Conditions: Sickle Cell Disease (SCD)
Keywords: SEG101 Sickle Cell Disease SCD Crizanlizumab Sickle cell nephropathy chronic kidney disease CKD albuminuria (ACR) renal function standard of care
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 58
Healthy volunteers: no

Brief summary:
The goal of the study was to evaluate descriptively the effect of crizanlizumab + standard of care and standard of care alone on renal function in sickle cell disease patients ≥ 16 years with chronic kidney disease due to sickle cell nephropathy.

Detailed description:
Approximately 50 patients were to be randomized 1:1 to receive either crizanlizumab (5 mg/kg) + standard of care or standard of care alone. Patients were stratified at randomization based on chronic kidney disease (CKD) risk category (moderate risk or high/very high risk) and hydroxyurea/hydroxycarbamide (HU/HC) prescription (Yes/No). The CKD risk categories used for stratification were based on both Estimated glomerular filtration rate(eGFR) and albuminuria assessed by Albumin/creatinine ratio (ACR).

Arms:
arm 1: 5 mg/kg by intravenous (i.v.) infusion at Week 1 Day 1, Week 3 Day 1 and Day 1 of every 4-week cycle until Week 51 in addition to their usual standard of care treatment. arm 2: Patients in the standard of care alone arm will continue to receive their usual standard of care treatment.

Interventions: intervention 1: Crizanlizuamb intervention 2: Standard of Care
Intervention descriptions: intervention 1: Crizanlizumab 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 intervention 2: HU/HC (hydroxyurea/hydroxycarbamide) and/or ACE (angiotensin-converting enzyme) inhibitors and/or ARBs (angiotensin-receptor blocker)

Protocol document:
Prot_000.pdf: 
Novartis Research and Development
SEG101/Crizanlizumab
Clinical Trial Protocol CSEG101A2203 / NCT04053764
A Phase II, multicenter, randomized, open label two arm 
study evaluating the effect of crizanlizumab + standard of 
care and standard of care alone on renal function in sickle 
cell disease patients ≥ 16 years with chronic kidney 
disease due to sickle cell nephropathy (STEADFAST)
Document type:
Amended Protocol Version
EUDRACT number:
2018-003608-38
Version number:
03 clean
Clinical Trial Phase:
II
Release date:
02-Dec-2021
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms...............................................................................................................11
Amendment 3 (02-Dec-2021)...................................................................................................13
Summary of previous amendments ..........................................................................................14
Amendment 2 (09-Mar-2021) ..................................................................................................14
Amendment 1 (08-Jul-2020) ....................................................................................................23
Protocol summary..............................................................................................................31
1
Introduction .......................................................................................................................36
1.1
Background............................................................................................................36
1.1.1
Overview of sickle cell disease pathogenesis .......................................36
1.1.2
Current treatment for sickle cell nephropathy.......................................38
1.1.3
Role of P-selectin in sickle cell disease ................................................39
1.1.4
Introduction to crizanlizumab ...............................................................39
1.2
Purpose ..................................................................................................................41
1.2.1
Study purpose and rationale..................................................................41
2
Objectives and endpoints...................................................................................................43
2.1
Primary estimands .................................................................................................44
2.2
Secondary estimands .............................................................................................45
3
Study design ......................................................................................................................45
4
Rationale............................................................................................................................47
4.1
Rationale for study design .....................................................................................47
4.1.1
Rationale for choice of background therapy.........................................48
4.2
Rationale for dose/regimen and duration of treatment ..........................................48
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................49
4.4
Purpose and timing of interim analyses/design adaptations..................................49
4.5
Risks and benefits..................................................................................................49
5
Population..........................................................................................................................53
5.1
Inclusion criteria ....................................................................................................53
5.2
Exclusion criteria...................................................................................................54
6
Treatment...........................................................................................................................56
6.1
Study treatment......................................................................................................56
6.1.1
Crizanlizumab .......................................................................................57


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6.1.2
Additional study treatments ..................................................................57
6.1.3
Treatment arms/group ...........................................................................57
6.1.4
Guidelines for continuation of treatment ..............................................58
6.1.5
Treatment duration................................................................................58
6.2
Other treatment(s)..................................................................................................58
6.2.1
Concomitant therapy.............................................................................58
6.2.2
Prohibited medication ...........................................................................60
6.3
Patient numbering, treatment assignment, randomization.....................................60
6.3.1
Patient numbering .................................................................................60
6.3.2
Treatment assignment, randomization ..................................................60
6.4
Treatment blinding.................................................................................................61
6.5
Dose escalation and dose modification..................................................................61
6.5.1
Dose modifications................................................................................61
6.5.2
Follow-up for toxicities.........................................................................66
6.6
Additional treatment guidance...............................................................................67
6.6.1
Treatment compliance...........................................................................67
6.7
Preparation and dispensation.................................................................................67
6.7.1
Handling of study treatment and additional treatment..........................68
6.7.2
Instruction for prescribing and taking study treatment .........................69
7
Informed consent procedures ............................................................................................69
8
Visit schedule and assessments .........................................................................................70
8.1
Screening ...............................................................................................................80
8.1.1
Eligibility screening ..............................................................................80
8.1.2
Information to be collected on screening failures.................................80
8.2
Patient demographics/other baseline characteristics .............................................81
8.3
Efficacy..................................................................................................................82
8.3.1
Urine albumin to creatinine ratio ..........................................................82
8.3.2
Urine protein to creatinine ratio............................................................82
8.3.3
Estimated glomerular filtration rate ......................................................83
8.3.4
Progression of chronic kidney disease ..................................................84
8.3.5
Appropriateness of efficacy assessments..............................................85
8.4
Safety.....................................................................................................................87
8.4.1
Laboratory evaluations..........................................................................88
8.4.2
Electrocardiogram (ECG) .....................................................................91
92
8.4.4
Pregnancy and assessments of fertility .................................................93
8.4.5
Immunogenicity ....................................................................................93


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8.4.6
Resource utilization...............................................................................93
8.4.7
Chest X-ray ...........................................................................................94
8.4.8
Appropriateness of safety measurements..............................................94
8.5
Additional assessments..........................................................................................94
94
8.5.2
Pharmacokinetics ..................................................................................96
97
100
8.5.5
Acute kidney injury and vaso-occlusive crisis assessments ...............100
8.5.6
Trial Feedback Questionnaire (optional) ............................................102
9
Study discontinuation and completion ............................................................................103
9.1
Discontinuation and completion..........................................................................103
9.1.1
Study treatment discontinuation..........................................................103
9.1.2
Discontinuation from study.................................................................104
9.1.3
Withdrawal of informed consent/Opposition to use data/biological 
samples................................................................................................104
9.1.4
Lost to follow-up.................................................................................105
9.1.5
Early study termination by the sponsor...............................................105
9.2
Study completion and post-study treatment ........................................................106
10 Safety monitoring and reporting......................................................................................107
10.1
Definition of adverse events and reporting requirements....................................107
10.1.1
Adverse events ....................................................................................107
10.1.2
Serious adverse events ........................................................................109
10.1.3
SAE reporting......................................................................................110
10.1.4
Pregnancy reporting ............................................................................111
10.1.5
Reporting of study treatment errors including misuse/abuse..............111
10.2
Additional safety monitoring...............................................................................112
10.2.1
Liver safety monitoring.......................................................................112
10.2.2
Data Monitoring Committee ...............................................................112
10.2.3
Steering Committee.............................................................................112
10.3
Protocol exempt adverse events and serious adverse events...............................113
11 Data collection and database management......................................................................113
11.1
Data collection.....................................................................................................113
11.2
Database management and quality control..........................................................114
11.3
Site monitoring ....................................................................................................114
12 Data analysis and statistical methods ..............................................................................115
12.1
Analysis sets ........................................................................................................115


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12.1.1
Full Analysis Set .................................................................................115
12.1.2
Safety Set ............................................................................................115
12.2
Patient demographics and other baseline characteristics.....................................116
12.3
Treatments ...........................................................................................................116
12.4
Analysis supporting primary objectives ..............................................................116
12.4.1
Definition of primary endpoint ...........................................................116
12.4.2
Statistical model, hypothesis, and method of analysis........................116
12.4.3
Handling of intercurrent events of primary estimand .........................117
12.4.4
Sensitivity analyses .............................................................................121
12.4.5
Supplementary analyses......................................................................121
12.5
Analysis supporting secondary objectives...........................................................121
12.5.1
Efficacy endpoints...............................................................................121
12.5.2
Safety endpoints..................................................................................122
12.5.3
Pharmacokinetics ................................................................................124
124
125
12.7
Interim analyses...................................................................................................125
12.8
Sample size calculation........................................................................................125
13 Ethical considerations and administrative procedures ....................................................125
13.1
Regulatory and ethical compliance......................................................................125
13.2
Responsibilities of the investigator and IRB/IEC................................................125
13.3
Publication of study protocol and results.............................................................126
13.4
Quality Control and Quality Assurance...............................................................126
14 Protocol adherence ..........................................................................................................126
14.1
Protocol amendments...........................................................................................127
15 References .......................................................................................................................128
16 Appendices ......................................................................................................................131
List of tables
Table 2-1
Objectives and related endpoints ..........................................................43
Table 3-1
Prognosis of chronic kidney disease by glomerular filtration rate 
and albuminuria categories (chronic kidney disease risk categories) ...46
Table 4-1
Rationale for study design.....................................................................47
Table 6-1
Standard of care drugs...........................................................................56
Table 6-2
Crizanlizumab .......................................................................................57
Table 6-3
Criteria for dose interruption and re-initiation of crizanlizumab due 
to adverse drug reactions.......................................................................63


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Table 8-1
Assessment Schedule ............................................................................71
Table 8-2
Assessments & Specifications...............................................................88
Table 8-3
Laboratory assessments.........................................................................90
Table 8-4
Central electrocardiogram (ECG) collection plan.................................91
92
Table 8-6
Pharmacokinetics and immunogenicity blood collection log ...............97
98
Table 8-8
Vaso-Occlusive Crisis or other acute pain crisis Assessment 
Collection Plan....................................................................................102
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .......................................................................................112
Table 12-1
Primary estimand ................................................................................119
124
Table 12-3
Confidence Intervals for the Difference between Two Proportions 
using Proportions Numeric Results for Two Sided Confidence 
Intervals for the Difference in Proportions Confidence interval 
method: Chi – Square – Simple Asymptotic (Pearson) ......................125
List of figures
Figure 3-1
Study design..........................................................................................47
Figure 8-1
Glomerular filtration rate and albuminuria grid to reflect the risk of 
chronic kidney disease progression.......................................................85
Figure 8-2
Timing of study procedures ..................................................................91


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List of abbreviations
Ab
Antibody
ACE
Angiotensin-Converting Enzyme
ACR
Albumin to Creatinine Ratio
ACS
Acute Chest Syndrome
ADA
Anti-Drug Antibody
ADR
Adverse Drug Reaction
AE
Adverse Event
AESI
Adverse Event of Special Interest
AKI
Acute Kidney Injury
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
ANCOVA
Analysis of Covariance
APC
Acute Pain Crisis
APTT
Activated Partial Thromboplastin Time
ARB
Angiotensin-Receptor Blocker
ASH
American Society of Hematology
AST
Aspartate Aminotransferase 
BUN
Blood Urea Nitrogen
C5b-9
Complement Membrane Attack Complex
CFR
Code of Federal Regulations
CI
Confidence Interval
CKD
Chronic Kidney Disease
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CMO & PS
Chief Medical Office and Patient Safety
COVID-19
Coronavirus Disease Caused by SARS-COV-2 virus
CPO
Country Pharma Organization
CRO
Contract Research Organization
CTCAE
Common Terminology Criteria for Adverse Events
CTT
Clinical Trial Team
CV
Coefficient of Variance
DAR
Dosage Administration Record
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report/Record Form


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EDC
Electronic Data Capture
EDTA
Ethylenediaminetetraacetic Acid
eGFR
Estimated Glomerular Filtration Rate
ELISA
Enzyme Linked Immunosorbent Essay
EMA
European Medicines Agency
EOS
End of Study
EOT
End of Treatment
ER
Emergency Room
ESA
Erythropoietin-Stimulating Agent
eSAE
Electronic Serious Adverse Event
FAS
Full Analysis Set
FDA
Food and Drug Administration
FSGS
Focal Segmental Glomerulosclerosis
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
GGT
Gamma-Glutamyltransferase
HA
Health Authority
Hb
Hemoglobin
HbA
Hemoglobin A
HbA2
Hemoglobin A2
HbC
Hemoglobin C 
HbcAb
Hepatitis B Core Antibody
HbF
Fetal Hemoglobin
HbS
Hemoglobin S
HbsAb
Hepatitis B Surface Antibody
HBsAg
Hepatitis B Surface Antigen
HbSS
Homozygous Hemoglobin S (sickle cell anemia)
HbSβ0-thal
Hemoglobin S with β-thalassemia
HBV
Hepatitis B Virus
HC
Hydroxycarbamide
HCV
Hepatitis C Virus
HDL
High-Density Lipoprotein
HIV
Human Immunodeficiency Virus
HPLC
High Performance Liquid Chromatography
HRQOL
Health Related Quality of Life
HU
Hydroxyurea
i.v.
Intravenous
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonization of Technical 
Requirements for Pharmaceuticals for Human Use
IEC
Independent Ethics Committee


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IFN
Interferon
IG
Immunoglobulin
IgG
Immunoglobulin G
INR
International Normalized Ratio
IRB
Institutional Review Board
IRR
Infusion-Related Reaction
IRT
Interactive Response Technology
IVIG
Intravenous Immune Globulin
KDIGO
Kidney Disease Improving Global Outcomes
KIM-1
Kidney Injury Molecule-1
LDH
Lactate Dehydrogenase
LDL
Low Density Lipoprotein
LFT
Liver Function Test
LLN
Lower Limit of Normal
LLOQ
Lower Limit of Quantification
LPT
Low Platelet Count
mAb
Monoclonal Antibody
MCH
Mean Corpuscular Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCS
Mental Component Summary
MCV
Mean Corpuscular Volume
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MI
Multiple Imputation
MID
Minimally Important Difference
NSAID
Non-Steroidal Anti-Inflammatory Drug
OTC
Over the Counter
PA
Posteroanterior
PCR
Protein to Creatinine Ratio
PCS
Physical Component Summary
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)


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PRO
Patient Reported Outcome(s)
PT
Prothrombin Time
PTA
Post-Trial Access
PTX3
Pentraxin-3
QMS
Quality Management System
QTcF
QT Interval Corrected by Fridericia’s Formula
RBC
Red Blood Cell
RNA
Ribonucleic Acid
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SC
Steering Committee
SC5-b9
Soluble complement 5b-9
SCA
Sickle cell anemia
SCD
Sickle Cell Disease
SCN
Sickle Cell Nephropathy
SD
Standard Deviation
SOC
Standard of care
SOP
Standard Operating Procedures
SUSAR
Suspected Unexpected Serious Adverse Reaction
TEAE
Treatment-Emergent Adverse Event
TNF-α
Tumor necrosis factor alpha
ULN
Upper Limit of Normal
US
United States
VCAM-1
Vascular cell adhesion molecular 1
VOC
Vaso-Occlusive Crisis
VWFag
Von Willebrand factor antigen


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Glossary of terms
Additional treatment
Medicinal products that may be used during the clinical trial as described in the protocol, 
but not as an investigational medicinal product (e.g., any pre-medication)
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 patient
Dosage
Dose of the study treatment given to the patient in a time unit (e.g., 100 mg once a day, 
75 mg twice a day)
End of the clinical 
trial
The end of the clinical trial is defined as the last visit of the last patient or at a later point 
in time as defined by the protocol
Enrollment
Point/time of patient entry into the study at which informed consent must be obtained 
Investigational drug
The drug whose properties are being tested in the study
Medication number
A unique identifier on the label of medication kits
Other treatment
Treatment that may be needed/allowed during the conduct of the study (i.e., 
concomitant or rescue therapy)
Patient
An individual with the condition of interest for the study
Period
The subdivisions of the trial design (e.g., Screening, Treatment, Follow-up) which are 
described in the Protocol. Periods define the study phases and will be used in clinical 
trial database setup and eventually in analysis
Personal data
Patient information collected by the investigator that is transferred to Novartis for the 
purpose of the clinical trial. This data includes patient identifier information, study 
information and biological samples. 
Premature patient 
withdrawal
Point/time when the patient exits from the study prior to the planned completion of all 
study drug administration and/or assessments; at this time all crizanlizumab 
administration is discontinued (if applicable), patients attend an end of treatment visit 
and follow-up visit, after which no further assessments are planned
Randomization 
number
A unique identifier assigned to each randomized patient
Screen Failure
A patient who did not meet one or more criteria that were required for participation in the 
study
SelG1
Reprixys humanized anti-P-selectin monoclonal antibody variant
SEG101
Novartis humanized anti-P-selectin monoclonal antibody variant
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
Start of the clinical 
trial
The start of the clinical trial is defined as the signature of the informed consent by the 
first patient
Study treatment
Any single drug or combination of drugs or intervention administered to the patient as 
part of the required study procedures. This includes crizanlizumab and standard of care 
medications
Study treatment 
discontinuation
When the patient permanently stops taking any of the study treatment(s) prior to the 
defined study treatment completion date for any reason; may or may not also be the 
point/time of study discontinuation 
Patient Number
A unique number assigned to each patient upon signing the informed consent. This 
number is the definitive, unique identifier for the patient and should be used to identify 
the patient throughout the study for all data collected, sample labels, etc
Treatment 
arm/group
A treatment arm/group defines the dose and regimen or the combination, and may 
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Withdrawal of study 
consent (WoC)/ 
Opposition to use of
data /biological 
samples
Withdrawal of consent from the study occurs when the patient 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 3 (02-Dec-2021)
Amendment rationale
The STEADFAST study achieved first patient first visit on 10-Dec-2019. However, there have 
been ongoing recruitment challenges due to difficulties in identifying the protocol specified 
patient population and high screen failure rate (57%). Despite various efforts to improve 
recruitment including two protocol amendments to broaden the eligibility criteria, at the time 
of this amendment, only 47 out of planned 148 patients were randomized after almost two years. 
It was assessed that this trial will not complete recruitment within the anticipated timelines. 
Therefore, a decision has been made to stop recruitment (screening) by November 17, 2021, 
and all eligible patients are expected to be enrolled by December 15, 2021.
This decision was not triggered by any new and/or unexpected safety concerns. The ongoing 
patients will continue the study until discontinuation or completion. The primary purpose of 
this amendment is to adjust the sample size and planned statistical analyses. As a result of the 
reduced sample size and low statistical power, no formal hypothesis testing will be conducted, 
and descriptive statistics with the 95% Confidence Intervals will be provided instead.
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.

Protocol summary: updated sections related to objectives, study design and data 
analysis according to other updates.

Table 2-1: Objectives and related endpoints updated to be descriptively evaluated.

Section 3: Study design updated to reflect the stopping of recruitment and the revised 
population.

Figure 3-1: Study design updated according to population changes.

Table 4-1: Table adjusted as analysis will be descriptive.

Section 4.1.1: Wording adjusted as analysis will be descriptive.

Section 5: Population, reduction of the patients enrolled according to the stopping of
recruitment.

Section 6.3.2: Treatment assignment, randomization section was updated to reflect the 
updated patient number. 

Section 6.5.2: Window for blood samples collection updated.

Table 8-3: Laboratory assessments, row related to cytokines/complement and 
additional tests were updated to clarify timepoint and patient population.
 


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
Section 9.2: Study completion and post-study treatment: Updates were provided on 
access to crizanlizumab for patients randomized to the standard of care alone arm. 

Section 10.1.3: SAE reporting updated as per Bundesinstitut für Arzneimittel und 
Medizinprodukte (BfArM) recommendations.

Section 12.4.2: Statistical methods adjusted following decision to stop recruitment: 
hypothesis testing removed as analysis will be descriptive. 

Section 12.4.4: Sensitivity analysis removed, no sensitivity analysis will be done as 
study will be descriptive.

Section 12.4.5: Supplementary analyses removed due to the reduction of sample size.

Section 12.5: Analysis supporting secondary objectives updated to indicate descriptive 
summary of data.

Section 12.5.1: Analysis of efficacy endpoints adjusted as analysis will be descriptive.
 

Section 12.8: Sample size calculation adjusted. Added table with precision estimates 
for sample sizes varying from 20 to 80.

Table 12-3: Confidence intervals table added.
Summary of previous amendments 
Amendment 2 (09-Mar-2021)
Amendment rationale 
At the time of this amendment, 23 patients have been enrolled.
The primary purpose of this amendment is to broaden the inclusion/exclusion criteria to allow 
for greater patient eligibility, modify study assessments, update sample collection requirements 
to reduce patient burden based on current clinical practice in the management of SCD-related 
CKD and amend the statistical power and sample size calculation.
Inclusion Criteria #4: Change in eGFR criteria
The eGFR upper limit of 130 mL/min/1.73 m2 for women was increased to 140 mL/min/1.73 m2 
consistent with the criteria for males as there is no confirmed gender specific correlation with 
hyperfiltration in SCD patients. 
Inclusion Criteria #9: Increase in upper limit for direct bilirubin 
The upper limit for direct (conjugated) bilirubin was increased from <2 x ULN to ≤ 3.0 x ULN 
based on evidence from clinical practice, that SCD patients at baseline may have a higher direct 
bilirubin and may otherwise meet the inclusion criteria. No hepatic safety concerns have been 
observed within the crizanlizumab program.
Exclusion Criteria #2: Clarified AKI criteria


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Though it can take 3 months for resolution of AKI, it has been noted that a patient’s renal 
function can return to pre-AKI values within 6 weeks. Thus, provision has been added that if 
the patient’s renal function has returned to pre-AKI values with 6 weeks of enrollment the 
patient can be eligible.
Exclusion Criteria #3: Increase in blood pressure limit
The blood pressure limit was increased from >130/80 to >140/90 mmHg. American Heart 
Association guidelines define hypertension as ≥130/80 and European Society of Hypertension 
guidelines define hypertension as ≥140/90.  It was assessed that changing this upper limit would 
still be consistent with guidelines and that changing the upper limit would expand patient 
eligibility without negatively impacting patient safety or the trial objectives.
Exclusion Criteria #5: Renal replacement therapy 
Renal replacement therapy encompasses all forms of dialysis and kidney transplantation that 
might be expected to impact the endpoint, and therefore the exclusion criteria was updated to 
reflect that patients undergoing renal replacement therapy (i.e. hemodialysis, peritoneal dialysis, 
hemofiltration and kidney transplantation) are not eligible for the trial.
Exclusion Criteria # 12: Modified language on prior use of crizanlizumab, monoclonal 
antibodies and immunoglobulin based agents
Prior use of monoclonal antibody was removed as part of the exclusion criteria due to limited 
reports of immunogenicity with crizanlizumab. Due to the unknown duration of efficacy of 
crizanlizumab after the drug is discontinued, any prior use of crizanlizumab is prohibited. Use
of immunoglobulin based agents was removed as an exclusion criteria as guidance is given in 
Section 6.2.1.1 permitted concomitant therapy requiring caution and/or action. Immunoglobulin 
based agents are to be used with caution. 
Exclusion Criteria #14: use of anticoagulants or antiplatelet therapy exclusion removed 
and concomitant therapy guidance added 
Exclusion criteria for therapeutic anticoagulant and antiplatelet usage is removed as current data 
shows that there is no safety concern for patients receiving anticoagulation/antiplatelet therapy.  
Section 6.2.1 Concomitant therapy was updated to note that antiplatelet agents or anticoagulants 
at doses targeting therapeutic levels should be used with caution.
eGFR calculation and use of the Creatinine-based “Bedside Schwartz” equation (2009)
The creatinine-based “Bedside Schwartz” equation (2009) will be used to calculate eGFR for 
patients under the age of 18 at screening as this is the most accurate calculation of eGFR for 
adolescents and will reduce the risk of overestimation of eGFR in adolescents. The same 
formula will continue to be used for the patient throughout the entire trial, independent from 
patient’s age at the time of sample collection.
 
 
 
 


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First morning void sample collection
First morning void sample collection requirement was changed to morning void sample 
collection to decrease patient burden. Based on current practices, sample collection any time 
during the morning will allow more flexibility with urine collection and will still adequately 
control for the variability in ACR values without negatively impacting the robustness of the 
results. The average of 3 ACR values at screening to determine eligibility and at subsequent 
timepoints will continue to be used to address the variability in ACR. Similar changes were 
made for morning voids where PCR is collected.
Laboratory results for patient eligibility
Based on operational challenges with central lab reporting timeframe, local results (with the 
exception of urine ACR and eGFR which can impact study endpoints) can be used to confirm 
patient eligibility only in the event that central results are not available within the timeframe 
required for patient randomization.
Pregnancy Follow-up
The pregnancy follow-up reporting period was updated to reflect pregnancy reporting will occur 
up to one year after the estimated date of delivery, which is aligned with the Novartis pregnancy 
follow-up standard requirement. This is consistent with the informed consent. 
Clarification of 105-day-follow-up period
The 105-day follow-up period was part of the original study design for both treatment arms to 
ensure the consistency of assessments as the study team was blinded to the treatment. The 
intention of the 105-day follow-up period is to capture any potential adverse events including 
development of anti-drug antibodies after study treatment discontinuation, taking into account 
the half-life of the drug. Patients who will receive crizanlizumab approximately 4 weeks after 
their last dose of study treatment, do not need to complete the 105-day follow-up. The end of 
the safety follow-up period for these patients will be the 30-day follow-up. All other patients 
are required to complete the 105-day follow-up.
Change to statistical power and sample size
The initial sample size was 170 patients with statistical power of 85%. Due to global impact of 
the COVID-19 pandemic and long recruitment duration, the feasibility of recruiting 170 patients
was reconsidered. It was assessed that 80% power, which results in a reduced sample size of 
148 patients total, would be sufficiently robust to satisfy the primary objective of this phase II 
trial.
Clarification on assessments for patients who discontinue study treatment early
To alleviate patient burden of assessment collection after early study treatment discontinuation, 
the recommendation that patients should return for all assessments was removed. In order to 
provide robust data, a mandatory Week 53 urine ACR/PCR visit was added to ensure this data 
was collected for patients who discontinue study treatment early. The Week 53 urine ACR/PCR 


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visit should be scheduled 12 months after the first dose of study treatment for patients who early 
discontinue treatment.
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:

Clarification of protocol amendment 1 date to 08-Jul-2020.

List of Abbreviations, Glossary of terms and Protocol summary updated to reflect changes 
throughout the document. Updated Section numbers, references and links based on 
changes.

Section 1.1.1 Overview of sickle cell disease pathogenesis, Section 3 Study design, 
Section 5.1 Inclusion criteria (inclusion criteria 4), Section 8.3.3 Estimated glomerular 
filtration rate, Section 8.3.5 Appropriateness of efficacy assessments and Section 12.5.1
Efficacy endpoints: updated to reflect addition of the Creatinine-based “Bedside 
Schwartz” equation (2009) for patients <18 and clarify that the CKD-EPI formula should 
be used for patients ≥ 18. 

Section 1.1.4.1 Crizanlizumab (SEG101): updated to reflect current regulatory approval 
status of crizanlizumab.

Section 1.2.1 Study purpose and rationale, Section 3 Study Design, Table 3-1, Section 5
Population, Section 5.1 Inclusion Criteria, Section 12.4.5 Supplementary analysis, and 
Figure 8-1 Glomerular filtration rate and albuminuria grid to reflect the risk of chronic 
kidney disease progression: updated eGFR upper limit to 140 mL/min/1.73 m2 regardless 
of gender.

Section 2.1 Primary estimands, Table 12-1 and Section 12.4.3 Handling of intercurrent 
events of primary estimand: Additional definition of primary estimands added. Additional 
attribute and intercurrent event added.

Section 3 Study design, Section 6.2.1 Concomitant therapy, Section 6.5.2 Follow-up for 
toxicities, Section 8 Visit schedule and assessments, Table 8-1, Table 8-6
Pharmacokinetics and immunogenicity blood collection log, Section 9.1.5 Early study 
termination by sponsor, Section 9.2 Study completion and post-study treatment, Section 
10.1.1 Adverse events, Section 10.1.3 SAE reporting, Section 12.5.2 Safety endpoints: 
added language that patients who will receive crizanlizumab approximately 4 weeks after 
their last dose of study treatment, do not need to complete the 105-day follow-up. The end 
of the safety follow-up period for these patients will be the 30-day follow-up. All other 
patients are required to complete the 105-day follow-up. Added language to these sections 
to clarify assessments for patients who will not perform the 105-day follow-up. Removed 
“EOS” language as end of study will refer to end of trial overall. Clarified study treatment 
discontinuation language. Updated on-treatment period for safety endpoints based on this 
update.

Section 3 Study Design, Section 5 Population, Section 6.3.2 Treatment assignment, 
randomization, updated to reflect change in sample size from 170 to 148 in Section 12.8.

Section 3 Study Design: updated language to clarify assessments and time points.


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
Section 3 Study Design, Table 8-1 Assessment Schedule, 
 
 
 

Section 3 Study Design, Section 8 Visit schedule and assessments, Table 8-1, Section 8.3
Efficacy, Section 8.3.1 Urine albumin to creatinine ratio, Section 8.3.2 Urine protein to 
creatinine ratio, Section 9.1.1 Study treatment discontinuation, Section 9.2 Study 
completion and post-study treatment: Removed recommendation that patients who 
discontinue study treatment early should return for all assessments. These patients will 
return for a mandatory Week 53 urine ACR/PCR assessment. The Week 53 urine 
ACR/PCR assessment should occur 12 months after the first dose of study treatment.

Figure 3-1: updated to reflect change to study design

Figure 3-1 and Figure 8-1: Updated to reflect that mg/g should be used for ACR 
assessments.

Section 4.5 Risks and benefits: Section updated to reflect new information based on latest 
version of the SEG101 Investigator’s Brochure. Section updated to note that no substantial 
additional risks for patients due to COVID-19 have been identified.

Section 5.1 Inclusion Criteria: updated inclusion criteria 5 to clarify that ACR will be 
reported as an average of three screening ACR values for eligibility for consistency with 
the rest of the protocol.

Section 5.1 Inclusion Criteria: updated inclusion criteria 6 for consistency with the rest of 
the protocol as not all patients will be receiving HU/HC.

Section 5.1 Inclusion Criteria: Inclusion criteria 9 updated direct bilirubin criteria to 
≤3.0 x ULN.

Section 5.2 Exclusion Criteria: update exclusion criteria 2 to add more details on 
exclusionary AKI parameters.

Section 5.2 Exclusion Criteria: Exclusion criteria 3 updated blood pressure from >130/80 
to >140/90 mmHg.

Section 5.2 Exclusion Criteria: Exclusion criteria 5 updated to include renal replacement 
therapy as part of the exclusion criteria which covers all forms of dialysis and kidney 
transplantation that might be expected to impact the endpoint (i.e. hemodialysis, peritoneal 
dialysis, hemofiltration and kidney transplantation).

Section 5.2 Exclusion Criteria: clarified exclusion criteria 12 that patients who have 
received crizanlizumab and/or other selectin inhibitor prior to the study or plans to receive 
it during the duration of the study are not eligible for the trial.

Section 5.2 Exclusion Criteria: removed exclusion criteria 14 “Use of therapeutic 
anticoagulation or antiplatelet therapy (other than aspirin or non-steroidal 
anti-inflammatory drugs [NSAIDs]) within the 10 days prior to Week 1 Day 1. Note: 
Prophylactic anticoagulant dose is permitted, as per local guidelines”


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
Section 5.2 Exclusion Criteria: removed exclusion 17 “Received a live vaccine against an 
infectious disease(s) within 4 weeks prior to Week 1 Day 1” as there is no evidence that 
this would be a safety concern.

Section 5.2 Exclusion Criteria: added new exclusion criteria 23. Patients with malignant 
disease (with exceptions) are not eligible for the trial.

Section 5.2 Exclusion Criteria: revised exclusion criteria 24 to remove resting QTcF 
parameter as crizanlizumab has not demonstrated an impact on QT parameters.

Section 5.2 Exclusion Criteria: added “bilateral” to tubal ligation in exclusion criteria 29
for clarification. Updated exclusion criteria 29 to separate the definition of post-
menopausal women and women of no childbearing potential for clarification.

Section 5.2 Exclusion Criteria: language added to clarify that it is up to the investigator 
discretion if a patient is included/excluded based on symptoms or positive test for 
COVID-19. These patients should be managed as per country specific guidelines 
surrounding COVID-19. Recommendation added that patients who test positive are re-
tested prior to initiating study treatment.

Table 6-3 Criteria for dose interruption: added “temporarily” for clarity on infusion 
interruption in the case of a Grade 2 IRR.

Section 6.2.1 Concomitant therapy and Section 6.2.1.1 Permitted concomitant therapy 
requiring caution and/or action: updated guidance around antiplatelet and anticoagulant 
therapy.

Section 6.2.1.1 Permitted concomitant therapy requiring caution and/or action and Section 
9.1.1 Study treatment discontinuation: provided guidance on patients who require renal 
replacement therapy. 

Section 6.2.2 Prohibited medication: Clarified that use of voxelotor within the last 6 
months prior to screening is prohibited to be consistent with the rest of the protocol. 
Removed immunoglobulin based agent as prohibited medication as it is permitted with 
caution. Added exclusionary statement that patients previously treated with crizanlizumab 
are not allowed for consistency with exclusion criteria.

Section 6.5.1.1 Crizanlizumab: Recommendations added for handling of crizanlizumab
administration in case of exposure to COVID-19. Amended CRF name.

Section 6.5.2 Follow-up for toxicities: Clarified requirement for IRR blood sample
collection.

Section 6.7 Preparation and dispensation: updated guidance on monitoring for potential 
IRRs.

Section 6.7.1.1 Handling of study treatment: clarifications added regarding drug 
accountability and study treatment handling responsibilities.

Section 7 Informed consent procedures: added additional details about optional genetic
consent.

Section 8 Visit schedule and assessments and Table 8-1 Assessment Schedule: Added visit 
window to safety follow-up visits to allow for more flexibility. Additional clarifications 
added for discontinuation of study treatment and withdrawal of consent/opposition to use 
of data/biological samples.

Table 8-1: Added separate line and footnote for IRR data collection for clarity.


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
Table 8-1: removed “Standard of care” duplicate line.
 
 

Table 8-1: removed requirement for hematology, clinical chemistry and coagulation panel 
to be collected at Week 7 Day 1 to reduce amount of blood draws for patients.

Table 8-1: removed Fetal hemoglobin (HbF) assessment at Week 39 Day 1 to reduce 
amount of blood draws for patients.

Table 8-1, Section 8.4.1 Laboratory evaluations, Table 8-3 Laboratory assessments: 
Added guidance that local platelet sampling should also be performed throughout the trial 
for adults and adolescents with body weight > 45kg. Patients < 45 kg will not have local 
platelet samples collected based on current guidance for blood volume collection.

Table 8-1: Footnote updated to clarify that only if an IRR occurs, blood samples should be 
collected immediately after the onset of the IRR.

Section 8.1 Screening: Modified re-screening language based on the impact of COVID-19 
and the changes to the inclusion/exclusion criteria across the different versions of the 
protocol. Added reference to Section 8.4.1.

Section 8.2 Patient demographics/other baseline characteristics: Rationale for patient 
demographic data collection added. Added language for concomitant medications and 
non-drug therapies collection for consistency with the rest of the protocol. Updated to 
reflect that healthcare resource utilization history including patient disease burden will be 
assessed. Added collection of coinheritance of alpha thalassemia as part of background 
medical information.

Section 8.3.1: updated header from “Albuminuria” to “Urine albumin to creatinine ratio” 
and clarified that creatinine concentrations will also be measured by the central laboratory.

Section 8.3.1 Urine albumin to creatinine ratio and Section 8.3.2 Urine protein and 
creatinine ratio: Additional clarifications and guidance added for urine sample collection

Section 8.4.1 Laboratory evaluations: removed re-sampling requirement for eligibility lab 
assessments and added detail that laboratory assessments can be repeated during the 
screening period. Clarified that local ACR and eGFR results should not be used for 
eligibility. Removed recommendation for using citrate tubes as there is no evidence from 
ongoing clinical trials that this reduces platelet clumping for samples analyzed via central 
laboratory. Added guidance that platelet count should also be assessed by local 
laboratories.

Section 8.4.2 Electrocardiogram (ECG): Removed language requiring results being 
reported on CRF as results will be captured centrally through vendor database. Additional 
guidance on ECGs collection added.

Figure 8-2 Timing of study procedures: Figure added.
 
 


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
Section 8.5.2.1 Pharmacokinetic and immunogenicity blood collection and handling and 
Table 8-6 Pharmacokinetics and immunogenicity blood collection logs: removed 
requirement for PK samples to be drawn prior to immunogenicity sample as order of 
sample collection is not expected to have impact on analysis.

Section 8.5.2.2 Analytical method: updated units from µg/mL to ng/mL for consistency 
with reporting units.
 

Section 8.5.5.2 Sickle cell vaso-occlusive crisis event and other acute pain crisis: Added 
recommendation to follow local guidance/practice for COVID-19 testing if the patient 
experiences a VOC/other APC and other subtypes of VOC events.

Section 9.1.1 Title updated from “Study treatment discontinuation and study 
discontinuation” to “Study treatment discontinuation.” New Section 9.1.2
“Discontinuation from study” added for clarity. Section language updated for 
clarifications on study treatment discontinuation and discontinuation from study.

Section 9.1.3: Title updated from “Withdrawal of informed consent” to “Withdrawal of 
informed consent/Opposition to use data/biological samples.” Text updated to define 
withdrawal of consent/opposition to use data/biological samples. Language updated to 
reflect use of data, including processing of biological samples after withdrawal of 
consent/opposition.

Section 9.1.4 Lost to follow-up: language updated to clarify status of patient who is
considered lost to follow-up.

Section 9.2 Study Completion and post-study treatment: clarified post-trial access 
language as there is no provision of comparator (SoC) after the study.

Section 10 Safety monitoring and reporting: added language for safety monitoring in the 
context of a public health emergency in the event on-site study visits are limited or 
prevented.

Section 10.1.3 SAE reporting: added language that SAEs should be reported immediately 
to Novartis to align with Health Authority requirements. Added additional language about 
SAE collection and reporting for clarity. 

Section 10.1.4 Pregnancy reporting: update language to match ICF that after consent is 
provided, the pregnancy reporting will occur up to one year after the estimated date of 
delivery. Added additional guidance for trial participants who become pregnant for 
consistency with the rest of the protocol.

Section 10.3 Protocol exempt adverse events and serious adverse events: added language 
to note that all details, procedures and hospitalizations related to VOCs will be collected 
and reported on the eCRF.

Section 12.3 Treatments: updated to remove “listed”


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
Section 12.4 Title updated from “Analysis of the primary endpoint(s)/estimands(s)” to 
“Analysis supporting primary objectives”

Section 12.4.3 Title updated from “Handling of missing 
values/censoring/discontinuations” to “Handling of intercurrent events of primary 
estimand.” Deleted the sentence “The imputation of missing data caused by intercurrent 
events will be handled by defining the estimand framework” as it is not technically 
accurate. Not all the intercurrent events will lead to missing data, intercurrent events and 
missing data are two different concepts.

Section 12.4.3 Handling of intercurrent events of primary estimand: Included the 
intercurrent event renal replacement therapy (i.e. hemodialysis, peritoneal dialysis, 
hemofiltration and kidney transplantation) as this is newly identified. Handling strategies 
of this intercurrent event was also added depending on different scenarios, define 
discontinuation due to renal replacement therapy as non-responders. For the patients who 
had hemodialysis and continued the treatment with their renal function return to within 
10% of their pre-AKI level, the hypothetical strategy will be applied.

Section 12.4.4 Title changed from “Supportive analysis” to “Sensitivity analysis.”
Updated the wording “supportive analyses” to “supplementary analyses.” Separated
sensitivity analysis to align with the primary estimands.

Added Section 12.4.5 Supplementary analysis: Updated the subgroup analysis on eGFR at 
baseline based on the inclusion criterion update on eGFR. Deleted the subgroup analysis 
on chronic NSAID use as there is no clear definition on chronic NSAID use. Updated 
“Supportive Estimands” to “Supplementary Estimands” as it is more in line with 
estimands terminology. 

Section 12.5 Title updated from “Analysis of secondary endpoints” to “Analysis 
supporting secondary objectives”

Section 12.5.2 Safety endpoints: Clarified that vital signs data and ECG data will be 
summarized and not listed. Updated language to clarify on-treatment and post-treatment 
period based on 105-day follow-up change.

Section 12.5.3 Pharmacokinetics: updated language to clarify descriptive summary 
statistics will be provide for the crizanlizumab + standard of care treatment arm.

Section 12.8 Sample size calculation: Reduced power from 85% to 80% resulting in 
sample size reduction from 170 to 148.

Section 15 References: updated reference list

Other administrative and editorial updates for clarity and consistency.
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.
Amendment 1 (08-Jul-2020)
Amendment rationale 
At the time of this amendment, 1 patient has been enrolled into the study.
The reasons why this amendment was undertaken was to refine the data collection for the 
assessment of the primary and secondary efficacy endpoints, reduce confounding factors, 
strengthen the primary estimand framework by providing additional clarity regarding the 
handling of intercurrent events and clarifying the summary measure, and providing additional 
clarity on the management of infusion related reactions. 
The collection window for urine samples to assess ACR and PCR was shortened due to the 
stability of urine samples (a clarification from the central laboratory was sent to all sites and a 
note to file dated 29-Aug-2019 was filed). It is emphasized that patients who discontinue from 
study treatment early should return for all of the assessments indicated in the Assessment 
Schedule, including ACR and other efficacy assessments. 
The stratification factor was updated from “CKD stage” to “CKD risk category” to include 
albuminuria, as well as eGFR, in the factor, as albuminuria also affects CKD outcomes. A new 
figure was added to define the CKD risk categories and, correspondingly, the subgroup analysis 
based on CKD stage was changed to be based on CKD risk category.
Additional guidance was provided on how to manage infusion-related reactions (IRRs), e.g. 
with regard to 

use of pre-medication as prophylaxis 

caution in the use of steroids 

slowing/reduction of infusion rate 
Blood sample collection was updated based on current data that suggest that administration 
of crizanlizumab can be associated with IRRs, including pain events, some of which can be 
severe and/or require hospitalization. In order to better characterize these IRRs, blood samples 
will be collected pre-dose and post-dose at different time points and analyzed for cytokines, 
complement analytes and tryptase.
EndariTM in United States of America (L-glutamine: hereafter referred to as HA approved 
form(s) of L-glutamine) was approved to reduce the acute complications of sickle cell disease 
in adult and pediatric patients 5 years and older in the United States in 2017. It is not known 
how EndariTM might affect the ACR values. Therefore, Health Authority (HA) approved 
form(s) of L-glutamine will be allowed only if the patient has been on a stable dose for the full 
6 months prior to screening and plans to continue on that dose.  Starting any new treatment with 
HA approved form(s) of L-glutamine during the study is now prohibited. Consistent with this, 
HA approved form(s) of L-glutamine has been added to the intercurrent event for the initiation 
or discontinuation of medications. Details to further define all intercurrent events have been 
added into the protocol with this amendment.


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OxbrytaTM (voxelotor: hereafter referred to as voxelotor) was approved by FDA on 25-Nov-
2019 for the treatment of sickle cell disease (SCD) in adult and pediatric patients 12 years of 
age and older. It is also not known how voxelotor might affect the ACR values. Therefore, the 
use of voxelotor is prohibited during the study and has been added to the intercurrent event 
estimand framework. 
Details of the primary analysis were revised to clarify that the test of the treatment effect will 
be based on the odds ratio estimated by the logistic regression model, and the null and 
alternative hypotheses were updated accordingly. It was added that the proportions of patients 
in each group with at least a 30% decrease in ACR will be presented along with a 95% 2-sided 
confidence interval for the difference in proportions. Sensitivity analyses of the primary 
endpoint to provide additional information regarding the treatment effect have been added, as 
have three new subgroup analyses to ascertain the treatment effect based on Hb, frequency of 
VOCs at baseline and chronic NSAID use. 
As albuminuria affects CKD outcomes, ACR was added into the stratification factor and 
analysis subgroup, which were revised from CKD stage (based on eGFR) to CKD risk category 
(based on ACR, as well as eGFR). Similarly, ACR was also incorporated into the definition of 
CKD progression.
Further review of the secondary endpoints led to clarifications concerning the PCR and PK 
endpoints.
 
Other changes were made to facilitate patient recruitment into the study, such as increasing the 
eGFR upper limit criteria, and adding the provision of a central laboratory for Hb 
electrophoresis if the country does not have local capabilities. Another such change was a
reduction in the dose requirements for SOC medications prior to study entry.
The partial blinding of the Novartis study team was removed due to the following challenges: 
unavoidable bias due to the fact that most Steering Committee (SC) members are investigators 
(they could be blinded to the aggregate data; however, they would not be blinded to their patient 
data), unavoidable bias which could occur by communication with the principal investigators, 
site staff and monitors who are unblinded and, finally, the necessity of a separate unblinded 
team to review the data. 
Finally, other changes were implemented to align the protocol with the overall crizanlizumab 
clinical trial program language, including replacement of the current drug or alcohol abuse 
exclusion criterion with a criterion based on a history of drug or alcohol abuse; changes to the 
process for the identification of adverse events of special interest; and the collection of data for 
acute pain crisis managed at home, which are protocol exempt AEs/SAEs.
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:


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Abbreviations: Added abbreviations for fetal hemoglobin (HbF), Health Authority (HA) and 
multiple imputation (MI), immunoglobulin G (IgG), standard of care (SOC), sickle cell anemia 
(SCA), antibody (Ab),  Kidney Disease Improving Global Outcomes (KDIGO), 
deoxyribonucleic acid (DNA), high-density lipoprotein (HDL), quality management system 
(QMS), coronavirus disease caused by SARS-COV-2 virus (COVID-19), low density 
lipoprotein (LDL), 
 
 
 hepatitis B surface antibody (HbsAb), hemoglobin A2 (HbA2), hemoglobin 
C (HbC), hemoglobin A (HbA), posteroanterior (PA), immunoglobulin (IG), acute pain crisis 
(APC),
, enzyme linked immunosorbent assay (ELISA), 
 
 physical component summary (PCS), mental 
component summary (MCS), activated partial thromboplastin time (APTT), Country pharma 
organization (CPO), 
 European Medicines Agency 
(EMA), high performance liquid chromatography (HPLC), mean corpuscular hemoglobin 
(MCH), minimally important difference (MID), mean corpuscular hemoglobin concentration 
(MCHC), 
 mean corpuscular volume (MCV), electronic 
serious adverse event (eSAE), intravenous immune globulin and (IVIG) and deleted LOCF and 
PAS.

Throughout: For clarity, added “/hydroxycarbamide” or “/HC” wherever hydroxyurea (HU) 
is mentioned.

Section 1.1.1: Added text that chronic organ damage due to SCD affects the liver, spleen, 
and eyes and added a summary from new publication on progression of albuminuria in 
sickle cell anemia (SCA)

Section 1.1.2: Clarified that the content of this section relates to treatment for SCN.

Section 1.1.4.1: Added text regarding the recent approval of crizanlizumab (Adakveo®) by 
the United States FDA.

Section 1.1.4.2: Deleted the reference to the Reprixys study code SelG1 as this is explained 
in the previous section.

Section 1.2.1: Clarified the grade of albuminuria in patients to be included in the study and 
updated with Farrell et al reference from ASH-FDA workshop.

Table 2-1, Section 8.3.5, Section 8.5.1.1 and Section 12.5.1: Consolidated the two PCR 
endpoints into a single endpoint assessing different categories of PCR improvement and 
stable and clarified that PCR improvement is defined as a ≥ 20% decrease in PCR from 
baseline.

Table 2-1: Replaced “PK parameter” in the secondary endpoint with “Crizanlizumab PK 
measurements” to avoid any confusion that traditional PK parameters will be assessed. 
Deleted “to evaluate the impact of immunogenicity on exposure (PK)” from the endpoint.
 
 
 


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
Table 2-1: Added measurement of vital signs and ECG assessments consistent with full list 
of secondary endpoints listed in Section 12.5.2

Section 3, Section 4.1.1, Section 4.3, Section 5.1 and Section 6.1: Clarified that patients 
included in this study must have been receiving at least one of the standard of care drug 
listed in the protocol. 

Section 3, Table 4-1, and Section 6.3.2: Updated the stratification factor from CKD stage to 
CKD risk category to include albuminuria, as well as eGFR, in the factor, as albuminuria 
also affects CKD outcomes. Added a new figure to define the CKD risk categories. 
Correspondingly, the subgroup analysis based on CKD stage was changed to be based on 
CKD risk category (Section 12.4.4).

Section 3: Added cross references to sections detailing the efficacy assessments.

Section 4.5: Expanded risk and benefit section to align with IB 10 and included additional 
information on IRRs. 

Section 4.5: Added language to risk and benefit section regarding the important potential 
risks of hemorrhages, infections, infusion related reactions and immunogenicity in line 
with phase III crizanlizumab clinical trial

Section 4.5: Added language to risk and benefit section regarding lack of evidence on 
mAb transmission in seminal fluid.

Section 5.1: Inclusion Criterion 3: Added that Hb electrophoresis to confirm the diagnosis 
of SCD can be done by a central laboratory if the country does not have local capabilities. 
Correspondingly, the requirement for local assessment was deleted from Table 8-1.

Section 5.1: Inclusion Criterion 6: Reduced the stable dose requirements for SOC from at 
least 6 months to at least 3 months prior to study entry for HU/HC. The dose requirements 
for ACEI/ARBs were changed to reduce the minimum duration of ACE inhibitor/ARB from 
6 months to 3 months prior to study entry. Correspondingly, the stable dose requirements 
were updated in Section 3, Section 4.1.1, Section 6.1, Section 6.5.1.2, Table 6-1 and Section 
8.3.5.

Section 5.1: Inclusion criterion 4: Increased upper limit of eGFR to ≤ 130 (women), ≤ 140 
(men) mg/min/1.73 m2 based on CKD-EPI formula. Correspondingly, Section 1.2.1, 
Section 3, Section 5, footnote of Figure 8-1, and Section 12.4.4 have been updated with this 
data.

Section 5.1: Inclusion criteria 8: updated for clarity (added “at the time of enrollment”)

Section 5.1: Inclusion criterion 11 was added: Up-to-date record of immunizations, as per 
local requirements

Section 5.2: Exclusion Criterion 3 blood pressure requirements were modified in line with 
the American Society of Hematology 2019 SCD guidelines.

Section 5.2: New Exclusion Criterion 4 added to exclude patients with a body mass index 
of ≥35 kg/m2

Section 5.2: Exclusion criteria 9: updated for clarity (added “defined as <25 g/L”)

Section 5.2: Exclusion Criterion 12 was modified to exclude any patients who have current 
or previous use of crizanlizumab within 12 months of screening. Section 5.2: New 
Exclusion Criterion 13 added to exclude patients currently on voxelotor or received 
voxelotor within 6 months of screening. 


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
Section 5.2: New Exclusion Criterion 15 added to exclude patients using HA approved 
form(s) of L-glutamine within 6 months prior to screening, unless it has been used at a stable 
dose for the full 6 months.

Section 5.2: New Exclusion Criterion 19 added to exclude patients with uncontrolled 
diabetes.

Section 5.2: Exclusion Criterion 24 (renumbered to 28), current drug or alcohol abuse, was 
replaced with a criterion to exclude patients with current drug or alcohol abuse as per 
investigator discretion. Correspondingly, the drug screen was deleted from Section 6.2.2, 
Table 8-1, Section 8.4.1, and Table 8-3.

Section 6.1: Added a new table and text to clarify the standard of care requirements, which 
have been updated. 

Section 6.1: Clarified that evidence that the patients have been receiving the standard of 
care medication(s) at a stable dose should be documented in the source documents.

Section 6.1.5 and Section 9.2: Added that Post-Trial Access (PTA) to crizanlizumab also 
applies to patients randomized to the standard of care alone arm if the study results show 
superiority of crizanlizumab + standard of care.

Section 6.2.1: Clarified that NSAID use should be avoided within 48 hours prior to ACR 
measurement.

Section 6.2.1.1: Language added on recommendations for pre-medication.

Section 6.2.1.1: Added an instruction for investigators to contact the Novartis medical 
monitor regarding the collection of PK/PD samples before and after transfusions.
Section 6.2.1.1: Clarified that use of HA approved form(s) of L-glutamine is permitted as 
long as the dose is stable for 6 months before screening. 

Section 6.2.2: Added voxelotor as prohibited medication.

Section 6.2.2: Added that starting any new treatment with HA approved form(s) of 
L-glutamine from within 6 months prior to study entry up to the end of the study is 
prohibited.

Section 6.4: Treatment blinding: Changed the language to remove partial blinding of the 
Novartis study team and deleted the Blinding and unblinding plan (previous table 6-2). 

Section 6.5.1.1 Added recommendation about COVID-19.

Section 6.5.1.1: Table 6-3 updated regarding management of IRRs.

Section 6.5.1.2: Amended heading to specify that the standard of care is for SCD-related 
CKD. 

Section 6.5.2: updated to include follow up of toxicities with addition of measuring 
cytokines, complement, tryptase and p-selectin.

Section 8, Section 8.3, Section 8.3.1, and Table 8-1: Added text to emphasize that patients 
who discontinue study treatment early should not be considered withdrawn from the study 
unless they withdraw their consent. Where possible, they should return for all of the 
assessments indicated in Table 8-1, including ACR, and other efficacy assessments.

Table 8-1 and Section 8.4.1.1: Added an assessment for fetal hemoglobin (HbF) and noted 
that the baseline HbF data will be recorded (Section 8.2).


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
Table 8-1: Added a footnote that other acute pain crises managed at home will also be 
collected. Correspondingly, the definition of other acute pain crisis managed at home was 
added (Section 8.5.5.2); Table 8-8 was updated with respect to the collection plan for other 
acute pain crisis; and other acute pain crisis was added as a protocol exempt AE (see the 
change for Section 10.3 below).

Table 8-1: Added a footnote to clarify safety procedures should be done as described on 
Table 8-2.

Section 8.3.1 and Section 8.3.2: Shortened the 7-day window for the collection of urine 
samples to assess albumin to creatinine and protein to creatinine ratios due to the stability 
of the urine samples. Per the revised schedule, patients will collect two of the three samples 
as first morning voids the day before and the morning of the applicable visits. The third 
sample will be taken during the patient’s visit.

Section 8.3.2: Added text to emphasize that patients who discontinue study treatment early 
should return for all of the assessments indicated in Table 8-1, including PCR.

Section 8.3.4 and Section 8.3.5: The method to assess CKD progression was updated to 
include ACR in addition to eGFR and Figure 8-1 was added for clarity.

Section 8.3.5: Added stable dose requirements for HA approved form(s) of L-glutamine use 
and provided the reason for these requirements and updated with Farrell et al reference from 
ASH-FDA workshop.

Table 8-2: Clarified that blood pressure will be based on an average of 3 measurements to 
reflect standard clinical practice.

Table 8-3 : Added RNA testing for viral load for consistency with the exclusion criterion.

Section 8.4.2, Table 8-4 and Section 12.5.2: Changed local ECG interpretation to 
interpretation by a central reader to improve standardization of ECG interpretations.
 

Section 8.4.5: clarified that diagnostic evaluation for the AKI event would be based on AKI 
stages 1, 2 and 3 from KDIGO 2012 guidelines

Section 8.5.2 and Section 12.5.3: Clarified that crizanlizumab pre-dose/trough PK samples 
will be collected along with the immunogenicity samples and will be used to evaluate the 
impact of immunogenicity on exposure (PK).

Section 8.5.3, Table 8-1, Table 8-3: Added cytokines, complement, tryptase and p-selectin 
collection.

Section 10.1.1: Revised the plan for the identification of AEs of special interest (AESIs). 
AESIs will not be identified by investigators based on an AESI list included in the eCRF, 
but will be identified at the analysis stage based on the AESIs included in the most recent 
version of the electronic case retrieval sheet for crizanlizumab trials available at the time of 
a database lock for an analysis.

Section 10.1.1: Added eGFR ranges for CTCAE Grade 1 and 2 AEs of CKD progression.

Section 10.2.3: Added SCD experts to the list of Steering Committee members.


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
Section 10.3: Added that other acute pain crises managed at home will be protocol exempt 
AEs/SAEs for consistency with the protocol exempt AEs/SAEs implemented in the SEG101 
program.

Section 10.3: Clarified reporting of VOC events.

Section 12.1: Section 12.1.3 was deleted the PK Analysis Set (PAS), as there will not be a 
PAS in this study. 

Section 12.4.2 and Section 12.4.3: Updated the details of the primary endpoint analysis to 
clarify that the test of the treatment effect will be based on the odds ratio estimated by the 
logistic regression model rather than the proportions of patients with a ≥30% decrease in 
ACR. The null and alternative hypotheses were correspondingly updated to be based on the 
odds ratio, as was the summary measure in the primary estimand framework. It was added 
that the proportions of patients in each group with at least a 30% decrease in ACR will be 
presented along with a 95% 2-sided confidence interval for the difference in proportions. 

Section 12.4.3 and Table 12-1: The primary estimand framework was updated with respect 
to the target population, addition of HA approved form(s) of L-glutamine and voxelotor into 
the intercurrent events, and modification of the summary measure to be based on the odds 
ratio of the treatment effect. Further details were added regarding the handling of 
intercurrent events.

Section 12.4.4: Supportive analyses of the primary efficacy endpoint were added to assess 
the effect of including all patients who discontinued treatment prior to the 12month 
assessment as non-responders, and the effect of including all observed on study data 
regardless of the usage of NSAIDs.

Section 12.4.4: Amended the subgroup analysis of CKD stage to be based on CKD risk at 
baseline (see the Section 3 change listed above); clarified that the subgroup analyses based 
on HU/HC use and age will be based on categories at baseline; and specified the race 
subgroups as this is now possible based on the countries of expected recruitment.

Section 12.4.4: Added three new subgroup analyses, based on chronic NSAID use, Hb at 
baseline and the frequency of VOCs at baseline.

Section 12.5: Added clarifications regarding the secondary endpoints; moved the text 
summarizing the analysis sets to be used into this section.

Section 12.5.2: Included cytokines, complement, tryptase and p-selection as part of the 
laboratory assessments for safety monitoring.
 
 

Section 12.8: Changed the sample size calculation to be based on a two sample z test (and 
not a two sample t test).

Section 15: Added the following additional references: Brandow et al., Farrell et al, Niss et 
al, Asnani and O’Lynch, Emerson and Lutty, Liem et al, and Saunthararajah and Vichinsky. 
The same changes were made wherever applicable in the protocol summary.
Additional minor changes such as the correction of typographical errors were also made.


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IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Protocol summary
Protocol number
CSEG101A2203
Full Title
A Phase II, multicenter, randomized, open label two arm study evaluating the
effect of crizanlizumab + standard of care and standard of care alone on renal 
function in sickle cell disease patients ≥16 years with chronic kidney disease 
due to sickle cell nephropathy (STEADFAST)
Brief title
Study exploring the effect of crizanlizumab on kidney function in patients with 
chronic kidney disease caused by sickle cell disease
Sponsor and 
Clinical Phase
Novartis/Phase II
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this study is to explore the effect of P-selectin inhibition with 
crizanlizumab on renal function in sickle cell disease (SCD) patients with 
chronic kidney disease (CKD) who are receiving standard of care 
medications for SCD-related CKD, have Grade A2 to A3 albuminuria and 
Stage 1-3a CKD, and who are at higher risk of rapid decline in their estimated 
glomerular filtration rate.
The presence of P-selectin expression in the kidneys has been established 
based on in vitro and in vivo data, and there is evidence that P-selectin is 
upregulated in the kidney in response to renal ischemia-reperfusion injury in 
SCD. Expression of P-selectin in a glomerulonephritis induced mouse model 
was associated with rapid accumulation of neutrophils in glomeruli and 
significant proteinuria. P-selectin inhibition in this model was shown to abrogate 
glomerular neutrophil accumulation and prevented development of proteinuria. 
It is assumed that administration of crizanlizumab, a P-selectin inhibitor, might 
have a beneficial effect in SCD patients with CKD by blocking P-selectin 
mediated multicellular adhesion (including leukocytes), and proteinuria, and 
also reducing vaso-occlusion and potentially its downstream effects in the renal
vasculature, which can be clinically demonstrated by a decrease in proteinuria 
and slowing the decline in glomerular filtration rate (GFR). 
Primary Objective 
The primary objective of this study is to evaluate descriptively the effect of 
crizanlizumab + standard of care and standard of care alone on albuminuria 
(ACR) decrease at 12 months, as assessed by the proportion of patients with 
≥30% decrease in ACR at 12 months from baseline.
The primary clinical question of interest is: What is the effect of crizanlizumab 
+ standard of care and standard of care alone on renal function in SCD patients 
with SCD-related CKD.


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Secondary 
Objectives

To evaluate descriptively the effect of crizanlizumab + standard of care and
standard of care alone on change in albuminuria (ACR), as assessed by 
the mean change in ACR from baseline to 3, 6, 9, and 12 months of 
treatment

To evaluate descriptively the effect of crizanlizumab + standard of care and
standard of care alone on albuminuria (ACR) decrease at 6 months, as 
assessed by the proportion of patients with ≥30% decrease in ACR at 
6 months from baseline

To evaluate descriptively the effect of crizanlizumab + standard of care and
standard of care alone on protein to creatinine ratio (PCR) at 12 months, 
as assessed by the proportion of patients with PCR improvement and 
stable PCR (improvement: ≥20% decrease in PCR from baseline; stable: 
within ± 20% change from baseline) at 12 months from baseline

To evaluate descriptively the effect of crizanlizumab + standard of care and
standard of care alone on the percentage change in eGFR, as assessed 
by the percentage change in eGFR from baseline to 3, 6, 9, and 12 months 
of treatment

To evaluate descriptively the effect of crizanlizumab + standard of care and
standard of care alone on ACR decline rate, as assessed by the slope of 
ACR decline from baseline to 12 months of treatment based on ACR 
values at baseline and at 3, 6, 9, and 12 months

To evaluate descriptively the effect of crizanlizumab + standard of care and
standard of care alone on eGFR decline rate, as assessed by the slope of 
eGFR decline from baseline to 12 months of treatment based on eGFR 
values at baseline and at 3, 6, 9, and 12 months

To evaluate descriptively the effect of crizanlizumab + standard of care and
standard of care alone on the progression of CKD at 12 months, as 
assessed by the proportion of patients with progression of CKD from 
baseline to 12 months

To evaluate descriptively overall safety and, tolerability of crizanlizumab + 
standard of care and standard of care alone, as assessed by the frequency 
and severity of adverse events (AEs), deaths, measurement of vital signs, 
ECG assessments, serious AEs (SAEs), and laboratory abnormalities

To assess descriptively the immunogenicity of crizanlizumab over the 
study period (treatment of 1 year + 105 days of follow-up), as assessed by 
measurement of anti-drug antibodies to crizanlizumab at select time points; 
crizanlizumab pharmacokinetic (PK) measurements will accompany 
immunogenicity measurements

To evaluate descriptively healthcare resource utilization (visits to 
emergency room (ER) and hospitalizations) in crizanlizumab + standard of 
care arm and standard of care alone, as assessed by the annualized rate 
of visits to ER and hospitalizations due to acute kidney injury (AKI) events, 
vaso-occlusive crises (VOCs), or other SCD complications
Study design
This is a multicenter, randomized two arm, open label study to evaluate 
descriptively the effect of crizanlizumab + standard of care and standard of 
care alone on renal function in SCD patients with SCD-related CKD. 
Approximately 50
patients will be randomized 1:1 to receive either 
crizanlizumab (5 mg/kg) + standard of care or standard of care alone. Patients 
will be stratified at randomization based on CKD risk category (moderate risk 
or high/very high risk) and HU/HC prescription (Yes/No). The CKD risk 


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categories used for stratification are based on both eGFR and albuminuria 
assessed by ACR.
Population
This study will include patients aged > 16 years with SCD-related CKD. 
Homozygous hemoglobin (Hb) S (sickle cell anemia) (HbSS) and Hb S (HbS) 
with β-thalassemia (HbSβ0-thal) SCD genotypes are eligible. Eligible patients 
will have an eGFR of ≥45 to ≤ 140 mL/min/1.73 m2 and an ACR of ≥100 to 
< 2000 mg/g; based on previous studies, this population of patients will likely 
include patients at risk for rapid eGFR decline.
Key Inclusion 
criteria

Male and female patients ≥16 years on the day that signed informed 
consent is obtained

Confirmed diagnosis of SCD by hemoglobin (Hb) electrophoresis by a 
central laboratory if the country does not have local capabilities) or high 
performance liquid chromatography (performed locally). HbSS and 
HbSβ0-thal SCD genotypes are eligible

Patients with eGFR ≥45 to ≤140mL/min/1.73 m2 based on Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) formula (patients ≥ 18) or 
the Creatinine-based “Bedside Schwartz” equation (patients < 18)

Patients with ACR of ≥100 to < 2000 mg/g (taken as an average of the 
three screening ACR values to determine eligibility).

Receiving at least 1 standard of care drug(s) for SCD-related CKD 
according to local guidelines. If receiving HU/HC, the patient must have 
been receiving HU/HC for at least 6 months and on a stable dose for 3 
months prior to study entry. If receiving an ACE inhibitor and/or ARB the 
patient must have been receiving the drug for 3 months and also on a 
stable dose for those 3 months prior to study entry, in all cases, patients 
must plan to continue taking the drug(s) at the same dose and schedule 
until the patient has reached the end of the study.

Hb ≥4.0 g/dL, absolute neutrophil count ≥1.0 x 109/L, and platelet count 
≥75 x 109/L

Patients who are clinically stable and are in a non-crisis state at the time 
of enrollment
Key Exclusion 
criteria

History of stem cell transplant

Patients with evidence of AKI within 3 months of study entry (can decrease 
interval to within 6 weeks of study entry only if renal function has returned 
to pre-AKI values prior to study entry)

Blood pressure > 140/90 mmHg despite treatment

Patients undergoing renal replacement therapy
(i.e. hemodialysis, 
peritoneal dialysis, hemofiltration and kidney transplantation) 

Received blood products within 30 days of Week 1 Day 1

Participating in a chronic transfusion program (pre-planned series of 
transfusions 
for 
prophylactic 
purposes). 
Transfusions 
for 
acute 
complications are permitted (acute chest syndrome, acute splenic 
sequestration, acute hepatic sequestration, worsened anemia)

History of kidney transplant

Patients with hypoalbuminemia defined as <25 g/L

Patient has received crizanlizumab and/or other selectin inhibitor or plans 
to receive it during the duration of the study. Use of HA approved form(s) 


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of L-glutamine within 6 months of screening, unless it has been used at a 
stable dose for the full 6 months

Currently on voxelotor or received voxelotor within 6 months of screening 

Patients with active human immunodeficiency virus, Hepatitis B and 
Hepatitis C infection

Evidence of CKD attributed to causes other than SCN

Evidence of current drug or alcohol abuse per investigator discretion
Study treatment
Patients will be randomly assigned to one of the following treatment arms in a 
ratio of 1:1:

Crizanlizumab + standard of care

Standard of care alone
Patients with SCD-related CKD will likely be receiving at least one of the 
following medications – HU/HC, ACE inhibitors, and/or ARBs, as established 
prior to study entry, and this will be considered their standard of care (patients 
included in this study must have been receiving at least one of these drugs). 
The efficacy of crizanlizumab added to standard of care and standard of care 
alone will be evaluated descriptively.
The patient will continue to take their usual standard of care drug(s) during the 
study; thus, there may be some variation in the standard of care regimens used 
by patients in the study. 
Efficacy 
assessments

Urine ACR

Urine PCR

eGFR (CKD-EPI formula (patients ≥ 18) or Creatinine-based “Bedside 
Schwartz” equation (2009) (in patients < 18))

Progression of CKD
PK assessments 
Crizanlizumab pre-dose/trough PK samples will be collected to accompany the 
immunogenicity samples in patients randomized to the crizanlizumab + 
standard of care arm to evaluate the impact of immunogenicity on exposure 
Key safety 
assessments

Monitoring and recording AEs based on Common Terminology Criteria for 
Adverse Events v5.0

Laboratory assessments, including hematology, cytokines, complement, 
tryptase, p-selectin, clinical chemistry, and urinalysis

Vitals signs and physical examination

Electrocardiogram (ECG)

Immunogenicity (assessed only in patients randomized to crizanlizumab + 
standard of care)

Resource utilization due to AKI, VOCs, and/or other SCD complications


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Data analysis
The primary endpoint, proportion of patients with ≥30% decrease in ACR at 
12 months from baseline, will be descriptively summarized based on the data 
from the Full Analysis Set (FAS). A logistic regression model that includes 
effects for treatment and randomization stratification factors will be utilized. 
Patients will be stratified at randomization based on CKD risk category 
(moderate risk or high/very high risk) and HU/HC prescription (Yes/No). The 
treatment effect based on the log-odds ratio will be estimated by the model. 
The odds ratio for the relative difference between treatments in the primary 
endpoint, and its corresponding 95% confidence interval, will be presented. In 
addition, the proportions of patients in each group with at least a 30% 
decrease in ACR will be presented, along with a 95% 2-sided confidence 
interval for the difference in proportions.
The secondary efficacy endpoints will be summarized using the FAS.
The mean change in ACR from baseline will be analyzed using an Analysis of
Covariance 
(ANCOVA) 
model 
that 
includes 
effects 
for 
treatment, 
randomization stratification factors, and baseline ACR.
The slope of ACR decline and the slope of eGFR decline will be estimated as 
a random coefficient in a linear mixed effect model.
For the percentage change in eGFR from baseline, an ANCOVA model that 
includes effects for treatment, HU/HC use (Yes vs No), and baseline eGFR, 
will be carried out for analysis using a logarithmic scale.
The proportion related secondary efficacy endpoints will be descriptively 
presented by the same statistical methods described for the primary endpoint.
For all safety analyses, the Safety Set will be used. AEs, vital signs, 12-lead 
ECG, clinical laboratory evaluations, immunogenicity data will be summarized.
Annualized rate of visits to ER and hospitalizations due to AKI events, VOCs, 
or other SCD complications will be used to evaluate the healthcare resource 
utilization (visits to clinic, ER and hospitalizations) in crizanlizumab + standard 
of care arm and standard of care alone.
Key words
Sickle cell disease; sickle cell nephropathy; chronic kidney disease; albumin 
to creatinine ratio (ACR); albuminuria; estimated glomerular filtration rate 
(eGFR); protein to creatinine ratio (PCR); crizanlizumab + standard of care


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1
Introduction
1.1
Background
1.1.1
Overview of sickle cell disease pathogenesis
Sickle cell disease (SCD) is a rare autosomal recessive blood disorder caused by a single 
missense mutation (Glu6Val) in the β-globin gene. It is the most common single gene disorder 
in African Americans, affecting approximately 1 in 375-600 people of African ancestry 
(Nietert et al 2002). Sickle cell disease is also common among people in Mediterranean 
countries, Africa, Middle East, India, Caribbean, and parts of South and Central America. The 
most severe forms of SCD are homozygous hemoglobin (Hb) S (sickle cell anemia) (HbSS) and 
the heterozygous form Hb S (HbS) with β-thalassemia (HbSβ0-thal) (Ware et al 2017).
The Glu6Val mutation in the β-globin gene renders the mutant Hb less soluble and prone to 
polymerization upon deoxygenation. The polymerization of Hb causes deformation of red blood 
cells (RBCs) to give them a sickle shape (Bookchin and Lew 1996), and leads to chronic 
hemolysis, anemia, and vaso-occlusion (Wethers 2000). In SCD, sickled RBCs, leukocytes, 
platelets, and the endothelium are activated due to the chronic pro-inflammatory state. In turn,
these circulating cells adhere to one another and to the microvasculature, resulting in 
vaso-occlusive events. Vaso-occlusion can in turn lead to vaso-occlusive crisis (VOC), which 
is the hallmark of the disease, as well as contributing to end organ damage (Powars et al 2005). 
Organ-specific vasculopathy often precedes clinical manifestations, decreases patient survival, 
and can occur in patients with SCD who do not have recurrent pain (Kassim and DeBaun 2013, 
Hoffmann et al 2013).
Common manifestations of SCD other than recurrent painful VOCs, include, but are not limited 
to chronic hemolytic anemia and chronic organ damage affecting the bones, brain, heart, 
kidneys, lungs, liver, spleen, eyes, and skin (Emerson and Lutty 2005, Saunthararajah and 
Vichinsky 2018). The manifestations of SCD start within the first few months of life as fetal 
Hb (HbF) levels decline as HbS levels increase.
Sickle cell disease is a complex disease and certain manifestations tend to be more common 
depending on the patient’s age. For example, certain infections and manifestations involving 
the spleen tend to predominate in children aged between 1 and 3 years, between 12 and 20 years, 
strokes, priapism, and pain crises are predominant. More chronic complications such as renal 
insufficiency and pulmonary hypertension begin to appear in adults aged 20 to 30 years. 
Chronic Kidney Disease (CKD) and congestive heart failure are among the predominant 
manifestations in adults with SCD aged over 30 years.
Sickle cell nephropathy (SCN) refers to the spectrum of renal complications in SCD which first 
manifest in early childhood. Some patients progress to CKD, which is diagnosed when 
abnormalities of kidney structure or function are present for more than 3 months and is 
classified in five stages (1-5) according to the level of GFR (irrespective of underlying CKD 
etiology). The higher the CKD stage, the worse are the implications for health. Each stage is 
further categorized by the degree of albuminuria; increases in albuminuria are correlated with 
greater risk of progressing to a higher CKD stage, (KDIGO 2013). The prevalence of CKD in 
patients with SCD increases with age, is associated with poor outcomes and progresses to 
end-stage renal disease (stage 5) in around 12% of patients (Powars et al 2005; Gosmanova et 


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al 2014). Risk factors associated with increased mortality among patients with SCD include 
proteinuria and reduced eGFR; approximately 16 to 18% of overall mortality in these patients 
is attributed to kidney disease (Nath and Hebbel 2015). Development of SCN is complex and 
several pathophysiological mechanisms have been proposed to explain its development. Vaso-
occlusion and hemolysis contribute substantially to the manifestations of SCN, which include 
glomerulopathies (such as hyperfiltration and proteinuria/albuminuria), hematuria, and tubular 
defects (Schnog et al 2004, Nasr et al 2006, Sharpe and Thein 2014, Hariri et al 2018). Focal 
segmental glomerulosclerosis (FSGS) and its variants are the major glomerular lesions.
Impaired urinary concentration and hyperfiltration are the earliest renal complications seen in 
patients with SCD. Hyperfiltration manifests as an increase in the glomerular filtration rate 
(eGFR) from a young age and can be defined as estimated GFR > 130 mL/min/1.73 m2 (Yee et 
al 2017). Hyperfiltration is most common in younger individuals and is associated with markers 
of excess hemolysis and increased renal plasma flow, most likely due to increased effective 
glomerular filtration surface area (glomerular enlargement) caused by raised pressure within 
each glomerulus (Haymann et al 2010; Hirschberg 2010). Over time, this raised glomerular 
pressure results in damage to the glomerular filtration barrier, leading to albuminuria which can, 
over time, progress as the damage gets worse. Eventually, damaged glomeruli scar (sclerose) 
and the nephron associated with that glomerulus is lost. As more nephrons are lost, the total 
GFR falls back towards the normal range, though this is made up of higher single nephron GFRs 
in fewer total nephrons than in a healthy kidney.  As the patient ages and this process continues, 
CKD progresses and the GFR continues to drop below the normal range as more nephrons are 
lost. As nephrons are lost, the pressure in the remaining nephrons increases exacerbating 
proteinuria and further decline. The proposed sequence of events described above, lead to 
worsening albuminuria and ultimately CKD and are mirrored in other causes of CKD such as 
diabetic nephropathy (Haymann et al 2017). 
GFR is estimated from serum creatinine levels. The recommended equation for calculating 
eGFR is the CKD Epidemiology Collaboration (CKD-EPI) formula, which matches the 
accuracy of the Modification of Diet in Renal Disease (MDRD) equation at glomerular filtration 
rates (GFRs) < 60 mL/min/1.73 m2 and offers greater accuracy at higher GFRs (Florkowski and 
Chew-Harris 2011). Further, among the typical estimating equations, the CKD-EPI formula 
appears to perform the best among sickle cell disease patients (Asnani and O’Neil Lynch 2013). 
The Creatinine-based “Bedside Schwartz” equation (2009) is recommended to calculate eGFR 
in those <18 years of age. The Schwartz equation to calculate eGFR in children has been 
recommended since 1970.  Recent data shows that the original Schwartz formula overestimates 
GFR based on new methods of creatinine calculation and thus an updated equation was used to 
calculate GFR based on data from 349 children.  This new formula called the “Bedside Schwartz” 
formula was noted to be the most accurate formula to avoid overestimation of eGFR in children 
(Schwartz et al 2009).
Microalbuminuria (30-300 mg/gram creatinine) is the earliest manifestation of hyperfiltration 
leading to glomerular injury in patients with SCD and marks the onset of sickle cell nephropathy 
(Bartolucci et al 2016). When assessed either as microalbuminuria or macroalbuminuria 
(> 300 mg/gram creatinine), proteinuria occurs in approximately 20% of patients in the first 
two decades, to 68% of older patients with HbSS (Guasch et al 2006; McPhearson et al 2011; 
Bartolucci et al 2016). Albuminuria is more common among patients with severe SCD 


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genotypes (HbSS and HbSβ0-thal) than milder genotypes (Guasch et al 2006; Derebail et al 
2019) and is a strong predictor of subsequent progression of CKD (Sasongko et al 2015). 
In a recent prospective, multicenter, longitudinal study evaluating 303 patients with SCA (HbSS 
and HbSβ0-thal) it was noted that patients with baseline albuminuria ≥100 mg/g developed 
persistent albuminuria and reinforced that persistent albuminuria was associated with rapid 
eGFR decline and CKD development in adults with SCA (Niss et al 2020).
Patients with albuminuria and SCD also exhibit increased urinary excretion markers of tubular 
injury (kidney injury molecule-1 [KIM-1] and N-acetyl-β-D-glycosaminidase [NAG]) 
(Nath and Hebbel 2015). Acute kidney injury (AKI) has been found to occur in approximately 
46% of patients with HbSS and HbSβ0-thal, and AKI and AKI severity are independent risk 
factors for CKD progression (Saraf et al 2018).
1.1.2
Current treatment for sickle cell nephropathy
There are no prospective randomized data demonstrating a long term benefit of any treatments 
for SCD-related CKD and no treatments are approved for this indication. Thus, treatment for 
SCD-related CKD is currently based on data obtained from clinical situations outside of SCD 
and short-term studies in SCD. These treatments typically consist of angiotensin converting 
enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and/or hydroxyurea 
(HU)/hydroxycarbamide (HC).
Angiotensin converting enzyme inhibitors reduce glomerular pressure and are used extensively 
in a variety of clinical situations outside of SCD. It is common practice to administer ACE 
inhibitors for patients with SCN due to their renoprotective properties, but little is known about 
their effectiveness and safety in this setting. A Cochrane review revealed five studies evaluating 
ACE inhibitors in SCD patients but only one study with 22 adult participants met the criteria to 
be included in the review, a randomized or quasirandomized controlled trial of ACE inhibitors 
(captopril) designed to reduce microalbuminuria and proteinuria in patients with SCD compared 
to either placebo or standard treatment regimen (Sasongko et al 2015). At 6 months, there was 
no significant difference in urinary albumin excretion between the two groups, but the absolute 
change did show significant changes between the two groups, with a mean difference of 
63 mg/24hours (95% confidence interval [CI]: -93.78 to -32.22). The authors of the Cochrane 
review concluded that though there is the potential for improvement with ACE inhibitors, there 
is not enough evidence to show that the administration of ACE inhibitors is associated with a 
reduction of microalbuminuria and proteinuria in patients with SCD (Sasongko et al 2015).
More recently, in a study of 42 adult HbSS patients with SCN (urine albumin to creatinine ratio 
(ACR) > 10 mg/mmol, treatment with ACE inhibitors led to a decrease in ACR from baseline 
at 6 months of > 30% in 62% of patients (mean ACR: 46.4 ± 7.6 and 26.4 ± 3.9 mg/mmol at 
baseline and 6 months respectively; P = 0.002). Furthermore, an ACR decrease was detected at 
1 month following initiation of ACE inhibitor treatment (32.9 ± 6.9, P = 0.02). Of note, 
approximately 
45% 
of 
patients 
were 
also 
receiving 
concomitant 
hydroxyurea/hydroxycarbamide (HU/HC) (Haymann et al 2017).
The reduction of proteinuria after treatment with an ARB has been studied as a secondary 
endpoint in 1513 patients with Type 2 diabetes and nephropathy. Losartan (an ARB) reduced 
the level of proteinuria, with an average ACR reduction of 35% after an average of 3.4 years 


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follow-up, whereas the urine ACR increased in the placebo group. The risk of end-stage renal 
disease was reduced by 28% with losartan versus the placebo group (Brenner et al 2001).
HU/HC is commonly used to treat SCD. Studies have indicated that HU/HC is associated with 
a lower prevalence of albuminuria in adults with SCD. In a cohort study of 58 adults with SCD 
who had not simultaneously received ACE inhibitors, the ACR in the patients taking HU/HC 
was significantly lower after 6 months of treatment with HU/HC with median ACR declining 
from 3.0 mg/mmol at baseline to 1.7 mg/mmol at 6 months. The results suggested that 6 months 
of HU/HC significantly attenuated the microalbuminuria observed during the early stages of 
SCN (Bartolucci et al 2016). Similarly, in a study of 149 adult patients with SCD, the 
prevalence of albuminuria (assessed by urine dipstick) was lower in the patients on HU/HC 
compared with patients not receiving HU/HC (34.7% vs. 55.4%, respectively; p = 0.01), as was 
median albumin excretion (17.9 mg/g vs. 40.5 mg/g; p = 0.04) (Laurin et al 2014).
1.1.3
Role of P-selectin in sickle cell disease 
A component of the innate immune system, P-selectin initiates binding between leukocytes, 
platelets, and the endothelium at sites of inflammation during infection and injury. Normally 
this is a beneficial process, but when activation of these cells occurs unnecessarily or is 
excessive, P-selectin-mediated cell-cell interactions can cause a cascade of events culminating 
in disease. Multiple human and mouse studies relating to SCD have demonstrated that 
P-selectin initiates binding between sickled RBCs, leukocytes, platelets, and the 
microvasculature. Further, blockade of, or targeted gene knock out of, P-selectin abrogates 
these interactions and prevents vaso-occlusion. Please refer to the crizanlizumab Investigator’s 
Brochure (IB) for details.
1.1.4
Introduction to crizanlizumab
1.1.4.1
Crizanlizumab (SEG101)
Crizanlizumab is a selective humanized monoclonal antibody (mAb) that binds to P-selectin 
with high affinity, blocking its interaction with its ligands, including P-selectin glycoprotein 
ligand-1.
Crizanlizumab was originally developed by Reprixys Pharmaceuticals Corporation under the 
investigational drug code SelG1 (completed studies SelG1-00003. Novartis study code: 
CSEG101A2101) and Se1G1-00005 (Novartis study code: CSEG101A2201). Novartis 
acquired the company on 18-Nov-2016, and is now the drug developer and sponsor for 
crizanlizumab, under the investigational drug code, SEG101. A Phase I study 
(CSEG101A2102) evaluated the pharmacokinetic (PK) and pharmacodynamic (PD) 
comparability of SelG1 and SEG101 at 5 mg/kg and 7.5 mg/kg doses in healthy volunteers. 
Results are available from an ongoing Phase II study (CSEG101A2202) to assess the PK/PD of 
crizanlizumab with or without HU/HC in adult SCD patients with VOC (Section 4.5).
Crizanlizumab was first authorized in the US on 15-Nov-2019 and is now authorized in more 
than 40 countries for the prevention/reduction of VOCs in adults and pediatric patients aged 
16 years and older with SCD under the invented names (Adakveo®/Ryverna®/Chylotrez®).
The approval was based on safety and efficacy data from the Phase II SUSTAIN study 
(Ataga et al 2017; see Section 1.1.4.2) below.   


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The crizanlizumab IB provides detailed information related to toxicology, non-clinical 
pharmacology, drug properties, clinical and pre-clinical data.
1.1.4.2
Phase II Clinical Study (SUSTAIN study CSEG101A2201)
The objective of this pivotal, randomized, placebo-controlled study was to assess the safety and 
efficacy of crizanlizumab with or without HU/HC therapy in SCD patients with a history of 
VOC leading to a healthcare visit. A total of 198 SCD patients aged 16 to 63 years (inclusive), 
with any SCD genotype, a history of crises within the previous 12 months, and either with a 
steady dose of HU/HC or not taking HU/HC, were randomized 1:1:1 to crizanlizumab 
5.0 mg/kg, crizanlizumab 2.5 mg/kg or placebo.
The median annual rate of VOC leading to a healthcare visit was 45.3% lower with 5 mg/kg 
crizanlizumab than with placebo (Hodges-Lehmann, median absolute difference of -1.01 versus 
placebo, 95% CI -2.00, 0.00). The difference between the 5 mg/kg arm and placebo arm was 
statistically significant (Wilcoxon rank sum test, p = 0.010). The median annual rate of 
uncomplicated crises and median number of days hospitalized, were 62.9% and 41.8% lower 
in the 5.0 mg/kg than in the placebo group, respectively. Crizanlizumab also delayed the time 
to onset of first and second VOC, and consistent benefit was further observed in a number of 
clinically relevant subgroups for the primary endpoint. Though patients on the 2.5 mg/kg dose 
showed reductions in VOCs, these were not statistically significantly different from placebo. 
Crizanlizumab was generally well tolerated with similar incidence of treatment-emergent 
adverse events (TEAEs) across the three groups, and overall low incidence of discontinuations 
due to TEAEs (<5%). The proportion of patients experiencing serious adverse events (SAEs) 
was 25.8% at 5.0 mg/kg, 31.3% at 2.5 mg/kg, and 27.4% in the placebo group. There were 
five deaths during the study (two at 5.0 mg/kg, one at 2.5 mg/kg, and two in the placebo group), 
and none was deemed to be treatment-related. Please refer to IB for further information.
Overall, treatment of SCD patients with crizanlizumab at 5.0 mg/kg showed positive clinical 
activity as demonstrated by a statistically significant and clinically relevant decrease in the 
annual VOC rate compared with placebo and it was also found to be well tolerated 
(Ataga et al 2017). Accordingly, the recommended dose of crizanlizumab for future studies is 
5 mg/kg dose and no studies are currently planned with the 2.5 mg/kg dose.
A post hoc analysis of the SUSTAIN data evaluated the development of proteinuria during the 
12-month duration of the trial (Ataga et al 2018). Of the patients in the crizanlizumab group 
(both 2.5 mg/kg and 5 mg/kg arms combined) 35/106 (33%) developed proteinuria. In the 
placebo group 17/50 (34%) developed proteinuria. There was no association between the use 
of crizanlizumab and the risk of developing proteinuria (relative risk = 0.97, 95% CI 0.61-1.56). 
Note that proteinuria was measured by urine dipstick and ACRs were not measured. The 
number of patients with abnormal eGFR (defined as < 60 mL/min/1.73 m2) and increased levels 
of serum creatinine was low in both treatment arms. 
It is important to note that the SUSTAIN population was unselected with respect to CKD and 
approximately 20% of patients had proteinuria at baseline. Patients with any SCD genotype 
history could be eligible for SUSTAIN. Therefore, the SUSTAIN population was not consistent 
with a population in which crizanlizumab could be expected to provide a benefit by reducing 
proteinuria/albuminuria. Based on the information in Section 1.1.1, such a population for this 


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current study ideally would consist of patients with severe SCD genotypes who have 
albuminuria and a rapid eGFR decline. Patients with hyperfiltration would need to be excluded 
to avoid confounding the study results.
1.2
Purpose
1.2.1
Study purpose and rationale
The purpose of this study is to explore the effect of P-selectin inhibition with crizanlizumab on 
renal function in SCD patients with CKD who are receiving standard of care for SCD-related 
CKD, have Grade A2-A3 albuminuria and Stage 1-3a CKD, and are at risk for rapid decline in 
their eGFR. Eligible patients will have an eGFR of ≥45 to ≤ 140 mL/min/1.73 m2 and an ACR 
of ≥100 to < 2000 mg/g; based on previous studies, this population of patients will likely 
include patients with a rapid eGFR decline.
The study will evaluate descriptively, the effect of crizanlizumab + standard of care and
standard of care alone on albuminuria (ACR) decrease at 12 months, as assessed by the 
proportion of patients with ≥30% decrease in ACR at 12 months from baseline in patients with 
SCD-related CKD.
Based on the recommendation of a consensus panel focused on SCD end organ considerations 
specifically evaluating renal endpoints in SCD trials, albuminuria was recommended as a 
potential endpoint. The outcome measure suggested that was deemed clinically relevant was a 
30% decrease in albuminuria evaluated by ACR (Farrell et al 2019). A meta-analysis of clinical 
trial data also suggests that each 30% decrease in geometric mean albuminuria by the treatment 
relative to the control was associated with an average 27% lower hazard for the clinical endpoint. 
This association strengthened after restricting analyses to patients with baseline albuminuria of 
more than 30 mg/g. The model from this analysis predicted that treatments that decrease the 
geometric mean albuminuria relative to the control group by 30% would have a high likelihood 
to confer clinical benefit (Heerspink et al 2019). See Section 8.3.5 for further details regarding 
the meta-analysis.
Previous trials conducted in patients with SCD-related CKD and non-SCD etiologies have 
evaluated drugs with varied mechanisms of action. ACE inhibitors, ARBs, and HU/HC have 
been evaluated in SCD-related CKD and other causes and have demonstrated a rapid decrease 
in proteinuria within 6 months. ACR was the most common measurement used to assess the 
reduction in proteinuria. The mechanism of action of ACE inhibitors in reducing albuminuria 
includes decreasing glomerular permeability to albumin (Sasongko et al 2015), that of ARBs is 
inhibiting angiotensin 1 signaling, which contributes to the glomerulopathy causing 
albuminuria, and though the mechanism is unknown for HU/HC it is hypothesized that it might 
result from decreased glomerular filtered load of albumin, improved glomerular permeability 
to macromolecules and it is thought that HU/HC might improve renal laboratory parameters by 
preventing VOCs that are associated with subclinical renal tubular injury (Bartolucci et al 2016). 
The reductions in ACR are limited to trials of 6 months duration and longer term data on the 
impact of decreasing proteinuria on progression of CKD are lacking. 
The presence of P-selectin expression in the kidneys has been established based on in vitro and 
in vivo data, and there is evidence that P-selectin is upregulated in the kidney in response to 


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renal ischemia-reperfusion injury in SCD (Zizzi et al 1997; Koo et al 1998; Singbartl et al 2000; 
Tam 2002).
A pre-clinical study was done to identify the role of P-selectin in ischemia-reperfusion-induced 
severe acute renal failure (Singbartl et al 2000). Mice with a null mutation in the P-selectin gene 
and wild type mice who received post-ischemic application of function-blocking monoclonal 
P-selectin antibody were studied. The P-selectin deficient mice had significantly smaller 
elevations in creatinine and blood urea nitrogen (BUN) concentrations after 24 and 48 hours of 
reperfusion. There was a significant reduction of neutrophil influx by 85% compared to wild 
type mice. In wild type mice, P-selectin was highly upregulated soon after reperfusion, reaching 
peak levels at 12 hours after reperfusion, at which time P-selectin was seen in the glomeruli 
(platelets and endothelial cells) and peritubular vessels (platelets), and to a lesser extent in the 
arteries and veins. The conclusions were that P-selectin was necessary to produce severe acute 
renal failure in response to ischemia-reperfusion. The authors also concluded that a causative 
role of P-selectin was further supported by the observation that neutrophil infiltration into post-
ischemic kidneys was dramatically reduced in P-selectin deficient mice.
Expression of P-selectin in a glomerulonephritis induced mouse model was associated with 
rapid accumulation of neutrophils in glomeruli and significant proteinuria. P-selectin inhibition 
in this model was shown to abrogate glomerular neutrophil accumulation and prevented 
development of proteinuria (Tipping et al 1994).
Though this study provides pre-clinical evidence that P-selectin expression is linked to 
proteinuria, it is unknown if blocking P-selectin in the renal vasculature in vivo will have a 
beneficial impact on glomerulopathy and will delay the progression of CKD. Based on this 
limited data, the hypothesis is that administration of crizanlizumab, a P-selectin inhibitor, might 
have a beneficial effect in SCD patients with CKD by blocking P-selectin mediated 
multicellular adhesion (including leukocytes), and proteinuria, and also reducing 
vaso-occlusion and potentially its downstream effects in the renal vasculature, which can be 
clinically demonstrated by a decrease in proteinuria and slowing the decline in GFR. In 
evaluating crizanlizumab’s impact on ACR reduction and eGFR decline over 1 year this will 
be correlated with progression of CKD during this 1-year period. If the study is able to 
demonstrate a positive effect of crizanlizumab on ACR reduction and the progression of CKD, 
this could provide positive evidence of a renoprotective effect of crizanlizumab. 
 
In addition, in the general population, there is an association between worsening proteinuria 
and eGFR, and cardiovascular complications. Albuminuria is an established risk marker for 
both cardiovascular and renal outcomes (de Zeeuw et al 2004). Cardiovascular complications 
are increasingly evident in patients with SCD and CKD, and reducing albuminuria has the 
potential to provide a beneficial effect on various cardiac parameters, such as tricuspid 
regurgitation velocity (TRV) (Haymann et al 2017).


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2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objectives
Endpoints
Primary objective
Endpoint for primary objective
To evaluate descriptively the effect of 
crizanlizumab + standard of care and standard 
of care alone on albuminuria (ACR) decrease 
at 12 months
Proportion of patients with ≥30% decrease in 
ACR at 12 months from baseline 
Secondary objective(s)
Endpoint(s) for secondary objective(s)
To evaluate descriptively the effect of 
crizanlizumab + standard of care and standard 
of care alone on change in albuminuria (ACR)
Mean change in ACR from baseline to 3, 6, 9, and 
12 months of treatment 
To evaluate descriptively the effect of 
crizanlizumab + standard of care and standard 
of care alone on albuminuria (ACR) decrease 
at 6 months
Proportion of patients with ≥30% decrease in 
ACR at 6 months from baseline 
To evaluate descriptively the effect of 
crizanlizumab + standard of care and standard 
of care alone on protein to creatinine ratio 
(PCR) at 12 months
Proportion of patients with PCR improvement and 
stable PCR (improvement: ≥20% decrease in 
PCR from baseline; stable: within ± 20% change 
from baseline) at 12 months from baseline
To evaluate descriptively the effect of 
crizanlizumab + standard of care and standard 
of care alone on the percentage change in 
eGFR 
Percentage change in eGFR from baseline to 3, 6, 
9, and 12 months of treatment 
To evaluate descriptively the effect of 
crizanlizumab + standard of care and standard 
of care alone on ACR decline rate
Slope of ACR decline from baseline to 12 months 
of treatment based on ACR values at baseline and 
at 3, 6, 9, and 12 months
To evaluate descriptively the effect of 
crizanlizumab + standard of care and standard 
of care alone on eGFR decline rate 
Slope of eGFR decline from baseline to 
12 months of treatment based on eGFR values at 
baseline and at 3, 6, 9, and 12 months
To evaluate descriptively the effect of 
crizanlizumab + standard of care and standard 
of care alone on the progression of CKD at 
12 months
Proportion of patients with progression of CKD 
from baseline to 12 months
To evaluate descriptively overall safety and, 
tolerability of crizanlizumab + standard of care 
and standard of care alone
Safety will be assessed by the frequency and 
severity of adverse events (AEs), deaths, 
measurement of vital signs, ECG assessments, 
SAEs, and laboratory abnormalities 
To assess the immunogenicity of 
crizanlizumab over the study period (treatment 
of 1 year + 105 days of follow-up)
Immunogenicity: measurement of anti-drug 
antibodies (ADA) to crizanlizumab at select time 
points
Crizanlizumab PK measurements will accompany 
immunogenicity measurements


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Objectives
Endpoints
To evaluate descriptively healthcare resource 
utilization (visits to emergency room [ER] and 
hospitalizations) in crizanlizumab + standard of 
care arm and standard of care alone
Annualized rate of visits to ER and 
hospitalizations due to AKI events, VOCs, or other 
SCD complications
2.1
Primary estimands
The estimand is the precise description of the treatment effect and reflects strategies to address 
events occurring during trial conduct which could impact the interpretation of the trial results 
(e.g. premature discontinuation of treatment).
The primary clinical question of interest is: What is the effect of crizanlizumab + standard of 
care and standard of care alone on renal function in SCD patients with SCD-related CKD.
The primary estimand is described by the following attributes:
1. The target population comprises patients with kidney dysfunction due to SCD. 
2. The primary variable is proportion of patients with ≥30% decrease in ACR at 12 months.


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3. The treatment of interest is the effect of crizanlizumab 5.0 mg/kg + standard of care on the
ACR value taken for the entire study duration with or without the intercurrent events.
4. The intercurrent events are the events occurring after randomization that may impact the 
treatment effect. The intercurrent events of interest are: 
a. Treatment discontinuation
b. Initiation or discontinuation of HU/HC, HA approved form(s) of L-glutamine, ACE 
and/or ARB
c. Intake of NSAIDs within 48 hours prior to ACR measurement
d. Intake of voxelotor  
e. Blood transfusion or VOC occurred within 7 days of urine and blood sample             
collection
f.
Renal replacement therapy (i.e. hemodialysis, peritoneal dialysis, hemofiltration and 
kidney transplantation)
5. The summary measure is the odds ratio of the treatment effect for patients with ≥30% 
decrease in ACR between crizanlizumab + standard of care and standard of care alone. 
The detailed information regarding strategies on handling intercurrent events can be found in 
Section 12.4.3.
2.2
Secondary estimands
Not applicable.
3
Study design
This is a Phase II, multicenter, randomized two arm, open label study to evaluate descriptively
the effect of crizanlizumab + standard of care and standard of care alone on renal function in 
SCD patients with SCD-related CKD.
The study will include patients ≥16 years of age with a confirmed diagnosis of SCD and SCD-
related CKD. Homozygous HbS (HbSS sickle cell anemia) and HbSβ0-thal SCD genotypes will 
be included. Patients eligible for the study will have:

eGFR ≥45 to ≤140 mL/min/1.73 m2 based on the CKD/-EPI formula (in patients ≥ 18) and 
Creatinine-based “Bedside Schwartz” equation (2009) (in patients <18)

ACR of ≥100 to < 2000 mg/g, despite standard of care treatment for SCD-related CKD
Eligible patients will be receiving standard of care drug(s) for SCD-related CKD according to 
institutional and local guidelines and the discretion of the physician. Any of the following drugs 
that the patient is receiving at study entry will be considered the patient’s standard of care: 
HU/HC, ACE inhibitors, and/or ARBs. The patient will continue to take their usual standard of 
care drug(s) during the study; thus, there may be some variation in the standard of care regimens 
used by the different patients in the study. Patients must have been receiving their standard of 
care drug(s) prior to study entry according to the dosing requirements in Table 6-1, and must 
plan to continue the same dose and schedule until the patient has reached the end of the study. 
The screening assessments will be done within 1 to 28 days prior to baseline (Week 1 Day 1).


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Overall, approximately 50 patients will be randomized 1:1 to receive either crizanlizumab 
(5 mg/kg) + standard of care or standard of care alone. Patients will be stratified at 
randomization based on CKD risk category (moderate risk or high/very high risk) and HU/HC 
prescription (Yes/No). The CKD risk categories used for stratification are based on both eGFR 
and albuminuria assessed by ACR as defined in Table 3-1:
Table 3-1
Prognosis of chronic kidney disease by glomerular filtration rate and 
albuminuria categories (chronic kidney disease risk categories)
ACR 
(30-300 mg/g
3-30 mg/mmol) 1
ACR 
(>300 mg/g
> 30 mg/mmol)
eGFR ≥90 mL/min/1.73 m2
1
2
eGFR 60-89 mL/min/1.73 m2
1
2
eGFR 45-59 mL/min/1.73 m2
2
3
1 = moderately increased risk; 2 = high risk; 3 = very high risk
1 ACR ranges included above are according to KDIGO (2013); Note that patients in this study will 
have eGFR ≥45 to ≤140 mL/min/1.73 m2 and ACR of ≥100 to < 2000 mg/g. Patients should be 
randomized based on ACR in mg/g.
Throughout this document, “study treatment” will refer to both treatment arms.
Patients randomized to crizanlizumab + standard of care will receive crizanlizumab by 
intravenous (i.v.) infusion over 30 minutes on Week 1 Day 1, followed by a second dose 
14 days later (Week 3 Day 1), and then on Day 1 of every 4 weeks for a total on-study treatment 
period of 12 months in addition to their usual standard of care treatment. The visit for the 
assessment of the primary endpoint will take place on Week 53 Day 1. Patients will be followed 
up for two safety assessments 30 days (phone call) and 105 days (study visit) after the Week 51 
Day 1 visit. Patients who will receive crizanlizumab approximately 4 weeks after their last dose 
of study treatment, do not need to complete the 105-day follow-up. The end of the safety follow-
up period for these patients will be the 30-day follow-up. All other patients are required to 
complete the 105-day follow-up.
Patients in the standard of care alone arm will continue to receive their usual standard of care 
treatment and will attend study visits per the same schedule as the patients randomized to 
crizanlizumab + standard of care (i.e., visits on Week 1 Day 1, Week 3 Day 1, then every 
4 weeks up to Week 51 Day 1, followed by a visit on Week 53 Day 1 and two safety follow-up 
assessments 30 days phone call and 105 days study visit after Week 51 Day 1 [as applicable]). 
Patients will discontinue the study due to unacceptable toxicity, death, or if they are lost to 
follow-up, and may also be discontinued from the study at the discretion of the investigator or 
patient if the study treatment is discontinued (however, please see Section 6.5.1 and Section 9.1
for further details). All patients who discontinue the study treatment early will attend an end of 
treatment (EOT) visit (visit EOT; within 7 days of the last dose of the discontinued study 
treatment) and be followed in the mandatory safety follow-up period, which includes safety 
assessments at 30 days (phone call) and 105 days (study visit, as applicable) after the last dose 
of the discontinued study treatment. These patients will also return for a mandatory Week 53


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urine ACR/PCR assessment. The Week 53 urine ACR/PCR assessment should occur 12 months
after the first dose of study treatment. 
AEs will be recorded throughout the study. All patients will have hematologic, clinical 
chemistry and coagulation assessments done according to Table 8-1. Efficacy assessments of 
albuminuria (urine ACR) (see Section 8.3.1), PCR (Section 8.3.2), eGFR (Section 8.3.3), and 
progression of CKD (Section 8.3.4) will be assessed based on these laboratory assessments. 
 
 
Electrocardiogram (ECG) assessments will be 
done at screening, at Week 53 Day 1, at visit EOT, and as clinically indicated. 
 
 
 
 
 
In addition, patients randomized to the crizanlizumab + standard of care arm will 
have immunogenicity and PK assessments at select time points. 
The study design is provided in Figure 3-1.
Figure 3-1
Study design
4
Rationale
4.1
Rationale for study design
The rationale for the study design is summarized in Table 4-1.
Table 4-1
Rationale for study design
Study Design Aspect
Rationale
Randomization (strata, allocation ratio)
Patients will be randomized 1:1 to receive either 
crizanlizumab + standard of care or standard of 
care alone. The 1:1 allocation ratio is acceptable 
as all patients will be receiving standard of care 
for SCD-related CKD, so it is not necessary to 
limit exposure to any of the treatment arms in this 
study.


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Chronic kidney disease stage and SCD treatment 
could affect ACR outcomes, so patients will be 
stratified at randomization based on CKD risk 
category and HU/HC prescription.
Blinding
This is an open label study as the benefits of a 
blinded study design incorporating a placebo 
infusion were deemed not to outweigh the burden 
to the study patients, particularly given the 
objective nature of the primary endpoint.
Duration of study periods
The treatment period will be 12 months, which 
should allow sufficient time to assess if 
crizanlizumab + standard of care provides 
additional decreases in ACR to standard of care 
alone per the primary study objective.
4.1.1
Rationale for choice of background therapy
In this study, crizanlizumab + standard of care will be descriptively evaluated to standard of 
care alone. 
Patients with SCD and CKD will likely be receiving at least one of the following medications 
– HU/HC, ACE inhibitors, and/or ARBs, as established prior to study entry according to local 
practice and the discretion of the physician, and this will be considered their standard of care or 
background therapy. The patients will continue to take their usual standard of care drug(s) 
during the study. Thus, there may be some variation in the standard of care regimens used by 
the different patients in the study. Patients must have been receiving their standard of care 
drug(s) prior to study entry according to the dosing requirements in Table 6-1, and must plan to 
continue taking the drug(s) at the same dose and schedule until the patient has reached the end 
of the study. No dose modifications in standard of care medications can be made during the 
study, except for dose modifications due to AEs or weight adjustments at the discretion of the 
physician. 
The assessment of crizanlizumab + standard of care to standard of care alone will enable the 
study patients to continue to receive and derive benefit from these medications. In blocking P-
Selectin, crizanlizumab has a different mechanism of action compared with the standard of care 
medications. Therefore, this study will assess whether crizanlizumab is able to provide a 
clinically meaningful improvement in decreasing albuminuria in patients who have albuminuria 
and a rapid decline in eGFR, despite having received standard of care for at least 3 or 6 months 
prior to study entry.
4.2
Rationale for dose/regimen and duration of treatment
The 5 mg/kg dose of crizanlizumab, as well as the dosing schedule, to be used in this current 
study are supported by evidence from the SUSTAIN study.
The doses chosen for the SUSTAIN study (see Section 1.1.4.2 for further details) were based 
on P-selectin inhibition by crizanlizumab evaluated in healthy patients, as well as the acceptable 
safety experience observed in the Phase I study (CSEG101A2101). 
The evidence of efficacy and safety on VOCs obtained from the Phase II SUSTAIN study 
supports the use of the 5 mg/kg dose in this current study. 


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4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Patients with SCD and CKD will likely be receiving at least one of the following medications 
– HU/HC, ACE inhibitors, and/or ARBs, as established prior to study entry, and this will be 
considered their standard of care. The efficacy of crizanlizumab added to standard of care and 
standard of care alone will be descriptively evaluated. 
A placebo-controlled study would allow a robust double-blind assessment of the efficacy of 
crizanlizumab added to standard of care. While acknowledging the limitations of an open-label 
study, the benefits of a blinded study design incorporating a placebo infusion were deemed not 
to outweigh the burden to the study patients for the current study. The open label nature of this 
study is considered acceptable as the assessment of the primary endpoint is based on an 
objective laboratory assessment, rather than a subjective measure.
4.4
Purpose and timing of interim analyses/design adaptations
Not applicable.
4.5
Risks and benefits
Please refer also to the latest version of the Investigator’s Brochure for the most recent 
information on the efficacy and safety of crizanlizumab.
Results from the randomized, placebo-controlled SUSTAIN study in SCD patients (aged 16 
years and older, any genotype) established the efficacy of crizanlizumab 5 mg/kg compared to 
placebo by showing a statistically significant and clinically meaningful reduction of the annual 
rate of VOC leading to healthcare visit. In addition, a more than a two-fold increase in the 
number of patients who remained completely free of VOC leading to healthcare visit during the 
study, and a three-fold increase in the median time to first VOC leading to healthcare was 
observed.
Thus, reduction in the rate of VOCs is a potential benefit for patients randomized to the 
crizanlizumab and standard of care arm in the current study, while acknowledging that this 
study population may have a lower background rate of VOCs than the SUSTAIN population. 
Regarding the potential effect of crizanlizumab on renal function, based on pre-clinical studies 
evaluating P-selectin in the renal vasculature and the upregulation of P-selectin in response to 
ischemia-reperfusion injury, inhibiting P-selectin in the renal vasculature may confer additional 
benefit on the kidney. A post hoc analysis of SUSTAIN data showed no association between 
the use of crizanlizumab and the risk of developing proteinuria. However, the SUSTAIN 
population was unselected with respect to CKD and approximately 20% of patients had 
proteinuria at baseline. Thus, data evaluating a potential benefit of crizanlizumab in patients 
with preexisting renal disease due to SCD are lacking. Because vaso-occlusion contributes to 
the development of SCN leading to CKD, it is hypothesized that crizanlizumab, by inhibiting 
P-selectin mediated vaso-occlusion, could have a beneficial effect on renal function in SCD 
patients with CKD randomized to the crizanlizumab and standard of care arm in the current 
study. See Section 1.1.4.2 and Section 1.2.1 for further details. Patients randomized to either 
treatment arm (standard of care and crizanlizumab versus standard of care alone) could benefit 
from this study due to the close monitoring of renal and cardiac function planned for the study.


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Pooled safety data from the SUSTAIN and CSEG101A2202 studies in patients treated with 
crizanlizumab 5 mg/kg (n=111 patients, Oct 2019 cutoff) showed that crizanlizumab is 
generally associated with a favorable safety profile. Adverse drug reactions (ADRs) were 
arthralgia (17.1%), nausea (16.2%), pyrexia (14.4%), back pain (14.4%), abdominal pain 
(10.8%), diarrhea (9.0%), pruritus (7.2%), vomiting (6.3%), myalgia (5.4%), musculoskeletal 
chest pain (4.5%), oropharyngeal pain (4.5%), infusion site reaction (2.7%), and infusion-
related reaction (2.7%). These ADRs may be signs and symptoms of an infusion related reaction 
when observed during/within 24 hours of an infusion.
In addition, in the randomized SUSTAIN study the overall frequency of AEs, SAEs and AEs 
leading to treatment discontinuation was similar among patients treated with crizanlizumab 5 
mg/kg and placebo. Use of crizanlizumab in combination with HU/HC did not result in any 
meaningful differences in the safety profile.
Based on class effects, pre-/clinical findings, and 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 3 (2.7%) patients treated with crizanlizumab 5 mg/kg in the pooled 
data set. The event reported for all 3 patients was “infusion-related reaction,” none of which 
was severe (all Grade 1 or 2, all non-serious), none required hospitalization or treatment 
discontinuation, and all events resolved without sequelae or complications on the same day. 
However, severe IRRs including cases requiring hospitalization have been described in ongoing 
clinical trials and in the post-marketing setting. Refer to Investigator’s Brochure for additional 
details regarding these IRRs.
Additionally, a broad search for IRRs using an extensive list of potential signs and symptoms 
related to infusion reactions, and occurring within 24 hours of the infusion, identified 37 patients 
(33.3%) in the safety pool with at least one event. Most of these events were reported in 1 or 2 
patients only, except for nausea (9.0%), headache (9%), arthralgia (6.3%) and back pain (4.5%), 
and fatigue, hypertension, dizziness and myalgia (2.7%). None of the events were grade 3 or 4 
in severity. In the SUSTAIN study, IRRs using this broader search were more frequent in the 5 
mg/kg arm (34.8%) compared to the placebo arm (21.0%). However, except for nausea, none 
of the events were reported with an absolute differences of more than 5% in the crizanlizumab 
5 mg/kg vs. the placebo arm and none was severe. Based on post marketing reports, IRRs may 
present as pain, refer to Investigator’s Brochure for additional details.
In summary, current data suggest that administration of crizanlizumab can be associated with 
IRRs, including pain events, some of which can be severe and/or require hospitalization. 
Participants should be monitored for potential signs and symptoms of IRRs, and participants 
instructed to contact the investigator/site when experiencing such events. In case of severe IRRs 
(eg. hypersensitivity/anaphylactic reaction), study treatment should be discontinued.
Immunogenicity
Administration of mAb can be associated with immunogenicity, including development of anti-
drug antibodies (ADA) or hypersensitivity following treatment with crizanlizumab (see above).


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In clinical studies, treatment-emergent ADAs were transiently detected in 1 patient among the 
111 patients who received crizanlizumab 5 mg/kg (0.9%). There was no evidence of an altered 
PK/PD or safety profile with ADA development.
Infections
Based on the mechanism of action and physiological role of P-selectin, crizanlizumab could 
potentially be associated with an increased infection risk.
Infection-related AEs (based on all preferred terms included in the system organ class 
“Infections”) were reported in 49.5% patients in the safety pool. The most frequently reported 
infections were urinary tract infection (11.7%), upper respiratory tract infections (9.9%), 
pneumonia (4.5%) and sinusitis (3.6%). Most infections were low in severity (grade 1 or 2). In 
the randomized SUSTAIN study, infection-related AEs was similar across the arms: 53.0% in 
the crizanlizumab 5 mg/kg and 53.2% in the placebo arm. In addition, there was no difference 
between the arms in the incidence of neutropenia or white blood cell counts.
In summary, no increased frequency or severity of infections has been observed in clinical 
studies with crizanlizumab so far, suggesting that crizanlizumab has no clinically relevant effect 
to induce or complicate infections in SCD patients. However, investigators are advised to 
monitor patients for signs/symptoms of infections; patients further should have received 
standard age-appropriate care for SCD, including penicillin prophylaxis and immunizations 
(refer to eligibility criteria of the protocol).
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, or abnormal laboratory parameters. In the safety pool, a search for hemorrhagic 
events identified 16 (14.4%) patients, mostly related to abnormal laboratory findings. Except 
for prolonged prothrombin time (PT), decreased hemoglobin, and epistaxis, reported in 3 
(2.7%) patients each, these events were reported in 1 or 2 patients only. None were grade 4 or 
led to study withdrawal, and none were considered treatment related as per investigator 
assessment. The only grade 3 event was decreased hemoglobin (2 patients), consistent with 
hemolysis and the underlying disease. 
In Study A2201, hemorrhagic events were reported in 11 (16.7%) patients in the 5 mg/kg and 
8 (12.9%) patients in the placebo arm, mostly related to laboratory abnormalities. Of note, 1 
event (intracranial hemorrhage) reported in the 2.5 mg/kg arm was considered serious (grade 4, 
hospitalization) and led to study drug discontinuation. Cerebrovascular accidents, including 
hemorrhagic stroke, are known complication and leading cause of death in patients with SCD.
In summary, bleeding events were rare, with the majority of the observed AEs being abnormal 
laboratory parameters on single occasions. The available data do not suggest an adverse effect 
of crizanlizumab on hemostasis. Nevertheless, patients should be monitored for 
signs/symptoms of bleeding; additionally, hematology and coagulation parameters will be 
regularly assessed during the study.
A separate search for potential AEs related to thrombosis did further not identify any patients 
with AEs related to thrombosis in the 5 mg/kg pooled data, suggesting that crizanlizumab does 
not have relevant a pro-aggregant or pro-thrombotic effect.


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Laboratory test interference with automated platelet counts
Interference with automated platelet counts (platelet clumping) has been observed in patients 
treated with crizanlizumab in clinical studies, in particular when tubes containing EDTA were 
used. This may lead to unevaluable or falsely decreased platelet counts. Current clinical and 
pre-clinical data suggest this is an ex vivo effect that is EDTA- and time-dependent, without 
indication of platelet clumping, true reduction in circulating platelets or pro-aggregant effect in 
vivo.
QT prolongation and hepatic safety
Based on the data generated to date, crizanlizumab does not have a clinically relevant effect on 
QT interval, and there is no evidence for severe or drug-induced hepatotoxicity.
Pregnancy and lactation
The potential risk to pregnant women is unknown, and there are no adequate and well-controlled 
studies in pregnant women to inform the associated risk. Animal reproduction studies in 
cynomolgus monkeys have not shown embryofetal toxicity or risk of increased fetal 
abnormalities with IV administration of crizanlizumab during gestation at doses up to 50 mg/kg 
(approximately 16 times the human clinical exposure based on AUC in patients with SCD at 5 
mg/kg once every 4 weeks). There was a numerical increase in fetal losses, the cause of which 
is unclear and may be related to development of antibodies against crizanlizumab in monkeys. 
No maternal toxicity was observed.
Pregnant or breastfeeding women as well as those of childbearing potential (unless using 
effective contraception) will not be allowed to participate in the study. Please refer to the 
Eligibility criteria of the protocol for details.
Monoclonal antibodies and male fertility
Regarding male fertility, IgG monoclonal antibodies can distribute to seminal fluid, however to 
an extent approximately one log lower than what could maximally be observed for a small 
molecule (Scialli et al 2015, Banholzer et al 2016). A clinical trial of denosumab, an IgG2 
monoclonal antibody in healthy male volunteers showed that denosumab was measurable at 
low concentrations in seminal fluid (approximately 2% of serum concentrations, Sohn et al 
2015). Data indicate that male-mediated mAb drug transfer via the semen provides negligible 
exposure of the mother to the mAb and that the mAb is not bioavailable to the fetus. Based on 
the pharmacokinetic features of IgG monoclonal antibodies including low distribution to the 
semen and very low absorption in the vagina, the expected mAb dose to the fetus via seminal 
drug delivery to the vagina would be approximately 10,000 to 30,000 fold lower than by 
intravenous dosing. Thus the potential of fetal harm from semen delivery of a monoclonal 
antibody is currently considered to be biologically implausible (Breslin et al 2014).
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 6.5. The risk to participants in this trial may be minimized by compliance 
with the eligibility criteria and study procedures and close clinical monitoring. If deemed 
clinically necessary, participants optionally could be kept in-the hospital for 24 hours following 
an investigational treatment dose. 
There may be unforeseen risks with crizanlizumab, which could be serious. 


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While the safety of crizanlizumab has been studied in patients with SCD, it has not been 
specifically studied in a population of patients with SCD-related CKD.
In summary, the sponsor considers that the benefit-risk ratio for conducting this study is 
favorable.
COVID-19 pandemic
No substantial additional risk for patients 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. In
case of active COVID-19 infection, please refer to Section 6.5.1 Dose Modifications. The
risk/benefit balance will be re-evaluated as and when required whilst the COVID-19 pandemic
continues.
5
Population
This study is designed to enroll approximately 50 SCD patients aged > 16 years with SCD-
related CKD. Homozygous HbS (HbSS sickle cell anemia) and HbSβ0-thal SCD genotypes are 
eligible. Eligible patients will have an eGFR of ≥45 to ≤ 140 mL/min/1.73 m2 and an ACR of 
≥100 to < 2000 mg/g; based on previous studies, this population of patients will likely 
comprise patients with a rapid eGFR decline.
The investigator or designee must ensure that only patients who meet all of the inclusion and 
none of the exclusion criteria are offered treatment in this study.
5.1
Inclusion criteria 
Patients eligible for inclusion in this study must meet all of the following criteria:
1. Signed informed consent must be obtained prior to participation in the study
2. Male and female patients ≥16 years on the day that signed informed consent is obtained
3. Confirmed diagnosis of SCD by Hb electrophoresis (performed locally, or by a central 
laboratory if the country does not have local capabilities) or high performance liquid 
chromatography (performed locally). Homozygous HbS (HbSS sickle cell anemia) and 
HbSβ0-thal SCD genotypes are eligible
4. Patients with eGFR ≥45 to ≤ 140 mL/min/1.73 m2 based on CKD EPI formula (patients ≥ 
18) or the Creatinine-based “Bedside Schwartz” equation (patients < 18)
5. Patients with ACR of ≥100 to < 2000 mg/g (taken as an average of the three screening 
ACR values to determine eligibility).
6. Receiving at least 1 standard of care drug(s) for SCD-related CKD according to local 
guidelines. If receiving HU/HC, the patient must have been receiving HU/HC for at least 6 
months and on a stable dose for 3 months prior to study entry. If receiving an ACE inhibitor 
and/or ARB the patient must have been receiving the drug for 3 months and also on a stable 
dose for those three months prior to study entry, in all cases, patients must plan to continue 
taking the drug(s) at the same dose and schedule until the patient has reached the end of the 
study.
7. Hb ≥4.0 g/dL, absolute neutrophil count (ANC) ≥1.0 x 109/L, and platelet count 
≥75 x 109/L
8. Patients who are clinically stable and are in a non-crisis state at the time of enrollment


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9. Adequate hepatic function as defined by:

Alanine aminotransferase (ALT) < 3.0 x upper limit of normal (ULN)

Direct (conjugated) bilirubin ≤3.0 x ULN
10. Eastern Cooperative Oncology Group (ECOG) performance status ≤2.0
11. Up-to-date record of immunizations, as per local requirements
5.2
Exclusion criteria
Patients meeting any of the following criteria are not eligible for inclusion in this study.
1. History of stem cell transplant
2. Patients with evidence of AKI within 3 months of study entry (can decrease interval to 
within 6 weeks of study entry only if renal function has returned to pre-AKI values prior to 
study entry) 
3. Blood pressure > 140/90 mmHg despite treatment
4. Body mass index of ≥35
5. Patients undergoing renal replacement therapy (ie. hemodialysis, peritoneal dialysis, 
hemofiltration and kidney transplantation)
6. Received blood products within 30 days of Week 1 Day 1
7. Participating in a chronic transfusion program (pre-planned series of transfusions for 
prophylactic purposes). Transfusions for acute complications are permitted (acute chest 
syndrome [ACS], acute splenic sequestration, acute hepatic sequestration, worsened 
anemia)
8. History of kidney transplant
9. Patients with hypoalbuminemia defined as <25 g/L
10. Contraindication or severe hypersensitivity to any drug or metabolites from similar class as 
crizanlizumab or to any excipients of the crizanlizumab formulation
11. History of severe hypersensitivity reaction to other mAb, which in the opinion of the 
investigator may pose an increased risk of serious infusion reaction
12. Patient has received crizanlizumab and/or other selectin inhibitor or plans to receive it 
during the duration of the study. 
13. Currently on voxelotor or received voxelotor within 6 months of screening. 
14. Use of HA approved form(s) of L-glutamine within 6 months of screening, unless it has 
been used at a stable dose for the full 6 months
15. Received an investigational compound within 30 days (or 5 half-lives of that agent, 
whichever is greater) prior to screening 
16. Uncontrolled diabetes
17. Concurrent severe and/or uncontrolled medical conditions which, in the opinion of the 
investigator, could cause unacceptable safety risks or compromise participation in the study
18. Clinically significant bleeding disorder
19. Significant active infection or immune deficiency (including chronic use of 
immunosuppressive drugs)
20. Patient with active human immunodeficiency virus (HIV) infection (detectable viral load)


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21. Patients with active Hepatitis B (HBV) infection (hepatitis B surface antigen [HbsAg] 
positive) will be excluded
Note: Patients with antecedent but no active HBV (i.e., hepatitis B core antibody [HbcAb] 
positive, HbsAg and HBV-deoxyribonucleic acid negative) are eligible
22. Positive test for hepatitis C (HCV) ribonucleic acid (RNA)
Note: Patients in whom HCV infection resolved spontaneously (positive HCV antibodies 
without detectable HCV RNA) or those that achieved a sustained virological response after 
antiviral treatment and show absence of detectable HCV RNA ≥ 6 months (with the use of 
interferon [IFN]-free regimes) or ≥ 12 months (with the use of IFN-based regimes) after 
cessation of antiviral treatment are eligible
23. Malignant disease. Exceptions to this exclusion include the following: malignancies that 
were treated curatively and have not recurred within 3 years prior to study treatment; 
completely resected basal cell and squamous cell skin cancers and any completely 
resected carcinoma in situ
24. History of or current diagnosis of ECG abnormalities indicating significant risk of safety 
such as:

Concomitant clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), 
and clinically significant second or third degree atrioventricular block without a 
pacemaker

History of familial long QT syndrome or known family history of Torsade’s de Pointes
25. Evidence of CKD attributed to causes other than SCN
26. Obstructions of the urinary tract
27. Current drug or alcohol abuse as per investigator discretion.
28. Pregnant or nursing (lactating) women
29. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
the study, and for patients randomized to crizanlizumab + standard of care, for 15 weeks 
after stopping crizanlizumab. Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or bilateral tubal ligation at least 6 weeks before 
Week 1 Day 1. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow-up hormone level assessment

Male sterilization (at least 6 months prior to screening). For female patients on the study, 
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 or intrauterine system, or other 
forms of hormonal contraception that have comparable efficacy (failure rate < 1%), for 
example hormone vaginal ring or transdermal hormone contraception.
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before Week 1 Day 1.


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Women are considered post-menopausal if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate history 
of vasomotor symptoms). Women are considered not of childbearing potential if they are 
post-menopausal or have had surgical bilateral oophorectomy (with or without 
hysterectomy), total hysterectomy or tubal ligation at least 6 weeks prior to Week 1 Day 1. 
In the case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow-up hormone level assessment is she considered not of 
childbearing potential.
If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the Informed Consent Form 
(ICF).
No additional exclusions should be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible patients.
Note: The investigator has the discretion to include/exclude a patient in the study, who will be 
found to have symptoms representative of COVID-19 or tested positive for COVID-19 during 
the screening phase. Such patients should be managed as per the country specific guidelines 
related to COVID-19. For patients who test positive for COVID-19, re-testing is recommended 
before initiating study treatment.  
6
Treatment
6.1
Study treatment
Patients will be randomized into one of two treatment arms, crizanlizumab + standard of care, 
or standard of care alone. 
Novartis will supply crizanlizumab (SEG101) as an open label medication. Patients in the 
crizanlizumab + standard of care arm will receive crizanlizumab dose of 5.0 mg/kg by i.v. 
infusion over 30 minutes on Week 1 Day 1, followed by a second dose 14 days later (Week 3 
Day 1), and then every 4 weeks for a total on-study treatment period of 12 months in addition 
to their usual standard of care treatment. Patients in the standard of care alone arm will continue 
to receive their usual standard of care treatment.
Study sites will continue to source the standard of care drug(s) for SCD-related CKD that the 
patient was receiving at study entry according to institutional and local guidelines and the 
discretion of the physician. Any of the following drugs that the patient is receiving at study 
entry will be considered the patient’s standard of care (patients included in this study must have 
been receiving at least one of the following): HU/HC, ACE inhibitors, and ARBs. The dosing 
requirements for these drugs prior to study entry are provided in Table 6-1.
Table 6-1
Standard of care drugs
Drug or drug class1
Required minimum 
duration of treatment 
prior to study entry
Required minimum 
duration on stable dose 
prior to study entry
Hydroxyurea (HU)/Hydroxycarbamide (HC)
6 months
3 months
Angiotensin-converting enzyme (ACE) inhibitor
3 months
3 months


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Angiotensin-receptor blocker (ARB)
3 months
3 months
1 Patients included in this study must have been receiving at least one of the drugs listed in 
this table
The patient will continue to take their usual standard of care drug(s) during the study; thus, there 
may be some variation in the standard of care regimens used by patients in the study. If receiving 
HU/HC the patient must have been on the drug for 6 months prior to study entry and on a stable 
dose for 3 months. If receiving an ACE inhibitor and/or ARB, the patient must have been 
receiving drug and on a stable dose for 3 months prior to study entry. In all cases, patients must 
plan to continue taking the drug(s) at the same dose and schedule until the patient has reached 
the end of the study. No dose modifications in standard of care medications may be made during 
the study, except for dose modifications due to AEs or weight adjustments at the discretion of 
the physician (see Section 6.5.1.2). Standard of care medication(s) being taken by the patient at 
the time of Interactive Response Technology (IRT) enrollment will be recorded in the Dosage 
Administration Record (DAR) electronic Case Report/Record Form (eCRF). Evidence that the 
patients have been receiving the standard of care medication(s) at a stable dose should be 
documented in the source documents.
Starting any new treatment with HU/HC within 6 months and ACE inhibitor and/or ARB within 
3 months prior to screening, up to the end of the study is prohibited and will be a protocol 
deviation (see Section 6.2.2). 
6.1.1
Crizanlizumab
Crizanlizumab will be supplied in single use vials containing 10 mL at a concentration of 
10 mg/mL. One vial contains 100 mg of crizanlizumab.
The patient will receive up to 14 doses of crizanlizumab by i.v. infusion, which will take 
approximately 30 minutes. Crizanlizumab must not be administered by i.v. push or bolus. On 
infusion day, the pharmacist or designated personnel will compound crizanlizumab in 
accordance with the Pharmacy Manual. See Table 6-2 for details of crizanlizumab.
Table 6-2
Crizanlizumab
Drug
Dose
Pharmaceutical 
Dosage Form 
and Route of 
Administration
Frequency 
and/or Regimen
Supply Type
Crizanlizumab 
(SEG101)
5.0 mg/kg
Concentrate for 
solution for 
infusion.
i.v. infusion
Week 1 Day 1
Week 3 Day 1
Day 1 of every 
4-week cycle
Open label vials
6.1.2
Additional study treatments
No other treatment beyond crizanlizumab and standard of care are included in this trial.
6.1.3
Treatment arms/group 
Patients will be randomly assigned at the Week 1 Day 1 visit to one of the following treatment 
arms in a 1:1 ratio:


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
Crizanlizumab + standard of care

Standard of care alone
6.1.4
Guidelines for continuation of treatment 
Refer to Table 6-3 for criteria for re-initiation of investigational drug following dose 
interruptions due to certain ADRs.
6.1.5
Treatment duration
The planned duration of treatment is 12 months. Patients will discontinue study treatment 
(crizanlizumab and/or at least one standard of care drug, as applicable) early due to 
unacceptable toxicity, and/or if study treatment is discontinued at the discretion of the 
investigator or the patient. Please see Section 9.1 on discontinuation of study treatment.
Patients who are deriving benefit from crizanlizumab based on the investigator’s evaluation 
may receive access to crizanlizumab post-trial as indicated in Section 9.2. In addition, patients 
randomized to the standard of care alone arm may receive post-trial access to crizanlizumab as 
per investigator discretion if benefit is demonstrated for patients in the crizanlizumab + 
standard of care arm.
6.2
Other treatment(s)
6.2.1
Concomitant therapy
In general, the use of any concomitant medication/therapies deemed necessary for the care of
the patient is permitted, except as specifically prohibited. The patient must notify the study site 
about any new medications he/she takes within 30 days prior to initial dosing (i.e., within 
30 days prior to Week 1 Day 1) until the completion of the safety follow-up period (i.e., 30-day 
safety follow-up or the 105-day follow-up visit [as applicable]). 
All medications (including prescription drugs, herbal medications/supplements, over the 
counter [OTC] medication, dietary and vitamin supplements) and significant non-drug therapies 
(including physical therapy and blood transfusions) taken or administered within the timeframe 
defined in the entry criteria until completion of the safety follow-up period must be listed on 
the Prior and Concomitant medications, Surgical and Medical Procedures or Transfusion page 
of the eCRF. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a patient or allowing a new medication to be started. If the patient is already 
randomized, contact Novartis medical monitor to determine if the patient should continue 
participation in the study. 
Concomitant treatment with erythropoietin -stimulating agents (ESA), aspirin, NSAIDs, and 
prophylactic doses (as per local guidelines) of anticoagulants are permitted, while other anti-
platelet agents or anticoagulants at doses targeting therapeutic levels should be used with 
caution (refer to Section 6.2.1.1). All approved forms of analgesia for pain are permitted as per 
physician’s discretion. Note that NSAID use should be avoided within 48 hours prior to ACR 


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measurements. Other approved medications for supportive care (antiemetics, anxiolytics, 
hypnotics, antihistamines) are permitted, including marinol.
Oral contraceptives are permitted in this study at the discretion of the investigator (see the 
contraception requirements outlined in the exclusion criteria (Section 5.2).
6.2.1.1
Permitted concomitant therapy requiring caution and/or action
Although transfusion of blood components is permitted (i.e., transfusions for acute 
complications [ACS], acute splenic sequestration, acute hepatic sequestration, worsened 
anemia), it is unclear how such transfusions will impact the PK/PD of crizanlizumab, so 
investigators are encouraged to obtain PK and PD samples before and after each transfusion 
session when possible; in this case, please contact the Novartis medical monitor. It should also 
be considered that the administration of products containing immunoglobulins (plasma, 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.
If a patient requires renal replacement therapy (i.e. hemodialysis, peritoneal dialysis, 
hemofiltration and kidney transplantation), study treatment should be discontinued. Renal 
replacement therapy should be recorded on the appropriate eCRF.
L-glutamine is approved in the United States to reduce the acute complications of SCD in adult 
and pediatric patients 5 years and older.
HA approved forms(s) of L-glutamine is permitted if the patient has been receiving a stable 
dose for at least 6 months prior to screening and plans to continue taking it at the same dose and 
schedule until the patient reaches the end of the study. Although HA approved form(s) of L-
glutamine is permitted, other OTC 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, jujube, angelica sinensis, lovage) are 
discouraged due to the unproven efficacy and variable quality and composition of these 
products. Vitamin and mineral supplements (e.g., fish oil, folic acid, L-arginine, L-citrulline, 
magnesium, riboflavin, vitamin C, vitamin D, vitamin E, and zinc) are also permitted, though 
caution is advised when taking amounts exceeding 100% of the recommended daily allowance. 
Avoid any live vaccines against infectious diseases within 4 weeks prior to Week 1 Day 1. 
There is no restriction on the administration of inactivated vaccines during the study.
Anti-platelets agents or anticoagulants at therapeutic doses should be used with caution due to
a potential effect of P-selectin inhibition on hemostasis.
Infusion related reactions have been observed with crizanlizumab administration. 
Prophylactic pre-medication is permitted, and sites should follow local practice and guidelines 
for administration of monoclonal antibodies; pre-medications may be adjusted based on clinical 
presentation as deemed appropriate (e.g. for pain management).
If a participant experiences a Grade 3 or 4 infusion related reaction, the study treatment must 
be discontinued.
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 


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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)
Please refer to Table 6-3 for further guidance on management of IRRs.
6.2.2
Prohibited medication
The use of investigational drugs other than crizanlizumab is prohibited during the study. The 
use of voxelotor is also prohibited during the study, as are stem cell transplants. In addition, the 
administration of mAb other than crizanlizumab is prohibited, due to the theoretical potential 
for cross-reactivity and/or overlapping toxicities with other mAb. 
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. Patients that have 
received prior treatment with crizanlizumab are not allowed to enroll in this study.
Voxelotor was approved by FDA on 25-Nov-2019 for the treatment of sickle cell disease (SCD) 
in adult and pediatric patients 12 years of age and older.  The impact of voxelotor on renal 
function is unknown, so use of voxelotor within the last 6 months prior to screening or current 
use of voxelotor is prohibited in this study. 
Abuse of drugs or alcohol is also prohibited during the study. 
Starting any new treatment with HU/HC, HA approved form(s) of L-glutamine, within 
6 months prior to screening and ACE inhibitors or ARBs within 3 months prior to screening up 
to the end of the study is prohibited and will be recorded as a protocol deviation. Note that any 
new treatment with HU/HC, HA approved form(s) of L-glutamine, ACE inhibitors, and/or 
ARBs started on or after Week 1 Day 1 will be recorded on the Concomitant Medications eCRF; 
they will not be recorded on the DAR eCRF. If any new treatment with HU/HC, HA approved 
form(s) of L-glutamine, ACE inhibitors, and/or ARBs is started during the study, changes 
should not lead by default to discontinuation of the patient from the trial (see Section 9.1); 
however, the Novartis medical monitor must be notified.
6.3
Patient numbering, treatment assignment, randomization
6.3.1
Patient numbering
Each patient will be identified in the study by a Patient Number (Patient No.), that is assigned 
when the patient is first enrolled for screening and is retained as the primary identifier for the 
patient throughout his/her entire participation in the trial. The Patient No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential Patient 
No. suffixed to it, so that each patient is numbered uniquely across the entire database. Upon 
signing the ICF, the patient is assigned to the next sequential Patient No. available.
6.3.2
Treatment assignment, randomization
At visit “Week 1 Day 1” all eligible patients will be randomized via IRT to one of the treatment 
arms. The investigator or his/her delegate will complete the eligibility checklist in IRT after 
confirming that the patient fulfills all the inclusion/exclusion criteria. The IRT will assign a 
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The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased. A patient randomization list will be produced by the IRT 
provider using a validated system that automates the random assignment of Patient Numbers to 
randomization numbers. These randomization numbers are linked to the different treatment 
arms, which in turn are linked to medication numbers, as applicable. A separate medication list 
will be produced by or under the responsibility of Novartis Global Clinical Supply using a 
validated system that automates the assignment of medication numbers to packs containing the 
study treatment.
Following the decision to stop recruitment, approximately 50 SCD patients will be randomized 
in a 1:1 ratio to either 5.0 mg/kg of crizanlizumab + standard of care, or standard of care alone.
Patients will be stratified at randomization based on CKD risk category (moderate risk or 
high/very high risk) and HU/HC prescription (Yes/No).
The randomization scheme for patients will be reviewed and approved by a member of the 
Randomization Office.
6.4
Treatment blinding
This is an open label study and no blinding will be applicable. Investigators, patients and 
sponsor have full knowledge of treatment allocation. In order to minimize the potential impact 
of treatment knowledge, until the final analysis is conducted, no aggregate statistical analysis 
(efficacy and safety across the study) shall be performed by treatment other than DMC safety 
review outputs which will be performed by independent programmer. Details of the data 
reviewed by the Clinical Trial Team (CTT) will be specified in the Data Quality Plan.
Randomization codes and the full randomization list will be kept strictly confidential until the 
time of safety analyses for DMC and the final analysis.
6.5
Dose escalation and dose modification
6.5.1
Dose modifications
6.5.1.1
Crizanlizumab
For patients who do not tolerate the protocol-specified dosing schedule, crizanlizumab dose 
interruptions are either recommended or mandated. Dose reductions are not allowed.
If a patient experiences drug-induced toxicity, the patient should be closely monitored and a 
decision to continue or discontinue the patient from the study should be made at the next dose 
scheduled.
These dose interruptions are summarized in Table 6-3. Deviations to mandatory dose 
interruptions are not allowed. Permanent treatment discontinuation is mandatory for specific 
events as indicated in Table 6-3. Every effort should be made to maintain the patient on the 
protocol-defined dosing schedule. In case of dose delay for any reason, the dose should be given 
as soon as possible. If that infusion visit occurs within ± 7 days of a protocol-scheduled visit, 
then the dose and all required assessments will be assigned to the nearest protocol-scheduled 
visit. However, if that infusion visit does not fall within ± 7 days of a protocol-scheduled visit, 
the dose and corresponding assessments will be documented as an unscheduled visit. At that 


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point, every effort should be made to bring the patient’s infusions back onto the protocol defined 
schedule (within the ± 7 day window). All doses of crizanlizumab (except the Week 3 Day 1 
loading dose) must be separated by at least 21 days from the prior dose. If a patient misses two 
consecutive doses of crizanlizumab due to ADR; i.e., an AE attributable to study drug), the 
patient should be discontinued from crizanlizumab. Patients with Grade 3 and 4 IRRs will be 
permanently discontinued from crizanlizumab and patients with other specified grade 4 ADRs 
will be permanently discontinued from crizanlizumab. Crizanlizumab dose interruptions must 
be recorded on the Study Treatment- Infusion eCRF.


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Table 6-3
Criteria for dose interruption and re-initiation of crizanlizumab due to 
adverse drug reactions
Dose interruption and re-initiation of crizanlizumab
Worst toxicity
CTCAEa Grade (CTCAE Version 5.0) 
during a cycle of therapy
Action on dose interruption and re-initiation of 
crizanlizumab
Investigations (hematologic)
Neutropenia (ANC)
Grade 1 (ANC < lower limit of normal 
[LLN] – 1500/mm3) and Grade 2 
(ANC < 1500 – 1000/mm3)
No action, continue treatment.
Grade 3 (ANC < 1000 – 500/mm3)
Mandatory:
Interrupt dose until resolved. If 
abnormality persists, permanently discontinue the 
patient from the study.
Grade 4 (ANC < 500/mm3)
Mandatory: Permanently discontinue the patient 
from the study.
Febrile neutropenia (ANC < 1.0 x 109/L, fever 
≥38.5°C)
Mandatory: Interrupt dose until resolved or next 
dose schedule. If abnormality persists, permanently 
discontinue the patient from the study.
Thrombocytopenia
Grade 1 (LPT < LLN – 75,000/mm3) and 
Grade 2 (LPT < 75,000 – 50,000/mm3)
No action, continue treatment.
Grade 3 (LPT < 50,000 – 25,000/mm3)
Recommendation: Interrupt dose until resolved to 
≤Grade 2 or next dose scheduled. If abnormality 
persists, permanently discontinue the patient from 
the study.
Grade 4 (LPT < 25,000/mm3)
Mandatory: Permanently discontinue the patient 
from the study.
Investigations (hepatic)
Isolated direct bilirubin
Grade 1 (> ULN – 2.0 x ULN)
No action, continue treatment. 
Grade 2 (> 2.0 – 3.0 x ULN) and Grade 3 
(> 3.0 – 10.0 x ULN)
Recommendation: interrupt dose. 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, then 
continue with next dose scheduled.
Grade 4 (> 10.0 x ULN)
Mandatory: Permanently discontinue the patient 
from treatment.
Isolated ALT elevation
Grade 1 (> ULN – 3.0 x ULN)
No action, continue treatment.
Grade 2 (> 3.0 – 5.0 x ULN)
No action, continue 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 resolved, 
then continue with next dose scheduled.


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Grade 3 (> 5.0 – 20.0 x ULN)
Recommendation: interrupt dose. Repeat LFTsb as 
soon as possible, preferably within 48-72 hours from 
awareness of the abnormal results; monitor 
LFTsb weekly, or more frequently if clinically 
indicated, until resolved to ≤3.0 x ULN. If resolved, 
then continue with next dose scheduled.
Grade 4 (> 20.0 x ULN)
Mandatory: Permanently discontinue the patient 
from the study.
Combined elevations of ALT and bilirubin (direct conjugated)

For patients with normal baseline ALT and 
direct bilirubin value: ALT ≥3.0 x ULN 
combined with direct bilirubin 
≥2.0 x ULN without evidence of 
cholestasis c OR

For patients with elevated baseline ALT 
or direct bilirubin 
value: ALT ≥2 x baseline AND 
≥2.0 x baseline direct bilirubin
Mandatory: in the absence of cholestasis (alkaline 
phosphatase [ALP] < ULN), patient should be 
immediately discontinued from treatment. Repeat 
LFTsb
as soon as possible, preferably within 
48 hours from awareness of the abnormal results, 
then with weekly monitoring of LFTsb), or more 
frequently if clinically indicated, until ALT, or bilirubin 
have resolved to baseline or stabilization over 
4 weeks. Refer to Section 6.5.2.1 for additional 
follow-up evaluations as applicable.
Infections
Grade 1 and 2
No action, continue treatment.
Grade 3
Mandatory: Interrupt dose until resolved. If resolved, 
then continue with next dose scheduled.
Grade 4
Mandatory: Permanently discontinue the patient 
from the study.
Infusion-related reactions (IRR)
Grade 1
Mild transient reaction; infusion interruption 
not indicated; intervention not indicated
Recommendation: 
•
Continue 
study 
treatment 
and 
increase 
monitoring of vital signs as medically indicated until 
the 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 hours
Recommendation:
•
Temporarily interrupt infusion and increase 
monitoring of vital signs as medically indicated until 
the participant is deemed medically stable in the 
opinion of the investigator. 
•
Administer appropriate medical therapy as per 
local 
institutional 
guidelines 
and 
clinical 
presentation. 
•
Steroids should be used with caution unless 
clinically 
indicated 
(e.g. 
management 
of 
hypersensitivity /anaphylaxis) (Brandow et al, 2020).
•
If symptoms resolve, restart infusion per 
investigator discretion at a slower rate (e.g. 50%) 
under continuous observation. Ensure a minimum of 
1 hour observation period prior to restarting the 
infusion.


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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 crizanlizumab 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 patients, re-testing is advised before re-initiating study 
treatment to ensure adequate recovery. Patients with suspected infection tested negative may 
continue study treatment. In case of trial participants who have been exposed to someone 
infected by COVID-19 and is in self-quarantine, it is recommended that administration of 
crizanlizumab be delayed until the trial participant completes the quarantine and remains 
asymptomatic and/or COVID-19 has been ruled out.
6.5.1.2
Standard of care for chronic kidney disease due to sickle cell disease
Any of the following drugs that the patient is receiving at study entry will be considered the 
patient’s standard of care: HU/HC, ACE inhibitors, and/or ARBs. Patient will continue to take 
their usual standard of care drug(s) during the study. Patients must have been receiving their 
standard of care drug(s) prior to study entry according to the dosing requirements in Table 6-1, 
and must plan to continue taking the drug(s) at the same dose and schedule until the patient has 
reached the end of the study. No dose modifications in standard of care medications may be 
•
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 for 
prophylaxis of infusion related reactions, including 
subsequent infusions.
•
In case of recurring infusion related reactions 
despite premedication and prolonged infusion, 
discontinue study treatment.
Grade 3 and 4
Prolonged (e.g., not rapidly responsive to 
symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial improvement; 
hospitalization indicated for clinical sequelae
Life-threatening consequences; urgent 
intervention indicated
Mandatory:
•
Permanently discontinue study treatment and 
initiate appropriate medical care.
•
Collect blood sample immediately after onset of 
AE occurs for further characterization of the IRR 
(see section 6.5.2).
General Note: Decision for dosing is made on prior lab results, not those from labs performed on the 
day of infusion. If lab results found to be abnormal, repeat (unscheduled) labs should be performed 
at least 1 week prior to scheduled dose in order to have results to show resolution of the 
abnormality before the scheduled dose is given
a Toxicity Criteria for AEs (Common Terminology Criteria for AEs [CTCAE] Version 5.0)
b Core LFTs consist of ALT, aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), 
total bilirubin (fractionated [direct and indirect], lactate dehydrogenase (LDH), albumin, creatinine 
kinase and ALP
c “Cholestasis” defined as ALP elevation (> 2.0 x ULN and 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 cholestasis (R ≤2), 
hepatocellular (R ≥5), or mixed (R > 2 and < 5) liver injury 


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made during the study, except for dose modifications due to AEs or weight adjustments at the 
discretion of the physician. Starting any new treatment with HU/HC, within 6 months prior to 
screening and ACE inhibitors, or ARBs from within 3 months prior to screening up to the end 
of the study is prohibited and will be a protocol deviation (see Section 6.2.2). If a physician 
deems it medically necessary to terminate or alter standard of care treatment(s) during the study, 
changes should not lead by default to discontinuation of the patient from the trial (see 
Section 9.1); however, the Novartis medical monitor must be notified.
6.5.2
Follow-up for toxicities
In case of a grade 3 or 4 infusion-related reaction additional blood samples for cytokines and 
complement will be collected as outlined in Table 6-3. Collection of additional blood samples 
for cytokines and complement include but are not limited to IFNy, IL-1, IL-2, IL-6, TNFa, C3a, 
C5a, SC5b-9, as well as p-selectin and tryptase. 
These blood samples should be collected immediately and no later than up to 1 hour post 
infusion. 
Once the above sample is obtained immediately post infusion it is at the discretion of the 
investigator if additional follow up blood samples should be obtained. 
Patients whose study treatment is interrupted or permanently discontinued due to an AE must 
be followed up at least once a week (or more frequently if required by institutional practices, or 
if clinically indicated) for 4 weeks, and subsequently at approximately 4-week intervals, until 
resolution or stabilization of the event, whichever comes first. Appropriate clinical experts (e.g., 
ophthalmologist, endocrinologist, dermatologist, psychiatrists) should be consulted as deemed 
necessary. All patients must be followed up for AEs and SAEs until the end of their safety 
follow-up period (ie. 30-day safety follow-up or 105-day follow-up [as applicable]).
6.5.2.1
Follow-up on potential drug-induced liver injury cases
Alanine aminotransferase increase combined with direct bilirubin increase may be indicative of 
potential drug-induced liver injury, and should be considered as clinically important events.
NOTE: Patients with SCD tend to have elevated transaminases, especially AST, and indirect 
bilirubin due to the hemolytic nature of this condition. Hence, ONLY ALT and direct bilirubin 
will be required in this criteria AST will NOT be considered.
Patients meeting the following criteria will require further follow-up as outlined below:

For patients with normal ALT and direct bilirubin value at baseline: ALT ≥3.0 x ULN 
combined with direct bilirubin ≥2.0 x ULN OR international normalized ratio (INR) > 1.5 
without evidence of cholestasis (no ALP elevation)

For patients with elevated baseline ALT or direct bilirubin value at baseline: ALT 
≥2 x baseline AND ≥2 x baseline direct bilirubin

For patients with normal ALT at baseline: ALT ≥5.0 x ULN for more than 2 weeks

For patients with elevated ALT at baseline: ALT ≥3.0 x baseline for more than 2 weeks
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2.


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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).
In the absence of cholestasis, these patients should be immediately discontinued from study 
treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions as described below:
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, LDH, prothrombin time (PT)/INR and ALP.
2. A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, and history of any pre-existing 
liver conditions or risk factors, should be collected.
3. Further 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 crizanlizumab.
5. Additional testing for other hepatotropic viral infection (cytomegalovirus, Epstein-Barr 
virus or herpes simplex virus), autoimmune hepatitis or liver biopsy may be considered as 
clinically indicated or after consultation with specialist/hepatologist.
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, and thus, meet the definition of SAE and should be reported as SAE using the term 
“potential drug-induced liver injury.” All events should be followed up with the outcome clearly 
documented.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
Crizanlizumab compliance will be assessed by administration of the crizanlizumab under the 
supervision of the investigator or his/her designee and will be verified by determinations of 
crizanlizumab in serum. This information must be captured in the source document and in the 
Drug Accountability Form.
Regarding standard of care compliance, the investigator must promote compliance by 
instructing the patient to take the study treatment exactly as prescribed and by stating that 
compliance is necessary for the patient’s safety and the validity of the study. The patient must 
also be instructed to contact the investigator if he/she is unable for any reason to take the study 
treatment as prescribed. Compliance will be assessed by the investigator and/or study personnel 
at each visit using pill counts (if applicable) and information provided by the patient. This 
information should be captured in the source document at each visit.
6.7
Preparation and dispensation
Each study site will be supplied with crizanlizumab in packaging as described in Section 6.1.1. 
A unique medication number is printed on the crizanlizumab label. 


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Investigator staff will identify the drug kits to dispense to the patient by contacting the IRT and 
obtaining the medication number(s). The drug has a 2-part label (base plus tear-off label), 
immediately before dispensing the medication kit to the patient, site personnel will detach the 
outer part of the label from the packaging and affix it to the source document.
Crizanlizumab solution will be prepared by a pharmacist or study personnel appropriately 
trained in the preparation of solutions for parenteral administration in accordance with the 
Pharmacy Manual.
Patients should be closely observed for potential IRRs including rigors, chills, wheezing, 
flushing, pruritus, rash, hypotension, hypoxemia, and fever, and vital signs monitored more 
frequently if clinically indicated, in accordance with the Pharmacy Manual. The same applies 
for the subsequent infusions, if medically indicated. If a patient experiences an IRR, he/she may 
receive pre-medication on subsequent dosing days as per institutional standard of care, at the 
discretion of the treating physician.
If a patient experiences a Grade 3 or 4 IRR, the patient will discontinue crizanlizumab. Please 
refer to Table 6-3 for further guidance on management of IRRs.
Standard of care medications will be prepared and dispensed according to the instructions 
specified on the labels and in the prescribing information, and in accordance with local standard 
practice.
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Crizanlizumab must be received by the pharmacist or delegate at the study site, handled and 
stored safely and properly, and kept in a secured location. Upon receipt, all of the drug must be 
stored according to the instructions specified on the labels and in the IB. Clinical supplies are 
to be dispensed only in accordance with the protocol. Technical complaints are to be reported 
to the respective Novartis CPO Quality Assurance.
The pharmacist or delegate will inventory and acknowledge receipt of all shipments of 
crizanlizumab. The pharmacist will also keep accurate records of the quantities of 
crizanlizumab dispensed and used by each patient. Monitoring of crizanlizumab will be 
performed by field monitors during site or remote monitoring visits, and at the completion of 
the trial.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the crizanlizumab but no information about 
the patient except for the medication number.
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
or delegate will destroy all unused crizanlizumab, packaging, drug labels as appropriate in 
compliance with site processes, monitoring processes, and per local regulation/guidelines.
Otherwise, the investigator will return all unused study treatment, packaging, drug labels, and 
a copy of the completed drug accountability log to the Novartis monitor or to the Novartis 
address provided in the investigator folder at each site.


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Investigators will instruct patients to store and take their standard of care medications according 
to the instructions specified on the labels and in the prescribing information. Patients should 
bring their standard of care medications to study visits for reconciliation of medications used. 
The investigator will keep accurate records of quantities of standard of care medications used 
by each patient. A monitor will ensure accountability of all standard of care medications used.
6.7.1.2
Handling of additional treatment
Not applicable.
6.7.2
Instruction for prescribing and taking study treatment
All kits of crizanlizumab assigned by the IRT will be recorded in the IRT system.
7
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC)-approved informed consent.
If applicable, in cases where the patient’s representative(s) gives consent (if allowed according 
to local requirements), the patient must be informed about the study to the extent possible given 
his/her level of understanding. If the patient is capable of doing so, he/she must indicate 
agreement by personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (e.g., all 
of the procedures described in the protocol). The process of obtaining informed consent must 
be documented in the patient source documents.
Novartis will provide to investigators in a separate document a proposed ICF that complies with 
the International Conference for Harmonization of Technical Requirements for Pharmaceuticals 
for Human Use (ICH) Good Clinical Practice (GCP) guidelines and regulatory requirements 
and is considered appropriate for this study. Any changes to the proposed consent form 
suggested by the investigator must be agreed by Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the IB. This information will be included in the patient informed consent and should 
be discussed with the patient 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 patient.
Women of childbearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study, they must adhere to the contraception requirements for the duration 
of the study. If there is any question that the patient will not reliably comply, then they should 
not be entered in the study.
The study includes an optional DNA component which requires a separate signature if the 
patient agrees to participate. It is required as part of this protocol that the Investigator presents 


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this option to the patient, as permitted by local governing regulations. The process for obtaining 
consent should be exactly the same as described above for the main informed consent. Declining 
to participate in these optional assessments will in no way affect the patient’s ability to join the 
main research study. Refer to Section 8.5.3 for additional details on these assessments.
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
Patients might be asked to complete optional questionnaires to provide feedback on their 
clinical trial experience. 
8
Visit schedule and assessments
The assessment schedule 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.
Patients should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible. Screening assessments can occur within 28 days 
prior to Week 1 Day 1 (IRT enrollment) as per Table 8-1. There is a ± 3-day visit window 
permitted on dosing and assessments to take into account scheduling over public holidays on 
Week 3 Day 1, a ± 7-day visit window from Week 7 Day 1 to Week 51 Day 1, a ± 3-day visit 
window on Week 53 Day 1, ± 5-day visit window for the 30-day safety follow-up visit, + 7-day
visit window for the 105-day follow-up (as applicable), and ± 7 day visit window for the Week 
53 urine ACR/PCR assessment (for patients who discontinue treatment early). Upon completion 
of the Week 53 Day 1 visit, the investigator will complete the EOT Disposition eCRF. Patients 
who discontinue study treatment early should not be considered withdrawn from the study 
unless they withdraw their consent (Section 9.1.1). Missed or rescheduled visits should not lead 
to automatic discontinuation. Patients who discontinue study treatment early should be 
scheduled for a visit as soon as possible (within 7 days of the last dose of the discontinued study 
treatment), at which time all of the assessments listed for visit EOT will be performed. Patients 
who discontinue treatment early will also return for a Week 53 urine ACR/PCR assessment. 
The Week 53 urine ACR/PCR assessment should occur 12 months after the first dose of study 
treatment. 
Patients who discontinue from study or withdraw their consent/oppose the use of their 
data/biological samples should be scheduled for a final evaluation visit if they agree, as soon as 
possible, at which time all of the assessments listed for the final visit will be performed.
All patients will be followed in the mandatory safety follow-up period, which includes safety 
assessments at 30 days (phone call) and 105 days (study visit, as applicable) after the Week 51 
Day 1 visit, or if the patient discontinued the study early, the last dose of discontinued study 
treatment.  Patients who will receive crizanlizumab approximately 4 weeks after their last dose 
of study treatment, do not need to complete the 105 day follow-up. The end of the safety follow-
up period for these patients will be the 30-day follow-up. All other patients are required to 
complete the 105-day follow-up.


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Table 8-1
Assessment Schedule
Period Screening
Treatment
End of Treatment 
(EOT)
Follow-up
Visit Name Screening
Week 1 Day 1
Week 3 Day 1
Week 7 Day 1
Week 11 Day 1
Week 15 Day 1
Week 19 Day 1
Week 23 Day 1
Week 27 Day 1
Week 31 Day 1
Week 35 Day 1
Week 39 Day 1
Week 43 Day 1
Week 47 Day 1
Week 51 Day 1
Week 53 Day 11
EOT2
30-day 
Follow-up 
phone call
105-
day 
Follow-
up 
Week 53 
urine 
ACR/PCR 
assessme
nt 20 (for 
patients who 
discontinue 
treatment 
early)
Visit Numbers3
1
101 102 103 104 105 106 107 108 109 110 111 112 113 114 115
199
201
202
299
Days
-28 to -1
1
15
± 3
43
± 7
71
± 7
99
± 7
127
± 7
155
± 7
183
± 7
211
± 7
239
± 7
267
± 7
295
± 7
323
± 7
351
± 7
365
± 3
Within 7 days of 
last dose
30-day 
Follow-up4 
± 5
105-
day 
Follow-
up4 + 7
365
± 7
Informed consent
X
IRT randomization
X5
Disposition
X
X
X
X
Demography
X
Inclusion/exclusion 
criteria
X
ECOG performance 
status
X
X5
Medical 
history/current 
medical conditions
X
Complications of 
SCD
X
Sickle cell VOC 
history
X
Alcohol history
X
Smoking history
X


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Protocol No. CSEG101A2203
Period Screening
Treatment
End of Treatment 
(EOT)
Follow-up
Visit Name Screening
Week 1 Day 1
Week 3 Day 1
Week 7 Day 1
Week 11 Day 1
Week 15 Day 1
Week 19 Day 1
Week 23 Day 1
Week 27 Day 1
Week 31 Day 1
Week 35 Day 1
Week 39 Day 1
Week 43 Day 1
Week 47 Day 1
Week 51 Day 1
Week 53 Day 11
EOT2
30-day 
Follow-up 
phone call
105-
day 
Follow-
up 
Week 53 
urine 
ACR/PCR 
assessme
nt 20 (for 
patients who 
discontinue 
treatment 
early)
Visit Numbers3
1
101 102 103 104 105 106 107 108 109 110 111 112 113 114 115
199
201
202
299
Days
-28 to -1
1
15
± 3
43
± 7
71
± 7
99
± 7
127
± 7
155
± 7
183
± 7
211
± 7
239
± 7
267
± 7
295
± 7
323
± 7
351
± 7
365
± 3
Within 7 days of 
last dose
30-day 
Follow-up4 
± 5
105-
day 
Follow-
up4 + 7
365
± 7
Hepatitis screen
X
HIV screen
X
Physical 
examination16
S
Abbreviated 
physical 
examination5
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Vital signs16
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Body height6; 16
X
X6
X6
Body weight5; 16
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BMI
X
Hematology5
X
X7
X
X
X
X
X
X
X
Platelets (local)21
X
X
X
X
X
X
X
X
X
Clinical chemistry5
X
X7
X
X
X
X
X
X
X
Coagulation panel5
X
X7
X
X
X
X
X
X
X


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Protocol No. CSEG101A2203
Period Screening
Treatment
End of Treatment 
(EOT)
Follow-up
Visit Name Screening
Week 1 Day 1
Week 3 Day 1
Week 7 Day 1
Week 11 Day 1
Week 15 Day 1
Week 19 Day 1
Week 23 Day 1
Week 27 Day 1
Week 31 Day 1
Week 35 Day 1
Week 39 Day 1
Week 43 Day 1
Week 47 Day 1
Week 51 Day 1
Week 53 Day 11
EOT2
30-day 
Follow-up 
phone call
105-
day 
Follow-
up 
Week 53 
urine 
ACR/PCR 
assessme
nt 20 (for 
patients who 
discontinue 
treatment 
early)
Visit Numbers3
1
101 102 103 104 105 106 107 108 109 110 111 112 113 114 115
199
201
202
299
Days
-28 to -1
1
15
± 3
43
± 7
71
± 7
99
± 7
127
± 7
155
± 7
183
± 7
211
± 7
239
± 7
267
± 7
295
± 7
323
± 7
351
± 7
365
± 3
Within 7 days of 
last dose
30-day 
Follow-up4 
± 5
105-
day 
Follow-
up4 + 7
365
± 7
Cytokines, 
complement, 
tryptase, p-
selectin17
Urinalysis (see
Table 8-3 for tests 
to be assessed 
locally)5
X
X7
X
X
X
X
X
Serum pregnancy 
test
X
X
X
X
Urine pregnancy 
test (assessed 
locally)5
S
S
S
S
S
S
S
S
S
S
S
S
S
S
Hemoglobin 
variants (Hb 
electrophoresis or 
HPLC)
X
Fetal hemoglobin 
(HbF)
X
X
X
X
X


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Protocol No. CSEG101A2203
Period Screening
Treatment
End of Treatment 
(EOT)
Follow-up
Visit Name Screening
Week 1 Day 1
Week 3 Day 1
Week 7 Day 1
Week 11 Day 1
Week 15 Day 1
Week 19 Day 1
Week 23 Day 1
Week 27 Day 1
Week 31 Day 1
Week 35 Day 1
Week 39 Day 1
Week 43 Day 1
Week 47 Day 1
Week 51 Day 1
Week 53 Day 11
EOT2
30-day 
Follow-up 
phone call
105-
day 
Follow-
up 
Week 53 
urine 
ACR/PCR 
assessme
nt 20 (for 
patients who 
discontinue 
treatment 
early)
Visit Numbers3
1
101 102 103 104 105 106 107 108 109 110 111 112 113 114 115
199
201
202
299
Days
-28 to -1
1
15
± 3
43
± 7
71
± 7
99
± 7
127
± 7
155
± 7
183
± 7
211
± 7
239
± 7
267
± 7
295
± 7
323
± 7
351
± 7
365
± 3
Within 7 days of 
last dose
30-day 
Follow-up4 
± 5
105-
day 
Follow-
up4 + 7
365
± 7
Optional DNA 
collection
X (once any time during the study)
Sickle cell – AKI 
event
X
Continuous
Sickle cell – VOC 
event8
X
Continuous
Chest X-ray
X9
If clinically indicated
If 
clinicall
y 
indicate
d
Healthcare resource 
utilization due to 
AKI, VOCs and/or 
other SCD 
complications10
X
Continuous
Missed school or 
work due to AKI, 
VOCs and/or other 
SCD 
complications10
X
Continuous


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Protocol No. CSEG101A2203
Period Screening
Treatment
End of Treatment 
(EOT)
Follow-up
Visit Name Screening
Week 1 Day 1
Week 3 Day 1
Week 7 Day 1
Week 11 Day 1
Week 15 Day 1
Week 19 Day 1
Week 23 Day 1
Week 27 Day 1
Week 31 Day 1
Week 35 Day 1
Week 39 Day 1
Week 43 Day 1
Week 47 Day 1
Week 51 Day 1
Week 53 Day 11
EOT2
30-day 
Follow-up 
phone call
105-
day 
Follow-
up 
Week 53 
urine 
ACR/PCR 
assessme
nt 20 (for 
patients who 
discontinue 
treatment 
early)
Visit Numbers3
1
101 102 103 104 105 106 107 108 109 110 111 112 113 114 115
199
201
202
299
Days
-28 to -1
1
15
± 3
43
± 7
71
± 7
99
± 7
127
± 7
155
± 7
183
± 7
211
± 7
239
± 7
267
± 7
295
± 7
323
± 7
351
± 7
365
± 3
Within 7 days of 
last dose
30-day 
Follow-up4 
± 5
105-
day 
Follow-
up4 + 7
365
± 7
Prior/concomitant 
medications10
X
Continuous
Prior/concomitant 
medications –
Analgesic10
X
Continuous
Prior/concomitant 
medications –
ESA10
X
Continuous
Prior/concomitant 
medications – HA 
approved form(s) of 
L-glutamine10
X
Continuous
Concomitant non-
drug 
therapies/procedure
s10
X
Continuous
Incidence of 
transfusion10
X
Continuous


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Protocol No. CSEG101A2203
Period Screening
Treatment
End of Treatment 
(EOT)
Follow-up
Visit Name Screening
Week 1 Day 1
Week 3 Day 1
Week 7 Day 1
Week 11 Day 1
Week 15 Day 1
Week 19 Day 1
Week 23 Day 1
Week 27 Day 1
Week 31 Day 1
Week 35 Day 1
Week 39 Day 1
Week 43 Day 1
Week 47 Day 1
Week 51 Day 1
Week 53 Day 11
EOT2
30-day 
Follow-up 
phone call
105-
day 
Follow-
up 
Week 53 
urine 
ACR/PCR 
assessme
nt 20 (for 
patients who 
discontinue 
treatment 
early)
Visit Numbers3
1
101 102 103 104 105 106 107 108 109 110 111 112 113 114 115
199
201
202
299
Days
-28 to -1
1
15
± 3
43
± 7
71
± 7
99
± 7
127
± 7
155
± 7
183
± 7
211
± 7
239
± 7
267
± 7
295
± 7
323
± 7
351
± 7
365
± 3
Within 7 days of 
last dose
30-day 
Follow-up4 
± 5
105-
day 
Follow-
up4 + 7
365
± 7
12-lead ECG
X
If clinically indicated
X
X
If 
clinicall
y 
indicate
d
AEs/SAEs
X
Continuous
IRR19
Continuous
Urine ACR5,11,
X
X
X
X
X
X
X
X
Urine PCR5,11
X
X
X
X
X
eGFR5,12
X12
X
X
X
X
X
X
Immunogenicity5,13
(see also Table 8-6)
X
X
X
X
X
X
X
X
PK5,13 (see also
Table 8-6)
X
X
X
X
X
X
X
X


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Protocol No. CSEG101A2203
Period Screening
Treatment
End of Treatment 
(EOT)
Follow-up
Visit Name Screening
Week 1 Day 1
Week 3 Day 1
Week 7 Day 1
Week 11 Day 1
Week 15 Day 1
Week 19 Day 1
Week 23 Day 1
Week 27 Day 1
Week 31 Day 1
Week 35 Day 1
Week 39 Day 1
Week 43 Day 1
Week 47 Day 1
Week 51 Day 1
Week 53 Day 11
EOT2
30-day 
Follow-up 
phone call
105-
day 
Follow-
up 
Week 53 
urine 
ACR/PCR 
assessme
nt 20 (for 
patients who 
discontinue 
treatment 
early)
Visit Numbers3
1
101 102 103 104 105 106 107 108 109 110 111 112 113 114 115
199
201
202
299
Days
-28 to -1
1
15
± 3
43
± 7
71
± 7
99
± 7
127
± 7
155
± 7
183
± 7
211
± 7
239
± 7
267
± 7
295
± 7
323
± 7
351
± 7
365
± 3
Within 7 days of 
last dose
30-day 
Follow-up4 
± 5
105-
day 
Follow-
up4 + 7
365
± 7
Standard of care –
HU/HC14
X
Administered as clinically indicated
Standard of care –
ACE inhibitors14
X
Administered as clinically indicated
Standard of care –
ARBs14
X
Administered as clinically indicated
Crizanlizumab 
administration15
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X Assessment to be recorded in the clinical database or received electronically from a vendor
S Assessment to be recorded in the source documentation only
1 Upon completion of the Week 53 Day 1 visit, the investigator will complete the EOT Disposition eCRF
2 Visit “EOT” is only for patients for whom the decision is made to discontinue the patient from the study early prior to visit Week 51 Day 1 
3 Visit structure given for internal programming purpose only
4 The 30 day follow up phone call and 105 day follow up visit are relative to the Week 51 Day 1 visit, or if discontinued study treatment early, the last 
dose of the discontinued study treatment.  Patients who will receive crizanlizumab approximately 4 weeks after their last dose of study treatment, do not
need to complete the 105 day follow-up. The end of the safety follow-up period for these patients will be the 30-day follow-up. All other patients are 
required to complete the 105-day follow-up.
6 At Week 53 Day 1 or visit EOT, height will only be assessed in patients aged 16 or 17 years


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Protocol No. CSEG101A2203
Period Screening
Treatment
End of Treatment 
(EOT)
Follow-up
Visit Name Screening
Week 1 Day 1
Week 3 Day 1
Week 7 Day 1
Week 11 Day 1
Week 15 Day 1
Week 19 Day 1
Week 23 Day 1
Week 27 Day 1
Week 31 Day 1
Week 35 Day 1
Week 39 Day 1
Week 43 Day 1
Week 47 Day 1
Week 51 Day 1
Week 53 Day 11
EOT2
30-day 
Follow-up 
phone call
105-
day 
Follow-
up 
Week 53 
urine 
ACR/PCR 
assessme
nt 20 (for 
patients who 
discontinue 
treatment 
early)
Visit Numbers3
1
101 102 103 104 105 106 107 108 109 110 111 112 113 114 115
199
201
202
299
Days
-28 to -1
1
15
± 3
43
± 7
71
± 7
99
± 7
127
± 7
155
± 7
183
± 7
211
± 7
239
± 7
267
± 7
295
± 7
323
± 7
351
± 7
365
± 3
Within 7 days of 
last dose
30-day 
Follow-up4 
± 5
105-
day 
Follow-
up4 + 7
365
± 7
7 Not to be repeated on Day 1 if screening assessment took place within 72 hours
8 Other acute pain crisis managed at home will also be collected
9 Within 3 months prior to Week 1 Day 1
10 Parameter refers to data to be collected (i.e., if any healthcare resource utilization or concomitant medication administration or procedure, etc, 
occurred). See also Table 8-8
11 Three urine samples will be collected for each visit time point for which ACR and/or PCR are to be assessed. See Section 8.3.1 and Section 8.3.2
for further details
12 Any available eGFR data for the 2-year period prior to screening will be collected
13 Immunogenicity and PK assessments are not required for patients randomized to the standard of care alone arm
14 Recording standard of care drugs: Any of the following drugs being taken at study entry will be considered the patient’s standard of care: HU/HC, 
ACE inhibitors, and/or ARBs. No dose modifications in standard of care medications may be made during the study, except for dose modifications due 
to AEs or weight adjustments at the discretion of the physician. Any dose modifications made to the patient’s standard of care drug(s) during the study 
will be recorded 
15 Only patients randomized to the crizanlizumab + standard of care arm. Refer to Section 6.5.1.1 for instructions in case of crizanlizumab dose delay.
16 See Table 8-2 for details
 


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Protocol No. CSEG101A2203
Period Screening
Treatment
End of Treatment 
(EOT)
Follow-up
Visit Name Screening
Week 1 Day 1
Week 3 Day 1
Week 7 Day 1
Week 11 Day 1
Week 15 Day 1
Week 19 Day 1
Week 23 Day 1
Week 27 Day 1
Week 31 Day 1
Week 35 Day 1
Week 39 Day 1
Week 43 Day 1
Week 47 Day 1
Week 51 Day 1
Week 53 Day 11
EOT2
30-day 
Follow-up 
phone call
105-
day 
Follow-
up 
Week 53 
urine 
ACR/PCR 
assessme
nt 20 (for 
patients who 
discontinue 
treatment 
early)
Visit Numbers3
1
101 102 103 104 105 106 107 108 109 110 111 112 113 114 115
199
201
202
299
Days
-28 to -1
1
15
± 3
43
± 7
71
± 7
99
± 7
127
± 7
155
± 7
183
± 7
211
± 7
239
± 7
267
± 7
295
± 7
323
± 7
351
± 7
365
± 3
Within 7 days of 
last dose
30-day 
Follow-up4 
± 5
105-
day 
Follow-
up4 + 7
365
± 7
19 Certain adverse events reported in the AE/SAE eCRF as Infusion Related Reactions will require the IRR eCRF to be completed. Refer to the CRF 
completion guidelines (CCGs) for further information.
20 Patients who discontinue treatment early will return for a Week 53 urine ACR/PCR assessment. The Week 53 urine ACR/PCR assessment should 
occur 12 months after the first dose of study treatment. The Week 53 urine ACR/PCR visit may fall before or after the safety follow-up visits depending 
on the patient’s last dose of study treatment. 
21 Local sampling for platelet assessment will also be performed throughout the trial for adults and adolescents with body weight >45kg 


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8.1
Screening
After signing the study ICF, the screening assessments will be done within 1 to 28 days prior 
to baseline (Week 1 Day 1) (see Table 8-1) for list of assessments to be performed. The 
investigator will obtain consent/assent of patients and/or parents according to local procedures. 
Rescreening of patients is allowed once per patient per protocol version (ie. a patient can be re-
screened under an amended protocol based on the changes in inclusion/exclusion criteria across 
versions). The investigator has the discretion to include/exclude a patient in the study, who will 
be found to have symptoms representative of COVID-19 or tested positive for COVID-19 
during the screening phase. Should the investigator choose to screen fail the patient based on 
symptoms or positive COVID-19 test, the patient can be re-screened more than once. In this 
case a new Patient Number will be assigned to the patient and the patient will be identified with 
this new number for the rest of his/her participation in the study. If patient has been enrolled 
and treated, re-screening of patient is not allowed. In case rescreening occurs, all evaluations 
re-assessed should meet the eligibility criteria. A new ICF must be signed only if there is an 
interruption in the patient’s eligibility evaluation and the investigator chooses to re-screen the 
patient following screen failure. If a new ICF is signed, AEs and medical history will be 
assessed relative to the new informed consent date.
For laboratory evaluations used to determine eligibility, a repeated evaluation within the 
screening window is permitted for screening results out of the defined range before screen 
failing the patient. If the repeated laboratory result meets the criteria, that result may be used to 
determine eligibility. If the repeated laboratory result does not meet the criteria, the patient will 
be considered a screening failure. For details of assessments, see Table 8-1 and Section 8.4.1.
8.1.1
Eligibility screening
The investigator is responsible to ensure only patients who meet all inclusion and none of the 
exclusion criteria are included in this study.
Following registration in the IRT for screening, patient eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT system. 
Please refer and comply with detailed guidelines in the IRT manual.
8.1.2
Information to be collected on screening failures
Patients who sign an ICF and subsequently found to be ineligible prior to randomization will 
be considered a screen failure. The reason for screen failure should be recorded on the 
appropriate eCRF. The demographic information, informed consent, and Inclusion/Exclusion 
pages must also be completed for screen failure patients. No other data will be entered into the 
clinical database for patients who are screen failures, unless the patient experienced a SAE 
during the screening phase (see SAE section for reporting details). If the patient fails to be 
randomized, the IRT must be notified within 2 days of the screen fail that the patient was not 
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Protocol No. CSEG101A2203
Patients who are randomized and fail to start treatment, e.g., patients randomized in error, will 
be considered an early terminator. The reason for early termination should be recorded on the 
appropriate eCRF. 
8.2
Patient demographics/other baseline characteristics
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with the eCRF.
Patient demographic and baseline characteristic data to be collected on all patients include age, 
sex, self-identified race, and ethnicity. Patient race /ethnicity are collected 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 sickle cell history, SCD genotype, coinheritance of 
alpha thalassemia, % HbF, ECG, relevant and current medical history, ECOG performance 
status, as well has history of alcohol and smoking will be recorded. Any available eGFR data 
for the 2-year period prior to screening will 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 6.2.1 Concomitant therapy 
for further details on what information must be recorded on the appropriate eCRF.
Healthcare resource utilization history including patient disease burden, as assessed by the 
following, will also be recorded:
1. Sickle cell VOC history, including the number of:
a. VOCs at home (not requiring healthcare resource utilization) in the previous 
12 months
b. VOCs requiring healthcare resource utilization in the previous 12 months, including 
the number of:

Hospitalizations in the 12 months

ER visits in the previous 12 months
c. SCD complications other than VOCs requiring healthcare resource utilization in the 
previous 12 months, including the number of:

Hospitalizations in the 12 months

ER visits in the previous 12 months
2. Data will be collected for complicated and uncomplicated VOCs. Complicated VOCs are 
defined as ACS, hepatic sequestration, splenic sequestration, and priapism
3. Number of missed school days or work days due to VOCs and/or other SCD 
complications in the previous 12 months. Data will be collected for complicated and 
uncomplicated VOCs
4. Other complications of SCD, including, but not limited to, stroke, leg ulcers, asthma, 
avascular necrosis, pulmonary hypertension, retinopathy, other (investigator to specify)


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Other baseline characteristics and assessments, including ACR, PCR, and eGFR, are detailed 
in Table 8-1.
8.3
Efficacy 
Samples for the assessment of albuminuria (urine ACR), urine PCR, eGFR, and progression of 
CKD will be collected at the time points indicated in Table 8-1. These assessments are described 
below and further details regarding the collection, storage, shipment, and analysis of these 
samples are provided in the laboratory manual.
Note that patients who discontinue study treatment early should not be considered withdrawn 
from the study unless they withdraw their consent (Section 9.1.1). A Week 53 urine ACR/PCR 
assessment is required for patients who discontinue study treatment early.
8.3.1
Urine albumin to creatinine ratio
Three urine samples will be collected for each visit time point for which albumin and creatinine 
concentrations are to be assessed for ACR (these will be the same samples that are assessed for 
PCR, as applicable (see Section 8.3.2)). Two of the three samples should be collected as 
morning voids. Morning void samples can be collected at any time during the screening and 
study visit windows on two consecutive days (refer to laboratory manual for sample stability 
requirements). The sample collected during the study visit can be collected either prior to, on
or after the day of the morning sample collections. The average of the 3 samples (2 morning 
void samples and 1 sample collected during the visit) will be used to determine patient eligibility. 
The samples will be obtained midstream and will be stored as defined in the laboratory manual.
As noted above (Section 8.3), patients who discontinue study treatment early will return for a 
Week 53 urine ACR/PCR assessment as indicated in Table 8-1.
Albumin and creatinine concentrations will be measured by the central laboratory using an 
immunological assay capable of specifically and precisely quantifying albumin at low 
concentrations and of producing quantitative results over the clinically relevant range. Albumin 
concentrations will be reported as a ratio to urinary creatinine concentration (mg/g) for each of 
the three samples. The ACR results will be expressed to whole numbers. Further details will be 
provided in the laboratory manual.
It is important to collect all 3 urine samples and that 2 of the samples are morning voids at all 
collection time points to help minimize the variability in ACR measurements. 
8.3.2
Urine protein to creatinine ratio
Three urine samples will be collected for each visit time point for which protein and creatinine 
concentrations are to be assessed for PCR (these will be the same samples that are assessed for 
ACR (see Section 8.3.1)). Two of the three samples should be collected as morning voids. 
Morning void samples should be collected during the study visit window on two consecutive 
days (refer to laboratory manual for sample stability requirements). The sample collected during 
the study visit can be collected either prior to, on or after the day of the morning sample


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collections. PCR is not required for eligibility and will be assessed starting W1D1 and 
subsequent timepoints. The samples will be obtained midstream and will be stored as defined 
in the laboratory manual. 
As noted above (Section 8.3), patients who discontinue study treatment early will return for a 
Week 53 urine ACR/PCR assessment as indicated in Table 8-1.
Protein and creatinine concentrations will be assessed by the central laboratory. Protein 
concentrations will be reported as a ratio to urinary creatinine concentration (mg/g) for each of 
the three samples. The PCR results will be expressed to whole numbers. Further details will be 
provided in the laboratory manual.
8.3.3
Estimated glomerular filtration rate
The eGFR will be calculated in the serum from the blood samples collected for assessment of 
clinical chemistry parameters. eGFR will be assessed by the central laboratory, as specified in 
the laboratory manual.
The central laboratory will calculate eGFR using the 2009 CKD-EPI formula for patients ≥ 18 
at screening and 2009 Creatinine-based “Bedside Schwartz” equation for patients < 18 at 
screening. While on the study, the patient’s eGFR will continue to be calculated by the same 
formula used at screening.
2009 CKD-EPI formula
The CKD-EPI formula (Levey et al 2009), without the correction for race, to be used in this 
study for patients ≥ 18 at screening to estimate GFR is as follows:
141 × min(Scr/k, 1)α × max(Scr/k, 1)-1.209 × 0.993Age
[× 1.018 if female], where:

Scr is serum creatinine (in mg/dL)

k is 0.7 for females and 0.9 for males

α is -0.329 for females and -0.411 for males

min is the minimum of Scr/k or 1

max is the maximum of Scr/k or 1
2009 Creatinine-based “Bedside Schwartz” equation
The 2009 Creatinine-based “Bedside Schwartz” equation will be used in this study to estimate 
eGFR for patients < 18 at screening (Schwartz et al 2009). The equation is as follows:
eGFR =
0.413 x (height/Scr) if height is expressed in centimeters
OR
41.3 x (height/Scr) if height is expressed in meters


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8.3.4
Progression of chronic kidney disease
The progression of CKD will be assessed based on the blood samples collected for the 
assessment of eGFR (Section 8.3.3). The progression of CKD, which is based on both eGFR 
and ACR, will be assessed according to the classification presented in Figure 8-1 (based on 
KDIGO 2013). Specifically, CKD progression will be defined as follows:

Increase in CKD progression category: i.e., Category 1 to ≥2; Category 2 to ≥3; or 
Category 3 to 4 (see Figure 8-1)

Accompanied by a 25% or greater drop in eGFR from baseline 

Decline in eGFR category:
Grade 1 (normal or high), eGFR ≥90 mL/min/1.73m2
Grade 2 (mildly decreased), eGFR 60-89 mL/min/1.73m2
Grade 3a (mildly to moderately decreased), eGFR 45-59 mL/min/1.73m2
Grade 3b (moderately to severely decreased), eGFR 30-44 mL/min/1.73m2
Grade 4 (severely decreased), eGFR 15-29 mL/min/1.73m2
Grade 5 (kidney failure), eGFR < 15 mL/min/1.73m2
A certain drop in eGFR is defined as a drop in eGFR category accompanied by a 25% or 
greater drop in eGFR from baseline

Rapid progression is defined as a sustained decline in eGFR of more than 
5 mL/min/1.73 m2/year

The confidence in assessing progression is increased with increasing number of serum 
creatinine measurements and duration of follow-up
A 50% increase in ACR for patients with severe (A3) albuminuria and a doubling of albumin 
levels in patients with moderate (A2) albuminuria. Predictors of progression include both the 
level of albuminuria and the level of GFR.


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Figure 8-1
Glomerular filtration rate and albuminuria grid to reflect the risk of 
chronic kidney disease progression
Persistent albuminuria categories
Description and range
A1
A2
A3
Normal to 
mildly 
increased
Moderately 
increased
Severely 
increased
< 30 mg/g
< 3 mg/mmol
30-300 mg/g
3-30 mg/mmol
> 300 mg/g
> 30 mg/mmol
GFR categories (mL/min/1.73 m2)
Description and range
G1
Normal or high
≥90
0
1
2
G2
Mildly decreased
60-89
0
1
2
G3a
Mildly to moderately 
decreased
45-59
1
2
3
G3b
Moderately to 
severely decreased
30-44
2
3
3
G4
Severely decreased
15-29
3
3
4
G5
Kidney failure
< 15
4
4
4
Glomerular filtration rate and albuminuria grid to reflect the risk of progression (where CKD 
progression category 0 is the lowest risk of progression and 4 is the highest risk)
1 CKD progression categories according to KDIGO (2013); patients in this study will have eGFR 
≥45 to  ≤140 mL/min/1.73 m2 and ACR of ≥100 to < 2000 mg/g (i.e., CKD progression categories 
1, 2, or 3). Assessment should be based on ACR in mg/g.
8.3.5
Appropriateness of efficacy assessments 
The primary endpoint of this study is the proportion of patients with ≥30% decrease in ACR at 
12 months from baseline. 
Based on the recommendation of a consensus panel focused on SCD end organ considerations 
specifically evaluating renal endpoints in SCD trials, albuminuria was recommended as a 
potential endpoint. The outcome measure suggested that was deemed clinically relevant was a 
30% decrease in albuminuria evaluated by ACR (Farrell et al 2019). A meta-analysis of clinical 
trial data also suggests that each 30% decrease in geometric mean albuminuria by the treatment 
relative to the control was associated with an average 27% lower hazard for the clinical endpoint. 
This association strengthened after restricting analyses to patients with baseline albuminuria of 
more than 30 mg/g. The model from this analysis predicted that treatments that decrease the 
geometric mean albuminuria relative to the control group by 30% would have a high likelihood 
to confer clinical benefit (Heerspink et al 2019).


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The meta-analysis was based on 41 eligible treatment comparisons from randomized studies 
that provided sufficient patient level data on 29979 participants (71% of whom had diabetes). 
Eligible participants were aged ≥18 years with an eGFR of ≥15 mL/min/1.73 m2, quantifiable 
measurements of albuminuria or proteinuria at baseline and within 12 months of follow up, and 
information on the incidence of end stage kidney disease. The primary objective of the meta-
analysis was to assess the validity of change in albuminuria as a surrogate endpoint for 
progression of CKD by modelling the association between treatment effects on 6-month change 
in urine ACR, and treatment effects on the composite clinical endpoint across the studies. The 
clinical endpoint (defined as a composite of treated end stage kidney disease, eGFR of 
< 15 mL/min/1.73 m2, or doubling of serum creatinine sustained at the subsequent visit) was 
reached in 13% participants over a median follow up of 3.4 years (Heerspink et al 2019). 
Microalbuminuria is one of the earliest signs of glomerular injury in patients with SCD, 
albuminuria in the early stages of CKD appears to be a sensitive marker of CKD progression, 
and an early decrease in albuminuria is considered to be indicative of a favorable response to 
treatment (Bartolucci et al 2016, Heerspink et al 2019). In a study of 1513 patients with Type 2 
diabetes and nephropathy, the most rapid change (decrease) in the level of proteinuria (assessed 
by ACR) occurred within the first 3 to 6 months of treatment with an ARB, and over the next 
6 months the decreases in proteinuria were much smaller, suggesting a stabilization of the effect 
of this ARB after 6 months (Brenner et al 2001).
Thus, the proportion of patients with ≥30% decrease in ACR at 12 months was selected as the 
primary variable in this study. To increase the precision of the treatment effect, it is planned to 
collect three ACR samples at each time point to calculate the mean. It is anticipated that 
standard of care medications in particular HU/HC may also have the most marked effect on 
proteinuria within the first 6 months. Therefore, the current study will require that patients have 
been taking a stable dose of their standard of care medications. Patients must have been on a 
stable dose of HU/HC, and ACE and/or ARB for at least 3 months prior to study entry. In 
addition, any patients receiving HA approved form(s) of L-glutamine as a concomitant 
medication, must have been on a stable dose for at least 6 months prior to study entry and plan 
to continue taking a stable dose throughout the study as it is not known how L-glutamine may 
affect ACR values.
The mean change in ACR from baseline to 3, 6, 9, and 12 months of treatment will be assessed 
as a secondary endpoint. An early decrease in albuminuria is considered to be indicative of a 
favorable response to treatment (Heerspink et al 2019) and the proportion of patients with 
≥30% decrease in ACR at 6 months will be assessed as a secondary endpoint, as will the slope 
of ACR decline from baseline to 12 months based on ACR values at baseline and at 3, 6, 9, and 
12 months.
Proteinuria has a role in the pathogenesis of CKD disease progression (KDIGO 2013). The 
KDIGO guidelines suggest that the two most preferred methods for initial testing of proteinuria 
comprise measuring urine ACRs or urine PCRs. As noted above, the primary endpoint of this 
study will be based on ACR. PCR will be assessed as a secondary endpoint: The proportion of 
patients with PCR improvement and stable PCR (improvement: ≥20% decrease in PCR from 


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baseline; stable: within ± 20% change from baseline) at 12 months compared to baseline (the 
20% threshold in this endpoint is based on expert assessment of clinically meaningful 
improvements).
An important secondary endpoint of this study is the percentage change in eGFR from baseline 
to 3, 6, 9, and 12 months of treatment with crizanlizumab + standard of care compared to 
standard of care alone. The US FDA have stated that they anticipate that eGFR could be an 
appropriate surrogate endpoint for use as an efficacy clinical trial endpoint in adult patients with 
CKD secondary to multiple etiologies (Levey et al 2014). 
As GFR cannot be measured directly, it may be estimated from the serum levels of endogenous 
filtration markers such as creatinine. The participants of a scientific workshop sponsored by the 
National Kidney Foundation and US FDA in 2012 agreed that an eGFR decline of 30% could 
be a valid and useful surrogate endpoint for progression to kidney failure in clinical trials of 
CKD, but the evidence was stronger for an eGFR decline of 40%, based on a follow-up duration 
of ≥2 to 3 years (Levey et al 2014). The patients to be included in the current study comprise 
SCD patients with CKD who are expected to be rapid decliners (see Section 5), despite having 
received standard of care for ≥6 months. Rapid decline can be defined as an annual rate of 
decline in eGFR of ≥3-5 mL/min/1.73 m2 (Tsai et al 2017). There has been much debate 
regarding the best method to estimate GFR. The CKD-EPI formula has been selected for use in 
this study for patients ≥ 18 at screening; it matches the accuracy of the MDRD equation at GFR 
< 60 mL/min/1.73 m2 and offers greater accuracy at higher GFRs (Florkowski and 
Chew-Harris 2011). The “Bedside Schwartz” formula will be used for patients <18 at screening.
This formula was noted to be the most accurate formula to avoid overestimation of eGFR in 
children (Schwartz et al 2009). Nonetheless, challenges remain regarding the accurate 
assessment of eGFR across the full range of eGFRs anticipated in this study. Though this study 
will enroll patients considered rapid decliners based on both the level of albuminuria and eGFR, 
a study of longer duration, and a larger sample size would likely be required, thus it was thus 
decided to have an eGFR-based secondary endpoint for this study, rather than an eGFR primary 
endpoint.
The proportion of patients with CKD progression (based on both ACR and eGFR) from baseline 
to 12 months will also provide a clinically relevant assessment of a potential benefit with 
crizanlizumab + standard of care and standard of care alone.
8.4
Safety
Safety assessments will consist of monitoring and recording all AEs, based on CTCAE v5.0. It 
will also include regular monitoring of laboratory assessments including hematology, clinical 
chemistry, complement, cytokines and urinalysis (see Section 8.4.1), measurement of vital 
signs and physical examination (see Table 8-2), and ECG evaluation (see Section 8.4.2).
The assessment schedule details when each assessment is to be performed (Table 8-1).
For details on AE collection and reporting, refer to Section 10.1.1.


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Table 8-2
Assessments & Specifications
8.4.1
Laboratory evaluations 
Clinical laboratory analyses (hematology, clinical chemistry, urinalysis, coagulation, cytokines, 
complement, hepatitis and HIV markers, and serum pregnancy test) are to be performed 
centrally, unless otherwise mentioned in the schedule of assessments. 
Novartis must be provided with a copy of the central laboratory’s certification (if applicable), 
and a tabulation of the normal ranges and units of each parameter collected in the eCRF. Any 
changes regarding normal ranges and units for laboratory values assessed during the study must 
be reported via an updated tabulation indicating the new effective date. Additionally, if at any 
time a patient 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 patients in the study and 
evaluating any abnormalities for clinical significance. Clinically significant abnormalities must 
be recorded as either medical history/current medical conditions or AEs as appropriate.
For assessment of patients’ eligibility to the study, only laboratory results from the central 
laboratory will be used (except in the event the results from the central laboratory are not yet 
Assessment
Specification
Physical 
examination
A complete physical examination will include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities, vascular, and neurological. If indicated 
based on medical history and/or symptoms, rectal, external genitalia, breast, and 
pelvic exams will be performed. A complete physical examination will be performed 
at screening.
An abbreviated (short) physical exam will include the examination of general 
appearance and vital signs (blood pressure [systolic blood pressure and diastolic 
blood pressure] and pulse), as well as additional components of the physical exam 
(e.g., lower extremity examination), as needed based on observed signs or reported 
symptoms. A short physical exam will be at all visits starting from the Week 1 Day 1 
visit. 
Information for all physical examinations must be included in the source 
documentation at the study site. Significant findings that are present prior to signing 
informed consent must be recorded in the Medical History page on the patient’s 
eCRF. Significant new findings that begin or worsen after informed consent must 
be recorded on the Adverse Event page of the patient’s eCRF.
Vital signs
Vital signs include blood pressure (supine position preferred when ECG is collected) 
based on an average of 3 measurements, pulse measurement, respiratory rate, and 
body temperature. Vital signs will be assessed at each visit. 
Height, weight 
and BMI
Height in centimeters (cm) will be measured at screening (all patients); then at the 
Week 53 Day 1 visit or visit EOT (only patients aged 16 or 17 years). Body weight 
(to the nearest 0.1 kilogram (kg) in indoor clothing, but without shoes) will be 
measured at every visit up to the Week 53 Day 1 visit or visit EOT.
BMI will be assessed at screening for eligibility.


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available or are partial at time of the first infusion, then eligibility may be based on the results 
from the local laboratory. In such a case, the results of the local laboratory will need to be 
recorded in the eCRF unscheduled pages and copy of the local lab normal ranges must be 
provided). Local laboratory values for ACR and eGFR results should not be used to confirm 
eligibility. Unscheduled local laboratory assessments may be performed if medically indicated 
to document a (potential) AE or when the treating physician cannot wait for central laboratory 
results for decision making. In this particular situation, if possible, the blood sample obtained 
at the same time point should be submitted to the central laboratory for analysis in parallel with 
local analysis. The results of the local laboratory will be recorded in the eCRF unscheduled 
pages if any the following criteria are met:

A treatment decision was made based on the local results, or

There are no concomitant central results available, or

Local lab results document an AE not reported by the central lab, or

Local lab results document an AE where the severity is worse than the one reported by the 
central lab, or

Eligibility had to be based on the local lab results due to pending/missing central lab 
results. 
Laboratory assessments (e.g. blood, urine) can be repeated during the screening period as 
deemed appropriate by the investigator. 
At any time during the study up to safety follow-up, abnormal laboratory parameters which are 
clinically relevant and require an action to be taken with study treatment (e.g., require dose 
modification and/or interruption of study treatment, lead to clinical symptoms or signs, or 
require therapeutic intervention), whether specifically requested in the protocol or not, will be 
recorded on the AE eCRF page. The severity of laboratory data will be graded using the 
CTCAE v5.0. Additional analyses are left to the discretion of the investigator.
Specifically, for platelet count, local sampling will also be performed throughout the trial for 
adults and adolescents with body weight > 45kg. To mitigate the potential for unevaluable or 
false LPTs, it is recommended to run blood samples as soon as possible. Based on in vitro data, 
platelet clumping was observed in some donor samples as early as 4 hours following the 
addition of crizanlizumab. When needed, manual platelet estimation via blood smear to assess 
adequacy of the platelet count may be considered. Additional details on the measures to be used 
will be provided in the laboratory manual.
The laboratory assessments are summarized in Table 8-3. Refer to the laboratory manual for 
further details of the laboratory evaluations to be performed in this study.


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Table 8-3
Laboratory assessments
Test Category
Test Name
Hematology
Hematocrit, Hb, mean corpuscular hemoglobin (MCH), MCH concentration 
(MCHC), mean corpuscular volume (MCV), Platelets*, Reticulocytes (%), 
RBCs, White blood cells, RBC Morphology, ANC, Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands, Other) 
(absolute value preferred, % are acceptable)
Clinical chemistry
eGFR (see Section 8.3.3 and Section 8.3.4)
Albumin, ALP, ALT, AST, GGT, LDH, Bicarbonate, Calcium, Magnesium, 
Phosphorus, Chloride, Sodium, Potassium, Creatinine, Creatine kinase,
Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, Total Cholesterol, LDL, 
HDL, Total Protein, Triglycerides, BUN or Urea, Uric Acid, Amylase, 
Lipase, Glucose (non-fasting)
Urinalysis
ACR (see Section 8.3.1)
PCR (see Section 8.3.2)
Albumin, protein, creatinine concentrations
Macroscopic Panel (Dipstick) will be done locally: Color, Bilirubin, Blood, 
Glucose, Ketones, Leukocytes esterase, Nitrite, pH, Protein, Specific 
Gravity, Urobilinogen
Microscopic Panel: RBCs, White Blood Cells, Casts, Crystals, Bacteria, 
Epithelial cells performed, if a positive dipstick result
Coagulation
Prothrombin time (PT), INR, Activated partial thromboplastin time (APTT)
Cytokines/complement 
(including but not 
limited to) and 
additional tests
IFNy, IL-1, IL-2, IL-6, TNFa, C3a, C5a, SC5b-9, as well as p-selectin and 
tryptase (to be collected pre-infusion and up to 1hr - post-infusion at Week 
1 Day 1, Week 3 Day 1 and Week 15 Day 1) and immediately after a grade 
3 or 4 IRR for patient treated with crizanlizumab.
Hepatitis markers
HBV-DNA, HbsAg, HbsAb, HbcAb, HCV RNA-Polymerase Chain 
Reaction, HCV Ab (at screening only)
Additional tests
HIV Ab and RNA test (for viral load) (at screening only), Hb variants (at 
screening only) (see Section 8.4.1.1)
Pregnancy Test
For all women: serum pregnancy text (at screening, Week 53 Day 1, visit 
EOT, and follow-up visit), Urine pregnancy test at all other visits. See 
Section 8.4.4 for further details
* Local sampling for platelet counts will also be performed throughout the trial for adults and 
adolescents with body weight >45kg
8.4.1.1
Hemoglobin variants
Hemoglobin electrophoresis or HPLC will be used to screen for Hb variants in whole blood, 
including HbA, HbS, HbC, and HbA2. Fetal Hb (HbF) will be assessed at the time points 
defined in Table 8-1. Hb electrophoresis can be performed locally or by central laboratory if 
the country does not have local capabilities or HPLC is to be performed locally.


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8.4.2
Electrocardiogram (ECG)
Figure 8-2
Timing of study procedures
Standard 12-lead ECGs will be performed (in the supine position) after the patient has been 
resting for at least 5 min (10 min resting period preferred) prior to each time point indicated in 
Table 8-4. Electrocardiogram assessments will be conducted as outlined. Triplicate 12 lead 
ECGs are to be recorded approximately 2 minutes apart. The mean QTcF value for each visit 
will be calculated from the triplicate ECGs for each patient. The suggested sequence of 
cardiovascular data collection during study visits is ECG 
 first, followed by vital signs, 
and blood sampling.
Table 8-4
Central electrocardiogram (ECG) collection plan
Week
Day
Time
ECG Type
Screening
-28 to -1
Anytime
Triplicate 12 Lead
Week 53 Day 1
Anytime
Triplicate 12 Lead
End of Treatment (visit 
EOT)
Anytime
Triplicate 12 Lead
Unscheduled
Anytime
Triplicate 12 Lead
Each ECG tracing should be labeled with the study number, patient initials (where regulations 
permit), Patient Number, date, and kept in the source documents at the study site. 
For any ECGs with patient safety concerns, triplicate ECGs must be performed to confirm the 
safety finding and copies forwarded to the central ECG laboratory for assessment. A monitoring 
or review process should be in place for clinically significant ECG findings throughout the 
study and especially at baseline before administration of study treatment.
Any identifier details must be redacted e.g., patient initials, date of birth.
In the event that a clinically significant ECG abnormality is identified at the site (e.g., severe 
arrhythmia, conduction abnormality of QTcF > 500 ms), a copy of the assessment is sent to the 
core laboratory for expedited review if applicable, and the ECG is repeated to confirm the 
diagnosis. If the patient is hemodynamically compromised, the investigator or a medically 
qualified person must initiate appropriate safety procedures without delay (for example 
cardioversion).
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 


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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 mean result of 
the ECGs will be entered into the study database and used for AE reporting. 
All ECGs, including unscheduled triplicate safety 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.
Clinically significant abnormalities present at screening should be reported on the Medical 
History eCRF page. Clinically significant findings must be discussed with Novartis prior to 
enrolling the patient in the study. New or worsened clinically significant findings occurring 
after informed consent must be recorded on the Adverse Events eCRF page.


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8.4.4
Pregnancy and assessments of fertility
All women will have serum human chorionic gonadotropin pregnancy testing at screening in 
order to confirm study eligibility. Additional pregnancy testing might be performed if requested 
by local requirements.
For all women, serum pregnancy testing is required at screening, at Week 53 Day 1, at visit 
EOT, and at the end of the follow-up visit. During the study, urine pregnancy testing will be 
performed locally; in the patients receiving crizanlizumab, a negative test result must be 
obtained prior to each dosing of crizanlizumab. The positive urine test needs to be confirmed 
with serum test. If positive, the patient must be immediately discontinued from crizanlizumab, 
and Novartis must be notified (see Section 10.1.4 for pregnancy reporting requirements).
Any discontinuation of the standard care drugs in patients with a positive serum pregnancy test 
will be at the discretion of the investigators in accordance with the prescribing information and 
local institutional practice.
Local pregnancy test and associated results will not be collected on eCRF.
8.4.5
Immunogenicity 
See Section 8.5.2.
8.4.6
Resource utilization
Results of one study showed that AKI occurred in approximately 46% of patients with HbSS 
and HbSβ0-thal and was responsible for 5% of hospitalizations. In many cases AKI occurs as a 
result of VOCs and ACS and can contribute to CKD progression (Saraf et al 2018). Resource 
utilization data will be collected for AKI events, VOCs both complicated and uncomplicated,
and other SCD complications. Complicated VOCs are defined as ACS, hepatic sequestration, 
splenic sequestration, and priapism.
VOCs (see Section 8.5.5.2 for VOC definition) can be managed at home or by a healthcare visit. 
Healthcare visit is defined as any visit to ER and/or hospital, which includes pain management 
of VOC in situ. Managed at home is defined as no visit to any medical facility and/or 
healthcare professional to receive treatment for VOC. Healthcare contact for medical advice is 
allowed.
At each study visit, the patient will be asked how many times since the previous study visit, 
they have been hospitalized or visited the ER due to 1) AKI events; 2) VOCs (both complicated 
and uncomplicated); and 3) SCD complications other than VOCs. 
For each healthcare visit assessed to be due to an AKI event, VOC, or other SCD complication, 
the following information must be documented in the eCRF: diagnostic evaluation for the AKI 
event (based on AKI stages 1, 2 and 3 from KDIGO Clinical Practice Guideline for Acute 
Kidney Injury 2012) (KDIGO 2012), VOC episode, or other SCD complication, patient 


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treatment, route of administration and management, course, duration of the AKI event, crisis, 
or other SCD complication, and outcome. For patients who are treated at medical facilities other 
than the study site, summary documents (e.g., ER or hospital discharge summaries) will need 
to be obtained. 
Vaso-occlusive crises managed at home (not requiring healthcare resource utilization) will be 
recorded in the eCRF. Patients will be asked to contact the investigator within 24 hours of VOC 
onset. VOCs managed at home (not requiring healthcare resource utilization) without 
contacting the investigator within 24 hours of onset should be captured in the corresponding 
VOC event page.
If a patient experiences an AKI event, VOC, or other SCD complication surrounding a protocol-
scheduled visit day, and the patient presents for this visit, it will be counted as an AKI event 
that led to a healthcare visit, a VOC that led to a healthcare visit (provided the event meets the 
criteria for VOC discussed above), or a SCD complication that led to a healthcare visit.
8.4.7
Chest X-ray
A standard chest X-ray (PA view) will be performed at screening except for those who have 
had a valid X-ray done within 3 months of first dosing. Chest X-rays may be repeated during 
the study at the discretion of the investigator, if clinically indicated (see Section 8.5.5.2). 
8.4.8
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/patient population.


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8.5.2
Pharmacokinetics
Crizanlizumab pre dose/trough PK samples will be collected along with immunogenicity 
samples at the visits defined in the assessment schedule (Table 8-1) and will be used to evaluate 
the impact of immunogenicity on exposure (PK). Follow instructions outlined in the laboratory 
manual regarding sample collection, numbering, processing and shipment. See the potential use 
of residual samples for more information. The number of samples/blood draws collected will 
not exceed those stated in the protocol.
Pharmacokinetic and immunogenicity assessments are not required for patients randomized to 
the standard of care alone arm.
8.5.2.1
Pharmacokinetic and immunogenicity blood collection and handling 
At specified time points described in Table 8-6, blood samples will be taken by either direct 
venipuncture or an indwelling cannula inserted in a forearm vein.
For PK/immunogenicity samples, blood draws will be collected into serum separator tubes 
(without anticoagulant) and allowed to clot for 30 minutes (undisturbed) at room temperature. 
The tubes will be centrifuged for 10 minutes at approximately 3000 x g in order to separate 
serum. Each serum sample will be aliquoted and transferred into freezer-proof polypropylene 
screw-cap tubes (2 tubes for PK and 3 tubes for immunogenicity at each specified time points). 
The serum tubes will be frozen within 90 minutes of the blood sample collection and kept 
at -80ºC in an upright position until shipment and analysis.
Each serum sample should be labeled with the appropriate study, center, and patient numbers, 
as well as the sequential PK/immunogenicity samples and PK/immunogenicity collection 
number with a unique sample number. The actual collection date and time of each sample will 
be entered on the PK/immunogenicity blood collection eCRF pages. The exact date and time of 
dosing, as well as the date and actual time of blood sampling must be recorded on the 
appropriate eCRF. Sampling problems will be noted in the relevant field of eCRF.
Refer to the [CSEG101A2203 Laboratory Manual] for detailed instructions for the collection, 
handling, and shipment of PK/immunogenicity samples.


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Table 8-6
Pharmacokinetics and immunogenicity blood collection log
Week
Day
PK collection number/Dose 
reference ID
PK sample 
No
IG sample 
No
1
1
1
101
1
101
3
1
2
201
2
102
11
1
3
301
3
103
23
1
4
401
4
104
39
1
5
501
5
105
53
1
6
601
6
106
End of 
Treatment (visit 
EOT)
-
7
-
7
107
105-day Follow-
up (as 
applicable)
-
8
-
8
108
Unscheduled 
samplea
-
-
-
1001+
2001+
Note: The PK samples must be taken within 24 hours before crizanlizumab administration.
a Including at onset and resolution of VOC event, fever, or suspected infection and at the time of 
transfusion (prior to and ≥24 hours after each of the listed events), if feasible.
8.5.2.2
Analytical method 
The crizanlizumab PK assay is a target capture ELISA to determine the concentration of 
crizanlizumab remaining in serum samples. Concentrations below the lower limit of 
quantification (LLOQ) will be reported as 0.00 ng/mL and missing samples will be labeled 
accordingly.
Immunogenicity determination will be performed using a bridging immunoassay format 
validated for immunogenicity screening in human serum samples.
Details of each analytical method will be given in bioanalytical data reports.


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8.5.5
Acute kidney injury and vaso-occlusive crisis assessments
Refer to Section 8.4.6 for resource utilization data to be collected for visits to ER and hospital 
due to AKI, VOCs, and/or other SCD complications.
8.5.5.1
Acute kidney injury events
Acute kidney injury will be defined based on the KDIGO Clinical Practice Guideline for AKI 
(KDIGO 2012):

Increase in serum creatinine by ≥0.3 mg/dL within 48 hours; or


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
Increase in serum creatinine to ≥1.5 times baseline, which is known or presumed to 
have occurred within the prior 7 days
Acute kidney injury will be staged based on the above KDIGO guideline and Saraf et al (2018).
8.5.5.2
Sickle cell – vaso-occlusive crisis event and other acute pain crisis
Vaso-occlusive crisis (VOC) 
Vaso-occlusive crisis is defined as pain crisis (defined as an acute onset of pain for which there 
is no other medically determined explanation other than vaso-occlusion) which requires therapy 
with oral or parenteral opioids or parenteral NSAID as well as other complicated crisis such as 
ACS, priapism and hepatic or splenic sequestration.
Vaso-occlusive crisis can be managed at home or by a healthcare visit. All sickle cell VOC 
events will be reported in the eCRF as follows:

VOCs at home (not requiring healthcare resource utilization)

VOCs requiring healthcare resource utilization – see Section 8.4.6
Patients should be encouraged to contact the investigator (or surrogate from the site) when they 
believe they are experiencing a VOC that they believe they can manage at home, both for 
treatment guidance and so that accurate information may be obtained for the VOC eCRF page 
(see Section 8.4.6).
Other acute pain crisis (APC)
In addition to VOCs as defined above, other APCs are of interest in this study. Other APC is 
defined as an acute episode of pain with no known cause for pain other than vaso-occlusion, 
and requiring treatment with analgesics other than opioids or parenteral NSAIDs.
-
Other APC leading to healthcare visit is defined as an APC with any visit to a medical 
facility such as an emergency room, hospital and/or office visit, which includes pain 
management of that APC in situ.
-
Other APC managed at home is defined as another APC with no visit to any medical 
facility and/or healthcare professional to receive treatment for APC
Resolution of other APCs will match the definition of resolution of uncomplicated 
VOCs (see above). A participant experiencing other APCs managed at home should 
contact the investigator within 24h, as indicated for VOCs managed at home (see 
above).
During COVID-19 pandemic, if a patient experiences a VOC/other APC and other subtypes of 
VOC event such as hepatic/splenic sequestration, priapism and especially acute chest syndrome, 
testing for COVID-19 is recommended as per local guidance/practice.
Chest X-ray


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Chest X-ray must be conducted within 3 months prior to Week 1 Day 1. Chest X-ray must be 
repeated during the study in case of suspected ACS and reported as an unscheduled assessment 
in eCRF.
Transfusions
Patients participating in a chronic transfusion program (pre-planned series of transfusions for 
prophylactic purposes) are not eligible. Transfusions for acute complications are permitted 
(ACS, acute splenic sequestration, acute hepatic sequestration, worsened anemia) and 
investigators are encouraged to obtain PK/PD samples before and after the simple or exchange 
transfusion is administered.
Table 8-8
Vaso-Occlusive Crisis or other acute pain crisis Assessment 
Collection Plan
Procedure/Assessment 
collection plan
Screening/Baseline
During Treatment/Follow-up
Chest X-Ray1
Mandated (screening)
If clinically indicated
VOC or other acute pain crisis 
information
Mandated (screening and 
baseline)
Mandated, when VOC or other 
acute pain crisis occurs
Concomitant medication –
Analgesics administration
If clinically indicated
Mandated, when VOC or other 
acute pain crisis occurs
Healthcare resource utilization
If clinically indicated
Mandated, when VOC occurs
Transfusion administration
If clinically indicated
If clinically indicated
Soluble biomarkers (e.g., 
P-selectin)
Mandated (baseline)
If possible, at time of VOC
(Mandated at time points 
indicated in Table 8-1)
PK and Immunogenicity 
samples
Mandated (baseline)
Optional at onset and 
resolution of VOC, fever or 
suspected infection. Optional 
before and after transfusion. 
(Mandated at time points 
indicated in Table 8-1 only for 
patients in the crizanlizumab + 
standard of care arm)
1 Within 3 months of Week 1 Day 1
8.5.5.3
Missed school or work 
At each study visit, the patient will be asked how many full days of school or work they have 
missed due to AKI, VOCs, and/or other SCD complications since their previous visit. This 
information will be recorded in the eCRF.
8.5.6
Trial Feedback Questionnaire (optional) 
This trial will include an option for subjects to complete an anonymized questionnaire, ‘Trial 
Feedback Questionnaire’. The intention of this questionnaire is to collect subject feedback on 


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their clinical trial experience. Individual subject level responses will NOT be reviewed by 
investigators. Novartis will use these responses to understand where improvements can be made 
in the clinical trial process. This questionnaire DOES NOT collect data about the subject's 
disease, symptoms, treatment effect or adverse events, and therefore would not be trial data. 
Should any spontaneous information be collected about AEs, this would be transferred to the 
clinical and safety databases.
9
Study discontinuation and completion
9.1
Discontinuation and completion
9.1.1
Study treatment discontinuation 
Discontinuation of study treatment for a patient occurs when study treatment is permanently
stopped for any reason (prior to the planned completion of study drug administration) and can 
be initiated by either the patient or the investigator.
The investigator must discontinue study treatment (crizanlizumab and/or at least one standard 
of care medication) for a given patient if, he/she believes that continuation would negatively 
impact the patient’s well-being.
Crizanlizumab must be discontinued under the following circumstances:

Patient/guardian decision

Pregnancy

Lactation

Grade 3 and 4 IRRs and other specified grade 4 ADRs and dose interruptions of 
crizanlizumab due to toxicity (see Section 6.5.1.1)

Use of prohibited treatment (see Section 6.2.2), except as noted in Section 6.2.2

Any other protocol deviation that results in a significant risk to the patient’s safety

Other reasons for earlier termination may include but are not limited to:
o
Decision based on recommendations from applicable board(s) after review of 
safety data
o
Discontinuation of study drug development

One or more standard of care drugs must be discontinued under the following 
circumstances:

Patient/guardian decision

If deemed medically necessary by the patient’s physician (see Section 6.5.1.2)

If a patient requires renal replacement therapy (i.e. hemodialysis, peritoneal dialysis, 
hemofiltration and kidney transplantation) 
If discontinuation of study treatment occurs (crizanlizumab and/or at least one standard of care 
drug), the investigator should make a reasonable effort to understand the primary reason for the 


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patient’s premature discontinuation of the study treatment and record this information. Patients 
who discontinue study treatment or who decide they do not wish to participate in the study 
further should NOT be considered withdrawn from the study UNLESS they withdraw their 
consent (see withdraw of informed consent section). Patients who discontinue treatment early 
will return for a Week 53 urine ACR/PCR assessment. The Week 53 urine ACR/PCR 
assessment should occur 12 months after the first dose of study treatment. 
If they fail to return for these assessments for unknown reasons, every effort (e.g., telephone, 
e-mail, and letter) should be made to contact the patient/pre-designated contact as specified in 
the lost to follow-up section. This contact should preferably be done according to the study visit 
schedule.
If the patient cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the patient, or with a person pre-designated by the patient. This telephone 
contact should preferably be done according to the study visit schedule.
The investigator must also contact the IRT to register the patient’s study treatment 
discontinuation.
9.1.2
Discontinuation from study 
Discontinuation from study is when the patient permanently stops receiving the study treatment, 
and further protocol-required assessments or follow-up, for any reason. If the patient agrees, a 
final evaluation at the time of the patient’s study discontinuation should be made as detailed in 
the assessment table (refer to Section 8).
9.1.3
Withdrawal of informed consent/Opposition to use data/biological 
samples
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent/opposition to use data/biological samples occurs when a patient:

Explicitly requests to stop use of their biological samples and/or data (opposition to use 
patient’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 patient’s decision to withdraw his/her 
consent/opposition to use data/biological samples and record this information.


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Where consent to the use of Personal and Coded Data is not required in a certain country's legal
framework, the patient therefore cannot withdraw consent. However, they still retain the right 
to object to the further collection or use of their Personal Data.
Crizanlizumab must be discontinued (i.e., patients in the crizanlizumab + standard of care arm) 
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 patient are not allowed unless safety findings require 
communicating or follow-up.
If the patient agrees, a final evaluation at the time of the patient’s withdrawal of 
consent/opposition to use data/biological samples should be made as detailed in the assessment 
table (refer to Section 8).
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation, including processing of biological samples that has already 
started at time of consent withdrawal/opposition. No new Personal Data (including biological 
samples) will be collected following withdrawal of consent/opposition.
9.1.4
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits 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 must show “due 
diligence” by documenting in the source documents steps taken to contact the patient, e.g., dates 
of telephone calls, registered letters, etc. A patient should not be considered as lost to follow-
up until due diligence has been completed.
9.1.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time. This may include reasons related to the 
benefit/risk assessment of participating in the study, practical reasons (including slow 
enrollment), for regulatory or medical reasons, or if crizanlizumab development is discontinued.
In taking the decision to terminate, Novartis will always consider patient welfare and safety. 
Should early termination be necessary, the study site must contact the patients who must be
seen as soon as possible (within 7 days, if possible, or by their next scheduled visit) for an EOT 
visit and treated as a patient who discontinued from study treatment. If the patient is in the 
crizanlizumab + standard of care arm, crizanlizumab will be discontinued (unless the decision 
to provide post-trial access to crizanlizumab has been made and is appropriate, see Section 9.2). 
Patients will then be followed in the mandatory safety follow-up period for two safety 
assessments 30 days (phone call) and 105 days (study visit, as applicable) after the visit prior 
to the EOT visit (i.e., 30 days and 105 days after the last crizanlizumab dose for patients 
randomized to crizanlizumab + standard of care). If the EOT visit occurs ≥30 days after the 
previous visit the 30-day phone call is not required. Patients who will receive crizanlizumab 
approximately 4 weeks after their last dose of study treatment, do not need to complete the 105 


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day follow-up. The end of the safety follow-up period for these patients will be the 30-day 
follow-up. All other patients are required to complete the 105-day follow-up.
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the patient’s interests. The investigator 
or sponsor depending on local regulation will be responsible for informing IRBs/IECs of the 
early termination of the trial.
9.2
Study completion and post-study treatment 
Study completion is defined as when the last patient completes their safety follow-up or Week 
53 urine ACR/PCR assessment (if patient discontinues study treatment early) and any repeat 
assessments associated with this visit have been documented and followed up appropriately by 
the investigator or, in the event of an early study termination decision, the date of that decision.
For individual patients, the study will be completed when the patient finishes their safety 
follow-up or Week 53 urine ACR/PCR assessment (if patient discontinues study treatment 
early) and any repeat assessments associated with this visit have been documented and 
followed-up appropriately by the investigator. Patients who will receive crizanlizumab 
approximately 4 weeks after their last dose of study treatment, do not need to complete the 105-
day follow-up. The end of the safety follow-up period for these patients will be the 30-day 
follow-up. All other patients are required to complete the 105-day follow-up.
The final analysis will occur at the end of the study. All available data from all patients up to 
this cut-off date will be analyzed and summarized in a final CSR.
Patients who participate in Novartis clinical trials and are deriving benefit from the treatment 
based on the investigator’s evaluation may receive post-trial access to the treatment. 
In addition, per investigator discretion and assessment of potential risk/benefit, the investigator 
may apply for access to crizanlizumab for patients randomized to the standard of care alone 
arm. Patient eligibility will be reviewed upon submission to Novartis.
In the context of this study, Post-Trial Access (PTA) means the provision of investigational 
treatment to clinical trial participants following trial completion.
Post-Trial Access will continue until the investigational treatment receives regulatory approval, 
is commercially available and a reimbursement decision has been made in the patient’s country, 
or the patient is no longer deriving benefit per the investigator’s evaluation. Safety will continue 
to be monitored while the patient receives PTA to the investigational drug.
Mechanisms for the provision of investigational treatment may include a post study drug supply 
(PSDS), a rollover protocol, provision of the drug in the respective indication outside of a 
clinical trial setting if no further safety or efficacy data is needed, or other mechanisms 
appropriate for the country.
The PTA mechanism must comply with the local laws and regulations in the participating trial 
countries. If Novartis discontinues the development of the study treatment due to reasons which 


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may include when study results are negative, Novartis will work with the investigators to 
transition the patients onto suitable locally available treatment or alternative treatment.
10
Safety monitoring and reporting 
During a public health emergency (i.e. COVID-19 pandemic) that limits or prevents on-site 
study visits, regular phone calls will occur for safety monitoring and discussion of the patient´s 
health status until the patient can again visit the site. This telephone contact should preferably 
be done according to the study visit schedule, or more frequently if needed.
10.1
Definition of adverse events and reporting requirements 
10.1.1
Adverse events
An AE is any untoward medical occurrence (e.g., any unfavorable and unintended sign 
[including abnormal laboratory findings], symptom or disease) in a patient or clinical 
investigation patient after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual patient and 
identifying AEs.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of AEs must be sought by non-directive questioning of the patient at each visit 
during the study. AEs also may be detected when they are volunteered by the patient during or 
between visits or through physical examination findings, laboratory test findings, or other 
assessments.
Adverse events must be recorded in the Adverse Events eCRF under the signs, symptoms, or 
diagnosis associated with them, accompanied by the following information (as far as possible) 
(if the event is serious refer to Section 10.1.2):
1. AEs will be assessed and graded according to the CTCAE version 5.0.
2. its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication – SCD-related CKD) the 
assessment of causality will usually be ‘Not suspected.’ The rationale for this guidance is 
that the symptoms of a lack of efficacy or progression of underlying illness are not caused 
by the trial drug, they happen in spite of its administration and/or both lack of efficacy and 
progression of underlying disease can only be evaluated meaningfully by an analysis of 
cohorts, not on a single patient.
3. its duration (start and end dates) or if the event is ongoing, an outcome of not recovered/not 
resolved must be reported.
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met.


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5. action taken regarding with study treatment.
All AEs must be treated appropriately. Treatment may include one or more of the following:

Dose not changed

Dose Reduced/increased (only applicable for standard of care medications)

Drug interrupted/withdrawn
6. its outcome (i.e., recovery status or whether it was fatal)
If the event worsens the event should be reported a second time in the eCRF noting the start 
date when the event worsens in toxicity. For Grade 3 and 4 AEs only, if improvement to a 
lower grade is determined a new entry for this event should be reported in the eCRF noting 
the start date when the event improved from having been Grade 3 or Grade 4.
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the patient.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued until the completion of the safety follow-up 
period (i.e., 30-day safety follow-up or the 105day follow-up visit [as applicable]). 
Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent (e.g., continuing at the end of the study), and assessment must be made at each visit 
(or more frequently, if necessary) of any changes in severity, the suspected relationship to the 
interventions required to treat it, and the outcome.
Adverse events of special interest include events that are known class effects, were identified 
pre-clinically or in prior clinical studies, or may be clinically relevant based on the mechanisms 
of action of crizanlizumab and the disease under study. Adverse events of special interest 
include the following, but may not be limited to: 

Infections

IRRs

Effect on hemostasis (hemorrhage)

Immunogenicity
Adverse events of special interest will be defined in the most recent version of the electronic 
case retrieval sheet for crizanlizumab trials available at the time of a database lock for an 
analysis. 
Progression of CKD (CTCAE Grade 1 [eGFR lower limit of normal to 60 mL/min/1.73 m2] and 
CTCAE Grade 2 [eGFR 59 to 30 mL/min/1.73 m2] only), if documented by use of appropriate 
method (e.g., per the KDIGO guidelines for definition and identification of CKD progression 
KDIGO 2013), should not be reported as an AE/SAE (see Section 10.3).
Information about ADRs for the investigational drug can be found in the IB.


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Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria:

they induce clinical signs or symptoms

they are considered clinically significant

they require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
the underlying disease.
10.1.2
Serious adverse events 
An SAE is defined as any AE (appearance of [or worsening of any pre-existing]) undesirable 
sign(s), symptom(s) or medical conditions(s)) which meets any one of the following criteria:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the patient was at 
risk of death at the time of the reaction; it does not refer to a reaction that hypothetically 
might have caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
o
routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition
o
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
o
social reasons and respite care in the absence of any deterioration in the patient’s 
general condition
o
treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g., defined as an event that jeopardizes the patient or may require 
medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life-threatening or result in death or hospitalization but might jeopardize the patient 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 
ER or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 


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hospitalization or development of dependency or abuse (please refer to the ICH-E2D 
Guidelines).
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered an SAE 
irrespective if a clinical event has occurred (Section 10.1.5).
10.1.3
SAE reporting
To ensure patient safety, every SAE must be reported, regardless of causality, occurring after 
the patient has provided informed consent and until completion of the safety follow-up period 
(ie. 30-day safety follow-up or 105-day follow-up period (as applicable).  If the patient 
discontinues from the study early, SAEs must be reported to Novartis safety immediately, 
without undue delay, and under no circumstances later than within 24 hours of learning of its 
occurrence until the end of the safety follow-up period. Patients who will receive crizanlizumab 
approximately 4 weeks after their last dose of study treatment, do not need to complete the 105 
day follow-up. The end of the safety follow-up period for these patients will be the 30-day 
follow-up. All other patients are required to complete the 105-day follow-up.
Serious AEs occurring after provision of informed consent until the time the patient is deemed 
a screen failure must be reported to Novartis. 
Information about all SAEs is collected and recorded on the electronic Serious Adverse Event 
Report Form; all applicable sections of the form must be completed in order to provide a 
clinically thorough report. The investigator must assess and record the relationship of each SAE 
to the study treatment, complete the eSAE Report Form in English, and submit the completed 
form within 24 hours to Novartis. Detailed instructions regarding the submission process and 
requirements are to be found in the investigator folder provided to each site. 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.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode
immediately, without undue delay, and under no circumstances later than within 24 hours of 
the investigator receiving the follow-up information. An SAE occurring at a different time 
interval or otherwise considered completely unrelated to a previously reported one must be 
reported separately as a new event.
Follow-up information is submitted in the same way as the original SAE Report and should 
describe whether the event has resolved or continues, if and how it was treated, and whether the 
patient continued or withdrew from study participation.


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If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is 
thought to be related to the study treatment, a 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 to inform all 
investigators involved in any study with the same study treatment that this SAE has been 
reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the 105-day period after the Week 51 Day 1 visit or if the patient 
discontinued the study early, 105-days after the last dose of discontinued study treatment, 
should only be reported to Novartis Safety if the investigator suspects a causal relationship to 
study treatment, unless otherwise specified by local law/regulations.
10.1.4
Pregnancy reporting 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial participant. The patient 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.
To ensure patient safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. Pregnancy in patients who 
received crizanlizumab should be followed up to determine outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications. After consent is provided, 
the pregnancy reporting will occur up to one year after the estimated date of delivery.
Pregnancy should be recorded and reported by the investigator to the Novartis CMO & PS. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment and any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported.
10.1.5
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient 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 appropriate eCRF irrespective of whether or not associated with an AE/SAE and reported 


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to Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
eCRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections.
10.2
Additional safety monitoring
10.2.1
Liver safety monitoring 
Refer to Section 6.5.2.1 Follow up on potential drug induced liver injury cases.
All follow-up information and procedures performed must be recorded as appropriate in the 
eCRF.
10.2.2
Data Monitoring Committee 
This study will include a DMC which will function independently of all other individuals 
associated with the conduct of this clinical trial, including the site investigators participating in 
the study. The DMC will assess at defined intervals the progress of a clinical trial safety data 
and recommend to the sponsor whether to continue, modify, or terminate a trial. The timing of 
the safety DMC analyses will be defined in the DMC Charter, as described in Section 12.7.
The DMC will consist of clinicians specialized in SCD and/or CKD. Details of the role of the 
DMC will be described in the DMC charter.
10.2.3
Steering Committee 
The Steering Committee (SC) will be established comprising SCD experts, nephrology experts 
and investigators participating in the trial (i.e., not being members of the DMC) and 
Novartis/sponsor representatives from the CTT.
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the CTT, the SC will also develop 
recommendations for publications of study results including authorship rules. The details of the 
role of the SC will be defined in the SC charter.


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10.3
Protocol exempt adverse events and serious adverse events 
Progression of CKD (CTCAE Grades 1 and 2 only), if documented by use of appropriate 
method (e.g., per the KDIGO guidelines for definition and identification of CKD progression 
KDIGO 2013), will be a Protocol Exempt AE and SAE for the current study. Information to 
confirm disease progression (i.e., eGFR) will be recorded in the eCRF. CKD progression 
(CTCAE Grades 1 and 2 only) SHOULD NOT be reported as AEs or SAEs for the purpose of 
this study. CKD progression (CTCAE Grades 1 and 2 only) will not be considered as an SAE 
in regards to reporting requirements. Additional events or complications which are not CKD 
progression itself will be reported as AE/SAEs. Details will be given in the eCRF completion 
guidance.
Protocol Exempt AEs and SAEs implemented in the SEG101 program include VOCs and other 
acute pain crisis, which must be reported on the VOC/other acute pain crisis page in the eCRF. 
As VOCs and other APCs will be analyzed for evaluation of efficacy, AEs and SAEs involving 
VOCs or other acute pain crisis SHOULD NOT be reported as AEs or SAEs for the purpose of 
this study. These events will not be considered as SAEs in regards to reporting requirements. 
All details, procedures and hospitalizations which are directly related to the VOC, e.g., 
ventilation of a patient with ACS are considered part of the VOC and will not be reported as 
AE/SAEs but entered on the applicable eCRF page. Additional events or complications which 
are not VOCs itself will be reported as AE/SAEs. Details will be given in the eCRF-completion 
guidance.
In case that new information arises which changes the diagnosis of a VOC, i.e., gives another 
medically determined explanation than vaso-occlusion in the opinion of the investigator, the 
event has to be reported according to the rules of Section 10.1 and must be reported to Novartis 
within 24 hours of learning of the new information.
However, in case a VOC event is suspected to be related to study treatment, and/or results in a 
fatal outcome, it will be reported as SAE in addition to recording on the VOC eCRF page.
The events in Section 8.5.5.2 are the VOCs and other acute pain crisis that will not be reported 
as AEs/SAEs (see also Section 10.3).
11
Data collection and database management
11.1
Data collection
All data captured for this study will have an external originating source (either written or 
electronic) with the eCRF not being considered as source.
Designated investigator staff will enter the data required by the protocol into the eCRF. The 
eCRFs have been built using fully validated secure web enabled software that conforms to 
21 Code of Federal Regulations (CFR) Part 11 requirements, investigator site staff will not be 
given access to the electronic data capture (EDC) system until they have been trained. 
Automatic validation programs check for [data discrepancies in the eCRFs, allow modification 


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and/or verification of the entered data by the investigator staff.
The investigator/designee is responsible for assuring that the data (recorded on eCRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The investigator must certify that the data entered are complete and accurate
After final database lock, the investigator will receive copies of the patient data for archiving at 
the investigational site.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation, and verification.
11.2
Database management and quality control
Novartis personnel (or designated contract research organization (CRO) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated investigator 
site staff are required to respond promptly to queries and to make any necessary changes to the 
data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization Drug Reference List, which employs the Anatomical Therapeutic 
Chemical classification system. Medical history/current medical conditions and AEs will be 
coded using the MedDRA terminology.
Randomization codes and data about crizanlizumab dispensed and used by the patient and all 
dosage changes will be tracked using an IRT. The system will be supplied by a vendor, who 
will also manage the database. The data will be sent electronically to Novartis (or a designated 
CRO) at specific timelines.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked made available for data analysis. Any changes to the 
database after that time can only be made after written agreement by Novartis development 
management.
Deoxyribonucleic acid samples: To maximize confidentiality, all samples and the information 
associated with the samples will be double-coded to prevent the exposure of the patient’s 
information and identity. This double-coding process allows Novartis to go back and destroy 
the sample at the patient’s request. In addition, sample information is stored in one secured 
database while genetic data is stored in an independent secured database. 
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e., eSource DDE or 


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eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of patient records, the accuracy 
of data capture/data entry, the adherence to the protocol and to GCP, the progress of enrollment, 
and to ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits. Continuous remote monitoring of each site’s data may be performed by a centralized 
Novartis Clinical Research Associate (CRA) organization. Additionally, a central analytics 
organization may analyze data & identify risks & trends for site operational parameters, and 
provide reports to Novartis clinical teams to assist with trial oversight.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, ECGs, and the results of any other tests or assessments. All 
information on eCRFs must be traceable to these source documents in the patient’s file. The 
investigator must also keep the original ICF signed by the patient (a signed copy is given to the 
patient).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
patients will be disclosed.
12
Data analysis and statistical methods 
The primary efficacy and safety analyses will be conducted on all patient data at the time the 
trial ends (see Section 9.2 for the definition of study completion).
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
A patient is considered to be enrolled into the study if signed informed consent has been 
obtained. Only patients with signed informed consent will be included in the analysis data sets.
12.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned 
by randomization. According to the intent to treat principle, patients will be analyzed according 
to the treatment they have been assigned to during the randomization procedure. 
12.1.2
Safety Set


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The Safety Set includes all patients who received at least one dose of study treatment. Patients 
will be analyzed according to the study treatment received, where treatment received is defined 
as the randomized treatment if the patient took at least one dose of that treatment or the first 
treatment received if the randomized treatment was never received.
12.2
Patient demographics and other baseline characteristics
Patient demographics and baseline characteristics will be summarized descriptively by 
treatment groups. Categorical data will be presented as frequencies and percentages. For 
continuous data, mean, standard deviation (SD), median, 25th and 75th percentiles, minimum, 
and maximum will be presented.
The analyses will be based on the FAS.
12.3
Treatments
The Safety Set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, SD, median, 25th and 75th percentiles, 
minimum, and maximum will be presented.
The duration in weeks of crizanlizumab, as well as the dose intensity (computed as the ratio of 
total dose received and actual duration) and the relative dose intensity (computed as the ratio of 
dose intensity and planned dose intensity), will be listed and summarized for all patients. The 
duration in weeks will also be summarized for the standard of care medications for both arms. 
The number of patients with dose adjustments (interruption, or permanent discontinuation) and 
the reasons will be summarized and all dosing data will be listed for crizanlizumab. The number 
of patients with dose adjustments (interruption, reduction, increase, or permanent 
discontinuation) and the reasons will be summarized and all dosing data will be listed for 
standard of care medications. 
Concomitant medications and significant non-drug therapies/procedures prior to and after the 
start of the study treatment, as well as the incidence of transfusion, will be summarized for all 
patients by treatment arm.
The Safety Set will be used.
12.4
Analysis supporting primary objectives
12.4.1
Definition of primary endpoint 
The primary endpoint of the study is the proportion of patients with ≥30% decrease in ACR at 
12 months from baseline. 
12.4.2
Statistical model, hypothesis, and method of analysis
The primary endpoint will be descriptively analyzed based on the data from the FAS. A logistic 
regression model that includes effects for treatment and randomization stratification factors will 
be utilized. The treatment effect based on the log odds ratio will be estimated by the model 


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The odds ratio for the relative difference between treatments in the primary endpoint, and its 
corresponding 95% confidence interval, will be presented. 
In addition, the proportions of patients in each group with at least a 30% decrease in ACR will 
be presented, along with a 95% 2-sided confidence interval for the difference in proportions. 
Details of the statistical model and methods will be described in the SAP.
12.4.3
Handling of intercurrent events of primary estimand
The primary estimand is described by the following attributes: 
1. The target population comprises patients with kidney dysfunction due to SCD. 
2. The primary variable is proportion of patients with ≥30% decrease in ACR at 12 months.
3. The treatment of interest is the effect of crizanlizumab 5.0mg/kg + standard of care on 
the ACR value taken for the entire study duration with or without the intercurrent events
4. The intercurrent events are the events occurring after randomization that may impact 
the treatment effect. The intercurrent events of interest are: 
a) Treatment discontinuation
b) Initiation or discontinuation of HU/HC, HA approved form(s) of L-glutamine, ACE 
and/or ARB
c) Intake of NSAIDs within 48 hours prior to ACR measurement
d) Intake of voxelotor 
e) Blood transfusion or VOC occurred within 7 days of urine and blood sample 
collection
f)
Renal replacement therapy (i.e. hemodialysis, peritoneal dialysis, hemofiltration and 
kidney transplantation)
5. The summary measure is the odds ratio of the treatment effect for patients with ≥30% 
decrease in ACR between crizanlizumab + standard of care and standard of care alone. 
Handling of the intercurrent events
The approach of accounting for intercurrent events is as follows:

For the intercurrent events 3.a: The composite strategy will be applied for treatment 
discontinuation due to death of any cause, drug-related AEs, and progressive disease. Define 
treatment discontinuation due to death of any cause, drug-related AEs, and progressive 
disease as non-responders. The hypothetical strategy will be applied for treatment 
discontinuation due to other reasons. The interest focuses on the treatment effect if patients 
stay on treatment for 12 months, if possible.

For the intercurrent events 3.b: The hypothetical strategy. The interest focuses on the 
treatment effect if patients had not initiated or discontinued HU/HC, HA approved form(s) 
of L-glutamine, ACE and/or ARB.

For the intercurrent events 3.c: The hypothetical strategy. The interest focuses on the 
treatment effect if patients had not received NSAIDs within 48 hours prior to ACR 
measurement.


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
For the intercurrent events 3.d: The hypothetical strategy. The interest focuses on the 
treatment effect if patients had not received voxelotor. 

For the intercurrent events 3.e: The hypothetical strategy. The interest focuses on the 
treatment effect if patients had not had blood transfusion or VOC occurred.

For the intercurrent events 3.f: The composite strategy will be applied for treatment 
discontinuation due to renal replacement therapy, define treatment discontinuation due to 
renal replacement therapy as non-responders. The hypothetical strategy will be applied if 
the renal replacement therapy occurred and patient did not discontinue. The interest 
focuses on the treatment effect if patients had not had renal replacement therapy.
The primary estimand is described in Table 12-1 below, together with its key attributes. The 
estimand outlined below will be described in further detail in the SAP.


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Table 12-1
Primary estimand
Estimand
Target population
Summary Measure
Handling of the intercurrent 
events
Rationale
Primary estimand
Patients with kidney 
dysfunction due to SCD
Odds ratio of treatment 
effect on ACR response
Exclude ACR data collected 
after treatment discontinuation. 
Treatment discontinuation due 
to death of any cause, 
drug-related AEs, progressive 
disease will be considered as 
non-responders; other reasons 
will use multiple imputation 
(MI).
Exclude ACR data after 
initiation or discontinuation of 
HU/HC, HA approved form(s) 
of L-glutamine, ACE and/or 
ARB. Will use MI.
Exclude ACR data collected 
after intake of NSAIDs within 
48 hours prior to ACR 
measurement. Will use MI.
Exclude ACR data collected 
after intake of Voxelotor. Will 
use MI. 
Exclude ACR data collected 
after blood transfusion or VOC 
occurred (if within 7 days 
before the ACR measure). Will 
use MI.
Exclude ACR data collected 
after renal replacement 
therapy. Treatment 
See Section 12.4.3
Handling of the intercurrent 
events


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Estimand
Target population
Summary Measure
Handling of the intercurrent 
events
Rationale
discontinuation due to renal 
replacement therapy will be 
considered as non-responders; 
If the patient required renal 
replacement therapy and did 
not discontinue study 
treatment, will use MI.


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12.4.4
Sensitivity analyses
No sensitivity analyses will be conducted.
12.4.5
Supplementary analyses
No supplementary analyses will be conducted.
12.5
Analysis supporting secondary objectives
The secondary objectives in this study are to describe the two treatment groups with respect to 
albuminuria/proteinuria, including change in ACR, ACR decline rate, PCR improvement and 
stable, and with respect to eGFR, percentage change in eGFR, eGFR decline rate, and the 
progression of CKD as defined in Section 8.3.4, safety, and healthcare resource utilization. 
Another secondary objective is to assess the immunogenicity and accompanying PK of 
crizanlizumab.
The secondary efficacy endpoints will be summarized descriptively using the FAS. For all 
safety endpoints, the Safety Set will be used.
12.5.1
Efficacy endpoints 
The mean change in ACR from baseline to 3, 6, 9, and 12 months of treatment
The mean change in ACR from baseline will be summarized and plotted over time by treatment 
arm. An Analysis of Covariance (ANCOVA) model that includes effects for treatment, 
randomization stratification factors, and baseline ACR, will be carried out for analysis.
The slope of ACR decline from baseline to 12 months of treatment based on 
ACR values at baseline and at 3, 6, 9, and 12 months
The slope of ACR decline will be estimated as a random coefficient in a linear mixed effect 
model: the model will be fitted to ACR data collected at baseline and at Months 3, 6, 9, and 12. 
It includes treatment, stratification factors, time and the interaction of treatment by time as the 
fixed effects, and intercept as a random effect. The mean slopes within each treatment and the 
difference in mean slopes between two treatments will be presented. The percentage change in 
eGFR from baseline to 3, 6, 9, and 12 months of treatment
The percentage change in eGFR is calculated as the post-baseline eGFR value minus the 
baseline eGFR divided by the eGFR at baseline. The calculation of eGFR is based on the CKD-
EPI (for patients ≥ 18 at screening) and Creatinine-based “Bedside Schwartz” (for patients < 18 
at screening) equations. Percentage change in eGFR from baseline will be summarized and 
plotted over time by treatment arm. An ANCOVA model that includes effects for treatment, 
HU/HC use (Yes vs. No), and baseline eGFR, will be carried out for analysis using a logarithmic 
scale.


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The slope of eGFR decline from baseline to 12 months of treatment based on 
eGFR values at baseline and at 3, 6, 9, and 12 months
The slope of eGFR decline will be estimated as a random coefficient in a linear mixed effect 
model: the model will be fitted to eGFR data collected at baseline and at Months 3, 6, 9, and 
12. It includes treatment, stratification factors, time and the interaction of treatment by time as 
the fixed effects, and intercept as a random effect. The mean slopes within each treatment and 
the difference in mean slopes between two treatments will be presented.
Other secondary efficacy endpoints
The following proportion related efficacy endpoints will be analyzed by the same statistical 
methods described in the primary endpoint analysis section. In addition, a shift table will be 
provided for patients with progression of CKD for each treatment.
The proportion of patients with ≥30% decrease in ACR at 6 months from baseline 
The proportion of patients with PCR improvement and stable PCR (improvement: ≥20% 
decrease in PCR from baseline; stable: within ± 20% change from baseline) at 12 months from
baseline
The proportion of patients with progression of CKD from baseline to 12 months
Details of the statistical methods will be described in the SAP.
12.5.2
Safety endpoints
Safety assessments will consist of monitoring and recording all AEs, based on CTCAE v5.0. It 
will also include regular monitoring of laboratory assessments including hematology and 
clinical chemistry, cytokines, complement, tryptase, p-selectin, urinalysis, measurement of vital 
signs, and physical examination. ECG assessments will be done at screening, Week 53 Day 1, 
visit EOT, and as clinically indicated.
The overall observation period will be divided into three mutually exclusive segments:
1. Pre-treatment period: from day of patient’s informed consent to Day -1 (i.e., the day before 
first dose of crizanlizumab/day before the Week 1 Day 1 visit)
2. On-treatment period: from Day 1 (i.e., day of first dose of crizanlizumab/day of Week 1 
Day 1 visit) to 105 days after last dose of discontinued study treatment or the end of the 
safety follow-up period (i.e., 30 or 105 days after the Week 51 Day 1 visit)
3. Post-treatment period: starting at Day 106 after last dose of discontinued study treatment or 
Day 31 or 106 after the Week 51 Day 1 visit.
Adverse events
Summary tables for AEs will include only AEs that started or worsened during the on-treatment 
period, the treatment-emergent AEs.
The incidence of TEAEs (new or worsening from baseline) will be summarized by system organ 
class and or preferred term, severity (based on CTCAE grades), type of AE, relation to study 
treatment.


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Serious AEs, non-serious AEs, and AESIs during the on-treatment period will be summarized.
All deaths (on-treatment and post-treatment) will be summarized.
All AEs, deaths, and SAEs (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.
Vital signs
All vital signs data will be summarized by treatment and visit/time.
12-lead ECG
12-lead ECGs including PR, QRS, QT, QTcF, and RR intervals will be obtained for each patient 
during the study. ECG data will be read and interpreted centrally.
All ECG data will be summarized by treatment and visit/time.
Clinical laboratory evaluations
Grading of laboratory values will be assigned programmatically as per National Cancer Institute 
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.
Common Terminology Criteria for AEs 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 v5.0, results will be categorized 
as low/normal/high based on laboratory normal ranges.
The following summaries will be generated separately for hematology, and biochemistry tests:

Listing of all laboratory data with values flagged to show the corresponding CTCAE v5.0 
grades if applicable and the classifications relative to the laboratory normal ranges
For laboratory tests where grades are defined by CTCAE v5.0

Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be 
counted only once for the worst grade observed post-baseline

Shift tables using CTCAE v5.0 grades to compare baseline to the worst on-treatment value
For laboratory tests where grades are not defined by CTCAE v5.0

Shift tables using the low/normal/high/ (low and high) classification to compare baseline to 
the worst on-treatment value.
Immunogenicity
Immunogenicity will be measured pre-dose on Week 1 Day 1, during treatment, at visit EOT, 
and at the 105-day follow-up visit (as applicable).
All immunogenicity results will be listed and summarized for the crizanlizumab + standard of 
care treatment group by patient and visit/time.
Immunogenicity will be characterized descriptively tabulating ADA incidence on-treatment.


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Resource utilization
Annualized rate of visits to ER and hospitalizations due to AKI events, VOCs, or other SCD 
complications will be used to evaluate the healthcare resource utilization (visits to clinic, ER 
and hospitalizations) in crizanlizumab + standard of care arm and standard of care alone.
12.5.3
Pharmacokinetics
Crizanlizumab pre-dose/trough PK samples will be taken to accompany immunogenicity 
measurements to evaluate the impact of immunogenicity on exposure (PK) (see Section 12.5.2).
Crizanlizumab predose serum concentration data will be summarized for the crizanlizumab + 
standard of care treatment arm by patient and visit/sampling time point. Descriptive summary 
statistics will be provided for the crizanlizumab + standard of care treatment arm by 
visit/sampling time point, including the frequency (n, %) of concentrations below the LLOQ 
and reported as zero.
Descriptive summary statistics will include mean (arithmetic and geometric), SD, coefficient 
of variance (CV; arithmetic and geometric), median, minimum and maximum. 


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12.7
Interim analyses
Formal interim analyses are not planned. However, safety DMC analyses will be performed at 
specified time points, as defined in the DMC Charter. Additional DMC meetings may be 
scheduled if unexpected safety findings arise.
12.8
Sample size calculation
The sample size was adjusted to reflect current recruitment status. 
When the estimation based approach for the 95% CI for the difference between treatment arms 
is used to calculate the precision estimates with sample size of 25 patients per treatment arm 
(total N=50 patients without drop-outs), then the width is 0.429 and the precision (half of the 
width) is around 0.215. See Table 12-3 for the 95% CI calculation of the difference (30% -
10%) varying the sample size per arm from 10 to 40.
Table 12-3
Confidence Intervals for the Difference between Two Proportions 
using Proportions Numeric Results for Two Sided Confidence 
Intervals for the Difference in Proportions Confidence interval 
method: Chi – Square – Simple Asymptotic (Pearson)
Confidence 
Level
N1
N2
Allocation 
Ratio
Actual 
Width
P1
P2
P1-P2
Lower 
Limit
Upper 
Limit
0.95
10
10
1.000
0.679
0.300
0.100
0.200
-0.139
0.539
0.95
15
15
1.000
0.554
0.300
0.100
0.200
-0.077
0.477
0.95
20
20
1.000
0.480
0.300
0.100
0.200
-0.040
0.440
0.95
25
25
1.000
0.429
0.300
0.100
0.200
-0.015
0.415
0.95
30
30
1.000
0.392
0.300
0.100
0.200
0.004
0.396
0.95
35
35
1.000
0.363
0.300
0.100
0.200
0.019
0.381
0.95
40
40
1.000
0.339
0.300
0.100
0.200
0.030
0.370
13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for GCP, with applicable local regulations 
(including European Directive 2001/20/EC, Article 3 Part 2 of the Directive 2005/28/EC, and 
US CFR Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the IRB/IEC for the trial protocol, written ICF, consent form updates, patient recruitment 
procedures (e.g., advertisements) and any other written information to be provided to patients. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 


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his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (see study completion definition in 
Section 9.2) and finalization of the study report the results of this trial will be submitted for 
publication and posted in a publicly accessible database of clinical trial results, such as the 
Novartis clinical trial results website and all required health authority websites (e.g., 
Clinicaltrials.gov, EudraCT etc.).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written SOPs as 
well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.
14
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of patients should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented.


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14.1
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for patient safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any patient included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations.


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15
References
References are available upon request
Aggarwal HK, Jain D, Pawar S, et al (2016) Health-related quality of life in different stages of 
chronic kidney disease. QJM; 109(11):711-6.
Asnani MR, Lynch O’Neil, Reid ME (2013) Determining glomerular filtration rate in 
homozygous sickle cell disease: utility of serum creatinine based estimating equations PLoS 
One; 8(7).
Ataga KI, Kutlar A, Kanter J, et al (2017). Crizanlizumab for the prevention of pain crises in
sickle cell disease. N Engl J Med; 376(5):429-39.
Ataga KI, Kutlar A, Cancado R, et al (2018). Crizanlizumab treatment is not associated with 
the development of proteinuria and hematuria in patients with sickle cell disease: A safety 
analysis from the SUSTAIN study. Abstract PF712, EHA Library; 215150.
Banholzer M, Wandel C, Barrow P, et al (2016). Clinical trial considerations on male 
contraception and collection of pregnancy information from female partner:update. Clin Trans 
Med ; 5(23).
Bartolucci P, Habibi A, Stehle T, et al (2016). Six months of hydroxyurea reduces 
albuminuria in patients with sickle cell disease. J Am Soc Nephrol; 27(6):1847-53.
Bookchin RM and 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): 2656-2701.
Brenner BM, Cooper ME, de Zeeuw D, et al (2001). Effects of losartan on renal and 
cardiovascular outcomes in patients with Type 2 diabetes and nephropathy. N Engl J Med; 
345(12):861-9.
Breslin W, Hilbish K, Page T, Coutant D (2014). Assessment of fetal exposure risk following 
seminal excretion of a therapeutic IgG4 (T-IgG4) monoclonal antibody using a rabbit model. 
Reproductive Toxicology; 48 (124-131)
Cruz MC, Andrade C, Urrutia M, et al (2011). Quality of life in patients with chronic kidney 
disease. Clinics (Sao Paulo); 66(6):991-5.
Derebail VK, Ciccone EJ, Zhou Q, et al (2019). Progressive decline in estimated GFR in 
patients with sickle cell disease: An observational cohort study. Am J Kidney Dis; 
doi:10.1053/j.ajkd.2018.12.027.
De Zeeuw D, Remuzzi G, Parving H, et al (2004). Albuminuria, a therapeutic target for 
cardiovascular protection in Type 2 diabetic patients with nephropathy. Circulation; 
110(8):921-7.
Emerson GG, GA Lutty GA (2005) Effects of sickle cell disease on the eye: clinical features 
and treatment. Hematol Oncol Clin N Am; 19(5): 957-73.


Novartis
Confidential
Page 129
Amended Protocol Version 03 (Clean)
Protocol No. CSEG101A2203
Farrell A, Panepinto J, Desai A, et al (2019). End points for sickle cell disease clinical trials: 
renal and cardiopulmonary, cure, and low-resource settings. Blood Advances; 3(23):4002-20.
Florkowski CM and Chew-Harris JS (2011). Methods of estimating GFR – different equations 
including CKD-EPI. Clin Biochem Rev; 32(2):75-9.
Gladwin MT and Sachdev V (2012). Cardiovascular abnormalities in sickle cell disease. J Am 
Coll Cardiol; 59(13):1123-33.
Gosmanova EO, Zaidi S, Wan JY, et al (2014). Prevalence and progression of chronic kidney 
disease in adult patients with sickle cell disease. J Investig Med; 62(5):804-7.
Guasch A, Navarrete J, Nass K, et al (2006). Glomerular involvement in adults with sickle 
cell hemoglobinopathies: Prevalence and clinical correlates of progressive renal failure. J Am 
Soc Nephrol; 17(8):2228-35.
Hariri E, Mansour A, El Alam A, et al (2018). Sickle cell nephropathy: an update on 
pathophysiology diagnosis, and treatment. Int Urol Nephrol; 50(6):1075-83.
Haymann JP, Stankovic K, Levy P, et al (2010). Glomerular hyperfiltration in adult sickle cell 
anemia: a frequent hemolysis associated feature. Clin J Am Soc Nephrol; 5(5):756-61.
Haymann JP, Hammoudi N, Stankovic Stojanovic K, et al (2017). Renin-angiotensin system 
blockade promotes a cardio-renal protection in albuminuric homozygous sickle cell patients. 
Br J Hematol; 179(5):820-8.
Heerspink HJL, Greene T, Tighiouart H, et al (2019). Change in albuminuria as a surrogate 
endpoint for progression of kidney disease: a meta-analysis of treatment effects in randomised 
clinical trials. Lancet Diabetes Endocrinol; 7(2):128-39.
Hirschberg R (2010). Glomerular hyperfiltration in sickle cell disease. Clin J Am Soc 
Nephrol; 5(5):748-9.
Hoffmann R, Benz EJ, Silbersten LE, et al (2013). Hematology. Basic Principles and Practice. 
Edition 6. Elsevier.
KDIGO (2012). KDIGO clinical practice guideline for acute kidney injury. Kidney 
International supplements; 2(1):1-138.
KDIGO (2013). KDIGO 2012 clinical practice guideline for the evaluation and management 
of chronic kidney disease. Kidney International supplements; 3(1):1-150.
Kassim AA and DeBaun MR (2013). Sickle cell disease, vasculopathy, and therapeutics. 
Annu Rev Med; 64:451-66.
Koo DD, Welsh KI, Roake JA, et al (1998). Ischemia/reperfusion injury in human kidney 
transplantation: an immunohistochemical analysis of changes after reperfusion. Am J Pathol; 
153(2):557-66. 
Laurin LP, Nachman PH, Desai PC, et al (2014). Hydroxyurea is associated with lower 
prevalence of albuminuria in adults with sickle cell disease. Nephrol Dial Transplant; 
29(6):1211-8.


Novartis
Confidential
Page 130
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Protocol No. CSEG101A2203
Liem R, Lanzkron S, Coates T, et al (2019).  American Society of Hematology 2019 
guidelines for sickle cell disease: cardiopulmonary and kidney disease. Blood Advances; 
3(23):3867-3897
Levey AS, Stevens LA, Schmid CH, et al (2009). A new equation to estimate glomerular 
filtration rate. Ann Intern Med; 150(9):604-12.
Levey AS, Inker LA, Matsushita K, et al (2014). GFR decline as an end point for clinical 
trials in CKD: A scientific workshop sponsored by the National Kidney Foundation and the 
US Food and Drug Administration. Am J Kidney Dis; 64(6):821-35.
Libório AB, Santos JPL, Minete NFA, et al (2012). Proteinuria is associated with quality of 
life and depression in adults with primary glomerulopathy and preserved renal function. PLoS 
ONE; 7(5):e37763.
McPhearson YM, Jabbar SF, Osunkwo I, et al (2011). Chronic kidney disease and 
albuminuria in children with sickle cell disease. Clin J Am Soc Nephrol; 6(11):2628-33.
Nasr SH, Markowitz GS, Sentman RL, et al (2006). Sickle cell disease, nephrotic syndrome, 
and renal failure. Kidney Int; 69(7):1276-80.
Nath KA and Hebbel RP (2015). Sickle cell disease: renal manifestations and mechanisms. 
Nat Rev Nephrol; 11(3):161-71.
Nietert PJ, Silverstein MD, Abboud MR (2002). Sickle cell anaemia: Epidemiology and cost 
of illness. Pharmacoeconomics; 20(6):357-66.
Niss O, Lane A, Asnani MR, et al (2020). Progression of albuminuria in patients with sickle 
cell anemia: a multicenter, longitudinal study. Blood Advance; 4(7):1501-11
Powars DR, Chan LS, Hiti A, et al (2005). Outcome of sickle cell anemia: a 4-decade 
observational study of 1056 patients. Medicine (Baltimore); 84(6):363-76.
Saraf SL, Viner M, Rischall A, et al (2018). HMOX1 and acute kidney injury in sickle cell 
anemia. Blood; 132(15):1621-5.
Sasongko TH, Nagalla S, Ballas SK (2015). Angiotensin-converting enzyme (ACE) inhibitors 
for proteinuria and microalbuminuria in people with sickle cell disease. Cochrane Database 
Syst Rev; (6):CD009191.
Saunthararajah Y, Vichinsky EP (2018). Sickle cell disease: clinical features and 
management. Hematology, Elsevier: 584-607. e7.
Schnog JB, Duits AJ, Muskiet FA, et al (2004). Sickle cell disease; a general overview. Neth J 
Med; 62(10):364-74.
Schwartz GJ, Muñoz A, Schneider MF et al (2009). New equations to estimate GFR in 
children with CKD. J Am Soc Nephrol;20(3):629-37. 
Scialli A, Bailey G, Beyer B, et al (2015). Potential seminal transport of pharmaceuticals to 
the conceptus. Reproductive Toxicology 58: 213-221


Novartis
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Sharpe CC and Thein SL (2014). How I treat renal complications in sickle cell disease. Blood; 
123(24):3720-6.
Singbartl, Green SA, Ley K (2000). Blocking P-selectin protects from ischemia/reperfusion-
induced acute renal failure. FASEB J; 14(1):48-54.
Sohn W, Lee E, Kankam M, et al (2015). An open-label study in healthy men to evaluate the 
risk of seminal fluid transmission of denosumab to pregnant partners. Br J Clin Pharmacol; 
81(2):362-369
Tam FW (2002). Role of selectins in glomerulonephritis. Clin Exp Immunol; 129(1):1-3.
Tipping PG, Huang XR, Berndt MC, et al (1994). A role for P selectin in 
complement-independent neutrophil-mediated glomerular injury. Kidney International; 
46:79-88.
Tsai CW, Ting IW, Yeh HC, et al (2017). Longitudinal change in estimated GFR among CKD 
patients: A 10-year follow-up study of an integrated kidney disease care program in Taiwan. 
PLoS One; 12(4):e0173843.
Ware RE, de Montalembert M, Tshilolo L, et al (2017). Sickle cell disease. Lancet; 
390(10091):311-323.
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.
Yee MEM, Lane PA, Archer DR, et al (2017). Estimation of glomerular filtration rate using 
serum cystatin C and creatinine in adults with sickle cell anemia. Am J Hematol;92(10):E598-
E599.
Zizzi HC, Zibari GB, Granger DN, et al (1997). Quantification of P-selectin expression after 
renal ischemia and reperfusion. Journal of Pediatric Surgery; 32(7):1010-3.
16
Appendices
Not applicable.

SAP_001.pdf: 
Clinical Development
SEG101/Crizanlizumab 
CSEG101A2203 / NCT04053764
A Phase II, multicenter, randomized, open label two arm 
study evaluating the effect of crizanlizumab + standard of 
care and standard of care alone on renal function in sickle 
cell disease patients ≥ 16 years with chronic kidney 
disease due to sickle cell nephropathy (STEADFAST)
Statistical Analysis Plan (SAP)
Author: 
Document type:
SAP Documentation
Document status:
Amendment 06
Release date:
26 June 2023
Number of pages:
56
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Page 2
SAP – amendment 6
CSEG101A2203
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for update
Outcome for 
update
Section and title 
impacted 
(Current)
01-Nov-
2019
Prior 
to 
FPFV
Creation of final 
version
N/A - First version
NA
16-Nov-
2020
Amend
ment 1
After 
protocol 
amendm
ent 01
Clarify that the test 
of the treatment 
effect will be based 
on the odds ratio 
estimated by the 
logistic regression 
model for the 
primary analysis
The null and 
alternative 
hypotheses were 
updated based on 
odds ratio 
estimated by the 
logistic regression 
model. It was 
added that the 
proportion of 
patients in each 
group with at least 
a 30% decrease in 
ACR will be 
presented along a 
95% 2-sided
confidence interval 
for the difference 
in proportions.  
Section 2.5.2 
Statistical 
hypothesis, 
model, and 
method of 
analysis
To update the 
definition of CKD 
progression. As 
albuminuria also 
affects CKD 
outcomes, ACR
should be 
incorporated into the 
definition of CKD 
progression. 
The stratification 
factor was updated 
from “CKD stage” 
to “CKD risk 
category” to 
include 
albuminuria, as 
well as eGFR, in 
the analysis. The 
subgroup analysis 
based on CKD 
stage was changed 
to be based on 
CKD risk category.
Section 1.1 study 
design
Section 2.5.2 
Statistical 
hypothesis, 
model, and 
method of 
analysis
To clarify 
Supportive analyses 
of the primary 
endpoint to provide 
Supportive 
analyses of the 
primary endpoint 
to provide 
Section 2.5.4 
Supportive 
analyses


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For business use only
Page 3
SAP – amendment 6
CSEG101A2203
Date
Time 
point
Reason for update
Outcome for 
update
Section and title 
impacted 
(Current)
additional 
information 
regarding the 
treatment effect 
additional 
information 
regarding the 
treatment effect 
have been added, 
as have three new 
subgroup analyses 
to ascertain the 
treatment effect 
based on Hb, 
frequency of 
VOCs at baseline 
and chronic 
NSAID use.
Section 2.2.3 
Subgroup of 
interest
To strengthen the 
primary estimand 
framework by 
providing additional 
clarity regarding the 
handling of 
intercurrent events 
and clarifying the 
summary measure
Primary estimands 
section was added 
after Study 
objectives and 
related endpoints 
table 1-2. 
Initiation or 
discontinuation of 
L glutamine, intake 
of Voxelotor, 
blood transfusion 
or VOC occurred 
within 7 days of 
urine and blood 
sample              
collection were 
added as additional 
intercurrent events. 
The summary 
measure has been 
revised. The details 
of handling of the 
intercurrent events 
were provided. The 
imputation method 
has been revised 
from last on 
treatment 
Section 1.2 Study 
objectives and 
endpoints
Section 2.5.3 
Handling of 
missing values/ 
censoring/disconti
nuations 


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Page 4
SAP – amendment 6
CSEG101A2203
Date
Time 
point
Reason for update
Outcome for 
update
Section and title 
impacted 
(Current)
observation carried 
forward (LOCF) to 
multiple 
imputation (MI)
To update the 
analysis on Protein 
to creatinine ratio 
(PCR) 
The analysis has 
been updated to be 
on combined PCR 
improvement and 
stable PCR data
Section 1.2 Study 
objectives and 
endpoints
Section 2.7 
Analysis of the 
key secondary 
objective
To clarify the CKD 
progression analysis
The details of 
CKD progression 
analysis were 
added 
Section 2.7.2 
Statistical 
hypothesis, 
model, and 
method of 
analysis
To strengthen the 
supplementary 
estimand framework
by providing 
additional clarity
regarding the 
handling of 
intercurrent events 
based on different 
rationale
The strategies of 
handling of the 
intercurrent events 
for supplementary 
estimands have 
been revised in 
Table 2-3
Section 2.5.3 
Handling of 
missing values/ 
censoring/disconti
nuations
Section 2.5.4 
Supportive 
analyses
To clarify on the 
models and 
statistical methods 
used for primary 
analysis, also to 
provide detailed 
instructions on how 
to do multiple 
imputation in SAS
The details for 
logistic regression, 
multiple 
imputation and 
SAS example code 
were added
Section 5.4.1 
Primary analysis
 
 
 
 
 
 


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SAP – amendment 6
CSEG101A2203
Date
Time 
point
Reason for update
Outcome for 
update
Section and title 
impacted 
(Current)
 
 
Correct typo in test 
used in EAST 
software
Changed the 
sample size 
calculation to be 
based on a two-
sample z test (and 
not a two sample t 
test)
Section 3 Sample 
size calculation
To update baseline 
stratification factors, 
the discordances 
between the stratum 
recorded in IRT and 
the actual stratum 
recorded in the 
eCRF is not 
necessarily needed
Removed the 
analysis of 
discordances 
between the 
stratum recorded in 
IRT and the actual 
stratum in eCRF
Section 2.3 
Patient 
disposition, 
demographics,
and other baseline 
characteristics
 
 
 
 
 
 
Claimed in the 
SAP that 
Pharmacokinetic 
endpoints, 
 
 will not 
be reported in CSR 
according to Lean 
CSR principles, 
these analyses will 
be presented in 
separate reports as 
appropriate
Section 2.9 
Pharmacokinetic 
endpoints
 
To update the word 
“subject” to 
“patient” to keep 
consistency through 
the document
Updated “subject” 
to “patient”
Through all the 
sections
16-Apr-
2021
After 
protocol 
amendm
ent 02
Due to global impact 
of the COVID-19 
pandemic and long 
recruitment duration, 
Reduced power 
from 85% to 80% 
resulting in sample 
Section 3 Sample 
size calculation


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Page 6
SAP – amendment 6
CSEG101A2203
Date
Time 
point
Reason for update
Outcome for 
update
Section and title 
impacted 
(Current)
Amend
ment 2
the feasibility of 
recruiting 170 
patients was 
reconsidered.
size reduction from 
170 to 148
To 
update 
eGFR 
criteria
The eGFR upper 
limit of 130 
mL/min/1.73 m2 
for women was 
increased to 140 
mL/min/1.73 m2 
consistent with the 
criteria for males 
as there is no 
confirmed gender 
specific correlation 
with hyperfiltration 
in SCD patients
Section 1.1 Study 
design and 
Section 2.2.3 
Subgroup of 
interest
To update eGFR 
calculation and use 
of the Creatinine-
based “Bedside 
Schwartz” equation 
(2009). The 
creatinine-based 
“Bedside Schwartz” 
equation (2009) will 
be used to calculate 
eGFR for patients 
under the age of 18 
at screening as this 
is the most accurate 
calculation of eGFR 
for adolescents and 
will reduce the risk 
of overestimation of 
eGFR in adolescents
Included “Bedside 
Schwartz” 
equation 2009 for 
eGFR calculation 
for patients under 
the age of 18
Section 1.1 study 
design, Section 
2.7 Analysis 
supporting 
secondary 
objectives
Renal replacement 
therapy (i.e. 
hemodialysis, 
peritoneal dialysis, 
hemofiltration and 
Included 
the 
intercurrent event 
renal replacement 
therapy 
(i.e. 
hemodialysis, 
Section 1.2.1 
Primary 
estimands, 
Section 2.5 
Analysis 


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Page 7
SAP – amendment 6
CSEG101A2203
Date
Time 
point
Reason for update
Outcome for 
update
Section and title 
impacted 
(Current)
kidney 
transplantation) is a 
newly identified 
intercurrent event
peritoneal dialysis, 
hemofiltration and 
kidney 
transplantation). 
Handling strategies 
of this intercurrent 
event 
was 
also 
added 
depending 
on 
different 
scenarios.
supporting 
primary 
objectives
To align with the 
updated SOC CRF 
page
dose reduction and 
dose increase were 
deleted 
from 
summary table for 
SOC 
as 
such 
information 
will 
not be collected in 
CRF. The number 
of patients with 
dose change will be 
presented instead.
Section 2.4.1 
Study 
treatment/complia
nce
Analysis on missing 
data not caused by 
intercurrent events is 
added
Missing data not 
caused by 
intercurrent events 
will be handled by 
multiple 
imputation by 
assuming missing 
at random.
Section 2.5.3 
Handling of 
intercurrent 
events of primary 
estimand
To delete subgroup 
analysis on NSAID 
use as there’s no 
clear definition 
Deleted the 
subgroup analysis 
on chronic NSAID 
use.
Section 2.2.3 
Subgroup of 
interest
To 
delete
the 
individual 
subject 
reticulocyte 
count 
plot
Deleted the figure 
‘Individual subject 
reticulocyte count 
plot for subjects 
with potential 
severe drug 
induced liver 
Section 2.8.3 
Laboratory data


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Page 8
SAP – amendment 6
CSEG101A2203
Date
Time 
point
Reason for update
Outcome for 
update
Section and title 
impacted 
(Current)
injury’ as it’s not 
applicable.
Clarification of 105-
day-follow-up 
period.
Patients who will 
receive 
crizanlizumab 
approximately 4 
weeks after their last 
dose of study 
treatment, do not 
need to complete the 
105-day follow-up. 
The end of the safety 
follow-up period for 
these patients will be 
the 30-day follow-
up. All other patients 
are required to 
complete the 105-
day follow-up.
Updated language 
to clarify on-
treatment and post-
treatment period 
based on 105-day 
follow-up change
Section 2.1.1 
General 
definitions, 
Section 1.1 study 
design
To 
clarify 
assessment 
for 
patients 
who 
discontinue 
study 
treatment early
In order to provide 
robust data, a 
mandatory Week 
53 urine ACR/PCR 
visit was added to 
ensure this data 
was collected for 
patients who 
discontinue study 
treatment early. 
Section 1.1 study 
design
 
 
 
 
 
 
 
 
 
 
 
 


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Date
Time 
point
Reason for update
Outcome for 
update
Section and title 
impacted 
(Current)
 
 
 
 
 
 
 
 
 
 
To update the listing 
of Prophylactic 
Anticoagulants to 
general 
Anticoagulants as 
anticoagulants at 
therapeutic doses is 
allowed
Prophylactic 
anticoagulants 
updated to 
anticoagulants
Section 2.4.2 
Prior, 
concomitant and 
post therapies
To update the title in 
alignment with 
protocol amendment
Title updated from 
“Analysis of the
primary 
objective(s)” to 
“Analysis 
supporting primary 
objectives”
Title updated from 
“Analysis of the 
secondary 
objective(s)” to 
“Analysis 
supporting 
secondary efficacy 
objectives”
Title updated from 
“Handling of 
missing 
values/censoring/di
scontinuations” to 
“Handling of 
intercurrent events 
of primary 
estimand”
Section 2.5 
Analysis 
supporting 
primary 
objectives,
Section 2.7 
Analysis 
supporting 
secondary 
objectives
Section 2.5.3 
Handling of 
intercurrent 
events of primary 
estimand


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Date
Time 
point
Reason for update
Outcome for 
update
Section and title 
impacted 
(Current)
To delete the 
unnecessary listings 
based on “lean 
principal” and in 
alignment with 
Protocol amendment 
Removed the 
listings for alcohol 
history, smoking 
history, hepatitis,
and human 
immunodeficiency 
virus (HIV) screen, 
pregnancy test, 
immunogenicity 
results and analysis 
set. Clarified that 
only the listing for 
notable vital sign 
values and notable 
ECG values will be 
presented, the full 
listings on all vital 
sign assessments
and ECG 
assessments will 
not be provided.
Section 2.3 
Patient 
disposition, 
demographics and 
other baseline 
characteristics, 
section 2.8.4 
Other safety data,  
To update the 
“supportive 
analyses” to 
“sensitivity 
analyses” in 
alignment with 
protocol amendment
Title updated from 
“supportive 
analyses” to 
“Sensitivity 
analyses” 
Section 2.5.4
Sensitivity 
analyses
Updates to consider 
COVID-19 
pandemic situation
Text 
added 
specifying 
summary 
of 
protocol deviations 
and other issues 
related to COVID-
19
Section 2.3
Disposition
Added 
text 
describing analysis 
of 
COVID-19 
related AEs
Section 2.8.1 
Adverse events
Some lab parameters 
have no normal 
Updated the shift 
tables will be using 
Section 2.8.3 
Laboratory data


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Date
Time 
point
Reason for update
Outcome for 
update
Section and title 
impacted 
(Current)
range defined by 
central lab
the 
pre-specified 
thresholds 
if 
to 
compare 
baseline 
to 
worst 
on-
treatment value
Summary statistics 
will be provided for 
concentration at 
each time point, and 
this analysis will be 
included in CSR
Deleted “Data from 
Pharmacokinetic 
endpoints will not 
be reported in the 
CSR but will be 
reported 
in 
a 
separate report, as 
appropriate”
Section 2.9 
Pharmacokinetic 
endpoints
06-June-
2022
Prior 
to 
Snapshot 
for DMC
Amendment 03
To clarify that any 
AEs and ConMeds
which are continuing 
as per data cut-off 
will be shown as 
‘ongoing’ and when 
an AE has a start 
date before cut-off 
and an end date post 
cut-off, the outcome 
should be reported 
as unknown. (This 
update was missed 
in SAP amendment 
4 so adding in 
amendment 5)
Sections 5.1.2
Added a baseline 
stratification (This 
was also not added 
in SAP amendment 
4)
Section 2.3
18-May-
2023
After 
Protocol 
amendme
nt v03, 
dated 02-
Dec-2021
Changes in Protocol
Updated latest 
protocol version 03
Section 1 
Introduction


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Date
Time 
point
Reason for update
Outcome for 
update
Section and title 
impacted 
(Current)
Updated study 
objective based on 
the protocol update
Section 1.1 Study 
Design
Updated study 
objective based on 
the protocol update
Section 1.2 Study 
objectives and 
endpoints
Updated "primary 
clinical question of 
interest "
Section 1.2.1 
Primary estimands
Removed 
comparison
Section 2.5 
Analysis 
supporting primary 
objectives
Removed 
comparison
Section 2.5.1 
Primary endpoint
Removed 
comparison and 
hypotheses
Section 2.5.2 
Statistical 
hypothesis, model, 
and method of 
analysis
Removed sensitivity 
analysis as per 
protocol amendment
Section 2.5.4 
Sensitivity analyses
Removed word 
compare and change 
to describe
Section 2.7 
Analysis 
supporting 
secondary 
objective(s)
Removed 
comparison from 
baseline
Section 2.7.1 
Secondary 
endpoints
1. Added 
"summarized 
descriptively" and 
removed word 
"analyzed".
2. Removed 
comparison from 
Section 2.7.2 
Statistical 
hypothesis, model, 
and method of 
analysis


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Date
Time 
point
Reason for update
Outcome for 
update
Section and title 
impacted 
(Current)
endpoint "Proportion 
of patients with ≥ 
30% decrease in 
ACR at 6 months"
3. Removed 
comparison from 
objective 
"Proportion of 
patients with PCR 
improvement and 
stable PCR 
(improvement: ≥ 
20% decrease in 
PCR from baseline; 
stable: within ± 20% 
change from 
baseline) at 12 
months"
Removed 
comparison
Section 2.11 
Resource 
utilization
 
 
 
 
 
 
 
 
 
 


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Date
Time 
point
Reason for update
Outcome for 
update
Section and title 
impacted 
(Current)
Updated Sample size 
section
Section 3 Sample 
size calculation
 
 
 
 
 
 
 


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Table of contents
Table of contents ...............................................................................................................15
List of abbreviations..........................................................................................................17
1
Introduction .......................................................................................................................19
1.1
Study design...........................................................................................................19
1.2
Study objectives and endpoints .............................................................................21
1.2.1
Primary estimands.................................................................................23
2
Statistical methods.............................................................................................................23
2.1
Data analysis general information .........................................................................24
2.1.1
General definitions................................................................................24
2.2
Analysis sets ..........................................................................................................28
2.2.1
Full Analysis Set ...................................................................................28
2.2.2
Safety Set ..............................................................................................28
2.3
Patient disposition, demographics, and other baseline characteristics ..................28
Patient disposition..................................................................................................29
2.4
Treatments (study treatment, concomitant therapies, compliance) .......................30
2.4.1
Study treatment / compliance................................................................30
2.4.2
Prior, concomitant and post therapies...................................................32
2.5
Analysis supporting primary objectives ................................................................33
2.5.1
Primary endpoint...................................................................................33
2.5.2
Statistical hypothesis, model, and method of analysis..........................33
2.5.3
Handling of intercurrent events of primary estimand ...........................34
2.5.4
Sensitivity analyses ...............................................................................38
2.6
Analysis of the key secondary objective ...............................................................38
2.7
Analysis supporting secondary objective(s)..........................................................38
2.7.1
Secondary endpoints .............................................................................38
2.7.2
Statistical hypothesis, model, and method of analysis..........................38
2.8
Safety analyses.......................................................................................................40
2.8.1
Adverse events (AEs)............................................................................40
2.8.2
Deaths....................................................................................................41
2.8.3
Laboratory data .....................................................................................41
2.8.4
Other safety data ...................................................................................43
2.9
Pharmacokinetic endpoints....................................................................................45
2.10
PD and PK/PD analyses.........................................................................................46
2.11
Resource utilization ...............................................................................................46
46


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47
48
2.15
Interim analysis......................................................................................................48
3
Sample size calculation .....................................................................................................48
4
Change to protocol specified analyses ..............................................................................49
5
Appendix ...........................................................................................................................49
5.1
Imputation rules.....................................................................................................49
5.1.1
Study drug.............................................................................................49
5.1.2
AEs, concomitant medications, and safety assessment date 
imputation .............................................................................................50
5.2
AEs coding/grading ...............................................................................................51
5.3
Laboratory parameters derivations ........................................................................52
5.4
Statistical models...................................................................................................52
5.4.1
Primary analysis....................................................................................52
5.4.2
Key secondary analysis.........................................................................56
6
Reference...........................................................................................................................56


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List of abbreviations
ACE
Angiotensin-converting Enzyme
ACR
Albumin to Creatinine Ratio
ACS
Acute Chest Syndrome
ADA
Anti-drug Antibody
AE
Adverse Event
AESI
Adverse Event of Special Interest
AKI
Acute Kidney Injury
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
APC
Acute Pain Crisis
ARB
Angiotensin-Receptor Blocker
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Classification
C5b-9
Complement Membrane Attack Complex
CKD
Chronic Kidney Disease
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
CI
Confidence Interval
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of Variance
DI
Dose Intensity
DMC
Data Monitoring Committee 
ECG
Electrocardiogram
eCRF
Electronic Case Report/Record Form
eGFR
Estimated Glomerular Filtration Rate
EOT
End of Treatment
ER
Emergency Room
ET-1
Endothelin
FAS
Full Analysis Set
GGT
Gamma-glutamyltransferase
Hb
Hemoglobin
Hbs
Hhemoglobin S
HbSβ0-thal
Hemoglobin S with β-thalassemia
HbSS
Homozygous Hemoglobin S (sickle cell anemia)
HC
Hydroxycarbamide
HIV
Human Immunodeficiency Virus
HU
Hydroxyurea
INR
International Normalized Ratio
IRT
Interactive Response Technology
i.v. 
Intravenous


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KDIGO
Kidney Disease Improving Global Outcomes
KIM-1
Kidney injury molecule-1
LLOQ
Lower Limit Of Quantification
MCS
Mental Component Summary
MedDRA
Medical Dictionary for Drug Regulatory Affairs
mg
Milligram(s)
mL
Milliliter(s)
MRI
Magnetic Resonance Imaging
NSAID
Non-Steroidal Anti-Inflammatory Drug
PCR
Protein to Creatinine Ratio
PD
pharmacodynamic(s)
PK
pharmacokinetics
PT
Prothrombin Time
RDI
Relative Dose Intensity 
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCD
Sickle Cell Disease
SD
Standard deviation
SOC
Standard of Care
TFLs
Tables, Figures, Listings
ULN
Upper Limit of Normal
VOC
Vaso-Occlusive Crisis
WHO
World Health Organization


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1
Introduction
This statistical analysis plan (SAP) provides detailed statistical methodology for the analyses 
of data which will be used for preparation of the CSEG101A2203 clinical study report (CSR) 
and is based on the study amended protocol v03, dated 02-Dec-2021.
The shells for the in-text tables and figures as well as the post-text tables, figures and listings 
(TFLs) are in the TFL shells document. Programming specifications for datasets, including 
derivation of variables, are given in the programming data specifications (PDS) document.
All data will be analyzed by Novartis using Novartis clinical data standards (NCDS). Analysis 
data sets and statistical outputs will be produced using the SAS system Version 9.4 or higher 
(UNIX environment) in the global programming & statistical (GPS) environment.
1.1
Study design
This is a Phase II, multicenter, randomized two arm, open label study to evaluate descriptively 
the effect of crizanlizumab + standard of care and standard of care alone on renal function in 
sickle cell disease (SCD) patients with SCD-related chronic kidney disease (CKD).
The study will include patients ≥16 years of age with a confirmed diagnosis of SCD and SCD-
related CKD. Homozygous HbS (HbSS sickle cell anemia) and HbSβ0-thal SCD genotypes will 
be included. Patients eligible for the study will have:

Estimated Glomerular Filtration Rate (eGFR) ≥45 to ≤140 mL/min/1.73 m2 based on the 
CKD/-EPI formula (in patients ≥ 18) and Creatinine-based “Bedside Schwartz” equation 
(2009) (in patients <18)

Albumin to Creatinine Ratio (ACR) of ≥100 to < 2000 mg/g, despite standard of care 
treatment for SCD-related CKD
Eligible patients will be receiving standard of care drug(s) for SCD-related CKD according to 
institutional and local guidelines and the discretion of the physician. Any of the following drugs 
that the patient is receiving at study entry will be considered the patient’s standard of care: 
hydroxyurea (HU)/ hydroxycarbamide (HC), angiotensin-converting enzyme (ACE) inhibitors, 
and/or angiotensin receptor blocker (ARB)s. The patient will continue to take their usual 
standard of care drug(s) during the study; thus, there may be some variation in the standard of 
care regimens used by the different patients in the study. Patients must have been receiving their 
standard of care drug(s) prior to study entry according to the dosing requirements (see amended 
protocol v03 Table 6-1) and must plan to continue the same dose and schedule until the patient 
has reached the end of the study. The screening assessments will be done within 1 to 28 days 
prior to baseline (Week 1 Day 1).
Overall, approximately 50 patients will be randomized 1:1 to receive either crizanlizumab 
(5 mg/kg) + standard of care or standard of care alone. Patients will be stratified at 
randomization based on CKD risk category (moderate risk or high/very high risk) and HU/HC 
prescription (Yes/No). The CKD risk categories used for stratification are based on both eGFR 
and albuminuria assessed by ACR as defined in Table 1-1:


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Table 1-1
Prognosis of chronic kidney disease by glomerular filtration rate and 
albuminuria categories (chronic kidney disease risk categories)
ACR 
(30-300 mg/g
3-30 mg/mmol) 1
ACR 
(>300 mg/g
> 30 mg/mmol)
eGFR ≥90 mL/min/1.73 m2
1
2
eGFR 60-89 mL/min/1.73 m2
1
2
eGFR 45-59 mL/min/1.73 m2
2
3
1 = moderately increased risk; 2 = high risk; 3 = very high risk
1 ACR ranges included above are according to KDIGO (2013); Note that patients in this 
study will have eGFR ≥45 to ≤140 mL/min/1.73 m2 and ACR of ≥100 to < 2000 mg/g. 
Patients should be randomized based on ACR in mg/g.
Throughout this document, “study treatment” will refer to both treatment arms.
Patients randomized to crizanlizumab + standard of care will receive crizanlizumab by 
intravenous (i.v.) infusion over 30 minutes on Week 1 Day 1, followed by a second dose 
14 days later (Week 3 Day 1), and then on Day 1 of every 4 weeks for a total on-study treatment 
period of 12 months in addition to their usual standard of care treatment. The visit for the 
assessment of the primary endpoint will take place on Week 53 Day 1. Patients will be followed 
up for two safety assessments 30 days (phone call) and 105 days (study visit) after the Week 51 
Day 1 visit. Patients who will receive crizanlizumab approximately 4 weeks after their last dose 
of study treatment, do not need to complete the 105-day follow-up. The end of the safety follow-
up period for these patients will be the 30-day follow-up. All other patients are required to 
complete the 105-day follow-up.
Patients in the standard of care alone arm will continue to receive their usual standard of care 
treatment and will attend study visits per the same schedule as the patients randomized to 
crizanlizumab + standard of care (i.e., visits on Week 1 Day 1, Week 3 Day 1, then every 
4 weeks up to Week 51 Day 1, followed by a visit on Week 53 Day 1 and two safety follow-up 
assessments 30 days phone call and 105 days study visit after Week 51 Day 1 [as applicable]). 
Patients will discontinue the study due to unacceptable toxicity, death, or if they are lost to 
follow-up, and may also be discontinued from the study at the discretion of the investigator or 
patient if the study treatment is discontinued (however, please see amended protocol v03
Section 6.5.1 and Section 9.1 for further details). All patients who discontinue the study 
treatment early will attend an end of treatment (EOT) visit (visit EOT; within 7 days of the last 
dose of the discontinued study treatment) and be followed in the mandatory safety follow-up 
period, which includes safety assessments at 30 days (phone call) and 105 days (study visit, as 
applicable) after the last dose of the discontinued study treatment. These patients will also return 
for a mandatory Week 53 urine ACR/PCR assessment. The Week 53 urine ACR/PCR 
assessment should occur 12 months after the first dose of study treatment.
AEs will be recorded throughout the study. All patients will have hematologic, clinical 
chemistry and coagulation assessments done according to amended protocol v03 Table 8-1.
Efficacy assessments of albuminuria (urine ACR) (see amended protocol v03 Section 8.3.1), 


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protein to creatinine ratio (PCR) (amended protocol v03 Section 8.3.2), eGFR (amended 
protocol v03 Section 8.3.3), and progression of CKD (amended protocol v03 Section 8.3.4) will 
be assessed based on these laboratory assessments.
 
 
 
 
 
 
 
 
In addition, patients 
randomized to the crizanlizumab + standard of care arm will have immunogenicity and PK 
assessments at select time points. 
The study design is provided in Figure 1-1.
Figure 1-1
Study design
No interim analysis will be conducted for this study. 
The final analysis will be performed after final database lock when all patients have completed 
the study (including their safety evaluation 30 and 105 days [as applicable] after the last dose 
of study treatment) or they have prematurely discontinued. 
1.2
Study objectives and endpoints
Objectives and related endpoints are provided in Table 1-2.
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Table 1-2
Objectives and related endpoints
Objectives
Endpoints
Primary objective
Endpoint for primary objective
To evaluate descriptively the effect of 
crizanlizumab + standard of care and standard 
of care alone on albuminuria (ACR) decrease 
at 12 months
Proportion of patients with ≥30% decrease in 
ACR at 12 months from baseline 
Secondary objective(s)
Endpoint(s) for secondary objective(s)
To evaluate descriptively the effect of 
crizanlizumab + standard of care and standard 
of care alone on change in albuminuria (ACR)
Mean change in ACR from baseline to 3, 6, 9, and 
12 months of treatment 
To evaluate descriptively the effect of 
crizanlizumab + standard of care and standard 
of care alone on albuminuria (ACR) decrease 
at 6 months
Proportion of patients with ≥30% decrease in 
ACR at 6 months from baseline 
To evaluate descriptively the effect of 
crizanlizumab + standard of care and standard 
of care alone on protein to creatinine ratio 
(PCR) at 12 months
Proportion of patients with PCR improvement and 
stable PCR (improvement: ≥20% decrease in 
PCR from baseline; stable: within ± 20% change 
from baseline) at 12 months from baseline
To evaluate descriptively the effect of 
crizanlizumab + standard of care and standard 
of care alone on the percentage change in 
eGFR 
Percentage change in eGFR from baseline to 3, 6, 
9, and 12 months of treatment 
To evaluate descriptively the effect of 
crizanlizumab + standard of care and standard 
of care alone on ACR decline rate
Slope of ACR decline from baseline to 12 months 
of treatment based on ACR values at baseline and 
at 3, 6, 9, and 12 months
To evaluate descriptively the effect of 
crizanlizumab + standard of care and standard 
of care alone on eGFR decline rate 
Slope of eGFR decline from baseline to 
12 months of treatment based on eGFR values at 
baseline and at 3, 6, 9, and 12 months
To evaluate descriptively the effect of 
crizanlizumab + standard of care and standard 
of care alone on the progression of CKD at 
12 months
Proportion of patients with progression of CKD 
from baseline to 12 months
To evaluate descriptively overall safety and, 
tolerability of crizanlizumab + standard of care 
and standard of care alone
Safety will be assessed by the frequency and 
severity of adverse events (AEs), deaths, 
measurement of vital signs, ECG assessments, 
SAEs, and laboratory abnormalities 
To assess the immunogenicity of 
crizanlizumab over the study period (treatment 
of 1 year + 105 days of follow-up)
To evaluate descriptively healthcare resource 
utilization (visits to emergency room [ER] and 
hospitalizations) in crizanlizumab + standard of 
care arm and standard of care alone
Immunogenicity: measurement of anti-drug 
antibodies (ADA) to crizanlizumab at select time 
points
Crizanlizumab PK measurements will accompany 
immunogenicity measurements
Annualized rate of visits to ER and 
hospitalizations due to AKI events, VOCs, or other 
SCD complications


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1.2.1
Primary estimands
The estimand is the precise description of the treatment effect and reflects strategies to address 
events occurring during trial conduct which could impact the interpretation of the trial results 
(e.g. premature discontinuation of treatment).
The primary clinical question of interest is: What is the effect of crizanlizumab + standard of 
care and standard of care alone on renal function in SCD patients with SCD-related CKD.
The detailed information regarding primary estimands can be found in section 2.5.3.
2
Statistical methods
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be presented.
The data from all centers that participate will be combined in the analyses.


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This study will be considered for Article 46 regulation. If at least 5 pediatric patients (<18 years 
of age) in each treatment are included in the study, all analysis outputs will be performed for 
pediatric patients separately. Otherwise, separate analyses will not be provided.   
2.1
Data analysis general information
Data will be analyzed by Novartis GMA Oncology Biostatistics and Statistical Programming 
personnel according to the data analysis plan in this SAP
. Important information is given in the 
following sections and details are provided, as applicable, in Section 5 
 
SAS® version 9.4 (or later version if available at time of database lock) will be used in all 
analyses.
Data from all patients with signed informed consent will be used in the analysis. Data collected 
after withdrawal of informed consent will not be reported. Due to expected small size of 
enrollment at individual centers, data from all centers will be pooled together for analysis.  
General analysis conventions
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small size of enrollment at individual centers, no center effect will 
be assessed. 
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables; 
a “missing” category will be included as applicable. Percentages will be calculated using the 
number of patients in the relevant population as the denominator.
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate descriptive 
statistics (i.e. mean, standard deviation, median, 25th and 75th percentiles, minimum, and 
maximum).
2.1.1
General definitions
Investigational drug and study treatment
Investigational drug refers to crizanlizumab only. Whereas study treatment refers to both 
treatment arms. The term investigational treatment may also be referred to as study treatment 
which is used throughout this document.
Treatment and group
For presentation in the outputs, treatment refers to crizanlizumab 5.0 mg/kg plus SOC; and 
SOC alone. 
Date of first administration of investigational drug
The date of first administration of investigational drug is defined as the first date when a 
non-zero dose of investigational drug is administered and recorded on the Study Treatment –


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Infusion case report form (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 non-
zero dose of investigational drug is administered and recorded on Study Treatment 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 the same as the date of first administration 
of non-zero dose of study treatment as per the Dosage Administration CRF. The date of first 
administration of study treatment will also be referred as start of study treatment.
For SOC arm, the date of first administration of study treatment is the first administration of 
SOC after randomization.
For crizanlizumab plus SOC arm, the date of first administration of study treatment is the first 
administration of crizanlizumab or SOC after randomization. 
Date of last administration of study treatment 
The date of last administration of study treatment is the same as the date of last administration 
of non-zero dose of study treatment as per the Dosage Administration CRF. 
For SOC arm, the date of last administration of study treatment is the last administration of 
SOC after randomization.
For Crizanlizumab plus SOC arm, the date of last administration of study treatment is the last 
administration of Crizanlizumab or SOC after randomization. 
Study day
The study day describes the day of the event or assessment date, relative to the reference start 
date. 
The study day is calculated as:
The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date + 1 if event is on or after the reference start date;

The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date if event precedes the reference start date.
The reference start date for safety assessments (e.g. AE onset, laboratory abnormality
occurrence, vital sign measurement, dose interruption, PK, electrocardiogram [ECG], etc.) is
the start of study treatment.
The reference start date for all other assessments, i.e. vaso-occlusive crisis (VOC), healthcare 
resource utilization, SCD-related renal and other organ function, other acute pain crisis not 
requiring a healthcare visit and managed at home, 
is the date of randomization.


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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.
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 efficacy evaluations, the last non-missing assessment, including unscheduled assessments 
on or before the date of randomization is taken as the “baseline” value or “baseline” assessment. 
 
For safety evaluations, the last available assessment on or before the date of start of study 
treatment is taken as the “baseline” assessment.
In case the time of assessment and time of treatment start are captured (e.g. pre-dose ECG), the 
last available assessment before the treatment start date/time is used for baseline. 
For safety parameters (e.g. ECGs), where the study requires multiple replicates per time point, 
the average of these measurements will be calculated for baseline (if not already available in 
the database).
In 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) or collected for 
ECGs or vital signs, then the last entry should be considered as baseline. Further details to cover 
case by case situations may be described in the programming data specifications.
If patients 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 
For AE reporting the overall observation period will be divided into three mutually exclusive 
segments: 
1. Pre-treatment period: from day of patient’s informed consent to Day -1 (i.e., the day 
before first dose of crizanlizumab/day before the Week 1 Day 1 visit)


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2. On-treatment period: from Day 1 (i.e., day of first dose of crizanlizumab/day of 
Week 1 Day 1 visit) to 105 days after last dose of discontinued study treatment or the
end of the safety follow-up period (i.e., 30 or 105 days after the Week 51 Day 1 visit)
3. Post-treatment period: starting at Day 106 after last dose of discontinued study 
treatment or Day 31 or 106 after the Week 51 Day 1 visit.
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 efficacy analysis
In order to summarize 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 are 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.
Statistical approaches to handle multiple assessments in a given visit window are specified 
below.

For ACR/eGFR and PCR assessments ±7 days time window was considered for the visits 
before week 53 and ±14 days time window was used for the visit time point at week 53.

Following rules are used to determine the visit windows post baseline for other Lab 
assessments:

“Lower limit” = “upper limit of prior applicable visit” + 1.

“Upper limit” = “target day of current visit” + integer part of (“target day of next
applicable visit” – “target day of current visit”)/2 with the exception of Day 365. For Day 
365 the upper limit is calculated as 365+14.
The mapped visits will be used in the by visit analyses. However, the listings will show all the
collected data regardless of used in the by visit analyses.


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Table 2-1
Analysis visit windows based on study day and time for ACR/eGFR, 
other Lab and PCR. 
Analysis Visit
Target day (days)
ACR/eGFR 
Clinical 
chemistry/
Hematology
PCR 
Baseline 
(Week 1 Day 1)
1
≤ Study Day 1
≤ Study Day 1
≤ Study Day 1
Week 3 Day 1
15
-
> 1 to 43
-
Week 7 Day 1
43
-
-
-
Week11 Day 1
71
-
> 43 to 85
-
Week 15 Day1
99
>91 to 106
> 85 to 141
-
Week 19 Day 1
127
-
-
-
Week 23 Day 1
155
-
-
-
Week 27 Day 1
183
>175 to 190
> 141 to 225
>175 to 190
Week 31 Day 1
211
-
-
-
Week 35 Day 1
239
-
-
-
Week 39 Day 1
267
>259 to 274
> 225 to 316
-
Week 43 Day 1
295
-
-
-
Week 47 Day 1
323
-
-
-
Week 51 Day 1
351
-
-
-
Week 53 Day 1
365
>350 to 379
>316 to 379
>350 to 379
End of treatment 
(EOT)
Assessment taken at 
EOT visit
Assessment taken 
at EOT visit
Assessment 
taken at EOT 
visit
105 days follow-
up
105 days after last 
infusion
From 29 days within 
last infusion
-
From 29 days 
within last 
infusion
2.2
Analysis sets
A patient is considered to be enrolled into the study if signed informed consent has been 
obtained. Only patients with signed informed consent will be included in the analysis data sets.
2.2.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned 
by randomization. According to the intent to treat principle, patients will be analyzed according 
to the treatment they have been assigned to during the randomization procedure. 
2.2.2
Safety Set
The Safety Set includes all patients who received at least one dose of study treatment. Patients 
will be analyzed according to the study treatment received, where treatment received is defined 
as the randomized treatment if the patient took at least one dose of that treatment or the first 
treatment received if the randomized treatment was never received.
2.3
Patient disposition, demographics, and other baseline 
characteristics
The FAS will be used for all baseline and demographic summaries and listings unless specified 
otherwise. Summaries will be reported by treatment group and for all patients, and listings will 
be reported by treatment group to assess baseline comparability. No inferential statistics will be 
provided.


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Basic demographic and background data
All demographic and baseline disease characteristics data will be summarized and listed by 
treatment group. Categorical data (e.g. age, gender, race, ethnicity, performance status) will be 
summarized by frequency counts and percentages; the number and percentage of patients with 
missing data will be provided. Continuous data (e.g. age, weight, height, body mass index
(BMI)) will be summarized by descriptive statistics (N, mean, median, standard deviation, 
minimum and maximum). For selected parameters, 25th and 75th percentiles will also be 
presented. BMI (kg/m2) will be calculated as weight[kg] / (height[m]2) using weight and height 
at screening.  
Summary statistics will also be tabulated for other baseline characteristics and assessments, 
including Hb, ACR, PCR, eGFR, CKD history and CKD progression category.
Baseline stratification factors
The number (%) of patients in each stratum (HU/HC usage: yes, no; CKD risk category: 
moderate risk, high/very high risk) based on data obtained from the IRT system and the CRF
will be summarized overall and by treatment group for the FAS. 
Sickle cell and VOC history
Summary statistics will be tabulated for sickle cell and VOC history (e.g., AKI event at baseline, 
Other acute pain crisis [APC] event at baseline, VOC history including genotype and HU/HC
or L-glutamine use, frequency of VOCs at baseline).
Medical history
Medical history and ongoing conditions entered on eCRF will be summarized and listed by 
treatment group. Separate summaries will be presented for ongoing and historical medical 
conditions.  The summaries will be presented by primary SOC, PT and treatment group. 
Medical history and current medical conditions will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) terminology. The MedDRA version used for reporting will 
be specified in the CSR and as a footnote in the applicable tables/listings.
Patient demographic data and other baseline characteristics (e.g., medical history, disease 
history etc.) will be listed.
Patient disposition
Enrollment will be summarized for all screened patients and also by treatment group using 
the FAS. The number (%) of randomized  patients included in the FAS will be presented overall 
and by treatment group. The number (%) of screened and not-randomized patients and the 
reasons for screening failure will also be displayed. The number (%) of patients in the FAS who 
are still on treatment, who discontinued the study phases and the reason for discontinuation will 
be presented overall and by treatment group.
The following summaries will be provided (with % based on the total number of FAS patients):

Number (%) of patients who were randomized (based on data from IRT system)


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
Number (%) of patients who were randomized but not treated (based on ‘Study Treatment 
– Infusion’ eCRF page not completed for any study treatment component)

Primary reason for not being treated (based on ‘disposition’ eCRF page) 

Number (%) of patients who were treated (based on ‘Study Treatment – Infusion’ eCRF 
pages with non-zero dose administered)

Number (%) of patients who are still on-treatment (based on the ‘disposition’ page not 
completed); 

Number (%) of patients who discontinued the study treatment phase (based on the 
‘disposition’ page) 

Primary reason for study treatment phase discontinuation (based on the ‘disposition’ page)

Number (%) of patients who have entered the follow-up

Number (%) of patients who have discontinued from the post-treatment follow-up (30 
days or 105 days as applicable)

Reasons for discontinuation from the post-treatment follow-up
Protocol deviations
The number (%) of patients in the FAS with any protocol deviation will be tabulated by 
deviation category (as specified in the study edit checks specifications) overall and by treatment 
group for the FAS. All protocol deviations will be listed. The protocol deviations are defined in 
the protocol deviations specifications, which will be finalized before final database lock.
In addition, COVID-19 related protocol deviations and issues with potential impact on quality
will be summarized.
Analysis sets
The number (%) of patients in each analysis set will be summarized by treatment group and 
stratum. 
2.4
Treatments (study treatment, concomitant therapies, 
compliance)
2.4.1
Study treatment / compliance
The duration of exposure in weeks to crizanlizumab, actual cumulative dose, dose intensity 
(computed as the ratio of total dose received and actual duration) and the relative dose intensity 
(computed as the ratio of dose intensity and planned dose intensity), will be summarized. The 
duration of exposure in weeks will also be summarized for the standard of care medications for 
both arms by standard of care categories (HU, ACE, ARB, etc.). Duration of exposure will be 
categorized into time intervals; frequency counts and percentages will be presented for the 
number (%) of patients in each interval.
The number of patients with dose adjustments (interruption, or permanent discontinuation) and 
the reasons will be summarized and all dosing data will be listed for crizanlizumab. The number 
of patients with dose modifications (dose interruption, dose change or permanent 


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discontinuation) and the reasons will be summarized and all dosing data will be listed for 
standard of care medications. 
The Safety Set will be used for all summaries and listings of study treatment. 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.
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 date between:

last date of treatment + 27 days (Infusion of crizanlizumab every 4 weeks)

date of death (if the patient died)
Summary of duration of exposure of study treatment in months will include categorical 
summaries (less than 3 months, at least 3 months, at least 6 months, at least 9 months, at least 
12 months) and continuous summaries (i.e. mean, SD 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. 
The planned cumulative dose for a study treatment component refers to the total planned dose 
as per the protocol up to the last date of investigational drug administration. 
The actual cumulative dose refers to the total actual dose administered, over the duration for 
which the patient is on the study treatment as documented in the Study Treatment – Infusion 
eCRF. In order to determine the actual cumulative dose, the dose administered as reported in 
the eCRF in mg will be divided by the last weight of a given patient at time of the dosing.
Dose intensity and relative dose intensity
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows: 
DI (mg/kg/28days) = (Actual cumulative dose (mg/kg) / Duration of exposure to study 
treatment (weeks)) 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.
Relative dose intensity (RDI) is defined as follows:
RDI = DI (mg/kg/28days) / PDI (mg/kg/28days).  


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Dose interruptions or permanent discontinuations
The number of patients who have permanent discontinuations or interruptions, and the reasons, 
will be summarized separately by treatment group. 
Interruptions are considered as infusion completely skipped or delayed. 
Interruption: A dose cannot be administered within 21 days of the scheduled day of infusion 
as per protocol. If a dose was temporarily stopped during infusion, it should not be considered 
as a dose interruption. Duration of a dose interruption is calculated as the time between the 
scheduled date of infusion and the actual date of infusion after the interruption.
‘Dose permanently discontinued’ fields from the Study Treatment CRF pages will be used to 
determine the dose permanent discontinuations.
The corresponding fields ‘Reason for dose interrupted’ and ‘Reason for permanent 
discontinuation’ will be used to summarize the reasons, respectively.
2.4.2
Prior, concomitant and post therapies
Concomitant medications and significant non-drug therapies/procedures prior to and after the 
start of the study treatment, as well as the incidence of transfusion, will be summarized and 
listed for all patients by treatment arm based on the Safety Set.
Concomitant medications
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a patient coinciding with the study treatment 
period. Concomitant therapy include medications (other than study drugs) starting on or after 
the start date of study treatment or medications starting prior to the start date of study treatment 
and continuing after the start date of study treatment. 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Reference Listing  (DRL)  dictionary  that  employs  the  WHO  Anatomical  Therapeutic 
Chemical (ATC) classification system and summarized by lowest ATC class and PT using 
frequency counts and percentages. Surgical and medical procedures will be coded using 
MedDRA and summarized by SOC and PT. These summaries will include:
1. Medications starting on or after the start of study treatment but no later than 30 or 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 by treatment arm. Separate listings will be provided for 
L-Glutamine, Analgesics, Anticoagulants, NSAIDS and opioids. Any concomitant therapies
starting and ending prior to the start of study treatment will be flagged in the listing. Unless 
otherwise specified, the Safety Set will be used for the concomitant medication tables and 
listings. Non-drug therapies and medical procedures will be coded using MedDRA and 
summarized by SOC and PT.


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L-Glutamine 
The number and percentage of patients who were treated with L-Glutamine (as recorded in the 
“Sickle cell – VOC History” eCRF page) prior to study start and the number of patients who 
started or stopped these medications during the on-treatment period (as recorded on the 
corresponding Prior and Concomitant Medications L-Glutamine eCRF pages) will be 
summarized by treatment group using FAS. 
L-Glutamine starting on or after the start date of study treatment will be listed using FAS. 
Analgesics
Separate summaries will be provided to present the number and percentage of patients who 
received analgesics (as entered on “Prior and Concomitant Medications Analgesics” eCRF page) 
on or after the start of study treatment but no later than 105 days after start of last dose of study 
treatment.

NSAIDS
The number and percentage of patients who were treated with NSAIDS on or after the 
start of study treatment will be summarized by treatment group using FAS.

Opioids
The number and percentage of patients who were treated with Opioids on or after the start 
of study treatment will be summarized by treatment group using FAS.
Transfusions
The proportion of patients who received transfusion and the number of transfusions during the 
on-treatment period will be summarized descriptively. All transfusion will be listed.
2.5
Analysis supporting primary objectives
The primary objective of this study is to evaluate the effect of crizanlizumab + standard of care 
and standard of care alone on albuminuria (ACR) decrease at 12 months, as assessed by the 
proportion of patients with ≥30% decrease in ACR at 12 months from baseline.
2.5.1
Primary endpoint
The primary endpoint of this study is the proportion of patients with ≥30% decrease in ACR at 
12 months from baseline. 
2.5.2
Statistical hypothesis, model, and method of analysis
The primary endpoint will be analyzed descriptively based on the data from the FAS. A logistic 
regression model that includes effects for treatment and randomization stratification factors will 
be utilized. The treatment effect based on the log-odds ratio will be estimated by the model.
The odds ratio for the relative difference between treatments in the primary endpoint, and its 
corresponding 95% confidence interval, will be presented. 
In addition, the proportions of patients in each group with at least 30% decrease in ACR will 
be presented, along with a 95% two-sided confidence interval for the difference in proportions.


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2.5.3
Handling of intercurrent events of primary estimand
The primary estimand is described by the following attributes: 
1. The target population comprises patients with kidney dysfunction due to SCD. 
2. The primary variable is proportion of patients with ≥30% decrease in ACR at 12 months.
3. The treatment of interest is the effect of crizanlizumab 5.0 mg/kg + standard of care on the 
ACR value taken for the entire study duration with or without the intercurrent events
4. The intercurrent events are the events occurring after randomization that may impact the 
treatment effect. The intercurrent events of interest are: 
a. Treatment discontinuation
b. Initiation or discontinuation of HU/HC, HA approved form(s) of L-glutamine 
(EndariTM in USA), ACE, and/or ARB
c. Intake of NSAIDs within 48 hours prior to ACR measurements 
d. Intake of Voxelotor  
e. Blood transfusion or VOC occurred within 7 days of urine and blood sample              
collection
f.
Renal replacement therapy (i.e. hemodialysis, peritoneal dialysis, hemofiltration and 
kidney transplantation) 
5. The summary measure is the odds ratio of treatment effect for patients with ≥30% decrease 
in ACR between crizanlizumab + standard of care and standard of care alone. 
Handling of the intercurrent events
The approach of accounting for intercurrent events is as follows:

For the intercurrent events 4.a: The composite strategy will be applied for treatment 
discontinuation due to death of any cause, drug-related AEs, and progressive disease. Define 
treatment discontinuation due to death of any cause, drug-related AEs, and progressive 
disease as non-responders. The hypothetical strategy will be applied for treatment 
discontinuation due to other reasons. The interest focuses on the treatment effect if patients 
stay on treatment for 12 months, if possible.

For the intercurrent events 4.b: The hypothetical strategy. The interest focuses on the 
treatment effect if patients had not initiated or discontinued HU/HC, HA approved form(s) 
of L-glutamine (EndariTM in USA), ACE and/or ARB.

For the intercurrent events 4.c: The hypothetical strategy. The interest focuses on the 
treatment effect if patients had not received NSAIDs within 48 hours prior to ACR
measurement.

For the intercurrent events 4.d: The hypothetical strategy. The interest focuses on the 
treatment effect if patients had not received Voxelotor 

For the intercurrent events 4.e: The hypothetical strategy. The interest focuses on the 
treatment effect if patients had not had blood transfusion or VOC occurred.

For the intercurrent events 4.f: The composite strategy will be applied for treatment 
discontinuation due to renal replacement therapy, define treatment discontinuation due to 
renal replacement therapy as non-responders. The hypothetical strategy will be applied if 
the renal replacement therapy occurred and patient did not discontinue. The interest focuses 


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on the treatment effect if patients had not had renal replacement therapy. The reason of 
using hypothetical strategy is because for patients who had renal replacement therapy and 
continued the treatment with their renal function return to within 10% of their pre-AKI level 
should not be considered as treatment failure.
The primary estimand is described in Table 2-2 below, together with its key attributes. The 
supplementary estimands are described in Table 2-3. 


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Table 2-2            Primary estimand
Estimand
Target population
Summary Measure
Handling of the intercurrent 
events
Rationale
Primary estimand
Patients with kidney 
dysfunction due to SCD
Odds ratio of treatment 
effect on ACR response
Exclude ACR data collected 
after treatment discontinuation. 
Treatment discontinuation due 
to death of any cause, 
drug-related AEs, progressive 
disease will be considered as 
non-responders; other reasons 
will use multiple imputation 
(MI).
Exclude ACR data after 
initiation or discontinuation of 
HU/HC, HA approved form(s) 
of L-glutamine (EndariTM in 
USA), ACE and/or ARB. Will 
use MI.
Exclude ACR data collected 
after intake of NSAIDs within 
48 hours prior to  ACR 
measurement. Will use MI.
Exclude ACR data collected 
after intake of Voxelotor. Will 
use MI. 
Exclude ACR data collected 
after blood transfusion or VOC 
occurred (if within 7 days 
before the ACR measure). Will 
use MI.
Exclude ACR data collected 
after renal replacement 
therapy. Treatment 
discontinuation due to renal 
See Section 2.5.3 Handling 
of the intercurrent events


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Estimand
Target population
Summary Measure
Handling of the intercurrent 
events
Rationale
replacement therapy will be 
considered as non-responders; 
If the patient required renal 
replacement therapy and did 
not discontinue study 
treatment, will use MI.


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2.5.4
Sensitivity analyses
No sensitivity analysis will be conducted.
2.6
Analysis of the key secondary objective
Not applicable.
2.7
Analysis supporting secondary objective(s)
The secondary objectives in this study are to describe the two treatment groups with respect to 
albuminuria/proteinuria, including change in ACR, ACR decline rate, and PCR improvement, 
and with respect to eGFR, percentage change in eGFR, eGFR decline rate, and the progression 
of CKD, also safety, and healthcare resource utilization will be evaluated. Another secondary 
objective is to assess the immunogenicity and accompanying PK of crizanlizumab.
2.7.1
Secondary endpoints
The secondary endpoints are the mean change in ACR from baseline to 3, 6, 9, and 12 months 
of treatment; the slope of ACR decline from baseline to 12 months of treatment based on ACR 
values at baseline and at 3, 6, 9, and 12 months, the percentage change in eGFR from baseline 
to 3, 6, 9, and 12 months of treatment, the slope of eGFR decline from baseline to 12 months 
of treatment based on eGFR values at baseline and at 3, 6, 9, and 12 months, the proportion of 
patients with ≥30% decrease in ACR at 6 months from baseline, the proportion of patients with 
PCR improvement and stable PCR (improvement: ≥ 20% decrease in PCR from baseline; stable: 
within ± 20% change from baseline) at 12 months from baseline and the proportion of patients 
with progression of CKD from baseline to 12 months.
2.7.2
Statistical hypothesis, model, and method of analysis
The secondary efficacy endpoints will be summarized descriptively using the FAS.
The mean change in ACR from baseline to 3, 6, 9, and 12 months of treatment
The mean change in ACR from baseline will be summarized and plotted over time by treatment 
arm. An Analysis of Covariance (ANCOVA) model that includes effects for treatment, 
randomization stratification factors, and baseline ACR, will be carried out for analysis.
The slope of ACR decline from baseline to 12 months of treatment based on 
ACR values at baseline and at 3, 6, 9, and 12 months
The slope of ACR decline will be estimated as a random coefficient in a linear mixed effect 
model: the model will be fitted to ACR data collected at baseline and at Months 3, 6, 9, and 12. 
It includes treatment, stratification factors, time and the interaction of treatment by time as the 
fixed effects, and intercept as a random effect. The mean slopes within each treatment and the 
difference in mean slopes between two treatments will be presented.


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The percentage change in eGFR from baseline to 3, 6, 9, and 12 months of 
treatment
The percentage change in eGFR is calculated as the post-baseline eGFR value minus the 
baseline eGFR divided by the eGFR at baseline. The calculation of eGFR is based on the 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) (for patients ≥ 18 at screening) 
and Creatinine-based “Bedside Schwartz” (for patients < 18 at screening) equations. Percentage 
change in eGFR from baseline will be summarized and plotted over time by treatment arm. An 
ANCOVA model that includes effects for treatment, HU/HC use (Yes vs. No), and baseline 
eGFR, will be carried out for analysis using a logarithmic scale.
The slope of eGFR decline from baseline to 12 months of treatment based on 
eGFR values at baseline and at 3, 6, 9, and 12 months
The slope of eGFR decline will be estimated as a random coefficient in a linear mixed effect 
model: the model will be fitted to eGFR data collected at baseline and at Months 3, 6, 9, and 
12. It includes treatment, stratification factors, time and the interaction of treatment by time as 
the fixed effects, and intercept as a random effect. The mean slopes within each treatment and 
the difference in mean slopes between two treatments will be presented.
Proportion of patients with progression of CKD from baseline to 12 months
The progression of CKD, which is based on both eGFR and ACR, will be assessed according 
to the classification presented based on KDIGO 2013 (See amended protocol v03 Figure 8-1).
The following analysis will be performed on CKD progression.

For the proportion of patients with progression of CKD from baseline to 12 months 
(including patients with increase in CKD progression category defined by Figure 8-1 in 
protocol v03, patients with a 25% or greater drop in eGFR from baseline and patients with 
at least 50% increase in ACR for patients with severe (A3) albuminuria and a doubling of 
albumin levels in patients with moderate (A2) albuminuria), a logistic regression model 
that includes effects for treatment, HU/HC use, will be carried out.  

For the proportion of patients with a 25% or greater drop in eGFR from baseline to 12 
months, a logistic regression model that includes effects for treatment, HU/HC use, will be 
carried out.  

For the proportion of patients with at least 50% increase in ACR for patients with severe 
(A3) albuminuria and a doubling of albumin levels in patients with moderate (A2) 
albuminuria, a logistic regression model that includes effects for treatment, HU/HC use,
will be carried out. 

A shift table will be provided for patients with increase in CKD progression category for 
each treatment based on Figure 8-1 in Protocol v03.
Proportion of patients with ≥30% decrease in ACR at 6 months from baseline
For the proportion of patients with ≥30% decrease in ACR at 6 months from baseline, a logistic 
regression model that includes effects for treatment, stratification factors, will be carried out.


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Proportion of patients with PCR improvement and stable PCR (improvement: ≥ 
20% decrease in PCR from baseline; stable: within ± 20% change from baseline) 
at 12 months from baseline
For the proportion of patients with PCR improvement and stable PCR (improvement: ≥20% 
decrease in PCR from baseline; stable: within ± 20% change from baseline) at 12 months from
baseline, a logistic regression model that includes effects for treatment, stratification factors, 
will be carried out.  
2.8
Safety analyses
For all safety analyses, the Safety Set will be used. Safety summaries will include only on-
treatment assessments; safety listings include all assessments with those that occur more than 
30-days or 105-days after last study treatment flagged. All listings and tables will be presented 
by treatment group.
For all safety analyses, the Safety Set will be used.
2.8.1
Adverse events (AEs)
AE summaries will include all AEs occurring during the on-treatment period. All AEs collected 
in the AE eCRF 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 patients having at least one AE, having 
at least one AE in each primary SOC and for each PT using MedDRA coding. A patient with 
multiple occurrences of an AE will be counted only once in the respective AE category. A 
patient with multiple CTCAE grades for the same PT 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 the crizanlizumab + SOC group.
The following AE summaries will be produced by treatment group; overview of AEs and deaths, 
AEs by SOC and PT, summarized by relationship, seriousness, leading to treatment 
discontinuation, leading to dose interruption, requiring additional therapy 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, with number of occurrences will be produced 
(an occurrence is defined as >1 day between start and prior end date of record of same PT).
All deaths (on-treatment and post-treatment) will be summarized.
All AEs, deaths, and SAEs (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.
AEs will be assessed according to the CTCAE version 5.0. 
Adverse events identified in the Novartis MedDRA Query (NMQ) topic of “COVID-19 
diagnosis, manifestations, risks and complications including death” will be summarized and 


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listed. Summaries will be provided overall for this COVID-19 topic and by different 
classification levels defined within the topic.
2.8.1.1
Adverse events of special interest / grouping of AEs
Data analysis of AESIs
An adverse event of special interest (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. 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 patients with at least one event of the AESI 
occurring during the on-treatment period will be summarized. The list of AESI to be taken into 
account for crizanlizumab trials is documented in electronic case retrieval sheet (eCRS) for the 
project. The most up to date version of the eCRS available at the time of a database 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 treatment group, (specifying grade, serious AE, 
relationship, leading to treatment discontinuation, leading to dose interruption).
A listing of all grouping levels down to the MedDRA PTs used to define each AESI will be 
generated. 
In addition, all AEs and serious AEs will be listed.
2.8.2
Deaths
Separate summaries for on-treatment and all deaths will be produced by treatment group, SOC 
and PT. 
All deaths will be listed, post treatment deaths will be flagged. A separate listing of deaths prior 
to starting treatment will be provided for all screened patients.
2.8.3
Laboratory data
Data handling
For urine sample replicates, the average of the parameters at that assessment will be used in the 
analyses.
Data analysis
On analyzing laboratory, data from all sources (central and local laboratories) will be combined, 
except ACR/PCR and eGFR parameters, these kidney-related parameters are from central lab. 
The summaries will include all assessments available for the lab parameter collected no later 
than 105 days (if applicable) after the last study treatment administration date.


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The following summaries will be produced for hematology (including coagulation), 
biochemistry, and urinalysis (macroscopic only) laboratory data (by laboratory parameter and 
treatment group):

Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient 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, shift tables using the pre-
specified thresholds 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 values flagged to show the corresponding CTCAE v5.0 
grades and classification relative to the laboratory normal range. Lab data collected during 
the post-treatment period will be flagged. 

Listing of all CTCAE Grade 3 or 4 laboratory toxicities
For hemoglobin and leukocytes parameters, a 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), direct bilirubin (DBILI), alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT)
and alkaline phosphatase (ALP). The number (%) of patients 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 and a similar plot of DBILI 
vs. ALT will also be generated. Individual patient plots will be produced for patients with 
potential severe drug-induced liver injury.  Plot of prothrombin time / international normalized 
ratio (PT-INR) and albumin over time will also be produced for the same patients. A 
corresponding listing of patients with potential severe drug induced liver injury will be 
generated. 
The following summaries will be produced:

ALT or AST > 3 x upper limit of normal (ULN)

ALT or AST > 5 x ULN

ALT or AST > 8 x ULN

ALT or AST > 10 x ULN

ALT or AST > 20 x ULN

TBL > 2 x ULN

TBL > 3 x ULN

ALT or AST > 3 x ULN & TBL > 2 x ULN

ALT or AST > 3 x ULN & TBL > 2 x ULN & ALP < 2 x ULN (potential Hy’s law)

ALT or AST > 3 x ULN & TBL > 2 x ULN & ALP ≥ 2 x ULN

ALT > 3 x ULN & DBILI > 2 x ULN & ALP < 2 x ULN


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Potential Hy’s Law events are defined as those events with concurrent occurrence of AST or 
ALT > 3 x ULN and TBL > 2 x ULN and ALP < 2 x ULN in the same assessment sample 
during the on-treatment period. Patients with potential severe drug-induced liver injury are 
defined as those patients with concurrent occurrence of ALT > 3 x ULN and DBILI > 2 x ULN 
and ALP < 2 x ULN in the same assessment sample during the on-treatment period. 
Other laboratory parameters
Hepatitis markers and additional tests only performed at screening will be listed only.
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
Data handling
For ECG replicates, the average of the ECG parameters at that assessment will be used in the 
analyses.
Data analysis
12-lead ECGs including PR, QRS, QT, QTcF and HR intervals will be obtained for each patient 
during the study. ECG data will be read and interpreted centrally.
The number and percentage of patients with notable ECG values will be presented by treatment 
group. 

QT, QTcF
-
New value of > 450 and ≤ 480 ms
-
New value of > 480 and ≤ 500 ms
-
New value of > 500 ms
-
Increase from Baseline of > 30 ms to ≤ 60ms
-
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
A listing of notable ECG values will be produced by treatment group. In the listing, the 
assessments collected during the post-treatment period will be flagged.
 


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2.8.4.2
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: height (cm), weight (kg), body temperature (°C), pulse 
rate (beats per minute), respiratory rate (breaths per minute), systolic and diastolic blood 
pressure (mmHg). 
Data handling
Vital signs collected on treatment will be summarized. Values measured outside of the 
on-treatment period will be flagged in the listings.
Data analysis
For analysis of vital signs the clinically notable criteria are provided in Table 2-4 below.
Table 2-4             Clinically notable changes in vital signs
Vital sign 
(unit)
Criteria
< 18 years at baseline 
and < 18 years at time 
of assessment
< 18 years at baseline 
and ≥ 18 years at time 
of assessment
≥ 18 years at 
baseline
Systolic 
blood 
pressure 
(mmHg)
High
≥ 95th percentile of the 
age and height group1
≥ 180 with increase from 
updated baseline5 of 
≥20
≥180 with increase 
from baseline of 
≥20
Low
≤ 5th percentile of the 
age and height group1
≤ 90 with decrease from 
updated baseline5 of 
≥20 
≤90 with decrease 
from baseline of 
≥20
Diastolic 
blood 
pressure 
(mmHg)
High
≥ 95th percentile of the 
age and height group1
≥ 105 with increase from 
updated baseline5 of 
≥15
≥105 with increase 
from baseline of 
≥15
Low
≤ 5th percentile of the 
age and height group1
≤ 50 with decrease from 
updated baseline5 of 
≥15
≤50 with decrease 
from baseline of 
≥15
Pulse rate 
(bpm)
High
≥16years: >92
≥120 with increase from 
updated baseline5 of 
≥15
≥100 with increase 
from baseline of 
>25%
Low
≥16 years: <58
≤50 with decrease from 
updated baseline5 of 
≥15
≤50 with decrease 
from baseline of 
>25%
Weight (kg)
High
increase from baseline3
of  ≥2 BMI-for-age 
percentile categories4
increase from updated 
baseline5 of ≥10%
increase >10% 
from baseline
Low
decrease from baseline3
of ≥2 BMI-for-age 
percentile categories4
decrease from updated 
baseline5 of ≥10%
decrease >10% 
from baseline
Respiratory 
rate (breath 
per 
minute)2,6,7
High
≥16years: ≥20
≥20
≥20


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Vital sign 
(unit)
Criteria
< 18 years at baseline 
and < 18 years at time 
of assessment
< 18 years at baseline 
and ≥ 18 years at time 
of assessment
≥ 18 years at 
baseline
Low
≥16 years: <12
<12
<12
Oral body 
temperature 
(°C)
High
≥38.4
≥39.1
≥39.1
Low
≤35.0
≤35.0
≤35.0
bpm=beats per minute; NHLBI= National Heart, Lung, and Blood Institute; 
1 Blood pressure percentiles are calculated for each blood pressure record using the method described in 
Appendix B of the following reference: The Fourth Report on Diagnosis, Evaluation and Treatment of High 
Blood Pressure in Children and Adolescents. Pediatrics 2004; 114; 555.
2 Fleming S, 2011
3 Baseline BMI-for-age weight status categories are underweight (less than the 5th percentile), healthy weight 
(5th percentile to less than the 85th percentile), overweight (85th to less than the 95th percentile) and obese 
(equal to or greater than the 95th percentile);
4 BMI-for-age percentiles categories (P3, P5, P10, P25, P50, P75, P85, P90, P95, P97) are obtained from the 
WHO Growth Charts;
5 Updated baseline is the last value collected before the 18th birthday.
6 Eldridge L, 2015; 
7 Kou .R, 2009.
The number and percentage of patients with notable vital sign values (high/low) will be 
presented by treatment group.         
A listing of notable vital sign values will be produced by treatment group. In the listing, the 
assessments collected outside of on-treatment period will be flagged. 
2.8.4.3
Immunogenicity
Immunogenicity will be measured pre-dose on Week 1 Day 1, during treatment, at visit EOT, 
and at the 105-day follow-up visit (as applicable).
All immunogenicity results will be summarized for the crizanlizumab + standard of care 
treatment group by patient and visit/time.
Immunogenicity will be characterized descriptively tabulating ADA incidence on-treatment.
2.9
Pharmacokinetic endpoints
Crizanlizumab pre-dose/trough PK samples will be taken to accompany immunogenicity 
measurements to evaluate the impact of immunogenicity on exposure (PK) (see amended 
protocol v03 Section 12.5.3).
Crizanlizumab pre-dose serum concentration data will be summarized for the crizanlizumab + 
standard of care treatment arm by patient and visit/sampling time point. Descriptive summary 
statistics will be provided for the crizanlizumab + standard of care treatment arm by 
visit/sampling time point, including the frequency (n, %) of concentrations below the LLOQ 
and reported as zero.


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Descriptive summary statistics will include mean (arithmetic and geometric), SD, coefficient 
of variance (CV; arithmetic and geometric), median, minimum, and maximum.
2.10
PD and PK/PD analyses
Not applicable.
2.11
Resource utilization
Annualized rate of visits to ER and hospitalizations due to AKI events, VOCs, or other SCD 
complications will be used to evaluate the healthcare resource utilization (visits to clinic, ER 
and hospitalizations) in crizanlizumab + standard of care arm and standard of care alone. In 
addition, the number/proportion of patients with VOC events managed at home (not requiring 
healthcare resource utilization) will also be summarized.
The frequency of hospitalization and ER visits over the treatment (overall and AKI events-
related, VOCs, or other SCD complications) will be summarized by treatment group. This
analysis will also include the baseline rate of VOCs leading to healthcare visit in 12 months 
prior to screening visit as per CRF. 

Sickle cell VOC history, including the number of:
o
VOCs at home (not requiring healthcare resource utilization) in the previous 
12 months
o
VOCs requiring healthcare resource utilization in the previous 12 months, including 
the number of:

Hospitalizations in the 12 months

ER visits in the previous 12 months
o
SCD complications other than VOCs requiring healthcare resource utilization in the 
previous 12 months, including the number of:

Hospitalizations in the previous 12 months

ER visits in the previous 12 months
Data will be collected for complicated and uncomplicated VOCs. Complicated VOCs are 
defined as Acute chest syndrome (ACS), hepatic sequestration, splenic sequestration, and 
priapism

Number of missed school days or work days due to VOCs and/or other SCD complications 
in the previous 12 months. Data will be collected for complicated and uncomplicated VOCs

Other complications of SCD, including, but not limited to, stroke, leg ulcers, asthma, 
avascular necrosis, pulmonary hypertension, retinopathy, other (investigator to specify)


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2.15
Interim analysis
No interim analysis is planned. However, safety DMC analyses will be performed at specified 
time points, as defined in the DMC Charter. Additional DMC meetings may be scheduled if 
unexpected safety findings arise.
3
Sample size calculation
The sample size was adjusted to reflect current recruitment status. 


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When the estimation based approach for the 95% CI for the difference between treatment arms 
is used to calculate the precision estimates with sample size of 25 patients per treatment arm 
(total N=50 patients without drop-outs), then the width is 0.429 and the precision (half of the 
width) is around 0.215. See Table 12-3 for the 95% CI calculation of the difference (30% - 10%) 
varying the sample size per arm from 10 to 40.
Table 3-1
Confidence intervals for the difference between two proportions using 
proportions numeric results for two-sided confidence intervals for the 
difference in proportions confidence interval method: Chi – Square –
Simple Asymptotic (Pearson)
Confidence 
Level
N1
N2
Allocation 
Ratio
Actual 
Width
P1
P2
P1-P2
Lower 
Limit
Upper 
Limit
0.95
10
10
1.000
0.679
0.300
0.100
0.200
-0.139
0.539
0.95
15
15
1.000
0.554
0.300
0.100
0.200
-0.077
0.477
0.95
20
20
1.000
0.480
0.300
0.100
0.200
-0.040
0.440
0.95
25
25
1.000
0.429
0.300
0.100
0.200
-0.015
0.415
0.95
30
30
1.000
0.392
0.300
0.100
0.200
0.004
0.396
0.95
35
35
1.000
0.363
0.300
0.100
0.200
0.019
0.381
0.95
40
40
1.000
0.339
0.300
0.100
0.200
0.030
0.370
4
Change to protocol specified analyses
No changes from the protocol-specified analysis were made.
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
The following rule will be used for the imputation of the dose end date for a given study 
treatment component:
Scenario 1: If the dose end date is completely missing and there is no end of treatment (EOT) 
page and no death date, the patient is considered as on-going: 
The patient should be treated as on-going and the cut-off date should be used as the dose end 
date. 
Scenario 2: If the dose end date is completely or partially missing and the EOT page is 
available: 
Case 1: The dose end date is completely missing, and the EOT completion date is complete, 
then this latter date should be used.  
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:  
Use Dec31yyyy
Case 3: Only Year(yyyy) of the dose end date is available and yyyy = the year of EOT date: 
Use EOT date


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Case 4: Both Year(yyyy) and Month (mm) are available for dose end date, and yyyy = the 
year of EOT date and mm < the month of  EOT date: 
Use last day of the Month (mm)
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study.
After imputation, compare the imputed date with start date of treatment, if the imputed date is 
< start date of treatment:
Use the treatment start date
Patients with missing start dates will be considered missing for all study treatment component 
related calculations and no imputation will be made. If start date is missing then end-date will 
not be imputed.
5.1.2
AEs, concomitant medications, and safety assessment date 
imputation
Table 5-1
Imputation of start dates (AEs, concomitant medications) and 
assessments (laboratory, ECG, vital signs)
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  
Table 5-2
Imputation of end dates (AE, concomitant medications) 
Missing 
Element
Rule 
(*=last treatment date plus 30 or 105 days not > (death date, withdrawal of 
consent date))
day, month, 
and year

Completely missing end dates (incl. ongoing events) will be imputed 
by the end date of the on-treatment period* 
day, month

If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period * 
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*
Any AEs and concomitant medications with partial/missing dates will be displayed as such in 
the data listings.
Any AEs and ConMeds 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.
5.2
AEs coding/grading
AEs are coded using the MedDRA terminology.
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 
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). 


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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 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 (Guideline for implementation of CTCAE version 6). For laboratory tests 
where grades are not defined by CTCAE v5.0, results will be graded by the low/normal/high
(or other project-specific ranges, if more suitable) 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  
CTCAE grading for blood differentials is based on absolute values. However,  this data may 
not be reported as absolute counts but rather as percentage of white blood cells (WBC). 
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X. 
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential
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 CTCAE grades 0 and 1, the normal range for derived 
corrected calcium is set to the same limits (in mg/dL) as for calcium.
CTCAE grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) 
and corrected calcium will be assigned as described above for grading
5.4
Statistical models
5.4.1
Primary analysis
Logistic regression
The primary endpoint will be analyzed based on the data from the FAS. A logistic regression 
model that includes effects for treatment and randomization stratification factors will be utilized. 


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The test of the treatment effect (based on the log-odds ratio estimated by the model) will be 
carried out at the 1-sided significance level of 0.025. The null hypothesis is that the odds ratio 
of the treatment effect is equal to 1 (i.e., there is no difference in the proportion of patients with 
≥30% decrease in ACR at 12 months between crizanlizumab + standard of care and standard 
of care alone). The alternative hypothesis is that the odds ratio is greater than 1 (i.e., the 
proportion of patients with ≥30% decrease in ACR at 12 months is higher in the crizanlizumab
+ standard of care group than in the standard of care alone group).
Odds ratios will be computed for comparisons of Crizanlizumab + SOC versus SOC utilizing 
the logistic regression model fitted. 
The odds ratio will be calculated such that an odds ratio >1 is favorable for Crizanlizumab + 
SOC arm. Using PROC GENMOD to calculate the confidence interval for the odds ratios
assumes asymptotic normality of the Wald estimate for the regression coefficient. The 95% 
confidence interval for the regression parameter of the active treatment effect relative to control 
will be calculated using an exponential transformation to create the confidence interval for the 
odds ratio. 
The SAS procedure GENMOD will be used with the following code:
proc genmod data=.... DESCENDING;
  class trt stratum1 stratum2;
  model aval = trt stratum1 stratum2/ 
                  dist=bin link=logit;
  lsmeans trt /diff;
  estimate “Crizanlizumab +SOC vs SOC” trt 1 -1;  ods output 
Estimates=imp_est;
run;
where binary event AVAL = The patient with at least a 30% decrease ACR (=1 or “Yes”)
trt
     = planned treatment
stratum1      = CKD risk category (moderate risk or high/very high risk)
stratum2      = HU/HC prescription (Yes/No)
In cases where logistic regression doesn’t converge, the following steps will be performed:
1. Run the PROC GENMOD procedure with EXACT statement;
2. If convergence not reached, perform Fisher’s exact test. In this case, no odds ratios or 
confidence intervals will be estimated, but p-values may be calculated.
Proc freq data=....;
Table TRT * AVAL / fisher;
Where TRT in (“crizanlizumab + SOC”, “SOC”);
Run;
Wald CI for absolute difference in response rates
The 100 × (1 – α) % Wald CI of the absolute difference between the proportion of 


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responders (binary outcome = 1 or “Yes”), for a given treatment arm X compared to that for 
treatment group Y, without applying a continuity correction, is obtained from the following:
proc freq data =
dataset;
where treatment group = Crizanlizumab+SOC or SOC;
table treatment group * binary event / riskdiff alpha = alpha
level;
Multiple imputations
Multiple imputation (MI) is a simulation based approach where missing values are replaced by 
multiple Bayesian draws from the conditional distribution of missing data given the observed 
data and covariates, creating multiple completed data sets. These completed data sets can then 
be analyzed using standard methods.  Rubin (1987) presented rules how to combine the multiple 
sets of estimates to produce overall estimates and confidence intervals that adequately 
incorporate missing data uncertainty. In the multiple imputation analysis, the response status 
will be imputed separately for each treatment group including CKD risk category and HU/HC 
use. 
The number of imputations will be set to 100 (NIMPUTE), the seed for the random function 
will be set to 101<studycode> for this study. To generate the multiple imputed data sets, the 
SAS procedure MI can be used as follows:
PROC MI DATA=<ACR> OUT=<impdata> SEED=1012203<studycode> NIMPUTE=100;
CLASS <AVAL> <stratum1> <stratum2> <trt>;
BY <treatment group>;
fcs logistic (<AVAL>=<trt> <stratum1> <stratum2>/details);
VAR <AVAL>;
RUN;
The ACR response rate will be calculated for each imputation and then combined using 
Rubin’s rules. In order to calculate the response rate for each imputation, PROC FREQ will 
be used as follows.
Calculate binomial proportion and standard error for each imputation.
proc freq data=<ACR>;
by treat visit _imputation_ ;
tables <response> / binomial (level=2 cl=wilson correct) ;
ods output BinomialProp=imp_bpr;
run;
Transpose the dataset for subsequent use with PROC MIANALYZE.
proc transpose data=imp_bpr out=imp_trs(drop=_name_) ;
by treat visit _imputation_ ;
var nvalue1; id name1; idlabel label1;
run;


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Apply LOGIT transformation: y=log(p/(1-p)) and std. err. transformation: <new se> = 
se/(p*(1-p))
data logit;
set imp_trs(rename=(_bin_=p e_bin=se));
by treat visit _imputation_ ;
lmean=log(p/(1-p));
lse=se/(p*(1-p));
run;
The transformed binomial proportion estimates and standard errors are combined by applying
Rubin’s rules for multiple imputed data sets.
proc mianalyze data=logit;
by treat;
modeleffects lmean;
stderr lse;
ods output ParameterEstimates=logitres;
run;
The combined data should be transformed back using the following formula: p=1/(1+exp(-y))
data miexpres;
set logitres;
by treat visit ;
resti = 1/(1+exp(-estimate));
rlow = 1/(1+exp(-lclmean));
rupp = 1/(1+exp(-uclmean));
run;
Of note, sometimes all responses may be imputed to 0 or 1 at a given combination of response
variable, treatment group and visit. Such cases should be considered separately. The 
combined final response rate would be the same as the original response but the 95% CI will 
be undefined.
The odds ratio will be derived using GENMOD for each imputation, then combined using
Rubin’s rules again.
proc genmod data = acr_mi descending;
by avisitn _imputation_;
class trt stratum1 stratum2;
model aval = trt stratum1 stratum2/ link=logit dist=bin;
lsmeans trt_ / diff;
estimate ' Crizanlizumab +SOC vs SOC' trt_ 1 -1;
ods output Estimates=imp_est;
run;
proc mianalyze data=imp_est;
by avisitn trt_ ;
modeleffects LBetaEstimate;
stderr StdErr;
ods output ParameterEstimates=_res;
run;
Details of Implementation
Steps in implementing MI and monotherapy response for binary variables 
1. Set ACR data collected after patient discontinued study treatment due to other reasons 
(except death, drug-related AEs, and progressive disease) to missing.
2. Set ACR data collected after patient initiatiated or discontinuationed of HU/HC, HA 
approved form(s) of L glutamine, ACE and/or ARB to missing.
3. Set ACR data collected after patient intook of NSAIDs within 48 hours prior to ACR 
measurement to missing.
4. Set ACR data collected after patient intook of Voxelotor to missing.


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5. Set ACR data collected after patient had blood transfusion or VOC occurred (if within 7 
days before the ACR measure) to missing.
6. Apply multiple imputation to create multiple sets of complete dataset.
7. Set as non-responder if the patient discontinued study treatment due to death of any cause, 
drug-related AEs, progressive disease.
8. Proceed with the analysis.
5.4.2
Key secondary analysis
Not applicable.
6
Reference
Eldridge, L. (2015). What is a normal respiratory rate? About Health. Web. 
http://lungcancer.about.com/od/Respiratory-System-Function/a/NormalRespiratory-Rate.htm.
Fleming S, Thompson M, Stevens R, et al (2011). 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.
377(9770):1011-8.
DOI:10.1016/S0140-
6736(10)62226-X.
Guideline for implementation of CTCAE version 5.0.
KDIGO (2013). KDIGO 2012 clinical practice guideline for the evaluation and management of 
chronic kidney disease. Kidney International supplements; 3(1):1-150.
Kou Y.R., Lin Y.S. (2009) Bradypnea. In: Lang F. (eds) Encyclopedia of Molecular 
Mechanisms of Disease. Springer, Berlin, Heidelberg.
National High Blood Pressure Education Program Working Group on High Blood Pressure in 
Children and Adolescents (2004). The fourth report on diagnosis, evaluation and treatment of 
high blood pressure in children and adolescents. Pediatrics; 114; 555-76.
Rubin, D.B. (1987). Multiple Imputation for Nonresponse in Surveys. New York: Wiley.
WHO Growth Charts. http://www.who.int/childgrowth/en/.