Conditions: Sickle Cell Disease (SCD)
Keywords: Sickle cell disease SCD sickle cell anemia vaso-occlusive crisis P-selectin SEG101 crizanlizumab monoclonal antibody Anemia, Sickle Cell HbS Disease Hemoglobin SC Disease Sickle Cell Disorders Sickling Disorder Due to Hemoglobin S
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 57
Healthy volunteers: no

Brief summary:
The purpose of the CSEG101A2202 study was to characterize the Pharmacokinetic (PK) and Pharmacodynamic (PD) of SEG101/crizanlizumab and to evaluate the safety and efficacy of SEG101/crizanlizumab in sickle cell disease (SCD) patients.

Detailed description:
Study CSEG101A2202 was designed as a Phase II, multicenter, open-label study. The first 45 patients (to identify 27 evaluable patients) were enrolled to the treatment group crizanlizumab 5.0 mg/kg to complete full Pharmacokinetic/Pharmacodynamic (PK/PD) sampling at week 1 and week 15. In all patients, trough PK/PD samples were collected prior to each dose. In addition, throughout the study (and when possible), all patients had blood drawn for serum to assess PK and PD drawn at times of onset and resolution of each VOC event, fever, or infection. Once the up to 45 patients were enrolled, 12 additional patients were enrolled to the exploratory treatment group and began at 7.5 mg/kg of crizanlizumab.

The study was initiated on 19-Dec-2017. This study provides five years follow up data that fully characterizes the safety, tolerability and treatment effect of the 5.0 mg/kg and 7.5 mg/kg doses of crizanlizumab along with the initially planned PK and PD data.

At the time of study closure, crizanlizumab 5.0 mg/kg was an FDA approved treatment in the United States (US) for patients with sickle-cell disease. Therefore, the patients treated with crizanlizumab 5.0 mg/kg dose were encouraged to transition to commercial supply of crizanlizumab. The patients treated with the not currently approved dose of crizanlizumab 7.5 mg/kg were allowed to join a multi-center, multi-national, rollover clinical trial (Study SEG101A2401B), for continued access to treatment with crizanlizumab.

Arms:
arm 1: SEG101 (crizanlizumab) drug at a dose of 5.0 mg/kg (or 7.5 mg/kg for exploratory group) by IV infusion.

Interventions: intervention 1: crizanlizumab
Intervention descriptions: intervention 1: Crizanlizumab was administered IV infusion over 30 minutes at the assigned dose on Week 1 Day 1, Week 3 Day 1, and then Day 1 of every 4-week cycle. Cycle = 28 days

Protocol document:
Prot_001.pdf: 
Clinical Development 
SEG101, Crizanlizumab 
Oncology Clinical Trial Protocol 
CSEG101A2202 / NCT03264989
A phase 2, Multicenter, Open-Label Study to Assess PK/PD 
of SEG101 (crizanlizumab), with or without 
Hydroxyurea/Hydroxycarbamide, in Sickle Cell Patients 
with Vaso-Occlusive Crisis 
Document type 
Amended Protocol Version 
EUDRACT number 
Not applicable 
Version number 
01 (Amended Protocol Version) Clean 
Development phase 
II 
Document status 
Final 
Release date 
04-Jun-2018
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template version 6-Apr-2017 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of figures....................................................................................................................... 5 
List of tables ........................................................................................................................ 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ................................................................................................................. 9 
Protocol summary .............................................................................................................. 11 
Amendment 01 (04-Jun-2018)........................................................................................... 14 
1 
Background ........................................................................................................................ 18 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 18 
1.2 
Introduction to investigational treatment(s) and other study treatment(s) ............. 20 
1.2.1 
Overview of Crizanlizumab (SEG101) ................................................. 20 
2 
Rationale ............................................................................................................................ 24 
2.1 
Study rationale and purpose ................................................................................... 24 
2.2 
Rationale for the study design ............................................................................... 24 
2.3 
Rationale for dose and regimen selection .............................................................. 25 
2.4 
Rationale for choice of combination ...................................................................... 25 
2.5 
Rationale for choice of comparators drugs ............................................................ 25 
2.6 
Risks and benefits .................................................................................................. 25 
3 
Objectives and endpoints ................................................................................................... 26 
4 
Study design ...................................................................................................................... 29 
4.1 
Description of study design ................................................................................... 29 
4.2 
Timing of interim analyses and design adaptations ............................................... 30 
4.3 
Definition of end of study ...................................................................................... 31 
4.4 
Early study termination .......................................................................................... 31 
5 
Population .......................................................................................................................... 32 
5.1 
Patient population .................................................................................................. 32 
5.2 
Inclusion criteria .................................................................................................... 32 
5.3 
Exclusion criteria ................................................................................................... 32 
6 
Treatment ........................................................................................................................... 35 
6.1 
Study treatment ...................................................................................................... 35 
6.1.1 
Dosing regimen ..................................................................................... 35 
6.1.2 
Ancillary treatments .............................................................................. 35 
6.1.3 
Rescue medication ................................................................................ 36 
6.1.4 
Guidelines for continuation of treatment .............................................. 36 
6.1.5 
Treatment duration ................................................................................ 36 


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6.2 
Dose escalation guidelines ..................................................................................... 36 
6.3 
Dose modifications ................................................................................................ 36 
6.3.1 
Dose modification and dose delay ........................................................ 36 
6.4 
Concomitant medications ...................................................................................... 47 
6.4.1 
Permitted concomitant therapy.............................................................. 47 
6.4.2 
Permitted concomitant therapy requiring caution and/or action ........... 47 
6.4.3 
Prohibited concomitant therapy ............................................................ 48 
6.4.4 
Use of Bisphosphonates (or other concomitant agents) ........................ 48 
6.5 
Subject numbering, treatment assignment or enrolment ....................................... 48 
6.5.1 
Subject numbering................................................................................. 48 
6.5.2 
Treatment assignment or Enrolment ..................................................... 49 
6.5.3 
Treatment blinding ................................................................................ 49 
6.6 
Study drug preparation and dispensation ............................................................... 49 
6.6.1 
Study treatment packaging and labeling ............................................... 50 
6.6.2 
Drug supply and storage ........................................................................ 50 
6.6.3 
Study drug compliance and accountability ........................................... 50 
6.6.4 
Disposal and destruction ....................................................................... 51 
7 
Visit schedule and assessments ......................................................................................... 51 
7.1 
Study flow and visit schedule ................................................................................ 51 
7.1.1 
Molecular pre-screening ........................................................................ 57 
7.1.2 
Screening ............................................................................................... 57 
7.1.3 
Run-in period......................................................................................... 58 
7.1.4 
Treatment period ................................................................................... 58 
7.1.5 
Discontinuation of study treatment ....................................................... 59 
7.1.6 
Withdrawal of consent .......................................................................... 60 
7.1.7 
Follow up for safety evaluations ........................................................... 60 
7.1.8 
Lost to follow-up ................................................................................... 60 
7.2 
Assessment types ................................................................................................... 61 
7.2.1 
Efficacy assessments ............................................................................. 61 
7.2.2 
Safety and tolerability assessments ....................................................... 63 
7.2.3 
Pharmacokinetics, pharmacodynamics, and immunogenicity .............. 70 
 
 72 
7.2.5 
Resource utilization ............................................................................... 73 
7.2.6 
Patient reported outcomes ..................................................................... 73 
8 
Safety monitoring and reporting ........................................................................................ 73 
8.1 
Adverse events ....................................................................................................... 73 


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8.1.1 
Definitions and reporting ...................................................................... 73 
8.1.2 
Laboratory test abnormalities ................................................................ 75 
8.1.3 
Adverse events of special interest ......................................................... 75 
8.2 
Serious adverse events ........................................................................................... 76 
8.2.1 
Definitions ............................................................................................. 76 
8.2.2 
Reporting ............................................................................................... 76 
8.3 
Emergency unblinding of treatment assignment ................................................... 77 
8.4 
Pregnancies ............................................................................................................ 77 
8.5 
Warnings and precautions ...................................................................................... 77 
8.6 
Data Monitoring Committee .................................................................................. 78 
8.7 
Steering Committee ............................................................................................... 78 
9 
Data collection and management ....................................................................................... 78 
9.1 
Data confidentiality ............................................................................................... 78 
9.2 
Site monitoring ...................................................................................................... 78 
9.3 
Data collection ....................................................................................................... 79 
9.4 
Database management and quality control ............................................................ 79 
10 Statistical methods and data analysis ................................................................................. 80 
10.1 
Analysis sets .......................................................................................................... 80 
10.1.1 
Full Analysis Set ................................................................................... 80 
10.1.2 
Safety set ............................................................................................... 80 
10.1.3 
Pharmacokinetic analysis set ................................................................. 80 
10.1.4 
Other analysis sets ................................................................................. 81 
10.2 
Patient demographics/other baseline characteristics .............................................. 81 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ....................... 81 
10.4 
Primary objective ................................................................................................... 82 
10.4.1 
Variables ............................................................................................... 82 
10.4.2 
Statistical hypothesis, model, and method of analysis .......................... 82 
10.4.3 
Handling of missing values/censoring/discontinuations ....................... 83 
10.4.4 
Supportive and Sensitivity analyses ...................................................... 83 
10.5 
Secondary objectives ............................................................................................. 84 
10.5.1 
Key secondary objective(s) ................................................................... 84 
10.5.2 
Other secondary efficacy objectives ..................................................... 84 
10.5.3 
Safety objectives ................................................................................... 84 
10.5.4 
Pharmacokinetics .................................................................................. 86 
 
 86 
10.5.6 
Resource utilization ............................................................................... 86 


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10.5.7 
Patient-reported outcomes ..................................................................... 86 
10.5.8 
Immunogenicity .................................................................................... 86 
 
 86 
 
 86 
 
 86 
 
 87 
 
 88 
 
 89 
10.7 
Interim analysis ...................................................................................................... 89 
10.8 
Sample size calculation .......................................................................................... 89 
10.9 
Power for analysis of key secondary variables ...................................................... 90 
11 Ethical considerations and administrative procedures ....................................................... 91 
11.1 
Regulatory and ethical compliance ........................................................................ 91 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ......................................... 91 
11.3 
Informed consent procedures ................................................................................. 91 
11.4 
Discontinuation of the study .................................................................................. 92 
11.5 
Publication of study protocol and results ............................................................... 92 
11.6 
Study documentation, record keeping and retention of documents ....................... 92 
11.7 
Confidentiality of study documents and patient records ....................................... 93 
11.8 
Audits and inspections ........................................................................................... 93 
11.9 
Financial disclosures .............................................................................................. 93 
12 Protocol adherence ............................................................................................................ 93 
12.1 
Amendments to the protocol .................................................................................. 94 
13 References (available upon request) .................................................................................. 95 
14 Appendices ........................................................................................................................ 98 
14.1 
Appendix 1 – List of prohibited CYP3A inhibitors and inducers .......................... 98 
14.2 
Appendix 2 – List of prohibited QT-prolonging drugs .......................................... 99 
List of figures 
Figure 4-1 
Study Design ......................................................................................... 30 


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List of tables 
Table 3-1 
Objectives and related endpoints ........................................................... 27 
Table 6-1 
Dose and treatment schedule ................................................................. 35 
Table 6-2 
Criteria for dose reduction / interruption and re-initiation of 
crizanlizumab treatment for adverse drug reactions. ............................ 37 
Table 6-3 
Management for drug-related toxicities ................................................ 45 
Table 6-4 
Packaging and labeling .......................................................................... 50 
Table 6-5 
Supply and storage of study treatments ................................................. 50 
Table 7-1 
Visit evaluation schedule ...................................................................... 52 
Table 7-2 
Vaso-Occlusion Crisis Assessment Collection Plan ............................. 62 
Table 7-3 
Clinical laboratory parameters collection plan ...................................... 65 
Table 7-4 
Central ECG collection plan ................................................................. 67 
Table 7-5 
Pharmacokinetic, pharmacodynamics and immunogenicity blood 
collection log ......................................................................................... 70 
 
 72 
Table 8-1 
List of VOC Events Not Requiring AE/SAE Reporting ....................... 75 
Table 10-1 
Non compartmental pharmacokinetic parameters ................................. 82 
Table 14-1 
List of prohibited CYP3A inhibitors and inducers ................................ 98 
Table 14-2 
List of prohibited QT prolonging drugs ................................................ 99 


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List of abbreviations 
 
ACS 
Acute Chest Syndrome 
ADA 
Anti-Drug Antibody 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
ALT 
Alanine aminotransferase / glutamic pyruvic transaminase /GPT 
AST 
Aspartate aminotransferase / glutamic oxaloacetic transaminase/GOT 
AUC 
Area Under the Curve 
BSA 
Body Surface Area 
CDP 
Clinical Development Plan 
CRD 
Chronic Renal Disease 
CRF 
Case Report/Record Form; the term CRF can be applied to either EDC or Paper 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CSR 
addendum 
An addendum to Clinical Study Report (CSR) that captures all the additional 
information that is not included in the CSR 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
Dose Limiting Toxicity 
DMC 
Data Monitoring Committee 
CMO&PS 
Chief Medical Office and Patient Safety 
ECG 
Electrocardiogram 
ER 
Emergency Room 
FAS 
Full Analysis Set 
FMI 
Final Market Image 
Hb 
Hemoglobin 
HbA 
Hemoglobin A 
HbS 
Human hemoglobin S (sickle cell hemoglobin) 
HbSC 
Heterozygous sickle Hemoglobin C disease (hemoglobin SC disease) 
HbS β 
Heterozygotes with one copy of the HbS gene and a β-thalassemia variant (β0 or 
β+) 
HbSS 
homozygous sickle cell disease (hemoglobin SS disease) 
HU/HC 
Hydroxyurea/Hydroxycarbamide 
GFR 
Glomerular Filtration Rate 
i.v. 
intravenous(ly) 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
LDH 
Lactate dehydrogenase 
MAP 
Master Analysis Plan documents project standards in the statistical methods 
which will be used within the individual clinical trial RAP documentation 
MDRD-GFR 
Modification of Diet in Renal Disease-Glomerular Filtration Rate 


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NSAID(s) 
PAS 
Non-Steroidal Anti-Inflammatory Drug(s) 
Pharmacokinetic Analysis Set 
PD 
Pharmacodynamics 
PDS 
Pharmacodynamics Analysis Set 
PHI 
Protected Health Information 
PK 
Pharmacokinetics 
PKPDS 
Pharmacokinetic-Pharmacodynamics Analysis Set 
popPK 
Population PK 
PSGL-1 
P-selectin glycoprotein ligand-1 
RAP 
The Report and Analysis Plan (RAP) is a regulatory document which provides 
evidence of preplanned analyses 
REB 
Research Ethics Board 
RR 
Risk Ratio 
SAE 
Serious Adverse Event 
SCD 
Sickle Cell Disease 
SCPC 
Sickle Cell-related Pain Crises 
SOP 
Standard Operating Procedure 
VOC 
Vaso-Occlusive Crisis 


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Glossary of terms 
 
 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), 
saliva, tissue, urine, stool, etc. taken from a study subject or study 
patient 
Cohort 
A group of newly enrolled patients treated at a specific dose and 
regimen (i.e. treatment group) at the same time 
Dose level 
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment 
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol) 
Investigational drug 
The study treatment whose properties are being tested in the study; 
this definition is consistent with US CFR 21 Section 312.3 and is 
synonymous with “investigational new drug.” 
Medication number 
A unique identifier on the label of each study treatment package 
which is linked to one of the treatment groups of a study 
Other study treatment 
Any drug administered to the patient as part of the required study 
procedures that was not included in the investigational treatment 
Period 
A subdivision of the study timeline; divides stages into smaller 
functional segments such as screening, baseline, titration, washout, 
etc. 
Perpetrator drug 
Drug which affects the pharmacokinetics of the other drug 
Personal Data 
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes 
subject identifier information, study information and biological 
samples. 
SEG101 
Novartis supply of crizanlizumab 
SelG1 
Reprixys supply of crizanlizumab 
Stage related to study 
timeline 
A major subdivision of the study timeline; begins and ends with 
major study milestones such as enrollment, randomization, 
completion of treatment, etc. 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or 
when study treatment was discontinued whichever is later 
Study treatment 
Includes any drug or combination of drugs in any study arm 
administered to the patient (subject) as part of the required study 
procedures, including placebo and active drug run-ins. 
In specific examples, it is important to judge investigational 
treatment component relationship relative to a study treatment 
combination; study treatment in this case refers to the investigational 
and non-investigational treatments in combination. 
Study treatment 
discontinuation 
Point/time when patient permanently stops taking study treatment for 
any reason 
Subject Number 
A unique identifying number assigned to each 
patient/subject/healthy volunteer who enrolls in the study 
Variable 
Identifier used in the data analysis; derived directly or indirectly from 
data collected using specified assessments at specified timepoints 


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Withdrawal of consent 
Withdrawal of consent occurs only when a patient 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 
Withdrawal of study consent 
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 allow any further collection of personal 
data 


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Protocol summary: 
Title 
A phase 2, Multicenter, Open-Label Study to Assess PK/PD of SEG101 
(crizanlizumab), with or without Hydroxyurea/Hydroxycarbamide, in 
Sickle Cell Patients with Vaso-Occlusive Crisis 
Brief title 
Pharmacokinetics and pharmacodynamics study of SEG101 
(crizanlizumab) in Sickle Cell Disease (SCD) patients with Vaso- 
Occlusive Crisis (VOC) 
Sponsor and Clinical 
Phase 
Novartis 
Phase II 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
Crizanlizumab is a humanized monoclonal antibody that binds P-selectin 
and was previously found to reduce the median annualized rate of VOC 
at 5 mg/kg by 45.3% compared to placebo. Clinical and toxicological 
studies performed to date for crizanlizumab were conducted using 
Reprixys material (SelG1 mAb). To ensure supply of future clinical 
studies as well as commercial demand, Novartis has optimized the 
production of crizanlizumab. The Novartis material (SEG101 mAb) drug 
substance (DS) and drug product (DP) will be manufactured at Novartis 
sites. The change in manufacturing cell line is not expected to impact the 
bioavailability or activity of the compound. 
The purpose of the CSEG101A2202 study is to characterize the PK and 
PD of SEG101 and to evaluate the safety and efficacy of SEG101. 
Primary Objective(s) 
and Key Secondary 
Objective 
To characterize PK of crizanlizumab at 5.0 mg/kg in SCD patients. 
To characterize PD (P-selectin inhibition) of crizanlizumab at 5.0 mg/kg 
in SCD patients 
Secondary Objectives 
To assess the efficacy of crizanlizumab in SCD patients in terms of 
annualized rate of VOC events leading to healthcare visit in 
clinic/ER/hospital, annualized rate of VOC events treated at home, 
annualized rate of hospitalizations and ER visits, annualized rate of 
ER/hospitalization, annualized rate of each subcategory of VOC event 
(uncomplicated pain crisis, acute chest syndrome, hepatic sequestration, 
splenic sequestration, priapism), annualized rate of VOC events. 
To assess the safety and tolerability of crizanlizumab in terms of the 
number, seriousness, severity, and causality assessments of treatment 
emergent adverse events and other safety data as considered 
appropriate and absolute change from baseline in hemoglobin 
Study design 
Open-label, single arm study of crizanlizumab therapy in SCD patients. 
Population 
55 male and female SCD patients ages 16-70 years who experienced at 
least 1 VOC over the preceding 12 months, and who are not planning to 
take HU/HC during the trial or are receiving stable treatment with 
HU/HC. 
Inclusion criteria 
• 
Male and non-pregnant female patients 16-70 years of age (inclusive) 
• 
Confirmed diagnosis of sickle cell disease by hemoglobin 
electrophoresis or high-performance liquid chromatography (HPLC) 
[performed locally]. All sickle cell disease genotypes are eligible. 
• 
Experienced at least 1 VOC within the preceding 12 months prior to 
Screening, as determined by medical history. 
• 
If receiving HU/HC or erythropoietin stimulating agent, must have 
been receiving the drug for at least 6 months prior to Screening 


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• 
Hemoglobin ≥4.0 g/dL. Absolute neutrophil count ≥1.0 x 109/L and 
platelet count ≥75 x 109/L 
• 
Adequate renal and hepatic function as defined: 
• 
GFR ≥45 mL/min/1.73 m2 calculated by CKD-EPI 
• 
ALT ≤3 x ULN 
• 
Direct (conjugated) bilirubin ≤2 x ULN 
• 
ECOG performance status ≤2 
• 
Written informed consent prior to any screening procedures 
Exclusion criteria 
• 
History of stem cell transplant. 
• 
Acute VOC ending within 7 days of W1D1 dosing 
• 
Received blood products within 30 days prior to W1D1 dosing. 
• 
Participating in a chronic transfusion program (pre-planned series of 
transfusions for prophylactic purposes) 
• 
History of severe hypersensitivity reactions to other monoclonal 
antibodies 
• 
Received a monoclonal antibody or immunoglobulin-based agent 
within 1 year of Screening, or has documented immunogenicity to a 
prior biologic. 
• 
Received active treatment on another investigational trial within 30 
days (or 5 half-lives of that agent, whichever is greater) prior to 
Screening 
• 
Significant active infection or immune deficiency (including chronic 
use of immunosuppressive drugs) in the opinion of the investigator 
• 
Resting QTcF ≥470 msec at pretreatment (baseline) or other cardiac 
or cardiac repolarization abnormality 
Investigational and 
reference therapy 
SEG101 (crizanlizumab) drug at a dose of 5.0 mg/kg (or 7.5 mg/kg for 
exploratory group) by IV infusion over 30 min on week 1 day 1, week 
3 day 1, and then day 1 of every 4-week cycle. 
Efficacy assessments 
-VOCs leading to healthcare visit in clinic/ER/hospital 
-VOCs treated at home, based on documentation by health care provider 
following telephone contact with patient 
-Each subcategory of VOC event (uncomplicated pain crisis, acute chest 
syndrome, hepatic sequestration, splenic sequestration, priapism) 
-Hospitalizations and ER visits (both overall and VOC-related) 


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Safety assessments 
Safety will be monitored by assessing the following parameters: 
-Vital signs 
-Physical exam 
-ECG in triplicates at all PK assessment timepoints [central review] 
-Hematology, blood chemistry, coagulation and urinalysis (additional 
laboratory tests will be performed at the investigator’s discretion for 
safety measures in the event of an adverse event) 
-Pregnancy 
 
 
 
-Monitoring of AEs/SAEs 
Data analysis 
PK parameters including AUC and Cmax will be derived from individual 
concentration-time profiles after the first dose and the 5th dose. The 
inter-subject variations and CV% will be presented for the primary PK 
parameters. The point estimate and the corresponding two-sided 90% 
confidence interval (CI) for the mean of the log-transformed primary PK 
parameters after single dose and multiple doses will be derived 
respectively. The point estimate and CI will be anti-log transformed to 
obtain the point estimate and the 90% confidence interval for the 
geometric mean on the original scale. The descriptive statistics (n, mean, 
CV%, standard deviation (SD), median, geometric mean, geometric 
CV%, minimum and maximum) will be presented for all PK parameters 
except Tmax, where only n, median, minimum and maximum will be 
presented. Descriptive statistics for crizanlizumab concentration will be 
presented at each scheduled timepoint. 
PD-AUCd15 and PD-AUCd29 will be derived from the %P-selectin 
inhibition time profiles of week 1 and week 15, respectively. The point 
estimate and the corresponding two-sided 90% CI for the mean of the 
log-transformed PD-AUC after single dose and multiple doses will also 
be provided. The point estimate and CI will be anti-log transformed to 
obtain the point estimate and the 90% confidence interval for the 
geometric mean on the original scale. Descriptive statistics for PD 
inhibition will be presented at each scheduled timepoint. 
Key words 
Sickle cell disease, sickle cell anemia, vaso-occlusive crisis, P-selectin 


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Amendment 01 (04-Jun-2018) 
Amendment rationale 
The study is currently open for enrollment with 21 subjects enrolled to date. 
Due to the ongoing high unmet medical need for prevention of VOC in SCD, particularly for 
patients age <18 years old, and the unexpected delay in start of the SEG101 phase 2 
(CSEG101B2201) trial for ages 6 months to 18 years, the decision was made to expand the 
inclusion age in CSEG101A2202 to include 16 and 17 year old subjects. This is based on the 
well-established and widely-accepted view that there is no meaningful difference in PK 
between adolescents (here ages 16-<18 years) and adults 18 years and older. Monoclonal 
antibodies are distributed within the vascular and extracellular spaces by mechanisms 
dominated by convection, and predominately catabolized by lysosomal enzymes to small 
peptides and amino acids. It is unlikely that these (the vascular and extracellular fraction in the 
body and enzyme activity) differ in age 16 vs. 18, therefore PK is expected to be similar between 
age 16 vs. 18. 
Participating investigators have provided feedback after enrolling their initial patients to the 
study. They suggested the protocol inclusion and exclusion criteria be examined and modified 
regarding the timing of prior VOCs and historical testing information as well as current 
treatment be clarified. 
This amendment also clarifies that the VOC events should not be reported as adverse events. 
Further review of the secondary endpoints led to the changes from the number of efficacy 
related endpoints to the annualized (rates) – this accounts for any early subject withdrawal by 
setting one year as a standard time period. 
Additional PK samples have been added to align with the IG sample collection timelines. 
Additional safety information has led to the adjustment of the dose modification guidance for 
this compound, including the removal of the dosing modification requirements for hypertension, 
the addition of dosing modification guidelines for QTc prolongation, as well the correction of 
editorial and typographical errors. 
 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
• Throughout: Typographical and grammatical errors addressed. 
• Throughout: Removed references to “adult” in protocol title, objectives, study design, 
endpoints. 
• Abbreviations: Added NSAID 
• Glossary: Added definitions for personal data and withdrawal of study consent. Removed 
supportive treatment from glossary. 
• Section 2.3: Clarified the two doses and the future Phase III trial design. 
• Section 2.6: Removed pre-clinical information. 


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• Table 3.1: Revised primary 
 objective from trough to pre-dose 
concentrations. Revised the secondary 
 endpoints from number, to 
annualized (rates). 
 
 
• Section 4.1: Clarified HU/HC dosing requirements. Removed requirement to be off 
HU/HC for 6 months if taking HU/HC at time of enrollment. Changed screening window 
from 28 to 35 days. Updated Figure 4.1 to reflect amendment changes. 
• Section 4.2: Added provision for additional ad hoc analyses. Revised interim analysis 
from will be, to may be performed. Revised the potential impact of the interim analysis. 
• Section 4.3: Clarified end of study participation criteria 
• Section 5.1: Revised patient population to include 16-17 year olds in the population 
• Section 5.2: Changed inclusion age to 16 from 18 years in inclusion criteria #1 
• Section 5.2: Clarified definitions for VOC treatments in inclusion criteria #3 
• Section 5.2: Removed inclusion criteria #5 – chest X-ray 
• Section 5.3: Revised exclusion #2 to reflect excluding VOCs ending within 7 days prior to 
first dose, instead of 15 days prior to screening. Removed Exclusion criteria #13 requiring 
male contraception due to monoclonal antibody pregnancy guidance. Revised exclusion 
criteria #15 to allow silent infarct only present on imaging. Revised exclusion criteria #19 
to allow for well controlled HIV positive subjects to be included. 
• Section 6.3.1: Revised the missed doses requirement for discontinuation to reflect 2 
consecutive missed for any reason within a 10 week period. 
• Table 6.2: Clarified total bilirubin to be total bilirubin (direct [conjugated] and/or total). 
Deleted hypertension dose modification requirements as per the change in program 
standard language. 
• Section 6.3.1.2: Added section of dose adjustments for QTcF prolongation. 
• Section 7.1: Changed screening window from 28 to 35 days. 
• Table 7-1: Changed screening window to 35 days. Removed visit numbers. Updated 
protocol sections. Changed location of pregnancy test results from Database to Source. 
For drug screen, clarified which results will be captured in source verses database. 
Updated Chest X-ray 
 to allow for procedure within 3 months of first 
dose.
 
• Section 7.1.2: Revised re-screening numbering per the new database standards. Changed 
screening window to 35 days. Removed sentence regarding ICF timing for re-screening. 
• Section 7.1.4: Revised to clarify the timing of the full PK/PD profiles if a dose is 
interrupted. 
• Section 7.1.5.1: Deleted replacement policy section as Not Applicable. 
• Section 7.1.6: Update withdrawal of consent section to reflect current Novartis legal 
language 


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• Section 7.2.1: Clarified language regarding end date for VOC based on pain medication 
management. Updated definition of ACS based on symptoms and end of priapism to 2 hours 
from 1 hour. Removed requirement to hold dosing until VOC resolves. Added sentence 
“VOC is not a known contra-indication, but dosing during a crisis should be at investigator’s 
discretion”. Clarified medications for VOC definition. 
• Table 7-2: Updated table to add optional PK/PD samples around transfusion. Added 
optional PK, soluble P-selectin and PD samples at onset and resolution of VOC events. 
• Section 7.2.2.5: Clarified laboratory testing should be done centrally unless otherwise 
noted. 
• Table 7-3: Updated to reflect which are local and which are central laboratory tests. 
• Section 7.2.2.2.5 Added “if central laboratory results are unevaluable or inconclusive” as a 
criteria to draw local labs 
• Section 7.2.2.5.2: Revised to note that blood alcohol test will be performed locally 
• Section 7.2.2.5.3: Revised to note that the macroscopic urinalysis will be done locally and 
the microscopic will be done centrally. 
• Section 7.2.2.5.5.: Revised to reflect the serum pregnancy testing will be performed 
centrally and the urine pregnancy testing will be performed locally. 
• Section 7.2.2.5.6: Added section regarding the Hepatitis markers testing. 
• 
 
 
 
 
 
• 
 
 
 
 based on tubes to be used. 
• Table 7.5: Added PK samples 33-38 (Weeks 75, 99, 123,147, 171). Added Follow up 
Phase time point and samples for PK and IG. Updated number of doses needed to reach 
steady state if dose(s) missed. 
• Section 8.1.1.: Removed sentence about VOC not being reported as AEs. 
• Section 8.1.1.1 and Table 8-1: Added section on Protocol Exempt AEs and SAEs. 
• Section 8.2.1: clarified VOCs not SAEs 
• Section 9.3: Added missing part of sentence for reconciliation of information. 
• Section 10: Added clarification that 5.0 mg/kg enrollment will end at 27 evaluable, or 45 
total patients, whichever occurs first. 
• Section 10.1.3: Added clarification regarding the timing of the full PK/PD profiles if a 
dose is interrupted. 
• Section 10.1.4.1: Added clarification regarding the timing of the full PK/PD profiles if a 
dose is interrupted. 
• Section 10.5.2: Changed secondary efficacy objectives from number of to annualized rate 
of VOC events and hospitalizations. 


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• Section 10.7: Added provision for additional ad hoc analyses. 
• Section 13: Updated the references 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
Sickle cell disease (SCD) is a rare autosomal recessive blood disorder caused by a single 
missense mutation (Glu6Val) in the β-globin gene that renders the mutant hemoglobin less 
soluble and prone to polymerization upon deoxygenation. The polymerization of hemoglobin 
causes deformation of the erythrocyte to give the cell a “sickle” shape (Bookchin 1996), and 
leads to chronic hemolysis, anemia, and vaso-occlusion (NHLBI, The Management of Sickle 
Cell Disease. NIH Publication No.022117; Wethers 2000). SCD is the most common single 
gene disorder in African Americans, affecting approximately 1 in 375-600 persons of African 
ancestry (Clinical Practice Guideline No. 6. April 1993; Nietert 2002). Sickle cell conditions 
are also common among people of Mediterranean countries, Africa, the Caribbean and parts of 
South and Central America (Clinical Practice Guideline No. 6. April 1993; Nietert 2002). 
In SCD, lysis of sickle red cells, cell membrane damage and oxidative stress, repeated ischemic 
damage, and microvasculature injury are due to the adhesive interactions between sickle red 
cells and the endothelium, which culminate in a pro-inflammatory environment (Embury 2004; 
Chiang 2005). In this environment of chronic vascular inflammation, the adherence of 
leukocytes, platelets and sickle red cells to activated blood vessel endothelium and to each other 
is believed to be the primary cause of microvasculature blockage and vaso-occlusive crisis 
(VOC), the clinical hallmark of SCD, typically associated with intense pain. Additional factors 
such as the rigidity of sickle red cells, increased blood viscosity, and local vasoconstriction have 
also been identified as potentially contributing to the vaso-occlusion process. VOC includes 
pain crises (defined as an acute onset of pain for which there is no other medically determined 
explanation other than vaso-occlusion and which requires therapy with oral or parenteral 
opioids or parenteral NSAIDs) as well as other complicated crises, such as acute chest syndrome 
(ACS), priapism, and hepatic or splenic sequestration (Maitre et al. 2000; Vichinsky et al. 2000). 
VOC accounts for over 90% of hospital admissions in adult SCD patients (Matsui et al. 2001; 
Chiang 2005; Okpala 2006). 
SCD patients also suffer from cerebrovascular complications, ranging from clinically evident 
acute stroke to transient silent ischemic infarct (Platt 2006). Other chronic complications 
include functional asplenia, leaving patients more susceptible to infection, (Clinical Practice 
Guideline No. 6. April 1993), bone growth retardation and avascular necrosis renal dysfunction 
(Saborio 1999), and issues of the biliary tree (gallstones, congestion), eyes (retinopathy) 
(Charache 1996), and soft tissue (leg ulcers) (Ashley-Koch 2000; Gladwin et al., 2004; Gladwin 
2005). Chronic pain and opioid abuse are also common (Smith 1996). As a result, there is an 
approximately 20 to 30 year reduction in life expectancy in SCD patients (Platt et al. 1994). 
Hemoglobin values for SCD patients vary, but typically range from 6 to 10 g/dL, but some 
patients can live with a baseline hemoglobin of 4 g/dL or lower. Chronic hemolysis results in 
other abnormal labs, including reticulocytosis, low haptoglobin, and increased free hemoglobin, 
LDH, indirect bilirubin (and, by extension, total bilirubin). In young SCD patients, glomerular 
filtration rate (GFR) is substantially increased (hyperfiltration: MDRD-GFR >130 in women, 
>140 ml/min per 1.73 m2 in men) but tends to decrease progressively with time, and 4-5% of 
these patients in the US develop stage 5 chronic renal disease (CRD) (Hirschberg 2010). SCD 


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patients are also more susceptible to parvovirus B19 infection which can arrest erythropoiesis 
and lead to aplastic crisis (Heegaard 2002). 
SCD has three common variants: homozygous SCD (hemoglobin SS disease), doubly 
heterozygous sickle hemoglobin C disease (hemoglobin SC disease) and the sickle β- 
thalassemia. The most common and severe form of the disease occurs in individuals who inherit 
two copies of the HbS variant (HbSS) and the primary hemoglobin in their red blood cells is 
sickle hemoglobin. Other individuals can be affected as compound heterozygotes with one copy 
of the HbS gene and one or more additional mutations, resulting in varying severities of the 
disease. HbSC results in a mild-to-moderate form of the disease. HbS β-thalassemia variants 
(β0 or β+) result in a range of clinical severities: HbSβ0 is a severe form, whereas HbSβ+ can be 
moderate or mild based on the contribution of each variant to the total hemoglobin of the patient. 
Other more rare variants can result if in addition to the HbS gene, another abnormal hemoglobin 
is inherited from the other parent, such as D, G or O-Arab. The sickle red cells gene is most 
commonly present in individuals heterozygous for HbS and HbA. These individuals carry the 
sickle cell trait and are asymptomatic (Clinical Practice Guideline No. 6. April 1993; Nietert et 
al. 2002). 
All individuals that are homozygous or compound heterozygous for HbS show some clinical 
manifestations of SCD. Clinical signs appear within the first 6 months of life but there is 
considerable variability in severity (Gill et al. 1995). Disease severity is thought to depend on 
a complex interaction of genetic, rheologic and hematologic factors, as well as microvascular 
and endothelial factors. Therefore, despite the capacity to determine genotype, the ability to 
predict disease course from birth is limited (Thomas 1997). The frequency of VOC and pain 
severity varies considerably among patients and in the same patient over time. Moreover, a 
recent study (PiSCES) evaluating health related quality of life issues in SCD patients indicated 
that VOC might be significantly underreported among SCD patients (McClish et al. 2005). 
Treatment for SCD includes supportive care for VOC. The two most common symptomatic 
treatments are blood transfusions and analgesics. Blood transfusions both increase hemoglobin 
level and lower the proportion of sickled cells, thereby increasing oxygen delivery to tissues 
and potentially reducing pain. Severe pain is often treated with narcotics but their use is 
controversial due to concerns of narcotic addiction and tolerance. Other complications of 
narcotic use are drug-seeking behavior, sedation and respiratory depression. Oxygen 
management has been utilized to treat VOC, despite the lack of strong evidence supporting its 
effectiveness. Rehydration is also used during VOC with some apparent benefit (NHLBI, The 
Management of Sickle Cell Disease. NIH Publication No.022117; Yale 2000). 
Preventative therapies for SCD include chronic red cell transfusion programs to reduce the 
incidence of stroke in high-risk patients, Hydroxyurea/Hydroxycarbamide (HU/HC, 
Droxia/Siklos) is approved for VOC. The mechanisms by which HU/HC produces its beneficial 
effects are uncertain but likely involve increasing hemoglobin F levels in RBCs, thereby 
decreasing the amount of hemoglobin S polymerization. Hydroxyurea is cytotoxic, 
myelosuppressive and teratogenic (Charache et al. 1995), and the long-term effects of 
hematologic toxicities, organ damage and carcinogenicity are currently unknown (NIH 
Consensus and State-of -the Science Statements 2008). L-glutamine was recently approved by 
the FDA to reduce the complications of sickle cell disease in adult and pediatric patients 5 years 
and older. Bone marrow transplantation may be considered and can be curative, but a limited 


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number of patients are eligible, and this carries a high risk of morbidity and mortality (NHLBI 
The Management of Sickle Cell Disease. NIH Publication No.022117). Thus, SCD is a life- 
threatening disease with severe morbidities and represents a major unmet medical need. 
The recognition that adherence of leukocytes, platelets and sickle red cells to blood vessel 
endothelium and to each other to have a primary role in VOC led to further research into the 
selectins, which mediate the first steps in the recruitment of leukocytes to specific tissues. Under 
shear flow in the blood, leukocytes first tether and begin rolling on vascular endothelium, 
eventually adhering firmly and infiltrating into the underlying tissue (Springer 1995). Selectins 
interact with glycoconjugated ligands on leukocytes to initiate this process (McEver 1995; 
Vestweber 1999). Transient adhesion mediated by selectins is a prerequisite for firm adhesion 
mediated by integrin receptors and subsequent transendothelial migration of leukocytes. Three 
selectins have been identified: P-, E- and L-selectin. P-selectin is the best characterized of the 
selectins and binding specificity and affinity to its physiological ligand P-selectin glycoprotein 
ligand-1 (PSGL-1) is well-documented (McEver 2004; Mehta 1998). P-selectin is stored in 
Weibel-Palade bodies in endothelial cells that line blood vessels and in α-granules in platelets. 
Extensive data have been published over the last decade that suggests a pivotal role for P- 
selectin in the pathophysiology of SCD (Matsui 2001). Much of this work has been conducted 
in mice engineered or altered to express human hemoglobin S (sickle cell hemoglobin) but not 
mouse β hemoglobin. These mice have a remarkably similar disease pathology and 
inflammatory profile to that observed in human SCD, including vaso-occlusion. Using these 
mice, investigators have demonstrated P-selectin interactions between the endothelium and 
sickled red blood cells, leukocytes, and platelets. Additional studies have demonstrated direct 
P-selectin-mediated binding of leukocytes with sickled red cells and platelets. All of these cell- 
cell interactions have been implicated in SCD vaso-occlusion. Further, blockade or genetic 
absence of P-selectin decreases or eliminates these cell-cell interactions and vaso-occlusion. 
Taken together, these studies establish P-selectin as a key mediator of vaso-occlusion in SCD. 
 
1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
1.2.1 
Overview of Crizanlizumab (SEG101) 
Crizanlizumab (SEG101) is a humanized monoclonal antibody that binds P-selectin in humans 
and primates and blocks the interaction of P-selectin with its ligands. The compound was 
previously developed by Reprixys under the investigational drug code, SelG1, and subsequently 
became a legal entity of Novartis Pharmaceuticals on 18-Nov-2016. 
 
1.2.1.1 
Non-clinical experience 
Crizanlizumab is administered intravenously (i.v.) with instantaneous absorption and assumed 
100% bioavailability. As a humanized, monoclonal antibody, distribution is expected to be 
typical of endogenous human antibodies within the vascular and extracellular spaces by 
mechanisms dominated by convection, fluid-phase endocytosis, receptor-mediated endocytosis 
and their interaction with FcRn receptors (Heegaard 2002). Crizanlizumab contains only 
naturally occurring amino acids and has no known active metabolites. Human antibodies are 


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predominately catabolized by lysosomal enzymes to small peptides and amino acids. The extent 
of catabolism is inversely proportional to FcRn receptor affinity (Dall’Acqua et al. 2002). 
No specific studies have been conducted to evaluate specific pathways of crizanlizumab 
excretion. Due to its predicted molecular size of approximately 148 kDa, it is expected that 
crizanlizumab, like other immunoglobulins, is not eliminated by efficient filtration through the 
glomerulus in kidneys. 
In addition to studies in rodents containing human sickled hemoglobin, other studies 
demonstrated that human sickled red cells adhere to human endothelial cells more frequently 
than normal red cells, and an anti-human P-selectin antibody inhibits this adherence (Matsui et 
al. 2001). 
In experiments performed with the parental anti-human P-selectin antibody G1, the following 
data were generated: 1) G1 blocks the binding of human P-selectin to its ligand PSGL-1 (Geng 
et al. 1990) 2) G1 blocks leukocyte rolling and firm adhesion to human vascular endothelium 
under shear stress (Geng et al. 1990; Jones et al. 1993); 3) G1 effectively inhibits the interaction 
of neutrophils with stimulated platelets (Hamburger 1990); 4) G1 completely blocks the binding 
of human sickled red cells to human endothelium under flow (Wagner 2006); and 5) in mice 
expressing human but not mouse P-selectin, G1 blocks the rolling and adherence of leukocytes 
on mouse venules and can reverse pre-established leukocyte adhesion (Liu et al. 2010). 
In experiments performed to confirm that the humanized form of G1 (SelG1) shares identical 
specificity and function with parental G1, SelG1 was shown to 1) bind P-selectin with an near 
identical affinity to that of G1; 2) maintain the same species restriction pattern as G1; 3) have 
the same epitope recognition pattern as G1; 4) effectively block the binding of P-selectin to its 
receptor on human cells and; 5) retain the receptor/ligand dissociative property of G1. 
Due to the species restriction of SelG1 binding, much of the data available to date have been 
obtained from rodent modeling using mice expressing human hemoglobin S (sickle cell 
hemoglobin) with surrogate antibodies that block mouse P-selectin or animals genetically 
deficient in P-selectin. Where possible, the SelG1 parental antibody G1 has been used in 
experimentation in which human P-selectin is present. In addition, confirmatory data with 
SelG1 were established. 
In mice expressing human sickled hemoglobin (human βS mice) the following data were 
generated: 1) an anti-mouse P-selectin antibody blocks leukocyte rolling (Kaul 2000); 2) vaso- 
occlusion is blocked in animals deficient in P-selectin (Frenette 2004); 3) platelet and leukocyte 
adhesion to vascular endothelium is absent in P-selectin deficient animals (Wood 2004); and 4) 
sickled red cell microvascular flow is increased and vaso-occlusion decreased with an anti- 
mouse P-selectin antibody (Embury et al. 2004). 
Finally, SelG1 has been administered to nonhuman primates in a single-dose and two separate 
GLP multi-dose studies. Administration of SelG1 by bolus IV injection once every 4 weeks to 
cynomolgus monkeys for a total of seven doses was well tolerated at doses ≤ 25 mg/kg/dose; 
the no observed adverse effect level (NOAEL) is therefore 25 mg/kg/dose. 
As SelG1 is specific to human and nonhuman primate P-selectin and in accordance with the ICH 
S6 Guidance, no genotoxicity or reproductive toxicology studies have been performed to date. 


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1.2.1.2 Clinical experience 
 
Phase I Clinical Study (CSEG101A2101) 
The objectives of this study (Reprixys study code: Se1G1-00003; Novartis study code: 
CSEG101A2101) were to evaluate the safety, PK, PD, and immunogenicity of intravenously 
administered SelG1 versus placebo in 27 healthy subjects at ascending dose levels (0.2, 0.5, 1.0, 
5.0 mg/kg and 8.0 mg/kg). 
Crizanlizumab concentrations slowly declined, with mean half-life ranging from 75.6 (at dose 
of 0.2 mg/kg) to 500 (at 5.0 mg/kg) hours. Therefore, clearance decreased with the increase in 
dose level: 88.6 mL/hr. (at 0.2 mg/kg) to 9.91 (at 5.0 mg/kg). Following two intravenous 
infusions of SelG1 at 8.0 mg/kg, the mean half-life was 363 hours, and the clearance was 3.86 
mL/hr. For subjects receiving a single dose of crizanlizumab at 5.0 mg/kg, P-selectin inhibition 
was complete for at least 28 days with a mean crizanlizumab concentration on Day 28 of 
19.9±3.8 μg/mL. 
There were no infection-related AEs, changes in coagulation parameters, increased bleeding 
tendencies, or notable treatment-related changes in peripheral blood immunophenotyping. The 
immunogenicity data generated during the Phase I clinical trial indicate that no specific antibody 
response to SelG1 occurred in any subjects receiving up to 2 doses of drug. 
Based on AEs, clinical laboratory evaluations, vital signs measurements, physical examinations, 
and ECG evaluations, administration of SelG1 was safe and well-tolerated in this group of 
healthy male and female subjects. 
 
Phase II Clinical Study (SUSTAIN – CSEG101A2201) 
The purpose of SUSTAIN (Reprixys study code: Se1G1-00005; Novartis study code: 
CSEG101A2201) study was to investigate the safety and tolerability of the humanized anti-P- 
selectin monoclonal antibody, crizanlizumab (SelG1), during chronic administration to SCD 
patients and to investigate the efficacy of crizanlizumab to affect the rate of sickle cell-related 
pain crises (SCPC) (also known as VOC leading to a healthcare visit) as well as a variety of 
other 
clinical 
endpoints, 
anemia- 
and 
hemolysis-related 
laboratory 
parameters, 
pharmacokinetics/pharmacodynamics (PK/PD), and patient reported outcomes. 
This trial was a multicenter, randomized, placebo-controlled, double-blind, parallel-group study 
to assess the safety and efficacy of crizanlizumab versus placebo in patients with SCD, both 
receiving and not receiving HU/HC. Crizanlizumab was administered at 2 different dose levels 
(2.5 mg/kg and 5.0 mg/kg). A total of 198 patients were randomized and included in the intent- 
to-treat (ITT) population, with 67 patients randomized to receive crizanlizumab at 5.0 mg/kg 
(5.0 mg/kg treatment arm), 66 patients to receive crizanlizumab at 2.5 mg/kg (2.5 mg/kg 
treatment arm), and 65 patients to receive placebo (placebo treatment arm). 
The primary efficacy parameter was the assessment of the annual rate of VOC leading to a 
healthcare visit, defined as an acute episode of pain, for which there is with no other medically 
determined explanation cause than a vaso-occlusive event, which requires a medical facility 
(clinic, emergency room (ER), or hospital) visit and treatment with oral or parenteral narcotics, 
or parenteral non-steroidal anti-inflammatory drugs. Acute chest syndrome, hepatic 
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were also considered VOC leading to a healthcare visit for analysis purposes. It was observed 
that treatment with 5.0 mg/kg crizanlizumab resulted in an annual rate of VOC leading to a 
healthcare visit that was 45.3% lower than the rate with placebo which was statistically 
significant (p = 0.010). The annual rate of VOC leading to a healthcare visit in the 2.5 mg/kg 
crizanlizumab treatment arm was compared with that of placebo, and although favorable (32.6% 
reduction with active treatment), it was not statistically significant (p = 0.180). In addition, in 
the 5.0 mg/kg crizanlizumab arm, numerical and clinically significant reductions in the annual 
rate of VOC leading to a healthcare visit were observed across important subgroups, including 
patients receiving concomitant HU (32.1%) and not receiving concomitant HU (50.0%), and in 
patients with the HbSS genotype (34.6%) and non-HbSS genotype (50.5%) (HbSC, HbSβ0- 
thalassemia, HbSβ+-thalassemia, and others). The median annual rate of days hospitalized was 
numerically reduced in the 5.0 mg/kg arm versus the placebo arm (4.00 versus 6.87, 
respectively); however this difference was not statistically significant. Treatment with 
crizanlizumab at 5.0 mg/kg was associated with longer median time to first VOC leading to a 
healthcare visit compared with placebo (4.07 versus 1.38 months, p = 0.001) and median time  
to second VOC leading to a healthcare visit compared to placebo (10.32 versus 5.09 months, p 
= 0.022). 
Crizanlizumab was well tolerated. Adverse events that occurred in ≥5% of patients in an active 
dose group and were more than 2 times higher than placebo were: arthralgia, pruritus, vomiting, 
chest pain, diarrhea, fatigue, myalgia, musculoskeletal chest pain, abdominal pain, influenza 
and oropharyngeal pain. There were 5 deaths during the study (2 at 5.0 mg/kg, 1 at 2.5 mg/kg 
and 2 in the placebo group), and no deaths were deemed related to study drug. The proportion 
of subjects experiencing SAEs was 25.8% at 5.0 mg/kg, 32.8% at 2.5 mg/kg and 27.4% in the 
placebo group. Adverse events that occurred in 10% or more of the patients in either active 
treatment group and at a frequency that was at least twice as high as that in the placebo group 
were arthralgia (5.0 mg/kg: 18.2% versus 2.5 mg/kg: 14.1% versus placebo: 8.1%), diarrhea 
(10.6% versus 7.8% versus 3.2%), pruritus (7.6% versus 10.9% versus 3.4%), vomiting (7.6% 
versus 10.9% versus 4.8%) and chest pain (1.5% versus 10.9% versus 1.6%). No patient 
developed anti-drug antibodies (ADA) against crizanlizumab during the course of the 
SUSTAIN study. 
A sub analysis of risk ratio (RR [95% confidence intervals]; p-value) of infections found no 
evidence of association between crizanlizumab and infections. For this analysis, two subgroups 
were analyzed: infections and serious infections. The results show for infections a RR of 1.03 
[0.82-1.29]: p=0.819; and for serious infections a RR of 1.07 [0.58-1.97]: p=0.820. The results 
suggest that the risk of infections and serious infections in crizanlizumab and placebo groups 
was similar. 
Overall, treatment of patients with SCD with crizanlizumab at 5.0 mg/kg showed positive 
clinical activity as demonstrated by a decrease in the annual VOC leading to a healthcare visit 
rate compared with placebo. Treatment with crizanlizumab at 5.0 mg/kg was also found to be 
well tolerated. 


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2 
Rationale 
2.1 
Study rationale and purpose 
Clinical and toxicological studies performed to date for crizanlizumab were conducted using 
Reprixys material (SelG1 mAb). To ensure supply of future clinical studies as well as 
commercial demand, Novartis has optimized the production of crizanlizumab. The Novartis 
material (SEG101 mAb) drug substance (DS) and drug product (DP) will be manufactured at 
Novartis sites. In vitro characterization and primate PK experiments conducted with both mAbs 
did not reveal significant differences that would influence PK/PD results. Therefore, the change 
in cell line is not expected to impact the bioavailability or activity of the compound. The 
CSEG101A2202 study will be the first trial to administer crizanlizumab to SCD adult patients. 
The purpose of this study is to characterize the PK and PD of crizanlizumab and to evaluate the 
safety and efficacy of crizanlizumab in SCD patients. 
 
2.2 
Rationale for the study design 
Study CSEG101A2202 is designed as a Phase II, multicenter, open-label study. The first 45 
patients (to identify 27 evaluable patients) will be enrolled to the treatment group crizanlizumab 
5.0 mg/kg to complete full PK and PD sampling at week 1 and week 15. In all patients, pre- 
dose PK and PD samples will also be collected prior to each dose.
 
 
 Once the first 45 
patients are enrolled, 10 additional patients will be enrolled to the exploratory treatment group 
and begin at 7.5 mg/kg of crizanlizumab. 
The patients will undergo a screening period from Day -35 to Day -1 in order to enable the 
study center to conduct the required tests for eligibility. The first 45 patients will be enrolled to 
receive infusion doses of crizanlizumab 5.0 mg/kg (test) on the first day (Week 1 Day 1), Week 
3 Day 1, and then day 1 of every 4-week cycle. No dose reductions are allowed in the study for 
patients assigned to 5.0 mg/kg dose. Patients will continue on study until 105 days after 
discontinuing drug or until receiving crizanlizumab commercially or through a different study 
or access program. Patients may need to stay at the study center for at least 24 hours following 
the first drug administration during which time blood samples for measurement of 
crizanlizumab will be collected, and then after the fifth dose (Week 15 Day 1). Patients will be 
discharged from the study site on Day 2 of Week 1 and Day 2 of Week 15 and will return on 
Week 1 Day 4, Week 2 Day 1, Week 3 Day 1, Week 7 Day 1, Week 11 Day 1, Week 15 Day 1 
(patients to stay at study site for 24 hours as described above), Week 15 Day 4, Week 16 Day 
1, Week 17 Day 1, Week 19 Day 1, and Day 1 of every 4 weeks for ambulatory visit for 
additional pharmacokinetic/pharmacodynamics and immunogenicity assessments and at 105 
days after the last dose for the safety follow-up visit. 
After 45 patients are enrolled at the 5.0 mg/kg dose, up to 10 additional patients (to identify 6 
evaluable patients) will be enrolled to the exploratory treatment group of 7.5 mg/kg 
crizanlizumab.
 
The 10 patients will receive 
infusion doses of crizanlizumab at 7.5 mg/kg on the same schedule and with the same 


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administration requirements as for the 5.0 mg/kg group. 
 
 
 
 
 
 
2.3 
Rationale for dose and regimen selection 
Patients will receive crizanlizumab at a dose of 5.0 or 7.5 mg/kg by IV infusion over 30 minutes. 
Dose number 2 is administered as a loading dose 2 weeks following the first dose to rapidly 
achieve steady-state serum concentrations. This is followed by repeated administration of the 
initial dose every 4-weeks ± 3 days to ensure that steady-state serum concentrations of 
crizanlizumab are maintained to provide a consistent blockade of P-selectin throughout the 
study. 
The SUSTAIN trial tested either 5.0 mg/kg or 2.5 mg/kg of SelG1 on this same dosing schedule 
and showed a statistically significant reduction in median annual rate of VOC leading to a 
healthcare visit 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 2016). The doses chosen for the SUSTAIN study were 
based on complete P-selectin inhibition of SelG1 in healthy subjects, as well as the acceptable 
safety experience observed with 5.0 mg/kg and 8.0 mg/kg dosing regimens during the Phase I 
safety study. As mentioned in Section 1.2.1.2, the phase I study (CSEG101A2101) found that 
a single dose of SelG1 at 5.0 mg/kg yielded at least 28 days of complete P-selectin inhibition. 
 
 
 
2.4 
Rationale for choice of combination 
Not applicable. 
 
2.5 
Rationale for choice of comparators drugs 
Not applicable 
 
2.6 
Risks and benefits 
Overall, treatment of SCD patients with crizanlizumab at 5.0 mg/kg demonstrated statistically 
significant, clinically meaningful, and robust efficacy results vs. placebo in reduction of annual 
rate of sickle cell-related pain crisis (SCPC) (also known as VOC leading to a healthcare visit) 
and delay of onset of VOC leading to a healthcare visit in a well-controlled Phase II clinical 
trial (SUSTAIN study) in a clearly defined SCD patient population. Treatment with 
crizanlizumab at 5.0 mg/kg was also found to be well tolerated 
 
 
 The substantial efficacy and acceptable safety 
of crizanlizumab suggest an overall favorable benefit-risk assessment and warrant further 
clinical development in SCD. 


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Crizanlizumab was well tolerated in SUSTAIN study. There were no unexpected safety findings; 
however, infusion-related reactions were observed in around 2% of subjects. 
The risk of infections and serious infections with the use of crizanlizumab has been evaluated 
and the results suggest that the risk of infections and serious infections in crizanlizumab and 
placebo groups was similar. 
Monoclonal antibodies (mAbs) are large molecules intended to bind to specific targets often 
expressed on the immune system, and to treat various immunopathological conditions. 
Therefore, mAbs can be considered to have a high potential for immunotoxicity, which is 
reflected in the clinical experience accumulated on mAbs-induced adverse effects related to 
immunosuppression, immunostimulation and hypersensitivity (immunogenicity) (Descotes J, 
2009). So far, clinical studies have shown no deleterious effects of the use of crizanlizumab in 
regards to immunotoxicity and immunogenicity. 
Appropriate eligibility criteria and stopping rules are included in this protocol. Recommended 
guidelines for prophylactic or supportive management of study-drug induced adverse events are 
provided in Section 6.4. The risk to subjects in this trial may be minimized by compliance with 
the eligibility criteria and study procedures, as well as, close clinical monitoring, and in-patient 
status for 24 hours following the first dose. There may be unforeseen risks with crizanlizumab, 
which could be serious. For additional safety information, refer to the latest Investigator’s 
Brochure. 
 
3 
Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 below. 


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Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
Refer to Section 10.4 
Characterize PK of crizanlizumab at 5.0 mg/kg 
in SCD patients 
Characterize PD (P-selectin inhibition) of 
crizanlizumab at 5.0 mg/kg in SCD patients 
-PK parameters after the starting dose and after multiple doses. 
-Pre-dose concentrations prior to each study drug dose. 
-%P-selectin inhibition and PD-AUC after the starting dose, after multiple 
doses, and prior to each study drug dose. 
Secondary 
Refer to Section 10.5 
Assess efficacy of crizanlizumab 
-Annualized rate of VOC events leading to healthcare visit in 
clinic/ER/hospital 
-Annualized rate of VOC events treated at home (based on documentation 
by health care provider following phone contact with patient) 
-Annualized rate of hospitalizations and ER visits (both total and VOC- 
related) 
-Annualized days of ER/hospitalization (both total and VOC-related) 
-Annualized rate of each subcategory of VOC event (uncomplicated pain 
crisis, acute chest syndrome, hepatic sequestration, splenic sequestration, 
priapism) 
-Annualized rate of VOC events (including both healthcare visit and home 
treatment) 
Assess safety and tolerability of crizanlizumab 
-Number, seriousness, severity, and causality assessments of treatment 
emergent adverse events and other safety data as considered appropriate 
-Absolute change from baseline in hemoglobin 
-Immunogenicity: measurement of anti-drug antibodies (ADA) to 
crizanlizumab 


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4 
Study design 
4.1 
Description of study design 
This is a multicenter, single-arm, open-label study to assess PK and PD of crizanlizumab in 
adult patients with SCD and VOC. 
Approximately 55 patients will be enrolled in the trial. 45 eligible patients (all screening criteria 
met) will be treated with crizanlizumab at a dose of 5.0 mg/kg and up to 10 additional eligible 
patients (all screening criteria met) will be treated with crizanlizumab at a dose of 7.5 mg/kg. 
The study will include adult patients, ages 16-70 years, with confirmed diagnosis of SCD 
(genotypes HbSS, HbSC, HbS β0-thalassemia, HbS β+-thalassemia, and others) who have 
experienced at least 1 VOC within the preceding 12 months. Patients may not plan to initiate 
HU/HC during the study. For patients who are already treated with HU/HC, they should be 
taking HU/HC for at least 6 months and plan to continue the same dose at the same schedule 
during the trial 
Patients will receive treatment until study treatment is permanently discontinued due to 
unacceptable toxicity, death, are lost to follow-up or discontinued from the study treatment for 
any other reasons. Patients will be followed in the mandatory safety follow-up period until 105 
days after the last dosing. Patients continuing to receive benefit, defined as no evidence of 
increased frequency of VOCs and no severe adverse events attributed to drug as per 
Investigator’s assessment, will remain on study until crizanlizumab is commercially available 
or until patients are rolled over in a different crizanlizumab study or access program. 
 
Screening phase 
Within 35 days before enrolment, the patient will provide a main signed informed consent form 
prior to any study related activities. All screening evaluations must be performed during the 
screening period (day-35 to day-1). 
 
Treatment phase 
Once eligibility criteria have been confirmed to Novartis via the eligibility checklist, the patient 
will be enrolled in the trial and will receive crizanlizumab. Study treatment should be started as 
soon as possible. 
Patients may be admitted to the study site prior to dosing for baseline evaluations. The first 45 
patients will receive crizanlizumab 5.0 mg/kg by IV infusion over 30 min on week 1 day 1, 
week 3 day 1, and then day 1 of every 4-week cycle. No dose change or modification will be 
allowed in the study for patients assigned to 5.0 mg/kg dose. Once 27 patients have evaluable 
PK/PD data (or a total of 45 patients are enrolled) at the 5.0 mg/kg dose, an exploratory cohort 
of 10 patients will be enrolled at a dose of 7.5 mg/kg. Patients will receive crizanlizumab 7.5 
mg/kg by IV infusion over 30 min on week 1 day 1, week 3 day 1, and then day 1 of every 4- 
week cycle. Dose change or modifications are described in the Section 6.3. 
All enrolled patients will have PK/PD sampling performed in order to characterize the PK/PD 
of crizanlizumab (see Table 7-5). On week 1 day 1 and week 15 day 1 the patients may be asked 


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to remain at the study site for at least 24 hours post dose in order to complete the PK/PD sample 
collection. 
In case of VOC, the related medical and treatment information will be collected. 
 
 
 
Safety will be monitored as outlined in Section 8. Patients will receive treatment until 
unacceptable toxicity, death, are lost to follow-up or discontinued from the study treatment for 
any other reasons. 
 
Post-treatment follow-up phase 
After the end of treatment visit, all patients will be followed up for safety up to 105 days (15 
weeks) after the last dose of study treatment. 
 
Figure 4-1 
Study Design 
 
 
 
 
4.2 
Timing of interim analyses and design adaptations 
Exploration of early access (EA) PK data may occur for preliminary PK analysis prior to clinical 
data base lock. PK samples may be batched and shipped for expedited EA PK analysis and data 
will be uploaded by the bioanalyst via PKLink. For the derivation of PK parameters nominal 
time instead of actual elapsed time may be used. 
An interim analysis may be performed when there are at least 27 patients with single dose 
evaluable PK profiles and approximately 5 patients with both single dose and multiple dose 
evaluable PK profiles in the 5.0 mg/kg treatment group in the Pharmacokinetic Analysis Set 1 
(PAS1). This interim analysis may further characterize the PK/PD profile for the pediatric study 
CSEG101B2201; however there is currently no plan for design adaptation of trial 
CSEG101A2202. Another interim analysis may be performed when there are approximately 15 
patients with multiple dose evaluable PK profiles in the 5.0 mg/kg treatment group in the PAS1, 
in order to inform the PK/PD/safety profile of crizanlizumab and potentially support the 
regulatory filing. Should the criteria for the two interim analyses be reached at similar times 


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compatible with both objectives, a single combined interim analysis will be performed. 
Additional earlier or later ad hoc interim analyses of PK/PD/safety may be performed in order 
to support potential Health Authority requests. 
 
4.3 
Definition of end of study 
The primary analysis will be conducted after the PK and PD parameters are available for at least 
27 patients in the 5.0 mg/kg treatment group in the Pharmacokinetic Analysis Set 1 (PAS1) and 
Pharmacodynamics Analysis Set 1 (PDS1) respectively. The primary analysis data will be 
summarized in the primary clinical study report (CSR). 
Following the cut-off date for the analysis reported in the primary CSR, the study will remain 
open. Ongoing patients will continue to receive study treatment and be followed as per the 
schedule of assessments, as long as patients derive benefit from crizanlizumab. The end of study 
is defined by the occurrence of one of the following: 
• All patients have died or discontinued from the study 
• Crizanlizumab is commercially available for this patient population, and patients obtain 
the commercial drug 
• Another clinical study becomes available that can continue to provide crizanlizumab in 
this patient population and all patients ongoing are transferred to that clinical study 
The final analysis will occur at the end of the study. All available data from all patients up to 
the trial end will be analyzed and summarized in a final CSR. 
 
4.4 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in Section 7 for a discontinued or withdrawn patient. 
Premature study termination must occur if one or more of the following reasons apply: 
• Decision of the Sponsor 
• Safety issues: If more than 25% of the subjects at any time point have been withdrawn due 
to adverse events or abnormal laboratory results and abnormal test procedure results 
related to the study drugs. 
• If information becomes available that the use of crizanlizumab would expose the subjects 
to an unacceptable risk. 
In the event the safety stopping criteria are met, the Sponsor and Principal Investigator will 
discuss the implications of study continuation. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the patient’s interests. The investigator 
will be responsible for informing IRBs and/or ECs of the early termination of the trial. 


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5 
Population 
5.1 
Patient population 
CSEG101A2202 will enroll up to 55 SCD patients (any genotype) ages 16-70 years who 
experienced at least 1 VOC over the preceding 12 months, and who are not planning to take 
HU/HC during the trial or who have been taking HU/HC for at least 6 months and plan to 
continue taking at the same dose and schedule during the trial. 
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study. 
 
5.2 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Male or female, 16 to 70 years of age (inclusive) on the day of informed consent signature. 
2. Confirmed diagnosis of sickle cell disease by hemoglobin electrophoresis or high- 
performance liquid chromatography (HPLC) [performed locally]. All sickle cell disease 
genotypes are eligible (HbSS, HbSβ0, HbSC, HbSβ+, and others), though genotyping is not 
required for study entry. 
3. Experienced at least 1 VOC within the preceding 12 months prior to Screening as 
determined by medical history. Prior VOC should include the occurrence of appropriate 
symptoms, a visit to a medical facility and/or healthcare professional, and receipt of 
parenteral opioid or NSAID analgesia or oral opioid. 
4. If receiving HU/HC or erythropoietin stimulating agent, must have been receiving the drug 
for at least 6 months prior to Screening and plan to continue taking at the same dose and 
schedule during the trial. 
5. Patient must meet the following laboratory values at the screening visit: 
• Absolute Neutrophil Count ≥1.0 x 109/L 
• Platelets ≥75 x 109/L 
• Hemoglobin (Hgb) ≥4.0 g/dL 
• Glomerular filtration rate ≥ 45 mL/min/1.73 m2 using CKD-EPI formula 
• Direct (conjugated) bilirubin ≤2.0 x ULN 
• Alanine transaminase (ALT) ≤ 3.0 x ULN 
6. ECOG performance status ≤2 
7. Written informed consent, and applicable adolescent assent and parental consent for minor 
subjects, must be obtained prior to any screening procedures. 
 
5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. History of stem cell transplant. 
2. Acute vaso-occlusive crisis ending within 7 days prior to Week 1 Day 1 dosing. 


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3. Received blood products within 30 days of Week 1 Day 1 dosing. 
4. Participating in a chronic transfusion program (pre-planned series of transfusions for 
prophylactic purposes). 
5. Planning on undergoing an exchange transfusion during the duration of the study; episodic 
transfusion in response to worsened anemia or vaso-occlusive crisis is permitted. 
6. Contraindication or hypersensitivity to any drug or metabolites from similar class as study 
drug or to any excipients of the study drug formulation. 
7. History of severe hypersensitivity reaction to other monoclonal antibodies, which in the 
opinion of the investigator may pose an increased risk of serious infusion reaction. 
8. Use of therapeutic anticoagulation (prophylactic doses permitted) or antiplatelet therapy 
(other than aspirin or NSAIDs) within the 10 days prior to Week 1 Day 1 dosing 
9. Received a monoclonal antibody or immunomodulatory agent within 1 year of Screening, 
or has documented immunogenicity to a prior biologic 
10. Received active treatment on another investigational trial within 30 days (or 5 half-lives of 
that agent, whichever is greater) prior to Screening or plans to participate in another 
investigational drug trial 
11. Pregnant or nursing women 
12. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
dosing and for 15 weeks after stopping treatment. Highly effective contraception methods 
include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment 
• Male sterilization (at least 6 months prior to screening). The vasectomized male 
partner should be the sole partner for that subject 
• Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception. 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
13. Current drug or alcohol abuse: 
• Has a positive qualitative urine drug test at Screening for cocaine, phencyclidine 
(PCP), or amphetamines 


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• Consumes >12 (for males) or >8 (for females) standard alcoholic beverages per week 
14. 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 allowed. 
15. Patients with bleeding disorders 
16. Planning to undergo a major surgical procedure during the duration of the study 
17. Hospitalized at Screening 
18. Poorly-controlled HIV infection (CD4 count <200 cells/mm3 or viral load >50 copies/mL) 
19. Patients with active Hepatitis B infection (HBsAg positive) will be excluded 
• 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 2 years prior to study treatment; 
completely resected basal cell and squamous cell skin cancers and any completely 
resected carcinoma in situ 
23. Has a serious mental or physical illness, which, in the opinion of the Investigator would 
compromise participation in the study 
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. 
25. Resting QTcF ≥470 msec at pretreatment (baseline) 
26. Cardiac or cardiac repolarization abnormality, including any of the following: 
• History of myocardial infarction (MI), angina pectoris, coronary artery bypass graft 
(CABG), or uncontrolled congestive heart failure within 6 months prior to starting 
study treatment 
• Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left 
bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II 
and third degree AV block) 
• Long QT syndrome, family history of idiopathic sudden death or congenital long QT 
syndrome, or any of the following: 
• Risk factors for Torsade de Pointes (TdP) including uncorrected hypokalemia or 
hypomagnesemia, history of cardiac failure, or history of clinically 
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• Concomitant medication(s) with a “Known risk of Torsade de Pointes” per 
wwwqtdrugsorg that cannot be discontinued or replaced by safe alternative 
medication (within 5 half-lives prior to starting study drug) 
• Inability to determine the QTcF interval 
27. Not able to understand and to comply with study instructions and requirements. 
 
6 
Treatment 
6.1 
Study treatment 
Novartis will supply crizanlizumab (SEG101) as an open label medication. The investigational 
drug will be the crizanlizumab - SEG101 Histidine/Citrate buffered solution – provided every 
4 weeks with an additional loading dose 2 weeks after the first dosing (i.e. dosing on first day 
of week1, week3, week7, and then every 4 weeks) until the end of study. 
 
6.1.1 
Dosing regimen 
 
Table 6-1 
Dose and treatment schedule 
Study treatments 
Pharmaceutical form 
and route of 
administration 
Dose 
Frequency and/or 
Regimen 
 
SEG101 
Intravenous infusion 
5.0 mg/kg or 7.5 mg/kg 
Week 1 Day 1, Week 3 
Day   1,   Week  7 
Day 1 and day 1 of 
every 
4-week 
cycle 
 
Crizanlizumab is provided in single use vials containing 10 mL at a concentration of 10 mg/mL. 
The crizanlizumab formulation is a Histidine/Citrate buffered solution which is supplied in 
single use vials at a concentration of 10 mg/mL. 
Each patient receives one dose of crizanlizumab on Week 1 Day 1, Week 3 Day 1, Week 7 Day 
1 and day 1 of every 4-week cycle. On infusion day, the pharmacist or designated personnel 
will compound individual doses of crizanlizumab for patients on a milligram per kilogram basis 
in a 100 mL infusion bag of a sterile 0.9% sodium chloride solution (0.9% Sodium Chloride 
Injection, USP) in accordance with the Pharmacy Manual. Study drug will be administered over 
30 minutes by IV infusion. 
After the primary analysis, and considering that the drug product development is still ongoing 
to provide robust shelf-life, crizanlizumab Histidine/Citrate buffered solution may be substitute 
by the Final Market Image (FMI), citrate buffered solution. Minor modifications in the final 
buffer composition are expected and will be covered by in-vitro comparability studies. 
 
6.1.2 
Ancillary treatments 
Not applicable. 


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6.1.3 
Rescue medication 
Not applicable. 
 
6.1.4 
Guidelines for continuation of treatment 
For guidelines for continuation of treatment, refer to Section 6.3 Dose modifications. 
Patients who permanently discontinue the study drug for any reason should follow the protocol 
safety assessments as scheduled. After discontinuing study treatment, further treatment is left 
to the physician’s discretion. 
 
6.1.5 
Treatment duration 
Patients will be treated until the earliest occurrence of one of the following (see Section 7.1.4): 
• All patients have died or discontinued from the study 
• Crizanlizumab is commercially available for this patient population, and patients are 
eligible to be prescribed the commercial drug 
• Another clinical study becomes available that can continue to provide crizanlizumab in 
this patient population and all patients ongoing are eligible to be transferred to that clinical 
study 
 
6.2 
Dose escalation guidelines 
Not applicable 
 
6.3 
Dose modifications 
6.3.1 
Dose modification and dose delay 
For patients who do not tolerate the protocol-specified dosing schedule, dose interruptions 
and/or reductions are either recommended or mandated in order to allow patients to continue 
the study treatment until the next dose scheduled. Dose reductions are only allowed for 
patients assigned to 7.5 mg/kg dose. No dose reductions are allowed in the study for 
patients assigned to 5.0 mg/kg dose who just have option for dose interruption. The dose 
reduction is only in one level: from 7.5 mg/kg to 5.0 mg/kg and it is recommended at the grade 
2 or 3 or higher for the CTCAE or otherwise mentioned in Table 6-2 and Table 6-3. If drug- 
induced toxicities are present, patients would have to be closely monitored and a decision to 
continue or discontinue the patient from the study would have to be done at the next dose 
scheduled. 
These dose interruptions / reductions are summarized in Table 6-4. Deviations to mandatory 
dose interruptions are not allowed. Permanent treatment discontinuation is mandatory for 
specific events indicated as such in Table 6-4 or listed in Section 7.1.5.1. 
Missing 2 consecutive doses (no dose for 10 weeks) would be considered criteria for 
permanently discontinuing the patient from the study. 
Any dose changes must be recorded on the Dosage Administration Record CRF. 


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Table 6-2 
Criteria for dose reduction / interruption and re-initiation of crizanlizumab treatment for adverse drug reactions. 
 
Dose modifications for crizanlizumab 
Worst toxicity 
CTCAEa Grade (value) during a cycle of therapy 
Investigations (Hematologic) 
Neutropenia (ANC) 
Grade 1 (ANC < LLN - 1500/mm3) 
Recommendation: maintain dose level 
Grade 2 (ANC < 1500 - 1000/mm3) 
Recommendation: maintain dose level 
Grade 3 (ANC < 1000 - 500/mm3) 
- Recommendation: interrupt dose until resolved to ≤ Grade 2 or next dose scheduled. If 
abnormality persists permanently discontinue the patient from the study. 
- Recommendation for 7.5 mg/kg dosed patients only: ↓ 1 dose level to 5 mg/kg. If after the 
reduction of dose the abnormality improves to ≤ Grade 2 re-escalation to 7.5 mg is allowed. 
Grade 4 (ANC < 500/mm3) 
Mandatory: Interrupt dose until resolved to ≤ Grade 2 or next dose scheduled. If abnormality 
persists permanently discontinue the patient from the study. 
Febrile neutropenia (ANC < 1.0 x 109/L, fever ≥ 
38.3°C) 
A disorder characterized by an ANC <1000/mm3 
and a single temperature of >38.3 degrees C (101 
degrees F) or a sustained temperature of ≥38 
degrees C 
Mandatory: Interrupt dose until resolved or next dose schedule. If abnormality persists 
permanently discontinue the patient from the study. 
Thrombocytopenia 
Grade 1 (PLT < LLN - 75,000/mm3) 
May maintain dose level 
Grade 2 (PLT < 75,000 - 50,000/mm3) 
May maintain dose level 
Grade 3 (PLT < 50,000 - 25,000/mm3) 
- Recommendation: interrupt dose until resolved to ≤ Grade 1 or next dose scheduled. If 
abnormality persists permanently discontinue the patient from the study, then: 
- If resolved in ≤ 7 days, then maintain dose level 


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Dose modifications for crizanlizumab 
Worst toxicity 
CTCAEa Grade (value) during a cycle of therapy 
- If resolved in > 7 days, then ↓ 1 dose level (for 7.5 mg/kg dosed patients only: reduction to 
5 mg/kg dose). If after the reduction of dose the abnormality improves to ≤ Grade 2 re- 
escalation to 7.5 mg is allowed. 
Grade 4 (PLT < 25,000/mm3) 
Mandatory: Interrupt dose until resolved to ≤ Grade 1 or next dose scheduled. If abnormality 
persists permanently discontinue the patient from the study. 
Investigations (Renal) 
Serum creatinine 
Grade 1 (>1.0 – 1.5 x baseline OR > ULN - 1.5 x 
ULN) 
May maintain dose level 
Grade 2 (> 1.5 – 3.0 x baseline OR > 1.5 - 3.0 x 
ULN) 
- Recommendation: interrupt dose until resolved to ≤ Grade 1 or baseline level or next dose 
scheduled. If abnormality persists permanently discontinue the patient from the study. 
- Recommendation for 7.5 mg/kg dosed patients only: ↓ 1 dose level to 5 mg/kg. If after the 
reduction of dose the abnormality improves to ≤ Grade 1 re-escalation to 7.5 mg is allowed. 
Grade 3 (> 3.0 x baseline OR > 3.0 - 6.0 x ULN) 
- Recommendation: interrupt dose until resolved to ≤ Grade 1 or baseline level or next dose 
scheduled. If abnormality persists permanently discontinue patient from study drug treatment. 
- Recommendation for 7.5 mg/kg dosed patients only: ↓ 1 dose level to 5 mg/kg. If after the 
reduction of dose the abnormality improves to ≤ Grade 1 re-escalation to 7.5 mg is allowed. 
Grade 4 (> 6.0 x ULN) 
- Mandatory: interrupt dose until resolved to ≤ Grade 1 or baseline level or next dose 
scheduled. If abnormality persists permanently discontinue the patient from the study. 
- Recommendation for 7.5 mg/kg dosed patients only: ↓ 1 dose level to 5 mg/kg. If after the 
reduction of dose the abnormality improves to ≤ Grade 1 re-escalation to 7.5 mg is allowed. 
Investigations (Hepatic) 
Isolated total Bilirubin elevation 
Grade 1 (> 1.5 x ULN) 
Recommendation: maintain dose level 


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Dose modifications for crizanlizumab 
Worst toxicity 
CTCAEa Grade (value) during a cycle of therapy 
Grade 2 (> 1.5 – 3.0 x ULN) 
Recommendation: maintain dose level 
Grade 3 (> 3.0 - 10.0 x ULN*) 
- Recommendation: 
- Interrupt dose. Monitor LFTsb weekly, or more frequently if clinically indicated, until resolved 
to ≤ 1.5 x ULN. 
- Monitor for hemolysis 
- If resolved, then continue with next dose scheduled 
- Recommendation for 7.5 mg/kg dosed patients only: ↓ 1 dose level to 5 mg/kg after 
confirmation of no hemolysis. If after the reduction of dose the abnormality improves to ≤ Grade 
2 re-escalation to 7.5 mg is allowed. 
Grade 4 (> 10.0 x ULN*) 
- Mandatory: 
- Interrupt dose. Monitor LFTsb weekly, or more frequently if clinically indicated, until resolved 
to ≤ 1.5 x ULN. 
- Monitor for hemolysis 
- If resolved, then continue with next dose scheduled 
- Recommendation for 7.5 mg/kg dosed patients only: ↓ 1 dose level to 5.0 mg/kg after 
confirmation of no hemolysis. If after the reduction of dose the abnormality improves to ≤ Grade 
1 re-escalation to 7.5 mg is allowed. 
- If abnormality persists permanently discontinue patient from study drug treatment. 
- The patient should be monitored weekly (including LFTsb), or more frequently if clinically 
indicated, until total bilirubin have resolved to baseline or stabilization over 4 weeks. 
Isolated AST or ALT elevation 
Grade 1 (> ULN - 3.0 x ULN) 
Recommendation: maintain dose level 
Grade 2 (> 3.0 - 5.0 x ULN) 


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Dose modifications for crizanlizumab 
Worst toxicity 
CTCAEa Grade (value) during a cycle of therapy 
- For patients with baseline value ≤ 3.0 x ULN 
- For patients with baseline value > 3.0 -5.0 x ULN 
- Recommendation: maintain dose level. 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 
- Maintain dose level 
Grade 3 (> 5.0 - 20.0 x ULN) 
- For patients with baseline value ≤ 3.0 x ULN 
- For patients with baseline value > 3.0 -5.0 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 Then 
If resolved, maintain dose level 
- Maintain dose level. 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 ≤ 5.0 x 
ULN 
Grade 4 (> 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 x ULN (or ≤ 5 x ULN for patients with baseline value > 
3.0-5.0 x ULN), if reoccurs at > 20 x ULN, permanently discontinue patient from study drug 
treatment. 
- Recommendation for 7.5 mg/kg dosed patients only: ↓ 1 dose level to 5.0 mg/kg. If after the 
reduction of dose the abnormality improves to ≤ Grade 2 re-escalation to 7.5 mg is allowed. 
Combined c elevations of AST or ALT and bilirubin (direct [conjugated] and/or total) 
For patients with normal baseline ALT and AST 
and (direct or total) bilirubin value: 
Mandatory: 
- Monitor for hemolysis. 


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Dose modifications for crizanlizumab 
Worst toxicity 
CTCAEa Grade (value) during a cycle of therapy 
• 
AST or ALT >3.0xULN combined with 
direct or total bilirubin >2.0 x ULN without 
evidence of cholestasis 
OR (Note to study team: If supported by available 
data) 
For patients with elevated baseline AST or ALT or 
direct or total bilirubin value: 
• 
AST or ALT>2x baseline AND > 3.0 x ULN 
OR 
• 
AST or ALT > 8.0 x ULN, combined with 
[direct or total bilirubin >2x baseline 
AND >2.0 x ULN] 
- If elevations of ALT and/or AST (>3.0 x ULN) and direct or total bilirubin (>2.0 x ULN) 
without evidence of cholestasisd (ALKP < 2 x ULN) are observed simultaneously at the 
 
visit: interrupt dose and monitor for hemolysis. If abnormality persists without evidence of 
hemolysis, permanently discontinue patient from study drug treatment. 
Recommendation: If elevations of direct or total bilirubin precede the elevations of ALT and or 
AST, monitor for hemolysis. 
Repeat 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 AST, ALT, or 
bilirubin have resolved to baseline or stabilization over 4 weeks. Refer to Section 6.3.1.1 for 
additional follow-up evaluations as applicable. 
Investigation (metabolic) 
Asymptomatic amylase and/or lipase elevation 
Grade 1 (> ULN - 1.5 x ULN) 
May maintain dose level 
Grade 2 (> 1.5 - 2.0 x ULN) 
May maintain dose level 
Grade 3 (> 2.0 - 5.0 x ULN) 
Recommendation: interrupt dose until resolved to Grade ≤1 or baseline then: 
- If resolved, then maintain dose level 
- If resolved in > 7 days, then ↓ 1 dose level (for 7.5 mg/kg dosed patients only: reduction to 
5 mg/kg dose). If after the reduction of dose the abnormality improves to ≤ Grade 2 re- 
escalation to 7.5 mg is allowed. 
Grade 4 (> 5.0 x ULN) 
Mandatory: interrupt dose until resolved to ≤ Grade 2 or next dose scheduled. If abnormality 
persists permanently discontinue the patient from the study. 


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Dose modifications for crizanlizumab 
Worst toxicity 
CTCAEa Grade (value) during a cycle of therapy 
Gastro intestinal 
Pancreatitis 
Grade 2 (Enzyme elevation or radiologic findings 
only) 
Recommendation : maintain dose level 
Grade ≥ 3 - Severe pain; vomiting; medical 
intervention indicated (e.g., analgesia, nutritional 
support) 
Mandatory: interrupt dose and permanently discontinue patient from study drug treatment 
Diarrhea*** 
Grade 1 (Increase of <4 stools per day over 
baseline) 
May maintain dose level but, initiate anti-diarrhea treatment 
Grade 2 (Increase of 4 - 6 stools per day over 
baseline) 
Recommendation: 
- Interrupt dose until resolved to ≤ grade 1, then maintain dose level. 
- If diarrhea returns as ≥ grade 2, then interrupt dose until resolved to ≤ grade 1. 
Grade 3 (Increase of >=7 stools per day over 
baseline; incontinence; hospitalization indicated) 
Recommendation: interrupt dose and permanently discontinue patient from study drug treatment 
Grade 4 (Life-threatening consequences; urgent 
intervention indicated) 
Mandatory: interrupt dose and permanently discontinue patient from study drug treatment 
Skin and subcutaneous tissue disorders 
Rash/photosensitivity 
Grade 1 - Macules/papules covering <10% Body 
Surface Area (BSA) with or without symptoms (e.g., 
pruritus, burning, tightness) 
May maintain dose level. Consider to initiate institute appropriate skin toxicity therapy (such as 
antihistamines, topical corticosteroids and low-dose systemic corticosteroids) 
Grade 2 - Macules/papules covering 10 - 30% BSA 
with or without symptoms (e.g., pruritus, burning, 
tightness) 
May maintain dose level, but initiate/intensify appropriate skin toxicity therapy (such as 
antihistamines, topical corticosteroids and low-dose systemic corticosteroids) 


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Dose modifications for crizanlizumab 
Worst toxicity 
CTCAEa Grade (value) during a cycle of therapy 
Grade 3, despite skin toxicity therapy - 
Macules/papules covering >30% BSA with or 
without associated symptoms 
Recommendation: 
- Interrupt dose until resolved to Grade ≤ 1, then: 
- If not resolved (despite appropriate skin toxicity therapy), then permanently discontinue 
patient from study drug treatment 
Grade 4, despite skin toxicity therapy 
Mandatory: interrupt dose and permanently discontinue patient from study drug treatment 
Fatigue (General disorders and administration site conditions). A disorder characterized by a state of generalized weakness with a pronounced 
inability to summon sufficient energy to accomplish daily activities. 
Grade 1 (Fatigue relieved by rest) 
May maintain dose level 
Grade 2 (Fatigue not relieved by rest) 
May maintain dose level 
Grade 3 (Fatigue not relieved by rest, limiting self- 
care Activities of Daily Living) 
Recommendation: 
- Interrupt dose until resolved to ≤ grade 1, then : 
- If resolved, then maintain dose level 
a Common Toxicity Criteria for Adverse Events (CTCAE Version 4.03) 
b Core LFTs consist of ALT, AST, GGT, total bilirubin (fractionated [direct and indirect], if total bilirubin > 2.0 x ULN), and alkaline phosphatase 
(fractionated [quantification of isoforms], if alkaline phosphatase > 2.0 x ULN.) 
c “Combined” defined as total bilirubin increase to the defined threshold concurrently with ALT/AST increase to the defined threshold 
If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please follow the instructions for isolated elevation of total 
bilirubin and isolated elevation of AST/ALT, and take a conservative action based on the degree of the elevations (e.g. discontinue treatment at the 
situation when omit dose is needed for one parameter and discontinue treatment is required for another parameter). After all elevations resolve to the 
defined thresholds that allow treatment re-initiation, re-start the treatment either at the same dose or at one dose lower if meeting a criterion for dose 
reduction. Dose reductions are only allowed for patients assigned to 7.5 mg/kg dose. No dose reductions are allowed in the study for patients 
assigned to 5.0 mg/kg dose. 
d “Cholestasis” defined as ALP elevation (>2.0 x ULN and R value <2 ) in patients without bone metastasis, or elevation of ALP liver fraction in patients 
with bone metastasis 
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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Dose modifications for crizanlizumab 
Worst toxicity 
CTCAEa Grade (value) during a cycle of therapy 
* Note: If total bilirubin > 3.0 x ULN is due to the indirect (non-conjugated) component only, and hemolysis as the etiology has been ruled out as per 
institutional guidelines (e.g., review of peripheral blood smear and haptoglobin determination), continue treatment at the discretion of the investigator. 
** Note: A CT scan or other imaging study to assess the pancreas, liver, and gallbladder must be performed within 1 week of the first occurrence of any 
≥ Grade 3 of amylase and/or lipase. If asymptomatic Grade 2 elevations of lipase and/or amylase occur again at the reduced dose, patients will be 
discontinued permanently from study treatment. 
*** Note: antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools or overt diarrhea 


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Table 6-3 
Management for drug-related toxicities 
 
Toxicity 
Management 
Infusion-related reactions 
Grade 1 
Decrease infusion rate until recovery 
Grade 2 
Stop infusion 
Before restarting - administer oral premedication (e.g.1000 mg of 
acetaminophen/paracetamol, 50-100 mg diphenhydramine hydrochloride 
or alternative antihistamine), within 60 minutes of restarting the infusion. 
Restart infusion at 50% of previous rate under continuous observation. 
Ensure that there is a minimum observation period of 1 hour prior to 
restarting the infusion(s). 
If the AE recurs at the reinitiated slow rate of infusion, and despite oral 
pre-medication, then discontinue patient from study. 
Grade 3 and 4 
Discontinue study treatment 
 
6.3.1.1 
Follow up on potential drug-induced liver injury (DILI) cases 
Patients with transaminase increase combined with TBIL increase may be indicative of 
potential DILI, and should be considered as clinically important events. 
The threshold for potential DILI may depend on the patient’s baseline AST/ALT and TBIL 
value; patients meeting any of the following criteria will require further follow-up as outlined 
below: 
• For patients with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN 
• For patients with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN] 
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in patients without bone metastasis, or elevation 
of ALP liver fraction in patients with bone metastasis. 
Monitoring for hemolysis in subjects with elevations of TBIL > 2.0 x ULN should be performed 
to rule out a plausible explanation of increase of TBIL. 
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury). 
In the absence of cholestasis, these patients should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc. 


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1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase. 
2. A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected. 
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary 
tract) may be warranted. 
4. Obtain PK sample, as close as possible to last dose of study drug. 
5. Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), 
autoimmune hepatitis or liver biopsy may be considered as clinically indicated or after 
consultation with specialist/hepatologist. 
6. If elevations of total bilirubin precede the elevations of ALT and or AST, monitoring for 
hemolysis. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 8.2.1) and reported as SAE using the term 
“potential drug-induced liver injury”. All events should be followed up with the outcome clearly 
documented. 
 
6.3.1.2 
Dose adjustments for QTcF prolongation 
In case of QTcF >500 msec, (or QTcF prolongation >60 msec from baseline) 
1. Assess the quality of the ECG recording and the QT value and repeat if needed 
2. Interrupt study treatment 
3. Determine the serum electrolyte levels (in particular hypokalemia, hypomagnesemia). If 
abnormal, correct abnormalities before resuming study drug treatment. 
4. Review concomitant medication associated with QT prolongation, including drugs with a 
“Known”, “Possible”, or “Conditional risk of Torsades de Pointes” and drugs with the 
potential to increase the risk of study drug exposure related QT prolongation (See 
Appendix 2) 
5. Check study drug dosing schedule and treatment compliance 
6. Consider collecting a time-matched PK sample and record time and date of last study drug 
intake. 
After confirming ECG reading at site, if QTcF > 500 msec (or QTcF prolongation >60 
msec from baseline) 
• Interrupt study treatment 
• Repeat ECG and confirm ECG diagnosis by a cardiologist or central ECG lab 
• If QTcF confirmed > 500 msec: 
• Correct electrolytes, eliminate culprit concomitant treatments, and identify and 
address clinical conditions that could potentially prolong the QT. 
• Consult with a cardiologist (or qualified specialist) 
• Increase cardiac monitoring as indicated, until the QTcF returns to ≤ 480 msec. 


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• After resolution to ≤ 480 msec, consider re-introducing treatment at reduced dose (for 7.5 
mg/kg only), and increase ECG monitoring for the next treatment(s): 
• If QTcF remains ≤ 500 msec after dose reduction, continue planned ECG monitoring 
during subsequent treatment 
• If QTcF recurs > 500 msec after dose reduction, discontinue patient from trial. 
6.4 
Concomitant medications 
In general, the use of any concomitant medication/therapies deemed necessary for the care of 
the patient is permitted (see Section 6.4.1), except as specifically prohibited (see Section 6.4.2). 
The patient must be told to notify the investigational site about any new medications he/she 
takes within 30 days prior to initial dosing until the completion of end of study (EOS) visit 
(through 105 days after the last dose of study treatment). All medications (including prescription 
drugs, herbal medications/supplements, over the counter (OTC) medication, dietary and vitamin 
supplements) and significant non-drug therapies (including physical therapy and blood 
transfusions) taken or administered within the timeframe defined in the entry criteria until 
completion of the EOS visit must be listed on the Prior and Concomitant medications, Surgical 
and Medical Procedures or Transfusion page of the CRF. 
 
6.4.1 
Permitted concomitant therapy 
Concomitant sickle cell therapy with hydroxyurea or hydroxycarbamide is permitted, provided 
the patient has been prescribed HU/HC consistently over at least the 6 months prior to 
enrollment, as stated in the Inclusion criteria. Erythropoietin-stimulating agents are also 
permitted to manage chronic symptomatic anemia with the same requirement for 6 months prior 
therapy as HU/HC. L-glutamine oral powder (Endari) is also permitted without restriction. 
Aspirin, NSAIDs and prophylactic doses of anticoagulants are permitted, while other anti- 
platelets agents or anticoagulants at doses targeting therapeutic levels are prohibited. 
All FDA-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. 
 
6.4.2 
Permitted concomitant therapy requiring caution and/or action 
Although transfusion of cellular blood products is permitted, it is unclear how such transfusions 
will impact the PK and/or PD of crizanlizumab, 
 
 It should also be 
considered that the administration of products containing immunoglobulins (plasma, IVIG, 
anti-globulins) may also impact the efficacy of crizanlizumab, and optional PK and PD testing 
may also be performed prior to and following administration of such therapies. 
Although Endari, the FDA-approved, version of L-glutamine, is permitted, other over-the- 
counter forms of L-glutamine are discouraged, as are other natural and herbal remedies (e.g. 
EvenFlo and/or products containing dang gui, ligustrum root, ginseng root, white peony, 
corydalis, salvia, copodonosis, poria, jujbe, angelica sinensis, lovage) due the unproven efficacy 
and variable quality and composition of these products. Vitamin and mineral supplements (e.g. 
fish oil, folic acid, L-arginine, L-citrulline, magnesium, riboflavin, vitamin C, vitamin D, 


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vitamin E, and Zinc) are also permitted, though caution is advised when taking amounts 
exceeding 100% of the recommended daily allowance. 
 
6.4.3 
Prohibited concomitant therapy 
As far as possible avoid co-administering drugs with a “Known”, “Possible”, or “Conditional” 
risk of Torsades de Pointes (TdP) as per wwwqtdrugsorg during the course of the study: 
• If concomitant administration of drugs with a “Known risk of Torsades de Pointes” is 
required and cannot be avoided, study drug must be interrupted. Study treatment may only 
be resumed after 5 half-lives (of the QT-prolonging drug) from last dose of the QT 
prolonging drug, and close ECG monitoring is advised. 
• If during the course of the study, concomitant administration of a drug with ¨Possible risk¨ 
or ¨Conditional risk of Torsades de Pointes¨ is required, based on the investigator 
assessment and clinical need, study treatment may be continued under close ECG 
monitoring to ensure patient safety. 
A list of drugs associated with QT prolongation and/or TdP is available online at 
wwwqtdrugsorg. 
The use of other investigational agents is prohibited during the study. In addition, the 
administration of monoclonal antibodies other than crizanlizumab is prohibited, due to the 
theoretical potential for cross-reactivity and/or overlapping toxicities with other monoclonal 
antibodies. If investigational agents or other monoclonal antibodies have been used in the past, 
they must have been discontinued at least 30 days (or 5 half-lives of that agent, whichever is 
greater) prior to Screening. 
Infusion-type reactions were rarely reported in prior studies with crizanlizumab, so prophylaxis 
for such reactions is not recommended. If a patient experiences severe infusion-related reaction, 
study drug should be discontinued and appropriate treatment provided. 
 
6.4.4 
Use of Bisphosphonates (or other concomitant agents) 
Not applicable 
 
6.5 
Subject numbering, treatment assignment or enrolment 
6.5.1 
Subject numbering 
Each patient is identified in the study by a Subject Number (Subject No.) (7 digits), that is 
assigned when the patient is first enrolled for screening and is retained as the primary identifier 
for the patient throughout his/her entire participation in the trial. The Subject No. consists of 
the Center Number (Center No. 4 digits) (as assigned by Novartis to the investigative site) with 
a sequential patient number suffixed to it (3 digits), so that each patient is numbered uniquely 
across the entire database. Upon signing the informed consent form, the patient is assigned to 
the next sequential Subject No. available to the investigator through the Clinical Data 
Management System interface. 


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6.5.2 
Treatment assignment or Enrolment 
The first 45 patients will be assigned to the 5.0 mg/kg crizanlizumab treatment, while the 10 
next enrolled patients will be assigned to the 7.5 mg/kg crizanlizumab treatment (Section 4.1 
and Section 6.1). The assignment of a patient to a particular treatment dose will be confirmed 
by the sponsor based on the actual enrolment. 
 
6.5.3 
Treatment blinding 
This is an open label study. Investigators, patients 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). 
 
6.6 
Study drug preparation and dispensation 
Crizanlizumab will be prepared by a pharmacist or study personnel appropriately trained in the 
preparation of liquids for parenteral administration (use aseptic techniques when preparing the 
study drug solution). Only compatible material tested during compatibility should be used for 
the administration of crizanlizumab. 
Prior to administration, the crizanlizumab admixture should be allowed to warm to room 
temperature by exposure to ambient air. Do not heat thecrizanlizumab admixture in a 
microwave or with any heat source other than ambient air temperature. The crizanlizumab 
study drug product should only be administered via IV infusion including a 0.2μm inline filter 
and must be diluted prior to administration. 
NOTE: DO NOT ADMINISTER THE STUDY DRUG AS AN IV PUSH OR BOLUS 
INJECTION. After administration of study drug (5.0 mg/kg crizanlizumab or 7.5 mg/kg 
crizanlizumab), a 25 mL flush of the IV line will occur. Site personnel should ensure availability 
of at least 25 mL of sterile 0.9% sodium chloride solution (0.9% Sodium Chloride Injection, 
USP) for administration after that of study drug. 
Prepared infusion solution in infusion bag should be used immediately, and must be within 4 
hours of preparation. 
If the selected center for the clinical study is located in US and is USP<797> compliant, the 
preparation and handling of the infusion bags shall comply with the guidance given in the USP 
but is limited to the physico-chemical stability demonstrated as indicated below. 
If the selected center for the clinical study is located in US and is NOT USP<797> compliant, 
from a microbiologic point of view, the ready mixed infusion bag shall be used immediately 
and not be held for longer than four hours at room temperature from the moment the first vial 
is pierced till the start of administration. 
The compounded 0.9% sodium chloride (saline) bag with crizanlizumab should be 
intravenously administered over 30 minutes. It is not necessary to protect the infusion bags from 
light (still direct sun light should be avoided) while study drug is being administered to the 
patient. At the site’s discretion, the crizanlizumab saline bag may be administered via gravity 
feed, a syringe-type pump, or an infusion pump. Following completion of the study drug 


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infusion, at least another 25 mL 0.9% sodium chloride should be administered in order to clear 
the infusion line of drug and ensure all study drug has been administered to the patient. The 
patient should be monitored for one (1) hour following infusion. For more details please refer 
to the [Pharmacist Manual]. 
 
6.6.1 
Study treatment packaging and labeling 
Study treatment, crizanlizumab, will be provided as global clinical open supply and will be 
packed and labeled under the responsibility of Novartis, Drug Supply Management. 
Study treatment labels will comply with the legal requirements of each country and will include 
storage conditions, a unique medication number (corresponding to study treatment and strength) 
or randomization number if appropriate. 
 
Table 6-4 
Packaging and labeling 
Study treatments 
Packaging 
Labeling (and dosing frequency) 
SEG101 
Vials containing 10 mL at a 
concentration of 10 mg/mL 
Labeled as ‘SEG101’ (at Week1 Day1, 
Week3 Day 1, Week 7 Day 1 and at 
Day 1 of every 4-weeks) 
 
 
6.6.2 
Drug supply and storage 
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly (protected from light, refer to the pharmacy manual and labels for more 
detail), and kept in a secured location to which only the investigator and designated site 
personnel have access. Upon receipt, the study treatment should be stored according to the 
instructions specified in the [Pharmacy Manual] and in the [Investigator’s Brochure]. 
 
Table 6-5 
Supply and storage of study treatments 
Study treatments 
Supply 
Storage 
 
SEG101 
Centrally supplied by Novartis 
Refer to study treatment label 
 
 
6.6.3 
Study drug compliance and accountability 
 
6.6.3.1 
Study drug compliance 
Compliance will be assessed by administration of the study treatment under the supervision of 
the investigator or his/her designee and will be verified by determinations of crizanlizumab in 
serum. This information must be captured in the source document and in the Drug 
Accountability Form. 
 
6.6.3.2 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. 
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 


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accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 
 
6.6.3.3 
Handling of other study treatment 
Not applicable. 
 
6.6.4 
Disposal and destruction 
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate 
 
7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. 
No CRF will be used as a source document. 
The table indicates which assessments produce data to be entered into the clinical database (D) 
or remain in source documents only (S) (“Category” column). 
Allowed visit windows are specified as follows: 
• Screening assessments, apart from those listed below, must occur within 35 days prior to 
the enrolment as per Table 7-1. 
• No visit window is allowed Week 1 Day 1 to Week 2 Day 1. And from Week 15 Day 1 to 
Week 16 Day 1 (or following the first week of steady state as specified in Table 7-5). 
• A ±1 days visit window is permitted on assessments Week 3 Day 1, Week 17 Day 1 and 
Week 18 Day 1 
• For all other visits a general ±3 days visit window is permitted on assessments to take into 
account scheduling over public holidays. 
• A + 7 days for the end of post-treatment phase (last infusion + 105 days) is allowed 
Every effort should be made to follow the schedule outlined in Table 7-1. 


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Table 7-1 
Visit evaluation schedule 
 
Category 
Protocol 
Section 
Screening 
phase 
Treatment phase 
End of 
treatmen 
t (EoT) 
Follow 
up 
phase 
Wk1 
Wk1 D2 
Wk1 D4 
Wk2 
Wk3 
Wk7 
WK11 
Wk15 
Wk15 D2 
Wk15 D4 
Wk16 
Wk17 
Wk18 
Wk 
Visit on Day1 of the 
week (unless 
otherwise specified)a 
D-35 to 
19, 
23, 
27, 
31, 
Within 7 
days of 
last 
Last 
infusio 
n + 
D-1 
4qWk 
infusion 
105d 
Screening 
Obtain Study Informed 
Consent 
D 
7.1.2 
X 
Disposition assessment 
Study disposition 
D 
7 
X 
X 
X 
Patient history 
Demography 
D 
7.1.2.3 
X 
Inclusion/exclusion 
criteria 
D 
7.1.2.1 
X 
Medical History 
D 
7.1.2.3 
X 
ECOG performance 
status 
D 
7.2.2.4 
X 
Sickle Cell – Vaso- 
Occlusive Crisis history 
D 
7.1.2.3 
X 
Alcohol history 
D 
7.1.2.3 
X 


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Category 
Protocol 
Section 
Screening 
phase 
Treatment phase 
End of 
treatmen 
t (EoT) 
Follow 
up 
phase 
Wk1 
Wk1 D2 
Wk1 D4 
Wk2 
Wk3 
Wk7 
WK11 
Wk15 
Wk15 D2 
Wk15 D4 
Wk16 
Wk17 
Wk18 
Wk 
Visit on Day1 of the 
week (unless 
otherwise specified)a 
D-35 to 
19, 
23, 
27, 
31, 
Within 7 
days of 
last 
Last 
infusio 
n + 
D-1 
4qWk 
infusion 
105d 
Smoking history 
D 
7.1.2.3 
X 
Drug Screen (drug, 
alcohol)d 
S 
/ 
D 
7.2.2.5 
X 
Physical examination 
Physical examination 
S 
7.2.2.1 
X 
X 
Abbreviated physical 
exam 
S 
7.2.2.1 
X 
X 
X 
X 
X 
X 
Vital signs 
D 
7.2.2.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
D 
7.2.2.3 
X 
Weight 
D 
7.2.2.3 
X 
X 
X 
X 
X 
X 
X 
Laboratory 
assessments 
7.2.2.5 
Hematology 
D 
7.2.2.5.1 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry 
D 
7.2.2.5.2 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
D 
7.2.2.5.4 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
(microscopic or 
macroscopic) 
D 
7.2.2.5.3 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Category 
Protocol 
Section 
Screening 
phase 
Treatment phase 
End of 
treatmen 
t (EoT) 
Follow 
up 
phase 
Wk1 
Wk1 D2 
Wk1 D4 
Wk2 
Wk3 
Wk7 
WK11 
Wk15 
Wk15 D2 
Wk15 D4 
Wk16 
Wk17 
Wk18 
Wk 
Visit on Day1 of the 
week (unless 
otherwise specified)a 
D-35 to 
19, 
23, 
27, 
31, 
Within 7 
days of 
last 
Last 
infusio 
n + 
D-1 
4qWk 
infusion 
105d 
Serum pregnancy test 
S 
7.2.2.5.5 
X 
X 
X 
Urine pregnancy test 
S 
7.2.2.5.5 
X 
X 
X 
X 
X 
X 
Hepatitis testing 
D 
7.2.2.5.6 
X 
HIV test 
D 
7.2.2.5.7 
X 
Efficacy assessments 
7.2.1 
Sickle Cell – Vaso- 
Occlusive Crisis Event 
D 
7.2.1 
Continuous 
Chest x-ray 
D 
7.2.1 
Xe 
Hospitalization 
D 
7.2.1 
Continuous 
Prior/concomitant 
medications – Analgesic 
D 
6.4 
X 
Continuous 
Prior/concomitant 
medications – 
Hydroxyurea 
D 6.4 
X 
Continuous 
Transfusion 
D 
7.2.1 
X 
Continuous 
Employment status and 
sick time 
D 
7.2.1 
X 
X 
X 
X 
X 
X 
X 
X 
Safety assessments 
ECG 
D 
7.2.2.6.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xc 
X 
X 


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Category 
Protocol 
Section 
Screening 
phase 
Treatment phase 
End of 
treatmen 
t (EoT) 
Follow 
up 
phase 
Wk1 
Wk1 D2 
Wk1 D4 
Wk2 
Wk3 
Wk7 
WK11 
Wk15 
Wk15 D2 
Wk15 D4 
Wk16 
Wk17 
Wk18 
Wk 
Visit on Day1 of the 
week (unless 
otherwise specified)a 
D-35 to 
19, 
23, 
27, 
31, 
Within 7 
days of 
last 
Last 
infusio 
n + 
D-1 
4qWk 
infusion 
105d 
Adverse Event/ Serious 
Adverse Event 
D 
8 
X 
Continuous 
Prior/concomitant 
medications 
D 6.4 
X 
Continuous 


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Category 
Protocol 
Section 
Screening 
phase 
Treatment phase 
End of 
treatmen 
t (EoT) 
Follow 
up 
phase 
Visit on Day1 of the 
week (unless 
otherwise specified)a 
D-35 to 
D-1 
Wk1 
Wk1 D2 
Wk1 D4 
Wk2 
Wk3 
Wk7 
WK11 
Wk15 
Wk15 D2 
Wk15 D4 
Wk16 
Wk17 
Wk18 
Wk 
19, 
23, 
27, 
31, 
4qWk 
Within 7 
days of 
last 
infusion 
Last 
infusio 
n + 
105d 
Pharmacokinetics 
PK samplingg 
D 
7.2.3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xc 
X 
Immunogenicity 
Immunogenicity 
sampling 
D 
7.2.3 
X 
X 
X 
X 
X 
Xc 
X 
Study Drug administration 
Crizanlizumab IV 
D 
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, all future visits should be 
rescheduled from the date of the last infusion. 
b Assessments to be done at within 14 days of Week 1 Day 1 dosing, if the screening assessments have been done more than 14 days before Week 1 Day 1.c From 
week 51 will be done every 24 weeks (Wk 75, 99, 123, 147 and 171 (See Table 7-4 and Table 7-5)) 
d Drug results will be captured in database. Blood alcohol screen result will be captured in source 
 
 
 
 


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7.1.1 
Molecular pre-screening 
Not applicable. 
 
7.1.2 
Screening 
After signing the study ICF, the screening assessments will be done within 1 to 35 days prior 
to Week 1 Day 1 (see Table 7-1 for list of assessments to be performed). The investigator will 
obtain consent / assent of patients and/or parents according to local procedures. 
Re-screening of patients is only allowed once per patient if the patient was not enrolled in the 
treatment phase before. In this case a new Subject Number will be assigned to the patient and 
the patient will be identified with this new number for the rest of his/her participation in the 
study. If patient has been enrolled and treated, re-screening of patient is not allowed. 
In case rescreening occurs, all evaluations re-assessed should meet the eligibility criteria. A new 
informed consent form must be signed only if there is an interruption in the patient’s eligibility 
evaluation and the investigator chooses to re-screen the patient following screen failure. If a 
new informed consent form is signed, AEs and medical history will be assessed relative to the 
new informed consent date. 
For laboratory evaluations used to determine eligibility, a repeated evaluation within the 
screening window is permitted for screening results out of the defined range before screen 
failing the patient. If the repeated laboratory result meets the criteria, that result may be used to 
determine eligibility. If the repeated laboratory result does not meet the criteria, the patient will 
be considered a screening failure. For details of assessments, see Table 7-1. 
 
 
 
7.1.2.1 
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. 
Patient 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 assign the patient either to the 5.0 mg/kg or 
7.5 mg/kg treatment group (according to the enrolment chronological order) and will return the 
signed eligibility check form via email to the site. The investigator site will then be allowed to 
assign treatment to the patient. Please refer and comply with detailed guidelines in the 
Eligibility check user guidelines. 
 
7.1.2.2 
Information to be collected on screening failures 
Patients who sign an informed consent but fail to be enrolled (patient 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 
information, informed consent, Inclusion/Exclusion pages and, if applicable, withdrawal of 
informed consent must also be completed for Screen Failure patients. No other data will be 


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entered into the clinical database for patients who are screen failures, unless the patient 
experienced an SAE during the Screening Phase (see Section 8 for SAE reporting details). 
If a screen failure patient 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 patient fails to be enrolled, the Sponsor must be notified within 2 days of the screen fail 
via email that the patient was not enrolled. 
 
7.1.2.3 
Patient demographics and other baseline characteristics 
Subject demographic characteristics, which include age, gender, self-identified race and 
ethnicity, will be collected. 
Background medical information, including Sickle Cell and Vaso –Occlusive Crisis History, 
ECG, relevant and current medical history and alcohol and smoking history will also be 
collected. 
Other baseline characteristics and assessments performed at screening for eligibility are detailed 
in Table 7-1. 
 
7.1.3 
Run-in period 
Not Applicable 
 
7.1.4 
Treatment period 
The first 45 patients will receive crizanlizumab at 5mg/kg on week 1 day 1, week 3 day 1 and 
then every 4 weeks (week 7 day 1, week 11 day 1, etc.). Once 27 patients have evaluable PK 
and PD data (or a total of up to 45 patients are enrolled) at the 5.0 mg/kg dose, 10 additional 
patients will receive crizanlizumab at 7.5 mg/kg on week 1 day 1, week 3 day 1 and then every 
4 weeks. 
All patients will continue to receive study treatment and be followed as per the schedule of 
assessments, as long as patients derive benefit from crizanlizumab until any combination of the 
following will apply to all patients: 
• All patients have died or discontinued from the study 
• Crizanlizumab is commercially available for this patient population, and patients are 
eligible to be prescribed the commercial drug 
• Another clinical study becomes available that can continue to provide crizanlizumab in 
this patient population and all patients ongoing are eligible to be transferred to that clinical 
study. 
Full PK and PD profiles will be collected on week 1 days 1, 2 and 4, on day 1 of weeks 2, 3, 7 
and 11. From week 15 day 1, additional full PK and PD profiles will be collected on days 
1, 2, and 4 of week 15 (or at the time of the fifth infusion), on day 1 of weeks 16, 17, 18 and 
19. 
However, if the dose was interrupted and/or an infusion was delayed before week 15, then 
after 3 consecutive infusions have been given without an interruption of >7 days, the 


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additional full PK and PD profiles will be collected on days 1, 2, 4 of the week of the third 
consecutive infusion, and day 1 of the 4 consecutive weeks following the third infusion). 
Pre-dose PK and PD sampling will be collected prior to each infusion until week 51.
 
 
 
For details of assessments, see Table 7-1 and Table 7-5. 
 
7.1.5 
Discontinuation of study treatment 
Patients may voluntarily discontinue from the study treatment for any reason at any time. If a 
patient decides to discontinue from the study treatment, the investigator should make a 
reas onab l e effort (e.g. telephone, e-mail, letter) to  understand  the  primary reason  for 
this decision and record this information in the patient’s chart and on the appropriate CRF 
pages. They may be considered withdrawn if they state an intention to withdraw, fail to return 
for visits, or become lost to follow-up for any other reason. 
The investigator may discontinue study treatment for a given patient if he/she believes that 
continuation would be detrimental to the patient’s well-being. 
In addition to the mandatory reasons for discontinuation of study treatment listed in Section 6.3, 
study treatment must also be discontinued under the following circumstances: 
• Pregnancy 
• Lactation 
• Death 
• Subject/Guardian decision 
• Adjustments to study treatment due to toxicity that result in treatment discontinuation (see 
Section 6.3) 
• Use of prohibited medication (see Section 6.4). 
• Any other protocol deviation that results in a significant risk to the patient’s safety. 
Patients who discontinue study treatment should NOT be considered withdrawn from the 
study. They should return for the assessments indicated in Section 7.2.1 for an EOT visit and a 
safety Follow-Up visit. If they fail to return for these assessments for unknown reasons, every 
effort (e.g. telephone, email, letter) should be made to contact them as specified in Section 
7.1.6. 
Patients who discontinue study treatment should undergo an End of Treatment (EOT) visit 
followed by a 105 day safety follow-up. At EOT visit, all the assessments as listed in Table 7- 
1 will be performed. If the decision to discontinue the patient occurs at a regularly scheduled 
visit, that visit may serve as the EOT visit rather than having the patient return for an additional 
visit. 
 
7.1.5.1 
Replacement policy 
Not Applicable 


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7.1.6 
Withdrawal of 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 allow further collection of personal data 
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 
communicating 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/sponsor will continue to keep and use collected study information (including any data 
resulting from the analysis of a subject’s samples until their time of withdrawal) according to 
applicable law. 
All biological samples not yet analyzed at the time of withdrawal may still be used for further 
testing/analysis in accordance with the terms of this protocol and of the informed consent form. 
 
7.1.7 
Follow up for safety evaluations 
All patients must have safety evaluations for 5 half-lives (105 days) after the last dose of study 
treatment. Once an AE is detected, investigators are required to follow this AE until its 
resolution or stabilization. Refer to Section 8.1.1 for definitions and reporting of AEs. Patients 
whose treatment is interrupted or discontinued due to an AE, including abnormal laboratory 
value, must be followed until resolution or stabilization of the event, whichever comes first. 
This could include all study assessments appropriate to monitor the event. 
Data collected should be added to the Adverse Events CRF and the Concomitant Medications 
CRF. 
Any SAEs experienced after the 105 day safety evaluation follow-up period should be reported 
to Novartis if the investigator suspects a causal relationship to the study treatment. 
If patients refuse to return for safety evaluation visits or are unable to do so, every effort should 
be made to contact them by telephone to determine their status. Attempts to contact the patient 
should be documented in the source documents (e.g., dates of telephone calls, registered letters, 
etc.). 
 
7.1.8 
Lost to follow-up 
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 


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the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow up should be recorded as such on the appropriate 
CRF. 
 
7.2 
Assessment types 
7.2.1 
Efficacy assessments 
VOC is defined as pain crises (defined as an acute onset of pain for which in the opinion of the 
investigator 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 (ACS), priapism, and hepatic or splenic 
sequestration. 
For purposes of this study, the following detailed definitions will be used to identify each sub- 
type of VOC event: 
1. Uncomplicated pain crisis is defined as an acute episode of pain with no known cause for 
pain other than a vaso-occlusive event; and requiring treatment with a parenteral or oral 
opioids or parenteral NSAIDs; but is NOT classified as an acute chest syndrome, hepatic 
sequestration, splenic sequestration or priapism. The end of an uncomplicated pain crisis 
will be considered the resolution of acute pain, such that residual pain (or absence of any 
pain) is considered to be chronic, and the current pain medication regimen is considered to 
be for this chronic pain. 
2. Acute Chest Syndrome (ACS) is defined on the basis of the finding of a new pulmonary 
infiltrate involving at least one complete lung segment that was consistent with alveolar 
consolidation, but excluding atelectasis (as indicated by chest X-ray). At least one of the 
following additional signs or symptoms needs to be present as well: chest pain, a 
temperature of more than 38.5°C, tachypnea, wheezing or cough. ACS will be considered 
resolved when the patient is no longer hospitalized (unless for reason other than the ACS 
episode) and none of the additional signs or symptoms above are present. 
3. Priapism is defined as an unwanted or painful penile erection lasting at least 30 minutes. 
The end of an acute priapism event will be when the unwanted erection has resolved for at 
least 2 hours. 
4. Hepatic sequestration is defined on the basis of findings of right upper quadrant pain, an 
enlarged liver, and an acute decrease in hemoglobin concentration (e.g. a decrease in 
hemoglobin of ~ 2 g/dL). Acute hepatic sequestration will be considered resolved when 
right upper quadrant pain has returned to baseline (pre-event) levels and hemoglobin has 
been stable for 24 hrs. 
5. Splenic sequestration if defined on the basis of findings of left upper quadrant pain, an 
enlarged spleen, and an acute decrease in hemoglobin concentration (e.g., a decrease in 
hemoglobin of ~ 2 g/dL). Acute splenic sequestration will be considered resolved when 
left upper quadrant pain has returned to baseline (pre-event) levels and hemoglobin has 
been stable for 24 hrs. 


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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 event. Similarly, complications such 
as pulmonary, cardiac, or renal failure are not themselves to be considered crises. If such events 
precipitate VOC, the VOC event will be documented separately. 
For each visit to a medical facility for a pain episode thought to be a VOC, the following 
information must be documented in the eCRF: diagnostic evaluation for the episode, patient 
treatment and management, course, duration of the crisis, and outcome. For patients who are 
treated at medical facilities other than the study site, summary documents (e.g. ER or hospital 
discharge summaries) will need to be obtained. Patients will be issued an investigational study 
participation card that requests this information and can be presented at each medical facility 
visit. 
Patients should be encouraged to contact the Investigator (or surrogate from the site) when they 
believe they are experiencing a VOC that they believe they can manage at home, both for 
treatment guidance and for accurate information may be obtained for the VOC eCRF page. 
VOCs treated at home but not documented by a telephone call within 24 hours of onset will not 
be counted as a VOC, due to concern over the accuracy of patient recall of all relevant details. 
If a patient experiences a VOC surrounding a protocol-scheduled visit day, and the patient 
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. 
Any VOC symptoms occurring within 7 days following the documented resolution of a VOC 
will be counted as part of the prior crisis, and the date for end of VOC will be revised. 
Chest X-Ray must be conducted within the 3 months prior to week 1 day 1 . Chest X-Ray must 
be repeated in case of suspected ACS. 
Transfusion data should be collected from 30 days prior to Screening until the patient EOT visit. 
Patients participating in a chronic transfusion program (pre-planned series of transfusions for 
prophylactic purposes) are not eligible. Episodic transfusion in response to worsened anemia or 
VOC is permitted. 
 
Table 7-2 
Vaso-Occlusion Crisis Assessment Collection Plan 
 
Procedure / Assessment 
collection plan 
Screening/Baseline 
During Treatment/Follow-up 
Chest X-Ray 
Mandated 
If clinically indicated 
Vaso-Occlusion 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 


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Procedure / Assessment 
collection plan 
Screening/Baseline 
During Treatment/Follow-up 
Employment status and sick 
time 
If clinically indicated 
If clinically indicated 
 
7.2.2 
Safety and tolerability 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 adverse events at every visit. For details on AE collection and reporting, refer to Section 
8. 
 
7.2.2.1 
Physical examination 
The physical examination must be performed by the Investigator as scheduled in Table 7-1. 
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
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 patient’s CRF. Significant new findings that begin or worsen 
after informed consent must be recorded on the Adverse Event page of the patient’s CRF. 
 
7.2.2.2 
Vital signs 
Vital signs include blood pressure (supine position preferred when ECG is collected), pulse 
measurement, respiratory rate and body temperature will be measured as specified in Table 7- 
1. 
 
7.2.2.3 
Height and weight 
Height will be measured at screening. 
Body weight (in indoor clothing, but without shoes) will be measured at screening and at all 
visits for which there is a scheduled study drug infusion (for dosing), as specified in Table 7-1. 
 
7.2.2.4 
Performance status 
ECOG performance status scale will be assessed at screening. 


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7.2.2.5 
Laboratory evaluations 
Clinical laboratory analyses (hematology, chemistry, urinalysis, coagulation, hepatitis and HIV 
markers and drug screen) are to be performed centrally unless otherwise noted in Table 7-3 
according to the schedule of assessments and collection plan outlined in Table 7-1. Details on 
the collection, shipment of samples and reporting of results by the central laboratory are 
provided to investigators in the Central Laboratory Manual/Flowchart. Visit windows are 
allowed for all visits (except from Week 1 Day to Week 2 Day 1 and Week 15 Day 1 to Week 
16 Day 1 (or following the first week of steady state) see Section 7.1). 
Novartis must be provided with a copy of the central laboratory’s certification (if applicable), 
and a tabulation of the normal ranges and units of each parameter collected in the eCRF. Any 
changes regarding normal ranges and units for laboratory values assessed during the study must 
be reported via an updated tabulation indicating the new effective date. Additionally, if at any 
time a patient has laboratory parameters obtained from a different (outside) laboratory, Novartis 
must be provided with a copy of the certification and a tabulation of the normal ranges and units 
for this laboratory as well. The investigator is responsible for reviewing all laboratory reports 
for patients in the study and evaluating any abnormalities for clinical significance. 
For assessment of patients’ eligibility for the study, only laboratory results from the 
central laboratory will be used (except in case of re-sampling at Day -14 and the results from 
the central laboratory are not yet available or are partial at time of the first infusion, then 
eligibility may be based on the results from the local laboratory. In such 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 
particular situation, if possible, the blood sample obtained at the same time point should be 
submitted to the central laboratory for analysis in parallel with local analysis. 
The results of the local laboratory will be recorded in the eCRF if any the following criteria are 
met: 
• A treatment decision was made based on the local results, or 
• There are no concomitant central results available, or 
• Local lab results document an AE not reported by the central lab, or 
• Local lab results document an AE where the severity is worse than the one reported by the 
central lab, or 
• Eligibility had to be based on the local lab results due to pending / missing central lab 
results. 
At any time during the study up to safety follow-up, abnormal laboratory parameters which are 
clinically relevant and require an action to be taken with study treatment (e.g., require dose 
modification and/or interruption of study treatment, lead to clinical symptoms or signs, or 
require therapeutic intervention), whether specifically requested in the protocol or not, will be 
recorded on the AE eCRF page. The severity of laboratory data will be graded using the 


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Common Terminology Criteria for Adverse events (CTCAE) version 4.03. Additional analyses 
are left to the discretion of the investigator. 
 
Table 7-3 
Clinical laboratory parameters collection plan 
 
Test Category 
Test Name 
Hematology 
Central: Hematocrit, Hemoglobin, MCH, MCHC, MCV, Hemoglobin 
electrophoresis or HPLC, 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 
Central: Albumin, Alkaline phosphatase, ALT, AST, Lactate dehydrogenase 
(LDH), Bicarbonate, Calcium, Magnesium, Phosphorus, Chloride, Sodium, 
Potassium, Creatinine, Creatine kinase, Direct Bilirubin, Indirect Bilirubin, Total 
Bilirubin, Total Cholesterol, LDL, HDL, Total Protein, Triglycerides, Blood Urea 
Nitrogen (BUN) or Urea, Uric Acid, Amylase, Lipase, Glucose (fasting), 
Creatinine Clearance (eGFR), 
Local: Blood alcohol screen 
Urinalysis 
Local: Macroscopic Panel (Dipstick) will be done locally (Color, Bilirubin, Blood, 
Glucose, Ketones, Leukocytes esterase, Nitrite, pH, Protein, Specific Gravity, 
Urobilinogen) 
Central: Microscopic Panel (Red Blood Cells, White Blood Cells, Casts, 
Crystals, Bacteria, Epithelial cells) performed, if a positive dipstick. 
Central: Urine Drug Screen (Amphetamine, Barbiturate, Benzodiazepine, 
Cannabinoids, Cocaine, Methadone, Phencyclidine, Opiate, Tricyclics, 
Methamphetamine) 
 
Coagulation 
Central: Prothrombin time (PT), International normalized ratio [INR], Partial 
thromboplastin time (PTT) or Activated partial thromboplastin time (APTT) 
Hepatitis markers 
Central: HBV-DNA, HBsAg, HBsAb, HBcAb, HCV RNA-PCR, HCV Ab (at 
Screening only) 
Additional tests 
Central: HIV Ab (at Screening only) 
Pregnancy Test 
Central: Serum pregnancy test (at Screening, EoT and end of safety follow-up 
only), 
Local: urine pregnancy test (before each infusion). 
 
7.2.2.5.1 Hematology 
Hematology tests are to be performed centrally according to the schedule of assessments and 
collection plan outlined in Table 7-1. Detailed hematology panel is described on Table 7-3. 
 
7.2.2.5.2 Chemistry 
Chemistry tests are to be performed centrally (except blood alcohol screen test) according to 
the schedule of assessments and collection plan outlined in Table 7-1. Detailed chemistry panel 
is described on Table 7-3. 


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Glomerular filtration rate (using CKD-EPI formula) will be done centrally: 
 
7.2.2.5.3 Urinalysis 
Macroscopic urinalysis dipstick analysis (WBC, blood, protein and glucose) will be performed 
locally according to the schedule of assessments and collection plan outlined in Table 7-1. 
Detailed urinalysis panel is described on Table 7-3. 
Microscopic analysis will be performed centrally only in case of positive dipstick. 
 
 
 
 
 
 
7.2.2.5.5 Pregnancy and assessments of fertility 
All female subjects of childbearing potential must perform a central serum hCG pregnancy test 
at screening in order to confirm study eligibility, at End of Treatment and at the end of the post 
treatment follow-up 105 days after the last infusion. 
At Week 1 Day 1 prior to receive the dose of crizanlizumab, and before all visits for which there 
is a scheduled study drug infusion, a locally performed urine pregnancy test will be performed. 
Additional pregnancy test can be performed as soon as indicated in case the subject is suspected 
to be pregnant (urine or serum). 
Each pregnancy in a subject on study drug must be reported to the sponsor within 24 hours of 
learning of its occurrence. See Section 8.4 for detailed reporting and follow up procedures. 
 
7.2.2.5.6 Hepatitis markers 
Hepatitis testing will be performed centrally as per Table 7-1. 


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7.2.2.5.7 Additional test 
HIV and Drug screen will be performed centrally as per Table 7-1. 
 
7.2.2.6 
Cardiac assessments 
 
7.2.2.6.1 Electrocardiogram (ECG) 
Standard 12-lead ECGs will be performed (in the supine position) after the patient has been 
resting for 5-10 min prior to each time point indicated in Table 7-4. ECG assessments are to be 
done prior to blood collection sampling. 
When triplicate ECG are required, the individual ECGs should be recorded approximately 2 
minutes apart. 
The QTcF values using Fridericia’s correction (formula is provided below) should be used. 
The mean QTcF value will be calculated from the triplicate ECGs for each patient. Unscheduled 
triplicate ECGs will be performed also in case QTcF ≥500 ms has been observed. 
 
Table 7-4 
Central ECG collection plan 
 
Period 
Week / Day 
Time a 
ECG Type 
Screening 
Day -28 to Day -1 
Anytime 
Triplicate 12 Lead 
Treatment 
Week 1 Day 1 
Pre-dose 
Triplicate 12 Lead 
0.5h post-dose (± 5 min end of 
infusion) 
Triplicate 12 Lead 
1h post-dose (± 5 min) 
Triplicate 12 Lead 
2h post-dose (± 30 min) 
Triplicate 12 Lead 
4h post-dose (± 30 min) 
Triplicate 12 Lead 
6h post-dose (± 30 min) 
Triplicate 12 Lead 
Week 1 Day 2 
24h post-dose (± 2 hr) 
Triplicate 12 Lead 
Week 1 Day 4 
72h post-dose (± 2 hr) 
Triplicate 12 Lead 
Week 2 Day 1 
7d post-dose (± 24 hr) 
Triplicate 12 Lead 
Week 3 Day 1 
Pre-dose b 
Triplicate 12 Lead 
Week 7 Day 1 
Pre-dose b 
Triplicate 12 Lead 
Week 11 Day 1 
Pre-dose b 
Triplicate 12 Lead 
Week 15 Day 1 
Pre-dose b 
Triplicate 12 Lead 
0.5h post-dose (± 5 min end of 
infusion) 
Triplicate 12 Lead 
1h post-dose (± 5 min) 
Triplicate 12 Lead 
2h post-dose (± 30 min) 
Triplicate 12 Lead 
4h post-dose (± 30 min) 
Triplicate 12 Lead 
6h post-dose (± 30 min) 
Triplicate 12 Lead 
Week 15 Day 2 
24h post-dose (± 2 hr) 
Triplicate 12 Lead 
Week 15 Day 4 
72h post-dose (± 2 hr) 
Triplicate 12 Lead 


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Period 
Week / Day 
Time a 
ECG Type 
Week 16 Day 1 
7d post-dose (± 24 hr) 
Triplicate 12 Lead 
Week 17 Day 1 
14d post-dose (± 24 hr) 
Triplicate 12 Lead 
Week 18 Day 1 
21d post-dose (± 24 hr) 
Triplicate 12 Lead 
Week 19 Day 1 
Pre-dose b 
Triplicate 12 Lead 
Week 23 Day 1 
Pre-dose b 
12 Lead 
Week 27 Day 1 
Pre-dose b 
12 Lead 
Week 31 Day 1 
Pre-dose b 
12 Lead 
Week 35 Day 1 
Pre-dose b 
12 Lead 
Week 39 Day 1 
Pre-dose b 
12 Lead 
Week 43 Day 1 
Pre-dose b 
12 Lead 
Week 47 Day 1 
Pre-dose b 
12 Lead 
Week 51 Day 1 
Pre-dose b 
12 Lead 
Week 75 Day 1 
Pre-dose b 
12 Lead 
Week 99 Day 1 
Pre-dose b 
12 Lead 
Week 123 Day 1 
Pre-dose b 
12 Lead 
Week 147 Day 1 
Pre-dose b 
12 Lead 
Week 171 Day 1 
Pre-dose b 
12 Lead 
End of Treatment 
EoT 
Anytime 
12 Lead (triplicate 
12 lead if EoT 
before wk 15) 
Follow-up 
Last dosing + 105 
days 
Anytime 
12 Lead 
Unscheduled 
Anytime 
Triplicate 12 Lead 
a The exact date and time of dosing must be recorded on the appropriate eCRF. The ECG 
assessments must be performed at the same timepoint as the PK timepoint. In case the PK 
timepoints are amended, the same amendment should apply to the ECG assessments. 
b within 24hr before dose administration 
Note: In order to ensure ECG evaluation is received from the central laboratory for eligibility 
assessment, it is advisable to perform the ECG at least 72 hours prior to the scheduled 
enrollment date. 
In the event that a QTcF value of > 470 ms is observed or if an unscheduled ECG is performed 
for safety reasons, it is recommended to collect a time-matched PK sample and record the time 
and date of the last study drug intake to determine the drug exposure (refer to Section 7.2.3). In 
case of QT prolongation, study drug should be discontinued until normalized as described in 
Section 6.3.1.2 
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. Unscheduled ECGs with clinically significant 
findings should be collected in triplicate. Local cardiologist ECG assessment may also be 
performed at any time during the study at the discretion of the investigator. 
All ECGs collected during the study, including unscheduled safety triplicate ECGs with 
clinically relevant findings, should be transmitted to the central core ECG laboratory for review. 
The results of the centrally assessed ECGs are automatically transferred into the clinical 


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database. Any original ECG not transmitted to a central laboratory should be forwarded for 
central review and a copy kept in the source documents at the study site. Interpretation of the 
tracing must be made by a qualified physician and documented on the ECG CRF page. Each 
ECG tracing should be labeled with the study number, patient 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. 
Timing of study procedures: 
 
 
 
 


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7.2.3 
Pharmacokinetics, pharmacodynamics, and immunogenicity 
Serial blood samples will be collected from all patients to assess PK and PD of crizanlizumab. 
Non-compartmental PK and PD parameters will be derived from each individual serum 
concentration- or inhibition-time profile using appropriate methods and software. Refer to 
Section 10.5.4 for a table of PK parameters that will be derived. 
 
 
 
7.2.3.1 
Pharmacokinetic, pharmacodynamic, and immunogenicity blood 
collection and handling 
At specified time points described in Table 7-5, blood samples should be collected from the 
arm opposite from the investigational drug infusion into serum separator tubes. All blood 
samples will be taken by either direct venipuncture or an indwelling cannula inserted in a 
forearm vein. 4.5 mL blood draws should be collected when PK and PD are specified. 8 mL 
blood draws should be collected when PK, PD and inmunogenicity (IG) samples are needed. 
The blood samples will be allowed to clot for approximately 30 minutes at room temperature 
and then centrifuged for 10 minutes at approximately 3000g. Each serum sample will be 
aliquoted, and transferred into freezer-proof polypropylene screw-cap tubes (2 tubes for PK, 2 
tubes for PD and 3 tubes for IG at each specified time points, at least 0.5 mL serum in each 
tube). The serum tubes will be frozen within 90 minutes of venipuncture and kept below -70°C 
in an upright position pending shipment and analysis. 
Each serum samples should be labeled with the appropriate study, center and subject numbers, 
as well as the sequential PK/PD/IG sample and PK/PD/IG collection number with a unique 
sample number. The actual collection date and time of each sample will be entered on the 
PK/PD/IG Blood Collection eCRF pages. 
Refer to the [CSEG101A2202 Laboratory Manual] for detailed instructions for the collection, 
handling, and shipment of samples. 
 
Table 7-5 
Pharmacokinetic, pharmacodynamics and immunogenicity blood 
collection log 
 
Week 
Day 
Scheduled timepoint 
following the 
initiation of infusion 
PK collection 
number/Dose 
reference ID 
PK 
sample 
No 
PD 
sample 
No 
IG 
sample 
No 
Sample 
volume 
(mL) 
1 
1 
Pre-dose 
1 
-- 
1 
101 
201 
8 
1 
1 
0.5h (± 5 min end of 
infusion) 
1 
-- 
2 
-- 
-- 
2.5 
1 
1 
1h (± 5 min) 
1 
-- 
3 
-- 
-- 
2.5 
1 
1 
2h (± 30 min) 
1 
-- 
4 
102 
-- 
4.5 
1 
1 
4h (± 30 min) 
1 
-- 
5 
-- 
-- 
2.5 
1 
1 
6h (± 30 min) 
1 
-- 
6 
-- 
-- 
2.5 
1 
2 
24h (± 2 hr) 
1 
-- 
7 
103 
-- 
4.5 
1 
4 
72h (± 2 hr) 
1 
-- 
8 
104 
-- 
4.5 
2 
1 
8 days (± 24 hr) 
1 
-- 
9 
105 
-- 
4.5 


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Week 
Day 
Scheduled timepoint 
following the 
initiation of infusion 
PK collection 
number/Dose 
reference ID 
PK 
sample 
No 
PD 
sample 
No 
IG 
sample 
No 
Sample 
volume 
(mL) 
3 
1 
Pre-dose (± 24 hrc) 
2 
101a 
10 
106 
202 
8 
7 
1 
Pre-dose (± 24 hrc) 
3 
201a 
11 
107 
203 
8 
11 
1 
Pre-dose (± 24 hrc) 
4 
301a 
12 
108 
204 
8 
15b 
1 
Pre-dose (± 24 hrc) 
5 
401a 
13 
109 
205 
8 
15b 
1 
0.5h (± 5 min end of 
5 
-- 
14 
-- 
-- 
2.5 
infusion) 
15b 
1 
1h (± 5 min) 
5 
-- 
15 
-- 
-- 
2.5 
15b 
1 
2h (± 30 min) 
5 
-- 
16 
110 
-- 
4.5 
15b 
1 
4h (± 30 min) 
5 
-- 
17 
-- 
-- 
2.5 
15b 
1 
6h (± 30 min) 
5 
-- 
18 
-- 
-- 
2.5 
15b 
2 
24h (± 2 hr) 
5 
-- 
19 
111 
-- 
4.5 
15b 
4 
72h (± 2 hr) 
5 
-- 
20 
112 
-- 
4.5 
16b 
1 
8 days (± 24 hr) 
5 
-- 
21 
113 
-- 
4.5 
17b 
1 
15 days (± 24 hr) 
5 
-- 
22 
114 
-- 
4.5 
18b 
1 
22 days (± 24 hr) 
5 
-- 
23 
115 
-- 
4.5 
19b 
1 
Pre-dose c 
6 
501a 
24 
116 
206 
8 
23 
1 
Pre-dose c 
7 
601a 
25 
117 
207 
8 
27 
1 
Pre-dose c 
8 
701a 
26 
118 
208 
8 
31 
1 
Pre-dose c 
9 
801a 
27 
119 
209 
8 
35 
1 
Pre-dose c 
10 
901a 
28 
120 
210 
8 
39 
1 
Pre-dose c 
11 
1001a 
29 
121 
211 
8 
43 
1 
Pre-dose c 
12 
1101a 
30 
122 
212 
8 
47 
1 
Pre-dose c 
13 
1201a 
31 
123 
213 
8 
51 
1 
Pre-dose c 
14 
1301a 
32 
124 
214 
8 
75 
1 
Pre-dose c 
15 
1401a 
33 
215 
6 
99 
1 
Pre-dose c 
16 
1501a 
34 
216 
6 
123 
1 
Pre-dose c 
17 
1601a 
35 
217 
6 
147 
1 
Pre-dose c 
18 
1701a 
36 
218 
6 
171 
1 
Pre-dose c 
19 
1801a 
37 
219 
6 
Follow 
1 
--- 
20 
1901a 
38 
220 
6 
up 
phase 
Unscheduled 
Sampled 
--- 
--- 
1001+ 
2001+ 
3001+ 
8 
a For the PK pre-dose samples (sample number 10-13 and 24-38), the actual date and time of 
administration of the previous dose of study medication should also be recorded with appropriate Dose 
reference IDs as indicated in the above table. 
b Sampling to occur at steady state (week 15). If dose is interrupted and an infusion is delayed before 
week 15, the steady state sampling will occur after the dose has been resumed and 3 consecutive 
infusions have been given without interruption. 
c within 24hr before dose administration. 
 
 
 
 


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7.2.3.2 
Analytical method 
The crizanlizumab PK assay is a target capture ELISA to determine the concentration of 
crizanlizumab remaining in serum samples. Concentrations below the lower limit of 
quantification will be reported as 0.00 ng/mL and missing samples will be labeled accordingly. 
A pharmacodynamic marker of crizanlizumab is the ex vivo P-selectin inhibition measured by 
a surface plasmon resonance assay using human serum samples. Crizanlizumab in serum 
samples binds to spiked Psel-Ig (P-selectin coupled to Ig) and inhibits its binding to a PSGL1 
peptide. 
Immunogenicity determination will be performed using a bridging immunoassay format 
validated for Immunogenicity screening in human serum samples. 
Details of each analytical method will be given in bioanalytical data reports. 
 


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7.2.5 
Resource utilization 
Not applicable. 
 
7.2.6 
Patient reported outcomes 
Not applicable. 
 
8 
Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained. 
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s). 
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. Adverse event monitoring should 
be continued for at least 105 days (5 half-lives of crizanlizumab) following the last dose of 
study treatment. Adverse events (including lab abnormalities that constitute AEs) should be 
described using a diagnosis whenever possible, rather than individual underlying signs and 
symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be 
reported as a separate Adverse Event. 
Adverse events will be assessed and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, death related to the AE corresponding respectively to Grades 1 - 5, will be 


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used. Information about any deaths (related to an Adverse Event or not) will also be collected 
though a Death form. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
during the screening process after signing informed consent and at each visit during the study. 
Adverse events also may be detected when they are volunteered by the patient during the 
screening process or between visits, or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine: 
• The severity grade (CTCAE Grade 1-5) 
• Its duration (Start and end dates) 
• Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) 
• Action taken with respect to study or investigational treatment (none, dose adjusted for the 
7.5 mg/kg dosage only, temporarily interrupted, permanently discontinued, unknown, not 
applicable) 
• Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
• Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1 
and which seriousness criteria have been met 
• Outcome (not recovered/not resolved, recovered/resolved, recovered/resolved with 
sequelae, 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 adverse events only, if improvement to a 
lower grade is determined a new entry for this event should be reported in the CRF noting the 
start date when the event improved from having been Grade 3 or Grade 4. 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome. 
 
8.1.1.1 
Protocol Exempt AEs & SAEs 
Protocol Exempt AEs & SAEs are implemented in the SEG101 program. VOCs must be 
reported on the VOC page in the eCRF. 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 
regards to reporting requirements.Vaso-occlusive crisis (including fatal outcomes), if 
documented by use of appropriate method and in accordance with the definition described in 
Section 7.2.1 of this protocol will not be reported as a serious adverse event to Novartis 
according to the requirements in Section 8.2 of this protocol. In case that new information arises 
which changes the diagnosis of a VOC, i.e. gives another medically determined explanation 


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than vaso-occlusion in the opinion of the investigator, the event has to be reported according to 
the rules of Section 8.1 and Section 8.2 and must be reported to Novartis within 24 hours of 
learning of the new information. 
The events in Table 8-1 are the VOCs that will not be reported as AEs/SAEs. 
 
Table 8-1 
List of VOC Events Not Requiring AE/SAE Reporting 
 
VOC Event 
Uncomplicated sickle cell-related pain crisis (SCPC) or vaso-occlusive crisis (VOC)* 
Acute chest syndrome 
Hepatic sequestration 
Splenic sequestration 
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 (ACS), priapism, and hepatic or splenic sequestration. 
 
8.1.2 
Laboratory test abnormalities 
 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events CRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such. 
 
8.1.3 
Adverse events of special interest 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may be 
appropriate. Such events may require further investigation in order to characterize and 
understand them. 


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Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. 
 
8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Note: fatal or life-threatening VOCs are not considered an SAE and should be recorded on 
the appropriate VOC eCRF page 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Note that hospitalizations for the following reasons should not be reported as serious 
adverse events: 
• Vaso-occlusive crisis as defined in the protocol 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event 
 
8.2.2 
Reporting 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 105 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
Any additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes must be reported as follow-up to the original episode within 24 hours of 
the investigator receiving the follow-up information. An SAE occurring at a different time 
interval or otherwise considered completely unrelated to a previously reported one should be 
reported separately as a new event. 
Any SAEs experienced after the 105 day safety evaluation follow-up period should only be 
reported to Novartis if the investigator suspects a causal relationship to the study treatment. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 


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thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site. 
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 patient continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure and is thought to be 
related to the Novartis study treatment, an oncology Novartis Chief Medical Office and Patient 
Safety (CMO&PS) department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN), to inform all investigators involved in any study with the same drug that this 
SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be 
collected and reported to the competent authorities and relevant ethics committees in 
accordance with Directive 2001/20/EC or as per national regulatory requirements in 
participating countries. 
 
8.3 
Emergency unblinding of treatment assignment 
Not applicable. 
 
8.4 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Chief Medical Office and Patient Safety (CMO&PS). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form. 
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. 
 
8.5 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 


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8.6 
Data Monitoring Committee 
Not applicable. 
 
8.7 
Steering Committee 
Not applicable. 
 
9 
Data collection and management 
9.1 
Data confidentiality 
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened AEs) at the end of their scheduled study period. 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training. 
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results. 
 
9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol 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. 


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The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria and documentation 
of SAEs. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. 
 
9.3 
Data collection 
The 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 and, allow modification or verification of the entered 
data by the investigator staff. 
The investigator must certify that the data entered into the eCase Report Form is complete and 
accurate, and that entry and updates are performed in a timely manner. 
For PK, PD 
 samples, information about Treatment Periods, Visits, time points, 
and date and time of sample collection will be recorded on the eCRFs and also on the requisition 
forms sent to Central labs. A reconciliation of information regarding subjects and samples 
between the eCRF database and the lab database will be carried out by designated Novartis 
personnel (or designated CRO). 
 
9.4 
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 adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
Any samples or data to be analyzed centrally (PK, PD, 
 central laboratory, central 
ECG reading) will be processed centrally and the results will be sent electronically to Novartis 
(or a designated CRO). 
At the conclusion of the study, the occurrence of any protocol violations will be determined. 
After these actions have been completed and the data has been verified to be complete and 


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accurate, the database will be declared locked and made available for data analysis. 
Authorization is required prior to making any database changes to locked data, by joint written 
agreement between the Global Head of Biostatistics, the Global Head of Data Management and 
the Global Head of Clinical Development. 
After database lock, the investigator will receive copies of the patient data for archiving at the 
investigational site. 
 
10 
Statistical methods and data analysis 
The analysis of study data for the primary clinical study report (CSR) will be based on all patient 
data up to the time after the primary PK and PD parameters are available for at least 27 patients 
for 5.0 mg/kg treatment group in the PAS1 and PDS1 respectively, or a total of 45 patients have 
been enrolled in the 5.0 mg/kg treatment group, whichever occurs first. 
The additional data for any patients continuing to receive study drug past this time, as allowed 
by the protocol, will be further summarized in a final study report once these patients have 
completed or discontinued the study. 
 
10.1 
Analysis sets 
10.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients to whom study treatment has been assigned 
and who received at least one dose of study treatment. Patients will be analyzed according to 
the crizanlizumab dose (5.0 mg/kg or 7.5 mg/kg) they have been assigned to. 
 
10.1.2 
Safety set 
The Safety Set includes all patients who received at least one dose of study treatment. Patients 
will be analyzed according to the dose level received (5.0 mg/kg or 7.5 mg/kg), where dose 
level received is defined as the assigned dose level if the patient took at least one dose of that 
treatment or the first dose received if the assigned dose level was never received. 
 
10.1.3 
Pharmacokinetic analysis set 
The Pharmacokinetic analysis set 1 (PAS1) includes all patients who provide at least one 
evaluable PK profile. A profile is considered evaluable if all of the following conditions are 
satisfied: 
• Patient receives the planned treatment of 5.0 mg/kg or 7.5 mg/kg before single dose PK 
profile or 3 consecutive doses of the planned treatment before the multiple dose PK profile 
• Patient provides at least one primary PK parameter 
• Patient does not have any transfusion of blood product in the last 4 weeks before the first 
PK sample of the full PK profile, or during the full PK profile 
The Pharmacokinetic analysis set 2 (PAS2) includes all patients who receive at least one 
planned treatment of 5.0 mg/kg or 7.5 mg/kg and provide at least one corresponding evaluable 
PK concentration. 


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10.1.4 
Other analysis sets 
 
10.1.4.1 Pharmacodynamics analysis set 
The pharmacodynamics analysis set 1 (PDS1) includes all patients who provide at least one 
evaluable PD profile. A profile is considered evaluable if all of the following conditions are 
satisfied: 
• Patient receives the planned treatment of 5.0 mg/kg or 7.5 mg/kg before single dose PD 
profile or 3 consecutive doses of the planned treatment before the multiple dose PD profile 
• Patients provides at least one PD-AUC (single dose or multiple dose) parameter 
• Patient does not have any transfusion of blood product in the last 4 weeks before the first 
PD sample of the full PD profile, or during the full PD profile 
The pharmacodynamics analysis set 2 (PDS2) includes all patients who receive at least one 
planned treatment of 5.0 mg/kg or 7.5 mg/kg and provide at least one corresponding evaluable 
PD assessment. 
 
10.1.4.2 Pharmacokinetic-Pharmacodynamics analysis set 
The pharmacokinetic-pharmacodynamics analysis set (PKPDS) includes all patients in the 
Safety set who have at least one trough concentration or one p-selectin inhibition. 
 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data will be listed and summarized descriptively by treatment 
group for all patients for the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. 
Relevant medical histories will be summarized by system organ class and preferred term. 
 
10.3 
Treatments (study treatment, concomitant therapies, 
compliance) 
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, minimum, 
and maximum will be presented. 
The duration of exposure in days 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 patients with dose adjustments (interruption or permanent discontinuation) and 
the reasons will be summarized for all patients by treatment group and all dosing data will be 
listed. 


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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 patients. 
 
10.4 
Primary objective 
The primary objective is to characterize the PK and PD of crizanlizumab at 5.0 mg/kg in adult 
SCD patients. 
 
10.4.1 
Variables 
The primary variables of the study are the PK and PD parameters after single dose and after 
multiple doses. 
 
Primary PK parameters: 
• AUCd15, AUCtau, Cmax 
The remaining PK parameters will be analyzed as secondary variables. 
 
PD parameters of crizanlizumab 
• PD-AUCd15 after single dose 
• PD-AUCd29 after multiple doses 
10.4.2 
Statistical hypothesis, model, and method of analysis 
The inter-subject variations and CV% will be presented for the primary PK parameters. The 
point estimate and the corresponding two-sided 90% confidence interval (CI) for the mean of 
the log-transformed primary PK parameters after single dose and multiple doses will be derived 
respectively. The point estimate and CI will be anti-log transformed to obtain the point estimate 
and the 90% confidence interval for the geometric mean on the original scale. 
The descriptive statistics (n, mean, CV%, standard deviation (SD), median, geometric mean, 
geometric CV%, minimum and maximum) will be presented for all PK parameters defined in 
Table 10-1 except Tmax, where only n, median, minimum and maximum will be presented. 
 
Table 10-1 
Non compartmental pharmacokinetic parameters 
 
AUCd15 
The AUC from time zero to the last measurable concentration sampling time (tlast) 
(mass x time x volume-1) after single dose 
AUCtau 
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x 
time x volume-1) 
Cmax 
The maximum (peak) observed serum drug concentration after dose administration 
(mass x volume-1) 
Tmax 
The time to reach maximum (peak) serum drug concentration after dose 
administration (time) 
Lambda_z 
Smallest (slowest) disposition (hybrid) rate constant (time-1) 
T1/2 
The half-life during a dose interval (time) 
The PAS1 for 5.0 mg/kg treatment group will be used for all PK analyses described above. 


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Descriptive statistics for crizanlizumab concentration will be presented at each scheduled 
timepoint. 
All individual concentration-time profiles for crizanlizumab with median will be displayed 
graphically on semi-log view after single and multiple doses respectively. In addition, the mean 
(+/- SD) and geometric mean concentration-time profiles over time will be displayed 
graphically on the linear and semi-log view. 
All individual PK parameters and PK concentration data for crizanlizumab will be listed. 
All individual pre-dose concentrations for crizanlizumab with median will be displayed 
graphically on semi-log view over time. In addition, the mean (+/- SD) and geometric mean 
pre-dose concentrations over time will be displayed graphically on the linear and semi-log view. 
The PAS2 for 5.0 mg/kg treatment group will be used for these PK analyses. 
PD-AUCd15 and PD-AUCd29 will be derived from the P-selectin inhibition data of week 1 and 
week 15, respectively. The point estimate and the corresponding two-sided 90% CI for the mean 
of the log-transformed PD-AUC after single dose and multiple doses will also be provided. The 
point estimate and CI will be anti-log transformed to obtain the point estimate and the 90% 
confidence interval for the geometric mean on the original scale. 
The PDS1 for 5.0 mg/kg treatment group will be used for all PD analyses described above. 
Descriptive statistics for PD inhibition will be presented at each scheduled timepoint. 
All individual PD-time profiles with median will be displayed graphically on semi-log view 
after single and multiple doses respectively. In addition, the mean (+/- SD) and geometric mean 
PD-time profiles over time will be displayed graphically on the linear and semi-log view. 
All individual PD parameters and PD data will be listed. 
Median pre-dose inhibition will be displayed graphically on semi-log view over time. In 
addition, the mean (+/- SD) and geometric mean pre-dose inhibition over time will be displayed 
graphically on the linear and semi-log view. 
The PDS2 for 5.0 mg/kg treatment group will be used for these PD analyses. 
 
10.4.3 
Handling of missing values/censoring/discontinuations 
Missing values for any PK parameters or concentrations will not be imputed and will be treated 
as missing. 
Below the limit of quantitation (BLQ) values will be set to zero by the Bioanalyst, and will be 
displayed in the listings as zero and flagged. BLQ values will be treated as missing for the 
calculation of the geometric means and geometric CV%. 
Missing values for the PD parameter or data will not be imputed and will be treated as missing. 
 
10.4.4 
Supportive and Sensitivity analyses 
Details will be provided in the Statistical Analysis Plan. 


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10.5 
Secondary objectives 
The secondary objectives in this study are to assess the efficacy, safety and tolerability of 
crizanlizumab at 5.0 mg/kg and 7.5 mg/kg in SCD patients. The FAS will be used for all 
analyses. 
 
10.5.1 
Key secondary objective(s) 
Not applicable. 
 
10.5.2 
Other secondary efficacy objectives 
The following endpoints will be summarized descriptively by treatment group. 
• Annualized rate of VOC events leading to healthcare visit in clinic/ER/hospital 
• Annualized rate of VOC events treated at home, based on documentation by health care 
provider following phone contact with patient 
• Annualized rate of all VOC events (including both healthcare visit and home treatment) 
• Annualized rate of each subcategory of VOC event (uncomplicated pain crisis, acute chest 
syndrome, hepatic sequestration, splenic sequestration, priapism) 
• Annualized rate of hospitalizations and ER visits (both overall and VOC-related) 
• Annualized days of hospitalizations and ER visits (both overall and VOC-related) 
10.5.3 
Safety objectives 
 
10.5.3.1 Analysis set and grouping for the analyses 
For all safety analyses, the safety set will be used. All safety data will be summarized by 
treatment group. 
The overall observation period will be divided into three mutually exclusive segments: 
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication 
2. on-treatment period: from day of first dose of study medication to 105 days after last dose 
of study medication 
3. post-treatment period: starting at day 106 after last dose of study medication. 
 
10.5.3.2 Adverse events (AEs) 
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment by treatment group. 
Serious adverse events, non-serious adverse events and adverse events of special interest (AESI) 
during the on-treatment period will be tabulated. 
All deaths (on-treatment and post-treatment) will be summarized. 


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All AEs, deaths and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged. 
 
10.5.3.3 Laboratory abnormalities 
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
For laboratory tests where grades are not defined by CTCAE v4.03, results will be categorized 
as low/normal/high based on laboratory normal ranges. 
The following summaries will be generated separately for hematology and biochemistry tests 
by treatment group: 
• Listing of all laboratory data with values flagged to show the corresponding CTCAE 
v4.03 grades if applicable and the classifications relative to the laboratory normal ranges 
For laboratory tests where grades are defined by CTCAE v4.03 
• Worst post-baseline CTCAE grade (regardless of the baseline status). Each patient will be 
counted only once for the worst grade observed post-baseline. 
• Shift tables using CTCAE v4.03 grades to compare baseline to the worst on-treatment 
value 
For laboratory tests where grades are not defined by CTCAE v4.03, 
• Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value. 
In addition to the above mentioned tables and listings, other 
 analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots might 
be specified in the analysis plan. 
10.5.3.4 Other safety data 
ECG 
12 lead ECGs including PR, QRS, QT, QTcF and HR intervals will be obtained centrally for 
each patient during the study. ECG data will be read and interpreted centrally. 
The number and percentage of patients with notable ECG values will be presented. In addition, 
a listing of these patients will be produced. 
 
Vital signs 
Data on vital signs will be tabulated and listed, notable values will be flagged. 


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10.5.3.5 Supportive analyses for secondary objectives 
Any supportive analyses that are considered appropriate for secondary variables will be 
described in the SAP prior to DBL. 
 
10.5.3.6 Tolerability 
Tolerability of study drug treatment will be assessed by summarizing the number of treatment 
dose interruptions. Reasons for dose interruption will be listed by patient and summarized by 
treatment group. 
 
10.5.4 
Pharmacokinetics 
Please refer to Section 10.4. 
 
 
 
 
 
10.5.6 
Resource utilization 
Not applicable. 
 
10.5.7 
Patient-reported outcomes 
Not applicable. 
 
10.5.8 
Immunogenicity 
Immunogenicity will be characterized descriptively tabulating antidrug antibodies (ADA) 
prevalence at baseline and ADA incidence on-treatment. 
 


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10.7 
Interim analysis 
An interim analysis may be performed when there are at least 27 patients with single dose 
evaluable PK profiles and approximately 5 patients with both single dose and multiple dose 
evaluable PK profiles in the PAS1 for 5.0 mg/kg treatment group. Point estimate and 90% 
confidence intervals for the primary PK parameters will be calculated. PopPK modeling will be 
performed. Another interim analysis may be performed when there are approximately 15 
patients with multiple dose evaluable PK profiles in the 5.0 mg/kg treatment group in the PAS1. 
Should the criteria for the two interim analyses be reached at similar times compatible with both 
objectives, a single combined interim analysis will be performed. Additional earlier or later ad 
hoc interim analyses of PK/PD/safety may be performed in order to support potential health 
authority requests. 
 
10.8 
Sample size calculation 
5.0 mg/kg treatment group: 
For sample size consideration, PK and PD data from Study CSEG101A2101 and study 
CSEG101A2201 were used. Currently, the inter-subject variability of PK parameters, such as 
AUC and Cmax, of VOC patients is not known and needs to be approximated from the Ctrough 
results of patient study A2201. In that study the inter-subject variability of Ctrough was found 
to be 50.8%. 
Data of study A2101 has revealed a high correlation between PK concentrations 336h post-dose 
and AUCt. Assuming this correlation holds true for patients together with the assumption of an 


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inter-subject CV = 50.8% of pre-dose concentrations allows an approximation of expected inter- 
subject CV = 46.1% for AUCt. 
Currently, the inter-subject variation of the P-Selectin inhibition at 5.0 mg/kg and the respective 
PDAUC672hr is not known. However, approximations utilizing results from lower dose groups 
tested in study CSEG101A2101 suggest an inter-subject coefficient of variation of 
approximately CV = 34.1%. 
When the sample size is 27 evaluable patients, a two-sided 90% confidence interval for a single 
mean of log-transformed AUC will extend 0.140 from the observed mean, ensuring a precision 
of 15%, assuming that the standard deviation is known to be 0.439 and the confidence interval 
is based on the large sample z statistic. 
Similarly, with the same sample size of 27 evaluable patients, a two-sided 90% confidence 
interval for a single mean of log-transformed PD-AUC will extend 0.105 from the observed 
mean, representing a precision of about 11%, assuming that the standard deviation is known to 
be 0.332 and the confidence interval is based on the large sample z statistic. 
After the start of trial A2202, new information was made available through the single dose HV 
study CSEG101A2102, in which PK variability for SEG101 was lower than for SelG1. Using 
the same process as described above, but this time starting from the CV% in A2102 SEG101 
rather than A2101 SelG1, leads to the CV% for AUCt in patients being projected to be 34.7%, 
instead of 46.1%. 
With such assumption for a lower CV%, a smaller sample size of 15 patients would be sufficient 
to ensure the same precision as originally expected with 27 evaluable patients: with 15 evaluable 
patients, a two-sided 90% confidence interval for a single mean of log-transformed AUC will 
extend 0.143 from the observed mean, still ensuring a precision of 15%, assuming that the 
standard deviation is known to be 0.3369 and the confidence interval is based on the large 
sample z statistic. 
However, considering the uncertainties around variability estimations (projected based on a 
single-dose HV study rather than directly observed in a multiple-dose patient study), the sample 
size of 27 for the primary analysis is maintained and an interim analysis will be conducted on 
15 evaluable patients. 
Exploratory 7.5 mg/kg treatment group: 
When the sample size for this dose group is 6, a two-sided 90% confidence interval for a single 
mean will extend 0.172 from the observed mean, assuming that the standard deviation is known 
to be 0.209 and the confidence interval is based on t-statistic. 
Considering a drop-out rate of 35% from the CSEG101A2201 study, and to account for the 
heterogeneity of patients in terms of genotype and renal function, the multiplication factor for 
enrollment versus evaluable patients is 67%, and 45 patients will need to be enrolled in the 5.0 
mg/kg treatment group. The same holds for the exploratory cohort, requiring enrollment of 10 
patients to yield 6 evaluable patients at the 7.5 mg/kg dose. 
 
10.9 
Power for analysis of key secondary variables 
Not applicable. 


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11 
Ethical considerations and administrative procedures 
11.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki. 
 
11.2 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required. 
 
11.3 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent 
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a subject’s Informed Consent was 
actually obtained will be captured in their CRFs. 
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval. 
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
 


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11.4 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 4.4. 
 
11.5 
Publication of study protocol and results 
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g. wwwclinicaltrials.gov before study start. 
In addition, results of interventional clinical trials in adult patients are posted on 
wwwnovartisclinicaltrials.com, a publicly accessible database of clinical study results within 1 
year of study completion (i.e., LPLV), those for interventional clinical trials involving pediatric 
patients within 6 months of study completion. 
Novartis follows the ICMJE authorship guidelines (wwwicmje.org) and other specific 
guidelines of the journal or congress to which the publication will be submitted 
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations. 
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable. 
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to wwwnovartiscom. 
 
11.6 
Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 


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at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines. 
 
11.7 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site. 
 
11.8 
Audits and inspections 
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities. 
 
11.9 
Financial disclosures 
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start. 
 
12 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR. 


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12.1 
Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such cases, 
Novartis should be notified of this action and the IRB/IEC at the study site should be informed 
according to local regulations (e.g. UK requires the notification of urgent safety measures 
within 3 days) but not later than 10 working days. 


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13 
References (available upon request) 
Ashley-Koch A, Yang Q, and Olney RS (2000) Sickle hemoglobin (HbS) allele and sickle cell 
disease: a HuGE review. Am J Epidemiol; 151(9):839-45. 
Ataga KI, Kutlar A, Kanter J (2017) Crizanlizumab for the Prevention of Pain Crises in Sickle 
Cell Disease. N Engl J Med; 376 (5): 429-439. 
Bookchin RM and VL Lew (1996) Pathophysiology of sickle cell anemia. Hematol Oncol 
Clin North Am; 10(6):1241-53. 
Charache S (1996) Eye disease in sickling disorders. Hematol Oncol Clin North Am; 
10(6):1357-62. 
Chiang EY and Frenette PS (2005) Sickle cell vaso-occlusion. Hematol Oncol Clin North 
Am; 19(5):771-84 v. 
Dall'Acqua, W.F., et al (2002) Increasing the affinity of a human IgG1 for the neonatal Fc 
receptor: biological consequences. J Immunol; 169(9): 5171-80. 
Embury SH (2004) The not-so-simple process of sickle cell vaso-occlusion. Microcirculation; 
11(2):101-13. 
Frenette PS (2004) Sickle Cell Vaso-occlusion: Heterotypic, Multicellular Aggregations 
Driven by Leukocyte Adhesion. Microcirculation; 11(2): 167-177. 
Geng JG, Bevilacqua MP, Moore KL, et al (1990) Rapid neutrophil adhesion to activated 
endothelium mediated by GMP-140. Nature; 343(6260):757-60. 
Gill FM, Sleeper LA, Weiner SJ, et al (1995) Clinical events in the first decade in a cohort of 
infants with sickle cell disease. Cooperative Study of Sickle Cell Disease. Blood; 86 (2): 776- 
83. 
Gladwin MT, Sachdev V, Jison ML, et al (2004) Pulmonary hypertension as a risk factor for 
death in patients with sickle cell disease. N Engl J Med; 350(9): 886-95. 
Gladwin MT and Kato GJ (2005) Cardiopulmonary complications of sickle cell disease: role 
of nitric oxide and hemolytic anemia. Hematology Am Soc Hematol Educ Program: 51-7. 
Hamburger SA, McEver RP (1990) GMP-140 mediates adhesion of stimulated platelets to 
neutrophils. Blood. 75(3): p. 550-4. 
Heegaard ED and KE Brown (2002) Human parvovirus 819. Clin Microbial Rev; 15(3):485- 
505. 
Hirschberg R (2010) Glomerular Hyperfiltration in Sickle Cell Disease. Clin J Am Soc 
Nephrol; 5:748-9. 
Jones DA, Abbassi O, McIntire LV, et al (1993) P-selectin mediates neutrophil rolling on 
histamine- stimulated endothelial cells. Biophys J; 65(4): p. 1560-9. 
Kaul DK and Hebbel RP (2000) Hypoxia/reoxygenation causes inflammatory response in 
transgenic sickle mice but not in normal mice. J Clin Invest; 106(3):411-20. 
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): p. 2975-87. 
Maitre B, Habibi A, Roudot-Thoraval F, et al (2000) Acute chest syndrome in adults with 
sickle cell disease. Chest; 117(5):1386-92. 


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Matsui NM, Borsig L, Rosen SD, et al (2001) P-selectin mediates the adhesion of sickle 
erythrocytes to the endothelium. Blood; 98(6):1955-62. 
McEver, R.P., K.L. Moore, and R.D. Cummings (1995) Leukocyte trafficking mediated by 
selectincarbohydrate interactions. J Biol Chem; 270(19): 11025-8. 
McEver, R.P. (2004) Interactions of selectins with PSGL-1 and other ligands. Ernst Schering 
Res Found Workshop; (44): 137-47. 
McClish DK, Penberthy LT, Bovbjerg VE, et al. (2005) Health related quality of life in sickle 
cell patients: The PiSCES project. Health and Quality of Life Outcomes; 3: 50. 
Mehta, P., R.D. Cummings, and R.P. McEver (1998) Affinity and kinetic analysis of P- 
selectin binding to P-selectin glycoprotein ligand-1. J Biol Chem; 273(49): 32506-13. 
NHBLI Available from: http//wwwnhlbi.nih.gov/health/dci/Diseases/Sca/. 
NHLBI (2002) The Management of Sickle Cell Disease. NIH Publication No.022117. 
Nietert PJ, Silverstein MD, and Abboud MR (2002) Sickle cell anaemia: epidemiology and 
cost of illness. Pharmacoeconomics; 20(6):357-66. 
NIH (2008) Hydroxyurea Treatment for Sickle Cell Disease February 25-27 2008. National 
Institutes of Health Consensus Development Conference Statement February 2008, 2008. 
NIH (2008) NIH State-of-the-Science Conference Statement on Hydroxyurea Treatment for 
Sickle Cell Disease. NIH Consensus and State-of -the Science Statements; February 25-27, 
2008. Vol. 25. 
Okpala I (2006) Leukocyte adhesion and the pathophysiology of sickle cell disease. Curr Opin 
Hematol; 13(1):40-4. 
Platt OS, Brambilla DJ, Rosse WF, et al (1994) Mortality in sickle cell disease. Life 
expectancy and risk factors for early death. N Engl J Med; 330(23):1639-44. 
Platt OS (2006) Prevention and management of stroke in sickle cell anemia. Hematology Am 
Soc Hematol Educ Program; 2006:54-7. 
Saborio P and Scheinman JI (1999) Sickle cell nephropathy. J Am Soc Nephrol; 10(1):187-92. 
Sickle Cell Disease Guideline Panel. (1993) Sickle Cell Disease: Screening, Diagnosis, 
Management and Counseling in Newborns and Infants. Clinical Practice Guideline No. 6. 
AHCPR Pub. No. 93 0562. Rockville, MD: Agency for Health Care Policy and Research, 
Public Health Service, U. S. Department of Health and Human Services. April 1993. 
Smith JA (1996) Bone disorders in sickle cell disease. Hematol Oncol Clin North Am; 
10(6):1345-56. 
Springer, T.A (1995) Traffic signals on endothelium for lymphocyte recirculation and 
leukocyte emigration. Annu Rev Physiol; 57: 827-72. 
Thomas PW, Higgs DR, and Serjeant GR (1997) Benign clinical course in homozygous sickle 
cell disease: a search for predictors. J Clin Epidemiol; 50(2):121-6. 
Vestweber, D. and J.E. Blanks (1999) Mechanisms that regulate the function of the selectins 
and their ligands. Physiol Rev; 79(1): 181-213. 


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Vichinsky EP, Neumayr LD, Earles AN, et al (2000) Causes and outcomes of the acute chest 
syndrome in sickle cell disease. National Acute Chest Syndrome Study Group. N Eng J Med; 
342(25):1855-65. 
Wagner MC, Eckman JR, and Wick TM (2006) Histamine increases sickle erythrocyte 
adherence to endothelium. Br J Haematol. 132(4): p. 512-22. 
Wethers, DL (2000) Sickle cell disease in childhood: Part II. Diagnosis and treatment of major 
complications and recent advances in treatment. Am Fam Physician; 62(6):1309-14. 
Wood, K., Russell J, Hebbel RP, et al (2004) Differential expression of E- and P-selectin in 
the microvasculature of sickle cell transgenic mice. Microcirculation. 11(4): p. 377-85. 
Yale SH, Nagib N, and Guthrie T (2000) Approach to the vaso-occlusive crisis in adults with 
sickle cell disease. Am Fam Physician; 61(5):1349-56, 1363-4. 
http//wwwaafporg/afp/2000/0301/p1349.html. 


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14 
Appendices 
14.1 
Appendix 1 – List of prohibited CYP3A inhibitors and inducers 
The list of prohibited CYP3A inhibitors and inducers is provided in Table 14-1 (this list may 
not be comprehensive). 
 
Table 14-1 
List of prohibited CYP3A inhibitors and inducers 
 
Strong CYP3A 
inhibitors 
Moderate CYP3A 
inhibitors 
Strong CYP3A 
inducers 
Moderate CYP3A 
inducers 
clarithromycin 
amprenavir 
carbamazepine * 
felbamate * 
conivaptan 
aprepitant 
phenobarbital * 
topiramate * (>200 mg/day) 
indinavir 
atazanavir 
phenytoin * 
oxcarbazepin * 
itraconazole 
cimetidine 
fosphenytoin * 
eslicarbazepin * 
ketoconazole 
ciprofloxacin 
primidone * 
rufinamide * 
lopinavir 
darunavir 
avasimibe 
bosentan 
mibefradil 
diltiazem 
rifabutin 
efavirenz 
nefazodone 
elvitegravir 
rifampin 
etravirine 
nelfinavir 
erythromycin 
St. John's Wort 
modafenil 
posaconazole 
fluconazole 
nafcillin 
ritonavir 
grapefruit juice 
ritonavir 
saquinavir 
schisandra sphenanthera 
talviraline 
telithromycin 
tipranavir 
tipranavir 
troleandomycin 
tofisopam 
voriconazole 
verapamil 
* These drugs are Enzyme Inducing Anti-Epileptic drugs. 
This database of CYP inhibitors and inducers was compiled from the Indiana University School of 
Medicine’s 
“Clinically Relevant” Table, from the University of Washington’s Drug Interaction Database based on 
in vitro studies and from the FDA’s “Guidance for Industry, Drug Interaction Studies;” from the 
Indiana University School of Medicine’s “Clinically Relevant” Table; and from (Pursche 2008). 


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14.2 
Appendix 2 – List of prohibited QT-prolonging drugs 
All QT-prolonging drugs listed in Table 14-2 are prohibited for all subjects from screening 
through permanent discontinuation of study. Table 14-2 lists drugs with a known risk for TdP 
as well as sensitive CYP3A substrates (with narrow TI) with a possible or conditional risk for 
TdP. 
 
Table 14-2 List of prohibited QT prolonging drugs 
 
Drug 
QT risk(*) 
Comment 
Amiodarone 
Known risk for TdP 
Females>Males, TdP risk regarded as low 
Arsenic trioxide 
Known risk for TdP 
Astemizole 
Known risk for TdP 
No Longer available in U.S. 
Bepridil 
Known risk for TdP 
Females>Males 
Chloroquine 
Known risk for TdP 
Chlorpromazine 
Known risk for TdP 
Cisapride 
Known risk for TdP 
Restricted availability; Females>Males. 
Disopyramide 
Known risk for TdP 
Females>Males 
Dofetilide 
Known risk for TdP 
Domperidone 
Known risk for TdP 
Not available in the U.S. 
Droperidol 
Known risk for TdP 
Halofantrine 
Known risk for TdP 
Females>Males 
Haloperidol 
Known risk for TdP 
When given i.v. or at higher-than- recommended doses, risk of 
sudden death, QT prolongation and torsades increases. 
Ibutilide 
Known risk for TdP 
Females>Males 
Levomethadyl 
Known risk for TdP 
Mesoridazine 
Known risk for TdP 
Methadone 
Known risk for TdP 
Females>Males 
Pentamidine 
Known risk for TdP 
Females>Males 
Pimozide 
Known risk for TdP 
Females>Males 
Probucol 
Known risk for TdP 
No longer available in U.S. 
Procainamide 
Known risk for TdP 
Quetiapine 
Possible risk for TdP 
Prohibited as this drug is a sensitive 3A4 substrate 
Quinidine 
Known risk for TdP 
Females>Males 
Sotalol 
Known risk for TdP 
Females>Males 
Sparfloxacin 
Known risk for TdP 
Tacrolimus 
Possible risk for TdP 
Prohibited as this drug is a sensitive 3A4 substrate with narrow 
TI 
Terfenadine 
Known risk for TdP 
No longer available in U.S. 
Thioridazine 
Known risk for TdP 
Vardenafil 
Possible risk for TdP 
Prohibited as this drug is a sensitive 3A4 substrate 
(*)Classification according to the Qtdrugs.org advisory board of the Arizona CERT 
Sensitive substrates: Drugs whose plasma AUC values have been shown to increase 5-fold or higher when co- 
administered with a potent inhibitor of the respective enzyme. 
Note: drugs with a known risk for TdP that are also moderate or strong inhibitors of CYP3A mentioned 
 

SAP_000.pdf: 
Clinical Development
SEG101/Crizanlizumab
CSEG101A2202 / NCT03264989
A phase 2, Multicenter, Open-Label Study to Assess PK/PD 
of SEG101 (crizanlizumab), with or without 
Hydroxyurea/Hydroxycarbamide, in Sickle Cell Patients 
with Vaso-Occlusive Crisis
Statistical Analysis Plan (SAP)
Author:
Trial Statistician, 
Document type:
SAP Documentation
Document status:
Final Amendment 1
Release date:
5-Nov-2018
Number of pages:
31
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
30-
Oct-
2017
Prior 
to 
FPFV
Creation of 
final 
version
N/A - First version
NA
25-
Oct-
2018
Prior 
to 
DBL
Amendment
1
Patient population has been changed 
from adults age 18-70 to age 16-70.
It has been clarified that the maximum 
number of patients enrolled is 45 for 5.0 
mg/kg treatment group.
SEG101 
has 
been 
changed 
to 
crizanlizumab.
The definition of PAS1 and PDS1 have 
been updated.
The definition of dose interruption has 
been added.
The individual plots of concentration-
time profile and P-selectin inhibition-
time profile have been removed.
Geometric mean has been replaced by 
median in the PK and PD plots.
Analyses about liver have been updated.
.
Title, Section 1
Sections 1.1, 1.2, 
2.1
Sections 
2.1.1, 
2.5.1, 2.8.1.1
Section 2.2
Section 2.4.1
Section 2.5.2
Sections 2.13.3, 
2.13.4
Section 2.8.3
Section 2.8.4.1
CTCAE version has been updated.
Section 5.2, 5.3


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Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.2
Study objectives and endpoints ...............................................................................8
2
Statistical methods...............................................................................................................9
2.1
Data analysis general information ...........................................................................9
2.1.1
General definitions................................................................................10
2.2
Analysis sets ..........................................................................................................13
2.3
Subject disposition, demographics and other baseline characteristics ..................15
2.3.1
Subject disposition ................................................................................15
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................16
2.4.1
Study treatment / compliance................................................................16
2.4.2
Prior, concomitant and post therapies...................................................17
2.5
Analysis of the primary objective..........................................................................18
2.5.1
Primary endpoint...................................................................................18
2.5.2
Statistical hypothesis, model, and method of analysis..........................19
2.5.3
Handling of missing values/censoring/discontinuations.......................20
2.5.4
Supportive analyses...............................................................................20
2.6
Analysis of the key secondary objective ...............................................................20
2.7
Analysis of secondary efficacy objective(s)..........................................................20
2.7.1
Secondary endpoints .............................................................................20
2.7.2
Statistical hypothesis, model, and method of analysis..........................20
2.7.3
Handling of missing values/censoring/discontinuations.......................20
2.8
Safety analyses.......................................................................................................21
2.8.1
Adverse events (AEs)............................................................................21
2.8.2
Deaths....................................................................................................22
2.8.3
Laboratory data .....................................................................................22
2.8.4
Other safety data ...................................................................................23
2.9
Pharmacokinetic endpoints....................................................................................25
2.10
PD and PK/PD analyses.........................................................................................25
2.11
Patient-reported outcomes .....................................................................................25
25
25


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25
..............................25
26
27
2.14
Interim analysis......................................................................................................27
3
Sample size calculation .....................................................................................................27
4
Change to protocol specified analyses ..............................................................................28
5
Appendix ...........................................................................................................................28
5.1
Imputation rules.....................................................................................................28
5.1.1
Study drug.............................................................................................28
5.1.2
AE, ConMeds and safety assessment date imputation..........................28
5.2
AEs coding/grading ...............................................................................................29
5.3
Laboratory parameters derivations ........................................................................30
6
Reference...........................................................................................................................30


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List of abbreviations
ACS
Acute Chest Syndrome
AE
Adverse event
AESI
Adverse events of special interest
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
BMI
Body Mass Index
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of Variation
DMC
Data Monitoring Committee 
FAS
Full Analysis Set
ECG
Electrocardiogram
ER
Emergency Room
CRF
Case Report Form
FAS
Full Analysis Set
HbS
Human hemoglobin S (sickle cell hemoglobin)
HbSβ
Heterozygotes with one copy of the HbS gene and β-thalassemia variants (β0 or β+)
HbSC
Heterozygous sickle Hemoglobin C disease (hemoglobin SC disease)
HbSS
Homozygous sickle cell disease (hemoglobin SS disease)
HGLT
High level group terms
HLT
High level terms
HU/HC
Hydroxyurea/Hydroxycarbamide
MedDRA
Medical Dictionary for Drug Regulatory Affairs
NCI
National Cancer Institute
NMQ
Novartis MedDRA Queries
PAS
Pharmacokinetics Analysis Set
PD
Pharmacodynamics
PDS
Pharmacodynamics Analysis Set
PFS
Progression-Free Survival
PK
Pharmacokinetics
popPK
Population PK
PPS
Per-Protocol Set
PRO
Patient-reported Outcomes
PT
Preferred Term
QoL
Quality of Life
RAP
Report and Analysis Process
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCD
Sickle Cell Disease
SCPC
Sickle Cell Pain Crisis
SMQ
Standardized MedDRA Queries


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SOC
System Organ Class
TFLs
Tables, Figures, Listings
VOC
Vaso-Occlusive Crisis
WHO
World Health Organization


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1
Introduction
This statistical analysis plan (SAP) describes all planned analyses for the Clinical Study 
Report (CSR) of study CSEG101A2202, a phase II, open label PK/PD study in sickle cell
disease (SCD) subjects with vaso-occulsive crisis (VOC).
The content of this SAP is based on protocol CSEG101A2202 v00, except an update of the 
definitions of PAS and PDS to be implemented in the next protocol amendment.
1.1
Study design
This is a multicenter, single-arm, open-label study to assess PK/PD of crizanlizumab in 
subjects with SCD and VOC. 
Approximately 55 subjects will be enrolled in the trial. Up to 45 eligible subjects will be 
treated with crizanlizumab at a dose of 5.0 mg/kg and up to 10 additional eligible subjects will 
be treated with crizanlizumab at a dose of 7.5 mg/kg.
The study will include subjects, aged 16-70 years, with confirmed diagnosis of SCD 
(genotypes HbSS, HbSC, HbS β0-thalassemia, HbS β+-thalassemia, and others) who have 
experienced at least 1 VOC within the preceding 12 months. Subjects may not plan to initiate
hydroxyurea/hydroxycarbamide (HU/HC) during the study. For subjects who are already 
treated with HU/HC, they should be taking HU/HC for at least 6 months and should accept to 
take the same dose at the same schedule during the trial.
The first 45 patients will receive crizanlizumab 5.0 mg/kg by IV infusion over 30 min on 
week 1 day 1, week 3 day 1, and then day 1 of every 4-week cycle. Once 27 patients have 
evaluable PK/PD data (or a total of up to 45 patients are enrolled) at the 5.0 mg/kg dose, an 
exploratory cohort of 10 patients will be enrolled at a dose of 7.5 mg/kg. Patients will receive
crizanlizumab 7.5 mg/kg by IV infusion over 30 min on week 1 day 1, week 3 day 1, and then
day 1 of every 4-week cycle. All enrolled patients will have PK/PD sampling performed in 
order to characterize the PK/PD of crizanlizumab.
Subjects will receive treatment until study treatment is permanently discontinued due to 
unacceptable toxicity, death, are lost to follow-up or discontinued from the study treatment for 
any other reasons. Subjects will be followed in the mandatory safety follow-up period until 
105 days after the last dosing. Subjects continuing to receive benefit, defined as no evidence 
of increased frequency of VOCs and no severe adverse events attributed to drug as per 
Investigator’s assessment, will remain on study until crizanlizumab is commercially available 
or until subjects are rolled over in a different crizanlizumab study or access program.
Exploration of early access (EA) PK data may occur for preliminary PK analysis prior to 
clinical data base lock. For the derivation of PK parameters nominal time instead of actual 
elapsed time may be used.
In addition, an interim analysis will be performed when there are at least 27 subjects with 
single dose evaluable PK profiles and 5 subjects with both single dose and multiple dose 
evaluable PK profiles in the 5.0 mg/kg treatment group in the Pharmacokinetic Analysis Set 1 


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(PAS1).This interim analysis will inform the PKPD part of the pediatric study 
CSEG101B2201.
The primary analysis will be conducted after the primary PK parameters and PD-AUC are 
available for at least 27 subjects in the 5.0 mg/kg treatment group in PAS1 and 
Pharmacodynamics Analysis Set 1 (PDS1) respectively, or a total of 45 patients have been 
enrolled in the 5.0 mg/kg treatment group, whichever occurs first. The primary analysis data 
will be summarized in the primary CSR.
The final analysis will occur at the end of the study. All available data from all subjects up to 
the trial end will be analyzed and summarized in a final CSR.
1.2
Study objectives and endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 2.5
Characterize PK of 
crizanlizumab at 5.0 mg/kg in 
SCD subjects
-PK parameters after the starting dose 
and after multiple doses.
-Trough concentrations prior to each 
study drug dose.
Characterize PD (P-selectin 
inhibition) of crizanlizumab at 
5.0 mg/kg in SCD subjects
-P-selectin inhibition and PD-AUC after 
the starting dose, after multiple dosing, 
and prior to each study drug dose. 
Secondary
Assess efficacy of crizanlizumab
-Number of VOC events leading to 
healthcare visit in clinic/ER/hospital over 
time
-Number of VOC events treated at home 
(based on documentation by health care 
provider following phone contact with 
subject) over time
-Number of hospitalizations and ER visits 
(both total and VOC-related) over time
-Days of ER/hospitalization (both total 
and VOC-related) over time
-Number of each subcategory of VOC 
event (uncomplicated pain crisis, acute 
chest syndrome, hepatic sequestration, 
splenic sequestration, priapism) over time
-Number of VOC events (including both 
healthcare visit and home treatment) over 
time
Refer to Section 2.7
Assess safety and tolerability of 
crizanlizumab
-Number, 
seriousness, 
severity, 
and 
causality 
assessments 
of 
treatment 
emergent adverse events and other 
safety data as considered appropriate
-Absolute 
change 
from 
baseline 
in 
hemoglobin
-Immunogenicity: measurement of anti-
drug antibodies (ADA) to crizanlizumab
Refer to Section 2.8


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2
Statistical methods
2.1
Data analysis general information
The analysis of study data for the primary CSR will be based on all subjects’ data up to a data 
cut-off date when the primary PK parameters and PD-AUC are available for at least 27 
subjects for 5.0 mg/kg treatment group in the PAS1 and PDS1 respectively, or a total of 45 
patients have been enrolled in the 5.0 mg/kg treatment group, whichever occurs first.
The additional data for any new subjects or subjects continuing to receive study drug past 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.
All analyses will be performed by Novartis and/or a designated CRO. SAS version 9.4 or later 
software will be used to perform all data analyses and to generate tables, figures and listings.
General analysis conventions
Unless otherwise specified, data from all study centers will be pooled for the analysis. No 
center effect will be assessed. Categorical data will be presented as frequencies and 


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percentages; continuous data will be presented as n, mean, standard deviation (SD), median, 
minimum, and maximum. 
For PK concentration and PK parameters, coefficient of variation (CV) (%), geometric mean, 
and geometric CV% will be presented in addition to the previously mentioned summary 
statistics.
CV (%) is calculated as follows: 
100*(SD/arithmetic mean).
Geometric CV (%) is calculated as follows:
sqrt (exp (variance for log transformed data)-1)*100.
Unscheduled assessments
The following points summarize the rules for unscheduled assessments:

Baseline: All unscheduled assessments before the first dose should be included for 
consideration when calculating the baseline value.  

In summary tables by visit, unscheduled assessments should not be included unless 
they qualify as baseline.

In shift and abnormality tables, all unscheduled assessments are included.
Unscheduled assessments will be reported with the scheduled assessments in the listings.
Data included in the analysis
The analysis cut-off date for the primary analysis of study data will be established after the 
primary PK parameters and PD-AUC are available for at least 27 subjects in the 5.0 mg/kg 
treatment group in the PAS1 and PDS1, respectively, or a total of 45 patients have been 
enrolled in the 5.0 mg/kg treatment group, whichever occurs first. 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 cut-
off 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
Investigational drug and study treatment
Both investigational drug and study treatment refer to crizanlizumab. The term investigational 
treatment may also be referred to as study treatment which is used throughout this document.


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Treatment
For presentation in the outputs, treatment refers to crizanlizumab 5.0 mg/kg and 7.5 mg/kg. 
Date of first administration of investigational drug
The date of first administration of investigational drug is defined as the first date when a 
nonzero dose of investigational drug is administered and recorded on the Dosage 
Administration Record CRF. The date of first administration of investigational drug will also 
be referred as start of investigational drug.
Date of last administration of investigational drug
The date of last administration of investigational drug is defined as the last date when a 
nonzero dose of investigational drug is administered and recorded on dose administration
CRF. The date of last administration of investigational drug will also be referred as end of 
investigational drug.
Date of first administration of study treatment 
The date of first administration of study treatment is derived as the first date when a nonzero 
dose of study treatment was administered as per the Dosage Administration CRF. The date of 
first administration of study treatment will also be referred as start of study treatment.
The date of first administration of study treatment is the same as the date of first 
administration of investigational drug.
Date of last administration of study treatment 
The date of last administration of study treatment is defined as the last date when a nonzero 
dose of study treatment was administered as per Dose Administration  CRF. 
The date of last administration of study treatment is the same as the date of last administration 
of investigational drug. 
Study day
The study day, describes the day of the event or assessment date, relative to the 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 treatement + 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.


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Time unit
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If 
duration is reported in months, duration in days will be divided by 30.4375.  If duration is  
reported in years, duration in days will be divided by 365.25.
Baseline 
For safety evaluations, the last available assessment on or before the date of start of study 
treatment is taken as ‘baseline’ assessment. In case time of assessment and time of treatment 
start is captured, the last available assessment before the treatment start date/time is used for 
baseline.
For safety parameters (e.g. ECGs), where the study requires multiple replicates per time point, 
the average of these measurements would be calculated (if not already available in the 
database) before determining baseline.
In rare cases where multiple measurements meet the baseline definition, with no further flag 
or label that can identify the chronological order, then the following rule should be applied: If 
values are from central and local laboratories, the value from central assessment should be 
considered as baseline. 
If subjects have no value as defined above, the baseline result will be missing.
For safety parameters other than ECG, scheduled pre-dose collections as well as unscheduled 
collections on Day 1 for which no time is available will be considered as pre-dose. 
For ECG, study Day 1 scheduled pre-dose ECGs will be considered to have been obtained 
prior to start of study treatment if dosing time or ECG time is missing and used in the 
calculation of the baseline value. If a scheduled pre-dose measurement actually occurred post-
dose, then the corresponding measurement will be treated and analyzed similar to an 
unscheduled post-dose measurement.
On-treatment assessment/event
The overall observation period will be divided into three mutually exclusive segments: 
1. Pre-treatment period: from day of subject’s informed consent to before date of first 
administration of study treatment
2. On-treatment period: from date of first administration of study treatment to 105 days 
after date of last administration of study treatment (including start and stop date)
3. Post-treatment period: starting at day 106 after last administration of study treatment.
Note: If dates are incomplete in a way that clear assignment to pre-, on-, post-treatment period 
cannot be made, then the respective data will be assigned to the on-treatment period.  
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change 
from baseline summaries). In addition, a separate summary for death including on-treatment 
and post-treatment deaths will be provided. In particular, summary tables for adverse events 


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(AEs) will summarize only on-treatment events, with a start date during the on-treatment 
period (treatment-emergent AEs).
However, all safety data (including those from the post-treatment period) will be listed and 
those collected during the post-treatment period will be flagged.
2.2
Analysis sets
Full analysis set
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been 
assigned and who received at least one dose of study treatment. Subjects will be analyzed 
according to the crizanlizumab dose (5.0 mg/kg or 7.5 mg/kg) they have been assigned to.
Safety set
The Safety Set includes all subjects who received at least one dose of study treatment. 
Subjects will be analyzed according to the dose level received (5.0 mg/kg or 7.5 mg/kg), 
where dose level received is defined as the assigned dose level if the subject took at least one 
dose of that treatment or the first dose received if the assigned dose level was never received.
Pharmacokinetic analysis set
The Pharmacokinetic analysis set 1 (PAS1) includes all subjects who provide at least one 
evaluable PK profile. A profile is considered evaluable if all of the following conditions are 
satisfied:

Subject receives the planned treatment of 5.0 mg/kg or 7.5 mg/kg before single dose PK 
profile or 3 consecutive doses of the planned treatment before the multiple dose PK profile

Subject provides at least one primary PK parameter

Subject does not have any transfusion of blood product in the last 4 weeks before the first 
PK sample of the full PK profile, or during the full PK profile
The Pharmacokinetic analysis set 2 (PAS2) includes all subjects who receive at least one 
planned treatment of 5.0 mg/kg or 7.5 mg/kg and provide at least one corresponding evaluable 
PK concentration.
A usbject is considered to receive the planned treatment if the actual dose received divided by 
the last weight measured before the dose is within a ±5% window of the planned dose.
Pharmacodynamics analysis set
The pharmacodynamics analysis set 1 (PDS1) includes all subjects who provide at least one 
evaluable PD profile. A profile is considered evaluable if all of the following conditions are 
satisfied:

Subject receives the planned treatment of 5.0 mg/kg or 7.5 mg/kg before single dose PD 
profile or 3 consecutive doses of the planned treatment before the multiple dose PD profile 

Subjects provides at least one PD-AUC (single dose or multiple dose) parameter


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
Subject does not have any transfusion of blood product in the last 4 weeks before the first 
PD sample of the full PD profile, or during the full PD profile
The pharmacodynamics analysis set 2 (PDS2) includes all subjects who receive at least one 
planned treatment of 5.0 mg/kg or 7.5 mg/kg and provide at least one corresponding evaluable 
PD assessment.
Details on pharmacokinetic analysis
If a profile is not evaluable per PAS definition, all scheduled concentrations for that profile as 
well as corresponding parameters will be flagged for exclusion from summaries and figures. 
Additionally, if Rsq_adj < 0.75 or AUC%Extrap > 20%, then Lambda_z, T1/2, AUCinf,  
Vz/F (VZ), CL/F (CL) will be flagged for exclusion from summaries and figures.
Only PK parameters and concentrations which are not flagged for exclusion programmatically 
or by the pharmacokineticist (e.g. due to conmeds, high concentration despite dose 
modification, etc.) will be used for figures and summaries. All values will be listed with 
excluded values flagged in the listings.
Subject classification
Subjects may be excluded from the analysis populations defined above based on the protocol 
deviations entered in the database and/or on specific subject classification rules defined in 
Table 2-1. 
Table 2-1
Subject classification based on protocol deviations and non-PD 
criteria
Analysis set
Protocol deviations leading to 
exclusion
Non protocol deviation leading to 
exclusion
FAS
No written inform consent
No dose of study treatment
Safety set
No written inform consent
No dose of study treatment
PAS1
No written inform consent 
No dose of study treatment
No evaluable PK profile
PAS2
No written inform consent
No dose of study treatment
No evaluable PK concentration
PDS1
No written inform consent
No dose of study treatment
No evaluable PD profile
PDS2
No written inform consent
No dose of study treatment
No evaluable assessment
Withdrawal of Informed Consent
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis.  The date on which a 
subject withdraws full consent is recorded in the CRF.  
 
 


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2.3
Subject disposition, demographics and other baseline 
characteristics
The FAS will be used for all baseline and demographic summaries and listings unless 
otherwise specified. 
Demographics and baseline data
Demographic and other baseline data (e.g. age, sex, race, ethnicity, height, weight, and Body 
Mass Index, ECOG, etc.) will be summarized descriptively by treatment group. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
Relevant medical histories will be summarized by system organ class and preferred term. 
BMI will be calculated based on height and weight at screening:
BMI (kg/m2) = weight [kg] / (height [m])2
All demographic data and other baseline characteristics (e.g., medical history, vaso-occlusive 
crisis history including genotype and HU/HC use, alcohol history, smoking history, hepatitis 
and HIV screen, drug screen and pregnancy test etc.) will be listed.
2.3.1
Subject disposition
Treated subjects included in the FAS will be presented. The number (%) of subjects in the 
FAS who are still on treatment, who discontinued the study phases and the reason for 
discontinuation will be presented overall and by treatment group.
The following summaries will be provided (with % based on the total number of FAS 
subjects):

Number (%) of subjects who are still on-treatment (based on the ‘Treatment 
Disposition’ page not completed); 

Number (%) of subjects who discontinued the study treatment phase (based on the 
‘Treatment Disposition’ page) 

Primary reason for study treatment phase discontinuation (based on the ‘Treatment 
Disposition’ page)

Number (%) of subjects who have entered the post-treatment follow-up (based on 
the ‘Treatment Disposition’ page);

Number (%) of subjects who have discontinued from the post-treatment follow-up 
(based on the Post-treatment follow-up Disposition page);

Reasons for discontinuation from the post-treatment follow-up (based on Post-
treatment follow-up Disposition page);
Subject disposition data will be listed. 
Screened subjects not treated will be listed.


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Protocol deviations
All protocol deviations will be listed.
Analysis sets
The number (%) of subjects in each analysis set (defined in Section 2.2) will be summarized
by treatment group. Subjects included in each analysis set will be listed.
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, mean, standard deviation, median, 
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 by means of descriptive statistics using the safety set.
The number of subjects with dose adjustments (interruption or permanent discontinuation or 
reduction for 7.5 mg/kg group only) and the reasons will be summarized for all subjects by 
treatment group and 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 is 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 6 weeks, at least 6 weeks, at least 54 weeks, at least 106 
weeks) and continuous summaries (i.e. mean, standard deviation 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 by treatment group. 
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. 


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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:
RDI = DI (mg/kg/28 days)  / PDI (mg/kg/28 days).  
DI and RDI will be summarized.
Dose reductions, interruptions or permanent discontinuations
The number of subjects who have dose reductions (for 7.5 mg/kg treatment group only), 
permanent discontinuations or interruptions, and the reasons, will be summarized by treatment 
group. 
‘Dose change’, ‘Dose interrupted’, and ‘Dose permanently discontinued’ fields from the 
Dosage Administration CRF pages (DAR) will be used to determine the dose reductions, dose 
interruptions, and permanent discontinuations, respectively.
The corresponding fields ‘Reason for dose change/dose interrupted’ and ‘Reason for 
permanent discontinuation’ will be used to summarize the reasons.
A dose change is either ‘change in prescribed dose level’ or ‘dosing error’ where actual dose 
administered/total daily dose is different from the prescribed dose.
Reduction: A dose change where the prescribed dose level is lower than the previous 
prescribed dose level or where the actual dose administered is lower than the calculated dose 
amount based on the prescribed dose. Therefore any dose change to correct a dosing error will 
not be considered a dose reduction.  Only dose change is collected in the CRF, and number of 
reductions will be derived programmatically based on the change and the direction of the 
change.
Interruption: A dose cannot be administered within 7 days of the scheduled day of infusion 
as per protocol. If a dose was temporarily stopped during infusion, it should not be considered 
as a dose interruption. Duration of a dose interruption is calculated as the time between the 
scheduled date of infusion and the actual date of infusion after the interruption.
2.4.2
Prior, concomitant and post therapies
Concomitant medications
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a subject coinciding with the study treatment 
period. Concomitant therapy include medications (other than study drugs) starting on or after 
the start date of study treatment or medications starting prior to the start date of study 
treatment and continuing after the start date of study treatment. 


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Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Reference Listing (DRL) dictionary that employs the WHO Anatomical Therapeutic 
Chemical (ATC) classification system using the latest version available prior to clinical 
database lock and summarized by lowest ATC class and preferred term. These summaries will 
include:
1. Medications starting on or after the start of study treatment but no later than 105
days after start of last dose of study treatment and
2. Medications starting prior to start of study treatment and continuing after the start of 
study treatment.
All concomitant therapies will be listed. Any concomitant therapies starting and ending prior 
to the start of study treatment or starting more than 105 days after the last date of study 
treatment will be flagged in the listing. The safety set will be used for all concomitant 
medication tables and listings.
2.5
Analysis of the primary objective
The primary objective is to characterize PK and PD of crizanlizumab at 5.0 mg/kg in SCD 
subjects.
2.5.1
Primary endpoint
The primary variables of the study are the PK and PD parameters after single dose and after 
multiple doses.
Primary PK parameters: 

AUCd15, AUCtau, Cmax 
All other PK parameters in Table 2-2 are considered to be secondary.
PD parameters of crizanlizumab

PD-AUCd15 after single dose

PD-AUCd29 after multiple doses
Table 2-2
Non-compartmental PK parameters for crizanlizumab
AUCd15
The AUC from time zero to the last measurable concentration sampling time (tlast) 
(mass x time x volume-1) after single dose
AUCtau
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x 
time x volume-1)
Cmax
The maximum (peak) observed serum drug concentration after dose administration 
(mass x volume-1)
Tmax
The time to reach maximum (peak) serum drug concentration after dose 
administration (time)
Lambda_z
Smallest (slowest) disposition (hybrid) rate constant (time-1) 
T1/2
The elimination half-life associated with the terminal slope (z) of a semi logarithmic 
concentration-time curve (time)


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The PK parameters are derived based on the non-compartmental methods using WinNonlin®
software with the most recent version available at the time of analysis. Refer to the Novartis 
Pharmacokinetic/Pharmacodynamic Analysis Manual (2015).
2.5.2
Statistical hypothesis, model, and method of analysis
The inter-subject variations and CV% will be presented for the primary PK parameters. The 
point estimate and the corresponding two-sided 90% confidence interval (CI) for the mean of 
the log-transformed primary PK parameters after single dose and multiple doses will be 
derived respectively. The point estimate and CI will be anti-log transformed to obtain the 
point estimate and the 90% confidence interval for the geometric mean on the original scale.
The descriptive statistics (n, mean, CV%, standard deviation (SD), median, geometric mean, 
geometric CV%, minimum and maximum) will be presented for all PK parameters defined in 
Table 2-2 except Tmax, where only n, median, minimum and maximum will be presented.
The PAS1 for 5.0 mg/kg treatment group will be used for all PK analyses described above.
Descriptive statistics for crizanlizumab concentration will be presented at each scheduled 
timepoint.
In addition, the mean (+/- SD) and median concentration-time profiles over time will be 
displayed graphically on the linear and semi-log view.
All individual PK parameters and PK concentration data for crizanlizumab will be listed.
All individual pre-dose concentrations for crizanlizumab with median will be displayed 
graphically on semi-log view over time. In addition, the mean (+/- SD) and median pre-dose 
concentrations over time will be displayed graphically on the linear and semi-log view.
The PAS2 for 5.0 mg/kg treatment group will be used for these PK analyses.
PD-AUCd15 and PD-AUCd29 will be derived from the P-selectin inhibition data of week 1 
and week 15, respectively. The point estimate and the corresponding two-sided 90% CI for 
the mean of the log-transformed PD-AUC after single dose and multiple doses will also be 
provided. The point estimate and CI will be anti-log transformed to obtain the point estimate 
and the 90% confidence interval for the geometric mean on the original scale.
The PDS1 for 5.0 mg/kg treatment group will be used for all PD analyses described above.
Descriptive statistics for PD inhibition will be presented at each scheduled timepoint.
In addition, the mean (+/- SD) and median PD-time profiles over time will be displayed 
graphically on the linear and semi-log view.
All individual PD parameters and PD data will be listed.
Median pre-dose inhibition will be displayed graphically on semi-log view over time. In 
addition, the mean (+/- SD) and median pre-dose inhibition over time will be displayed 
graphically on the linear and semi-log view.
The PDS2 for 5.0 mg/kg treatment group will be used for these PD analyses.


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2.5.3
Handling of missing values/censoring/discontinuations
Missing values for any PK parameters or concentrations will not be imputed and will be 
treated as missing. 
Below the limit of quantitation (BLQ) values will be set to zero by the Bioanalyst, and will be 
displayed in the listings as zero and flagged. BLQ values will be treated as missing for the 
calculation of the geometric means and geometric CV%.
Missing values for the PD parameter or data will not be imputed and will be treated as 
missing.
2.5.4
Supportive analyses
No supportive analyses are planned.
2.6
Analysis of the key secondary objective
There is no key secondary objective.
2.7
Analysis of secondary efficacy objective(s)
2.7.1
Secondary endpoints
The secondary efficacy endpoints include the following. 

Annualized rate of VOC events leading to healthcare visit in clinic/ER/hospital 

Annualized rate of VOC events treated at home (based on documentation by health 
care provider following phone contact with subject) 

Annualized rate of all VOC events (including both healthcare visit and home treatment)

Annualized rate of each subcategory of VOC event (uncomplicated pain crisis, acute 
chest syndrome, hepatic sequestration, splenic sequestration, priapism) 

Annualized rate of hospitalizations and ER visits (both total and VOC-related) 

Annualized days of ER/hospitalization (both total and VOC-related) 
Annualized rate of a VOC event = Total number of VOC events × 365.25/(end date –
treatment start date + 1), and annualized days of ER/hospitalization = Total number of days × 
365.25/(end date – treatment start date + 1), where end date is the date of the last treatment 
date + 27.
2.7.2
Statistical hypothesis, model, and method of analysis
All the above mentioned efficacy endpoints will be summarized descriptively based on FAS
by treatment group in the final CSR only and not at the time of the primary analysis CSR, due 
to the expected short follow-up that will not allow valid efficacy assessment.
2.7.3
Handling of missing values/censoring/discontinuations
Missing values or data will not be imputed and will be treated as missing.


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2.8
Safety analyses
All safety analyses will be based on the Safety Set unless otherwise specified. Safety 
summaries include only on-treatment assessments (refer to Section 2.1.1); safety listings 
include all assessments with those more than 105 days after last study treatment flagged.
2.8.1
Adverse events (AEs)
AE summaries will include all AEs occurring during on-treatment period. All AEs collected 
in the AE CRF page will be listed along with the information collected on those AEs e.g. AE 
relationship to study drug, AE outcome etc. AEs starting during the post-treatment period will 
be flagged in the listings. 
AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT)
using MedDRA coding. A subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event. 
AE with missing CTCAE grade will be included in the ‘All grades’ column of the summary 
tables.
In AE summaries, the primary system organ class will be presented alphabetically and the 
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.
The following adverse event summaries will be produced by treatment group:

AEs by SOC and PT (Post-text)

AEs by PT (In-text only)

Treatment-related AEs by SOC and PT (Post-text)
In addition, for EudraCT requirements a summary of (1) Serious AEs and deaths, with 
number of occurrences and (2) Non-serious AEs, with number of occurrences will be 
produced (an occurrence is defined as >1 day between start and prior end date of record of 
same preferred term).
2.8.1.1
Adverse events of special interest / grouping of AEs
Data analysis of AESIs
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to compound crizanlizumab. These groupings are defined using 
MedDRA terms, SMQs (standardized MedDRA queries), HGLTs (high level group terms), 
HLT (high level terms) and PTs (preferred terms). Customized SMQs (Novartis MedDRA 
queries, NMQ) may also be used. A NMQ is a customized group of search terms which 
defines a medical concept for which there is no official SMQ available or the available SMQ 
does not completely fit the need. It may include a combination of single terms and/or an 
existing SMQ, narrow or broad. For each specified AESI, number and percentage of subjects 
with at least one event of the AESI occurring during on treatment period will be summarized.


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Summaries of these AESIs will be provided by treatment group, (specifying grade, SAE, 
relationship, leading to treatment discontinuation, leading to dose adjustment/interruption, 
hospitalization, death etc.). If sufficient number of events occurred, analysis of time to first 
occurrence will be applied.
A listing of all grouping levels down to the MedDRA preferred terms used to define each 
AESI will be generated.
2.8.2
Deaths
Separate summaries for on-treatment and all deaths (including post-treatment death) will be 
produced by treatment group, system organ class and preferred term.
All deaths will be listed using Safety set and post treatment deaths will be flagged. A separate 
listing of deaths prior to starting treatment will be provided for all screened subjects.
2.8.3
Laboratory data
On analyzing laboratory values, data from all sources (central and local laboratories) will be 
combined. The summaries will include all assessments available for the lab parameter 
collected no later than 105 days after the last study treatment administration date (see Section 
2.1.1).
The following summaries will be produced for hematology and biochemistry laboratory data 
by laboratory parameter and treatment group:

Worst post-baseline CTCAE grade (regardless of the baseline status). Each subject
will be counted only once for the worst grade observed post-baseline.

Shift tables using CTC grades to compare baseline to the worst on-treatment value; 
for laboratory tests where CTC grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value.
The following listings will be produced for the laboratory data:

Listings of all laboratory data, with CTC grades and classification relative to the 
laboratory normal range. Lab data collected during the post-treatment period will be 
flagged.  

Listing of all CTC grade 2, 3, or 4 laboratory toxicities
Liver function parameters 
Liver function parameters of interest are total bilirubin (TBL), ALT, AST and alkaline 
phosphatase (ALP). The number (%) of patients with worst post-baseline values as per 
Novartis Liver Toxicity guidelines will be summarized, in addition to the baseline values. 
Shift tables using ALT, AST and total bilirubin will be generated, respectively. eDISH plot 
will be produced. A similar plot of direct bilirubin (DBILI) vs. ALT will also be generated. 
Individual subject plots will be produced for subjects matching liver function criteria ALT > 
3xULN, DBILI > 2xULN and ALP < 2xULN. Individual subject reticulocyte count plots, and 
a plot of PT-INR and albumin over time will also be produced for the same patients.


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The following summaries will be produced:

ALT or AST > 3xULN 

ALT or AST > 5xULN

ALT or AST > 8xULN

ALT or AST > 10xULN

ALT or AST > 20xULN

TBL > 2xULN

TBL > 3xULN

ALT or AST > 3xULN & TBL > 2xULN

ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN  (potential Hy’s law)

ALT or AST > 3xULN & TBL > 2xULN & ALP ≥ 2xULN

ALT > 3xULN & DBILI >2xULN & ALP <2xULN   
Potential Hy’s Law events are defined as those subjects with concurrent occurrence of AST or 
ALT > 3xULN and TBL > 2xULN and ALP < 2xULN  in the same assessment sample during 
the on-treatment period. Further medical review has to be conducted to assess potential 
confounding factor such as, liver metastates, liver function at baseline etc.
Renal disorders will be evaluated using estimated Glomerular Filtration Rate (eGFR) shift 
table, and serum creatinine shift table.
Hematuria (defined as urinanalysis RBC of 6-8/HPF or more), glycosuria (defined as urine 
glucose of 1+ or more), and proteinuria (defined as urine protein of 1+ or more) will be 
evaluated using frequency table by time (baseline vs. post-baseline).
Shift table for leucocytosis (leucocytes: ≤ 100,000 mm3; > 100,000 mm3) will be produced.
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
Data handling
When ECG triplicates are collected at any assessment, the average of the ECG parameters at 
that assessment will be used in the analyses.
Data analysis
12-lead ECGs including PR, QRS, QT, QTcF and HR intervals will be obtained centrally for 
each subject during the study. ECG data will be read and interpreted centrally. 
The number and percentage of subjects with notable ECG values will be presented by 
treatment group. In addition, a listing of these subjects will be produced.

QT, QTcF


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-
New value of > 450 and ≤ 480 ms
-
New value of > 480 and ≤ 500 ms
-
New value of > 500 ms
-
Increase from baseline of > 30 ms to ≤  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 > 110 ms
-
New values of QRS > 110 ms 
 
2.8.4.2
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: weight (kg), body temperature (°C), pulse rate (beats per 
minute), systolic and diastolic blood pressure (mmHg).
Data handling
Vital signs collected on-treatment will be summarized. Values measured during the post-
treatment period will be flagged in the listings.
Data analysis
The number and percentage of subjects with notable vital sign values (high/low) will be 
presented  by treatment group. A listing of all vital sign assessments will be produced by 
treatment group with the notable values flagged. In the listing, the assessments collected 
outside of on-treatment period will be flagged.
For analysis of vital signs the clinically notable vital sign criteria are provided in Table 2-3
below.
Table 2-3
Clinically notable changes in vital signs
Vital sign (unit)
Clinically notable criteria
above normal value 
below normal value
Weight (kg)
increase ≥10% from Baseline
decrease  ≥10% from Baseline
Systolic blood 
pressure (mmHg)
≥ 180 and
increase from baseline of ≥ 20
≤ 90 and
decrease from baseline of ≥ 20
Diastolic blood 
≥ 105 and
≤ 50 and


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Vital sign (unit)
Clinically notable criteria
above normal value 
below normal value
pressure (mmHg)
increase from baseline of ≥ 15
decrease from baseline of ≥ 15
Pulse rate (bpm)
≥ 100 and
increase from baseline of > 25%
≤ 50 and
decrease from baseline of > 25%
Body temperature
(°C)
≥ 39.1 
-
2.8.4.3
Immunogenicity
Immunogenicity will be characterized descriptively tabulating antidrug antibodies (ADA) 
prevalence at baseline and ADA incidence on-treatment.
2.9
Pharmacokinetic endpoints
Refer to Section 2.5
2.10
PD and PK/PD analyses
Refer to Section 2.5
2.11
Patient-reported outcomes
Not applicable.
 


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3
Sample size calculation
5.0 mg/kg treatment group:
For sample size consideration, PK and PD data from study CSEG101A2101 and study 
CSEG101A2201 were used. Currently, the inter-subject variability of PK parameters, such as 
AUC and Cmax, of VOC subjects is not known and needs to be approximated from the 
Ctrough results of subject study A2201. In that study the inter-subject variability of Ctrough 
was found to be 50.8%.
Data of study A2101 has revealed a high correlation between PK concentrations 336h post-
dose and AUCt. Assuming this correlation holds true for subjects together with the 
assumption of an inter-subject CV = 50.8% of pre-dose concentrations allows an 
approximation of expected inter-subject CV = 46.1% for AUCt.
Currently, the inter-subject variation of the P-Selectin inhibition at 5.0 mg/kg and the 
respective PDAUC672hr is not known. However, approximations utilizing results from lower 


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dose groups tested in study CSEG101A2101 suggest an inter-subject coefficient of variation 
of approximately CV = 34.1%.
When the sample size is 27 evaluable subjects, a two-sided 90% confidence interval for a 
single mean of log-transformed AUC will extend 0.140 from the observed mean, ensuring a 
precision of 15%, assuming that the standard deviation is known to be 0.439 and the 
confidence interval is based on the large sample z statistic.
Similarly, with the same sample size of 27 evaluable subjects, a two-sided 90% confidence 
interval for a single mean of log-transformed PD-AUC will extend 0.105 from the observed 
mean, representing a precision of about 11%, assuming that the standard deviation is known 
to be 0.332 and the confidence interval is based on the large sample z statistic.
Exploratory 7.5 mg/kg treatment group:
When the sample size for this dose group is 6, a two-sided 90% confidence interval for a 
single mean will extend 0.172 from the observed mean, assuming that the standard deviation 
is known to be 0.209 and the confidence interval is based on t-statistic. 
Considering a drop-out rate of 35% from the CSEG101A2201 study, and to account for the 
heterogeneity of subjects in terms of genotype and renal function, the multiplication factor for 
enrollment versus evaluable subjects is 67%, and 45 subjects will need to be enrolled in the 
5.0 mg/kg treatment group. The same holds for the exploratory cohort, requiring enrollment of 
10 subjects to yield 6 evaluable subjects at the 7.5 mg/kg dose.
4
Change to protocol specified analyses
No change from protocol specified analyses was made.
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
Missing dates for study drug administraton should be queried and will not be imputed.
5.1.2
AE, ConMeds and safety assessment date imputation
Table 5-1
Imputation of start dates (AE, CM) and assessments (LB, EG, VS)
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. 


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Missing 
Element
Rule

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  
Table 5-2
Imputation of end dates (AE, CM) 
Missing 
Element
Rule
(*=last treatment date plus 105 days not > (death date, cut-off date, 
withdrawal of consent date))
day, month, 
and year

Completely missing end dates (incl. ongoing events) will be imputed by 
the end date of the on-treatment period* 
day, month

If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period * 
day

If partial end date contains month and year, set end date = earliest of last 
day of the month or end date of the on-treatment period*
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data 
listings.
Any AEs and ConMeds which are continuing as per data cut-off will be shown as ‘ongoing’ 
rather than the end date provided. 
5.1.2.1
Other imputations
5.2
AEs coding/grading
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology.
Note: The latest available MedDRA version at the time of the analyses should be used. The 
MedDRA version used should be specified in the footnote of relevant tables.  
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0.
The CTCAE represents a comprehensive grading system for reporting the acute and late 
effects of cancer treatments. CTCAE grading is by definition a 5-point scale generally 
corresponding to mild, moderate, severe, life threatening, and death. This grading system 


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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 
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  
CTC grading for blood differentials is based on absolute values. However, this data may not 
be reported as absolute counts but rather as percentage of WBC. 
If laboratory values are provided as ‘< X’ (i.e. below limit of detection) or ‘> X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X. 
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential
xxx count = (WBC count) * (xxx %value / 100)
Further derivation of laboratory parameters might be required for CTCAE grading. For 
instance, corrected calcium can be derived using the reported total calcium value and albumin 
at the same assessment using the following formula:
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4]
In order to apply the above formula, albumin values in g/L will be converted to g/dL by 
multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 
0.2495. For calculation of laboratory CTC grades 0 and 1, the normal range for derived
corrected calcium is set to the same limits (in mg/dL) as for calcium.
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium will be assigned as described above for grading.
6
Reference
Pharmacokinetic / Pharmacodynamic Analysis Manual, Novartis, 17 Dec 2015.


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