinuation from study treatment. 
• Section 7.1.6 
• This section “Discontinuation from study” was added as per latest Novartis Global 
Clinical Trial Protocol Template v4.0 (15-Feb-2021). 
• Section 7.1.7 
• Section header was updated to also refer to Opposition to use data/biological samples. 
• Update to the requirement to have a 105 days post-treatment follow-up visit for all 
participants, as exception is made to the participants continuing under crizanlizumab 
beyond their EOT visit. 
• Update wording for withdrawal of consent and Opposition to use data/biological 
samples as per latest Novartis Global Clinical Trial Protocol Template v4.0 (15-Feb- 
2021). 


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• Section 7.1.8 
• Update to the requirement to have a 105 days post-treatment follow-up visit for all 
participants, as exception is made to the participants continuing under crizanlizumab 
beyond their EOT visit. 
• Clarification on the SAE collection for participants continuing in post-treatment 
follow-up. 
• Section 7.1.9 
• Clarification added for participants failing to appear for study visits resulting in unclear 
status. 
• Section 7.2.1.1 
• Clarification added for vaso-occlusion crisis/dactylitis/transfusion information to be 
collected until last protocol visit. 
• Section 7.2.2.6 
• Clarification added that middle cerebral artery (MCA) velocity is included in cerebral 
blood flow velocity (CBF-V) measurements. 
• Section 7.2.2.7 
• Clarification added that if participants cannot visit the site for protocol specified 
safety lab assessments, an alternative lab (local) collection site may be used. 
• Clarification that clinically relevant abnormal laboratory parameters have to be 
collected until last protocol visit. 
• Section 7.2.3.1 
• Table 7-5, Table 7-6, Table 7-7, Table 7-8 
• PK collection number/Dose reference ID was added for post-treatment follow-up 
visit (last infusion + 105 days). 
• Footnote added that participants continuing crizanlizumab after their EOT visit do 
not have to complete the 105 days post-treatment follow-up visit. 
• Table 7-7 
• Footnote added clarifying that Part B in Group 3 (2 to <6 years old) is only 
applicable in case of dose alteration of HU/HC, L-glutamine or erythropoietin 
stimulating agent in Part A participants. 
• Section 8 
• Wording added to address ongoing or future public health emergency mitigation 
procedures. 
• Section 8.1.1 
• Clarification added that monitoring of adverse events as part of this study will stop from 
the time the participant performed EOT visit for participants continuing under 
crizanlizumab beyond EOT visit. 
• Adverse events should be evaluated to determine action taken with respect to study 
treatment for which the possibility “dose reduced” was added for consistency with the 
eCRF. 


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• Section 8.3.1 
• The entire Section 8.3.1 was moved under Section 8.2 as new Section 8.2.2. The 
following additional changes were made: 
• Update made to the monitoring of AEs to mention that for participants continuing 
crizanlizumab after their EOT, via commercial drug or post-trial access, 
monitoring of AEs as part of this study will stop from the time the participant 
completed their EOT visit. 
• Update to the requirement to have a 105 days post-treatment follow-up visit for all 
participants, as exception is made to the participants continuing under 
crizanlizumab beyond their EOT visit. 
• Section 8.5 
• Clarification added regarding pregnancy consent form process. 
• Section 9.2 
• Clarification added that Novartis ensures protocol and GCP compliance and the 
quality/integrity of the sites’ data. 
• Clarification added that Novartis monitoring standards require also full verification of 
data that will be used for all primary variables. 
• Clarification added that no information in source documents will disclose the identity 
of the participants. 
• Section 10 
• Reference to Week 27 Day 1, which was in brackets, deleted for indicating the 
completed first 26-weeks of treatment period. 
• Section 10.5.2 
• Clarification added regarding VOC events and Dactylitis. 
• Section 10.5.3.1 
• Clarification added regarding the definition of the on-treatment and post-treatment 
periods. 
• Section 11.3 
• Wording added to address ongoing or future public health emergency mitigation 
procedures. 
• Clarification about information given to participant added in case his/her representative 
gives consent. 
• Section 11.5 
• Examples added for publicly accessible database of clinical study results. 
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. 


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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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Amendment 3 (21-Jul-2020) 
At the time of this amendment, 63 participants were enrolled in the study, under SEG101 at 5 
mg/kg dose. It includes 50 participants in Group 1 (split between 11 participants in Group 1 
Part A and 39 participants in Group 1 Part B) and 13 participants in Group 2 Part A. The dose 
of SEG101 at 5 mg/kg was confirmed following single and multiple dose analysis in Group 1 
Part A. However, the dose of 5 mg/kg was not confirmed in Group 2 Part A based on the results 
from the single dose analysis. The Data Monitoring Committee (DMC) did not raise any 
particular safety concerns related to the 5 mg/kg dose tested. However, the PK results were at 
the lower end of the pre-set boundaries defined in the protocol and suggested that the dose of 5 
mg/kg may not be efficacious in achieving adequate inhibition of P-selectin. In order to ensure 
an efficacious dose in patients <12 years, Novartis, in agreement with the DMC, proposed 
testing a new adjusted dose for patients in Group 2 based on revised SEG101 PopPK modeling. 
Group 2 Part B and Group 3 had not yet been initiated at the time of this protocol amendment. 
The main reasons of this amendment are: 
1. To update and clarify the criteria used for dose confirmation following single-dose analysis 
in Part A of each group. The decision is based on first dose PK results, key safety data, and 
Novartis’s assessment in conjunction with Data Monitoring Committee (DMC) 
recommendations. Previous wording considered the dose confirmed if the PK results were 
found to be within the pre-set boundaries defined in the protocol which might not be 
sufficient to confirm the appropriate dose. Current protocol clarifies that all relevant data 
will be used to make a decision on the dose. This amendment will thus allow evaluation of 
the newly defined dose in a new cohort of patients enrolled into Group 2 Part A (see study 
status above). 
2. To include language 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 were added. 
3. To adjust weight from 6 to 7 kg in inclusion criterion 1 and increase minimum eGFR value 
from 45 to 75 mL/min/1.73m2 in inclusion criterion 8, in light of the higher doses that will 
be used in younger age groups, in order to avoid potentially exceeding recommended 
endotoxin and sucrose limits, particularly in very young children. 
4. To consider uptake of voxelotor within 30 days of screening or plan to start voxelotor during 
the course of the study as an exclusion criterion. At the time of this protocol amendment, 
voxelotor is a newly approved drug for Sickle Cell Disease in the U.S.; there is no 
combination of safety or PK data with SEG101 (Drug-Drug Interaction is always a 
possibility). In anticipation that some patients may have been on voxelotor prior to start in 
the study, the protocol is requesting that participant has permanently stopped voxelotor prior 
to screening and to allow a wash-out period of 30 days or 5 half-lives, which is the typical 
duration for a wash-out (of exposure and potential lagging adverse events). 




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• Section 2.6: 
• added language in line with the latest version of the investigator’s brochure (Edition 
10, released on 12-May-2020), including the potential risks of hemorrhages, 
infections, infusion related reactions and immunogenicity, as well as potential risks 
pertaining to laboratory text interference with automated platelet counts, QT 
prolongation and hepatic safety, and pregnancy and lactation 
• strategy to mitigate risk of interference with automated platelet counts was removed 
as this section is not appropriate for management instructions or guidance and 
instructions were given to the sites through a specific letter addressed to investigators 
• option to keep the participant in the hospital for 24 hours following first infusion 
extended to subsequent infusions after first dose 
• removed referenced articles of Descotes 2009, Sing JA 2011, and Qi X 2014 
• Section 4.1: 
• addition of requirement of having permanently discontinued voxelotor at least 30 days 
prior to screening and to not plan initiation of the drug during the course of the study 
• ‘should’ has been updated by ‘must’ to clarify that participants receiving HU/HC, L- 
glutamine or erythropoietin stimulating agent at study entry must have been taking it 
for at least 6 months prior to study entry and plan to take the same dose at the same 
schedule during the course of the study 
• clarification that for dose confirmation decision, PK results obtained from Group 1 
following single and multiple dose analysis will be compared to the exposure level 
observed in adults from the CSEG101A2202 study, yet PK results obtained from Group 
2 and Group 3 following single and multiple dose analysis will be compared to the 
exposure level predicted using PopPK model 
• clarification that participants from Part A switching to the new dose will be considered 
as Part B participants from the time they will start the new dose, but will not be counted 
among the minimum 26 participants planned for the group 
• clarification on the process applied in each group to confirm the dose based on single 
and multiple dose analysis 
• addition of the possibility to get the study treatment provisioned via post-trial access 
upon study discontinuation 
• clarification that the 5 mg/kg dose is the starting dose in Group 1 Part A 
• Figure 4-1: 
• updated to reflect the possibility to separate or combine the different primary analysis 
for each group, 
• reference to ‘participants’ instead of ‘patients’ 
• number of participants in each part included 
• ‘wk 0’ updated in ‘wk 7’to indicate the cutoff date of the single dose analysis 
• Section 4.3: addition of the possibility to get study treatment provisioned by Novartis 
following study completion by participant in case crizanlizumab is not available 
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• Section 5 and Section 5.1: 
• headings of Section 5 and Section 5.1 updated as ‘Study population’ to be aligned 
with the latest Novartis Global Clinical Trial Protocol Template v3.0 (31-Jan-2020) 
• clarification that at least one VOC having led to healthcare/medical facility visit 
within 12 months prior to screening has to be reported to make the patient eligible 
• Section 5.2: 
• To update the lower bound weight from 6 to 7 kg in inclusion criterion 1 
• To replace ‘should’ by ‘must’ in inclusion criterion 3 
• To update minimum eGFR value required from 45 to 75 mL/min/1.73m2 in inclusion 
criterion 8 
• To clarify that for TCD assessment in inclusion criterion 9, the age of the participant 
at screening is considered 
• Section 5.3: 
• exclusion criteria 5 and 27 that were removed with protocol amendment 2 were 
deleted from exclusion criteria section, instead of retaining them and mentioning they 
are not applicable anymore, to follow Novartis standard guidance 
• wording added to mention that local regulations must be followed in case of deviation 
from the contraception methods listed in the protocol 
• exclusion criterion 32 added to mention that uptake of voxelotor within 30 days prior 
to screening or planned during the course of the study excludes the patient from study 
participation 
• Section 6.1.5: addition of the possibility to provide study treatment via post-trial access 
after trial completion 
• Section 6.3.1.1: 
• clarification of the process and criteria used to confirm the dose in each group 
following single dose PK analysis 
• clarification that the investigator cannot decide to modify the dose at their own 
discretion 
• Section 6.3.1.2: recommendations added for handling of study treatment in case of active 
or suspected COVID-19 infection, and recommendation to get COVID-19 tested in case of 
VOC 
• Table 6-3: To modify guidance given to manage infusion-related reactions and 
corresponding dose interruption and re-initiation 
• Section 6.3.3.1: 
• wording added in regards to use of clinical information to assess a medical diagnosis 
of the cause of the observed liver laboratory abnormalities 
• reference to ‘without evidence of cholestasis’ removed to match with updates made 
with protocol amendment 2 


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• Section 6.4.2: 
• paragraph on the use of pre-medications in case of infusion-related reactions moved 
from Section 6.4.3 (prohibited concomitant therapy) to Section 6.4.2 (permitted 
concomitant therapy requiring caution and/or action) 
• addition of requirement to get study treatment discontinued in case of Grade 3 or Grade 
4 IRRs 
• addition on uptake of steroids that is permitted but with caution 
• reference to Brandon et al 2020 added 
• Section 6.4.3: addition of washout period for voxelotor 
• Section 7.1: language added to request maintenance of virtual/phone contacts with the 
participants in case on-sites visits cannot be performed 
• Table 7-1: 
• category corrected for informed consent from source (‘S’) to data capture in the 
clinical database (‘D’) 
• removal of optional pharmacogenetics informed consent 
• removal of buccal swab for pharmacogenetics analysis 
• footnote added for ECG assessment scheduled at Week 15 to request alignment with 
steady state for Part A participants 
• footnote added for school/work employment status and sick time absence at screening 
to highlight that information based on last month prior to screening will be asked to 
be recorded in the clinical database 
• addition of collection of Hospitalization details at screening 
• addition of head circumference measure 
• table updated to correct that VOCs and Dactylitis events occurring during screening 
and prior to the first dose will be recorded on the History CRFs in alignment with 
other sections 
• addition of Prior/concomitant medications – L-glutamine 
• referenced section for concomitant medications updated to Section 6.4 
• addition of collection of PK and IG samples at the 105 days safety follow-up visit 
• Section 7.1.2.3: 
• language added in regards to reason to collect race and ethnicity as part of 
demographics information, aligned with the latest Novartis Global Clinical Trial 
Protocol Template v3.0 (31-Jan-2020) 
• clarification that ‘diagnosis of SCD’ is collected, as well as Dactylitis history in 
addition to VOC history 
• addition of the collection of prior use of HU/HC and reason for discontinuation as 
part of background medical information 
• Section 7.1.5: circumstances for study treatment discontinuation updated to add decision 
based on applicable board(s) after review of safety data and discontinuation of study drug 
development 


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• Table 7-2: corrected to make collection of Hospitalizations details at Screening/Baseline 
as mandatory 
• Section 7.2.1.1: 
• clarification that at least one VOC having led to healthcare/medical facility visit within 
12 months prior to screening is required to make the patient eligible 
• clarification that VOCs or Dactylitis events occurring during screening period and prior 
to first dose have to be collected on the respective History CRFs 
• Section 7.2.2.3: addition of Head Circumference measure for participants aged 6 months to 
2.5 years old at time of enrollment, until participants turn 3 years old 
• Section 7.2.2.5.1: note added to clarify that in case of Stage V is reached, Tanner stagingmay 
be discontinued 
• Section 7.2.2.6: clarifications on which participants are expected to get TCD assessments 
• Section 7.2.2.7.5: clarification that age of the participant refers to age at time of enrollment 
• Section 7.2.2.7.6: correction in section referenced 
• Section 7.2.2.8.1: correction of minimum QTcF value from 500 to 480 ms to request 
additional unscheduled ECG evaluation to align text with Table 7-4 
• Table 7-4: footnote added to clarify that for participants in Part A the ECG assessment at 
Week 15 Day 1 has to be aligned with steady sate 
• Section 7.2.31: change of collecting PK/IG samples until safety follow-up visit (previously 
until EOT) 
• Tables 7-5, 7-6, 7-7, 7-8: 
• addition of the time window allowed for PK/PD samples collection 
• addition of PK and IG samples collection at safety follow-up visit 
• Section 7.2.4: deletion of the paragraph related to optional buccal swab collection for 
pharmacogenetics analysis 
• Table 7-9: removal of optional buccal swab for pharmacogenetics analysis 
• Section 8: 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 8.2.1: text revised based on the latest Novartis Global Clinical Trial Protocol 
Template v3.0 (31-Jan-2020) to clarify the definition of serious adverse event (SAE) 
• Section 8.3: 
• clarification on adverse events (AEs) and SAEs exempt from protocol 
• addition that VOCs suspected to be related to study treatment, as well as fatal VOCs 
will have to be reported as serious adverse events in addition to the VOC CRF 
• clarification that any follow-up for SAE needs to be reported within 24 hours from 
investigator’s awareness 


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• Section 8.3.1: 
• removal of reference to blinding as not relevant on this trial 
• addition of EU guidance for reporting of SUSARs to relevant authorities and ethics 
committees 
• Section 8.5: 
• text 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 
• addition of the duration of the follow-up period 
• Section 8.6: added to clarify the reporting of study treatment errors including misuse/abuse 
in alignment with the latest Novartis Global Clinical Trial Protocol Template v3.0 (31-Jan- 
2020) 
• Section 9.3: reference to buccal swab collection for optional PG deleted 
• Section 9.4: 
• clarification of WHO as World Health Organization 
• addition of data collected in IRT in alignment with the latest Novartis Global Clinical 
Trial Protocol Template v3.0 (31-Jan-2020) 
• Section 10: correction to mention that at time of primary analysis of each group, available 
data from other groups may be included in the reporting, if deemed necessary 
• Section 10.1.5 and Section 10.1.6: reference to ‘other tested dose’ added to 5 mg/kg dose 
which is the starting dose 
• Section 10.3: definition of dose adjustment updated based on data actually collected in the 
clinical database on study treatment CRF 
• Section 10.4.1: 
• correction of ‘Week 3’ into ‘Week 1’ to match with Table 3-1 
• language added to clarify that the endpoint pertaining to the frequency of any AEs 
during the on-treatment period is pertaining to the primary ‘safety’ endpoint for Part A 
and B ‘of all age groups’ 
• Section 10.4.2: 
• clarification that dose is not considered as confirmed only based on PK results 
• clarification that for group 1 primary PK parameters will be compared against observed 
adult PK parameters of study CSEG101A2202; yet for the other groups these 
parameters will be compared to predicted PK parameters for these participants derived 
from adults from the population PK model. 
• mention of ‘predicted’ removed in comparison of geometric means between observed 
and reference primary PK parameters 
• paragraph headers updated to clarify that both PK and safety data are part of the analysis 
for dose confirmation and primary analyses 
• Section 10.5.2: 
• clarification that only VOCs having led to healthcare visits will be considered at 
baseline for consistency with the other sections of the protocol 


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• Section 11.1 updated to align with latest Novartis Global Clinical Trial Protocol Template 
v3.0 (31-Jan-2020) and update of the local regulations references 
• Section 11.2 updated to align with latest Novartis Global Clinical Trial Protocol Template 
v3.0 (31-Jan-2020) and addition that in case of clinical site inspection by a regulatory 
authority, the investigator must inform Novartis immediately 
• Section 11.3: 
• text aligned on the latest Novartis Global Clinical Trial Protocol Template v3.0 (31- 
Jan-2020) and reference to IB added 
• informed consent included in the study listed 
• deletion of additional consent form for optional pharmacogenetics component 
• Section 13: 
• referenced articles of Descotes 2009, Sing JA 2011, and Qi X 2014 removed 
• new reference to Brandon et al 2020 added 
• missing references to Miller et al (2000) 
 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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1. Update sample time collection for coagulation from visit W15D2 to W19D1 to avoid 
patients from Part B to have to come back at W15D2. 
2. PK/PD/IG Tables have been updated to clarify which samples time points are collected in 
each Part of the study and the samples required for steady state. 
3. Conduct of primary analyses have been separated in order to gain flexibility with making 
data available as soon as possible for Group 1 and Group 2 in order to avoid to run analyses 
only once both of them are completed. 
4. Following scientific advice for study A2301 and further alignment on the estimand 
framework for SEG101 project, the secondary endpoint on annual rate of VOC will exclude 
data collected post initiation/discontinuation of HU/HC or L-glutamine on treatment 
(instead of including them). A sensitivity analysis will be done, including those data. 
5. Correction of editorial and typographical errors. 
Changes to the protocol 
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: clarifications added 
• Glossary of terms: including definitions of “Study treatment interruption” and “Multiple 
dose” to be used in this study, removed definitions not used in the protocol 
• Protocol Summary: updated in alignment with the protocol sections updated 
• Section 1.1: including OxbrytaTM (voxelotor) as approved by US FDA on 25-Nov-2019 for 
SCD treatment 
• Section 1.2.1: including crizanlizumab as approved by US FDA on 15-Nov-2019 for SCD 
treatment 
• Section 1.2.1.2: clarified that SCPC are also known as VOC leading to healthcare visit, and 
updated information on anti-drug antibodies development. 
• Section 2.3: removed SCPC to refer to ‘VOC leading to healthcare visit’ instead, and 
removed the infusion time to refer to Pharmacy Manual 
• Section 2.6: removed SCPC to refer to ‘VOC leading to healthcare visit’ instead. 
Consideration that infusion-related reactions can be considered as an identified risk deleted. 
Updates based on new data available on immunogenicity and interference with automated 
platelets counts in line with the current version of the IB. 
• Table 3-1: objectives endpoints clarified for Primary, Secondary 
 
 
• Section 4.1: 
• Clarifying full PK/PD sampling collection at single dose and multiple dose in Part A 
and possibility for the patient to remain at site for the full PK/PD sampling 
• Clarifying that a minimum of at least 8 patients is required in Part A of Group 1 and 
Group 2 
• Clarifying the reason for study treatment permanently discontinued. 


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• Removed sentence mentioning that all the screening evaluations must be done within a 
28 days period prior to dosing. 
• Reference to “eligibility checklist” embedded in IRT system removed as not used in 
this study 
• Section 5.1: conditions on HU/HC, L-glutamine or erythropoietin stimulating agent uptake 
prior to screening clarified. 
• Section 5.2: 
• Including recommendation on confirmation of local SCD diagnosis by two methods in 
criterion #2 
• Period of time to experience at least 1 VOC for eligibility clarified in inclusion criterion 
#3 
• Including L-glutamine in criterion #4 as approved by US FDA for SCD treatment. 
Update made to mention that patients off HU/HC, L-glutamine or erythropoietin 
stimulating agent must have stopped treatment for at least 6 months prior to screening 
• Update made to inclusion criterion #7 to refer to ‘prior to Week 1 Day 1’, instead of 
screening visit 
• Clarify inclusion criterion # 9 regarding screening TCD, including requiring TCD only 
for ages 2 to <16 yrs, for certain genotypes/hemoglobin phenotypes, based on SOC and 
proof of relevance of TCD in these populations. 
• Section 5.3: 
• Exclusion criterion #5 is no longer required as it has been merged with exclusion 
criterion #3 and revised to clarify the episodic transfusion (simple or exchange). 
• Clarifying exclusion criterion #11 to not exclude patients with silent infarcts only 
present on imaging. 
• Revised exclusion criterion #12 to exclude abnormal TCD within the past 12 months. 
• Exclusion criterion #14 has been updated to clarify timelines of hospitalization prior to 
Week 1 Day 1. 
• Exclusion criterion #16 updated to include L-glutamine as approved by US FDA for 
SCD treatment 
• Exclusion criteria #25 regarding impacting the cardiac or cardiac repolarization 
abnormality has been revised based on current program safety profile to remove 
exclusion of the use of concomitant medication with “Known Risk of Torsade de 
Pointes. 
• Exclusion criterion #27 related to the current drug and alcohol abuse has been removed. 
• Adding a new exclusion criteria #31 for patients already exposed to crizanlizumab. 
• Section 6.1: removing the infusion time and referring to Pharmacy Manual. 
• Section 6.3.1.2: clarifying guidance to restart study drug as soon as possible following dose 
delay. Change made to allow dose administration during VOC. Clarify permanent treatment 
discontinuation as per Table 6-2 and for Grade 4 adverse events deemed related to study 
drug. Deletion of redundancy. 


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• Table 6-2 revised as per crizanlizumab safety profile and for bringing additional guidance 
on criteria for dose interruption and dose re-initiation: 
• Change the wording “May maintain dose level” to “Recommendation continue study 
treatment” throughout the table as no dose change is allowed 
• Language updated for consistency for permanent study treatment discontinuation in 
case of Grade 4 toxicity 
• Language updated for consistency for study treatment interruption in case of Grade 3 
toxicity 
• Modified criteria for interruption and dose re-initiation for Neutropenia G3 and febrile 
neutropenia 
• Removed eGFR as redundant with criteria for serum creatinine, and no safety issue 
with renal toxicity 
• Clarified criteria for dose re-initiation in case of Grade 2 and Grade 3 isolated direct 
bilirubin elevation 
• Removed isolated AST from the table. 
• Clarified criteria for dose re-initiation in case of Grade 2 and Grade 3 isolated ALT 
elevation 
• Changed total bilirubin by direct bilirubin 
• Updated criteria for dose interruption, re-initiation and monitoring of LFTs in case of 
combined elevations of ALT and direct bilirubin 
• Clarified wording for serious and non-serious infections to refer to CTCAE grade. For 
infections with toxicity Grade 3 (or Serious) or Grade 4, change made to clarify the 
conditions for permanent discontinuation. 
• Diarrhea replaced by GI toxicity (including diarrhea, nausea, vomiting) 
• Removed fatigue as not applicable 
• Table 6-3: management of drug-related reactions have been revised to align with the 
CTCAE grade definition. 
• Section 6.3.2: removed based on the current safety profile of the compound showing no 
clinically significant events of QTcF prolongation in SCD patients receiving crizanlizumab. 
• Section 6.3.3.1: Reviewed the DILI criteria requiring follow-up based on ALT and direct 
bilirubin results at baseline. Removed reference to bone metastasis. 
• Section 6.4.1: clarifying the use of vaccines in this study 
• Section 6.4.3: modified the required discontinuation period in case of use of antibody or 
immunoglobulin therapy and including voxelotor as prohibited medication during the study. 
• Section 6.5.1: clarifying the re-screening conditions 
• Section 6.6: removed information on study drug preparation and dispensation and refer to 
the Pharmacy Manual. Clarifying that monitoring of patient after 6 months will be done as 
per local medical practices. 
• Section 6.6.1: removed sentence referring to 2 parts (base plus tear of label) as not in 
alignment with the study treatment label. 


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• Section 7.1: 
• Specified the screening period for the chest X-ray, echocardiogram, auditory and ocular 
assessments. 
• Modified the window period to +/- 7 days for all visits after Week 3 Day 1. 
• Specified that a period of at least 21 days is required between 2 doses after Week 3 Day 
1. 
• Specified that the dose at Week 3 Day 1 has to be given within 14 days +/-3 days after 
Week 1 Day 1 dose 
• Table 7-1: 
• Added screening time details period. 
• Added group information for assessments. 
• Added IRT/IWRS registration at EOT visit 
• Modified the second coagulation test to be done at Wk19D1. 
• Removed drug screen assessment, as well as alcohol and smoking history. 
• Modified the type of optional buccal swab samples and clarified the time to collect the 
sample. 
• Modified TCD assessment time points. 
• Adding footnotes to clarify when the assessments are done based on the group the 
patient is enrolled to. 
• Correct typos in the table 
• Section 7.1.2: wording simplified. 
• Section 7.1.2.1: reference to “eligibility checklist” embedded in IRT system removed as not 
used in this study 
• Section 7.1.2.2: information collected for screening failures updated as per current Novartis 
protocol template wording 
• Section 7.1.4: full PK/PD sample collection clarified and reference to “eligibility checklist” 
embedded in IRT system removed as not used in this study 
• Section 7.1.5: revised wording for discontinuation of study treatment and including a 
window of 7 days for EOT visit after decision for treatment discontinuation. 
• Section 7.1.6: Withdrawal section updated to be aligned with the last Novartis protocol 
template wording 
• Section 7.1.7: update of the CRFs requiring data collection at the time of safety follow-up 
visit. 
• Section 7.2.1.1: 
• Definition of VOC was updated with the requirement to receive therapy with 
oral/parenteral opioids or parenteral NSAIDs 
• Definition of resolved Acute Chest Syndrome was clarified 
• Information to be collected for VOC in the CRF was removed 
• Removed drug infusion restriction during VOC. 
• Information to be collected in regards to dactylitis was clarified 


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• Information updated for the chest X-ray required at screening to assess patient’s 
eligibility. 
• Information regarding collection of transfusion data was modified 
• Section 7.2.2.1: removed reference to EOT visit within 7 days following last infusion. 
• Section 7.2.2.6: clarified TCD requirements. 
• Section 7.2.2.7: 
• Allow local testing for hematology panel 
• Added requirement to get safety laboratory analysis repeated prior to Week Day 1 in 
case of hospitalization at screening 
• Added non allowance to get two consecutive lab tests used to assess dose 
interruption/disconnection missing 
• Table 7-3: revised lab assessments in alignment with changes in different protocol sections. 
• Section 7.2.2.7.1: change in the hematology panel testing method from central to local. 
Added possibility to use blood smear for manual platelet estimation. 
• Section 7.2.2.7.3: urine drug screen test removed 
• Section 7.2.2.7.4: second coagulation sample time-point at Week 15 Day 2 has been 
modified to Week 19 Day 1. 
• Section 7.2.2.7.5: extend the collection of fetal hemoglobin sample to patients above 2 
years. 
• Section 7.2.2.7.6: adding report of child bearing potential status change during the study in 
the source document 
• Section 7.2.2.7.7: including wording for EOT visit in alignment with VES 
• Section 7.2.2.8.1: clarified time to collect ECG as per Table 7-4. Range of QTcF to define 
cardiac AEs corrected. 
• Section 7.2.2.8.2: clarified echocardiogram assessment collection. 
• Section 7.2.2.9: clarified the time window period for the screening auditory examination. 
• Section 7.2.2.10: clarified the time window period for the screening ocular and retinal 
examination. 
• Section 7.2.2.11: clarifying PFT assessment at screening for patients with existing lung 
disease. 
• Section 7.2.3: collection of IG samples added. 
• Section 7.2.3.1: removed instructions for PK/PD/IG blood collection as already described 
in the central lab manual. Clarifications for the blood sampling at steady state for Part A 
patients. 
• Tables 7-5, 7-6, 7-7 and 7-8: 
• Removed the Sample blood volume column. 
• Included clarification on sample collection for Part A and Part B. 
• Footnote updated to clarify PK/PD sampling at steady state and collection of 0.5 hr 
post-dose sample 
• Addition of Dose reference ID at EOT (for last infusion prior to EOT) 


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• Section 7.2.4: modified optional swab collection type to buccal. 
 
 
• Section 8.1.1: list of outcome removed 
• Section 8.3: removed the sentence related to fatal VOCs. 
• Table 8-1: removed the SCPC wording. 
• Section 9.3: section wording revised in alignment with protocol. 
• Section 10: definition of cut-off for formal analysis revised 
• Section 10.1.5: Pharmacokinetic analysis set revised taking in account the multiple dose 
definition. 
• Section 10.1.6: Pharmacodynamics analysis set revised taking in account the multiple dose 
definition. Clarification about evaluability of % inhibition value. 
• Section 10.4: cut off for the primary analysis revised 
• Section 10.4.1: reference to ‘fifth dose’ replaced by ‘multiple dose’. Information updated 
on primary PK/PD parameters for Group 3 
• Section 10.4.2: clarification on the statistical model used. List of studies removed. 
• Section 10.5.2: the annual rate of VOC will exclude data post initiation/discontinuation of 
HU/HC or L-glutamine (instead of including them). A sensitivity analysis will evaluate 
results with inclusion of those data. The definition of end date is also updated accordingly 
until the initiation/discontinuation of HU/HC or L-glutamine. 
• Table 10-1: clarified the T1/2 definition. 
 
. 
• Table 10-2: update in the number of patients from 89 to 86. 
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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Amendment 1 (23-Oct-2018) 
Amendment rationale 
At the time of the amendment, 1 patient has been enrolled in the study. 
The purpose of this amendment is as followed: 
1. To update inclusion exclusion criteria in order to : 
• Clarify criteria #4 for patients receiving HU/HC, as dose alterations of HU/HC 
performed during part A will be not allowed to avoid any potential influence with the 
study treatment and PK results. 
• Re-word and clarify criteria #17 to ensure that patients with active HIV will be excluded 
as immunological effects of crizanlizumab are not sufficiently explored so far. 
• Including 2 new exclusion criteria as per GCP guidance. 
2. Addition of a DMC to be in charge of the review of the key safety and PK data review at 
each dosing confirmation in Part A including the recommendation to open the next age 
group and to open enrolment in Part B to ensure pediatric patient safety is monitored. 
3. To clarify the minimum observation period after the administration of the drug to monitor 
the patient safety following drug infusion. 
4. Pregnancy test was extended to all females of childbearing potential 
5. To update the declaration of Helsinki directive to fit to the last directive version (Art. 3 Par. 
2 of the Directive 2005/28/EC). 
6. To include mandatory reasons to terminate study prematurely due to safety reasons. 
7. Dose interruption due to Adverse Drug Reaction table 6-2 has been updated as following to 
clarify the requirements in case of ADR: 
• Addition of the mandatory study treatment discontinuation in case of any grade 4 ADR. 
• Clarification on the timelines required to permanently discontinue the study drug in 
case of persistent abnormality. 
• Updates performed to align the grades values with CTCAE version 5 
• Footnotes clarifications including removal of “*Note” and “**Note” as they are not 
applicable for the table. 
8. Drug-induced liver injury (DILI) section has been updated as subjects with SCD tend to 
have elevated transaminases, especially AST, and indirect bilirubin due to the hemolytic 
nature of this condition. In order to reduce the number of false positives, AST will not be 
considered and only ALT and bilirubin will be required in this criteria. The criteria in table 
6-2 has been adapted accordingly. 
9. Addition of mandatory dose interruption in case of confirmed QTc prolongation. 
10. Drug treatment details has been updated as only SEG101 FMI is used from the start of the 
study and the preparation of the individual doses of SEG101 for patients are defined in the 
Pharmacy Manual. 


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11. Clarification of concomitant medication permitted during the study: 
• Use of live and inactivated vaccines as permitted concomitant medication during the 
trial. Live vaccines to be given at least 4 weeks prior first dose in accordance with 
guidelines for monoclonal antibodies 
• Use of HU/HC and L-Glutamine as per local guidelines and standard of care 
• Use of HU/HC during the Part A as dose modifications are not allowed. 
12. Clarification that urine pregnancy tests will be done for all female childbearing potential or 
for all female becoming of childbearing potential during the study. 
13. Clarification of the pre-dose PK/PD/IG samples time points for patients enrolled in 
Part B 
14. Optional pharmacogenetics sample will be collected using a saliva swab instead of blood 
sample to reduce the blood volume collection in the 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. 
• List of Abbreviations: Added ADR (Adverse drug Reactions) and NSAIDs (Non-steroidal 
anti-inflammatory drugs) 
• Protocol Summary: Made updates to align the changes in protocol sections. 
• Section 1.1: Nietert 2002 publication has been included 
• Section 1.2.1.2: Clarification of non-steroidal anti-inflammatory drugs (NSAIDs) included. 
• Section 2.2: inclusion of key safety data for the single dosing confirmation 
• Section 4.1: a inclusion of key safety data for the single dosing confirmation 
• Section 5.2: Inclusion criteria #4 updated to do not allow alterations of HU/HC during Part 
A 
• Section 5.3: Exclusion criteria #17 clarified to exclude patients with active HIV 
• Section 5.3: Addition of exclusion criteria # 29 and # 30 
• Section 6.1.1: Drug treatment details updated as only SEG101 Final Market Image (FMI) 
is used from the start of the study and the preparation of the individual doses of SEG101 for 
patients are defined in the Pharmacy Manual. 
• Section 6.3.1.1: Addition of DMC recommendation to be considered on the dose 
confirmation. 
• Section 6.3.1.2: Clarification added for the permanent treatment discontinuation and typo 
corrected. 
• Table 6-2: Addition of the mandatory study treatment discontinuation in case of any grade 
4 ADR, clarification made on the timelines required to permanently discontinue the study 
drug in case of persistent abnormality, alignment with CTCAE grade version 5 and 
footnotes clarifications have been performed in the table. 
• Table 6-3: clarification of the management of the infusion-related reactions for Grade 2. 
• Section 6.3.3.1: Drug-induced liver injury (DILI) cases section updated 


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• Section 6.3.2: Section title updated to be in alignment with the section and addition of 
mandatory dose interruption in case of confirmed QTc prolongation. 
• Section 6.4.1: addition of the vaccines administration (live and inactivated) as permitted 
concomitant therapy, concomitant use of HU/HC and L-Glutamine as per local guidelines 
and  standard  of  care  and  clarification  on  the  use  of  HU/HC  during  the 
Part A. 
• Section 6.6: clarification of the place where the drug infusion have to be performed and the 
patient monitoring timing after drug infusion. 
• Table 7-1: updates performed in the table to be in alignment with protocol sections 
• Section 7.2.1.1: addition of NSAIDs (Non-steroidal anti-inflammatory drugs) and typos 
corrected. 
• Section 7.2.2.7.6: Clarification on the pregnancy analysis for females of child bearing 
potential. 
• Section 7.2.2.7.7: typo corrected 
• Section 7.2.3.1: correction of the pre-dose PK/PD/IG samples timelines collection for Part 
B 
• Section 7.2.4 and Table 7-9: saliva swab will be used for the optional pharmacogenetics 
sample 
• Section 8.1.1: CTCAE version updated and clarifications provided on the reporting of the 
AE in the CRF. 
• Table 8-1 footnote: addition of NSAIDs (Non-steroidal anti-inflammatory drugs) 
• Section 8.7: addition of the Data Monitoring Committee section 
• Section 10: inclusion of key safety data for the single dosing confirmation 
• Section 10.5.3.3: CTCAE version updated 
• Section 11.1: Update of the European directive 
• Section 11.4: Update of the study discontinuation section to include the mandatory reasons 
to terminate study prematurely due to safety reasons 
• Section 13: duplicate reference removed 
• In addition, clarifications were added to correct typographical errors and inconsistencies in 
different sections. 
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 
Title 
A phase 2, multicenter, Open-Label Study to Assess Appropriate Dosing and to 
Evaluate Safety of Crizanlizumab, with or without 
Hydroxyurea/Hydroxycarbamide, in Sequential, Descending Age Groups of 
Pediatric Sickle Cell Disease Patients with Vaso-Occlusive Crisis. 
Brief title 
Study of dose confirmation and safety of Crizanlizumab in Pediatric Sickle Cell 
Disease Patients 
Sponsor and Clinical 
Phase 
Novartis 
Phase 2 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
The purpose of the Phase 2 CSEG101B2201 study is to confirm and to establish 
appropriate dosing and to evaluate the safety in pediatric participants ages 2 to 
<18 years with a history of VOC with or without HU/HC, receiving crizanlizumab 
for 2 years. The efficacy and safety of crizanlizumab was already demonstrated 
in adults with sickle cell disease. The approach is to extrapolate from the PK/ 
pharmacodynamics (PD) already established in the adult population. The study is 
designed as a Phase II, multicenter, open-label study. 
Primary Objective(s) and 
Key Secondary Objective 
• 
Primary Objective: 
• To confirm and establish appropriate dosing in participants from 2 to less 
than 18 years of age (Parts A and B) 
• To evaluate the safety of crizanlizumab in participants from 2 to less than 
18 years of age (Parts A and B). 
• 
Key Secondary objectives: none 
Secondary Objectives 
• 
To assess the long-term efficacy of crizanlizumab in participants aged 2 to <18 
year old, as measured by annualized rate of VOC events leading to healthcare 
visit in clinic/ER/hospital, annualized rate of VOC events treated at home, 
annualized rate of each subcategory of VOC event (uncomplicated pain crisis, 
acute chest syndrome, hepatic sequestration, splenic sequestration, 
priapism), annualized rate of Hospitalizations and ER visits (both overall and 
VOC-related), annualized rate of days of ER/hospitalization (both overall and 
VOC-related), annualized rate of Dactylitis events 
• 
To assess other safety measures in participants aged 2 to < 18 year old in 
terms of frequency, seriousness, severity and causality of treatment emergent 
AEs, absolute change from baseline in hemoglobin, measurement of anti-drug 
antibodies (ADA) to crizanlizumab, ECG measures at the time of PK, growth 
and sexual maturation assessments. 
• 
Characterize the long-term PK and PD of crizanlizumab in participants aged 
2 to <18 years at the time of study entry as measured by pre-dose 
concentrations prior to each study drug dose and percentage of P-selectin 
inhibition prior to dosing. 
Study design 
Open-label, single arm study of crizanlizumab in SCD (sickle-cell disease) 
pediatric participants. In Part A of the study across the ages 2- to <18 years, the 
dose for each group will be first confirmed on the basis of single & multiple dose 
(steady state) PK data and key safety data from an initial subgroup of 
participants. In Part B of Groups 1 and 2, safety and efficacy data will be 
collected from additional participants from 6 to <18 years. 


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Study population 
The study will include at least 100 pediatric participants, ages 2 years to less than 
18 years, with confirmed diagnosis of SCD (all genotypes, as in Table 1-1), who 
have experienced at least 1 VOC within the preceding 12 months. 
Group 1 will include at least 26 participants ages 12 to <18 years, group 2 will 
include at least 26 participants ages 6 to <12 years, and group 3 will include at 
least 8 participants ages 2 to <6 years. 
Participants must not plan to initiate voxelotor, HU/HC, L-glutamine or 
erythropoietin stimulating agent during the study. For participants who are already 
treated with HU/HC, L-glutamine or erythropoietin stimulating agent, they must be 
taking such drugs for at least 6 months prior to study entry and accept to take the 
same dose at the same schedule during the trial. Voxelotor must have been 
permanently discontinued at least 30 days prior to study entry. 
Inclusion criteria 
• 
Male or female patients ages 2 to <18 years 
• 
Confirmed diagnosis of SCD (any genotype including HbSS, HbSC, HbSβ0- 
thalassemia, HbSβ+-thalassemia, and others) by hemoglobin electrophoresis 
and/or high-performance liquid chromatography (HPLC) performed locally. 
Confirmation of diagnosis by two accepted methods is recommended. 
• 
Experienced at least 1 VOC within the preceding 12 months prior to screening, 
as determined by medical history. Prior VOC must have resolved at least 7 
days prior to the first dose in the study and must include all the following: 
• the occurrence of appropriate symptoms (see VOC definition in 
Section 7.2.1.1) 
• either a visit to a medical facility or healthcare professional 
• receipt  of  oral/parenteral  opioid  or  parenteral  non-steroidal  anti- 
inflammatory drugs (NSAID). 
• 
If receiving HU/HC, L-glutamine or erythropoietin stimulating agent, must 
have been receiving the drug consistently for at least 6 months prior to 
Screening and plan to continue taking it at the same dose and schedule during 
the trial. Patients not receiving such drugs must have been off them for at 
least 6 months prior to screening. 
• 
Received standard age-appropriate care for SCD, including penicillin 
prophylaxis, pneumococcal immunization, and parental education. 
• 
Transcranial Doppler (TCD) for patients aged 2 to < 16 years at the time of 
screening, with HbSS, HbSβ0-thalassemia, and HbSD disease, indicating low 
risk for stroke (per investigator) as outlined in Section 7.2.2.6 
Exclusion criteria 
• 
History of stem cell transplant 
• 
Received any blood products within 30 days prior to Week 1 Day 1 dosing 
• 
Plan to participate in a chronic transfusion program (pre-planned series of 
transfusions 
for 
prophylactic 
purposes) 
or 
undergo 
exchange 
transfusions/plasmapheresis during the study. Patients requiring episodic 
transfusion (simple or exchange) in response to worsened anemia or VOC 
are permitted. 
• 
Patients with bleeding disorders 
• 
Contraindication or hypersensitivity to any drug from similar class as study 
drug or to any excipients of the study drug formulation. 
• 
Planning to initiate or terminate HU/HC or L-glutamine while on study, other 
than for safety reasons. 
• 
Significant active infection or immune deficiency (including chronic use of 
immunosuppressive drugs) in the opinion of the investigator. 
• 
Patients under voxelotor within 30 days prior to screening or planning to 
initiate voxelotor while on study. 
Investigational and 
reference therapy 
SEG101 (crizanlizumab) 
Efficacy assessments 
• 
VOC events leading to healthcare visit in clinic/ER/hospital 




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Data analysis 
There will be multiple cut-off dates and formal analyses. 
PK, dose, demography, baseline characteristics and key safety data after a single 
dose for part A in each group will occur when at least 6 participants with evaluable 
PK have been enrolled and have completed the Week 7 Day 1 visit. 
Analysis of PK, PD, dose, demography, baseline characteristics and key safety 
data for part A of each group after multiple doses will occur when there are at least 
6 evaluable participants who completed the full PK/PD sampling following at least 
3 full consecutive doses after Week 3 Day 1. The primary analyses for parts A+B 
of Group 1, Group 2, and part A of Group 3 will occur consecutively when all the 
participants enrolled in each of these groups have completed 26-weeks of the 
treatment or discontinued the study treatment. PK, PD, demography and other 
baseline characteristics, efficacy and safety data will be reported. 
Additional data for any participants continuing to receive study treatment, as 
allowed by the protocol, will be further summarized in a final study report once all 
participants from all groups have either completed or early discontinued from the 
study. 
Key words 
Sickle cell disease, crizanlizumab, pediatric, pharmacokinetic, P-selectin 


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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
Sickle cell disease (SCD) is a rare autosomal recessive blood disorder caused by a single 
missense mutation (Glu6Val) in the β-globin gene that renders the mutant hemoglobin (Hb) less 
soluble and prone to polymerization upon deoxygenation. The polymerization of hemoglobin 
causes deformation of the erythrocyte to give the cell a “sickle” shape (Bookchin and Lew 1996), 
and leads to chronic hemolysis, anemia, and vaso-occlusion (NHLBI, The Management of 
Sickle Cell Disease. NIH Publication No.022117, Wethers 2000). SCD is the most common 
single gene disorder in African Americans, affecting approximately 1 in 375-600 persons of 
African ancestry (Clinical Practice Guideline No. 6. April 1993, Nietert et al 2002). Sickle cell 
conditions are also common among people of Mediterranean countries, Africa, the Caribbean 
and parts of South and Central America (Clinical Practice Guideline No. 6. April 1993, Nietert 
et al 2002). 
In SCD, lysis of sickle red cells, cell membrane damage and oxidative stress, repeated ischemic 
damage, and microvasculature injury are due to the adhesive interactions between sickle red 
cells and the endothelium, which culminate in a pro-inflammatory environment (Embury 2004, 
Chiang and Frenette 2005). In this environment of chronic vascular inflammation, the 
adherence of leukocytes, platelets and sickle red cells to activated blood vessel endothelium and 
to each other is believed to be the primary cause of microvasculature blockage and vaso- 
occlusive crisis (VOC), the clinical hallmark of SCD, typically associated with intense pain. 
Additional factors such as the rigidity of sickle red cells, increased blood viscosity, and local 
vasoconstriction have also been identified as potentially contributing to the vaso-occlusion 
process. VOC includes pain crises (defined as an acute onset of pain for which there is no other 
medically determined explanation other than vaso-occlusion and which requires therapy with 
oral or parenteral opioids or parenteral non-steroidal anti-inflammatory drugs (NSAIDs)) as 
well as other complicated crises, such as acute chest syndrome (ACS), priapism, and hepatic or 
splenic sequestration and carries a high risk of mortality (Maitre et al 2000, Vichinsky et al 
2000). VOC accounts for over 90% of hospital admissions in adult SCD patients (Matsui et al 
2001, Chiang and Frenette 2005, Okpala 2006). 
SCD patients also suffer from cerebrovascular complications, ranging from clinically evident 
acute stroke to transient silent ischemic infarct (Platt et al 2006). Other chronic complications 
include functional asplenia, leaving patients more susceptible to infection, (Clinical Practice 
Guideline No. 6. April 1993), bone growth retardation and avascular necrosis renal dysfunction 
(Saborio and Scheinman1999), and issues of the biliary tree (gallstones, congestion), eyes 
(retinopathy) (Charache 1996), and soft tissue (leg ulcers) (Ashley-Koch et al 2000, Gladwin et 
al 2004, Gladwin and Kato 2005). Chronic pain and opioid use are also common (Smith et al 
2008). As a result of the totality of these complications, there is an approximately 20 to 30 year 
reduction in life expectancy in SCD patients (Platt et al 1994). 
Hemoglobin values for SCD patients vary, typically ranging from 6 to 10 g/dL, but some 
patients can live with baseline hemoglobin of 4 g/dL or lower. Chronic hemolysis results in 
other abnormal labs, including reticulocytosis, low haptoglobin, and increased free hemoglobin, 
lactate dehydrogenase (LDH), and indirect bilirubin (and, by extension, total bilirubin). In 


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young SCD patients, glomerular filtration rate (GFR) is substantially increased (hyperfiltration: 
MDRD-GFR >130 in females, >140 ml/min per 1.73 m2 in males) but tends to decrease 
progressively with time, and 4-5% of these patients develop stage 5 chronic renal disease (CRD) 
(Hirschberg 2010). SCD patients are also more susceptible to parvovirus B19 infection which 
can arrest erythropoiesis and lead to aplastic crisis (Heegaard and Brown 2002). 
SCD has three common variants: homozygous SCD (hemoglobin SS disease), doubly 
heterozygous sickle hemoglobin C disease (hemoglobin SC disease) and the sickle β- 
thalassemias. The most common form of the disease occurs in individuals who inherit two 
copies of the HbS variant (HbSS), and the primary hemoglobin in their red blood cells (RBCs) 
is sickle hemoglobin. Other individuals can be affected as compound heterozygotes with one 
copy of the HbS gene and one or more additional mutations, resulting in varying severities of 
the disease. HbSC results in a mild-to-moderate form of the disease. HbS β-thalassemia 
variants (β0 or β+) result in a range of clinical severities: HbSβ0 is a severe form, whereas HbSβ+ 
can be moderate or mild based on the contribution of each variant to the total hemoglobin of the 
patient. Other more rare variants can result if in addition to the HbS gene, another abnormal 
hemoglobin is inherited from the other parent, such as D, G or O-Arab. The sickle cells gene is 
most commonly present in individuals heterozygous for HbS and HbA. These individuals carry 
the sickle cell trait and are asymptomatic (Clinical Practice Guideline No. 6. April 1993, Nietert 
et al 2002). 
While SCD is genetically determined, clinical symptoms generally do not occur until 6 months 
of age, as elevated fetal hemoglobin (HbF) levels retard the polymerization of deoxy sickle 
hemoglobin (Miller 2000). 
There is considerable variability in disease severity (Gill et al 1995), likely due to a complex 
interaction of genetic, rheologic and hematologic factors, as well as microvascular and 
endothelial factors. Therefore, despite the capacity to determine genotype, the ability to predict 
disease course from birth is limited (Thomas et al 1997). A prospective study of SCD 
participants with HbSS in the U.S. reported 54% of 0-9 year olds (n=1093), 68% of 10-19 year 
olds (n=635), and 73% of 20-29 year olds (n=424) experienced pain crises. Similarly, the 
average pain rate for the first 3 years of the study was 0.40 per year for 272 participants who 
entered the study at age 0-4 years and 0.56 for the 223 participants who entered the study at age 
5-9 years (Platt et al 1991). Moreover, a recent study (PiSCES) evaluating health related quality 
of life issues in SCD participants indicated that VOC might be significantly underreported 
among SCD participants (McClish et al 2005). 
Treatment for SCD includes supportive care for VOC. The two most common symptomatic 
treatments are blood transfusions and analgesics. Blood transfusions both increase hemoglobin 
level and lower the proportion of sickled cells, thereby increasing oxygen delivery to tissues 
and potentially reducing pain. Severe pain is often treated with narcotics but their use is 
controversial due to the risk of tolerance, physical and psychological dependence, drug-seeking 
behavior, chronic constipation, sedation and respiratory depression. Oxygen management has 
been utilized to treat VOC, despite the lack of strong evidence supporting its effectiveness. 
Intravenous (i.v.) fluid hydration is also used during VOC with some apparent benefit (NHLBI, 
The Management of Sickle Cell Disease. NIH Publication No.022117, Yale et al 2000). 


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Preventative therapies for SCD include chronic red cell transfusion programs to reduce the 
incidence of stroke in high-risk patients and hydroxyurea/hydroxycarbamide (HU/HC, 
Droxia/Siklos), one drug approved for VOC. The mechanisms by which HU/HC produces its 
beneficial effects are uncertain, but likely involve increasing HbF levels in RBCs, thereby 
decreasing the amount of hemoglobin S polymerization. Hydroxyurea is cytotoxic, 
myelosuppressive and teratogenic (Charache et al 1995), and the long-term effects of 
hematologic toxicities, organ damage and carcinogenicity are currently unknown 
(NIH Consensus and State-of -the Science Statements, 2008). Additionally, many patients 
continue to experience acute painful episodes despite HU/HC. Unmet medical need is even 
more acute in the pediatric population, as HU/HC is not approved for pediatric use in the US. 
According to the Droxia US PI: “Section 8.4 Pediatric Use: Safety and effectiveness in pediatric 
patients have not been established”. In the EU, Siklos (HU/HC) is approved in pediatric patients 
aged 2 years and above. L-glutamine (Endari™) is approved for oral administration by the US 
Food and Drug Administration (FDA) to reduce the acute complications of SCD in adult and 
pediatric patients 5 years and older (Endari label). Patients taking L-glutamine still experience 
pain crises and the treatment is not approved for patients under 5 years of age. OxbrytaTM 
(voxelotor) has been approved by US FDA on 25-Nov-2019 for the treatment of SCD in adults 
and pediatric patients 12 years of age and older, and received an accelerated approval on 17- 
Dec-2021 for patients aged 4 years to less than 12 years. OxbrytaTM (voxelotor) also received 
approval from the European Medicines Agency (EMA) for the treatment of hemolytic anemia 
due to SCD in adults and pediatric patients 12 years of age and older on 16-Feb-2022. 
In summary, despite standard of care management, many children and adolescents with SCD 
still experience VOC. 
In some patients, bone marrow transplantation may be considered and can be curative, but a 
limited number of patients are eligible, and this carries a high risk of morbidity and mortality 
(NHLBI, The Management of Sickle Cell Disease. NIH Publication No.022117). Thus, SCD is 
a life-threatening disease with severe morbidities and represents a major unmet medical need. 
The recognition that adherence of leukocytes, platelets and sickle red cells to blood vessel 
endothelium and to each other to 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. Under 
shear flow in the blood, leukocytes first tether and begin rolling on vascular endothelium, 
eventually adhering firmly and infiltrating into the underlying tissue (Springer 1995). Selectins 
interact with glycoconjugated ligands on leukocytes to initiate this process (McEver et al 1995, 
Vestweber and Blanks1999). Transient adhesion mediated by selectins is a prerequisite for firm 
adhesion mediated by integrin receptors and subsequent transendothelial migration of 
leukocytes. Three selectins have been identified: P-, E- and L-selectin. 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 (Mehta et al 1998, McEver 2004). 
P-selectin is stored in Weibel-Palade bodies in endothelial cells that line blood vessels and in 
α-granules in platelets. 
Extensive data have been published over the last decades that suggests a pivotal role for P- 
selectin in the pathophysiology of SCD (Matsui et al 2001). Much of this work has been 
conducted in mice engineered or altered to express human hemoglobin S (sickle cell 
hemoglobin) but not mouse β hemoglobin. These mice have a remarkably similar disease 


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pathology and inflammatory profile to that observed in human SCD, including vaso-occlusion. 
Using these mice, investigators have demonstrated P-selectin interactions between the 
endothelium and sickled red blood cells, leukocytes, and platelets. Additional studies have 
demonstrated direct P-selectin-mediated binding of leukocytes with sickled red cells and 
platelets. Platelet and leucocyte activation was observed in pediatric SCD patients (Inwald et al 
2000, Yip et al 2015), similar to what was described in adults (Ruf et al 1997, Majumdar et al 
2013). Soluble P-selectin, a surrogate marker of protein expression in endothelium and platelets, 
was elevated and appeared to be similar in adult and pediatric SCD patients (Krishnan et al 
2010, Setty et al 2012, Hatzipantelis et al 2013, Colombatti et al 2013). All of these cell-cell 
interactions have been implicated in SCD vaso-occlusion. Further, blockade or genetic absence 
of P-selectin decreases or eliminates these cell-cell interactions and vaso-occlusion. Taken 
together, these studies establish P-selectin as a key mediator of vaso-occlusion in SCD. 
Table 1-1 
Sickle Cell Disease genotypes 
 
Severe sickle-cell disease 
Characteristics 
 
HbS/S (β6Glu>Val/β6Glu>Val); sickle-cell anemia 
The most common form of sickle-cell disease 
HbS/β⁰ thalassaemia 
Most prevalent in the eastern Mediterranean region 
and India 
Severe HbS/β⁺ thalassaemia 
Most prevalent in the eastern Mediterranean region 
and India; 1–5% HbA present 
HbS/O Arab (β6Glu>Val/β121Glu>Lys) 
Reported in north Africa, the Middle East, and the 
Balkans; relatively rare 
HbS/D Punjab (β6Glu>Val/β121Glu>Gln) 
Predominant in northern India but occurs worldwide 
HbS/C Harlem (β6Glu>Val/β6Glu>Val/β, β73Asp>Asn 
Electrophoretically resembles HbSC, but clinically 
severe; double mutation in β-globin gene; very rare 
HbC/S Antilles (β6Glu>Lys/β6Glu>Val, β23Val–Ile) 
Double mutation in β-globin gene results in severe 
sickle-cell disease when co-inherited with HbC 
HbS/Quebec-CHORI (β6Glu>Val/β87Thr>Ile) 
Two cases described; resembles sickle-cell trait with 
standard analytical techniques 
Moderate sickle-cell disease 
 
HbS/C (β6Glu>Val/β6Glu>Lys) 
25–30% cases of sickle-cell disease in populations of 
African origin 
Moderate HbS/β⁺ thalassaemia 
Most cases in the eastern Mediterranean region; 6– 
15% HbA present 
HbA/S Oman (βA/β6Glu>Val, β121Glu>Lys) 
Dominant form of sickle-cell disease caused by 
double mutation in β-globin gene; very rare 
Mild sickle-cell disease 
 
Mild HbS/β⁺⁺ thalassaemia 
Mostly in populations of African origin; 16–30% HbA 
present 
HbS/E (β6Glu>Val/β26Glu>Lys) 
HbE predominates in southeast Asia and so HbSE 
uncommon, although frequency is increasing with 
population migration 
HbA / Jamaica Plain (βA/β6Glu>Val, β68Leu/Phe) 
Dominant form of sickle-cell disease; double mutation 
results in Hb with low oxygen aﬃnity; one case 
described 
Very mild sickle-cell disease HbS/HPFH 
 
HbS/HPFH 
Group of disorders caused by large deletions of the β- 
globin gene complex; typically 30% HbF 
HbS/other Hb variants 
HbS is co-inherited with many other Hb variants, and 
symptoms develop only in extreme hypoxia 


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Severe sickle-cell disease 
Characteristics 
Sickle Cell Disease genotypes (Rees et al 2010) 
 
 
1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
1.2.1 
Overview of crizanlizumab (SEG101) 
Crizanlizumab (SEG101) is a humanized monoclonal antibody that binds P-selectin in humans 
and nonhuman primates and blocks the interaction of P-selectin with its ligands including 
PSGL-1. SelG1 has negligible binding activities to human E-selectin or L-selectin in in vitro 
binding assays. 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 current drug developer and 
sponsor for crizanlizumab. First global approval for crizanlizumab for SCD treatment has been 
obtained from the US FDA on 15-Nov-2019. 
1.2.1.1 
Non-clinical experience 
In experiments performed with the parental anti-human P-selectin antibody G1, the following 
data were generated: 1) G1 blocks the binding of human P-selectin to its ligand PSGL-1 
(Geng et al 1990) 2) G1 blocks leukocyte rolling and firm adhesion to human vascular 
endothelium under shear stress (Geng et al 1990, Jones et al 1993); 3) G1 effectively inhibits 
the interaction of neutrophils with stimulated platelets (Hamburger and McEver 1990); 4) G1 
completely blocks the binding of human sickled red cells to human endothelium under flow 
(Wagner et al 2006); and 5) in mice expressing human but not mouse P-selectin, G1 blocks the 
rolling and adherence of leukocytes on mouse venules and can reverse pre-established leukocyte 
adhesion (Liu et al 2010). 
Due to the species restriction of crizanlizumab binding, much of the data available to date have 
been obtained from rodent modeling using mice expressing human hemoglobin S (sickle cell 
hemoglobin) with surrogate antibodies that block mouse P-selectin or animals genetically 
deficient in P-selectin. Where possible, the SelG1 parental antibody G1 has been used in 
experimentation in which human P-selectin is present. In addition, confirmatory data with 
SelG1 were established. 
In mice expressing human sickled hemoglobin (human βS mice) the following data were 
generated: 1) an anti-mouse P-selectin antibody blocks leukocyte rolling (Kaul and Hebbel 
2000); 2) vaso-occlusion is blocked in animals deficient in P-selectin (Frenette 2004); 3) platelet 
and leukocyte adhesion to vascular endothelium is absent in P-selectin deficient animals 
(Wood et al 2004); and 4) sickled red cell microvascular flow is increased and vaso-occlusion 
decreased with an anti-mouse P-selectin antibody (Embury 2004). 
Finally, SelG1 has been administered to nonhuman primates in a single-dose and two separate 
GLP multi-dose studies. Administration of SelG1 by bolus i.v. injection once every 4 weeks to 
cynomolgus monkeys for a total of seven doses was well-tolerated at doses ≤ 25 mg/kg/dose; 
the no observed adverse effect level (NOAEL) is therefore 25 mg/kg/dose. 


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As crizanlizumab is specific to human and nonhuman primate P-selectin, and in accordance with 
the International Council for Harmonization (ICH) S6 Guidance, one reproductive toxicology 
study with SEG101 was conducted and completed in March 2019. In this study, administration of 
crizanlizumab to pregnant cynomolgus monkeys once every two weeks during gestation did not 
elicit maternal toxicity and there were no effects on infant growth and development through 6- 
months postpartum directly attributable to crizanlizumab. All drug treated monkeys and their 
offspring were exposed to crizanlizumab, indicating that crizanlizumab was able to cross the 
placental barrier. Serum analyses showed dose-dependent inhibition of P-selectin by 
crizanlizumab in an ex vivo assay. The amount of inhibition was similar in adult females and 
infants. 
There was a numerical increase in the proportion of pregnant monkeys that aborted or 
experienced an infant death, the cause of which is unclear and likely multifactorial. Some of 
these were attributed to common non drug-related effects such as maternal neglect or breech 
positioning. There were no teratological findings (external or visceral) in the aborted fetuses, 
infant deaths or those otherwise born alive. 
This reproductive study 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. The maternal and developmental NOAEL for crizanlizumab in this study, 
therefore, was 50 mg/kg once every 2 weeks. 
1.2.1.2 
Clinical experience 
Phase I Clinical Study (CSEG101A2101) 
The objectives of this study (Reprixys study code: Se1G1-00003; Novartis study code: 
CSEG101A2101) were to evaluate the safety, pharmacokinetics (PK), pharmacodynamics (PD), 
and immunogenicity (IG) of i.v. administered crizanlizumab (SelG1) versus placebo in 27 
healthy participants at ascending dose levels (0.2, 0.5, 1.0, 5.0 and 8.0 mg/kg). Throughout this 
description of CSEG101A2101, the study drug is denoted as crizanlizumab and refers to SelG1. 
Crizanlizumab concentrations slowly declined, with mean half-life ranging from 75.6 (at dose 
of 0.2 mg/kg) to 500 (at 5.0 mg/kg) hours. Therefore, clearance decreased with the increase in 
dose level: 88.6 mL/hr (at 0.2 mg/kg) to 9.91 mL/hr (at 5.0 mg/kg). Following two i.v. infusions 
of crizanlizumab at 8.0 mg/kg, the mean half-life was 363 hours, and the clearance was 3.86 
mL/hr. 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 generated during the Phase I clinical trial indicate that no specific antibody 
response to crizanlizumab occurred in any participants receiving up to 2 doses of drug. 
Based on AEs, clinical laboratory evaluations, vital signs measurements, physical examinations, 
and electrocardiogram (ECG) evaluations, administration of crizanlizumab was safe and well- 
tolerated in this group of healthy male and female participants. 


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Phase II Clinical Study (SUSTAIN – CSEG101A2201) 
The purpose of SUSTAIN (Reprixys study code: Se1G1-00005; Novartis study code: 
CSEG101A2201) study was to investigate the safety and tolerability of the humanized anti-P- 
selectin monoclonal antibody, crizanlizumab (SelG1), during chronic administration to SCD 
participants and to investigate the efficacy of crizanlizumab to affect the rate of sickle cell- 
related pain crises (SCPC, also known as VOC leading to healthcare visit) as well as a variety 
of other clinical endpoints, anemia- and hemolysis-related laboratory parameters, PK/PD, and 
patient reported outcomes. Throughout this description of SUSTAIN, the study drug is denoted 
as crizanlizumab and refers to SelG1 
This trial was a multicenter, randomized, placebo-controlled, double-blind, parallel-group study 
to assess the safety and efficacy of crizanlizumab versus placebo in participants with SCD, both 
receiving and not receiving HU/HC. Crizanlizumab was administered at 2 different dose levels 
(2.5 mg/kg and 5.0 mg/kg). A total of 198 participants were randomized and included in the 
intent-to-treat (ITT) population, with 67 participants randomized to receive crizanlizumab at 
5.0 mg/kg (5.0 mg/kg treatment arm), 66 participants to receive crizanlizumab at 2.5 mg/kg (2.5 
mg/kg treatment arm), and 65 participants to receive placebo (placebo treatment arm). 
The primary efficacy parameter was the assessment of the annual rate of VOC leading to 
healthcare visit, defined as an acute episode of pain, for which there is no other medically 
determined explanation or cause other than a vaso-occlusive event, which required a medical 
facility (clinic, emergency room (ER), or hospital) visit and treatment with oral or parenteral 
narcotics, or parenteral NSAIDs. ACS, hepatic sequestration, splenic sequestration and priapism 
events requiring a visit to a medical facility were also considered VOC leading to healthcare visit 
for analysis purposes. It was observed that treatment with 5.0 mg/kg crizanlizumab resulted in 
an annual rate of VOC leading to healthcare visit that was 45.3% lower than the rate with 
placebo which was statistically significant (p = 0.010). The annual rate of VOC leading to 
healthcare visit in the 2.5 mg/kg crizanlizumab treatment arm was compared with that of 
placebo, and although favorable (32.6% reduction with active treatment), it was not statistically 
significant (p = 0.180). In addition, in the 5.0 mg/kg crizanlizumab arm, numerical and 
clinically significant reductions in the annual rate of VOC leading to healthcare visit were 
observed across important subgroups, including participants receiving concomitant HU/HC 
(32.1%) and not receiving concomitant HU/HC (50.0%), and in participants with the HbSS 
genotype (34.6%) and non-HbSS genotype (50.5%) (HbSC, HbSβ0-thalassemia, HbSβ+- 
thalassemia and others). The median annual rate of days hospitalized was numerically reduced 
in the 5.0 mg/kg arm versus the placebo arm (4.00 versus 6.87, respectively); however, this 
difference was not statistically significant. Treatment with crizanlizumab at 5.0 mg/kg was 
associated with longer median time to first VOC leading to healthcare visit compared with 
placebo (4.07 versus 1.38 months, p = 0.001) and median time to second VOC leading to 
healthcare visit compared to placebo (10.32 versus 5.09 months, p = 0.022). 
Crizanlizumab was well-tolerated. Adverse events that occurred in ≥5% of participants in an 
active dose group (either 2.5 mg/kg or 5.0 mg/kg) and were more than 2 times higher than 
placebo were: arthralgia, pruritus, vomiting, chest pain, diarrhea, fatigue, myalgia, 
musculoskeletal chest pain, abdominal pain, influenza, oropharyngeal pain and traffic accident. 
Adverse events that occurred in 10% or more of the participants in either active treatment group 
and at a frequency that was at least twice as high as that in the placebo group were arthralgia 


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(5.0 mg/kg: 18.2% versus 2.5 mg/kg: 14.1% versus placebo: 8.1%), diarrhea (10.6% versus 7.8% 
versus 3.2%), pruritus (7.6% versus 10.9% versus 3.4%), vomiting (7.6% versus 10.9% versus 
4.8%) and chest pain (1.5% versus 10.9% versus 1.6%). 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 no deaths were deemed related 
to study drug. The proportion of participants experiencing serious adverse events (SAEs) was 
25.8% at 5.0 mg/kg, 32.8% at 2.5 mg/kg and 27.4% in the placebo group. 
Treatment-induced anti-crizanlizumab antibodies were transiently detected in 2 out of 175 
(1.1%) participants. 
There was no evidence for any increase in infections: the frequency across treatment arms in 
the SOC of Infections and Infestations were evenly distributed (51.5%, 45.3% and 53.2% in the 
5.0 mg/kg, 2.5 mg/kg and placebo treatment arms, respectively). 
Overall, treatment of participants with SCD with crizanlizumab at 5.0 mg/kg showed positive 
clinical activity as demonstrated by a decrease in the annual VOC leading to healthcare visit 
rate compared with placebo. Treatment with crizanlizumab at 5.0 mg/kg was also found to be 
well-tolerated. 
Phase III Clinical Study (STAND – CSEG101A2301) 
The purpose of the phase III, multicenter, randomized, double-blind study CSEG101A2301 was 
to compare the efficacy and safety of two doses of crizanlizumab versus placebo in adolescent 
and adult patients with SCD who had a history of VOCs (at least 2 in the 12 months prior to 
screening period) leading to healthcare visits. This study included patients aged 12 years and 
older with a confirmed diagnosis of SCD, where all genotypes were eligible. The primary 
objective of this study was to compare the efficacy of crizanlizumab at doses of 7.5 mg/kg and 
5 mg/kg, respectively, versus placebo (in addition to standard of care) in preventing VOCs 
leading to healthcare visits over the first-year post-randomization. 
A total of 252 participants were randomized in Study A2301. Of these, 85 participants were 
assigned to the placebo arm, 84 participants to the crizanlizumab 5 mg/kg arm, and 83 
participants to the crizanlizumab 7.5 mg/kg arm. The primary analysis, with a data cutoff (DCO) 
date of 31-Aug-2022, was performed when all 252 participants completed at least one year (52 
weeks) of investigational treatment or discontinued within one year. 
Study CSEG101A2301 did not demonstrate the superiority of crizanlizumab over placebo on 
its primary endpoint, which is the annualized incidence rate of VOC (Vaso-Occlusive Crises) 
events leading to a healthcare visit. This conclusion is based on a negative binomial regression 
analysis. The adjusted annualized incidence rate ratio of the crizanlizumab 5 mg/kg arm, 
compared with the placebo arm, was 1.08 with a 95% confidence interval of 0.76 to 1.55. The 
adjusted p-value was greater than 0.999, indicating that there is no statistically significant 
difference between the two treatment groups. In post-hoc analyses for the subgroup of 
participants located in the United States (n=22) a trend toward a treatment benefit in rates of 
VOC leading to a healthcare visit in the crizanlizumab 5 mg/kg vs. placebo arm was apparent. 
This positive trend was less apparent in the crizanlizumab 7.5 mg/kg arm vs. placebo arm. 
The proportion of patients experiencing at least one adverse event (AE) was similar across the 
treatment arms: 90.6% in the placebo arm, 88.1% in the crizanlizumab 5 mg/kg arm, and 92.8% 
in the crizanlizumab 7.5 mg/kg arm. Grade 3/4 AEs were reported for a higher percentage of 


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patients in the crizanlizumab 5 mg/kg arm (56.0%) compared to the crizanlizumab 7.5 mg/kg 
arm (38.6%) and the placebo arm (31.8%). AEs leading to discontinuation were reported with 
a similarly low incidence in each arm (2.4%). Serious adverse events (SAEs) were reported for 
a higher percentage of patients in the crizanlizumab 5 mg/kg arm (41.7%) compared to the 
crizanlizumab 7.5 mg/kg arm (26.5%) and the placebo arm (30.6%). The reported SAEs 
generally did not have a suspected relationship to the study treatment. No treatment-induced 
ADAs were noted at 5 mg/kg. One participant, in the 7.5 mg/kg arm, presented with treatment 
induced transient ADA and no safety issue had been associated to the positive ADA tests. 
At the time of this amendment, the study is still ongoing. Overall, the safety profile in study 
CSEG101A2301 was comparable across treatment arms and consistent with the safety results 
from previous studies involving crizanlizumab, with no new safety concerns identified. 
 
2 
Rationale 
2.1 
Study rationale and purpose 
Children and adults with SCD share the same etiology and genetic variability, leading to a 
similar range of clinical manifestations and prognostic factors. However, within the pediatric 
population, infants with SCD typically have milder and less frequent symptoms than older 
children and adults, due to higher levels of fetal hemoglobin (HbF), which results in less 
sickling (Akinsheye et al 2011). A prospective study of the natural history of SCD in the U.S. 
reported the increased incidence of pain crises with increasing age. Of those with HbSS, 46% 
of 0-9 year olds (n=1093) had a pain rate of 0 events per year, versus only 32% of 10-19 year 
olds (n=635), and 27% of 20-29 year olds (n=424). Similarly, the average pain rate for the first 
3 years of the study was 0.40 per year for 272 participants who entered the study at age 0-4 
years and 0.56 for the 223 participants who entered the study at age 5-9 years (Platt et al 1991). 
In the Dallas Newborn Cohort, 168 children who presented within the first year of life were 
followed for a mean of 7.1 years, and only 4 (2.4%) had frequent pain crises requiring 
hospitalization (defined as an average of ≥ 2 painful events per year for the entire follow-up 
period, with ≥ 2 events per year for 3 consecutive years) (Quinn et al 2008). 
In contrast to the pain crises experienced by adults, crises in infants and children more 
commonly manifest as hand-foot syndrome, a painful swelling of hands and/or feet due to 
dactylitis (Stuart and Nagel 2004). 
The expression of P-selectin in endothelium was shown in both healthy and SCD children 
(Miura et al 2004, Pryce et al 2014) and adults (Kutlar and Embury 2014, Chai and Song 2014, 
Souza et al 2015). P-selectin expression on platelets is activated in response to a range of 
physiologically relevant platelet agonists (Ferroni et al 2012). Platelet and leucocyte activation 
was observed in pediatric patients (Inwald et al 2000, Yip et al 2015), similar to what was 
described in adults (Ruf et al 1997, Majumdar et al 2013). Soluble P-selectin, a surrogate marker 
of protein expression in endothelium and platelets, was detected in blood of both adult 
(Blann et al 2008, Kanavaki et al 2012, Al Najjar et al 2017) and pediatric SCD patients 
(Krishnan et al 2010, Setty et al 2012, Hatzipantelis et al 2013, Colombatti et al 2013). The 
identified range of concentrations of soluble P-selectin in adult patients ranged from 42.5 ng/ml 




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2.1.2 
Study design consideration 
The posology of crizanlizumab in this study (CSEG101B2201) follows that of the SUSTAIN 
study: first dose is administered on week 1, second dose on week 3, and then every four weeks 
thereafter. The similarity evaluation will be performed using the PK and PD (%P-selectin 
inhibition) data from the 5.0 mg/kg dose in participants in the CSEG101A2202 study. The 
CSEG101A2202 study has rich sample collection to characterize the drug exposure as well as 
the time-course of P-selectin inhibition. Given that the PK of crizanlizumab is best characterized 
by a 2-compartment model and that the distribution of crizanlizumab is slow, the sample 
collection should be optimized to gather the delayed time of maximum drug concentration, 
which is 2-3 hours after the end of infusion, as well as the time that the initial rapid decline 
transitions to the slower decline in the drug concentration-time profile. In order to characterize 
well the PK of crizanlizumab, at least 5 samples are required to capture the concentration-time 
profile sufficient for similarity evaluation; these are pre-dose, end of infusion, 2 hours after end 
of infusion, time of the transition from rapid decline to slow decline, and 24 hour sample. 
The strong positive relationship between trough drug concentration and the percentage of P- 
selectin inhibition indicates that the PD sampling for computing area under the curve should be 
optimized in a similar manner as that for the PK of SEG101. The PD-AUC (area under the 
curve) is assumed to have lesser variability than the pre-dose percentage of P-selectin inhibition. 
The sample size is calculated based on the assumption of a smaller variability using PD-AUC 
rather than the pre-dose P-selectin inhibition. 
2.2 
Rationale for the study design 
The purpose of the proposed Phase 2 CSEG101B2201 study is to confirm and to establish 
appropriate dosing and to evaluate the safety in pediatric participants ages 2 years to <18 years 
receiving crizanlizumab for 2 years. 
Study CSEG101B2201 is designed as a Phase II, multicenter, open-label study. Indeed, the 
efficacy and safety of crizanlizumab was already demonstrated in adults with SCD (already 
receiving or not receiving HU/HC as concomitant treatment), it would thus not be considered 
ethical to randomize pediatric patients in a placebo-controlled study. The approach instead will 
consist in extrapolating from the PK/PD established in the adult population. 
At least 100 participants will be enrolled in this trial in 3 sequential groups: group 1 (ages 12 to 
<18 years), group 2 (ages 6 to <12 years), and group 3 (ages 2 to <6 years). 
Within the age groups, Group 1 and 2 of the study consists of two parts*: 
• Part A: To confirm and establish appropriate dosing sequentially for each age group. 
Sequential enrollment of descending age groups will be based on first dose PK data and key 
safety data. Steady-state PK/PD data will be used as well, at a later point, to further evaluate 
the dose selection. Both after first dose PK and multi-dose PK/PD, the evaluation will 
combine the data of the particular age group with an extrapolation from the data of the 
previous age group. The PD marker used is an ex vivo P-selectin inhibition assay. 
• Part B: To evaluate safety in additional pediatric participants with the confirmed dose in 
each age group. Enrollment into Part B will be opened after the dose is confirmed in the 
particular age group via first dose PK and key safety data in Part A. 




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2.5 
Rationale for choice of comparators drugs 
Not Applicable. 
2.6 
Risks and benefits 
Crizanlizumab offers the potential advantage of reducing the occurrence of VOCs leading to 
healthcare visits. This benefit is evident in Study CSEG101A2201, where crizanlizumab 
demonstrated a decrease in the annual rate of VOC leading to healthcare visits (primary 
endpoint), an increase in the proportion of patients free from VOC leading to healthcare visits, 
and a longer time to the first VOC leading to a healthcare visit (secondary endpoint) compared 
to placebo. The evidence supporting the key benefits of crizanlizumab 5 mg/kg in patients aged 
16 years and older with SCD is primarily based on the efficacy results from the randomized, 
placebo-controlled registration Study CSEG101A2201. These results are further supported by 
the efficacy outcomes from the open-label study CSEG101A2202 (SOLACE-adults). On the 
other hand, Study CSEG101A2301, a phase III randomized, placebo-controlled study, did 
not demonstrate the superiority of crizanlizumab over placebo in terms of its primary endpoint, 
which evaluated the annualized incidence rate of VOC events leading to healthcare visits 
The contrasting results between Study CSEG101A2201 and Study CSEG101A2301 (except for 
the subgroup of US patients) may be attributed to the impact of the global COVID-19 pandemic 
and variations in the geographic distribution of participating patients. Differences in healthcare 
access, practices, and reduced triggers during the pandemic could have led to a decrease in 
VOCs, thereby diluting the treatment effect. The 52-week treatment period of the trial coincided 
at least partially with the pandemic, and the sites were affected differently as waves of infection 
spread worldwide. 
Pooled data from studies CSEG101A2201 (SUSTAIN), CSEG101A2202 (DCO: 01-Jun-2022), 
CSEG101A2301 (DCO: 31-Aug-2022) and CSEG101B2201 (DCO: 05-May-2022) in SCD 
patients show that crizanlizumab 5 mg/kg is associated with an acceptable safety profile. The 
most frequently reported adverse drug reactions (≥10% of patients) in the crizanlizumab 
5 mg/kg group were nausea, pyrexia, pain, and vomiting. These adverse drug reactions, along 
with diarrhea, fatigue, dizziness, pruritus may be signs and symptoms of an IRR when observed 
during/within 24 hours of an infusion. The majority of the adverse drug reactions were mild to 
moderate (grade 1 to 2). Severe events (Grade 3 and above) were observed in 16 (6.5%) patients 
for pain (12 patients, [4.9%]), pyrexia (2 patients, [0.8%]), diarrhoea, fatigue and infusion 
related reaction (1 patient for each, [0.4%]. 
Crizanlizumab is generally well tolerated, with the only defined key risk being IRRs. However, 
the review of potential IRR events revealed very few cases that supported typical IRRs. 
Eighteen (7.3%) patients experienced severe IRR reported in 5 mg/kg pool (n=245). Events 
developed in >2% patients were Infusion related reaction (15, 6.1%). Most of the events were 
grade 1 or grade 2. Only 2 (0.8%) patients experienced grade 3 severe IRR (anaphylactic 
reaction, infusion related reaction; one each, 0.4%) In 7.5 mg/kg pool (n=95), five (5.3%) 
patients experienced severe IRR. Events developed in >2% patients were infusion related 
reaction and anaphylactic reaction (2 each; 2.1%). None of these adverse events suggested a 
severe allergic or anaphylactic reaction to crizanlizumab. The majority of IRR events were mild 
to moderate in severity and non-serious. Only a small percentage of patients (3/245, 1.2%) in 


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the overall 5 mg/kg group discontinued treatment due to an IRR: bradycardia, infusion related 
reaction, and pain (one patient each, 0.4%), and most events resolved on the day of onset or the 
following day. Cases of infusion-related reactions including severe pain events have been reported, 
with the majority occurring during the first and second infusions, sometimes indistinguishable from 
vaso-occlusive crisis. 
Crizanlizumab is not known to be associated with myelosuppression, genotoxicity, or 
carcinogenicity, which are risks associated with other treatments like HU/HC. 
There is no evidence to suggest an association between treatment with crizanlizumab and renal 
or hepatic toxicity. Therefore, no dose adjustment is recommended for patients with renal or 
hepatic impairment. 
The available data indicate a low potential for immunogenicity with crizanlizumab. 
In conclusion, except for the results from Study A2301, all the data support the benefits of using 
crizanlizumab 5 mg/kg in patients with SCD. 
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 18 (7.3%) participants treated with crizanlizumab 5 mg/kg in the 
pooled data set; Events occurring in >2% patients were Infusion related reaction (15, 6.1%). 
Most of the events were grade 1 or grade 2. Only 2 (0.8%) patients experienced grade 3 severe 
IRR (anaphylactic reaction, infusion related reaction; one each, 0.4%). One (0.4%) patient had 
SAE due to anaphylactic reaction. Fourteen (5.7%) patients experienced treatment related AEs 
-infusion related reaction (14; 5.7%). Crizanlizumab was discontinued due to severe infusion 
related reaction in 1 (0.4%) patient. Crizanlizumab dose was reduced in 2 (0.8%) patients due 
to severe infusion related reaction (2; 0.8%). Fifteen (6.1%) patients required 
medication/therapy for severe IRR. Severe IRR events resolved in all patients. 
From the safety pool of 7.5 mg/kg crizanlizumab (CSEG101A2202 + CSEG101A2301; N=95), 
five (5.3%) patients experienced severe IRR reported in 7.5 mg/kg pool. Events occurring in >2% 
patients were infusion related reaction and anaphylactic reaction (2 each; 2.1%). Anaphylactic 
reaction was not related to crizanlizumab. Grade 3 severe IRRs were reported in 2 (2.1%) 
patients (PTs-anaphylactic reaction, hypersensitivity; one each, 1.1%). Crizanlizumab was 
discontinued due to hypersensitivity in 1 (1.1%) patient. Five (5.3%) patients required treatment 
and all patients recovered. 
Additionally, a broad search for IRRs presenting with symptoms of severe pain in various 
locations occurring within 24 hours of the infusion, identified 58 participants (23.7%; n=245) 
in the safety pool with at least one event. Among these patients, reactions experienced by at 
least 2% patients were headache (19 patients, 7.8%), pain in extremity (13 patients, 5.3%), back 
pain (12 patients, 4.9%) and arthralgia (9 patients, 3.7%). Other events experienced by <2% 
patients were abdominal pain, abdominal pain upper, chest pain, musculoskeletal chest pain, 
myalgia, neck pain, pain and oropharyngeal pain. The median duration from the onset of the 


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event to resolution was 2 days. Crizanlizumab was permanently discontinued in 2 patients 
(0.8%) due to an infusion related reaction manifesting as pain. 
Immunogenicity 
Administration of mAb can be associated with immunogenicity, including development of anti- 
drug antibodies (ADA) or hypersensitivity following treatment with crizanlizumab (see above). 
In clinical studies of adult patients, treatment-emergent ADA were transiently detected in 1 
patient among the 195 patients who received crizanlizumab 5 mg/kg (0.5%). 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. 
Incidence of infection was 62.4% (n=245) in 5 mg/kg safety pool (CSEG101A2201+ 
CSEG101A2202+ CSEG101A2301+ CSEG101B2201). The higher incidence in 5 mg/kg pool 
was mainly driven by COVID-19 (39; 15.9%), upper respiratory tract infection (31; 12.7%), 
urinary tract infection (29; 11.8%), and pneumonia (23; 9.4%). Forty (16.3%) patients 
developed grade 3 AEs, pneumonia (12; 4.9%) and COVID-19 (7; 2.9%), being the most 
common grade 3 infections. Two patients had grade 4 AE-COVID-19 and wound sepsis (one 
each) and 3 patients had fatal outcomes due to infections. Twenty-three patients (9.4%) required 
treatment interruption due to infection. Most of the treatment interruption was due to COVID- 
19 (14; 5.7%). 
Sixty-three (66.3%; n=95) patients experienced infection in the 7.5 mg/kg safety pool 
(CSEG101A2202+ CSEG101A2301). The higher incidence in the 7.5 mg/kg pool was mainly 
driven by COVID-19 (30; 31.6%), pneumonia (12; 12.6%), urinary tract infection (9; 9.5%), 
and upper respiratory tract infection (8; 8.4%). Fourteen (14.3%) patients developed grade 3 
infections, and the most common grade 3 infection was pneumonia (6; 6.3%). Thirteen patients 
(13.7%) required treatment interruption due to infection. Most of the treatment interruption was 
due to COVID-19 (7; 7.4%). 
The incidence of infection was 55.1% (n=147) in placebo safety pool (CSEG101A2201+ 
CSEG101A2301) with the higher incidence coming from COVID-19 (17, 11.6%) and urinary 
tract infection (16, 10.9%). Fourteen (9.5%) patients developed grade 3 AEs. One patient had 
grade 4 AE-COVID-19 and one patient had fatal outcome dure to infection. Eight patients (5.4%) 
required treatment interruption due to infection. Most of the treatment interruption was due to 
COVID-19 (7; 4.8%). 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. 
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 of the hemostatic system, or thrombosis. 
Forty-one (16.7%) patients experienced hemorrhage related events in 5 mg/kg safety pool. 
Events occurring in more than 2% patients were: epistaxis (9; 3.7%) and hemoglobin decreased 


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(6; 2.4%). Grade 3 AEs due to hemostasis (hemorrhage) were developed in 4 (1.6%) patients. 
Eight (3.3%) patients experienced treatment related AEs. Two patients (0.8%) required 
treatment interruption due to heavy menstrual bleeding and postmenopausal hemorrhage one 
each, 0.4%). Most of the patients (40; 16.3%) recovered/resolved except two (0.8%) patients. 
Nine (9.5%) patients experienced hemorrhagic events in the 7.5 mg/kg safety pool. The only 
event occurring in at least 2% of patients was epistaxis (3; 3.2%). Grade 3 AEs hemorrhagic 
events developed in 2 (2.1%) patients. One patient had a fatal outcome to event Intracranial 
hemorrhage. Treatment related AEs were experienced in none of the patients. None of the 
patients required crizanlizumab treatment discontinuation/interruption due to hemorrhagic 
events. Most of the patients (5; 5.3%) recovered/resolved from hemorrhagic events. 
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 not further identify any 
participants with AEs related to thrombosis in the 5 mg/kg pooled data, suggesting that 
crizanlizumab does not have a relevant pro-aggregant or pro-thrombotic effect. 
Laboratory test interference with automated platelet counts 
Interference with automated platelet counts (platelet clumping) has been observed in 
participants treated with crizanlizumab in clinical studies, in particular when tubes containing 
EDTA (ethylenediaminetetraacetic acid) were used. This may lead to unevaluable or falsely 
decreased platelet counts. Current clinical and pre-clinical data suggest this is an ex vivo effect 
that is EDTA- and time-dependent, without indication of platelet clumping, true reduction in 
circulating platelets or pro-aggregant effect in vivo. 
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 is no evidence of 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 participants 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. 
Pregnant or breastfeeding women as well as those of child-bearing potential (unless using 
highly effective contraception) will not be allowed to participate in the study. Please refer to 
the Eligibility criteria of the protocol for details. 
Appropriate eligibility criteria and stopping rules are included in this protocol. Recommended 
guidelines for prophylactic or supportive management of study-drug induced adverse events are 
provided in Section 6.4. The risk to participants in this trial may be minimized by compliance 


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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. 
2.7 
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. 
 
3 
Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 below. 


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Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
Refer to Section 10.4 
To confirm and establish appropriate dosing of 
crizanlizumab in participants aged 2 to <18 years at 
the time of study entry (Part A and B) 
Participants aged 2 to <18 years (Part A): 
• PK parameters after the starting dose and at multiple dose 
• PD parameter (%P-selectin inhibition) after starting dose and at multiple dose 
 
To evaluate the safety of crizanlizumab in 
participants aged 2 to <18 years at the time of study 
entry (Parts A and B) 
• Frequency of any adverse events 
 
 
Secondary 
Refer to Section 10.5 
To assess the long-term efficacy of crizanlizumab in 
participants aged 2 to < 18 years at the time of study 
entry (Parts A and B) 
 
 
 
 
 
 
 
To assess other safety measures in participants 
aged 2 to < 18 years at the time of study entry 
• Annualized rate of VOC events leading to healthcare visit in clinic/ER/hospital 
• Annualized rate of VOC events treated at home (based on documentation by 
health care provider following phone contact with participant) 
• Annualized rate of each subcategory of VOC event (uncomplicated pain crisis, 
acute chest syndrome, hepatic sequestration, splenic sequestration, priapism) 
• Annualized rate of hospitalizations and ER visits (both overall and VOC- 
related) 
• Annualized rate of days of ER/hospitalization (both overall and VOC-related) 
• Annualized rate of dactylitis events 
• Number, seriousness, severity, and causality assessments of treatment 
emergent adverse events and other safety data as considered appropriate 
• Absolute change from baseline in hemoglobin 
• Immunogenicity: measurement of anti-drug antibodies (ADA) to crizanlizumab 
• ECGs at relevant PK time points 
• Growth and sexual maturation assessments (Tanner stage) 


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Objective 
Endpoint 
Analysis 
Characterize long-term PK and PD of crizanlizumab 
in participants aged 2 to <18 years at the time of 
study entry. 
• Pre-dose concentrations prior to each study drug dose. 
• % P-selectin inhibition prior to dosing 
 








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Figure 4-1 
Study Design 
 
Note: In Group 3, single dose PK/PD, multiple dose PK/PD and safety will be evaluated in Part A and no patients 
will be enrolled in Part B. 
 
4.2 
Timing of interim analyses and design adaptations 
No formal interim analysis is planned in this trial. However, statistical analyses for Part A of 
each group will be performed at two time points: when there are at least 6 participants with 
single dose evaluable PK profiles and key safety data for at least 6 weeks and when there are at 
least 6 evaluable participants with multiple dose PK and PD profiles. 
In addition, exploration of early access (EA) PK data may occur for preliminary PK and PD 
analysis prior to clinical database lock. PK samples may be batched and shipped for expedited 
EA PK analysis, and data will be uploaded by the bioanalyst via PKLink. For the derivation of 
PK and PD parameters, nominal time instead of actual elapsed time may be used. 
Additional cut-off dates and analyses will also be performed during Part B conduct (refer to 
Section 10). 
4.3 
Definition of end of study 
The end of the study is defined as the date of last visit of the last participant in the study and 
will occur when all the participants have either completed or discontinued the study treatment 
and/or have completed the last scheduled procedure as defined in Section 7.1 (105-days post- 
treatment follow-up visit when applicable). 
The final analysis will occur at the end of the study. All available data from all participants up 
to the trial end will be analyzed and summarized in a final CSR. 


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5 
Study Population 
5.1 
Study population 
CSEG101B2201 will enroll at least 100 SCD participants (any genotype), ages 2 to <18 years 
who experienced at least 1 VOC leading to healthcare/medical facility visit within the preceding 
12 months, and who are either 
• not on HU/HC, L-glutamine or erythropoietin stimulating agent (for at least 6 months prior 
to screening) and not on voxelotor (since at least 30 days prior to screening) and are not 
planning to initiate such drugs during the trial, 
• or who have been taking HU/HC, L-glutamine, erythropoietin stimulating agent 
consistently for at least 6 months and plan to continue at the same dose and schedule during 
the trial. 
At least one hundred participants are planned to be enrolled in the trial in total, split into 3 age 
groups: 
• Group 1 (age 12 to <18 years): at least 26 participants, 
• Group 2 (age 6 to <12 years): at least 26 participants, 
• Group 3 (age 2 to <6 years): at least 8 participants. 
• The remaining participants needed to achieve a total of at least 100 are planned to be 
recruited via trial Part B in either Group 1 or 2 age groups defined above without 
restriction. 
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study. 
5.2 
Inclusion criteria 
1. Male or female patients aged 2 to <18 years 
2. Confirmed diagnosis of SCD (any genotype including HbSS, HbSC, HbSβ0-thalassemia, 
HbSβ+-thalassemia patients, and others) by hemoglobin electrophoresis or/and high- 
performance liquid chromatography (HPLC) [performed locally]. Confirmation of 
diagnosis by two accepted methods is recommended. 
3. Experienced at least 1 VOC within the preceding 12 months prior to screening, as 
determined by medical history. Prior VOC must have resolved at least 7 days prior to the 
first dose in the study and must include all the following: 
a. the occurrence of appropriate symptoms (see VOC definition in Section 7.2.1.1). 
b. either a visit to a medical facility or healthcare professional 
c. receipt of oral/parenteral opioid or parenteral NSAIDs 
4. If receiving HU/HC, L-glutamine or erythropoietin stimulating agent, must have been 
receiving the drug consistently for at least 6 months prior to screening and plan to continue 
taking it at the same dose and schedule during the trial. Patients who have not been receiving 
such drugs must have been off them for at least 6 months prior to screening. Dose alterations 
of HU/HC, L-glutamine or erythropoietin stimulating agent during Part A are not allowed, 
and if this occurs, the participant will enter directly to Part B. 


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5. Received standard age-appropriate care for SCD, including penicillin prophylaxis, 
pneumococcal immunization, and parental education. 
6. Performance status: Karnofsky ≥ 50% for patients >10 years of age, and Lansky ≥ 50 for 
patients ≤ 10 years of age. 
7. Patient must meet the following laboratory values prior to Week 1 Day 1: 
• Absolute Neutrophil Count ≥1.0 x 109/L 
• Platelets ≥75 x 109/L 
• Hemoglobin (Hgb) > 5.5 g/dL 
8. Patient must have adequate renal and hepatic function as defined: 
• Estimated Glomerular filtration rate (eGFR) ≥ 75 mL/min/1.73 m2 using Schwartz 
formula 
• Direct (conjugated) bilirubin ≤ 2.0 x ULN 
• Alanine transaminase (ALT) ≤ 3.0 x ULN 
9. Transcranial Doppler (TCD) for patients aged 2 to < 16 years at time of screening, with 
HbSS, HbSβ0-thalassemia, and HbSD disease indicating low risk for stroke (per 
investigator). Please refer to Section 7.2.2.6 for details 
10. Written informed consent/assent, according to local guidelines, signed by the patient and / 
or by the parents or legal guardian prior to any study related screening procedures are 
performed. 
11. Female of non-childbearing potential or with negative serum pregnancy test on Screening 
and a negative urine pregnancy test (dipstick) prior to dosing on Day 1. 
5.3 
Exclusion criteria 
Participants eligible for this study must not meet any of the following criteria: 
1. History of stem cell transplant. 
2. Received any blood products within 30 days prior to Week 1 Day 1 dosing. 
3. Plan to participate in a chronic transfusion program (pre-planned series of transfusions for 
prophylactic purposes) or undergo exchange transfusions/plasmapheresis during the study. 
Patients requiring episodic transfusion (simple or exchange) in response to worsened 
anemia or VOC are permitted. 
4. Patients with bleeding disorders 
6. Contraindication or hypersensitivity to any drug from similar class as study drug or to any 
excipients of the study drug formulation. 
7. 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 
8. Received a monoclonal antibody or immunoglobulin-based therapy within 6 months of 
Screening, or has documented immunogenicity to a prior monoclonal antibody. 
9. Received active treatment on another investigational trial within 30 days (or 5 half -lives of 
that agent, whichever is greater) prior to Screening or plans to participate in another 
investigational drug trial. 
10. Pregnant females or females who have given birth within the past 90 days or who are 
breastfeeding. 


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11. Any documented history of a clinical stroke or intracranial hemorrhage, or an uninvestigated 
neurologic finding within the past 12 months. Silent infarcts (only present on imaging) are 
not excluding patients from study participation. 
12. Any abnormal TCD within the past 12 months. 
13. Use of therapeutic anticoagulation (prophylactic doses permitted) or antiplatelet therapy 
(other than aspirin) within the 10 days prior to Week 1 Day 1 dosing. 
14. Hospitalized within 7 days prior to Week 1 Day 1 dosing. 
15. Planning to undergo a major surgical procedure during the duration of the study. 
16. Planning to initiate or terminate HU/HC or L-glutamine while on study (except if needed to 
terminate for safety reasons). 
17. Patient with active human immunodeficiency virus (HIV) infection (detectable viral load). 
18. Patients with known active Hepatitis B infection. 
19. Patients with known Hepatitis C history. 
20. Significant active infection or immune deficiency (including chronic use of 
immunosuppressive drugs) in the opinion of the investigator. 
21. Malignant disease. Exceptions to this exclusion include the following: malignancies that 
were treated curatively and have not recurred within 2 years prior to study treatment; any 
completely resected carcinoma in situ. 
22. Has a serious mental or physical illness, which, in the opinion of the Investigator would 
compromise participation in the study. 
23. Any condition which, in the opinion of the investigator, is likely to interfere with the 
successful collection of the measurements required for the study 
24. Resting QTcF ≥450 msec at pretreatment (baseline) for patients under 12 years of age and 
≥450 msec for males and ≥460 msec for female patients 12 years and older. 
25. Cardiac or cardiac repolarization abnormality, including any of the following: 
a. History of myocardial infarction (MI), uncontrolled congestive heart failure, unstable 
angina, or coronary bypass graft (CABG) within 6 months prior to starting study 
treatment 
b. Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left 
bundle branch block, high-grade AV block (bifascicular block, Mobitz Type II, and 
third degree AV block) 
c. Long QT syndrome, family history of idiopathic sudden death or congenital long QT 
syndrome 
• Risk factors for Torsade de Pointes (TdP), including uncorrected hypokalemia or 
hypomagnesemia, history of cardiac failure, or history of clinically significant/ 
symptomatic bradycardia 
• Inability to determine the QTcF 
26. Sexually active females who are unwilling to comply with reliable method of birth control 
until 15 weeks following last dose of study drug. 
Females of childbearing potential, defined as 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: 


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• 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 bilateral tubal ligation, female sterilization (have had surgical bilateral 
oophorectomy with or without hysterectomy), or total hysterectomy 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 (estrogen and progesterone), injected, or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), 
or other forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception. 
In case of use of oral contraception, females should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
If local regulations are more stringent than the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the informed consent form (ICF). 
28. Not able to understand and to comply with study instructions and requirements. 
29. Patients who are an employee of the sponsor or investigator or otherwise dependent on 
them. 
30. Patients who are committed to an institution by virtue of an order issued either by the 
judicial or the administrative authorities. 
31. Patients who received prior crizanlizumab treatment and/or other selectin targeting agents 
are not allowed. 
32. Patients having taken voxelotor less than 30 days prior to screening, or planning to take 
voxelotor while on study are not allowed. 
 
6 
Treatment 
6.1 
Study treatment 
Novartis will supply crizanlizumab (SEG101) as an open label medication. The investigational 
drug will be the crizanlizumab administered every 4 weeks with a loading dose 2 weeks after 
the first dosing (i.e., by i.v. infusion (refer to Pharmacy Manual) on Week 1 Day 1, Week 3 
Day 1, and then day 1 of every 4-week) for up to 2 years. 
Table 6-1 
Investigational and control drug 
 
Treatment Title 
Crizalizumab 
Treatment 
Description 
5.0 mg/kg and 8.5 mg/kg* 
Type 
biologic 


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Dose Formulation 
Concentrate for solution for infusion 
Unit Dose 
Strength(s) 
Crizanlizumab (SEG101) concentrate for solution for infusion is supplied in single use 
10 mL vials at a concentration of 10 mg/mL. One vial contains 100 mg of 
crizanlizumab (SEG101) 
Dosage Level(s) 
and Regimen 
5.0 mg/kg and 8.5 mg/kg Week 1 Day 1, Week 3 Day 1, and Day 1 of every 4-week 
cycle* 
Route of 
Administration 
IV infusion 
Use 
experimental 
IMP 
Yes 
Sourcing 
Novartis 
Packaging and 
Labeling 
Study treatment will be provided in vials. Each vial will be labeled as required per 
country requirement. 
* dose was adjusted based on the dose confirmation step (refer to Section 6.3.1.1) as the initial dose 
was not confirmed for Group 2 and Group 3. Initial dose of 5 mg/kg dose for Group 1 participants was 
later adjusted to 8.5 mg/kg for Group 2 and 3 based on final dose confirmation and safety considerations 
as planned in the protocol. 
 
6.1.1 
Dosing regimen 
SEG101 is supplied in single use 10 mL vials at a concentration of 10 mg/mL. One vial contains 
100 mg of crizanlizumab. 
On infusion day, the pharmacist or designated personnel will compound individual doses of 
SEG101 for participants by diluting it in accordance with the Pharmacy Manual. 
6.1.2 
Ancillary treatments 
Not Applicable. 
6.1.3 
Rescue medication 
Not Applicable. 
6.1.4 
Guidelines for continuation of treatment 
For guidelines for continuation of treatment, refer to Section 6.3 Dose modification. 
Participants who permanently discontinue from the study drug for any reason, and will not 
continue crizanlizumab after their EOT visit (i.e., via commercial supply) should follow the 
protocol post-treatment assessments as scheduled for 105 days following the last dose. After 
discontinuing study treatment, further treatment is left to physician’s discretion. 


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6.1.5 
Treatment duration 
The total planned duration of treatment in the study for each patient is planned to be up to 2 
years. 
Participants may be permanently discontinued from treatment earlier due to unacceptable 
toxicity, death, lost to follow-up or discontinued from the study treatment for any other reasons 
at the discretion of the investigator or the participant. 
For participants who complete participation in this trial and who in the opinion of the 
investigator are still deriving clinical benefit from SEG101, every effort will be made to 
continue provision of study treatment via post-trial access, as indicated in Section 6.1.6. 
6.1.6 
Post trial access 
Participants who complete participation in this trial and continue to derive clinical benefit from 
the treatment based on the Investigator’s evaluation, may receive post-trial access. 
Post Trial Access (PTA) means the provision of treatment to trial participants following their 
completion of trial participation. PTA will be provided until one of the following is met: 
• participant no longer derives clinical benefit, 
• Investigator discontinues treatment, 
• treatment receives regulatory approval, is commercially available and a reimbursement 
decision has been made in the patient’s country (where applicable), 
• treatment fails to achieve registration in the trial participant’s country, or the clinical 
program is discontinued for any other reason. 
Mechanisms for provision of PTA may include a rollover protocol, provision of the Novartis 
investigational product in a non-trial setting (known as post-study drug supply [PSDS]) when 
no further safety or efficacy data are required, or any other mechanism appropriate as per the 
country regulations. 
The PTA mechanism must comply with local laws and regulations in the participating trial 
countries. If Novartis discontinues the development of the study treatment due to reasons which 
may include when study results are negative, Novartis will work with Investigators to transition 
participants onto locally available alternative treatment or standard of care. 
6.2 
Dose escalation guidelines 
Not Applicable. 


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6.3 
Dose modifications 
6.3.1 
Dose modification and dose delay 
6.3.1.1 
Dose modification 
The investigator is not allowed to modify the study-defined dose at their own discretion. In case 
of unexpected emergent safety findings during the trial, the dosage of the corresponding age 
group will be reassessed at that time. 
During Part A of each group, if the dose is not confirmed then an appropriate dose adjustment 
will be defined based on the PopPK model or other methods (see Section 4.1 and Section 10). 
At least an additional 8 participants will be enrolled in Part A of that group, and the process will 
be restarted at the newly defined dose. The decision on whether to confirm a test dose will be 
made internally at Novartis, in consideration of DMC recommendations, and will be 
documented. Investigators will be informed by Novartis of this decision promptly. If the 
decision is to adjust the dose, the previous cohort of participants enrolled in Part A of this 
particular group will then begin receiving the newly defined dose at the next scheduled 
treatment visit, and will enter Part B from the time they receive the new dose. 
6.3.1.2 
Dose interruptions/delay 
For participants who do not tolerate the protocol-specified dosing schedule, dose interruptions 
are either recommended or mandated in order to allow participants to continue the study 
treatment until the next dose scheduled. The criteria for interruption and re-initiation of SEG101 
for Adverse Drug Reaction are provided in Table 6-2. 
If drug-induced toxicities occur, participants will have to be closely monitored, and a decision 
to continue or discontinue the participant from the study treatment will have to be made at the 
next dose scheduled. 
It is recommended that trial participants with confirmed active COVID-19 or presenting with 
symptoms indicative of COVID-19 such as fever, cough, difficulty breathing, sore throat or 
feeling unwell should interrupt study treatment until the trial participant has fully recovered; in 
case of suspected COVID-19, testing for COVID-19 is recommended as per local 
guidance/practice. For confirmed participants, re-testing is encouraged if signs or symptoms 
indicative of COVID-19 newly develop or persist before re-initiating study treatment to ensure 
adequate recovery. Participants with suspected infection tested negative may continue study 
treatment. 
During COVID-19 pandemic, if a participant experiences a VOC and other subtypes of VOC 
event such as hepatic/splenic, priapism and especially acute chest syndrome, testing for 
COVID-19 is recommended as per local guidance/practice (refer to Section 7.2.1.1 for VOC 
definition). 
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 infection 
has been ruled out. 


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Every effort should be made to maintain the participant on the protocol-defined dosing schedule. 
In the case of dose delay for any reason, the dose should be given as soon as possible but by 
keeping at least 21 days between 2 consecutive doses. 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), as planned per 
Table 7-1. If a participant misses 2 consecutive doses, the participant must be permanently 
discontinued from study treatment. 
Deviations to mandatory dose interruptions are not allowed. Permanent treatment 
discontinuation is mandatory for grade 4 adverse events deemed related to study drug and for 
specific adverse events as indicated in Table 6-2 or listed in Section 7.1.5. 
Dose interruptions must be recorded on the Dosage Administration Record CRF. 


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Table 6-2 
Criteria for dose interruption and re-initiation of SEG101 treatment for adverse drug reactions 
 
Dose interruptions for SEG101 
Worst toxicity a 
CTCAE Grade (value) during a cycle of therapy 
Investigations (Hematologic) 
Neutropenia (ANC) 
Grade 1 (ANC < lower limit of normal (LLN) - 1500/mm3) 
Recommendation: continue study treatment. 
Grade 2 (ANC < 1500 - 1000/mm3) 
Recommendation: continue study treatment. 
Grade 3 (ANC < 1000 - 500/mm3) 
Recommendation: interrupt study treatment until resolved to ≤ Grade 2. If abnormality persists beyond 
the next planned dose, permanently discontinue study treatment. 
Grade 4 (ANC < 500/mm3) 
Mandatory: permanently discontinue study treatment. 
Febrile neutropenia (ANC < 1.0 x 109/L, fever ≥ 38.3°C) 
A disorder characterized by an ANC <1000/mm3 and a 
single temperature of >38.3 degrees C (101 degrees F) 
or a sustained temperature of ≥38 degrees C 
Mandatory: Interrupt study treatment until resolved. If abnormality persists more than 7 days, 
permanently discontinue study treatment. 
Thrombocytopenia 
Grade 1 (PLT < LLN - 75,000/mm3) 
Recommendation: continue study treatment. 
Grade 2 (PLT < 75,000 - 50,000/mm3) 
Recommendation: continue study treatment. 
Grade 3 (PLT < 50,000 - 25,000/mm3) 
Recommendation: interrupt dose until resolved to ≤ Grade 1. If abnormality persists more than 7 days, 
permanently discontinue study treatment. 
Grade 3 (PLT < 50,000 – 25,000/mm3) associated with 
bleeding 
Mandatory: permanently discontinue study treatment. 
Grade 4 (PLT < 25,000/mm3) 
Mandatory: permanently discontinue study treatment. 
Investigations (Renal) 
Serum creatinine 
Grade 1 (>1.0 – 1.5 x baseline OR > ULN - 1.5 x ULN) 
Recommendation: continue study treatment. 
Grade 2 (> 1.5 – 3.0 x baseline OR > 1.5 - 3.0 x ULN) 
Recommendation: interrupt study treatment until resolved to ≤ Grade 1 or baseline level. If abnormality 
persists beyond the next planned dose, permanently discontinue study treatment. 
Grade 3 (> 3.0 x baseline OR > 3.0 - 6.0 x ULN) 
Recommendation: interrupt study treatment until resolved to ≤ Grade 1 or baseline level. If abnormality 
persists more than 7 days, permanently discontinue study treatment. 


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Dose interruptions for SEG101 
Worst toxicity a 
CTCAE Grade (value) during a cycle of therapy 
Grade 4 (> 6.0 x ULN) 
Mandatory: permanently discontinue study treatment. 
Investigations (Hepatic) 
Isolated direct Bilirubin elevation 
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 liver function tests (LFTs)b 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 
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. 
If abnormality persists >2 weeks, refer to Section 6.3.3.1 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 study treatment. 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. 
Combinedc elevations of ALT and direct bilirubin 


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Dose interruptions for SEG101 
Worst toxicity a 
CTCAE Grade (value) during a cycle of therapy 
For participants with normal baseline ALT and direct 
bilirubin value: ALT >3.0 x ULN combined with direct 
bilirubin >2.0 x ULN 
OR 
For participants with elevated baseline ALT or direct 
bilirubin value: ALT>2x baseline AND > 2.0 x baseline 
direct bilirubin 
Mandatory: Interrupt study treatment. Repeat LFTs as soon as possible, preferably within 48-72 hours 
from awareness of the abnormal results; follow-up for symptoms and initiate workup for competing 
etiologies. 
Monitor of LFTs b weekly, 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 6.3.3.1 for additional follow-up evaluations as applicable. 
Gastro intestinal 
GI toxicity (diarrhea, nausea, vomiting) 
Grade 1 
Recommendation: continue study treatment; initiate concomitant therapy as per institutional guidelines. 
Grade 2 and Grade 3 
Recommendation: interrupt study treatment until recovery to G1 or baseline. 
Grade 4 
Mandatory: permanently discontinue study treatment. 
Infections 
Grade 1 and 2 
Recommendation: continue study treatment. 
Grade 3 or Serious (meeting definition for SAE) 
Mandatory: Interrupt study treatment until recovery to ≤ Grade 1. 
If abnormality persists more than 7 days, permanently discontinue study treatment. 
Grade 4 
Mandatory: permanently discontinue study treatment. 
a Common Toxicity Criteria for Adverse Events (CTCAE Version 5) 
b Core LFTs consist of ALT, AST, GGT, bilirubin (fractionated [direct and indirect], if total bilirubin > 2.0 x ULN), and alkaline phosphatase (fractionated 
[quantification of isoforms], if alkaline phosphatase > 2.0 x ULN.) 
c “Combined” defined as direct bilirubin increase to the defined threshold concurrently with ALT increase to the defined threshold 
If combined elevations of ALT and direct bilirubin do not meet the defined thresholds, please follow the instructions for isolated elevation of direct bilirubin and 
isolated elevation of ALT, and take the most conservative action recommended (e.g., permanently discontinue treatment in the situation when interrupt dose is 
needed for one parameter and permanently discontinue treatment is required for another parameter). 


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Table 6-3 
Management for drug-related toxicities 
 
Toxicitya 
Management 
Infusion-related reactions 
Grade 1 
Mild transient reaction; infusion 
interruption not indicated; 
intervention not indicated 
Recommendation: 
• 
Continue study treatment and increase monitoring of vital signs 
as medically indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
• 
Consider slowing infusion rate. 
Grade 2 
Therapy or infusion interruption 
indicated but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, narcotics, 
IV fluids); prophylactic medications 
indicated for <=24 hrs 
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. 
• 
Steroids should be used with caution unless clinically indicated 
(e.g., management of hypersensitivity/anaphylaxis). 
• 
If symptoms resolve, restart infusion per investigator discretion 
at a slower rate (e.g., 50%) under continuous observation. 
Ensure a minimum of 1 hour observation period prior to 
restarting the infusion. 
• 
Before restarting, administer premedication (e.g., analgesics 
such as paracetamol/acetaminophen or NSAIDs and anti- 
histamines within 1 hour prior to dosing) as per local 
institutional guidelines, including subsequent infusions. 
• 
In case of recurring infusion reactions despite premedication 
and prolonged infusion, consider discontinuation from 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. 
a Common Toxicity Criteria for Adverse Events (CTCAE Version 5) 
6.3.2 
Recommended actions and dose adjustments for QTcF prolongation 
Not Applicable. 
6.3.3 
Follow-up for toxicities 
6.3.3.1 
Follow-up on potential drug-induced liver injury (DILI) cases 
Transaminase increases combined with a total bilirubin (TBIL) increase may be indicative of 
potentially severe DILI, and should be considered as a clinically important event and assessed 
appropriately to establish the diagnosis. The required laboratory values, as detailed below, 
should be sought to obtain the medical diagnosis of the most likely cause of the observed 
laboratory abnormalities. 


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• Treatment-emergent elevations in ALT (>3x ULN for patients with normal baseline 
and >2x baseline for patient with elevated baseline) in combination with direct 
bilirubin >2x ULN for patients with normal baseline and >2 x baseline with elevated 
baseline or 
• Elevations in ALT alone (>5x ULN for patients with normal baseline for more than 2 
weeks and >3x baseline for patients with an elevated baseline for more than 2 weeks) 
Patients with SCD tend to have elevated AST and indirect bilirubin due to the hemolytic nature 
of this condition. In order to reduce the number of false positives, AST will be considered for 
safety monitoring, but LFT monitoring/ follow-up will be conducted only if ALTand direct 
bilirubin criteria are met for DILI definition. 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 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, 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). 
For this reason, a potential case meeting the above criteria requires expedited reporting, and 
will be handled as a serious unexpected adverse event (assessing it as medically significant in 
the absence of any other seriousness criteria). It must be reported as an SAE to the sponsor 
promptly (i.e., even before all other possible causes of liver injury have been excluded) using 
the term “potential drug-induced liver injury.” Reporting should include all available 
information, especially that needed for evaluating the diagnosis, severity and likelihood that the 
study treatment caused the reaction. For patient monitoring and to better understand potential 
etiologies, the investigator must initiate a close follow-up until complete resolution of the 
problem and completion of all attempts to obtain supplementary data. 
In the absence of cholestasis or 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 obstructions/compressions, etc. 
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total and direct 
bilirubin, GGT, prothrombin time (PT)/ International Normalized Ratio (INR) and alkaline 
phosphatase. 
2. A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, including over the counter medications such as acetaminophen, herbal remedies, 
supplement consumption, history of any pre-existing liver conditions or risk factors, should 
be collected. 
3. Further 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 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. 


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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”, thus, meeting the definition of SAE (Section 8.2.1) and reported as SAE using the 
term “potential drug-induced liver injury”. All events should be followed up with the outcome 
clearly documented. 
6. 4 
Concomitant medications 
In general, the use of any concomitant medication/therapies deemed necessary for the care of 
the participant is permitted (see Section 6.4.1), except as specifically prohibited (see 
Section 6.4.3). 
The participant/legal representative must be told to notify the investigational site about any new 
medications he/she takes within 30 days prior to initial dosing until the completion of the last 
protocol visit (EOT or post-treatment follow-up visit, 105 days after the last dose of study 
treatment as applicable); except for HU/HC, L-glutamine, and Erythropoietin Stimulating 
Agent medications for which information within 6 months prior to screening should be collected, 
and for analgesics within 12 months prior to screening. 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) taken or 
administered within the timeframe defined in the entry criteria until completion of the last 
protocol visit must be listed on the Prior and Concomitant medications, Surgical and Medical 
Procedures or Transfusion pages of the CRF. 
6.4.1 
Permitted concomitant therapy 
Concomitant sickle cell therapy with HU, HC or L-glutamine (Endari™) is permitted as per 
local guidelines and standard of care, provided the participant has been prescribed HU/HC or 
L-glutamine consistently over at least the 6 months prior to screening, as stated in the Inclusion 
criteria. During the course of the study HU/HC or L-glutamine must not be initiated or 
terminated, except if termination is for safety reasons. Dose alterations, other than for safety 
reasons or for weight adjustments should not occur. Erythropoietin-stimulating agents are also 
permitted to manage chronic symptomatic anemia with the same requirement for 6 months prior 
therapy as HU/HC/L-glutamine. The dosing should not be altered or terminated, other than for 
safety reasons or to maintain hemoglobin level. 
During Part A, HU/HC, L-glutamine or erythropoietin stimulating agent dose change other than 
for reasons mentioned above are not allowed. In case a dose modification (other than for weight 
adjustment) occurred, the participant will be moved to Part B. If a physician deems it medically 
necessary to terminate, or alter HU/HC treatment, L-glutamine or erythropoietin stimulating 
agent, changes should not lead by default to discontinuation from the study treatment; however, 
the Novartis medical monitor must be notified. 
Aspirin, NSAIDs and prophylactic doses of anticoagulants are permitted. 
All approved forms of analgesia for pain are permitted per standard of care. Other approved 
medications for supportive care (antiemetics, anxiolytics, hypnotics, antihistamines) are 
permitted, including marinol. 


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It is recommended to avoid any live or live-attenuated vaccines within 4 weeks prior to the first 
dose of study treatment (Week 1 Day 1) and during study duration. However, the decision to 
administer or withhold a vaccine should be done on a case-by-case basis considering the 
potential benefit/risk such as developing severe infection, adverse effects from the vaccination, 
or vaccination failure. 
6.4.2 
Permitted concomitant therapy requiring caution and/or action 
Although transfusion of blood products 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. It should also be considered that the 
administration of products containing immunoglobulins (plasma, intravenous immunoglobulin 
(IVIG), anti-globulins) 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 FDA-approved, version of L-glutamine, is permitted, other over- the 
counter forms of L-glutamine are discouraged, as are other natural and herbal remedies (e.g., 
EvenFlo and/or products containing dang gui, ligustrum root, ginseng root, white peony, 
corydalis, salvia, copodonosis, poria, jujbe, angelica sinensis, lovage) due the unproven efficacy 
and variable quality and composition of these products. Vitamin and mineral supplements (e.g., 
fish oil, folic acid, L-arginine, L-citrulline, magnesium, riboflavin, vitamin C, vitamin D, 
vitamin E, and Zinc) are also permitted, though caution is advised when taking amounts 
exceeding 100% of the recommended daily allowance. 
Infusion related reactions have been observed with crizanlizumab administration. Pre- 
medication with analgesics (e.g., paracetamol/acetaminophen or NSAID) and anti-histamines 
(e.g., diphenhydramine or alternative, or in combination with H2 blocker) should be considered 
as per institutional standard of care, and at the discretion of the investigator (refer to Table 6-3 
for further guidance on the management of crizanlizumab infusion reactions). 
Steroids should be used with caution, and when clinically indicated (e.g., to manage 
hypersensitivity/anaphylactic reactions). There is no existing clinical data on concomitant use 
of crizanlizumab and corticosteroids. For patients presenting for acute pain related to sickle cell 
disease, the 2020 guideline from American Society of Hematology suggests against 
corticosteroids for acute pain management (Brandow et al 2020). 
If a participant experiences a grade 3 or grade 4 infusion related reaction, study drug must be 
discontinued. 
Anti-platelets agents or anticoagulants at therapeutic doses should be used with caution due to 
a potential effect of P-selectin on hemostasis. 
6.4.3 
Prohibited concomitant therapy 
The use of other investigational agents is prohibited during the study. In addition, the 
administration of monoclonal antibodies other than crizanlizumab is prohibited, due to the 
theoretical potential for cross-reactivity and/or overlapping toxicities with other monoclonal 
antibodies. If investigational agents 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 
Screening.  Monoclonal  antibodies  or  immunoglobulin-based  therapy  must  have  been 


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discontinued at least 6 months prior to Screening. Patients who received prior crizanlizumab 
are not allowed. If voxelotor was taken in the past, it must have been permanently discontinued 
at least 30 days prior to Screening. The concomitant treatment with voxelotor is prohibited 
during the study. 
Prior use of other selectin targeting agents and use during the entire study duration are 
prohibited. New treatments to treat SCD and/or to prevent/reduce VOCs are not permitted 
(except as outlined above) during the study. 
6.5 
Participant numbering, treatment assignment or randomization 
6.5.1 
Participant numbering 
Each participant is identified in the study by a 7 Digit Participant Number (Participant No.) that 
is assigned when the participant starts screening and is retained as the primary identifier for the 
participant throughout his/her entire participation in the trial. The Participant No. consists of 
the Center Number (4 digits) (as assigned by Novartis to the investigative site) with a sequential 
participant number suffixed to it, so that each participant is numbered uniquely across the entire 
database. Upon signing the ICF, the participant is assigned to the next sequential Participant 
No. available to the investigator through the Rave EDC (Electronic Data Capture) interface. 
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the participant to register them into the IRT. Once assigned, the Participant No. 
must not be reused for any other patient. 
It is permissible to re-screen a participant, one time, if she/he fails the initial screening. 
If the participant is re-screened, a new unique Participant No. will be assigned to the re-screened 
participant and the original assigned number will be captured in the rescreening page. If the 
participant fails to start treatment for any reason, the reason should be recorded on the 
appropriate Case Report Form. 
IRT must be notified within 2 days that the participant was not enrolled in the study. 
6.5.2 
Treatment assignment or randomization 
No randomization will be performed in this study. 
All participants who fulfill all inclusion/exclusion criteria will be assigned to be treated with 
crizanlizumab. The IRT system will assign the study medication kits to be dispensed at each 
participant visit. 
6.5.3 
Treatment blinding 
This is an open label study. Investigators, participants and Sponsor will have full knowledge of 
the treatment allocation. 
6.6 
Study drug preparation and dispensation 
Crizanlizumab will be prepared by a pharmacist or study personnel appropriately trained in the 
preparation of solutions for parenteral administration (use aseptic techniques when preparing 
the study drug solution) in accordance with the Pharmacy Manual. 


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Infusion must take place in a facility with appropriate resuscitation equipment available at the 
bedside and a physician readily available during the period of drug administration. 
Participants should be closely observed for potential infusion-related reactions including rigors, 
chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever, and vital signs 
monitored more frequently if clinically indicated, during and for at least 2 hours after the 
crizanlizumab infusion during the first 6 months of the study (after that monitoring would be 
based on local medical practice). The same may apply for the subsequent crizanlizumab 
infusions if medically indicated. 
6.6.1 
Study treatment packaging and labeling 
Study treatment, crizanlizumab, will be provided as global clinical open supply and will be 
packed and labeled under the responsibility of Novartis, Drug Supply Management. 
Study treatment will be sourced as local commercial supply when available (in the locally 
approved formulation and packaging configuration) and labeled in the country when possible. 
Study treatment labels will comply with the legal requirements of each country and will include 
storage conditions, a unique medication number (corresponding to study treatment and strength). 
A unique medication number is printed on the study medication label. Investigator staff will 
identify the study medication kits to dispense to the participant by contacting the IRT system 
and obtaining the medication number(s). Drug accountability and reconciliation data is recorded 
in the IRT system. 
Table 6-4 
Packaging and labeling 
 
Study treatments 
Packaging 
Labeling (and dosing frequency) 
Crizanlizumab (SEG101) 
Vials containing 10 mL at a 
concentration of 10 mg/mL 
Labeled as ‘SEG101’ (at Week 1 Day1, 
Week 3 Day 1, Week 7 Day 1 and at Day 1 
of every 4-weeks). 
 
 
6.6.2 
Drug supply and storage 
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Refer to the Pharmacy Manual and labels for more details. Upon 
receipt, the study treatment should be stored according to the instructions specified in the 
Pharmacy Manual and in the Investigator’s Brochure. 
Table 6-5 
Supply and storage of study treatments 
 
Study treatments 
Supply 
Storage 
Crizanlizumab 
(SEG101) 
Centrally supplied by Novartis 
or local commercial supply when 
available. 
Refer to study treatment label 
 
 


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6.6.3 
Study drug compliance and accountability 
6.6.3.1 
Study drug compliance 
Infusions will be administered in the clinic. This information must be captured in the source 
document, the appropriate CRFs. Compliance will be assured by administrations of the study 
treatment under the supervision of investigator or his/her designee, and will be verified by 
determinations of crizanlizumab in serum. All study treatment dispensed and returned must be 
recorded in the Drug Accountability and Returns Management functionality in the IRT system. 
6.6.3.2 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be monitored by the 
field monitor during site or remote monitoring visits and at the completion of the study. 
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 
6.6.3.3 
Handling of other study treatment 
Not Applicable. 
6.6.4 
Disposal and destruction 
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate in compliance with site processes, monitoring process and as per 
local regulation/guidelines. 
 
7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. 
No CRF will be used as a source document. 
The table indicates which assessments produce data to be entered into the clinical database or 
received electronically from a vendor (D) or remain in source documents only (S) (“Category” 
column) 
As per Section 2.7, 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, national and local 
regulations and depending on operational capabilities, telephone contacts and/or virtual contacts 
(e.g., teleconsultation) with the participant, can replace certain protocol assessments, for the 


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duration of the disruption until it is safe for the participant to visit the site again. These 
telephone/virtual contacts should preferably be done according to the study visit schedule. 
Screening assessments, apart from those listed below, must occur within 28 days prior to the 
enrolment as per Table 7-1. 
• Auditory and Ocular assessments to be done at screening if not done within the last 24 
weeks prior to Week 1 Day 1 dosing, refer to Section 7.2.2.9 and Section 7.2.2.10 for 
additional details. 
• Chest-X ray and echocardiogram to be done at screening if not done within the last 12 
weeks prior to Week 1 Day 1 dosing, refer to Section 7.2.1.1 and Section 7.2.2.8.2 for 
additional details. 
Allowed visit windows are specified as follows: 
There is a ± 7 day visit window permitted for every dosing visit (with a minimum of 21 days to 
be respected between 2 doses following Week 3 Day 1), except Week 3 Day 1 where a visit 
window of ±3 days is allowed (and dose is given within 14±3 days of Week 1 Day 1 dose). 
For participants discontinuing from study treatment (prior to completion of the planned 2 years 
of study treatment, i.e. prior to completion of Week 103 Day 1 visit) and not continuing under 
crizanlizumab outside the study, the EOT visit is to be performed within 7 days from the 
decision to discontinue from the study treatment. 
For participants discontinuing from study treatment (prior to completion of the planned 2 years 
of study treatment, i.e. prior to completion of Week 103 Day 1 visit) and continuing under 
crizanlizumab outside the study, and for all participants completing the 2 years of study 
treatment (completion of Week 103 Day 1 visit) whether they continue on crizanlizumab 
outside the study or not, the EOT visit should be completed 4 weeks (+/- 7 days) from last dose 
of study treatment. 
In case of early discontinuation, TCD, echocardiogram, ocular and retinal exam, auditory exam, 
urine albumin/creatinine ratio, will need to be assessed at EOT visit if the latest available exams 
were not done within the last 12 weeks (denoted by Xb in the EOT column in Table 7-1). 
There is a ± 7 day visit window permitted for the 105 day post-treatment follow-up visit. 
Participants who discontinue from study should be scheduled for a final evaluation visit (EOT 
visit or post-treatment follow-up visit) if they agree, as soon as possible, at which time all of 
the assessments listed for the final visit will be performed. At this final visit, adverse events, 
VOCs, Dactylitis, transfusions and concomitant medications not previously reported must be 
recorded on the CRF. 
Every effort should be made to follow the schedule outlined in Table 7-1. 








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Visit Name 
Category 
Protocol Section 
Screening 
Wk1 D1 
Wk1D2 d 
Wk1D4 e 
Wk2D1 d 
Wk3D1 
Wk7D1 
WK11D1 
Wk15D1 
Wk15D2 d, f 
Wk15D4 e, f 
Wk16D1 d, f 
Wk17D1 d, f 
Wk18D1 d, f 
Wk 
19D1, 
23D1, 
27D1, 
31D1, 
4qWk till 
103 D1 
End of 
treatment 
(EOT) j 
Post 
Treatm 
ent 
Follow 
up k 
Visit Numbers 
1 
110 
120 
130 
140 
150 
160 
170 
180 
190 
200 
210 
220 
230 
240 … 
1997 
2000 
Visit Day 
-28 
through 
Day -1 
1 
2 
4 
8 
15 
43 
71 
99 
100 
102 
106 
113 
120 
Hematology 
D 
7.2.2.7.1 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry 
D 
7.2.2.7.2 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation (Group 
1 and 2 only) 
D 
7.2.2.7.4 
X 
Wk 19 
D1, Wk 
27 D1 
and 
every 12 
weeks 
X 
X 
HbF 
D 
7.2.2.7.5 
X 
Wk 
27D1, 
51D1, 
75D1, 
103D1 
X 
Urinalysis 
(microscopic +/- 
macroscopic) 
D 
7.2.2.7.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum pregnancy 
test 
S 
7.2.2.7.6 
X 
X 
X 






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Visit Name 
Category 
Protocol Section 
Screening 
Wk1 D1 
Wk1D2 d 
Wk1D4 e 
Wk2D1 d 
Wk3D1 
Wk7D1 
WK11D1 
Wk15D1 
Wk15D2 d, f 
Wk15D4 e, f 
Wk16D1 d, f 
Wk17D1 d, f 
Wk18D1 d, f 
Wk 
19D1, 
23D1, 
27D1, 
31D1, 
4qWk till 
103 D1 
End of 
treatment 
(EOT) j 
Post 
Treatm 
ent 
Follow 
up k 
Visit Numbers 
1 
110 
120 
130 
140 
150 
160 
170 
180 
190 
200 
210 
220 
230 
240 … 
1997 
2000 
Visit Day 
-28 
through 
Day -1 
1 
2 
4 
8 
15 
43 
71 
99 
100 
102 
106 
113 
120 
Pulmonary function 
test (in participants 6 
years and older) 
D 
7.2.2.11 
If 
clinically 
indicate 
da 
If clinically indicated 
Ocular and retinal 
exam (only for 
Groups 1 and 2) 
D 
7.2.2.10 
Xg 
Wk 51D1 
Xb 
Growth and sexual 
maturation 
assessment 
D 
7.2.2.5 
X 
Wk 51D1 
X 
Auditory exam (only 
for Groups 1 and 2) 
D 
7.2.2.9 
Xg 
Wk 51D1 
Xb 
Adverse Event/ 
Serious Adverse 
Event 
D 
8 
X 
Continuous 
IRR l 
D 
Continuous 




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Visit Name 
Category 
Protocol Section 
Screening 
Wk1 D1 
Wk1D2 d 
Wk1D4 e 
Wk2D1 d 
Wk3D1 
Wk7D1 
WK11D1 
Wk15D1 
Wk15D2 d, f 
Wk15D4 e, f 
Wk16D1 d, f 
Wk17D1 d, f 
Wk18D1 d, f 
Wk 
19D1, 
23D1, 
27D1, 
31D1, 
4qWk till 
103 D1 
End of 
treatment 
(EOT) j 
Post 
Treatm 
ent 
Follow 
up k 
Visit Numbers 
1 
110 
120 
130 
140 
150 
160 
170 
180 
190 
200 
210 
220 
230 
240 … 
1997 
2000 
Visit Day 
-28 
through 
Day -1 
1 
2 
4 
8 
15 
43 
71 
99 
100 
102 
106 
113 
120 
a 
 
b Assessment to be done at EOT if not done within the last 12 weeks prior to EOT 
c 
 
d Only for participants enrolled in Part A of Groups 1, 2 or 3 
e Only for participants enrolled in Part A of Groups 1 or 2 
f For participants in Part A only: In case the dose is interrupted, partially administered and/or delayed prior to Week 15 Day 1, all the assessments planned between 
Week 15 Day 2 and Week 18 Day 1 (inclusive) will not be collected at these visits but will be performed on the same day of the full PK/PD collection after at least 3 full 
consecutive doses administered (following the loading dose at Week 3 Day 1). 
g Assessment to be done at screening if not done up to 24 weeks prior to start of study drug 
h For participants in Part A, 2hr post dose ECG measure planned at Week 15 Day 1 has to be aligned with 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. For participants in Part B, Week 15 Day 1 2hr post dose 
ECG should still be performed at the designated visit regardless of steady-state. 
i 
 
j For participants discontinuing from study treatment (prior to completion of Week 103 Day 1 visit) and not continuing under crizanlizumab outside the study, the EOT visit 
is to be performed within 7 days from the decision to discontinue from the study treatment. 
For participants discontinuing from study treatment (prior to completion of Week 103 Day 1 visit) and continuing under crizanlizumab outside the study, and for all 
participants completing the 2 years of study treatment (completion of Week 103 Day 1 visit) whether they continue on crizanlizumab outside the study or not, the EOT 
visit should be completed 4 weeks (+/- 7 days) from last dose of study treatment. 
k Participants continuing under crizanlizumab after their EOT visit, via commercial supply or post-trial access (e.g., enrollment in a Novartis roll-over protocol or in a non- 
trial setting to provide continued drug treatment) will not have to complete the post-treatment follow-up visit. 


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Visit Name 
Category 
Protocol Section 
Screening 
Wk1 D1 
Wk1D2 d 
Wk1D4 e 
Wk2D1 d 
Wk3D1 
Wk7D1 
WK11D1 
Wk15D1 
Wk15D2 d, f 
Wk15D4 e, f 
Wk16D1 d, f 
Wk17D1 d, f 
Wk18D1 d, f 
Wk 
19D1, 
23D1, 
27D1, 
31D1, 
4qWk till 
103 D1 
End of 
treatment 
(EOT) j 
Post 
Treatm 
ent 
Follow 
up k 
Visit Numbers 
1 
110 
120 
130 
140 
150 
160 
170 
180 
190 
200 
210 
220 
230 
240 … 
1997 
2000 
Visit Day 
-28 
through 
Day -1 
1 
2 
4 
8 
15 
43 
71 
99 
100 
102 
106 
113 
120 
l Certain adverse events reported in the AE/SAE eCRF as Infusion Related Reactions will require the IRR eCRF to be completed. 


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7.1.1 
Molecular pre-screening 
Not Applicable. 
7.1.2 
Screening 
Prior to commencement of the screening examination, the patient / legal representative must 
have given full informed consent on the appropriate form. Investigators will also obtain 
consent/assent of patients according to local guidelines. Once this has been signed and dated by 
the patient and/or by the legal representative, the investigator can take the participant through 
the study inclusion and exclusion criteria to make sure that the participant is fully eligible. 
Refer to Table 7-1 for the full screening assessment. 
7.1.2.1 
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. 
Following registering in the IRT for screening, participant eligibility will be checked once all 
screening procedures are completed. Please refer and comply with detailed guidelines in the 
IRT manual. 
7.1.2.2 
Information to be collected on screening failures 
A participant who signs an informed consent/assent but fails to be enrolled for any reason will 
be considered a screen failure. The reason for screen failure should be recorded on the 
appropriate Case Report Form. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for Screen Failure participants. No other data 
will be entered into the clinical database for participants who are screen failures, unless the 
participant experienced a Serious Adverse Event during the Screening Phase (see Section 8 for 
SAE reporting details). Data and samples collected from participants prior to screen failure may 
still be analyzed. 
If a screen failure participant experiences an AE which does not meet the SAE criteria, details 
about the AE will be recorded only in the investigator’s source documents. In case of an SAE 
after signing of the main study informed consent, data must be recorded on both the AE and 
SAE forms of the CRF. 
If the participant fails to be assigned to study treatment, the IRT must be notified within 2 days 
of the screen fail. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once. A participant who is rescreened is not required to sign another ICF if the 
rescreening occurs within 28 days from the previous ICF signature date, unless re-consent is 
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Participants who are enrolled and fail to start treatment, e.g., participants enrolled in error, will 
be considered an early terminator. The reason for early termination should be recorded on the 
appropriate Case Report Form. 
7.1.2.3 
Participant demographics and other baseline characteristics 
Participant demographic characteristics, which include age, gender, self-identified race and 
ethnicity, will be collected. 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF. Participant race and ethnicity are collected as 
part of the Demographics characteristics, and analyzed to identify variations in safety or 
efficacy due to these factors as well as to assess the diversity of the study population as required 
by Health Authorities. 
Background medical information, including diagnosis of SCD and dactylitis/VOC history, prior 
use of HU/HC and reason for discontinuation (as applicable), ECG, relevant and current 
medical history (until date of informed consent) will also be collected. 
All prescription medications, over-the-counter drugs and significant non-drug therapies prior to 
the start of the study must be documented. See the protocol Section 6.4 Concomitant 
medications for further details on what information must be recorded on the appropriate page 
of the eCRF. 
Other baseline characteristics and assessments performed at screening for eligibility are detailed 
in Table 7-1. 
7.1.3 
Run-in period 
Not Applicable. 
7.1.4 
Treatment period 
Once eligibility criteria have been confirmed, the participant will be enrolled to receive 
crizanlizumab on Week 1 Day 1, Week 3 Day 1, and then on Day 1 of every 4-week cycle (see 
Table 7-1). Participants may be admitted to the study site prior to dosing for baseline evaluations. 
Initiation of treatment in the three study groups will occur sequentially. The first participants in 
the study will be enrolled in Group 1 and will receive crizanlizumab 5.0 mg/kg by i.v. infusion 
on Week 1 Day 1, Week 3 Day 1, and then on Day 1 of every 4-week cycle. The first 
participants of each study group will be enrolled in Part A of the study to confirm and establish 
appropriate dosing, before treatment is initiated in Part B and in Part A of the next study group 
(refer to Section 4.1). 
No dose change or modification by the investigator of the study defined dose will be allowed 
in the study. Dose interruptions for safety reasons are described in the Section 6.3. 
All enrolled participants will have PK/PD sampling performed in order to characterize the 
PK/PD of crizanlizumab (see Table 7-5, Table 7-6, and Table 7-7 ). On Week 1 Day 1 and 
Week 15 Day 1, the participants enrolled in Part A may be asked to remain at the study site for 
at least 24 hours post-dose in order to complete the full PK/PD sample collection. In case the 




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Participants who prematurely discontinue from study treatment (prior to completion of Week 
103 Day 1 visit) should NOT be considered discontinued from the study. The participants 
discontinuing from study treatment and not continuing under crizanlizumab outside of the study 
should return for the assessments indicated in Table 7-1 for an EOT visit within 7 days from 
the decision to permanently discontinue the study treatment, and the 105 day post-treatment 
follow-up visit (105 days after last dose of study treatment +/- 7 days). If the decision to 
discontinue the participant occurs at a regularly scheduled visit, that visit may serve as the EOT 
visit rather than having the participant return for an additional visit 7 days later. 
The participants discontinuing from study treatment but continuing under crizanlizumab outside 
of the study (i.e. via commercial supply) should return for the assessments indicated in 
Table 7-1 for an EOT visit within 4 weeks (+/-7 days) from the last dose of study treatment. 
These participants will not have to complete the post-treatment follow-up visit. 
Participants completing the 2 years of study treatment (Week 103 Day 1 visit) will perform the 
EOT visit as indicated in Table 7-1, within 4 weeks (+/-7 days) from last dose of study treatment. 
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. 
If the participants fail to return for these EOT assessments for unknown reasons, every effort 
(e.g., telephone, email, letter) should be made by the site staff to maintain regular telephone 
contact with them. This telephone contact should preferably be done according to the study visit 
schedule. 
After discontinuation from study treatment, at a minimum, the following data should be 
collected at clinic visits or via telephone/email contacts: 
• New / concomitant treatments 
• Adverse events / Serious Adverse Events 
7.1.6 
Discontinuation from study 
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason. If the 
participant agrees, a final evaluation (EOT visit, or post-treatment follow-up visit) at the time 
of the participant’s study discontinuation should be made as detailed in the assessment table 
(refer to Section 7.1). 
7.1.6.1 
Replacement policy 
If the initial number of at least 8 participants in Part A of each group treated at the initial dose 
for the group leads to less than 6 evaluable participants, enrollment in the group Part A will 
continue until 6 participants have successfully completed all study procedures and are evaluable 
for the first dose PK analysis (see Section 10). 
7.1.7 
Withdrawal of consent/Opposition to use data/biological samples 
Withdrawal of consent/opposition to use data/biological samples occurs only when a participant: 


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• 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 his/her 
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, all efforts should be made to complete a final evaluation prior to 
participant’s withdrawal of consent/opposition to use data/biological samples (refer to 
Section 7). 
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 to use data/biological 
samples. 
7.1.8 
Post-treatment Follow-up 
All participants must have safety and efficacy evaluations for 5 half-lives (105 days) after the 
last dose of study treatment, except the ones continuing crizanlizumab after their EOT visit, via 
commercial supply or post-trial access (e.g., enrollment in a Novartis roll-over study or in a 
non-trial setting to provide continued drug treatment). The post-treatment follow-up visit should 
occur 105 days +/-7 days after the last dose of study treatment. 
Once an AE is detected, investigators are required to follow this AE until its resolution or 
stabilization. Refer to Section 8.1.1 for definitions and reporting of AEs. Participants whose 
treatment is interrupted or discontinued due to an AE, including abnormal laboratory value, 
must be followed until resolution or stabilization of the event, whichever comes first. This could 
include all study assessments appropriate to monitor the event. 
Data collected should be added to the Adverse Events, VOCs, Dactylitis, Transfusion and 
Concomitant Medications CRFs. 


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For participants followed until 105 days after last dose of study treatment, any SAEs 
experienced after the completion of the 105 day post-treatment follow-up visit should be 
reported to Novartis if the investigator suspects a causal relationship to the study treatment, 
unless otherwise specified by local law/regulations. 
If participants refuse to return for a post-treatment follow-up visit or are unable to do so, every 
effort should be made to contact them by telephone to determine their status. Attempts to contact 
the participant should be documented in the source documents (e.g., dates of telephone calls, 
registered letters, etc.). 
7.1.9 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits or fail to 
respond to any site attempts to contact them without stating an intention to discontinue from 
study treatment or discontinue from study or withdraw consent/oppose to the use of their 
data/biological samples, the investigator should show "due diligence" by contacting the 
participant, family or family physician as agreed in the informed consent and 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 lost to follow-up until due 
diligence has been completed. Participants lost to follow-up should be recorded as such on the 
Disposition CRF. 
7.2 
Assessment types 
7.2.1 
Efficacy assessments 
7.2.1.1 
VOC assessments 
Definitions 
VOC is defined as pain crises (defined as an acute onset of pain for which there is no other 
medically determined explanation other than vaso-occlusion and which requires therapy with 
oral/parenteral opioids or parenteral NSAIDs as well as other complicated crises, such as ACS, 
priapism, and hepatic or splenic sequestration. 
For purposes of this study, the following detailed definitions will be used to identify each sub- 
type of VOC event: 
1. Uncomplicated pain crisis 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 
opioids or parenteral NSAIDs; but is NOT classified as an acute chest syndrome, hepatic 
sequestration, splenic sequestration or priapism. The end of an uncomplicated pain crisis 
will be considered the resolution of acute pain, such that residual pain (or absence of any 
pain) is considered to be chronic, and the current pain medication regimen is considered to 
be for this chronic pain. 
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 


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temperature of more than 38.5°C, tachypnea, wheezing or cough. ACS will be considered 
resolved 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 (unless for 
reason other than the ACS) or have returned to pre-event baseline. 
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 be considered resolved when 
right upper quadrant pain has returned to baseline (pre-event) levels and hemoglobin has 
been stable for 24 hrs. 
5. Splenic sequestration if 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 be considered resolved when left 
upper quadrant pain has returned to baseline (pre-event) levels and hemoglobin has been 
stable for 24 hrs. 
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 VOC events. Similarly, complications such 
as pulmonary, cardiac, or renal failure are not to be considered crises if they occur completely 
independently from a VOC event. If such events progress to VOC, the VOC event will be 
documented separately. 
Table 7-2 
Vaso-Occlusion Crisis Assessment Collection Plan 
 
Procedure / Assessment 
collection plan 
Screening/Baseline 
During Treatment/Post-treatment 
Follow-up 
Chest X-ray 
Mandated 
If clinically indicated 
Vaso-Occlusion Crisis 
information 
Mandated 
Mandated, when VOC crisis occurs 
Dactylitis 
Mandated 
Mandated when dactylitis occurs 
Concomitant medication – 
Analgesics 
If clinically indicated 
Mandated, when VOC crisis occurs 
Hospitalization details 
Mandated 
Mandated, when VOC crisis occurs and 
hospitalization is done 
Transfusion 
If clinically indicated 
If clinically indicated 
School/ Employment status and 
sick time 
If clinically indicated 
If clinically indicated 
Blood for PK/PD 
Not Applicable 
If possible 




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Dactylitis event CRF. Any dactylitis symptoms occurring within 7 days following the 
documented resolution of a dactylitis event will be counted as part of the prior crisis, and the 
date for end of dactylitis will be revised. 
If a single event meets criteria for both dactylitis and VOC, then both CRF forms should be 
completed. 
Chest X-ray 
Chest X-ray must be conducted at screening unless there is one available in the last 12 weeks 
prior to Week 1 Day 1, to establish the participant’s baseline and confirm no significant new 
findings prior to enrolment. Chest X-ray must be repeated during the study in case of a VOC 
with suspected ACS and reported as unscheduled assessment in the CRF. 
Transfusions 
Transfusion data should be collected from 28 days prior to Week 1 Day 1 until the participant 
last protocol visit (EOT or post-treatment follow-up visit, as applicable). Participants planning 
to participate in a chronic transfusion program during study (pre-planned series of transfusions 
for prophylactic purposes) are not eligible. Episodic transfusion in response to worsened anemia 
or VOC is permitted and will be collected on the Transfusion CRF page. 
7.2.2 
Safety and tolerability assessments 
Safety will be monitored by conducting physical examinations and by assessing vital signs, 
ECG, by doing laboratory assessments including hematology, chemistry, coagulation, and 
urinalysis, as well as by collecting the adverse events at every visit. For details on AE collection 
and reporting, refer to Section 8. 
7.2.2.1 
Physical examination 
The physical examination must be performed by the Investigator as scheduled in Table 7-1. 
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
and extremities, 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 at the EOT visit. 
An abbreviated (short) physical exam will include the examination of general appearance and 
vital signs (blood pressure and pulse), 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 study drug infusion. 
Information for all physical examinations must be included in the source documentation at the 
study site. Significant findings that were present prior to the signing of informed consent must 
be included in the Medical History page on the participant’s CRF. Significant new findings that 
begin or worsen after informed consent must be recorded on the Adverse Event page of the 
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7.2.2.2 
Vital signs 
Vital signs include blood pressure (supine position preferred when ECG is collected), pulse 
measurement, respiratory rate and body temperature will be measured at each visit as specified 
in Table 7-1. 
7.2.2.3 
Height, weight and head circumference 
Height and body weight (in indoor clothing, but without shoes) will be measured at screening 
and at all visits for which there is a scheduled study drug infusion (for dosing calculation), as 
specified in Table 7-1. Additionally, head circumference will be measured for participants aged 
2 to 2.5 years old at time of enrollment, at all visits where weight and height are measured, until 
the participant turns 3 years old. 
7.2.2.4 
Performance status 
The Karnofsky performance status scale (Appendix 1) will be used for children >10 years and 
the Lansky Play-Performance Status Scale Clinical Classification (Appendix 2) for children ≤ 
10 years of age will be assessed as described in the Table 7-1. 
7.2.2.5 
Growth and sexual maturation 
7.2.2.5.1 Pubertal stage 
Pubertal stage according to Tanner staging will be scored at screening, at the end of the first 
year of treatment (Week 51 Day 1) and at the EOT visit. This assessment may be discontinued 
once Stage V is reached. 
7.2.2.6 
Transcranial Doppler 
Transcranial Doppler (TCD) is a noninvasive ultrasound assessment used to measure cerebral 
blood flow velocity (CBF-V) including the middle cerebral artery (MCA) velocity in the major 
intracranial arteries. 
It will be required for participants aged from 2 to <16 years old at the time of screening, with 
HbSS, HbSβ0-thalassemia, and HbSD disease. For participants with other SCD types, 
performance of TCD is by investigator discretion. 
In case TCD assessment during the screening period is not feasible, an acceptable TCD done 
within 12 weeks prior to Week 1 Day 1 can be used. 
An acceptable TCD is defined as 
• a TCD that was not performed within 60 days following a transfusion 
• a TCD that was not impacted by change in treatment such as HU/HC or L-glutamine (e.g., 
stopped treatment or significant dose change) within 60 days prior to TCD assessment, or 
after TCD assessment and Week 1 Day 1 
Only when screening TCD is unevaluable due to cranial ossification, a participant may be 
eligible based on investigator interpretation of “low risk” for the most recent, evaluable TCD 
within 12 months prior to enrollment (Week 1 Day 1). If all TCDs from the past 12 months are 


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unevaluable, intracranial flow MRI (if available) will be considered for enrollment. In case no 
evaluable TCD or MRI is available at screening visit the participant will not be eligible. 
Subsequent TCDs will be required at Week 27 Day 1, Week 51 Day 1, Week 103 Day 1 and at 
the EOT visit, unless it was already done within 12 weeks prior to the EOT visit as outlined in 
Table 7-1, for participants aged from 2 to <16 years old at time of screening, with HbSS, HbSβ0- 
thalassemia, and HbSD disease. For participants with other SCD types, performance of TCD is 
by investigator discretion. 
During the study in case a transfusion was performed or in case of a change in HU/HC or L- 
glutamine (e.g., stopped treatment or significant dose change) within 60 days prior to the 
expected date of TCD, then the planned TCD will be skipped and an unscheduled TCD will 
need to be performed at least 60 days after. 
7.2.2.7 
Laboratory evaluations 
Clinical laboratory analyses (hematology, chemistry, urinalysis, coagulation) are to be 
performed at the central lab or locally at site according to the schedule of assessments and 
collection plan outlined in Table 7-1. As per Section 2.7, during a Public Health emergency as 
declared by Local or Regional authorities (i.e. pandemic, epidemic or natural disaster), if 
participants cannot visit the site for protocol specified safety lab assessments, an alternative 
certified local lab other than the study site may be used. Details on the collection, shipment of 
samples and reporting of results by the central laboratory are provided to investigators in the 
Central Laboratory Manual/Flowchart. 
Screening assessments, apart from those identified in the visit evaluation schedule (VES) and 
in Section 7.1, must occur within 28 days prior to the enrolment as per Table 7-1 
(see Section 7.1). If the participant was hospitalized at time of screening visit, safety laboratory 
analysis must be repeated prior to Week 1 Day 1 to verify participant’s eligibility. 
Novartis must be provided with a copy of the central and local laboratory’s certifications and a 
tabulation of the normal ranges and units of each parameter collected in the CRF. 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, laboratory results from the central 
laboratory will be used, except for hematology (always performed locally), and other lab tests 
deemed for eligibility, in case of missing results from central lab. 
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 (except for hematology which will be only performed locally at site). 


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The results of the local laboratory will be recorded in the CRF if any of 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. 
Every effort should be made in order to perform local lab tests in case no concomitant central 
results are available (due to any reason). Missing of 2 consecutive lab tests deemed to assess 
dose interruption/discontinuation (as per Table 6-2) during the study is not permitted. 
At any time during the study up to last protocol visit (EOT or post-treatment follow-up visit, as 
applicable), abnormal laboratory parameters which are clinically relevant and require an action 
to be taken with study treatment (e.g., require interruption of study treatment, lead to clinical 
symptoms or signs, or require therapeutic intervention), whether specifically requested in the 
protocol or not, will be recorded on the AE CRF 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 7-3 
Central and Local Clinical laboratory parameters collection plan 
 
Test Category 
Test Name 
Hematology 
Local (performed at site): Hematocrit, Hemoglobin, Mean cell hemoglobin 
(MCH), Mean corpuscular hemoglobin concentration (MCHC), Mean corpuscular 
volume (MCV), Reticulocytes (%), Platelets, Red blood cells, White blood cells, , 
Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands, 
Other: absolute value preferred). 
Chemistry 
Central: Albumin, Alkaline phosphatase, ALT, AST, Lactate dehydrogenase (LDH), 
Bicarbonate, Calcium, Magnesium, Phosphorus, Chloride, Sodium, Potassium, 
Creatinine, Creatine kinase, Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, , estimated 
Glomerular filtration rate (eGFR). 
Urinalysis 
Local (performed at site): Macroscopic Panel (Dipstick): Color, Bilirubin, Blood, 
Glucose, Ketones, Leukocytes esterase, Nitrite, pH, Protein, Specific Gravity, 
Urobilinogen. 
Central: 
• 
Microscopic Panel: Red Blood Cells, White Blood Cells, Casts, Crystals, Bacteria 
and Epithelial cells performed if a positive dipstick. 
• 
 
Coagulation (only 
for Groups 1 and 2) 
Central: Prothrombin time (PT), International normalized ratio [INR]), Activated partial 
thromboplastin time (APTT) 
Additional tests 
Central: HbA, S, C, F, A2 
Pregnancy Test (for 
female participants 
of childbearing 
potential) 
Central: Serum pregnancy test (at Screening, EOT and post-treatment follow-up visit 
only). 
Local (performed at site): urine pregnancy test (before each infusion). 


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7.2.2.7.1 Hematology 
Hematology tests 
 are to be performed locally at site 
according to the schedule of assessments and collection plan outlined in Table 7-1. 
When needed, manual platelet estimation via blood smear to assess adequacy of the platelet 
count may be considered. 
Detailed hematology panel is described on Table 7-3. 
7.2.2.7.2 Chemistry 
Chemistry tests are to be performed centrally according to the schedule of assessments and 
collection plan outlined in Table 7-1. Detailed chemistry panel is described on Table 7-3 . 
The estimated Glomerular Filtration Rate (eGFR) using Schwartz formula will be calculated 
centrally. 
7.2.2.7.3 Urinalysis 
Macroscopic urinalysis dipstick analysis will be performed locally at site according to the 
schedule of assessments and collection plan outlined in Table 7-1. Microscopic analysis will be 
performed centrally only in case of positive dipstick. 
Detailed urinalysis panel is described on Table 7-3 . 
7.2.2.7.4 Coagulation 
Prothrombin time (PT), international normalized ratio (INR), and partial thromboplastin time 
(PTT) or activated partial thromboplastin time (APTT) will be assessed centrally according to 
the schedule of assessments samples outlined in Table 7-1 in Group 1 and 2 only. Samples will 
be collected at Week 1 Day 1, Week 19 Day 1, at Week 27 Day 1, and then every 12 weeks 
from Week 27 Day 1: at Week 39 Day 1, at Week 51 Day 1, at Week 63 Day 1, at Week 75 
Day 1, at Week 87 Day 1, at Week 99 Day 1, at EOT and at the end of the post-treatment follow- 
up. 
7.2.2.7.5 Fetal Hemoglobin 
Fetal Hemoglobin by HPLC will be performed at the central lab in participants at time of 
enrollment 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, Week 51 Day 1, Week 75 Day 1, 
Week 103 Day 1 and EOT visits as outlined in Table 7-1. 
7.2.2.7.6 Pregnancy and assessments of fertility 
A female participant is considered of childbearing potential from menarche and until becoming 
postmenopausal unless permanently sterile. Permanent sterilization methods include 
hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Medical documentation of 
oophorectomy, hysterectomy, or tubal ligation must be retained as source documents. 


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A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause and an appropriate clinical profile. 
In absence of the medical documentation confirming permanent sterilization, or if the post- 
menopausal status is not clear, the investigator should use his medical judgment to appropriately 
evaluate the fertility state of the woman and document it in the source document. 
All female participants of childbearing potential must perform a serum hCG pregnancy test at 
screening in order to confirm study eligibility, at EOT visit and at the end of the post treatment 
follow-up 105 days after the last infusion of the study treatment. In case the childbearing 
potential status changes during the course of the study compared to screening, site will record 
the childbearing status on source documents, as required. 
At Week 1 Day 1 before the administration of the crizanlizumab dose and before all visits for 
which there is a scheduled study drug infusion, a urine pregnancy test will be performed locally 
in females of childbearing potential. 
Additional pregnancy test can be performed as soon as indicated in case the participant is 
suspected to be pregnant (urine or serum). 
Each pregnancy in a participant on study drug must be reported to the sponsor within 24 hours 
of learning of its occurrence. See Section 8.5 for detailed reporting and follow-up procedures. 
7.2.2.7.7 Urine albumin/creatinine ratio 
At Screening, a urine sample (at least 15 ml) will be collected and sent to the central laboratory 
for urinary albumin/creatinine ratio. The assessment will be repeated at Week 27 Day 1, Week 
51 Day 1 and EOT visits (if not done within 12 weeks prior EOT already) as outlined in 
Table 7-1. First morning void samples must not be used for this analysis. 
7.2.2.8 
Cardiac assessments 
7.2.2.8.1 Electrocardiogram (ECG) 
Standard 12-lead ECGs will be performed (in the supine position) after the participant has been 
resting for 5-10 min prior to each time point indicated in Table 7-4. When triplicate ECG are 
required, the individual ECGs should be recorded approximately 2 minutes apart. 
The QTcF values using Fridericia’s correction (formula is provided below) should be used. 
 
The mean QTcF value will be calculated from the triplicate ECGs for each participant. 
Unscheduled triplicate ECGs will be performed also in case QTcF >480 ms has been observed. 
Note: In order to ensure ECG evaluation is received from the central laboratory for eligibility 
assessment, it is advisable to perform the ECG at least 72 hours prior to the scheduled 
enrollment date. 
In the event that a QTcF value of > 480 ms is observed or if an unscheduled ECG is performed 
for safety reasons, it is recommended to collect a time-matched PK sample and record the time 


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and date of the last study drug intake to determine the drug exposure (refer to Section 7.2.3). In 
case of QT prolongation, study drug must be discontinued (refer to Section 6.3.2). 
Additional, unscheduled, safety 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. Local cardiologist ECG assessment may also be 
performed at any time during the study at the discretion of the investigator. The local QTcB 
results must be captured in the source documents only. 
All ECGs, including unscheduled safety triplicate ECGs with clinically relevant findings, 
collected during the study should be transmitted to the central core ECG laboratory for review. 
The results of the centrally assessed ECGs are automatically transferred into the clinical 
database. Any original ECG not transmitted to a central laboratory should be forwarded for 
central review and a copy kept in the source documents at the study site. Interpretation of the 
tracing must be made by a qualified physician and documented on the ECG CRF page. Each 
ECG tracing should be labeled with the study number, participant number, date, and kept in the 
source documents at the study site. 
Clinically significant ECG abnormalities present at screening should be reported on the Medical 
History CRF page. New or worsened clinically significant findings occurring after informed 
consent must be recorded on the Adverse Events CRF page. 
Figure 7-1 
Timing of study procedures: 
 
 
Table 7-4 
ECG collection plan 
 
Week 
Day 
Time 
ECG Type 
Type of reading 
Screening 
-28 to -1 
Anytime 
12 Lead, Triplicate 
Central reading 
W7 
D1 
Post-dose (within 2 hours 
post-infusion) 
12 Lead, Single 
Central reading 
W11 
D1 
Post-dose (within 2 hours 
post-infusion) 
12 Lead, Single 
Central reading 
W15a 
D1 
Post-dose (within 2 hours 
post-infusion) 
12 Lead, Triplicate 
Central reading 
W27 
D1 
Post-dose (within 2 hours 
post-infusion) 
12 Lead, Single 
Central reading 
W51 
D1 
Post-dose (within 2 hours 
post-infusion) 
12 Lead, Single 
Central reading 
W103 
D1 
Post-dose (within 2 hours 
post-infusion) 
12 Lead, Single 
Central reading 
EOT 
Anytime 
12 Lead, Single 
Central reading 
Unscheduled ECG (triplicate) 
central reading 
Anytime in response to 
cardiac AEs (arrhythmias, 
12 Lead, Triplicate 
Central reading 






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Refer to the SEG101B2201 Laboratory Manual for detailed instructions for the collection, 
handling, and shipment of PK samples. 
Participants enrolled in Part B, following dose confirmation, will have only pre-dose PK/PD/IG 
samples collected starting from Week 1 Day 1 until EOT (PD) or post-treatment follow-up visit 
(PK, IG), as described in Tables Table 7-5, Table 7-6, and Table 7-7. 
Specific instructions for the blood sampling at steady state (on Week 15 Day 1 or later) – 
Part A only 
The full blood sampling for PK and PD intended to describe the steady state (PK samples 11 to 
20 and PD samples 109 to 116) will only be performed between Week 15 Day 1 and Week 19 
Day 1 if 3 full consecutive doses of crizanlizumab following the loading dose at Week 3 Day 1 
were received by the participant. Otherwise if dose is interrupted, partially administered or 
delayed prior to Week 15, 3 full consecutive infusions (administered within allowed visit 
window) are required to reach the steady state after the dose has been resumed. In the case the 
steady state is not reached at Week 15, only the pre-dose samples will be collected at Week 15 
Day 1 (PK sample 11 and PD sample 109). The other samples (PK samples 12 to 19 and PD 
samples 110 to 115) should not be collected as the PK/PD profile will not reflect the PK/PD 
steady-state. 
In case steady state is reached after Week 15, unscheduled laboratory kits provided by the 
central laboratory (labeled UNS PK/PD STEADY STATE) should be used for the 
corresponding blood collection for full PK/PD sampling. 
Maximum allowed infusion time to allow PK/PD profile sampling at steady state is 2 hours, 
beyond which PK/PD sampling for profile purpose will not proceed, meaning full PK/PD 
sampling should not occur in case infusion lasts more than 2 hours at presumed steady state. 
However, if full dose is administered at the visit, then multiple dose PK/PD profile sampling 
may occur at the next dose instead. 
Table 7-5 
Pharmacokinetic, pharmacodynamics and immunogenicity blood 
collection log Group 1 
 
Week 
Day 
Scheduled time point 
following the initiation of 
infusion (hr) 
PK collection 
number/Dose 
reference ID 
PK 
sample 
No 
PD 
sample 
a No 
IG 
sample 
No 
Study part 
sample 
collection 
1 
1 
Pre-dose 
1 
-- 
1 
101 
201 
Part A 
Part B 
1 
1 
0.5d (± 10 min after end of 
infusion) 
1 
-- 
2 
-- 
-- 
Part A 
-- 
1 
1 
2 (± 30 min) 
1 
-- 
3 
102 
-- 
Part A 
-- 
1 
1 
4 (± 30 min) 
1 
-- 
4 
-- 
-- 
Part A 
-- 
1 
2 
24 (± 2 hr) 
1 
-- 
5 
103 
-- 
Part A 
-- 
1 
4 
72 (± 2 hr) 
1 
-- 
6 
104 
-- 
Part A 
-- 
2 
1 
168 (± 24 h) 
1 
-- 
7 
105 
-- 
Part A 
-- 
3 
1 
Pre-dose 
2 
101b 
8 
106 
202 
Part A 
Part B 
7 
1 
Pre-dose 
3 
201b 
9 
107 
-- 
Part A 
Part B 
11 
1 
Pre-dose 
4 
301b 
10 
108 
-- 
Part A 
Part B 
15c 
1 
Pre-dose 
5 
401b 
11 
109 
203 
Part A 
Part B 


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Week 
Day 
Scheduled time point 
following the initiation of 
infusion (hr) 
PK collection 
number/Dose 
reference ID 
PK 
sample 
No 
PD 
sample 
a No 
IG 
sample 
No 
Study part 
sample 
collection 
15 c 
1 
0.5d (± 10 min after end of 
infusion) 
5 
-- 
12 
-- 
-- 
Part A 
-- 
15 c 
1 
2 (± 30 min) 
5 
-- 
13 
110 
-- 
Part A 
-- 
15 c 
1 
4 (± 30 min) 
5 
-- 
14 
-- 
-- 
Part A 
-- 
15 c 
2 
24 (± 2 hr) 
5 
-- 
15 
111 
-- 
Part A 
-- 
15 c 
4 
72 (± 2 hr) 
5 
-- 
16 
112 
-- 
Part A 
-- 
16 c 
1 
168 (± 24 h) 
5 
-- 
17 
113 
-- 
Part A 
-- 
17 c 
1 
336 (± 24 h) 
5 
-- 
18 
114 
-- 
Part A 
-- 
18 c 
1 
504 (± 24 h) 
5 
-- 
19 
115 
-- 
Part A 
-- 
19 c 
1 
Pre-dose 
6 
501b 
20 
116 
-- 
Part A 
Part B 
23 
1 
Pre-dose 
7 
601b 
21 
117 
-- 
Part A 
Part B 
27 
1 
Pre-dose 
8 
701b 
22 
118 
204 
Part A 
Part B 
31 
1 
Pre-dose 
9 
801b 
23 
119 
-- 
Part A 
Part B 
35 
1 
Pre-dose 
10 
901b 
24 
120 
-- 
Part A 
Part B 
39 
1 
Pre-dose 
11 
1001b 
25 
121 
-- 
Part A 
Part B 
43 
1 
Pre-dose 
12 
1101b 
26 
122 
-- 
Part A 
Part B 
47 
1 
Pre-dose 
13 
1201b 
27 
123 
-- 
Part A 
Part B 
51 
1 
Pre-dose 
14 
1301b 
28 
124 
-- 
Part A 
Part B 
EOT 
-- 
-- 
1401 
29 
-- 
205 
Part A 
Part B 
Post- 
treatment 
Follow-up 
(last infusion 
+ 105 days) 
e 
-- 
-- 
1501 
30 
-- 
206 
Part A 
Part B 
Unscheduled 
Sample 
--- 
--- 
1001+ 
2001+ 
3001+ 
Part A 
Part B 
a PD: P-selectin inhibition 
b For the PK pre-dose samples (sample number 8-11 and 20-28), the actual date and time of administration of 
the previous dose of study medication should also be recorded with appropriate Dose reference IDs as indicated 
in the above table. 
c Sampling to occur at steady state (week 15) or later, if dose was interrupted, partially administered or delayed 
prior to Week 15. 
d 0.5 hr sample is collected at end of typical 30 minutes infusion. In the rare instance that infusion time is 
prolonged beyond 30 minutes, for example for up to 1 hr, then 0.5 hr sample is not collected and end of infusion 
sample will be collected at 1 hr instead. 
e Participants continuing crizanlizumab after their EOT visit, via commercial supply or post-trial access (e.g., 
enrollment into a Novartis roll-over protocol or in a non-trial setting), will not have to complete the 105 days post- 
treatment follow-up visit. 
 
Table 7-6 
Pharmacokinetic, pharmacodynamics and immunogenicity blood 
collection log Group 2 
 
Week 
Day 
Scheduled 
time point 
following the 
initiation of 
infusion (hr) 
PK collection 
number/Dose 
reference ID 
PK 
sample 
No 
PD 
samplea 
No 
IG 
sample 
No 
Study part sample 
collection 
1 
1 
Pre-dose 
1 
-- 
1 
101 
201 
Part A 
Part B 


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Protocol No. CSEG101B2201 
 
 
 
 
Week 
Day 
Scheduled 
time point 
following the 
initiation of 
infusion (hr) 
PK collection 
number/Dose 
reference ID 
PK 
sample 
No 
PD 
samplea 
No 
IG 
sample 
No 
Study part sample 
collection 
1 
1 
0.5d (± 10 min 
after end of 
infusion) 
1 
-- 
2 
-- 
-- 
Part A 
-- 
1 
1 
2 (± 30 min) 
1 
-- 
3 
102 
-- 
Part A 
-- 
1 
1 
4 (± 30 min) 
1 
-- 
4 
-- 
-- 
Part A 
-- 
1 
2 
24 (± 2 hr) 
1 
-- 
5 
103 
-- 
Part A 
-- 
1 
4 
72 (± 2 hr) 
1 
-- 
6 
104 
-- 
Part A 
-- 
2 
1 
168 (± 24 h) 
1 
-- 
7 
105 
-- 
Part A 
-- 
3 
1 
Pre-dose 
2 
101b 
8 
106 
202 
Part A 
Part B 
7 
1 
Pre-dose 
3 
201b 
9 
107 
-- 
Part A 
Part B 
11 
1 
Pre-dose 
4 
301b 
10 
108 
-- 
Part A 
Part B 
15 c 
1 
Pre-dose 
5 
401b 
11 
109 
203 
Part A 
Part B 
15 c 
1 
0.5d (± 10 min 
after end of 
infusion) 
5 
-- 
12 
-- 
-- 
Part A 
-- 
15 c 
1 
2 (± 30 min) 
5 
-- 
13 
110 
-- 
Part A 
-- 
15 c 
1 
4 (± 30 min) 
5 
-- 
14 
-- 
-- 
Part A 
-- 
15 c 
2 
24 (± 2 hr) 
5 
-- 
15 
111 
-- 
Part A 
-- 
15 c 
4 
72 (± 2 hr) 
5 
-- 
16 
112 
-- 
Part A 
-- 
16 c 
1 
168 (± 24 h) 
5 
-- 
17 
113 
-- 
Part A 
-- 
17 c 
1 
336 (± 24 h) 
5 
-- 
18 
114 
-- 
Part A 
-- 
18 c 
1 
504 (± 24 h) 
5 
-- 
19 
115 
-- 
Part A 
-- 
19 c 
1 
Pre-dose 
6 
501b 
20 
116 
-- 
Part A 
Part B 
23 
1 
Pre-dose 
7 
601b 
21 
117 
-- 
Part A 
Part B 
27 
1 
Pre-dose 
8 
701b 
22 
118 
204 
Part A 
Part B 
31 
1 
Pre-dose 
9 
801b 
23 
119 
-- 
Part A 
Part B 
35 
1 
Pre-dose 
10 
901b 
24 
120 
-- 
Part A 
Part B 
39 
1 
Pre-dose 
11 
1001b 
25 
121 
-- 
Part A 
Part B 
43 
1 
Pre-dose 
12 
1101b 
26 
122 
-- 
Part A 
Part B 
47 
1 
Pre-dose 
13 
1201b 
27 
123 
-- 
Part A 
Part B 
51 
1 
Pre-dose 
14 
1301b 
28 
124 
-- 
Part A 
Part B 
EOT 
-- 
-- 
1401 
29 
-- 
205 
Part A 
Part B 
Post- 
treatment 
Follow-up 
(last infusion 
+ 105 days)e 
-- 
-- 
1501 
30 
-- 
206 
Part A 
Part B 
Unscheduled 
Sample 
--- 
--- 
1001+ 
2001+ 
3001+ 
Part A 
Part B 


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Protocol No. CSEG101B2201 
 
 
Week 
Day 
Scheduled 
time point 
following the 
initiation of 
infusion (hr) 
PK collection 
number/Dose 
reference ID 
PK 
sample 
No 
PD 
samplea 
No 
IG 
sample 
No 
Study part sample 
collection 
a PD: P-selectin inhibition 
b For the PK pre-dose samples (sample number 8-11 and 20-28), the actual date and time of administration of the 
previous dose of study medication should also be recorded with appropriate Dose reference IDs as indicated in 
the above table. 
c Sampling to occur at steady state (week 15) or later, if dose was interrupted, partially administered or delayed 
prior to Week 15. 
d 0.5 hr sample is collected at end of typical 30 minutes infusion. In the rare instance that infusion time is 
prolonged beyond 30 minutes, for example for up to 1 hr, then 0.5 hr sample is not collected and end of infusion 
sample will be collected at 1 hr instead. 
e Participants continuing crizanlizumab after their EOT visit, via commercial supply or post-trial access (e.g., 
enrollment into a Novartis roll-over protocol or in a non-trial setting), will not have to complete the 105 days post- 
treatment follow-up visit. 
Table 7-7 
Pharmacokinetic, pharmacodynamics and immunogenicity blood 
collection log Group 3 (2 to 6 years) 
 
Week 
Day 
Scheduled 
time point 
following the 
initiation of 
infusion (hr) 
PK collection 
number/Dose 
reference ID 
PK 
sample 
No 
PDa 
sample 
No 
IG sample 
No 
Study part 
sample 
collection 
1 
1 
Pre-dose 
1 
-- 
1 
101 
201 
Part A 
1 
1 
0.5d (± 10 min 
after end of 
infusion) 
1 
-- 
2 
-- 
-- 
Part A 
1 
2 
24 (± 2 hr) 
1 
-- 
5 
-- 
-- 
Part A 
2 
1 
168 (± 24 h) 
1 
-- 
7 
105 
-- 
Part A 
3 
1 
Pre-dose 
2 
101b 
8 
106 
202 
Part A 
7 
1 
Pre-dose 
3 
201b 
9 
107 
-- 
Part A 
11 
1 
Pre-dose 
4 
301b 
10 
108 
-- 
Part A 
15 c 
1 
Pre-dose 
5 
401b 
11 
109 
203 
Part A 
15 c 
1 
0.5d (± 10 min 
after end of 
infusion) 
5 
-- 
12 
-- 
-- 
Part A 
15 c 
2 
24 (± 2 hr) 
5 
-- 
15 
-- 
-- 
Part A 
16 c 
1 
168 (± 24 h) 
5 
-- 
17 
113 
-- 
Part A 
17 c 
1 
336 (± 24 h) 
5 
-- 
18 
114 
-- 
Part A 
18 c 
1 
504 (± 24 h) 
5 
-- 
19 
115 
-- 
Part A 
19 c 
1 
Pre-dose 
6 
501b 
20 
116 
-- 
Part A 
23 
1 
Pre-dose 
7 
601b 
21 
117 
-- 
Part A 
27 
1 
Pre-dose 
8 
701b 
22 
118 
204 
Part A 
31 
1 
Pre-dose 
9 
801b 
23 
119 
-- 
Part A 
35 
1 
Pre-dose 
10 
901b 
24 
120 
-- 
Part A 
39 
1 
Pre-dose 
11 
1001b 
25 
121 
-- 
Part A 
43 
1 
Pre-dose 
12 
1101b 
26 
122 
-- 
Part A 
47 
1 
Pre-dose 
13 
1201b 
27 
123 
-- 
Part A 
51 
1 
Pre-dose 
14 
1301b 
28 
124 
-- 
Part A 






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8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained. 
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s). 
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the participant’s CRF. Adverse event monitoring 
should be continued for 105 days (or 5 half-lives) following the last dose of study treatment, 
except for participants continuing crizanlizumab after their EOT visit, via commercial supply 
or post-trial access (e.g., enrollment in a Novartis roll-over protocol or in a non-trial setting to 
provide continued drug treatment). For these participants, monitoring of adverse events as part 
of this study will stop from the time the participant performed EOT visit. Adverse events 
(including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. When a clear 
diagnosis cannot be identified, each sign or symptom should be reported as a separate Adverse 
Event. 
Adverse events will be assessed and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 5. 
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
life-threatening and death related to the AE corresponding respectively to Grades 1 - 5, will be 
used. Information about any deaths (related to an Adverse Event or not) will also be collected 
though a Death form. 
The occurrence of adverse events should be sought by non-directive questioning of the 
participant during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the participant 
during the screening process or between visits, or through physical examination, laboratory test, 
or other assessments. As far as possible, each adverse event should be evaluated to determine: 
1. The severity grade (CTCAE Grade 1-5) 
2. Its duration (Start and end dates) 
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) 
4. Action taken with respect to study treatment (none, temporarily interrupted, dose reduced, 
permanently discontinued, unknown, not applicable) 
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
6. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1 
and which seriousness criteria have been met 


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Protocol No. CSEG101B2201 
 
7. Outcome 
If an event worsens in severity, the same event should be reported a second time in the CRF 
noting the start date when the event worsened in severity. For grade 3 and 4 adverse events 
only, if improvement to a lower grade is determined, a new entry for this event should be 
reported in the CRF noting the start date when the event improved from having been Grade 3 
or Grade 4. 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded accordingly on the Adverse Event CRF page. 
Once an adverse event is detected, it should be followed-up until its resolution or until it is 
judged to be not recovered/not resolved (e.g., continuing at the end of the study), and assessment 
should be made at each visit (or more frequently, if necessary) on any changes in severity, on 
suspected relationship to the study treatment, on the interventions required to treat it, and on the 
outcome. 
Vaso-occlusive crisis (including fatal outcomes), if documented by use of appropriate method 
(for example, as per VOC Event page), should not be reported as a serious adverse event, please 
refer to Section 8.3. 
8.1.2 
Laboratory test abnormalities 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events CRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g., anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event. 
Laboratory abnormalities that do not meet the definition of an adverse event should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such. 
8.1.3 
Adverse events of special interest 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may be 
appropriate. Such events may require further investigation in order to characterize and 
understand them. 


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Protocol No. CSEG101B2201 
 
AESI are defined on the basis of an ongoing review of the safety data. 
8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious adverse event (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 one 
of the following criteria: 
• Is fatal or 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 
• Is medically significant, i.e., defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
Note that hospitalizations for the following reasons should not be reported as serious 
adverse events: 
• VOC or dactylitis event, as defined in the protocol (Section 7.2.1.1) 
• 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 
• Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event. 
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. 


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All reports of study treatment errors and uses outside of what is foreseen in the protocol, 
intentional misuse and abuse of the product are also considered serious adverse event 
irrespective if a clinical event has occurred. 
8.2.2 
Reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until at least 105 days after the participant has stopped study 
treatment must be reported to Novartis safety immediately, without undue delay, but under no 
circumstances later than within 24 hours of obtaining knowledge of the events (Note: If more 
stringent, local regulations regarding reporting timelines prevail), except for participants 
continuing crizanlizumab after their EOT visit, via commercial supply or post-trial access (e.g., 
enrollment in a Novartis roll-over protocol or in a non-trial setting to provide continued drug 
treatment). For these participants, monitoring of adverse events as part of this study will stop 
from the time the participant performed EOT visit. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE, and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). Follow-up information is submitted in the same way as 
the original SAE Report. The follow-up information should describe whether the event has 
resolved or continues, if and how it was treated, and whether the participant continued or 
withdrew from study participation. An SAE occurring at a different time interval or otherwise 
considered completely unrelated to a previously reported one should be reported separately as 
a new event. 
For participants followed until 105 days after last dose of study treatment, any SAEs 
experienced after completion of the 105-day post-treatment follow-up visit should only be 
reported to Novartis if the investigator suspects a causal relationship to the study treatment. 
Information about all SAEs is collected and recorded on the 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 study 
treatment, complete the SAE Report Form in English, and submit the completed form 
immediately, without undue delay, but under no circumstances later than within 24 hours to 
Novartis. Detailed instructions regarding the SAE submission process and requirements for 
signatures are to be found in the investigator folder provided to each site. 
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 Novartis study treatment, an oncology Novartis 
Chief Medical Office and Patient Safety (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 drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with EU Guidance 2011/C 172/01, EU Clinical Trial 


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Regulation (CTR) 536/2014 once transfer is completed or as per national regulatory 
requirements in participating countries. 
8.3 
Protocol Exempt AEs & SAEs 
Protocol Exempt AEs & SAEs are implemented in the SEG101 program. As VOCs are 
considered secondary endpoints for the purpose of evaluation of efficacy, these events 
SHOULD NOT be reported as AEs or SAEs for the purpose of this study and will not be 
considered as SAEs in regard to reporting requirements. Instead, VOCs must be reported on the 
dedicated VOC CRF. 
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 themselves will be reported as AE/SAEs. Details will be 
given in the eCRF completion guidelines. 
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 8 and must be reported to Novartis 
immediately, without undue delay, but under no circumstances later than within 24 hours of 
learning of the new information. 
The events in Table 8-1 are the VOCs that will not be reported as AEs/SAEs. 
However in case a VOC event is suspected to be related to study treatment, and/or resulting in 
a fatal outcome, it will be reported as SAE in addition to the VOC CRF. 
Table 8-1 
List of VOC Events Not Requiring AE/SAE Reporting 
 
VOC* Event 
Uncomplicated vaso-occlusive crisis (VOC)* 
Acute chest syndrome 
Hepatic sequestration 
Splenic sequestration 
Priapism 
*VOC is defined as pain crises (defined as an acute onset of pain for which there is no other medically 
determined explanation other than vaso-occlusion and which requires therapy with oral or parenteral opioids or 
parenteral NSAIDs) as well as other complicated crises, such as ACS, priapism, and hepatic or splenic 
sequestration. 
Dactylitis events will also be covered by the protocol exempt SAEs and AEs. The information 
of VOCs and/or dactylitis events should be placed in their respective CRF forms “Sickle Cell - 
Vaso-Occlusive Crisis (VOC) Event” and/or “Dactylitis” form. 
8.4 
Emergency unblinding of treatment assignment 
Not Applicable. 


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8.5 
Pregnancies 
If a female trial participant becomes pregnant, the study treatment must be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review and sign the pregnancy consent form. This consent form is 
necessary to allow the investigator to collect and report information regarding the pregnancy. 
Once consent for pregnancy follow-up given, information about pregnancy and health of the 
baby will be collected at different times, and until 12 months after the date of delivery (for a 
live birth). 
To ensure participant safety, each pregnancy occurring while the participant is on study 
treatment 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 on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology 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 any 
pregnancy outcome. Any SAE experienced during pregnancy must be reported on the SAE 
Report Form. 
8.6 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the Study treatment CRF irrespective of whether or not associated with an AE/SAE. Study 
treatment errors and uses outside of what is foreseen in the protocol, 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. For more information on AE and SAE definition 
and reporting requirements, please see the respective sections Section 8.1.1 and Section 8.2. 
8.7 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between Investigator’s Brochure updates will 
be communicated in the form of Investigator Notifications. This information will be included 
in the participant informed consent and should be discussed with the participant during the study 
as needed. 


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8.8 
Data Monitoring Committee 
This study will institute 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 be constituted prior to the first dosing 
confirmation for Group 1 in Part A. The DMC will be responsible to regularly review key safety 
and PK data prior to opening the next age group and enrolment in part B. 
Specific details regarding composition, responsibilities, meeting frequency, documentation of 
DMC reports, minutes, and recommendations will be described in a separate DMC charter. 
8.9 
Steering Committee 
The steering committee will be established comprising investigators participating in the 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 recommendations for publications of study results including authorship rules. The 
details of the role of the Steering Committee will be defined in a Steering Committee charter. 
 
9 
Data collection and management 
9.1 
Data confidentiality 
Information about study participant will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed participant authorization informing the 
participant of the following: 
• What protected health information (PHI) will be collected from participants in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research participant to revoke their authorization for use of their PHI. 
In the event that a participant revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 
participant authorization. For participants that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect follow-up safety information (e.g., has 
the participant experienced any new or worsened AEs) at the end of their scheduled study period. 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training. 
9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator meeting, Novartis personnel 
(or designated CRO) will review the protocol and CRFs with the investigators and their staff. 


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During the study, Novartis employs several methods of ensuring protocol and GCP compliance 
and the quality/integrity of the sites’ data. The field monitor will perform ongoing source data 
verification to check the completeness of participant records, the accuracy of entries on the 
CRFs, the adherence to the protocol and to Good Clinical Practice, the progress of enrollment, 
and to ensure that study 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. 
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 recorded on CRFs must be traceable to source documents in the 
participant's file. The investigator must also keep the original signed ICF (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 CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria and documentation 
of SAEs, and of data that will be used for all primary variables. Additional checks of the 
consistency of the source data with the CRFs are performed according to the study-specific 
monitoring plan. No information in source documents about the identity of the participants will 
be disclosed. 
9.3 
Data collection 
The designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (CRF). The eCRFs have been built using fully validated secure web-enabled 
software that conforms to 21 Code of Federal Regulations (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 CRFs and, allow 
modification or verification of the entered data by the investigator staff. 
The Principal Investigator is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner. 
Blood/Urine samples for safety laboratory data, blood samples for 
, PK, 
PD and IG analysis, will be collected by sites and sent to the Novartis designated central 
laboratory for processing. The laboratory results will be sent electronically to Novartis. 
ECG data will be collected at the sites and the data will be transmitted to a designated CRO for 
centralized analysis, as well as further processing. 
Data entered into IRT will be transferred electronically to Novartis according to the 
specifications described in the Data Transfer Specifications for the designated IRT vendor. 
9.4 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered in the CRFs 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 


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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. 
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO). 
Dates of screening, enrollment, screen failures and study completion, as well as data about all 
study treatments dispensed to the participant and all IRT assigned dosage changes/interruptions 
will be tracked using IRT. The system will be supplied by a vendor(s), who will also manage 
the database. The data will be sent electronically to Novartis personnel (or designated CRO). 
The occurrence of any protocol violations will be determined. After these actions have been 
completed and the data has been verified to be complete and accurate, the database will be 
declared locked and made available for data analysis. Authorization is required prior to making 
any database changes to locked data, by joint written agreement between the Global Head of 
Biostatistics and Data Management and the Global Head of Clinical Development. 
For EDC studies, after final database lock, the investigator will receive a CD-ROM or paper 
copies of the participant data for archiving at the investigational site. 
 
10 
Statistical methods and data analysis 
There will be multiple cut-off dates and formal analysis during this trial. 
• The cut-off for the first dose PK analysis for Part A of each group will occur when at least 
6 participants with evaluable PK have been enrolled in Part A and have completed the Week 
7 Day 1 visit. This evaluation would be based on PK, dose, demography, other baseline 
characteristics data and key safety data (mainly AEs). If for a given age group the dose is 
not confirmed, then another group of participants will be recruited and an additional cut-off 
will be defined. 
• The cut-off for the multiple dose analysis for Part A of each group (participants > 24 months) 
will occur when at least 6 participants with evaluable PK and PD have been enrolled in Part 
A and have completed multiple dose PK/PD sampling. This evaluation would be based on 
PK, PD, dose, demography, other baseline characteristics and key safety data. 
• The cut-off for the primary analysis for Part A+B of Group 1 and 2 will occur after the 
multiple dose analysis and when all the participants enrolled in that group have completed 
the first 26-weeks of treatment period or discontinued the study treatment in that group. The 
intent is to be able to evaluate data for participants from each group without having to wait 
for next group. However, should the cut-off dates for groups 1 and 2 be close to each other, 
the primary analyses time points will be grouped together. At the time of the primary 
analysis for Parts A+B of group 1 and 2, available data of the other groups up to the same 
cutoff date may be included in the reporting, if needed to support regulatory filings or 
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2) Participant does not have a transfusion of blood product in the last 4 weeks before the pre- 
dose sample. 
If the planned dose is newly defined, the new dose group will be added to the PAS1 accordingly. 
The Pharmacokinetic Analysis Set 2 (PAS2) includes all participants of part A and part B who 
receive at least one dose of crizanlizumab and provide at least one corresponding evaluable PK 
concentration. A pre-dose concentration is considered evaluable if not flagged out by 
pharmacokineticist. 
10.1.6 
Other analysis sets 
The Pharmacodynamics Analysis Set 1 (PDS1) includes all participants of part A 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 other tested dose before single 
dose PD profile or before multiple dose PD profile 
• Participant 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 
If the planned dose is newly defined, the new dose group will be added to the PDS1 accordingly. 
The Pharmacodynamics Analysis Set 2 (PDS2) includes all participants of part A and B who 
receive at least one dose of crizanlizumab and provide at least one corresponding evaluable PD 
assessment.  A  %  inhibition  value  is  considered  evaluable  if  not  flagged  out  by 
pharmacokineticist. 
The Pharmacokinetic-Pharmacodynamics Analysis Set (PKPDS) includes all participants of 
part A and B included in the Safety set who have at least one measured pre-dose concentration 
and one matching P-selectin % inhibition value. 
10.1.6.1 Efficacy/evaluable set 
Not Applicable. 
10.2 
Participant demographics/other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by age group for the Safety Set. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum and maximum values will be presented. 
Relevant medical history at baseline will be summarized by system organ class, preferred term 
and age group. 


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10.3 
Treatments (study treatment, concomitant therapies, 
compliance) 
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 drug 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 (interruptions i.e. fully skipped infusions, or 
reductions derived based on dose change records i.e. partially administrated doses or dosing 
error) and the reasons will be summarized by age 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 age group. 
10.4 
Primary objective 
The primary objectives of this trial are to confirm and establish the appropriate dosing in 
participants ages 2 to <18 years (Part A) and to evaluate the safety of SEG101 in participants 
aged 2 to <18 years (Part A for group 3 and Parts A+B for group 1 and 2). 
The cut-off for the analysis for Part A of each group will occur when at least 6 participants with 
evaluable PK and PD have been enrolled in Part A and have completed the multiple dose PK/PD 
sampling (at Week 15 or later). If for a given group the dose is not confirmed, then an additional 
cut-off will be defined. 
The cut-off for the primary analysis for Parts A+B of group 1 will occur after the multiple dose 
analysis for Part A of group 1 and when all participants aged 12 years and above at the time of 
study entry have completed the first 26-week of the treatment period or discontinued the study 
treatment. The cut-off for the primary analysis for Parts A+B of group 2 will occur after the 
multiple dose analysis for Part A of group 2 and when all participants aged 6 years to <12 years 
at the time of study entry have completed the first 26-week of the treatment period or 
discontinued the study treatment. 
However, in case the cut-off dates for groups 1 and 2 or groups 1, 2 and 3 will be close to each 
other, the analyses time points will be grouped together. 
10.4.1 
Variable 
Part A: 
The primary PK/PD variables of Part A are the PK and PD parameters after single dose and 
after multiple doses. 


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Primary PK Parameters 
AUCd15 (week 1) after first dose, AUCtau after multiple dose, Cmax 
The remaining PK parameters will be analyzed as secondary variables. 
Primary PD Parameters 
PD-AUCd15 (week 1) after first dose, PD-AUCtau after multiple dose. 
Parts A and B: 
1) Pre-dose PK concentrations from week 1 to week 19. 
Pre-dose PD % inhibition from week 3 to week 19 will be analyzed as secondary variables. 
2) The primary safety endpoint for Part A and B of all age groups is the frequency of participants 
with  any  adverse  events  during  the  on-treatment  period  (as  defined  in 
Section 10.5.3.1). 
10.4.2 
Statistical hypothesis, model, and method of analysis 
Primary PK/PD analysis 
Part A (patients from 24 months to < 18 years): 
In order to confirm and establish appropriate dosing, the following methods will be used for 
each group and the defined dose: 
For each group and defined dose, geometric means of the primary PK parameters will be derived 
for participants included in the PAS1. For group 1 these PK parameters will be compared 
against observed adult PK parameters of study CSEG101A2202; for the other groups these 
parameters will be compared to predicted PK parameters for these participants derived from 
adult from the population PK model. 
Geometric mean ratio of observed (test) versus reference primary PK parameters and its 90% 
confidence interval will be derived and compared against the boundaries of 2 and 0.5, 
respectively. If the 90% confidence intervals of both PK parameters are within the boundaries, 
it is considered that there is no meaningful change in exposure versus the reference. 
For estimation, a linear model will be fitted to the log-transformed PK parameters, mean and 
90% confidence intervals will be estimated, and, finally, back-transformed to retain the 
geometric means and ratios and their respective 90% confidence intervals. 
The data to be used for developing the population PK model will come from pooled study data 
of the previous studies. PK parameter prediction will be based on the population PK model. 
Methods will be specified and detailed in a separate document. 
For each group and defined dose, geometric means of the primary PD parameters will be derived 
for participants included in the PDS1. Theses parameters will be compared against predicted 
PD parameters for these participants. For group 1 PD parameters will be compared against adult 
PD parameters of study CSEG101A2202. 


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Geometric mean ratio of observed (test) versus predicted (reference) PD parameters and its 95% 
confidence interval will be derived. 
For estimation a linear model will be fitted to the log-transformed PD parameters, mean and 95% 
confidence intervals will be estimated, and, finally, back-transformed to retain the geometric 
means and ratios and their respective 95% confidence intervals. 
Primary safety analysis 
Part A+B (all age groups): 
Number and percentage of participants with any adverse events will be provided by age group, 
and by starting dose within each age group (if applicable). 
10.4.3 
Handling of missing values/censoring/discontinuations 
Missing values for any PK parameters or concentrations will not be imputed and will be treated 
as missing. 
Below the limit of quantitation (BLQ) values for PK concentrations will be set to zero by the 
Bioanalyst, and will be displayed in the listings as zero and flagged. BLQ values will be treated 
as missing for the calculation of the geometric means and geometric CV%. 
Missing values for the P-selectin inhibition will not be imputed and will be treated as missing. 
Details of the imputations rules for missing start and end dates or AE will be provided in the 
SAP. 
10.4.4 
Supportive and Sensitivity analyses 
Part A: 
Not Applicable. 
Part A and B: 
Not Applicable. 
10.5 
Secondary objectives 
The secondary objectives are to assess the Long-term efficacy of crizanlizumab and to assess 
other safety measures in 2 to < 18 year old participants. 
10.5.1 
Key secondary objective(s) 
Not Applicable. 
10.5.2 
Other secondary efficacy objectives 
VOC 
VOC includes pain crises (defined as an acute onset of pain for which there is no other medically 
determined explanation other than vaso-occlusion and which requires therapy with oral or 


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parenteral opioids or parenteral NSAID) as well as other complicated crises, such as ACS, 
priapism, and hepatic or splenic sequestration. The occurrence of VOC events will be recorded 
in the case report form. 
The number of VOCs leading to healthcare visit in clinic/ER/hospital will be summarized 
descriptively by age group in the FAS. The number of participants with 0 events will be 
presented. Summaries will be provided for the corresponding annualized rate of VOC leading 
to healthcare visit in clinic/ER/hospital overall and per year. 
 
where End date is defined as the minimum of (last dose date until treatment discontinuation + 
27 days, date of 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, cut-off date). 
The change from baseline of the annualized rate of VOC leading to healthcare visit in 
clinic/ER/hospital will be provided overall and per year and corresponding figures (e.g., 
spaghetti plot) may be proposed in the analysis plan. The baseline annualized rate of VOC will 
be defined as the number of VOCs leading to healthcare visit reported in the last 12 months in 
the eCRF. 
Despite all attempt to ensure complete follow-up for all participants, some participants may not 
be followed for VOC for the whole planned study duration. The annualized rate of VOC 
calculation will account for early discontinuation by extrapolating the VOC rate of every 
participant to one year. All VOC occurring until the End date will be taken into account in the 
summaries. If a participant initiates or discontinues HU/HC or L-glutamine (or other therapies 
to treat SCD and or to prevent/reduce VOCs such as voxelotor and erythropoietin) during the 
study, VOC occurring after the initiation/discontinuation of such therapy will not be taken into 
account in the analyses. A sensitivity analysis will be performed, including the crises post 
initiation/discontinuation of HU/HC or L-glutamine (or other therapies to treat SCD and or to 
prevent/reduce VOCs such as voxelotor and erythropoietin) in the numerator and the 
corresponding duration of extra follow-up in the denominator 
Subgroup analyses will be performed by HU/HC use at time of study entry and number of VOC 
leading to healthcare visit at baseline. 
The same analyses will be repeated for the number of VOCs treated at home based on 
documentation by health care provider following phone contact with participant, for the number 
of VOCs leading to healthcare visit and treated at home combined and for each subcategory of 
VOC event (uncomplicated pain crisis, acute chest syndrome, hepatic sequestration, splenic 
sequestration, and priapism) leading to healthcare visit in clinic/ER/hospital and treated at home 
combined or separately. 
Time to first occurrence of VOC will be summarized by age group using Kaplan-Meier 
methods. Median time, 25th and 75th percentiles will be summarized and Kaplan-Meier plots 
will be generated. The time to first occurrence of VOC will be defined as the time from the date 
of the first dose of study treatment to the date of the first occurrence of the VOC. In the absence 
of a VOC, participants will be censored. 


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Dactylitis 
The number of dactylitis events will be summarized descriptively in the FAS for participants 
from 2 to < 6 years of age (Group 3). Summaries will be provided for the corresponding 
annualized rate of dactylitis events overall and per year, defined in the same way as the 
annualized rate of VOC. The change from baseline of the annualized rate of dactylitis events 
will be provided and corresponding figures may be proposed in the analysis plan. 
Subgroup analyses will be performed by HU/HC use, number of dactylitis at baseline. 
Hospitalization 
The number of hospitalizations and ER visits (both overall and VOC-related) will be 
summarized descriptively by age group in the FAS. Summaries will be provided for the 
corresponding annualized rate of hospitalizations and ER visits overall and per year, defined in 
the same way as the annualized rate of VOC. The change from baseline of the annualized rate 
will be provided and corresponding figures may be proposed in the analysis plan. 
Subgroup analyses will be performed by HU/HC use. 
The number of days of ER/hospitalization (both total and VOC-related) will be summarized 
descriptively by age group in the FAS. Summaries will be provided for the corresponding 
annualized rate of days hospitalized overall and per year. 
Chest X-ray 
The data on the chest X-ray will be listed and notable findings will be flagged. 
10.5.3 
Other safety objectives 
10.5.3.1 Analysis set and grouping for the analyses 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
age group. If the target dose is different within a given age group (dose not confirmed in Part 
A for the participants enrolled) then the safety analyses may be repeated by starting dose within 
each age group for key selected analyses 
The overall observation period will be divided into three mutually exclusive segments: 
• pre-treatment period: from day of participant’s informed consent to the day before first dose 
of study medication 
• 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) 
• 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 
post-trial access). 
10.5.3.2 Adverse events (AEs) 
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs. 


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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 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. 
10.5.3.3 Laboratory abnormalities 
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 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 overtime will be provided. 
In addition to the above mentioned tables and listings, 
, 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 liver function tests will be performed and described 
in the analysis plan. 


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10.5.3.4 Other safety data 
ECG 
12-lead ECGs including PR, QRS, QT, QTcF, QTcB, RR 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. 
The number and percentage of participants with notable ECG values will be presented. In 
addition, a listing of these participants will be produced. 
Vital signs 
Data on vital signs will be tabulated and listed, notable values will be flagged. 
Growth and sexual maturation 
Data on growth and sexual maturation (Tanner stage) will be tabulated and listed. 
10.5.3.5 Tolerability 
Refer to Section 10.5.3 and Section 10.5.8. 
10.5.4 
Pharmacokinetics and Pharmacodynamics 
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 10-1 except Tmax. Since Tmax is generally evaluated by a nonparametric method, 
median values and ranges will be given for this parameter, where only n, median, minimum and 
maximum will be presented. Zero concentrations will not be included in the geometric mean 
calculation. This summary will be provided by weight-adjusted dose and by group for the PAS1 
and by weight-adjusted dose and by age group for the PAS2. 
PK 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. 
Table 10-1 
Noncompartmental pharmacokinetic and pharmacodynamic 
parameter 
 
AUCd15 
The AUC from time zero to the last measurable concentration sampling time (tlast) 
or dosing interval (mass x time x volume-1) following the first dose 
AUCtau 
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x 
time x volume-1) 
PD-AUCd15 
The AUC of %inhibition from time zero to the last measurable inhibition sampling 
time (tlast)following the first dose 
PD-AUCtau 
The AUC of %inhibition calculated to the end of a dosing interval (tau) after multiple 
dose 
Cmax 
The maximum (peak) observed, serum, drug concentration after single or multiple 
dose administration (mass x volume-1) 
Tmax 
The time to reach maximum (peak), serum, drug concentration after single or 
multiple dose administration (time) 


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Lambda_z 
Smallest (slowest) disposition (hybrid) rate constant (time-1) may also be used for 
terminal elimination rate constant (time-1) 
T1/2 
The half-life during a dosing interval (time). 
The following analyses will be done by weight-adjusted dose and by age group. 
Descriptive statistics for crizanlizumab concentration will be presented at each scheduled time 
point. 
All individual concentration-time profiles for crizanlizumab with median will be displayed 
graphically on semi-log view after single and multiple doses respectively. 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. 
All individual pre-dose concentrations for crizanlizumab with median will be displayed 
graphically on semi-log view over time. In addition, the mean (± SD) and median pre-dose 
concentrations over time will be displayed graphically on the linear and semi-log view. 
Descriptive statistics for P-selectin inhibition will be presented at each scheduled time point. 
All individual inhibition-time profiles with median will be displayed graphically on semi-log 
view after single and multiple doses respectively. 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. 
Median pre-dose inhibition will be displayed graphically on semi-log view over time. In 
addition, the mean (±SD) and median pre-dose inhibition over time will be displayed 
graphically on the linear and semi-log view. 
10.5.4.1 Data handling principles 
Refer to Section 10.4.3 
 
 
 
10.5.6 
Resource utilization 
Refer to Section 10.5.2 
10.5.7 
Patient-reported outcomes 
Not Applicable. 
10.5.8 
Immunogenicity 
Immunogenicity will be characterized descriptively tabulating antidrug antibodies (ADA) 
prevalence at baseline and ADA incidence on-treatment. 








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of the Part A and feasibility of enrollment in this younger age group, at least 8 participants will 
be enrolled. 
Table 10-2    Probability to observe at least one AE for different incidence rates 
 
Incidence rate of 
an AE 
Probability that at least one participant 
out of 52 experiences the AE 
Probability that at least one participant 
out of 86 experiences the AE 
1% 
0.41 
0.58 
2% 
0.65 
0.82 
3% 
0.79 
0.93 
4% 
0.88 
0.97 
5% 
0.93 
0.99 
10.9 
Power for analysis of key secondary variables 
Not Applicable. 
 
11 
Ethical considerations and administrative procedures 
11.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, EU CTR 536/2014 once transfer 
is completed, US Code of Federal Regulations Title 21), and with the ethical principles laid 
down in the Declaration of Helsinki. 
11.2 
Responsibilities of the investigator and IRB/IEC/REB 
Before initiating a trial, the trial protocol, the proposed informed consent/assent forms, any 
participant recruitment procedures (e.g., advertisements) and any other written information 
provided to the participant, must be reviewed and approved by a properly constituted 
Institutional 
Review 
Board/Independent 
Ethics 
Committee/Research 
Ethics 
Board 
(IRB/IEC/REB). 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. Protocols and any substantial amendments/modifications to the 
protocol may require Health Authority approval (as per local regulations) prior to initiation 
except for changes necessary to eliminate an immediate hazard to study participants. 
The Investigator will be responsible for the following: 
Signing a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Quality Assurance representatives, designated agents of Novartis, IRBs/IECs/REBs 
and regulatory authorities as required. 


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Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC. 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures. 
Providing oversight of the conduct of the study at the site and adherence to requirements of 21 
CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations. 
Informing Novartis immediately if an inspection of the clinical site is requested by a regulatory 
authority. 
11.3 
Informed consent procedures 
The Investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the participant and/or their legally authorized representative and answer all 
questions regarding the study. Participants must be informed that their participation is voluntary. 
Eligible participants may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent. 
In cases where the participant’s representative(s) gives consent, the participant must be 
informed about the study to the extent possible given his/her level of understanding. 
Informed consent / assent as per local regulations must be obtained before conducting any 
study-specific procedures (i.e. all of the procedures described in the protocol). The process of 
obtaining informed consent should be documented in the participant source documents. The 
medical record must include a statement that written informed consent was obtained before the 
participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. The date when a 
participant’s Informed Consent was actually obtained will also be captured in their CRFs. A 
copy of the ICF(s) must be provided to the participant or their legally authorized representative. 
Novartis will provide to investigators, in a separate document, a proposed ICF that is considered 
appropriate for this study and complies with the requirements of 21 CFR 50, local regulations, 
ICHE6 Good Clinical Practice (GCP) guidelines, privacy and data protection requirements, 
where applicable and regulatory requirements and is considered appropriate for this study. Any 
changes to this ICF suggested by the investigator must be agreed by Novartis before submission 
to the IRB/IEC/REB, and a copy of the approved version must be provided to the Novartis 
monitor after IRB/IEC/REB approval. 
The main ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional additional research. The Investigator or authorized designee will explain 
to each participant the objectives of the additional research. Participants will be told that they 
are free to refuse to participate and may withdraw their consent at any time and for any reason 
during the storage period. A separate signature will be required to document a participant’s 
agreement to allow any remaining specimens to be used for additional research. Participants 
who decline to participate in this optional additional research will have this documented. 


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As per Section 2.7, during a Public Health emergency as declared by Local or Regional 
authorities (i.e. pandemic, epidemic or natural disaster) that may challenge the ability to obtain 
a standard written informed consent due to limits that prevent an on-site visit, Investigator may 
conduct the informed consent discussion remotely (e.g., telephone, videoconference) if 
allowable by a local Heath Authority. Guidance issued by local regulatory bodies on this aspect 
prevail and must be implemented and appropriately documented (e.g., the presence of an 
impartial witness, sign/dating separate ICFs by trial participant and person obtaining informed 
consent, etc.). 
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the participant 
informed consent and should be discussed with the participant upon obtaining consent and also 
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 for parents / legal guardians to give consent for their child 
• Main Study Consent for participants entering adulthood 
Both Main Study Consents include 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 and an ‘Optional consent for activities that may be done outside of the study 
site’. 
• Model Participant Information and Adolescent Assent 12-17 years old 
• Model Participant Information and Adolescent Assent 7-11 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 pregnant participants 
Women of childbearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
11.4 
Data Protection 
Participants will be assigned a unique identifier by Novartis. Any participant records or datasets 
that are transferred to Novartis will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by 
Novartis in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent. 


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The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by Novartis, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. Novartis has appropriate 
processes and policies in place to handle personal data breaches according to applicable privacy 
laws. 
11.5 
Discontinuation of the study 
The study can be terminated by Novartis at any time. 
Reasons for earlier termination may include but not limited to: 
• Major safety reasons: unexpected, significant, or unacceptable safety risk to participants 
enrolled in the study. 
• Decision based on recommendations from applicable board(s) after review of safety 
• Discontinuation of study drug development 
In taking the decision to terminate, Novartis will always consider the participant welfare and 
safety. Should early termination be decided, participants must be seen as soon as possible 
(please refer to Section 7.1) and treated as a participant who discontinued from study treatment 
The investigator will be informed of any additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the participant’s interests. The 
investigator or sponsor depending on local regulation will be responsible for informing 
IRBs/IECs of the early termination of the trial. 
11.6 
Publication of study protocol and results 
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g., clinicaltrials.gov and as required in 
EudraCT before study start. In addition, results of this interventional clinical trial will be 
submitted for publication and posted on a publicly accessible database of clinical study results 
such as the Novartis clinical trial results website (novartisclinicaltrials.com) and all required 
Health Authority websites (e.g., Clinicaltrials.gov, EudraCT or CTIS (Clinical Trials 
Information System) public website once transfer to EU CTR 536/2014 is completed, etc.) after 
study completion (i.e., Last Participant Last Visit (LPLV)) and finalization of the study report. 
Novartis follows the International Committee of Medical Journal Editors (ICMJE) authorship 
guidelines (icmje.org) and other specific guidelines of the journal or congress to which the 
publication will be submitted. 
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations. 
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 


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potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable. 
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to novartis.com. 
Any data analysis carried out independently by the Investigator should be submitted to Novartis 
before publication or presentation. 
Summary results of primary and secondary endpoints will be disclosed based on the global 
LPLV date, since multinational studies are locked and reported based upon the global LPLV. 
11.7 
Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of participant. As part of participating in a Novartis- 
sponsored study, each site will permit authorized representatives of the sponsor(s) and 
regulatory agencies to examine (and when required by applicable law, to copy) clinical records 
for the purposes of quality assurance reviews, audits and evaluation of the study safety and 
progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, participant’s diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, X-rays, and participant files and records 
kept at the pharmacy, at the laboratories, and medico-technical departments involved in the 
clinical trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
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Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines. 
11.8 
Confidentiality of study documents and participants records 
The investigator must ensure anonymity of the participants; participants must not be identified 
by names in any documents submitted to Novartis. Signed ICFs and patient enrollment log must 
be kept strictly confidential to enable participant identification at the site. 
11.9 
Audits and inspections 
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities. 
11.10 
Financial disclosures 
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of participants at the site - prior to study start. 
 
12 
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 the study treatment 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. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR. 
12.1 
Amendments to the protocol 
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/REB prior 
to implementation. 
Only amendments that are required for participant safety may be implemented immediately, 
without prior approval by relevant authorities, provided the Health Authorities and reviewing 


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


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13 
References (available upon request) 
Akinsheye I, Alsultan A, Solovieff N, et al (2011) Fetal hemoglobin in sickle cell anemia. 
Blood; 118(1): 19-27. 
Al Najjar S, Adam S, Ahmed N, et al. (2017) Ann Hematol 96:141–146. 
Ashley-Koch A, Yang Q, Olney RS (2000) Sickle hemoglobin (HbS) allele and sickle cell 
disease: a HuGE review. Am J Epidemiol; 151(9):839-45. 
Ataga KI, Kutlar A, Kanter J (2017) Crizanlizumab for the Prevention of Pain Crises in Sickle 
Cell Disease. N Engl J Med; 376 (5): 429-439. 
Blann AD, Mohan JS, Bareford D, et al (2008) Soluble P-selectin and vascular endothelial 
growth factor in steady state sickle cell disease: relationship to genotype. J Thromb 
Thrombolysis; 25(2):185-9. 
Bookchin RM, Lew VL (1996) Pathophysiology of sickle cell anemia. Hematol Oncol Clin 
North Am; 10(6):1241-53. 
Brandow AM, Carroll CP, Creary S, et al. (2020) American Society of Hematology 2020 
guidelines for sickle cell disease: management of acute and chronic pain. Blood Advances; 
4(12): 2656-701. 
Chai J, Song Q. (2014) Quantitative and multiplexed study of endothelial cell inflammation. 
Cell Biochem Biophys; 70(3):1783-90. 
Charache S (1996) Eye disease in sickling disorders. Hematol Oncol Clin North Am; 
10(6):1357-62. 
Charache S, Terrin ML, Moore RD, et al (1995) Effect of hydroxyurea on the frequency of 
painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in 
Sickle Cell Anemia. N Eng J Med; 332(20):1317-22. 
Chiang EY,Frenette PS (2005) Sickle cell vaso-occlusion. Hematol Oncol Clin North Am; 
19(5):771-84 v. 
Colombatti R, De Bon E, Bertomoro A, et al (2013) Coagulation activation in children with 
sickle cell disease is associated with cerebral small vessel vasculopathy. PLoS One; 25; 
8(10):e78801. 
Embury SH (2004) The not-so-simple process of sickle cell vaso-occlusion. Microcirculation; 
11(2):101-13. 
Ferroni P, Riondino S, Vazzana N, et al (2012) Biomarkers of platelet activation in acute 
coronary syndromes. Thromb Haemost; 108(6):1109-23. 
Frenette PS (2004) Sickle Cell Vaso-occlusion: Heterotypic, Multicellular Aggregations 
Driven by Leukocyte Adhesion. Microcirculation; 11(2): 167-177. 
Geng JG, Bevilacqua MP, Moore KL, et al (1990) Rapid neutrophil adhesion to activated 
endothelium mediated by GMP-140. Nature; 343(6260):757-60. 
Gill FM, Sleeper LA, Weiner SJ, et al (1995) Clinical events in the first decade in a cohort of 
infants with sickle cell disease. Cooperative Study of Sickle Cell Disease. Blood; 86 (2): 776- 
83. 


Novartis 
Amended Protocol Version 06 (Clean) 
Confidential 
Page 154 of 158 
Protocol No. CSEG101B2201 
 
Gladwin MT, Kato GJ (2005) Cardiopulmonary complications of sickle cell disease: role of 
nitric oxide and hemolytic anemia. Hematology Am Soc Hematol Educ Program: 51-7. 
Gladwin MT, Sachdev V, Jison ML, et al (2004) Pulmonary hypertension as a risk factor for 
death in patients with sickle cell disease. N Engl J Med; 350(9): 886-95. 
Hamburger SA, McEver RP (1990) GMP-140 mediates adhesion of stimulated platelets to 
neutrophils. Blood. 75(3): p. 550-4. 
Hanley JA, Lippman-Hand A (1983), If Nothing goes wrong, is everything all right? JAMA; 
249 (13): 1743-1745. 
Hatzipantelis ES, Pana ZD, Gombakis N et al, (2013) Endothelial activation and inflammation 
biomarkers in children and adolescents with sickle cell disease, Int J Hematol 98:158–163 
Heegaard ED, Brown KE (2002) Human parvovirus 819. Clin Microbial Rev; 15(3):485-505. 
Hirschberg R (2010) Glomerular Hyperfiltration in Sickle Cell Disease. Clin J Am Soc 
Nephrol; 5:748-9. 
Inwald DP, Kirkham FJ, Peters MJ, et al (2000) Platelet and leucocyte activation in childhood 
sickle cell disease: association with nocturnal hypoxaemia. Br J Haematol; 111(2):474-81. 
Jones DA, Abbassi O, McIntire LV, et al (1993) P-selectin mediates neutrophil rolling on 
histamine- stimulated endothelial cells. Biophys J; 65(4): p. 1560-9. 
Kanavaki I, Makrythanasis P, Lazaropoulou C, et al. (2012) Adhesion molecules and high- 
sensitivity C-reactive protein levels in patients with sickle cell beta-thalassaemia. Eur J Clin 
Invest; 42(1):27-33. 
Kaul DK,Hebbel RP (2000) Hypoxia/reoxygenation causes inflammatory response in 
transgenic sickle mice but not in normal mice. J Clin Invest; 106(3):411-20. 
Krishnan S, Setty Y, Betal SG, et al. (2010) Increased levels of the inflammatory biomarker 
C-reactive protein at baseline are associated with childhood sickle cell vasocclusive crises. Br 
J Haematol; 148(5):797-804. 
Kutlar A, Embury SH (2014) Cellular adhesion and the endothelium: P-selectin. Hematol 
Oncol Clin North Am; 28(2):323-39. 
Liu Z, Miner JJ, Yago T, et al (2010) Differential regulation of human and murine P-selectin 
expression and function in vivo. J Exp Med; 207(13): p. 2975-87. 
Maitre B, Habibi A, Roudot-Thoraval F, et al (2000) Acute chest syndrome in adults with 
sickle cell disease. Chest; 117(5):1386-92. 
Majumdar S, Webb S, Norcross E, et al. (2013) Stroke with intracranial stenosis is associated 
with increased platelet activation in sickle cell anemia. Pediatr Blood Cancer; 60(7):1192-7. 
Matsui NM, Borsig L, Rosen SD, et al (2001) P-selectin mediates the adhesion of sickle 
erythrocytes to the endothelium. Blood; 98(6):1955-62. 
McClish DK, Penberthy LT, Bovbjerg VE, et al. (2005) Health related quality of life in sickle 
cell patients: The PiSCES project. Health and Quality of Life Outcomes; 3: 50. 
McEver RP, Moore KL, Cummings RD (1995) Leukocyte trafficking mediated by 
selectincarbohydrate interactions. J Biol Chem; 270(19): 11025-8. 




Novartis 
Amended Protocol Version 06 (Clean) 
Confidential 
Page 156 of 158 
Protocol No. CSEG101B2201 
 
Smith WR, Penberthy LT, Bovbjerg VE et al. (2008) Daily assessment of pain in adults with 
sickle cell disease. Ann Int Med; 148: 94-102. 
Souza Jd, Sousa JR, Hirai KE, et al. (2015) E selectin and P-selectin expression in 
endothelium of leprosy skin lesions. Acta Trop; 149:227-31. 
Springer TA (1995) Traffic signals on endothelium for lymphocyte recirculation and 
leukocyte emigration. Annu Rev Physiol; 57: 827-72. 
Stuart MJ, Nagel RL (2004) Sickle-cell disease. Lancet; 364 (9442): 1343-60. 
Thomas PW, Higgs DR, Serjeant GR (1997) Benign clinical course in homozygous sickle cell 
disease: a search for predictors. J Clin Epidemiol; 50(2):121-6. 
Vestweber D, Blanks JE (1999) Mechanisms that regulate the function of the selectins and 
their ligands. Physiol Rev; 79(1): 181-213. 
Vichinsky EP, Neumayr LD, Earles AN, et al (2000) Causes and outcomes of the acute chest 
syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Eng J Med; 
342(25):1855-65. 
Wagner MC, Eckman JR, ick TM (2006) Histamine increases sickle erythrocyte adherence to 
endothelium. Br J Haematol. 132(4): p. 512-22. 
Wethers, DL (2000) Sickle cell disease in childhood: Part II. Diagnosis and treatment of 
major complications and recent advances in treatment. Am Fam Physician; 62(6):1309-14. 
Wood, K., Russell J, Hebbel RP, et al (2004) Differential expression of E- and P-selectin in 
the microvasculature of sickle cell transgenic mice. Microcirculation. 11(4): p. 377-85. 
Yale SH, Nagib N, Guthrie T (2000) Approach to the vaso-occlusive crisis in adults with 
sickle cell disease. Am Fam Physician; 61(5):1349-56, 1363-4. 
aafp.org/afp/2000/0301/p1349.html. 
Yip C, Linden MD, Attard C, et al. (2015) Platelets from children are hyper-responsive to 
activation by thrombin receptor activator peptide and adenosine diphosphate compared to 
platelets from adults. Br J Haematol; 168(4):526-32. 


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Protocol No. CSEG101B2201 
 
14 
Appendices 
14.1 
Appendix 1 - Karnofsky performance Status 
Table 14-1 
Karnofsky performance status scale rating (10%) criteria 
Condition 
Percentage 
Comments 
Able to carry on normal activity and to 
work; no special care needed. 
100 
Normal, no complaints; no evidence of 
disease. 
90 
Able to carry on normal activity; minor signs 
or symptoms of disease. 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
Unable to work; able to live at home and 
care for most personal needs; varying 
amount of assistance needed. 
70 
Cares for self; unable to carry on normal 
activity or to do active work. 
60 
Requires occasional assistance, but is able 
to care for most of his personal needs. 
50 
Requires considerable assistance and 
frequent medical care. 
Unable to care for self; requires 
equivalent of institutional or hospital 
care; disease may be progressing 
rapidly. 
40 
Disabled; requires special care and 
assistance. 
30 
Severely disabled; hospitalization is 
indicated although death not imminent. 
20 
Very sick; active supportive treatment 
necessary. 
10 
Moribund; fatal processes progressing 
rapidly. 
0 
Dead. 


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14.2 
Appendix 2 – The Lansky Play-Performance Status Scale Clinical 
Classification 
Table 14-2 
The Lansky Play-Performance Status Scale Clinical Classification 
rating (10%) criteria 
Rating 
Description 
100 
fully active, normal 
90 
minor restrictions with strenuous physical activity 
80 
active, but gets tired more quickly 
70 
both greater restriction of, and less time spent in, active play 
60 
up and around, but minimal active play; keeps busy with quieter activities 
50 
lying around much of the day, but gets dressed; no active play; participates in all quiet play and 
activities 
40 
mostly in bed; participates in quiet activities 
30 
stuck in bed; needs help even for quiet play 
20 
often sleeping; play is entirely limited to very passive activities 
10 
does not play nor get out of bed 
0 
unresponsive 
 

SAP_001.pdf: 
Clinical Development 
SEG101/Crizanlizumab 
CSEG101B2201 / NCT03474965
A phase 2, Multicenter, Open-Label Study to Assess Appropriate Dosing 
and to Evaluate Safety of Crizanlizumab, with or without 
Hydroxyurea/Hydroxycarbamide, in Sequential, Descending Age Groups 
of Pediatric Sickle Cell Disease Patients with Vaso-Occlusive Crisis 
Statistical Analysis Plan (SAP) 
Document type: 
SAP Documentation 
Document status: 
Final 
Release date: 
15 October, 2024 
Number of pages: 
50 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


Novartis 
SAP Final CSR 
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CSEG101B2201 
 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time point 
Reason for 
update 
Outcome for update 
Section and 
title 
impacted 
(Current) 
24- 
August- 
2018 
Prior 
to 
FPFV 
CSR_1_Primary: 
Creation of final 
version 
N/A - First version 
NA 
21- 
January- 
Prior 
to 
first 
CSR_1_Primary: 
Amendment 
1 
V2.0 
NA 
2019 
 
29 
– 
July 
2019 
analysis 
 
Prior to the 
first single 
dose 
analysis 
Added section on 
DMC 
CSR_1_Primary: 
Amendment 2 
 
 
Updated planned dose window 
for PAS1 
 
 
The disposition summaries for 
all screened patients will not 
be provided. All protocol 
deviations 
are 
already 
analyzed and displayed by 
types in one analysis, there is 
thus no need to redo a 
dedicated table for major 
protocol deviations leading to 
exclusion from analysis sets 
Added the definition for dose 
interruption 
Deleted the text relating to 
urinalysis listing, boxplot for 
hemoglobin 
parameter, 
neutropenia 
and 
thrombocytopenia summaries 
in line with project standards 
for safety assessment and to 
avoid 
overlap 
with 
other 
analyses 
Analyses about liver have been 
updated to take into account 
project standards related to 
known 
liver 
function 
specificities in SCD patients 
 
 
Section 2.2 
 
 
 
Section 2.3 
 
 
 
 
 
 
 
 
 
Section 
2.4.1 
Section 
2.8.3 
 
 
 
 
 
 
 
Section 
2.8.3 


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Date 
Time point 
Reason for 
update 
Outcome for update 
Section and 
title 
impacted 
(Current) 
Deleted the repetition in the 
text 
of 
QTcF 
categories 
provided earlier in the same 
section 
Analysis of protein/creatinine 
ratio is added in line with 
project 
standard 
safety 
analyses 
Updated CTCAE version to 
5.0 
Addressed typographical and 
Section 
2.8.4.1 
 
 
Section 
2.13.2 
 
Throughout 
Throughout 
 
editorial errors 
 
17 
– 
August 
2020 
Prior 
to 
Group 
1 
primary 
analysis 
DBL 
CSR_1_Primary: 
Amendment 3 
Updated reference to protocol 
version. 
Implement 
updates 
from 
protocol v03, mainly: 
• Update and clarify the 
criteria and process for 
dose confirmation in Part 
A of each group. 
• Clarify that at the time of 
primary analysis for each 
group, it will be possible to 
also conduct an analysis of 
data from other groups, if 
needed 
to 
support 
regulatory 
filings 
or 
potential Health Authority 
requests. 
Implement 
updates 
from 
protocol v02 which remain 
valid in protocol v03, mainly: 
• 
 
Section 1 
 
 
 
 
Section 1.1 
 
 
 
Section 2.1 
 
 
 
 
 
 
 
 
 
Sections 
1.2, 
2.2, 
2.5.1 
Section 1.2 




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Date 
Time point 
Reason for 
update 
Outcome for update 
Section and 
title 
impacted 
(Current) 
Clarify the analysis of dose 
interruptions/reductions. 
Update data to be presented as 
per data collected in CRF. 
Clarify the start date of 
concomitant medication to be 
included in summaries, aligned 
with other SEG101 studies. 
Mention and detail separate 
listings will be provided for 
HU/HC, 
L-Glutamine 
and 
Analgesics. 
As per protocol v02-03, the 
analysis of annual rate of VOC 
will 
exclude 
data 
post 
initiation/discontinuation 
of 
HU/HC or L-glutamine. A 
sensitivity 
analysis 
will 
evaluate results with inclusion 
of those data. The end date for 
the VOC analyses is defined 
accordingly. Add clarifications 
for efficacy analysis as needed. 
Add subgroup analyses for 
main efficacy end-points as 
required for SCE. 
Update list of AE summaries 
to accommodate AEs leading 
to 
dose 
reduction, 
for 
consistency 
with 
data 
collection. 
Specify that summary over 
time for change from baseline 
of hemoglobin parameter will 
be performed. Update criteria 
to be used in reviewing and 
presenting hepatic lab values, 
following 
Novartis 
Hepatotoxicity Guideline 2019 
 
 
 
Section 
2.4.2 
 
 
 
 
 
 
Section 
2.7.2 
 
 
 
 
 
 
 
 
 
 
Section 
2.8.1 
 
 
 
 
Section 
2.8.3 
 
and standard output updates. 
 


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Date 
Time point 
Reason for 
update 
Outcome for update 
Section and 
title 
impacted 
(Current) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
21 
– 
May 
2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior 
to 
Group 
2 
multiple 
dose 
analysis 
DBL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CSR_2_Primary: 
Updates 
applicable 
starting from 
Group 2 multiple 
dose analysis, 
Remove 
shift 
table 
for 
leukocytosis by ≤ 100,000 
mm3 vs > 100,000 mm3, 
considering the overlap with 
the shift table by CTC grade 
for this parameter. 
Update vital signs section to 
add head circumference in the 
list of vital sign data collected. 
Add the notable criteria for 
participants 6-12 months and 
clarify 
footnote 
for 
baseline/post-baseline notable 
weight change in Table 2.2. 
 
Add derivation of age at a 
given assessment as it is 
relevant in a study including 
adolescents. 
Address 
typographical 
and 
editorial errors. Updates as per 
SAP template/ LEAN SAP 
principle. Update “subject” or 
“patient” to “participant” to 
align with protocol template. 
Add 
clarifications 
when 
needed. 
Implement 
updates 
from 
protocol v04, mainly: 
• Update definition of 
the on-treatment and 
post-treatment periods, 
as patients continuing 
Section 
2.8.4.2 
 
 
 
 
 
 
Section 
2.13.2 
 
Section 2.12 
 
 
Throughout 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 
2.1.1 
 
 


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Date 
Time point 
Reason for 
update 
Outcome for update 
Section and 
title 
impacted 
(Current) 
unless otherwise 
specified. 
crizanlizumab via 
commercial supply or 
post-trial access will 
not need to be 
followed after their 
EOT. 
Update disposition 
summary accordingly. 
• Clarify definition of 
End date for 
observation period in 
efficacy analyses. 
 
 
 
Section 
2.3.1 
 
Sections 
2.7.1 
and 
2.13.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4 – June 
2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior 
to 
Group 
2 
multiple 
dose DBL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CSR_2_Primary: 
Amendment 1 
Update imputation rule of AE 
start date, once the AE CRF 
will be updated to collect 
precise information on timing 
of infusion related reactions 
(not applicable yet to Group 2 
multiple dose analysis). 
Clarify that shift tables based 
on normal ranges are 
performed only on parameters 
for which normal ranges are 
provided by the laboratory. 
Replace urine protein 
creatinine ratio by urine 
albumin creatinine ratio, as 
per protocol schedule of 
assessment. 
Address typographical and 
editorial errors. 
Clarify the baseline definition 
rule in time window section. 
Remove 
reference 
to 
the 
version of Novartis guidance 
for CTCAE v5, i.e. the latest 
version available at time of the 
analysis will be used. 
Section 
5.1.2 
 
 
 
 
Section 
2.8.3 
 
 
 
 
Section 
2.13.2 
 
Throughout 
 
 
Section 
2.1.1 
 
Section 5.3 
 


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Date 
Time point 
Reason for 
update 
Outcome for update 
Section and 
title 
impacted 
(Current) 
24-Nov- 
2021 
CSR_2_Primary: 
Amendment 2 
Update 
concomitant 
medication 
 
listings: 
Erythropoietin 
simulating 
agent (collected on specific 
page as per updated CRFs) will 
be displayed in separate listing 
(with 
HU/HC 
and 
L- 
glutamine). 
Add summary table of HU/HC 
treatment status at study entry, 
and 
reason 
for 
non- 
administration, as collected on 
“Sickle Cell – Reasons for 
Non-Administration 
of 
HU/HC” CRF 
Clarify definition of baseline 
VOCs leading to healthcare 
visit. Update definition of 
baseline 
hospitalizations/ER 
visits to align with baseline 
VOC definition. 
Replace the parameter name 
“reticulocyte 
count” 
by 
“reticulocyte” (reported in %). 
Section 
2.4.2 
 
 
 
 
 
 
Section 
2.4.2 
 
 
 
Section 
2.7.1 
 
 
 
 
Sections 
2.8.3, 2.13.2 
 
Throughout 
 
 
 
13- 
April- 
2022 
 
 
 
06- 
June- 
2022 
 
 
Prior 
finalization 
of group 1 
primary 
analysis 
CSR 
Prior 
finalization 
of group 1 
analysis 
CSR 
Address typographical and 
editorial errors. 
Amendment 4   To clarify that when an AE has 
a start date before cut-off and 
an end date post cut-off, the 
outcome for this AE should be 
reported as unknown. 
 
Amendment 3   Clarify the definition of End 
date for calculation of the 
annualized 
rate 
of 
VOC, 
dactylitis, hospitalizations and 
transfusions, 
 
 
Sections 2.1 
and 5.1.2 
 
 
 
 
Sections 
2.7.2 
 




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Table of contents 
Table of contents ................................................................................................................ 10 
1 
Introduction ........................................................................................................................ 14 
1.1 
Study design ........................................................................................................... 14 
1.2 
Study objectives and end points ............................................................................. 16 
2 
Statistical methods ............................................................................................................. 18 
2.1 
Data analysis general information .......................................................................... 18 
General analysis conventions ................................................................................. 19 
Unscheduled assessments....................................................................................... 19 
2.1.1 
General definitions ................................................................................ 20 
2.2 
Analysis sets ........................................................................................................... 23 
2.2.1 
Subgroup of interest .............................................................................. 26 
2.3 
Participant disposition, demographics and other baseline characteristics .............. 26 
2.3.1 
Participant disposition ........................................................................... 27 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 28 
2.4.1 
Study treatment / compliance ................................................................ 28 
2.4.2 
Prior, concomitant and post therapies ................................................... 29 
2.5 
Analysis of the primary objective .......................................................................... 30 
2.5.1 
Primary endpoint ................................................................................... 30 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 31 
2.5.3 
Handling missing values/censoring/discontinuations ............................ 31 
2.5.4 
Supportive analyses ............................................................................... 32 
2.6 
Analysis of the key secondary objective ................................................................ 32 
2.7 
Analysis of secondary efficacy objective(s) ........................................................... 32 
2.7.1 
Secondary endpoints .............................................................................. 32 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 32 
2.7.3 
Handling of missing values/censoring/discontinuations ........................ 35 
2.8 
Safety analyses ....................................................................................................... 35 
2.8.1 
Adverse events (AEs) ............................................................................ 35 
2.8.1.1 Adverse events of special interest (AESI) .............................. 36 
2.8.2 
Deaths .................................................................................................... 36 
2.8.3 
Laboratory data ...................................................................................... 36 
2.8.4 
Other safety data .................................................................................... 38 
2.8.4.1 ECG and cardiac imaging data ............................................... 38 
2.8.4.2 Vital signs ............................................................................... 39 
2.8.4.3 Growth and sexual maturation ................................................ 42 
2.8.4.4 Immunogenicity ...................................................................... 42 




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List of abbreviations 
ADA 
Anti-Drug Antibody 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Curve 
BLQ 
Below the limit of quantitation 
BMS 
Body mass index 
CD40L 
CD40 Ligand 
CM 
Concomitant Medications 
CRP 
C-Reactive Protein 
CSR 
Clinical Study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
DI 
Dose intensity 
DAR 
Dosage Administration Record 
DRL 
Drug Reference Listing 
ECG 
Electrocardiogram 
(e)CRF 
Electronic Case Report Form 
EA 
Early access 
ER 
Emergency Room 
ET 
Endothelin 
FAS 
Full Analysis Set 
HU/HC 
Hydroxyurea/Hydroxycarbamide 
HLGT 
High level group terms 
HLT 
High level terms 
ICAM 
Intercellular Adhesion Molecule 
IL 
Interleukin 
i.v. 
intravenous(ly) 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
MIP-1a 
Macrophage Inflammatory Protein 1-alpha 
NCI 
National Cancer Institute 
NMQ 
Novartis MedDRA queries 
PAI-1 
Plasminogen Activator Inhibitor-1 Antigen 
PD 
Pharmacodynamics 
PDI 
Planned dose intensity 
PK 
Pharmacokinetics 
PKPDS 
Pharmacokinetic-Pharmacodynamics Analysis Set 
PT 
Preferred term 


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RDI 
Relative dose intensity 
SAE 
Serious adverse events 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SMQ 
Standardized MedDRA queries 
SOC 
System Organ Class 
TAT 
Thrombin Antithrombin Complexes 
TBL 
Total Bilirubin 
TNF 
Tumor Necrosis Factor Alpha 
TSP1 
Thrombospondin-1 
ULN 
Upper Limit Normal 
VCAM 
Vascular Cell Adhesion Molecule 
VOC 
Vaso-Occlusive Crisis 
vWF 
von Willebrand factor antigen 
WHO 
World Health Organization 


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1 
Introduction 
This statistical analysis plan (SAP) describes all planned analyses for the clinical study report(s) 
(CSR) of study CSEG101B2201, a Phase II, multicenter, open-label study to confirm and to 
establish appropriate dosing and to evaluate the safety in pediatric participants aged 2 to <18 
years receiving crizanlizumab for up to 2 years. 
The content of this SAP is based on protocol CSEG101B2201 version 06. All decisions as 
defined in the present SAP document, are applicable starting from Group 2 multiple dose DMC 
analysis (post Group 1 primary CSR), unless otherwise specified. 
1.1 
Study design 
This is a multicenter, single-arm, open-label study to confirm and to establish appropriate 
dosing and to collect safety data in pediatric participants aged 2 to <18 years receiving 
crizanlizumab for up to 2 years. 
In Part A of the study across the ages 2 to <18 years, the dose for each group will be first 
confirmed on the basis of single & multiple dose PK data and key safety data from an initial 
subgroup of participants. In Part B of Group 1 and Group 2, safety and efficacy data will be 
collected from additional participants from 6 to <18 years. 
At least 100 participants are planned to be enrolled in the trial in total, split in 3 age groups: 
• Group 1 (age 12 to <18 years): at least 26 participants (at least 8 in Part A and at least 18 
in Part B), 
• Group 2 (age 6 to <12 years): at least 26 participants (at least 8 in Part A and at least 18 in 
Part B), 
• Group 3 (age 2 to <6 years): at least 8 participants (in Part A) 
• The remaining participants needed to achieve a total of at least 100 are planned to be 
recruited via trial Part B in either Group 1 or 2 age groups defined above without 
restriction. 
All participants will receive SEG101. The first participants enrolled in Group 1 via trial Part A 
will receive SEG101 at 5.0 mg/kg intravenous (IV) on Week 1 Day 1, Week 3 Day 1 and then 
every 4 weeks. Full PK/Pharmacodynamics (PD) sampling will occur following the first dose 
and at presumed steady state. Those enrolled participants are expected to provide at least 6 
evaluable participants for first dose PK evaluation. 
Dose confirmation decision for each group will be based on: i) comparability of first dose 
pediatric PK results of evaluable participants compared against observed adult PK data (Group 
1) or predicted exposure from adult popPK model with matching pediatric covariates (Groups 
2 and 3), ii) key safety results up to the cut-off date of the single dose analysis, and iii) Novartis’s 
assessment, in conjunction with DMC recommendations and in light of all available relevant 
data, to either confirm the test dose or to evaluate a potentially more appropriate dose. 
At the time of the single dose PK analysis for Group 1 Part A, PK results will be compared to 
the exposure level observed in adults from the CSEG101A2202 study. Key safety data collected 
till the time of the cut-off for all the participants enrolled in Group 1 Part A will be evaluated. 
These PK and safety results will be reviewed by Novartis and DMC. 




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1.2 
Study objectives and end points 
 
Objective 
Endpoint 
Analysis 
Primary 
To confirm and establish 
appropriate dosing of 
crizanlizumab in 
participants aged 2 to <18 
years at the time of study 
entry (Part A and B) 
Participants aged 2 to <18 years (Part A) 
-PK parameters after the starting dose and 
at multiple dose 
-PD Parameter (%P-Selectin inhibition) 
after starting dose and at multiple dose 
Refer to 
Section 2.5 
 
To evaluate the safety of 
crizanlizumab in 
participants aged 2 to <18 
years at the time of study 
entry (Parts A and B) 
Secondary 
To assess the long-term 
efficacy of crizanlizumab in 
participants aged 2 to < 18 
year old participants at the 
time of study entry (Parts A 
and B) 
 
 
 
 
 
 
 
 
 
 
 
 
To assess other safety 
measures in participants 
aged 2 to < 18 years at the 
time of study entry 
 
- Frequency of any adverse events (AE) 
 
 
 
 
- Annualized rate of Vaso-Occlusive Crisis 
(VOC) events leading to healthcare visit in 
clinic/Emergency Room (ER)/hospital 
- Annualized rate of VOC events treated at 
home (based on documentation by health 
care provider following phone contact with 
participant) 
- Annualized rate of each subcategory of 
VOC event (uncomplicated pain crisis, 
acute chest syndrome, hepatic 
sequestration, splenic sequestration, 
priapism) 
- Annualized rate of hospitalizations and 
ER visits (both overall and VOC-related) 
- Annualized rate of days of ER/ 
hospitalization (both overall and VOC- 
related) 
- Annualized rate of dactylitis events 
- Number, seriousness, severity, and 
causality assessments of treatment 
emergent AEs and other safety data as 
considered appropriate 
- Absolute change from baseline in 
hemoglobin 
- Immunogenicity: measurement of anti- 
drug antibodies (ADA) to crizanlizumab 
Refer to 
Section 2.8 
 
 
 
 
Refer to 
Section 2.7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Refer to 
Section 2.8 


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Objective 
Endpoint 
Analysis 
- ECGs at relevant PK time points 
- Growth and sexual maturation 
assessments (Tanner stage) 
 
 
 
 
Characterize long-term PK 
and PD of crizanlizumab in 
participants aged 2 to <18 
years at the time of study 
entry. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
- Trough (pre-dose) concentrations prior to 
each study drug dose. 
- % P-Selectin inhibition prior to dosing 
 
 
Refer to 
Section 2.10 
 
 
 
 




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All events with start date before or on the cut-off date and end date after the cut-off date will be 
reported as ‘ongoing’. The same rule will be applied to events starting before or on the cut-off 
date and not having documented end date. This approach applies, in particular, to AE and 
concomitant medication (CM) reports. For these events, the end date will not be imputed and 
therefore will not appear in the listings. 
 
The additional data for any participants continuing to receive study treatment, as allowed 
by the protocol, will be further summarized in a final study report once all participants from 
all groups included in the trial (aged 2 to <18 years), have completed or early discontinued 
from the study. 
General analysis conventions 
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small number of participants enrolled at each center, no center 
effect will be assessed. 
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables 
by age group and by starting dose within each age group as applicable; a missing category will 
be included as applicable. Percentages will be calculated using the number of participants in the 
relevant population or subgroup as the denominator. 
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate descriptive 
statistics (i.e. mean, standard deviation, median, minimum, maximum, 1st quartile and 3rd 
quartile) by age group and by starting dose within each age group as applicable. 
For PK concentration and PK parameters, CV%, geometric mean, and geometric CV% will be 
presented in addition to the previously mentioned summary statistics. 
Coefficient of variation (CV) (%) is calculated as follows: 
100*(Standard deviation (SD)/arithmetic mean). 
Geometric CV (%) is calculated as follows: 
sqrt (exp (variance for log transformed data)-1)*100. 
Unscheduled assessments 
The following points summarize the rules for unscheduled assessments, unless otherwise 
specified: 
• Baseline: All unscheduled assessments before the first dose should be included for 
consideration when calculating the baseline value. 
• In summary tables by visit, unscheduled assessments should not be included unless they 
qualify as baseline. 
• In shift and abnormality tables, all unscheduled assessments are included. 
Unscheduled assessments will be reported with the scheduled assessments in the listings. 


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2.1.1 
General definitions 
Investigational drug and study treatment 
Investigational drug will refer to SEG101. The term investigational treatment may also be 
referred to as study treatment which is used throughout this document. 
Date of first administration of investigational drug 
The date of first administration of investigational drug is defined as the first date when a nonzero 
dose of investigational drug is administered and recorded on the Study Treatment – Infusion 
(e)CRF. The date of first administration of investigational drug will also be referred as start of 
investigational drug. 
Date of last administration of investigational drug 
The date of last administration of investigational drug is defined as the last date when a nonzero 
dose of investigational drug is administered and recorded on the Study Treatment - infusion 
(e)CRF. The date of last administration of investigational drug will also be referred as end of 
investigational drug. 
Date of first administration of study treatment 
The date of first administration of study treatment is derived as the first date when a nonzero 
dose of study treatment was administered as per the Study treatment- infusion (e)CRF. The date 
of first administration of study treatment will also be referred as start of study treatment. 
The date of first administration of study treatment is the same as the date of first administration 
of investigational drug. 
Date of last administration of study treatment 
The date of last administration of study treatment is defined as the last date when a nonzero 
dose of study treatment was administered as per the Study Treatment- infusion (e)CRF. 
The date of last administration of study treatment is the same as the date of last administration 
of investigational drug. 
Study day 
Study day 1 for all assessments is taken to be the start of study treatment. 
The study day for all assessments will be calculated as follows: 
1. If date of assessment occurred on or after the start of study treatment, then 
Study day = Date of assessment - Start of study treatment + 1. 
2. If date of assessment occurred before the start of study treatment, then 
Study day = Date of assessment - Start of study treatment. 
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative. 


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Time unit 
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration 
is reported in months, duration in days will be divided by 30.4375. If duration is reported in 
years, duration in days will be divided by 365.25. 
Baseline 
For safety evaluations, the last available assessment on or before the date of start of study 
treatment is taken as ‘‘baseline” assessment. In case time of assessment and time of treatment 
start is captured, the last available assessment before the treatment start date/time is used for 
baseline. 
For safety parameters (e.g. Electrocardiogram (ECG)), where the study requires multiple 
replicates per time point, the average of these measurements would be calculated (if not already 
available in the database) before determining baseline. 
In rare cases where multiple measurements meet the baseline definition, with no further flag or 
label that can identify the chronological order, then the following rule should be applied: If 
values are from central and local laboratories, the value from central assessment should be 
considered as baseline. If multiple values are from the same laboratory (local or central), then 
the last value should be considered as baseline. In case of ECG’s these measurements are the 
average of triplicates. 
If participants have no value as defined above, the baseline result will be missing. 
For safety parameters other than ECG, scheduled pre-dose collections as well as unscheduled 
collections on Day 1 for which no time is available will be considered as pre-dose. 
For ECG, study Day 1 scheduled pre-dose ECGs will be considered to have been obtained prior 
to start of study treatment if dosing time or ECG time is missing and used in the calculation of 
the baseline value. If a scheduled pre-dose measurement actually occurred post-dose, then the 
corresponding measurement will be treated and analyzed similar to an unscheduled post-dose 
measurement. 
On-treatment assessment/event and observation periods 
The overall observation period will be divided into three mutually exclusive segments: 
1. pre-treatment period: from day of participant’s informed consent to before date of first 
administration of study treatment 
2. on-treatment period: from date of first administration of study treatment till: 
o For participants who completed the treatment and entered into the post treatment 
follow-up consider the end date of on treatment period as 105 days after the date 
of last administration of study treatment . 
o For participants who continue crizanlizumab after their EOT via commercial 
supply or post-trial access where SVSPID is marked as “OUTSIDE” in SV 
domain then consider the end date of on treatment period as DSSTDTC from the 
DS data set where DSSCAT = “TREATMENT DISPOSITION”. 


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o For patient who were recruited before protocol amendment v04 where patients 
could have switched under crizanlizumab after EOT (via commercial supply or 
post-trial access) but still have completed the FU period, for such cases the end 
date of on treatment period will be the earliest date the patient has record in CM 
data with concomitant medication as “Adakveo” after the last administration of 
the Treatment from the disposition. 
o In case of death, data cut-off or withdrawal of consent, the end date of on 
treatment period will be death date, cut-off date or the withdrawal of consent 
date respectively. 
3. post-treatment period: starting at day 106 after last administration of study treatment, 
or after EOT date for participants continuing crizanlizumab after their EOT via 
commercial supply or post-trial access program. 
Note: If dates are incomplete in a way that clear assignment to pre-, on-, post-treatment period 
cannot be made, then the respective data will be assigned to the on-treatment period. 
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 AEs will summarize 
only on-treatment events, with a start date during the on-treatment period (treatment-emergent 
AEs). 
However, all safety data (including those from the post-treatment period) will be listed and 
those collected during the post-treatment period will be flagged. 
Windows for multiple assessments 
In order to summarize laboratory assessments over time (including unscheduled visits) by time 
point, the assessments will be time slotted. The following general rule will be applied in creating 
the assessment windows (for baseline refers to definition above): If more than one assessment 
is done within the same time window, the assessment performed closest to the target date will 
be used. If 2 assessments within a time window are equidistant from the target date, then the 
earlier of the 2 assessments will be used. If multiple assessments on the same date then the 
worst case will be used (minimum or maximum depending of the parameter direction). Data 
from all assessments (scheduled and unscheduled), including multiple assessments, will be 
listed. 
 
Time windows for laboratory assessments 
 
 
Assessment 
Target day of assessment 
Time Interval 
Baseline 
1 
≤ Day 1 
Week 3 Day 1 
15 
Day 2 to day 29 
Week 7 Day 1 
43 
Day 30 to day 57 
Week11 Day 1 
71 
Day 58 to day 85 
Week 15 Day1 
99 
Day 86 to day 113 


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Assessment 
Target day of assessment 
Time Interval 
Week 19 Day 1 
127 
Day 114 to day 141 
Week 23 Day 1 
155 
Day 142 to day 169 
Week 27 Day 1 
183 
Day 170 to day 197 
Week 31 Day 1 
211 
Day 198 to day 225 
Week 35 Day 1 
239 
Day 226 to day 253 
Week 39 Day1 
267 
Day 254 to day 281 
Week 43 Day 1 
295 
Day 282 to day 309 
Week 47 Day 1 
323 
Day 310 to day 337 
Week 51 Day 1 
351 
Day 338 to day 365 
Week 55 Day 1 
379 
Day 366 to day 393 
Week 59 Day 1 
407 
Day 394 to day 421 
Week 63 Day 1 
435 
Day 422 to day 449 
Week 67 Day1 
463 
Day 450 to day 477 
Week 71 Day 1 
491 
Day 478 to day 505 
Week 75 Day 1 
519 
Day 506 to day 533 
Week 79 Day 1 
547 
Day 534 to day 561 
Week 83 Day 1 
575 
Day 562 to day 589 
Week 87 Day 1 
603 
Day 590 to day 617 
Week 91 Day 1 
631 
Day 618 to day 645 
Week 95 Day1 
659 
Day 646 to day 673 
Week 99 Day 1 
687 
Day 674 to day 701 
Week 103 Day 1 
715 
Day 702 to day 729 
Note: Data from End of 
Treatment visit will be 
included in the time window 
for the Week X Day 1 visit 
of the last infusion, if 
obtained within 28 days 
from last infusion 
End of treatment 
Assessment taken at the end 
of treatment visit 
105 days post 
treatment 
105 days after last infusion 
Any time after last infusion 
date + 27 days 
 
2.2 
Analysis sets 
The different analysis sets are described in the following sections. Whatever the analysis set, 
the analysis will be presented overall and according to the 3 following age groups and by dose 
at the time of study entry: 
• Group 1: 12 years to <18 years, 5 mg/kg 
• Group 2: 6 years to <12 years, 5 mg/kg 
• Group 2: 6 years to <12 years, 8.5 mg/kg 


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• Group 3: 2 to <6 years, 8.5 mg/kg. 
Full analysis set 
The Full Analysis Set (FAS) comprises all participants (enrolled in Part A or in Part B) to whom 
study treatment has been assigned and who received at least one dose of study treatment. 
Safety set 
The Safety Set includes all participants (enrolled in Part A or in Part B) who received at least 
one dose of study treatment. 
Pharmacokinetic analysis set 
The Pharmacokinetic Analysis Set 1 (PAS1) includes all participants of part A 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 other tested dose before single 
dose PK profile, or before multiple dose PK profile (ie. at least 3 full consecutive doses 
administered following the loading dose at Week 3 Day 1) 
• Participant provides at least one primary 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. 
 
If the planned dose is newly defined, the new dose group will be added to the PAS1 accordingly. 
 
The Pharmacokinetic Analysis Set 2 (PAS2) includes all participants of part A and part B who 
receive at least one dose of crizanlizumab and provide at least one corresponding evaluable PK 
concentration. A pre-dose concentration is considered evaluable if not flagged out by 
pharmacokineticist. 
A participant is considered to receive the planned treatment if the actual dose received divided 
by the last weight measured before the dose is within a ±x% window of the planned dose (e.g. 
x = 5 for participants 40 kg and above, x = 10 for participants 6 kg to below 40 kg, as per current 
Pharmacy Manual). 
Other analysis sets 
The pharmacodynamics analysis set 1 (PDS1) includes all participants of Part A 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 tested dose before single dose 
PD profile, or before multiple dose PD profile (ie. at least 3 full consecutive doses 
administrated following the loading dose at Week 3 Day 1) 
• Participant 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 


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If the planned dose is newly defined, the new dose group will be added to the PDS1 accordingly. 
The pharmacodynamics analysis set 2 (PDS2) includes all participants of Part A and B who 
receive at least one dose of crizanlizumab and provide at least one corresponding evaluable PD 
assessment. A P-selectin % inhibition value is considered evaluable if not flagged by the 
pharmacokineticist. 
The pharmacokinetic-pharmacodynamics analysis set (PKPDS) includes all participants of Part 
A and B included in the Safety set who have at least one measured pre-dose concentration and 
one matching P-selectin % inhibition value. 
Details on pharmacokinetic analysis 
If a profile is not evaluable per PAS1 or PAS2 definition, all scheduled concentrations for that 
profile as well as corresponding parameters will be flagged for exclusion from summaries and 
figures. Additionally, if Rsq_adj < 0.75 or AUC%Extrap > 20%, then Lambda_z, T1/2, AUCinf, 
Vz/F (VZ), CL/F (CL) will be flagged for exclusion from summaries and figures. 
Only PK parameters and concentrations which are not flagged for exclusion programmatically 
or by the pharmacokineticist (e.g. due to CMs, high concentration despite dose modification, 
etc.) will be used for figures and summaries. All values will be listed with excluded values 
flagged in the listings. 
Participant classification 
Participants may be excluded from the analysis populations defined above based on the protocol 
deviations entered in the database and/or on specific participant classification rules defined in 
Table 2-1. 
Table 2-1 
Participant classification based on protocol deviations and non-PD 
criteria 
 
Analysis set 
Protocol deviations leading 
to exclusion 
Non protocol deviation 
leading to exclusion 
FAS 
No written informed consent 
No dose of study treatment 
Safety set 
No written informed consent 
No dose of study treatment 
PAS1 
No written informed consent 
No dose of study treatment 
No evaluable PK profile 
PAS2 
No written informed consent 
No dose of study treatment 
No evaluable PK 
concentration 
PDS1 
No written informed consent 
No dose of study treatment 
No evaluable PD profile 
PDS2 
No written informed consent 
No dose of study treatment 
No evaluable PD assessment 
PKPDS 
No written informed consent 
No dose of study treatment 
No pre-dose concentration 
No p-selectin inhibition data 


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Withdrawal of Informed Consent 
Any data collected in the clinical database after a participant withdraws informed consent from 
all further participation in the trial will not be included in the analysis. The date on which a 
participant withdraws full consent is recorded in the CRF. 
Additional data for which there is a separate informed consent, (e.g. PK, 
etc.), 
collected in the clinical database without having obtained that consent will not be included in 
the analysis. These data will be excluded by the presence of the appropriate protocol deviation 
criterion. 
2.2.1 
Subgroup of interest 
Wherever applicable, subgroup analyses of the main efficacy and/or safety analyses will be 
performed by: 
• Age (Group 1 age 12 to <18 years; Group 2 age 6 to <12 years; Group 3 aged 2 to <6 
years), 
• HU/HC use at time of study entry 
• Categories of number of VOC leading to healthcare visit at baseline (< 5 vs ≥ 5) or 
categories of number of dactylitis at baseline (0 vs ≥1). Depending on the distribution of 
the events (VOC’s and dactylitis), alternate categories can be suggested. 
• Gender 
• Race (black vs non black) 
Details of which analyses will be performed on which subgroup are provided in the dedicated 
sections. 
2.3 
Participant disposition, demographics and other baseline 
characteristics 
The Full Analysis Set (FAS) will be used for all baseline and demographic summaries and 
listings unless otherwise specified. Summaries and listings will be reported by age group and 
dose to assess baseline comparability. No inferential statistics will be provided. 
Basic demographic and background data 
All demographic and baseline disease characteristics data will be summarized and listed by age 
group and dose. Categorical data (e.g. gender, race, ethnicity, genotype, HU/HC use at baseline, 
VOC history, dactylitis history, Lansky Performance Status) will be summarized by frequency 
counts and percentages; the number and percentage of participants with missing data will be 
provided. Continuous data (e.g. age, weight, height, body mass index, Karnofsky Performance 
Status) will be summarized by descriptive statistics (N, mean, median, standard deviation, 
minimum, maximum, 1st quartile and 3rd quartile). Body mass index (BMI) (kg/m2) will be 
calculated as (weight[kg] / (height[m])2) using weight at screening. 
Medical history 
Medical history and ongoing conditions entered on (e) CRF will be summarized and listed by 
age group and dose. The summaries will be presented by primary system organ class (SOC), 
preferred term (PT) and age group. Medical history and current medical conditions will be 


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coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. The 
MedDRA version used for reporting will be specified in the CSR and as a footnote in the 
applicable tables/listings. 
All demographic data and other baseline characteristics (e.g., medical history, vaso-occlusive 
crisis history including genotype and HU/HC use, and pregnancy test etc.) will be listed. 
2.3.1 
Participant disposition 
The number (%) of treated participants included in the FAS will be presented overall,by age 
group and dose. The number (%) of participants in the FAS who are still on treatment, who 
discontinued the study phases and the reason for discontinuation will be presented overall and 
by age group and dose. 
The following summaries will be provided (with % based on the total number of FAS 
participants (overall or within the age group and dose described as applicable)): 
• Number (%) of participants who are still on-treatment (based on ‘Treatment 
Disposition’ page not completed) 
• Number (%) of participants who discontinued the study treatment phase (based on 
‘Treatment Disposition’ page completed); 
• Primary reason for study treatment phase discontinuation (based on the ‘Treatment 
Disposition’ page) 
• Number (%) of participants who have continued crizanlizumab via commercial 
supply or post-trial access 
• Number (%) of participants who have entered the post-treatment follow-up (based 
on the ‘Participant status follow up’ page); 
• Number (%) of participants who have discontinued from the post-treatment follow- 
up (based on the ‘Study Disposition’ page); 
• Reasons for discontinuation from the post-treatment follow-up (based on ‘Study 
Disposition’ page); 
Participant disposition data will be listed. 
Screened participants not treated will be listed. 
Protocol deviations 
The number (%) of participants in the FAS with any protocol deviation will be tabulated by 
deviation category (as specified in the study edit checks specification) overall and by age group 
and dosefor the FAS. In addition, COVID-19 related protocol deviations and issues with 
potential impact on quality will be summarized. 
All protocol deviations and COVID-19 related issues will be listed. 
Analysis sets 
The number (%) of participants in each analysis set (defined in Section 2.2) will be summarized 
for the FAS by age group and dose. Participants included in each analysis set will be listed. 


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2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
Duration of exposure, actual cumulative dose, dose intensity (DI) and relative dose intensity 
(RDI) will be summarized by age group and dose. Duration of exposure will be categorized into 
time intervals; frequency counts and percentages will be presented for the number (%) of 
participants in each interval. The number (%) of participants who have dose interruptions, and 
the reasons, will be summarized by age group and dose. 
Participant level listings of all doses administered on treatment along with dose change reasons 
will be produced. 
The safety set will be used for all summaries and listings of study treatment. 
Duration of exposure to study treatment 
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to the investigational drug: 
Duration of exposure to study treatment (weeks) = ((last date of exposure to study treatment) – 
(date of first administration of study treatment) + 1)/7. 
The last date of exposure to study treatment is the earliest of the last date of treatment + 27 
days, the date of death (if the participant died), and the date of data cutoff. 
Summary of duration of exposure of study treatment in appropriate time units will include 
categorical summaries (less than 6 weeks, at least 6 weeks, at least 26 weeks, at least 54 
weeks, at least 106 weeks) and continuous summaries (i.e. mean, standard deviation etc.). 
Cumulative dose 
Cumulative dose of a study treatment is defined as the total dose given during the study 
treatment exposure and will be summarized by age group and dose. 
The planned cumulative dose refers to the total planned dose as per the protocol up to the last 
date of investigational drug administration. 
The actual cumulative dose refers to the total actual dose administered, over the duration for 
which the participant is on the study treatment as documented in the Study Treatment – Infusion 
eCRF. 
Dose intensity and relative dose intensity 
Dose intensity (DI) for participants with non-zero duration of exposure is defined as follows: 
DI (mg/kg/28days) = (Actual Cumulative dose (mg/kg) / Duration of exposure to study 
treatment (weeks)) x 4. 
Planned dose intensity (PDI) is defined as follows: 
PDI (mg/kg/28days) = (Planned Cumulative dose (mg/kg) / Duration of exposure (weeks) ) x 
4. 


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Relative dose intensity (RDI) is defined as follows: 
RDI = DI (mg/kg/28days) / PDI (mg/kg/28days). 
DI and RDI will be summarized. 
Dose reductions or interruptions 
The number of participants who have dose reductions or interruptions, and the reasons for it, 
will be summarized separately by age group and dose, and all dosing data will be listed. 
Following rules will be used to derive dose reductions and interruptions in exposure analysis. 
Reduction: determined from dose change records where actual non-zero dose administered is 
different from the protocol intended dose. 
Dose reduction is a dose change where the actual dose administered is lower than the calculated 
dose amount based on the protocol intended dose. Therefore any dose change to correct a dosing 
error will not be considered a dose reduction. Only dose change is collected in the Study 
Treatment – Infusion CRF, and number of reductions will be derived programmatically based 
on the change and the direction of the change. 
Interruption: a dose cannot be administered within 7 days of the scheduled day of infusion and 
flagged as “dose interrupted” in the CRF. Interruptions are considered as infusion completely 
skipped or delayed. If a dose was temporarily stopped/paused during infusion and re-started to 
complete the infusion, it should not be considered as a dose interruption. 
Duration of a dose interruption is calculated as follows whichever is earlier: 
• the time between the scheduled date of infusion and the actual date of infusion after the 
interruption or 
 
• the time between the scheduled date of infusion and the treatment discontinuation after 
the interruption or 
• the time between the scheduled date of infusion and the data cut-off after the interruption 
In case of subsequent continuous interruptions of more than 1 infusion, if the reason for 
interruption is different for each interruption, all the reasons will be reported though it will 
be counted as one single interruption. 
‘Dose change’ and ‘Dose interrupted’ fields from the Study Treatment - Infusion CRF pages 
will be used to determine the dose reductions and the dose interruptions. The corresponding 
field ‘Reason for dose change/dose interrupted’ will be used to summarize the reasons. 
2.4.2 
Prior, concomitant and post therapies 
Concomitant medications 
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures), 
other than the study treatment, administered to a participant coinciding with the study treatment 
period. Concomitant therapy include medications (other than study drug) starting on or after the 


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start date of study treatment or medications starting prior to the start date of study treatment and 
continuing after the start date of study treatment. 
CMs will be coded using the World Health Organization (WHO) Drug Reference Listing (DRL) 
dictionary that employs the WHO Anatomical Therapeutic Chemical (ATC) classification 
system and summarized by lowest ATC class and preferred term using frequency counts and 
percentages. These summaries will include: 
1. Medications starting on or after the start of study treatment but no later than 105 days 
after start of last dose of study treatment and 
2. Medications starting prior to start of study treatment and continuing after the start of 
study treatment. 
All concomitant therapies will be listed. Separate listings will be provided for HU/HC, 
L-Glutamine, Erythropoietin simulating agent and Analgesics. Any concomitant therapies 
starting and ending prior to the start of study treatment or starting more than 105 days after the 
last date of study treatment will be flagged in the listing. The safety set will be used for all 
concomitant medication tables and listings. Non-drug therapies, surgical and medical 
procedures will be coded using MedDRA and summarized by SOC and PT. 
The number and percentage of participants who were receiving HU/HC at study entry will be 
summarized. For participants not receiving HU/HC at study entry, the reason for prior 
discontinuation of HU/HC (or reason for never having received HU/HC, as applicable) will also 
be summarized. 
2.5 
Analysis of the primary objective 
2.5.1 
Primary endpoint 
Part A: 
The primary variables of Part A (participants from 24 months of age) are the PK and PD 
parameters after single dose and after multiple doses. 
Primary PK/PD Parameters 
AUCd15 (week 1) after first dose, AUCtau (steady state) after multiple dose, Cmax 
The remaining PK parameters will be analyzed as secondary variables. 
Primary PD Parameters 
PD-AUCd15 (week 1) after first dose, PD-AUCtau (steady state) after multiple dose. 
Parts A + B: 
The primary safety endpoint for Part A + B of all age groups is the frequency of participants 
with any AEs during the on-treatment period. 


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2.5.2 
Statistical hypothesis, model, and method of analysis 
Primary PK/PD analysis: 
Part A (participants from 24 months of age): 
In order to confirm and establish appropriate dosing, the following methods will be used for 
each group and the defined dose: 
For each group and defined dose, geometric means of the primary PK parameters will be derived 
for participants included in the PAS1. For group 1, these PK parameters will be compared 
against observed adult PK parameters of study CSEG101A2202; for the other groups, these 
parameters will be compared to the predicted PK parameters for these participants derived from 
the adult population PK model. 
Geometric mean ratio of observed (test) versus predicted (reference) primary PK parameters 
and its 90% confidence interval will be derived and compared against the boundaries of 2 and 
0.5, respectively. If the 90% confidence intervals of both PK parameters are within the 
boundaries, it is considered that there is no meaningful change in exposure versus the reference. 
For estimation, a linear model will be fitted to the log-transformed PK parameters, mean and 
90% confidence intervals will be estimated, and, finally, back-transformed to retain the 
geometric means and ratios and their respective 90% confidence intervals. 
The data to be used for developing the population PK model will come from pooled study data 
of the previous studies. PK parameter prediction will be based on the population PK model. 
Methods will be specified and detailed in a separate document. 
For each group and defined dose, geometric means of the primary PD parameters will be derived 
for participants included in the PDS1. These parameters will be compared against predicted PD 
parameters for these participants. For group 1, PD parameters will be compared against adult 
PD parameters of study CSEG101A2202. 
Geometric mean ratio of observed (test) versus predicted (reference) PD parameters and its 95% 
confidence interval will be derived. 
For estimation, a linear model will be fitted to the log-transformed PD parameters, mean and 
95% confidence intervals will be estimated, and, finally, back-transformed to retain the 
geometric means and ratios and their respective 95% confidence intervals. 
Primary safety analysis 
Part A+B (all age groups): Number and percentage of participants with any AEs will be 
provided by age group, and by starting dose within each age group as applicable. Safety analysis 
set will be used for this purpose. 
2.5.3 
Handling missing values/censoring/discontinuations 
Missing values for any PK parameters or concentrations will not be imputed and will be treated 
as missing. 


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Below the limit of quantitation (BLQ) values for PK concentrations will be set to zero by the 
Bioanalyst, and will be displayed in the listings as zero and flagged. BLQ values will be treated 
as missing for the calculation of the geometric means and geometric CV%. 
Missing values for the P-selectin inhibition will not be imputed and will be treated as missing. 
2.5.4 
Supportive analyses 
Part A: 
Not applicable 
Parts A + B: 
Not applicable. 
2.6 
Analysis of the key secondary objective 
There is no key secondary objective. 
2.7 
Analysis of secondary efficacy objective(s) 
2.7.1 
Secondary endpoints 
The secondary efficacy endpoints include the following. 
• Annualized rate of VOC events leading to healthcare visit in clinic/ER/hospital 
• Annualized rate of VOC events treated at home (based on documentation by health 
care provider following phone contact with participant) 
• Annualized rate of each subcategory of VOC event (uncomplicated pain crisis, acute 
chest syndrome, hepatic sequestration, splenic sequestration, priapism) 
• Annualized rate of hospitalizations and ER visits (both total and VOC-related) 
• Annualized days of ER/hospitalization (both total and VOC-related) 
• Annualized rate of dactylitis events 
2.7.2 
Statistical hypothesis, model, and method of analysis 
All analyses will be based on all FAS participants, unless otherwise specified. The summary 
and spaghetti plot of annualized rates per year mentioned below for an age group and dose will 
be performed when all participants of that group have completed or discontinued from the study. 
VOC 
The number of VOCs leading to healthcare visit in clinic/ER/hospital will be summarized 
descriptively by age group and dose in the FAS. The number of participants with 0 events will 
be presented. Summaries will be provided for the corresponding annualized rate of VOC leading 
to healthcare visit in clinic/ER/hospital overall and per year. 
The absolute and relative change from baseline of the annualized rate of VOC leading to 
healthcare visit in clinic/ER/hospital will be provided overall and per year and corresponding 
spaghetti plot will be presented. The baseline annualized rate of VOC will be defined as the 


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number of VOCs leading to healthcare visit in clinic/ER/hospital occurring within 12 months 
prior to screening until first dose, reported in the baseline VOC eCRF. 
Number of VOC reported until End date × 365.25 
Annualized rate of VOC = 
 
 
End date − date of first dose of study treatment + 1 
where End date is defined as the minimum of (last dose date until treatment discontinuation + 
27 days, date of 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, cut-off date). 
Despite all attempt to ensure complete follow-up for all participants, some participants may not 
be followed for VOC for the whole planned study duration. The annualized rate of VOC 
calculation will account for early discontinuation by extrapolating the VOC rate of every 
participant to one year. All VOC occurring until the End date will be taken into account in the 
summaries. If a participant initiates or discontinues HU/HC or L-glutamine (or other therapies 
to treat SCD and/or to prevent/reduce VOCs such as voxelotor and erythropoietin) during the 
study, VOC occurring after the initiation/discontinuation of such therapy will not be taken into 
account in the analyses. A sensitivity analysis will be performed, including the crises post 
initiation/discontinuation of HU/HC or L-glutamine (or other therapies to treat SCD and or to 
prevent/reduce VOCs such as voxelotor and erythropoietin) in the numerator and the 
corresponding duration of extra follow-up in the denominator, ie. with End date defined as the 
minimum of (last dose date until treatment discontinuation + 27 days, cut-off date). 
Subgroup analyses of annual rate and the change from baseline in annual rate of VOC will be 
performed by HU/HC use at time of study entry, number of VOC leading to healthcare visit at 
baseline, gender and race. 
The summary statistics on annualized rate along with change from baseline in annualized rate 
of VOC events leading to healthcare visit in clinic/ER/hospital will be performed for each 
subcategory of VOC events (uncomplicated pain crisis, acute chest syndrome, hepatic 
sequestration, splenic sequestration, and priapism). These analyses will be performed on the 
subset of FAS participants having at least one qualified VOC for the considered subcategory, 
either at baseline or on treatment. 
The summary statistics on annualized rate of events will also be performed on: 
• VOCs treated at home (based on documentation by health care provider following phone 
contact with participant), based on the subset of FAS participants having at least one home 
VOC. 
• VOCs leading to healthcare visit and treated at home combined, based on all FAS 
participants. 
• VOCs treated at home, as well as VOCs leading to healthcare visit and treated at home 
combined, for each subcategory of VOC event: uncomplicated pain crisis, and priapism; 
on the subset of FAS participants having at least one qualified VOC for the considered 
subcategory. 
Time to first occurrence of VOC leading to healthcare visit will be summarized by age group 
and dose using Kaplan-Meier methods. Median time, 25th and 75th percentiles will be 
summarized and Kaplan-Meier plots will be generated. The time to first occurrence of VOC 
leading to healthcare visit will be defined as the time from the date of the first dose of study 


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treatment to the date of the first occurrence of the VOC. In the absence of a VOC, participants 
will be censored at the time of their respective end date of VOC observation period: defined 
above as the minimum of (last dose date until treatment discontinuation + 27 days, date of 
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, cut-off date). Subgroup analyses 
of time to first occurrence of VOC will be performed by HU/HC use at time of study entry, 
number of VOC leading to healthcare visit at baseline, gender and race. 
Dactylitis 
The number of dactylitis events will be summarized descriptively in the FAS for participants 
from 2 to < 6 years of age (Group 3). Summaries will be provided for the corresponding 
annualized rate of dactylitis events overall and per year, defined in the same way as the 
annualized rate of VOC. The absolute and relative change from baseline of the annualized rate 
of dactylitis events will be provided and corresponding spaghetti plot will be presented. 
Number of dactylitis reported until End date × 365.25 
Annualized rate of dactylitis = 
End date − date of first dose of study treatment + 1 
where End date = End date is defined as the minimum of (last dose date until treatment 
discontinuation + 27 days, date of 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, cut-off date). 
Subgroup analyses of the annual rate and change from baseline in annual rate of dactylitis will 
be performed by HU/HC use at time of study entry and number of dactylitis at baseline. 
Listing of all dactylitis events experienced by all participants during the study will be provided 
by age group and dose. 
Hospitalization 
The number of hospitalizations and ER visits (both overall and VOC-related) will be 
summarized descriptively by age group and dose in the FAS. Summaries will be provided for 
the corresponding annualized rate of hospitalizations and ER visits overall and per year, defined 
in the same way as the annualized rate of VOC. The absolute and relative change from baseline 
of the annualized rate will be provided and corresponding spaghetti plot will be presented. The 
baseline rate of hospitalizations and ER visits are defined based on the number of these events 
occurring within 12 months prior to screening (reported on Baseline Hospitalization eCRF), 
and during screening until first dose (reported on Healthcare Resource Utilization - 
Hospitalization eCRF). 
Annualized rate of hospitalizations and ER visits 
Number of hospitalizations and ER visits reported until End date × 365.25 
= 
End date − date of first dose of study treatment + 1 
where End date is defined as the minimum of (last dose date until treatment discontinuation + 
27 days, date of 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, cut-off date). 


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Subgroup analyses of the annual rate and change from baseline in annual rate will be performed 
by HU/HC use at time of study entry and number of hospitalizations at baseline, gender and 
race. 
The number of days of ER/hospitalization (both total and VOC-related) will be summarized 
descriptively by age group and dose in the FAS. Summaries will be provided for the 
corresponding annualized rate of days hospitalized overall and per year. 
Chest x-ray 
The data on the chest x-ray will be listed and notable findings will be flagged. 
2.7.3 
Handling of missing values/censoring/discontinuations 
Missing values or data will not be imputed and will be treated as missing, except that when 
computing annualized rates of events, the assumption is done that the frequency of events 
observed over the period of follow up can be extrapolated to a year, even in participants who 
may have less than a year of follow up. 
2.8 
Safety analyses 
All safety analyses will be based on the Safety set unless otherwise specified. Safety summaries 
include only on-treatment assessments; safety listings include all assessments with those more 
than 105 days after last study treatment flagged. All safety analyses described below will be 
performed by age group and by starting dose within each age group if applicable. 
2.8.1 
Adverse events (AEs) 
AE summaries will include all AEs occurring during on-treatment period. All AEs collected in 
the AE (e)CRF page will be listed along with the information collected on those AEs (e.g. AE 
relationship to study drug, AE outcome, etc.). AEs with start date outside of on-treatment period 
will be flagged in the listings. 
AEs will be summarized by number and percentage of participants having at least one AE, 
having at least one AE in each primary SOC and for each PT using MedDRA coding. A 
participant with multiple occurrences of an AE will be counted only once in the respective AE 
category. A participant with multiple Common Terminology Criteria for Adverse Events 
(CTCAE) grades for the same preferred term will be summarized under the maximum CTCAE 
grade recorded for the event. AE with missing CTCAE grade will be included in the ‘All grades’ 
column of the summary tables. 
In AE summaries, the primary SOC will be presented alphabetically and the PTs will be sorted 
within primary SOC in descending frequency. The sort order for the PT will be based on their 
frequency in all participants. 
The following AE summaries will be produced by age group and dose; overview of AEs and 
deaths, AEs by SOC and PT, summarized by relationship, seriousness, leading to treatment 
discontinuation, leading to dose interruption/reduction and leading to fatal outcome. In addition, 
for EudraCT requirements a summary of (1) Serious AEs and deaths, with number of 
occurrences and (2) Non-serious AEs, number of occurrences will be produced (an occurrence 
is defined as >1 day between start and prior end date of record of same preferred term). 


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Adverse events identified in the Novartis MedDRA Query (NMQ) topic of “COVID-19 
Diagnosis including positive, suspected and negative” will be summarized and listed. 
Summaries for these AEs will be provided by age group and dose and by different classification 
levels defined within this topic COVID-19 topic, as well as by PT within each level. 
2.8.1.1 
Adverse events of special interest (AESI) 
Data analysis of AESIs 
An AESI is a grouping of AEs that are of scientific and medical concern specific to compound 
crizanlizumab. These groupings are defined using MedDRA terms, SMQs (standardized 
MedDRA queries), HGLTs (high level group terms), HLT (high level terms) and PTs (preferred 
terms). Customized SMQs (Novartis MedDRA queries, NMQ) may also be used. A NMQ is a 
customized group of search terms which defines a medical concept for which there is no official 
SMQ available or the available SMQ does not completely fit the need. It may include a 
combination of single terms and/or an existing SMQ, narrow or broad. For each specified AESI, 
number and percentage of participants with at least one event of the AESI occurring during on 
treatment period will be summarized. The list of AESI to be taken into account for SEG101 
trials is documented in the eCRS for the project. The most up to date version of the eCRS 
available at the time of a DB lock for an analysis will be used to define on which AESIs the 
analysis will be conducted. 
Summaries of these AESIs will be provided by age group and dose, (specifying grade, SAE, 
relationship, leading to treatment discontinuation, leading to dose interruption, hospitalization, 
death etc.). If sufficient number of events occurred, analysis of time to first occurrence will be 
applied. 
A listing of all grouping levels down to the MedDRA preferred terms used to define each AESI 
will be generated. 
2.8.2 
Deaths 
Separate summaries for on-treatment and all deaths (including post-treatment death) will be 
produced by age group and dose, SOC and PT. 
All deaths will be listed and post-treatment deaths will be flagged. A separate listing of deaths 
prior to starting treatment will be provided for all screened participants. 
The death summaries cover participants from the Safety Set. 
2.8.3 
Laboratory data 
Grading of laboratory values will be assigned programmatically as per National Cancer Institute 
(NCI) CTCAE version 5.0. The calculation of CTCAE grades will be based on the observed 
laboratory values only; clinical assessments will not be taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used. 
On analyzing laboratory, data from all sources (central and local laboratories) will be combined. 
The summaries will include all assessments available for the lab parameter collected no later 
than 105 days after the last study treatment administration date. 


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The following summaries will be produced for hematology, biochemistry and urinalysis 
(macroscopic only) laboratory data (by laboratory parameter, age group and dose): 
• Worst post-baseline CTCAE grade (regardless of the baseline status). Each participant 
will be counted only for the worst grade observed post-baseline. 
• Shift tables using CTCAE grades to compare baseline to the worst on-treatment value 
• For laboratory tests where CTCAE grades are not defined and normal ranges are provided, 
shift tables using the low/normal/high/(low and high) classification to compare baseline to 
the worst on-treatment value. 
The following listings will be produced for the laboratory data: 
• Listings of all laboratory data with corresponding CTC grades relative to the laboratory 
normal range. Lab data collected during the post-treatment period will be flagged. 
• Listing of all CTC grade 3 or 4 laboratory toxicities 
For hemoglobin parameter, summary and box plot of the absolute change from baseline over 
time based on time windows will be provided. 
Liver function parameters 
Liver function parameters of interest are total bilirubin (TBL), Alanine aminotransferase (ALT), 
Aspartate aminotransferase (AST) and alkaline phosphatase (ALP). The number (%) of 
participants with worst post-baseline values as per Novartis Liver Toxicity guidelines will be 
summarized in addition to the baseline values. 
Shift tables using ALT, AST and TBL will be generated, respectively. Evaluation of drug 
induced serious hepatotoxicity (eDISH) plot will be produced. A similar plot of direct bilirubin 
(DBILI) vs. ALT will also be generated. Individual participant plots will be produced for 
participants with potential severe drug induced liver injury (DILI) as defined below. Individual 
participant reticulocyte plots, and a plot of PT-INR and albumin over time will also be produced 
for the same participants. A corresponding listing of participants with potential severe DILI will 
be generated. 
The following summaries will be produced based on peak post-baseline values for each 
parameter during on-treatment period (i.e. not necessarily concurrent assessments for 
combinations of parameters): 
• ALT or AST > 3xULN (upper limit of normal) 
• ALT or AST > 5xULN 
• ALT or AST > 8xULN 
• ALT or AST > 10xULN 
• ALT or AST > 20xULN 
• TBL > 2xULN 
• TBL > 3xULN 
• DBILI > 2xULN 
• DBILI > 3xULN 


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For participants with AST and ALT ≤ ULN at baseline: 
• Elevated ALT or AST (*) & TBL > 2xULN 
• Elevated ALT or AST (*) & TBL > 2xULN & ALP < 2xULN (potential Hy’s law) 
• Elevated ALT or AST (*) & TBL > 2xULN & ALP ≥ 2xULN 
• Elevated ALT (*) & DBILI > 2xULN & ALP < 2xULN (potential severe DILI) 
For participants with AST or ALT > ULN at baseline (Bsl): 
• Elevated ALT or AST (*) & TBL (> 2xBsl and 2xULN) 
• Elevated ALT or AST (*) & TBL (> 2xBsl and 2xULN) & ALP < 2xULN (potential 
Hy’s law) 
• Elevated ALT or AST (*) & TBL (> 2xBsl and 2xULN) & ALP ≥ 2xULN 
• Elevated ALT (*) & DBILI (> 2x Bsl and 2xULN) & ALP < 2xULN (potential severe 
DILI) 
(*) Elevated ALT or AST is defined as: >3xULN if ≤ ULN at baseline, or (> 3xBsl or 8xULN) 
if > ULN at baseline. 
Other Laboratory parameters 
Renal disorders will be evaluated using serum creatinine shift table. 
Hematuria (defined as urinalysis RBC of 6-8/HPF or more), glycosuria (defined as urine 
glucose of 1+ or more), and proteinuria (defined as urine protein of 1+ or more) will be 
evaluated using frequency table by time (baseline vs. post-baseline). 
2.8.4 
Other safety data 
2.8.4.1 
ECG and cardiac imaging data 
Data handling 
When ECG triplicates are collected at any assessment, the average of the ECG parameters at 
that assessment should be used in the analyses. 
Data analysis 
12-lead ECGs including PR, QRS, QT, QTcF, QTcB, RR and HR intervals will be obtained 
centrally for each participant during the study. ECG data will also be read and interpreted 
centrally. 
The number and percentage of participants with notable ECG values will be presented by age 
group and dose. In addition, a listing of these participants will be produced. 
• QT, QTcF, or QTcB 
- 
New value of > 450 and ≤ 480 ms 
- 
New value of > 480 and ≤ 500 ms 
- 
New value of > 500 ms 


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- 
Increase from Baseline of > 30 ms to ≤ 60ms 
- 
Increase from Baseline of > 60 ms 
• HR 
- 
Increase from baseline >25% and to a value > 100 bpm 
- 
Decrease from baseline >25% and to a value < 50 bpm 
• PR 
- 
Increase from baseline >25% and to a value > 200 ms 
- 
New value of > 200 ms 
• QRS 
- 
Increase from baseline >25% and to a value > 120 ms 
- 
New values of QRS > 120 ms 
• RR 
- 
Increase from baseline >25% and to a value > 1200 ms 
- 
Decrease from baseline >25% and to a value < 600 ms 
 
A listing of all ECG assessments will be produced by age group and dose, and notable values 
will be flagged. In the listing, the assessments collected during the post-treatment period will 
be flagged. 
For cardiac imaging data, LVEF shift table based on CTC grade will be presented by age group 
and dose. In addition, all data will be listed. 
2.8.4.2 
Vital signs 
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: height (cm), weight (kg), head circumference (cm, for 
participants aged 2 years to 2.5 years old at time of study entry, until the participants turns 3 
years old), body temperature (°C), pulse rate (beats per minute), respiratory rate (breaths per 
minute), systolic and diastolic blood pressure (mmHg). 
Data handling 
Vital signs collected on-treatment will be summarized. Values measured during the post- 
treatment period will be flagged in the listings. 
Data analysis 
For analysis of vital signs the clinically notable vital sign criteria are provided in Table 2-2 
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Table 2-2 Clinically notable changes in vital signs 
Vital sign 
Participant age at visit 
 
< 18 years 
≥ 18 years 
Systolic blood 
pressure [mmHg] 
 
 
 
 
Diastolic blood 
pressure [mmHg] 
High 
≥ 95th percentile of the age and 
height group1 
Low 
≤ 5th percentile of the age and 
height group1 
High 
≥ 95th percentile of the age and 
height group1 
Low 
≤ 5th percentile of the age and 
height group1 
≥ 180 with increase from 
updated baseline4 of ≥20 
mmHg 
≤ 90 with decrease from 
updated baseline4 of ≥20 
mmHg 
≥ 105 with increase from 
updated baseline4 of ≥15 
mmHg 
≤ 50 with decrease from 
updated baseline4 of ≥15 
mmHg 
Oral body 
temperature [°C] 
High 
≥ 38.4°C 
≥ 39.1°C 
Low 
≤ 35.0°C 
≤ 35.0°C 
 
Pulse rate [bpm] 2 
High 
6-12 months 
12-18 months 
>150 
> 140 
≥120 with increase 
from updated 
18-24 months 
> 135 
baseline4 of ≥15 bpm 
2-3 years 
> 128 
3-4 years 
> 123 
4-6 years 
> 117 
6-8 years 
> 111 
8-12 years 
> 103 
12-15 years 
> 96 
≥ 15 years 
> 92 
Low 
6-12 months 
12-18 months 
18-24 months 
2-3 years 
3-4 years 
4-6 years 
6-8 years 
8-12 years 
12-15 years 
≥ 15 years 
<110 
≤50 with decrease from 
< 103 
updated baseline4 of ≥15 
< 98 
bpm 
< 92 
< 86 
< 81 
< 74 
< 67 
< 62 
< 58 


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Vital sign 
Participant age at visit 
< 18 years 
≥ 18 years 
Weight 
High 
increase from baseline of ≥ 2 
BMI-for-age percentile 
categories3 
Low 
decrease from baseline of ≥ 2 
BMI-for-age percentile 
categories3 
Weight increase from 
updated baseline4 of ≥ 
10% 
Weight decrease from 
updated baseline4 of ≥ 
10% 
 
 
> 40 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
bpm=beats per minute; NHLBI= National Heart, Lung, and Blood Institute; 
1 Blood pressure percentiles are calculated for each blood pressure record using the method described in 
Appendix B of the following reference: The Fourth Report on Diagnosis, Evaluation and Treatment of High 
Blood Pressure in Children and Adolescents. Pediatrics 2004; 114; 555. 
2 Fleming S, Thompson M, Stevens R, et al. Normal ranges of heart rate and respiratory rate in children from 
birth to 18 years of age: a systematic review of observational studies. Lancet 2011; published online March 
15. DOI:10.1016/S0140-6736(10)62226-X. 
3 BMI-for-age percentiles categories (P3, P5, P10, P25, P50, P75, P85, P90, P95, P97) are obtained from the 
WHO Growth Charts (http://www.who.int/childgrowth/en/); 
Note: For participants less than 2 years old, growth charts are based on recumbent length instead of height, 
which is not collected in the study. As an approximation, height collected in the study is considered as equal 
to the recumbent length; 
4 Updated baseline is the last value collected before the 18th birthday. 
5 Eldridge L. What is a Normal Respiratory Rate?, Updated May 16, 2014; 
6 Kou .R., Shuei L., Bradypnea, Department of Physiology, School of Medicine, National Yang-Ming 
University, Taipei, Taiwan, http://rd.springer.com/referenceworkentry/10.1007%2F978-3-540-29676-8_246 
Respiratory rate 
High 
[breath per 
minute]2,5,6 
6-12 months 
12-18 months 
18-24 months 
2-3 years 
3-4 years 
4-6 years 
6-8 years 
8-12 years 
12-15 years 
≥ 15 years 
> 50 
> 46 
> 34 
> 29 
> 27 
> 24 
> 22 
> 21 
> 20 
≥30bpm 
Low 
6-12 months 
12-18 months 
18-24 months 
2-3 years 
3-4 years 
4-6 years 
6-8 years 
8-12 years 
12-15 years 
15-18 years 
<30 
< 28 
< 25 
< 22 
< 21 
< 20 
< 18 
< 16 
< 15 
< 13 
≤ 10bpm 


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The number and percentage of participants with notable vital sign values (high/low) will be 
presented by age group and dose. A listing of all vital sign assessments will be produced by age 
group and dose, and notable values will be flagged. In the listing, the assessments collected 
outside of on-treatment period will be flagged. 
2.8.4.3 
Growth and sexual maturation 
Data on growth and sexual maturation (Tanner stage) will be tabulated and listed. 
Age at menarche will be summarized by age group and dose using Kaplan-Meier methods for 
female participants with Tanner Stage <=4 at baseline. Median time, 25th and 75th percentiles 
will be summarized. The time to menarche will be defined as the completed number of years 
from the date of birth to the date menarche attained. In the absence of menarche occurrence, 
patients will be censored at the date of latest assessment. 
2.8.4.4 
Immunogenicity 
Immunogenicity will be characterized descriptively tabulating ADA prevalence at baseline 
and ADA incidence on-treatment. 
2.9 
Pharmacokinetic endpoints 
Refer to Section 2.5 
2.10 
PD and PK/PD analyses 
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 2-3 except Tmax. Since Tmax is generally evaluated by a nonparametric method, median 
values and ranges will be given for this parameter, where only n, median, minimum and 
maximum will be presented. Zero concentrations will not be included in the geometric mean 
calculation. Summary statistics will be provided by weight-adjusted dose and by age group for 
the PAS1 and/or PAS2. 
PK 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. 
The PK parameters are derived based on the non-compartmental methods using Phoenix 
WinNonlin® software version with the most recent version available at the time of analysis. 
Refer to the Novartis Pharmacokinetic/Pharmacodynamic Analysis Manual (2015). 
Table 2-3 Noncompartmental pharmacokinetic and pharmacodynamic parameters 
AUCd15 
The AUC from time zero to the last measurable concentration sampling 
time (tlast) (mass x time x volume-1) following the first dose 
AUCtau 
The AUC calculated to the end of a dosing interval (tau) at steady-state 
(amount x time x volume-1) 
PD-AUCd15 
The AUC of %inhibition from time zero to the last measurable inhibition 
sampling time (tlast) following the first dose 








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assessment of the primary safety analysis for Part A + B of groups 1 and 2 based on the Rule 
of Three. For the primary safety analysis of group 3, no statistical computation was performed 
to assess the sample size. Based on the objective of the Part A and feasibility of enrollment in 
this younger age group, at least 8 participants will be enrolled.. 
Table 3-1 
Probability to observe at least one AE for different incidence rates 
 
Incidence rate 
of an AE 
Probability that at least one 
participant out of 52 experiences 
the AE 
Probability that at least one 
participant out of 86 experiences 
the AE 
1% 
0.41 
0.58 
2% 
0.65 
0.82 
3% 
0.79 
0.93 
4% 
0.88 
0.97 
5% 
0.93 
0.99 
 
4 
Change to protocol specified analyses 
No change from protocol specified analyses was made. 
 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
Missing dates for study drug administration should be queried and will not be imputed. 
5.1.2 
AE, concomitant medications and safety assessment date imputation 
Table 5-1 
Imputation of start dates/times (AE, concomitant medications) 
 
Missing 
Element 
Rule 
day, month, 
and year 
• No imputation will be done for completely missing dates 
day, month 
• If available year = year of study treatment start date then 
o If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date = 01JanYYYY 
o Else set start date = study treatment start date. 
• If available year > year of study treatment start date then 01JanYYYY 
• If available year < year of study treatment start date then 01JulYYYY 


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Missing 
Element 
Rule 
day 
• If available month and year = month and year of study treatment start 
date then 
o If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date= 01MONYYYY. 
o Else set start date = study treatment start date. 
• If available month and year > month and year of study treatment start 
date then 01MONYYYY 
• If available month and year < month year of study treatment start date 
then 15MONYYYY 
time (for AE 
only) 
Applicable following AE CRF update to include precise information on 
timing of infusion related reactions: 
• If available day, month and year = day, month and year of study 
treatment start date then 
o If stop date/time contains a full date/time (time, day, month and 
year) and stop date/time is earlier than study treatment start 
date/time then set start date/time = DDMONYYYY-00:01. 
o If Infusion related reaction = “Yes” and “when did the Infusion 
related reaction start” = “During the infusion” then set start 
date/time = study treatment start date/time 
o If Infusion related reaction = “Yes” and “when did the Infusion 
related reaction start” = “Within 24 hours after the infusion” 
then set start date/time = study treatment infusion end date/time 
+01 min of that day of AE 
o Else set start time = study treatment start time 
• Otherwise if day, month and year < day, month and year of study 
treatment start date or if day, month and year > day, month and year of 
study treatment start date do not impute the AE start time and leave it 
blank. 


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Table 5-2 
Imputation of end dates (AE, concomitant medications) 
 
Missing 
Element 
Rule 
(*=last treatment date plus 105 days not > (death date, cut-off date, 
withdrawal of consent date)) 
day, month, 
and year 
• 
Completely missing end dates will be imputed by the end date of the 
on-treatment period only if start date ≤ end date of the on-treatment 
period. 
day, month 
• 
If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period. 
If start date > end date of the on-treatment period, set end date = 
31DecYYYY 
day 
• 
If partial end date contains month and year, set end date = earliest of 
last day of the month or end date of the on-treatment period. 
If start date > end date of the on-treatment period, set end date = last 
day of the month 
Any AEs and CMs with partial/missing dates will be displayed as such in the data listings. 
Any AEs and CMs which are continuing as per data cut-off will be shown as ‘ongoing’ rather 
than the end date provided. 
For AEs with start date before or on the cut-off date and end date after the cut-off date, the 
outcome will be reported as unknown. 
5.1.3 
Age at time of assessment 
In order to calculate the age at time of a given assessment (for assigning notable vital signs 
criteria and laboratory normal ranges or CTC grading), the following rules will be applied: 
If the age at screening visit in months is known, the age at visit x will be calculated based on an 
estimated date of birth: 
Considering, screening visit date on ddmmmyyyy, 
estimated day of birth = dd, with dd the day of the screening visit 
estimated month and year of birth = screening visit date – age in months 
For example, if a participant is 15 years + 4 months (total of 184 months) at screening visit on 
15Jun2020, then estimated date of birth is 15Feb2005. 
5.2 
AEs coding/grading 
AEs are coded using the Medical dictionary for regulatory activities (MedDRA) terminology. 
Note: The latest available MedDRA version at the time of the analyses should be used. The 
MedDRA version used should be specified in the footnote of relevant tables. 
AEs will be assessed according to the CTCAE version 5.0. 
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding 
to mild, moderate, severe, life threatening, and death. This grading system inherently places a 


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value on the importance of an event, although there is not necessarily proportionality among 
grades (a grade 2 is not necessarily twice as bad as a grade 1). 
5.3 
Laboratory parameters derivations 
Grade categorization of lab values will be assigned programmatically as per CTCAE version 
5.0. The calculation of CTCAE grades will be based on the observed laboratory values only, 
clinical assessments will not be taken into account. The criteria to assign CTCAE grades are 
given in the Novartis internal criteria for CTCAE grading of laboratory parameters. The latest 
available version of the document based on the underlying CTCAE version 5.0 at the time of 
analysis will be used. 
For laboratory tests where grades are not defined by CTCAE version 5.0, results will be graded 
by the low/normal/high classifications based on laboratory normal ranges. 
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 will not be used. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labelled by direction, e.g., sodium will be summarized 
as hyponatremia and hypernatremia. 
Imputation Rules 
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X. 
CTC grading for blood differentials is based on absolute values. However, this data may not be 
reported as absolute counts but rather as percentage of WBC. 
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential 
xxx count = (WBC count) * (xxx %value / 100) 
Further derivation of laboratory parameters might be required for CTCAE grading. For 
instance, corrected calcium can be derived using the reported total calcium value and albumin 
at the same assessment using the following formula: 
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4] 
In order to apply the above formula, albumin values in g/L will be converted to g/dL by 
multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 
0.2495. For calculation of laboratory CTC grades 0 and 1, the normal range for derived 
corrected calcium is set to the same limits (in mg/dL) as for calcium. 
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium will be assigned as described above for grading. 
 
6 
Reference 
Oncology Guideline for Safety Analyses, Novartis, 9 June 2016. 
Pharmacokinetic / Pharmacodynamic Analysis Manual, Novartis, 17 Dec 2015. 


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SAP Final CSR 
Confidential 
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Smith B, Vandenhende FR, DeSante KA, Farid NA, Welch PA, Callaghan JT and Forgue ST . 
Confidence Interval Criteria for Assessment of Dose Proportionality. Pharmaceutical 
Research, 17(10), 1278-83 (2000).