Clinical trial NCT02187003
Conditions: Anemia, Sickle Cell
Keywords: Sickle Cell Anemia Sickle Cell Disease Sickle Cell Disorders pain crisis vaso-occlusive crisis rivipansel GMI-1070 selectin inhibitor SCD VOC
Sponsor: Biossil Inc.
Start date: 2015-06-17; Completion date: 2019-06-27
Enrollment: 345 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a clinical study evaluating the efficacy and safety of rivipansel (GMI-1070) in treating subjects with sickle cell disease (SCD) who are 6 years of age or older experiencing a pain crisis necessitating hospitalization.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Rivipansel intervention 2: Placebo
Intervention descriptions: intervention 1: Rivipansel (GMI-1070) will be infused intravenously every 12 hours up to 15 doses maximum. Subjects aged 12 and over who weigh more than 40 kilograms will receive a dose of 1680 mg of rivipansel, followed by a dose of 840 mg of rivipansel every 12 hours. All subjects aged 6 to 11 years and any subject who weighs 40 kilograms or less, will receive weight-based dosing (mg/kg) of 40 mg/kg of rivipansel (maximum of 1680 mg) followed by a dose of 20 mg/kg of rivipansel (maximum of 840 mg) every 12 hours. intervention 2: Placebo (phosphate buffered saline) will be infused intravenously every 12 hours up to 15 doses maximum.

Protocol documents:
Prot_000.pdf: 
 
4 Devonshire Place | Toronto, Ontario M5S 2E, Canada | biossil.co 
 
14 February 2025 
Re: Cover Letter for ClinicalTrials.gov NCT02187003 
 
This Cover Letter accompanies the final Protocol (Amendment 3; 01 April 2019) for the 
completed trial, NCT02187003.  
 
Sincerely,  
 
 
 
Debora Manning, MPH  
Head of Regulatory 
Biossil Inc. 
debora@biossil.ai 
 
 
 
Docusign Envelope ID: 03C8F23D-76C1-45C5-A4A6-36ACFAD01C94






PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 3
Document
Version Date
Summary of Changes 
- Clarified that Readiness-for-Discharge 
assessments will occur at regular pre-defined 
intervals during the daytime hours (6am to 
10pm) and removed the requirement for routine 
assessments during the night-time hours (10pm 
to 6am). Indicated that an ad hoc assessment 
would be required if a subject is considered to 
have achieved readiness-for-discharge during the 
night-time hours;
- Extended the period of time a subject is able to 
screen into the Open Label Extension Study 
(B5201003) to 180 days from last visit in 
B5201002;
- Removed the option to sign consent for the 
Open Label Extension Study (B5201003) at 
hospital discharge in Study B5201002;
- Added eligibility criterion excluding subjects 
currently receiving, or expected to receive, 
transdermal analgesics;
- Added eligibility criterion excluding subjects 
who were previously randomized into the current 
study;
- Clarified that the adjudication committees will 
only evaluate adverse events occurring from the 
time of the subject’s first dose of study drug to 
the subject’s last study visit;
- Removed requirement to completely shroud the 
study drug IV infusion line with tinted tubing 
covers;
- Updated information regarding the  
compatibility of rivipansel with other IV fluids;
- Restructured the concomitant treatment section 
(Section 5.8) to include newly added prohibited 
medications (transdermal analgesics and 
systemic steroids [when used exclusively for 
treatment of uncomplicated VOC]) as well as to
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)










PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 8
Document
Version Date
Summary of Changes 
Plans (SAP), and to streamline and simplify the 
analysis methods for subgroups and exploratory 
endpoints.- Clarified in Section 9.2.3 how 
subgroup analysis will be performed.
- Removed specific outside organization 
weblinks for eGFR calculators and replaced with 
reference to study specific web-portal under 
study team control.
- In addition to changes described above, 
administrative and editorial changes were made
throughout the document for clarity, 
completeness and to improve readability.
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and, institutional review boards (IRBs)/ethics 
committees (ECs).  
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)








PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 12
SCHEDULE OF ACTIVITIES
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to Study Procedures and 
Assessments sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol.
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct 
evaluations or assessments required to protect the wellbeing of the subject.
Table 1.
Schedule of Activities
Study 
Procedure
Pre-VOC/
Study 
Entry 
Screening
Monthly 
Contactso
VOC/
Treat-
ment -
Ready 
Screening
Double-Blind Treatment
Post-
Treatment 
Daily 
Assess-
ments
Discharge
Post-Discharge 
Daily 
Assessments
Post-Discharge 
Follow-Up
Phone
Callx
Post-
Discharge 
Follow-Up 
Visitx
Loading 
Dose
First 
24
Hoursp
Daily 
Assess-
ments
End of 
Treat-me
ntv
Visit Number
Visit 1: During Hospitalization
2
3
4
Study Day
Day 1 through 8
Post-Discharge 
Day 1 up to 
Day 10
Post-
Disch
arge 
Day 
7±3
Post-
Disch
arge 
Day 
21 ±5
Post-
Discharge 
Day 35 ±5
Informed 
consent/
assent
(X)n
(X)n
Enter subject into 
electronic system 
to document 
entry into 
Screening period
(X)
X
Affirmation of 
informed consent
(X)n
Demographics
X
Medical History
X
SCD History
X
Complete 
Physical 
Examination
X
Targeted 
Physical 
Examination
Xs
Xs
X
X
Height, weight
X
Vital Signsa
X
Xtt
Xt
Xt
X
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 13
Study 
Procedure
Pre-VOC/
Study 
Entry 
Screening
Monthly 
Contactso
VOC/
Treat-
ment -
Ready 
Screening
Double-Blind Treatment
Post-
Treatment 
Daily 
Assess-
ments
Discharge
Post-Discharge 
Daily 
Assessments
Post-Discharge 
Follow-Up
Phone
Callx
Post-
Discharge 
Follow-Up 
Visitx
Loading 
Dose
First 
24
Hoursp
Daily 
Assess-
ments
End of 
Treat-me
ntv
Visit Number
Visit 1: During Hospitalization
2
3
4
Study Day
Day 1 through 8
Post-Discharge 
Day 1 up to 
Day 10
Post-
Disch
arge 
Day 
7±3
Post-
Disch
arge 
Day 
21 ±5
Post-
Discharge 
Day 35 ±5
Clinical 
Laboratoriesb
X
X
X
Urinalysisc
X
X
X
Pregnancy Testd
X
X
X
Contraception 
check
X
X
X
X
Hemoglobin 
Electrophoresisg
(X)
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 14
Study 
Procedure
Pre-VOC/
Study 
Entry 
Screening
Monthly 
Contactso
VOC/
Treat-
ment -
Ready 
Screening
Double-Blind Treatment
Post-
Treatment 
Daily 
Assess-
ments
Discharge
Post-Discharge 
Daily 
Assessments
Post-Discharge 
Follow-Up
Phone
Callx
Post-
Discharge 
Follow-Up 
Visitx
Loading 
Dose
First 
24
Hoursp
Daily 
Assess-
ments
End of 
Treat-me
ntv
Visit Number
Visit 1: During Hospitalization
2
3
4
Study Day
Day 1 through 8
Post-Discharge 
Day 1 up to 
Day 10
Post-
Disch
arge 
Day 
7±3
Post-
Disch
arge 
Day 
21 ±5
Post-
Discharge 
Day 35 ±5
Inclusion/
Exclusion 
criteria
X
Randomization 
X
Study Drug 
Administrationj
X
X
X
Readiness-for-
Discharge 
Criteria)k
X
X
X
X
X
Date and Time of 
Discharge
X
Telephone 
Contact
(X)
X
X
Adverse Events 
(X)
(X)
(X)
X
X
Xt
X
X
X
X
X
X
Prior/Concomita
nt Medications
X
X
X
Xt
X
X
X
X
X
X
Parenteral 
Opioidsl
X
X
X
Xt
X
X
X
Prior/Concomita
nt Non-drug 
Treatments/
Procedures
X
X
X
X
X
X
X
X
X
X
Informed 
consent/assent 
for Open-Label 
Extension Studym
(X)
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)






PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 17
TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................21
APPENDICES .........................................................................................................................22
1. INTRODUCTION ...............................................................................................................23
1.1. Mechanism of Action/Indication.............................................................................25
1.2. Background and Rationale ......................................................................................25
1.2.1. Drug Development Rationale .....................................................................25
1.2.2. Pre-Clinical Development of Rivipansel....................................................26
1.2.3. Clinical Experience with Rivipansel ..........................................................26
1.2.4. Study Rationale...........................................................................................28
1.2.5. Dose Rationale............................................................................................28
1.3. Summary of Benefit Risk Assessment....................................................................29
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................30
2.1. Objectives................................................................................................................30
2.1.1. Primary Objective.......................................................................................30
2.1.2. Secondary Objective...................................................................................30
2.2. Endpoints.................................................................................................................30
2.2.1. Efficacy Endpoints......................................................................................30
2.2.1.1. Primary......................................................................................30
2.2.1.2. Secondary..................................................................................30
2.2.2. Safety..........................................................................................................31
3. STUDY DESIGN.................................................................................................................33
3.1. Study Overview.......................................................................................................33
3.2. Approximate Number of Subjects...........................................................................36
3.3. Approximate Duration of Subject Participation......................................................36
3.4. Approximate Duration of Study..............................................................................37
4. SUBJECT SELECTION......................................................................................................37
4.1. Inclusion Criteria.....................................................................................................37
4.2. Exclusion Criteria....................................................................................................38
4.3. Life Style Guidelines...............................................................................................41
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 18
4.3.1. Contraception..............................................................................................41
4.3.2. Surgery........................................................................................................41
4.4. Sponsor Qualified Medical Personnel.....................................................................42
5. STUDY TREATMENTS.....................................................................................................42
5.1. Allocation to Treatment ..........................................................................................43
5.3. Subject Compliance.................................................................................................44
5.4. Drug Supplies..........................................................................................................44
5.4.1. Dosage Form(s) and Packaging..................................................................44
5.4.2. Preparation and Dispensing........................................................................45
5.5. Administration.........................................................................................................46
5.6. Drug Storage ...........................................................................................................47
5.7. Drug Accountability................................................................................................48
5.8. Concomitant Treatment(s).......................................................................................48
5.8.1. Prohibited Prior to Study Entry ..................................................................48
5.8.2. Prohibited During the Study.......................................................................48
5.8.3. Permitted During the Study ........................................................................48
5.8.4. Pain Management .......................................................................................49
5.8.5. Transfusion .................................................................................................50
6. STUDY PROCEDURES .....................................................................................................50
6.1. Screening.................................................................................................................52
6.1.1. Pre-VOC/Study Entry Screening................................................................52
6.1.1.1. Consent of Subjects...................................................................52
6.1.1.2. Monthly Telephone Contacts ....................................................52
6.1.2. VOC/Treatment-Ready Screening..............................................................52
6.1.2.1. Visit 1, VOC/Treatment-Ready Screening................................52
6.2. Study Period ............................................................................................................55
6.2.1. Visit 1, Day 1 – Loading Dose ...................................................................55
6.2.2. Visit 1, Day 1 – First 24 Hours After Loading Dose..................................56
6.2.3. Visit 1, Day 2 through Day 8 (or End of Treatment)..................................57
6.2.4. Visit 1, Post-Treatment Daily Assessments................................................59
6.2.5. Discharge ....................................................................................................59
6.3. Post-Discharge Daily Assessments .........................................................................60
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)




PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 20
7.7. Total Blood Volume................................................................................................80
8. ADVERSE EVENT REPORTING......................................................................................81
8.1. Adverse Events........................................................................................................81
8.2. Reporting Period .....................................................................................................82
8.3. Definition of an Adverse Event...............................................................................82
8.4. Medication Errors....................................................................................................83
8.5. Abnormal Test Findings..........................................................................................84
8.6. Serious Adverse Events...........................................................................................84
8.6.1. Protocol-Specified Serious Adverse Events...............................................85
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................85
8.7. Hospitalization ........................................................................................................86
8.8. Severity Assessment................................................................................................87
8.9. Causality Assessment..............................................................................................88
8.10. Exposure During Pregnancy..................................................................................88
8.11. Occupational Exposure .........................................................................................89
8.12. Withdrawal Due to Adverse Events (See Also the Section on Subject 
Withdrawal)...............................................................................................................90
8.13. Eliciting Adverse Event Information ....................................................................90
8.14. Reporting Requirements........................................................................................90
8.14.1. Serious Adverse Event Reporting Requirements .....................................91
8.14.2. Non-Serious Adverse Event Reporting Requirements .............................91
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ................91
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................92
9.1. Sample Size Determination.....................................................................................92
9.2. Efficacy Analysis ....................................................................................................93
9.2.1. Analysis of Primary Endpoint ....................................................................94
9.2.2. Analysis of Key Secondary Endpoints .......................................................95
9.2.4. Analysis of Other Secondary Endpoints.....................................................96
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 21
9.4. Safety Analysis........................................................................................................97
9.5. Interim Analysis ......................................................................................................97
9.6. Safety Endpoint Adjudication Committees.............................................................98
9.6.1. Acute Chest Syndrome Safety Endpoint Adjudication Committee............98
9.6.2. Cutaneous Manifestations Safety Endpoint Adjudication Committee.......98
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................99
11. DATA HANDLING AND RECORD KEEPING .............................................................99
11.1. Case Report Forms/Electronic Data Record .........................................................99
11.2. Record Retention.................................................................................................100
12. ETHICS............................................................................................................................101
12.1. Institutional Review Board (IRB)/Ethics Committee (EC).................................101
12.2. Ethical Conduct of the Study ..............................................................................101
12.3. Subject Information and Consent........................................................................102
12.4. Subject Recruitment ............................................................................................103
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP .........................................................................................................................103
13. DEFINITION OF END OF TRIAL.................................................................................104
13.1. End of Trial in all Participating Countries ..........................................................104
14. SPONSOR DISCONTINUATION CRITERIA ..............................................................104
15. PUBLICATION OF STUDY RESULTS........................................................................104
15.1. Communication of Results by Pfizer ..................................................................104
15.2. Publications by Investigators ..............................................................................105
16. REFERENCES ................................................................................................................106
LIST OF TABLES
Table 1.
Schedule of Activities...........................................................................................12
Table 2.
Sample Dosing Schedule (example of acceptable dosing schedule)....................47
Table 3.
Clinical Laboratory Evaluations – Local Laboratory...........................................72
Table 4.
Triggered Requirements .......................................................................................72
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 22
Table 7.
Total Blood Volume in Adults ( ≥ 18 year of age)...............................................80
Table 8.
Total Blood Volume in Pediatrics 12-17 years of age..........................................80
Table 9.
Total Blood Volume in Pediatrics 6-11 years of age............................................81
APPENDICES
Appendix 1. Estimated Glomerular Filtration Rate (eGFR) Calculations.............................109
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 23
1. INTRODUCTION
Sickle cell disease (SCD) is one of the most prevalent genetic disorders in the United States 
(US), affecting approximately 100,000 people.1 It is a chronic condition with substantial 
morbidity and mortality, and is responsible for more than 75,000 hospitalizations per year in 
the US with an average stay of 6.1 days.2 Both children and adults are affected, and greater 
mortality is seen in those with more severe disease. 
SCD refers to a group of autosomal recessive inherited disorders of the β-globin gene.  A 
single nucleotide substitution results in the presence of valine instead of glutamic acid in the 
β-globin chain.  The resulting polymerization of Hemoglobin S (Hb S) when deoxygenated is 
the primary indispensable event in the molecular pathogenesis of SCD.3 Individuals 
homozygous for Hb S have sickle cell anemia (SCD-SS).  Those who are compound (double) 
heterozygotes have 1 copy of Hb S and 1 copy of either Hb C (SCD-SC), Hb β+-thalassemia 
(SCD-Sβ+-thal), or Hb β0-thalassemia (SCD-Sβ0-thal).4
SCD is associated with a number of serious and potentially disabling conditions that have 
similar symptoms but vary in severity by genotype.  Most notable is vaso-occlusive crisis 
(VOC), an extremely painful and serious consequence of SCD, presumably resulting from 
acute ischemic tissue injury. 
Over the course of a year, about 60% of patients with SCD-SS will have at least 1 severe 
VOC5, which typically presents as episodes of pain and inflammation, at 1 or more sites, in 
varying degrees of severity, and occurring at varying intervals throughout life.  These pain 
crises, as VOC episodes are also known, are the clinical hallmark of SCD, are responsible for 
the vast majority of hospitalizations (>90%), and result in significant morbidity, mortality, 
and interruption of daily functioning.  Other problems include ischemic and hemorrhagic 
stroke, acute chest syndrome (ACS), splenic sequestration, dactylitis, osteonecrosis, 
priapism, leg ulcers, and nephropathy.3,6,7,8 Most SCD-related deaths occur during acute 
VOC, and are due to ACS or stroke.9 Patients can become symptomatic with pain, infection, 
or splenic sequestration as early as 6 months of age; thus, VOCs are an important cause of 
morbidity throughout life, resulting in disruption to the individual’s education, psychosocial 
development, and employment as well as causing severe pain, hospitalization, and premature 
death.
Current medical management of SCD includes use of hydroxyurea, which is used to increase 
fetal hemoglobin (Hb F) concentration and reduce the number of pain crises.  Treatment of 
acute VOC includes mainly supportive measures such as opioid analgesics, hydration, 
oxygen, and transfusion.  There is no mechanism-based treatment currently available, so this 
remains an unmet medical need.  Most patients attempt pain management at home, and seek 
medical care only when this fails.  Therefore, the majority of painful episodes do not come to 
medical attention.10
The etiology of VOC involves dual mechanisms: a mechanical component, by which the 
sickled red blood cells (RBCs) become caught in the post-capillary venules, and an 
associated inflammatory response in which white blood cells (WBCs) adhere to the 
endothelium.
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 24
The underlying pathogenesis of Red Blood Cell (RBC) Sickling is the deoxygenation of Hb 
S, which results in polymerization of the Hb, distortion of the RBC, and loss of deformability 
of the cell.11 These “sickled” RBCs are a primary component of the occlusive process and 
cause vascular injury through interactions with endothelial cells.6
The other primary component is adhesive: stickiness of the cells which causes cell aggregates 
of WBC-RBC, WBC-WBC, and WBC-platelet to form.  This adhesion is selectin-mediated 
and contributes to the VOC process.  Cell aggregates block the vasculature and create a trap 
for the sickled RBCs, resulting in obstruction of blood flow4,12
Finally, vaso-occlusion resulting from sickled and adherent RBCs also causes slowing of 
blood flow in post-capillary venules, local tissue hypoxia, and further tissue inflammation, 
resulting in more deoxygenation and sickling of RBCs, and propagation of the occlusion, 
sometimes called secondary recruitment of sickled cells and occluded vessels.3 Diapedesis 
(leukocyte migration into the tissues) and sickle-related microvascular occlusion also take 
place in postcapillary venules.  Pain is the result of initial and ongoing occlusion and 
ischemia,8 which results in higher mortality in patients with the SCD-SS genotype, compared 
to other genotypes.9
Of note is that soluble E-selectin, vascular cell adhesion molecules (VCAM)-1, and 
intracellular adhesion molecules (ICAM)-1 levels are higher in sickle cell patients at baseline 
than in normal volunteers.  There is also some evidence to suggest that soluble E-selectin and 
ICAM-1 are increased in acute VOC when compared to baseline in patients with SCD.13 In 
addition, increased soluble E-selectin levels have been shown to correlate with increased 
mortality in SCD patients.14 Leukocytes adherent to the endothelial cell wall in postcapillary 
and collecting venules interact with sickled RBCs, leading to vaso-occlusion in sickle cell 
mice.  However, sickle cell mice lacking E- and P-selectin were protected from developing 
vaso-occlusion.15 Understanding of the role that selectins play in cell aggregation and the 
pathophysiology of VOC is increasing.3,16
Selectins are a family of adhesion molecules involved in trafficking and extravasation of 
leukocytes.17 During the inflammatory response, leukocytes extravasate from the 
bloodstream and migrate to the sites of inflammation where they participate in the defense 
against pathogens or other inflammatory processes.  This recruitment of leukocytes, which 
begins with the initial recognition and binding of the leukocytes to the endothelial cells that 
line the walls of the vasculature, is mediated by selectins.18
Three selectins are known to bind carbohydrate structures on cells in interactions 
characterized by fast kinetics that allow cell adhesion to proceed under the shear forces of 
blood flow.19 P-selectin is located on platelets and is also pre-formed and stored in 
Weibel-Palade bodies within the endothelial cells.  It is a “first responder” and is expressed at 
the endothelial cell surface within 30 minutes of an acute inflammatory response.20
E-selectin is not pre-formed and stored, but requires de novo protein synthesis and is 
expressed on the endothelium 3 to 5 hours after activation.21 Both of these selectins are 
responsible for the early recognition and adhesion of leukocytes to the vascular endothelium.  
L-selectin is located on a subset of leukocytes and participates in rolling and adhesion and 
plays a major role in homing to the lymph nodes.17
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 25
The natural ligands for the selectins are carbohydrate structures of the sialylated Lewis 
antigens present on scaffolds of glycoproteins and glycolipids (eg, PSGL-1, ESL-1, 
MAdCAM-1).  Following initial selectin-mediated recognition and rolling, the leukocytes 
activate a second phase of adhesion while in close contact with the endothelium through 
integrin receptors.  As these events mostly occur in a stepwise fashion, the selectins have 
been viewed as a target for upstream inhibition of the inflammatory response.  By inhibiting 
the initial recognition, and thereby decreasing or preventing stickiness of 
RBC/WBC/endothelial cells in SCD, the pathophysiologic process of VOC may be 
interrupted and/or prevented.  Damage caused by these infiltrating cells in an inflammatory 
response is therefore prevented and blood flow may be improved.
Inhibition of E-, P-, and L-selectins, a pan-selectin inhibition approach, offers potential 
promise as a useful therapeutic option. 
Data in the literature support a key role for the selectins in VOC.  In particular, Turhan et al 
(2002) have shown that E-selectin and P-selectin are key to the vaso-occlusion in a mouse 
model with the sickle genotype.15  They have also suggested that drugs affecting 
leukocyte-endothelial interactions or leukocyte-sickle RBC aggregation may have an 
important role in treatment of VOC.  In addition, Embury et al (2004) have shown the 
importance of P-selectin in contributing to microcirculatory abnormalities.22  Kato et al 
(2005) have shown that increased soluble E-selectin levels in patients were associated with 
increased mortality over a 4-year period.14
GMI-1070 (rivipansel) is a pan-selectin antagonist, a compound found to inhibit selectin 
binding in vitro and to inhibit selectin-mediated effects in vivo.  Selectin binding is a key 
early step in the inflammatory process leading to leukocyte adhesion and recruitment to 
inflamed tissue.  Selectin binding has been shown to be involved in most – if not all – disease 
processes that involve inflammation.  There are no other known approved therapeutic agents 
in this class.
This study is designed to evaluate the efficacy and safety of rivipansel as treatment for VOC 
in hospitalized subjects with SCD. 
1.1. Mechanism of Action/Indication
Rivipansel is being developed as a pan-selectin antagonist for the treatment of VOC in 
subjects with SCD (including SCD-SS, SCD-SC, SCD-Sβ+-thalassemia, and 
SCD-Sβ0-thalassemia). 
1.2. Background and Rationale
1.2.1. Drug Development Rationale
Both P-selectin and E-selectin are responsible for the early recognition and adhesion of 
leukocytes to the vascular endothelium.  L-selectin is located on a subset of leukocytes and 
participates in rolling and adhesion and plays a major role in homing to the lymph nodes.
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 26
By inhibiting the initial recognition, and thereby decreasing or preventing stickiness of 
RBC/WBC/endothelial cells in SCD, the pathophysiologic process of VOC may be 
interrupted and/or prevented.  Damage caused by these infiltrating cells in an inflammatory 
response is therefore prevented and blood flow may be improved.
Rivipansel is a pan-selectin antagonist developed at GlycoMimetics that inhibits selectin 
binding in vitro as well as selectin-mediated effects in vivo.  Inhibition of selectins offers 
potential promise as a useful therapeutic option for patients with SCD. Rivipansel has potent 
anti-inflammatory effects in a number of animal models, including the sickle cell mouse, in 
which it has been shown to normalize blood flow, reduce blood cell aggregation, and to 
improve survival in a model of VOC.  In addition, the Phase 2 study (GMI-1070-201) data 
have shown that such effects in SCD patients have led to a reduction in the length and 
intensity of SCD pain crises.  Treatment of VOC with mechanism-based therapies is an area 
of unmet medical need in both adult and pediatric patients with SCD.  Both pediatric and 
adult patients would be expected to benefit substantially from a therapy that could treat VOC 
and therefore measurably reduce the associated suffering and adverse clinical outcomes.
1.2.2. Pre-Clinical Development of Rivipansel
For information on nonclinical pharmacology, pharmacokinetics and product metabolism in 
animals, and toxicology studies, please refer to the Investigator’s Brochure.
1.2.3. Clinical Experience with Rivipansel
Clinical information is available from three completed Phase 1 studies, and a completed 
Phase 2 study, all conducted by GlycoMimetics.  Additionally, data are available from a 
completed Pfizer sponsored Phase 1 study to assess the effect of rivipansel on corrected QT
interval (QTc).
GlycoMimetic Studies  
In the first Phase 1 study (GMI-1070-101), healthy volunteer subjects received single 
intravenous (IV) doses of 2, 5, 10, 20, or 40 mg/kg rivipansel or placebo.  In the second 
Phase 1 study (GMI-1070-102), healthy volunteer subjects received multiple IV doses of 
5, 10, or 20 mg/kg rivipansel or placebo every 8 hours for a total of 13 doses.  An additional 
group of subjects received a loading dose of 40 mg/kg, followed by multiple doses of 
20 mg/kg rivipansel every 8 hours for a total of 6 doses.  These studies evaluated a total of 
72 healthy adult subjects (54 active, 18 placebo).
Pharmacokinetic (PK) data are available from these studies in healthy volunteers.  Mean 
values for Cmax, area under the curve (AUC)(0-t), and AUC(inf) increased in a dose-proportional 
manner, providing evidence of linear pharmacokinetics.  After a single 20 minute infusion of 
20 mg/kg, the mean standard deviation Cmax was 25643.7 mg/L.  The time of peak 
concentrations corresponds to the time of the end of infusion and the collection of the first 
blood sample for determination of GMI-1070.  The volume of distribution was consistent 
across dose levels, 0.130 to 0.181 L/kg.  Clearance was consistent across dose levels 
(0.211 to 0.284 mL/min/kg) and the mean elimination half-life (t½) ranged from 6.67 hours to 
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 27
7.41 hours.  Urine collection after the multiple dose administration showed a minimum of 
89% of the dose was recovered intact in the urine, and CLr was less than filtration clearance, 
consistent with tubular reabsorption. 
The third Phase 1 study (GMI-1070-103) was an open-label study of IV rivipansel in 15 adult 
subjects with stable SCD who received a 20 mg/kg loading dose of IV rivipansel, followed 
10 hours later by a 10 mg/kg dose of IV rivipansel.  The pharmacokinetics were observed to 
be consistent with those in the healthy volunteers.
In these three Phase 1 studies there were no clinically significant electrocardiogram (ECG) or 
physical examination findings.  With one exception, all adverse events in subjects receiving 
rivipansel were Grades 1 or 2.  Severe symptomatic anemia (Grade 4) that occurred in 
1 subject with stable SCD was considered to be remotely related to the study medication, and 
resolved with therapy.  No serious adverse events were reported in these studies.
A randomized, placebo-controlled Phase 2 trial (GMI-1070-201), evaluating the efficacy, 
safety, and pharmacokinetics of multiple IV doses of rivipansel in 76 subjects 12 to 60 years 
of age who were hospitalized for sickle cell VOC is now complete.  This study included two 
dosing schedules; the first cohort received 20 mg/kg loading dose, then 10 mg/kg every 
12 hours for up to 7 days, (maximum 15 doses) and the second cohort received 40 mg/kg 
loading dose, then 20 mg/kg every 12 hours for up to 7 days, (maximum 15 doses).
In the phase 2 study, the primary endpoint, time to resolution of VOC, was shorter for the 
rivipansel treated group versus the placebo group.  The mean time to VOC resolution was 
110 hours and 148 hours for the rivipansel treated group and the placebo group, respectively. 
Treatment with rivipansel was also associated with improvement in clinical measures of 
VOC. The rivipansel treatment group had a shorter median time to transition from parenteral 
to oral pain medications, time to discharge from the hospital, and time to first sustained 
reduction in VAS pain score.  Mean use of opioid analgesics during hospitalization was also
lower in the rivipansel treated group.
Total treatment-emergent adverse event (TEAE) rates were comparable across groups.  
Serious Adverse Events (SAE) and those SAEs “related to treatment” were also comparable 
across groups. Eleven (11, 14.4%) subjects discontinued study drug treatment due to adverse 
events (8 [10.5%] subjects in the active group, and 3 [3.9%] subjects in the placebo group). 
No subjects discontinued participation in the study due to adverse events. A total of 
28 serious adverse events (SAEs) were reported, encompassing 29 event terms across 
23 subjects.  A 30% SAE rate was seen in both active and placebo groups. The most 
common SAE in both treatment groups was re-hospitalization for VOC. One (1) SAE of 
acute generalized exanthematous pustulosis (AGEP) rash was seen in a subject who received 
the high dose; other less severe rash events were distributed across treated and placebo 
groups.  No subjects died.
Of note, the drug product formulation that will be used in this study is a 30 mg/mL solution 
for injection in which the concentration is 30 mg/mL based on the active moiety of 
rivipansel. The drug product used in the Phase 1 and Phase 2 studies described previously 
(conducted by GlycoMimetics) was a 30 mg/mL solution for injection based on the salt of 
rivipansel which is equivalent to 28.28 mg/mL of the active moiety rivipansel.
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 28
Pfizer Sponsored Studies
A Phase 1 placebo and active controlled study to evaluate the effect of intravenous rivipansel 
on QTc interval in 48 healthy African-American adult subjects (Pfizer Study B5201001) has 
been completed. The rivipansel dose in the study was 4 grams (expressed as active moiety) 
as a single intravenous infusion and the active control was a single dose of moxifloxacin 
400mg orally.
The study was deemed negative; the statistical analyses of the ECG measurements 
demonstrated a lack of a QTc effect with rivipansel compared to placebo as the upper bound 
of the 2-sided 90% confidence interval (CI) for mean differences between rivipansel and 
placebo at all 11 post-dose time points was below the International Council for
Harmonisation (ICH) E14 criteria of 10 milliseconds (msec).  The highest observed upper 
bound of the 2-sided 90% CIs was 3.22 msec at 3 hours post-dose.  The moxifloxacin 
positive control performed as expected, thus the study should be deemed adequately
sensitive.
Single doses of rivipansel were well tolerated in these healthy male African-American 
subjects with an adverse event profile largely consistent with that which had been reported in 
the previous studies undertaken by GlycoMimetics. The only new event reported was 
alanine aminotransferase (ALT) elevation that occurred in a single male subject after 
receiving rivipansel. The ALT elevation was moderate (maximum ALT 3 times the upper 
limit of normal [xULN]), was not associated with any clinical signs or symptoms and 
recovered to normal levels on subsequent follow-up. The event was confounded by the 
subject having a mildly elevated ALT at baseline (<1.5xULN) and having reported a 
previous episode of transient “liver function test” elevation which occurred while 
participating in another healthy volunteer drug study, undertaken at a different clinical 
research unit.
1.2.4. Study Rationale
Rivipansel is a glycomimetic inhibitor of E-, P-, and L-selectins in vitro.  Rivipansel has been 
shown to inhibit inflammation in several animal models of disease, including the mouse 
model of vaso-occlusive crisis (VOC) of sickle cell disease (SCD).  It has also been shown to 
consistently improve multiple clinically meaningful measures of the VOC experience, for 
both the pediatric and adult subjects enrolled in the Phase 2 study (GMI-1070-201).  This
Phase 3 study will continue to examine rivipansel for the treatment of VOC in patients with 
SCD. 
1.2.5. Dose Rationale
Rivipansel is administered intravenously.  In this current Phase 3 study, rivipansel IV 
solution for injection contains 30 mg/mL of active moiety rivipansel. 
The dosing regimen in this Phase 3 study is as follows:

Subjects aged 12 and over who weigh >40 kg, will receive study drug as a loading 
dose of 1680 mg followed by a maintenance dose of 840 mg every 12 2 hours. 
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 29

Subjects aged 6 to 11 years, or any subject who weighs 40 kg, will receive 
weight-based dosing (mg/kg) administered as a loading dose of 40 mg/kg (maximum 
of 1680 mg) followed by a maintenance dose of 20 mg/kg (maximum of 840 mg) 
every 12 2 hours. 
The selection of the dose in this Phase 3 study was based on efficacy, safety, and 
pharmacokinetic results from the Phase 2 study, where a low dose (20 mg/kg loading 
dose/10 mg/kg every 12 hours) and a high dose (40 mg/kg loading dose/20 mg/kg every 
12 hours) were studied (the doses were studied in a sequential fashion). In the Phase 2 study, 
the differences between the median time to discharge for rivipansel and placebo treatment 
groups were similar for the low rivipansel dose (56 hours) and the high dose (55 hours).  
Phase 2 treatment-emergent adverse events (AEs) by dose, as well as other safety data, 
indicates there were no apparent safety differences for either the low or high dose relative to 
placebo.  The pharmacokinetic data from the Phase 2 study support fixed flat dosing for 
subjects 12 years of age and above. Furthermore, fixed flat dosing is a common approach for 
the administration of small molecules with a favorable safety margin, and offers a simpler 
approach with the potential for fewer dosing errors.  Pharmacokinetic modeling and 
simulations predict that the dose will result in exposures similar to that observed with the low 
dose in the Phase 2 study and a minimum plasma concentration above 10 g/mL will be
maintained throughout the dosing interval.  This concentration has shown improved blood 
flow, rolling flux and survival rate in a SCD mouse efficacy model.23 In order for subjects 
12 years of age not to exceed the high dose of 40/20 mg/kg studied in the Phase 2 study, the 
weight cut off was chosen to be 40 kg.  Based on the similarity of efficacy and safety results 
between the 2 doses studied in the Phase 2 study, only a single dose will be studied. 
Weight-based dosing for subjects 6 to 11 years of age will be used in this study.  This is the 
most conservative approach given that children in this age range have not been previously 
studied.  In the Phase 2 study, GMI-1070-201, subjects 12 years old with the regimen of 
20 mg/kg loading dose followed by 10 mg/kg every 12 hours were studied and the dose was 
found to be efficacious.  Because the exposures resulting from this dosing should result in 
similar efficacy in the younger subjects, modeling and simulation exercises were performed 
to identify dosing regimens that predict similar exposures. The simulations showed that for 
children 6 to 11 years old, a 40 mg/kg loading dose (maximum 1680 mg) followed by 
20 mg/kg every 12 hours (maximum 840 mg) will result in concentrations similar to those 
observed with the 20/10 mg/kg dosing in the GMI-1070-201 study.
1.3. Summary of Benefit Risk Assessment
The available safety results from non-clinical and clinical studies support further 
investigation of rivipansel in subjects. 
The beneficial effects of rivipansel are postulated to be the result of mechanism-based 
resolution of VOC via the inhibition of selectin-mediated adhesion of leukocytes to the 
endothelium.  This prevents propagation of the vaso-occlusion and promotes early resolution 
of the VOC episode. 
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)








PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 33
3. STUDY DESIGN
3.1. Study Overview
This Phase 3 randomized, double-blind, placebo-controlled, parallel group, multicenter study 
is designed to demonstrate the efficacy of rivipansel in treating subjects with SCD who are 
6 years of age experiencing an acute VOC event necessitating hospitalization.  This study 
has two cohorts: Cohort 1 includes one adult stratum (≥18 years old) and one pediatric 
stratum (12-17 years old), Cohort 2 includes one pediatric stratum (6-11 years old). The 
primary analysis population will be Cohort 1 and Cohort 2 combined (see Section 9.1) but 
the two cohorts will also be analysed separately.
There are two entry points into this study.  The first point of entry is referred to as 
“Pre-VOC/Study Entry Screening” and occurs while the subject is well.  The second entry 
point is while the subject is experiencing a pain crisis and is termed “VOC/Treatment-Ready 
Screening”.
Pre-VOC/Study Entry Screening: Investigators may choose to identify, through chart review, 
those subjects who may be appropriate for the study before they develop VOC.  These 
subjects may be educated about the study when they are well, such as in the office setting,
and approached for consent/assent while not experiencing a pain crisis.  These subjects will 
receive monthly telephone calls from the study site staff (or attend clinic visits, if preferred) 
until the time of their next VOC necessitating hospitalization. At the time of VOC, the 
subject will be asked if they want to continue participating in the VOC/Treatment-Ready 
Screening and if eligible, be randomly assigned to blinded study drug. The subject’s 
affirmation must be documented.
VOC/Treatment-Ready Screening: In addition to approaching subjects prior to VOC, 
investigators are encouraged to identify subjects with VOC in settings that could include 
emergency department, clinic, day hospital or other acute care outpatient facilities, who are 
planned or likely to be admitted to the hospital, and approach them for consent/assent and 
eligibility criteria early in the process of treatment for VOC. 
Subjects with acute VOC who complete the VOC/Treatment-Ready screening assessments 
and meet all eligibility criteria are enrolled into the study and will be randomized in a 
1:1 ratio to receive multiple IV doses of rivipansel or placebo for the treatment of VOC.  
Randomization will be stratified by age (6-11, 12-17, and 18 years of age) and genotype 
(category 1: HbSS, HbS0 thalassemia and HbSD; category 2: HbSC, HbS+ thalassemia and 
HbS-Variant [other than HbSD]). 
Dosing of eligible subjects with acute VOC will be initiated as early as possible, but no later 
than 24 hours from the administration of the first dose of IV opioids.  For subjects aged 
12 and over who weigh >40 kg, study drug will be administered as a loading dose of 
1680 mg followed by a maintenance dose of 840 mg every 12 2 hours.  Subjects aged 6 to 
11 years, or any subject who weighs 40 kg, will receive a loading dose of 40 mg/kg 
(maximum of 1680 mg) followed by a maintenance dose of 20 mg/kg (maximum of 840 mg)
every 12 2 hours.  Study drug will be administered until criterion 1 of the
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)








PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 37
complications may occur during the subject’s hospitalization and the subject’s participation 
in the study may exceed 44 days.
Subjects who enter the Pre-VOC period of the study while well (ie, not in VOC) will 
participate in the study for more than 44 days.  The duration of the pre-VOC period for these 
subjects is variable and unpredictable.  Once the subject has a VOC requiring hospitalization,
affirms informed consent and meets all eligibility criteria, their participation in the
double-blind treatment period and follow-up period of the study will be approximately 
44 days, as described above. 
3.4. Approximate Duration of Study
This study will be completed in approximately 48 months.  The end of the study is the date of 
the last contact with the last subject on the study (ie, Last Subject Last Visit).
4. SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom protocol treatment is considered 
appropriate.  All relevant medical and non-medical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.
An eligibility card will be provided to ensure review of all inclusion and exclusion criteria.
4.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. 6 years of age.
2. Documented diagnosis of sickle cell disease (HbSS, HbS-thalassemia [HbS0 and 
Hb S+thalassemia], HbSC or HbS-Variant, including HbSD and HbSE).
3. Diagnosis of VOC at the time of enrollment; necessitating admission to the hospital with 
treatment including IV opioids.  This applies to the VOC/Treatment-Ready Screening 
entry point.
4. Able to commence the first dose of study drug within 24 hours from the administration of 
the first dose of IV opioids (Subjects treated as an outpatient within the past 48 hours for 
the same VOC episode may be enrolled if dosing with study drug is expected within 
24 hours from the administration of the first dose of IV opioids for this admitting 
presentation).
5. Evidence of a personally signed and dated informed consent (and assent, where 
applicable) document indicating that the subject (or a legally acceptable 
representative/parent(s)/legal guardian) has been informed of all pertinent aspects of the 
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 38
study.  This applies to consent/assent at the time of Pre-VOC/Study Entry Screening or
VOC/Treatment-Ready Screening.
6. Subjects who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
7. Male subjects able to father children and female subjects of childbearing potential and at 
risk for pregnancy must agree to use a highly effective method of contraception 
throughout the duration of the active treatment period (starting at VOC/Treatment-Ready 
Screening) and for at least 28 days after the last dose of assigned treatment.  
Female subjects who are not of childbearing potential (ie, meet at least one of the 
following criteria):

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure;  

Have achieved post-menopausal status, defined as cessation of regular menses for 
at least 12 consecutive months with no alternative pathological or physiological 
cause and a serum follicle-stimulating hormone (FSH) level confirming the 
post-menopausal state.  If FSH result is not available by the end of the screening 
period the decision will be based on the investigator’s judgment and subject’s 
medical history.
All other female subjects (including females with tubal ligations and females that do 
NOT have a documented hysterectomy, bilateral oophorectomy and/or ovarian 
failure) will be considered to be of childbearing potential.
4.2. Exclusion Criteria
Subjects presenting with any of the following, from the time of VOC/Treatment-Ready 
Screening up to the time of randomization unless otherwise stated, will not be included in the 
study:
1. Serious systemic infection, evidenced by clinical signs and symptoms, and/or 
microbiological investigations, consistent with this diagnosis.  Subjects with fever < 39°C 
(102.2°F) may be considered for enrollment if in the opinion of the investigator there is 
no evidence of any serious systemic infection. Subjects with fever ≥ 39C (102.2F) are 
excluded.
2. Subjects presenting with the following clinical risk factors of acute chest syndrome: 

Hypoxia – defined as O2 saturation of <90% (by pulse oximetry) on room air on 
2 separate readings 15 minutes apart, or single value of PaO2 <60 mmHg on 
arterial blood gas,
and/or

Hemoglobin <5 gm/dL.
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 39
3. Acute chest syndrome, at the time of presentation, as defined by the National Institutes of 
Health (NIH) treatment guidelines:24,25
New pulmonary infiltrate involving at least one complete lung segment consistent with 
the presence of alveolar consolidation, (excluding atelectasis) AND one or more of the 
following:

Chest pain;

Temperature >38.5o C;

Tachypnea;

Wheezing or rales;

Cough.
4. SCD pain atypical of VOC, including hepatic or splenic sequestration, cholecystitis, or 
pneumonia.
5. At the time of presentation:

acute stroke, or

severe avascular necrosis of the hip/shoulder when the presenting pain is only in 
the affected hip/shoulder.
6. Estimated glomerular filtration rate (eGFR) 60 mL/min/1.73 m2 (refer to 
Appendix 1 for calculation).
7. History consistent with rapidly progressive decrease or decrement in renal function, in 
the opinion of the investigator.
8. Alanine aminotransferase (ALT/SGPT) >3 times the upper limit of normal (X ULN)
(based on clinic laboratory normal range).
9. Platelets <50,000/mm3.
10. Subjects currently receiving transdermal analgesics and/or the expectation that 
transdermal analgesics may be used during the study for treatment of this episode of 
VOC (see Section 5.8.2).
11. Recent (within the past 30 days) major surgery (see definition in Section 4.3.2), 
hospitalization for reasons other than VOC, documented serious infection requiring IV 
antibiotic treatment, or significant bleeding.
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 40
12. Hospitalization for uncomplicated VOC, or treatment with parenteral pain medications in 
other medical settings such as the emergency department or day hospital for 
uncomplicated VOC, from 48 hours to 14 days prior to admitting presentation. 

Subjects may be included if treated as an outpatient within the past 48 hours for 
the same VOC episode.
13. Recent (within the past 14 days) diagnosis of cerebrovascular accident, or transient 
ischemic attack.
14. Greater than 5 episodes of hospitalization for VOC in the past 6 months (180 days).
15. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality 
that may increase the risk associated with study participation or study drug administration 
or may interfere with the interpretation of study results and, in the judgment of the 
investigator, would make the subject inappropriate for entry into this study.
16. Any condition(s) that compromises the subject’s ability to comply with and/or perform 
study-related activities or that poses a clinical contraindication to study participation 
(these conditions include, but are not limited to, inadequate medical history to assure 
study eligibility; inadequate venous access).
17. Subjects previously randomized in the current study.
18. Participation in other studies involving investigational drug(s) (Phases 1-4) within 
4 weeks before the current study begins and/or during study participation.
19. Expectation that the subject will not be able to be followed for the duration of the study.
20. Pregnant female subjects or breastfeeding female subjects;
21. Male subjects able to father children and female subjects of childbearing potential who 
are unwilling or unable to use a highly effective method of contraception as outlined in 
this protocol for the duration of the active treatment period (starting at 
VOC/Treatment-Ready Screening) and for at least 28 days after last dose of study drug.
22. Subjects who are investigational site staff members directly involved in the conduct of 
the study and their family members, site staff members otherwise supervised by the 
Investigator, or subjects who are Pfizer employees directly involved in the conduct of the 
study.
23. Active use of illicit drugs and/or alcohol dependence, as determined by the investigator.
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 41
4.3. Life Style Guidelines
4.3.1. Contraception
All male subjects who are able to father children and female subjects who are of childbearing 
potential and in the opinion of the investigator are sexually active and at risk for pregnancy
must agree to use a highly effective method of contraception consistently and correctly for 
the duration of the active treatment period (ie, starting at the time of VOC/Treatment-Ready 
Screening) and for at least 28 days after the last dose of study drug.  The investigator or 
his/her designee, in consultation with the subject, will confirm the subject has selected an 
appropriate method of contraception for the individual subject and their partner from the 
permitted list of contraception methods (see below), and instruct the subject in its consistent 
and correct use.  Subjects need to affirm that they meet the criteria for correct use of at least 
one of the selected methods of contraception.  The investigator or his/her designee will 
discuss with the subject the need to use highly effective contraception consistently and 
correctly according to the Schedule of Activities (see Table 1) and document such 
conversation in the subject’s chart.  In addition, the investigator or his/her designee will 
instruct the subject to call immediately if the selected contraception method is discontinued 
or if pregnancy is known or suspected in the subject or the subject’s partner. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include:
1. Established use of oral, inserted, injected, implanted or transdermal hormonal 
methods of contraception are allowed provided the subject plans to remain on the 
same treatment throughout the entire study and has been using that hormonal 
contraceptive for an adequate period of time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD).
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
suppository).  For countries where spermicide is not available or condom plus 
spermicide is not accepted as highly effective contraception, this option is not 
appropriate.
4. Male sterilization with absence of sperm in the post-vasectomy ejaculate.
5. Bilateral tubal ligation / bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
4.3.2. Surgery
Elective Surgery: Elective surgery during the active treatment period (ie, starting at the time 
of VOC/Treatment-Ready Screening) through Day 35 Post-Discharge Follow-Up visit, 
should not be scheduled without first consulting with the Pfizer medical monitor. 
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 42
Non-elective Surgery: Investigators should contact the Pfizer medical monitor regarding 
subjects who undergo non-elective surgery to discuss their suitability to remain in the study.
As indicated, recent major surgery is an exclusion criterion for this study.  For the purposes 
of this study, major surgical intervention is defined as surgery involving open abdominal, 
intracranial or complex orthopedic procedures. Retroperitoneal and thoracic procedures are
also considered major surgery.  For other major surgeries contact the sponsor’s medical 
monitor.
4.4. Sponsor Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the Investigator Site File that is 
maintained at the study site.
To facilitate access to appropriately qualified medical personnel on study related medical 
questions or problems, subjects are provided with a contact card. The contact card contains, 
at a minimum, protocol and investigational compound identifiers, subject study number, 
contact information for the investigational (study) site and contact details for a contact center
in the event that the study site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study. The contact number can also be used by study site staff if 
they are seeking advice on medical questions or problems, however it should only be used in 
the event that the established communication pathways between the study site and the 
sponsor study team are not available. It is therefore intended to augment, but not replace the 
established communication pathways between the study site and the sponsor study team for 
advice on medical questions or problems that may arise during the study (consult the Study 
Reference Manual for additional details on communication pathways and contact 
information). The contact number is not intended for use by the subject directly and if a 
subject calls that number they will be directed back to the study site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Council on Harmonisation (ICH) 
guidelines, investigational product is defined as a pharmaceutical form of an active 
ingredient or placebo being tested or used as a reference/comparator in a clinical trial, 
including a product with a marketing authorization when used or assembled (formulated or 
packaged) in a way different from the approved form, or when used for an unapproved 
indication, or when used to gain further information about an approved use (ICH E6 1.33).  
For this study, the investigational products are Rivipansel and a phosphate buffered saline 
Placebo.
Subjects will be randomized at a 1:1 ratio to one of two treatment groups:

Rivipansel;

Placebo.
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)






PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 45
clear, but a fine swirl or haze of particulate matter may be observed on agitation of the 
solution.
A phosphate buffered saline (PBS) placebo, clear, colorless solution will also be supplied by 
the sponsor.  The placebo will be supplied as a sterile solution for single use administration 
in a 30 mL clear glass vial sealed with a grey stopper and aluminum over-seal for 
administration by intravenous infusion.
Vials will be packaged in individual cartons and identified with a unique identification (ID)
number for subsequent unit dose preparation according to the Investigational Product (IP) 
Handling Manual. 
Each packaged lot of blinded drug supplies will look visually identical up to the carton 
containing the vials being opened. Therefore when the drug supplies are received at the site 
no special procedures are required to maintain the blind (ie, both the active and placebo vial 
cartons should be handled and stored the same).  However, to avoid unblinding due to 
potential color difference between the active and placebo solutions, only unblinded study site 
staff should open the cartons containing the vials. 
Vial adapters and syringe filters will be supplied by the sponsor for dose preparation.  
For further details regarding the composition of the drug product and the placebo, please 
refer to the Investigator Brochure for Pfizer compound PF-06460031 (GMI-1070, rivipansel).
5.4.2. Preparation and Dispensing
The randomization system will identify the specific vials to be used to prepare the dose for 
each subject according to the randomization list.
Subjects aged 12 and over who weigh >40 kg, will receive a loading dose of 1680 mg 
followed by a maintenance dose of 840 mg every 12 2 hours.  Two vials will be assigned 
by the randomization system for the loading dose and a single vial for each of the subsequent 
maintenance doses.
Subjects aged 6 to 11 years, or any subject who weighs 40 kg, will receive a loading dose of 
40 mg/kg (maximum of 1680 mg) followed by a maintenance dose of 20 mg/kg (maximum 
of 840 mg) every 12 2 hours.  The weight measured as part of the VOC/Treatment-Ready 
screening procedures will be used to determine the appropriate dose to be administered 
during the study. 
Study drug will be administered until criterion 1 of the readiness-for-discharge criteria (see
Section 7.1.1) has been met, or up to 15 doses of study drug (1 loading dose and a maximum 
of 14 maintenance doses), whichever comes first. 
Active or placebo sterile solution for intravenous infusion will be prepared and stored 
according to details specified in the IP Handling Manual.  
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


P F -0 6 4 6 0 0 3 1
B 5 2 0 1 0 0 2
Fi nal Pr ot oc ol A me n d me nt 3, 0 1 A pril 2 0 1 9
Pa ge 4 6
T he u n bli n de d p har mac ist ( or desi g nee) will pre pare t he st u d y dr u g a n d, as descri be d i n t he 
I P Ha n dli n g Ma n ual, t his will i ncl u de t he re q uire me nt f or t he st u d y dr u g t o be filtere d u p o n 
tra nsfer t o t he i nf usi o n ba g or syri n ge t hr o u g h a 0. 2 2 micr o n s yri n ge filter.  A sec o n d 
u n bli n de d pers o n o n t he st u d y  site staff m ust verif y t he c orrect d ose was pre pare d pri or t o 
dis pe nsi n g.
T o a v oi d u n bli n di n g d ue t o a p ote ntial c ol or differe nce bet wee n t he acti ve a n d place b o 
s ol uti o ns, o nl y u n bli n de d st u d y site staff s h o ul d o pe n t he vial cart o ns a n d pre pare t he d ose.
T he u n bli n de d p har macist ( or desi g nee) will pre pare t he st u d y dr u g i n a ma n ner t hat will 
c o nceal a n y p ote ntial c ol or differe nce bet wee n t he acti ve a n d place b o s ol uti o ns , as descri be d 
i n t he I P Ha n dli n g Ma n ual .  F or i nf usi o ns a d mi nistere d wit h a s yri n ge p u m p , t he s p o ns or will 
pr o vi de sites wit h ti nte d tra nsl uce nt ta pe t o c o ver t he s yri n ge a n d t he i n-li ne filter i n t he I V 
li ne.  F or i nf usi o ns a d mi nistere d via i nf usi o n ba g, s p o ns or-pr o vi de d c o vers will be place d 
o ver t he ba g a n d ti nte d tra nsl uce nt ta pe w ill be use d t o c o ver t he dri p c ha m ber a n d t he i n-li ne
filter i n t he I V li ne.  T he u n bli n de d p har macist ( or desi g nee) will la bel t he st u d y dr u g i n a 
ma n ner t hat d oes n ot i de ntif y t he c o nte nts.  Bli n de d site staff will recei ve t he st u d y  dr u g i n a 
bli n de d ma n ner fr o m t he p har mac y .
5. 5. A d mi nistr ati o n
D osi n g of eli gi ble s u bjects will be i nitiate d as earl y as p ossi ble, b ut n o l ate r t ha n 2 4 h o u rs 
fr o m t he a d mi nistrati o n of t he first d ose of I V o pi oi ds.  St u d y  treat me nt will be a d mi nistere d 
e ver y 1 2 2 h o urs u ntil criteri o n 1 of t he rea di ness-f or-disc har ge criteria (see Secti o n 7. 1. 1 )
has bee n met , or u p t o 1 5 d oses of st u d y  dr u g ( 1 l oa di n g d ose a n d a ma xi m u m of 
1 4 mai nte na nce d oses), w hic he ver c o mes first.
Pri or t o i nitiati o n of st u d y  dr u g i nf usi on, t he I V access s h o ul d be fl us he d wit h n or mal sali ne 
t o pre ve nt a ny p ote ntial i nc o m pati bilities wit h resi d ual s ol uti o ns i n t he access li ne.  
Ri vi pa nsel or place b o s ol uti o n will be i nf use d i ntra ve n o usly o ver a peri o d of 2 0 mi n utes ( u p 
t o 4 0 mi n utes is all o wa ble) fr o m t he start of t he st u d y dr u g I V i nf usi o n usi n g a n 
a d mi nistrati o n set t hat i ncl u des a 0. 2 or 0. 2 2 micr o n i n- li ne filter, or a n e xte nsi o n set wit h a 
0. 2 or 0. 2 2 micr o n i n -li ne filter.  T he d osi n g I V li ne m ust be fl us he d wit h n or mal sali ne t o 
ens ure c o m plete a d mi nistrati o n of t he st u d y  dr u g.
Details of t he I V i nf usi o n will be descri be d i n t he I P Ha n dli n g Ma n ual a n d t he St u d y Dr u g 
A d mi nistrati o n G ui da nce D oc u me nt .
T h e  p l a n n e d  s c h e d u l e  f o r  d o s i n g  e v e r y  1 2 2 h o u r s  s h o u l d  r e m a i n  a s  
pl a n ne d, i r r e s p e c t i v e  o f  a d j u s t m e n t s  f o r  t i m i n g  b a s e d  o n  t h e  2 h o u r  w i n d o w  
f o r  d o s i n g .   D o s i n g  s c h e d u l e  s h o u l d  n o t  b e  a d j u s t e d  f o r  a c t u a l  d o s i n g  
t i m e s .   S e e  e x a m p l e  i n  Ta ble 2 b e l o w .
0 9 0 1 7 7 e 1 9 1 5 d a 0 1 b\ A p pr o v e d\ A p pr o v e d O n: 1 6- J ul- 2 0 1 9 1 8: 4 4 ( G M T)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 47
Table 2.
Sample Dosing Schedule (example of acceptable dosing schedule)
Dose 
Planned Start Time
Actual Start Time
First dose/Loading dose (am)
9 am
9 am
Second dose (pm)
9 pm
10 pm
Third dose (am)
9 am
8:30 am
Fourth dose (pm)
9 pm
10:30 pm
Rivipansel sterile solution has been shown to be compatible with 5% Dextrose in Water 
(D5W), Normal Saline (0.9% sodium chloride, [NS]), or any combinations of the two; for 
example, 5% Dextrose in 0.9% sodium chloride (D5/NS), 5% Dextrose in 0.45% sodium 
chloride (D5/ ½ NS), and 5% Dextrose in 0.225% sodium chloride (D5/ ¼ NS). Any of these 
solutions may be co-administered alone or in combination with up to 20 mEq/L KCl. 
Co-administration with any other IV medications or fluids administered through the same 
IV line is not permitted. 
5.6. Drug Storage 
Vials of rivipansel and placebo solutions are required to be stored in their original container 
and in accordance with the study drug label.
The investigator, or an approved representative, eg, pharmacist, will ensure that all study 
drug, including placebo, are stored in a secured area with controlled access under 
recommended storage conditions and in accordance with applicable regulatory requirements.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of study drug receipt throughout the study.  Even for continuous 
monitoring systems, a log or site procedure which ensures active evaluation for excursions 
should be available.  The intent is to ensure that the minimum and maximum temperature is 
checked each business day to confirm that no temperature excursion occurred since the last 
evaluation and to provide the site with the capability to store or view the minimum/maximum 
temperature for all non-working days upon return to normal operations.  The operation of the 
temperature monitoring device and storage unit (for example, refrigerator), as applicable, 
should be regularly inspected to ensure they are maintained in working order.
Any excursions from the product label storage conditions should be reported to Pfizer upon 
discovery. The site should actively pursue options for returning the product to labeled storage 
conditions, as soon as possible.  Deviations from the storage requirements, including any 
actions taken, must be documented and reported to Pfizer.  
Once an excursion is identified, the study drug must be quarantined and not used until Pfizer
provides documentation of permission to use the study drug.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion.  Use of the investigational product prior to Pfizer approval will be 
considered a protocol deviation.  Specific details regarding information the site should report 
for each excursion will be provided to the site.  
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 48
Receipt of materials, door opening and closing, and other routine handling operations where 
the product(s) are briefly out of labeled temperature range are not considered excursions.
More specific details will be provided to the sites separately.  Refer to the Investigational 
Product manual for additional details regarding excursion reporting requirements for the 
sites.  
5.7. Drug Accountability
The investigator’s site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the drug supplies.  Study drug inventory and accountability forms will be 
maintained by the unblinded pharmacist or designee, and examined and reconciled by the 
unblinded monitor.
The sponsor, or designee, will provide guidance on the destruction of unused study drug (eg, 
at the site).  If destruction is authorized to take place at the study site, the investigator must 
ensure that the materials are destroyed in compliance with applicable environmental 
regulations, institutional policy, and any special instructions provided by Pfizer and all 
destruction must be adequately documented.
5.8. Concomitant Treatment(s)
5.8.1. Prohibited Prior to Study Entry
Subjects receiving transdermal analgesics at the time of study entry will be excluded from 
enrolling into the study. 
Active use of illicit drugs at the time of study entry is prohibited.  The term “illicit drugs” 
includes, but is not limited to, cocaine, heroin, ecstasy, and phencyclidine (commonly known 
as ‘PCP’).  Investigators are encouraged not to enroll subjects for whom inappropriate use of 
prescribed opioids may interfere with interpretation of study endpoints.
5.8.2. Prohibited During the Study
Use of transdermal analgesics (including, but not limited to fentanyl or lidocaine patches) is 
not allowed for treatment of the qualifying episode of VOC during the study. The following 
are not considered transdermal analgesics: Transcutaneous Electrical Nerve Stimulation 
(TENS) units; skin patches that only deliver heat therapy such as a ThermaCare® patch,
topical anesthetic creams, gels, or ointments (such as Lidocaine cream), or topical anesthetic 
sprays, provided they are not being administered to treat the episode of VOC.
Systemic steroid therapy used specifically for the treatment of an uncomplicated VOC is not 
permitted during the study.   However, systemic steroid use for other indications (eg, severe 
reactive airway disease) is allowed.
5.8.3. Permitted During the Study
Treatments intended for other indications may be administered as usual.  The use of inhaled 
or topical steroids, hydroxyurea, and nonsteroidal anti-inflammatory drugs (NSAIDs)will be 
allowed.  The use of medical marijuana is not excluded for the purposes of this study.  
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 49
All concomitant treatments taken during the study (1 week prior to signing or affirming 
VOC/Treatment-Ready informed assent/consent and through the last post-dose follow-up 
assessment) should be recorded in the source document and Case Report Form (CRF). All 
concomitant treatments should be confirmed and reviewed by the investigator or his/her 
designee prior to each dose for the duration of the study.  
5.8.4. Pain Management
Pain management should follow the usual standard of care considering the institution’s usual 
procedures and determined by the sickle cell disease clinical team which may include the 
hematologist, emergency medicine staff, pain specialist, hospitalist and nurse coordinator.  
Specific medications, dosing and infusion parameters should be individualized according to 
the subject’s acute pain characteristics taking into account past medical history, concomitant 
medications, concurrent clinical concerns, and protocol restrictions as noted in Section 5.8.2..  
The following suggestions are offered to standardize management:

Recommended IV pain medications include, but are not limited to, morphine, 
hydromorphone, ketorolac, or fentanyl, used in accordance with standard clinical 
practice.  Study site staff should contact Pfizer’s medical monitor when considering 
medications not included in this list;

Initial treatment should aim to achieve pain control; pain control is defined as pain 
that does not require further escalation of pain medication OR subject reports pain is 
controlled;

Ongoing treatment should aim to maintain pain control; consider weaning IV opioids 
once pain is controlled;

Patient-controlled analgesia (PCA) use (basal and bolus dosing) is encouraged for all 
subjects, per hospital procedure;

In addition to IV pain medications, subjects should receive other supportive care and 
treatments according to standard of care.  These may include, but are not limited to, 
the following:

adequate hydration per routine procedure;

incentive spirometry at regular intervals and/or other respiratory therapies
(which are highly encouraged);

supplemental oxygen

adjunctive mechanical treatments such as massage, application of heat packs, 
etc.
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)






PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 52
6.1. Screening
6.1.1. Pre-VOC/Study Entry Screening
6.1.1.1. Consent of Subjects
A written, Pfizer and institutional review board (IRB)/ ethics committee (EC)-approved, 
informed consent/assent (as appropriate) must be obtained before initiating study procedures.  
See Section 12.3.
Investigators may choose to identify, through chart review, those subjects who may be 
appropriate for the study before they develop VOC.  These subjects may be educated about 
the study
when they are well, such as in the office setting, and approached 
for consent/assent while not experiencing a pain crisis. 
After consent, subject information will be entered into the sponsor’s randomization system to 
document the subject has entered into the Pre-VOC/Study Entry Screening period.  A subject
identification number will be generated. Serious adverse events must be reported to Pfizer 
from the time of signing Pre-VOC/Study Entry informed consent.
Formal assessment for eligibility will not be performed at this time.  No blood samples will 
be collected for laboratory analysis.  The subject will not be enrolled, or randomized to a 
treatment arm at this time.  Subjects who sign consent pre-VOC may discontinue the study at 
any time. At the time of VOC, the subject will be asked if they want to continue 
participating in the VOC/Treatment-Ready Screening and if eligible, be randomly assigned to 
blinded study drug. The subject’s affirmation must be documented.
These subjects will have the option of using a transportation service to take them to and from
the hospital at the time of their crisis.
6.1.1.2. Monthly Telephone Contacts
Study site staff will be encouraged to contact the subject by telephone every 4 weeks
(7 days).  During these phone contacts, the study site staff will ask the subject how they 
have been feeling, as well as remind the subject about the appropriate procedures to follow 
when experiencing an acute VOC event necessitating hospitalization (including use of the 
transportation service provided by the sponsor).  If the subject or investigator prefer, the 
monthly contacts may be a clinic visit.  
6.1.2. VOC/Treatment-Ready Screening
6.1.2.1. Visit 1, VOC/Treatment-Ready Screening
In addition to consenting a subject in the office setting, prior to a pain crisis, some subjects 
may be initially approached for consent when presenting to the emergency room/clinic in 
VOC.  Investigators are encouraged to identify subjects with VOC who are planned or likely 
to be admitted, and approach them for consent/assent and eligibility criteria early in the 
process of treatment for VOC. 
A written, Pfizer and institutional review board (IRB)/ethics committee (EC)-approved, 
informed consent/assent (as appropriate) must be obtained before initiating study procedures.  
See Section 12.3.
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)






PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 55
10. Collect demographic information and medical history.
11. Collect Sickle Cell Disease-specific history (eg, SCD genotype, start time of this 
VOC event, medications used to treat this pain event, frequency of painful crises 
requiring hospitalization, SCD related complications such as history of ACS, 
priapism, etc).
12. Record prior and concomitant medication: all medications administered within 
1 week of signing the VOC/Treatment-Ready informed assent/consent or affirmation 
of informed consent (if applicable).  
13. Record prior and on-going parenteral opioids administered.
14. Record prior and concomitant non-drug treatments/procedures: all non-drug 
treatments/procedures administered within 1 week of signing the 
VOC/Treatment-Ready informed assent/consent or affirmation of informed consent
(if applicable).
15. Review and confirm study eligibility criteria.
16. If subject has met all eligibility criteria, enter subject information using sponsor’s 
electronic randomization system to document the subject has been enrolled and obtain 
randomization information.
If the subject is determined to be a screen failure due to inability to initiate dosing within
24 hours from the administration of the first dose of IV opioids, presence of serious infection, 
ACS, or other recent clinical events excluding the subject from participating, rescreening will
be allowed at the time of the subject’s next VOC, pending approval from the sponsor’s 
medical monitor.  All screening procedures would have to be repeated, including the consent 
process, as part of the re-screening process. 
6.2. Study Period
6.2.1. Visit 1, Day 1 – Loading Dose
All subjects should be dosed with study drug as early as possible, but the start of study drug 
dosing should be no later than 24 hours from the administration of the first dose of IV 
opioids.
At this visit, the following will be performed:
1. Record adverse events.
2. Record concomitant medications, including parenteral opioid use.  Record IV opioid 
use approximately every 4 hours for the first 48 hours from the start time of the study 
drug loading dose.
3. Record concomitant non-drug treatments/procedures.
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)












P F -0 6 4 6 0 0 3 1
B 5 2 0 1 0 0 2
Fi nal Pr ot oc ol A me n d me nt 3, 0 1 A pril 2 0 1 9
Pa ge 6 1
6. 4. P ost -Disc h ar ge F oll o w - Up Visit s
6. 4. 1. Visit 2, D a y 7 P ost- Disc h ar ge F oll o w -U p P h o ne C all
A p pr o xi matel y  7 (3 ) da ys after disc har ge, t he i n vesti gat or ( or desi g nee) will c o ntact t he 
s u bject b y tele p h o ne i n or der t o c ollect i nf or mati o n re gar di n g t he occ urre nce of a ny A Es , t he 
use of c o nc o mita nt me dicati o ns a n d treat me nts/ pr oce d ures , a n d t o re mi n d t he s u bject a b o ut 
usi n g a p pr o priate c o ntrace pti o n (if a p plica ble) a n d t he u pc o mi n g Day 3 5 P ost -Disc har ge 
F oll o w -U p visit ( N ote: If t he s u bject or i n vesti gat or prefer, t he Da y 7 P ost -Disc har ge c o ntact 
ma y  be a cli nic visit).  
 
 
6. 4. 2. Visit 3, D a y 2 1 P ost -Disc h ar ge F oll o w -U p P h o ne C all
A p pr o xi matel y  2 1 (5) da y s after disc har ge, t he i n vesti gat or ( or desi g nee) will c o ntact t he 
s u bject b y tele p h o ne i n or der t o c ollect i nf or mati o n re gar di n g t he occ urre nce of a ny A Es, t he 
use of c o nc o mita nt me dicati o ns a n d treat me nts/ pr oce d ures , a nd t o re mi n d t he s u bject a b o ut 
usi n g a p pr o priate c o ntrace pti o n (if a p plica ble) a n d t he u pc o mi n g Da y 3 5 P ost -Disc har ge 
F oll o w -U p visit ( N ote: If t he s u bject or i n vesti gat or prefer, t he Da y 2 1
P ost -Disc har ge c o ntact ma y be a cli nic visit).
6. 4. 3. Visit 4, D a y 3 5 P ost -Disc h ar ge F oll o w -U p / E arl y Ter mi n ati o n
T he f oll o wi n g acti vities are t o be perf or me d 3 5 (5) da y s after disc har ge.  H o we ver, if t he 
s u bject is e x perie nci n g a V O C or ot her ac ute S C D- relate d e ve nt, t he visit s h o ul d be dela ye d 
u ntil t he ac ute e ve nt has res ol ve d.  If t he s u bject ter mi nates fr o m t he st u d y early, t hese sa me 
pr oce d ures are t o be perf or me d n o s o o ner t ha n 2 8 da y s fr o m t he last d ose of st u d y dr u g.
1.
C o n d uct a tar gete d p h ys ical e xa m assessi n g t he f oll o wi n g at a mi ni m u m: s ki n, c hest, 
res pirat or y, car di o vasc ular, a b d o mi nal a n d m usc ul os keletal s yste ms.  Partic ular atte nti o n 
will be directe d at areas affecte d b y pai n.  A d d i t i o n a l  b o d y  s y s t e m s  m a y  b e  
e x a m i n e d  a t  t h e  d i s c r e t i o n  o f  t h e  i n v e s t i g a t o r .
2.
Rec or d a d verse e ve nts.
3.
Rec or d c o nc o mita nt me dicati o ns.
4.
Rec or d c o nc o mita nt n o n -dr u g treat me nts/ pr oce d ures.
5.
C ollect vital si g ns (te m perat ure [ Celsi us], res pirat or y rate, p ulse, bl o o d press ure, a n d 
p ulse o xi me tr y).
6.
C ollect bl o o d sa m ples f or: 

He mat ol o g y  pa nel (see Ta ble 3 ); l ocal la b orat or y;

Ser u m C he mistr y  (see Ta ble 3 ); l ocal la b orat or y;
0 9 0 1 7 7 e 1 9 1 5 d a 0 1 b\ A p pr o v e d\ A p pr o v e d O n: 1 6- J ul- 2 0 1 9 1 8: 4 4 ( G M T)






PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 64
The reason for a subject discontinuing from the study will be recorded in the CRF.  A 
discontinuation occurs when a randomized subject ceases participation in the study, 
regardless of the circumstances, prior to completion of the protocol.  The investigator must 
determine the primary reason for discontinuation.  Should a subject withdraw from the study
after receiving study drug, but prior to End of Treatment or Discharge, the subject should 
complete the procedures as per the End of Treatment visit (Visit 1, see Table 1, Schedule of 
Activities) at the time of the study discontinuation or as soon as possible thereafter.  Subjects 
withdrawn from the study after End of Treatment or Discharge should return for safety 
evaluation as per Day 35 Post-Discharge Follow-Up visit (Visit 4) no sooner than 28 days 
from the last dose of study drug.  The investigator will record the reason for study 
discontinuation, provide or arrange for appropriate follow-up for each such subject, and 
document the course of the subject’s condition.
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety or behavioral 
reasons, or the inability of the subject to comply with the protocol required schedule of study 
visits or procedures at a given study site.  In any circumstance, every effort should be made 
to document subject outcome, if possible.  The investigator should inquire about the reason 
for withdrawal, request the subject to return for a final visit, if applicable, and follow-up with 
the subject regarding any unresolved adverse events.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  All attempts to contact the subject and information received during contact attempts 
must be documented in the subject’s medical record.  In accordance with due diligence 
requirements, if a subject fails to return for scheduled visit(s), the site shall record 
information concerning attempts to contact the subject in the subject source documents, 
including method of contact (eg, letter, phone call) and date of each attempted contact.  It is 
recommended that the investigational site makes two phone calls to a subject who missed the 
visit, documenting each call in the source documents.  A third contact attempt should be a 
certified letter to the subject, and this letter and the response received become part of the 
source documents.  If a site has made at least 3 unsuccessful attempts to contact the subject
and 60 days have elapsed since discharge, the subject is considered lost to follow up (LTFU).  
Subject’s status should be designated LTFU in the CRF and in the study monitoring report.
If it is determined that the subject has died, the site will use permissible local methods to 
obtain the date and cause of death.  If after all attempts, the subject remains LTFU, then the 
last known alive date as determined by the investigator should be reported and documented 
in the subject’s medical records.  If the subject returns to the site beyond 60 days post-
discharge after having been determined to be LTFU, Visit 4, Day 35 study procedures do not 
need to be performed.  Any safety events (SAE/AEs) that occurred up to the date when the 
subject’s Visit 4, Day 35 Post Discharge should have occurred are to be recorded in both the 
medical records and the eCRF.  In addition, SAEs (including any SAEs that may have 
occurred beyond the subject’s Visit 4, Day 35 Post Discharge) will be reported as defined in 
Section 8.2 of the protocol.
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 65
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as described.  However it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test.  In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the subject.  When a protocol required test cannot be performed the 
investigator will document the reason for this and any corrective and preventive actions 
which he/she has taken to ensure that normal processes are adhered to as soon as possible.  
The sponsor study team will be informed of these incidents in a timely fashion.
7.1. Efficacy
Methods of measuring the efficacy of rivipansel in treating subjects hospitalized for acute 
VOC that will be used throughout the study are described in this section.
7.1.1. Readiness-for-Discharge Criteria
The primary endpoint is time to readiness-for-discharge, where readiness-for-discharge is 
met when all of the applicable 6 criteria are documented to have occurred – the criteria are to 
be assessed in relation to treatment for this VOC event and acute complication(s) directly 
related to this VOC event:  
1. Only oral pain medication is required.
2. Acute complications related to VOC (such as ACS, stroke, priapism) have resolved to 
the extent that management can be in an outpatient setting, if applicable.
3. IV opioids have been discontinued.
4. IV hydration has been discontinued, if applicable.
5. IV antibiotics have been discontinued, if applicable.
6. RBC transfusion is no longer required for the treatment of this VOC, if applicable.
Refer to the current version of the Readiness-for Discharge Assessments guidance document 
for examples and further information.   
All criteria will be assessed by a member of the study site staff who will complete the 
readiness-for-discharge questionnaire in the eClinRO web-based data capture system, and
enter data in the eCRFs (as appropriate). Once criteria 1 and/or 2 are met, they must be 
confirmed by the Investigator or qualified designee in the eClinRO web-based data capture
system.  The Investigator or qualified designee should be deemed, according to the 
institution’s standard of care, appropriately qualified to determine discharge readiness and 
could be a physician, nurse practitioner, physician assistant, or other medical personnel.  To 
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 66
clarify, if criteria 1 and/or 2 are determined to be met by a member of the study site staff 
other than the Investigator or qualified designee, then the Investigator or qualified designee 
must confirm that assessment in the eClinRO web-based data capture system prior to the time 
the next scheduled assessment is to be made, or the time the subject is discharged, whichever 
comes first.  Confirmation in the eClinRO web-based data capture system will also be 
required if there is a reversal in subsequent assessments of criteria 1 or 2.  The Investigator or 
qualified designee will be notified in real-time via the eClinRO system whenever criteria 
3 through 6 are noted to have been met by the assessor in the system.  Site-staff will ensure 
that relevant data corresponding to criteria 3 through 6 are entered into the eCRF in a timely 
manner based on the subject’s medical records.
The readiness-for-discharge criteria will be assessed in all subjects at pre-defined intervals 
(and ad hoc as necessary) from the start time of the loading dose until discharge.  Routine 
assessments are to be performed during “daytime hours” only (defined as 6:01am to 
10:00pm).  Assessments are not to be performed during “night-time hours” (defined as 
10:01pm to 6:00am), unless it becomes apparent that the subject has become 
ready-for-discharge during the “night-time hours”, in which case an ad hoc assessment 
should be undertaken.  If all readiness-for-discharge criteria are confirmed to be met prior to 
the discharge order being issued, and there are no reversals of the readiness-for-discharge 
status, further evaluations are not required to be documented in the eClinRO system
following the time of the discharge order.  However, all subjects should be followed until 
they have left the hospital (i.e., even after the discharge order is issued) to ensure there are no 
subsequent updates required to the readiness-for-discharge evaluation in the eClinRO system.
The schedule of readiness-for-discharge assessments may be different for the day the study 
drug loading dose is administered than for subsequent days.  The details around the 
difference in these schedules are as follows: 
If a subject receives their loading dose during the “daytime hours”, 
readiness-for-discharge assessments for that day will be performed every 4 (±1) hours 
from the start time of the loading dose until 10:00pm.  At 10:00pm (±1 hour) an 
assessment will be performed, signaling the end of the “daytime hours” and the start 
of the “night-time hours”.  The next routine assessment will then be at 6:01am (±1 
hour) the following morning, signaling the start of the “daytime hours” for that day.  
The schedule will then be reset such that, further assessments will be performed at 4 
(±1) hourly intervals until 10:00pm (±1 hour) that night and this schedule of 
assessments (6:01am, 10:00am, 2:00pm, 6:00pm and 10:00pm, each ±1 hour) will 
continue for all subsequent days of Visit 1, until the subject is discharged from the 
hospital.  
If a subject receives their loading dose during the “night-time hours” then the first 
routine assessment of readiness-for-discharge will be at 6:01am (±1 hour) at the end 
of the “night-time hours” and the start of the “daytime hours”.  Further assessments 
will then be performed at 4 (±1) hourly intervals until 10:00pm (±1 hour) that night 
and this schedule of assessments (6:01am, 10:00am, 2:00pm, 6:00pm and 10:00pm, 
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 67
each ±1 hour) will continue for all subsequent days of Visit 1, until the subject is 
discharged from the hospital.   
In addition, an assessment should always be made at the time the decision is made to 
discharge the subject, regardless of the hour. 
If the subject is asleep during “daytime hours” and IV opioids have not yet been 
discontinued, the subject does not have to be woken to perform the assessment as this can be 
undertaken while the subject remains asleep.  However, if IV opioids have been discontinued 
then it may be necessary to wake the subject to determine the answer to Question 1 (Only 
oral pain medication is required?).
The study site staff, including the investigator (or qualified designee), will use an electronic 
device (eg, smart phone, tablet, or computer) to access the eClinRO web -based data capture 
system to record and confirm responses to the criteria in the readiness-for-discharge 
questionnaire. Example screen shots of the readiness-for-discharge questionnaire are 
included in the eClinRO reference document.  
If the study site staff attempts, but is unable to complete the readiness-for discharge 
questionnaire in the eClinRO system, a back-up data capture method will be utilized as 
outlined in the Readiness-for-Discharge Assessments guidance document.
If a subject did not receive any IV hydration, IV antibiotics or RBC transfusions, or had no 
acute complications related to VOC, then these criteria will not affect the  determination of 
the primary endpoint (ie, they are not applicable).
The derivation of the primary endpoint of time to readiness-for-discharge makes use of the 
dates and times when each of the individual criteria are met. In this derivation:

For criteria 1 , the earliest date and time of “yes” reported by assessor and confirmed 
by the Investigator or qualified designee after the last “no” response recorded in the 
eClinRO web-based data capture system will be used.

For criteria 2 , the earliest date and time of “yes” reported by assessor and confirmed 
by the Investigator or qualified designee after the last “no” response, or a confirmed 
“not applicable” response, in the eClinRO web-based data capture system will be 
used.

For criteria 3 through 6, the latest stop date and time in the corresponding eCRF will 
be used.  
After the date and time are determined as above for each of the applicable criteria, the date 
and time of readiness-for-discharge is defined as the latest of the dates and times among the 
applicable criteria.
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)








P F -0 6 4 6 0 0 3 1
B 5 2 0 1 0 0 2
Fi nal Pr ot oc ol A me n d me nt 3, 0 1 A pril 2 0 1 9
Pa ge 7 1
7. 2. 1. P h ysic al E x a mi n ati o n
A c o m plete p h ys ical e xa mi nati o n will be perf or me d at t he V O C/ Treat me nt-Rea d y S cree ni n g
visit (see Ta ble 1 , Sc he d ule of Acti vities).  T he f oll o wi n g para meters a n d b o d y sys te ms will 
be assesse d a n d a n y a b n or malities descri be d: ge neral a p peara nce, s ki n, hea d, ears, e y es, n ose, 
m o ut h, t hr oat, s pi ne, nec k, t h yr oi d, c hest, res pirat or y, car di o vasc ular , a b d o mi nal (i ncl u di n g 
li ver a n d ki d ne ys), m usc ul os keletal, e xtre mities, ne ur ol o gical, ge nit o uri nar y a n d l ym p h 
n o des.   Partic ular atte nti o n will be directe d at areas affecte d b y  pai n as well as t o t he 
res pirat or y sys te m f or cli nical si g ns of A C S s uc h as c hest wall pai n, tac h y p nea a n d w heezi n g 
or rales o n c hest a usc ultati o n a n d t he ge nit o uri nar y s ys te m f or cli nical si g ns of pria pis m.
A t ar gete d p h ys ical e xa mi nati o n will be perf or me d dail y  w hile t he s u bject is i n t he h os pital
t hr o u g h 2 4 h o urs after t he last d ose of st u d y  dr u g (if n ot disc har ge d first), at disc har ge, a n d at 
D a y  3 5 P ost -Disc har ge F oll o w -U p visit ( Visit 4) (see Ta ble 1 Sc he d ule of Acti vities ) 
assessi n g t he f oll o wi n g at a mi ni m u m : s ki n, c hest, res pirat or y, car di o vasc ular, a b d o mi nal a n d 
m usc ul os keletal e xa mi nati o ns.  Partic ular atte nti o n will be directe d at areas affecte d b y pai n.  
A d d i t i o n a l  b o d y  s y s t e m s  m a y  b e  a s s e s s e d a t  t h e  d i s c r e t i o n  o f  t h e  
i n v e s t i g a t o r .
7. 2. 2. Vit al Si g ns
Te m perat ure, res pirat or y  rate, p ulse, bl o o d press ure, a n d p ulse o xi me tr y will be c ollecte d 
t hr o u g h o ut t he st u dy at t he V O C/ Treat me nt -Rea d y  Scree ni n g visit , dail y w hile t he s u bject is 
i n t he h os pital, a n d at Da y 3 5 P ost -Disc har ge F oll o w -U p visit ( Visit 4) (see Ta ble 1 Sc he d ule 
of Acti vities) .
Te m perat ure will be c ollecte d as oral, t y m pa nic, te m p oral, or a xillar y  te m perat ure meas ure d 
i n de grees Celsi us.  Sites are e nc o ura ge d t o use t he sa me met h o d t hr o u g h o ut t he st u d y.
Bl o o d press ure s h o ul d be meas ure d i n t he s u bject’s d o mi na nt ar m a n d rec or de d t o t he nearest 
m m H g.  Sites are e nc o ura ge d t o use t he sa me ar m t hr o u g h o ut t he st u d y .  All bl o o d press ure 
s h o ul d be meas ure d c o nsiste ntl y t hr o u g h o ut t he st u d y wit h t he s u bject i n a s u pi ne p ositi o n or 
i n a sitti n g p ositi o n, de pe n di n g o n t he s u bject’s cli nical stat us. 
T he use of a ut o mate d de vices f or meas uri n g bl o o d press ure a n d p ulse rate are acce pta ble, 
alt h o u g h, w he n d o ne ma n uall y , p ulse rate will be meas ure d i n t he brac hial/ra dial arter y f or at 
least 3 0 sec o n ds.  W he n t he ti mi n g of t hese meas ure me nts c oi nci des wit h a bl o o d c ollecti o n, 
bl o o d press ure a n d p ulse rate s h o ul d be o btai ne d first.
Wei g ht is t o be meas ure d i n kil o gra ms. 
Hei g ht is t o be meas ure d i n ce nti meters a n d rec or d e d t o o ne deci mal place usi n g a 
sta di o meter, if a vaila ble.  T he hei g ht s h o ul d be meas ure d wit h t he s u bject n ot weari n g s h oes.  
If necessar y, hei g ht ca n be meas ure d w hile s u bject is l yi n g d o w n.
P ulse o xi me tr y will be meas ure d wit h a p ulse o xi me ter a n d re p orte d as a perce nt ( use of 
o x y ge n s u p ple me ntati o n will als o be rec or de d) . 
0 9 0 1 7 7 e 1 9 1 5 d a 0 1 b\ A p pr o v e d\ A p pr o v e d O n: 1 6- J ul- 2 0 1 9 1 8: 4 4 ( G M T)


P F -0 6 4 6 0 0 3 1
B 5 2 0 1 0 0 2
Fi nal Pr ot oc ol A me n d me nt 3, 0 1 A pril 2 0 1 9
Pa ge 7 2
7. 2. 3. Cli nic al L a b or at or y E v al u ati o n
Bl o o d a n d uri ne sa m ples will be c ollecte d at eac h s pecifie d st u d y visit (see Ta ble 1 , Sc he d ule 
of Acti vities) .  U nsc he d ule d cli nical la bs ma y be o btai ne d at a ny ti me d uri n g t he st u d y t o 
assess a n y percei ve d safet y  c o ncer ns or i n acc or da nce wit h t he g ui deli nes f or s u bject safet y 
m o nit ori n g a n d disc o nti n uati o n.  Cli nicall y  si g nifica nt a b n or mal fi n di n gs s h o ul d be rec or de d 
as A Es per Secti o n 8. 5 .
T he f oll o wi n g la b orat or y tests will be perf or me d l ocall y d uri n g t he st u d y at t he 
V O C/ Treat me nt -Rea d y  Scree ni n g visit, E n d of Treat me nt, a n d t he Da y  3 5 P ost -Disc har ge 
F oll o w -U p visit :
T a ble 3.
Cli nic al L a b or at or y E v al u ati o ns – L oc al L a b or at or y
H e m at ol o g y
   H e m o gl o bi n
   Retic ul oc yte c o u nt
   H e m at ocrit
   Platelet c o u nt
   R e d bl o o d cell ( R B C ) c o u nt
   W B C c o u nt wit h differe ntial
Ser u m C he mistr y
   B l o o d  u r e a  n i t r o g e n ( B U N )
   A l a n i n e  a m i n o t r a n s f e r a s e ( A L T / S G P T )
   C r e a t i n i n e
   A s p a r t a t e  a m i n o t r a n s f e r a s e ( A S T / S G O T )
   E l e c t r o l y t e s  ( S o di u m, P otassi u m, C hl ori de 
a n d    
       Bicar b o nate) w i t h  g l u c o s e
   F r a c t i o n a t e d  b i l i r u b i n
   L a c t a t e  d e h y d r o g e n a s e  ( L D H )
   
Uri n al ysis
   Pr otei n
   Bl o o d
   Gl uc ose
   Nitrite
   Ket o nes
   L e u k o c y t e  e s t e r a s e
Esti m ate d Gl o mer ul ar Filtr ati o n R ate (e G F R) at V O C/ Tre at m e nt -Re a d y Scree ni n g visit ( calc ulate d 
usi n g a ge a p pr o priate f or m ula i n A p pe n di x 1 )
N ote: A h e m o gl o bi n electr o p h oresis sa m ple will be c ollecte d at t he V O C/ Treat me nt -Rea d y
Scree ni n g visit a n d a nal yze d at t he ce ntral la b orat or y o nl y if t he s u bject’s dia g n osis 
(ie, la b orat or y res ult by he m o gl o bi n electr o p h oresis, H P L C, or ge n ot y pe a nal y sis) ca n n ot be 
s o urce d oc u me nte d.
7. 2. 4. Tri g gere d Re q uire me nts
T his secti o n prese nts s pecific safet y  para meters of c o ncer n f or t he st u d y dr u g t hat re q uire 
f oll o w-u p acti o n.
T a ble 4.
Tri g gere d Re q uire me nts
C o n diti o n
Acti o n
C h a n ges i n Re n al F u ncti o n
      If t he re peat e G F R res ult is 6 0 m L/ mi n/ 1. 7 3 m 2
St o p st u d y dr u g a d mi nistrati o n
Se vere Ac ute C hest S y n dr o me (Secti o n 7. 2. 4. 2. 1 )
St o p st u d y dr u g a d mi nistrati o n
Se vere C ut a ne o us M a nifest ati o ns (Secti o n 7. 2. 4. 3. 1 )
St o p st u d y dr u g a d mi nistrati o n
0 9 0 1 7 7 e 1 9 1 5 d a 0 1 b\ A p pr o v e d\ A p pr o v e d O n: 1 6- J ul- 2 0 1 9 1 8: 4 4 ( G M T)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 73
7.2.4.1. Changes in Renal Function
The identification of deteriorating renal function could be based on rising serum creatinine or 
blood urea nitrogen (BUN), worsening proteinuria, or other abnormalities on urinalysis (with 
or without microscopic evaluation), or a change in clinical features (such as changes in urine 
output or physical findings such as pedal edema).  Based on the clinical judgment of the 
investigator if any of these or other clinical features develop, the eGFR is to be repeated
(refer to Appendix 1 for calculation).  Given that subjects are eligible to participate in this 
study if their eGFR is >60 mL/min/1.73 m2, if the repeat eGFR is 
60 mL/min/1.73 m2 treatment is to be stopped.
7.2.4.2. Acute Chest Syndrome Events
For the purposes of this protocol, ACS will be defined by NIH treatment guidelines24,25 as 
follows:

New pulmonary infiltrate involving at least one complete lung segment consistent 
with the presence of alveolar consolidation, (excluding atelectasis) AND one or more 
of the following:
a.
Chest pain;
b. Temperature >38.5C;
c.
Tachypnea;
d. Wheezing or rales;
e.
Cough.
Note: the clinical signs and symptoms of ACS were updated in the NIH Evidence-Based 
Management of Sickle cell Disease: Expert Panel Report (2014), however, for the purposes 
of this protocol the above definition will continue to be used29  
Subjects will be monitored for development of ACS throughout the study.  The identification 
of ACS will be made by the study site staff and communicated to Pfizer or designee.  Clinical 
events that might represent ACS may be identified by the Pfizer Study Team or designee 
during the review of subject data listings or by site monitors during routine monitoring of 
subject study records.  The Pfizer study team will notify the study site staff if they identify a
potential ACS event that has not been reported by the site.  All reported cases of potential 
ACS that occur from the time of the subject’s first dose of study drug through the subject’s
last visit will be evaluated by the Acute Chest Syndrome Safety Endpoint Adjudication 
Committee (ACS-SEAC; see Section 9.7.1).
The Pfizer Study Team or designee will provide a listing of specific documents needed to 
support ACS event adjudication by the ACS-SEAC.  Obtaining the documentation will be the 
responsibility of the study site staff.  ACS event documentation will include, but is not 
limited to any of the following: daily hospital/clinic notes and physical examination 
documentation, hospital discharge summaries, operative and procedural reports, chest x-rays, 
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 74
vital signs including oximetry, laboratory reports and results of other diagnostic tests, 
autopsy reports and death certificate information.
7.2.4.2.1. Severe ACS (Withdraw from Study Drug Administration) 
For the purposes of this protocol, severe acute chest syndrome is defined as an ACS 
diagnosis as above (Section 7.2.4.2), and the requirement for at least one of the following:

ICU Transfer;

Mechanical ventilation;

Oxygen requirement of >50% FiO2, or the use of high flow oxygen delivery system, 
or bilevel positive airway pressure (BiPAP) or continuous positive airway pressure
(CPAP).
Subjects that develop severe ACS are to be terminated from study drug administration.  
Subjects that develop mild or moderate cases of ACS may continue to receive treatment with 
study drug.
7.2.4.3. Cutaneous Manifestations
The identification of cutaneous manifestations and acute skin rashes will be made by the 
study site staff and communicated to Pfizer or designee.  Clinical events of cutaneous 
manifestations and/or acute skin rashes may also be identified by the Pfizer Study Team or 
designee during the review of subject data listings or by site monitors during routine 
monitoring of subject study records.  The Pfizer study team will notify the study site staff if 
they identify a potential event that has not been reported by the study site staff.  All cases of 
cutaneous manifestations and acute skin rashes that develop from the time of the subject’s 
first dose of study drug through the subject’s last visit will be independently evaluated by the 
Cutaneous Manifestations Safety Endpoint Adjudication Committee (CM-SEAC; see Section 
9.7.2) to determine if they constitute severe and/or generalized cutaneous events. 
A dermatologic evaluation of severe and/or generalized acute skin rashes should be 
undertaken locally.  Evaluation of less severe cases should also be undertaken where feasible.  
A biopsy should be considered based upon this dermatologic evaluation. For severe and/or 
generalized cutaneous reactions and any reactions that are considered “unexpected” or 
unusual, photographs should be obtained per instructions provided in a separate study manual
and differential blood count and serum aminotransferase assays performed.   Photographs 
and blood samples are strongly encouraged at the time of the event in cases of mild or 
transient cutaneous manifestations (eg, mild and transient allergic reactions or exacerbation 
of pre-existing conditions such as eczema).
The Pfizer Study Team or designee will provide a list of specific documents needed to 
support rash adjudication by the CM-SEAC.  Obtaining the documentation will be the 
responsibility of the study site staff.  Rash event documentation will include, but is not 
limited to any of the following: photographs, hospital discharge summaries including 
dermatologic evaluation at the time of rash, operative reports, pathology reports of biopsy (if 
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)
















PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 82
serious adverse event (SAE) requiring immediate notification to Pfizer or its designated 
representative.  For all AEs, sufficient information should be obtained by the investigator to 
determine the causality of the AE.  The investigator is required to assess causality.  
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious adverse event 
that is determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  
To assist in the determination of case seriousness further information may be requested from 
the investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the subject or subject’s parent(s)/legal guardian/legally acceptable 
representative provides informed consent/assent (either Pre-VOC/Study Entry consent or 
VOC/Treatment-Ready consent depending on the subject’s entry point into the study), which 
is obtained prior to the subject’s participation in the study, ie, prior to undergoing any 
study-related procedure and/or receiving study drug, through and including the subject’s last 
visit or 28 calendar days after the last administration of the study drug, whichever is longer.  
Serious adverse events occurring to a subject after the active reporting period has ended 
should be reported to the Sponsor if the investigator becomes aware of them; at a minimum, 
all serious adverse events that the investigator believes have at least a reasonable possibility 
of being related to study drug are to be reported to the Sponsor.
AEs (serious and non-serious) should be recorded on the CRF from the time the subject has 
taken at least one dose of study drug through the subject’s last visit.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 83
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.4. Medication Errors
Medication errors may result, in this study, from:

Incorrect route of administration;

Administration of expired study drug;

Administration of the wrong product;

Administration to the wrong subject;

Administration at the wrong time;

Administration at the wrong dosage strength;

Administration of incorrect dose of study drug;

Administration of study drug 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 for use.
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF which is a specific version of the AE page, and on the SAE form when 
appropriate.  In the event of medication dosing error, the sponsor should be notified 
immediately.
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 84
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the study drug;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page
and, if applicable, any associated adverse event(s) is captured on an AE CRF page.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms; and/or

Test result requires additional diagnostic testing or medical/surgical intervention;
and/or

Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment, or other therapy; and/or

Test result is considered to be an AE by the investigator or the sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 85
the subject or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.6.1. Protocol-Specified Serious Adverse Events 
Unless the investigator believes that there is a causal relationship between study drug and the 
event specified below, this event should not be reported by the investigator as an SAE as 
described in the Serious Adverse Event Reporting Requirements section of this protocol.  
However, this event should still be captured as an AE in the CRF if it meets reporting 
requirements detailed in Section 8.2.
The protocol-specified event that will not normally be reported in an expedited manner: 

The initial, uncomplicated VOC prompting entry into Treatment- Ready 
Screening.  Note: If a subject signs Pre-VOC consent and has a VOC requiring 
hospitalization, but does not enter into Treatment-Ready Screening, the VOC is to 
be reported as an SAE.  In addition, for all subjects, any re-hospitalization for 
VOC occurring during the safety follow-up period is to be reported as an SAE. 
Should an aggregate analysis indicate that these prespecified events occur more frequently 
than expected based on the expectation of frequency of the event(s) in question in the 
population for comparison, eg, based on epidemiological data, literature, or other data,  then 
this will be submitted and reported in accordance with Pfizer’s safety reporting requirements.  
Aggregate analysis of safety data will be performed on a regular basis per internal standard 
operating procedures.
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s Law cases) and should always be considered 
important medical events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions.  Subjects who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Subjects with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT 3 times the upper limit of normal (×
ULN) concurrent with a total bilirubin 2 × ULN with no evidence of hemolysis and 
an alkaline phosphatase 2 × ULN or not available;
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 86

For subjects with preexisting ALT OR AST OR total bilirubin values above the 
ULN, the following threshold values should be used in the definition mentioned 
above:

For subjects with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT values 2 times the baseline values and 3 × ULN, or 
8 × ULN (whichever is smaller).
Concurrent with:

For subjects with pre-existing values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 × ULN or
if the value reaches ≥3 × ULN (whichever is smaller).
The subject should return to the investigational 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, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/international normalized ratio (INR), and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug, and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced person, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure, should be collected.  
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) 
may be warranted.  All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for liver function test (LFT) abnormalities identified at 
the time should be considered potential Hy’s Law cases irrespective of availability of all the 
results of the investigations performed to determine etiology of the abnormal LFTs.  Such 
potential Hy’s Law cases should be reported as SAEs.
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 87

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, 
clinical AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
work-up of persistent pre-treatment lab abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical exam);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Pre-planned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.8. Severity Assessment
If required on the AE CRFs, the investigator will use the adjectives MILD, MODERATE, 
or SEVERE to describe the maximum intensity of the AE.  For purposes of consistency, 
these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 88
subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the serious adverse reporting requirements 
if applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the study drug caused or contributed to an AE; generally 
the facts (evidence) or arguments to suggest a causal relationship should be provided.  If the 
investigator does not know whether or not the study drug caused the event, then the event 
will be handled as “related to study drug” for reporting purposes, as defined by the Sponsor 
(see the Section on Reporting Requirements).  If the investigator's causality assessment is 
"unknown but not related to study drug", this should be clearly documented on study records. 
In addition, if the investigator determines an SAE is associated with study procedures, the 
investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the study drug; or 
the female becomes or is found to be pregnant after discontinuing and/or being 
exposed to the study drug; 
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
2. A male has been exposed (eg, because of treatment or environmental exposure) to the 
study drug prior to or around the time of conception and/or is exposed during his 
partner’s pregnancy.
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the study drug, the investigator must submit this information 
to the Pfizer Drug Safety Unit on an SAE report form and an EDP supplemental form, 
regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
subject reports that she is pregnant and has been exposed to a cytotoxic product by inhalation 
or spillage) using the EDP supplemental form.  This must be done irrespective of whether an 
AE has occurred and within 24 hours of awareness of the exposure. The information 
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 89
submitted should include the anticipated date of delivery (see below for information related 
to termination of pregnancy).
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 Pfizer of the outcome as a follow up 
to the initial EDP supplemental form.  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).
If the outcome of the pregnancy meets the criteria 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 intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

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 
serious adverse events when the investigator assesses the infant death as related or 
possibly related to exposure to the study drug.
Additional information regarding the EDP may be requested by the investigator.  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 study subject with the Pregnant Partner Release of Information 
Form to deliver to his partner. The Investigator must document in the source documents that 
the subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.11. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
Investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a subject enrolled in the study, 
the information is not reported on a CRF, however a copy of the completed SAE report form 
is maintained in the investigator site file.
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 90
8.12. Withdrawal Due to Adverse Events (See Also the Section on Subject Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.
When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject/parent(s)/legal guardian/legally acceptable representative.  In addition, each 
study subject/parent(s)/legal guardian/legally acceptable representative will be questioned 
about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 91
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.
As noted in the Protocol-Specified Serious Adverse Events section, should an investigator 
judge the identified protocol-specified SAE to have a causal relationship with the study drug 
the investigator must report the event to the sponsor within 24 hours of investigator 
awareness, even if that event is a component of the endpoint.
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This timeframe also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of EDP, exposure via breastfeeding, and 
occupational exposure cases. 
In the rare event that the investigator does not become aware of the occurrence of an SAE
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his/her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the timeframes for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or illnesses must be provided.  In the case of a subject death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
8.14.2. Non-Serious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities
Adverse event reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations.
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)






PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 94
9.2.1. Analysis of Primary Endpoint 
The primary endpoint is time to readiness-for-discharge from the hospital.  Time to 
readiness-for-discharge is defined as the difference between the readiness-for-discharge date 
and time (see Section 7.1.1 for detail) and the start date and time of the first infusion of study 
drug in hours. 
Below are examples of scenarios where subjects receive an infusion of study drug but do not 
meet the primary endpoint criteria: 

If one or more applicable criteria are not met for a subject before the subject is 
discharged or are missing, then the time to readiness-for-discharge will be treated as 
censored.  If a subject dies in the hospital before all criteria are met, then the time to 
readiness-for-discharge will be treated as censored.

If a subject is not hospitalized and prematurely terminates from the study before all 
criteria are met, the time to readiness-for-discharge will be treated as censored.If a 
subject is randomized but not infused with study drug, the time to 
readiness-for-discharge will be defined as the time from randomization to the time of 
the subject’s termination and will be treated as censored.
Details on censoring rules for the time to readiness-for-discharge are provided in the SAP.
The primary analysis will be performed using the Cohort 1 and Cohort 2 populations 
combined, as well as Cohort 1 and Cohort 2 populations separately.  The primary analysis to 
test the difference between the rivipansel and placebo groups will utilize a stratified log-rank 
test where the stratifications are age group (Cohort 1 and Cohort 2 combined or Cohort 1 
only) and genotype, For Cohort 2, a log-rank test stratified by genotype will be performed.
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)






PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 97
9.4. Safety Analysis
The safety data (eg, AEs, SAEs, physical exams, laboratory tests, vital signs) will be 
summarized in accordance with the Clinical Data Interchange Standards Consortium 
(CDISC) and Pfizer Standards (CaPS).  Safety data that will be specifically summarized 
include:

Adverse events according to CaPS;

Safety laboratory tests according to CaPS;

Physical exams and vital signs assessments according to CaPS;

Incidence of adjudicated ACS and incidence of adjudicated severe and/or generalized 
cutaneous manifestations analyzed using exact methods.

Percent of subjects re-hospitalized for VOC within 7, 14 and 30 days of discharge
analyzed using exact methods.
The safety analysis set will be all subjects who receive at least one infusion of study drug.
9.5. Interim Analysis
An E-DMC will review unblinded safety data on a regular basis.  In addition, the study was
designed to have a possible interim futility analysis for Cohort 1 after 150 subjects in Cohort 
1 had completed the study.  No interim analysis was planned for Cohort 2.  The conditional 
power would have been used for the futility decision-making  to maintain the overall nominal 
significance level for the final efficacy analysis at 0.05 (2-sided test).
If an interim analysis for futility were conducted, the details of the objectives, decision 
criteria and method of maintaining the study blind as per Pfizer’s SOPs would have been
documented and approved in an E-DMC charter and the detailed analysis plan documented 
and approved in a SAP.
9.6. Data Monitoring Committee 
This study will use an External Data Monitoring Committee (E-DMC).  The E-DMC will be 
responsible for ongoing monitoring of safety of subjects in the study according to the 
Charter.  The E-DMC will include members, external to the Sponsor, with expertise in the 
clinical management of adult and pediatric SCD patients, statistics, or clinical pharmacology.  
The E-DMC will receive safety summaries and subject listings presented by masked 
treatment groups but will have the option to review fully unblinded safety data and/or 
efficacy data if necessary.  
The E-DMC will review accumulating data from this study on a regular basis, at least every 
6 months and particular focus will be placed upon evaluation of the pediatric safety data.  
The initial data review meeting will occur after the first 6 pediatric subjects (6-11 years of 
age) have completed the study, or approximately 6 months after first subject first visit 
(FSFV), whichever comes first.  An additional review of subjects 6-11 years of age will 
occur after 12 of these subjects have completed the study.  The sponsor and the E-DMC can 
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)




PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 99
adjudicate the events.  Further information about the adjudication process can be found in the 
CM-SEAC charter, including a specific description of the scope of responsibilities, a plan 
where communication timelines are defined, and the exact process and definitions used by 
the committee to adjudicate the safety events.
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs is accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.
The study site may be subject to review by the Institutional Review Board (IRB)/Ethics 
Committee (EC), and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
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 is devoted to the 
process.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic / original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the hospital's or the physician's subject chart.  In 
these cases data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigator’s site as well as at Pfizer and clearly 
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)




PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 101
retained by the investigator according to International Council for Harmonisation (ICH), 
according to local regulations, or as specified in the Clinical Study Agreement (CSA), 
whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
Study sites will retain 
 eClinRO records as required under their contracts with 
Pfizer and the Investigator Initiation Package.  These records will include archives of clinical 
data and study documentation to be sent to them by the 
eClinRO vendor.  The study 
sites will review the contents of 
 eClinRO archives when they are first provided by 
the 
eClinRO vendor.  Once the sites have determined that the archived data is 
complete and accurate, they will send signed acknowledgement forms to the Pfizer study 
team.
Pfizer will retain records of the design, development, testing, rollout, maintenance and close 
out of 
eClinRO and store such records per the relevant SOPs.  Pfizer will also retain 
the acknowledgement forms sent by the study sites regarding their archives per the relevant 
SOPs.
12. ETHICS
12.1. Institutional Review Board (IRB)/Ethics Committee (EC)
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent/assent documents, and other relevant documents, eg,
recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the Investigator File.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 2008). 
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 102
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where
required by laws, or as requested by government agencies including the Centers for Medicare 
and Medicaid Services.
With the exception of
 data requested by government agencies including the Centers 
for Medicare and Medicaid Services, when study data 
 are compiled for 
transfer to Pfizer and other authorized parties, subject names, addresses, and other 
identifiable data will be replaced by a numerical code consisting of a numbering system 
provided by Pfizer in order to de-identify study subjects. The study site will maintain a 
confidential list of subjects who participated in the study linking their numerical code to the 
subject’s actual identity.  In case of data transfer, Pfizer will maintain high standards of 
confidentiality and protection of subject personal data consistent with applicable privacy 
laws, and requirements of government agencies including the Centers for Medicare and 
Medicaid Services.
The informed consent/assent documents must be in compliance with ICH GCP, local 
regulatory requirements, and legal requirements, including applicable privacy laws.
The informed consent/assent documents used during the informed consent process must be 
reviewed by the sponsor, approved by the IRB/EC before use, and available for inspection.
The investigator must ensure that each study subject, or his/her legally acceptable
representative, or parent(s) or legal guardian if a minor, is fully informed about the nature 
and objectives of the study and possible risks associated with participation. 
Prior to any screening procedures, at the Pre-VOC/Study Entry Screening and/or 
VOC/Treatment-Ready Screening, the study will be thoroughly explained to the subject’s 
parent/legally acceptable representative and/or the subject.  If the subject wishes to 
participate in the study and, if appropriate, the parent/legally acceptable representative also
desires the subject to participate in the study, an IRB/EC-approved informed consent will be 
signed and dated by the subject or the legally acceptable representative, before any screening 
procedures are performed that are specific to the study.  
Whenever consent is obtained from a subject’s legally acceptable representative/parent(s) or 
legal guardian, the subject’s assent (affirmative agreement) must subsequently be obtained 
when the subject has the capacity to provide assent, as determined by the IRB/EC.  If the 
investigator determines that a subject’s decisional capacity is so limited he/she cannot 
reasonably be consulted, as permitted by the IRB/EC and consistent with local regulatory and 
legal requirements, then the subject’s assent may be waived with source documentation of 
the reason assent was not obtained.  If the study subject does not provide his/her own 
consent, the source documents must record why the subject did not provide consent (eg, 
minor, decisionally impaired adult), how the investigator determined that the person signing 
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 103
the consent was the subject’s legally acceptable representative, the consent signer’s 
relationship to the study subject (eg, parent, spouse) and that the subject’s assent was 
obtained, or waived.  If assent is obtained verbally it must be documented in the source 
documents. The signed documents will be retained at the site and the investigator must 
document in the source documents that informed consent and assent were obtained. 
The Investigator will need to make the determination as to whether or not the potential 
subject receiving IV opioids is capable of understanding the information in the consent 
document.  If not, the subject will need a legally acceptable representative to consent on the 
subject’s behalf.  The determination of capacity to consent should be documented in the 
source records.
In determining which potential subjects are capable of providing assent, the Investigator 
and/or IRB/EC should take into account the age, maturity, and psychological state of the 
potential subjects. The American Academy of Pediatrics advises that assent usually should 
be obtained from all subjects with an intellectual age of 7 years or more. 
If a subject signed assent for a study, consent must be signed once the subject turns legal age, 
based on local requirements.  If the minor subject reaches the age of majority during the 
study, as recognized under local law, they must be re-consented as adults to remain in the 
study.  If the enrollment of ‘emancipated minors’ is permitted by the study, the IRB/EC, and 
local law, they must provide documentation of legal status to give consent without the 
permission of a parent or legal guardian.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the subject's legally acceptable representative, parent(s) or legal 
guardian and the subject’s assent, when applicable, before any study-specific activity is 
performed, unless a waiver of informed consent has been granted by an IRB/EC. The 
investigator will retain the original of each subject's signed consent/assent document.
12.4. Subject Recruitment
Advertisements and patient-centric engagement tools and activities approved by ethics 
committees and investigator databases may be used as recruitment procedures.  To facilitate 
possible logistical burdens for subjects, transportation services will be made available to 
subjects to and from study visits.
12.5. 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 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the study drug, 
Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 104
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in all Participating Countries
End of Trial in all participating countries is defined as the Last Subject Last Visit. 
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue development of rivipansel at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) within 1 week.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.
In all cases, study results are reported by Pfizer 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
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
Primary completion date is defined as the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the primary completion date for studies in adult populations or 
within 6 months of the primary completion date for studies in pediatric populations.
www.pfizer.com
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 105
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer has no objection to publication by Investigators of any information collected or 
generated by Investigators, whether or not the results are favorable to the Investigational 
Drug. However, to ensure against inadvertent disclosure of Confidential Information or 
unprotected Inventions, Investigators will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
Investigators will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) to Pfizer 
at least 30 days before they are submitted for publication or otherwise disclosed. If any 
patent action is required to protect intellectual property rights, Investigators agree to delay 
the disclosure for a period not to exceed an additional 60 days.
Investigators will, on request, remove any previously undisclosed Confidential Information 
(other than the Study results themselves) before disclosure.
If the Study is part of a multi-center study, Investigators agree that the first publication is to 
be a joint publication covering all centers. However, if a joint manuscript has not been 
submitted for publication within 12 months of completion or termination of the Study at all 
participating sites, Investigators are free to publish separately, subject to the other 
requirements of this Section.
For all publications relating to the Study, Institutions will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement.
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 106
16. REFERENCES
1.
Centers for Disease Control and Prevention Sickle Cell Disease homepage. Available 
at: http://www.cdc.gov/ncbddd/sicklecell/data.html. Accessed February 12, 2014.  
2.
Davis H, Roscoe M, Moore J, et al. Cost of hospitalizations associated with sickle cell 
disease in the US. Public Health Rep. 1997;112:40-3.
3.
Stuart MJ, Nagel RL. Sickle-cell disease. Lancet. 2004;364:1343-60.
4.
Frenette PS, Atweh GF. Sickle cell disease: old discoveries, new concepts, and future 
promise. J Clin Invest. 2007;117:850-8.
5.
Platt OS, Thorington BD, Brambilla DJ, et al. Pain in sickle cell disease: rates and risk 
factors. N Engl J Med. 1991;325:11-6.
6.
Steinberg MH. Management of sickle cell disease. N Engl J Med. 1999;340:1021-30.
7.
American Academy of Pediatrics, Section on Hematology/Oncology and Committee on 
Genetics. Health supervision for children with sickle cell disease. Pediatrics. 
2002;109:526-35.
8.
Ballas SK. Pain management of sickle cell disease. Hematol Oncol Clin North Am. 
2005;19:785-802.
9.
Platt OS, Brambilla DJ, Rosse WF, et al. Mortality in sickle cell disease -- Life 
expectancy and risk factors for early death. N Engl J Med. 1994;330(23):1639-44.
10.
Smith WR, Penberthy LT, Bovbjerg VE, et al. Daily assessment of pain in adults with 
sickle cell disease. Ann Intern Med. 2008;148(2):94-101.
11.
Bunn HF. Pathogenesis and treatment of sickle cell disease. N Engl J Med. 
1997;337:762-9.
12.
Okpala I. Leukocyte adhesion and the pathophysiology of sickle cell disease. Curr Opin 
Hematol. 2006;13:40-4.
13.
Blum A, Yeganeh S, Peleg A, et al. Endothelial function in patients with sickle cell 
anemia during and after sickle cell crises. J Thromb Thrombolysis. 2005;19(2):83-6.
14.
Kato GJ, Martyr S, Blackwelder WC, et al. Levels of soluble endothelium-derived 
adhesion molecules in patients with sickle cell disease are associated with pulmonary 
hypertension, organ dysfunction, and mortality. Br J Haematol. 2005;130:943-53.
15.
Turhan A, Weiss LA, Mohandas N, et al. Primary role for adherent leukocytes in sickle 
cell vascular occlusion: A new paradigm. Proc Natl Acad Sci. 2002;99:3047-51.
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 107
16.
Kaul DK, Hebbel RP. Hypoxia/reoxygenation causes inflammatory response in 
transgenic sickle mice but not in normal mice. J Clin Invest. 2000;106(3):411-20.
17.
Tedder TF, Steeber DA, Chen A, et al. The selectins: vascular adhesion molecules. Br J 
Rheumatol. 1995;34:1101-4.
18.
Ebnet K, Vestweber D. Molecular mechanisms that control leukocyte extravasation: 
The selectins and chemokines. Histochem Cell Biol. 1999;112:1-23.
19.
Chen S, Springer TA. Selectin receptor-ligand bonds: Formation limited by shear rate 
and dissociation governed by the Bell model. Proc Natl Acad Sci. 2001;98:950-5.
20.
Blann AD, Nadar SK, Lip GYH. The adhesion molecule P-selectin and cardiovascular 
disease. Eur Heart J. 2003;24:2166-79.
21.
Kansas GS. Selectins and their Ligands: Current concepts and controversies. Blood. 
1996;88: 3259-87.
22.
Embury SH, Matsui NM, Ramanujam S, et al. The contribution of endothelial cell 
P-selectin to the microvascular flow of mouse sickle erythrocytes in vivo. Blood. 
2004;104(10):3378-85.
23.
Chang J, Patton JT, Sarkar A, et al. GMI-1070, a novel pan-selectin antagonist, reverses 
acute vascular occlusions in sickle cell mice.  Blood. 2010; 116: 1779-1786.
24.
Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest 
syndrome in sickle cell disease. N Engl J Med. 2000;342:1855-1865.
25.
National Institutes of Health; Division of Blood Diseases and Resources. The 
management of sickle cell disease. 4th ed. NIH Publication No. 02-2117. Bethesda, 
MD: US Department of Health and Human Services; 2002.
26.
Farrar JT, Young JP Jr, LaMoreaux L, et al. Clinical importance of changes in chronic 
pain intensity measured on an 11-point numerical pain rating scale. Pain. 2001 
Nov;94(2):149-58.
27.
Wong-Baker Faces Foundation homepage. Available at: http://wongbakerfaces.org/.  
Accessed February 25, 2015.
28.
Cleeland CS. Pain assessment in cancer. In: Osaba D(ed). Effect of Cancer on Quality 
of Life, Chapter 21. CRC Press, Boca Raton FL, 1991.
29.
National Institutes of Health. Evidence-Based Management of Sickle Cell Disease: 
Expert Panel Report.  Bethesda, MD: US Department of Health and Human Services; 
2014.  Available at: www.nhlbi.nih.gov/guidelines.
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 108
30.
Hackshaw A: A Concise Guide to Clinical Trials, 29 APR 2009; Wiley Online Library.  
Available at: 
http://onlinelibrary.wiley.com.proxy1.athensams.net/doi/10.1002/9781444311723.oth2/
pdf
31.
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A 
new equation to estimate glomerular filtration rate. Ann Intern Med. 
2009;150(9):604-12
32.
Schwartz GJ, et al. New equations to estimate GFR in children with CKD. J Am Soc 
Nephrol. 2009; 20: 629-637.
33.
Schwartz GJ and Work DF. Measurement and estimation of GFR in children and 
adolescents. Clin J Am Soc Nephrol. 2009; 4 (11): 1832-43.
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)


PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 109
Appendix 1. Estimated Glomerular Filtration Rate (eGFR) Calculations
Calculation for subjects 18 years of age:
The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation estimates
glomerular filtration rate (GFR) from serum creatinine, age, sex, and race for adults aged
≥18 years.31
CKD-EPI Equation
A CKD-EPI Calculator for investigator and/or site staff is provided via the study-
specific Firecrest web-portal.
  Calculation for subjects < 18 years of age:
Bedside Schwartz Equation32, 33
eGFR = 0.413 x (Height in cm) / (Serum Creatinine in mg/dl)
A Bedside Schwartz Calculator for investigator and/or site staff is provided via the 
study-specific Firecrest web-portal.
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)










PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 114
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)






PF-06460031
B5201002
Final Protocol Amendment 3, 01 April 2019
Page 117
090177e1915da01b\Approved\Approved On: 16-Jul-2019 18:44 (GMT)

SAP_001.pdf: 
 
4 Devonshire Place | Toronto, Ontario M5S 2E, Canada | biossil.co 
 
14 February 2025 
Re: Cover Letter for ClinicalTrials.gov NCT02187003 
 
This Cover Letter accompanies the final Statistical Analysis Plan (Version 5; 10 July 
2019) for the completed trial, NCT02187003.  
 
Sincerely,  
 
 
 
Debora Manning, MPH  
Head of Regulatory 
Biossil Inc. 
debora@biossil.ai 
 
 
 
Docusign Envelope ID: E93BBAA4-EEEF-47E5-B7CA-F22ABB5CB78D


Statistical Analysis Plan B5201002 v5
Page 1 of 56
Protocol B5201002
A PHASE 3, MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED, 
PARALLEL-GROUP STUDY TO EVALUATE THE 
EFFICACY AND SAFETY OF RIVIPANSEL (GMI-
1070) IN THE TREATMENT OF VASO-OCCLUSIVE 
CRISIS IN HOSPITALIZED SUBJECTS WITH SICKLE 
CELL DISEASE
Final Statistical Analysis Plan 
(SAP)
Version:
5 (Final)
Authors:
Date:
10 July 2019
090177e19152273c\Approved\Approved On: 12-Jul-2019 12:42 (GMT)


Statistical Analysis Plan B5201002 v5
Page 2 of 56
TABLE OF CONTENTS
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................5
2. INTRODUCTION .................................................................................................................8
2.1. Study Design .............................................................................................................9
2.2. Study Objectives .....................................................................................................13
3. INTERIM ANALYSES, FINAL ANALYSES AND REVIEW OF UNBLINDED 
DATA..................................................................................................................................13
3.1. Interim Analysis ......................................................................................................13
3.2. Final Analysis..........................................................................................................14
3.3. Review of Unblinded Data......................................................................................14
4. HYPOTHESES AND DECISION RULES.........................................................................14
4.1. Statistical Hypotheses .............................................................................................14
4.2. Statistical Decision Rules........................................................................................17
5. ANALYSIS SETS ...............................................................................................................18
5.1. Full Analysis Set .....................................................................................................18
5.2. ‘PER PROTOCOL’ Analysis Set............................................................................18
5.3. Safety Analysis Set..................................................................................................18
5.5. Treatment Misallocations........................................................................................18
5.6. Protocol Deviations.................................................................................................19
6. ENDPOINTS AND COVARIATES ...................................................................................19
6.1. Efficacy Endpoints ..................................................................................................19
6.1.1. Primary Efficacy Endpoint .........................................................................19
6.1.2. Secondary Efficacy Endpoints....................................................................23
6.2. Safety Endpoints .....................................................................................................24
6.4. Covariates................................................................................................................26
7. HANDLING OF MISSING VALUES ................................................................................26
090177e19152273c\Approved\Approved On: 12-Jul-2019 12:42 (GMT)




Statistical Analysis Plan B5201002 v5
Page 4 of 56
10.2. Definition and Use of Visit Windows in Reporting..............................................48
10.3. Shift Tables for Reporting of Laboratory Test Results.........................................50
10.4. Futility Interim Analysis .......................................................................................50
10.5. Estimated mean for time to event endpoints .........................................................51
10.6. SCHEDULE OF ACTIVITIES.............................................................................52
090177e19152273c\Approved\Approved On: 12-Jul-2019 12:42 (GMT)








Statistical Analysis Plan B5201002 v5
Page 8 of 56
2. INTRODUCTION
Note: in this document any text taken directly from the protocol is italicized.
Sickle cell disease (SCD) is one of the most prevalent genetic disorders in the United States 
(US), affecting approximately 100,000 people.  It is a chronic condition with substantial 
morbidity and mortality and is responsible for more than 75,000 hospitalizations per year in 
the US with an average stay of 6.1 days.  Both children and adults are affected, and greater 
mortality is seen in those with more severe disease.
SCD is associated with a number of serious and potentially disabling conditions that have 
similar symptoms but vary in severity by genotype.  Most notable is vaso-occlusive crisis 
(VOC), an extremely painful and serious consequence of SCD, presumably resulting from
acute ischemic tissue injury.  
Current medical management of SCD includes use of hydroxyurea, which is used to increase 
fetal hemoglobin (Hb F) concentration and reduce the number of pain crises.  Treatment of 
acute VOC includes mainly supportive measures such as opioid analgesics, hydration, 
oxygen, and transfusion.  There is no mechanism-based treatment currently available, so this 
remains an unmet medical need.  Most patients attempt pain management at home, and seek 
medical care only when this fails.  Therefore, the majority of painful episodes do not come to 
medical attention.
Inhibition of E-, P-, and L-selectins, a pan-selectin inhibition approach, offers potential 
promise as a useful therapeutic option.
GMI-1070 (rivipansel) is a pan-selectin antagonist, a compound found to inhibit selectin 
binding in vitro and to inhibit selectin-mediated effects in vivo.  Selectin binding is a key 
early step in the inflammatory process leading to leukocyte adhesion and recruitment to 
inflamed tissue.  Selectin binding has been shown to be involved in most – if not all – disease 
processes that involve inflammation.  There are no other known approved therapeutic agents 
in this class.
This study is designed to evaluate the efficacy and safety of rivipansel as treatment for VOC 
in hospitalized subjects with SCD. 
090177e19152273c\Approved\Approved On: 12-Jul-2019 12:42 (GMT)




Statistical Analysis Plan B5201002 v5
Page 10 of 56
The two cohorts and the two age strata in Cohort 1 will be also analyzed separately.
Entry points
There are two entry points into this study (see Figure 1 above).  The first point of entry is 
referred to as “Pre-VOC/Study Entry Screening” and occurs while the subject is well.  The 
second entry point is while the subject is experiencing a pain crisis and is termed 
“VOC/Treatment-Ready Screening”.

Pre-VOC/Study Entry Screening
Investigators may choose to identify, through chart review, those subjects who may be 
appropriate for the study before they develop VOC.  These subjects may be educated 
about the study when they are well, such as in the office setting, and approached for 
consent/assent while not experiencing a pain crisis.  These subjects will receive 
monthly telephone calls from the study site staff (or attend clinic visits, if preferred) 
until the time of their next VOC necessitating hospitalization.  At the time of VOC, the 
subject will be asked if they want to continue participating in the VOC/Treatment-
Ready Screening and if eligible, be randomly assigned to blinded study drug.  The 
subject’s affirmation must be documented. 

VOC/Treatment-Ready Screening
In addition to approaching subjects prior to VOC, investigators are encouraged to 
identify subjects with VOC in settings that could include emergency department, 
clinic, day hospital or other acute care outpatient facilities, who are planned or likely 
to be admitted to the hospital, and approach them for consent/assent and eligibility 
criteria early in the process of treatment for VOC. 
Randomization
Subjects with acute VOC who complete the VOC/Treatment-Ready screening assessments 
and meet all eligibility criteria are enrolled into the study and will be randomized in a 1:1 
ratio to receive multiple IV doses of rivipansel or placebo for the treatment of VOC.
Randomization will be stratified, forming a distinct stratum for each combination of age and 
genotype, using the categories shown below:

Age

6-11 years old;

12-17 years old;

≥18 years old.

Genotype

Category 1: HbSS, HbS0 thalassemia and HbSD;
090177e19152273c\Approved\Approved On: 12-Jul-2019 12:42 (GMT)


Statistical Analysis Plan B5201002 v5
Page 11 of 56

Category 2: HbSC, HbS+ thalassemia and HbS-Variant (other than HbSD).
Dosing
Dosing of eligible subjects with acute VOC will be initiated as early as possible but no later 
than 24 hours from the administration of the first dose of IV opioids for the current VOC.  
For subjects aged 12 and over who weigh >40 kg, study drug will be administered as a 
loading dose of 1680 mg followed by a maintenance dose of 840 mg every 12 2 hours.  
Subjects aged 6 to 11 years, or any subject who weighs 40 kg, will receive a loading dose of 
40 mg/kg (maximum of 1680 mg) followed by a maintenance dose of 20 mg/kg (maximum of 
840 mg) every 12 2 hours.  Study drug will be administered until criterion 1 of the 
readiness-for-discharge criteria (see below) has been met, or up to 15 doses of study drug 
(1 loading dose and a maximum of 14 maintenance doses), whichever comes first.
Primary Endpoint Assessment
The primary endpoint is time to readiness-for-discharge (TTRFD). The event of readiness-
for-discharge (RFD) occurs when all of the 6 protocol-specified criteria listed below have
been met and appropriately documented.  These six criteria are to be assessed in relation to 
treatment for the VOC event and acute complication(s) directly related to the VOC event. 
1. Only oral pain medication is required.
2. Acute complications related to VOC (such as ACS, stroke, priapism) have resolved to 
the extent that management can be in an outpatient setting, if applicable.
3. IV opioids have been discontinued.
4. IV hydration has been discontinued, if applicable.
5. IV antibiotics have been discontinued, if applicable.
6. RBC transfusion is no longer required for the treatment of this VOC, if applicable.
The RFD criteria will be assessed by site-staff in all subjects at pre-defined intervals (and ad 
hoc as necessary) using an RFD questionnaire, from the start time of the loading dose of 
study drug until discharge (see Section 6.1.1).
The RFD questionnaire is presented through the electronic Clinician Reported Outcome 
(eClinRO) system which is accessible via a web portal called TrialManager from a computer 
or mobile device. The appropriate electronic case report forms (eCRFs) are completed 
contemporaneously by site-staff to document the actual time and date at which criteria 3-6 
are met. 
090177e19152273c\Approved\Approved On: 12-Jul-2019 12:42 (GMT)






Statistical Analysis Plan B5201002 v5
Page 14 of 56
3.2. Final Analysis
Cohort 1 and Cohort 2 combined will provide pivotal efficacy and safety data from subjects 
aged 6 years and older for the indication of treatment of VOC in SCD patients.  
Analyses will also be performed separately for Cohort 1 (alone and/or by age group) and 
Cohort 2. 
3.3. Review of Unblinded Data
Safety Data: The E-DMC will review safety data provided by treatment group but with 
treatment assignment masked, with reviews occurring approximately every 6 months.  The 
treatment assignment decode will be provided to the E-DMC in a password-protected file, 
which they will review if considered necessary for accurate benefit/risk assessment.  
Efficacy Data: Unblinded efficacy data will be available to the committee in the following 
scenarios:
a.
If an interim analysis of Cohort 1 is performed, to assess futility (as described in 
Sections 3.1 and 4.2).
b. With every safety review. The efficacy data will be provided in a password-protected 
file, but this will only be reviewed by the E-DMC, if an unplanned review of efficacy 
is considered necessary for accurate risk-benefit assessment. 
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses

Hypothesis-testing will be performed only for Cohort 1 and Cohort 2 combined. 

The primary objective of separate Cohort 1 (alone and/or by age group) and Cohort 2 
statistical analyses is estimation rather than hypothesis-testing.
This protocol is designed to establish the superiority of rivipansel to placebo in Cohort 1 and 
Cohort 2 combined for the following:

Primary endpoint:

TTRFD in hours.

Key secondary endpoints:

Time to discharge in hours (date and time of “discharge” is the date and time of 
the hospital discharge order by a qualified health care professional not the date 
and time of physical exit from the hospital).

Cumulative IV opioid consumption in MEU/kg (cumulative IV opioid 
consumption is standardized using morphine equivalents and normalized by body 
weight in kilograms) from the start time of the first infusion (loading dose) of 
090177e19152273c\Approved\Approved On: 12-Jul-2019 12:42 (GMT)


Statistical Analysis Plan B5201002 v5
Page 15 of 56
study drug to discharge (ie, all available IV opioid data that is post-loading dose
while the subject is hospitalized).

Time to discontinuation of IV opioids in hours.
A gatekeeping approach (see Section 4.2) will be used for Cohort 1 and Cohort 2 combined 
to control the overall Type I error rate for the statistical hypothesis-testing of the primary and 
key secondary endpoints (all using 2-sided tests) at 0.05.
Primary Efficacy Analysis
The statistical hypothesis to be tested in the primary analysis, in support of the primary 
objective of the study is
H0: SRivipansel(t) = SPlacebo(t), for all t > 0,
where 

SRivipansel(t) is the survivor distribution of TTRFD in the rivipansel group; and 

SPlacebo(t) is the corresponding survivor distribution in the placebo group.
The alternative hypothesis is:
HA: SRivipansel(t) ≠ SPlacebo(t), for some t > 0.
Key Secondary Analysis
For each of the key secondary endpoints, the null hypothesis is that there is no difference 
between the rivipansel group and the placebo group with respect to the specific key 
secondary endpoint, and the alternative hypothesis is that there is a difference between the 
rivipansel group and the placebo group. 
Sample Size Rationale

Cohort 1 and Cohort 2 combined (all subjects ≥ 6 years old):
For the Primary Analysis Population (Cohort 1 and Cohort 2 combined), the sample size 
calculation was based on the following assumptions:

Distribution of TTRFD is exponential.

Median times to readiness-for-discharge are 156 and 106 hours, for the placebo 
and rivipansel groups, respectively (based on observed data in the Phase 2 trial).
090177e19152273c\Approved\Approved On: 12-Jul-2019 12:42 (GMT)








Statistical Analysis Plan B5201002 v5
Page 19 of 56

Randomized but took at least one dose of incorrect treatment: Subjects will be 
reported under their randomized treatment group for all efficacy analyses. For safety 
analyses, if any subjects received at least one dose of rivipansel, they will be reported 
under the rivipansel treatment group. These subjects will not be included in the 
PPAS. They will be also excluded from the biomarker analyses. If a subject was 
randomized to rivipansel but received incorrectly at least one dose of placebo, he/she 
will be still reported in the rivipansel group with appropriate adjustment for PK 
analyses. Otherwise the subject will be excluded from PK analyses.
5.6. Protocol Deviations
Protocol deviations will be reviewed and compiled based on reported deviations from 
inclusion/exclusion criteria, deviations in study drug administration, and other specifications 
as appropriate. These deviations will be reported in the CSR and will be compiled prior to 
database closure.
6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoints
6.1.1. Primary Efficacy Endpoint 
The primary efficacy endpoint is TTRFD from the hospital (in hours).  The event of interest, 
RFD, is said to occur when all applicable criteria among C1-C6 below have been 
appropriately documented as being met:
C1. Only oral pain medication is required.
C2. Acute complications related to VOC (such as ACS, stroke, priapism) have 
resolved to the extent that management can be in an outpatient setting, if applicable.
C3. IV opioids have been discontinued.
C4. IV hydration has been discontinued, if applicable.
C5. IV antibiotics have been discontinued, if applicable.
C6. RBC transfusion is no longer required for the treatment of this VOC, if 
applicable.
To be specific, in order for RFD to be achieved, for a given subject, the response to C1 must 
be appropriately documented as “YES” in the eClinRO system, the response to C2 must be 
appropriately documented as “YES” or “NA” in the eClinRO system, and the final stop dates 
and times for IV opioids (C3), IV hydration (C4), IV antibiotics (C5) and RBC transfusion
(C6) must be appropriately documented (as applicable) in the electronic Case Report Form.
TTRFD is defined as the difference (in hours) between the date and time when RFD is 
achieved and the start date and time of the first infusion (loading dose) of study drug. 
Assessment of RFD for a subject
A brief description of the RFD evaluation is given below.
090177e19152273c\Approved\Approved On: 12-Jul-2019 12:42 (GMT)


Statistical Analysis Plan B5201002 v5
Page 20 of 56
All criteria will be assessed by a member of the study site staff who will complete the RFD 
questionnaire.  The corresponding eCRFs (related to IV opioids, IV hydration, IV antibiotics 
and RBC transfusion) will also need to be completed by a member of the study site staff. 
When C1 and/or C2 (as applicable) are documented as being met in the RFD questionnaire
by a member of the study site staff other than the Investigator or qualified designee, they 
must be confirmed by the Investigator or qualified designee, prior to the time the next 
scheduled assessment is to be made, or the time the subject is discharged, whichever comes 
first.  Confirmation will also be required if there is a change in subsequent assessments of 
criteria C1 or C2.  The Investigator or qualified designee should be deemed, according to the 
institution’s standard of care, appropriately qualified to determine discharge readiness.  
The readiness-for-discharge criteria will be assessed in all subjects at pre-defined intervals 
(and ad hoc as necessary) from the start time of the loading dose until discharge.  Routine 
assessments are to be performed during “daytime hours” only (defined as 6:01am to 
10:00pm).  Assessments are not to be performed during “night-time hours” (defined as 
10:01pm to 6am), unless it becomes apparent that the subject has become 
ready-for-discharge during the “night-time hours”, in which case an ad hoc assessment 
should be undertaken.  
The schedule of readiness-for-discharge assessments may be different for the day the study 
drug loading dose is administered than for subsequent days.  The details around the 
difference in these schedules are as follows: 
If a subject receives their loading dose during the “daytime hours”, 
readiness-for-discharge assessments for that day will be performed every 4 (±1) 
hours from the start time of the loading dose until 10:00pm.  At 10:00pm (±1 hour) 
an assessment will be performed, signaling the end of the “daytime hours” and the 
start of the “night-time hours”.  The next routine assessment will then be at 6:01am 
(±1 hour) the following morning, signaling the start of the “daytime hours” for that 
day.  The schedule will then be reset such that, further assessments will be performed 
at 4 (±1) hourly intervals until 10:00pm (±1 hour) that night and this schedule of 
assessments (6:01am, 10:00am, 2:00pm, 6:00pm and 10:00pm, each ±1 hour) will 
continue for all subsequent days of Visit 1, until the subject is discharged from the 
hospital.  
If a subject receives their loading dose during the “night-time hours” then the first 
routine assessment of readiness-for-discharge will be at 6:01am (±1 hour) at the end 
of the “night-time hours” and the start of the “daytime hours”.  Further assessments 
will then be performed at 4 (±1) hourly intervals until 10:00pm (±1 hour) that night 
and this schedule of assessments (6:01am, 10:00am, 2:00pm, 6:00pm and 10:00pm, 
each ±1 hour) will continue for all subsequent days of Visit 1, until the subject is 
discharged from the hospital.   
090177e19152273c\Approved\Approved On: 12-Jul-2019 12:42 (GMT)






Statistical Analysis Plan B5201002 v5
Page 23 of 56
6.1.2. Secondary Efficacy Endpoints  
Key Secondary Endpoints:

Time to discharge, defined as the difference (in hours) between the date and time of 
the hospital discharge order issued by a qualified health care professional and the date 
and time of the start of the first infusion (loading dose) of study drug, ie,
Time to Discharge (in hours)
= [Date and time of hospital discharge order] ─ [Start date and time of 1st
infusion (loading dose) of study drug]

Cumulative IV opioid consumption in MEU/kg while the subject is in the hospital, 
beginning from the start date and time of the first infusion (loading dose) of study 
drug. 

See Appendix Section 10.1.1 for derivation details.  

Time to discontinuation of IV opioids, defined as the difference (in hours) between 
the latest IV opioid stop date and time and the start date and time of the first infusion
(loading dose) of study drug, ie,
Time to discontinuation of IV opioids (in hours) 
= [Latest stop date and time for IV Opioids] ─ [Start date and time of 1st infusion
(loading dose) of study drug]
Note: A bolus injection of an IV opioid and a continuous infusion of IV opioids can occur 
simultaneously.  Therefore, care needs to be taken when identifying the latest stop date and 
time and/or in the imputation for missing start and/or stop time data for IV opioids.
Other Secondary Endpoints:

Cumulative IV opioid consumption in MEU/kg within the first 24 hours post the start 
of the first infusion (loading dose) of study drug.

See Appendix Section 10.1.1 for derivation details.

Percent of subjects re-hospitalized for VOC within 3 days of discharge.
090177e19152273c\Approved\Approved On: 12-Jul-2019 12:42 (GMT)














Statistical Analysis Plan B5201002 v5
Page 30 of 56
7.3. IV opioids use endpoints
This section describes the handling of missing data for the IV opioids (IVO) use endpoints 
of:

Cumulative IV opioid consumption while hospitalized;

Cumulative IV opioid in the first 24 hours;

Hourly IV opioid in the first 48 hours;

Daily IV opioid use.
The study site staff will monitor and record all IV opioids used during the study, based on 
directions provided in the protocol. We do not expect to have an entire missing record for 
any administration of IVO, but scenarios below describe the derivation of the IVO use 
endpoints when one or more fields in an individual record are missing:

Missing final stop date and time (start date/time present) for the final IVO administration:
If the start date with or without the corresponding start time for the final IV opioid dose is 
known but the corresponding stop date and/or time are missing, rules defined for 
handling of missing values/censoring (see Table 8) for the endpoint of time to 
discontinuation of IV opioids will be used to define the stop date and/or time for the final 
IV opioid dose.

Missing start and/or stop time, but the start and stop date, route of administration, opioid 
dose amount and unit of IV opioid is recorded:
Depending on the route of administration, the start and/or stop time will be imputed.
Typically bolus injections have a total maximum duration of 15 minutes. Missing stop or
start time for a bolus injection will be imputed accordingly from the available start or 
stop time, respectively. For continuous infusions with a missing stop time, the start time 
for the subsequent infusion will be imputed as the stop time for the previous infusion.  
For continuous infusions with a missing start time, the stop time of the preceding infusion 
will be used. When prior or subsequent continuous infusions are not present, then 0:00 
will be used as the start time and 23:59 will be used as the stop time. If both start and stop 
times are missing for a bolus injection, then 12:00 (24-hr clock) noon will be used as the 
start time and 12:15 as the stop time.  

Dosage for any IV opioid dose missing:
For any administration of IV opioid for which the opioid dose amount is missing, the 
primary analysis of IV opioid use endpoints (Cumulative use, daily use, and hourly use 
from 4-hour interval data for first 48 hours), will not use any imputation for the missing 
IV opioid dose amount, and the record will be excluded. Therefore the primary analysis 
of IV opioid used-related endpoints will be based only on the available IV opioid dosage 
090177e19152273c\Approved\Approved On: 12-Jul-2019 12:42 (GMT)










Statistical Analysis Plan B5201002 v5
Page 35 of 56
Counts and percentages of subjects who experienced the event as well as counts and 
percentages of subjects who were censored and the type of censoring (eg, death or missing 
data) will be reported for each of the treatment groups.
8.1.2. Analysis of Binary Data
Descriptive statistics of binary data will include the number of non-missing observations and 
frequencies of the observed endpoint as well as the observed proportions. A two-sided 95% 
CI for the difference in proportions and the corresponding p-value will be provided (when 
appropriate) using the exact method proposed by Chan and Zhang (1999).
8.1.3. Analysis of Continuous Data
For continuous variables that have skewed data (eg, cumulative IV opioid use, hourly and 
daily opioid use), the data will be rank-transformed and ANCOVA, with the covariates of 
Age Group (for analyses of Cohort 1 and Cohort 2 combined) and Genotype (for all analysis 
groups), will be used to obtain p-values for the hypothesis of interest.  The difference 
between medians of the untransformed data will be used to estimate the treatment effect.  A 
bootstrap (with stratification by Age Group and Genotype) 95% confidence interval for this 
difference in medians will be reported.
8.2. STATISTICAL ANALYSES 
8.2.1. Primary Endpoint Analysis
Analysis of the primary endpoint TTRFD will be performed using the FAS and the methods 
described in Section 8.1.1 with specific details provided below. The primary endpoint will 
be analyzed in Cohort 1 and Cohort 2 combined (as the primary analysis population), as well 
as Cohort 1 (alone and by age group) and Cohort 2 separately.
Cohort 1 and Cohort 2 Combined:
Primary Efficacy Analysis: The primary analysis will consist of a stratified log-rank 
test to compare the survival distributions of the primary endpoint TTRFD between the 
rivipansel and placebo groups, where the stratifications are age group and genotype. 
The trial will meet the primary objective if this stratified log-rank test is statistically 
significant using an alpha of 5% (ie, 2-sided log-rank test p-value ≤ 0.05).
090177e19152273c\Approved\Approved On: 12-Jul-2019 12:42 (GMT)












Statistical Analysis Plan B5201002 v5
Page 41 of 56
8.5. Analysis of Safety Data
For Cohort 1 and Cohort 2 combined, Cohort 1 by age group and Cohort 2 alone based on the 
Safety Analysis Set, the safety data (eg, AEs, SAEs, vital signs, physical examinations, 
laboratory tests) will be summarized in accordance with CDISC and Pfizer Standards
(CaPS). In addition, for Cohort 1 and Cohort 2 combined ONLY, a 3-tier approach described 
below will be used for summarizing AE data. Safety data that will be specifically 
summarized include:

Adverse events:
The analyses of adverse events will make use of the 3-tiered approach described 
below for Cohort 1 and Cohort 2 combined ONLY.  These analyses will be 
considered exploratory. Under the 3-tier approach, AEs are classified into one of 
three tiers with different analyses performed for different tiers.

Tier-1 events: These are events that are pre-specified events of clinical 
importance and are maintained in the custom AE term list system (CAETeLiSt).

Tier-2 events: These are events that are not ier-1 but are “common”. A MedDRA 
Preferred Term (PT) is defined as a Tier-2 event (“common” event) if there are at 
least 4 in any treatment group.

Tier-3 events: These are events that are neither tier-1 nor tier-2 events. Tier-3 
events will be reported with observed proportions by treatment group without 
comparative statistics.
For Tier-1 events, the unconditional exact method for 95% CI for risk difference and 
p-value proposed by Chan and Zhang (1999) will be used to compare rivipansel with 
placebo. For Tier-2 events, the normal approximation will be used for calculating the
95% CI for risk difference.  There will be no adjustment for multiple comparisons or 
stratification factors in the analyses.

Safety laboratory tests reported according to CDISC and Pfizer standards (CaPS). Shift 
tables summarizing the changes in laboratory test results from baseline will be presented 
(see Appendix Section 10.3 for details on shift tables).

Incidence of clinically significant changes in physical examination will be summarized
using descriptive statistics.

Change from baseline at End of Treatment and at the Day 35 Post-discharge Visit in vital 
signs (eg, blood pressure, heart rate, temperature, respiratory rate, and pulse oximetry)
will be reported using descriptive statistics.

Incidence of adjudicated AEs will be analyzed using the same approach as for Tier-1 
events.
090177e19152273c\Approved\Approved On: 12-Jul-2019 12:42 (GMT)






Statistical Analysis Plan B5201002 v5
Page 44 of 56
9. REFERENCES
1.
Chan ISF, Zhang Z. (1999) Test-based exact confidence intervals for the difference of 
two binomial proportions. Biometrics, 55:1201–1209.
2.
Chang M (2008) Classical and Adaptive Clinical Trial Designs. John Wiley & Sons. 
Hoboken, New York.
3.
Jennison C, Turnbull B (2000) Group Sequential Methods with Applications to Clinical 
Trials. Chapman & Hall/CRC.
4.
Veterans Health Administration/Department of Defense: VHA/DoD Clinical Practice 
Guideline for the Management of Post-Operative Pain, Version 1.2 July 2001/Update 
May 2002.
5.
Guidance Document: Readiness-for-Discharge-Assessments, v3.0, 10 Nov 2016.
6.
Pfizer B5201002 & BF201003 Site User Manual PF-10089 for Trial Manager, v3, 25 
May 2016.
7.
B5201002 Protocol Administrative Change Letter, 11 January 2017.
8.
B5201002 Special Protocol – No Agreement to Modification letter, 7 July 2016.
9.
Schoenfeld D. Chi-squared goodness-of-fit tests for the proportional hazards regression 
model. Biometrika 1980; 67:145-53.
10.
Therneau, T. M. and Grambsch, P. M. (2000) Modeling Survival Data: Extending the 
Cox Model, Springer-Verlag, New York.
11.
T. Qi and J. Wang (2018) Calculating Restricted Mean Survival Time, PharmaSUG 
2018 – Paper AA-04.
090177e19152273c\Approved\Approved On: 12-Jul-2019 12:42 (GMT)


Statistical Analysis Plan B5201002 v5
Page 45 of 56
10. APPENDICES
10.1. Derivation for Endpoints
10.1.1. Cumulative IV Opioid Consumption
The cumulative amount of IV opioid use will be standardized using morphine equivalent 
units (MEU). The conversion to MEU will be performed using the formula below:
Cumulative MEU = 

n
i 1
(Total dose of the ith IV medication in mg)/(Ei)x10      (1) 
where Ei is the equianalgesic dose for the ith IV medication. 
Alternatively the cumulative MEU could be calculated using the following formula:
Cumulative MEU = 

n
i 1
(Total dose of the ith IV medication in mg) x CFi         (2)
where CFi is the conversion factor for the ith IV medication.
Equianalgesic doses for opioids, shown in below table, were obtained from the VHA/DoD 
Guideline for the Management of Postoperative Pain
(https://www.healthquality.va.gov/guidelines/Pain/pop/pop_fulltext.pdf). 
Equianalgesic Doses for IV Opioids
Medication
Route
Equianalgesic Dose 
(mg)
Conversion 
Factor (CF) to Give 
Morphine Equivalent* 
Buprenorphine
IV
0.3
33.33
Butorphanol
IV
2
5
Codeine
IV
120
0.083
Dezocine
IV
10
1
Fentanyl
IV
0.1**
100
Hydromorphone
IV
1.4
7.14
Levorphanol
IV
2
5
Meperdine
IV
87.5**
0.114
Methadone
IV
10
1
Morphine
IV
10
1
Nalbuphine
IV
10
1
Oxymorphone
IV
1
10
Pentazocine
IV
30
0.333
*Conversion Factor = 10 / (Equianalgesic Dose) which is based on 10mg morphine.
** The morphine conversions for doses administered via IM or IV are equivalent. Reference: 
https://cha.com/wp-content/uploads/2018/04/Colorado-Opioid-Safety-Pilot-Conversion-Table-1.pdf.   
Once the cumulative opioid usage is expressed in MEU, this dosage will be normalized by 
dividing by the subject’s body weight (ie, MEU/kg).
090177e19152273c\Approved\Approved On: 12-Jul-2019 12:42 (GMT)












Statistical Analysis Plan B5201002 v5
Page 51 of 56
If conditional power were low (≤ 20%) this would have been considered to indicate futility 
and hence a lack of identifiable efficacy benefit from the addition of rivipansel to standard of 
care for the treatment of sickle cell VOC.  However, as this futility IA was only to be 
conducted in the presence of a significant safety concern, the safety profile would also need 
to have been carefully assessed to determine overall risk/benefit. Consequently, the E-DMC 
could potentially have recommended stopping the study for futility with conditional power 
>20%. 
Detailed calculation for conditional power is provided below:
Conditional power (
)
(
P
, 1-sided) at look k
)
,...,
,...,
0
(
K
k
is calculated as shown below 
(Chang, 2008): 














k
K
k
K
K
k
k
I
I
I
I
I
z
I
P
)
(
)
(
975
.0


where 
)
/
log(
)
log(
r
p
HR





, 
p
, 
r
are the hazard rates for placebo group and 
rivipansel group respectively.  From the protocol assumption, 
)
log(HR


= – 0.386417. 
is the cumulative distribution function of the standard normal distribution, 
k
k
k
I
S
Z
/

is the 
test statistic,
k
S is the log-rank score statistic at look k , 
)
1(
1
1
P
P
E
I
k
k


is the information 
level, 
k
E is the number of events and 
1P is the proportion of the subjects assigned to the 
placebo group.
10.5. Estimated mean for time to event endpoints
Three methods will be used to calculate the mean time to event.
The first method calculates the mean survival time using all of the available data 
(TIMELIM=observed option in SAS PROC LIFETEST).
The second method provides the restricted mean survival time (RMST). The RMST 
methodology is applicable independently of the proportional hazards (PH) assumption and 
can be used, at a minimum, as a supplemental analysis to explore the robustness of the 
primary analysis results.  A restricted mean time is calculated up to a cut-off point in time, 
which is defined as the minimum between the largest observed times in rivipansel and
placebo groups.  The PROC LIFETEST procedure is applied with a data step (Qi and Wang, 
2018) to overcome the limitation of the procedure.
The third method provides the modified restricted mean, which is calculated up to the cut-off 
point in time of the maximum of the maximum observed times in rivipansel and placebo 
groups. If the smaller maximum observed time is censored, the smaller maximum 
observation is imputed with the maximum of maximum observed times in the two treatment 
groups prior to calculation.
090177e19152273c\Approved\Approved On: 12-Jul-2019 12:42 (GMT)


Statistical A nal ysis Pla n B 5 2 0 1 0 0 2 v 5 
Pa ge 5 2 of 5 6
F or eac h met h o d, S A S pr oce d ure P R O C LI F E T E S T is use d t o esti mate t he mea n (x 1 a n d x 2) 
a n d sta n dar d err or ( s1 a n d s2) f or eac h treat me nt gr o u p. 
T he differe nce bet wee n t he mea ns i n t he t w o treat me nt gr o u p s is esti mate d b y   −  .
T he sta n dar d err or ( S E) of t he differe nce is esti mate d b y  
       =    +  T he ass ociate d 9 5 % CI f or t he differe nce bet wee n mea ns is
(  −  ) ±   .   ∗      1 0. 6. S C H E D U L E O F A C TI VI TI E S
T he Sc he d ule of Acti vities ta ble bel o w pr o vi des a n o ver vie w of t he pr ot oc ol visits a n d 
pr oce d ures.  T he i n vesti gat or ma y  sc he d ule visits ( u n pla n ne d visits) i n a d diti o n t o t h ose 
liste d o n t he sc he d ule of acti vities, i n or der t o c o n d uct e val uati o ns or assess me nts re q uire d t o 
pr otect t he well bei n g of t he s u bject.
0 9 0 1 7 7 e 1 9 1 5 2 2 7 3 c\ A p pr o v e d\ A p pr o v e d O n: 1 2- J ul- 2 0 1 9 1 2: 4 2 ( G M T)


Statistical Analysis Plan B5201002 v5
Page 53 of 56
Schedule of Activities
090177e19152273c\Approved\Approved On: 12-Jul-2019 12:42 (GMT)