Conditions: Priapism
Keywords: Priapism sickle cell disease SCD crizanlizumab P-selectin SEG101 monoclonal antibody prolonged erection painful erection
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 36
Healthy volunteers: no

Brief summary:
The goal of the study was to evaluate the efficacy and safety of crizanlizumab in sickle cell disease (SCD) patients with priapism.

Detailed description:
Before participating in this study, information to determine key eligibility criteria was collected as a part of a 14-week Pre-Screening period. The study included a 12-week Screening period and a 52-week (1 year) Treatment period. Eligible participants received crizanlizumab 5 mg/kg by intravenous infusion (IV). Study treatment was received at clinic visits on Week 1 Day 1, Week 3 Day 1, and then on Day 1 of every 4-week cycle. Efficacy assessments included evaluation of priapic and vaso-occlusive (VOC) events. Safety assessments included laboratory tests, electrocardiograms (ECGs), vital signs and physical examinations. Participants had a safety follow-up for up to 15 weeks after the last dose.

Arms:
arm 1: Participants received 5 mg/kg by IV infusion on Week 1 Day 1, Week 3 Day 1, and on Day 1 of every 4-week cycle until Week 51.

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

Protocol document:
Prot_000.pdf: 
Novartis Research and Development
[SEG101/Crizanlizumab]
Clinical Trial Protocol CSEG101AUS05 / NCT03938454
A Prospective Phase II, Open-Label, Single-arm, 
Multicenter, Study to Assess Efficacy and Safety of 
SEG101 (crizanlizumab), in Sickle Cell Disease Patients 
with Priapism (SPARTAN)
Document type:
Amended Protocol Version
Version number:
03 Clean (Amended Protocol)
Clinical Trial Phase:
II
Release date:
16-Dec-2022
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 2.0 (01-Aug-2018)


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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.................................................................................................................9
Protocol summary..............................................................................................................27
1
Introduction .......................................................................................................................31
1.1
Background............................................................................................................31
1.1.1
Overview of Sickle Cell Disease pathogenesis, epidemiology and 
current treatment ...................................................................................31
1.1.2
Overview of SCD-related priapism, epidemiology and current 
treatment................................................................................................32
1.1.3
Role of P-Selectin in VOC....................................................................33
1.1.4
Role of P-Selectin in SCD-related priapism .........................................33
1.2
Introduction to investigational treatment(s) and other study treatment(s).............34
1.2.1
Overview of crizanlizumab (SEG101)..................................................34
1.2.2
Clinical experience................................................................................35
1.3
Purpose ..................................................................................................................36
2
Objectives and endpoints...................................................................................................37
2.1
Primary estimands .................................................................................................37
3
Study design ......................................................................................................................38
4
Rationale............................................................................................................................40
4.1
Rationale for study design .....................................................................................40
4.2
Rationale for dose/regimen and duration of treatment ..........................................40
4.3
Rationale for choice of control drugs ....................................................................41
4.4
Purpose and timing of interim analyses.................................................................41
4.5
Risks and benefits..................................................................................................41
5
Population..........................................................................................................................44
5.1
Inclusion criteria ....................................................................................................44
5.2
Exclusion criteria...................................................................................................45
6
Treatment...........................................................................................................................46
6.1
Study treatment......................................................................................................46
6.1.1
Investigational and control drugs..........................................................46
6.1.2
Additional study treatments ..................................................................47
6.1.3
Treatment arm/group.............................................................................47
6.1.4
Treatment duration................................................................................47


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6.2
Other treatments.....................................................................................................47
6.2.1
Concomitant therapy.............................................................................47
6.2.2
Prohibited medication ...........................................................................49
6.2.3
Rescue medication ................................................................................49
6.3
Subject numbering, treatment assignment, randomization....................................50
6.3.1
Subject numbering ................................................................................50
6.3.2
Treatment assignment, randomization ..................................................50
6.4
Treatment blinding.................................................................................................50
6.5
Dose modification..................................................................................................50
6.5.1
Follow-up for toxicities.........................................................................56
6.6
Additional treatment guidance...............................................................................57
6.6.1
Treatment compliance...........................................................................57
6.6.2
Recommended treatment of adverse events..........................................57
6.7
Handling of study treatment and additional treatment ..........................................57
6.7.1
Handling of study treatment..................................................................57
6.7.2
Instruction for prescribing and taking study treatment .........................58
7
Informed consent procedures ............................................................................................58
8
Visit schedule and assessments .........................................................................................59
8.1
Screening ...............................................................................................................64
8.1.1
Eligibility screening ..............................................................................64
8.1.2
Information to be collected on screening failures.................................64
8.1.3
Subject demographics/other baseline characteristics............................65
8.2
Efficacy..................................................................................................................65
8.2.1
Primary efficacy endpoint.....................................................................65
8.2.2
Secondary efficacy endpoints ...............................................................66
68
8.2.4
Collection of priapic event information................................................68
8.2.5
Appropriateness of efficacy assessments..............................................69
8.3
Safety assessments.................................................................................................69
8.3.1
Physical assessments.............................................................................69
8.3.2
Laboratory evaluations..........................................................................70
8.3.3
Urinalysis ..............................................................................................72
8.3.4
Coagulation ...........................................................................................73
8.3.5
Cardiac assessments..............................................................................73
8.3.6
Hepatitis markers ..................................................................................73
8.3.7
Urine protein/creatinine ratio................................................................74
8.3.8
Additional test.......................................................................................74


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8.3.9
Appropriateness of safety measurements..............................................74
8.4
Additional assessments..........................................................................................74
74
75
8.5
Optional use of biological samples........................................................................75
9
Study discontinuation and completion ..............................................................................76
9.1
Discontinuation......................................................................................................76
9.1.1
Discontinuation of study treatment .......................................................76
9.1.2
Withdrawal of informed consent...........................................................77
9.1.3
Lost to follow-up...................................................................................77
9.1.4
Early study termination by the sponsor.................................................77
9.2
Study completion and post-study treatment ..........................................................78
10 Safety monitoring and reporting........................................................................................78
10.1
Definition of adverse events and reporting requirements......................................78
10.1.1
Adverse events ......................................................................................78
10.1.2
Protocol exempt AEs & SAEs ..............................................................80
10.1.3
Serious adverse events ..........................................................................80
10.1.4
SAE reporting........................................................................................81
10.1.5
Pregnancy reporting ..............................................................................82
10.1.6
Reporting of study treatment errors including misuse/abuse................82
10.2
Additional safety monitoring.................................................................................83
10.2.1
Steering committee................................................................................83
11 Data Collection and Database Management......................................................................83
11.1
Data collection.......................................................................................................83
11.2
Database management and quality control............................................................84
11.3
Site monitoring ......................................................................................................84
12 Data analysis and statistical methods ................................................................................85
12.1
Analysis sets ..........................................................................................................85
12.2
Subject demographics and other baseline characteristics......................................85
12.3
Treatments .............................................................................................................85
12.4
Analysis of the primary endpoint ..........................................................................86
12.4.1
Definition of primary endpoint .............................................................86
12.4.2
Statistical model, hypothesis, and method of analysis..........................86
12.4.3
Handling of missing values/censoring/discontinuations.......................87
12.4.4
Sensitivity and supportive analyses ......................................................88
12.5
Analysis of secondary endpoints ...........................................................................89
12.5.1
Efficacy endpoints.................................................................................89


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12.5.2
Methods of analyses..............................................................................89
12.6
Safety endpoints.....................................................................................................90
12.6.1
Clinical laboratory evaluations .............................................................90
12.6.2
Other safety evaluations........................................................................91
91
91
91
92
92
92
12.8
Interim analyses.....................................................................................................92
12.9
Sample size calculation..........................................................................................92
13 Ethical considerations and administrative procedures ......................................................93
13.1
Regulatory and ethical compliance........................................................................93
13.2
Responsibilities of the investigator and IRB .........................................................93
13.3
Publication of study protocol and results...............................................................93
13.4
Quality control and quality assurance....................................................................93
14 Protocol adherence ............................................................................................................94
14.1
Protocol amendments.............................................................................................94
15 References .........................................................................................................................95
16 Appendices ........................................................................................................................99
List of tables
Table 2-1
Objectives and related endpoints ..........................................................37
Table 6-1
Dose and treatment schedule.................................................................47
Table 6-2
Criteria for dose interruption and re-initiation of crizanlizumab 
treatment for adverse drug reactions.....................................................52
Table 8-1
Assessment Schedule ............................................................................60
Table 8-2
Vaso-Occlusive Crisis Assessment Collection Plan .............................68
Table 8-3
Physical assessments.............................................................................70
Table 8-4
Laboratory Assessments........................................................................72
Table 10-1
List of Events Not Requiring AE/SAE Reporting ................................80
Table 10-2
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................83
Table 16-1
List of non-antipsychotic and non-antidepressant drugs that may 
Induce Priapism...................................................................................112


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Table 16-2
List of Antidepressants and Antipsychotics that may induce 
priapism...............................................................................................113
List of figures
Figure 1-1
P-selectin expression in penis of wild-type (WT) and sickle cell 
transgenic (βS) mice..............................................................................34
Figure 3-1
Study Design .........................................................................................40


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List of abbreviations
ADA
ADR
AE
Anti-Drug Antibody
Adverse Drug Reaction
Adverse Event
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
APTT
Activated partial thromboplastin time
AST
Aspartate Aminotransferase
CI
Confidence interval 
CK
Creatinine Kinase
CMO&PS
Chief Medical Office and Patient Safety
CMV
Cytomegalovirus
CRA
CRF
Clinical Research Associate
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CTCAE
Common Terminology Criteria for Adverse events
CV
coefficient of variation
DDE
Direct Data Entry
DILI
Drug Induced Liver Injury
EBV
Epstein-Barr Virus
ECG
Electrocardiogram
ECHO
Echocardiogram
EDC
Electronic Data Capture
EDTA
Ethylenediaminetetraacetic acid
ELISA
Enzyme-linked immunosorbent assay
EOI
End of Infusion
EOT
End of treatment
eSource
Electronic Source
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
HbsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HSV
Herpes simplex virus
HU/HC
Hydroxyurea/hydroxycarbamide
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
INR
International Normalized Ratio
IRB
Institutional Review Board
IRR
Infusion-related Reaction
IRT
IV
Interactive Response Technology
Intravenous
LFT
Liver function test 
LPT
Low Platelet Count
LLN
Lower Limit of Normal
LVEF
Left ventricular ejection fraction


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MedDRA
Medical dictionary for regulatory activities 
mg
milligram(s)
ml
milliliter(s)
NOAEL
No observed adverse effect level
PAP
Pulmonary Arterial Pressure
PD
Pharmacodynamic(s)
PLT
Platelet
PK
Pharmacokinetic(s)
PSGL-1
P-selectin glycoprotein ligand 1
PT
Prothrombin time
QTcF
QT interval corrected by Fridericia’s formula
RAP/SAP
The Report and Analysis Plan (RAP) is a regulatory document which 
documents preplanned statistical analyses
RBC
Red blood cell(s)
RVSP
Right ventricular systolic pressure
SAE
Serious Adverse Event
SCD
Sickle cell disease
SD
Standard deviation
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBIL
Total bilirubin
TEAEs
Treatment emergent adverse events
TRV
Tricuspid Regurgitant Jet Velocity
ULN
USAN
Upper limit of normal
United States Adopted Name
VOC
Vaso-occlusive crisis 
WBC
White blood cell(s)
WHO
World Health Organization 


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Glossary of terms
Additional treatment
Medicinal products that may be used during the clinical trial as described 
in the protocol, but not as an investigational medicinal product (e.g. any 
background therapy)
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. taken from a study subject 
Dosage
Dose of the study treatment given to the subject in a time unit (e.g.
100 mg once a day, 75 mg twice a day)
Electronic Data Capture 
(EDC)
Electronic data capture (EDC) is the electronic acquisition of clinical 
study data using data collection systems, such as Web-based 
applications, interactive voice response systems and clinical laboratory 
interfaces. EDC includes the use of Electronic Case Report Forms 
(eCRFs) which are used to capture data transcribed from paper source 
forms used at the point of care.
End of the clinical trial
The end of the clinical trial is defined as the last visit of the last subject or 
at a later point in time as defined by the protocol. 
Enrollment
Point/time of subject entry into the study at which informed consent must 
be obtained 
eSource (DDE)
eSource Direct Data Entry (DDE) refers to the capture of clinical study 
data electronically, at the point of care. eSource Platform/Applications 
reduce the use of paper capture source data during clinical visits. 
eSource combines source documents and case report forms (eCRFs) 
into one application, allowing for the real time collection of clinical trial 
information to sponsors and other oversight authorities, as appropriate.
Estimand
As defined in the ICH E9(R1) addendum, estimand is a precise description 
of the treatment effect reflecting the clinical question posed by the trial 
objective. It summarizes at a population-level what the outcomes would be 
in the same participants under different treatment conditions being 
compared. Attributes of an estimand include the population, variable (or 
endpoint) and treatment of interest, as well as the specification of how the 
remaining intercurrent events are addressed and a population-level 
summary for the variable
Intercurrent events
Events occurring after treatment initiation that affect either the 
interpretation or the existence of the measurements associated with the 
clinical question of interest
Investigational 
drug/treatment
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 
(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
Perpetrator drug
A drug which affects the pharmacokinetics of the other drug
Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and/or assessments; at this 
time all study drug administration is discontinued and no further 
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Run-in Failure
A subject who is screened but not randomized/treated after the run-in 
period (where run-in period requires adjustment to subject’s intervention 
or treatment)
Screen Failure
A subject who did not meet one or more criteria that were required for 
participation in the study
Source Data/Document
Source data refers to the initial record, document, or primary location 
from where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource.
Start of the clinical trial
The start of the clinical trial is defined as the signature of the informed 
consent by the first subject.
Study treatment
Any single drug or combination of drugs or intervention administered to 
the subject as part of the required study procedures.
Study treatment 
discontinuation
When the subject permanently stops taking any of the study drug(s) prior 
to the defined study treatment completion date (if any) for any reason; 
may or may not also be the point/time of study discontinuation 
Subject
A trial participant 
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject 
and should be used to identify the subject throughout the study for all 
data collected, sample labels, etc.
Treatment arm/group
A treatment arm/group defines the dose and regimen or the combination 
and may consist of 1 or more cohorts.
Variable
A measured value or assessed response that is determined from specific 
assessments and used in data analysis to evaluate the drug being tested 
in the study
Withdrawal of study 
consent 
Withdrawal of consent from the study occurs only when a subject does 
not want to participate in the study any longer, and does not want any 
further visits or assessments, and does not want any further study related 
contact
Amendment 3 (16-Dec-2022)
At the time of this amendment, the required number of 36 patients for the study has been reached. 
The study is closed to further enrollment.
The primary purpose of this amendment is to clarify some statistical elements used to evaluate 
the study. In particular, the following points were addressed in the current protocol:
1. Section 2.1 was added to describe the primary estimand by the following attributes:
a.
Population: Sickle Cell Disease patients with priapism.
b. Endpoint: Percent reduction from baseline period in priapic events (priapism 
defined as unwanted, or painful erection lasting at least 60 min self-reported) by 
26 weeks.
c.
Treatment of interest: investigational drug will be a crizanlizumab solution 
provided every 4 weeks with an additional loading dose 2 weeks after the first 
dosing.


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d. List of intercurrent events:
i. Treatment discontinuation 
ii.
Initiation or discontinuation of HU/HC or l-glutamine (or other therapies 
to treat SCD and or to prevent/reduce VOCs such as voxelotor and 
erythropoietin) or of prophylactic treatment
iii. Intake of analgesic (including opioids) or ad hoc transfusions 
administered temporarily.
e.
The summary measure: Median percentage change from baseline period in 
priapic events (priapism defined as unwanted, or painful erection lasting at least 
60 min self-reported) by 26 weeks.
2. It was clarified that a formal interim analysis for this study is not planned, shall not be 
performed and that for publication purposes, only descriptive data will be reported, as 
needed. 
3. It was clarified that the FAS include all enrolled subjects to whom the study treatment 
has been assigned regardless of whether or not they have received at least 1 dose of 
study treatment or have at least 1 post-baseline assessment. 
4. Lower quartile (Q1) and upper quartile (Q3) were included in the summary statistics 
5. The handling of missing values was described. It will be imputed using Poisson 
distribution, assuming the same effect as observed data. Imputed datasets will be created, 
and each dataset will be analyzed using the method described for primary endpoint. The 
results will be combined using Rubin’s rule (Barnard J and Rubin DB 1999) 
6. Sensitivity analyses were modified to include the following:
a.
To explore the robustness of analysis,  sensitivity analysis as a 'tipping point 
approach will be performed for the primary endpoint to evaluate the impact of a 
deviation from the missing at random (MAR).
b. As part of the sensitivity analysis, treatment policy strategy (that is, data after 
the intercurrent events will be included) will also be applied for the intercurrent 
events 4a and 4b, described in Section 12.4.2.
c.
As part of the sensitivity analysis, the primary analysis will be analyzed on all 
subjects in FAS without missing data.
7. It was clarified that the assumption that the relative risk reduction of 25% (approved for 
VOC events) observed with L-glutamine (Endari™) would be similar for priapism was 
used for the purpose of study sample size calculation.
Other minor corrections are also applied throughout the protocol.
Changes to the Protocol

Throughout: typographical and grammatical errors addressed.


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
List of abbreviations: AUC, AUCinf, AUCt, Cmax, t1/2 are not required and were
removed. IV was added.

Glossary of terms: The definitions of estimand and Intercurrent events were added.
“Randomization number” is not required as this is a single-arm study and was removed.

Section 2.1:
o
Section added to define what an estimand is. Language was added to describe 
the attributes of the primary estimand for this study: population, endpoint, 
treatment of interest, list of intercurrent events and the summary measure. 
Correspondingly similar changes were made in Section 12.4.2.

Section 4.4:
o
Language was added to clarify that for publication purposes, descriptive data 
will be reported and that any decision on study continuation will not be based on 
the reports. Correspondingly similar changes were made in Section 12.8.
o
Changed the word patient to subject when the term refers to a participant of this
study. Correspondingly similar changes were made throughout the protocol as 
appropriate.

Section 6.3.2:
o
Language was added to clarify that the trial is a single arm study.

Section 9.2:
o
Language was added to specify that the recommendation applies to  “subjects 
who will receive commercially approved crizanlizumab”.

Section 12:
o
Included lower quartile (Q1) and upper quartile (Q3) in the summary statistics. 
Correspondingly similar changes were made in Sections 12.2, 12.3, 12.4.2 and 
12.5.2.
o
Definition of the baseline period was clarified by removing the minus sign 
before 12 weeks and correcting “from” with “prior to”.

Section 12.1:
o
The  definition of the FAS was corrected to: The FAS include all enrolled 
subjects to whom the study treatment has been assigned regardless of whether 
or not they have received at least 1 dose of study treatment or have at least 1 
post-baseline assessment.

Section 12.3:
o
Duration  of exposure will be assessed in weeks rather than days to align with 
other Novartis SEG101 studies.

Section 12.4.1:


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o
The sentence “The primary time point is week 26” was deleted as it was 
redundant given the previous sentence.

Section 12.4.2:
o
The <7 category was included as a new number of priapic events category in a 
subgroup analysis of the primary endpoint.
o
The approach of accounting for the intercurrent events 4a, 4b and 4c was defined.

Section 12.4.3:
o
This section was modified to specify that missing values will be imputed using 
Poisson distribution and imputed datasets will be created with each dataset 
analyzed using the method described for primary endpoint. The results will be 
combined using Rubin’s rule.

Section 12.4.4:
o
This section was re-written to outline a new sensitivity analysis as a 'tipping 
point approach will be performed for the primary endpoint to evaluate the impact 
of a deviation from the MAR assumption.
o
The titles of the two subsections were removed. The paragraph related to the 
Annualized Priapic Event Rate was kept under “Supportive Analyses” and the 
paragraphs on the COVID-19 sensitivity analyses were moved in the upper part 
of Section 12.4.4.

Sections 12.5.1 and 12.5.2:
o
The words “(i.e. evaluation at Week 27, Day 1)” and  “(i.e. evaluation at Week 
53, Day 1)” were deleted after “by week 26” and “by week 52” respectively.

Section 12.6.1:
o
The words “or not” were removed.

Section 12.8:
o
Sentence was added to specify that no decision on study continuation will be 
based on these descriptive reports, and as such, no alpha adjustment will be 
needed.
o
The paragraph on the primary analysis was removed for clarity. Similar 
information was already  detailed in Section 12.4.

Section 12.9:


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o
The paragraph related to the basis of the calculations was moved earlier on in 
the section.
o
Two sentences , referring the risk reduction of Endari™ were added

Section 15:
o
References from Barnard and co; Edmond and co, Ratich and co as well as the 
ICH E9(R1) guideline were added.
Amendment 2 (16-Dec-2021)
At the time of this amendment, 25 patients have been enrolled in the study.
The primary purpose of this amendment is described below:
1. Modify selected Exclusion Criteria including:

Exclusion Criteria #8: Use of therapeutic anticoagulants or antiplatelet therapy (other 
than aspirin or NSAIDs) within 10 days prior to Week 1 Day 1. Prophylactic 
anticoagulant dose is now permitted, as per local guidelines.

Exclusion Criteria #10: Patients who have received crizanlizumab and/or other selectin 
inhibitor or plan to receive it during the duration of the study will be excluded.

Exclusion Criteria #22: It was changed timing of “malignancies that were treated 
curatively and have not recurred within... ” from 2 years to 3 years, to align with program 
guidelines.
2. The study design was changed to lower the age of inclusion to 12 years old. A large 
review of published literature cases reported that approximately half of all reported 
events of priapism in patients with sickle cell disease had their first episode before 18 
years of age (Rogers et al 2005; Hamre et al 1991).  An interview survey of male patients 
with sickle cell disease reported that there was a prevalence of priapism of 27.5% by 15 
years of age and reported literature calculated actuarial probability of 50.5% of 
experiencing priapism by the age of 15 years. (Mantadakis et al 1999; Rogers et al 2005).  
The safety and the PK analysis of crizanlizumab was evaluated as part of the 
CSEG101B2201 trial in 50 participants aged 12 to <18 years of age.  The dose of 5 
mg/kg was confirmed in this group based on the results of the first dose PK analysis and 
the CSEG101B2201 data monitoring committee did not raise any particular safety 
concerns with this dose in this age group.  
3. Due to challenges identifying and recruiting adequate population at sites, the statistical 
power of the study will be changed from 90% to 80% in Section 12.9, which reduces 
the number of evaluable patients from 44 to 34. The anticipated drop-out rate for the 
study is also revised from 20% to 5% based on the current status of the trial, which 
reduces the targeted number of enrolled patients from 56 to 36 (Section 12.9).
4. The baseline for the primary analysis will be changed from a combination of the 14-
weeks pre-screening period plus the 12-weeks screening period to only the 12 weeks 
of the screening period. The change is prompted by the observed difficulties for 
patients and site to accurately recall and collect all the required information on the 


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priapic events during the pre-screening period resulting in inconsistent data quality 
between patients and sites. The number of pre-screening priapic events to qualify for 
the study (4) will remain the same. The change will also ensure consistency between 
the priapic event reporting methods for the baseline period and the treatment period
(Section 12).
5. Specify that the subjects who will receive commercially approved crizanlizumab 
approximately 4 weeks after their last dose of study treatment, do not need to complete 
the 105-day follow-up.
6. The recommendations for handling of study treatment in case of active or suspected 
COVID-19 infection were added in Section 6.5.
7. In the laboratory assessments, the word “albumin” was deleted from Table 8.4 to clarify 
the panel.
Other minor corrections are also applied throughout the protocol.
Changes to the Protocol

Throughout: typographical and grammatical errors addressed.

Protocol Summary: updated in alignment to the protocol sections updated.

Section 1.1.1:
o
Updated list of treatments to include voxelotor.

Section 1.2.1:
o
Updated approval information language and deleted “non-clinical experience” 
to reflect the fact that the information can be found in the IB.

Section 1.2.2:
o
Deleted the “clinical experience” related to CSEG101A2101, CSEG101A2102 
and CSEG101A2202 and CSEGB2201 to reflect the fact that the most updated 
information can be found in the IB.

Section 1.3:
o
Updated baseline duration from 26 weeks to 12 weeks. Correspondingly, similar 
language was added in Section 3 and Section 12.

Section 3:
o
The total number of patients to be eligible for the study was updated from 56 to 
36 patients. Correspondingly this number was also changed in Figure 3-1 Study 
Design, Section 5, and 12.9 Sample size calculation.
o
Study duration language changed from ‘will be 79 weeks’ to ‘will be up to 79 
weeks’ - in parentheses, ‘15 weeks of follow-up period’ was changed to ‘15 
weeks of follow-up period if applicable’: Correspondingly, the study duration 
was changed in Follow-up phase and Figure 3-1 Study Design.


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o
Removed the phrase ‘Mandatory safety follow-up period’ and replaced with 
‘followed for safety for up to...’.
o
Added a paragraph to clarify the follow-up period for subjects who receive 
commercially approved crizanlizumab after study treatment. Correspondingly, a 
footnote was added in Table 8.1 to clarify “as applicable”.
o
Pre-screening: The date, number, and duration of the priapic events in a 14-week 
period required prior to consenting was added to clarify the purpose of the form. 
Correspondingly, a footnote was added in the visit evaluation schedule (Table 
8.1).

Section 4.2:
o
Added reference to study CSEG101B2201 to support dosage of 5 mg/kg.

Section 4.5:
o
Updated section on infusion-related reactions (IRRs) according to IBv11: 
percentages of certain events changed, events ‘hypertension’ and ‘dizziness’ 
were added.
o
Infections percentages updated based on IBv11.
o
Effect on hemostasis updated: ‘decreased hemoglobin, and epistaxis’ added; 
reference to eligibility criteria and permitted/prohibited concomitant 
medications removed.
o
Laboratory test interference with automated platelet counts: deleted language on 
mitigation of the laboratory test interference.
o
Changed the world participant to subject for language harmonization. 
Correspondingly similar changes were made in Section 6.2.1.3, Table 6.2, 
Section 12.4.4 and Section 14.
o
Statement added on how Novartis finds risk-benefit ratio favorable.
o
Small paragraph on risk for patients due to COVID-19 vaccine added.

Section 5.1:
o
Inclusion criteria #2: Age of inclusion language changed from 16 to 12 years old. 
Correspondingly, the minimum age was changed to 12 in Section 3, Figure 3.1
and Section 5.

Section 5.2:
o
Exclusion Criteria # 3 – added ‘(Lupron) or any other gonadotropin-releasing 
hormone receptor (GnRHR) agonist agents’.
o
Exclusion Criteria # 8 original – deleted use of therapeutic anticoagulants.
o
New Exclusion Criteria # 8is ‘received crizanlizumab’ to reflect already existing 
language in Section 6.2.2.


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o
Exclusion Criteria #10 – deleted original criteria and changed to ‘received other 
selectin inhibitor or plans to receive it during the duration of study. To reflect 
the fact that another experimental selectin inhibitor is being developed.
o
Exclusion Criteria #22 – revision in timeline for exception to malignant disease: 
‘malignancies that were treated curatively and have not recurred within 2 years’ 
changed to ‘malignancies that were treated curatively and have not recurred
within 3 years to align with other SEG101 clinical trial protocols.

Section 6.2.1.1:
o
Change in timeline for notifying investigational site about any new medications 
taken with 30 days prior to initial dosing from ‘until the completion of (EOS)’ 
to ‘until the safety follow-up or EOT-visit as applicable’ throughout the section. 
Correspondingly, similar changes were also made in Section 6.5.1, Section 9.1.1, 
Section 9.2, Section 10.1.1, Section 10.1.4 and Section 12.6.
o
Language on 105-day follow-up timeline removed.
o
Sentence starting with ‘Aspirin, NSAIDs and prophylactic doses...’ changed: 
‘should be used with caution (refer to Section 6.2.1.3)’ added at the end to reflect 
the fact that anticoagulants at doses targeting therapeutic levels are no longer 
prohibited. Correspondingly, a new sentence was added in Section 6.2.1.3.

Section 6.2.1.3:
o
Clarification that the decision to administer or withhold a vaccine should be done 
on case-by-case basis.

Section 6.2.2:
o
Corrected that patients who have received a monoclonal antibody or an 
immunomodulatory agent within 1 year of screening or have documented 
immunogenicity to a prior biologic are not allowed to participate as per 
Exclusion criteria #9.

Section 6.5:
o
The discontinuation rules for patients missing 2 consecutive doses were 
clarified: initially said patient should be discontinued; changed to ‘if a subject 
misses two consecutive doses of crizanlizumab due to ADR (i.e., an AE 
attributable to study drug), the subject should be discontinued from 
crizanlizumab. In addition, the criteria for subjects experiencing IRR already 
present in Table 6-2 was inserted in the text: A subject with Grade 3 or 4 IRR 
will be permanently discontinued from crizanlizumab.’
o
Added crizanlizumab program language on course of treatment for patients with 
confirmed active COVID-19 or presenting symptoms of COVID-19.

Table 6-2:
o
Infusion-related reactions: clarified first recommendation in grade 2 AE from 
“interrupt infusion and increase monitoring …" to “temporarily interrupt 
infusion and increase monitoring...”.


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
Section 6.7.1:
o
Clarified the monitoring visits related to drug accountability – will be performed 
by field monitors during onsite / remote visits and at completion of trial.
o
Clarified the language on end of study drug disposition - “at the conclusion 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 as per local regulations/guidelines.”

Section 8:
o
In allowed visit windows specified, ‘a + 7-day visit window for end of post-
treatment phase’ changed to ‘a + 7-day visit window for the end of the safety 
follow-up phase.’

Table 8-1:
o
Removed the Category column.
o
Last column, ‘follow up phase’ changed to ‘follow up phase (as applicable)’.
o
For Priapism History, added an explicative footnote  stating that: The date, 
number, and duration of the priapic events in the 14-week period prior to 
consenting will be captured in a separate CRF.
o
For laboratory assessments, a row is added for ‘platelets (local)’ with an 
explicative footnote reference also inserted at the end of the table.
o
In safety assessments, a row was added for ‘IRR’ with an explicative footnote 
reference also inserted at the end of the table.

Section 8.2.3:
o
The word ‘physician’ was changed to ‘health care professional.’

Section 8.3.2:
o
Paragraph starting with ‘for assessment of subject’s eligibility to the study...’, 
parentheses section revised to correct grammatical errors.
o
Following sentence added after bullet points on criteria for lab results being 
recorded in the eCRF: ‘laboratory assessments can be repeated during the 
screening period as deemed appropriate by the investigator.’
o
Paragraph added before Table 8-4 on platelet counts and local sampling.

Table 8-4:
o
In the chemistry assessment, the word ‘albumin’ was removed (subsequently 
removed from urinalysis as well); transferase typo corrected; ‘glucose (fasting)’ 
changed to ‘glucose (non-fasting)’.

Section 9.2:


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o
Study Completion visit definition was defined as last patient last visit.

Section 10.1.2:
o
“In regards to” was corrected to “in regard to”.

Section 10.2.1:
o
Revised language on composition of steering committee: “investigators 
participating in the clinical trial...” changed to “SCD and priapism medical 
experts...”

Section 12.4.2:
o
Added language on the uniformity in the occurrence of priapic events before 
exposure to crizanlizumab treatment.
o
Added text to specify that the baseline will be adjusted for 26 weeks for analysis 
purpose.

Section 12.4.4:
o
Added language to specify that the number of priapic events will be 
summarized in the screening period (12 weeks baseline), in first 12 weeks on 
treatment (0-12 weeks), and in the last 12 weeks on treatment (15-26 weeks) 
and percent reduction from baseline will also be summarized in supportive 
analyses.
o
Paragraph related to the methods of analyzes using a mixed regression model 
was removed and will be instead included separately in the statistical analysis 
plan.

Section 12.6:
o
The on-treatment and post-treatment period segments of the overall observation 
period were edited to reflect that some patients might receive commercial 
crizanlizumab after their study EOT.

Section 12.6.2:
o
Clarification that an ECG will also be conducted at end of treatment: “... at 
screening and end of treatment visit.”

Section 12.8:
o
It was clarified that the primary analysis of the study will be performed after 
the last subject has completed Week 26 visit or discontinued earlier. Also, it 
was clarified that the analysis will be carried out on all visit-based safety 
assessments.

Section 12.9:
o
Sample size calculation: The power of the study was changed from 90% to 80%. 
The drop-out rate was reduced to from 20 to 5% to reflect the higher-than-
expected retention rate observed for the study.  Based on the modification of 
these two parameters, the sample size calculation was revised to 34 evaluable 
subjects and approximately 36 subjects enrolled in the study.


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
Section 15:
o
Two new references (Rogers et al 2005; Hamre et al 1991) were added.

IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
Amendment 1 (31-July-2020)
At the time of this amendment, 7 patients have been enrolled in the study.
The primary purpose of this amendment is described below:
1. Modify selected Inclusion/Exclusion Criteria including:

Inclusion criteria 6: OxbrytaTM (hereafter referred to as voxelotor) to be allowed on 
stable dose. The therapy was approved by the US FDA on 25-Nov-2019 for SCD 
treatment in adults and pediatric patients 12 years of age and older.  Voxelotor has 
no reported beneficial effect on priapism.

Exclusion criteria 1: The timeframe for penile shunts was clarified. Instances of 
SCD patients suffering from priapism after having undergone penile shunt surgeries 
were reported to the team indicating that such procedures may not always prevent 
future occurrence of the complication.

Exclusion criteria 14: The drug or alcohol tests were replaced with a criterion based 
on a history of drug or alcohol abuse.
3. The visit windows were clarified throughout the protocol to remove any discrepancies 
and align with the other Novartis crizanlizumab clinical studies.
4. Following a literature review of antidepressants and antipsychotic drugs reported to 
cause priapism, the list of prohibited drugs was revised. These classes of drugs are now
separately listed in Table 16-2 in Appendix 5. Ten drugs were added. Lithium was 
removed from the list as no literature reference was uncovered.
5. The guidelines for the management of infusion-related reactions (IRRs) were clarified 
with regards to the rules for interrupting and restarting infusions. It was also added that 
steroids should be used with caution unless clinically indicated (e.g. management of 
hypersensitivity/anaphylaxis). Sections related to IRRs were modified accordingly 


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throughout the protocol for consistency with other Novartis crizanlizumab clinical 
studies.
Other minor corrections are also applied throughout the protocol.
Changes to the Protocol
Changes to specific sections of the protocol are shown in track changes version of the protocol 
using strike through red font for deletions and red underline for insertions

Throughout: typographical and grammatical errors addressed.

List of abbreviations: Anti-Drug Antibody (ADA), Adverse-Drug Reaction (ADR), Clinical 
Research Associate (CRA) and United States Adopted Name (USAN) were added. 
Ultrasonography (USG) was removed.

Protocol Summary: updated in alignment to the protocol sections updated.

Section 1.1:
o
Including Oxbryta™(voxelotor) as approved by US FDA on 25-Nov-2019 for SCD 
treatment in adults and pediatric patients 12 years of age and older.

Section 1.2.1:
o
Including first global approval for crizanlizumab obtained from the US FDA on 15-
Nov-2019.

Section 1.3 and Table 2-1:
o
Replaced “greater than” and “more than” by “at least” for clarity.

Table 2-1:
o
Added the word “or” to align the definition of acute priapic events to that of priapism 
as defined in Section 8.2.1. Correspondingly the Protocol Summary and Section 
8.2.2.2 were updated.
o
 
 Correspondingly, Table 8-1 was updated and the relevant sub-section 
in Section 8.2. was deleted.

Section 3:
o
Pre-screening: Corrected that information to determine key eligibility criteria may 
be collected using an optional pre-screening form.
o
Screening Phase: Deleted the words “electronic” and “from Day 84 to Day 1” and 
referred to Section for schedule.

Section 4.5:
o
Expanded risk and benefit section to align with IBv10 and included additional 
information on IRRs. 
o
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.


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o
Added language to risk and benefit section regarding lack of evidence on mAb 
transmission in seminal fluid.

Section 5.1:
o
Inclusion Criteria #6: Included voxelotor as a permitted concomitant therapy. 
Correspondingly, voxelotor was added in the Protocol Summary and four times in 
Section 6.2.1.1.
o
Inclusion Criteria #8: Clarified that the renal and hepatic function should be assessed 
prior to Week 1 Day 1.
o
Inclusion Criteria #9: Clarified that laboratory values should be assessed prior to 
Week 1 Day 1.

Section 5.2:
o
Exclusion Criteria #1: Clarified that only patients who had a shunt surgical 
procedure on the penis performed within 12 months prior to consenting are not 
allowed. Correspondingly, the clarification was added in the Protocol Summary.
o
Exclusion Criteria #12 was modified to exclude patients on the basis of their family 
history of long QT syndrome or Torsades rather than a QTcF equal or superior to 
470 msec.
o
Exclusion Criteria #13 was modified to remove History of myocardial infarction, 
angina pectoris, coronary artery bypass graft, or uncontrolled congestive heart 
failure within 6 months prior to starting study treatment as an exclusion factor. 
Specified the criteria indicating a significant risk of safety as “Concomitant 
clinically significant cardiac arrhythmias (e.g ventricular tachycardia), and clinically 
significant second- or third-degree AV block without a pacemaker”.
o
Exclusion Criterion #14: current drug or alcohol abuse was replaced with a criterion 
to exclude patients with current drug or alcohol abuse as per investigator discretion. 
Correspondingly, drug and alcohol screens were deleted or changed to drug and/or 
alcohol history in Table 8-1 (row and Footnote b), Section 8.1.3, Section 8.3.2 and 
Table 8-4.
o
Exclusion Criterion #15: Language edited for clarity.

Section 6.1.1:
o
Removed some irrelevant instruction related to the tear-off label on the medication 
package.
o
Deleted the composition of the formulation for the infusion solution. All allowed 
formulation are listed in the Pharmacy Manual.

Section 6.2.1.1:
o
Added information on pre-medication in case of Infusion Related Reactions and a 
recommendation to use steroids with caution to treat IRR. Correspondingly, similar 
language was added in Section 6.2.1.3.

Section 6.2.1.3.


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o
Text related to PK/PD was deleted because such procedures are not implemented in 
the protocol.
o
Clarified the text by adding “as outlined above”.
o
Clarified the data collection method if other forms of L-Glutamine are used.
o
Clarified the restrictions for administration of vaccines.
o
Added text related to the use of pre-medication in case of infusion-related reactions. 
Clarified that there is no clinical data on the concomitant use of crizanlizumab and 
corticosteroids. Added a reference to Table 6-2 for further information on the 
management of infusion-related reactions.
o
Added a recommendation to hold drug administration 4 weeks prior to a major 
surgery.

Section 6.2.2:
o
Clarified that subjects that prior use of crizanlizumab, other selectin targeting agents 
or new treatment to treat SCD and/or to prevent/reduce VOCs are not permitted.

Section 6.5:
o
Deleted that dose changes must recorded in the CRF.

Table 6-2:
o
Clarified that version 5 of the CTCAE dictionary is used a reference.
o
Updated the units for Neutropenia and Thrombocytopenia to International System 
units.
o
Criteria for body temperature in febrile neutropenia changed from ≥38.5 °C to ≥ 
38.3 °C.
o
Range for Grade 1 to Grade 4 isolated direct bilirubin has been clarified.
o
Clarified the recommendations for dose interruptions for Grades 1-4.
o
Range for Grade 1 to Grade 4 Infusion-related reactions has been clarified.
o
Updated recommendation to continue study treatment for Grade 1 infusion related 
reactions.
o
For Grade 2 infusion-related reaction, recommendation is updated to clarify the 
conditions to interrupt, administer pre-medication and res-start infusion.
o
Updated recommendation to discontinue study treatment for Grade 3 and 4 infusion 
related reactions.
o
Foot note has been deleted regarding recommendation to continue study treatment 
at Investigator’s discretion if total bilirubin > 3.0 × ULN is only due to indirect 
component.

Section 6.5.1.1:


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o
Modified definition of potential DILI to include normal ALP along with elevation 
of transaminases and increase in TBIL.
o
Deleted the mention that AST will not be considered.
o
Criteria for subjects with normal ALT and Direct BIL value at baseline modified to 
include that the subjects should be without evidence of cholestasis.
o
Text modified to reflect that LFTs will be repeated for certain defined criteria 
preferably within 48-72 hours.

Section 6.7.1:
o
Reference to the Pharmacy Manual has been added.
o
The language related to the management of IRRs was deleted as it was not relevant 
to this section. Management of IRRs is described in Table 6-2

Section 8: Updating and clarifying the permitted visit windows:
o
Screening assessments must occur within 84 days (12 weeks) ± 7 days prior to the 
enrollment.
o
For all screening visits a general ± 7 day visit window is allowed.
o
A ± 7 day visit window is allowed at Week 1 Day 1 (calculated from day of consent).
o
A ± 3 day visit window is permitted on assessments at Week 3 Day 1.
o
For all other dosing visits a general ± 7 day visit window is permitted on assessments.
o
Deleted “to take into account scheduling over public holidays”.
o
Corresponding text was updated in Section 8.3.2.

Table 8-1:
o
Deleted “microscopic or macroscopic” as a microscopic panel is not always done. 
The conditions for urinalysis with a microscopic panel are detailed in Section 8.3.3.
o
Prior/concomitant medications-“Hydroxyurea” row was reformatted to highlight the 
continuous need to be recorded. The rows for “Transfusion, 
 Adverse 
Event/Serious Adverse Event and Prior/concomitant medications” were similarly 
modified.
o
ECG assessment was moved from Screening Visit 1 to Screening Visit 3 as it needs 
to be done closer to start of dosing. Corresponding language was clarified in Section 
12.6.2.
o
Footnote “a” was updated to clarify that if the dose is delayed for more than 7 days, 
every effort should be made to bring the subject's infusions back onto the protocol-
defined schedule (Section 6.5).
o
Footnote “c” became Footnote “b”.

Section 8.1:
o
Text modified in line with the modification of the screening windows in Section 8.


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o
Deleted “use the electronic device(s) require” and added “as described in Section 
8.2.4” to reflect the possibility of using a paper diary to record the priapic episodes. 
Correspondingly, text was deleted in Section 8.2.1 and modified in Section 8.2.4.
o
Added text to clarify the conditions for local testing when the results from the central 
laboratory are partial unavailable. Corresponding text was modified in Section 8.3.2.
o
Added text to clarify that re-screening of subjects is allowed under certain conditions 
and the steps that need to be undergone.

Section 8.2.1:
o
Added text to clarify that In order to be treated as independent priapic events, two 
events will have to be separated by at least 2 hours, and the event would have to 
return to baseline during those 2 hours.  

Section 8.2.2.1:
o
Added “efficacy” to clarify that priapism was the primary efficacy endpoint as 
specified in Section 8.2.1.

Section 8.3.2:
o
Deleted Flowchart as no central laboratory document other than the laboratory 
manual has been developed.

Section 8.3.3:
o
Added text to clarify that a microscopic panel will be performed centrally if dipstick 
is positive.

Section 8.3.5.1:
o
Removed two portions of text related ECG evaluation with a central laboratory. 
ECG are only done and interpreted locally.

Section 8.3.5.2:
o
Parameters to be assessed by Echocardiogram are re-defined: PAP replaced with 
mPAP.

Section 8.3.7:
o
Timeframe for the repeat assessment was removed at EOT to align with EOT being 
conducted with 2 weeks of the last infusion.

Section 8.4.1:
o
Text modified as PROs will not administered electronically but via paper.

Section 9.1.1:
o
Clarification that an EOT visit should be performed within 14 days of the last dose 
of the discontinued study treatment.

Section 10.1.1:


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o
Updated the list of outcomes to be recorded in the eCRF to include 
recovering/resolving AEs.

Section 10.1.5:
o
Deleted the redundant word “Pregnancies”.

Section 11.1:
o
Text of the Section was simplified by removing unnecessary or redundant language 
related to data capture in CRF, data storage and transfer, methods of monitoring and 
data verification.

Section 11.3:
o
Clarified that continuous remote monitoring of each site’s data may be performed 
by a centralized Novartis-affiliated Clinical Research Associate (CRA) organization.

Section 12.4.2:
o
Added that additional analyses will also be performed for the subgroups of subjects 
who have experienced priapic episodes lasting less than one hour and not for 
stuttering priapism. Corrected that these analyses are not for the primary endpoint.

Section 12.4.3 and Section 12.4.4:
o
Added additional analyses to assess the impact of the COVID-19 crisis. 

Section 15:
o
Added the following additional references: Banholzer et al., Brandow et al., Scialli 
et al. and and Vichinsky et al.. The same changes were made wherever applicable in 
the protocol summary.

Appendix 5:
o
Table 16-1 was modified to exclude the antipsychotics and anti-depressant drugs. 
The title was revised accordingly.
o
Table 16-2 was created to emphasize the list of anti-depressants and Antipsychotics 
that may induce priapism form other substances. Additional drugs uncovered from 
a systemic literature search were added. Tradenames were added for easier 
identification by the investigator. References were also included.

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
CSEG101AUS05
Full Title
A Prospective Phase II, Open-Label, Single-arm, Multicenter, Study to 
Assess Efficacy and Safety of SEG101 (crizanlizumab), in Sickle Cell 
Disease Patients with Priapism (SPARTAN)
Brief title
Study of efficacy and safety SEG101 (crizanlizumab) in Sickle Cell Disease
(SCD) Patients with Priapism (SPARTAN)
Sponsor and Clinical 
Phase
Novartis
Phase of the trial: II
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this study is to evaluate the effect of crizanlizumab on 
priapic events in sickle cell disease patients with a history of priapism. 
During screening, we will be collecting data for 12 weeks prior to the
treatment phase to create a baseline for priapic events (defined as an
event of an unwanted painful erection lasting at least 60 minutes), acute 
priapic events (which is defined as an event of an unwanted or painful 
erection lasting at least 4 hours), uncomplicated and complicated vaso-
occlusive crisis (VOC). Our hypothesis is that crizanlizumab treatment will 
reduce priapic events by at least 25% in SCD patients with priapism.
Primary Objective 
To evaluate the clinical efficacy (percent reduction from baseline) of 
crizanlizumab in SCD-related priapism
Secondary 
Objectives

To evaluate the clinical efficacy (rate of priapic events) of 
crizanlizumab in SCD--related priapism

To evaluate the clinical efficacy of crizanlizumab in SCD-related 
acute priapism

To evaluate the clinical efficacy of crizanlizumab for 
uncomplicated VOC (defined as an acute event of pain with no 
known cause for pain other than a vaso-occlusive event; and 
requiring treatment with a parenteral or oral opioids or other 
parenteral analgesic; but is NOT classified as an acute chest 
syndrome, hepatic sequestration, splenic sequestration or 
priapism and these events will not be adjudicated)

To evaluate the clinical efficacy of crizanlizumab in complicated 
VOCs (acute chest syndrome, hepatic sequestration, splenic 
sequestration, and acute priapism) 

To assess the safety and tolerability of crizanlizumab
Study design
This is a multicenter, prospective, phase II, single-arm, open-label study to 
assess the efficacy and safety of crizanlizumab in SCD patients with 
priapism. A total of approximately 36 male subjects aged ≥12 years, who 
meet all of the inclusion criteria and none of the exclusion criteria will be 
eligible for the study. 
The baseline period is defined as the 12 weeks screening period. Eligible 
subjects will be treated with crizanlizumab at a dose of 5.0 mg/kg. From the 
first screening visit until the end of follow-up, the total study duration will be 
up to 79 weeks (including 12 weeks of screening, 52 weeks of treatment 
and 15 weeks of follow-up period if applicable). The primary analysis of the 
study will be conducted by 26 weeks to assess efficacy of crizanlizumab in 


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this patient population. The secondary 
 endpoints will be 
assessed by 26 weeks and/or 52 weeks. Subjects will be followed in the 
safety follow-up period until 105 days (15 weeks) after the last dosing.
Subjects 
who 
will 
receive 
commercially 
approved 
crizanlizumab 
approximately 4 weeks after their last dose of study treatment, do not need 
to complete the 105-day follow-up.
Population
A total of approximately 36 male patients with SCD-related priapism aged
≥ 12 years will be recruited across the United States. To be considered for 
this study, patients must have had ≥ 4 priapic events during the 14 weeks 
prior to screening and having at least 3 priapic events during the 12 week 
screening period with at least 1 event occurring within 4 weeks prior to the 
first treatment.
Key Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following 
criteria:
1.
Signed informed consent and applicable adolescent assent 
and/or parental consent for adolescent subjects, must be 
obtained prior to participation in the study
2.
Male patients aged 12 years and above
3.
Confirmed diagnosis of SCD by hemoglobin electrophoresis or 
high performance liquid chromatography. All SCD genotypes are 
eligible (HbSS, HbSβ0, HbSC, HbSβ+, and others) 
4.
Patients who have experienced ≥ 4 priapic events (unwanted 
erection lasting at least 60 minutes) over 14 week pre-screening 
5.
Patients who have experienced at least 3 priapic events 
(unwanted erection lasting at least 60 minutes) during the 
12 week screening period with at least 1 event occurring within 
4 weeks prior to the first treatment.
6.
If receiving hydroxyurea/hydroxycarbamide, L-glutamine, 
erythropoietin stimulating agent or voxelotor, must have been 
receiving the drug for at least 14 weeks prior to screening and 
plan to continue taking the drug at the same dose and schedule 
during the trial
7.
If receiving prophylactic treatment for priapism, must have been 
receiving the drug for at least 14 weeks prior to screening and 
plan to continue taking the drug at the same dose and schedule 
during the trial
Key Exclusion 
criteria
Following are the key exclusion criteria:
1.
Patients who have penile prosthetic implants. Shunts or any 
other surgical procedure on the penis performed within 12 
months prior to consenting are not allowed.
2.
Patients who have taken drugs/medications that may induce 
priapism (as per Appendix 5) over the 14 weeks pre-screening 
period
3.
Patients who have received leuprolide acetate (Lupron) or any 
other gonadotropin-releasing hormone receptor (GnRHR) 
agonist agents within 3 months before pre-screening.
4.
Patients who had an erection lasting more than 12 hours over 
the 14 week pre-screening period
5.
Patients who had an erection lasting more than 12 hours during 
the 12 weeks of the screening period
Study treatment
Crizanlizumab (SEG101) at 5.0 mg/kg


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Efficacy 
assessments
Following
are the key primary and secondary planned efficacy 
assessments:
!
Percent reduction in priapic events by 26 weeks of treatment
!
The rate of priapic events by 26 and 52 weeks of treatment
!
Percent reduction in acute priapic events by 26 and 52 weeks of 
treatment
!
The rate of complicated/uncomplicated VOCs by 26 and 
52 weeks of treatment
Key safety 
assessments
Following are the key safety assessment planned for this study:
!
Monitoring of AEs/SAEs
!
Vital signs, Physical assessments
!
Hematology, chemistry, coagulation, urinalysis, Hepatitis markers
!
Presence of HIV Antibody (at screening only)
!
Cardiac assessments: ECGs and echocardiogram
Other assessments 
Data analysis
The primary endpoint of the study is the percent reduction from baseline in 
priapic events by 26 weeks (i.e. up to pre-infusion Week 27, Day 1). 
Efficacy endpoints will be analyzed using all FAS subjects who have 
completed treatment. It is hypothesized that crizanlizumab treatment will 
reduce the priapic events by at least 25% in SCD subjects with priapism. 
Assuming uniformity of the events occurrence before exposure to
crizanlizumab treatment, baseline will be adjusted for 26 weeks for primary 
analysis purpose. Percent reduction from baseline in priapic events will be 
tested using a nonparametric test (i.e. Wilcoxon’s Sign Rank test) along with
Hodges-Lehmann estimate of median percent reduction Number of priapic 
events and percent reduction from baseline by Week 26 will be summarized 
descriptively.
As part of the supportive analysis the primary analysis will be repeated on 
all subjects in FAS. In addition the annualized rate of priapic events will be 
summarized for all subjects in FAS that have completed treatment. Three 
additional supportive analyses will also be performed, the total number of 
priapic episodes in the screening period (12 weeks baseline) will be 
compared to the total number of priapic episodes occurring in the first 12 
weeks on treatment (0-12 weeks) using a nonparametric test (i.e. 
Wilcoxon’s Sign Rank test). A similar analysis will be performed to compare 
to the total number of priapic episodes occurring in the last 12 weeks on 
treatment (15-26 weeks). Finally an analysis using a mixed effects 
regression model will be performed using median event counts within pre-
specified time windows. 
Similar analyses on percent reduction in acute priapic events for subjects 
will be conducted, as was completed for primary endpoint. Descriptive 
summary statistics will be presented for the rate of events and number of 
priapic events at Baseline, by Week 26 and by Week 52. In addition, the 
rate of uncomplicated VOC events and VOC events will be summarized. 
Safety analyses will be based on the safety analysis set. Adverse events 
PI


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will be summarized by system organ class and or preferred term, 
seriousness, CTCAE grade based severity, type of adverse event, relation 
to study treatment. Other safety assessments (e.g. ECG, vital signs) will be
summarized by treatment group.
Key words
Priapism, sickle cell disease, crizanlizumab, P-selectin, vaso-occlusive 
crisis


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1
Introduction
1.1
Background
1.1.1
Overview of Sickle Cell Disease pathogenesis, epidemiology and 
current treatment 
Sickle cell disease (SCD) is a genetic blood disorder, caused by a single missense mutation 
(Glu6Val) in the β-globin gene, which early on progresses into a systemic disease. 
Vaso-occlusion is the hallmark of SCD and can lead to serious acute and chronic complications. 
Vascular dysfunction, inflammation, and P-selectin mediated cell
-to
-cell and 
cell -to -endothelium adhesion play an important role in the pathophysiology of SCD. 
Uncomplicated vaso-occlusive crisis (VOC) is the most common clinical manifestation of SCD. 
Complicated VOCs include acute chest syndrome, hepatic and splenic sequestration, and 
priapism. Every VOC increases morbidity and can result in organ damage/failure and/or death 
(Ballas et al 2010, Brousseau et al 2010, Powars et al 2005). Additionally, VOCs lead to 
significant health care utilization and are the most common cause of emergency room visits and 
hospital admissions in SCD patients, with total medical costs exceeding 1.1 billion USD 
annually (Kauf et al 2009).
Sickle cell disease is the most common single gene disorder in African Americans, affecting 
approximately 1 in 375-600 people of African ancestry (Nietert et al 2002). Sickle cell 
conditions are also common among people of Mediterranean countries, Africa, Middle East, 
India, Caribbean, and parts of South and Central America (Clinical Practice Guideline No. 6. 
1993,
Nietert et al 2002).
The 
most 
frequent 
and 
typically most severe 
form is homozygous HbSS (sickle cell anemia)
(α2 βs2, HbS). Other forms of SCD
include compound heterozygous conditions, such as hemoglobin C (HbC) with HbS (HbSC), 
HbS with β-thalassemia (HbS/β0-thalassemia or HbS/β+-thalassemia), and HbS with other 
variants (Ware et al 2017). Clinical signs appear within the first 6 months of life, but there is 
considerable variability in severity (Gill et al 1995) resulting from genetic and environmental 
factors. Patients describe acute pain crises and chronic pain clearly as the most debilitating 
effects on their lives, affecting them physically and emotionally. Fatigue and cognitive 
effects also emerge as other debilitating effects. In addition, organ-damage and long-term 
complications have also a severe effect on them. As a result of these complications, patients 
often have reduced quality of life, significant anxiety, depression, and short life expectancy 
(Piel et al 2017, Kanter and Kruse-Jarres 2013).
Stem cell bone transplantation remains the only curative modality for SCD patients. However, a 
limited number of patients are eligible, and substantial concerns remain about transplant-related 
mortality and long-term toxicities, including infertility (Ware et al 2017).
Blood transfusions are commonly used as a single transfusion to ameliorate acute, even -life-
threatening complications, and/or as chronic transfusions to prevent long-term complications 
most frequently related to stroke prevention.
Vaso-occlusive crises are typically treated symptomatically with pain management and with 
other supportive care (Bender 2003, Rees et al 2010). Severe pain is often treated with opioids,
but their use is controversial due to the risk of opioid-related adverse events (AEs).


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Preventive 
treatments 
to 
reduce 
the 
number 
of 
VOCs 
are 
limited. 
Hydroxyurea/hydroxycarbamide (HU/HC) is approved to reduce the frequency of painful crises 
and the need for transfusions in SCD patients aged 2 years and older with a history of recurrent, 
moderate-to-severe painful crises. Treatment with HU/HC presents several limitations, 
including significant toxicities and need for blood monitoring leading to poor patient 
compliance. It is cytotoxic, myelosuppressive and teratogenic, potentially carcinogenic, impacts 
fertility and has a number of contraindications or special warnings and precautions for use
(Charache et al 1995, Pászty et al 1997, Hydrea-USPI 2016, Droxia-USPI 2017).
L-glutamine (Endari™), is approved in the United States to reduce the acute complications of 
SCD in adult and pediatric patients 5 years and older (Niihara et al 2018) and voxelotor
(Oxbryta™) has been approved by FDA since 25 Nov 2019 for the treatment of SCD in adult 
and pediatric patients 12 years of age and older (Vichinski et al 2019).
Despite the use of HU/HC, transfusions, L-glutamine and/or voxelotor, patients with SCD may 
still experience VOCs. In particular, complicated VOCs such as priapism represent a major 
unmet medical need.
1.1.2
Overview of SCD-related priapism, epidemiology and current 
treatment
Priapism is an involuntary, painful, and persistent erection, in the absence of sexual activity or 
desire (Furtado et al 2012). It was found that 29% of male children and adolescents with SCD 
reported priapism, and projected that up to 89% of men with SCD would experience priapism 
by the age of 20 (Mantadakis et al 1999). The vast majority of cases are ischemic, in which 
increased pressure, compromises the vascular circulation (i.e. a type of compartment syndrome). 
Its ischemic form, presenting as a single, major event, or recurrence, is associated with penile 
pain, erectile tissue destruction and loss, and permanent erectile inability (Montague et al 2003,
El-Bahnasawy et al 2002). The sickled erythrocytes predispose to venous stasis, which therefore 
perpetuates the priapism. Cavernosography shows that this stasis results in obstruction of the 
deep dorsal penile vein (Adeyoju et al 2002). The stagnation of blood within the sinusoids of 
the corpora cavernosa during a physiological erection increases erythrocyte rigidity and impairs 
the venous outflow from the corporeal bodies. Prolongation of the erection and pain induced by 
ischemia of the corporeal tissues are potential consequences of these events. (Fowler Jr et al 
1991). Most of the affected patients had repeated events that lasted for less than 3 hours and a 
majority of the attacks occurred during sleep, which could be due to the physiological 
dehydration and metabolic acidosis that accompany sleep and that increase the rigidity of 
erythrocytes in patients with sickle cell anemia (Fowler Jr et al 1991). Priapism may be one 
reflection of the vasculopathy of SCD. (Kato et al 2017).
Apart from anecdotal experiences, there is no clear evidence-based guidelines in management 
or medical prevention strategies. The goal of priapism treatment is to achieve detumescence 
and preserve erective dysfunction (Montague et al 2003). Treatment for SCD-related priapism
are lacking due to the clinical misunderstanding and the ideal medical interventions have not 
been developed. In recent years, major scientific progress has advanced the understanding of 
pathophysiology especially in molecular effector pathways mediating penile erection. The 
medical management of recurrent or stuttering SCD-related priapism is difficult and frustrating, 


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often involving sequential attempts with several different drugs, and clearly, more rigorous 
clinical research is needed in this area.
1.1.3
Role of P-Selectin in VOC
Extensive data have been published over the last decade that suggests a pivotal role for 
P-selectin in the pathophysiology of SCD. Adhesion of leukocytes to the endothelium during 
inflammation can involve multiple molecules and the process is initiated by P-selectin
(Lawrence and Springer 1991). P-selectin expression increases the specificity of endothelial 
cell interactions with platelets and leucocytes during inflammation, coagulation and 
atherosclerosis. P-selectin expressed on endothelial cells also increases sickle erythrocyte 
adhesion, although the precise ligand interaction involved is not known. P-selectin is found in 
storage granules of resting endothelial cells and platelets and is rapidly transferred to the cell 
membrane on activation of the cell during processes such as inflammation. It is expressed on 
the surface of endothelium that mediates abnormal rolling and static adhesion of sickle 
erythrocytes to the vessel surface in vitro (Matsui et al 2001, Matsui et al 2002). Translocation 
of endothelial P-selectin to the cell surface results in the prompt adhesion of sickle erythrocytes 
to vessels and the development of vascular occlusion in transgenic mice with SCD (Embury et 
al 2004).
The role of P-selectin in SCD is further substantiated by the fact that transgenic mice with SCD
that are deficient in P-selectin and E-selectin have defective leukocyte recruitment to the vessel 
wall and are protected from vaso-occlusion (Turhan et al 2012). The adherence of sickle 
erythrocytes and leukocytes to the endothelium is substantially reduced when P-selectin is 
blocked in transgenic mice expressing human HbS (Embury et al 2004, Gutsaeva et al 2011).
These data support the concept that blockade of P-selectin could reduce the risk of 
vaso-occlusion, inflammation, and sickle cell–related pain crises (Ataga et al 2017).
In addition to the studies done in animals, human sickle red cells frequently interacted and 
adhered directly to the vascular endothelium (Matsui et al 2001). Platelets also respond to 
inflammation with the upregulation of P-selectin and are known to bind to leukocytes and 
endothelium, thereby contributing to vaso-occlusion in SCD (Wood et al 2004, Inwald et al 
2000, Lee et al 2007). The adhesion of sickled human erythrocytes to activated endothelium in 
SCD is also an important contributor to vaso-occlusion and pain crisis (Wagner et al 2006,
Hebbel et al 1980, Stuart and Johnson 1987).
1.1.4
Role of P-Selectin in SCD-related priapism
Preclinical studies in transgenic mice have shown that SCD promotes an increased P-selectin 
expression in several vascular beds of various organs (e.g. lung, heart, small bowel, large bowel, 
penis etc.). The penis is the only organ where the vascular bed exhibited an increased expression 
of both P- and E-selectin, which may be relevant to a SCD-related priapism. Although, priapism 
has been attributed to both ischemic and non-ischemic causes, vaso-occlusion-induced ischemia 
is generally thought to account for the priapism associated with SCD. This raises the possibility 
of an inflammatory process in priapism (Wood et al 2004).


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Figure 1-1
P-selectin expression in penis of wild-type (WT) and sickle cell 
transgenic (βS) mice
Constitutive expression of P-selectin in the penis of wild-type (WT) and sickle cell (βS) mice. While 
significant P-selectin expression is detected in the penis of βS mice, it was not be detected in the WT 
penis (P < .0005).
As P-selectin expression is increased in the penis and vaso-occlusion induced ischemia is 
thought to account for the priapic events, a study evaluating the effects of P-selectin inhibition 
on priapism associated with SCD is warranted.
1.2
Introduction to investigational treatment(s) and other study 
treatment(s)
1.2.1
Overview of crizanlizumab (SEG101)
Crizanlizumab is a selective IgG2 kappa humanized monoclonal antibody that binds to 
P-selectin with high affinity by blocking its interaction with its ligands, including P-selectin 
glycoprotein ligand 1 (PSGL-1). Extensive pre-clinical data have established P-selectin as a key 
mediator of VOC in SCD (Matsui et al 2001) and suggest that blockade of P-selectin could 
eliminate or reduce VOC. 
The compound, crizanlizumab was initially developed by Reprixys Pharmaceuticals 
Corporation under the investigational drug code, SelG1. Novartis acquired the company on 
18-Nov-2016, and is now the drug developer and sponsor for crizanlizumab, under the 
investigational drug code, SEG101. On 15-November-2019, the US FDA approved 


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ADAKVEO® (crizanlizumab-tmca), for the reduction of the frequency of VOCs in adults and
pediatric patients aged 16 years and older with sickle cell disease.
The approval was based on safety and efficacy data from the Phase II SUSTAIN study (Ataga 
et al 2017; see Section 1.2.2) below. 
The crizanlizumab IB provides detailed information related to toxicology, nonclinical 
pharmacology, drug properties, clinical and preclinical data.
1.2.2
Clinical experience 
Phase II Clinical Study (SUSTAIN – CSEG101A2201) 
Throughout this description of SUSTAIN, the study drug is denoted as crizanlizumab and refers 
to SelG1. The objective of this pivotal, randomized, placebo-controlled SUSTAIN study 
(Reprixys study code: [Se1G1-00005]; Novartis study code: [CSEG101A2201]) was to assess 
the safety and efficacy of crizanlizumab with or without HU/HC therapy in SCD patients with 
a history of VOC leading to a healthcare visit. A total of 198 SCD patients aged 16-65 years 
(inclusive), with any SCD genotype, a history of crisis within the previous 12 months, and either 
with a steady dose of HU/HC or not taking HU/HC, were randomized 1:1:1 to crizanlizumab 
5.0 mg/kg, crizanlizumab 2.5 mg/kg or placebo. 
The median annual rate of VOC leading to a healthcare visit was 45.3% lower with 5 mg/kg 
crizanlizumab than with placebo (Hodges-Lehmann, median absolute difference of -1.01 versus 
placebo, 95% confidence interval (CI) [-2.00, 0.00]). The difference between the 5 mg/kg arm 
and placebo arm was statistically significant (Wilcoxon rank sum test, p=0.010). The median 
annual rate of uncomplicated crises and median number of days hospitalized were 62.9% and 
41.8% lower in the 5.0 mg/kg than in the placebo group, respectively. Crizanlizumab also 
delayed the time to onset of first and second VOC, and consistent benefit was further observed 
in a number of clinically relevant subgroups for the primary endpoint. 
Crizanlizumab was generally well tolerated with similar incidence of treatment emergent 
adverse events (TEAEs) across the 3 groups, and overall there were low incidence of 
discontinuations due to TEAEs (< 5%). The proportion of subjects experiencing serious adverse 
events (SAEs) was 25.8% at 5.0 mg/kg, 32.8% at 2.5 mg/kg and 27.4% in the placebo group. 
There were 5 deaths during the study (2 at 5.0 mg/kg, 1 at 2.5 mg/kg and 2 in the placebo group), 
and none was deemed to be treatment related. Please refer to Investigator’s Brochure for further 
information. 
Overall, treatment of SCD patients with crizanlizumab at 5.0 mg/kg showed positive clinical 
activity as demonstrated by a statistically significant and clinically relevant decrease in the 
annual VOC rate compared with placebo and it was also found to be well tolerated.
All completed clinical studies described above were performed by Reprixys Pharmaceuticals 
Corporation. These studies were conducted using monoclonal antibodies produced in Invitrogen 
CHO-S cells (SelG1). To ensure supply of future clinical studies as well as commercial demand, 
Novartis has optimized the production of crizanlizumab. SEG101 will be used in future 
clinical/toxicological studies and as a commercial product.


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1.3
Purpose
The purpose of this study is to evaluate the effect of crizanlizumab on priapic events in sickle 
cell patients with a history of priapism. We will be collecting data for 12 weeks prior to the 
treatment phase to create a baseline for priapic events (defined as an event of an unwanted 
painful erection lasting at least 60 minutes), acute priapic events (which is defined as an event 
of an unwanted or painful erection lasting at least 4 hours), uncomplicated and complicated 
VOCs. Our hypothesis is that crizanlizumab treatment will reduce priapic events by at least 
25% in SCD patients with priapism.
 


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2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Primary Objective
Endpoint for primary objective
To evaluate the clinical efficacy of crizanlizumab 
in SCD-related priapism
Percent reduction from baseline period in priapic 
events (priapism defined as unwanted, or painful 
erection lasting at least 60 min self-reported) by 26
weeks
Secondary Objectives
Endpoints for secondary objectives
To evaluate the clinical efficacy of crizanlizumab 
in SCD-related priapism
Rate of priapic events by 26 and 52 weeks
To evaluate the clinical efficacy of crizanlizumab
in SCD-related acute priapism
Percent reduction from baseline in acute priapic 
events (defined as an unwanted or painful erection 
lasting at least 4 hours and mandates a visit to ER) 
by 26 weeks and 52 weeks
To evaluate the clinical efficacy of crizanlizumab 
for uncomplicated vaso-occlusive crisis (VOC) 
(defined as an acute event of pain with no 
known cause for pain other than a 
vaso-occlusive event; and requiring treatment 
with a parenteral or oral opioids or other 
parenteral analgesic; but is NOT classified as an 
acute chest syndrome, hepatic sequestration, 
splenic sequestration or priapism and these 
events will not be adjudicated)
Rate of uncomplicated VOC events (including both 
healthcare visit and self-reported) by 26 and 
52 weeks
To evaluate the clinical efficacy of crizanlizumab
in complicated VOCs (acute chest syndrome, 
hepatic sequestration, splenic sequestration, 
and acute priapism) 
Rate of complicated crisis (recorded by healthcare 
visit) by 26 and 52 weeks
To assess the safety and tolerability of 
crizanlizumab
Number, seriousness, severity, and causality 
assessments of treatment emergent adverse events 
and other safety data as considered appropriate by 
52 weeks (Safety assessments will consist of 
monitoring and recording all adverse events, based 
on Common Terminology Criteria for Adverse events 
(CTCAE) V5.0. 
It will also include regular monitoring of laboratory 
testing of hematology, serum chemistry, and 
urinalysis, measurement of vital signs, and physical 
examination.)
2.1
Primary estimands


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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 on reduction 
from baseline period in priapic events, by week 26?
The primary estimand is described by the following attributes:
1. Population: Sickle Cell Disease patients with priapism. Further details about the population 
are provided in Section 5.
2. Endpoint: Percent reduction from baseline period in priapic events (priapism defined as 
unwanted, or painful erection lasting at least 60 min self-reported) by 26 weeks.
3. Treatment of interest: investigational drug will be a crizanlizumab solution provided every 
4 weeks with an additional loading dose 2 weeks after the first dosing. Further details about 
the investigational treatment are provided in Section 6.  
4. List of intercurrent events:
a) Treatment discontinuation 
b)
Initiation or discontinuation of HU/HC or l-glutamine (or other therapies to treat 
SCD and or to prevent/reduce VOCs such as voxelotor and erythropoietin) or of 
prophylactic treatment for priapism as described in the Sections 6.2.1, 6.2.2, 6.2.3
c) Intake of analgesic (including opioids) or ad hoc transfusions administered 
temporarily as described in the Section 6.5.
5. The summary measure: Median percentage change from baseline period in priapic events 
(priapism defined as unwanted, or painful erection lasting at least 60 min self-reported) by 
26 weeks
Handling of intercurrent events is discussed in Section 12.4.2.
3
Study design
This is a multicenter, prospective, phase II, single-arm, open-label study to assess the efficacy 
and safety of crizanlizumab in SCD patients with priapism.
A total of approximately 36 male subjects aged ≥12 years, who meet all of the inclusion criteria 
and none of the exclusion criteria will be eligible for the study. Subjects with ≥4 priapic events 
during the 14 week pre-screening period and having at least 3 priapic events during the 12 week 
screening period with at least 1 event occurring within 4 weeks prior to the first treatment, will 
be included in the study.
The baseline period is defined as the 12 weeks screening period. Eligible subjects will be treated 
with crizanlizumab at a dose of 5.0 mg/kg. From the first screening visit until the end of follow-
up, the total study duration will be up to 79 weeks (including 12 weeks of screening, 52 weeks 
of treatment and 15 weeks of follow-up as applicable). The primary analysis of the study will 
be conducted by 26 weeks to assess efficacy of crizanlizumab in those patient population, who
have completed 26 weeks of treatment. The secondary 
 endpoints will be 
assessed by 26 weeks and/or 52 weeks. Subjects will be followed for safety for up to 105 days
(15 weeks) after the last dosing if applicable. Subjects who will receive commercially approved 


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crizanlizumab approximately 4 weeks after their last dose of study treatment, do not need to 
complete the 105-day follow-up. The safety follow-up of these subjects will be at the End of 
Treatment (EOT) visit. All other subjects are required to complete the 105-day follow-up visit.
Pre-screening
Before participating in the study, information to determine key eligibility criteria may be 
collected as a part of a pre-screening form. In particular, the date, number and duration of the 
priapic events in a 14-week period required prior to consenting may be captured on this form.
The use of this form is optional.
Screening phase
Eighty-four days (12 weeks) before start of treatment, written informed consent, according to 
local guidelines, will be signed by the subjects and prior to any study related screening 
procedures are performed. 
During this period, subjects will have 3 visits and be monitored for priapic events to determine 
their eligibility to the trial using a reporting system. All screening evaluations must be 
performed during the screening period (see Section 8 for schedule).
Treatment phase
Once eligibility criteria have been confirmed by Novartis via the eligibility checklist, the subject 
will receive investigational treatment. 
Subjects will receive investigational treatment by IV infusion over 30 min on Week 1 Day 1, 
Week 3 Day 1, and then on Day 1 of every 4-week cycle. 
Safety will be monitored as outlined in Section 8. Subjects will receive investigational treatment 
for a maximum of 1 year (52 weeks) or until unacceptable toxicity, death, lost to follow-up or 
discontinued from the study treatment for any other reasons prior to 52 weeks.
Following the treatment discontinuation, subjects will perform an end of treatment (EOT) visit.
Follow-up phase
After the end of treatment visit, all subjects will be followed up for safety up to 105 days 
(15 weeks) after the last infusion of study treatment if applicable (see Section 9.2).


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Figure 3-1
Study Design
4
Rationale
4.1
Rationale for study design
The efficacy of crizanlizumab in SCD for the treatment of VOCs was established in the 
SUSTAIN study but was not fully investigated in priapism due to the limited number of cases 
observed during the study. The primary aim of this study is to demonstrate the clinical benefit 
of crizanlizumab in SCD-related priapism. A duration of 26 weeks was set to evaluate the
primary efficacy of crizanlizumab on SCD-related priapism. This was based on studies
conducted by Burnett and Olujohungbe, where recurrent ischemic priapic patients were 
evaluated over 16 and 26 weeks, respectively (Burnett et al 2014, Olujohungbe et al 2011). In 
addition, steady state concentrations for crizanlizumab were considered achieved by 15 weeks 
in the SEG101A2202 study.
The total duration of 52 weeks of treatment will enable evaluation of additional secondary 
 
 endpoints for the study.
4.2
Rationale for dose/regimen and duration of treatment
In this study, subjects will receive crizanlizumab 5.0 mg/kg every 4 weeks by IV infusion. A 
loading dose of 5.0 mg/kg will be administered 2 weeks after the first dose to rapidly achieve 
the steady-state serum concentration. This will be followed by dosing of 5.0 mg/kg every 
4 weeks to ensure that steady-state serum concentration of crizanlizumab are maintained to 
provide a consistent blockade of P-selectin throughout the study.
In the SUSTAIN trial (SEG101A2201), both 5.0 mg/kg and 2.5 mg/kg of crizanlizumab on this 
same dosing schedule was tested and showed a statistically significant reduction in median 
annual rate of SCPC in the 5.0 mg/kg dose group versus placebo, while the 2.5 mg/kg group 
did not have a statistically significant reduction. The overall safety was well-balanced across 
treatment and placebo groups (5.0 mg/kg: 86% AE and 26% SAE; 2.5 mg/kg: 88% AE and 
33% SAE; placebo: 89% AE and 27% SAE) (Ataga et al 2017). In addition, further PK 
modeling of 5.0 mg/kg and 2.5 mg/kg every 4 weeks demonstrates that the 5.0 mg/kg dose will 
provide trough PK levels of crizanlizumab above that necessary to achieve consistent blockade 
of P-selectin during the 12-month Phase II study.


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Crizanlizumab 5 mg/kg dose is further supported by the data from healthy subjects in the 
Phase I Study CESG101A2102, and by data from SCD patients in the Phase II Study 
CSEG101A2202 and the 1st cohort of CSEG101B2201.
4.3
Rationale for choice of control drugs
This is a single arm study. Therefore, no control group will be assigned.
4.4
Purpose and timing of interim analyses
A formal interim analysis for this study is not planned and shall not be performed. For 
publication purposes, only descriptive data will be reported, as needed. Any decision on study 
continuation will not be based on these reports, as such no alpha adjustment will be needed.
4.5
Risks and benefits
Please refer also to the latest version of the Investigator 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. 
Pooled safety data from the SUSTAIN and CSEG101A2202 studies in patients treated with 
crizanlizumab 5 mg/kg (n=111 patients, Mar Oct 2019 cutoff) showed that crizanlizumab is 
generally associated with a favorable safety profile. Adverse drug reactions (ADRs) were 
nausea (16.2%), back pain (15.3%), arthralgia (14.4%), pyrexia (14.4%), abdominal pain 
(9.0%), diarrhea (8.1%), pruritus (7.2%), vomiting (5.4%), myalgia (4.5%), musculoskeletal 
chest pain (4.5%), oropharyngeal pain (3.6%), infusion site reaction (2.7%), and infusion-
related reaction (1.8%).  
In addition, in the randomized SUSTAIN study the overall frequency of AEs, SAEs and AEs 
leading to treatment discontinuation was similar among patients treated with crizanlizumab 5 
mg/kg and placebo. Use of crizanlizumab in combination with HU/HC did not result in any 
meaningful differences in the safety profile. 
Based on class effects, pre-/clinical findings, the mechanism of action of crizanlizumab, 
identified and potential risks include the following: 
Infusion-related reactions (IRRs) 
Administration of monoclonal antibodies (mAbs) can be associated with IRRs. A focused 
search for potentially “severe” IRRs (i.e. indicative of hypersensitivity/anaphylaxis or cytokine-
release syndrome) identified 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. 


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However, severe IRRs including cases requiring hospitalization have been described in ongoing 
clinical trials and 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%), 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 difference of more than 5% in the crizanlizumab 5 
mg/kg vs. the placebo arm and none were 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 commonly 
associated with infusion related reactions, some of which can be severe and/or require 
hospitalization. Patients should be monitored for potential signs and symptoms of IRRs, and 
subjects 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). 
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 55 (49.5%) patients in the safety pool. The most frequently 
reported infections were urinary tract infection (13 patients, 11.7%), upper respiratory tract 
infections (11 patients, 9.9%), pneumonia (5 patients, 4.5%) and sinusitis (4 patients, 3.6%). 
Most infections were low in severity (Grade 1 or 2). In the randomized SUSTAIN study, 
infection-related AEs were 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.


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Effect on hemostasis 
Considering the mode of action of crizanlizumab and physiological role of P-selectin, a 
potential effect on the hemostatic system was evaluated by searching for AEs related to 
hemorrhage, abnormal laboratory parameters. In the safety pool, a search for hemorrhagic 
events identified 16 (14.4%) patients. Except for prolonged prothrombin time, 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, subjects 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. 
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. 
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 


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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 subjects in this trial may be minimized by compliance with 
the eligibility criteria and study procedures and close clinical monitoring. If deemed clinically 
necessary, subjects 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.
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. The risk/benefit balance will be 
re-evaluated as and when required whilst the COVID-19 pandemic continues.
5
Population
A total of approximately 36 male patients with SCD-related priapism aged ≥ 12 years will be 
recruited across the United States. To be considered for this study, subjects must have had ≥4 
priapic events during the 14 weeks prior to screening and having at least 3 priapic events during
the 12 week screening period with at least 1 event occurring within 4 weeks prior to the first 
treatment.
The investigator or designee must ensure that only subjects who meet all the following inclusion 
and none of the exclusion criteria are enrolled in the study.
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria:
1. Signed informed consent and applicable adolescent assent and/or parental consent for 
adolescent subjects, must be obtained prior to participation in the study
2. Male patients aged 12 years and above
3. Confirmed diagnosis of SCD by hemoglobin electrophoresis or high performance liquid 
chromatography. All SCD genotypes are eligible (HbSS, HbSβ0, HbSC, HbSβ+, and 
others)
4. Patients who have experienced ≥4 priapic events (unwanted erection lasting at least 
60 minutes) over 14 week pre-screening
5. Patients who have experienced at least 3 priapic events (unwanted erection lasting at least 
60 minutes) during the 12 week screening period with at least 1 event occurring within 
4 weeks prior to the first treatment.


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6. If receiving HU/HC or L-glutamine or erythropoietin stimulating agent or voxelotor, must 
have been receiving the drug for at least 14 weeks prior to screening and plan to continue 
taking the drug at the same dose and schedule during the trial
7. If receiving prophylactic treatment for priapism, must have been receiving the drug for at 
least 14 weeks prior to screening and plan to continue taking the drug at the same dose and 
schedule during the trial
8. Adequate renal and hepatic function as defined prior to Week 1 Day 1:

Glomerular filtration rate ≥45 mL/min/1.73 m2 calculated by CKD-EPI

Alanine aminotransferase (ALT) ≤3 × ULN

Direct (conjugated) bilirubin ≤2 × ULN
9. Patient must meet the following laboratory values prior to Week 1 Day 1:

Absolute Neutrophil Count ≥1.0 × 109/L 

Hemoglobin > 4.0 g/dL

Platelets ≥75 × 109/L
5.2
Exclusion criteria
Subjects meeting any of the following criteria are not eligible for inclusion in this study.
1. Patients who have penile prosthetic implants. Shunts or any other surgical procedure on 
the penis performed within 12 months prior to consenting are not allowed.
2. Patients who have taken drugs/medications that may induce priapism (as per Appendix 5)
over the 14 weeks pre-screening period
3. Patients who have received leuprolide acetate (Lupron) or any other gonadotropin-
releasing hormone receptor (GnRHR) agonist agents within 3 months before pre-
screening.
4. Patients who had an erection lasting more than 12 hours over the 14 week pre-screening 
period
5. Patients who had an erection lasting more than 12 hours during the 12 weeks of the 
screening period
6. History of severe hypersensitivity reaction to other monoclonal antibodies, which in the 
opinion of the investigator may pose an increased risk of serious infusion reaction
7. Contraindication or hypersensitivity to any drug or metabolites from similar class as study 
drug or to any excipients of the study drug formulation
8. Received crizanlizumab
9. Received a monoclonal antibody or immunomodulatory agent within 1 year of screening, 
or has documented immunogenicity to a prior biologic
10. Received other selectin inhibitor or plans to receive it during the duration of the study
11. Patients should not be receiving another investigational trial within 30 days (or 5 half-lives 
of that agent, whichever is greater) prior to Screening or plans to participate in another 
investigational drug trial
12. History of familial long QT syndrome or know family history of Torsades de Pointes
13. History or current diagnosis of ECG abnormalities indicating significant risk of safety 
such as:


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
Concomitant clinically significant cardiac arrhythmias (e.g ventricular tachycardia), 
and clinically significant second or third degree AV block without a pacemaker
14. Subjects with evidence of current alcohol/drug abuse:
15. Any documented history of a clinical stroke or intracranial hemorrhage, or an 
uninvestigated neurologic finding within the past 12 months before screening. Silent 
infarct only present on imaging is not excluded
16. Clinically significant bleeding disorder
17. Planning to undergo a major surgical procedure during the duration of the study
18. Patient with active HIV infection (detectable viral load)
19. Patients with active Hepatitis B infection (HBsAg positive) 
Note: Patients with antecedent but no active Hepatitis B (i.e. anti-HBc positive, HBsAg 
and HBV-DNA negative) are eligible
20. Patients with positive test for hepatitis C ribonucleic acid (HCV RNA)
Note: Patients in whom HCV infection resolved spontaneously (positive HCV antibodies 
without detectable HCV-RNA) or those that achieved a sustained virological response 
after antiviral treatment and show absence of detectable HCV RNA ≥ 6 months (with the 
use of IFN-free regimes) or ≥ 12 months (with the use of IFN-based regimes) after 
cessation of antiviral treatment are eligible
21. Significant active infection or immune deficiency (including chronic use of 
immunosuppressive drugs)
22. 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
23. Not able to understand or comply with study instructions and requirements
24. Any condition which, in the opinion of the investigator, is likely to interfere with the 
successful collection of the measurements required for the study
6
Treatment
6.1
Study treatment
Novartis will supply crizanlizumab (SEG101) as an open-label medication. The investigational 
drug will be a crizanlizumab solution provided every 4 weeks with an additional loading dose 
2 weeks after the first dosing (i.e. dosing on first day of Week 1, Week 3, Week 7, and then 
every 4 weeks until Week 51).
6.1.1
Investigational and control drugs
Crizanlizumab will be supplied in single use vials containing 10 mL at a concentration of 
10 mg/mL for administration by IV infusion. Each study site will be supplied with study drug 
in packaging as described under investigational drugs section.
A unique medication number is printed on the study medication label.


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On infusion day, the pharmacist or designated personnel will prepare individual doses of 
crizanlizumab for subjects on a milligram per kilogram basis in a 100 mL infusion bag in 
accordance with the Pharmacy Manual. Study drug will be administered over 30 minutes by IV 
infusion. Please refer to Table 6-1 for dose and treatment schedule.
Table 6-1
Dose and treatment schedule
Study treatments
Pharmaceutical form 
and route of 
administration
Dose
Frequency and/or 
Regimen
Crizanlizumab
Intravenous infusion
5.0 mg/kg 
Week 1 Day 1, Week 3 
Day 1, Week 7 Day 1 
and Day 1 of every 
4-week cycle until 
Week 51
6.1.2
Additional study treatments
No additional treatments beyond investigational drug are included in this trial.
6.1.3
Treatment arm/group
This is single arm study, all the subjects enrolled in this study will receive crizanlizumab 
(5.0 mg/kg).
6.1.4
Treatment duration
The total duration of treatment in the study for each subject is planned to be up to 52 weeks.
Subjects may be permanently discontinued due to unacceptable toxicity, death, lost to -follow-
up or discontinued from the investigational treatment for any other reasons at the discretion of 
the investigator or the subject, prior to 52 weeks.
6.2
Other treatments
6.2.1
Concomitant therapy
6.2.1.1
Permitted concomitant therapy for the management of SCD
In general, the use of any concomitant medication/therapies deemed necessary for the care of 
the subject is permitted, except prohibited treatments (Section 6.2.2). The subject must be told 
to notify the investigational site about any new medications he/she takes within 30 days prior 
to initial dosing until the completion of the safety follow-up or EOT 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 or EOT visit as applicable 
must be listed on the Prior and Concomitant medications, Surgical and Medical Procedures, or 
Transfusion page of the Case Report/Record Form (CRF). 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 allowing a new medication to 


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be started. If the subject is already enrolled, contact Novartis/sponsor to determine if the subject 
should continue participation in the study. Concomitant sickle cell therapy with HU/HC, L-
glutamine or voxelotor is permitted, provided the subject has been prescribed HU/HC, L-
glutamine or voxelotor consistently over at least the 14 weeks prior to screening, as stated in 
the Inclusion criteria. The dosing should not be altered or terminated, other than for safety 
reasons until the subject has completed 1-year of investigational treatment. In subjects not on 
HU/HC,L-glutamine or voxelotor, treatment should not be initiated during the first year of 
investigational treatment. If a physician deems it is medically necessary to terminate or alter 
HU/HC treatment, L-glutamine or voxelotor during the first year of crizanlizumab treatment, 
changes should not lead by default to discontinuation of the trial; however, the medical monitor 
must be notified. Erythropoietin-stimulating agents are also permitted to manage chronic 
symptomatic anemia with the same requirement for 6 months prior therapy. Aspirin, 
nonsteroidal -anti-inflammatory drug (NSAIDs) and prophylactic doses (as per local 
guidelines) of anticoagulants are permitted, while other anti-platelets agents or anticoagulants 
at doses targeting therapeutic levels should be used with caution (refer to Section 6.2.1.3). All 
approved forms of analgesia for pain are permitted per standard of care. Other approved 
medications for supportive care (antiemetics, anxiolytics, hypnotics, antihistamines) are 
permitted, including marinol (dronabinol).
6.2.1.2
Permitted concomitant therapy for the management of SCD-related 
priapism
Concomitant prophylactic treatment for SCD-related priapism is permitted provided the subject 
has been prescribed the same medication consistently for at least 14 weeks prior to screening 
as per inclusion criterion 7. Dosing should not be altered or terminated other than for safety 
during the duration of the study. In subjects not on prophylactic medications, treatment should 
not be initiated during the study. If a physician deems it necessary to terminate or alter treatment 
during the study, the monitor must be notified immediately to determine whether the subject
may continue the study.
6.2.1.3
Permitted concomitant therapy requiring caution and/or action
Although transfusion of cellular blood products is permitted, it is unclear how such transfusions 
will impact crizanlizumab. It should also be considered that the administration of products 
containing immunoglobulins (plasma, IVIG, anti-globulins) may also impact the efficacy of 
crizanlizumab.
Although EndariTM, the FDA-approved version of L-glutamine, is permitted as outlined above, 
other over-the counter forms of L-glutamine are discouraged, as are other natural and herbal 
remedies (e.g. EvenFlo and/or products containing dang gui, Ligustrum root, ginseng root, 
white peony, corydalis, salvia, copodonosis, poria, jujube, angelica sinensis, lovage) due the 
unproven efficacy and variable quality and composition of these products. If other forms of L-
glutamine not approved by the FDA are used, the treatment information will be collected in the 
eCRF.  Vitamin and mineral supplements (e.g. fish oil, folic acid, L-arginine, L-citrulline, 
magnesium, riboflavin, vitamin C, vitamin D, vitamin E, and zinc) are also permitted, though 
caution is advised when taking amounts exceeding 100% of the recommended daily allowance.
It is recommended to avoid any live vaccines within 4 weeks prior to the first dose of 
investigational treatment and during study duration. However, the decision to administer or 


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withhold a vaccine should be done on case-by-case basis considering the potential 
benefits/risks such as developing severe infection, adverse effects from the vaccination, or 
vaccination failure.
Anti-platelets agents or anticoagulants at therapeutic doses should be used with caution due to
a potential effect of P-selectin on hemostasis.
Infusion related reactions have been observed with crizanlizumab administration. Prophylactic 
pre-medication with analgesics (e.g. paracetamol/acetaminophen or NSAID) and anti-
histamines (e.g. diphenhydramine or alternative, or in combination with H2 blocker) should be 
considered as per institutional standard of care, and at the discretion of the investigator. Steroids 
should be used with caution, and when clinically indicated (e.g. to manage 
hypersensitivity/anaphylactic reactions).
There is no existing clinical data on concomitant use of crizanlizumab and corticosteroids. For 
patients presenting for acute pain related to sickle cell disease, the 2020 guideline from 
American Society of Hematology suggests against corticosteroids for acute pain management 
(Brandow et al, 2020).
Further guideline on management of crizanlizumab infusion related reactions is provided in 
Table 6-2. If a subject experiences a Grade 3 or 4 infusion related reaction, the study treatment 
will be discontinued.
In the event that a major surgery becomes necessary, it is recommended to hold crizanlizumab 
for at least 4 weeks prior to the procedure, and then restart once the patient has fully recovered, 
at the investigator discretion.
6.2.2
Prohibited medication
The use of other investigational drugs is prohibited during the study. In addition, the 
administration of monoclonal antibodies other than the investigational treatment is prohibited, 
due to the theoretical potential for cross-reactivity and/or overlapping toxicities with other 
monoclonal antibodies. If investigational agents have been used in the past, they must have 
been discontinued at least 30 days or 5 half-lives of that agent, (whichever is greater) prior to 
the screening visit. Patients who have received a monoclonal antibody or immunomodulatory 
agent within 1 year of screening, or have documented immunogenicity to a prior biologic are 
not allowed to participate. Patients that have received prior treatment with crizanlizumab are 
not allowed to enroll in this study. Use of approved crizanlizumab or other selectin targeting 
agents is prohibited during the entire study duration.  
6.2.3
Rescue medication
Any standard medications that are used for management of VOC and acute priapic events are 
allowed.


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6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
Each subject is identified in the study by a Subject Number (Subject No.) that is assigned when 
the subject is first enrolled for screening and is retained as the primary identifier for the subject
throughout his entire participation in the trial. The Subject No. consists of the Center Number 
(as assigned by Novartis to the investigative site) with a sequential subject number suffixed to 
it, so that each subject is numbered uniquely across the entire database. Upon signing the 
informed consent form, the subject is assigned to the next sequential Subject No. available to 
the investigator through the Clinical Data Management System interface.
6.3.2
Treatment assignment, randomization
This is a single arm study. Therefore, no randomization will be performed in this study.
6.4
Treatment blinding
This is an open-label study. Investigators, subjects and sponsor will have full knowledge of the 
treatment allocation. In order to minimize the potential impact of the treatment knowledge, until 
the primary analysis is conducted, no aggregated statistical analyses (efficacy or safety across 
the study) shall be performed by treatment (other than analyses as specified in the study 
protocol).
6.5
Dose modification
If a subject does not tolerate the protocol-specified dosing schedule, dose interruptions are either 
recommended or mandated in order to allow subjects to continue the study treatment until the 
next scheduled dose. Dose reductions are not allowed.
If a subject experiences drug-induced toxicity, the subject should be closely monitored and a 
decision to continue or discontinue the subject from the study should be done at the next 
scheduled dose.
These dose interruptions are summarized in Table 6-2. Deviations to mandatory dose 
interruptions are not allowed. Permanent treatment discontinuation is mandatory for specific 
events indicated as such in Table 6-2.
Dose interruptions must be recorded in the Dosage Administration Record CRF. Every effort 
should be made to maintain the subject on the protocol-defined dosing schedule. In case of dose 
delay for any reason, the dose should be given as soon as possible. If that infusion visit occurs 
within ± 7 days of a protocol-scheduled visit, then the dose and all required assessments will be 
assigned to the nearest protocol-scheduled visit. However, if that infusion visit does not fall 
within ± 7 days of a protocol-scheduled visit, the dose and corresponding assessments will be 
documented as an unscheduled visit. At that point, every effort should be made to bring the 
subject's infusions back onto the protocol-defined schedule (within the ± 7 day window).. If a 
subject misses two consecutive doses of crizanlizumab due to ADR (i.e., an AE attributable to 
study drug), the subject should be discontinued from crizanlizumab. A subject with Grade 3 or 
4 IRR will be permanently discontinued from crizanlizumab. A subject with a Grade 4 ADR
will be permanently discontinued from the study.


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It is recommended that trial subjects 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 subject 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 subjects 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 subject completes the quarantine and remains asymptomatic and/or COVID-19 
has been ruled out.


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Table 6-2
Criteria for dose interruption and re-initiation of crizanlizumab treatment for adverse drug reactions.
Dose modifications for crizanlizumab
Worst toxicity
CTCAEa Grade (CTCAE version 5) during a cycle of therapy
Investigations (Hematologic)
Neutropenia (ANC)
Grade 1 (ANC < LLN - 1.5 x 109/L)
Recommendation: Maintain dose 
Grade 2 (ANC < 1.5 x 109/L-1.0 x 109/L )
Recommendation: Maintain dose 
Grade 3 (ANC < 1.5 x 109/L-0.5 x 109/L )
Mandatory: Interrupt dose until resolved to ≤ Grade 2 or next dose scheduled. If 
abnormality persists, permanently discontinue the subject from the study.
Grade 4 (ANC < 0.5 x 109/L)
Mandatory: Permanently discontinue the subject from the study.
Febrile neutropenia (ANC < 1.0 x 109/L, fever ≥ 38.3°C)
Mandatory: Interrupt dose until resolved or next dose schedule. If abnormality persists,
permanently discontinue the subject from the study.
Trombocytopenia
Grade 1 (PLT < LLN - 75 x 109/L)
Recommendation: Maintain dose 
Grade 2 (PLT < 75 - 50 x 109/L)
Recommendation: Maintain dose
Grade 3 (PLT < 50 - 25 x 109/L)
Recommendation: Interrupt dose until resolved to ≤ Grade 2 or next dose scheduled. If 
abnormality persists, permanently discontinue the subject from the study. 
Grade 4 (PLT < 25 x 109/L)
Mandatory: Permanently discontinue the subject from the study.
Investigations (Hepatic)
Isolated Direct Bilirubin
Grade 1
(>ULN - 1.5 x ULN if baseline was normal; > 1.0 - 1.5 x
baseline if baseline was abnormal)
Recommendation: Continue study treatment 
PI


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Grade 2 and 3
(>1.5 - 10.0 x ULN if baseline was normal; >1.5 - 10.0
x baseline if baseline was abnormal)
Recommendation: Interrupt study treatment. Monitor Iiver function tests (LFTs)b weekly, or 
more frequently if clinically indicated, until resolved to ≤ 1.5 x ULN or baseline. If resolved
to ≤Grade 1 or baseline, then continue study treatment.
Grade 4 (>10.0 x ULN if baseline was normal; >10.0
x baseline if baseline was abnormal)
Mandatory: Permanently discontinue from study treatment. 
Isolated ALT elevation 
Grade 1 (> ULN - 3.0 x ULN)
Recommendation: Maintain dose 
Grade 2 (> 3.0 - 5.0 x ULN)
Recommendation: Maintain dose. 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.
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 subject from the study.
Combined c elevations of ALT and bilirubin (direct [conjugated])
For subjects with normal baseline ALT and direct 
bilirubin value:

ALT > 3.0 x ULN combined with direct bilirubin 
> 2.0 x ULN without evidence of cholestasisc
OR 
For subjects with elevated baseline ALT or direct 
bilirubin value:

ALT > 2 x baseline AND direct bilirubin > 2.0 x 
baseline 
Mandatory: In the absence of cholestasisc (ALP < ULN), subject should be immediately 
discontinued from study 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 6.5.1.1 for additional follow-up evaluations as applicable.
Infections


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Grade 1
Recommendation: Maintain dose level
Grade 2
Recommendation: Maintain dose level
Grade 3
Mandatory: Interrupt dose until resolved. If resolved, then continue with next dose 
scheduled.
Grade 4 
Mandatory: Permanently discontinue the subject from the study.
Infusion-related reactions
Grade 1
Mild transient reaction; infusion interruption not 
indicated; intervention not indicated
Recommendation: 

Continue study treatment and increase monitoring of vital signs as medically 
indicated until the subject is deemed medically stable in the opinion of the 
investigator. 

Consider slowing infusion rate.
Grade 2
Therapy or infusion interruption indicated but responds 
promptly to symptomatic treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); prophylactic medications 
indicated for <=24 hrs
Recommendation:

Temporarily interrupt infusion and increase monitoring of vital signs as medically 
indicated until the subject is deemed medically stable in the opinion of the 
investigator. 

Administer appropriate medical therapy (e.g. analgesics such as paracetamol 
/acetaminophen or NSAIDs and anti-histamines), as per local institutional 
guidelines and clinical presentation.
o
Steroids should be used with caution unless clinically indicated (e.g. 
management of hypersensitivity/anaphylaxis).

If symptoms resolve, restart infusion per investigator discretion at a slower rate 
under continuous observation. Ensure a minimum of 1 hour observation period 
prior to restarting the infusion.
o
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 reactions despite premedication and prolonged 
infusion, consider discontinuation of study treatment. 


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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.
General Note: Decision for dosing is made on prior lab results, not those from labs performed on the day of infusion. If lab results are found to be abnormal, repeat 
(unscheduled) labs should be performed at least 1 week prior to scheduled dose in order to have results showing resolution of the abnormality before the scheduled 
dose is given. 
a Common Terminology Criteria for Adverse Events (CTCAE Version 5.0)
b Core LFTs consist of ALT, AST, GGT, total bilirubin (fractionated [direct and indirect], and alkaline phosphatase 
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 cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R > 2 and < 5) liver injury


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6.5.1
Follow-up for toxicities
Subjects whose study drug 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 etc.) should 
be consulted as deemed necessary. All subjects must be followed up for AEs and SAEs for 
105 days as applicable following the last dose of study of treatment.
6.5.1.1
Follow up on potential drug-induced liver injury (DILI) cases
Subjects with an elevation of transaminases in combination with an increase of total bilirubin 
(TBIL) and a normal ALP may be indicative of potential DILI, and should be considered as 
clinically important events.
NOTE: Subjects with SCD tend to have elevated transaminases, especially AST and indirect 
bilirubin, due to the hemolytic nature of their condition. Hence, ONLY ALT and direct bilirubin 
will be required in this criteria. 
Subjects meeting any of the following criteria will require further follow-up as outlined below:

For subjects with normal ALT and direct bilirubin value at baseline:
ALT > 3.0 × ULN combined with direct bilirubin > 2.0 × ULN without evidence of 
cholestasis

For subjects with elevated ALT or direct bilirubin value at baseline:
ALT > 2 × baseline AND direct bilirubin > 2 × baseline 

For subjects with normal ALT at baseline: ALT > 5.0 × ULN for more than 2 weeks

For subjects with elevated ALT at baseline: ALT > 3.0 × baseline for more than 
2 weeks
For these subjects, repeat LFTs as soon as possible, preferably within 48-72 hours. Subjects
should be closely monitored and workup for competing etiologies initiated, including hemolysis 
or cholestasis, defined as ALP elevation > 2.0 × ULN with R value < 2.
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R > 2 and < 5) liver injury).
In the absence of cholestasis or an alternative explanation, these subjects should be immediately 
discontinued from study treatment. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of new liver lesions, obstructions/compressions
as described below.
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, gamma-glutamyl transferase (GGT), prothrombin time (PT)/INR,
and ALP.
2. A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected.


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3. Further central testing for acute hepatitis A, B, C or E infection and liver imaging (e.g.
biliary tract) may be warranted.
4. Additional central testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist.
All cases confirmed on repeat testing and meets the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant”, thus, meet the definition of SAE and should be reported as a SAE using the term 
“potential drug-induced liver injury”. All events should be followed up with the outcome clearly 
documented.
6.6
Additional treatment guidance
6.6.1
Treatment compliance
Compliance will be assessed by administration of the investigational treatment under the 
supervision of the investigator or his/her designee. This information must be captured in the 
source document and in the Drug Accountability Form.
6.6.2
Recommended treatment of adverse events
Treatment for AEs will be determined by the study investigator. Medication used to treat AEs 
must be recorded on the appropriate CRF Preparation and dispensation.
6.7
Handling of study treatment and additional treatment
6.7.1
Handling of study treatment
Investigational treatment 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 
investigational treatment must be stored according to the instructions specified on the labels
and in the Investigator’s Brochure. Clinical supplies are to be dispensed only in accordance 
with the protocol and Pharmacy Manual. Technical complaints are to be reported to the 
respective Novartis CPO Quality Assurance.
The pharmacist or delegate will inventory and acknowledge receipt of all shipments of 
investigational treatment. The pharmacist will also keep accurate records of the quantities of 
study drug dispensed and used by each subject. Monitoring of drug accountability will be 
performed by field monitors during onsite 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 investigational treatment but no 
information about the subject except for the medication number.
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.


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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 as per local regulation/guidelines.  
Otherwise, the investigator or delegate will return all unused study treatment, packaging, drug 
labels, and a copy of the completed drug accountability log to the Novartis monitor or to the 
Novartis address provided in the investigator folder at each site.
6.7.2
Instruction for prescribing and taking study treatment
All the instructions will be provided in the pharmacy manual.
7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB-approved informed consent.
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent 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 subject source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB.
Information about common side effects already known about the investigational drug can be 
found in the Investigator’s Brochure. This information will be included in the subject informed 
consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between 
Investigator’s Brochure 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 subject.
Male subjects must be informed that if a female partner becomes pregnant while he is enrolled 
in the study, contact with the female partner will be attempted to request her consent to collect 
pregnancy outcome information.
The study includes an optional biomarker component which requires a separate signature if the 
subject agrees to participate. It is required as part of this protocol that the investigator presents 
this option to the subjects, as permitted by local governing regulations. The process for 
obtaining consent should be exactly the same as described above for the main informed consent.
Declining to participate in these optional biomarker assessments will in no way affect the 
subject’s ability to participate in the main research study.


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A copy of the approved version of all consent forms must be provided to Novartis/sponsor after 
IRB/IEC approval.
Subjects might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience.
8
Visit schedule and assessments
Table 8-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the subject’s source 
documentation.
Subjects should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time as possible. Missed or rescheduled visits 
should not lead to automatic discontinuation. Subjects who prematurely discontinue the study 
for any reason should be scheduled for a visit as soon as possible, at which time all of the 
assessments listed for the final visit will be performed. At this final visit, all dispensed 
investigational product should be reconciled, and the AE and concomitant medications recorded 
on the CRF.
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule.
The table indicates which assessments produce data to be entered into the clinical database (D) 
or remain in source documents only (S) (“Category” column).
Allowed visit windows are specified as follows:

Screening assessments must occur within 84 days (12 weeks) ± 7 days prior to the 
enrollment as per Table 8-1.

For all screening visits a general ± 7 day visit window is allowed

A ± 7 day visit window is allowed at Week 1 Day 1 (calculated from day of consent)

A ± 3 day visit window is permitted on assessments at Week 3 Day 1.

For all other dosing visits a general ± 7 day visit window is permitted on assessments 

A ± 7 day visit window for the end of treatment phase (last infusion + 2 weeks) is allowed.

A + 7 day visit window for the end of the safety follow-up phase (last infusion + 105 
days) is allowed.
Every effort should be made to follow the schedule outlined in Table 8-1.


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Table 8-1
Assessment Schedule
Reference 
to protocol 
section
Screening phase
Treatment phase
End of 
treatment 
(EOT)
Follow up 
phase
(as applicable)f
Visit Number
1
2
3
101
102
In every 
4th Cycle
108
In every 
4th Cycle
114
Visit on Day1 of the 
week (unless otherwise 
specified)a
Screening
(-Day 84 to Day -1)
Wk1
Wk3
Wk7, 11, 
4qWk
Wk27
Wk31, 
35, 4qWk
Wk 51: last 
infusion
Wk 53
Last infusion + 
105d
Day -84 
to 
Day -57
Day -56 
to 
Day -29
Day-28 
to 
Day -1
Screening
Obtain Study Informed 
Consent
8.1
X
Priapism medical 
history questionnaire
8.1
X
Obtain optional 
Informed Consent for 
future biomarker 
studies
8.1
X
Disposition assessment
End of phase 
disposition
8
X
X
X
Subject history
Demography
8.1.3
X
Inclusion/exclusion 
criteria
5.1/5.2
X
Medical History
8.1.3
X
Sickle Cell – VOC
history
8.1
X
Priapism Historye
8.1
X
Alcohol history
8.1
X


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Reference 
to protocol 
section
Screening phase
Treatment phase
End of 
treatment 
(EOT)
Follow up 
phase
(as applicable)f
Visit Number
1
2
3
101
102
In every 
4th Cycle
108
In every 
4th Cycle
114
Visit on Day1 of the 
week (unless otherwise 
specified)a
Screening
(-Day 84 to Day -1)
Wk1
Wk3
Wk7, 11, 
4qWk
Wk27
Wk31, 
35, 4qWk
Wk 51: last 
infusion
Wk 53
Last infusion + 
105d
Day -84 
to 
Day -57
Day -56 
to 
Day -29
Day-28 
to 
Day -1
Smoking history
8.1
X
Drug history
8.1.3
X
Physical rxamination
Physical examination
8.3.1
X
X
Abbreviated physical 
exam
8.3.1
X
X
X
X
X
X
Vital signs
8.3.1
X
X
X
X
X
X
X
X
Height 
8.3.1
X
Weight
8.3.1
X
X
X
X
X
X
X
Laboratory assessments
Hematology
8.3.2
X
X
X
X
X
X
X
X
X
Platelets (Local)d
8.3.2
X
X
X
X
X
X
X
X
X
Chemistry
8.3.2
X
X
X
X
X
X
X
X
X
Coagulation
8.3.4
X
X
X
X
X
X
X
X
X
Urinalysis 
8.3.3
X
X
X
X
X
X
X
X
X
Hepatitis testing
8.3.6
X
HIV test
8.3.8
X
Optional blood sample 
for future biomarker
8.5
X
X
Efficacy assessments
Priapic Events
8.2.2.1 and 
8.2.2.2
X
X
X
Continuous
.


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Reference 
to protocol 
section
Screening phase
Treatment phase
End of 
treatment 
(EOT)
Follow up 
phase
(as applicable)f
Visit Number
1
2
3
101
102
In every 
4th Cycle
108
In every 
4th Cycle
114
Visit on Day1 of the 
week (unless otherwise 
specified)a
Screening
(-Day 84 to Day -1)
Wk1
Wk3
Wk7, 11, 
4qWk
Wk27
Wk31, 
35, 4qWk
Wk 51: last 
infusion
Wk 53
Last infusion + 
105d
Day -84 
to 
Day -57
Day -56 
to 
Day -29
Day-28 
to 
Day -1
Sickle Cell – VOC
Event
8.2.2
Continuous
Chest x-rayb
8.2.2
X
As clinically indicated
Hospitalization
8.2.2
X
X
X
Continuous
Prior/concomitant 
medications –
Analgesic
8.2.2
X
X
X
Continuous
Prior/concomitant 
medications -
Hydroxyurea
8.2.2
Continuous
Transfusion
8.2.2
Continuous
Employment status and 
sick time
8.2.2
X
X
X
X
Safety assessments
ECG
8.3.5.1
-
X
X
Cardiac imaging
8.3.5.2
X
X
Urine protein/creatinine 
ratio
8.3.7
-
X
X


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Reference 
to protocol 
section
Screening phase
Treatment phase
End of 
treatment 
(EOT)
Follow up 
phase
(as applicable)f
Visit Number
1
2
3
101
102
In every 
4th Cycle
108
In every 
4th Cycle
114
Visit on Day1 of the 
week (unless otherwise 
specified)a
Screening
(-Day 84 to Day -1)
Wk1
Wk3
Wk7, 11, 
4qWk
Wk27
Wk31, 
35, 4qWk
Wk 51: last 
infusion
Wk 53
Last infusion + 
105d
Day -84 
to 
Day -57
Day -56 
to 
Day -29
Day-28 
to 
Day -1
Adverse Event/ Serious 
Adverse Event
10
Continuous
IRRc
4.5
Continuous
Prior/concomitant 
medications
6.2.1
Continuous
Study Drug administration
Crizanlizumab IV
6.1.1
X
X
X
X
X
X
a In case the study drug is interrupted, the dose should be resumed as soon as possible. If the dose is delayed for more than 7 days, every effort should be made to bring the 
subject's infusions back onto the protocol-defined schedule (Section 6.5).
b Chest X-ray must be conducted during the screening period and must be repeated in case of suspected acute chest syndrome, during the during the treatment or follow-up.
c Certain adverse events reported in the AE/SAE eCRF as Infusion Related Reactions will require the IRR eCRF to be completed.
d Local sampling for platelet assessment will be performed throughout the trial for all subjects.
e The date, number, and duration of the priapic events in the 14-week period prior to consenting will be captured in a separate CRF.
f Subjects who will receive commercially approved crizanlizumab approximately 4 weeks after their last dose of study treatment, do not need to complete the 105-day follow-up.


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8.1
Screening
After signing the study informed consent form (ICF), the screening assessments will be done 
within the screening window prior to Week 1 Day 1 (see Table 8-1 for list of assessments to be 
performed). During this screening period, the prospective subjects will need to come to clinic 
for 3 visits: at Day -84, at Day -56, and at Day-28. At the first screening visit after signing the 
ICF (at Day -84), subjects will be briefed about the study requirements, including the instruction 
on how to record the priapic event(s) information as described in Section 8.2.4. At the first 
screening visit, the prospective subjects will also be asked about their prior medical history 
related to priapism. This information will be collected via a priapism medical history
questionnaire. The investigator will obtain consent/assent of subjects and/or parents according 
to local procedures. The additional details of the procedure of informed consent has been 
provided in Section 7.
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 subject. If the results from the central laboratory are partial or unavailable before the 
first infusion, local sampling is allowed. In addition, local re-sampling for platelet count test is 
allowed at any time in case of clumping or other issues reported from the central laboratory. 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 subject will be considered a 
screening failure. For details of assessments, see Table 8-1. Assessments of subject reported 
outcomes should be collected prior to any clinical assessments, drug dosing or diagnostic testing.
Re-screening of subjects is allowed if the subject has not been treated and was screened failed. 
In case of re-screening, site should enter this patient as a new subject with a new ID. A new 
informed consent form must also be signed. AEs and medical history will be assessed relative 
to the new informed consent date.
The study includes an optional biomarker component which requires a separate signature if the 
subject agrees to participate. For details, see Section 7.
8.1.1
Eligibility screening
The investigator is responsible to ensure only subjects who meet all inclusion and do not meet 
any exclusion criteria are included in the study.
Subject eligibility will be checked by the sponsor once all screening procedures are completed. 
The eligibility check form will be sent from the site to the sponsor via email for evaluation. 
Upon confirmation of eligibility, the sponsor will return the signed eligibility check form via 
email to the site. The investigator site will then be allowed to start treatment to the subject. 
Please refer and comply with detailed guidelines in the eligibility check user guidelines for the 
manual process.
8.1.2
Information to be collected on screening failures
Subjects who sign an informed consent but fail to be enrolled (subject who does not enter in the 
treatment phase) for any reason will be considered a screen failure. The reason for not being 
started on treatment will be entered on the screening phase disposition page. The demographic 


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information, informed consent, Inclusion/Exclusion pages and, if applicable, withdrawal of 
informed consent must also be completed for screen failure subjects. No other data will be 
entered into the clinical database for subjects who are screen failures, unless the subject
experienced an SAE during the screening Phase (see Section 10 for SAE reporting details).
If a screen failure subject experiences an AE which does not meet the SAE criteria, details about 
the AE will be recorded only in the investigator’s source documents. In case of an SAE after 
signing of main study informed consent, data must be recorded on both the AE and SAE forms.
If the subject fails to be enrolled, the sponsor must be notified within 2 days of the screen fail 
via email that the subject was not enrolled.
8.1.3
Subject demographics/other baseline characteristics
Subject demographic characteristics, which include age, gender, self-identified race and 
ethnicity, will be collected.
Following are the examples of the procedures that will be performed at the baseline: 

Background medical information including sickle cell and VOC history, priapism history, 
blood transfusion history, leg ulcer, ECG, cardiac imaging and urine protein/creatinine 
ratio. 

Relevant and current medical history; SCD genotypes (HbSS, HbSβ0, HbSC, HbSβ+, and 
others).

Concomitant medication use; history of analgesic and hydroxyurea use.

Complete physical examination.

Vital signs (blood pressure pulse measurement, respiratory rate, oxygen saturation, and 
body temperature), weight and height.

Clinical laboratory evaluations

Chest X-ray, if none has been performed within 3 months of Day 1
Drug, alcohol and smoking history will also be collected. The details of other baseline 
characteristics and assessments that will be performed at the screening for eligibility are detailed 
in Table 8-1.
8.2
Efficacy
8.2.1
Primary efficacy endpoint
Priapism is defined as an unwanted or painful penile erection lasting at least 60 minutes. The 
end of the priapic event will be the duration when the unwanted erection has resolved. This 
event will be self-reported, and this data should be collected throughout the study period. In 
order to be treated as independent priapic events, two events will have to be separated by at 
least 2 hours, and the event would have to return to baseline during those 2 hours. Primary 
efficacy endpoint will be assessed by evaluating the percent reduction in priapic events by 26 
weeks.


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8.2.2
Secondary efficacy endpoints
For purposes of this study, the following detailed definitions will be used to identify each 
sub-type of VOC event:
8.2.2.1
Priapic events
Priapism, as defined in the primary efficacy endpoint (Section 8.2.1), will also be assessed by 
evaluating the rate of priapic events by weeks 26 and 52.
8.2.2.2
Acute priapic events
Acute priapic events are defined as unwanted or painful erections that last at least 4 hours and 
need a visit to the emergency room. Management of ischemic priapism requires aggressive and 
stepwise procedures to achieve prompt resolution. Aspiration/irrigation, in combination with 
intracavernous injections of α-agonist is usually the first-line therapy. Penile blood aspiration 
involves using a transglanular intracorporal angiocatheter insertion or a proximal penile shaft 
needle access. The percent reduction in acute priapic events from baseline by 26 and 52 weeks 
of treatment will be assessed.
8.2.2.3
Uncomplicated VOC
An uncomplicated pain crisis is defined as an acute event of pain with no known cause for pain 
other than a vaso-occlusive event; and requiring treatment with a parenteral or oral opioids or 
other parenteral analgesic; but is NOT classified as an acute chest syndrome, hepatic 
sequestration, splenic sequestration, or priapism. The end of an uncomplicated pain crisis will 
be considered the resolution of acute pain, such that residual pain (or absence of any pain) is
considered to be chronic, and the current pain medication regimen is considered to be for this 
chronic pain.
8.2.2.4
Complicated VOC
8.2.2.4.1 Acute Chest Syndrome
Acute Chest Syndrome is defined on the basis of the finding of a new pulmonary infiltrate 
involving at least 1 complete lung segment that was consistent with alveolar consolidation, but 
excluding atelectasis (as indicated by chest X-ray). At least 1 of the following additional signs 
or symptoms needs to be present as well: chest pain, a temperature of more than 38.5°C, 
tachypnea, wheezing, or cough. Acute chest syndrome will be considered resolved when the 
subject is no longer hospitalized (unless for reason other than the acute chest syndrome event) 
and none of the additional signs or symptoms above are present.
8.2.2.4.2 Hepatic sequestration
Hepatic sequestration is defined on the basis of findings of right upper quadrant pain, an 
enlarged liver, and an acute decrease in hemoglobin concentration (e.g. a decrease in 
hemoglobin of ~ 2 g/dL). Acute hepatic sequestration will be considered resolved when right 
upper quadrant pain has returned to baseline (pre-event) levels and hemoglobin has been stable 
for 24 hrs.


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8.2.2.4.3 Splenic sequestration
Splenic sequestration if defined on the basis of findings of left upper quadrant pain, an enlarged 
spleen, and an acute decrease in hemoglobin concentration (e.g. a decrease in hemoglobin of 
~ 2 g/dL). Acute splenic sequestration will be considered resolved when left upper quadrant 
pain has returned to baseline (pre-event) levels and hemoglobin has been stable for 24 hrs.
General considerations for VOC assessments
Associated conditions in SCD (e.g. intermittent or chronic pain due to ankle/leg ulcers, aseptic 
necrosis of bone or gout) should not be considered VOC events. Similarly, complications such 
as pulmonary, cardiac, or renal failure are not themselves to be considered. If such events 
precipitates VOC, the VOC event will be documented separately.
For each visit to a medical facility for a pain event thought to be a VOC, the following 
information must be documented in the eCRF; diagnostic evaluation for the event, subject
treatment and management, course, duration of the crisis, and outcome. For subjects 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. 
Subjects should be encouraged to contact the investigator (or surrogate from the site) when they 
believe they are experiencing a VOC, which they believe they can manage at home, both for 
treatment guidance and for accurate information which may be obtained for the VOC eCRF 
page. VOCs and other acute pain crisis managed at home will be reconciled at regular study 
visits and captured in the corresponding VOC eCRF.
If a subject experiences a VOC surrounding a protocol-scheduled visit day, and the subject
presents for this visit, it will be counted as a VOC that led to a healthcare visit (provided the 
event meets the criteria for VOC discussed above). VOC is not a known contra-indication, but 
dosing during a crisis should be at investigator’s discretion.
General considerations for Chest X-Rays and transfusions
Chest X-Ray must be conducted during the screening period. Chest X-Ray must be repeated in 
case of suspected acute chest syndrome.
Transfusion data should be collected during the screening period until the subject end of 
treatment (EOT). Episodic transfusion in response to worsened anemia or VOC is permitted.


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Table 8-2
Vaso-Occlusive Crisis Assessment Collection Plan 
Procedure / Assessment 
collection plan
Screening/Baseline
During Treatment/Follow-up
Chest X-Ray
Mandated
If clinically indicated
Vaso-Occlusive Crisis 
information 
Mandated
Mandated, when VOC crisis 
occurs
Concomitant medication -
Analgesic
If clinically indicated
Mandated, when VOC crisis 
occurs
Hospitalization details
If clinically indicated
Mandated, when VOC crisis 
occurs and hospitalization is 
done
Transfusion
If clinically indicated
If clinically indicated
Employment status and sick 
time 
If clinically indicated
If clinically indicated
 
8.2.4
Collection of priapic event information
Electronic reporting tools have been shown in adolescents to have additional advantages over 
the paper format for accuracy as well as compliance in recording PROs (McGrath et al 2008). 
In SCA subjects, daily reporting tool have been shown a more sensitive means of capturing 
reported pain frequency than through retrospective interviews (Porter et al 1998).


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In this study, an electronic event reporting system, paper system or a call center will be used to 
collect information on the event by answering a few simple questions. The questionnaire will 
include information on what triggered the event, the event duration, and how the event was 
managed.. Subjects will receive daily reminders to record whether or not they have experienced 
a priapic event. Reconciliation of the events will be conducted by the site personnel at each 
scheduled study visit.
8.2.5
Appropriateness of efficacy assessments
The primary objective of this study is to evaluate the clinical efficacy of crizanlizumab in 
SCD-related priapism. A very significant proportion of male patients, ranging from 35% to 89%, 
with SCD have a history of priapism (Howard and Telfer 2015). Scientific evidences suggested 
a role of P-selectin for the priapic events. In this study, the hypothesis is that crizanlizumab 
treatment will reduce priapic events by at least 25% in SCD patients with priapism. Therefore, 
the current efficacy assessment plan of quantifying the reduction in priapic event is considered 
appropriate.
Sickle cell–related pain crises were defined as acute events of pain, with no medically 
determined cause other than a vaso-occlusive event that resulted in a medical facility visit and 
treatment with oral or parenteral narcotic agents or with a parenteral nonsteroidal 
anti-inflammatory drugs. The acute chest syndrome, hepatic sequestration, splenic 
sequestration, and priapism were also considered to be crisis events. Therefore, the planned 
assessment could be considered appropriate for this indication.
8.3
Safety assessments
Safety will be monitored by assessing physical examinations, vital signs, ECG, laboratory 
assessments including hematology, chemistry, coagulation, urinalysis and as well as collecting 
of the AEs at every visit. For details on AE collection and reporting, refer to Section 10.
8.3.1
Physical assessments
The physical assessments must be performed by the investigator as scheduled in Table 8-3.


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Table 8-3
Physical assessments
Assessment
Specification
Physical 
examination
A complete physical examination will include the examination of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities, vascular, and neurological. If indicated 
based on medical history and/or symptoms, rectal, external genitalia, breast, and 
pelvic exams will be performed. A complete physical examination will be 
performed at screening and within 7 days following last infusion.
An abbreviated (short) physical exam will include the examination of general 
appearance and vital signs (blood pressure [BP] and pulse), as well as additional 
components of the physical exam, as needed based on observed signs or reported 
symptoms. A short physical exam will be performed at all visits for which there is a 
scheduled study drug infusion.
Significant findings that were present prior to the signing of informed consent must 
be included in the Medical History page on the subject’s CRF. Significant new 
findings that begin or worsen after informed consent must be recorded on the 
Adverse Event page of the subject’s CRF.
Vital sign
Vital signs include blood pressure (supine position preferred when ECG is 
collected), pulse measurement, respiratory rate, oxygen saturation, and body 
temperature will be measured as specified in Table 8-1.
Height and 
weight
Height in centimeters (cm) will be measured at screening.
Body weight (to the nearest 0.1 kilogram (kg) in indoor clothing, but without shoes) 
will be measured at screening and all visits for which there is a scheduled study 
drug infusion (for dosing), as specified in Table 8-1.
8.3.2
Laboratory evaluations
Clinical laboratory analyses (hematology, chemistry, urinalysis, coagulation, hepatitis and HIV 
markers) are to be performed centrally according to the schedule of assessments and collection 
plan outlined in Table 8-1. Details on the collection, shipment of samples and reporting of 
results by the central laboratory are provided to investigators in the Central Laboratory Manual/. 
Visit windows are allowed for all visits (see Section 8).
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 subject 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 subjects in the study and evaluating any abnormalities for clinical significance.
For assessment of subjects’ eligibility to the study, only laboratory results from the central 
laboratory will be used (except in the event that the results from the central laboratory are not 
available 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).
Unscheduled local laboratory assessments may be performed if medically indicated to 
document a (potential) AE if central laboratory results are unevaluable or inconclusive, or when 
the treating physician cannot wait for central laboratory results for decision making. In this 


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particular situation, if possible, the blood sample obtained at the same time point should be 
submitted to the central laboratory for analysis in parallel with local analysis.
The results of the local laboratory will be recorded in the eCRF if any the following criteria are 
met:

A treatment decision was made based on the local results, or

There are no concomitant central results available, or

Local lab results document an AE not reported by the central lab, or

Local lab results document an AE where the severity is worse than the one reported by the 
central lab, or

Eligibility had to be based on the local lab results due to pending/missing central lab 
results.
Laboratory assessments 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 
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 Common Terminology 
Criteria for Adverse events (CTCAE) version 5.0 or later. Additional analyses are left to the 
discretion of the investigator.  
Specifically, for platelet count, local sampling will also be performed throughout the trial. To 
mitigate the potential for unevaluable or false low platelet counts (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.


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Table 8-4
Laboratory Assessments
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, MCH, MCHC, MCV, reticulocytes (%), Platelets*, Red 
blood cells, White blood cells, RBC Morphology, Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils, Bands, Other (absolute value 
preferred, %s are acceptable)
Chemistry
, Alkaline phosphatase, ALT, AST, Gamma-glutamyl-transferase (GGT), Lactate 
dehydrogenase (LDH), Bicarbonate, Calcium, Magnesium, Phosphorus, Chloride, 
Sodium, Potassium, Creatinine, Creatine kinase, Direct Bilirubin, Indirect Bilirubin, 
Total Bilirubin, Total Cholesterol, LDL, HDL, Total Protein, Triglycerides, Blood 
Urea Nitrogen (BUN) or Urea, Uric Acid, Amylase, Lipase, Glucose (non-fasting), 
estimated glomerular filtration rate (eGFR).
Urinalysis
Macroscopic Panel (Dipstick) will be done locally: Color, Bilirubin, Blood, 
Glucose, Ketones, Leukocytes esterase, Nitrite, pH, Protein, , Specific Gravity, 
Urobilinogen
Microscopic Panel will be performed if dipstick is positive: Red Blood Cells, 
White Blood Cells, Casts, Crystals, Bacteria, Epithelial cells
Urine creatinine/protein ratio, Microalbumin
Coagulation
Prothrombin time (PT) , International normalized ratio [INR]), Activated partial 
thromboplastin time (APTT)
Hepatitis 
markers
HBV-DNA, HbsAg, HbsAb, HbcAb, HCV RNA-PCR, HCV Ab (at screening only)
Additional 
tests
HIV Ab (at screening only)
Glomerular filtration rate (using CKD-EPI formula):
Glomerular filtration rate = 141 × min (Scr/κ,1)α × max(Scr/κ,1)-1.209 × 0.993Age × 1.159 [if 
black]
κ = 0.9 if male.
α = -0.411 if male
min = the minimum of Scr/κ or 1
max = the maximum of Scr/κ or 1
Scr: Serum creatinine (mg/dL)
8.3.3
Urinalysis
Macroscopic urinalysis dipstick analysis (blood, protein and glucose) will be performed locally
according to the schedule of assessments and collection plan outlined in Table 8-1. Detailed 
urinalysis panel is described on Table 8-4. Microscopic panel will be performed centrally if 
dipstick is positive.


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8.3.4
Coagulation
Prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin 
time (APTT) will be assessed centrally according to the schedule of assessments and collection 
plan outlined in Table 8-1.
8.3.5
Cardiac assessments
8.3.5.1
Electrocardiogram (ECG)
Standard 12-lead ECG will be performed (in the supine position) after the subject has been 
resting for 5-10 min prior to ECG assessments. 
A standard 12 lead ECG will be performed

at screening 

at the end of treatment
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. Unscheduled ECGs with clinically significant 
findings should be collected in triplicate. Local cardiologist ECG assessment may also be 
performed at any time during the study at the discretion of the investigator.
Interpretation of the tracing must be made by a qualified physician and documented on the ECG 
CRF page. Each ECG tracing should be labeled with the study number, subject initials (where 
regulations permit), subject number, date, and kept in the source documents at the study site.
Clinically significant ECG abnormalities present at screening should be reported on the Medical 
History CRF page. New or worsened clinically significant findings occurring after informed 
consent must be recorded on the Adverse Events CRF page.
8.3.5.2
Cardiac imaging 
Cardiac imaging will be performed by Echocardiogram (ECHO) in order to assess the left 
ventricular ejection fraction (LVEF) and mean pulmonary arterial pressure (mPAP), as 
estimated from the tricuspid regurgitation jet velocity (TRV) if assessable, or otherwise by other 
formula (per institutional preference). This assessment will be performed locally, interpreted 
by site personnel as per Table 8-1, and documented on the CRF page. Each echocardiography 
must be kept in the source documents at the study site. Clinically significant echocardiography 
abnormalities present at screening when the subject signed informed consent should be reported 
on the Medical History CRF page. Clinically significant findings must be discussed with 
Novartis prior to enrolling the subject.
New or worsened clinically significant findings occurring after informed consent must be 
recorded on the Adverse Events CRF page.
8.3.6
Hepatitis markers
Hepatitis testing will be performed centrally as per Table 8-1.


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8.3.7
Urine protein/creatinine ratio
At screening a urine sample (at least 15 ml) will be collected and sent to the central laboratory 
for urinary protein/creatinine ratio to assess the eligibility of the subject. The assessment will 
be repeated at the EOT. First morning void samples must not be used for this analysis.
8.3.8
Additional test
HIV screening will be performed centrally as per Table 8-1.
8.3.9
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/subject population.
8.4
Additional assessments


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8.4.2
VOCs as defined above, can be managed at home or by a healthcare visit.
 
 
 
 
 
 
 
8.5
Optional use of biological samples
If the subject agrees, additional blood sample will be collected at screening visit and EOT for 
future biomarker analysis outside of this study. The sample may be stored up to 15 years for 
future biomarker analysis and additional studies related to crizanlizumab or SCD. This may
include research to help develop ways to detect, monitor or treat SCD. A decision to perform 
such exploratory biomarker research studies would be based on outcome data from this study 
or from new scientific findings related to the drug class or disease, as well as assay availability.
The biological sample collection is optional and necessitates the consenting of the subject as 
described in Section 7.


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9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration and can be initiated by either the subject or the investigator.
The investigator must discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being.
Study treatment must be discontinued under the following circumstances 

Subject/guardian decision

Death

Use of prohibited treatment as per recommendations in the prohibited treatment section
(Section 6.2.2)

Any situation in which study participation might result in a safety risk to the subject

Discontinuation to study treatment due to toxicity that result in treatment discontinuation 
(see Section 6.5)

Any laboratory abnormalities that in the judgment of the investigator, taking into 
consideration the subject’s overall status, prevents the subject from continuing 
participation in the study
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information.
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see withdrawal of informed consent section,). Where possible, they should 
return for the assessments indicated in the assessment schedule. If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone, e-mail, and letter) should be 
made to contact the subject/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 subject cannot or is unwilling to attend any visits, the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule.
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:

new/concomitant treatments

AE/SAE
Subjects who discontinue study treatment should undergo an EOT visit within 14 days of the 
last dose of the discontinued study treatment, followed by a 105 day safety follow-up as 
applicable. At EOT visit, all the assessments as listed in Table 8-1 will be performed. If the 


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decision to discontinue the subject occurs at a regularly scheduled visit, that visit may serve as 
the EOT visit rather than having the subject return for an additional visit.
9.1.2
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore
and

Does not want any further visits or assessments
and

Does not want any further study related contacts
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued, and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communication or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made, as detailed in the 
assessment table.
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation.
All biological samples that have already been collected may be retained and analyzed at a later 
date (or as required by local regulations).
9.1.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed. Subjects lost to follow up should be recorded as such on the 
appropriate CRF.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the subject welfare and safety. Should early termination be 
necessary, subjects must be seen as soon as possible (provide instruction for contacting the 
subject, when the subject should stop taking drug, when the subject should come for a final 


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visit) and treated as a prematurely withdrawn subject. The investigator may be informed of 
additional procedures to be followed in order to ensure that adequate consideration is given to 
the protection of the subject’s interests. The investigator or sponsor depending on the local 
regulation will be responsible for informing IRBs of the early termination of the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last subject finishes their Study Completion visit
(defined as last patient last visit), and any repeat assessments associated with this visit have 
been documented and followed-up appropriately by the investigator, or in the event of an early 
study termination decision, the date of that decision. Subjects who will receive commercially 
approved crizanlizumab approximately 4 weeks after their last dose of study treatment, do not 
need to complete the 105-day follow-up. All other subjects are required to complete the 105-
day follow-up.
10
Safety monitoring and reporting
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 subject or clinical 
investigation subject after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual subject and 
identifying 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 subject at each visit 
during the study. Adverse events also may be detected when they are volunteered by the subject 
during or between visits or through physical examination findings, laboratory test findings, or 
other assessments.
Adverse events must be recorded 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 10.1.3):
1. The Common Terminology Criteria (CTC) AE grade (version 5.0 or higher). If CTCAE 
grading does not exist for an AE, the severity of mild, moderate, severe, and 
life-threatening, death related to the AE corresponding respectively to Grades 1 - 5, will 
be used. Information about any deaths (related to an AE or not) will also be collected 
though a Death form.
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected’. The rationale for this guidance is that the symptoms of a 


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lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single subject.
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported.
4. Whether it constitutes a SAE (see Section 10.1.3 for definition of SAE) and which 
seriousness criteria have been met
5. Action taken regarding with study treatment.
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Drug interrupted/withdrawn

Its outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown).
If the event worsens, the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. For Grade 3 and 4 AEs only, if improvement to a lower 
grade is determined a new entry for this event should be reported in the CRF noting the start 
date when the event improved from having been Grade 3 or Grade 4.
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 105 days following the last dose of 
study treatment as applicable
Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent (i.e. continuing at the end of the study), and assessment must be made at each visit 
(or more frequently, if necessary) of any changes in severity, the suspected relationship to the 
interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator’s Brochure.
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 subjects with 
the underlying disease.


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10.1.2
Protocol exempt AEs & SAEs
Protocol Exempt AEs & SAEs are implemented in the crizanlizumab program. VOCs must be 
reported on the VOC page in the eCRF. As VOCs are considered secondary endpoints for the 
purpose of evaluation of efficacy, AEs and SAEs involving VOCs SHOULD NOT be reported 
as AEs or SAEs for the purpose of this study. These events will not be considered as SAEs in 
regard to reporting requirements. Procedures which are directly related to the VOC, e.g.
ventilation of a patient with acute chest syndrome are considered part of the VOC and will not 
be reported as AE/SAEs but entered in
the CRF-page "concomitant non-drug 
therapies/procedures". Additional events or complications which are not VOCs itself will be 
reported as AE/SAEs. Details will be given in the CRF-completion guidance. In case that new 
information arises which changes the diagnosis of a VOC, i.e. gives another medically 
determined explanation than vaso-occlusion in the opinion of the investigator, the event has to 
be reported according to the rules of Section 10.1 and must be reported to Novartis within 
24 hours of learning of the new information.
The events in Table 10-1 will not be reported as AEs/SAEs.
Table 10-1
List of Events Not Requiring AE/SAE Reporting
VOC Events

Uncomplicated sickle cell-related pain crisis (SCPC) or vaso-occlusive crisis (VOC)*

Acute chest syndrome

Hepatic sequestration

Splenic sequestration

Acute priapism requiring a visit to a medical facility
*VOC is defined as pain crises (defined as an acute onset of pain for which there is no other medically 
determined explanation other than vaso-occlusion and which requires therapy with oral or parenteral 
opioids or parenteral NSAIDs) as well as other complicated crises, such as acute chest syndrome, 
acute priapism, and hepatic or splenic sequestration.
10.1.3
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 subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines).

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

routine treatment or monitoring of the studied indication, not associated with any 
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
elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization, or development of dependency or abuse.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered SAE irrespective 
if a clinical event has occurred. 
10.1.4
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until up to105 days after the subject has stopped study treatment 
must be reported to Novartis within 24 hours of learning of its occurrence. Detailed instructions 
regarding the submission process and requirements are to be found in the investigator folder 
provided to each site.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent events must be reported as follow-up to the original event 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.
Any SAEs experienced after the end of the safety evaluation follow-up period should only be 
reported to Novartis if the investigator suspects a causal relationship to the study treatment.
Each re-occurrence, complication, or progression of the original event should be reported as a 
follow-up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the subject continued or withdrew from study participation.


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Follow-up information is submitted in the same way as the original SAE Report and should 
describe whether the event has resolved or continues, if and how it was treated, and whether the 
patient continued or withdrew from study participation.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a Novartis Chief Medical Office 
and Patient Safety (CMO & PS) Department associate may urgently require further information 
from the investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same 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.
10.1.5
Pregnancy reporting
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. To ensure subject safety, each pregnancy occurring after 
signing the informed consent must be reported to Novartis within 24 hours of learning of its 
occurrence. The pregnancy should be followed up to determine outcome, including spontaneous 
or voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications.
Pregnancy should be recorded and reported by the investigator to the CMO&PS. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment any pregnancy outcome. Any SAE experienced 
during pregnancy must be reported.
10.1.6
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 
safety database irrespective of it being associated with an AE/SAE within 24 hours of 
investigator’s awareness.


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Table 10-2
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
CRF (Yes/No)
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the
respective sections.
10.2
Additional safety monitoring 
10.2.1
Steering committee
The steering committee will be established and comprised of SCD and priapism medical experts 
as well as Novartis representatives from the Clinical Trial Team.
The steering committee 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 clinical trial team, the SC 
will also develop recommendations for publications of study results including authorship rules. 
The details of the role of the steering committee will be defined in the steering committee 
charter.
11
Data Collection and Database Management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure 
web -enabled software that conforms to 21 CFR Part 11 requirements, investigator site staff 
will not be given access to the EDC system until they have been trained. Automatic validation 
programs check for data discrepancies in the eCRFs, allow modification and/or verification of 
the entered data by the investigator staff.
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The investigator must certify that the data entered is complete and accurate.
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.


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11.2
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and AEs will be coded using the Medical 
dictionary for regulatory activities (MedDRA) terminology.
At the conclusion of a non-IRT study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused supplies to Novartis.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and made available for data analysis/moved to restricted 
area to be accessed by independent programmer and statistician. Any changes to the database 
after that time can only be made after a written agreement by Novartis development 
management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eSource DDE or 
eCRFs) with the investigators and their staff. During the study, Novartis employs several 
methods of ensuring protocol and GCP compliance and the quality/integrity of the sites’ data. 
The field monitor will visit the site to check the completeness of subject records, the accuracy 
of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, the 
progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist the 
field monitor during these visits. Continuous remote monitoring of each site’s data may be 
performed by a centralized Novartis-affiliated 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/sponsor clinical teams to assist with 
trial oversight.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, ECGs, and the results of any other tests or assessments. All 
information on CRFs must be traceable to these source documents in the subject’s file. The 
investigator must also keep the original informed consent form signed by the subject (a signed 
copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 


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study-specific monitoring plan. No information in source documents about the identity of the
subjects will be disclosed.
12
Data analysis and statistical methods
Summary statistics for continuous variables will generally include the number of subjects, mean, 
standard deviation (SD), lower quartile (Q1), median, upper quartile (Q3), minimum, and 
maximum. For categorical or binary variables, the number and percent of subjects in each 
category will be presented.
The primary analysis of study data for the primary clinical study report (CSR) will be based on 
all subject data up to the Week 26 (up to assessments taken on Week 27 Day 1 before infusion). 
The additional data for any subjects continuing to receive study drug after this time, as allowed 
by the protocol, will be further summarized in a final study report once these subjects have 
completed or discontinued the study.
Baseline period is defined as the 12 weeks screening period prior to the first infusion of 
crizanlizumab 5 mg/kg at Week 1 Day 1.
12.1
Analysis sets
Full Analysis Set (FAS): The FAS include all enrolled subjects to whom the study treatment 
has been assigned regardless of whether or not they have received at least 1 dose of study 
treatment or have at least 1 post-baseline assessment.
Safety Analysis Set (SAF): The SAF will consist of all subjects who received at least 1 dose of 
study treatment.
All efficacy analyses will be performed on subjects in FAS who have completed treatment.
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline disease characteristics will be listed and summarized 
descriptively for all subjects in the FAS as well as for those subjects in FAS who have 
completed the treatment.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation (SD), lower quartile (Q1), median, upper quartile (Q3), minimum and 
maximum will be presented.
Relevant medical histories and current medical conditions at baseline will be summarized 
separately, by system organ class and preferred term.
Prior disease information will also be summarized.
12.3
Treatments
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation (SD), lower quartile 
(Q1), median, upper quartile (Q3), minimum and maximum will be presented.


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The duration of exposure in weeks to study drug as well as the dose intensity (computed as the 
ratio of actual cumulative dose received and actual duration of exposure) and the relative dose 
intensity (computed as the ratio of dose intensity and planned dose intensity) will be 
summarized by means of descriptive statistics using the Safety set.
The number of subjects with dose interruption or permanent discontinuation and the reasons 
will be summarized for all subjects and all dosing data will be listed.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system for all subjects.
12.4
Analysis of the primary endpoint
The primary objective of this study is to evaluate clinical efficacy of crizanlizumab 5 mg/kg, 
over 26 weeks compared to baseline in sickle cell subjects with a history of priapism.
12.4.1
Definition of primary endpoint
The primary endpoint of the study is percent reduction from baseline in priapism events by 
26 weeks (i.e. up to pre-infusion Week 27, Day 1). Priapism event is defined as unwanted, or 
painful erection lasting at least 60 minutes, self-reported.
12.4.2
Statistical model, hypothesis, and method of analysis
It is expected that crizanlizumab treatment reduces priapic events by at least 25% in SCD 
subjects with priapism. Demonstration of significant percent reduction from baseline in priapic 
events will be evaluated using the following hypothesis:
H0: p < 0.25, where p is the percent reduction in priapic events by 26 weeks.
H1: p ≥0.25, where p is the percent reduction in priapic events by 26 weeks.
If the above null hypothesis is rejected, significant reduction in priapic events will be
demonstrated statistically.
Assuming uniformity in the occurrence of priapic events before exposure to crizanlizumab 
treatment, baseline will be adjusted for 26 weeks for analysis purpose.
Percent reduction from baseline in priapic events will be tested using a nonparametric test (i.e.
Wilcoxon’s Sign Rank test). Hodges-Lehmann estimate of median percent reduction in priapic 
events will also be reported, along with corresponding 95% confidence intervals. The 
significance of the efficacy endpoints will be assessed at α = 0.05 level.
The primary analysis will be performed on all FAS subjects who have completed 26 weeks on 
treatment.
Number of priapic events will be summarized at baseline (adjusted for 26 weeks) and by Week 
26, and percent reduction from adjusted baseline by Week 26 will be summarized by mean, 
standard deviation (SD), lower quartile (Q1), median, upper quartile (Q3), minimum and 
maximum. In addition, subgroup analysis of the primary endpoint will also be performed based 
on the number of priapic events categories (i.e. <7, 7 – 13, 14 – 21, ≥ 22) at baseline. The priapic 
events categories may be re-grouped to ensure that there is adequate number of subjects in each 


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category for analysis. Additional analyses will also be performed for the subgroups of subjects 
with acute priapism and subjects who have experienced priapic episodes lasting less than one 
hour.
Further details will be provided in the SAP.
The imputation of missing data caused by intercurrent events will be handled by defining the 
estimand framework. The primary estimand is described by the following four attributes:
1. The target population comprises Sickle Cell Disease Patients with Priapism
2. The primary variable is percent reduction from baseline period in priapic events (priapism 
defined as unwanted, or painful erection lasting at least 60 min self-reported) by 26 weeks.
3. Treatment of interest: investigational drug will be a crizanlizumab solution provided every 
4 weeks with an additional loading dose 2 weeks after the first dosing. Further details about 
the investigational treatment are provided in Section 6.  
4. The intercurrent events are the events occurring after enrollment that may impact the 
treatment effect. The intercurrent events of interest are listed below:
a.
Treatment discontinuation 
b. Initiation or discontinuation of HU/HC or L-Glutamine (or other therapies to treat 
SCD and or to prevent/reduce VOCs such as voxelotor and erythropoietin) or of 
prophylactic treatment for priapism
c.
Intake of analgesic (including opioids) or ad hoc transfusions administered 
temporarily
5. The summary measure is the median percentage change from baseline period in priapic 
events (priapism defined as unwanted, or painful erection lasting at least 60 min self-
reported) by 26 weeks.
Handling of the intercurrent events:
The approach of accounting for intercurrent events is as follows:

For the intercurrent events 4a: Only data before study treatment discontinuation will be 
included. The data between treatment discontinuation and week 26 will be imputed using 
Poisson distribution (primary method to handle missing data).

For the intercurrent events 4b: Only data before initiation or discontinuation of HU/HC 
or L-Glutamine (or other therapies to treat SCD and or to prevent/reduce VOCs such as 
voxelotor and erythropoietin) or of prophylactic treatment for priapism will be included. 
The data between initiation or discontinuation of therapies to treat SCD or of prophylactic 
treatment for priapism and week 26 will be imputed using Poisson distribution (primary 
method to handle missing data).

For the intercurrent events 4c: Data after intake of analgesic (including opioids) or ad hoc 
transfusions administered temporarily will be included (treatment policy strategy). 
12.4.3
Handling of missing values/censoring/discontinuations
The missing values will be imputed for the primary analysis. Missing values will be imputed 
using Poisson distribution, assuming the same effect as observed data. Imputed datasets 


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(approximately 1,000) will be created, and each dataset will be analyzed using the method 
described for primary endpoint. The results will be combined using Rubin’s rule (Barnard J and 
Rubin DB 1999) Further details will be outlined in the SAP. 
As stated in Section 12.4.4 , the volume of missing data generated due to COVID-19 crisis will 
also be assessed and sensitivity analyses will be performed. 
12.4.4
Sensitivity and supportive analyses
Sensitivity analyses

To explore the robustness of analysis, sensitivity analysis as a 'tipping point approach
will be performed for the primary endpoint to evaluate the impact of a deviation from 
the MAR assumption. The basic idea is to first impute the missing values using the 
multiple imputation (MI) method based on the missing at random (MAR) assumption,
then adjusted by a delta value. The delta adjusting approach described in Ratitch et al 
(2013) will be used to find the tipping point, in a spectrum of conservative missing not 
at random (MNAR) assumptions, at which conclusions change from being favorable to 
being unfavorable. After such a tipping point is determined, clinical judgment can be 
applied as to the plausibility of the assumptions underlying this tipping point. A 
detailed description of the analysis will be provided in SAP.

As part of the sensitivity analysis, treatment policy strategy (that is, data after the 
intercurrent events will be included) will also be applied for the intercurrent events 4a 
and 4b, described in Section 12.4.2.

As part of the sensitivity analysis, the primary analysis will be analyzed on all subjects 
in FAS without missing data.

Additionally, as the study is ongoing during COVID 19 pandemic, the impact of 
COVID-19 (if any) on the primary endpoint will be assessed in accordance to FDA’s 
guideline entitled “Statistical Considerations for Clinical Trials During the COVID-19 
Public Health Emergency”. The analysis (as stated below) will be repeated on the FAS 
excluding the subjects with missing data due to COVID-19. 
o
Percent reduction from baseline in priapic events will be tested using a 
nonparametric test (i.e., Wilcoxon’s Sign Rank test). Hodges-Lehmann 
estimate of median percent reduction in priapic events will also be reported, 
along with corresponding 95% confidence intervals. The significance of the 
efficacy endpoints will be assessed at α = 0.05 level.
Further details will be provided in the SAP, as needed.
Supportive analyses

The supportive analyses described below will be performed on all FAS subjects who 
have completed 26 weeks on treatment.  Missing values will be imputed as stated in
Section 12.4.3.Annualized priapic Events Rate: The annualized rate of priapic events is 
defined as the total number of priapic events for a subject occurring from the date of 
initial infusion to the last contact date of the Treatment Phase of the study × 365.25
divided by the number of days during that same time period. This calculation accounts 
for early dropouts or lost to follow-up by extrapolating the priapism events rate of every 
subject to 1 year.


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
Percent reduction from baseline in priapic events will also be assessed by Week 52.

The total number of priapic episodes in the screening period (12 weeks baseline) will 
be compared to the total number of priapic episodes occurring in the first 12 weeks on 
treatment (0-12 weeks) using a nonparametric test (i.e. Wilcoxon’s Sign Rank test). 
Additionally, a similar analysis will be performed to compare to the total number of 
priapic episodes occurring in the last 12 weeks on treatment (15-26 weeks).

Number of priapic events will be summarized in the screening period (12 weeks 
baseline), in first 12 weeks on treatment (0-12 weeks), and in the last 12 weeks on 
treatment (15-26 weeks) and percent reduction from baseline will also be summarized.
12.5
Analysis of secondary endpoints
The secondary objectives in this study are to assess efficacy, safety and tolerability of 
crizanlizumab 5.0 mg/kg in SCD subjects. 
12.5.1
Efficacy endpoints
The following secondary endpoints will be analyzed on all FAS subjects who have completed 
52 weeks on treatment to evaluate clinical efficacy of crizanlizumab 5 mg/kg:
a. The rate of priapic events by 26 and 52 weeks of treatment.
b. The percent reduction from baseline in acute priapic events by 26 and 52 weeks of 
treatment. 
c. The rate of uncomplicated VOC events (defined as an acute event of pain with no known 
cause for pain other than a vaso-occlusive event; and requiring treatment with a parenteral 
or oral opioids or other parenteral analgesic; but is NOT classified as an acute chest 
syndrome, hepatic sequestration, splenic sequestration or priapism and these events will 
not be adjudicated) by 26 and 52 weeks of treatment. Events include both healthcare and 
self-reported events.
d. The rate of complicated VOCs (defined as acute chest syndrome, hepatic sequestration, 
splenic sequestration, and acute priapism) recorded by healthcare visit, by 26 and 
52 weeks of treatment.
The efficacy endpoints will be assessed by 26 weeks and by 52 weeks.
12.5.2
Methods of analyses
Similar analyses on percent reduction in acute priapic events for subjects from full analysis set 
will be conducted, as done for primary endpoint.
Descriptive summary statistics including n, mean, standard deviation (SD), lower quartile (Q1),, 
median, upper quartile (Q3), minimum and maximum will be presented for the rate of events 
and number of priapic events at Baseline, by Week 26 and by Week 52. The change from 
baseline in Rates of Events at Week 26 (i.e. evaluation at Week 27, Day 1) and Week 52 (i.e.
evaluation at Week 53, Day 1) will be summarized by n, mean, standard deviation (SD), lower 
quartile (Q1), median, upper quartile (Q3), minimum and maximum.
As appropriate, the estimated median change from Baseline at 26 weeks (i.e. evaluation at
Week 27, Day 1) and 52 (i.e. evaluation at Week 53, Day 1) weeks in events or events with 


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associated 95% CI using a non-parametric approach will be reported. The median percent 
reduction will also be presented by Week 26 and Week 52.
12.6
Safety endpoints
All the safety analyses will be based on the safety set.
The overall observation period will be divided into 3 mutually exclusive segments:
1. Pre-treatment period: from day of subject’s informed consent to the day before first dose 
of study medication
2. On-treatment period: from day of first dose of study medication to 105 days after last dose 
of study medication (or until EOT date for subjects continuing crizanlizumab after their 
EOT via commercial supply)
3. Post-treatment period: starting at Day 106 after last dose of study medication (or after 
EOT date for subjects continuing crizanlizumab after their EOT via commercial supply or 
a post-trial access program).
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.
Serious adverse events will be tabulated.
All deaths (on-treatment death and post-treatment death) 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.
Separate summaries will be provided for other significant AEs leading to discontinuation and 
AEs leading to dose adjustment.
12.6.1
Clinical laboratory evaluations
For results reported by the central laboratory, continuous hematology and chemistry results will 
be summarized descriptively in SI units at each scheduled time point. Visits summaries will 
include baseline and post baseline visits, including early termination and Follow-Up. Changes 
from baseline will also be summarized at each time point.
In addition, shift tables will be provided for all parameters to compare a subject’s baseline 
laboratory evaluation relative to the visit’s observed value. For the shift tables, the normal 
laboratory ranges will be used to evaluate whether a particular laboratory test value was normal, 
low or high for each visit value relative to whether the baseline value was normal, low or high.
These summaries will be presented by laboratory test.
Coagulation parameters (as described in Section 8.3.4) will be summarized descriptively at each 
time-point. Changes from baseline will also be summarized.
Urinalysis results will be listed in individual subject data listings only. In addition, a listing 
containing individual subject hematology, chemistry, and coagulation values outside the 


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reference ranges will be provided. This listing will include data from scheduled and 
unscheduled time points.
Hepatitis markers and additional tests results will be summarized descriptively at screening only.
12.6.2
Other safety evaluations
Vital signs
Data on vital signs, including systolic and diastolic blood pressure, pulse rate, respiratory rate, 
oxygen saturation, and body temperature) will be tabulated and listed for each visit, notable 
values will be flagged.
12-Lead ECG
12-lead ECGs including PR, QRS, QT, QTcF and HR intervals will be obtained for each subject
during the study. ECG data will be read and interpreted locally.
The number and percentage of subjects with notable ECG values will be presented. In addition, 
a listing of these subjects will be produced.
Notable/abnormal values for safety data will be further specified in the RAP.
Echocardiogram
The assessments for Cardiac Imaging using ECHO will be summarized at screening and end of 
treatment visit.
Urine protein/creatinine ratio
The assessments for urine protein/creatinine ratio will be summarized descriptively at screening 
and end of treatment visit.


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12.8
Interim analyses
No formal interim analysis will be performed for this study. As required, interim analyses will 
be performed for publication purposes only. No decision on study continuation will be based 
on these descriptive reports, and as such, no alpha adjustment will be needed.
12.9
Sample size calculation
A total of 34 evaluable subjects is required for the study to have approximately 80% power to 
detect at least 25% reduction in rates of priapic events (defined as an unwanted erection lasting 
at least 60 min reported via daily diary tool) with a mean baseline priapism event rate of 10.0 
and standard deviation of the difference of 5.0, by 26 weeks.
The calculations were based on simulation with 5,000 repetitions (from Poisson distribution) 
using one-sample Wilcoxon’s Signed-Rank Test and 2-sided α=0.05.
Retaining the same above assumptions, robustness of the estimated sample size was also 
validated using a one-sample t test.
Assuming a 5% dropout rate, approximately 36 subjects will be enrolled in the study.
Recruitment of the required number of subjects with priapism will be challenging as the 
incidence of priapic events are sporadic and varies over time intervals. Also, in the absence of 
relevant clinical data on priapism, the expected reduction and higher variability in events rates 
have been conservatively assumed. The above expected 25% reduction in rates of priapic events 
from baseline is based on medical expert opinion and feedback. L-glutamine (Endari™) was 
approved by the US FDA in July 2017 for the reduction of vaso-occlusive crises (VOCs), based 
on a 25% reduction. Since priapism is also considered to be a complicated VOC, the assumption 
was that the relative risk reduction of 25% (approved for VOC events), would be similar for 
priapism.


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13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board (IRB) for the trial protocol, written informed consent form, 
consent form updates, subject recruitment procedures (e.g. advertisements) and any other 
written information to be provided to subjects. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Quality Assurance representatives, designated agents of Novartis, IRBs, and
regulatory authorities as required. If an inspection of the clinical site is requested by a regulatory 
authority, the investigator must inform Novartis immediately that this request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
13.4
Quality control and quality assurance
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk-based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes.


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14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study subjects. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case-by-case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study subjects.
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 and health authorities, where required, it cannot be implemented.
14.1
Protocol amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation.
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB at the study site should be informed according to local 
regulations.


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15
References
References are available upon request
Adeyoju AB, Olujohungbe AB, Morris J, et al (2002) Priapism in sickle-cell disease; 
incidence, risk factors and complications - an international multicenter study. BJU Int.; 
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Ataga KI, A. Kutlar, J. Kanter, et al (2017) Crizanlizumab for the Prevention of Pain Crises in 
Sickle Cell Disease. N Engl J Med; 376(5):429–439.
Ballas SK, Bauserman RL, McCarthy WF, et al (2010) Hydroxyurea and acute painful crises 
in sickle cell anemia: effects on hospital length of stay and opioid utilization during 
hospitalization, outpatient acute care contacts, and at home. J Pain Symptom Manage; 
40(6):870-82.
Banholzer M, Wandel C, Barrow P, et al (2016). Clinical trial considerations on male 
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Barnard J and Rubin DB (1999). Small-sample degrees of freedom with multiple imputation.
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Bender MA (2003) Sickle Cell Disease. GeneReviews®. Seattle (WA): University of 
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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.
Brousseau DC, Owens PL, Mosso AL, et al (2010) Acute care utilization and 
rehospitalizations for sickle cell disease. JAMA; 303(13):1288-94.
Burnett AL, Anele UA, Trueheart IN, et al (2014) Randomized controlled trial of sildenafil 
for preventing recurrent ischemic priapism in sickle cell disease. Am J Med; 127(7):664-8.
Charache S, Terrin ML, Moore RD, et al (1995) Effect of hydroxyurea on the frequency of 
painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in 
Sickle Cell Anemia. N Engl J Med; 332(20):1317-22.
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dysfunction. BJU Int.; 89(3):285-290.
Embury SH, Matsui NM, Ramanujam S, et al (2004) The contribution of endothelial cell 
P-selectin to the microvascular flow of mouse sickle erythrocytes in vivo. Blood; 
104(10):3378-85.
Emond AM, BChir MB, et al (1980) Priapism and Impotence in Homozygous Sickle Cell
Disease. Archives of Internal Medicine, Volume 140, Issue 11, 1434-1437.
Fowler JE Jr, Koshy M, Strub M, et al (1991) Priapism associated with the sickle cell 
hemoglobinopathies: prevalence, natural history and sequelae. J Urol; 145(1):65-8. 


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Frenette PS (2004) Sickle Cell Vasoocclusion: heterotypic, multicellular aggregations driven 
by leukocyte adhesion. Microcirculation; 11(2):167-77.
Furtado PS, Costa MP, Ribeiro do Prado, et al (2012) The prevalence of priapism in children 
and adolescents with sickle cell disease in Brazil. Int J Hematol; 95(6):648-51.
Geng JG, Bevilacqua MP, Moore KL, et al (1990) Rapid neutrophil adhesion to activated 
endothelium mediated by GMP-140. Nature; 343(6260):757-60.
Gill FM, Sleeper LA, Weiner SJ, et al (1995) Clinical events in the first decade in a cohort of 
infants with sickle cell disease. Cooperative Study of Sickle Cell Disease. Blood; 
86(2):776-83.
Gutsaeva DR, Parkerson JB, Yerigenahally SD, et al (2011) Inhibition of cell adhesion by 
anti-P-selectin aptamer: a new potential therapeutic agent for sickle cell disease. Blood; 
117(2):727-35.
Hamre MR, Harmon EP, Kirkpatrick DV, et al (1991) Priapism as a complication of sickle 
cell disease. J Urol; 145:1-5.
Hamburger SA, McEver RP (1990) GMP-140 mediates adhesion of stimulated platelets to 
neutrophils. Blood, 75(3):550-4.
Hebbel RP, Boogaerts MA, Eaton JW, et al (1980) Erythrocyte adherence to endothelium in 
sickle-cell anemia. A possible determinant of disease severity. N Engl J Med; 302(18):992-5.
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at: 
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trials to the guideline on statistical principles for clinical trials. Final version adopted on 20 
November 2019.
Inwald DP, Kirkham FJ, Peters MJ, et al(2000) Platelet and leucocyte activation in childhood 
sickle cell disease: association with nocturnal hypoxaemia. Br J Haematol; 111(2):474-81.
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2015.
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Kanter J, Kruse-Jarres R (2013) Management of sickle cell disease from childhood through 
adulthood. Blood Rev; 27(6):279-87.
Kato GJ, Steinberg MH, Gladwin MT (2017) Intravascular hemolysis and the 
pathophysiology of sickle cell disease. J Clin Invest; 127(3):750-60.
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with sickle cell disease. Am. J. Hematol; 84(6):323-7.
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transgenic sickle mice but not in normal mice. J Clin Invest; 106(3):411-20.


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Lawrence MB, Springer TA (1991) Leukocytes roll on a selectin at physiologic flow rates: 
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Lee SP, Ataga KI, Zayed M, et al (2007) Phase I study of eptifibatide in patients with sickle 
cell anaemia. Br J Haematol; 139(4): 612-20.
Liu Z, Miner JJ, Yago T, et al (2010) Differential regulation of human and murine P-selectin 
expression and function in vivo. J Exp Med; 207(13):2975-87.
Mantadakis E, Cavender JD, Rogers ZR, et al (1999) Prevalence of priapism in children and 
adolescents with sickle cell anemia. J Pediatr Hematol Oncol; 21(6):518–22.
Matsui NM, Borsig L, Rosen SD, et al (2001) P-selectin mediates the adhesion of sickle 
erythrocytes to the endothelium. Blood; 98(6):1955-62.
Matsui NM, Varki A, Embury SH (2002) Heparin inhibits the flow adhesion of sickle red 
blood cells to P-selectin. Blood; 100(10):3790-6.
McGrath PJ, Walco GA, Turk DC, et al (2008) Core outcomes domains and measures for 
pediatric acute and chronic/recurrent pain clinical trials: PedIMMPACT recommendations. 
J Pain; 9(9):771-783.
Montague DK, Jarow J, Broderick GA, et al (2003) American Urological Association 
guideline on the management of priapism. J Urol; 170(4 Pt 1):1318-24.
Nietert PJ, Silverstein MD, Abboud MR (2002) Sickle cell anaemia: epidemiology and cost of 
illness. Pharmacoeconomics; 20(6):357-66.
Niihara Y, Smith WR, Stark CW (2018) A Phase 3 Trial of l-Glutamine in Sickle Cell 
Disease. N Engl J Med; 379(19):1880
Olujohungbe AB, Adeyoju A, Yardumian A, et al (2011) A prospective diary study of 
stuttering priapism in adolescents and young men with sickle cell anemia: report of an 
international randomized control trial – the priapism in sickle cell 
study. J Androl; 32(4):375-82.
Pászty C, Brion CM, Manci E, et al (1997) Transgenic knockout mice with exclusively human 
sickle hemoglobin and sickle cell disease. Science; 278(5339):876-8.
Piel FB, Steinberg MH, Rees DC (2017) Sickle Cell Disease. N Engl J Med; 
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Porter LS, Gil KM, Sedway JA, et al (1998) Pain and stress in sickle cell disease: an analysis 
of daily pain records. Int J Behav Med; 5(3):185-203.
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.
Ratitch, Bohdana ; O'Kelly, Michael ; Tosiello, Robert (2013) Missing data in clinical trials: 
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Rees DC, Williams TN, Gladwin MT (2010) Sickle-cell disease. Lancet; 376(9757):2018-31.
Rogers ZR (2005) Priapism in Sickle Cell Disease. Hematol Oncol Clin N Am 19: 917–928.
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the conceptus. Reproductive Toxicology 58: 213-221.
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Turhan A, Weiss LA, Mohandas N, et al (2012) Primary role for adherent leukocytes in sickle 
cell vascular occlusion: a new paradigm. Proc Natl Acad Sci U S A.; 99(5):3047-51.
Vichinski E, Hoppe C, Ataga K, et al (2019) A Phase 3 Randomized Trial of Voxelotor in 
Sickle Cell Disease. N Engl J Med; 381(6):509-519.
Wagner MC, Eckman JR, Wick TM (2006) Histamine increases sickle erythrocyte adherence 
to endothelium. Br J Haematol, 132(4):512-22.
Ware RE, de Montalembert M, Tshilolo L, et al (2017) Sickle cell disease. Lancet;
390(10091):311-23.
Wood K, Russell J, Hebbel RP, et al (2004) Differential Expression of E- and P-Selectin in 
the Microvasculature of Sickle Cell Transgenic Mice. Microcirculation; 11(4):377-85.


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Appendices


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Appendix 3: Priapism medical history questionnaire


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Appendix 5: List of drugs that may induce priapism
Table 16-1
List of non-antipsychotic and non-antidepressant drugs that may 
Induce Priapism
Category
Substances
Medicines associated with increased risk of priapism*
Vasoactive erectile agents**
alprostadil, papaverine, phentolamine
α-adrenergic receptor antagonists
doxazosin, tamsulosin, terazosin, prazosin
Antihypertensives
hydralazine, propranolol, guanethidine
Anticoagulants
heparin, warfarin
Hormones
testosterone, gonadotropin-releasing hormone
Medicines that have been reported to cause priapism*
Phosphodiesterase type 5 inhibitors
sildenafil, tadalafil
Anti-anxiety agents (including ADHD drugs)
methylphenidate, atomoxetine, hydroxyzine
Recreational Drug
Cocaine, crack cocaine
Herbal Supplement
Any herbal supplement to treat ED: including (but not 
limited to) the following products containing Tribulus 
terrestris, Saw palmetto extract, Panax ginseng, 
Dehydroepiandrosterone (DHEA), L-arginine, 
Rhodiola rosea, Yohimbe, Propionyl-L-carnitine, 
Horny goat weed (epimedium)
* PO drugs unless specified; ** Injectable solutions
References
Salonia A, Eardley I, Giuliano F, et al. 2014. European Association of Urology Guidelines on 
Priapism. European Urology 65: 480-489
Broderick GA, Kadioglu A, Bivalacqua TJ, et al. 2010. Priapism: Pathogenesis, 
epidemiology, and management. The Journal of Sexual Medicine 7: 476-500.
Food and Drug Administration. 2013. FDA warns of rare risk of long-lasting erections in 
males taking methylphenidate ADHD medications and has approved label changes. Drug 
Safety Communication 17 December 2013. URL: 
www.fda.gov/Drugs/DrugSafety/ucm375796.htm
https://potencyup.com/what-is-priapism-definition-types-causes-symptoms-diagnosis-and-
treatment/
https://www.mayoclinic.org/diseases-conditions/erectile-dysfunction/in-depth/erectile-
dysfunction-herbs/art-20044394
https://www.webmd.com/erectile-dysfunction/features/natural-remedies-for-erectile-
dysfunction#1


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Table 16-2
List of Antidepressants and Antipsychotics that may induce priapism
USAN
Trade Names*
Type of Medication
Reference*
Buproprion
Wellbutrin, Zyban
Antidepressant
Am J Psychiatry. 1995;152(5):813
Trazodone
Desyrel
Antidepressant
Prim Care Companion J Clin Psychiatry. 2010; 
12(2): PCC.09l00816.
Risperidone
Risperdal
Antipsychotic
Prim Care Companion J Clin Psychiatry. 2009; 
11(4): 174–175. J Clin Psychiatry 2010-12(5)-
e1–e2
Olanzapine
Zyprexa
Antipsychotic
J Clin Psychopharmacol. 1998 Aug;18(4):351-
3; Am J Psychiatry. 2000;157(4):659; J Clin 
Psychiatry 2010-12(5)-e1–e2
Clozapine
Clozaril 
Antipsychotic
Am J Psychiatry. 2000;157(4):659; J Clin 
Psychiatry 2010-12(5)-e1–e2
Choropromazine
Thorazine and Largactil 
Antipsychotic
Int J Clin Pract. 1999 Mar;53(2):152-3.
Quetiapine
Seroquel
Antipsychotic
West J Emerg Med. 2014 Feb; 15(1): 114–
116.
Sertraline
Zoloft
Antidepressant
J Am Acad Child Adolesc Psychiatry 46:7-July 
2007
Citalopram
Celexa
Antidepressant
Pharmacotherapy 2002;22(4):538–541
Escitalopram
Lexapro
Antidepressant
Fed Pract. 2019 Feb 36(2), 92-96; J Inst Med. 
2014;36(1):118–120.
Fluoxetine
Prozac, Sarafem 
Antidepressant
J Pak Med Assoc 1996; 46: 45–6
Trifluoperazine
Stelazine 
Antipsychotic
Pericyazine
Neulactil
Antipsychotic
Postgrad Med J. 1974 Aug; 50(586): 523–
524. 
Paroxetine
Paxil, Seroxat
Antidepressant
Int J Psychiatry Med. 2015;50(3):326-34
Fluvoxamine
Faverin, Luvox
Antidepressant
Same MoA as citalopram, paroxetine and 
fluoxetine
Aripiprazole
Abilify
Antipsychotic
Ind Psychiatry J. 2016 Jan-Jun; 25(1): 119–
121.
Haloperidol
Haldol 
Antipsychotic
Encephale. 2014 Dec;40(6):518-21.
Amisulpride
Solian
Antipsychotic
Bulletin of Clinical Psychopharmacology 
2016;26(1):85-6
Duloxetine
Cymbalta
Antidepressant
Ment Health Clin [Internet]. 2016;6(4):197-
200.
Ziprasidone
Geodon 
Antipsychotic
Pharmacotherapy 2002;22(8):1070–1073
Venlafaxine
Effexor 
Antidepressant
J Am Acad Child Adolesc Psychiatry. 2000 
Jan; 39(1):16-7.
Desvenlafaxine
Pristiq 
Antidepressant
Same MoA as duloxetine and venlafaxine
Mirtazapine
Remeron
Antidepressant
Klinik Psikofarmakoloji Bulteni, suppl. S1; 
Istanbul Vol. 28, (2018): 233-234
*Other tradenames may exist for the same USAN. ** References are quoted as examples only 
and are non-exhaustive.

SAP_001.pdf: 
Clinical Development
SEG101/Crizanlizumab/Adakveo®
CSEG101AUS05 / NCT03938454
A Prospective Phase II, Open-Label, Single-arm, 
Multicenter, Study to Assess Efficacy and Safety of 
SEG101 (crizanlizumab), in Sickle Cell Disease Patients 
with Priapism (SPARTAN)
Statistical Analysis Plan (SAP)  
Property of Novartis
 Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Template Version 4.0, Effective from 23-Apr-2021
Parent document: SOP-7012383
Author:
Trial Statistician; Lead Statistician
Document type:
SAP Documentation
Document status:
Final Amendment 4
Release date:
20-Feb-2024
Number of pages:
50


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SAP Amendment 4
Study No. CSEG101AUS05
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted (Current)
12-Jul-2019
Prior 
to DB 
Lock
Creation of 
final version
Not applicable - First version
Not applicable
24-Jan-2023
Prior 
to DB 
Lock
Creation of 
amendment 1
Alignment with most recent
protocol (protocol v1.0, v2.0 
and v3.0) and minor edits 
(including fixing typos)
All 
Update study design; The total 
number of subjects eligible for 
the study updated from 56 to 
36 patients; The study design 
changed from age 16 years to 
lower the age of inclusion to 12 
years old; Updated definition 
of baseline; Removed the 
phrase 
‘Mandatory 
safety 
follow-up period’; Information 
added related to safety follow-
up period
Update on primary and 
secondary endpoints 
(Replaced “greater than” and 
“more than” by “at least”); 
Added the word “or” to align 
the definition of acute priapic 
events to that of priapism
Section 1.1
Study design
Section 1.2 
Study objectives 
and endpoints
Added information on primary 
estimand(s) 
Section 1.2.1 
Primary estimand(s)
Lower quartile (Q1) and upper 
quartile (Q3) were included  in 
Section 2 Statistical 
methods


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SAP Amendment 4
Study No. CSEG101AUS05
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted (Current)
the summary statistics of sub-
sections of section 2 
statistical methods
Updated definition of baseline 
period and added definition 
for Baseline (adjusted for 26 
weeks); detailed summary 
measure is percentage 
change from baseline; Added 
text for reduction; Updated 
visit windows
Section 2.1.1
General definitions
Updated 
definition 
of 
full 
analysis set (FAS)
Section 2.2 
Analysis sets
Added 
information 
on 
subgroup analyses by age 
group and other updates
Added information on duration  
of exposure will be assessed 
in weeks rather than days to 
align 
with 
other 
Novartis 
SEG101 studies
The sentence “The primary 
time point is week 26” was 
deleted as it was redundant 
given the previous sentence.
Text 
added 
related 
to 
uniformity of occurrence of 
priapic events, how baseline 
was adjusted for 26 weeks for 
analysis purpose; The <7 
category was included as  a 
new number of priapic events 
category 
in 
a 
subgroup 
analysis 
of 
the 
primary 
endpoint
Section 2.2.1 
Subgroup of 
interest
2.4.1
Study 
treatment / 
compliance
2.5.1
Primary 
endpoint(s)
2.5.2
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)
Added 
information 
on 
estimand framework to handle 
missing 
data 
caused 
by 
intercurrent events (Primary 
estimand)
2.5.3
Handling of 
intercurrent events  
Information on handling of 
missing values added
Information on sensitivity 
analyses added
Information updated on 
secondary endpoints; added 
definition for end date of 
annualize rate of priapic 
events
Updated information on AEs; 
detailed legal requirement of 
clinicaltrials.gov and EudraCT
Updated 
information 
on 
deaths
The word “albumin” deleted 
from the laboratory data; 
other information updated
2.5.4   Handling of 
missing values not 
related 
 
to 
intercurrent event
2.5.5
Sensitivity 
analyses  
2.6.2
Statistical 
hypothesis, model, 
and 
method 
of 
analysis
2.7.1
Adverse 
events (AEs)
2.7.2
Deaths
Section 2.7.3
Laboratory data
Information updated on other 
safety data
Section 
2.7.4.1 
ECG and cardiac 
imaging data


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Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted (Current)
Added additional relevant 
information required for 
statistical analysis 
implementation which are not 
detailed in study protocol
The statistical power of the 
study changed from 90% to 
80% , which reduces the 
number of evaluable subjects 
from 44 to 34. The anticipated 
drop-out rate for the study is 
also revised from 20% to 5% 
based on the current status of 
the trial, which reduces the 
targeted number of enrolled 
patients from 56 to 36; It was 
clarified that the assumption 
that the relative risk reduction 
of 25% (approved for VOC 
events) observed with L-
glutamine (Endari™) would 
be similar for priapism was 
used for the purpose of study 
sample size calculation
Section 2.13 Interim 
analysis
Section 3
Sample size 
calculation


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Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted (Current)
To 
clarify 
the 
change 
information in this section
A detailed description of the 
analysis provided
Section 4
Change to protocol 
specified analyses
Section 
5.4.1 
Analysis supporting 
primary objective(s)
Added relevant references 
Barnard and co; Edmond and 
co, Ratich and co, ICH 
E9(R1) guideline and A 
Phase 3 Trial of l-Glutamine 
in Sickle Cell Disease 
(Endari™) as well as the 
SAS/STAT® 14.2 User’s 
Guide were added.
Section 
6  
Reference
22-Nov-2023
Prior 
to DB 
Lock
Creation of 
amendment 2
Update on visit window; 
Added text for visit windows,  
upper limit extension for EoT. 
Note- Based on medical 
judgement and data, upper 
limit of EoT extended upto 
maximum value day 403.
To 
clarify 
the 
change 
information in this section
Section 2.1.1
General definitions
Section 4
Change to protocol 
specified analyses
15-Dec-2023
Prior 
to DB 
Lock
Creation of 
amendment 3
Update on visit window, 
change EoT upper limit from 
day 403 to day 447.
Section 2.1.1
General definitions


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Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted (Current)
20-Feb-2024
Prior 
to DB 
Lock
Creation of 
amendment 4
Added note on tipping point 
analysis will be performed if 
there are significant number 
of missing data.
Information on “baseline 
adjusted for 52 weeks for 
analysis purpose“ included in 
supportive analysis 2. This 
decision was made based 
clinical trial team (CTT) 
suggestion.
Based on clinical trial team 
(CTT) suggestion, note added 
for secondary endpoint 
analysis 2 “this analysis will 
only be performed if an 
adequate number of subjects 
are present”.
The word “tricuspid 
regurgitation jet velocity 
(TRV)” added for cardiac 
imaging data.
 
2.5.5
Sensitivity 
analyses
2.5.6
Supportive 
analyses
2.6.1
Secondary 
endpoint(s)
Section 
2.7.4.1 
ECG and cardiac 
imaging data


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Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted (Current)
Section 6
Reference


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Table of contents
Table of contents..................................................................................................................9
List of abbreviations ..........................................................................................................11
1
Introduction........................................................................................................................13
1.1
Study design...........................................................................................................13
1.2
Study objectives, endpoints and estimands............................................................15
1.2.1
Primary estimand(s)...............................................................................16
1.2.2
Secondary estimand(s)...........................................................................17
2
Statistical methods .............................................................................................................17
2.1
Data analysis general information..........................................................................17
2.1.1
General definitions ................................................................................18
2.2
Analysis sets...........................................................................................................21
2.2.1
Subgroup of interest ..............................................................................21
2.3
Subject disposition, demographics and other baseline characteristics...................22
2.3.1
Subject disposition.................................................................................22
2.3.2
Demographics and other baseline characteristics..................................22
Medical History......................................................................................................23
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................24
2.4.1
Study treatment / compliance................................................................24
2.4.2
Prior, concomitant and post therapies ...................................................25
2.5
Analysis supporting primary objective(s)..............................................................26
2.5.1
Primary endpoint(s)...............................................................................26
2.5.2
Statistical hypothesis, model, and method of analysis ..........................26
2.5.3
Handling of intercurrent events.............................................................27
2.5.4
Handling of missing values not related to intercurrent event................28
2.5.5
Sensitivity analyses ...............................................................................28
2.5.6
Supportive analyses...............................................................................29
2.6
Analysis supporting secondary objectives.............................................................30
2.6.1
Secondary endpoint(s)...........................................................................30
2.6.2
Statistical hypothesis, model, and method of analysis ..........................30
2.6.3
Handling of intercurrent events.............................................................31
2.6.4
Handling of missing values not related to intercurrent event................31
2.6.5
Sensitivity analyses ...............................................................................31
2.6.6
Supplementary analyses ........................................................................32
2.7
Safety analyses.......................................................................................................32


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2.7.1
Adverse events (AEs)............................................................................32
2.7.2
Deaths....................................................................................................33
2.7.3
Laboratory data......................................................................................34
2.7.4
Other safety data....................................................................................35
2.8
Pharmacokinetic endpoints ....................................................................................38
2.9
PD and PK/PD analyses.........................................................................................38
38
2.11
Biomarkers.............................................................................................................39
39
39
40
40
40
40
2.13
Interim analysis......................................................................................................40
3
Sample size calculation......................................................................................................41
4
Change to protocol specified analyses...............................................................................41
5
Appendix............................................................................................................................43
5.1
Imputation rules .....................................................................................................43
5.1.1
Study drug .............................................................................................43
5.1.2
AE date imputation................................................................................44
5.1.3
Concomitant medication date imputation..............................................45
5.2
AEs coding/grading................................................................................................47
5.3
Laboratory parameters derivations.........................................................................47
5.4
Statistical models ...................................................................................................48
5.4.1
Analysis supporting primary objective(s) ............................................48
5.4.2
Analysis supporting secondary objective(s)..........................................49
5.5
Rule of exclusion criteria of analysis sets .............................................................49
6
Reference ...........................................................................................................................50


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List of abbreviations
AE
Adverse Event
ALT
Alanine Aminotransferase
APTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Classification
BUN
Blood Urea Nitrogen
CI
Confidence Interval
CM
Concomitant Medication
CRF
Case Report/Record Form (paper or electronic)
CSR
Clinical Study Report
CTC
Common Toxicity Criteria
CTCAE
DI
Common Terminology Criteria for Adverse Events
Dose Intensity
DRL
Drug Reference List
eCRF
Electronic Case Report Form
ECG
Electrocardiogram
eGFR
Estimated Glomerular Filtration Rate
EoT
End of Treatment
ER
Emergency Room
FAS
Full Analysis Set
GGT
Gamma-glutamyl Transferase
GPS
Global Programming and Statistical environment
HDL
High-density Lipoproteins
HR
Heart Rate
INR
International Normalized Ratio
IV
Intravenous
LDH
Lactate Dehydrogenase
LDL
Low-density Lipoproteins
LVEF
Left Ventricular Ejection Fraction
MCH
Mean Cell Hemoglobin
MCHC
Mean Corpuscular Hemoglobin Concentration
MCV
Mean Corpuscular Volume
mg
milligram(s)
MedDRA
PD
PDI
Medical Dictionary for Drug Regulatory Affairs
Pharmacodynamic
Planned Dose Intensity
PK
Pharmacokinetics
PT
Preferred Term
RAP
Reporting and Analysis Process
RBC
Red Blood Cells


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RDI
SAF
Relative Dose Intensity
Safety Set
SAP
SAS
Statistical Analysis Plan
Statistical Analysis System
SCD
SD
SEG101
Sickle Cell Disease
Standard Deviation
Novartis humanized anti-P-selectin monoclonal antibody variant
SOC
System Organ Class
TBIL
Total Bilirubin
TFLs
Tables, Figures, Listings
VOC
Vaso-occlusive Crisis
WHO
World Health Organization


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1
Introduction
This document describes the planned statistical methods for all safety and efficacy analyses, 
which will be used in the phase II clinical trial SEG101AUS05. 
The main purpose of this document is to provide summary of the statistical methodology that 
will be used for this clinical study; this includes a detailed description of data summaries. 
Analyses plan in this document refers to the related statistical analysis sections in clinical study 
report.
Data will be analyzed by Novartis using statistical software SAS version 9.4 according to the 
data analysis section 12 of the study protocol, which is available in Appendix 16.1.1 of the CSR. 
The statistical methodology is described below and any deviations from the protocol are 
documented. Additional detailed information regarding the analysis methodology is contained 
in the Appendix section 16.1.9 of CSR.
The content of this SAP is based on protocol CSEG101AUS05 Amendment (version 3.0, 
release date 16-Dec-2022). All decisions regarding final analysis, as defined in the SAP 
document, have been made prior to database lock of the study data. 
CSR deliverables (shells for tables, figures, listings) and further programming specifications 
are described in Tables, Figures, and Listings, (TFL) shells and Programming Datasets 
Specifications (PDS) documents, respectively.
This document is written in the future tense. It will be reviewed and updated (including 
conversion to past tense) for entry into the CSR after the analysis has taken place.
1.1
Study design
This is a multicenter, prospective, phase II, single-arm, open-label study to assess the efficacy 
and safety of crizanlizumab in SCD (Sickle Cell Disease) subjects with priapism.
A total of approximately 36 male subjects aged ≥ 12 years, who meet all of the inclusion criteria 
and none of the exclusion criteria will be eligible for the study. Subjects with ≥ 4 priapic events 
during the 14 week pre-screening period and having at least 3 priapic events during the 12 week 
screening period with at least 1 event occurring within 4- weeks prior to the first treatment, will 
be included in the study.
The baseline period is defined as the 12 weeks screening period. Eligible subjects will be treated 
with crizanlizumab at a dose of 5.0 mg/kg. From the first screening visit until the end of follow-
up, the total study duration will be 79-weeks (including 12 weeks of screening, 52 weeks of 
treatment and 15 weeks of follow-up period). The primary analysis of the study will be 
conducted by 26 weeks to assess efficacy of crizanlizumab in those subject population, who 
have completed 26 weeks of treatment. The secondary 
 endpoints will be 
assessed by 26 weeks and/or 52 weeks.  Subjects will be followed for safety for up to 105 days 
(15 weeks) after the last dosing if applicable. Subjects who will receive commercially approved 
crizanlizumab approximately 4 weeks after their last dose of study treatment, do not need to 


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complete the 105-day follow-up. The safety follow-up of these subjects will be at the End of 
Treatment (EOT) visit. All other subjects are required to complete the 105-day follow-up visit.


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Figure 1-1
Study design 
1.2
Study objectives, endpoints and estimands 
Table 1-1
Study Objectives and endpoints
Primary Objective
Endpoint for primary objective
To evaluate the clinical efficacy of 
crizanlizumab in SCD-related priapism
Percent reduction from baseline period in 
priapic events (priapism defined as 
unwanted, or painful erection lasting at least 
60 min self-reported) by 26 weeks
Secondary Objectives
Endpoints for secondary objectives
To evaluate the clinical efficacy of 
crizanlizumab in SCD-related priapism
Rate of priapic events by 26 and 52 weeks
To evaluate the clinical efficacy of 
crizanlizumab in SCD-related acute 
priapism
Percent reduction from baseline in acute 
priapic events (defined as an unwanted or 
painful erection lasting at least 4 hours and 
mandates a visit to ER) by 26 weeks and 52 
weeks
To evaluate the clinical efficacy of 
crizanlizumab for uncomplicated vaso-
occlusive crisis (VOC) (defined as an acute 
event of pain with no known cause for pain 
other than a vaso-occlusive event; and 
requiring treatment with a parenteral or oral 
opioids or other parenteral analgesic; but is 
NOT classified as an acute chest syndrome, 
hepatic sequestration, splenic sequestration 
or priapism and these events will not be 
adjudicated)
Rate of uncomplicated VOC events 
(including  both healthcare visit and self-
reported) by 26 and 52 weeks
To evaluate the clinical efficacy of 
crizanlizumab in complicated VOCs (acute 
chest syndrome, hepatic sequestration, 
splenic sequestration, and acute priapism)
Rate of complicated crisis (recorded by 
healthcare visit) by 26 and 52 weeks
To assess the safety and tolerability of 
crizanlizumab
Number, seriousness, severity, and causality 
assessments of treatment emergent adverse 


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events and other safety data as considered 
appropriate by 52 weeks (Safety assessments 
will consist of monitoring and recording all 
adverse events, based on Common 
Terminology Criteria for Adverse events 
(CTCAE) V5.0.
It will also include regular monitoring of 
laboratory testing of hematology, serum 
chemistry, and urinalysis, measurement of 
vital signs, and physical examination.)
1.2.1
Primary estimand(s)
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 on reduction 
from baseline period in priapic events, by week 26?
The primary estimand is described by the following attributes: 
1. Population: Sickle Cell Disease patients with priapism.  
2. Endpoint: Percent reduction from baseline period in priapic events (priapism defined as 
unwanted, or painful erection lasting at least 60 min self-reported) by 26 weeks
3. Treatment of interest: Investigational drug will be a crizanlizumab solution provided every 
4 weeks with an additional loading dose 2 weeks after the first dosing. 
4. List of intercurrent events:
a) Treatment discontinuation.
b) Initiation or discontinuation of HU/HC or l-Glutamine (or other therapies to treat 
SCD and or to prevent/reduce VOCs such as voxelotor and erythropoietin) or of 
prophylactic treatment for priapism. 
c) Intake of analgesic (including opioids) or ad hoc transfusions administered 
temporarily.  


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5. The summary measure: Median percentage change from baseline period in priapic events 
(priapism defined as unwanted, or painful erection lasting at least 60 min self-reported) by 
26 weeks
Handling of intercurrent events is discussed in Section 2.5.3
1.2.2
Secondary estimand(s) 
Not applicable
2
Statistical methods
2.1
Data analysis general information
The data will be analyzed by Novartis and/or  a designated contract research organization (CRO) 
(if applicable). It is planned that the data from all centers that participate in this protocol will 
be used for analysis. Analysis datasets and statistical outputs will be produced using the most 
recent SAS® Version 9.4 (SAS Institute Inc., Cary, NC, USA), and stored in Novartis global 
programming & statistical environment (GPS).  
General analysis conventions
Descriptive statistics for continuous variables will include number of subjects (n), mean, 
standard deviation (SD), minimum, lower quartile (Q1), median, upper quartile (Q3), maximum. 
Summary statistics for discrete variables will be presented in the number and percent of subjects 
in each category. Summary statistics will also be presented graphically wherever applicable. 
If not otherwise specified, p-values and confidence interval (CI) will be presented as two-sided. 
Unless otherwise stated, the default level of significance will be set to 5%.
For categorical data, percentages will be rounded up to one decimal place. For continuous data, 
mean, and median will be rounded up to one additional decimal place compared to the original 
data. Standard deviation will be rounded up to two additional decimal places. Minimum and 
maximum will be displayed with the same accuracy as in the original data. Wherever changes 
from baseline will be used, change will be calculated as “post-baseline value – baseline value”. 
The number of decimal places for the “change from baseline” variables will be the same as for 
the original measurement.
The analysis will be conducted on all subjects' data at Week 26 and at the time, the trial ends 
(Week 52).
Unscheduled assessments
The following points summarize the rules for unscheduled assessments:
•
All unscheduled assessments at the baseline before the first dose should be included 
for consideration when calculating the baseline value.
•
In summary tables by visit, unscheduled assessments should not be included unless 
they qualify as baseline.


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•
In shift and abnormality tables, all unscheduled assessments are included.
Unscheduled assessments will be reported along with the scheduled assessments in the listings.
Data included in analysis
All statistical analyses will be performed using all data collected in the database up to the data 
cut-off date. All data with an assessment date or event start date (e.g., vital sign assessment date 
or start date of an adverse event) prior to or on the cut-off date will be included in the analysis. 
Any data collected beyond the cut-off date will not be included in the analysis and will not be 
used for any derivations at the time of the primary analysis.
All events with start date before or on the cut-off date and end date after the cut-off date will be 
reported as ‘ongoing’. The same rule will be applied to events starting before or on the cutoff 
date and not having documented end date. This approach applies, in particular, to adverse event 
and concomitant medication reports. For these events, the end date will not be imputed and 
therefore will not appear in the listings.
For the final analysis, all data collected will be used, without notion of cut-off date.
2.1.1
General definitions 
Study treatment: Study treatment refers to Crizanlizumab (SEG101) 5.0 mg/kg provided by 
IV infusion.
Study treatment start and end date: Study treatment start date is defined as the first date 
when a non-zero dose of study drug is administered and recorded on the Drug Administration 
Record (DAR) CRF page. Similarly, study drug end date is defined as the last date when a non-
zero dose of study drug is administered and recorded on the DAR CRF page of the core study.
Baseline: Baseline period is defined as 12 weeks screening period prior to the first infusion of 
crizanlizumab 5 mg/kg at Week 1 Day 1.
•
For the analysis purpose, in the tables and figures, baseline is considered from Day -91 
to one day prior to dosing. Similarly, for “by week 26 analysis” from the first dose date 
to one day prior to Week 27 Day 1 visit date and for “by week 52 analysis” from the 
first dose date to one day prior to Week 53 Day 1 visit date will be considered. 
•
For subjects missing "Week 27 Day 1" visit or "Week 53 Day 1" visit, the scheduled 
visit day will be considered for cut-off.
•
For listings, all available data will be considered.
For safety evaluations, the last available assessment on or before the date of start of study 
treatment is taken as ‘‘baseline” assessment. In case time of assessment and time of treatment 
start is captured, the last available assessment before the treatment start date/time is used for 
baseline. 
For safety parameters (e.g. ECGs), where study requires multiple replicates per time point, the 
average of these measurements will be calculated for baseline (if not already available in the 
database).


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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.
If subjects have no value as defined above, the baseline result will be missing.
Post baseline: Any measurements taken after baseline will be considered as post-baseline 
measurements.
Change from baseline: Post baseline value – baseline value 
Percent change from baseline: (Post baseline value – baseline value) *100/ Baseline value; 
(relative change from baseline).
Reduction: The negative change from baseline.
Study day: The study day, describes the day of the event or assessment date, relative to the 
start of study treatment. Study Day 1 for all assessments is taken to be the start of study 
treatment.
The study day is defined as:
•
The date of the event (visit date, onset date of an event, assessment date etc.) – Start of 
study treatment + 1, if event is on or after the start of study treatment;
•
The date of the event (visit date, onset date of an event, assessment date etc.) – Start of 
study treatment, if event precedes the start of study treatment.
The study day will be displayed in the data listings. If an event starts before start of study 
treatment, the study day displayed in the listing will be negative.
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 subject’s informed consent to the day before first dose
of study medication
2. On-treatment period: from day of first dose of study medication to 105 days after last dose
of study medication (or until EOT date for subjects continuing crizanlizumab after their
EOT via commercial supply)
3. Post-treatment period: starting at Day 106 after last dose of study medication (or after
EOT date for subjects continuing crizanlizumab after their EOT via commercial supply or
a post-trial access program)
Note: If dates are incomplete in a way that clear assignment to pre-, on-, post-treatment period 
cannot be made, then the respective data will be assigned to the on-treatment period.
Safety summaries (tables, figures) include only data from the on-treatment period, unless 
specified otherwise, with the exception of baseline data which will also be summarized where 
appropriate (e.g., change from baseline summaries). 


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Time unit: A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). 
If duration is reported in months, duration in days will be divided by 30.4375. If duration is 
reported in years, duration in days will be divided by 365.25.
Visit windows
Visit-windows will be applied for vital signs, laboratory and PRO assessments. 
Visit-windows will be used for the data that is summarized by visit; they are based on the study 
evaluation schedule and comprise a set of days around the nominal visit day. For any 
assessment, there are the protocol defined scheduled visits around which visit windows were 
created to cover the complete range of days within the study.  The visit windows are shown in 
Table 2-1. These apply to measurements taken at every visit. 
When visit windows are used, all visits will be re-aligned, i.e., they will be mapped into one of 
the visit windows ( e.g., if the Week 4 visit of a subject is delayed and occurs on Day 46 instead 
of on Day 29, say, it will be re-aligned to visit window Week 8). In the case of major deviations 
from the visit schedule, or due to unscheduled visits, several assessments of a subject may fall 
in a particular visit window (either scheduled or unscheduled). Statistical approaches to handle 
multiple assessments in a given visit window are specified below.
Table 2-1
Assessment windows for scheduled visits 
Analysis Visit
Week (k)
Scheduled Day/ 
Target day        
[d=(k-1)*7+1]
Visit Window         
(in study days)
Baseline
BSL
-91 days to Day -1*
Week 1 Day1
1
1
Day 1-7
Week 3 Day 1
3
15
Day 8-29
Week 7 Day1
7
43
Day 30-57
Week 11 Day 1
11
71
Day 58-85
Week 15 Day 1
15
99
Day 86-113
Week 19 Day 1
19
127
Day 114-141
Week 23 Day 1
23
155
Day 142-169
Week 27 Day 1
27
183
Day 170-197
Week 31 Day 1
31
211
Day 198-225
Week 35 Day 1
35
239
Day 226-253
Week 39 Day 1
39
267
Day 254-281
Week 43 Day 1
43
295
Day 282-309
Week 47 Day 1
47
323
Day 310-337
Week 51 Day 1
51
351
Day 338-358
EoT
53
365
Day 359-371**
*Baseline measurement prior to first infusion of study drug.


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**Based on medical judgement and data, upper limit of EoT will be extended upto 
maximum value day 447.
Laboratory assessments will be taken from Screening Visit 3 as per the protocol and the window 
does not include pre-screening period. Thus, window for laboratory assessments will be Day -
28 to Day -1.
Multiple assessments within visit windows
In order to summarize laboratory assessments over time (including unscheduled visits), the 
assessments will be time slotted. The following general rule will be applied: 
•
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.
2.2
Analysis sets 
The analysis sets to be used are defined as below.  
All efficacy analyses will be performed on subjects in FAS who have completed treatment. The 
Safety Set will be used for all the safety analysis. 
Full Analysis Set (FAS)
The FAS include  all enrolled subjects to whom the study treatment has been assigned regardless 
of whether or not they have received at least 1 dose of study treatment or have at least 1 post-
baseline assessment.
Safety Set (SAF)
The SAF will consist of all subjects who received at least 1 dose of study treatment.
2.2.1
Subgroup of interest
•
The primary analysis will be conducted on a subgroup of subjects with stuttering 
(duration of priapic events from 1 to <=4 hours) and acute priapism. Acute priapic 
events are defined as an unwanted, painful erection that lasts more than 4 hours and 
need a visit to emergency room. 


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•
Additional subgroup analysis will be performed based on duration of priapic events (i.e., 
<1, 1 to ≤4, >4 to ≤6,  >6 to ≤12, >12 hours).
•
Subgroup analysis of the primary endpoint will also be performed based on the number 
of priapic events categories (i.e. <7, 7 – 13, 14 – 21, ≥ 22) at baseline (12 weeks) and 
baseline (adjusted for 26 weeks). The priapic events categories may be re-grouped to 
ensure that there is adequate number of subjects in each category for analysis. 
•
Note that, subgroup analyses of the primary endpoint by age group will only be 
performed if an adequate number of subjects are present in each subgroup class.
2.3
Subject disposition, demographics and other baseline 
characteristics
2.3.1
Subject disposition
The following summaries will be provided for subject disposition in different study phases:
•
Number (%) of subjects who were screened, screen failures, reasons of discontinuation 
from screening phase (based Screening phase disposition page), with % based on all 
subjects in Screening phase).
•
Number (%) of subjects who completed study treatment phase, discontinued study 
treatment, primary reason for study treatment phase discontinuation (based on the 
‘Treatment disposition’ page), with % based on FAS subjects.
•
Number (%) of subjects who have entered post-treatment follow up phase, completed 
the follow up phase, discontinued from follow up phase and reasons for discontinuation 
(based on Follow-up disposition page), with % based on FAS subjects. 
Subject disposition data will be listed.
Screened subjects not treated will be listed.
Protocol Deviations
The number (%) of subjects in the FAS with any protocol deviation will be tabulated by 
deviation category (as specified in the edit checks specifications). All protocol deviations will 
be listed.
In addition, pandemic related protocol deviations will be summarized by category and 
relationship. All COVID-19 related protocol deviations will also be listed.
2.3.2
Demographics and other baseline characteristics
Demographic and other baseline characteristics will be listed and summarizes descriptively for 
all subjects in the FAS. 
Continuous variables will be summarized using n, mean, standard deviation (SD), lower quartile 
(Q1), median, upper quartile (Q3), minimum, and maximum. Categorical variables will be 
summarized using frequency and percentage.


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Following demographic variables will be summarized:
•
Age (years)
•
Ethnicity
•
Race
Following baseline characteristic variables will be summarized:
•
Height (cm)
•
Weight (kg)
•
BMI (kg/m2)
•
VOC events
Medical History
Any condition recorded on the Medical History CRF will be coded using the MedDRA 
dictionary. These will be summarized by system organ class (SOC) and preferred term (PT) of 
the MedDRA dictionary. The MedDRA version used for reporting will be specified in the CSR 
and as a footnote in the applicable tables/listings. 
Following are the examples of the procedures that will be performed at the baseline: 
•
Background medical information including sickle cell and VOC history, priapism history, 
blood transfusion history, leg ulcer, ECG, cardiac imaging and urine protein/creatinine ratio. 
•
Relevant and current medical history; SCD genotypes (HbSS, HbSβ0, HbSC, HbSβ+, and 
others).
•
Concomitant medication use; history of analgesic and hydroxyurea use.
•
Complete physical examination.
•
Vital signs (blood pressure, pulse measurement, respiratory rate, oxygen saturation, and 
body temperature), weight and height.
•
Clinical laboratory evaluations
•
Chest X-ray, if none has been performed within 3 months of Day 1
Drug, alcohol and smoking history will also be collected. 
All above baseline characteristics will be summarized and listed. 
Analyses will be based on FAS subjects.


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2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, n, mean, standard deviation (SD), lower 
quartile (Q1), median, upper quartile (Q3), minimum, and maximum will be presented.
The duration of exposure in weeks to study drug as well as the dose intensity (computed as the 
ratio of actual cumulative dose received and actual duration of exposure) and the relative dose 
intensity (computed as the ratio of dose intensity and planned dose intensity), will be 
summarized descriptively.
The number (%) of subjects with dose interruption or permanent discontinuation and the reasons 
will be summarized.
All dosing data will be listed.
Duration of exposure to study treatment
Duration of exposure to study treatment (week) = ((last date of exposure to study treatment) – 
(date of first administration of study treatment) + 1)/7.
The last date of exposure to study treatment the earliest of the last date of treatment + 27 days, 
the date of death (if the subject died), and the date of data cutoff. 
Summary of duration of exposure of study treatment in appropriate time units will include   
categorical summaries (less than 1 weeks, at least 4 weeks, at least 14 weeks, at least 26 weeks, 
at least 52 weeks) and continuous summaries (i.e. mean, standard deviation (SD) etc.).
Cumulative dose
Cumulative dose of the study treatment is defined as the total dose given during the study 
treatment exposure and will be summarized.
The planned cumulative dose refers to the total planned dose as per the protocol up to the last 
date of investigational drug administration.
The actual cumulative dose refers to the total actual dose administered, over the duration for 
which the subject is on the study treatment as documented in the Dose Administration CRF.
Dose intensity and relative dose intensity
Dose Intensity (DI) for subjects with non-zero duration of exposure is defined as follows:
DI (mg/kg/28 days) = Actual Cumulative dose (mg/kg) / Duration of exposure to study 
treatment (week) × 4.
Planned dose intensity (PDI) is defined as follows:
PDI (mg/kg/28 days) = Planned Cumulative dose (mg/kg) / Duration of exposure (week) × 4.
Relative dose intensity (RDI) is defined as follows:


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RDI = DI (mg/kg/28 days) / PDI (mg/kg/28 days).
DI and RDI will be summarized.
2.4.2
Prior, concomitant and post therapies
Prior and Concomitant medications will be coded using the World Health Organization (WHO) 
Drug Reference List (DRL) dictionary that employs the WHO Anatomical Therapeutic 
Chemical (ATC) classification system using the latest version available prior to clinical 
database lock and summarized by lowest ATC class and preferred term.
The ATC class will be presented in alphabetical order. Preferred terms will be sorted by 
decreasing proportion and alphabetical order.
Prior medications are defined as treatments taken and stopped prior to first dose of study 
treatment.
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a subject coinciding with the study treatment 
period. Concomitant therapy includes medications (other than study treatments) 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.
Summaries for concomitant medications will include:
1. Medications starting on or after the start of study treatment but no later than 105 days 
after start of last dose of study treatment and
2. Medications starting prior to start of study treatment and continuing after the start of 
study treatment.
Medications will be presented in alphabetical order, by Anatomical Therapeutic Classification 
(ATC) codes and grouped by anatomical main group. Tables will show the overall number and 
percentage of subjects receiving at least one treatment of a particular ATC code and at least one 
treatment in a particular anatomical main group. 
Prior and concomitant medications for analgesics and hydroxyurea will be summarized 
separately.
Prior and concomitant non-drug therapies/procedures will be summarized according to the 
Anatomical Therapeutic Chemical (ATC) classification system for all subjects.
All prior and concomitant therapies will be listed. Any concomitant therapies starting and 
ending prior to the start of study treatment or starting more than 105 days after the last date of 
study treatment will be flagged in the listing. The safety set will be used for all concomitant 
medication tables and listings.
Rescue medications
Rescue medication is defined as medication used to control symptoms that are not adequately 
controlled on study treatment.


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As per protocol, any standard medications that are used for management of VOC 
 
 should follow the 
recommendation from Dr Minniti publication (Minniti et al 2010). Thus, these medications will 
be identified by the medical team and provided for analysis.
Rescue medication will be summarized similarly to concomitant medication.
2.5
Analysis supporting primary objective(s)
The primary objective of this study is to evaluate clinical efficacy of crizanlizumab 5 mg/kg, 
over 26 weeks compared to baseline in sickle cell subjects with a history of priapism.
2.5.1
Primary endpoint(s)
The primary endpoint of the study is percent reduction from baseline in priapism events by 26 
weeks (i.e., up to pre-infusion Week 27 Day 1). Priapism event is defined as unwanted, or 
painful erection lasting at least 60 minutes, self-reported. 
Percentage change from baseline = (Post baseline value –Baseline value) * 100 / Baseline value; 
(relative change from baseline).
Percentage reduction from baseline is the negative percentage change from baseline.
2.5.2
Statistical hypothesis, model, and method of analysis 
It is expected that crizanlizumab treatment reduces priapic events by at least 25% in SCD 
subjects with priapism.
Demonstration of significant percent reduction from baseline in priapic events will be evaluated 
using following hypothesis:
H0: p < 0.25, where p is the percent reduction in priapic events by 26 weeks.
H1: p ≥ 0.25, where p is the percent reduction in priapic events by 26 weeks.
If the above null hypothesis is rejected, significant reduction in priapic events will be 
demonstrated statistically.
Assuming uniformity in the occurrence of priapic events before exposure to crizanlizumab
treatment, baseline will be adjusted for 26 weeks for analysis purpose.
Baseline (adjusted for 26 weeks): Number of priapic events in 12 weeks screening period * 
(26/12) and percentage change from baseline = (Post baseline value –Baseline (adjusted to 26 
weeks) value) * 100 / Baseline (adjusted to 26 weeks) value.
Percentage reduction from baseline is the negative percentage change from baseline.
Percent reduction from baseline in priapic events will be tested using a non-parametric test (i.e., 
Wilcoxon’s Sign Rank test) and p-value will be reported. The study would be declared a success, 
if percentage reduction in events is ≥ 25 % and p<0.05 is obtained from Wilcoxon’s Sign Rank 
test.  


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Hodges-Lehmann estimate of median percent reduction in  priapic events will also be reported, 
along with corresponding 95% confidence intervals. 
Number of priapic events will be summarized at baseline (adjusted for 26 weeks) and by Week 
26, and percent reduction from adjusted baseline by Week 26 will be summarized by n, mean, 
standard deviation (SD), lower quartile (Q1), median, upper quartile (Q3), minimum and 
maximum. 
Graphical representation of percentage reduction, through box plot or bar graph or waterfall 
plot, will be performed as appropriate by 26 weeks.
In addition, subgroup analysis of the primary endpoint will be performed based on the number 
of priapic events categories (i.e. <7, 7 – 13, 14 – 21, ≥ 22) at baseline (12 weeks) and baseline 
(adjusted for 26 weeks). Additional analyses of the primary endpoint will also be performed for 
the subgroups of subjects with stuttering and acute priapism. Summary statistics for percentage 
reduction by 26 weeks will be presented for each subgroup.
The priapic events categories may be re-grouped to ensure that there is adequate number of 
subjects in each category for analysis. Additional analyses will also be performed for the 
subgroups of subjects with acute priapism and subjects who have experienced priapic episodes 
lasting less than one hour.
The primary analysis will be performed only on all FAS subjects who have completed 26 weeks 
on treatment.
2.5.3
Handling of intercurrent events 
The imputation of missing data caused by intercurrent events will be handled by defining the 
estimand framework. 
The primary estimand is described by the following four attributes:
1. The target population comprises Sickle Cell Disease Patients with Priapism.
2. The primary variable is percent reduction from baseline period in priapic events (priapism 
defined as unwanted, or painful erection lasting at least 60 min self-reported) by 26 weeks.
3. Treatment of interest: investigational drug will be a crizanlizumab solution provided every 
4 weeks with an additional loading dose 2 weeks after the first dosing. 
4. The intercurrent events are the events occurring after enrollment that may impact the 
treatment effect. The intercurrent events of interest are listed below:
a.
Treatment discontinuation 
b. Initiation or discontinuation of HU/HC or l-Glutamine (or other therapies to treat 
SCD and or to prevent/reduce VOCs such as voxelotor and erythropoietin) or of 
prophylactic treatment for priapism
c.
Intake of analgesic (including opioids) or ad hoc transfusions administered 
temporarily
5. The summary measure is the median percentage change from baseline period in priapic 
events (priapism defined as unwanted, or painful erection lasting at least 60 min self-
reported) by 26 weeks.


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Handling of the intercurrent events:
The approach of accounting for intercurrent events is as follows:
•
For the intercurrent events 4a: Only data before study treatment discontinuation will be 
included. The data between treatment discontinuation and week 26 will be imputed using 
Poisson distribution (primary method to handle missing data as described in Section 2.5.4).
•
For the intercurrent events 4b: Only data before initiation or discontinuation of HU/HC 
or L-Glutamine (or other therapies to treat SCD and or to prevent/reduce VOCs such as 
Voxelotor and erythropoietin) or of prophylactic treatment for priapism will be included. 
The data between initiation or discontinuation of therapies to treat SCD or of prophylactic 
treatment for priapism and week 26 will be imputed using Poisson distribution (primary 
method to handle missing data as described in Section 2.5.4).
•
For the intercurrent events 4c: Data after intake of analgesic (including opioids) or ad hoc 
transfusions administered temporarily will be included (treatment policy strategy).
2.5.4
Handling of missing values not related to intercurrent event
The missing values will be imputed for the primary analysis. 
Missing values will be imputed using Poisson distribution, assuming the same effect as 
observed data. Imputed datasets (approximately 1,000) will be created, and each dataset will be 
analyzed using the method described for primary endpoint. The results will be combined using 
Rubin’s rule (Barnard J and Rubin DB 1999). 
Further details are mentioned in the Section 5.4.1.
2.5.5
Sensitivity analyses 
Sensitivity analysis 1: Tipping point analysis
To explore the robustness of analysis,  sensitivity analysis as a 'tipping point approach will be 
performed for the primary endpoint to evaluate the impact of a deviation from the MAR 
assumption. The basic idea is to first impute the missing values using the multiple imputation 
(MI) method based on the missing at random (MAR) assumption, then adjusted by a delta value. 
The delta adjusting approach described in Ratitch et al (2013) will be used to find the tipping 
point, in a spectrum of conservative missing not at random (MNAR) assumptions, at which 
conclusions change from being favorable to being unfavorable. After such a tipping point is 
determined, clinical judgment can be applied as to the plausibility of the assumptions underlying 
this tipping point. Note that, tipping point analysis will be performed if there are significant 
number of missing data.
Further details are provided in Section 5.4.1. 
Sensitivity analysis 2


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As part of the sensitivity analysis, treatment policy strategy (that is, data after the intercurrent 
events will be included) will also be applied for the intercurrent events 4a and 4b, described in 
Section 2.5.3.
Note: Handling of intercurrent event 4c and missing data not related to intercurrent event will 
be same as described for the primary analysis.
Sensitivity analysis 3: Observed case analysis
As part of the sensitivity analysis, the primary analysis will be analyzed on all subjects in FAS 
without missing data.
Sensitivity analysis 4: For COVID 19 impact
Additionally, as the study is ongoing during COVID 19 pandemic, the impact of COVID-19 (if 
any) on the primary endpoint will be assessed in accordance to FDA’s guideline entitled 
“Statistical Considerations for Clinical Trials During the COVID-19 Public Health Emergency”. 
The analysis (as stated below) will be repeated on the FAS excluding the subjects with missing 
data due to COVID-19. 
Percent reduction from baseline in priapic events will be tested using a 
nonparametric test (i.e., Wilcoxon’s Sign Rank test). Hodges-Lehmann estimate 
of median percent reduction in priapic events will also be reported, along with 
corresponding 95% confidence intervals. 
2.5.6
Supportive analyses
The supportive analyses described below will be performed on all FAS patients who have 
completed 26 weeks on treatment.  Missing values will be imputed as stated in Section 2.5.4
Supportive analysis 1:
Annualized priapic Events Rate: The annualized rate of priapic events is defined as the total 
number of priapic events for a subject occurring from the date of initial infusion to the last 
contact date of the Treatment Phase of the study × 365.25 divided by the number of days during 
that same time period. This calculation accounts for early dropouts or lost to follow-up by 
extrapolating the priapism events rate of every subject to 1 year.
Supportive analysis 2:
Percent reduction from baseline in priapic events will also be assessed by Week 52. Assuming 
uniformity in the occurrence of priapic events before exposure to crizanlizumab treatment, 
baseline will be adjusted for 52 weeks for analysis purpose.
Baseline (adjusted for 52 weeks): Number of priapic events in 12 weeks screening period * 
(52/12) and percentage change from baseline = (Post baseline value –Baseline (adjusted to 52 
weeks) value) * 100 / Baseline (adjusted to 52 weeks) value.
Percentage reduction from baseline is the negative percentage change from baseline.
Supportive analysis 3:


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The total number of priapic episodes in the screening period (12 weeks baseline) will be 
compared to the total number of priapic episodes occurring in the first 12 weeks on treatment 
(0-12 weeks) using a nonparametric test (i.e. Wilcoxon’s Sign Rank test). Additionally, a 
similar analysis will be performed to compare to the total number of priapic episodes occurring 
in the last 12 weeks on treatment (15-26 weeks).  For the analysis purpose, for 0-12 weeks: Day 
1 to Day 84 and for 15-26 weeks: Day 105 to Day 182 will be used.
Supportive analysis 4:
Number of priapic events will be summarized in the screening period (12 weeks baseline), in 
first 12 weeks on treatment (0-12 weeks), and in the last 12 weeks on treatment (15-26 weeks) 
and percent reduction from baseline will also be summarized. For the analysis purpose, for 0-
12 weeks: Day 1 to Day 84 and for 15-26 weeks: Day 105 to Day 182 will be used.
2.6
Analysis supporting secondary objectives 
Not applicable
2.6.1
Secondary endpoint(s)
The secondary objectives in this study are to assess efficacy, safety and tolerability of 
crizanlizumab 5.0 mg/kg in SCD subjects.
The following secondary efficacy endpoints will be analyzed on all FAS subjects who have 
completed 26 and 52 weeks on treatment to evaluate clinical efficacy of crizanlizumab 5 mg/kg:
a.
The rate of priapic events by 26 and 52 weeks of treatment.
b. The percent reduction from baseline in acute priapic events (defined as an unwanted, 
painful erection that lasts more than 4 hours and need a visit to emergency room) by 26 
and 52 weeks of treatment. Note that, this analysis will only be performed if an adequate 
number of subjects are present.
c.
The rate of uncomplicated VOC events (defined as an acute event of pain with no known 
cause for pain other than a vaso-occlusive event; and requiring treatment with a 
parenteral or oral opioids or other parenteral analgesic; but is NOT classified as an acute 
chest syndrome, hepatic sequestration, splenic sequestration or priapism and these 
events will not be adjudicated) by 26 and 52 weeks of treatment. Events include both 
healthcare and self-reported events.
d. The rate of complicated VOCs (defined as acute chest syndrome, hepatic sequestration, 
splenic sequestration, and acute priapism) recorded by healthcare visit, by 26 and 52 
weeks of treatment.
The efficacy endpoints will be assessed and summarized by 26 weeks  and by 52 weeks . 
2.6.2
Statistical hypothesis, model, and method of analysis
Similar analyses on percent reduction in acute priapic events for subjects from full analysis set 
will be conducted, as done for primary endpoint.
Annualized rates will be calculated for the secondary endpoints.


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The annualized rate of events is defined as the total number of events for a subject occurring 
from the date of initial infusion to the last contact date of the Treatment Phase of the study x 
365.25 divided by the number of days during that same time period. This calculation accounts 
for early dropouts or lost to follow-up by extrapolating the priapism events rate of every subject 
to 1 year.
Annualized events rate = Total number of events x 365.25 / (end date – treatment start date +1), 
where end date is defined as the minimum of (last dose date until treatment discontinuation + 
27 days, date of initiation or discontinuation of HU/HC or L-glutamine - or other therapies to 
treat SCD and or to prevent/reduce VOCs such as voxelotor and erythropoietin, cut-off date).
Descriptive summary statistics including n, mean, standard deviation (SD), lower quartile (Q1), 
median, upper quartile (Q3), minimum, and maximum will be presented for the annualized rate 
of events and number of priapic events at Baseline, by Week 26  and by Week 52 . 
The change from baseline in rates of events at Week 26 (i.e. evaluation at Week 27, Day 1) and 
Week 52 (i.e. evaluation at Week 53, Day 1) will be summarized by n, mean, median, standard 
deviation (SD), lower quartile (Q1), median, upper quartile (Q3), and minimum and maximum.
Graphical representation of annualized rates, through box plots or bar graphs or swimmer plot, 
as appropriate, will also be performed.
The  Annualized Rates of Events at Week 26 (i.e. evaluation at Week 27, Day 1) and Week 52 
(i.e. evaluation at Week 53, Day 1) will be summarized by n, mean, standard deviation (SD),  
lower quartile (Q1), median, upper quartile (Q3), standard deviation and minimum and 
maximum.
Additionally, cumulative number of acute priapic events, uncomplicated and complicated VOC 
events will also be summarized over time (like 0-12 weeks, 0-26 weeks, 0-40 weeks and 0-52 
weeks). 
Subgroup analyses displaying annualized rate, for complicated and uncomplicated VOC events 
will be performed based on use of hydroxyurea versus no use of hydroxyurea by 26 weeks and 
52 weeks.
As appropriate, the estimated median change from Baseline at 26 weeks (i.e. evaluation at Week 
27, Day 1) and 52 (i.e. evaluation at Week 53, Day 1) weeks in acute priapic events with 
associated 95% CI using a Hodges-Lehmann estimate will be reported. The median percent 
reduction will also be presented by Week 26 and Week 52.
2.6.3
Handling of intercurrent events 
Not applicable
2.6.4
Handling of missing values not related to intercurrent event
Not applicable
2.6.5
Sensitivity analyses
Not applicable


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2.6.6
Supplementary analyses
Not applicable
2.7
Safety analyses
All safety analyses will be based on the Safety Set unless otherwise specified. Safety summaries 
include only on-treatment assessments. Safety listings include all assessments with those more 
than 105 days after last study treatment, flagged.
2.7.1
Adverse events (AEs)
For reporting of AEs, the overall observation period will be divided into three mutually 
exclusive segments:
1. Pre-treatment period: from day of subject’s informed consent to the day before first dose
of study medication
2. On-treatment period: from day of first dose of study medication to 105 days after last 
dose of study medication (or until EOT date for subjects continuing crizanlizumab after 
their EOT via commercial supply)
3. Post-treatment period: starting at Day 106 after last dose of study medication (or after
EOT date for subjects continuing crizanlizumab after their EOT via commercial supply or
a post-trial access program)
Reporting of AEs will be based on MedDRA version 25.0 or higher and the Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0 or higher.
AE summaries will include all AEs occurring during on-treatment period. All AEs collected in 
the AE CRF page will be listed along with the information collected on those AEs e.g. AE 
relationship to study drug, AE outcome etc. AEs outside of on-treatment period will be flagged 
in the listings.
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. 
AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT) 
using MedDRA coding. A subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event. 
AE with missing CTCAE grade will be included in the ‘All grades’ column of the summary 
tables.
In AE summaries, the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order for 
the preferred term will be based on their frequency in all subjects.


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Serious adverse events will be tabulated. All deaths (on-treatment death and post-treatment 
death) will be summarized.
All AEs 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. SAEs will 
be summarized and listed.
Separate summaries for 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 the legal requirements of clinicaltrials.gov and EudraCT, two required tables 
(plus standard safety XML files) on on-treatment adverse events which are not SAEs with an 
incidence greater than 5% and on on-treatment serious adverse events and SAEs suspected to 
be related to crizanlizumab will be provided by SOC and PT.
If for the same patient, several consecutive AEs (irrespective of study treatment causality,
seriousness and severity) occurred with the same SOC and PT:
•
A single occurrence will be counted if there is ≤ 1 day gap between the end date of the
preceding AE and the start date of the consecutive AE.
•
More than one occurrence will be counted if there is > 1 day gap between the end date of
the preceding AE and the start date of the consecutive AE. 
For occurrence, the presence of at least one SAE/SAE suspected to be related to crizanlizumab
/non-SAE has to be checked in a block e.g., among AEs in a ≤ 1 day gap block, if at least one
SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
2.7.1.1
Adverse events of special interest / grouping of AEs
Not applicable
2.7.2
Deaths
All deaths (on-treatment death and post-treatment death) will be summarized. Separate 
summaries for on-treatment and all deaths (including post-treatment death) will be produced 
system organ class and preferred term. 
All deaths will be listed using Safety set. All deaths those collected during the pre-treatment 
and post treatment period will be flagged. A separate listing of deaths prior to starting treatment 
will be provided for all screened subjects.


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2.7.3
Laboratory data
On analyzing laboratory values, data from all sources (central and local laboratories) will be 
combined as per Section 8.3.2 of the protocol. The summaries will include all assessments 
available for the lab parameter collected no later than 105 days after the last study treatment 
administration date. Following lab parameters will be analyzed :
Table 2-1
Test category
Test name
Hematology
Hematocrit, Hemoglobin, MCH, MCHC, MCV, reticulocytes (%), 
Platelets, Red blood cells, White blood cells, RBC Morphology, 
Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, 
Neutrophils, Bands, Other
Chemistry
 Alkaline phosphatase, ALT, AST, Gamma-glutamyl transferase 
(GGT), Lactate dehydrogenase (LDH), Bicarbonate, Calcium, 
Magnesium, Phosphorus, Chloride, Sodium, Potassium, Creatinine, 
Creatine kinase, Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, 
Total Cholesterol, LDL, HDL, Total Protein, Triglycerides, Blood 
Urea Nitrogen (BUN) or Urea, Uric Acid, Amylase, Lipase, Glucose 
(non-fasting), estimated glomerular filtration rate (eGFR).
Urinalysis
Macroscopic Panel (Dipstick), done locally: Color, Bilirubin, Blood,
Glucose, Ketones, Leukocytes esterase, Nitrite, pH, Protein,  Specific 
Gravity, Urobilinogen 
Microscopic Panel (performed if dipstick is positive): Red Blood 
Cells, White Blood Cells, Casts, Crystals, Bacteria, Epithelial cells
Urine creatinine/protein ratio, Microalbumin
Coagulation
Prothrombin time (PT) , International normalized ratio [INR]), 
Activated partial thromboplastin time (APTT)
Hepatitis
markers
HBV-DNA, HbsAg, HbsAb, HbcAb, HCV RNA-PCR, HCV Ab 
Additional
tests
HIV Ab 
For results reported by the central laboratory, continuous hematology and chemistry results will 
be summarized descriptively in SI units at each scheduled time point. Visits summaries will 
include baseline and post baseline visits, including early termination and Follow-Up. Changes 
from baseline will also be summarized at each time point.
The following summaries will be produced for laboratory data by laboratory parameters:
Separate summaries of change from baseline for each lab test category.
•
Worst post-baseline CTCAE grade (regardless of the baseline status). Each subject will 
be counted only once for the worst grade observed post-baseline.


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•
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 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value.
The following listings will be produced for the laboratory data:
•
Listings of all laboratory data, with CTCAE 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 2, 3, or 4 laboratory toxicities.
Coagulation parameters will be summarized descriptively at each time-point. Changes from 
baseline will also be summarized.
Urinalysis results will be listed in individual subject data listings only. In addition, a listing 
containing individual subject hematology, chemistry, and coagulation values outside the 
reference ranges will be provided. This listing will include data from scheduled and 
unscheduled time points.
Hepatitis markers and additional tests only performed at screening will be summarized and 
listed. 
Urine creatinine/protein ratio will be summarized descriptively at screening visit 3 and EoT 
visit, and summary of change will be presented.
2.7.4
Other safety data
2.7.4.1
ECG and cardiac imaging data
Standard 12-lead ECG will be performed (in the supine position) after the subject has been 
resting for 5-10 min prior to ECG assessments.
A standard 12 lead ECG will be performed
•
at screening 
•
at the end of treatment 
When ECG triplicates are collected at any assessment, the average of the ECG parameters at 
that assessment will be used in the analyses.
12-lead ECGs including PR, QRS, QT, QTcF and HR intervals were obtained for each subject 
during the study. ECG data was read and interpreted centrally.
The number and percentage of subjects with notable ECG values will be presented at 
screening visit and EoT visit. In addition, a listing of these subjects will be produced.
•
QT, QTcF
-
New value of > 450 and ≤ 480 ms
-
New value of > 480 and ≤ 500 ms


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-
New value of > 500 ms
-
Increase from baseline of > 30 ms to ≤ 60 ms
-
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
For cardiac imaging data, left ventricular ejection fraction (LVEF), mean pulmonary arterial 
pressure (mPAP), and tricuspid regurgitation jet velocity (TRV) will be summarized at 
screening and end of treatment visit. In addition, all data will be listed.
2.7.4.2
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: weight (kg), body temperature (oC), pulse rate (beats per 
minute), systolic and diastolic blood pressure (mmHg), respiratory rate and oxygen saturation.
Vital signs collected on-treatment will be summarized descriptively. Values measured during 
pre- and post- treatment period will be flagged in listings.
The number and percentage of subjects with notable vital sign values will be presented over 
time. Notable values will be flagged in the listings. For analysis, clinically notable vital sign 
criteria are provided in Table 2-2 below:
Table 2-2
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
High
≥ 95th percentile of the 
age and height group1
≥ 180 with increase from 
updated baseline5 of 
≥20
≥180 with increase 
from baseline of 
≥20
Systolic 
blood 
pressure 
(mmHg)
Low
≤ 5th percentile of the 
age and height group1
≤ 90 with decrease from 
updated baseline5 of 
≥20 
≤90 with decrease 
from baseline of 
≥20


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Vital sign 
(unit)
Criteria
< 18 years at baseline 
and < 18 years at time 
of assessment
< 18 years at baseline 
and ≥ 18 years at time 
of assessment
≥ 18 years at 
baseline
High
≥ 95th percentile of the 
age and height group1
≥ 105 with increase from 
updated baseline5 of 
≥15
≥105 with increase 
from baseline of 
≥15
Diastolic 
blood 
pressure 
(mmHg)
Low
≤ 5th percentile of the 
age and height group1
≤ 50 with decrease from 
updated baseline5 of 
≥15
≤50 with decrease 
from baseline of 
≥15
High
12-15 years: >96
≥15 years: >92
≥120 with increase from 
updated baseline5 of 
≥15
≥100 with increase 
from baseline of 
>25%
Pulse rate 
(bpm)
Low
12-15 years: <62
≥15 years: <58
≤50 with decrease from 
updated baseline5 of 
≥15
≤50 with decrease 
from baseline of 
>25%
High
increase from baseline3 
of  ≥2 BMI-for-age 
percentile categories4
increase from updated 
baseline5 of ≥10%
increase >10% 
from baseline
Weight (kg)
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
12-15 years: >21
≥15 years: >20
≥30
≥30
Low
12-15 years: < 15
≥15 years: <13
≤10
≤10
Oral body 
temperatur
e (°C)
High
≥38.4
≥39.1
≥39.1
Low
≤35.0
≤35.0
≤35.0
bpm=beats per minute; NHLBI= National Heart, Lung, and Blood Institute; 
1 Blood pressure percentiles are calculated for each blood pressure record using the method described in 
Appendix B of the following reference: The Fourth Report on Diagnosis, Evaluation and Treatment of High 
Blood Pressure in Children and Adolescents. Pediatrics 2004; 114; 555.
2 Fleming S, 2011
3 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, 2014; 
7 Kou .R, 2009.


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2.8
Pharmacokinetic endpoints  
Not applicable
2.9
PD and PK/PD analyses
Not applicable 


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2.11
Biomarkers
No biomarker analyses will be included in the CSR. Separate reports will be generated if 
applicable.


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2.13
Interim analysis
A formal interim analysis for this study is not planned and shall not be performed. For 
publication purposes, only descriptive data will be reported, as needed. Any decision on study 
continuation will not be based on these reports, as such no alpha adjustment will be needed.


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The primary analysis of the study will be performed after the last subject has completed Week 
26 visit or discontinued earlier. For this analysis, all subjects will have completed the 
assessments related to the primary, secondary 
 objectives including all variables 
outlined up to Week 26 and all available visit-based safety assessments. Separate SAP 
documentation will be prepared for this primary analysis if applicable.
3
Sample size calculation
A total of 34 evaluable subjects is required for the study to have approximately 80% power to 
detect at least 25% reduction in rates of priapic events (defined as an unwanted erection lasting  
at least 60 min reported via daily diary tool) with a mean baseline priapism event rate of 10.0 
and standard deviation of the difference of 5.0, by 26 weeks.
The calculations were based on simulation with 5,000 repetitions (from Poisson distribution) 
using one-sample Wilcoxon’s Signed-Rank Test and 2-sided α=0.05.
Retaining the same above assumptions, robustness of the estimated sample size was also 
validated using a one-sample t test.
Assuming a 5% dropout rate, approximately 36 subjects will be enrolled in the study.
Recruitment of the required number of subjects with priapism will be challenging as the 
incidence of priapic events are sporadic and varies over time intervals. Also, in the absence of 
relevant clinical data on priapism, the expected reduction and higher variability in events rates 
have been conservatively assumed. The above expected 25% reduction in rates of priapic events 
from baseline is based on medical expert opinion and feedback. L-glutamine (Endari™) was 
approved by the US FDA in July 2017 for the reduction of vaso-occlusive crises (VOCs), based 
on a 25% reduction. Since priapism is also considered to be a complicated VOC, the assumption 
was that the relative risk reduction of 25% (approved for VOC events), would be similar for 
priapism.
4
Change to protocol specified analyses
After finalization of the protocol amendment, CSEG101AUS05 Protocol Version 03, the study 
team noted that a few sentences which were intended to be deleted were still in the document. 
The changed information will be incorporated into the next version of the protocol, if amended. 
Team has incorporated those changes in this SAP amendment 1. These changes do not alter the 
purpose or intent of the amendment. The aim of this memorandum is to clarify these sentences.
Protocol amendment version 03: 
•
Protocol summary: Finally an analysis using a mixed effects regression model will be 
performed using median event counts within pre-specified time windows.
o
The above line is proposed to be removed, as this was added in error in only this 
part of the protocol.
•
Section 2.6.1: Secondary efficacy endpoints will be analyzed on all FAS subjects who 
have completed 52 weeks on treatment to evaluate clinical efficacy of crizanlizumab 5 
mg/kg.


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o
Secondary efficacy endpoints will be analyzed on all FAS subjects who have 
completed 26 and 52 weeks on treatment to evaluate clinical efficacy of 
crizanlizumab 5 mg/kg.
•
Section 12.4.2:  Percent reduction from baseline in priapic events will be tested using a 
nonparametric test (i.e. Wilcoxon’s Sign Rank test). Hodges-Lehmann estimate of 
median percent reduction in priapic events will also be reported, along with 
corresponding 95% confidence intervals. The significance of the efficacy endpoints will 
be assessed at α = 0.05 level.
o
Percent reduction from baseline in priapic events will be tested using a 
nonparametric test (i.e. Wilcoxon’s Sign Rank test) with α = 0.05.
Hodges-Lehmann estimate of median percent reduction in priapic events will also  
be reported, along with corresponding 95% confidence intervals.
•
Section 12.4.4:  Additionally, as the study is ongoing during COVID 19 pandemic, the 
impact of COVID-19 (if any) on the primary endpoint will be assessed in accordance to 
FDA’s guideline entitled “Statistical Considerations for Clinical Trials During the 
COVID-19 Public Health Emergency”. The analysis (as stated below) will be repeated 
on the FAS excluding the subjects with missing data due to COVID-19.
o
Percent reduction from baseline in priapic events will be tested using a 
nonparametric test (i.e., Wilcoxon’s Sign Rank test). Hodges-Lehmann estimate 
of median percent reduction in priapic events will also be reported, along with 
corresponding 95% confidence intervals. The significance of the efficacy 
endpoints will be assessed at α = 0.05 level.
•
Additionally, as the study is ongoing during COVID 19 pandemic, the impact of COVID-
19 (if any) on the primary endpoint will be assessed in accordance to FDA’s guideline 
entitled “Statistical Considerations for Clinical Trials During the COVID-19 Public 
Health Emergency”. The analysis (as stated below) will be repeated on the FAS 
excluding the subjects with missing data due to COVID-19.
•
Percent reduction from baseline in priapic events will be tested using a nonparametric 
test (i.e. Wilcoxon’s Sign Rank test). Hodges-Lehmann estimate of median percent 
reduction in priapic events will also be reported, along with corresponding 95% 
confidence intervals. 
o
Percent reduction from baseline in priapic events will be tested using a 
nonparametric test (i.e. Wilcoxon’s Sign Rank test) with α = 0.05.
Hodges-Lehmann estimate of median percent reduction in priapic events will 
also be reported, along with corresponding 95% confidence intervals.


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The below change is incorporated into SAP amendment 2 as per clinical trial team 
(CTT)suggestion. This change do not alter the purpose or intent of the amendment. The aim of 
this memorandum is to clarify this sentence.
Protocol amendment version 03:
•
Section 12.2: Demographic and other baseline disease characteristics will be listed and 
summarized descriptively for all subjects in the FAS as well as for those subjects in FAS 
who have completed the treatment.
o
Demographic and other baseline disease characteristics will be listed and 
summarized descriptively for all subjects in the FAS.
The below changes are incorporated into SAP amendment 4 as per clinical trial team (CTT) 
suggestion. These changes do not alter the purpose or intent of the amendment. The aim of this 
memorandum is to clarify these sentences.
Protocol amendment version 03:
•
Section 12.4.4 (Supportive analyses): Percent reduction from baseline in priapic events 
will also be assessed by Week 52.
o
Percent reduction from baseline in priapic events will also be assessed by Week 
52. Assuming uniformity in the occurrence of priapic events before exposure to 
crizanlizumab treatment, baseline will be adjusted for 52 weeks for analysis 
purpose.
•
Section 12.5.1: The percent reduction from baseline in acute priapic events by 26 and 
52 weeks of treatment.
o
The percent reduction from baseline in acute priapic events (defined as an 
unwanted, painful erection that lasts more than 4 hours and need a visit to 
emergency room) by 26 and 52 weeks of treatment. Note that, this analysis will 
only be performed if an adequate number of subjects are present. 
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 subject is considered as on-going: 


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The subject 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
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
Subjects 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
AE date imputation
Table 5-1
Imputation of start date 
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 date 
Missing 
Element
Rule 
(*=last treatment date plus 105 days not > (death date, cut-off date, 
withdrawal of consent date))
day, month, 
and year
•
Completely missing end dates (incl. ongoing events) will be imputed 
by the end date of the on-treatment period 
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 with partial/missing dates will be displayed as such in the data listings.
Any AEs which are continuing as per data cut-off will be shown as ‘ongoing’ rather than the 
end date provided. 
For AEs with start date before or on the cut-off date and end date after the cut-off date, the 
outcome will be reported as unknown.
5.1.3
Concomitant medication date imputation
Table 5-3
Imputation of start dates 
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


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Missing 
Element
Rule
•
If available year < year of study treatment start date then 01JulYYYY
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 5-4
Imputation of end dates 
Missing 
Element
Rule 
(*=last treatment date plus 105 days not > (death date, cut-off date, 
withdrawal of consent date))
day, month, 
and year
•
Completely missing end dates (incl. ongoing events) will be imputed 
by the end date of the on-treatment period 
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 concomitant medications with partial/missing dates will be displayed as such in the data 
listings.
Any concomitant medications which are continuing as per data cut-off will be shown as 
‘ongoing’ rather than the end date provided. 
5.1.3.1
Prior therapies date imputation
Refer Section 5.1.3
5.1.3.2
Post therapies date imputation
Refer Section 5.1.3


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5.1.3.3
 Other imputations
Table 5-5
Imputation of start dates 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
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  
5.2
AEs coding/grading
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology.
Note: The latest available MedDRA version at the time of the analyses should be used. The 
MedDRA version used should be specified in the footnote of relevant tables. AEs will be 
assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) version 
5.0. The CTCAE represents a comprehensive grading system for reporting the acute and late 
effects of cancer treatments. CTCAE grading is by definition a 5-point scale generally 
corresponding to mild, moderate, severe, life threatening, and death. This grading system 
inherently places a value on the importance of an event, although there is not necessarily 
proportionality among grades (a grade 2 is not necessarily twice as bad as a grade 1).
5.3
Laboratory parameters derivations
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. The criteria to assign CTCAE grades are given in the Novartis internal 


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criteria for CTCAE grading of laboratory parameters. The latest available version of the 
document based on the underlying CTCAE version 5.0 at the time of analysis will be used. 
For laboratory tests where grades are not defined by CTCAE version 5.0, results will be graded 
by the low/normal/high classifications based on laboratory normal ranges. 
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 will not be used. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labelled by direction, e.g., sodium will be summarized 
as hyponatremia and hypernatremia.
Imputation Rules  
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
Analysis supporting primary objective(s) 
 
Primary analysis
 Wilcoxon signed rank test
 The SAS procedure  PROC UNIVARIATE will be used to perform Wilcoxon signed-rank test.
Hodges-Lehmann Estimation
The SAS procedure PROC NPAR1WAY will be used to compute the Hodges-Lehmann 
estimate.


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Handling of missing data
      Generating the multiple imputation
The missing values will be imputed for the primary analysis. 
•
To filled in the missing values (i.e. number of priapic events by 26 weeks), generate 
Poisson distributed random variables with a rate parameter based on the same effect as 
observed data. Compute 1000 such complete datasets. Use seed 10105.
•
Each datasets will be analyzed using the same method as described in primary analysis. 
      Analyzing the imputated data
•
The resulting estimates and standard errors will be combined using Rubin’s rule 
(Barnard J and Rubin DB 1999), by the SAS procedure MIANALYZE.
Tipping point analysis for priapic events by 26 weeks 
As a sensitivity analysis to evaluate the impact of missing data, a tipping point analysis will be
performed for the primary endpoint. 
The primary endpoint will be re-analyzed on the delta-adjusted datasets to see if the conclusions 
change. If not, a larger delta is chosen and the process will be repeated until the conclusion is 
overturned. The tipping point is the delta value which will cause the primary endpoint to be no 
longer statistically significant. A series of analyses on a range of delta values (i.e.,1,2,3,......) 
will be performed to find the tipping point. 
For each delta value, the following steps will be performed.
1. Impute the missing values (i.e. number of priapic events by 26 weeks) by generating Poisson 
distributed random variables with a rate parameter based on the same effect as observed 
data. Use seed 10105.
2. After the imputation obtained in above step, make the imputed value worse by a value of 
delta (i.e., add delta to the imputed value). Note: delta = 0 represents the standard missing 
at random (MAR).
3. The final imputed delta-adjusted dataset where all missing values are filled, will be analyzed 
using method as described in the primary analysis.
4. The results from the 1000 delta-adjusted datasets will then be combined using Rubin’s rule. 
If the combined results does not change the conclusion (i.e., if percentage reduction in 
events is ≥ 25 % statistically significant), a larger delta will be chosen and Steps 1-4 will be 
repeated using the datasets from Step 1 until the tipping point is found (when p > 0.05).
5.4.2
Analysis supporting secondary objective(s)
Not applicable 
5.5
Rule of exclusion criteria of analysis sets 
Not applicable


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6
Reference
Barnard J and Rubin DB (1999). Small-sample degrees of freedom with multiple imputation.
Biometrika. Volume 86, Issue 4, 948-955.
Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival Time, 
Biometrics 38, 29 - 41.  
Collett D (1994). Modelling survival data in medical research. London, Chapman & Hall.
Eldridge L. What is a Normal Respiratory Rate?, Updated May 16, 2014
Fleming S, Thompson M, Stevens R, et al. Normal ranges of heart rate and respiratory rate in 
children from birth to 18 years of age: a systematic review of observational studies. Lancet 
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