A Randomized, Double-blind, Placebo-controlled, Multicenter Study to Assess the Safety and Efficacy of Inclacumab in Participants With Sickle Cell Disease Experiencing Vaso-occlusive Crises
Phase: PHASE3
Conditions: Sickle Cell Disease, Vaso-occlusive Pain Episode in Sickle Cell Disease, Vaso-occlusive Crisis
Sponsor: Pfizer

Global Blood Therapeutics, Inc.
Protocol Amendment 4
GBT2104-131
CONFIDENTIAL
1
CLINICAL STUDY PROTOCOL
Study Number
GBT2104-131 (C5361001)
Study Title
A Randomized, Double-blind, Placebo-controlled, Multicenter 
Study to Assess the Safety and Efficacy of Inclacumab in 
Participants with Sickle Cell Disease Experiencing 
Vaso-occlusive Crises
Investigational Product
Inclacumab
IND Number
144073
EudraCT Number
2020-005286-13
Sponsor Legal Address
Global Blood Therapeutics, Inc., A Wholly Owned Subsidiary 
of Pfizer Inc.
181 Oyster Point Blvd, 
South San Francisco, CA 94080
United States of America
Original Protocol
Amendment 1
Amendment 2
Amendment 3
Amendment 4
06 November 2020, Version 1.0
17 December 2020, Version 2.0
21 January 2021, Version 3.0
11 April 2022, Version 4.0
13 July 2023, Version 5.0
CONFIDENTIALITY STATEMENT
The information in this protocol is strictly confidential and is available for review to 
investigator(s), study center personnel, the ethics committee, and health authorities. It will 
not be disclosed to third parties without written authorization from the Sponsor, except to 
obtain informed consent from persons receiving study treatment. Once the protocol is signed, 
its terms are binding for all parties.
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Protocol Amendment 4
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CONFIDENTIAL
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SUMMARY OF CHANGES 
Amendment 4 (13 July 2023)
Overall Rationale for the Amendment: 
To add a futility analysis and align the protocol with language in Pfizer Protocol Template 
and Standard Operating Procedures
Protocol Amendment Summary of Changes Table
Section
Change
Brief Rationale
Substantial 
(Y/N)
Statement of Approval and 
Compliance
Deleted
To align with 
Pfizer Protocol 
Template following 
the acquisition of 
Global Blood 
Therapeutics 
(GBT) by Pfizer
The information 
will be captured in 
a separate 
document.
N
Cover page
Synopsis
Sections:

1.3 (Rationale for 
Inclacumab in SCD)

3. Investigational Plan

3.1 (Study Design)

7.2.3 (Abnormal Laboratory 
Values)

7.2.1 (General – Adverse 
Event Reporting)

7.3 (Adverse Events of 
Special Interest, Serious 
Adverse Events, Serious 
Adverse Drug Reactions, 
and Requirements for 
Immediate Reporting)

7.4 (Reporting and 
Treatment of Overdose) -
new section

7.5 (Adverse Events that are 
VOC Endpoint Events)
Added and/or revised 
language 
To align with 
Pfizer Protocol 
Template following 
the acquisition of 
Global Blood 
Therapeutics 
(GBT) by Pfizer
Y
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Protocol Amendment 4
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CONFIDENTIAL
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Section
Change
Brief Rationale
Substantial 
(Y/N)

7.6 (Environmental 
Exposure, Exposure During 
Pregnancy or Breastfeeding, 
and Occupational Exposure) 
- new section

7.8 (Follow-up of AEs and 
SAEs)

7.6.5 (Medication Errors) –
new section

9.4 (Sponsor’s Medically 
Qualified Individual) - new 
section

9.5.1 (Regulatory and 
Ethical Considerations)

9.5.2 (Reporting of Safety 
Issues and Serious Breach 
of the Protocol or ICH 
GCP) - new section

9.5.3 (Informed 
Consent/Assent Process)

9.5.5 (Data Protection) -
new section

9.5.7 (Dissemination of 
Clinical Study Data) - new 
section

9.5.8 (Data Quality 
Assurance) - new section

9.5.9 (Study and Site Start 
and Closure) - new section

9.7 (Publication Policy)
Synopsis
Sections:

3 (Investigational Plan)

3.1 (Study Design)

3.2.5 (Exploratory 
Pharmacology Endpoints)

3.3.1.1 (Inclusion Criteria)

3.3.1.2 (Exclusion Criteria)

3.3.3.1.1 (Early 
Discontinuation of Study 
Treatment)

4.8.3 (Blinding Procedures)
Integrated country
specific instructions 
and guidelines into the 
global protocol
To align with 
Pfizer Protocol 
Template following 
the acquisition of 
GBT by Pfizer
N
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CONFIDENTIAL
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Section
Change
Brief Rationale
Substantial 
(Y/N)

5 (Study Assessments)

5.3.4 (Clinical Laboratory 
Tests)

5.4.2 (Pregnancy Screen)

5.5 (Pharmacology 
Assessments (PK, ADA, 
PD, Biomarkers)

6.1.2 (Prohibited 
Medications and Therapies)

7.2.1 (General – Adverse 
Events Reporting)

7.2.3 (Abnormal Laboratory 
Values)

7.5 (Adverse Events That 
are VOC Endpoint Events)

7.7 (Data Monitoring 
Committee)

8.4.4 (PK, ADA, and PD 
Analyses)

8.4.4.1 (Pharmacokinetic 
Analyses)
Appendices:

1 (Schedule of 
Assessments)

5 (Liver Safety) – new 
section

6 (Country-Specific 
Amendments) – new section
Synopsis
Section 3.3.1.2 (Exclusion Criteria)
Updated the unit for 
estimated glomerular 
filtration rate (eGFR) 
from absolute (ie, 
mL/min) to adjusted 
for body surface area 
(BSA; ie, mL/min/1.73
m2)
eGFR adjusted for 
BSA is more 
commonly reported 
by local 
laboratories.
N
Synopsis
Section 8.4.3.4 (Interim Futility 
Analysis)
Added a futility 
analysis
To allow the 
potential to stop the 
trial early if futile
Y
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Protocol Amendment 4
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Section
Change
Brief Rationale
Substantial 
(Y/N)
Section 1.3 (Rationale for 
Inclacumab in SCD)
Removed reference to 
safety and efficacy of 
crizanlizumab
In January 2023, 
Novartis, the 
manufacturer of 
crizanlizumab 
reported lack of the 
drug’s efficacy 
(annualized rates of 
vaso-occlusive 
crises) in patients 
with sickle cell 
disease relative to 
placebo.
N
Sections:

3.3.4 (Lost to Follow-up)

4.9 (Assessment of 
Treatment Compliance)

5.4.4 (Quality of Life 
Assessments)

5.4.5 (VOC Incidence)

7 (Assessment of Safety)

7.1.1 (Definition of Adverse 
Events)

7.2.1 (General – Adverse 
Events Reporting)

7.5 (Reporting Overdose)
Appendix 1 (Schedule of 
Assessments)
Added the following 
two sentences, where 
applicable:
“(and/or their parent or 
legal guardian for 
participants under 18 
years of age)”
“Collect at presentation 
for VOC as feasible.”
Clarification
N
Appendix 1 (Schedule of 
Assessments)
Specified that 
laboratory assessments 
that are not routinely 
collected as part of 
management of a VOC 
(ie, unscheduled visits 
for a VOC) will be 
requested, as feasible.
Clarification
N
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Protocol Amendment 4
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CONFIDENTIAL
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SYNOPSIS
Study Number:
GBT2104-131 (C5361001)
Study Title:
A Randomized, Double-blind, Placebo-controlled, Multicenter Study to 
Assess the Safety and Efficacy of Inclacumab in Participants with Sickle 
Cell Disease Experiencing Vaso-occlusive Crises
Investigational 
Product:
Inclacumab
Sponsor:
Global Blood Therapeutics, Inc., A Wholly Owned Subsidiary of Pfizer Inc.
181 Oyster Point Blvd.
South San Francisco, CA 94080
United States of America
Phase:
Phase 3
Note: In France, this study is considered Phase 2.
Number of Sites 
The study will be conducted at up to approximately 75 clinical sites.
Number of Study 
Participants:
Approximately 240 participants will be enrolled. 
Duration of 
Treatment:
The total duration of treatment for each participant will be 48 weeks. Doses 
will be administered at Day 1 and Weeks 12, 24, and 36 with blood levels 
expected to be in the target range through at least Week 48.
Objective:
The primary objective of this study is to evaluate the safety and efficacy of 
treatment every 12 weeks (Q12W) with inclacumab to reduce the incidence of 
vaso-occlusive crises (VOCs) in participants with sickle cell disease (SCD).
Additional objectives of the study are to evaluate the pharmacokinetics (PK) 
and pharmacodynamics (PD) of inclacumab, the presence of anti-drug 
antibodies (ADAs), and changes in quality of life (QOL).
Endpoints:
Primary Efficacy Endpoint:
The primary efficacy endpoint of the study is the rate of VOCs during the 
48-week treatment period. 
A VOC is defined as an acute episode of pain that:

Has no medically determined cause other than a vaso-occlusive event, 
and 

Results in a visit to a medical facility (hospitalization, emergency 
department, urgent care center, outpatient clinic, or infusion center), or 
results in a remote contact with a healthcare provider; and

Requires parenteral narcotic agents, parenteral nonsteroidal 
anti-inflammatory drugs (NSAIDs), or an increase in treatment with 
oral narcotics.
Complicated VOCs of acute chest syndrome (ACS), hepatic sequestration, 
splenic sequestration, and priapism, that meet the requirements listed above 
will be included in the primary endpoint.
To ensure consistency across study sites, all on-study VOCs reported by the 
study investigators will be adjudicated by an independent, blinded panel 
comprised of experts in SCD. The primary efficacy analysis will be performed 
on adjudicated data.
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Secondary Efficacy Endpoints:
The secondary efficacy endpoints of the study are the following: 

Time to first VOC during the 48-week treatment period.

Time to second VOC during the 48-week treatment period.

Proportion of participants with no VOCs during the 48-week treatment 
period. 

Rate of VOCs that required admission to a healthcare facility and 
treatment with parenteral pain medication during the 48-week 
treatment period where admission includes:

A hospital admission, or

An admission to an emergency room, observation unit, or 
infusion center for ≥ 12 hours, or

2 visits to an emergency room, observation unit, or infusion 
center over a 72-hour period, or

Number of days of inpatient hospitalization for a VOC during the 48-
week treatment period.
Safety Endpoints:
The safety endpoints of the study are the following:

Incidence of treatment-emergent adverse events (TEAEs).

Change from Baseline in laboratory assessments (complete blood 
count [CBC], chemistry, and coagulation).
Exploratory Endpoints:
The exploratory endpoints of the study are the following:

Rate of all SCD-related urgent care visits to the clinic, emergency 
room, and hospital during the 48-week treatment period.

Proportion of total days missed from school or work due to SCD 
during the 48-week treatment period.

Rate of complicated VOCs during the 48-week treatment period.

Rate of red blood cell (RBC) transfusions during the 48-week 
treatment period.

Rate of inpatient hospital admissions for any reason during the 
48-week treatment period.

Number of days of inpatient hospitalization for any reason during the 
48-week treatment period.

Proportion of participants rated as “very much improved” or “much
improved” based on the Patient’s Global Impression of Change (PGI-
C) at Weeks 12, 24, 36, and 48.

Proportion of participants rated as “very much improved” or “much
improved” based on the Clinician’s Global Impression of Change 
(CGI-C) at Weeks 12, 24, 36, and 48.

Change from Baseline in the cumulative score for the Adult Sickle 
Cell Quality of Life Measurement (ASCQ-Me) Pain Impact –
Short Form over time to Week 48.
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Exploratory Pharmacology Endpoints:

Plasma PK of inclacumab as assessed by population PK analysis using 
nonlinear mixed-effects modeling.

Incidence of ADA to inclacumab.

Pharmacodynamics including changes in non-activated and thrombin 
receptor activating peptide (TRAP)-activated platelet leukocyte 
aggregates (PLAs), platelet (PLT) P-selectin expression, serum 
P-selectin inhibition measured by surface plasmon resonance (SPR), 
and plasma total and free soluble P-selectin (sP-selectin-) over time.

Biomarkers including changes in RBC adhesion (selected sites), 
genomic markers (optional), protein markers in the blood, urine 
markers of kidney function, and voxelotor plasma and whole blood
concentrations (as applicable)
Relationships between PK, PD, biomarkers, clinical labs, safety, and efficacy
will be explored.
Note: In Egypt, blood samples for PK, PD, ADA, and biomarker endpoints
samples will not be collected.
Study Design:
This study will be a randomized, placebo-controlled, double-blind, multicenter, 
parallel-group study to assess the safety and efficacy of inclacumab in reducing 
the frequency of VOCs in approximately 240 adult and adolescent participants 
(≥12 years of age) with SCD globally. Initial enrollment will include 
participants ≥16 years of age until the Data Monitoring Committee (DMC)
recommends to the Sponsor that adequate safety and PK data support the 
enrollment of participants 12 to 15 years of age.
Eligible participants will be randomized with a 1:1 ratio into one of two 
treatment arms as follows:

Inclacumab 30 mg/kg administered intravenously (IV) Q12W (Day 1, 
Week 12, Week 24, and Week 36); or 

Placebo administered IV Q12W (Day 1, Week 12, Week 24, and 
Week 36). 
At the time of randomization, participants will be stratified by Baseline 
hydroxyurea (HU) use (yes; no), number of VOCs (2 to 4; 5 to 10) in the 
preceding 12 months, and geographic region (North America; sub-Saharan 
Africa; Europe/rest of world).
An independent DMC will regularly review the totality of accumulated safety 
data from all ongoing inclacumab studies on an ongoing, unblinded basis, with 
specific emphasis on adolescent participants. Details are provided in the DMC 
Charter.
Participants that complete the study through Week 48 will be provided the 
opportunity to enroll in an open-label extension (OLE) study.
Note: For France-, Germany-, UK-, and Egypt-specific study design, refer to 
Appendix 6-1, Appendix 6-2, Appendix 6-3, and Appendix 6-5, respectively, 
in the body of the protocol.
Investigational 
Product, Dose, 
and Mode of 
Administration:
Inclacumab drug product is a sterile, clear to opalescent liquid concentrate for 
infusion with an approximate pH of 5.5 provided in colorless, 10 mL single-
use vials. Each vial contains 500 mg of inclacumab and the following 
excipients: L-histidine-acetate, sucrose, and poloxamer 188. An inclacumab 
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dose of 30 mg/kg will be administered IV. Participants will be monitored for 
60 minutes after completion of study drug infusion for adverse reactions.
Comparator 
Product:
The comparator product is a placebo for inclacumab containing the same 
ingredients without the active drug. Placebo will be prepared and administered 
in the same manner as active study drug. 
Eligibility
Criteria:
Inclusion Criteria:
1.
Participant has a confirmed diagnosis of SCD (HbSS, HbSC, HbSβ0
thalassemia, or HbSβ+ thalassemia genotype).
Documentation of SCD genotype is required and may be based on 
documented history of laboratory testing or confirmed by laboratory 
testing during Screening.
2.
Participant is male or female, ≥12 years of age at the time of informed 
consent.
NOTE: Initial study enrollment will include participants ≥ 16 years of 
age until the DMC recommends to the Sponsor that adequate safety and 
PK data support the enrollment of participants 12 to 15 years of age. 
Sites will be informed by the Sponsor when participants 12 to 15 years of 
age may be enrolled.
Note: For France-, Germany-, and UK-specific study design, refer to 
Appendix 6-1, Appendix 6-2, and Appendix 6-3, respectively, in the 
body of the protocol.
3.
Participant has experienced between 2 and 10 VOCs within the 
12 months prior to the Screening Visit as determined by documented 
medical history. A prior VOC is defined as an acute episode of pain 
which:

Has no medically determined cause other than a 
vaso-occlusive event, and 

Results in a visit to a medical facility (hospital, emergency 
department, urgent care center, outpatient clinic, or infusion 
center) or results in a remote contact with a healthcare 
provider; and 

Requires parenteral narcotic agents, parenteral NSAIDs, or 
an increase in treatment with oral narcotics.
4.
Participants receiving erythropoiesis-stimulating agents 
(ESA, eg, erythropoietin [EPO]) must be on a stable dose for at 
least 90 days prior to the Screening Visit and expected to continue 
with the stabilized regimen throughout the course of the study. 
5.
Participants receiving HU, L-glutamine, or voxelotor must be on a 
stable dose for at least 30 days prior to the Screening Visit and 
expected to continue with the stabilized regimen throughout the course 
of the study. 
6.
Participant has adequate venous access, in the opinion of the 
Investigator, to comply with study procedures.
7.
Participant understands the study procedures and agrees to participate 
in the study by giving written informed consent or parental 
permission/written assent.
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Note: For the France-specific criterion, Appendix 6-1 in the body of 
the protocol.
8.
Women of childbearing potential (WOCBP) are required to have a 
negative serum pregnancy test at the Screening visit and negative urine 
pregnancy test on all subsequent clinic visits and must agree to use a 
highly effective method of contraception throughout the study period
and for at least 165 days after dosing. 
Female participants will not be considered of childbearing potential if 
they are pre-menarchal, surgically sterile (hysterectomy, bilateral 
salpingectomy, tubal ligation, or bilateral oophorectomy) or 
postmenopausal (no menses for 12 months without an alternative 
medical cause, confirmed by follicle-stimulating hormone test results).
Note: For the UK-specific criterion, Appendix 6-3 in the body of the 
protocol.
Exclusion Criteria:
1.
Participant is receiving regularly scheduled RBC transfusion therapy 
(also termed chronic, prophylactic, or preventative transfusion).
2.
Participant is taking or has received crizanlizumab (ADAKVEO®)
within 90 days prior to the Screening Visit.
3.
Participant weighs > 133 kg (292 lbs). 
4.
Participant has a significant active and poorly controlled (unstable) 
hepatic disorder clearly unrelated to SCD. 
Note: For UK-specific criterion, refer to Appendix 6-3 in the body of 
the protocol.
5.
Participant has any of the following laboratory values at Screening:
a.
Absolute neutrophil count (ANC) < 1.0 × 109/L
b.
Platelet count < 80 × 109/L
c.
Hemoglobin < 4.0 g/dL for adults and < 5.0 g/dL for participants 
ages 12 to < 18
d.
Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2
using Chronic Kidney Disease-Epidemiology Collaboration
(CKD-EPI) formula in adults, and Schwartz formula in 
adolescents
Note: For France- and Germany-specific criterion, refer to 
Appendix 6-1 and Appendix 6-2, respectively, in the body of the 
protocol.
6.
Participant has known active (symptomatic) coronavirus disease 2019
(COVID-19) infection or tests positive for COVID-19 during 
Screening.
7.
Participant has a history of unstable or deteriorating cardiac or 
pulmonary disease within 6 months prior to consent including severe 
or unstable pulmonary hypertension. 
8.
Participant has had treatment for a malignancy within the 12 months 
prior to the Screening Visit (except non-melanoma skin cancer and in 
situ cervical cancers).
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9.
Participant has had a stroke within the 2 years prior to the Screening 
Visit.
10. Participant has a positive test indicative of active malaria infection at 
Screening. Testing to be conducted at local laboratories in 
malaria -endemic regions at the discretion of the Investigator.
11. Participant has any confirmed clinically significant drug allergy and/or 
known hypersensitivity to monoclonal antibody therapeutics or 
formulation components of the study drug or a related drug.
12. Participant has been in another investigational trial within 30 days or 
5 half-lives of the investigational agent (whichever is greater) prior to 
the Screening Visit.
13. Participant has had a major surgery within 8 weeks prior to the 
Screening Visit.
14. Participant is pregnant, breastfeeding, or planning to become pregnant 
during the 48-week treatment period.
15. Participant, parent, or legal guardian are unlikely to comply with the 
study procedures.
Note: For France-specific criterion, refer to Appendix 6-1 in the body 
of the protocol.
16. Participant has any other medical, or psychological, or behavioral
conditions that, in the opinion of the Investigator, would confound or 
interfere with evaluation of safety, efficacy, and/or PK of the 
investigational drug; prevent compliance with the study protocol; 
preclude informed consent; or render the participant, parent, or 
caretaker unable/unlikely to comply with the study procedures.
Note: For the France-specific criterion, Appendix 6-1 in the body of 
the protocol.
Outcomes 
Measures:
Efficacy:
The outcome measure for efficacy is the incidence of VOCs as defined for the 
primary endpoint along with requirements for hospitalizations, RBC 
transfusions, and QOL assessments.
Safety:
Participants will be monitored from the time the informed consent is signed 
through the end of study (EOS) for TEAEs. Severity of TEAEs will be 
determined based on the Common Terminology Criteria for Adverse Events 
(CTCAE). 
Safety assessments also include physical examinations (PEs), vital signs 
measurements (blood pressure (BP), heart rate (HR), and body temperature), 
clinical laboratory evaluations including a chemistry panel and CBC, 
additional laboratory evaluations including prothrombin time, activated partial 
thromboplastin time (aPTT), and reticulocyte count, pregnancy tests as 
appropriate, and concomitant medications.
Additional assessments for safety will be collected when a participant presents 
with VOC on a non-study visit day, as feasible.
Pharmacokinetics:
In all participants, plasma samples will be collected for measurement of 
inclacumab concentrations before and after each dose, at the Week 6 visit, and 
at the end of the Treatment Period (Week 48). Samples will also be collected at 
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the Week 60 EOS Visit in all participants not proceeding to the OLE study. 
Additional samples for PK will be collected when a participant presents with 
VOC on a non-study visit day, as feasible. Population PK analysis using 
nonlinear mixed effects modeling will be performed to characterize 
inclacumab PK in plasma. 
Anti-Drug Antibodies:
In all participants, plasma samples will be collected for characterization of 
ADA incidence on Day 1 (pre-dose), Week 12 (pre-dose), Week 24 (pre-dose), 
and the Week 48 Study Visit. Samples will also be collected at the Week 60 
EOS Visit in all participants not proceeding to the OLE study. 
Pharmacodynamics:
At selected study visits (Appendix 2), whole blood samples will be collected 
for assessment of non-activated and TRAP-activated PLA formation and PLT 
P selectin expression. Serum samples will be collected for assessment of 
P-selectin inhibition by SPR. Plasma samples will be collected for assessment 
of circulating soluble free and total P-selectin. Additional samples for PD will 
be collected when a participant presents with VOC on a non-study visit day, as 
feasible. 
Biomarkers including changes in red blood cell (RBC) adhesion (selected 
sites), genomic markers (optional), protein markers in the blood, urine markers 
of kidney function, and voxelotor plasma and whole blood concentrations (as 
applicable) will be collected.
The relationships between PK, PD, clinical labs, safety, and efficacy will be 
explored.
Note: In Egypt, blood samples for PK, PD, ADA, and biomarker endpoints
samples will not be collected.
Study
Procedures:
The Schedule of Assessments is provided in Appendix 1 and the schedule for 
collection of PK, ADA, and PD samples is provided in Appendix 2. The 
schedule for collection of biomarkers is provided in Appendix 3.
Participants will be screened for eligibility for up to 28 days prior to 
randomization. Eligible participants will be randomized on Day 1 (Baseline) 
and receive the first dose of study drug. Participants will return to the clinical 
site at Week 6, Week 12, then Q12W for safety, pharmacology, and efficacy 
assessments. Infusion of study drug will occur at Week 12, Week 24, and 
Week 36. The majority of participants receiving active study drug are expected 
to maintain target concentrations through Week 48. Participants will record 
responses to the ASCQ-Me questionnaire weekly, when available. Each month 
between study visits, the participant will be contacted to assess VOCs, pain 
crises events, adverse events (AEs), and changes in concomitant medications. 
Participants that complete the 48-week treatment period will be provided the 
opportunity to enroll the OLE study at Week 48. For participants enrolling in 
the OLE study, the Week 48 Visit will be the EOS Visit and participants will 
receive the first dose of open-label inclacumab at this same visit. For 
participants not enrolling in the OLE study, an additional required Follow-up 
Visit at Week 60 will be the EOS Visit.
Note: For UK- and Egypt-specific procedures, refer to Appendix 6-3 and 
Appendix 6-5, respectively, in the body of the protocol.
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Statistical
Methods:
Detailed specifications of the methods for summary and analyses of the data 
collected in this study will be documented in the Statistical Analysis Plan 
(SAP).
Sample Size:
A sample size of approximately 240 participants (120 participants per 
treatment arm [inclacumab and placebo]) provides approximately 90% power 
to detect a targeted 45% reduction in the rate of VOCs, from an average rate of 
3.0 VOCs per year on placebo to 1.65 VOCs per year on inclacumab, using a 
2-sided test at an overall α = 0.05 level. 
Calculations assume the number of VOCs per year follows a negative binomial 
distribution with a dispersion parameter of 1.04. For the purposes of sample 
size calculation, a drop-out rate of 25% by Week 48 was assumed.
Efficacy Populations and Analysis:
Efficacy analyses will be based on an intent-to-treat (ITT) population 
consisting of all randomized participants, with participants grouped according 
to the treatment assigned at randomization. 
Primary Efficacy Endpoint:
For the primary efficacy endpoint, the rate of VOCs during the 48-week 
treatment period will be compared between the inclacumab and placebo arms 
with the use of negative binomial regression model. 
The regression model will include covariates for treatment group (inclacumab, 
placebo) and the randomization stratification factors. The logarithm of 
observed patient-time at risk will be used as an offset term in the model. The 
rate of VOCs adjusted for the specified Baseline covariates will be estimated 
for each treatment arm based on the regression model. Similarly, the ratio of 
the VOC rate (inclacumab versus placebo) along with the associated 95% 
confidence interval (CI) and p-value will be estimated from the regression 
model.
The regression model will be fit based on all observed data from randomized 
participants, regardless of adherence to study drug or to the protocol. 
Sensitivity analyses will be performed to assess the robustness of the primary 
analysis results. Details will be specified in the SAP.
Secondary Efficacy Endpoints:
For the secondary endpoints of time to first VOC and time to second VOC, 
treatment comparison between inclacumab and placebo will be performed 
based on a stratified log-rank test. Kaplan-Meier plots will be generated. Time 
to first and time to second VOC will be measured from randomization (Day 1) 
to onset date of the corresponding VOC event. A Cox regression model will be 
used to estimate the hazard ratio between the inclacumab and placebo groups, 
as appropriate.
For the proportion of participants with no VOCs during the 48-week treatment 
period, the exact Cochran-Mantel-Haenszel (CMH) general association test, 
stratified by the randomization stratification factors, will be used.
For the rate of VOCs that required admission to a healthcare facility and 
treatment with parenteral pain medication during the 48-week treatment period
and number of days of inpatient hospitalization for VOC during the 48-week 
treatment period, the same statistical method used for the primary endpoint 
will be used. 
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Interim Futility Analysis:
One interim analysis for futility will be performed at an information fraction of 
approximately 48%. The futility analysis will include subjects who have the 
potential for at least 24 weeks of treatment (ie, 2 doses of study drug) by the 
selected data cutoff date. 
For the futility analysis, the primary efficacy endpoint will be evaluated by the 
independent DMC. The study team will remain blinded. A Gamma family (-1) 
β-spending function will be used to determine the futility boundary. The 
futility boundary is non-binding. Additional details will be provided in the 
SAP.  
Adjustment for Multiple Comparisons:
A fixed sequence hierarchical test procedure will be used to control Type I 
error when evaluating the treatment effect of inclacumab compared with 
placebo for the primary and secondary efficacy endpoints. The endpoints will 
be tested in a pre-specified order, with formal testing of endpoints continuing 
until the first non-significant result. 
Safety Population and Analysis:
Safety analysis will be based on all randomized participants receiving 
treatment with study drug.
Adverse events will be classified according to the Medical Dictionary for 
Regulatory Activities (MedDRA). The incidence of TEAEs, defined as events 
that occur on or after Day 1 of study treatment or the worsening of a 
pre-existing condition on or after Day 1 of study treatment, will be tabulated 
by System Organ Class and Preferred Term. Additional summaries for TEAEs 
by severity, relationship to study drug, and leading to study drug 
discontinuation, as well as for adverse events of special interest (AESIs), 
serious adverse events (SAEs), and deaths will be generated. 
Vaso-occlusive crises events will be collected and summarized separately 
(including ACS, hepatic sequestration, splenic sequestration, and priapism).
Changes in laboratory parameters (hematology, serum chemistry, and 
coagulation) and vital signs (eg, blood pressure, heart rate, and body 
temperature) over time will be summarized descriptively.
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TABLE OF CONTENTS
SUMMARY OF CHANGES.....................................................................................................2
SYNOPSIS.................................................................................................................................6
LIST OF TABLES...................................................................................................................19
LIST OF FIGURES .................................................................................................................19
APPENDICES .........................................................................................................................20
LIST OF ABBREVIATIONS..................................................................................................21
1. INTRODUCTION ...............................................................................................................24
1.1. Sickle Cell Disease..................................................................................................24
1.2. Current Therapy for Sickle Cell Anemia ................................................................24
1.3. Rationale for Inclacumab in SCD ...........................................................................25
1.3.1. Study Design Rationale ..............................................................................26
1.3.2. Rationale for Dose Regimen.......................................................................26
1.3.3. Use of a Placebo Control............................................................................27
2. OBJECTIVES......................................................................................................................27
3. INVESTIGATIONAL PLAN..............................................................................................27
3.1. Study Design ...........................................................................................................27
3.2. Study Endpoints ......................................................................................................28
3.2.1. Primary Efficacy Endpoint .........................................................................28
3.2.2. Secondary Efficacy Endpoints....................................................................29
3.2.3. Safety Endpoints.........................................................................................29
3.2.4. Exploratory Endpoints................................................................................29
3.2.5. Exploratory Pharmacology Endpoints........................................................30
3.3. Selection of Study Population.................................................................................30
3.3.1. Eligibility....................................................................................................31
3.3.1.1. Inclusion Criteria.......................................................................31
3.3.1.2. Exclusion Criteria......................................................................32
3.3.2. Participant Completion...............................................................................33
3.3.3. Study Discontinuation ................................................................................33
3.3.3.1. Early Discontinuation of Individual Participants......................34
3.3.4. Lost to Follow-up .......................................................................................34
3.4. Study Duration ........................................................................................................35
3.5. Treatments...............................................................................................................35
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4. STUDY DRUG INFORMATION.......................................................................................35
4.1. Description of Active Study Drug – Inclacumab....................................................35
4.2. Description of Placebo for Inclacumab...................................................................35
4.3. Packaging and Labeling ..........................................................................................35
4.4. Storage and Handling..............................................................................................36
4.5. Instructions for Use and Administration .................................................................36
4.6. Management of Infusion-Related Reactions (IRR).................................................36
4.7. Accountability .........................................................................................................36
4.8. Methods of Assigning Participants to Treatment Groups .......................................37
4.8.1. Participant Screening..................................................................................37
4.8.2. Randomization Method ..............................................................................37
4.8.3. Blinding Procedures....................................................................................37
4.9. Assessment of Treatment Compliance....................................................................38
5. STUDY ASSESSMENTS ...................................................................................................38
5.1. Primary Efficacy Assessment..................................................................................38
5.2. Secondary and Exploratory Efficacy Assessments .................................................39
5.3. Safety Assessments .................................................................................................40
5.3.1. Adverse Events...........................................................................................40
5.3.2. Physical Examination .................................................................................40
5.3.3. Vital Signs ..................................................................................................40
5.3.4. Clinical Laboratory Tests ...........................................................................40
5.4. Clinical Assessments...............................................................................................42
5.4.1. Demographic/Medical History ...................................................................42
5.4.2. Pregnancy Screen........................................................................................42
5.4.3. SARS-CoV-2 (COVID-19) Infection.........................................................42
5.4.4. Quality of Life Assessments.......................................................................42
5.4.5. VOC Incidence ...........................................................................................42
5.5. Pharmacology Assessments (PK, ADA, PD, Biomarkers) .....................................43
5.5.1. Pharmacokinetics........................................................................................43
5.5.2. Anti-drug Antibodies..................................................................................43
5.5.3. Pharmacodynamics.....................................................................................43
5.5.4. Biomarkers..................................................................................................44
5.6. Unscheduled Visits for a VOC................................................................................44
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5.7. Additional Unscheduled Visits................................................................................44
5.8. Missed Visits...........................................................................................................45
5.9. Post-study Follow-up ..............................................................................................45
5.10. Study Completion..................................................................................................45
5.10.1. Early Study Termination...........................................................................45
6. CONCOMITANT MEDICATIONS AND PROCEDURES...............................................45
6.1. Concomitant Medications .......................................................................................45
6.1.1. Prohibited Medications and Therapies .......................................................45
6.2. Concomitant Procedures .........................................................................................46
6.3. Contraception Requirements...................................................................................46
6.3.1. Instructions for Female Participants of Childbearing Potential..................46
6.3.2. Instructions for Male Participants Capable of Fathering a Child ...............46
6.3.3. Acceptable Forms of Contraception for Sexually Active Participants.......47
6.4. Continuation of Treatment ......................................................................................47
7. ASSESSMENT OF SAFETY..............................................................................................48
7.1. Adverse Events........................................................................................................48
7.1.1. Definition of Adverse Events .....................................................................48
7.1.2. Definition of Serious Adverse Events ........................................................49
7.1.3. Severity of Adverse Events ........................................................................49
7.1.4. Relationship to Investigational Product......................................................50
7.2. Adverse Event Reporting ........................................................................................50
7.2.1. General........................................................................................................50
7.2.2. Diagnosis Versus Signs and Symptoms .....................................................51
7.2.3. Abnormal Laboratory Values .....................................................................51
7.3. Adverse Events of Special Interest, Serious Adverse Events, Serious 
Adverse Drug Reactions, and Requirements for Immediate Reporting....................52
7.3.1. Reporting Suspected Unexpected Serious Adverse Reactions and 
Urgent Safety Issues ........................................................................................52
7.4. Adverse Events That are VOC Endpoint Events ....................................................53
7.4.1. Procedures for Reporting and Documenting VOC Event Data..................54
7.4.2. Source Document Collection for VOC Event Adjudication.......................55
7.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure..............................................................................................55
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7.5.1. Exposure During Pregnancy.......................................................................56
7.5.2. Exposure During Breastfeeding..................................................................57
7.5.3. Occupational Exposure...............................................................................57
7.5.4. Lack of Efficacy .........................................................................................58
7.5.5. Medication Errors .......................................................................................58
7.6. Data Monitoring Committee ...................................................................................58
7.7. Follow-up of AEs and SAEs ...................................................................................59
7.8. Safety Responsibilities ............................................................................................59
7.8.1. Investigator .................................................................................................59
7.8.2. Sponsor .......................................................................................................60
7.8.3. Reporting of SAEs......................................................................................60
8. STATISTICAL METHODS................................................................................................61
8.1. Study Endpoints ......................................................................................................61
8.2. Determination of Sample Size.................................................................................61
8.3. Analysis Populations...............................................................................................61
8.4. Statistical Analysis ..................................................................................................62
8.4.1. Summaries of Study Conduct .....................................................................62
8.4.2. Summaries of Demographics, Baseline Characteristics, and 
Concomitant Medications................................................................................62
8.4.3. Efficacy Analyses .......................................................................................62
8.4.3.1. Primary Endpoint ......................................................................62
8.4.3.2. Secondary Endpoints.................................................................62
8.4.3.3. Exploratory Endpoints...............................................................63
8.4.3.4. Interim Futility Analysis ...........................................................63
8.4.3.5. Adjustment for Multiple Comparisons......................................63
8.4.3.6. Safety Analyses.........................................................................64
8.4.4. PK, ADA, and PD Analyses.......................................................................64
8.4.4.1. Pharmacokinetic Analyses ........................................................64
8.4.4.2. Anti-drug Antibody Analyses ...................................................64
8.4.4.3. Pharmacodynamic Analyses .....................................................64
9. STUDY ADMINISTRATION.............................................................................................65
9.1. Direct Access to Source Data/Documents ..............................................................65
9.1.1. Source Data.................................................................................................65
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9.2. Data Collection........................................................................................................66
9.3. Quality Control and Quality Assurance ..................................................................66
9.3.1. Monitoring..................................................................................................66
9.3.2. Quality Control and Quality Assurance......................................................66
9.3.3. Laboratory Accreditation............................................................................67
9.4. Sponsor’s Medically Qualified Individual ..............................................................67
9.5. Regulatory, Ethical, and Study Oversight Considerations......................................67
9.5.1. Regulatory and Ethical Considerations ......................................................67
9.5.2. Reporting of Safety Issues and Serious Breaches of the Protocol or 
ICH GCP..........................................................................................................68
9.5.3. Informed Consent/Assent Process ..............................................................68
9.5.3.1. Adult Participants......................................................................68
9.5.3.2. Pediatric Participants.................................................................69
9.5.4. Data Protection ...........................................................................................70
9.5.5. IRB/EC and Regulatory Approval..............................................................71
9.5.6. Essential Documentation Requirements.....................................................71
9.5.7. Dissemination of Clinical Study Data ........................................................72
9.5.8. Data Quality Assurance ..............................................................................73
9.5.9. Study and Site Start and Closure ................................................................74
9.5.10. Confidentiality..........................................................................................74
9.6. Publication Policy ...................................................................................................75
10. REFERENCES ..................................................................................................................76
LIST OF TABLES
Table 1:
Clinical Laboratory Tests .........................................................................41
Table 2:
Grading for Adverse Events not Covered in the NCI-CTCAE ................49
Table 3:
VOC Events Not Requiring AE/SAE Reporting......................................53
Table 4:
Reporting of Medication Errors................................................................58
Table 5:
Infusion-related Reactions........................................................................83
LIST OF FIGURES
Figure 1:
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APPENDICES
Appendix 1. Schedule of Assessments ....................................................................................78
Appendix 2. Schedule of Assessments for Inclacumab PK, ADA, PD...................................81
Appendix 3. Schedule of Assessments for Biomarkers...........................................................82
Appendix 4. Infusion-Related Reaction Grading.....................................................................83
Appendix 5. Liver Safety: Suggested Actions and Follow-Up Assessments and Study 
Drug Rechallenge Guidelines...................................................................84
Appendix 6. Country-specific amendments.............................................................................86
Appendix 6.1. France-Specific Amendment............................................................................86
Appendix 6.2. Germany-Specific Amendment........................................................................89
Appendix 6.3. UK-Specific Amendment.................................................................................92
Appendix 6.4. Ghana-Specific Amendment ..........................................................................101
Appendix 6.5. Egypt-Specific Amendment...........................................................................105
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LIST OF ABBREVIATIONS
Abbreviation
Definition
ACS
acute chest syndrome
ADA
anti-drug antibodies
ADL
activities of daily living
AE
adverse event
AESI
adverse event of special interest
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
ASCQ-Me
adult sickle-cell quality of life measurement
BP
blood pressure
CBC
complete blood count
CFR
Code of Federal Regulations
CGI-C
Clinician’s Global Impression of Change
CHO
Chinese hamster ovary
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CKD-EPI
chronic kidney disease – epidemiology collaboration
ClinRO
clinician reported outcomes
CMH
Cochran-Mantel-Haenszel
COVID-19
coronavirus disease 2019 
CRO
clinical contract research organization
CRP
C-reactive protein
CSR
clinical study report
CT
clinical trial
CTCAE
Common Terminology Criteria for Adverse Events
CTIS
Clinical Trials Information System
DMC
Data Monitoring Committee
DCT
data collection tool
DILI
drug-induced liver injury
EC
Ethics Committee
ECC
emergency contact card
eCRF
electronic case report form
EDB
exposure during breastfeeding
EDC
electronic data capture
EDP
exposure during pregnancy
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Abbreviation
Definition
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EOS
End of Study
EPO
erythropoietin
ESA
erythropoiesis-stimulating agent
EU
European Union
Eudra
European Union Drug Regulating Authorities Clinical Trials Database
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GBT
Global Blood Therapeutics Inc
GCP
Good Clinical Practices
GMP
Good Manufacturing Practice 
HC
hydrocarbamide
HDL
high density lipoprotein
HIV
human immunodeficiency virus
HR
heart rate
hs-CRP
high sensitivity C-Reactive protein
HSCT
hematopoietic stem cell transplantation
HU
hydroxyurea
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ID
identifier
IgG
immunoglobulin G
IRB
Institutional Review Board
IRR
infusion-related reaction
IRT
interactive response technology
ITT
intent-to-treat
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous(ly)
LDL
Low density lipoprotein
MedDRA
Medical dictionary for regulatory activities
MQI
Medically Qualified Individual
NCI
National Cancer Institute
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Abbreviation
Definition
NSAID
non-steroidal anti-inflammatory drug
OLE
open-label extension
PAD
peripheral arterial disease
PD
pharmacodynamics
PE
physical examination
PGI-C
Patient’s Global Impression of Change
PK
pharmacokinetics
PLA
platelet-leukocyte aggregate
PLT
platelet
PNH
paroxysmal nocturnal hemoglobinuria
PRO
patient reported outcome
PSGL-1
P-selectin glycoprotein ligand-1
Q12W
every 12 weeks
QOL
quality of life
RBC
red blood cell
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SCD
sickle cell disease
SOC
standard of care
sP-selectin
soluble P-selectin
SPR
surface plasmon resonance
sRBC
sickled red blood cell
SRSD
Single Reference Safety Document
SUSAR
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event
TIBC
total iron binding capacity
TRAP
thrombin receptor activating peptide
ULN
upper limit of normal
UK
United Kingdom
US
United States
WHO
World Health Organization
WOCBP
women of child-bearing potential
VOC
vaso-occlusive crisis
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1. INTRODUCTION
1.1. Sickle Cell Disease
Sickle cell disease (SCD) is an autosomal recessive disease characterized by chronic 
hemolysis and inflammation, vaso-occlusion presenting as recurrent pain episodes (variously 
termed sickle cell-related pain crises or vaso-occlusive crises [VOCs]), multiorgan 
dysfunction, and early death (Kato, 2018). 
Vaso-occlusion in SCD is driven by a series of complex and often redundant receptor–ligand 
interactions involved in the adhesion of circulating cells to the damaged endothelium and 
exposed sub-endothelium.
Extensive research demonstrates that P-selectin mediated cellular interactions with sickled 
red blood cells (sRBCs), leukocytes, and platelets (PLTs) play a crucial role in the 
pathophysiology of vaso-occlusion in SCD. By contrast, blocking P-selectin-mediated 
cellular interactions or reducing the levels of P-selectin reduces or eliminates vaso-occlusion 
in animal models. Taken together, these data led to the hypothesis that blocking P-selectin 
could reduce the risk of VOCs in SCD patients.
Results from a randomized, placebo-controlled Phase 2b trial of crizanlizumab, a humanized 
monoclonal antibody, in SCD bolstered the hypothesis that blocking the interaction of P-
selectin with its receptors could prevent vaso-occlusion and VOCs (Ataga, 2017). 
1.2. Current Therapy for Sickle Cell Anemia
Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative therapy 
for SCD. HSCT in children with SCD is associated with overall and event-free survival rates 
of 95% and 92%, respectively. However, HSCT use is limited by the paucity of suitable 
donors, the risk of graft-versus-host-disease, infections, infertility, and other long-term 
transplant-related complications. Moreover, HSCT is generally available only in high-income 
countries and not commonly used in older patients with significant morbidity (Kassim, 
2017). 
Three therapies, hydroxyurea (HU [DROXIA®, 2017]; also known as hydroxycarbamide), 
L-glutamine (ENDARI, 2017) and crizanlizumab (ADAKVEO®, 2019), have been approved 
by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) to 
reduce VOCs in patients with SCD (Niihara, 2018; Ataga, 2017; Charache, 1995). However, 
the effectiveness of HU is impaired by low compliance rates and frequent treatment 
discontinuation (Shah, 2019).
Moreover, while L-glutamine is also approved to reduce the frequency of VOCs in patients 
with SCD but provides a modest 25% reduction in annual VOC rates (Niihara, 2018). 
Crizanlizumab, a monoclonal antibody directed against human P-selectin, can be used alone 
and in combination with HU to reduce the frequency of VOCs in patients with SCD. 
However, patients are required to travel to an infusion center for drug administration once 
every 4 weeks, a potentially limiting factor in continued adherence to a life-long therapy. 
Treatment adherence is essential for quality care and non-adherence leads to poor health 
outcomes and increased healthcare costs, especially among patients with chronic conditions
(Roebuck, 2011; Simpson, 2006; Osterberg, 2005). Furthermore, medications with less 
frequent dosing result in better adherence (Saini, 2009; Richter, 2003). Patient preference for 
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less frequent dosing has been established across many chronic conditions including 
inflammatory diseases such as rheumatoid arthritis and hematological diseases such as 
hemophilia and paroxysmal nocturnal hemoglobinuria (PNH) (Kaiser, 2020; Wells, 2019; 
Tkacz, 2015). Frequent intravenous (IV) infusions also extract a cost on patient and caregiver 
productivity because of the substantial time commitments and work absence required from 
both for such infusions. One recent study demonstrated that PNH patients receiving
eculizumab every 2 weeks had three times higher productivity losses compared to PNH 
patients treated every 8 weeks with ravulizumab solely due to more frequent dosing 
(Levy, 2019). Moreover, patients report that therapies with less frequent dosing regimens 
enable them to feel independent, better plan future activities, and lead more active lives, all 
important considerations in developing treatments for SCD, which is a debilitating disease 
characterized by idiosyncratic and unpredictable exacerbations (Kaiser, 2020; Wells, 2019).
In summary, despite the recent availability of new options to treat VOCs, an unmet medical 
need exists to further reduce the frequency of VOCs while reducing patient burden and 
enhancing patient adherence to therapy. 
1.3. Rationale for Inclacumab in SCD
Inclacumab is a recombinant, fully human, monoclonal antibody based on a human
immunoglobulin 4 (IgG4)-type framework containing heavy chain VH gamma 4 and light 
chain VL kappa subgroup sequences. Inclacumab is directed against the human P-selectin 
(CD62P).
The monoclonal antibody consists of two heavy chains (451 amino acid residues each) and 
two light chains (214 amino acid residues each) with inter- and intra-chain disulfide bonds 
that are typical of IgG4 antibodies. 
 
 
Inclacumab binds to P-selectin, which is a cell adhesion molecule produced by endothelial 
cells and PLTs. Upon activation of these cells (eg, by thrombin, cytokines, complement 
components, hypoxia, and heme), P-selectin is translocated to the cell surface where it binds 
to its primary ligand P-selectin glycoprotein ligand-1 (PSGL-1) in leukocytes and mediates 
leukocytes recruitment by PLTs or endothelial cells. The same mechanism is also responsible 
for abnormal adhesion of sRBC to the endothelium, initiating acute vascular occlusion and 
chronically impairing microvascular blood flow in patients with SCD. Inclacumab binding of 
P-selectin and prevention of P-selectin binding to its ligands is the putative mechanism by 
which inclacumab effectively blocks interactions between endothelial cells, PLTs, sRBCs 
and leukocytes, thereby preventing VOCs.
Nonclinical studies have been conducted to characterize inclacumab include primary and 
secondary pharmacodynamics (PD), safety pharmacology, pharmacokinetics (PK), and 
toxicology. The nonclinical studies are described in detail in the inclacumab Investigator’s 
Brochure (IB), which is the Single Reference Safety Document (SRSD) for this study.
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1.3.1. Study Design Rationale
This study is a randomized, placebo-controlled, double-blind study to evaluate the safety and 
efficacy of inclacumab compared to placebo when administered once every 12 weeks 
(Q12W) (Day 1, Week 12, Week 24, and Week 36) to patients with a diagnosis of SCD who
have experienced between 2 and 10 VOCs in the 12 months preceding enrollment in this 
study. Given the long half-life of inclacumab (terminal half-life of 21 to 28 days) at the dose 
to be evaluated in this study, the majority of participants receiving active study drug are 
expected to maintain target concentrations through Week 48.
The primary endpoint of the study is the rate of VOCs occurring over a 48-week treatment 
period. The safety of treatment with inclacumab over the 48-week period will also be 
assessed. This study builds on experience from previous clinical studies in patients with SCD 
in reducing the incidence of VOCs. 
A placebo-controlled trial represents the most common and acceptable approach for 
determining the safety and efficacy for a therapeutic through a well-designed, controlled 
study. Some notable distinctions from prior studies include the definition of a VOC that
allows for telemedicine in addition to the previous definitions which required a visit to a 
healthcare facility. This distinction has been incorporated based on the changes in treatment 
practices that have occurred as a result of the coronavirus disease 2019 (COVID-19)
pandemic. Patients with SCD are less likely to visit a healthcare facility and are more 
frequently reaching out to their healthcare provider for pain medication changes/prescriptions
(McFarling, 2020; Powell, 2020). Even though patients are not making as many visits to a 
healthcare facility for a VOC, the telemedicine visit nonetheless represents a crisis on the 
part of the patient that requires intervention by a healthcare practitioner. Use of a 
telemedicine-based VOC is therefore justified. 
1.3.2. Rationale for Dose Regimen
In this study, an IV dose of 30 mg/kg will be administered Q12W for a total of 4 doses over a 
48-week period to reduce the frequency of VOCs in patients with SCD. More than 
700 participants in prior studies (healthy or cardiovascular disease patients) have been 
exposed to inclacumab; a maximum tolerated dose was not identified. The maximum single 
dose tested, 40 mg/kg, has not demonstrated any drug-related safety or tolerability signals in 
a Phase 1 study in healthy participants. Chronic IV dosing of inclacumab (20 mg/kg every
4 weeks for 32 weeks) in a cohort of 142 patients with severe cardiovascular disease was 
shown to be safe and well tolerated with the majority of adverse events (AEs) considered 
unrelated to study drug.
In a recent Phase 1 study in healthy participants, the safety and tolerability of a single IV 
dose of up to 40 mg/kg of inclacumab was consistent with the safety profile of previous 
studies with inclacumab at doses up to 20 mg/kg IV performed in healthy participants and in 
individuals with cardiovascular disease (refer to the current version of the IB for details).
Inclacumab plasma concentrations above 10 µg/mL have been associated with maximal 
inhibition of ex vivo thrombin receptor activating peptide (TRAP)-induced platelet leukocyte 
aggregate (PLA) formation in healthy volunteers and patients with peripheral arterial disease 
(PAD) from prior clinical studies. Chronic dosing to maintain inclacumab plasma 
concentrations above 10 µg/mL is expected to be required for maximal sustained benefit. 
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Population PK simulations project that the inclacumab dose regimen of 30 mg/kg Q12W will 
maintain concentrations above 10 µg/mL throughout the 48-week study period in the 
majority of participants, thereby maximizing the pharmacology required for effective 
reduction of VOC in the SCD population. 
1.3.3. Use of a Placebo Control
This study uses placebo as a comparator on the background of standard of care (SOC)
treatment for a VOC. Placebo was chosen as the control because it is necessary to determine 
the safety and efficacy of inclacumab by allowing efficacy to be estimated controlling for 
background VOCs with SOC and safety signals to be distinguished from AEs occurring due 
to SCD.
Treatments with stable SOC are allowed including stable doses of HU, erythropoiesis-
stimulating agents (ESAs), voxelotor, and L-glutamine. However, initiation of these agents
during screening or after randomization and use of crizanlizumab for 90 days prior and 
during the study is prohibited. Crizanlizumab has a similar mechanism of action that would 
confound interpretation of this study. All other standard therapeutic interventions for SCD 
(eg, hydration, analgesia, acute transfusions) are allowed under this protocol. 
Randomization to placebo treatment in this study does not place study participants at 
increased risk, as the SOC (other than the use of crizanlizumab) for patients with VOCs will 
be provided during the study.
2. OBJECTIVES
The primary objective of this study is to evaluate the safety and efficacy of treatment every 
12-week with inclacumab to reduce the incidence of VOCs in participants with SCD.
Additional objectives of the study are to evaluate the PK and PD of inclacumab, the presence 
of anti-drug antibodies (ADAs), and changes in quality of life (QOL).
3. INVESTIGATIONAL PLAN
This is a Phase 3, randomized, double-blind, placebo-controlled, 2-arm, multi-center, 
parallel-group study. 
Note: In France, this study is considered Phase 2.
3.1. Study Design
This study will assess the safety and efficacy of inclacumab in reducing the frequency of 
VOCs in approximately 240 adult and adolescent participants (≥12 years of age) with SCD
globally. Initial enrollment will include participants ≥16 years of age until the independent 
Data Monitoring Committee (DMC) recommends to the Sponsor that adequate safety and PK 
data support the enrollment of participants 12 to 15 years of age.
Eligible participants will be randomized with a 1:1 ratio into one of two treatment arms as 
follows:

Inclacumab 30 mg/kg administered IV Q12W; or

Placebo administered IV Q12W.
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At the time of randomization, participants will be stratified by Baseline HU use (yes; no), 
number of VOCs (2 to 4; 5 to 10) in the preceding 12 months, and geographic region
(North America; sub-Saharan Africa; Europe/rest of world).
All participants will undergo safety, efficacy, and PK/PD assessments at Baseline and 
through Week 48. Visits to the clinical site for infusion of study drug will occur at Baseline 
(Day 1) and Q12W (Weeks 12, 24, and 36) for a total of 4 infusions. An additional visit at 
Week 6 will occur for safety, PK, and PD monitoring. The incidence of VOC events will be
recorded weekly by the participant and collected every 4 weeks, with participants contacted 
by phone at Weeks 4, 8, 16, 20, 28, 32, 40, and 44. 
Following completion of the Week 48 Visit, eligible participants will be given the option to 
enroll in an open-label extension (OLE) study (under a separate protocol) to receive 
inclacumab. Participants will receive their first dose in the OLE study at the same Week 48 
Visit. Participants enrolling in the OLE study will not be required to return to clinic for the 
Week 60 Visit. Safety, efficacy, and PK/PD assessments will occur at Week 60 for 
participants not enrolling on the OLE study.
The DMC will regularly review the totality of accumulated safety data from all ongoing 
inclacumab studies on an ongoing, unblinded basis with additional emphasis on adolescent 
participants. Details are provided in the DMC Charter.
Note: For France-, Germany-, UK-, Ghana-, and Egypt-specific study design, refer to 
Appendix 6-1, Appendix 6-2, Appendix 6-3, Appendix 6-4, and Appendix 6-5, respectively.
A diagram of the study design is provided in Figure 1.
Figure 1:
GBT2104-131 Study Design 
Abbreviations: IV, intravenous; OLE, open-label extension.
3.2. Study Endpoints
3.2.1. Primary Efficacy Endpoint
The primary efficacy endpoint for the study is the rate of VOCs during the 48-week 
treatment period. A VOC is defined as an acute episode of pain that:

Has no medically determined cause other than a vaso-occlusive event, and 
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
Results in a visit to a medical facility (hospitalization, emergency department, 
urgent care center, outpatient clinic, or infusion center), or results in a remote 
contact with a healthcare provider; and

Requires parenteral narcotic agents, parenteral nonsteroidal anti-inflammatory 
drugs (NSAIDs), or an increase in treatment with oral narcotics.
Complicated VOCs of acute chest syndrome (ACS), hepatic sequestration, splenic 
sequestration, and priapism that meet the requirements listed above will be included in the 
primary endpoint.
To ensure consistency across study sites, all VOCs identified will be adjudicated by an 
independent, blinded panel comprised of experts in SCD. The primary efficacy analysis will 
be performed on adjudicated data.
3.2.2. Secondary Efficacy Endpoints
The secondary efficacy endpoints for the study are the following:

Time to first VOC during the 48-week treatment period.

Time to second VOC during the 48-week treatment period.

Proportion of participants with no VOCs during the 48-week treatment period. 

Rate of VOCs that required admission to a healthcare facility and treatment with 
parenteral pain medication during the 48-week treatment period where admission 
includes:

A hospital admission, or

An admission to an emergency room, observation unit, or infusion center for
≥12 hours, or

2 visits to an emergency room, observation unit, or infusion center over a 
72--hour period.

Number of days of inpatient hospitalization for a VOC during the 48-week 
treatment period.
3.2.3. Safety Endpoints
Safety endpoints for the study are the following: 

Incidence of treatment-emergent adverse events (TEAEs).

Change from Baseline in laboratory assessments (complete blood count [CBC],
chemistry, and coagulation).
3.2.4. Exploratory Endpoints
The exploratory endpoints for the study are the following:

Rate of all SCD-related urgent care visits to clinic, emergency room, and hospital 
during the 48-week treatment period.
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
Proportion of total days missed from school or work due to SCD during the 
48-week treatment period.

Rate of complicated VOCs (defined in Section 5.1) during the 48-week treatment 
period.

Rate of red blood cell (RBC) transfusions during the 48-week treatment period.

Rate of inpatient hospital admissions for any reason during the 48-week treatment 
period.

Number of days of inpatient hospitalization for any reason during the 48-week 
treatment period.

Proportion of participants rated as “very much improved” or “much improved” 
based on the Patients Global Impression of Change (PGI-C) at Weeks 12, 24, 36, 
and 48.

Proportion of participants rated as “very much improved” or “much improved” 
based on the Clinician’s Global Impression of Change (CGI-C) at Weeks 12, 24, 
36, and 48.

Change from Baseline in the cumulative score for the Adult Sickle Cell Quality of 
Life Measurement (ASCQ-Me) Pain Impact – Short Form over time to Week 48.
3.2.5. Exploratory Pharmacology Endpoints
The following exploratory pharmacology endpoints will be assessed:

Plasma PK of inclacumab as assessed by population PK analysis using nonlinear 
mixed-effects modeling.

The incidence of ADA to inclacumab.

Pharmacodynamics including changes in non-activated and TRAP-activated 
PLAs, PLT P--selectin expression, serum P-selectin inhibition measured by 
surface plasmon resonance (SPR), and plasma total and free soluble P-selectin 
(sP-selectin-) over time.

Biomarkers including changes in RBC adhesion (selected sites), genomic markers 
(optional), protein markers in the blood, urine markers of kidney function, and 
voxelotor plasma and whole blood concentrations (as applicable)
Relationships between PK, PD, biomarkers, clinical labs, safety, and efficacy will be 
explored.
Note: In Egypt, blood samples for PK, PD, ADA, and biomarker endpoints will not be 
collected.
3.3. Selection of Study Population 
A total of up to 240 participants (120 per treatment group) at approximately 75 global 
clinical sites will be enrolled in this study.
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3.3.1. Eligibility
Eligibility assessment will be conducted during Screening and prior to receiving study drug 
on Day 1. 
Participants who meet all of the following inclusion criteria and none of the exclusion criteria 
will be eligible for enrollment in this study.
For Investigator questions regarding participant eligibility or clinical significance of 
abnormalities, discussion with the study Medical Monitor is strongly encouraged.
3.3.1.1. Inclusion Criteria 
1. Participant has a confirmed diagnosis of SCD (HbSS, HbSC, HbSβ0 thalassemia, or 
HbSβ+ thalassemia genotype).
Documentation of SCD genotype is required and may be based on documented 
history of laboratory testing or confirmed by laboratory testing during Screening.
2. Participant is male or female, ≥12 years of age at the time of informed consent.
NOTE: Initial study enrollment will include participants ≥16 years of age until the 
DMC recommends to the Sponsor that adequate safety and PK data support the 
enrollment of participants 12 to 15 years of age. Sites will be informed by the 
Sponsor when participants 12 to 15 years of age may be enrolled.
Note: For France-, Germany-, and UK-specific study design, refer to Appendix 6-1, 
Appendix 6-2, and Appendix 6-3, respectively.
3. Participant has experienced between 2 and 10 VOCs within the 12 months prior to the 
Screening Visit as determined by documented medical history. A prior VOC is 
defined as an acute episode of pain that:

Has no medically determined cause other than a vaso-occlusive event, and

Results in a visit to a medical facility (hospital, emergency department, urgent 
care center, outpatient clinic, or infusion center) or results in a remote contact 
with a healthcare provider; and

Requires parenteral narcotic agents, parenteral NSAIDs, or an increase in
treatment with oral narcotics.
4. Participants receiving ESA, eg, EPO must be on a stable dose for at least 90 days 
prior to the Screening Visit and expected to continue with the stabilized regimen 
throughout the course of the study. 
5. Participants receiving HU, L-glutamine, or voxelotor must be on a stable dose for at 
least 30 days prior to the Screening Visit and expected to continue with the stabilized 
regimen throughout the course of the study. 
6. Participant has adequate venous access, in the opinion of the Investigator, to comply 
with study procedures.
7. Participant understands the study procedures and agrees to participate in the study by 
giving written informed consent or parental permission/written assent.
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Note: For the France-specific criterion, Appendix 6-1 in the body of the protocol.
8. Women of childbearing potential (WOCBP) are required to have a negative serum 
pregnancy test at the Screening Visit and negative urine pregnancy test on all 
subsequent clinic visits and must agree to use a highly effective method of 
contraception throughout the study period and for at least 165 days after dosing. See 
Section 6.3 for details on methods of contraception.
Note: For the UK-specific criterion, refer to Appendix 6-3.
Female participants will not be considered of childbearing potential if they are 
pre-menarchal, surgically sterile (hysterectomy, bilateral salpingectomy, tubal 
ligation, or bilateral oophorectomy) or postmenopausal (no menses for 12 months 
without an alternative medical cause, confirmed by follicle-stimulating hormone 
(FSH) test results).
3.3.1.2. Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist 
at Screening or Baseline visits or at the timepoint specified in the individual criterion listed.
1. Participant is receiving regularly scheduled RBC transfusion therapy (also termed 
chronic, prophylactic, or preventative transfusion). 
2. Participant is taking or has received crizanlizumab (ADAKVEO) within 90 days prior 
to the Screening Visit. 
3. Participant weighs > 133 kg (292 lbs).
4. Participant has a significant active and poorly controlled (unstable) hepatic disorder 
clearly unrelated to SCD.
Note: For the UK-specific criterion, refer to Appendix 6-3.
5. Participant has any of the following laboratory values at screening:
a.
Absolute neutrophil count (ANC) < 1.0 × 109/L
b. Platelet count < 80 × 109/L
c.
Hemoglobin < 4.0 g/dL for adults and < 5.0 g/dL for participants ages 12 to 
< 18 years of age
d. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 using 
Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) formula in 
adults, and Schwartz formula in adolescents
Note: For France- and Germany-specific criterion, refer to Appendix 6-1 and 
Appendix 6-2, respectively.
6. Participant has known active (symptomatic) COVID-19 infection or tests positive for 
COVID-19 during Screening.
7. Participant has a history of unstable or deteriorating cardiac or pulmonary disease 
within 6 months prior to consent including severe or unstable pulmonary 
hypertension.
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8. Participant has had treatment for a malignancy within the 12 months prior to the 
Screening Visit (except non-melanoma skin cancer and in situ cervical cancers).
9. Participant has had a stroke within the 2 years prior to the Screening Visit.
10. Participant has a positive test indicative of malaria infection at Screening. Testing to 
be conducted at local laboratories in malaria-endemic regions at the discretion of the 
Investigator.
11. Participant has any confirmed clinically significant drug allergy and/or known 
hypersensitivity to monoclonal antibody therapeutics or formulation components of
the study drug or a related drug.
12. Participant has been in another investigational trial within 30 days or 5 half-lives of 
the investigational agent (whichever is greater) prior to the Screening Visit.
13. Participant has had a major surgery within 8 weeks prior to the Screening Visit.
14. Participant is pregnant, breastfeeding, or planning to become pregnant during the 
48-week treatment period.
15. Participant, parent, or legal guardian are unlikely to comply with the study 
procedures.
Note: For France-specific criterion, refer to Appendix 6-1.
16. Participant has any other medical, psychological, or behavioral conditions that, in the 
opinion of the Investigator, would confound or interfere with evaluation of safety, 
efficacy, and/or PK of the investigational drug; prevent compliance with the study 
protocol; preclude informed consent; or render the participant, parent, or caretaker 
unable/unlikely to comply with the study procedures.
3.3.2. Participant Completion
Participants not enrolling in the OLE study will complete the study at the time of the last 
scheduled study procedures at the Week 60 Visit. For participants who enroll into the 
OLE study, the Week 48 Visit will be the final study visit. Participants will receive their first 
dose in the OLE study on the same day as the completion of the Week 48 Visit. Participants 
who terminate the study prior to the Week 48 Visit will be requested to complete the 
assessments as outlined for the Early Termination (ET) (Week 48) Visit. Participants not 
enrolling in OLE that complete the Week 48 Visit but terminate prior to the Week 60 Visit 
will be requested to complete the assessments as outlined for the End of Study (EOS; 
Week 60) Visit. Participants who require further follow-up for an AE/serious adverse event 
(SAE) will be followed according to Section 7.8.
3.3.3. Study Discontinuation
The Sponsor has the right to terminate this study at any time. In any instance of ET of the 
study, the Sponsor will notify, in writing, the Investigators, regulatory authorities, and
Institutional Review Boards (IRBs)/Ethics Committees (ECs) and will specify the reason(s) 
for termination. 
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3.3.3.1. Early Discontinuation of Individual Participants 
3.3.3.1.1. Early Discontinuation of Study Treatment 
Participants may discontinue study treatment for any of the following reasons: 

Adverse event

Withdrawal of consent

Discretion of the Investigator

Participant is lost to follow-up

Participant is noncompliant

Pregnancy. Study drug must be discontinued immediately. Report the pregnancy 
according to the instructions in Section 1.1.
Participants who discontinue from study treatment will be encouraged to continue to 
participate in the study assessments, as applicable. Participants who are discontinued from
study treatment due to pregnancy will also be discontinued from the study (Section 1.1). A 
participant may be discontinued from study treatment at any time at the discretion of the 
Investigator in accordance with his or her clinical judgment.
Note: For UK-specific guidelines, refer to Appendix 6-3.
3.3.3.1.2. Withdrawal of Consent
Participants will be informed that they are free to withdraw from the study at any time and 
for any reason. The Investigator must withdraw from the study any participant who requests 
to be withdrawn. Participants who ask to leave the study early (withdraw consent) should be 
encouraged to undergo the tests and evaluations listed for the ET Visit (ie, ET is intended for 
participants who withdraw consent). If a participant withdraws before completing the study, 
the date and reason for withdrawal is to be documented on the electronic case report form 
(eCRF).
A participant that withdraws from the study or is lost to follow-up will not be replaced.
3.3.4. Lost to Follow-up
Participants (and/or their parent or legal guardian for participants under 18 years of age) who 
do not return for a scheduled visit, as defined by the visit schedule, and cannot be reached to 
determine the reason for the missed visit, may be considered lost to follow-up. The site will 
attempt to contact the participant (and/or their parent or legal guardian for participants under 
18 years of age) through a minimum of 2 telephone calls. If the participant (and/or their 
parent or legal guardian for participants under 18 years of age) still cannot be contacted, the 
site will send a certified letter to the last known address of the participant. If no contact is 
made by the participant (and/or their parent or legal guardian for participants under 18 years 
of age), the site will consider the participant lost to follow-up. All follow-up attempts will be 
documented and kept with the participant’s source documentation, and the applicable eCRFs 
will be completed.
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3.4. Study Duration
The total study duration for each participant will be up to 64 weeks, including a 28-day 
Screening period, a 48-week treatment period, and a 12-week follow-up period.
Participants who enroll in the OLE study after Week 48 will have a total study duration of 
52 weeks, including the 28-day Screening period and 48-week treatment period.
3.5. Treatments
Study drug will be provided to the study sites in a blinded fashion as a solution for IV 
infusion. All study drug will be administered at the clinical study site.
Participants will be randomized into one of 2 treatment groups: inclacumab or placebo. The 
active inclacumab and placebo solutions will look identical to maintain the blind. The 
Investigator, site staff, participant, and Sponsor study personnel (or their designees) will be 
blinded to the study group to which the participant is randomized. Participants will be dosed 
as follows:

Inclacumab: 30 mg/kg inclacumab administered IV Q12W (Day 1, Week 12, 
Week 24, and Week 36)

Placebo: placebo administered IV Q12W (Day 1, Week 12, Week 24, and Week 
36)
4. STUDY DRUG INFORMATION 
4.1. Description of Active Study Drug – Inclacumab
The inclacumab drug substance is manufactured by fermentation cell culture using Chinese 
hamster ovary (CHO) cells followed by purification. The drug substance and drug product 
are manufactured in accordance with Good Manufacturing Practice (GMP).
Inclacumab drug product is a sterile, clear to opalescent liquid concentrate for infusion with 
an approximate pH of 5.5 provided in colorless, 10 mL single-use vials. Each vial contains 
500 mg of inclacumab and the following excipients: L-histidine-acetate, sucrose, and 
Poloxamer 188. 
4.2. Description of Placebo for Inclacumab
The placebo for inclacumab to be used in this study will be a matched placebo for IV 
infusion with the same excipients found in inclacumab without the active product. 
4.3. Packaging and Labeling
The study drug will be packaged and labeled in a manner consistent with the study design.
Vials of study drug will be labeled according to applicable regulations for an investigational 
drug. 
If the packaging is damaged, or if there is anything unusual about the appearance or attributes 
of the vials or study drug, do not use the study drug. The vial in question should be saved at 
the study site and the problem immediately reported to the Sponsor, or designee per the 
Pharmacy Manual (provided separately).
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4.4. Storage and Handling
The inclacumab and placebo vials are to be stored at 2°C to 8°C (36°F to 46°F) prior to 
dilution in a monitored, locked refrigerator with limited access. Detailed instructions for 
storage and handling of study drug after dilution are provided in the Pharmacy Manual.
Study drug must be stored in a secure location and should not be used after the expiration, 
expiry, or use-by date.
The study drug will be provided by the Sponsor in 10 mL single-use vials that should be 
protected from light. 
4.5. Instructions for Use and Administration 
Detailed instructions for preparation and administration of study drug can be found in the 
Pharmacy Manual. 
4.6. Management of Infusion-Related Reactions (IRR)
Participants will be monitored throughout the infusion and for 60 minutes after completion of 
study drug infusion for adverse reactions. If an infusion-related reaction (IRR) or 
hypersensitivity reaction of Grade 3 or higher (Appendix 4) occurs during study drug
administration, the infusion will be discontinued, and the participant should be treated for the 
reaction per site standard operating procedures as indicated. The participant will not receive 
further treatment with study drug but will continue on study until the EOS/ET (Week 60)
Visit. The exact time when the infusion was stopped must be recorded.
If a Grade 1 or Grade 2 (mild or moderate) IRR occurs, the study drug infusion should be 
temporarily interrupted at the discretion of the Investigator. Upon re-initiation of infusion, 
the infusion rate should be reduced, and the new rate, as well as the stop and restart times for 
the infusion will be recorded. Specific instructions for re-initiation of infusion are provided in 
the Pharmacy Manual.
All IRRs will be recorded as adverse events of special interest (AESIs, Section 7.3) or SAE
(if serious criterion is met; Section 7.1.2). If study drug is permanently discontinued, the 
participant should continue on study to complete all safety, PK, and PD assessments through 
Week 48. However, the participant will be ineligible for the OLE study.
4.7. Accountability
A Drug Accountability Record will be used for the study drug. The record must be kept 
current and should contain the dates and quantities of study drug received, study number, lot 
or batch number(s), participants receiving study drug, the date and quantity of study drug
dispensed and remaining, and the initials of the dispenser.
All study drug inventory forms must be made available for inspection by an authorized 
representative of the Sponsor or designee. The Investigator is responsible for the 
accountability and security of all used and unused study supplies at the site.
The Investigator must return all used and unused vials of study drug as instructed by the 
Sponsor, or designee, unless approved for onsite destruction. If any study drug supplies are to 
be destroyed at the study site, the institution or appropriate site personnel must obtain prior 
approval from the Sponsor, or designee, by providing, in writing, the destruction policy or 
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details of the method of destruction. After such destruction, the Sponsor, or designee, must 
be notified, in writing, of the details of the study drug destruction (eg, lot or kit numbers, 
quantities).
4.8. Methods of Assigning Participants to Treatment Groups
4.8.1. Participant Screening
A signed and dated informed consent or parental/guardian consent and participant assent
must be obtained before any Screening procedures or study-specific tests may be performed. 
All participants will be given a participant identifier (ID) upon signing the informed consent. 
This number will be used to identify the participant throughout the clinical study and must be 
used on all study documentation related to that participant. Re-screening may be considered 
at the discretion of the Investigator and in consultation with the Sponsor. Participants who 
re-screen will have all assessments redone and a new participant ID assigned.
The Screening Period for a particular participant will commence when the participant 
undergoes the first study-specific Screening assessment and must be completed within 28
days after signing the informed consent/assent document (ICD). 
All study visits are to be scheduled relative to the Day 1 Visit date.
4.8.2. Randomization Method 
After all Screening assessments have been completed and the participant is deemed eligible 
per criteria in Section 3.3.1, participants will be randomized on Day 1 through a central
interactive response technology (IRT) system. 
Participants will be randomized with a 1:1 ratio to receive treatment with inclacumab or 
placebo. A stratified permuted block design will be used, with randomization stratified by 
Baseline HU use (yes; no), number of VOCs (2 to 4; 5 to 10) in the preceding 12 months, and 
geographic region (North America; sub-Saharan Africa; Europe/rest of world).
The first dose of study drug is to be administered on the same day as randomization (Day 1). 
No participant may begin treatment with study drug prior to randomization. Any participant
identification numbers that are assigned will not be reused even if the participant does not 
receive treatment.
4.8.3. Blinding Procedures 
This is a randomized, double-blinded, placebo-controlled study. Investigators, study site 
staff, the Sponsor’s study staff, the Sponsor’s clinical contract research organization (CRO), 
and study participants, as well as members of the VOC Adjudication Committee, will remain 
blinded to the randomized treatment assignments. During the study, access to participant 
treatment assignment will be limited to DMC members and service providers supporting 
DMC reviews, including the independent Data Coordinating Center and the independent
PK/PD bioanalytical laboratory and analysis personnel.
The Investigator must contact the Medical Monitor prior to unblinding of study drug for any 
participant. In an emergency, however, where knowledge of the study drug is critical to 
participant safety, the code may be broken. In cases where the Investigator is unable to 
contact the Medical Monitor prior to unblinding, the Investigator must notify the Sponsor, or 
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designee, as soon as possible (ie, within 24 hours) after unblinding. In addition, the 
Investigator must record the date, time, and reason for unblinding the study drug treatment in 
the source documentation.
Note: For UK-specific guidelines, refer to Appendix 6-3.
4.9. Assessment of Treatment Compliance
Drug disposition records will be maintained, specifying the amount of study drug dispensed 
to each participant (and/or their parent or legal guardian for participants under 18 years of 
age) and the date of dispensation. This record will be available for Sponsor review at any 
time. Compliance will be determined by used/unused vial count.
5. STUDY ASSESSMENTS
The Schedule of Assessments (Appendix 1) summarizes the clinical procedures to be 
performed. Appendix 2 provides the schedule for collection of PK, ADA, and PD samples
and Appendix 3 provides the schedule for collection of samples for biomarkers. Assessments 
and procedures are described in detail below. Additional evaluations/testing may be deemed 
necessary by the Investigator or designee and/or the Sponsor for reasons related to participant
safety.
Note: In Egypt, blood samples for PK, PD, ADA, and biomarker endpoints will not be 
collected.
5.1. Primary Efficacy Assessment
Efficacy will be assessed through collection of VOCs during the 48-week treatment period. 
A VOC is defined as an acute episode of pain that:

Has no medically determined cause other than a vaso-occlusive event, and 

Results in a visit to a medical facility (hospitalization, emergency department, 
urgent care center, outpatient clinic, or infusion center), or results in a remote 
contact with a healthcare provider; and

Requires parenteral narcotic agents, parenteral NSAIDs, or an increase in
treatment with oral narcotics.
Complicated VOCs of ACS, hepatic sequestration, splenic sequestration, and priapism, that 
meet the requirements listed above will be included in the primary endpoint.
Participants will be instructed to visit the clinical site for VOCs requiring a visit to a 
healthcare facility. However, in cases where visits to other healthcare facilities are required 
for treatment of their VOCs, (eg, emergency room, hospital, urgent care center, outpatient 
clinic or infusion center), participants will be instructed to notify the clinical site within 
48 hours when one of these visits occurs.
VOCs are categorized as:
Uncomplicated VOC: a VOC that is NOT classified as ACS, hepatic sequestration, splenic 
sequestration, or priapism.
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Complicated VOCs:

Acute Chest Syndrome, defined as a finding of a new pulmonary infiltrate, but 
excluding atelectasis (as indicated by chest X-ray). Must also present with at least 
one of the following signs or symptoms: patient-reported chest pain, body 
temperature of more than 38.5°C, tachypnea, wheezing, or cough.

Hepatic sequestration, defined as findings of right upper quadrant pain, an 
enlarged liver, and an acute decrease in hemoglobin concentration.

Splenic sequestration, defined as findings of left upper quadrant pain, an enlarged 
spleen, and an acute decrease in hemoglobin concentration.

Priapism, defined as having a sustained penile erection requiring a visit to a 
medical facility.
To ensure consistency across study sites, all on-study VOCs reported by the study 
investigators will be adjudicated by an independent, blinded panel comprised of experts in 
SCD (See Section 7.4.2). The primary efficacy analysis will be performed on adjudicated 
data.
5.2. Secondary and Exploratory Efficacy Assessments
The secondary efficacy endpoints are based on collection of the incidence and timing of 
VOCs (per the definition in the primary endpoint) after randomization, QOL assessments and 
on hospital durations.
For the exploratory efficacy endpoints, in addition to incidence and timing of VOCs, the 
following will be collected:

All visits to healthcare facilities for a VOC regardless of treatment administered.

Number of days with a VOC leading to a healthcare visit.

Total days missed from school or work due to SCD.

Red blood cell (RBC) transfusions.
For all VOCs, the medications and doses used to treat the VOC will be collected. This 
includes:

IV/oral opioid analgesics,

IV/oral non-opioid analgesics,

Transfusions, and

Volume replacement/hydration.
Quality of life (QOL) assessments will be collected as patient reported outcomes (PROs) or 
clinician reported outcomes (ClinRO), when available in local language, including:

Patient’s Global Impression of Change (PGI-C).

Clinician’s Global Impression of Change (CGI-C).

ASCQ-Me Pain Impact – Short Form.
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5.3. Safety Assessments
5.3.1. Adverse Events
Safety will be monitored throughout the study as outlined in the Schedule of Assessments 
(Appendix 1). Adverse events will be collected throughout the study and graded for severity 
and relationship to study drug. Reported TEAEs will be analyzed. See Section 7 for details 
on definitions and requirements for AE collection.
5.3.2. Physical Examination
A full physical examination (PE) will be performed at each visit. A full PE will include 
examination of the following: general appearance, head, ears, eyes, nose, throat, neck, skin, 
cardiovascular system, respiratory system, gastrointestinal system, musculoskeletal system, 
lymph nodes, and nervous system.
5.3.3. Vital Signs
Measurements of heart rate (HR), blood pressure (BP), and body temperature will be 
obtained. Additional vital signs may be taken at any other times, if deemed necessary.
HR and BP measurements will be performed with participants in a supine position for at least 
5 minutes, except when they are seated or semi-reclined because of study procedures and/or 
AEs (eg nausea, dizziness) or if deemed necessary by the Investigator or designee.
At visits where participants receive study drug vital signs will be measured prior to study 
drug administration. When scheduled at the same time as a blood draw, vital signs will be 
performed prior to the blood collection.
Vital signs will also be collected at the completion of infusion and at one hour after 
completion of infusion. Participants should be clinically well with stable vital signs and 
without signs or symptoms of an IRR prior to release from observation.
5.3.4. Clinical Laboratory Tests
It is the responsibility of the Investigator to assess the clinical significance of all abnormal
clinical laboratory values as defined by the list of normal values on file for the central
laboratory. All clinically significant laboratory value abnormalities are to be recorded as 
AEs.
For the purpose of this study, a clinically significant laboratory value will be any abnormal 
result that, in the judgment of the Investigator, is an unexpected or unexplained laboratory 
value or if medical intervention or corrective action (transfusion, hydration, initiation of 
antibiotics or other concomitant medication) is required. Any abnormal values that persist 
should be followed at the discretion of the Investigator.
Additional and repeat laboratory safety testing for the evaluation of abnormal results and/or 
AEs during the study may be performed at the discretion of the Investigator or upon request 
of the Sponsor. Repeat laboratory testing of abnormal potentially clinically significant or 
clinically significant results for the Screening evaluation of the participant may be repeated 
once at the discretion of the Investigator.
Laboratory safety testing is intended to be performed by a central laboratory. Exceptions may
be made as necessary for local laboratory testing.
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Tests listed in Table 1 will be performed as outlined in the Schedule of Assessments 
(Appendix 1). Details on collection, preparation, and shipping of blood samples are provided 
in the Laboratory Manual.
Note: For Egypt-specific guidelines, refer to Appendix 6-5.
Table 1:
Clinical Laboratory Tests
Hematology
Hemoglobin
Hematocrit 
Total and differential leukocyte count
Red blood cell count
Percent and absolute reticulocyte count
Iron panel (iron, TIBC, ferritin)
Platelet count
Coagulation
Prothrombin time
Activated partial thromboplastin time
D-dimer
Von Willebrand factor
Fibrinogen
Serum Chemistry
Blood Urea Nitrogen
Bilirubin (total, direct, and indirect)
Alkaline phosphatase
Aspartate aminotransferase
Alanine aminotransferase
Albumin
Sodium
Potassium
Magnesium
Calcium
Chloride
Bicarbonate 
Glucose
Creatine kinase
Creatinine
Lactate dehydrogenase
CRP
hs-CRP
Total globulin
Total protein
IgG
Cystatin C
Lipid Panel
-
Total cholesterol
-
HDL
-
LDL 
-
Triglycerides
Additional Tests
Hemoglobin genotype (if not previously 
determined)
Fetal hemoglobin
Serum pregnancy test (WOCBP only)
Urine pregnancy test (WOCBP only)
Follicle-stimulating hormone (FSH) for 
post-menopausal women
Abbreviations: CRP, C-reactive protein; HDL, high density lipoprotein; hs-CRP, High sensitivity C-Reactive 
protein; LDL, low density lipoprotein; TIBC, total iron binding capacity; WOCBP, women of child-bearing 
potential.
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5.4. Clinical Assessments
5.4.1. Demographic/Medical History
Demographic information (sex, date of birth, race/ethnicity, height, weight) will be recorded. 
Participants will be asked to provide a thorough medical history, including VOC history. 
Weight will also be measured on Day 1 for study drug dosing.
5.4.2. Pregnancy Screen
Pregnancy tests will be performed on female participants of childbearing potential as 
indicated in the Schedule of Assessments (Appendix 1). A serum pregnancy test will be 
conducted at Screening with urine pregnancy tests conducted thereafter. If the Day 1 urine 
test is positive, a pre-dose serum pregnancy test should be performed and dosing should be 
postponed until a negative result is confirmed; if positive, the participant will be considered a 
screen failure.
Female participants will not be considered of childbearing potential if they are pre-
menarchal, surgically sterile (hysterectomy, bilateral salpingectomy, tubal ligation or 
bilateral oophorectomy) or postmenopausal (no menses for 12 months without an alternative 
medical cause, confirmed by follicle-stimulating hormone test results).
Note: For UK-specific study design, refer to Appendix 6-3.
5.4.3. SARS-CoV-2 (COVID-19) Infection
During the study, participants who are exposed to, are suspected of having, or have 
documented COVID-19 should be tested, evaluated, and treated per institutional 
requirements. Participants that acquire COVID-19 during the study are not required to be 
withdrawn from study.
5.4.4. Quality of Life Assessments
Participants (and/or their parent or legal guardian for participants under 18 years of age) will 
be asked to provide responses to 2 QOL surveys (PGI-C and ASCQ-Me) as well as to track 
their pain medication intake and any school or work missed due to their SCD symptoms.
Participants (and/or their parent or legal guardian for participants under 18 years of age) will 
complete the ASCQ-Me questionnaire weekly, when available. Administration of some of 
these surveys may occur over the phone with the clinic staff and will only be administered 
when available in local language. 
Clinicians will also complete a QOL assessment (CGI-C) on their global impression of 
participant change in QOL. 
5.4.5. VOC Incidence
The incidence of VOC events will be recorded weekly by the participant (and/or their parent
or legal guardian for participants under 18 years of age) and collected every 4 weeks. Each 
month on non-treatment visit days, participants (and/or their parent or legal guardian for 
participants under 18 years of age) will be contacted by phone to determine if a VOC event 
or a pain crisis leading to contact with a healthcare provider without a visit to a medical 
facility has occurred, to collect AEs, and to record changes to concomitant medications.
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Note: For France-, Germany-, UK-, and Ghana-specific guidelines, refer to Appendix 6-1, 
Appendix 6-2, Appendix 6-3, and Appendix 6-5, respectively.
5.5. Pharmacology Assessments (PK, ADA, PD, Biomarkers)
The schedule for collection of plasma, serum, and/or whole blood samples for inclacumab 
PK, ADA, and PD samples is provided in Appendix 2. The schedule for collection of 
inclacumab biomarkers is provided in Appendix 3. The analyses are intended to be 
performed at central laboratories. Details on collection, processing, and shipping of samples 
is provided in the Laboratory Manual. Samples collected for analysis of inclacumab PK,
immunogenicity, or PD may additionally be used for further development and validation of 
the respective assay.
Note: In Egypt, blood samples for PK, PD, ADA, and biomarker endpoints will not be 
collected.
5.5.1. Pharmacokinetics
In all participants, plasma samples will be collected for measurement of inclacumab 
concentrations at a central laboratory using a validated ligand-binding assay under the 
supervision of the Sponsor. Plasma concentrations of inclacumab will be measured before 
and after each dose, at the Week 6 Visit, at the end of the treatment period (Week 48), and –
in all participants not enrolling in the OLE – at the Week 60 EOS Visit. Population PK 
analysis using nonlinear mixed effects modeling will be performed to characterize 
inclacumab PK in plasma. 
5.5.2. Anti-drug Antibodies
In all participants, plasma samples will be collected for characterization of ADA on Day 1
(pre-dose), Week 12 (pre-dose), Week 24 (pre-dose), at Week 48, and – in all participants not 
enrolling in the OLE – at the Week 60 EOS Visit. The detection and characterization of 
anti-inclacumab antibodies will be performed at a central laboratory using validated bridging 
ADA assays under the supervision of the Sponsor. Other analyses may be performed to 
further characterize the immunogenicity of inclacumab, including assessment of neutralizing 
antibodies.
5.5.3. Pharmacodynamics
Blood-based PD will be evaluated in all participants and will be assessed pretreatment, on-
treatment, and post-treatment with inclacumab. Assessments for PD include:

Whole blood samples for PD assessment of non-activated and TRAP-activated 
PLA formation and PLT P-selectin expression by flow cytometry. 

Serum samples for PD assessment of P-selectin inhibition by SPR. 

Plasma samples for PD assessment of circulating soluble free and total P-selectin. 
Additional samples for PK and PD will be collected when a participant presents with VOC 
on a non-study visit day, as feasible.
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5.5.4. Biomarkers
Biomarkers to be evaluated include:

Whole blood samples for assessment of RBC adhesion by microfluidic channels (at 
selected sites)

Whole blood samples for genomic analysis (optional)

Serum samples for assessment of protein markers by multiplex assay

Urine samples for assessment of kidney function

Plasma and whole blood samples for assessment of voxelotor concentrations (as 
applicable)
The relationships between PK, PD, biomarkers, clinical labs, safety, and efficacy will be 
explored.
Biological samples will be retained for up to 10 years, unless local regulatory requirements 
are for longer storage. These stored samples may be used by GBT or their research partners 
to help answer questions about the study drug, SCD and its associated conditions, or clinical 
laboratory testing to provide additional safety data. No human genetic testing will be 
performed without express consent of the study participant. The samples will be handled 
such that neither the participants name nor other identifying information will be recorded in 
the data belonging to the sample.
Note: For Egypt-specific assessments, refer to Appendix 6-5.
5.6. Unscheduled Visits for a VOC
Participants that visit a medical facility for treatment of a VOC will have blood samples 
obtained for CBC, chemistry, coagulation, PK/PD, and biomarkers as outlined in 
Appendix 1, Appendix 2, and Appendix 3. Instructions for collection, preparation, and 
shipping of blood samples are provided in the Laboratory Manual.
5.7. Additional Unscheduled Visits
Additional visits may be scheduled, as necessary, to ensure the safety and well-being of 
participants. All additional exams should be fully documented in the source documents and 
on Unscheduled Visit eCRFs, as appropriate. Visits intended to fulfill scheduled visit
requirements that fall outside the designated scheduled visit range are not Unscheduled 
Visits. In these cases, the visit data will be collected and transcribed to the appropriate 
scheduled visit eCRF.
If a participant is seen for multiple visits during a given visit window, the data from the visit 
that is intended to meet the protocol requirements for the scheduled visit should be captured 
on the visit eCRF. Where such a determination cannot be made, the first visit within the 
scheduled visit interval will be used for completion of the protocol required scheduled visit 
eCRF. Data from any additional visits within a scheduled visit interval will be captured on an 
Unscheduled Visit eCRF. 
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5.8. Missed Visits 
Missed visits should be rescheduled and performed as close to the original scheduled date as 
possible. If a participant misses any scheduled visit outside of the window for that visit, the 
visit is considered missed and will be recorded as a protocol deviation.
5.9. Post-study Follow-up 
If a participant requires further follow-up of AEs/SAEs upon discontinuation or completion 
of the study, the Investigator must schedule post-study follow-up visits, as necessary. Refer 
to Section 7.8 for follow-up of AEs following study exit. If a post-study follow-up occurs, 
document the visit on the Unscheduled Visit eCRF.
5.10. Study Completion 
The Sponsor, or designee, will notify the Investigator when to contact the IRB/EC to inform 
them that the study is complete.
5.10.1. Early Study Termination
If during the study it becomes evident to the Sponsor that the study should be stopped 
prematurely, the study will be terminated and appropriate notification will be given to the 
Investigator(s), IRB/EC, FDA, and local health authority, as applicable. The Sponsor, or 
designee, will instruct the Investigators to stop dispensing study materials/treatment and to 
arrange for study closeout at each site.
6. CONCOMITANT MEDICATIONS AND PROCEDURES
6.1. Concomitant Medications
A concomitant medication is any drug or substance administered between the signing of the 
informed consent and the EOS/ET Visit.
Enrollment in any other drug, biologic, or device clinical study or treatment with an approved 
therapy for investigational development or unapproved investigational drug under
development is not allowed.
Adverse events related to administration of concomitant medication must be documented in 
the appropriate eCRF.
Other than the medications listed in Section 6.1.1, medications that are used as the standard 
of care for SCD will be allowed during the study. 
Participants receiving HU, ESA, (eg, EPO), L-glutamine, or voxelotor should maintain a 
stable dose throughout the study.
6.1.1. Prohibited Medications and Therapies
Treatment with the following is not allowed during the study:

Initiation of treatment with HU, ESA, (eg, EPO), voxelotor, crizanlizumab, or 
L-glutamine.

Stem cell transplant.

Active treatment on another investigational trial, including gene therapy for SCD.
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
Initiation of a chronic transfusion program (pre-planned series of transfusions for 
prophylactic purposes).
Note: For UK-specific guidelines, refer to Appendix 6-3.
6.2. Concomitant Procedures
A concomitant procedure is any therapeutic intervention (eg, surgery/biopsy, physical 
therapy) or diagnostic assessment (eg, blood gas measurement, bacterial cultures) performed 
between the time the participant is enrolled in the study and the EOS/ET Visit.
The use of concomitant therapies or procedures must be recorded on the participant’s eCRF, 
according to instructions for eCRF completion. Adverse events related to administration of 
these therapies or procedures must be documented in the appropriate eCRF.
6.3. Contraception Requirements
All female participants of childbearing potential (post-menarche) should avoid pregnancy
during the study, and all sexually active male participants should avoid fathering a child
during the study.
Female participants will not be considered of childbearing potential if they are pre-
menarchal, surgically sterile (hysterectomy, bilateral salpingectomy, tubal ligation, or 
bilateral oophorectomy) or postmenopausal (no menses for 12 months without an alternative 
medical cause, confirmed by follicle-stimulating hormone test results).
6.3.1. Instructions for Female Participants of Childbearing Potential
For female participants of childbearing potential (post-menarche) who are sexually active, 
pregnancy should be avoided by the use of a highly effective method of contraception (as 
outlined in Section 6.3.3) consistently throughout the study and for at least 165 days after 
dosing.
Female participants who become pregnant during the study will be withdrawn from the 
study. Pregnancy reporting requirements are outlined in Section 1.1.
6.3.2. Instructions for Male Participants Capable of Fathering a Child
No information is available about the effects inclacumab may have on the development of the 
fetus in humans. Therefore, it is important that the partners of male participants do not 
become pregnant during the study and for a total period of 165 days after the male participant
has received his last dose of inclacumab. Sperm donation should be avoided for this same 
period.
Male participants who are not surgically sterilized must agree to practice true abstinence or 
agree to use acceptable contraception (see Section 6.3.3) if sexually active with a female 
partner of childbearing potential, throughout the study, and for at least 165 days after dosing. 
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6.3.3. Acceptable Forms of Contraception for Sexually Active Participants
For Female Participants
Highly effective methods of birth control are defined as those that result in a low failure rate 
(ie, < 1% per year) when used consistently and correctly. Highly effective methods of birth 
control are as follows:

Hormonal contraceptives:

Combined (estrogen- and progestogen-containing) hormonal contraception
associated with inhibition of ovulation: oral; intravaginal; injected; implanted; 
or transdermal.

Progestogen-only hormonal contraception associated with inhibition of
ovulation: oral; injectable; or implantable.

Hormonal contraception must be supplemented with a barrier method 
(preferably male condom).

Intrauterine device (IUD).

Intrauterine hormone-releasing system (IUS).

Bilateral tubal occlusion.

Sexual abstinence:

Sexual abstinence is a highly effective method only if the participant is 
refraining from heterosexual intercourse during the entire period of risk
associated with the study treatment. The reliability of sexual abstinence needs 
to be evaluated in relation to the duration of the clinical study and the 
preferred and usual lifestyle of the participant.

Male partner who has been vasectomized with confirmation of azoospermia 
(verbal confirmation is acceptable).
For Male Participants with Female Partners Capable of Reproduction: 

For male participants who are not surgically sterile with confirmed absence of 
sperm, condom plus effective contraception for their female partners (ie,
established use of oral, injected, or implanted hormonal contraception, or an IUD 
or IUS). 

Vasectomy at least 3 months prior to Day 1 with confirmation of azoospermia 
(verbal confirmation is acceptable).
Pregnancy reporting is described in Section 1.1.
6.4. Continuation of Treatment
Participants who complete the treatment and study through Week 48 will not receive any 
further treatment with the study drug on this study. Participants who complete the study, and 
meet eligibility requirements, will be provided with the opportunity to receive open-label 
inclacumab in the OLE study. The first dose administered in the OLE study will occur after 
completion of the end-of-study evaluations at the Week 48 Visit. 
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7. ASSESSMENT OF SAFETY
Safety assessments will consist of AE and SAE monitoring, protocol-specified hematology,
serum chemistry, and coagulation tests, PEs, protocol-specified vital sign measurements, and 
the results from other protocol-specified tests that are deemed critical to the safety evaluation 
of inclacumab.
The determination, evaluation, reporting, and follow-up of AEs will be performed as outlined 
in this section. At each visit, the study participant or participant caregiver (and/or their parent 
or legal guardian for participants under 18 years of age) will be asked about any new or 
ongoing AE since the previous visit. Assessments of AEs will occur at each study visit and 
during monthly phone calls. See Section 7.2 for details regarding the required time periods 
for AE reporting.
Clinically significant changes from study Baseline in PE findings, weight, vital signs, and 
clinical laboratory test results will be recorded as AEs or SAEs, as appropriate.
7.1. Adverse Events
7.1.1. Definition of Adverse Events
An AE is defined as any untoward medical occurrence in a participant administered a 
pharmaceutical product during the course of a clinical investigation. An AE can therefore be 
any unfavorable and unintended sign, symptom, or disease temporally associated with the use 
of an investigational product, whether or not thought to be related to the investigational 
product. In addition to new events, any increase in the severity or frequency of a pre-existing 
condition that occurs after the participant (and/or their parent or legal guardian for 
participants under 18 years of age) signs the ICD for participation is considered an AE. This 
includes any side effect, injury, toxicity or sensitivity reaction.
A suspected adverse reaction is any AE for which there is a reasonable possibility that the 
drug caused the AE. For the purposes of expedited safety reporting, “reasonable possibility” 
means there is evidence to suggest a causal relationship between the drug and the AE. 
Suspected adverse reaction implies a lesser degree of certainty about causality than adverse 
reaction, which means any AE caused by a drug.
Life-threatening AE or life-threatening suspected adverse reaction is an AE or suspected 
adverse reaction that, in the view of either the Investigator or Sponsor, places the study 
participant at immediate risk of death. It does not include an AE or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death.
An AE or suspected adverse reaction is considered to be “unexpected” if it is not listed in the 
Reference Safety Information section of the current IB or is not listed at the specificity or 
severity that has been observed.
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7.1.2. Definition of Serious Adverse Events
An SAE or serious suspected adverse reaction is an AE or suspected adverse reaction that, at 
any dose, in the view of the either the Investigator or Sponsor, results in any of the following 
outcomes:

Death

A life-threatening AE

Inpatient hospitalization or prolongation of existing hospitalization

Persistent or significant incapacity or disability (substantial disruption of the 
ability to conduct normal life functions)

A congenital anomaly/birth defect

Important medical events that may not result in death, be immediately 
life-threatening, or require hospitalization may be considered serious when, based 
upon medical judgment, they may jeopardize the study participant and may 
require medical or surgical intervention to prevent one of the outcomes listed in 
this definition.
NOTE: Hospitalization planned prior to study enrollment (eg, for elective surgeries) is not 
considered to be an SAE. Any complications arising from a planned hospitalization may be 
considered an AE and should be reported as applicable. Hospitalizations that occur for pre-
existing conditions that are scheduled after study enrollment are considered SAEs.
The Investigator will assess each AE for seriousness, severity, and relationship to 
investigational product.
7.1.3. Severity of Adverse Events
Whenever possible, the severity of all AEs will be graded using the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0.
The CTCAE quick reference guide can be found at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CT
CAE_v5_Quick_Reference_8.5x11.pdf
For AEs not adequately addressed in the NCI CTCAE, Version 5.0, the criteria presented in
Table 2 should be used.
Table 2:
Grading for Adverse Events not Covered in the NCI-CTCAE
Severity
Description
Grade 1 – Mild
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated
Grade 2 – Moderate
Minimal, local, or noninvasive intervention indicated; limited 
age-appropriate instrumental activities of daily living (ADL)
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Table 2:
Grading for Adverse Events not Covered in the NCI-CTCAE
Severity
Description
Grade 3 – Severe
Medically significant but not immediately life -threatening; 
hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care ADL
Grade 4 – Life-threatening
Life-threatening consequences; urgent intervention indicated
Grade 5 – Fatal
Death
Abbreviations: ADL, activities of daily living; NCI-CTCAE, National Cancer Institute - Common 
Terminology Criteria for Adverse Events.
To make sure that there is no confusion or misunderstanding between the terms “serious” and 
“severe”, which are not synonymous, the following note of clarification is provided. The 
term “severe” is often used to describe the intensity (severity) of a specific event (ie, mild, 
moderate, or severe); the event itself, however, may be of relatively minor medical 
significance (eg, severe headache). This is not the same as “serious”, which is based on the 
study participant/event outcome or action criteria associated with events that pose a threat to 
a participant’s life or functioning. Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations.
7.1.4. Relationship to Investigational Product
The relationship of an AE to the study drug should be determined by the Investigator
according to the following definitions:

Not Related: Evidence exists that the AE has an etiology other than the study drug 
and/or the temporal relationship of the AE/SAE to the investigational product 
administration makes the relationship unlikely. If an SAE is not considered to be 
related to study drug, then an alternative explanation should be provided.

Related: A temporal relationship exists between the event onset and the 
administration of the study drug and makes a causal relationship possible or 
probable. It cannot be readily explained by the participant’s clinical state or 
concomitant therapies and may appear, with some degree of certainty, to be 
related based on the known therapeutic and pharmacologic actions of the drug. 
Good clinical judgment should be used for determining causal assessment.
7.2. Adverse Event Reporting
7.2.1. General
All AEs/SAEs will be recorded from the time the study participant (and/or their parent or 
legal guardian for participants under 18 years of age) signs the ICD/assent form until 
3 months after last dose (Week 48)/or 6 months after last dose (Week 60) EOS Visit or ET
Visit, whichever comes first. All AEs/SAEs must be reported on the AE eCRF via the 
electronic data capture (EDC) system and reported to Pfizer Safety. The Investigator is 
responsible for evaluating all AEs/SAEs, obtaining supporting documents, and ensuring that 
documentation of the event is complete. Details of each reported AE/SAE must include at a 
minimum severity, relationship to study treatment, duration, and outcome. All (both serious 
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and nonserious) AEs must be followed until they are resolved or stabilized, or until 
reasonable attempts to determine resolution of the event are exhausted.
Any participant who experiences an AE/SAE may be discontinued from study treatment at 
any time at the discretion of the Investigator. The Sponsor and the Study Medical Monitor 
must be notified of the study participant discontinuation.
Follow-up by the Investigator continues throughout the active collection period and until the 
AE or SAE or its sequelae resolve or stabilize at a level acceptable to the Investigator.
When a clinically important AE remains ongoing at the end of the active collection period, 
follow-up by the Investigator continues until the AE or SAE or its sequelae resolve or 
stabilize at a level acceptable to the Investigator and Pfizer concurs with that assessment
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant permanently discontinues or temporarily discontinues study intervention
because of an AE or SAE, the AE or SAE must be recorded on the eCRF and the SAE 
reported to Pfizer Safety).
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the Investigator learns of any 
SAE, including a death, at any time after a participant has completed the study, and they 
consider the event to be reasonably related to study intervention, the Investigator must 
promptly report the SAE to the Sponsor.
Note: For UK-specific information, refer to Appendix 6-3.
7.2.2. Diagnosis Versus Signs and Symptoms
If known, a diagnosis should be recorded on the eCRF rather than individual signs and 
symptoms (eg, record only liver failure or hepatitis rather than jaundice, asterixis, and 
elevated transaminases). However, if a constellation of signs and/or symptoms cannot be 
medically characterized as a single diagnosis or syndrome at the time of reporting, each 
individual event should be recorded separately on the eCRF. If a diagnosis is subsequently 
established, it should be reported as follow-up information.
7.2.3. Abnormal Laboratory Values
Clinically significant laboratory abnormalities will be recorded in the AE eCRF (eg, 
abnormalities that have clinical sequelae, more frequent follow-up assessments, or further 
diagnostic investigation). If the clinically significant laboratory abnormality is a sign of a 
disease or syndrome (eg, alkaline phosphatase and bilirubin 5 × upper limit of normal (ULN)
associated with cholecystitis), only the diagnosis (eg, cholecystitis) needs to be recorded in 
the eCRF.
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If the clinically significant laboratory abnormality is not a sign of a disease or syndrome, the 
abnormality itself should be recorded on the eCRF. If the laboratory abnormality can be 
characterized by a precise clinical term, the clinical term should be recorded. For example, an 
elevated serum potassium level of 7.0 mEq/L should be recorded as “hyperkalemia”.
Observations of the same clinically significant laboratory abnormality from visit to visit 
should not be repeatedly recorded on the AE eCRF, unless their severity, seriousness, or 
etiology changes.
Note: Potential drug-induced liver injury (DILI; Hy’s law) cases are to be reported as SAEs 
(Section 7.3). For suggested actions and follow-up assessments in the event of potential 
DILI, refer to Appendix 5. 
7.3. Adverse Events of Special Interest, Serious Adverse Events, Serious Adverse Drug 
Reactions, and Requirements for Immediate Reporting
Any biologic agent given IV may have the potential to cause IRRs (refer to the current 
version of the IB for details). In this study, IRRs should be reported as AESIs. Signs or 
symptoms of IRRs may include chills/rigors, myalgias, headache, rash, fatigue, nausea, 
vomiting, dyspnea, and/or hypotension. Shock may occur during or shortly after infusion and 
usually occurs during and/or up to 24 hours after the first infusion.
All AESIs or SAEs, regardless of causal attribution, must be reported by the Investigator or 
designee or site personnel within 24 hours of AESI or SAE awareness. The AESI or SAE 
will be reported by completing the SAE eCRF. AESIs will be recorded on the SAE eCRF 
within 24 hours of the site’s awareness of them, even if they do not meet criteria for an SAE.
In addition, an AESI that is also an SAE must be reported to Pfizer Safety.
The Sponsor or designee may request additional source documentation pertaining to the 
AESI or SAE from the investigational site. Follow-up reports must be submitted within 24 
hours of awareness, and participant ID information (eg, name, medical record number) must 
be redacted in the hospital discharge summaries, autopsy reports, and/or death certificates.
Follow-up AESI or SAE information must be submitted within 24 hours of awareness as 
additional information becomes available. 
7.3.1. Reporting Suspected Unexpected Serious Adverse Reactions and Urgent Safety 
Issues
The Sponsor or designee is responsible for reporting suspected unexpected serious adverse 
reactions (SUSARs) to regulatory agencies, competent authorities, IRBs/ECs, and 
investigators as per local laws and regulations. Fatal and life-threatening SUSARs will be 
submitted no later than 7 calendar days of the Sponsor’s or designee’s first knowledge of the 
event and follow-up information submitted within an additional 8 calendar days, or as 
otherwise required per local laws and regulations. All other SUSARs will be submitted 
within 15 calendar days of the Sponsor’s or designee’s first knowledge of the event. The 
Investigator is responsible for notifying the local IRBs or ECs of all SAEs that occur at his or 
her site as required by local regulations or IRB/EC policies, if this responsibility resides with 
the site.
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Investigators are required to report any urgent safety matters to the Sponsor or designee 
within 24 hours of awareness. The Sponsor or designee will inform regulatory authorities, 
IRBs/ECs, and investigators, as applicable, of any events (eg, change to the safety profile of 
inclacumab, major safety findings that may place study participants at risk) that may occur 
during the clinical trial that do not fall within the definition of a SUSAR but may adversely 
affect the safety of study participants.
1.1.
Reporting and Treatment of Overdose
If a participant receives more than the protocol-defined dose of study drug and experiences a 
drug related- AE, this will be reported as an overdose (AEs must be recorded on the AE 
eCRF) and a protocol deviation. However, if the participant did not experience any AEs, this 
will only be reported as a protocol deviation.
The Investigator will discuss the risks and concerns of investigational agent exposure with 
the participant (and/or their parent or legal guardian for participants under 18 years of age). 
An overdose with associated AEs must be reported within 24 hours of the Investigator, 
designee, or site personnel learning of the overdose and reported to the Study
Director/Medical Monitor. An overdose must be followed until any adverse effects are 
resolved or stabilized, or until reasonable attempts to determine resolution of the event are 
exhausted.
In the event of an overdose, the Investigator or treating physician should:

Contact the study Medical Monitor within 24 hours.

Closely monitor the participant for any AEs/SAEs and laboratory abnormalities as 
medically appropriate and follow up until resolution, stabilization, the event is 
otherwise explained, or the participant is lost to follow-up. 

Document the quantity of the excess dose as well as the duration of the overdose 
in the eCRF.

Obtain a blood sample for PK analysis if requested by the study medical monitor 
(determined on a case-by-case basis). Document both the date of the last dose of 
study intervention and the time of sample collection.

Report to Sponsor Safety only when associated with an SAE.
7.4. Adverse Events That are VOC Endpoint Events
VOC events that are listed in Table 3 are being captured as endpoints and SHOULD NOT be 
reported as an AE or SAE for purposes of this study. These events will not be considered as 
SAEs for reporting requirements.
Note: For UK-specific guidelines, refer to Appendix 6-3.
Table 3:
VOC Events Not Requiring AE/SAE Reporting
Uncomplicated VOC*
ACS
Hepatic sequestration
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Table 3:
VOC Events Not Requiring AE/SAE Reporting
Uncomplicated VOC*
Splenic sequestration
Priapism requiring a visit to a medical facility
Abbreviations: ACS, acute chest syndrome; AE, adverse event; NSAID, nonsteroidal anti-inflammatory 
drug; SAE, serious adverse event; VOC, vaso-occlusive crisis.
* Defined as an acute episode of pain with no medically determined cause other than a vaso-occlusive 
event, results in a visit to a medical facility (hospitalization, emergency department, urgent care center, 
outpatient clinic, or infusion center), or results in a remote contact with a healthcare provider, and 
requires parenteral narcotic agents, parenteral NSAIDs, or an increase in treatment with oral narcotics, 
but is NOT classified as an ACS, hepatic sequestration, splenic sequestration, or priapism.
7.4.1. Procedures for Reporting and Documenting VOC Event Data
All VOCs, as defined in Section 5.1, are to be documented within the eCRF within 5 days of 
a site becoming aware of such event. Each VOC is to be recorded only once on the 
“Vaso-Occlusive Event” eCRF page. All VOCs are to be recorded throughout the entire 
treatment period, up to Week 48, and should continue until the Follow-Up Visit at Week 60
for participants who do not enroll in the OLE study (or earlier if participant discontinues 
from the study). The Investigator will classify and provide all the following information for 
each VOC as follows:

Diagnosis, which will be limited to one of the five pre-defined VOC events as 
described in Section 5.1:

Uncomplicated VOCs

Acute chest syndrome

Hepatic sequestration

Splenic sequestration

Priapism (requiring a visit to a medical facility)

Onset date,

Stop date,

Action taken (None, Required concomitant medication, Temporarily withheld 
study drug, Permanent discontinuation of study drug, or Other [explain]),

Whether or not hospitalization or a visit to emergency department, urgent care 
center, outpatient clinic, or infusion center was required,

Concomitant medications given, and

Outcome (Recovered without sequelae, Resolved with sequelae, Ongoing, 
Unknown, Death).
If a subject is hospitalized due to a VOC and during hospitalization develops a non-VOC 
event that meets the criteria for a SAE, then that event should be reported as a SAE. Any 
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prolongation of a hospitalization due to a non-VOC event (even though they may have 
initially been hospitalized due to a VOC) is reportable as a SAE in the eCRF and to Pfizer 
Safety within 24 hours.
7.4.2. Source Document Collection for VOC Event Adjudication
For each reported VOC, blinded source documentation to support the reported diagnosis will 
be submitted by the site to Sponsor, or designee, for review during the VOC adjudication 
process. Adjudication of all potential VOC events reported by the Investigator will be 
performed by a study Adjudication Committee – an independent, blinded panel comprised of 
experts in SCD. Responsibilities of the Adjudication Committee and definition of VOCs for 
adjudication will be provided in the Adjudication Committee Charter. 
Source documents may include (but are not limited to) the following:

Clinical notes (including history and PE findings),

Emergency Department notes (including history and PE findings),

Hospital discharge summary,

Clinical laboratory values (eg, hemoglobin concentration values for diagnoses of 
hepatic or splenic sequestration),

PE findings,

Concomitant medications, and

Chest X-ray (required for reporting an ACS).
Any SAE that is adjudicated by the endpoint adjudication committee NOT to meet endpoint 
criteria is reported back to the Investigator site of incidence. The Investigator must report the 
SAE to Sponsor Safety within 24 hours of being made aware that the SAE did not meet 
endpoint criteria. The Investigator’s SAE awareness date is the date on which the 
Investigator site of incidence receives the SAE back from the endpoint adjudication 
committee.
7.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure
Environmental exposure occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to study intervention. Such exposure may 
or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include exposure during pregnancy (EDP), exposure during 
breastfeeding (EDB), and occupational exposure.
Any such exposures to study intervention under study are reportable to Pfizer Safety or 
designee within 24 hours of Investigator awareness.
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7.5.1. Exposure During Pregnancy
An EDP occurs if:

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention.

A male participant who is receiving or has discontinued study intervention 
inseminates a female partner.

A female nonparticipant is found to be pregnant while being exposed or having 
been exposed to study intervention because of environmental exposure. Below is 
an example of environmental EDP:
o
A female family member of healthcare provider reports that she is 
pregnant after having been exposed to study intervention by all possible 
routes of exposure, eg, ingestion, inhalation, or skin contact.
o
A male family member or healthcare provider who has been exposed to 
study intervention by all possible routes of exposure, eg, ingestion, 
inhalation, or skin contact, then inseminates his female partner prior to or 
around the time of conception.
The Investigator must report EDP to Pfizer Safety within 24 hours of the Investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below of information related to 
termination of pregnancy). 

If EDP occurs in a participant/participant’s partner, the Investigator must report 
this information to Pfizer Safety regardless of whether an SAE has occurred. 
Details of the pregnancy will be collected after the start of study intervention and 
until at least 165 days after the last dose.

If EDP occurs in the setting of environmental exposure, the Investigator must 
report information to Pfizer Safety. Since the exposure information does not 
pertain to the participant enrolled in the study, the information is not recorded on 
the eCRF; however, a copy of the completed report is maintained in the 
Investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The Investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify the Sponsor of the outcome as a 
follow-up to the initial report. In the case of a live birth, the structural integrity of the neonate 
can be assessed at the time of birth. In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless pre-procedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criterial for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
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intrauterine fetal demise, or a neonatal death), the Investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows:

Spontaneous abortion including miscarriage and missed abortion should be 
reported as an SAE;

Neonatal deaths that occur within 1 month of birth should be reported, without 
regard to causality, as SAEs. In addition, infant deaths after 1 month should be 
reported as SAEs when the Investigator assesses the infant death as related or 
possibly related to exposure to study intervention.
Additional information regarding the EDP may be requested by the Sponsor. Further follow-
up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on preterm 
infants to identify developmental delays). In the case of paternal exposure, the Investigator 
will provide the participant with the Parental Partner: Information Sheet and Informed 
Consent Form to deliver to his partner. The Investigator must document in the source 
documents that the participant was given the Pregnant Partner Release of Information Form 
to provide to his partner. 
7.5.2. Exposure During Breastfeeding
An EDB occurs if:

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention.

A female nonparticipant is found to be breastfeeding while exposed or having 
been exposed to study intervention (ie, environmental exposure). An example of 
environmental EDB is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to study intervention 
by all possible routes of exposure, eg, ingestion, inhalation, or skin contact.
The Investigator must report EDB to Pfizer Safety within 24 hours of the Investigator’s 
awareness, irrespective of whether an SAE has occurred. When EDB occurs in the setting of 
environmental exposure, the exposure information does not pertain to the participant enrolled 
in the study, so the information is not recorded on the eCRF. However, a copy of the 
completed report is maintained in the Investigator site file. An EDB report is not created 
when a Pfizer drug specifically approved for use in breastfeeding women (eg, vitamins) is 
administered in accordance with authorized use. However, if the infant experiences an SAE 
associated with such a drug, the SAE is reported together with the EDB.
7.5.3. Occupational Exposure
The Investigator must report any instance of occupational exposure to Pfizer Safety within 
24 hours of the Investigator’s awareness using the report form regardless of whether there is 
an associated SAE. Since the information about the occupational exposure does not pertain to 
a participant enrolled in the study, the information is not recorded on the eCRF; however, a 
copy of the completed report is maintained in the Investigator site file.
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7.5.4. Lack of Efficacy 
The Investigator must report signs, symptoms, and/or clinical sequelae resulting from lack of 
efficacy. Lack of efficacy or failure of expected pharmacological action is reportable to 
Pfizer Safety only if associated with an SAE.  
7.5.5. Medication Errors
Medication errors may result from the administration or consumption of study intervention 
by the wrong participant, or at the wrong time, or at the wrong dosage strength.
Medication errors are recorded and reported as follows:
Table 4:
Reporting of Medication Errors
Recorded on the Medication 
Page of the eCRF
Recorded on the Adverse 
Event Page of the eCRF
Reported to the Pfizer Safety 
Within 24 Hours of Awareness
All (regardless of whether 
associated with an AE)
Any AE or SAE associated with 
the medication error
Only if associated with an SAE
Abbreviations: AE, adverse event; CRF, case report form; SAE, serious adverse event.
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that 
do or do not involve the study participant;

The administration of an incorrect dosage;

The administration of expired study intervention;

The administration of an incorrect study intervention;

The administration of study intervention that has undergone temperature 
excursion from the specified storage range unless it is determined by the Sponsor 
that the study drug under question is acceptable to use.
Whether or not the medication error is accompanied by an AE, as determined by the 
Investigator, such medication errors occurring to a study participant are recorded on the 
medication page of the eCRF, which is a specific version of the AE page. and, if applicable, 
any associated serious and nonserious AE(s) are recorded on the AE page of the eCRF.
In the event of a medication dosing error, the Sponsor should be notified within 24 hours.
Medication errors resulting in a SAE should be reported to Pfizer Safety within 24 hours.
7.6. Data Monitoring Committee
In addition to the Sponsor’s pharmacovigilance oversight, an independent, unblinded DMC 
will oversee the safety of participants, the interim futility analysis, and overall study conduct
for the Phase 3 program, with the support of an independent data coordinating center. 
Initial enrollment of study participants will be limited to adults and adolescents 16 years of 
age or older. The DMC will review all available safety data and PK/PD data (as applicable)
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from the first 20 participants who have completed a minimum of 12 weeks of study 
participation in the Phase 3 program in order to make a recommendation about enrollment of 
participants 12 to 15 years of age. Should the DMC recommend enrollment of participants 12 
to 15 years of age, sites will be informed by the Sponsor. The DMC will continue close 
monitoring by meeting to review data of each 20 participants 12 to 15 years of age, or every 
6 months, whichever occurs first. The DMC may also schedule ad hoc meetings at their 
discretion or at the Sponsor’s request.
Afull description of the DMC structure and responsibilities, as well as details of data to be 
reviewed and the frequency of the meetings, is described in the DMC Charter. 
Note: For France-, Germany-, UK-specific guidelines, refer to Appendix 6-1, Appendix 6-2, 
and Appendix 6-3.
7.7. Follow-up of AEs and SAEs
All AEs and SAEs must be followed until resolution, until the condition stabilizes, until the 
event is otherwise explained, or the participant is lost to follow-up. This includes AEs/SAEs 
ongoing at completion of the study. The Investigator is responsible to ensure that follow-up 
includes any supplemental investigations as may be indicated to elucidate as completely as 
practical the nature and/or causality of the AE or SAE. This may include additional 
laboratory tests or investigations, histopathological examinations, relevant hospital records 
(ie, discharge summary), or consultation with other health care professionals. The site must 
ensure that all participant IDs are redacted from supportive documentation prior to 
submission.
The Sponsor may request that the Investigator perform or arrange for the conduct of 
supplemental measurements and/or evaluations. If a participant dies during participation in 
the study or during a recognized follow-up period, the Sponsor should be provided with a 
copy of any postmortem findings, including histopathology, if available.
New or updated information obtained during SAE follow-up should be recorded on the 
originally completed SAE eCRF form with all changes signed and dated by the Investigator 
or designee. By signing the SAE eCRF form, the Investigator or designee attests to the 
accuracy and completeness of the data and that he/she has reviewed the report being 
submitted and approved. 
Investigators are not obligated to actively seek SAE information from subjects that complete 
the study, but investigators are encouraged to notify the Sponsor, or designee, of any SAEs of 
which they become aware occurring at any time after a subject has discontinued or completed 
the study that they judge may be reasonably related to treatment with study drug or study 
participation.
7.8. Safety Responsibilities
7.8.1. Investigator
The Investigator’s responsibilities include the following:

Monitor and record all AEs, including SAEs, regardless of the severity or 
relationship to study drug.

Determine the seriousness, relationship, and severity of each event.
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
Determine the onset and resolution dates of each event.

Monitor and record all pregnancies and follow-up on the outcome of the 
pregnancy in female participants or the partners of male participants.

Report all SAEs to Pfizer Safety within 24 hours.

Complete the AE/SAE and/or AESI eCRF within 24 hours of the study site staff 
becoming aware of the event.

Pursue AESI or SAE follow-up information actively and persistently. Follow-up 
information must be reported to Sponsor, or designee, within 24 hours of the 
study site staff becoming aware of new information.

Ensure all AE and SAE reports are supported by documentation in the 
participants’ medical records and submit documentation (with participant IDs 
redacted) with SAE reports as required.

Pursue AE follow-up information, if possible, until the event has resolved or 
become stable.

Report SAEs to IRB/EC, as required by local law.
7.8.2. Sponsor
The Sponsor’s responsibilities include the following:

Safety monitoring/surveillance of AEs and SAEs.

Before study site activation and participant enrollment, the Medical Monitor, or 
designee, is responsible for reviewing with study site staff the definitions of AE 
and SAE, as well as the instructions for monitoring, recording, and reporting AEs 
and SAEs.

The Sponsor, or designee, is to notify all appropriate regulatory authorities, 
central IRBs/ECs, and Investigators of SUSARs, as required by local law, within 
required time frames.
7.8.3. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool (DCT)

The primary mechanism for reporting an SAE to Pfizer Safety will be the electronic
DCT.

If the electronic system is unavailable, then the site will use the paper SAE report 
form (see next section) to report the event within 24 hours.

The site will enter the SAE data into the electronic DCT as soon as the data become 
available.

After the study is completed at a given site, the electronic DCT will be taken off-line 
to prevent the entry of new data or changes to existing data.
If a site receives a report of a new SAE from a study participant or receives updated data on a 
previously reported SAE after the electronic DCT has been taken off-line, then the site can 
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report this information on a paper SAE form (see next section) or to Pfizer Safety by 
telephone.
SAE Reporting to Pfizer Safety via the Clinical Trial (CT) SAE Report Form

Facsimile transmission of the CT SAE Report Form is the back-up method to transmit 
this information to Pfizer Safety in case the electronic DCT is unavailable for more 
than 24 hours.

In circumstances when the facsimile is not working, an alternative method should be 
used, eg, secured (Transport Layer Security) or password-protected email. If none of 
these methods can be used, notification by telephone is acceptable with a copy of the 
CT SAE Report Form sent by overnight mail or courier service.

Initial notification via telephone does not replace the need for the Investigator to 
complete and sign the CT SAE Report Form/ pages within the designated reporting 
time frames.
8. STATISTICAL METHODS
Detailed specifications of the methods for summary and analysis of the data collected in this 
study will be documented in the Statistical Analysis Plan (SAP).
8.1. Study Endpoints
Study endpoints are provided in Section 3.2.
8.2. Determination of Sample Size
A sample size of approximately 240 participants (120 participants per treatment arm 
[inclacumab and placebo]) provides approximately 90% power to detect a targeted 45% 
reduction in the rate of VOCs, from an average rate of 3.0 VOCs per year on placebo to 
1.65 VOCs per year on inclacumab, using a 2-sided test at an overall α = 0.05 level. 
Calculations were based on the methodology of Zhu and Lakkis (Zhu, 2014) and assume the 
number of VOCs per year follows a negative binomial distribution with a dispersion 
parameter of 1.04. For the purposes of sample size calculation, a drop-out rate of 25% by 
Week 48 was assumed.
8.3. Analysis Populations
Two main analysis populations are defined for this study: the intent-to-treat (ITT) population 
and the safety population.

The ITT population includes all randomized participants. For analyses based on 
this population, participants will be grouped according to treatment assigned at
randomization. The ITT population will be the main analysis population for 
efficacy analyses and summaries of demographic and Baseline characteristics.

The safety population includes randomized participants who received treatment 
with study drug. For analyses based on this population, participants will be 
grouped according to the actual treatment received. The safety population will be 
the main analysis population for safety analyses and summaries of study drug 
exposure.
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Additional analysis populations, such as a per protocol population, will be defined in the 
SAP, as appropriate. 
8.4. Statistical Analysis
8.4.1. Summaries of Study Conduct
The number of participants randomized will be tabulated by region, country, study site, and 
treatment group. Participant disposition (the number of participants randomized, treated, 
completing study treatment, and completing the study) will be tabulated by treatment group. 
Reasons for early study drug discontinuation and study discontinuation will be summarized. 
Any eligibility criteria deviations, dosing errors, and other major protocol deviations will also
be tabulated and evaluated for potential impact on the interpretation of study results.
8.4.2. Summaries of Demographics, Baseline Characteristics, and Concomitant 
Medications
Demographic and baseline characteristics, such as age, sex, race, sickle cell genotype, 
number of VOCs in the prior 12 months, concomitant HU/hydrocarbamide (HC) use, prior 
crizanlizumab use, and geographic region, will be summarized for the ITT population by 
treatment group. Concomitant medications will be coded using the World Health 
Organization (WHO) Drug Dictionary and summarized. Exposure to study drug (number of 
study drug treatments) and time on study will also be summarized.
8.4.3. Efficacy Analyses
8.4.3.1. Primary Endpoint
For the primary efficacy endpoint, the rate of VOCs during the 48-week treatment period will 
be compared between the inclacumab and placebo arms with the use of negative binomial 
regression model. 
The regression model will include covariates for treatment group (inclacumab, placebo) and 
the randomization stratification factors (Baseline HU use [yes; no], number of VOCs [2 to 4; 
5 to 10] in the preceding 12 months, and geographic region [North America; sub-Saharan 
Africa; Europe/rest of world]). The logarithm of observed patient-time at risk will be used as 
an offset term in the model. The rate of VOCs adjusted for the specified Baseline covariates 
will be estimated for each treatment arm based on the regression model. Similarly, the ratio 
of the VOC rate (inclacumab versus placebo) along with the associated 95% confidence 
interval (CI) and p-value will be estimated from the regression model.
The regression model will be fit based on all observed data from randomized participants, 
regardless of adherence to study drug or to the protocol. Sensitivity analyses will be 
performed to assess the robustness of the primary analysis results. Details will be specified in 
the SAP.
8.4.3.2. Secondary Endpoints
For the secondary endpoints of time to first VOC and time to second VOC, treatment 
comparison between inclacumab and placebo will be performed based on a stratified log-rank 
test. Kaplan-Meier plots will be generated. Time to first and time to second VOC will be 
measured from randomization (Day 1) to onset date of the corresponding VOC event. A Cox 
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regression model will be used to estimate the hazard ratio between the inclacumab and 
placebo groups, as appropriate.
For the proportion of participants with no VOCs during the 48-week treatment period, the 
exact Cochran-Mantel-Haenszel (CMH) general association test, stratified by the 
randomization stratification factors, will be used.
For the rate of VOCs that required admission to a healthcare facility and treatment with 
parenteral pain medication and number of days of inpatient hospitalization for a VOC during 
the 48-week treatment period, the same statistical method used for the primary endpoint will 
be used.
8.4.3.3. Exploratory Endpoints
Exploratory endpoints will be summarized by descriptive statistics. Details will be provided 
in the SAP.
8.4.3.4. Interim Futility Analysis
One interim analysis for futility will be performed at an information fraction of 
approximately 48%. The futility analysis will include subjects who, by the selected data 
cutoff date, have the potential for at least 24 weeks of treatment (ie, 2 doses of the study 
drug). 
For the futility analysis, the primary efficacy endpoint will be evaluated by the independent 
DMC. The study team will remain blinded. A Gamma family (-1) β-spending function will 
be used to determine the futility boundary. The futility boundary is considered non-binding. 
Additional details will be provided in the SAP.
8.4.3.5. Adjustment for Multiple Comparisons
A fixed sequence hierarchical test procedure will be used to control Type I error when
evaluating the treatment effect of inclacumab compared with placebo for the primary and 
secondary efficacy endpoints. The endpoints will be tested sequentially based on the 
following pre-specified order:
1. Rate of VOCs during the 48-week treatment period (primary endpoint)
2. Time to first VOC during the 48-week treatment period
3. Time to second VOC during the 48-week treatment period
4. Proportion of participants with no VOCs during the 48-week treatment period
5. Rate of VOCs that required admission to a healthcare facility and treatment with 
parenteral pain medication during the 48-week treatment period
6. Number of days of inpatient hospitalization for a VOC during the 48-week treatment 
period
Each endpoint will be tested at a 2-sided alpha level of 0.05. Formal testing of endpoints will 
continue until the first non-significant result. Testing of endpoints subsequent to a 
non-significant result will be considered exploratory in nature.
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8.4.3.6. Safety Analyses
Safety will be assessed through descriptive summaries of adverse events, laboratory test 
results, and vital signs.
Adverse events will be classified according to the Medical Dictionary for Regulatory 
Activities (MedDRA). The incidence of TEAEs, defined as events that occur on or after Day 
1 of study treatment or the worsening of a preexisting condition on or after Day 1 of study 
treatment, will be tabulated by System Organ Class and Preferred Term. Additional 
summaries for TEAEs by severity, relationship to study drug, and leading to study drug 
discontinuation, as well as for AESIs, SAEs, and deaths will be generated.
VOC events will be collected and summarized separately (including ACS, hepatic 
sequestration, splenic sequestration, and priapism).
Changes in laboratory parameters (hematology, serum chemistry, and coagulation) and vital 
signs (eg, BP, HR, and body temperature) over time will be summarized descriptively.
8.4.4. PK, ADA, and PD Analyses
Note: In Egypt, blood samples for the determination of PK, PD, ADA, and biomarker 
endpoints will not be collected.
8.4.4.1. Pharmacokinetic Analyses
Population PK analysis will include data from all participants who receive active study drug
and have at least 1 measurable post-dose concentration. If any participants are found to have 
incomplete data, protocol deviations, or clinical events affecting PK, a decision will be made 
on a case-by-case basis as to their inclusion in the analysis. The influence of demographic 
covariates (such as body weight, sex, age, race) on inclacumab PK parameters will be 
investigated. If appropriate, the inclacumab PK data may be pooled with PK data from other 
studies. Results of population PK analyses will be reported separately.
A review of PK/PD data from at least 20 participants in the Phase 3 program for dose 
confirmation will be performed by the DMC.
Note: For France-specific guidelines, refer to Appendix 6-1.
8.4.4.2. Anti-drug Antibody Analyses 
Analysis for ADAs will include data from all participants who receive active study drug and 
have at least 1 assessment for ADA after the start of dosing. Anti-drug antibody 
characterization will include but is not limited to, incidence, timing, and persistence of ADA. 
If any participants are found to have incomplete data, protocol deviations, or clinical events 
affecting ADA, a decision will be made on a case-by-case basis as to their inclusion in the 
analysis. The percentage of participants with confirmed ADA positivity during the study out 
of the total number tested will be summarized. The results of additional characterization will 
be reported separately. Correlation of ADA with PK, safety, and efficacy observations will 
be explored.
8.4.4.3. Pharmacodynamic Analyses
Pharmacodynamic results will be displayed graphically over time to observe changes from 
Baseline. For markers demonstrating correlative trends, population-based analyses, eg, 
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PK/PD or mechanistic modeling, may be explored to characterize the relationships between 
PK, PD, clinical labs, safety, and/or efficacy observations. The results of these exploratory 
analyses will be reported elsewhere.
9. STUDY ADMINISTRATION
9.1. Direct Access to Source Data/Documents
The Investigator will permit study-related monitoring, audits, IRB/EC review, and regulatory 
inspection, as appropriate, by providing direct access to source data/documents.
The Sponsor, or designee, will determine a risk evaluation plan and implement an action plan 
considering the need to reduce unnecessary contacts in the context of the COVID-19 
pandemic or another epidemiological emergency. Site visits may be replaced by an enhanced 
centralized monitoring or local visits may be postponed. These methods will be described in 
a monitoring plan by the Sponsor, or designee.
9.1.1. Source Data
Original documents, data, records (eg, clinic records, laboratory notes, memoranda, 
participant diaries or evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being accurate 
and complete, participant files, and records kept at the pharmacy, laboratories, and medico-
technical departments involved in the clinical study), and all relevant sections of the 
participant’s medical records and all other data collection made specific to this study 
constitute source documents.
Before an investigational site can enter a patient into the study, a representative of the 
Sponsor and/or designee will visit the investigational study site to:

Determine the adequacy of the facilities; and

Discuss with the Investigator and other personnel their responsibilities with 
respect to protocol adherence, and the responsibilities of the Sponsor or its 
representatives. This will be documented in a Clinical Study Agreement between 
the Sponsor and the Investigator.
During the study, a monitor from the Sponsor or representative will have regular contact with 
the investigational site, for the following:

Provide information and support to the investigator(s).

Confirm that facilities remain acceptable.

Confirm that the investigational team is adhering to the protocol, that data are 
being accurately recorded in the eCRF, and that investigational product 
accountability checks are being performed.

Perform source data verification. This includes a comparison of the data in the 
eCRF with the patient’s medical records at the hospital or practice, and other 
records relevant to the study. This will require direct access to all original records 
for each patient (eg, clinic charts).

Record and report any protocol deviations not previously sent to the Sponsor.
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
Confirm AEs and SAEs have been properly documented on eCRFs and confirm 
any SAEs have been forwarded to the Sponsor or safety designee and those SAEs
that met criteria for reporting have been forwarded to the IRB/EC.
The monitor will be available between visits if the Investigator or other staff needs 
information.
9.2. Data Collection
The Investigator will be responsible for maintaining accurate and adequate source 
documents. All relevant observations and data related to the study will be recorded. This will 
include medical and medication history, PEs, a review of inclusion and exclusion criteria, 
investigational treatment administration, a record of sample collection, clinical assessments, 
AEs, and final evaluation(s). 
Data for each participant will be recorded on the eCRF. An eCRF must be completed for 
every participant enrolled in the study. When data are complete, the Investigator or medically 
qualified sub-investigator listed on FDA Form 1572, or similar document, will apply his/her 
signature on the eCRF indicating he/she has reviewed and approves of the data collected on 
the eCRF. The monitor will review all eCRFs and compare data to those contained in clinic 
notes and participants’ source documents/medical records.
9.3. Quality Control and Quality Assurance
9.3.1. Monitoring
Site personnel will be provided with training on how to collect quality data for the study, and 
a Sponsor monitor or designee will be contacting the site periodically to review study 
conduct and data recorded at the site. At the Sponsor’s discretion, on-site monitoring visits 
may be conducted pre-study, during the study, and following study completion. These visits 
are to provide the Sponsor with the opportunity to evaluate study progress; verify the 
accuracy and completeness of source data and eCRFs; and ensure that all protocol and Good 
Clinical Practice (GCP) requirements, applicable country-specific regulations, and 
Investigator obligations are being fulfilled. The Sponsor may terminate study participation if 
study-site personnel do not follow the protocol or GCP requirements. Additionally, 
individual participants may be excluded if a medical record review indicates protocol 
violations or if other factors appear to jeopardize the validity of the study.
The Investigator agrees to cooperate with the monitor to ensure that any problems detected 
during the monitoring visits are resolved.
9.3.2. Quality Control and Quality Assurance
The Sponsor may conduct quality assurance audits of this study. If such an audit occurs, the 
Investigator agrees to allow the auditor direct access to all relevant documents (eg, all 
participant records, medical records, and eCRFs) and access to all corresponding portions of 
the office, clinic, laboratory, or pharmacy that may have been involved with the study. The 
Investigator will allocate his or her time and that of the study-site personnel to the auditor to 
discuss findings and any relevant issues.
In addition, regulatory agencies may conduct a regulatory inspection of this study. If such an 
inspection occurs, the Investigator agrees to notify the Sponsor upon notification by the 
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regulatory agency. The Investigator agrees to allow the inspector direct access to all relevant 
documents and to allocate his or her time and that of the study-site personnel to the inspector 
to discuss findings and any relevant issues. The Investigator will allow Sponsor personnel to 
be present as an observer during a regulatory inspection, if requested.
9.3.3. Laboratory Accreditation
The laboratory facilities used for analysis of clinical laboratory samples must provide 
evidence of adequate licensure or accreditation. Copies of laboratory certification, licensure, 
and reference ranges (as appropriate) will be supplied to the Sponsor prior to study initiation. 
The Sponsor or designee should be notified of any changes in reference range values or 
certification/license renewal during the study.
9.4. Sponsor’s Medically Qualified Individual
The contact information for the sponsor’s Medically Qualified Individual (MQI; ie, Medical 
Monitor) for the study is documented in the study contact list located in the Study Binder. 
To facilitate access to their Investigator and the Sponsor’s MQI for study-related medical 
questions or problems from nonstudy healthcare professionals, participants are provided with 
an emergency contact card (ECC) at the time of informed consent. The ECC contains, at a 
minimum (a) protocol and study intervention identifiers, (b) participant’s study identification 
number, and (c) site emergency phone number active 24 hours/day, 7 days per week.
The ECC is intended to augment, not replace, the established communication pathways 
between the participant and their Investigator and site staff, and between the Investigator and 
Sponsor study team. The ECC is only to be used by healthcare professionals not involved in 
the research study, as a means of reaching the Investigator or site staff related to the care of a 
participant.
9.5. Regulatory, Ethical, and Study Oversight Considerations
9.5.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines;

Applicable International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use (ICH) GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents (eg, 
advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC by 
the Investigator, and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
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Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants.
The Investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH GCP guidelines, the 
IRB/EC, European regulation 536/2014 for clinical studies, European Medical 
Device Regulation 2017/745 for clinical device research, and all other applicable 
local regulations.
9.5.2. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the Investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, the Sponsor should be informed immediately. 
In addition, the Investigator will inform the Sponsor immediately of any urgent safety 
measures taken by the Investigator to protect the study participants against any immediate 
hazard, and of any serious breaches of this protocol or of the ICH GCP guidelines that the 
Investigator becomes aware of.
9.5.3. Informed Consent/Assent Process
9.5.3.1. Adult Participants
The Investigator or the Investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant (and/or their parent or legal guardian for 
participants under 18 years of age) and answer all questions regarding the study. The 
participant (and/or their legal guardian for participants under 18 years of age) should be 
given sufficient time and opportunity to ask questions and to decide whether or not to 
participate in the trial.
Participants must be informed that their participation is voluntary. Participants (or their 
legally authorized representative [if allowed by local regulation]) will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, privacy and data protection requirements, where applicable, and the IRB/EC 
or study center. 
The Investigator must ensure that each participant (and/or their legal guardian for participants 
under 18 years of age) is fully informed about the nature and objectives of the study, the 
sharing of data related to the study, and possible risks associated with participation, including 
the risks associated with the processing of the participant’s personal data.
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The participant (or their legally authorized representative) must be informed that their 
personal study-related data will be used by the Sponsor in accordance with local data 
protection law. The level of disclosure must also be explained to the participant (or their 
legally authorized representative).
The participant (and/or their legal guardian for participants under 18 years of age) must be 
informed that their medical records may be examined by Clinical Quality Assurance auditors 
or other authorized personnel appointed by the Sponsor, by appropriate IRB/EC members, 
and by inspectors from regulatory authorities.
The Investigator further must ensure that each study participant (and/or their legal guardian 
for participants under 18 years of age) is fully informed about their right to access and correct 
their personal data and to withdraw consent for the processing of their personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date on which the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD.
Participant (and/or their legal guardian for participants under 18 years of age) must be 
reconsented to the most current version of the IRB/EC-approved ICD(s) during their 
participation in the study as required per local regulations.
A copy of the ICD(s) must be provided to the participant (and/or their legal guardian for 
participants under 18 years of age).
Participants who are rescreened are required to sign a new ICD.
9.5.3.2. Pediatric Participants
The Investigator or their representative will explain the nature of the study to the 
participant and their parent(s)/legal guardian and answer all questions regarding the 
study. The participant and their parent(s)/legal guardian should be given sufficient time and 
opportunity to ask questions and to decide whether or not to participate in the trial.
When consent is obtained from a participant’s parent(s)/legal guardian, the participant’s 
assent (affirmative agreement) must be subsequently obtained when the participant has the 
capacity to provide assent, as determined by the IRB/EC. If the Investigator determines that 
a participant’s decisional capacity is so limited they cannot reasonably be consulted, then, as 
permitted by the IRB/EC and consistent with local regulatory and legal requirements, the 
participant’s assent may be waived with source documentation of the reason assent was not 
obtained. If the study participant does not provide his or her own assent, the source 
documents must record why the participant did not provide assent (for example, child is not 
of assenting age per local regulations or policies), how the Investigator determined that the 
person signing the consent was the participant’s parent(s)/legal guardian, the consent signer’s 
relationship to the study participant, and that the participant’s assent was obtained or 
waived. If assent is obtained verbally, it must be documented in the source documents.
If study participants are minors who reach the age of majority or if a child reaches the age of 
assent (per local IRB/IEC requirements) during the study, as recognized under local law, the 
child or adolescent must then provide the appropriate assent or consent to document their 
willingness to continue in the study. For an adolescent, who reaches the age of consent, 
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parental consent would no longer be valid. If the enrollment of emancipated minors is 
permitted by the IRB/EC and local law, the participant must provide documentation of legal 
status to give consent without the permission of a legally authorized representative.
Participants and their parent(s)/legal guardian must be informed that their participation is 
voluntary. Participant’s parent(s)/legal guardian will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, HIPAA requirements, where applicable, and the IRB/EC or study center.
The Investigator must ensure that each study participant’s parent(s)/legal guardian and the 
study participant as applicable are fully informed about the nature and objectives of the 
study, the sharing of data related to the study, and possible risks associated with 
participation, including the risks associated with the processing of the participant’s personal 
data.
The participant’s parent(s)/legal guardian must be informed that the participant’s personal 
study-related data will be used by the sponsor in accordance with local data protection 
law. The level of disclosure must also be explained to the participant’s parent(s)/legal 
guardian.
The participant’s parent(s)/legal guardian must be informed that the participant’s medical 
records may be examined by Clinical Quality Assurance auditors or other authorized 
personnel appointed by the sponsor, by appropriate IRB/EC members, and by inspectors 
from regulatory authorities.
The Investigator further must ensure that each study participant’s parent(s)/legal guardian is 
fully informed about his or her right to access and correct his or her child’s personal data and 
to withdraw consent for the processing of his or her child’s personal data keeping in mind the 
privacy rights that may restrict access of older adolescents’ medical records by their 
parent(s)/legal guardian in certain regions.
The source documentation must include a statement that written informed consent and as 
applicable, assent, was obtained before the participant was enrolled in the study and the date 
the written consent/assent was obtained. The authorized person obtaining the informed 
consent must also sign the ICD.
Parent(s)/legal guardian and the participant must be reconsented to the most current version 
of the ICD(s)/assent during their participation in the study.
A copy of the ICD(s) and assent, if written, must be provided to the parent(s)/legal 
guardian and the participant.
Participants who are rescreened are required to sign a new ICD.
9.5.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
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Participant’s personal data will be stored at the study site in encrypted electronic and/or paper 
form and will be password protected or secured in a locked room to ensure that only authorized 
study staff have access. The study site will implement appropriate technical and organizational 
measures to ensure that the personal data can be recovered in the event of disaster. In the event 
of a potential personal data breach, the study site will be responsible for determining whether a 
personal data breach has in fact occurred and, if so, providing breach notifications as required 
by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the Sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
Sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to their actual identity and medical record ID. In case of data 
transfer, the Sponsor will protect the confidentiality of participant’ personal data consistent 
with the clinical study agreement and applicable privacy laws.
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access.
The Sponsor maintains standard operating procedures on how to respond in the event of 
unauthorized access, use, or disclosure of Sponsor information or systems.
9.5.5. IRB/EC and Regulatory Approval
The Investigator must inform and obtain approval from the IRB/EC for the conduct of the 
study at named sites and for the protocol, the participant ICD, and any other written 
information that will be provided to the participants and any advertisements that will be used. 
Written approval must be obtained prior to enrollment of participants into the study and 
shipment of investigational product.
Proposed amendments to the protocol and documents must be discussed with the Sponsor 
and CRO, and then submitted to the IRB/EC for approval, as well as submitted to regulatory 
authorities for approval prior to implementation. Amendments may be implemented only 
after a copy of the local IRB/EC approval letter has been transmitted to the Sponsor. 
Amendments that are intended to eliminate an apparent immediate hazard to participants may 
be implemented prior to receiving Sponsor or IRB/EC approval. However, in this case, 
approval must be obtained as soon as possible after implementation.
The Investigator will be responsible for ensuring that an annual update is sent to the IRB/EC
to facilitate their continuing review of the study (if needed) and that the IRB/EC is informed 
about the end of the study. Copies of the update, subsequent approvals, and final letter must 
be sent to the Sponsor. The Investigator will inform the IRB/EC of any reportable AEs.
9.5.6. Essential Documentation Requirements
The Sponsor or Sponsor’s representative will collect from the investigational site the required 
essential regulatory documents per ICH guidance prior to investigational product shipment to 
the site.
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9.5.7. Dissemination of Clinical Study Data
The Sponsor fulfills its commitment to publicly disclose clinical study results through 
posting the results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European 
Union Drug Regulating Authorities Clinical Trials Database/Clinical Trials Information 
System (EudraCT/CTIS), and/or www.pfizer.com, and other public registries and websites in 
accordance with applicable local laws/regulation. In addition, the Sponsor reports study 
results outside of the requirement of local laws/regulations pursuant to its standard operating 
procedures.
In all cases, study results are reported by the Sponsor in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
The Sponsor posts clinical trial results on www.clinicaltrials.gov for GBT/Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
product, regardless of the geographical location in which the study is conducted. These 
results are submitted for posting in accordance with the format and timelines set forth by US 
law.
EudraCT/CTIS
The Sponsor posts clinical trial results on EudraCT/CTIS for GBT/Pfizer-sponsored 
interventional studies in accordance with the format and timelines set forth by the European 
Union (EU) requirements.
www.pfizer.com
The Sponsor posts clinical study report (CSR) synopses and plain-language study results 
summaries on www.pfizer.com for GBT/Pfizer-sponsored interventional studies at the same 
time the corresponding study results are posted to www.clinicaltrials.gov. CSR synopses will 
have personally identifiable information anonymized.
Documents within marketing applications
The Sponsor complies with applicable local laws/regulations to publish clinical documents 
included in marketing applications. Clinical documents include summary documents and 
CSRs including the protocol and protocol amendments, sample CRFs, and SAPs. Clinical 
documents will have personally identifiable information anonymized.
Data sharing
The Sponsor provides researchers secure access to participant-level data or full CSRs for the 
purposes of “bona-fide scientific research” that contributes to the scientific understanding of 
the disease, target, or compound class. The Sponsor will make data from these trials available 
18 months after study completion. Participant -level data will be anonymized in accordance 
with applicable privacy laws and regulations. CSRs will have personally identifiable 
information anonymized.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
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be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
9.5.8. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
Guidance on completion of CRFs will be provided in the CRF Completion Requirement 
document
The Investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password-protected or secured in a locked room to 
prevent access by unauthorized third parties.
Quality tolerance limits (QTLs) are predefined parameters that are monitored during the 
study. Important deviations from the QTLs and any remedial actions taken will be 
summarized in the CSR.
The Investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source records and documents. 
This verification may also occur after study completion. It is important that the 
Investigator(s) and their relevant personnel are available during the monitoring visits and 
possible audits or inspections and that sufficient time in devoted to the process.
Monitoring details describing strategy, including definition of study-critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, virtual, or on-site monitoring), are provided in the data management plan maintained 
and utilized by the Sponsor or designee.
The Sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor. The 
Investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the Investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The Investigator(s) will notify the Sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the Investigator will cooperate 
with the Sponsor or its agents to prepare the Investigator site for the inspection and will allow 
the Sponsor or its agent, whenever feasible, to be present during the inspection. The 
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Investigator site and Investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant’s medical records. The Investigator will promptly 
provide copies of the inspection findings to the Sponsor or its agent. Before response 
submission to the regulatory authorities, the Investigator will provide the Sponsor or its 
agents with an opportunity to review and comment on responses to any such findings. 
9.5.9. Study and Site Start and Closure
The study start date is the date of the first participant’s first visit.
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor, including (but not limited to) 
regulatory authority decision, change in opinion of the IRB/EC, or change in benefit-risk 
assessment. Study sites will be closed upon study completion. A study site is considered 
closed when all required documents and study supplies have been collected and a study-site 
closure visit has been performed.
The Investigator may initiate study-site closure at any time upon notification to the Sponsor 
or designee/CRO if requested to do so by the responsible IRB/EC or if such termination is 
required to protect the health of study participants.
Reasons for the early closure of a study site by the Sponsor may include but are not limited 
to:

Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the Sponsor’s procedures, or the ICH GCP 
guidelines;

Inadequate recruitment of participants by the Investigator;

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights. 
9.5.10. Confidentiality
The Investigator must ensure that the participant’s privacy is maintained. In the eCRF and 
other documents submitted to the Sponsor, participants will be identified by a participant 
studynumber only. Documents that are not submitted to the Sponsor (eg, signed ICD) should 
be kept in a strictly confidential file by the Investigator.
The Investigator shall permit authorized representatives of the Sponsor, regulatory agencies, 
and IRBs/ECs to review the portion of the participant’s medical record that is directly related 
to the study. As part of the required content of informed consent, the participant must be 
informed that his/her records will be reviewed in this manner.
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1.2.
Insurance and Financial Disclosure
The Sponsor has subscribed to an insurance policy covering, in its terms and provisions, its 
legal liability for injuries caused to participating persons and arising out of this research 
performed strictly in accordance with the scientific protocol, as well as with applicable law 
and professional standards.
Financial disclosure statements will be handled in a separate agreement apart from the 
protocol, kept on file, and submitted as applicable with any subsequent license application.
9.6. Publication Policy
For multicenter trials, the primary publication will be a joint publication developed by the 
Investigator and the Sponsor reporting the primary endpoint(s) of the study covering all study 
sites. The Investigator agrees to refer to the primary publication in any subsequent 
publications. The Sponsor will not provide any financial compensation for the Investigator’s 
participation in the preparation of the primary congress abstract, poster, presentation, or 
primary manuscript for the study.
Investigators are free to publish individual center results that they deem to be clinically 
meaningful after publication of the overall results of the study or 12 months after primary 
completion date or study completion at all sites, whichever occurs first, subject to the other 
requirements described in this section.
The Investigator will provide the Sponsor an opportunity to review any proposed publication 
or any other type of disclosure of the study results (collectively, “publication”) before it is 
submitted or otherwise disclosed and will submit all publications to the Sponsor 30 days 
before submission. If any patent action is required to protect intellectual property rights, the 
Investigator agrees to delay the disclosure for a period not to exceed an additional 60 days 
upon request from the Sponsor. This allows the Sponsor to protect proprietary information 
and to provide comments, and the Investigator will, on request, remove any previously 
undisclosed confidential information before disclosure, except for any study-intervention or 
Sponsor-related information necessary for the appropriate scientific presentation or
understanding of the study results. For joint publications, should there be disagreement 
regarding interpretation and/or presentation of specific analysis results, resolution of, and 
responsibility for, such disagreements will be the collective responsibility of all authors of 
the publication.
For all publications relating to the study, the Investigator and the Sponsor will comply with 
recognized ethical standards concerning publications and authorship, including those 
established by the International Committee of Medical Journal Editors. The Investigator will 
disclose any relationship with the Sponsor and any relevant potential conflicts of interest, 
including any financial or personal relationship with the Sponsor, in any publications. All 
authors will have access to the relevant statistical tables, figures, and reports (in their original 
format) required to develop the publication.
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10. REFERENCES
ADAKVEO® (crizanlizumab) US Prescribing Information. Novartis Pharmaceuticals 
Corporation. November 2019.
Ataga K, Kutlar A, Kanter J, Liles D, Cancado R, Friedrisch J, et al. Crizanlizumab for the 
Prevention of Pain Crises in Sickle Cell Disease. N Engl J Med. 2017;376(5):429–39.
Charache S, Terrin M, Moore R, Dover GJ, Barton FB, Eckert SV, et al. Effect of 
Hydroxyurea on the Frequency of Painful Crisis in Sickle Cell Anemia. N Engl J Med.
1995;332(20):1317-22.
DROXIA® (hydroxyurea capsules, USP) US Prescribing Information. Bristol-Myers Squibb. 
December 2017.
ENDARI (L-glutamine Oral Powder) US Prescribing Information. Emmaus Medical, Inc. 
July 2017.
Kaiser K, Yount SE, Martens CE, Webster KA, Shaunfield S, Sparling A, et al. Assessing 
Preferences for Rare Disease Treatment: Qualitative Development of the Paroxysmal 
Nocturnal Hemoglobinuria Patient Preference Questionnaire (PNH-PPQ©). Patient Prefer 
Adherence. 2020 Apr 5;14:705-15.
Kassim A, Sharma D. Hematopoietic Stem Cell Transplantation for Sickle Cell Disease: 
The Changing Landscape. Hematol Oncol Stem Cell Ther. 2017;10:259-66.
Kato G, Piel F, Reid C, Gaston MH, Ohene-Frempong K, Krishnamurti L, et al. Sickle Cell 
Disease. Nature Reviews – Disease Primers. 2018;4(18010):1-22.
Levy AR, Dysart L, Patel Y, Briggs A, Schneider J, Myren KJ, et al. Comparison of Lost 
Productivity Due to Eculizumab and Ravulizumab Treatments for Paroxysmal Nocturnal 
Hemoglobinuria in France, Germany, Italy, Russia, Spain, the United Kingdom, and the 
United States. Blood. 2019;134:4803.
McFarling UL. ‘They are really afraid’: Fears about Covid-19 are complicating care for 
patients with sickle cell. STATNews September 17, 2020.
(https://www.statnews.com/2020/09/17/sickle-cell-treatment-covid19-pandemic/
Niihara Y, Miller ST, Kanter J, Lanzkron S, Smith WR, Hsu LL, et al. A Phase 3 Trial of l-
Glutamine in Sickle Cell Disease. N Engl J Med. 2018;379(3):226-35. 
Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005 Aug 4;353(5):487-
97.
Powell L. Sickle Cell Disease Brings Higher Risk of Coronavirus Death, but Inconsistent 
Treatment. The City, Jul 14, 2020. 
(https://www.thecity.nyc/coronavirus/2020/7/14/21324875/sickle-cell-disease-coronavirus-
death-new-york-city).
Richter A, Anton SF, Koch P, Dennett SL. The impact of reducing dose frequency on health 
outcomes [published correction appears in Clin Ther. 2015 Aug;37(8):1870. Anton, Susan E 
[corrected to Anton, Susan F]]. Clin Ther. 2003;25(8):2307-2306. 
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Roebuck MC, Liberman JN, Gemmill-Toyama M, Brennan TA. Medication adherence leads 
to lower health care use and costs despite increased drug spending. Health Aff (Millwood). 
2011;30(1):91-9. 
Saini SD, Schoenfeld P, Kaulback K, Dubinsky MC. Effect of medication dosing frequency 
on adherence in chronic diseases. Am J Manag Care. 2009;15(6):e22-e33. Published 2009 
Jun 1
Shah N, Bhor M, Xie L, Halloway R, Arcona S, Paulose J, et al. Treatment Patterns and 
Economic Burden of Sickle-Cell Disease Patients Prescribed Hydroxyurea: A Retrospective 
Claims-Based Study. Healthy and Quality of Life Outcomes. 2019;17(155):1-11.
Simpson SH, Eurich DT, Majumdar SR, Padwal RS, Tsuyuki RT, Varney J, Johnson JA. 
A meta-analysis of the association between adherence to drug therapy and mortality. BMJ. 
2006 Jul 1;333(7557):15. 
Tkacz J, Ingham MP, Brady BL, Meyer R, Ruetsch C. Novel Adherence Measures for 
Infusible Therapeutic Agents Indicated for Rheumatoid Arthritis. Am Health Drug Benefits. 
2015;8(9):494-505.
Wells JR, Gater A, Marshall C, Tritton T, Vashi P, Kessabi S. Exploring the Impact of 
Infusion Frequency in Hemophilia A: Exit Interviews with Patients Participating in BAY 94-
9027 Extension Studies (PROTECT VIII). Patient. 2019;12(6):611-19.
Zhu H and Lakkis H. Sample size calculation for comparing two negative binomial rates. 
Statistics in Medicine. 2014;33(3):376-87.
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Appendix 1. Schedule of Assessments
Note: For UK-, Ghana- and Egypt-specific schedule of assessments, refer to Appendix 6-3, Appendix 6-4, and Appendix 6-5, 
respectively.
Study Period
Screening
Treatment Period
Follow-up
Upon 
Presentation 
for VOC
Week 6
Week 12
Week 24
Week 36
Week 48
Week 60 b
Procedure
Day -28 to -1
Baseline
Day 1 a
Day 43
±7 days
Day 85
±7 days
Day 169
±7 days
Day 253
±7 days
Day 337
(EOS c/ET)
±7 days
Day 421
EOS c
±7 days
Informed consent/assent
X
Review of eligibility criteria
X
X
Demographics 
X
Medical history
X
VOC History
X
X
Height (cm) & Weight (kg) d
X
X
X
X
X
X
Vital Signs e
X
X
X
X
X
X
X
Physical Examination
X
X
X
X
X
X
X
Chest X-ray f
CBC/diff g & Chemistry h (w 
FSH i)
X
X
X
X
X
X
X
X
X
Hemoglobin Genotype j
X
Fetal Hemoglobin
X
Coagulation Assessments k
X
X
X
X
X
X
X
Pregnancy Test for WOCBP i
X
X
X
X
X
X
X
X
Assessment of VOC & Other 
Pain Crises Events l
Randomization
X
CGI-C
X
X
X
X
PGI-C
X
X
X
X
ASCQ-Me weekly at home by 
participant (and/or their parent 
or legal guardian for 
X
X
X
X
X
X
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Study Period
Screening
Treatment Period
Follow-up
Upon 
Presentation 
for VOC
Week 6
Week 12
Week 24
Week 36
Week 48
Week 60 b
Procedure
Day -28 to -1
Baseline
Day 1 a
Day 43
±7 days
Day 85
±7 days
Day 169
±7 days
Day 253
±7 days
Day 337
(EOS c/ET)
±7 days
Day 421
EOS c
±7 days
participants under 18 years of 
age) m
ASCQ-Me m
X
X
X
X
X
X
Study Drug Infusion
X
X
X
X
PK, ADA, PD and biomarker sampling – Refer to the Schedule of Assessments in Appendix 2 and Appendix 3.
Adverse Events
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
Abbreviations: ACS, acute chest syndrome; ADA, anti-drug antibody; aPTT, activated partial thromboplastin time; ASCQ-Me, Adult Sickle Cell Quality of 
Life Measurement; CBC, complete blood count; CGI-C, clinician’s global impression of change; EOS, end of study; ET, early termination;
FSH, follicle-stimulating hormone; HDL, high-density lipoprotein, HIV, human immunodeficiency virus; LDL, low-density lipoprotein; OLE, open-label 
extension; PD, pharmacodynamics; PGI-C, patient’s global impression of change; PK, pharmacokinetics; PLT, platelet; PT, prothrombin time; VOC, 
vaso-occlusive crisis. 
Note: During the treatment period, study assessments are to be collected pre-dose unless otherwise specified.
a.
All blood draws for Baseline assessments will be obtained prior to study drug administration.
b.
Week 60 (Day 421) Visit will be for participants who choose not to enroll, or are ineligible for, the OLE study. At this visit, safety and efficacy 
assessments and samples for PK, ADA, PD will be collected.
c.
For participants electing to enroll in the OLE study, the Day 337 (Week 48) Visit will be the EOS Visit. For participants not enrolling in the OLE study, an 
additional required visit will occur on Day 421 (Week 60) for safety and PK/ADA/PD follow-up.
d.
Height and weight to be captured at Screening with only weight captured thereafter.
e.
Vital signs (blood pressure, heart rate, body temperature) will be measured after a participant has rested for at least 5 minutes in the supine or recumbent 
position, as age appropriate and feasible. Vital signs will also be collected at the completion of infusion and at one hour after completion of infusion. 
Participants should be clinically well with stable vital signs and without signs or symptoms of an infusion-related reaction prior to release from 
observation. A repeat measurement of any of the vital sign parameters will be taken within 5 minutes if the first reading is outside the normal range and 
deemed clinically significant.
f.
Chest X-ray required for all suspected cases of ACS.
g.
Hematology assessments include the following: hemoglobin, hematocrit, white blood cells with differential, red blood cells, % and absolute reticulocytes, 
and PLTs. An iron panel will also be performed (iron, ferritin, total iron binding capacity [TIBC]). Collect at presentation for VOC as feasible.
h.
Chemistry assessments include the following: blood urea nitrogen, bilirubin (total, direct and indirect), alkaline phosphatase, aspartate aminotransferase, 
alanine aminotransferase, serum albumin, sodium, potassium, magnesium, calcium, chloride, glucose, bicarbonate, creatinine kinase, serum creatinine, total 
protein, total globulin, IgG. lactate dehydrogenase, cystatin-C, C-reactive protein (CRP), high sensitivity-reactive protein (hs-CRP), and lipid panel (total 
cholesterol, HDL, LDL, triglycerides). Collect at presentation for VOC as feasible.
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Study Period
Screening
Treatment Period
Follow-up
Upon 
Presentation 
for VOC
Week 6
Week 12
Week 24
Week 36
Week 48
Week 60 b
Procedure
Day -28 to -1
Baseline
Day 1 a
Day 43
±7 days
Day 85
±7 days
Day 169
±7 days
Day 253
±7 days
Day 337
(EOS c/ET)
±7 days
Day 421
EOS c
±7 days
i.
Pregnancy tests will be performed on women of child-bearing potential (WOCBP). A serum test will be conducted at screening and a urine test at 
subsequent visits. A positive urine pregnancy test at any time during the study requires confirmation via a serum pregnancy test. Female participants will 
not be considered of childbearing potential if they are pre-menarchal, surgically sterile (hysterectomy, bilateral salpingectomy, tubal ligation, or bilateral 
oophorectomy) or postmenopausal (no menses for 12 months without an alternative medical cause, confirmed by follicle-stimulating hormone test results).
j.
Hemoglobin genotyping will be performed if the genotype is unknown.
k.
Coagulation parameters are PT, aPTT, D-dimer, von Willebrand factor (vWF), and fibrinogen. Collect at presentation for VOC as feasible. 
l.
The incidence of VOC events will be recorded weekly by the participant (and/or their parent or legal guardian for participants under 18 years of age) and 
collected every 4 weeks (±7 days). On non-visit days (Week 4 [Day 29], Week 8 [Day 57], Week 16 [Day 113], Week 20 [Day 141], Week 28 [Day 197], 
Week 32 [Day 225], Week 40 [Day 281], and Week 44 [Day 309], participants (and/or their parent or legal guardian for participants under 18 years of age) 
will be contacted by phone to determine if a VOC event or a pain crisis leading to contact with a healthcare provider without a visit to a medical facility has 
occurred, to collect adverse events (AEs), and record changes to concomitant medications.
m. The participant (and/or their parent or legal guardian for participants under 18 years of age) will complete the ASCQ-Me questionnaire weekly, when 
available. Questionnaires will be distributed to sites once available in local language. The ASCQ-Me questionnaire completed by participants (and/or their 
parent or legal guardian for participants under 18 years of age) at home will be collected during the participant’s visits to the clinical site at Weeks 6, 12, 
24, 36, and 48. In addition, the ASCQ-Me questionnaire will be administered during the participant’s visits to the clinical site at Weeks 6, 12, 24, 36, and 
48.
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Appendix 2. Schedule of Assessments for Inclacumab PK, ADA, PD
Timepoint
Time 
Window
PK
ADA
SPR 
P-selectin 
Inhibition
PLA
and PLT 
P-selectin
Free and 
Total 
sP-selectin
Plasma
Plasma
Serum
Whole 
Blood
Plasma
Day 1 pre-dose
-30 min
X
X
X
X
X
Day 1 EOI
+5 min
X
Day 1 EOI +45
min
± 15 min
X
X
X
X
Week 6 
±7 days
X
X
X
X
Week 12 pre-dose
-30 min
X
X
X
X
X
Week 12 EOI
+5 min
X
X
Week 24 pre-dose
-30 min
X
X
X
X
X
Week 24 EOI
+5 min
X
X
Week 36 pre-dose
-30 min
X
X
X
X
Week 36 EOI
+5 min
X
X
Week 48
±7 days
X
X
X
X
X
Week 60 a
±7 days
X
X
X
X
X
Upon presentation 
for VOC b
X
X
X
Abbreviations: ADA, anti-drug antibody; EOI, end of infusion; OLE, open-label extension; PD, 
pharmacodynamics; PK, pharmacokinetics; PLA, platelet leukocyte aggregate; PLT, platelet; sP-selectin, 
soluble P-selectin; SPR, surface plasmon resonance; VOC, vaso-occlusive crisis.
a Week 60 (Day 421) Visit will be for participants who choose not to enroll, or are ineligible for, the OLE
study.
b As feasible.
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Appendix 3. Schedule of Assessments for Biomarkers
Timepoint
Time 
Window
RBC 
Adhesion a
Genomic 
Biobank b
Protein 
Multiplex
Urine 
Panel c
Voxelotor 
PK d
Whole 
blood
Whole 
blood
Serum
Urine
Plasma & 
Whole 
Blood
Day 1 pre-dose
-30 min
X
X
X
X
X
Day 1 EOI +45m
±15 min
X
Week 6 
±7 days
X
Week 12 pre-dose
-30 min
X
X
X
Week 48
±7 days
X
X
X
X
X
Upon presentation 
for VOC e
X
X
Abbreviations: EOI, end of infusion; PK, pharmacokinetics; RBC, red blood cell; VOC, vaso-occlusive crisis.
a The RBC adhesion assay will be performed in a subset of participants at selected sites, if feasible.
b The Genomic Biobank sample is optional and should be performed in consenting subjects.
c A single spot urine will be collected on Day 1 (pre-dose) and Week 48. Urine panel assessments may include 
but are not limited to albumin, protein, creatinine, hemoglobin. 
d Plasma/whole blood for assessment of voxelotor PK should be collected within 30 minutes prior to the dose 
of voxelotor. Voxelotor PK assessment is only applicable to subjects on a stable dose of voxelotor at 
Screening.
e As feasible.
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Appendix 4. Infusion-Related Reaction Grading
The severity of infusion-related reactions (IRRs)will be graded using the National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 5.0 per 
Table 5, below. The CTCAE quick reference guide can be found at: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTC
AE_v5_Quick_Reference_8.5x11.pdf
Table 5:
Infusion-related Reactions
Grade 1
Mild transient reaction; infusion interruption not indicated; intervention not 
indicated
Grade 2
Therapy of infusion interruption indicated but responds promptly to symptomatic 
treatment (eg, antihistamines, NSAIDs, narcotics, IV fluids); prophylactic 
medications indicated for ≤24 hours
Grade 3
Prolonged (eg, not rapidly responsive to symptomatic medication and/or brief 
interruption of infusion); recurrence of symptoms following initial improvement;
hospitalization indicated for clinical sequelae
Grade 4
Life-threatening consequences; urgent intervention indicated
Grade 5
Death
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Appendix 5. Liver Safety: Suggested Actions and Follow-Up Assessments and Study 
Drug Rechallenge Guidelines
This appendix is included to support Study transition to Pfizer Pharmacovigilance processes 
and systems.
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
“susceptible” to progressive and serious liver injury, commonly referred to as DILI. 
Participants who experience a transaminase elevation above 3 × the upper limit of normal 
(ULN) should be monitored more frequently to determine if they are “adaptors” or are 
“susceptible.”
Liver function tests (LFTs) are not required as a routine safety monitoring procedure in this 
study. However, should an Investigator deem it necessary to assess LFTs because a 
participant presents with clinical signs/symptoms, such LFT results should be managed and 
followed as described below.
In the majority of DILI cases, elevations in AST (aspartate transaminase) and/or ALT 
(alanine transaminase) precede total bilirubin elevations (> 2 × ULN) by several days or 
weeks. The increase in total bilirubin typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and total bilirubin values will be elevated within the same 
laboratory sample). In rare instances, by the time total bilirubin elevations are detected, 
AST/ALT values might have decreased. This occurrence is still regarded as a potential DILI. 
Therefore, abnormal elevations in either AST or ALT in addition to total bilirubin that meet 
the criteria outlined below are considered potential DILI (assessed per Hy’s law criteria) 
cases and should always be considered important medical events, even before all other 
possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions. Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and total bilirubin values within the normal range
who subsequently present with AST/ALT values ≥3 × ULN AND a total 
bilirubin value ≥2 × ULN with no evidence of hemolysis and an alkaline 
phosphatase value < 2 × ULN or not available.
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
For participants with baseline AST OR ALT OR total bilirubin values above the 
ULN, the following threshold values are used in the definition mentioned above, 
as needed, depending on which values are above the ULN at baseline:
o
Preexisting AST/ALT baseline values above the normal range: AST/ALT 
values ≥2 times the baseline values AND ≥3 × ULN; or ≥8 × ULN 
(whichever is smaller).
o
Preexisting values of total bilirubin above the normal range: total bilirubin 
level increased from baseline value by an amount of ≥1 × ULN or if the value 
reaches ≥3 × ULN (whichever is smaller).
Rises in AST/ALT and total bilirubin separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 
The participant should return to the Investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and total bilirubin for suspected Hy’s 
law cases, additional laboratory tests should include albumin, creatine kinase, direct and 
indirect bilirubin, gamma-glutamyl transferase, prothrombin time/international normalized 
ratio, eosinophils (%), and alkaline phosphatase. Consideration should also be given to 
drawing a separate tube of clotted blood and an anticoagulated tube of blood for further 
testing, as needed, for further contemporaneous analyses at the time of the recognized initial 
abnormalities to determine etiology. A detailed history, including relevant information, such 
as review of ethanol, acetaminophen/paracetamol (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, or supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected. Further testing for acute 
hepatitis A, B, C, D, and E infection, total bile acids, liver imaging (eg, biliary tract), and 
collection of serum samples for acetaminophen/paracetamol drug and/or protein adduct 
levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
total bilirubin elevation defined above should be considered potential DILI (Hy’s law) cases 
if no other reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s 
law) cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
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Appendix 6. Country-specific amendments
Appendix 6.1. France-Specific Amendment
3. Investigational Plan
This is a Phase 2, randomized, double-blind, placebo-controlled, 2-arm, multi-center, 
parallel-group study. 
3.1. Study Design
This study will assess the safety and efficacy of inclacumab in reducing the frequency of 
VOCs in approximately 240 adult and adolescent participants (≥12 years of age) globally 
with SCD. Initial enrollment will include participants ≥16 years of age until the independent 
Data Monitoring Committee (DMC) determines that adequate safety and PK data support the 
enrollment of participants 12 to 15 years of age. In France, only participants ≥18 years of 
age will be enrolled. 
Eligible participants will be randomized with a 1:1 ratio into one of two treatment arms as 
follows:

Inclacumab 30 mg/kg administered IV Q12W; or

Placebo administered IV Q12W.
At the time of randomization, participants will be stratified by Baseline HU use (yes; no), 
number of VOCs (2 to 4; 5 to 10) in the preceding 12 months, and geographic region 
(North America; sub-Saharan Africa; Europe/rest of world).
All participants will undergo safety, efficacy, and PK/PD assessments at Baseline and 
through Week 48. Visits to the clinical site for infusion of study drug will occur at Baseline 
(Day 1) and Q12W (Weeks 12, 24, and 36) for a total of 4 infusions. An additional visit at 
Week 6 will occur for safety, PK, and PD monitoring. The incidence of VOC events will be 
collected every 4 weeks, with participants contacted by phone at Weeks 4, 8, 16, 20, 28, 32, 
40, and 44. 
Following completion of the Week 48 visit, eligible participants will be given the option to
enroll in an open-label extension (OLE) study (under a separate protocol) to receive 
inclacumab. Participants will receive their first dose in the OLE study at the same Week 48 
visit. Participants enrolling in the OLE study will not be required to return to clinic for the 
Week 60 visit. Safety, efficacy, and PK/PD assessments will occur at Week 60 for 
participants not enrolling on the OLE study.
The DMC will regularly review the totality of accumulated safety data from all ongoing 
inclacumab studies on an ongoing, unblinded basis with additional emphasis on adolescent 
participants. Details will be provided in the DMC Charter. 
A diagram of the study design is provided in Figure 1.
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3.3.1.1. Inclusion Criteria
1. Participant has a confirmed diagnosis of SCD (HbSS, HbSC, HbSβ0 thalassemia, 
or HbSβ+ thalassemia genotype).
Documentation of SCD genotype is required and may be based on documented 
history of laboratory testing or confirmed by laboratory testing during Screening.
2. Participant is male or female, ≥18 years of age at the time of informed consent.
3. Participant has experienced between 2 and 10 VOCs within the 12 months prior to the 
Screening Visit as determined by documented medical history. A prior VOC is 
defined as an acute episode of pain that:

Has no medically determined cause other than a vaso-occlusive event, and

Results in a visit to a medical facility (hospital, emergency department, urgent 
care center, outpatient clinic, or infusion center) or results in a remote contact 
with a healthcare provider; and 

Requires parenteral narcotic agents, parenteral nonsteroidal anti-inflammatory 
drugs (NSAIDs), or an increase in treatment with oral narcotics.
4. Participants receiving erythropoiesis-stimulating agents (ESA, eg, EPO) must be on a 
stable dose for at least 90 days prior to the Screening Visit and expected to continue 
with the stabilized regimen throughout the course of the study. 
5. Participants receiving HU, L-glutamine, or voxelotor must be on a stable dose for at 
least 30 days prior to the Screening Visit and expected to continue with the stabilized 
regimen throughout the course of the study. 
6. Participant has adequate venous access, in the opinion of the Investigator, to comply 
with study procedures.
7. Participant understands the study procedures and agrees to participate in the study by 
giving written informed consent.
8. Women of childbearing potential (WOCBP) are required to have a negative serum 
pregnancy test at the Screening Visit and negative urine pregnancy test on all 
subsequent clinic visits and must agree to use a highly effective method of 
contraception throughout the study period and for at least 165 days after dosing. See 
Section 6.3 for details on methods of contraception.
Female participants will not be considered of childbearing potential if they are 
pre-menarchal, surgically sterile (hysterectomy, bilateral salpingectomy, tubal 
ligation, or bilateral oophorectomy) or postmenopausal (no menses for 12 months 
without an alternative medical cause, confirmed by follicle stimulating hormone test 
results).
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3.3.1.2 Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist 
at Screening or Baseline visits or at the timepoint specified in the individual criterion listed.
1. Participant is receiving regularly scheduled RBC transfusion therapy (also termed 
chronic, prophylactic, or preventative transfusion). 
2. Participant is taking or has received crizanlizumab (ADAKVEO) within 90 days prior 
to the Screening Visit. 
3. Participant weighs > 133 kg (292 lbs.).
4. Participant has a significant active and poorly controlled (unstable) hepatic disorder 
clearly unrelated to SCD.
5. Participant has any of the following laboratory values at screening:
a.
Absolute neutrophil count (ANC) < 1.0 × 109/L
b. Platelet count < 80 × 109/L
c.
Hemoglobin < 4.0 g/dL
d. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 using 
Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) formula
6. Participant has known active (symptomatic) COVID infection or tests positive for 
COVID-19 during Screening.
7. Participant has a history of unstable or deteriorating cardiac or pulmonary disease 
within 6 months prior to consent including severe or unstable pulmonary 
hypertension.
8. Participant has had treatment for a malignancy within the 12 months prior to the 
Screening Visit (except non-melanoma skin cancer and in situ cervical cancers).
9. Participant has had a stroke within the 2 years prior to the Screening Visit.
10. Participant has a positive test indicative of malaria infection at Screening. Testing to 
be conducted at local laboratories in malaria-endemic regions at the discretion of the 
Investigator.
11. Participant has any confirmed clinically significant drug allergy and/or known 
hypersensitivity to monoclonal antibody therapeutics or formulation components of
the study drug or a related drug.
12. Participant has been in another investigational trial within 30 days or 5 half-lives of 
the investigational agent (whichever is greater) prior to the Screening Visit.
13. Participant has had a major surgery within 8 weeks prior to the Screening Visit.
14. Participant is pregnant, breastfeeding, or planning to become pregnant during the 
48-week treatment period.
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15. Participant is unlikely to comply with the study procedures; OR adult participant is 
subject to legal protection, unable to express consent or deprived of their liberty by a 
judicial or administrative decision.
16. Participant has other medical, psychological, or addictive condition that, in the 
opinion of the Investigator, would confound or interfere with evaluation of safety, 
efficacy, and/or PK of the investigational drug; prevent compliance with the study 
protocol; preclude informed consent; or render the participant unable/unlikely to 
comply with the study procedures.
5.4.5. Incidence of VOCs
The incidence of VOC events will be collected every 4 weeks. Each month on non-treatment 
visit days, participants will be contacted by phone to determine if a VOC event or a pain 
crisis leading to contact with a healthcare provider without a visit to a medical facility has 
occurred, to collect AEs, and to record changes to concomitant medications.
7.7. Data Monitoring Committee
In addition to the Sponsor’s pharmacovigilance oversight, an independent, unblinded Data 
Monitoring Committee (DMC) will oversee the safety of participants and overall study 
conduct, with the support of an independent data coordinating center. 
The full description of the DMC structure and responsibilities, as well as details of data to be 
reviewed and the frequency of the meetings, will be described in the DMC Charter. 
8.4.4.1. Pharmacokinetic Analyses
Population PK analysis will include data from all participants who receive active study drug
and have at least 1 measurable post-dose concentration. If any participants are found to have 
incomplete data, protocol deviations, or clinical events affecting PK, a decision will be made 
on a case-by-case basis as to their inclusion in the analysis. The influence of demographic 
covariates (such as body weight, sex, age, race) on inclacumab PK parameters will be 
investigated. If appropriate, the inclacumab PK data may be pooled with PK data from other 
studies. Results of population PK analyses will be reported separately.
A review of PK/PD data from at least 20 participants in the program for preliminary dose 
confirmation will be performed by the DMC. 
9.5.3. Informed Consent/Assent Process
France-specific content is now replaced with new language per Pfizer (refer to Section 9.5.3).
Appendix 6.2. Germany-Specific Amendment
3.1. Study Design
This study will assess the safety and efficacy of inclacumab in reducing the frequency of 
VOCs in approximately 240 adult and adolescent participants (≥ 12 years of age) globally 
with SCD. Initial enrollment will include participants ≥ 16 years of age until the independent 
Data Monitoring Committee (DMC) determines that adequate safety and PK data support the 
enrollment of participants 12 to 15 years of age. In Germany, only participants ≥ 18 years of 
age will be enrolled. 
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Eligible participants will be randomized with a 1:1 ratio into one of two treatment arms as 
follows: 
• Inclacumab 30 mg/kg administered IV Q12W; or 
• Placebo administered IV Q12W. 
At the time of randomization, participants will be stratified by Baseline HU use (yes; no), 
number of VOCs (2 to 4; 5 to 10) in the preceding 12 months, and geographic region (North 
America; sub-Saharan Africa; Europe/rest of world). 
All participants will undergo safety, efficacy, and PK/PD assessments at Baseline and 
through Week 48. Visits to the clinical site for infusion of study drug will occur at Baseline 
(Day 1) and Q12W (Weeks 12, 24, and 36) for a total of 4 infusions. An additional visit at 
Week 6 will occur for safety, PK, and PD monitoring. The incidence of VOC events will be 
collected every 4 weeks, with participants contacted by phone at Weeks 4, 8, 16, 20, 28, 32, 
40, and 44. 
Following completion of the Week 48 visit, eligible participants will be given the option to 
enroll in an open-label extension (OLE) study (under a separate protocol) to receive 
inclacumab. Participants will receive their first dose in the OLE study at the same Week 48 
visit. Participants enrolling in the OLE study will not be required to return to clinic for the 
Week 60 visit. Safety, efficacy, and PK/PD assessments will occur at Week 60 for 
participants not enrolling on the OLE study. 
The DMC will regularly review the totality of accumulated safety data from all ongoing 
inclacumab studies on an ongoing, unblinded basis with additional emphasis on adolescent 
participants. Details will be provided in the DMC Charter. 
A diagram of the study design is provided in Figure 1. 
3.3.1.1. Inclusion Criteria
1. Participant has a confirmed diagnosis of SCD (HbSS, HbSC, HbSβ0 thalassemia, or HbSβ+
thalassemia genotype). 
Documentation of SCD genotype is required and may be based on documented history of 
laboratory testing or confirmed by laboratory testing during Screening. 
2. Participant is male or female, ≥ 18 years of age at the time of informed consent. 
3. Participant has experienced between 2 and 10 VOCs within the 12 months prior to the 
Screening Visit as determined by documented medical history. A prior VOC is defined as an 
acute episode of pain that: 
• Has no medically determined cause other than a vaso-occlusive event, and 
• Results in a visit to a medical facility (hospital, emergency department, urgent care 
center, outpatient clinic, or infusion center) or results in a remote contact with a 
healthcare provider; and 
• Requires parenteral narcotic agents, parenteral nonsteroidal anti-inflammatory drugs 
(NSAIDs), or an increase in treatment with oral narcotics. 
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4. Participants receiving erythropoiesis-stimulating agents (ESA, eg, EPO) must be on a 
stable dose for at least 90 days prior to the Screening Visit and expected to continue with the 
stabilized regimen throughout the course of the study. 
5. Participants receiving HU, L-glutamine, or voxelotor must be on a stable dose for at least 
30 days prior to the Screening Visit and expected to continue with the stabilized regimen 
throughout the course of the study. 
6. Participant has adequate venous access, in the opinion of the Investigator, to comply with 
study procedures. 
7. Participant understands the study procedures and agrees to participate in the study by 
giving written informed consent or parental permission/written assent. 
8. Women of childbearing potential (WOCBP) are required to have a negative serum 
pregnancy test at the Screening Visit and negative urine pregnancy test on all subsequent 
clinic visits and must agree to use a highly effective method of contraception throughout the 
study period and for at least 165 days after dosing. See Section 6.3 for details on methods of 
contraception. 
Female participants will not be considered of childbearing potential if they are pre-
menarchal, surgically sterile (hysterectomy, bilateral salpingectomy, tubal ligation, or 
bilateral oophorectomy) or postmenopausal (no menses for 12 months without an alternative 
medical cause, confirmed by follicle stimulating hormone test results).
3.3.1.2. Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
Screening or Baseline visits or at the timepoint specified in the individual criterion listed.
1. Participant is receiving regularly scheduled RBC transfusion therapy (also termed chronic, 
prophylactic, or preventative transfusion). 
2. Participant is taking or has received crizanlizumab (ADAKVEO) within 90 days prior to 
the Screening Visit. 
3. Participant weighs > 133 kg (292 lbs.). 
4. Participant has a significant active and poorly controlled (unstable) hepatic disorder 
clearly unrelated to SCD. 
5. Participant has any of the following laboratory values at screening: 
a. Absolute neutrophil count (ANC) < 1.0 × 109/L 
b. Platelet count < 80 × 109/L 
c. Hemoglobin < 4.0 g/dL for adults 
d. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 using Chronic 
Kidney Disease-Epidemiology Collaboration (CKD-EPI) formula in adults 
6. Participant has known active (symptomatic) COVID infection or tests positive for 
COVID-19 during Screening. 
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7. Participant has a history of unstable or deteriorating cardiac or pulmonary disease within 6 
months prior to consent including severe or unstable pulmonary hypertension. 
8. Participant has had treatment for a malignancy within the 12 months prior to the 
Screening Visit (except non-melanoma skin cancer and in situ cervical cancers). 
9. Participant has had a stroke within the 2 years prior to the Screening Visit. 
10. Participant has a positive test indicative of malaria infection at Screening. Testing to be 
conducted at local laboratories in malaria-endemic regions at the discretion of the 
Investigator. 
11. Participant has any confirmed clinically significant drug allergy and/or known 
hypersensitivity to monoclonal antibody therapeutics or formulation components of the 
study drug or a related drug. 
12. Participant has been in another investigational trial within 30 days or 5 half-lives of the 
investigational agent (whichever is greater) prior to the Screening Visit. 
13. Participant has had a major surgery within 8 weeks prior to the Screening Visit. 
14. Participant is pregnant, breastfeeding, or planning to become pregnant during the 48-
week treatment period. 
15. Participant are unlikely to comply with the study procedures. 
16. Participant has other medical, psychological, or addictive condition that, in the opinion 
of the Investigator, would confound or interfere with evaluation of safety, efficacy, and/or
PK of the investigational drug; prevent compliance with the study protocol; preclude 
informed consent; or render the participant or caretaker unable/unlikely to comply with the 
study procedures. 
5.4.5. Incidence of VOCs
The incidence of VOC events will be collected every 4 weeks. Each month on non-treatment 
visit days, participants will be contacted by phone to determine if a VOC event or a pain 
crisis leading to contact with a healthcare provider without a visit to a medical facility has 
occurred, to collect AEs, and to record changes to concomitant medications.
7.7. Data Monitoring Committee
In addition to the Sponsor’s pharmacovigilance oversight, an independent, unblinded Data 
Monitoring Committee (DMC) will oversee the safety of participants and overall study conduct 
for the Phase 3 program, with the support of an independent data coordinating center.
The full description of the DMC structure and responsibilities, as well as details of data to be 
reviewed and the frequency of the meetings, will be described in the DMC Charter.
Appendix 6.3. UK-Specific Amendment
3.1. Study Design
This study will assess the safety and efficacy of inclacumab in reducing the frequency of VOCs 
in approximately 240 adult and adolescent participants (≥ 12 years of age) with SCD. Initial 
enrollment will include participants ≥ 16 years of age until the independent Data Monitoring 
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Committee (DMC) determines that adequate safety and PK data support the enrollment of 
participants 12 to 15 years of age, and the DMC recommendation has been approved by the 
regulatory authority. 
Eligible participants will be randomized with a 1:1 ratio into one of two treatment arms as 
follows: 

Inclacumab 30 mg/kg administered IV Q12W; or 

Placebo administered IV Q12W. 
At the time of randomization, participants will be stratified by Baseline HU use (yes; no), number 
of VOCs (2 to 4; 5 to 10) in the preceding 12 months, and geographic region (North America; 
sub-Saharan Africa; Europe/rest of world). 
All participants will undergo safety, efficacy, and PK/PD assessments at Baseline and through 
Week 48. Visits to the clinical site for infusion of study drug will occur at Baseline (Day 1) and 
Q12W (Weeks 12, 24, and 36) for a total of 4 infusions. An additional visit at Week 6 will occur 
for safety, PK, and PD monitoring. The incidence of VOC events will be recorded weekly by 
the participant and collected every 4 weeks, with participants contacted by phone at Weeks 4, 
8, 16, 20, 28, 32, 40, and 44. 
Following completion of the Week 48 visit, eligible participants will be given the option to enroll 
in an open-label extension (OLE) study (under a separate protocol) to receive inclacumab. 
Participants will receive their first dose in the OLE study at the same Week 48 visit. Participants 
enrolling in the OLE study will not be required to return to clinic for the Week 60 visit. Safety, 
efficacy, and PK/PD assessments will occur at Week 60 for participants not enrolling on the OLE 
study. 
The DMC will regularly review the totality of accumulated safety data from all ongoing 
inclacumab studies on an ongoing, unblinded basis with additional emphasis on adolescent 
participants. Details will be provided in the DMC Charter.
A diagram of the study design is provided in Figure 1.
3.3.1.1. Inclusion Criteria
1. Participant has a confirmed diagnosis of SCD (HbSS, HbSC, HbSβ0 thalassemia, or 
HbSβ+ thalassemia genotype).
Documentation of SCD genotype is required and may be based on documented 
history of laboratory testing or confirmed by laboratory testing during Screening.
2. Participant is male or female, ≥12 years of age at the time of informed consent.
NOTE: Initial study enrollment will include participants ≥16 years of age until the 
DMC determines that adequate safety and PK data support the enrollment of 
participants 12 to 15 years of age, and the DMC recommendation has been approved 
by the regulatory authority. Sites will be informed by the Sponsor when participants 
12 to 15 years of age may be enrolled.
3. Participant has experienced between 2 and 10 VOCs within the 12 months prior to the 
Screening Visit as determined by documented medical history. A prior VOC is 
defined as an acute episode of pain that:
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
Has no medically determined cause other than a vaso-occlusive event, and

Results in a visit to a medical facility (hospital, emergency department, urgent 
care center, outpatient clinic, or infusion center) or results in a remote contact 
with a healthcare provider; and 

Requires parenteral narcotic agents, parenteral nonsteroidal anti-inflammatory 
drugs (NSAIDs), or an increase in treatment with oral narcotics.
4. Participants receiving erythropoiesis-stimulating agents (ESA, eg, EPO) must be on a 
stable dose for at least 90 days prior to the Screening Visit and expected to continue 
with the stabilized regimen throughout the course of the study. 
5. Participants receiving HU, L-glutamine, or voxelotor must be on a stable dose for at 
least 30 days prior to the Screening Visit and expected to continue with the stabilized 
regimen throughout the course of the study. 
6. Participant has adequate venous access, in the opinion of the Investigator, to comply 
with study procedures.
7. Participant understands the study procedures and agrees to participate in the study by 
giving written informed consent or parental permission/written assent.
8. Women of childbearing potential (WOCBP) are required to have a negative serum 
pregnancy test at the Screening Visit and negative urine pregnancy test monthly on all 
subsequent clinic or telephone visits and must agree to use a highly effective method 
of contraception throughout the study period and for at least 165 days after dosing. 
See Section 6.3 for details on methods of contraception.
Female participants will not be considered of childbearing potential if they are pre-
menarchal, surgically sterile (hysterectomy, bilateral salpingectomy, tubal ligation, or 
bilateral oophorectomy) or postmenopausal (no menses for 12 months without an 
alternative medical cause, confirmed by follicle stimulating hormone test results).
3.3.1.2. Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist 
at Screening or Baseline visits or at the timepoint specified in the individual criterion listed.
1. Participant is receiving regularly scheduled RBC transfusion therapy (also termed 
chronic, prophylactic, or preventative transfusion). 
2. Participant is taking or has received crizanlizumab (ADAKVEO) within 90 days prior 
to the Screening Visit. 
3. Participant weighs > 133 kg (292 lbs.).
4. Participant has severe hepatic impairment unrelated to SCD.
5. Participant has any of the following laboratory values at screening:
a.
Absolute neutrophil count (ANC) < 1.0 × 109/L
b. Platelet count < 80 × 109/L
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c.
Hemoglobin < 4.0 g/dL for adults and < 5.0 g/dL for participants ages 12 to 
< 18 years of age
d. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 using 
Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) formula in 
adults, and Schwartz formula in adolescents
6. Participant has known active (symptomatic) COVID infection or tests positive for 
COVID-19 during Screening.
7. Participant has a history of unstable or deteriorating cardiac or pulmonary disease 
within 6 months prior to consent including severe or unstable pulmonary 
hypertension.
8. Participant has had treatment for a malignancy within the 12 months prior to the 
Screening Visit (except non-melanoma skin cancer and in situ cervical cancers).
9. Participant has had a stroke within the 2 years prior to the Screening Visit.
10. Participant has a positive test indicative of malaria infection at Screening. Testing to 
be conducted at local laboratories in malaria-endemic regions at the discretion of the 
Investigator.
11. Participant has any confirmed clinically significant drug allergy and/or known 
hypersensitivity to monoclonal antibody therapeutics or formulation components of
the study drug or a related drug.
12. Participant has been in another investigational trial within 30 days or 5 half-lives of 
the investigational agent (whichever is greater) prior to the Screening Visit.
13. Participant has had a major surgery within 8 weeks prior to the Screening Visit.
14. Participant is pregnant, breastfeeding, or planning to become pregnant during the 
48-week treatment period.
15. Participant, parent, or legal guardian are unlikely to comply with the study 
procedures.
16. Participant has other medical, psychological, or addictive condition that, in the 
opinion of the Investigator, would confound or interfere with evaluation of safety, 
efficacy, and/or PK of the investigational drug; prevent compliance with the study 
protocol; preclude informed consent; or render the participant, parent, or caretaker 
unable/unlikely to comply with the study procedures.
3.3.3.1.1. Early Discontinuation of Study Treatment
Participants may discontinue study treatment for any of the following reasons: 

Adverse event 

Withdrawal of consent 

Discretion of the Investigator 
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
In case of worsening of disease or disease progression, if the Investigator considers it 
is in the best interest of the participant to initiate any standard of care treatment 
prohibited in Section 6.1.1. 

Participant is lost to follow-up 

Participant is noncompliant 

Pregnancy. Study drug must be discontinued immediately. Report the pregnancy 
according to the instructions in Section 3.3.3.1. 
Participants who discontinue from study treatment will be encouraged to continue to 
participate in the study assessments, as applicable. Participants who are discontinued from 
study treatment due to pregnancy will also be discontinued from the study (Section 3.3.3.1). 
A participant may be discontinued from study treatment at any time at the discretion of the 
Investigator in accordance with his or her clinical judgment.
4.8.3. Blinding Procedures 
This is a randomized, double-blinded, placebo-controlled study. Investigators, study site staff, 
the Sponsor’s study staff, the Sponsor’s clinical contract research organization (CRO), and 
study participants, as well as members of the VOC Adjudication Committee, will remain 
blinded to the randomized treatment assignments. During the study, access to participant 
treatment assignment will be limited to DMC members and service providers supporting 
DMC reviews, including the independent Data Coordinating Center and the independent 
PK/PD bioanalytical laboratory and analysis personnel.
The Investigator must contact the Medical Monitor prior to unblinding of study drug for any 
participant. In an emergency, however, where knowledge of the study drug is critical to 
participant safety, the code may be broken. In cases where the Investigator is unable to 
contact the Medical Monitor prior to unblinding, the Investigator must notify the Sponsor, or 
designee, as soon as possible (ie, within 24 hours) after unblinding. In addition, the 
Investigator must record the date, time, and reason for unblinding the study drug treatment in 
the source documentation.
5.4.2. Pregnancy Screen
Pregnancy tests will be performed on female participants of child-bearing potential as 
indicated in the Schedule of Assessments (Appendix 1). A serum pregnancy test will be 
conducted at Screening with urine pregnancy tests conducted thereafter. If the Day 1 urine 
test is positive, a pre-dose serum pregnancy test should be performed and dosing should be 
postponed until a negative result is confirmed; if positive, the participant will be considered a 
screen failure.
Female participants will not be considered of childbearing potential if they are pre-
menarchal, surgically sterile (hysterectomy, bilateral salpingectomy, tubal ligation or 
bilateral oophorectomy) or postmenopausal (no menses for 12 months without an alternative 
medical cause, confirmed by follicle-stimulating hormone test results).
6.1.2. Prohibited Medications and Therapies
Treatment with the following is not allowed during the study: 
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
Initiation of treatment with HU, ESA, (eg, EPO), voxelotor, crizanlizumab, or L-
glutamine. 

Stem cell transplant. 

Active treatment on another investigational trial, including gene therapy for SCD. 

Initiation of a chronic transfusion program (pre-planned series of transfusions for 
prophylactic purposes). 
If the Investigator believes that treatment with any of these prohibited medications and 
therapies during the study is in the best interest of the participant, treatment with these 
medications should be initiated and discontinuation of the participant from further treatment 
with study drug or discontinuation of the participant from the study should be considered 
(Section 3.3.3.1.1).
7.2.1 General (Adverse Events)
All AEs/SAEs will be recorded from the time the study participant (and/or their parent or 
legal guardian for participants under 18 years of age) signs the ICD/assent form until 3 
months after last dose (Week 48)/or 6 months after last dose (Week 60) EOS Visit or ET 
Visit, whichever is later. All AEs/SAEs must be reported on the AE eCRF via the electronic 
data capture (EDC) system and reported to Pfizer Safety. The Investigator is responsible 
for evaluating all AEs/SAEs, obtaining supporting documents, and ensuring that 
documentation of the event is complete. Details of each reported AE/SAE must include at a 
minimum severity, relationship to study treatment, duration, and outcome. All (both serious 
and nonserious) AEs must be followed until they are resolved or stabilized, or until 
reasonable attempts to determine resolution of the event are exhausted.
Any participant who experiences an AE/SAE may be discontinued from study treatment at 
any time at the discretion of the Investigator. The Sponsor and the Study Medical Monitor 
must be notified of the study participant discontinuation.
Follow-up by the Investigator continues throughout the active collection period and until the 
AE or SAE or its sequelae resolve or stabilize at a level acceptable to the Investigator.
When a clinically important AE remains ongoing at the end of the active collection period, 
follow-up by the Investigator continues until the AE or SAE or its sequelae resolve or 
stabilize at a level acceptable to the Investigator and Pfizer concurs with that assessment
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant permanently discontinues or temporarily discontinues study intervention
because of an AE or SAE, the AE or SAE must be recorded on the eCRF and the SAE 
reported to Pfizer Safety).
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Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the Investigator learns of any 
SAE, including a death, at any time after a participant has completed the study, and they 
consider the event to be reasonably related to study intervention, the Investigator must 
promptly report the SAE to the Sponsor.
7.7. Data Monitoring Committee
In addition to the Sponsor’s pharmacovigilance oversight, an independent, unblinded DMC 
will oversee the safety of participants and overall study conduct, with the support of an 
independent data coordinating center. 
The full description of the DMC structure and responsibilities, as well as details of data to be 
reviewed and the frequency of the meetings, will be described in the DMC Charter.
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Appendix 1. Schedule of Assessments
Study Period
Screening
Treatment Period
Follow-up
Upon 
Presentation 
for VOC
Week 6
Week 12
Week 24
Week 36
Week 48
Week 60 b
Procedure
Day -28 to -
1
Baseline
Day 1 a
Day 43
±7 days
Day 85
±7 days
Day 169
±7 days
Day 253
±7 days
Day 337
(EOS c/ET)
±7 days
Day 421
EOS c
±7 days
Informed Consent/Assent
X
Review of Eligibility Criteria
X
X
Demographics 
X
Medical History
X
VOC History
X
X
Height (cm) & Weight (kg) d
X
X
X
X
X
X
Vital Signs e
X
X
X
X
X
X
X
Physical Examination
X
X
X
X
X
X
X
Chest X-ray f
CBC/diff g & Chemistry h (w 
FSH i)
X
X
X
X
X
X
X
X
X
Hemoglobin Genotype j
X
Fetal Hemoglobin
X
Coagulation Assessments k
X
X
X
X
X
X
X
Pregnancy Test for WOCBP i
X
X
X
X
X
X
X
X
Assessment of VOC & Other 
Pain Crises Events l
Randomization
X
CGI-C
X
X
X
X
PGI-C
X
X
X
X
ASCQ-Me m
Study Drug Infusion
X
X
X
X
PK, ADA, PD and Biomarker Sampling – Refer to the Schedule of Assessments in Appendix 2 and Appendix 3.
Adverse Events
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
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Study Period
Screening
Treatment Period
Follow-up
Upon 
Presentation 
for VOC
Week 6
Week 12
Week 24
Week 36
Week 48
Week 60 b
Procedure
Day -28 to -
1
Baseline
Day 1 a
Day 43
±7 days
Day 85
±7 days
Day 169
±7 days
Day 253
±7 days
Day 337
(EOS c/ET)
±7 days
Day 421
EOS c
±7 days
Abbreviations: ADA, anti-drug antibody; aPTT, activated partial thromboplastin time; ASCQ-Me, Adult Sickle Cell Quality of Life Measurement; CBC, complete blood count; CGI-C, 
clinician’s global impression of change; EOS, end of study; ET, early termination; FSH, follicle stimulating hormone; HDL, high-density lipoprotein, HIV, human immunodeficiency 
virus; LDL, low-density lipoprotein; OLE, open-label extension; PD, pharmacodynamics; PGI-C, patient’s global impression of change; PK, pharmacokinetics; PT, prothrombin time; 
VOC, vaso-occlusive crisis. 
Note: During the treatment period, study assessments are to be collected pre-dose unless otherwise specified.
a.
All blood draws for Baseline assessments will be obtained prior to study drug administration.
b.
Week 60 (Day 421) visit will be for participants who choose not to enroll, or are ineligible for, the open-label extension study. At this visit, safety and efficacy assessments and 
samples for PK, ADA, PD will be collected.
c.
For participants electing to enroll in the OLE study, the Day 337 (Week 48) visit will be the EOS Visit. For participants not enrolling in the OLE study, an additional required visit 
will occur on Day 421 (Week 60) for safety and PK/ADA/PD follow-up.
d.
Height and weight to be captured at Screening with only weight captured thereafter.
e.
Vital signs (blood pressure, heart rate, body temperature) will be measured after a participant has rested for at least 5 minutes in the supine or recumbent position, as age appropriate 
and feasible. Vital signs will also be collected at the completion of infusion and at one hour after completion of infusion. Participants should be clinically well with stable vital signs 
and without signs or symptoms of an infusion-related reaction prior to release from observation. A repeat measurement of any of the vital sign parameters will be taken within 5 
minutes if the first reading is outside the normal range and deemed clinically significant.
f.
Chest X-ray required for all suspected cases of acute chest syndrome (ACS).
g.
Hematology assessments include the following: hemoglobin, hematocrit, white blood cells with differential, red blood cells, % and absolute reticulocytes, and platelets. An iron panel 
will also be performed (iron, ferritin, total iron binding capacity [TIBC]). Collect at presentation for VOC, as feasible.
h.
Chemistry assessments include the following: blood urea nitrogen, bilirubin (total, direct and indirect), alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, 
serum albumin, sodium, potassium, magnesium, calcium, chloride, glucose, bicarbonate, creatinine kinase, serum creatinine, total protein, total globulin, IgG. lactate dehydrogenase, 
cystatin-C, C-reactive protein (CRP), high sensitivity-reactive protein (hs-CRP), and lipid panel (total cholesterol, HDL, LDL, triglycerides). Collect at presentation for VOC, as 
feasible.
i.
Pregnancy tests will be performed on women of child-bearing potential (WOCBP). A serum test will be conducted at screening and a urine test at subsequent visits. Urine pregnancy
tests will be conducted monthly, including during clinic visits every 12 weeks. The site will query the participant for results of the monthly UPT at each monthly telephone call. A 
positive urine pregnancy test at any time during the study requires confirmation via a serum pregnancy test. Female participants will not be considered of childbearing potential if 
they are pre-menarchal, surgically sterile (hysterectomy, bilateral salpingectomy, tubal ligation, or bilateral oophorectomy) or postmenopausal (no menses for 12 months without an 
alternative medical cause, confirmed by follicle-stimulating hormone test results).
j.
Hemoglobin genotyping will be performed if the genotype is unknown.
k.
Coagulation parameters are PT, aPTT, D-dimer, von Willebrand factor (vWF), and fibrinogen, as feasible.
l.
The incidence of VOC events will be collected every 4 weeks (±7 days). On non-visit days (Week 4 [Day 29], Week 8 [Day 57], Week 16 [Day 113], Week 20 [Day 141], Week 28 
[Day 197], Week 32 [Day 225], Week 40 [Day 281], and Week 44 [Day 309], participants will be contacted by phone to determine if a VOC event or a pain crisis leading to contact 
with a healthcare provider without a visit to a medical facility has occurred, to collect adverse events (AEs), and record changes to concomitant medications.
m.
The participant will complete the ASCQ-Me questionnaire weekly. Questionnaires will be distributed to sites once available in local language. The ASCQ-Me will be collected 
during the participant’s visits to the clinical site at Weeks 6, 12, 24, 36, and 48.
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Appendix 6.4. Ghana-Specific Amendment
Section 3.1. Study Design
This study will assess the safety and efficacy of inclacumab in reducing the frequency of 
VOCs in approximately 240 adult and adolescent participants (≥ 12 years of age) with SCD
globally. Initial enrollment will include participants ≥ 16 years of age until the independent 
Data Monitoring Committee (DMC) determines that adequate safety and PK data support the 
enrollment of participants 12 to 15 years of age. 
Eligible participants will be randomized with a 1:1 ratio into one of two treatment arms as 
follows: 
• Inclacumab 30 mg/kg administered IV Q12W; or 
• Placebo administered IV Q12W. 
At the time of randomization, participants will be stratified by Baseline HU use (yes; no), 
number of VOCs (2 to 4; 5 to 10) in the preceding 12 months, and geographic region (North 
America; sub-Saharan Africa; Europe/rest of world). 
All participants will undergo safety, efficacy, and PK/PD assessments at Baseline and 
through Week 48. Visits to the clinical site for infusion of study drug will occur at Baseline 
(Day 1) and Q12W (Weeks 12, 24, and 36) for a total of 4 infusions. An additional visit at 
Week 6 will occur for safety, PK, and PD monitoring. The incidence of VOC events will be 
collected every 4 weeks, with participants contacted by phone at Weeks 4, 8, 16, 20, 28, 32, 
40, and 44. 
Following completion of the Week 48 visit, eligible participants will be given the option to 
enroll in an open-label extension (OLE) study (under a separate protocol) to receive 
inclacumab. Participants will receive their first dose in the OLE study at the same Week 48 
visit. Participants enrolling in the OLE study will not be required to return to clinic for the 
Week 60 visit. Safety, efficacy, and PK/PD assessments will occur at Week 60 for 
participants not enrolling on the OLE study. 
The DMC will regularly review the totality of accumulated safety data from all ongoing 
inclacumab studies on an ongoing, unblinded basis with additional emphasis on adolescent 
participants. Details will be provided in the DMC Charter. 
A diagram of the study design is provided in Figure 1.
Section 5.4.5. VOC Incidence
The incidence of VOC events will be collected every 4 weeks. Each month on non-treatment 
visit days, participants will be contacted by phone to determine if a VOC event or a pain 
crisis leading to contact with a healthcare provider without a visit to a medical facility has 
occurred, to collect AEs, and to record changes to concomitant medications.
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Appendix 1.
Schedule of Assessments
Study Period
Screening
Treatment Period
Follow-up
Upon 
Presentati
on for 
VOC
Week 6
Week 12
Week 24
Week 36
Week 48
Week 60 b
Procedure
Day -28 to -
1
Baseline
Day 1 a
Day 43
±7 days
Day 85
±7 days
Day 169
±7 days
Day 253
±7 days
Day 337
(EOS c/ET)
±7 days
Day 421
EOS c
±7 days
Informed consent/assent
X
Review of eligibility criteria
X
X
Demographics 
X
Medical history
X
VOC History
X
X
Height (cm) & Weight (kg) d
X
X
X
X
X
X
Vital Signs e
X
X
X
X
X
X
X
Physical Examination
X
X
X
X
X
X
X
Chest X-ray f
CBC/diff g & Chemistry h (w 
FSH i)
X
X
X
X
X
X
X
X
X
Hemoglobin Genotype j
X
Fetal Hemoglobin
X
Coagulation Assessments k
X
X
X
X
X
X
X
Pregnancy Test for WOCBP i
X
X
X
X
X
X
X
X
COVID-19 Test
X
Malaria Test l
X
Assessment of VOC & Other 
Pain Crises Events m
Randomization
X
CGI-C
X
X
X
X
PGI-C
X
X
X
X
ASCQ-Me weekly at home by 
participant (and/or their parent 
or legal guardian for participants 
under 18 years of age) n
X
X
X
X
X
X
Study Drug Infusion
X
X
X
X
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Study Period
Screening
Treatment Period
Follow-up
Upon 
Presentati
on for 
VOC
Week 6
Week 12
Week 24
Week 36
Week 48
Week 60 b
Procedure
Day -28 to -
1
Baseline
Day 1 a
Day 43
±7 days
Day 85
±7 days
Day 169
±7 days
Day 253
±7 days
Day 337
(EOS c/ET)
±7 days
Day 421
EOS c
±7 days
PK, ADA, PD and Biomarker Sampling – Refer to the Schedule of Assessments in Appendix 2 and Appendix 3.
Adverse Events
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
Abbreviations: ACS, acute chest syndrome; ADA, anti-drug antibody; aPTT, activated partial thromboplastin time; ASCQ-Me, Adult Sickle Cell Quality of 
Life Measurement; CBC, complete blood count; CGI-C, clinician’s global impression of change; COVID-19, corona virus disease 2019; EOS, end of study; 
ET, early termination; FSH, follicle-stimulating hormone; HDL, high-density lipoprotein, HIV, human immunodeficiency virus; LDL, low-density lipoprotein; 
OLE, open-label extension; PD, pharmacodynamics; PGI-C, patient’s global impression of change; PK, pharmacokinetics; PLT, platelet; PT, prothrombin time; 
VOC, vaso-occlusive crisis. 
Note: During the treatment period, study assessments are to be collected pre-dose unless otherwise specified.
a.
All blood draws for Baseline assessments will be obtained prior to study drug administration.
b.
Week 60 (Day 421) Visit will be for participants who choose not to enroll, or are ineligible for, the OLE study. At this visit, safety and efficacy assessments and samples for
PK, ADA, PD will be collected.
c.
For participants electing to enroll in the OLE study, the Day 337 (Week 48) Visit will be the EOS Visit. For participants not enrolling in the OLE study, an additional 
required visit will occur on Day 421 (Week 60) for safety and PK/ADA/PD follow-up.
d.
Height and weight to be captured at Screening with only weight captured thereafter.
e.
Vital signs (blood pressure, heart rate, body temperature) will be measured after a participant has rested for at least 5 minutes in the supine or recumbent position, as age 
appropriate and feasible. Vital signs will also be collected at the completion of infusion and at one hour after completion of infusion. Participants should be clinically well 
with stable vital signs and without signs or symptoms of an infusion-related reaction prior to release from observation. A repeat measurement of any of the vital sign 
parameters will be taken within 5 minutes if the first reading is outside the normal range and deemed clinically significant.
f.
Chest X-ray required for all suspected cases of ACS.
g.
Hematology assessments include the following: hemoglobin, hematocrit, white blood cells with differential, red blood cells, % and absolute reticulocytes, and PLTs. An iron 
panel will also be performed (iron, ferritin, total iron binding capacity [TIBC]). Collect at presentation for VOC as feasible.
h.
Chemistry assessments include the following: blood urea nitrogen, bilirubin (total, direct and indirect), alkaline phosphatase, aspartate aminotransferase, alanine 
aminotransferase, serum albumin, sodium, potassium, magnesium, calcium, chloride, glucose, bicarbonate, creatinine kinase, serum creatinine, total protein, total globulin, 
IgG. lactate dehydrogenase, cystatin-C, C-reactive protein (CRP), high sensitivity-reactive protein (hs-CRP), and lipid panel (total cholesterol, HDL, LDL, triglycerides).
Collect at presentation for VOC as feasible.
i.
Pregnancy tests will be performed on women of child-bearing potential (WOCBP). A serum test will be conducted at screening and a urine test at subsequent visits. A 
positive urine pregnancy test at any time during the study requires confirmation via a serum pregnancy test. Female participants will not be considered of childbearing 
potential if they are pre-menarchal, surgically sterile (hysterectomy, bilateral salpingectomy, tubal ligation, or bilateral oophorectomy) or postmenopausal (no menses for 12 
months without an alternative medical cause, confirmed by follicle-stimulating hormone test results).
j.
Hemoglobin genotyping will be performed if the genotype is unknown.
k.
Coagulation parameters are PT, aPTT, D-dimer, von Willebrand factor (vWF), and fibrinogen. Collect at presentation for VOC as feasible. 
l.
Testing to be conducted at local laboratories in malaria-endemic regions at the discretion of the Investigator. 
m.
The incidence of VOC events will be collected every 4 weeks (±7 days). On non-visit days (Week 4 [Day 29], Week 8 [Day 57], Week 16 [Day 113], Week 20 [Day 141], 
Week 28 [Day 197], Week 32 [Day 225], Week 40 [Day 281], and Week 44 [Day 309], participants (and/or their parent or legal guardian for participants under 18 years of 
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Study Period
Screening
Treatment Period
Follow-up
Upon 
Presentati
on for 
VOC
Week 6
Week 12
Week 24
Week 36
Week 48
Week 60 b
Procedure
Day -28 to -
1
Baseline
Day 1 a
Day 43
±7 days
Day 85
±7 days
Day 169
±7 days
Day 253
±7 days
Day 337
(EOS c/ET)
±7 days
Day 421
EOS c
±7 days
age) will be contacted by phone to determine if a VOC event or a pain crisis leading to contact with a healthcare provider without a visit to a medical facility has occurred, 
to collect adverse events (AEs), and record changes to concomitant medications.
n.
The participant (and/or their parent or legal guardian for participants under 18 years of age) will complete the ASCQ-Me questionnaire weekly, when available. 
Questionnaires will be distributed to sites once available in local language. The ASCQ-Me questionnaire completed by participants (and/or their parent or legal guardian for 
participants under 18 years of age) at home will be collected during the participant’s visits to the clinical site at Weeks 6, 12, 24, 36, and 48. In addition, the ASCQ-Me 
questionnaire will be administered during the participant’s visits to the clinical site at Weeks 6, 12, 24, 36, and 48.
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Appendix 6.5. Egypt-Specific Amendment
3.1. Study Design
This study will assess the safety and efficacy of inclacumab in reducing the frequency of 
VOCs in approximately 240 adult and adolescent participants (≥ 12 years of age) with SCD
globally. Initial enrollment will include participants ≥ 16 years of age until the independent 
Data Monitoring Committee (DMC) recommends to the Sponsor that adequate safety and PK 
data
support the enrollment of participants 12 to 15 years of age. Eligible participants will be 
randomized with a 1:1 ratio into one of two treatment arms as follows:

Inclacumab 30 mg/kg administered IV Q12W; or

Placebo administered IV Q12W.
At the time of randomization, participants will be stratified by Baseline HU use (yes; no), 
number of VOCs (2 to 4; 5 to 10) in the preceding 12 months, and geographic region (North 
America; sub-Saharan Africa; Europe/rest of world). 
All participants will undergo safety and efficacy assessments at Baseline and through Week 
48. Visits to the clinical site for infusion of study drug will occur at Baseline (Day 1) and 
Q12W (Weeks 12, 24, and 36) for a total of 4 infusions. The incidence of VOC events will 
be recorded weekly by the participant and collected every 4 weeks, with participants 
contacted by phone at Weeks 4, 8, 16, 20, 28, 32, 40, and 44.
Following completion of the Week 48 Visit, eligible participants will be given the option to 
enroll in an open-label extension (OLE) study (under a separate protocol) to receive 
inclacumab. Participants will receive their first dose in the OLE study at the same Week 48 
Visit. Participants enrolling in the OLE study will not be required to return to clinic for the 
Week 60 Visit. Safety and efficacy assessments will occur at Week 60 for participants not 
enrolling on the OLE study.
The DMC will regularly review the totality of accumulated safety data from all ongoing
inclacumab studies on an ongoing, unblinded basis with additional emphasis on adolescent
participants. Details are provided in the DMC Charter.
A diagram of the study design is provided in Figure 1.
3.2.5. Exploratory Pharmacology Endpoints
The following exploratory pharmacology endpoints will be assessed:

Plasma PK of inclacumab as assessed by population PK analysis using nonlinear 
mixed-effects modeling.

The incidence of ADA to inclacumab.

Pharmacodynamics including changes in non-activated and TRAP-activated PLA, 
PLT P-selectin expression, serum P-selectin inhibition measured by surface plasmon 
resonance (SPR), and plasma total and free soluble P-selectin (sP-selectin) over time.
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
Biomarkers including changes in RBC adhesion (selected sites) genomic markers 
(optional), protein markers in the blood, urine markers of kidney function, and 
voxelotor plasma and whole blood concentrations (as applicable).
Relationships between PK, PD, biomarkers, clinical labs, safety, and efficacy will be 
explored.
Note: blood samples for the determination of PK, PD, ADA, and biomarker endpoints will 
not be collected at sites located in Egypt.
3.3.1.2. Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist 
at Screening or Baseline visits or at the timepoint specified in the individual criterion listed.
1. Participant is receiving regularly scheduled RBC transfusion therapy (also termed 
chronic, prophylactic, or preventative transfusion). 
2. Participant is taking or has received crizanlizumab (ADAKVEO) within 90 days prior 
to the Screening Visit. 
3. Participant weighs > 133 kg (292 lbs).
4. Participant has a significant active and poorly controlled (unstable) hepatic disorder 
clearly unrelated to SCD.
5. Participant has any of the following laboratory values at screening:
a.
Absolute neutrophil count (ANC) < 1.0 × 109/L
b. Platelet count < 80 × 109/L
c.
Hemoglobin < 4.0 g/dL for adults and < 5.0 g/dL for participants ages 12 to 
< 18 years of age
d. Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 using 
Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) formula in 
adults, and Schwartz formula in adolescents
6. Participant has known active (symptomatic) COVID-19 infection or tests positive for 
COVID-19 during Screening.
7. Participant has a history of unstable or deteriorating cardiac or pulmonary disease 
within 6 months prior to consent including severe or unstable pulmonary 
hypertension.
8. Participant has had treatment for a malignancy within the 12 months prior to the 
Screening Visit (except non-melanoma skin cancer and in situ cervical cancers).
9. Participant has had a stroke within the 2 years prior to the Screening Visit.
10. Participant has a positive test indicative of malaria infection at Screening. Testing to 
be conducted at local laboratories in malaria-endemic regions at the discretion of the 
Investigator.
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11. Participant has any confirmed clinically significant drug allergy and/or known 
hypersensitivity to monoclonal antibody therapeutics or formulation components of
the study drug or a related drug.
12. Participant has been in another investigational trial within 30 days or 5 half-lives of 
the investigational agent (whichever is greater) prior to the Screening Visit.
13. Participant has had a major surgery within 8 weeks prior to the Screening Visit.
14. Participant is pregnant, breastfeeding, or planning to become pregnant during the 
48-week treatment period.
15. Participant, parent, or legal guardian are unlikely to comply with the study 
procedures.
Participant has any other medical, psychological, or behavioral conditions that, in the opinion 
of the Investigator, would confound or interfere with evaluation of safety, efficacy, and/or 
PK of the investigational drug; prevent compliance with the study protocol; preclude 
informed consent; or render the participant, parent, or caretaker unable/unlikely to comply 
with the study procedures. (Note: blood samples for the determination of PK, PD, ADA, and 
biomarker endpoints will not be collected at sites located in Egypt.)
5. Study Assessments
The Schedule of Assessments (Appendix 1) summarizes the clinical procedures to be 
performed. Assessments and procedures are described in detail below. Additional 
evaluations/testing may be deemed necessary by the Investigator or designee and/or the 
Sponsor for reasons related to participant safety.
5.3.4. Clinical Laboratory Tests
It is the responsibility of the Investigator to assess the clinical significance of all abnormal
clinical laboratory values as defined by the list of normal values on file for the local 
laboratory. All clinically significant laboratory value abnormalities are to be recorded as 
AEs. 
For the purpose of this study, a clinically significant laboratory value will be any abnormal 
result that, in the judgment of the Investigator, is an unexpected or unexplained laboratory 
value or if medical intervention or corrective action (transfusion, hydration, initiation of 
antibiotics or other concomitant medication) is required. Any abnormal values that persist 
should be followed at the
discretion of the Investigator.
Additional and repeat laboratory safety testing for the evaluation of abnormal results and/or 
AEs during the study may be performed at the discretion of the Investigator or upon request 
of the Sponsor. Repeat laboratory testing of abnormal potentially clinically significant or 
clinically significant results for the Screening evaluation of the participant may be repeated 
once at the discretion of the Investigator.
Laboratory safety testing will be performed by a local laboratory. Tests listed in Table 1 will 
be performed as outlined in the Schedule of Assessments (Appendix 1). Details on collection 
and preparation of blood and urine samples are provided in the Laboratory Manual.
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5.5. Pharmacology Assessments (PK, PD, and Biomarkers)
A urine sample will be collected on Day 1 (pre-dose) and Week 48 for the assessment of 
biomarkers, including albumin, protein, creatinine, and hemoglobin.
Note: blood samples for the determination of PK, PD, ADA, and biomarker endpoints will 
not be collected at sites located in Egypt.
8.4.4. PK, PD, and ADA Analyses
Note: blood samples for the determination of PK, PD, ADA, and biomarker endpoints will 
not be collected at sites located in Egypt.
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Appendix 1.
Schedule of Assessments
Study Period
Screening
Treatment Period
Follow-up
Upon 
Presentation 
for VOC
Week 6
Week 12
Week 24
Week 36
Week 48
Week 60 b
Procedure
Day -28 to -1
Baseline
Day 1 a
Day 43
±7 days
Day 85
±7 days
Day 169
±7 days
Day 253
±7 days
Day 337
(EOS 
c/ET)
±7 days
Day 421
EOS c
±7 days
Informed 
consent/assent
X
Review of eligibility 
criteria
X
X
Demographics 
X
Medical history
X
VOC History
X
X
Height (cm) & Weight 
(kg) d
X
X
X
X
X
X
Vital Signs e
X
X
X
X
X
X
X
Physical Examination
X
X
X
X
X
X
X
Chest X-ray f
CBC/diff g & 
Chemistry h (w FSH i)
X
X
X
X
X
X
X
X
X
Hemoglobin 
Genotype j
X
Fetal Hemoglobin
X
Coagulation 
Assessments k
X
X
X
X
X
X
X
Urine spot test l
X
X
X
Pregnancy Test for 
WOCBP i
X
X
X
X
X
X
X
X
Assessment of VOC & 
Other Pain Crises 
Events m
Randomization
X
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Study Period
Screening
Treatment Period
Follow-up
Upon 
Presentation 
for VOC
Week 6
Week 12
Week 24
Week 36
Week 48
Week 60 b
Procedure
Day -28 to -1
Baseline
Day 1 a
Day 43
±7 days
Day 85
±7 days
Day 169
±7 days
Day 253
±7 days
Day 337
(EOS 
c/ET)
±7 days
Day 421
EOS c
±7 days
CGI-C
X
X
X
X
PGI-C
X
X
X
X
ASCQ-Me weekly at 
home by participant n
X
X
X
X
X
X
ASCQ-Me n
X
X
X
X
X
X
Study Drug Infusion
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
Concomitant 
Medications
X
X
X
X
X
X
X
X
Abbreviations: ACS, acute chest syndrome; aPTT, activated partial thromboplastin time; ASCQ-Me, Adult Sickle Cell Quality of Life Measurement; CBC, complete blood 
count; CGI-C, clinician’s global impression of change; EOS, end of study; ET, early termination; FSH, follicle-stimulating hormone; HDL, high-density lipoprotein, HIV, human 
immunodeficiency virus; LDL, low-density lipoprotein; OLE, open-label extension; PGI-C, patient’s global impression of change; PLT, platelet; PT, prothrombin time; VOC, 
vaso-occlusive crisis; WOCBP, women of child-bearing potential. 
Note: During the treatment period, study assessments are to be collected pre-dose unless otherwise specified.
a.
All blood draws for Baseline assessments will be obtained prior to study drug administration.
b.
Week 60 (Day 421) Visit will be for participants who choose not to enroll, or are ineligible for, the OLE study. At this visit, safety, and efficacy assessments will be 
collected.
c.
For participants electing to enroll in the OLE study, the Day 337 (Week 48) Visit will be the EOS Visit. For participants not enrolling in the OLE study, an additional 
required visit will occur on Day 421 (Week 60) for safety follow-up.
d.
Height and weight to be captured at Screening with only weight captured thereafter.
e.
Vital signs (blood pressure, heart rate, body temperature) will be measured after a participant has rested for at least 5 minutes in the supine or recumbent position, as age 
appropriate and feasible. Vital signs will also be collected at the completion of infusion and at one hour after completion of infusion. Participants should be clinically well 
with stable vital signs and without signs or symptoms of an infusion-related reaction prior to release from observation. A repeat measurement of any of the vital sign 
parameters will be taken within 5 minutes if the first reading is outside the normal range and deemed clinically significant.
f.
Chest X-ray required for all suspected cases of ACS.
g.
Hematology assessments include the following: hemoglobin, hematocrit, white blood cells with differential, red blood cells, % and absolute reticulocytes, and PLTs. An iron 
panel will also be performed (iron, ferritin, total iron binding capacity [TIBC]). Collect at presentation for VOC, as feasible.
h.
Chemistry assessments include the following: blood urea nitrogen, bilirubin (total, direct and indirect), alkaline phosphatase, aspartate aminotransferase, alanine 
aminotransferase, serum albumin, sodium, potassium, magnesium, calcium, chloride, glucose, bicarbonate, creatinine kinase, serum creatinine, total protein, total globulin, 
IgG. lactate dehydrogenase, cystatin-C, C-reactive protein (CRP), high sensitivity-reactive protein (hs-CRP), and lipid panel (total cholesterol, HDL, LDL, triglycerides).
Collect at presentation for VOC, as feasible.
i.
Pregnancy tests will be performed on WOCBP. A serum test will be conducted at screening and a urine test at subsequent visits. A positive urine pregnancy test at any time 
during the study requires confirmation via a serum pregnancy test. Female participants will not be considered of childbearing potential if they are pre-menarchal, surgically 
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Study Period
Screening
Treatment Period
Follow-up
Upon 
Presentation 
for VOC
Week 6
Week 12
Week 24
Week 36
Week 48
Week 60 b
Procedure
Day -28 to -1
Baseline
Day 1 a
Day 43
±7 days
Day 85
±7 days
Day 169
±7 days
Day 253
±7 days
Day 337
(EOS 
c/ET)
±7 days
Day 421
EOS c
±7 days
sterile (hysterectomy, bilateral salpingectomy, tubal ligation, or bilateral oophorectomy) or postmenopausal (no menses for 12 months without an alternative medical cause, 
confirmed by follicle-stimulating hormone test results).
j.
Hemoglobin genotyping will be performed if the genotype is unknown.
k.
Coagulation parameters are PT, aPTT, D-dimer, von Willebrand factor (vWF), and fibrinogen. Collect at presentation for VOC as feasible. 
l.
A urine sample will be collected on Day 1 (pre-dose) and Week 48 for the assessment of albumin, protein, creatinine, and hemoglobin.
m.
The incidence of VOC events will be recorded weekly by the participant and collected every 4 weeks (±7 days). On non-visit days (Week 4 [Day 29], Week 8 [Day 57], 
Week 16 [Day 113], Week 20 [Day 141], Week 28 [Day 197], Week 32 [Day 225], Week 40 [Day 281], and Week 44 [Day 309], participants will be contacted by phone to 
determine if a VOC event or a pain crisis leading to contact with a healthcare provider without a visit to a medical facility has occurred, to collect adverse events (AEs), and 
record changes to concomitant medications.
n.
The participant will complete the ASCQ-Me questionnaire weekly, when available. Questionnaires will be distributed to sites once available in local language. The ASCQ-
Me questionnaire completed by participants at home will be collected during the participant’s visits to the clinical site at Weeks 6, 12, 24, 36, and 48. In addition, the 
ASCQ-Me questionnaire will be administered during the participant’s visits to the clinical site at Weeks 6, 12, 24, 36, and 48.
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