Clinical trial NCT02871570
Conditions: Moderate Hepatic Impairment Normal Hepatic Function
Keywords: Hepatic Impairment Rivipansel
Sponsor: GlycoMimetics Incorporated
Start date: 2016-09-01; Completion date: 2017-03-01
Enrollment: 16 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the effect of hepatic impairment on rivipansel PK and safety.

Detailed description:

Arms: arm 1: A single dose of IV Rivipansel over 20 minutes arm 2: A single dose of IV Rivipansel over 20 minutes
Interventions: intervention 1: Rivipansel
Intervention descriptions: intervention 1: A single dose of IV Rivipansel over 20 minutes

Protocol documents:
Prot_000.pdf: 
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A PHASE 1, NON-RANDOMIZED, OPEN-LABEL, PARALLEL-GROUP 
SINGLE-DOSE STUDY TO EVALUATE THE PHARMACOKINETICS, SAFETY, 
AND TOLERABILITY OF INTRAVENOUS RIVIPANSEL (PF-06460031) IN 
SUBJECTS WITH MODERATE HEPATIC IMPAIRMENT AND IN HEALTHY 
SUBJECTS WITH NORMAL HEPATIC FUNCTION
Investigational Product Number:
PF-06460031
Investigational Product Name:
Rivipansel
United States (US) Investigational New 
Drug (IND) Number:
77,984
European Clinical Trials Database 
(EudraCT) Number:
Not Applicable
Protocol Number:
B5201006
Phase:
1
 
 
 
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Document History
Document
Version Date
Summary of Changes
Original protocol
27 June 2016
Not Applicable (N/A)
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................6
APPENDICES ...........................................................................................................................6
SCHEDULE OF ACTIVITIES..................................................................................................7
1. INTRODUCTION ...............................................................................................................10
1.1. Mechanism of Action/Indication.............................................................................10
1.2. Background .............................................................................................................10
1.3. Rationale..................................................................................................................13
1.3.1. Study Rationale...........................................................................................13
1.3.2. Dose Rationale............................................................................................13
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................13
3. STUDY DESIGN.................................................................................................................14
3.1. Study Overview.......................................................................................................14
4. SUBJECT ELIGIBILITY CRITERIA.................................................................................15
4.1. Inclusion Criteria.....................................................................................................16
4.1.1. All Subjects.................................................................................................16
4.1.2. Healthy Subjects with Normal Hepatic Function.......................................16
4.1.3. Subjects with Hepatic Impairment..............................................................17
4.2. Exclusion Criteria....................................................................................................17
4.2.1. All Subjects.................................................................................................17
4.2.2. Healthy Subjects with Normal Hepatic Function.......................................19
4.2.3. Subjects with Hepatic Impairment..............................................................20
4.3. Lifestyle Requirements ...........................................................................................21
4.3.1. Meals and Dietary Restrictions...................................................................21
4.3.2. Alcohol, Caffeine and Tobacco ..................................................................21
4.3.3. Activity .......................................................................................................21
4.3.4. Contraception..............................................................................................22
4.3.4.1. Females - Childbearing Potential ..............................................22
4.3.4.2. Males .........................................................................................22
4.4. Sponsor’s Qualified Medical Personnel..................................................................23
5. STUDY TREATMENTS.....................................................................................................23
5.1. Allocation to Treatment ..........................................................................................23
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5.2. Subject Compliance.................................................................................................23
5.3. Investigational Product Supplies.............................................................................24
5.3.1. Dosage Form and Packaging ......................................................................24
5.3.2. Preparation and Dispensing........................................................................24
5.3.3. Administration............................................................................................24
5.4. Investigational Product Storage ..............................................................................25
5.5. Investigational Product Accountability...................................................................25
5.5.1. Destruction of Investigational Product Supplies ........................................26
5.6. Concomitant Treatment(s).......................................................................................26
6. STUDY PROCEDURES .....................................................................................................26
6.1. Screening.................................................................................................................26
6.2. Study Period ............................................................................................................28
6.2.1. Day 0...........................................................................................................28
6.2.2. Day 1...........................................................................................................29
6.2.3. Day 2...........................................................................................................30
6.2.4. Day 3...........................................................................................................30
6.2.5. Day 4...........................................................................................................30
6.2.6. Day 5...........................................................................................................30
6.3. Follow-up Contact...................................................................................................31
6.4. Subject Withdrawal/Early Termination ..................................................................31
7. ASSESSMENTS..................................................................................................................32
7.1. Safety.......................................................................................................................33
7.1.1. Laboratory Tests .........................................................................................33
7.1.2. Physical Examinations................................................................................34
7.1.3. Blood Pressure and Pulse Rate ...................................................................34
7.1.4. Temperature................................................................................................35
7.1.5. Electrocardiogram.......................................................................................35
7.2. Pharmacokinetics ....................................................................................................35
7.2.1. Plasma for Pharmacokinetic Analysis of Rivipansel..................................35
7.2.2. Plasma for Unbound Fraction Determination of Rivipansel ......................36
7.3. Blood Volume .........................................................................................................37
8. ADVERSE EVENT REPORTING......................................................................................37
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8.1. Requirements...........................................................................................................37
8.1.1. Additional Details on Recording Adverse Events on the CRF...................38
8.1.2. Eliciting Adverse Event Information..........................................................39
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the 
Subject Withdrawal section)............................................................................39
8.1.4. Time Period for Collecting AE/SAE Information......................................39
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................39
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF .................39
8.1.5. Causality Assessment .................................................................................40
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................40
8.2. Definitions...............................................................................................................40
8.2.1. Adverse Events...........................................................................................40
8.2.2. Abnormal Test Findings .............................................................................41
8.2.3. Serious Adverse Events ..............................................................................41
8.2.4. Hospitalization............................................................................................42
8.3. Severity Assessment................................................................................................43
8.4. Special Situations ....................................................................................................43
8.4.1. Potential Cases of Drug-Induced Liver Injury............................................43
8.4.2. Exposure to the Investigational Product During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................45
8.4.2.1. Exposure During Pregnancy......................................................45
8.4.2.2. Exposure During Breastfeeding ................................................47
8.4.2.3. Occupational Exposure .............................................................47
8.4.3. Medication Errors .......................................................................................47
8.4.3.1. Medication Errors......................................................................47
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................48
9.1. Sample Size Determination.....................................................................................48
9.2. Pharmacokinetic Analysis.......................................................................................48
9.2.1. Plasma.........................................................................................................49
9.3. Safety Analysis........................................................................................................49
9.4. Interim Analysis ......................................................................................................50
9.5. Data Monitoring Committee ...................................................................................50
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................50
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11. DATA HANDLING AND RECORD KEEPING .............................................................51
11.1. Case Report Forms/Data Collection Tools/Electronic Data Record.....................51
11.2. Record Retention...................................................................................................51
12. ETHICS..............................................................................................................................52
12.1. Institutional Review Board/Ethics Committee......................................................52
12.2. Ethical Conduct of the Study ................................................................................52
12.3. Subject Information and Consent..........................................................................52
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................53
13. DEFINITION OF END OF TRIAL...................................................................................53
13.1. End of Trial in the United States...........................................................................53
14. SPONSOR DISCONTINUATION CRITERIA ................................................................53
15. PUBLICATION OF STUDY RESULTS..........................................................................54
15.1. Communication of Results by Pfizer ....................................................................54
15.2. Publications by Investigators ................................................................................54
16. REFERENCES ..................................................................................................................56
LIST OF TABLES
Table 1.
Assessment of Hepatic Impairment: Child-Pugh Score .......................................14
Table 2.
Safety Laboratory Tests........................................................................................33
APPENDICES
Appendix 1. Determination of Encephalopathy for the Calculation of the Child Pugh 
Score .....................................................................................................................58
Appendix 2. Abbreviations......................................................................................................60
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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the 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 table, in order to 
conduct evaluations or assessments required to protect the well-being of the subject.  
Visit Identifier
Screeninga
Day 0
Day 1
Day
2
Day
3
Day
4
Day
5
28-day Follow-up 
Phone Call
Hours Relative to Dosing
0
0.33 1
3
4
6
8
10 12 16
24
48
72
96
Informed consent
X
Inclusion/exclusion criteria
X
X
CRU confinement
X







Medical history 
X
Xb
Medication history
X
X
Physical examinationc
X
X
X
Demography
X
Heightd and Weight 
X
Alcohol Teste
X
X
Child-Pugh Classificationf
Xh
X
Ascites evaluationf
Xh
X
Encephalopathy Grade evaluationf,g
Xh
X
Serologic tests: HIV-1 antibody, HBsAg and HCV antibody
X
Safety laboratory testsi
X
X
X
Reproductive status
X
Contraception check
X
X
Serum FSHj
X
Urine drug test
X
X
Supine 12-lead electrocardiogram (ECG)
X
Xk
X
Single supine blood pressure/pulse rate and temperature
X
Xk
Xm
Xl,m
Xl,m
X
X
Study medication administration after fasting for at least 4 hours
X
Serious and non-serious adverse event monitoring
X







X
Xp
Insertion of intravenous cathetern
Xk
Standardized meals
X
X
X
X
X
X
X
X
Concomitant treatment(s)
X





X
Blood sample for determination of rivipansel unbound fractiono
X
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Visit Identifier
Screeninga
Day 0
Day 1
Day
2
Day
3
Day
4
Day
5
28-day Follow-up 
Phone Call
Hours Relative to Dosing
0
0.33 1
3
4
6
8
10 12 16
24
48
72
96
Discharge from CRU
X
Abbreviations: = ongoing/continuous event; CRU = clinical research unit; FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; 
HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; INR = international normalized ratio; PT = prothrombin time
a.
Subject will be screened within 28 days prior to administration of study medication.  For hepatic impairment subjects, see footnote f.
b.
On Day 0, review changes in medical history since screening visit.
c.
Full physical examination at screening and on Day 5, limited physical examination on Day 0.
d.
Height measurement only at screening when full physical examination is performed.
e.
Breath or blood alcohol test (method based on discretion of the investigator) for hepatic impairment subjects.  For healthy subjects, the alcohol test can be 
done at the discretion of the investigator.
f.
Hepatic impairment subjects only: Child-Pugh classification, encephalopathy grade and ascites evaluations to be performed within the 14 days prior to 
administration of study medication.
g.
Encephalopathy grade evaluation includes number connection test and blood ammonia level (Described in Appendix 1).
h.
Second screening visit to be performed for hepatic impairment subjects if a subject is not able to provide documentation of stable hepatic disease (ie, copy of 
recent lab tests, in addition to medical chart) within the last 30 days (no worsening clinical signs of hepatic impairment, or no worsening of total bilirubin or 
prothrombin time by more than 50%).  See Screening section for details.
i.
Includes chemistry, hematology (including PT/INR) and urinalysis, and after fasting for at least 4 hours.
j.
To be conducted for females who have achieved postmenopausal status, defined as cessation of regular menses for at least 12 consecutive months with no 
alternative pathological or physiological cause.  
k.
Pre-dose.
l.
The Day 1 Hour 4 and Hour 8 vital signs will be collected on the source document only.
m. Temperature does not need to be collected at this timepoint.
n.
Insertion of the intravenous catheter for collection of blood samples is optional.
o.
Sample will be analyzed only if a pharmacokinetic difference in subject groups is observed.
p.
Each subject will have a follow up phone call no earlier than 28 days and no later than 31 days after study drug administration to assess for adverse events 
(AEs) and serious adverse events (SAEs).
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Pharmacokinetic Sampling Schema
Visit Identifier
1
2
3
4
5
Hours After Dose
0
0.33
1
3
4
6
8
10
12
16
24
36
48
72
96
Study treatment administration
X
Pharmacokinetic blood sampling 
Xa
Xb
X
X
X
X
X
X
X
X
X
X
X
X
X
a.
Pre-dose sample collection.
b.
Timing of sample collection based on stop time of infusion of study medication.
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1. INTRODUCTION
1.1. Mechanism of Action/Indication
Rivipansel is being developed as a pan-selectin antagonist for the treatment of vaso-occlusive 
crisis (VOC) in subjects with Sickle Cell Disease (SCD) and a Phase 3 study is ongoing.
1.2. Background 
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 in-patient 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 hemoglobin -globin 
gene in which a single nucleotide substitution results in the presence of valine instead of 
glutamic acid in the -globin chain and leads to the presence of Hemoglobin S (Hb S).  Hb S 
tends to polymerize when deoxygenated, this being 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 the gene for 
Hb S and 1 copy of the gene for either Hb C (SCD-SC), Hb +-thalassemia (SCD-S+-thal), 
or Hb 0-thalassemia (SCD-S0-thal).4
SCD is associated with a number of serious and potentially disabling conditions that manifest 
similar symptoms although there may be variation in severity by genotype.  Most notable is 
the VOC, an extremely painful and serious consequence of SCD, 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 
VOC,5 which typically presents as an episode of pain and inflammation, at 1 or more sites.  
VOC episodes occur with varying degrees of severity, and at varying intervals throughout 
life and, as the clinical hallmark of SCD, are responsible for the vast majority of 
hospitalizations (>90%).  They result in significant morbidity, interruption of daily 
functioning and mortality.  Other problems that occur in patients with SCD 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 episodes of acute VOC, and are due to ACS or stroke.9 Patients can become 
symptomatic with pain as early as 6 months of age; thus, VOCs are an important cause of 
morbidity throughout life, resulting in disruption to the individual’s psychosocial 
development, education and employment consequent upon the severe pain and the frequent 
need for hospitalization.  They also potentially contribute to premature death.
Current medical management of SCD includes hydroxyurea, which is used to increase fetal 
hemoglobin (Hb F) concentration with the aim of reducing the number of VOC’s.  Treatment 
of acute VOC includes mainly supportive measures such as opioid analgesics, hydration and 
supplemental oxygen.  There is no mechanism-based treatment currently available, so this 
remains an unmet medical need.  Most patients attempt pain management at home, and seek 
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medical care only when this fails.  Therefore, many 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 component in which white blood cells (WBCs) adhere to the 
endothelium. Together, these 2 mechanisms lead to vascular occlusion and tissue ischemia.
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
Rivipansel is a pan-selectin antagonist, a compound found to inhibit selectin binding in vitro 
and to inhibit selectin-mediated effects in vivo.  There are no other known approved 
therapeutic agents in this class.
Pharmacokinetic (PK) data for rivipansel (GMI-1070) are available from 2 studies in healthy 
volunteers (GMI-1070-101 and GMI-1070-102), and from a third study conducted in patients 
with SCD 18 to 50 years of age who, at the time of the study, were not experiencing a VOC
(GMI-1070-103). All of these studies were undertaken by Glycomimetics (GMI), from 
whom Pfizer in-licensed rivipansel.  Rivipansel doses used in all GMI studies were based on 
the salt whereas in all Pfizer studies, including the current study, the dose will be based on 
the active moiety of rivipansel.
In the first study (GMI-1070-101), subjects received single intravenous (IV) doses of
rivipansel 2, 5, 10, 20, or 40 mg/kg or placebo over 20 minutes.  In the second study 
(GMI-1070-102), subjects received multiple IV doses of rivipansel 5, 10, or 20 mg/kg 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 rivipansel 20 mg/kg every 8 hours 
for a total of 6 doses.  These studies evaluated a total of 72 healthy adult subjects 
(54 rivipansel, 18 placebo).
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Mean values for Cmax (maximum observed concentration), AUClast (area under the 
concentration-time curve [AUC] from time 0 to the time of the last quantifiable 
concentration), and AUCinf (AUC from time 0 to infinity) increased in a dose-proportional 
manner, providing evidence of linear PK.  After a single 20 mg/kg dose, the mean standard 
deviation (SD) Cmax was 25643.7 mg/L.  The time of peak concentration (Tmax)
corresponded to the time of the end of infusion and the collection of the first blood sample 
for determination of rivipansel.  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 to 7.41 hours.  
Urine collection after multiple dose administration showed a minimum of 89% of the dose 
was recovered intact in the urine, and renal clearance (CLr) was less than filtration clearance, 
consistent with tubular reabsorption.
The third study (GMI-1070-103) was an open-label study of IV rivipansel in 15 adult 
subjects with stable SCD who received a loading dose of IV rivipansel 20 mg/kg over 
20 minutes, followed 10 hours later by a dose of IV rivipansel 10 mg/kg over 20 minutes.  
The PK was observed to be consistent with that in the healthy volunteers.
In these 3 studies, there were no clinically significant electrocardiogram (ECG) or physical 
examination findings.  With 1 exception, all adverse events (AE) in subjects receiving 
rivipansel were Grade 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 (SAE) were reported in these studies. 
B5201001, a thorough QT (time from ECG Q wave to the end of the T wave) study in 
48 healthy African-American subjects who received a single dose of rivipansel 4 g active 
over 20 minutes, showed a lack of QTc (QT corrected for heart rate) effect.  There were no 
SAEs, no AE’s with clinical sequelae and no deaths due to AEs. No new Adverse Drug 
Reactions (ADRs) for rivipansel were identified in the study but 1 subject discontinued the 
study due to an AE of “alanine aminotransferase (ALT) increased” following treatment with 
rivipansel.
A randomized, placebo-controlled Phase 2 trial (GMI-1070-201), evaluating the efficacy, 
safety, and PK of multiple IV doses of rivipansel in 76 subjects 12 to 60 years of age who 
were hospitalized for sickle cell VOC has also been undertaken.  This study included two 
dosing schedules; the first cohort received 20 mg/kg loading dose, then 10 mg/kg every 
12 hours (q12 h) until 7 days, (maximum 15 doses) and the second cohort received 40 mg/kg 
loading dose, then 20 mg/kg q12 h until 7 days, (maximum 15 doses).  Each IV dose was 
administered over 20 minutes.  There were no clinically significant ECG or clinical findings 
associated with cardiac toxicity in these subjects.  Total treatment-emergent adverse event 
(TEAE) rates were comparable across groups.  SAE’s and those SAEs considered “related to 
treatment” were also comparable across groups.  Eleven (11, 14.4%) subjects discontinued 
study drug due to AEs (8 subjects in the active group, and 3 subjects in the placebo group).  
No subjects discontinued the study due to AEs.  A total of 28 SAEs were reported, 
encompassing 29 events across 23 subjects.  A 30% SAE rate was seen in both active and 
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placebo groups.  The most common SAE was re-hospitalization for VOC.  No subjects died 
during the study.
Additional information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the Investigator Brochure (IB).
1.3. Rationale
1.3.1. Study Rationale 
Sickle cell disease can cause progressive injury to the liver with fibrosis and decreased liver 
function by adulthood.22  Although rivipansel is known to be primarily eliminated by the 
kidney (>90% of dose excreted in urine based on data from the Single Ascending Dose study 
GMI-1070-101), hepatic function can have an effect on the PK of drugs for which the 
excretion is primarily renal.  This study is therefore being conducted to evaluate the effect of 
hepatic impairment on the PK, safety and tolerability of rivipansel.  Results from this study 
will be used in conjunction with collective safety, efficacy, and PK/pharmacodynamic (PD)
data from other rivipansel studies to provide recommendations on dosing for subjects with 
hepatic impairment.  
1.3.2. Dose Rationale
A single 840 mg dose of IV rivipansel will be used in this study as it is the dose selected for 
maintenance dosing in the rivipansel Phase 3 program.  IV doses of rivipansel as high as
4 g (as a single dose) have been well tolerated in healthy volunteers. In the Phase 2 study 
multiple doses, using a loading dose of 40 mg/kg followed by doses of 20 mg/kg given every 
12 hours for up to 7 days were also well tolerated.  Therefore, it is expected that potential 
increases in exposure due to hepatic impairment with a single dose of 840 mg should not 
pose a safety concern.  Single-dose administration was chosen because time-independent PK
of rivipansel have been demonstrated at the anticipated concentrations, and thus single-dose 
PK will be able to adequately predict multiple-dose PK.
2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objectives:
Primary Endpoints:

To evaluate the effect of moderate hepatic 
impairment on the PK of rivipansel following a 
single 840 mg IV dose.

To evaluate the safety and tolerability of a 
single 840 mg IV dose of rivipansel in subjects 
with moderate hepatic impairment and in 
healthy subjects with normal hepatic function.

Primary: AUCinf (or AUClast, as data permit), 
CL.

Safety will be assessed by physical 
examinations, AE monitoring, 12-lead ECGs, 
supine blood pressure (BP) and pulse rate, and 
safety laboratory tests. 
Secondary Objective(s):
Secondary Endpoint(s):

To evaluate the effect of moderate hepatic 
impairment on additional PK parameters for
rivipansel following a single 840 mg IV dose.

Secondary: AUClast, Cmax, t½, Vss.
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3. STUDY DESIGN
3.1. Study Overview
This study is a Phase 1 open-label, single-dose, single-treatment, non-randomized study of 
rivipansel in subjects with moderate hepatic impairment and healthy subjects with normal 
hepatic function.  Since rivipansel is primarily eliminated renally, a reduced study design 
with two groups (control subjects and subjects with moderate hepatic impairment) was 
considered adequate to characterize the PK in subjects with hepatic impairment.
The Child-Pugh Score will be utilized to assess entry criteria and to assign subjects to the 
appropriate hepatic-impairment group.  Child-Pugh assessments will be performed within the 
14 days prior to study medication administration and Day 0 (baseline).  Subjects should 
satisfy the criteria for Child-Pugh classification as Moderate Hepatic Impairment 
(Class B Score 7-9) for both assessments in order to be enrolled into the study.  The subjects’
hepatic function will be ranked based on clinical signs and liver function test results 
(Table 1).
Table 1.
Assessment of Hepatic Impairment: Child-Pugh Score
Assessment Parameters
Assigned Score for Observed Findings
1 point
2 points
3 points
Encephalopathy Gradea
0
1 or 2
3 or 4
Ascites
Absent
Slight
Moderate
Serum Bilirubin (mg/dL)
<2
2 to 3
>3
Serum Albumin (g/dL)
>3.5
2.8 to 3.5
<2.8
Prothrombin Time (seconds 
prolonged)
<4
4 to 6
>6
Classification of clinical severity:
Mild (Class A): Total score 5-6 points
Moderate (Class B): Total score 7-9 points
Severe (Class C): Total score >9 points
a.
Grade 0: Normal consciousness, personality, neurological examination, electroencephalogram.
Grade 1: Restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps (cycles per sec) 
waves.
Grade 2: Lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves.
Grade 3: Somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slow waves.
Grade 4: Unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity.
See Appendix 1 for details.
A total of approximately 16 subjects will be enrolled; 8 subjects with moderate hepatic 
impairment and 8 healthy subjects with normal hepatic function. Healthy subjects with 
normal hepatic function will be enrolled after all of the subjects with moderate hepatic 
impairment have completed the in-patient portion of the study and will be matched for age, 
weight, and gender to the mean demographics of subjects in the moderate hepatic impairment
group.  Healthy subjects with normal hepatic function will be enrolled to enable comparison 
of PK parameters between healthy subjects and subjects with moderate hepatic impairment.
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Reasonable efforts will be made to enroll an adequate number of subjects (1 to 3 subjects) 
with Child-Pugh scores of 8 or 9 (based on assessment on Day 0) to ensure that the entire 
range of moderate hepatic impairment is represented.  
Subjects who withdraw from the normal hepatic function or moderate hepatic impairment 
groups for non-safety related reasons and who are considered to be non-evaluable with 
respect to the primary PK objective will be replaced at the discretion of the investigator and 
sponsor such that the number of completed subjects in each group equals eight.
Screening will occur within the 28 days prior to administration of study medication.  All 
subjects will provide informed consent and undergo Screening evaluations to determine their 
eligibility. 
Eligible subjects will be admitted to the Clinical Research Unit (CRU) on Day 0 and will be 
confined in the CRU until Day 5.  On Day 1, subjects will receive a single 840 mg IV dose of 
rivipansel.  Serial blood samples will be collected at specified intervals for 96 hours 
post-dose for PK assessments, prior to discharge from the CRU on Day 5. 
Age/Weight/Gender Matching Criteria:
Subjects with Child-Pugh Class B (moderate) hepatic impairment will be enrolled first and 
their demographics will be pooled.  Enrollment of age-, weight-, and gender-matched healthy 
subjects with normal hepatic function will begin after all of the moderate hepatic impairment 
subjects have completed the in-patient portion of the study.  Demographics of the healthy 
subjects will be matched to the pooled demographics of the moderate impairment group such 
that the body weight of each healthy subject is within 15 kg of the mean body weight of the 
subjects with hepatic impairment, age is within 10 years of the mean age of the subjects 
with hepatic impairment and the gender ratio for the group is similar (2 subjects per gender) 
to the subjects with hepatic impairment.  In general, care should be taken when recruiting the 
healthy subjects such that the entire group is as closely matched as possible in age and body 
weight to the subjects with hepatic impairment.
Safety assessments (as specified in the Schedule of Activities) will be performed during 
screening, prior to dosing on Day 1 and post dosing.  The total participation time (ie, CRU 
confinement time for study procedures) for each subject in this study will be approximately 
5 nights/6 days (excluding screening).  Subjects will have a follow-up phone call no earlier 
than 28 days and no later than 31 days after study drug administration, to assess for 
AEs/SAEs.
All procedures and their timelines follow the Schedule of Activities.
4. SUBJECT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.
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4.1. Inclusion Criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment in the 
study:
4.1.1. All Subjects
1. Female subjects of non-childbearing potential or male subjects who, at the time of 
screening, are between the ages of 18 and 75 years, inclusive. 
2. Female subjects of non-childbearing potential must meet at least 1 of the following 
criteria:
a.
Achieved postmenopausal status, defined as follows: 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 
consistent with the post-menopausal state;  
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
c.
Have medically confirmed ovarian failure.
All other female subjects (including female subjects with tubal ligations) are
considered to be of childbearing potential.
3. Body mass index (BMI) of 17.5 to 40 kg/m2; and a total body weight >50 kg (110 lb).
4. Evidence of a personally signed and dated informed consent document indicating that 
the subject has been informed of all pertinent aspects of the study.  
5. Willing and able to comply with all scheduled visits, treatment plan, laboratory tests, 
and other study procedures.
4.1.2. Healthy Subjects with Normal Hepatic Function
1. Healthy, defined as no clinically relevant abnormalities identified by a detailed 
medical history, full physical examination, including BP and pulse rate measurement, 
12-lead ECG and safety laboratory tests.
2. Normal hepatic function with no known or suspected impairment.
3. Demographically comparable to subjects with hepatic impairment:

Body weight will be within 15 kg of the mean body weight of the pooled group 
of subjects with moderate hepatic impairment.

Age will be within 10 years of the mean age of the pooled group of subjects with 
moderate hepatic impairment.
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
The gender ratio for the group will be similar (2 subjects per gender) to the 
pooled group of subjects with moderate hepatic impairment.
4.1.3. Subjects with Hepatic Impairment
1. Satisfy the criteria for Child-Pugh classification as Moderate Hepatic Impairment 
(Class B - Score 7-9) within the 14 days prior to administration of study medication
and Day 0 (baseline) [Note: As stated in the STUDY DESIGN section, reasonable 
efforts will be made to enroll an adequate number of subjects (1 to 3 subjects) with 
Child-Pugh scores of 8 and 9 (based on assessment at Day 0) to ensure that the entire 
range of moderate hepatic impairment is represented].
2. Hepatic impairment due to primary liver disease and not secondary to other diseases, 
confirmed and documented by medical history, physical examination, liver biopsy,
hepatic ultrasound, computed tomography (CT) scan or magnetic resonance imaging 
(MRI).
3. Stable hepatic impairment, defined as no clinically-significant change in disease 
status within at least the last 30 days, (no worsening clinical signs of hepatic 
impairment, or no worsening of total bilirubin or prothrombin time by more than 
50%) as documented by the subject’s recent medical history.  If subjects do not have 
adequate available records, 2 screening visits (Screening and Day 0 visit) will be 
performed to demonstrate stability of hepatic disease.  The 2 visits (if performed) for 
demonstrating stability of hepatic disease must be at least 7 days apart. 
4. On stable doses of medication and/or treatment regimens for at least 4 weeks prior to 
screening.  Such medications would also need to be held stable from screening 
through study completion.  Subjects who are receiving a fluctuating treatment 
regimen may be considered for inclusion on a case-by-case basis if the underlying 
disease is under control in the opinion of the investigator and sponsor.
4.2. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
4.2.1. All Subjects
1. Known hypersensitivity or intolerance to rivipansel.
2. History of febrile illness within 5 days prior to administration of study medication.
3. Any medical or surgical condition that might significantly interfere with the 
distribution, metabolism, or excretion of rivipansel.
4. A positive urine drug test for illicit drugs.  However, subjects with hepatic 
impairment who test positive for a prescribed medicine can be enrolled.
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5. History of abuse of alcohol or binge drinking and/or any other illicit drug use or 
dependence within 6 months of screening.  Binge drinking is defined as a pattern of 
5 or more alcoholic drinks (male), or 4 or more alcoholic drinks (female) in about 
2 hours.  As a general rule, alcohol intake should not exceed 2 drinks per day or 
14 drinks per week (1 drink = 5 ounces of wine (150 mL) or 12 ounces (360 mL) of 
beer or 1.5 ounces (45 mL) of spirit).
6. Treatment with an investigational drug within 30 days (or as determined by the local 
requirement) or 5 half-lives preceding the administration of study medication
(whichever is longer). 
7. Any prior history of malignancy with the exception of:

Basal cell carcinoma of the skin; or 

Squamous cell carcinoma of the skin that has been recurrence-free for 5 years; 
or

Other malignancies (regardless of site) that have been recurrence-free for 
10 years.
8. Pregnant or breastfeeding females; male subjects with partners currently pregnant; 
fertile male subjects who are unwilling or unable to use a highly effective method of 
contraception as outlined in the protocol for the duration of the study and for 28 days 
after the last dose of study medication.
9. Use of herbal supplements within 28 days prior to administration of study medication.
10. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 56 days prior to administration of study medication.
11. History of sensitivity to heparin or heparin-induced thrombocytopenia (if heparin is 
used to flush intravenous catheters). 
12. An estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2 based on the 
four-variable Modification of Diet in Renal Disease (MDRD) equation. 
13. Subjects who are unwilling or unable to comply with the criteria in the Lifestyle 
Requirements section of this protocol.  
14. Subjects who are investigator site staff members directly involved in the conduct of 
the study (including their family members), site staff members otherwise supervised 
by the investigator, or subjects who are Pfizer employees (including their family 
members), directly involved in the conduct of the study.
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15. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior or laboratory abnormality that may 
increase the risk associated with study participation or investigational product 
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.
4.2.2. Healthy Subjects with Normal Hepatic Function
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, or 
allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing).
2. Screening supine 12-lead ECG demonstrating QTcF (QTc using Fridericia’s formula) 
>450 msec or a QRS interval >120 msec at screening.  If QTcF exceeds 450 msec, or 
QRS exceeds 120 msec, the ECG should be repeated two more times and the average 
of the three QTcF or QRS values should be used to determine the subject’s eligibility.
3. Screening supine BP 140 mm Hg (systolic) or 90 mm Hg (diastolic), on a single 
measurement following at least 5 minutes of rest.  If BP is 140 mm Hg (systolic) or 
90 mm Hg (diastolic), the BP should be repeated two more times and the average of 
the three BP values should be used to determine the subject’s eligibility.
4. History of alcohol abuse with a positive alcohol test at screening or on Day 0 at the 
discretion of the investigator.  
5. Subjects with ANY of the following abnormalities in safety laboratory tests at 
screening, as assessed by the study-specific laboratory and confirmed by a single 
repeat test, if deemed necessary:

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
level > upper limit of normal (ULN);

Total bilirubin level ULN.
6. Use of prescription drugs, vitamins, or dietary supplements within 7 days or 
5 half-lives (whichever is longer) prior to administration of study medication.  As an 
exception, acetaminophen may be used at doses of 1 g/day.  Limited use of 
nonprescription medications that are not believed to affect subject safety or the 
overall results of the study may be permitted on a case-by-case basis following 
approval by the sponsor.
7. Positive serologic findings for human immunodeficiency virus (HIV) antibodies, 
hepatitis B surface antigen (HBsAg) and /or hepatitis C virus (HCV) antibodies. 
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4.2.3. Subjects with Hepatic Impairment
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, psychiatric, neurological, or allergic 
disease (including drug allergies, but excluding untreated, asymptomatic, seasonal 
allergies at the time of dosing).
2. Hepatic carcinoma or hepatorenal syndrome or life expectancy less than 1 year.
3. Prior portal-caval shunt surgery.  A subject with a transjugular intrahepatic 
portosystemic shunt (TIPS) is not excluded provided they meet the Child-Pugh 
criteria.
4. A positive alcohol test at screening or Day 0 (past history of alcohol abuse is 
permissible providing that the results of alcohol tests are negative at screening and on 
Day 0).
5. History of gastrointestinal hemorrhage due to esophageal varices or peptic ulcers less 
than 4 weeks prior to study entry.
6. Any clinically-significant laboratory abnormality except for those parameters 
influenced by hepatic impairment.
7. Positive serologic findings for human immunodeficiency virus (HIV) antibodies. 
8. Subjects with transaminases >5 × upper limit of normal (ULN).  Subjects with 
transaminases >5 × ULN may be considered for inclusion on a case-by-case basis if, 
in the opinion of the Investigator and Sponsor, these levels will not affect subject 
safety.
9. Signs of significant hepatic encephalopathy (> Grade II Portal Systemic 
Encephalopathy score).
10. Severe ascites and/or pleural effusion.
11. Prior kidney, heart or liver transplant.
12. Twelve (12)-lead ECG demonstrating QTcF >470 msec or a QRS interval >120 msec 
at screening.  If QTcF exceeds 470 msec, or QRS exceeds 120 msec, the ECG should 
be repeated two more times and the average of the three QTcF or QRS values should 
be used to determine the subject’s eligibility.
13. Screening supine BP 160 mm Hg (systolic) or 90 mm Hg (diastolic), on a single 
measurement following at least 5 minutes of rest. If BP is 160 mm Hg (systolic) or 
90 mm Hg (diastolic), the BP should be repeated two more times and the average of 
the three BP values should be used to determine the subject’s eligibility.
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4.3. Lifestyle Requirements 
The following guidelines are provided:
4.3.1. Meals and Dietary Restrictions

Subjects must abstain from all food and drink (except water) for at least 4 hours prior 
to any safety laboratory evaluations and to administration of study medication.  Water 
is permitted until 1 hour prior to study medication administration.  Water may be 
consumed without restriction beginning 1 hour after dosing.  Non-caffeinated drinks 
(except grapefruit or grapefruit-related citrus fruit juices – see below) may be 
consumed with meals and the evening snack.

Breakfast will be provided approximately 1 hour after dosing.

Lunch will be provided approximately 4 hours after dosing.

Dinner will be provided approximately 9 to 10 hours after dosing.

An evening snack may be permitted.

Meals will be provided following the site’s normal schedule on non-dosing days.

Subjects will not be allowed to eat or drink grapefruit or grapefruit-related citrus 
fruits (eg, Seville oranges, pomelos) from 7 days prior to the dose of study medication
until collection of the final PK blood sample. While in the clinical research unit 
(CRU), the total daily nutritional composition should be approximately 
55% carbohydrate, 30% fat and 15% protein.  The daily caloric intake per subject 
should not exceed approximately 3200 kcal.
4.3.2. Alcohol, Caffeine and Tobacco

Subjects will abstain from alcohol from 24 hours prior to admission to the CRU until 
collection of the final PK sample.  Healthy subjects with normal hepatic function may 
undergo an alcohol breath test or blood alcohol test at the discretion of the 
investigator.

Subjects will abstain from caffeine-containing products from 24 hours prior to the 
dose of study medication until collection of the final PK sample.  Subjects will 
abstain from the use of tobacco- or nicotine-containing products from 24 hours prior
to the dose of study medication until the end of their confinement in the research unit.  
4.3.3. Activity

Subjects will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, and aerobics) for at least 48 hours prior to each blood collection for 
safety laboratory tests.  Walking at a normal pace will be permitted.
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4.3.4. Contraception
4.3.4.1. Females - Childbearing Potential
Females of childbearing potential are excluded from participation.
4.3.4.2. Males
All fertile male subjects who are, in the opinion of the investigator, sexually active and at risk 
for pregnancy with their partner(s) must agree to use a highly effective method of 
contraception consistently and correctly for the duration of the active treatment period and 
for at least 28 days after the last dose of study medication.  The investigator or his or her 
designee, in consultation with the subject, will confirm that the subject has selected an
appropriate method of contraception for the individual subject and his partner from the 
permitted list of contraception methods (see below) and will confirm that the subject has 
been instructed in its consistent and correct use.  At time points indicated in the Schedule of 
Activities, the investigator or designee will inform the subject of the need to use highly 
effective contraception consistently and correctly and document the conversation and the 
subject’s affirmation in the subject’s chart (subjects need to affirm their consistent and 
correct use of at least 1 of the selected methods of contraception).  In addition, the 
investigator or 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
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 the following:
1. Established use of hormonal methods of contraception associated with inhibition of 
ovulation (eg, oral, inserted, injected, implanted, transdermal) provided subject or
male subject’s female partner 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 separate spermicide product (ie, foam, 
gel, film, cream, or 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).  
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NOTE: Sexual abstinence, defined as completely and persistently refraining from all 
heterosexual intercourse (including during the entire period of risk associated with the study 
treatments) may obviate the need for contraception ONLY if this is the usual and preferred 
lifestyle of the subject.
4.4. Sponsor’s 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 team SharePoint 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 product identifiers, subject study numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator 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 investigator
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigator site 
and the study team are not available. It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study. For sites other than 
a Pfizer CRU, the contact number is not intended for use by the subject directly, and if a 
subject calls that number, he or she will be directed back to the investigator site.
5. STUDY TREATMENTS
For the purposes of this study, and per International Conference 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 product is rivipansel (PF-06460031).  
5.1. Allocation to Treatment
The investigator will assign subject identification numbers sequentially to the subjects as 
they are screened for the study.  This identifying number will be retained throughout the 
study.  All subjects enrolled will receive a single IV dose of rivipansel 840 mg on Day 1. 
5.2. Subject Compliance
Investigational product will be administered under the supervision of investigative site 
personnel.  
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5.3. Investigational Product Supplies
5.3.1. Dosage Form and Packaging
Rivipansel (as the sodium salt) will be supplied by Pfizer in vials. Vials will contain 
rivipansel as a 30 mg/mL solution and the concentration of the solution is based on the active 
moiety.  Rivipansel is presented as a sterile, colorless to pale brown 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. The content of the rivipansel vials should be
clear, but a fine swirl or haze of particulate matter may be observed on agitation of the
solution.
Sterile vials will be packaged individually and supplied for subsequent unit dose preparation 
according to the Investigational Product Manual (IPM). Vial adapters and syringe filters will 
be supplied by Pfizer for dose preparation.  
5.3.2. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the investigational product ready for administration or dispensing to the subject/caregiver by 
qualified staff.  Dispensing is defined as the provision of investigational product, 
concomitant treatments, and accompanying information by qualified staff member(s) to a 
healthcare provider, subject, or caregiver in accordance with this protocol.  Local health 
authority regulations or investigator site guidelines may use alternative terms for these 
activities.  
Rivipansel sterile solution for IV infusion will be prepared according to details specified in 
the IPM.  This will include the requirement for the study drug to be filtered through a 
0.22 micron syringe filter upon transfer to the syringe that will be used for administration to 
the subject.  Investigational product should be prepared and dispensed by an appropriately 
qualified and experienced member of the study staff (eg, physician, nurse, physician’s 
assistant, nurse practitioner, pharmacy assistant/technician, or pharmacist) as allowed by 
local, state, and institutional guidance.  
5.3.3. Administration
Following an overnight fast of at least 4 hours, subjects will receive investigational product 
at approximately 0800 hours (2 hours).
Rivipansel will be infused over 20 2 minutes using an administration set that includes a 
0.2 or 0.22 micron in-line filter.  The details of the IV infusion will be described in the IPM.  
The start and stop time of the infusion will be recorded.
In order to standardize the conditions on PK sampling days, all subjects will be required to 
refrain from lying down (except when required for BP, pulse rate, and ECG measurements)
during the first 4 hours after dosing.  
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5.4. Investigational Product Storage
The investigator, or an approved representative, eg, pharmacist, will ensure that all 
investigational products are stored in a secured area with controlled access under required 
storage conditions and in accordance with applicable regulatory requirements.  
Investigational product should be stored in its original container and in accordance with the 
label. See the IPM for storage conditions of the product.
Any storage conditions stated in the SRSD (IB for this study) will be superseded by the
storage conditions stated on the product label. 
Site staff will follow the standard operating procedure (SOP) for temperature and relative 
humidity monitoring in the CRU pharmacy.  
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 investigational product receipt throughout the study.  Even for 
continuous monitoring systems, a log or site procedure that 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 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 it is 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 the storage 
conditions described in the labeling, 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 investigational product must be quarantined and not used 
until Pfizer provides permission to use the investigational product.  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. 
5.5. Investigational Product Accountability
The investigator site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All investigational products will be 
accounted for using a drug accountability form/record. 
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5.5.1. Destruction of Investigational Product Supplies 
The sponsor or designee will provide guidance on the destruction of unused investigational 
product.  If destruction is authorized to take place at the investigator 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.
5.6. Concomitant Treatment(s)
Healthy subjects with normal hepatic function will abstain from all concomitant treatments, 
except for the treatment of AEs, as described in the Healthy Subjects with Normal Hepatic 
Function section of this protocol.  Use of prescription drugs, vitamins, or dietary supplements 
within 7 days or 5 half-lives (whichever is longer) prior to administration of study medication 
is not allowed.  As an exception, acetaminophen may be used at doses of 1 g/day.  Limited 
use of nonprescription medications that are not believed to affect subject safety or the overall 
results of the study may be permitted on a case-by-case basis following approval by the 
sponsor.
For subjects with impaired hepatic function, treatments intended for other indications should 
be administered as usual (Subjects with Hepatic Impairment). 
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration.  
Treatments taken within 28 days before the dose of investigational product will be 
documented as prior treatments.  Treatments taken after the dose of investigational product
will be documented as concomitant treatments.  
6. STUDY PROCEDURES
6.1. Screening
Subjects will be screened within 28 days prior to administration of investigational product to 
confirm that they meet the subject eligibility criteria for the study.  The investigator (or an 
appropriate delegate at the investigator site) will obtain informed consent from each subject 
in accordance with the procedures described in the Subject Information and Consent section.  
If the time between screening and dosing exceeds 28 days as a result of unexpected delays 
(eg, delayed drug shipment), then subjects do not require re-screening if the Day 0 laboratory 
results meet the eligibility criteria.
The following procedures will be completed:

Obtain written informed consent.

Confirm and document that the subject meets inclusion and exclusion criteria.

Collect demography.
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
Collect height and weight.

Obtain medical history, including history of illegal drug, alcohol and tobacco use.

Obtain complete medication history of all prescription or nonprescription drugs, and 
dietary and herbal supplements taken within 28 days prior to the planned first dose.

Check reproductive status.

Perform contraception check.

Obtain single supine BP, pulse rate and temperature.

Conduct full physical examination.  

Perform supine 12-lead electrocardiogram (ECG).

Following at least a 4-hour fast, collect blood and urine specimens for the following:

Safety laboratory tests;

Serologic tests: HIV-1 antibody, HBsAg and HCV antibody;

Urine drug test;

Serum FSH concentration for any female subject who has been amenorrheic 
for at least 12 consecutive months with no alternative pathological or 
physiological cause.

Obtain breath or blood alcohol test (method based on discretion of the investigator) 
for hepatic impairment subjects.  For healthy subjects, the alcohol test can be done at 
the discretion of the investigator.  

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a non-leading question such as “How do you feel?”

Hepatic impairment subjects only: Perform Child-Pugh classification, encephalopathy 
and ascites evaluations within the 14 days prior to administration of study medication. 
Encephalopathy grade evaluation includes number connection test and blood 
ammonia level. Subjects should satisfy the criteria for Child-Pugh classification as 
Moderate Hepatic Impairment (Class B - Score 7-9). Perform a second screening 
visit for hepatic impairment subjects if a subject is not able to provide documentation 
of stable hepatic disease (ie, copy of recent laboratory tests, in addition to medical 
chart) within the last 30 days (no worsening clinical signs of hepatic impairment, or 
no worsening of total bilirubin or prothrombin time by more than 50%).  
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To prepare for study participation, subjects will be instructed on the information in the
Lifestyle Requirements and Concomitant Treatment(s) sections of the protocol.  
6.2. Study Period
For the study period described below, when multiple procedures are scheduled at the same 
time point(s) relative to dosing, the following chronology of events should be adhered to, 
where possible.

ECGs: obtain prior to vital signs measurements and as close as possible to the 
scheduled time, but prior to blood specimen collection;

BP/pulse rate: obtain as close as possible to the scheduled time, but prior to blood 
specimen collection;

PK blood specimens: obtain at the scheduled time;

All other procedures: obtain as close as possible to the scheduled time, but may be 
obtained before or after blood specimen collection.
When an IV catheter is utilized for blood sample collections, ECGs and vital sign (pulse rate
and BP and temperature) assessments should be collected prior to the insertion of the 
catheter.
6.2.1. Day 0
Subjects will be admitted to the CRU on Day 0. The following procedures will be completed
following admission to the CRU:

Review inclusion and exclusion criteria.

Review changes in the subject’s medical history including medication history since 
screening.

Conduct limited physical examination.

Obtain breath or blood alcohol test (method based on discretion of the investigator) 
for hepatic impairment subjects.  For healthy subjects, the alcohol test can be done at 
the discretion of the investigator.  

Obtain blood and urine samples for safety laboratory tests after fasting for at least 
4 hours.  The results must have no clinically significant findings, as judged by the 
investigator, in order for a subject to be given study medication on Day 1.

Collect urine for drug testing.
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
Hepatic impairment subjects only: Re-perform Child-Pugh classification (considered 
as baseline score), encephalopathy and ascites evaluations. Encephalopathy grade 
evaluation includes number connection test and blood ammonia level. Subjects 
should satisfy the criteria for Child-Pugh classification as Moderate Hepatic 
Impairment (Class B - Score 7-9).  

Assess baseline symptoms/AEs.

Provide standardized meals as described in the Lifestyle Requirements section.  
Subjects will begin fasting at least 4 hours prior to dosing on Day 1.
6.2.2. Day 1
Prior to dosing, the following procedures will be completed: 

Collect supine 12-lead ECG.

Obtain single supine BP, pulse rate and temperature.

Insert the IV catheter for collection of blood samples (optional).

Collect a blood sample for PK analysis.

Commence concomitant treatment monitoring.

Assess baseline symptoms/AEs.

After all pre-dose procedures have been completed and after fasting for at least 
4 hours, administer the study medication (see the STUDY TREATMENTS and 
Administration sections). 
After dosing, the following procedures will be completed:

Collect blood samples for PK analysis of rivipansel 0.33, 1, 3, 4, 6, 8, 10, 12 and 
16 hours after dosing.

Collect blood samples for determination of rivipansel unbound fraction 1 hour after
dosing.  

Obtain single supine BP and pulse rate 1, 4 and 8 hours after dosing.  Hour 4 and 
Hour 8 collections will be documented on source document only.

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a non-leading question such as “How do you feel?”

Monitor concomitant treatments.
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
Provide standardized meals 1, 4, and 10 hours after dosing as described in Lifestyle 
Requirements section.
6.2.3. Day 2
The following procedures will be completed:

Collect blood samples for PK analysis 24 and 36 hours after dosing on Day 1.

Obtain single supine BP, pulse rate and temperature.

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a non-leading question such as “How do you feel?”

Monitor concomitant treatments.

Provide standardized meal(s).  
6.2.4. Day 3
The following procedures will be completed:

Collect blood samples for PK analysis of rivipansel 48 hours after dosing on Day 1.

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a non-leading question such as “How do you feel?” 

Monitor concomitant treatments.

Provide standardized meal(s).  
6.2.5. Day 4

Collect blood samples for PK analysis of rivipansel 72 hours after dosing on Day 1.

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a non-leading question such as “How do you feel?” 

Monitor concomitant treatments.

Provide standardized meal(s).  
6.2.6. Day 5

Collect blood samples for PK analysis of rivipansel 96 hours after dosing on Day 1.

Conduct full physical examination.

Perform contraception check.
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
Collect supine 12-lead ECG.

Obtain single supine BP, pulse rate and temperature.

Collect blood and urine specimens for safety laboratory tests after a fast of at least 
4 hours.

Assess symptoms by spontaneous reporting of AEs and by asking the subjects to 
respond to a non-leading question such as “How do you feel?” 

Monitor concomitant treatments.

Provide standardized meal(s).  

Discharge from CRU confinement.  
If a subject has any clinically significant, study-related abnormalities at the conclusion of a 
scheduled inpatient portion of the study, the Pfizer medical monitor (or designated 
representative) should be notified and the subject may be asked to remain in the CRU until 
such abnormalities are no longer deemed clinically significant, or it is considered safe for 
outpatient follow-up.  If the subject is unable or unwilling to remain in the CRU and/or when 
outpatient follow-up is deemed appropriate, the Pfizer medical monitor (or designated 
representative) should be so notified, and the investigator should make every effort to arrange 
follow-up evaluations at appropriate intervals to document the course of the abnormalities.
6.3. Follow-up Contact

Each subject will have a follow-up phone call no earlier than 28 days and no later 
than 31 days after study medication administration to assess for AEs and SAEs.  
6.4. Subject Withdrawal/Early Termination
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 (see also the 
Withdrawal From the Study due to Adverse Events section) or behavioral reasons, or the 
inability of the subject to comply with the protocol-required schedule of study visits or 
procedures at a given investigator site.  The early termination visit applies only to subjects 
who are randomized and then are prematurely withdrawn from the study.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  The investigator or site staff should attempt to contact the subject twice.  After 
2 attempts, CRU staff may send a registered letter.  If no response is received from the 
subject, the subject will be considered lost to follow-up.  All attempts to contact the subject 
and information received during contact attempts must be documented in the subject’s 
medical record.  In any circumstance, every effort should be made to document subject 
outcome, if possible.  The investigator should inquire about the reason for withdrawal, 
request that the subject return for a final visit, if applicable, and follow-up with the subject 
regarding any unresolved AEs.
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It may be appropriate for the subject to return to the clinic for final safety assessments to be 
scheduled as early as practically feasible following the decision to withdraw from the study.  
Subjects should be questioned regarding their reason for withdrawal.  At the early withdrawal 
visit, every effort must be made to complete the following assessments:

Full physical examination, if there is a new or ongoing AE or clinically significant 
abnormal physical finding from the last visit;

Supine BP and pulse rate measurements;

12-lead ECG measurement;

Blood and urine specimens for safety laboratory tests after fasting for at least 4 hours;

Blood sample for PK analysis.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the subject’s safety was preserved.
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 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
Subjects who withdraw from the study may be replaced at the discretion of the investigator 
upon consultation with the sponsor.  
7. ASSESSMENTS
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside the control of the investigator that may make it unfeasible to perform 
the test.  In these cases, the investigator must 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 the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible.  The study team must be informed of these incidents in a timely manner.  
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.  
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7.1. Safety
7.1.1. Laboratory Tests
The following safety laboratory tests will be performed at times defined in the STUDY 
PROCEDURES section of this protocol.  Additional laboratory results may be reported on 
these samples as a result of the method of analysis or the type of analyzer used by the clinical 
laboratory; or as derived from calculated values.  These additional tests would not require 
additional collection of blood.  Unscheduled safety laboratory measurements may be 
obtained at any time during the study to assess any perceived safety concerns.
The laboratory tests shown in Table 2 will be performed at the timepoints stated in the
Schedule of Activities.
Table 2.
Safety Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils 
(Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
PT/INR
BUN/urea and Creatinine
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
pH
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopya
FSHb
Urine drug testc
Serologic tests: HIV-1 
antibody, HBsAg and 
HCV antibodyd
Additional Tests (If 
required for assessment 
of potential Hy’s law 
cases)
AST, ALT (repeat)
Total bilirubin (repeat)
Albumin (repeat)
Alkaline phosphatase 
(repeat)
Direct bilirubin
Indirect bilirubin
Creatine kinase
GGT
PT/INR
Total bile acids
Acetaminophen drug 
and/or protein adduct 
levels
a Only if urine dipstick is positive for blood, protein, nitrites or leukocyte esterase.
b At screening only, in females who are amenorrheic for at least 12 consecutive months to assess childbearing potential. 
c At screening and Day 0 only.
d At screening only.
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
The minimum requirement for drug testing includes cocaine, tetrahydrocannabinol 
(THC), opiates/opioids, benzodiazepines, and amphetamines.

Subjects may undergo random urine drug testing at the discretion of the investigator.  
Drug testing conducted prior to dosing must be negative for subjects to receive study 
medication. 

Any remaining serum/plasma from samples collected for safety laboratory 
measurements at baseline and at all times after dose administration may be retained 
and stored for the duration of the study. Upon completion of the study, retained 
safety samples may be used for the assessment of exploratory safety biomarkers or 
unexpected safety findings.  These data will not be included in the clinical study 
report (CSR).  Samples to be used for this purpose will be shipped to either a Pfizer 
approved Biospecimen Banking System (BBS) facility or other designated laboratory 
and retained for up to 1 year following the completion of the study.
7.1.2. Physical Examinations
Physical examinations may be conducted by a physician, trained physician's assistant, or 
nurse practitioner as acceptable according to local regulations.  A full physical examination 
will include assessment of head, ears, eyes, nose, mouth, skin, heart and lung examinations, 
lymph nodes and gastrointestinal, musculoskeletal, and neurological systems.  The limited or 
abbreviated physical examination will be focused on general appearance and the respiratory 
and cardiovascular systems, and subject-reported symptoms.
For measuring weight, a scale with appropriate range and resolution is used and must be 
placed on a stable, flat surface. Subjects must remove shoes, bulky layers of clothing, and 
jackets so that only light clothing remains.  They must also remove the contents of their 
pockets and remain still during measurement of weight. 
7.1.3. Blood Pressure and Pulse Rate
BP and pulse rate will be measured at times specified in the STUDY PROCEDURES section 
of this protocol.  Additional collection times, or changes to collection times of BP and pulse 
rate will be permitted, as necessary, to ensure appropriate collection of safety data.
Supine BP will be measured with the subject’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after approximately 5 minutes of rest.  The same arm 
(preferably the dominant arm) will be used throughout the study. Blood pressure should not 
be taken from the arm with an intravenous infusion. Subjects should be instructed not to 
speak during measurements.  
The same properly sized and calibrated BP cuff will be used to measure BP each time.  The 
use of an automated device for measuring BP and pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds.  When the timing of these measurements coincides with a blood collection, BP
and pulse rate should be obtained prior to the nominal time of the blood collection.  
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7.1.4. Temperature
Temperature will be measured orally.  No eating, drinking or smoking is allowed for 
15 minutes prior to the measurement.
7.1.5. Electrocardiogram 
ECGs should be collected at times specified in the STUDY PROCEDURES section of this 
protocol.
All scheduled ECGs should be performed after the subject has rested quietly for at least 
10 minutes in a supine position. 
To ensure safety of the subjects, a qualified individual at the investigator site will make 
comparisons to baseline measurements.  If the QTcF interval is increased by ≥45 msec from 
the baseline, or an absolute QTcF value is 500 msec for any scheduled ECG, then 
2 additional ECGs will be collected, approximately 2 to 4 minutes apart, to confirm the 
original measurement.  If either of the QTcF values from these repeated ECGs remains above 
the threshold value (ie, ≥45 msec from the baseline, or 500 msec), then a single ECG must 
be repeated at least hourly until QTcF values from 2 successive ECGs fall below the 
threshold value that triggered the repeat measurement. 
If QTcF values remain ≥500 msec (or ≥45 msec from the baseline) for greater than 4 hours 
(or sooner at the discretion of the investigator) or QTcF intervals get progressively longer, 
the subject should undergo continuous ECG monitoring.  A cardiologist should be consulted 
if QTcF intervals do not return to less than 500 msec (or to <45 msec above the baseline) 
after 8 hours of monitoring (or sooner at the discretion of the investigator).
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality.  It is important that leads are placed in the 
same positions each time in order to achieve precise ECG recordings.  If a machine-read 
QTcF value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTcF values are in the 
acceptable range.
7.2. Pharmacokinetics
7.2.1. Plasma for Pharmacokinetic Analysis of Rivipansel
During all study periods, blood samples 4.0 mL to provide a minimum of 1.5 mL plasma for 
PK analysis will be collected into appropriately labeled tubes containing K2EDTA at times 
specified in the STUDY PROCEDURES section of the protocol.  
The actual times may change but the number of samples will remain the same.  All efforts 
will be made to obtain the PK samples at the exact nominal time relative to dosing.  
However, samples obtained within 10% of the nominal time (eg, within 6 minutes of a 
60 minute sample) from dosing will not be captured as a protocol deviation, as long as the 
exact time of the sample collection is noted on the source document and data collection tool 
(eg, case report form [CRF]/DCT).
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
Samples will be centrifuged at approximately 1700 × g for about 10 minutes at 4C.  
The plasma will be stored in appropriately labeled screw-capped polypropylene tube 
at approximately -20C within 1-hour of collection. 

Samples will be analyzed using a validated analytical method in compliance with 
Pfizer SOPs.  

The PK samples must be processed and shipped as indicated in the instructions 
provided to the investigator site to maintain sample integrity.  Any deviations from 
the PK sample handling procedure (eg, sample collection and processing steps, 
interim storage or shipping conditions), including any actions taken, must be 
documented and reported to the sponsor.  On a case by case basis, the sponsor may 
make a determination as to whether sample integrity has been compromised.  Any 
deviation from the specified sample handling procedure resulting in compromised 
sample integrity will be considered a protocol deviation.  

As part of understanding the PK of the study drug, samples may be used for 
metabolite identification and/or evaluation of the bioanalytical method.  These data 
will be used for internal exploratory purposes and will not be included in the CSR.  
7.2.2. Plasma for Unbound Fraction Determination of Rivipansel
On Day 1, a blood sample (10.0 mL to provide a minimum of 5.0 mL plasma) for PK
analysis will be collected into appropriately labeled tubes containing K2EDTA at the time 
specified in the STUDY PROCEDURES section of the protocol.  Sample will be analyzed 
only if a PK difference in subject groups is observed.  
All efforts will be made to obtain the PK sample at the exact nominal time relative to dosing.  
However, a sample obtained within 10% of the nominal time (eg, within 6 minutes of a 
60 minute sample) from dosing will not be captured as a protocol deviation, as long as the 
exact time of the sample collection is noted on the source document and data collection tool 
(eg, CRF/DCT).

Samples will be centrifuged at approximately 1700 × g for about 10 minutes at 4C.  
The plasma will be stored in appropriately labeled screw-capped polypropylene tube 
at approximately -20C within 1-hour of collection. 

Samples will be analyzed using a validated analytical method in compliance with 
Pfizer SOPs.
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
The PK samples must be processed and shipped as indicated in the instructions 
provided to the investigator site to maintain sample integrity.  Any deviations from 
the PK sample handling procedure (eg, sample collection and processing steps, 
interim storage or shipping conditions), including any actions taken, must be 
documented and reported to the sponsor.  On a case by case basis, the sponsor may 
make a determination as to whether sample integrity has been compromised.  Any 
deviation from the specified sample handling procedure resulting in compromised 
sample integrity will be considered a protocol deviation.  

As part of understanding the PK of the study drug, samples may be used for 
metabolite identification and/or evaluation of the bioanalytical method.  These data 
will be used for internal exploratory purposes and will not be included in the CSR.  
7.3. Blood Volume
The total blood sampling volume for individual subjects in this study is approximately 
91 mL.  The actual collection times of blood sampling may change.  Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 60 consecutive 
days.
8. ADVERSE EVENT REPORTING
8.1. Requirements
The table below summarizes the requirements for recording safety events on the CRF and for 
reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report Form 
to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs; 
(2) non-serious adverse events (AEs); and (3) exposure to the investigational product under 
study during pregnancy or breastfeeding, and occupational exposure. 
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE
All
None
Exposure to the 
investigational product under 
study during pregnancy or 
breastfeeding, and 
occupational exposure
All (regardless of whether 
associated with an AE), 
except occupational 
exposure
Exposure during pregnancy
(EDP), exposure via 
breastfeeding, occupational 
exposure (regardless of 
whether associated with an 
AE)
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All observed or volunteered events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to an 
investigational product under study.  In particular, if the SAE is fatal or life-threatening, 
notification to Pfizer Safety must be made immediately, irrespective of the extent of available 
event information.  This time frame also applies to additional new (follow-up) information on 
previously forwarded reports.  In the rare situation that the investigator does not become 
immediately aware of the occurrence of an event, the investigator must report the event 
within 24 hours after learning of it and document the time of his/her first awareness of the 
event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the CRF.  In general, this will include 
a description of the event in sufficient detail to allow for a complete medical assessment of 
the case and independent determination of possible causality.  Any information relevant to 
the event, such as concomitant medications and 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 Safety.  Any pertinent additional information must be reported on the CT SAE 
Report Form; additional source documents (eg, medical records, CRF, laboratory data) are to 
be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious AE 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.
8.1.1. Additional Details on Recording Adverse Events on the CRF
All events detailed in the table above will be recorded on the AE page(s) of the CRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE Report 
Form for reporting of SAE information.
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8.1.2. Eliciting Adverse Event Information
The investigator is to record on the CRF all directly observed AEs and all AEs spontaneously 
reported by the study subject.  In addition, each study subject will be questioned about the 
occurrence of AEs in a non-leading manner.
8.1.3. Withdrawal From the Study Due to Adverse Events (see also the Subject 
Withdrawal section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the CRF. 
When a subject withdraws from the study because of an SAE, the SAE must be recorded on 
the CRF and reported, as appropriate, on the CT SAE Report Form, in accordance with the 
Requirements section above.
8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each subject begins from the time the subject provides informed consent, which 
is obtained before the subject’s participation in the study (ie, before undergoing any 
study-related procedure and/or receiving investigational product), through and including a 
minimum of 28 calendar days after the last administration of the investigational product.
For subjects who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a subject during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
SAEs occurring in a subject after the active collection period has ended are reported to Pfizer 
Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
8.1.4.2. Recording Non-serious AEs and SAEs on the CRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
CRF.
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.
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8.1.5. 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 on the CRF, and report such 
an assessment in accordance with the SAE reporting requirements, if applicable.  An 
investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product 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 investigational product caused the event, then 
the event will be handled as “related to investigational product” for reporting purposes, as 
defined by the sponsor.  If the investigator's causality assessment is “unknown but not 
related” to investigational product, this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study 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 signs and symptoms;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease;

Drug abuse;

Drug dependency.
Additionally, AEs may include signs and symptoms resulting from:

Drug overdose;
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
Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.
8.2.2. Abnormal Test Findings
Abnormal objective test findings should be recorded as AEs when any of the following 
conditions are met: 

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 (outside of any protocol-specified dose 
adjustments) 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 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 
recording as an AE.
8.2.3. 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);
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
Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.
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 
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.
8.2.4. 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 is assessed for medical importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

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 
workup of a persistent pretreatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);
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
Administrative admission (eg, for yearly physical examination);

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;

Preplanned 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 noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.
8.3. Severity Assessment
If required on the AE page of the CRF, 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 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some subjects, transaminase elevations are a harbinger of a more 
serious potential outcome.  These subjects fail to adapt and therefore are "susceptible" to 
progressive and serious liver injury, commonly referred to as drug-induced liver injury 
(DILI).  Subjects who experience a transaminase elevation above 3 times the upper limit of 
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normal (× ULN) should be monitored more frequently to determine if they are an “adaptor” 
or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions.  Subjects who present with the 
following laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) 
cases to definitively determine the etiology of the abnormal laboratory values:

Subjects with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For subjects with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting 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).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.  
The subject should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment.  .
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In addition to repeating measurements of AST and ALT and TBili, laboratory tests should 
include albumin, creatine kinase (CK), direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), total bile 
acids, alkaline phosphatase and acetaminophen drug and/or protein adduct levels.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (either by 
itself or as a coformulated product in prescription or over-the-counter medications), 
recreational drug, supplement (herbal) use and consumption, family history, sexual history, 
travel history, history of contact with a jaundiced person, surgery, blood transfusion, history 
of liver or allergic disease, and potential occupational exposure to chemicals, should be 
collected.  Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging 
(eg, biliary tract) may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
8.4.2. Exposure to the Investigational Product During Pregnancy or Breastfeeding, and 
Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.4.2.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an EDP occurs if:

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 investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

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).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
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If a subject or subject’s partner becomes or is found to be pregnant during the subject’s 
treatment with the investigational product, the investigator must report this information to 
Pfizer Safety on the CT 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) to Pfizer Safety 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 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 Safety 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 to Pfizer Safety 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 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product. 
Additional information regarding the EDP may be requested by the sponsor.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays).  In the case of paternal exposure, the 
investigator will provide the 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.
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8.4.2.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer 
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.
8.4.2.3. 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 Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a subject enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.4.3. Medication Errors
Other exposures to the investigational product under study may occur in clinical trial settings, 
such as medication errors.
Safety Event
Recorded on the CRF 
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors 
All (regardless of whether 
associated with an AE) 
Only if associated with an 
SAE 
8.4.3.1. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong subject, or at the wrong time, or at the wrong dosage strength. 
Medication errors include:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
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In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.  
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definition or its 
analysis will also be reflected in a protocol amendment.
9.1. Sample Size Determination
Hepatic impairment subjects will be enrolled based on their Child-Pugh scores at Screening
and Day 0.
Eight (8) subjects will be enrolled into each of the two study groups (moderate hepatic 
impairment and healthy with normal hepatic function).  
This is an estimation study.  The sample size is based on recommendations from the Food 
and Drug Administration (FDA) Guidance for Industry “Pharmacokinetics in Patients with 
Impaired Hepatic Function: Study Design, Data Analysis, and Impact on Dosing and 
Labeling.”23
9.2. Pharmacokinetic Analysis
The PK concentration population is defined as all subjects treated with study drug who have 
at least 1 concentration measurement.
The PK parameter analysis population is defined as all subjects treated with study drug who 
have at least 1 of the PK parameters of interest.
Analysis of variance (ANOVA) will be used to compare the natural log transformed AUCinf
(if data permit), AUClast and Cmax between normal hepatic function group and the impaired 
hepatic function group. The geometric least squares mean point estimate and the associated 
90% confidence intervals (CIs) for the difference of each comparison will be estimated. 
Rivipansel PK parameters AUCinf, Cmax, AUClast, Tmax, t½, CL Vsswill be summarized
descriptively by group.
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Boxplots of mean, median and individual subject parameters will be made across all the 
groups for AUCinf, AUClast and Cmax. Concentrations will be listed and summarized 
descriptively by PK sampling time and group. Summary profiles (means and medians) of the
concentration- time data will be plotted across different groups. Individual subject 
concentration time profiles will be also presented. For summary statistics and summary plots 
by sampling time, the nominal PK sampling time will be used, for individual subject plots by 
time, the actual PK sampling time will be used.
9.2.1. Plasma
PK parameters of rivipansel following single dose administration will be derived from the 
concentration-time profiles as follows:
Parameter
Definition
Method of Determination
AUClast
Area under the plasma concentration-time 
profile from time zero to time of the last 
quantifiable concentration (Clast)
Linear/Log trapezoidal rule
AUCinf
a
Area under the plasma concentration-time 
profile from time zero extrapolated to 
infinite time
AUClast + (Clast*/kel), where Clast* is the 
predicted plasma concentration at the 
last quantifiable time point estimated 
from the log-linear regression analysis
Cmax
Maximum plasma concentration
Observed directly from data
Tmax
Time for Cmax
Observed directly from data as time of 
first occurrence
t½
a
Terminal elimination half-life
Loge(2)/kel, where kel is the terminal 
phase rate constant calculated by a linear 
regression of the log-linear 
concentration-time curve. Only those 
data points judged to describe the 
terminal log-linear decline will be used 
in the regression
CLa
Total clearance of drug from plasma
Dose/AUCinf
Vss
a
Volume of distribution at steady state
CL * MRT, where MRT is the mean 
residence time
a If data permit
Actual PK sampling times and non-compartmental methods will be used in the derivation of 
PK parameters.
9.3. Safety Analysis
AEs, ECGs, BP, pulse rate, and safety laboratory data will be reviewed and summarized on 
an ongoing basis during the study to evaluate the safety of subjects.  Any safety laboratory, 
ECG, BP, or pulse rate abnormalities of potential clinical concern will be described.  Safety 
data will be presented in tabular and/or graphical format and summarized descriptively, 
where appropriate.
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Medical history and information from physical and/or neurological examination collected 
during the course of the study will be considered source data and will not be required to be 
reported, unless otherwise noted.  However, any untoward findings identified on physical 
and/or neurological examinations conducted during the active collection period will be 
captured as an AE, if those findings meet the definition of AEs. Data collected at screening 
that are used for inclusion/exclusion criteria, such as laboratory data, ECGs, and vital signs 
will be considered source data, and will not be required to be reported, unless otherwise 
noted.  Demographic data collected at screening will be reported.
9.4. Interim Analysis 
No formal interim analysis will be conducted for this study. However, as this is a 
sponsor-open study, the sponsor may conduct unblinded reviews of the data during the 
course of the study for the purpose of safety assessment, facilitating dose-escalation 
decisions, facilitating PK/PD modeling, and/or supporting clinical development.  Unblinded 
results will be reviewed by a designated limited number of sponsor colleagues within the 
study team. Refer to the study Data Blinding Plan and/or SAP for specific details including 
delineation of study team members who will be involved in these unblinded reviews as well 
as steps to be instituted ahead of initiation of any unblinded review to ensure study integrity 
is maintained.
9.5. Data Monitoring Committee 
This study will not use a data monitoring committee.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct for studies 
conducted at non-Pfizer investigator sites, 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/DCTs are 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.  This verification may also occur 
after study completion.
During study conduct and/or after study completion, the investigator site may be subject to 
review by the IRB/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.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study. Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection. The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the subject’s medical records. The investigator will promptly provide copies of the 
inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
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authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
For studies conducted at non-Pfizer investigator sites, 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/Data Collection Tools/Electronic Data Record
As used in this protocol, the term CRF/DCT 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/DCT is required and should be completed for each included subject.  The completed 
original CRFs/DCTs 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/DCTs 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/DCTs must be signed by the investigator or by an authorized staff 
member to attest that the data contained on the CRFs/DCTs are true. Any corrections to 
entries made in the CRFs/DCTs 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 or the physician's chart.  In these cases, 
data collected on the CRFs/DCTs must match those charts. 
In some cases, the CRF/DCT may also serve as the source document.  In these cases, a 
document should be available at the investigator site and at Pfizer that clearly identifies those 
data that will be recorded on the CRF/DCT, and for which the CRF/DCT will stand as the 
source document.  
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating subjects 
(sufficient information to link records, eg, CRFs/DCTs and hospital records), all original 
signed informed consent documents, copies of all CRFs/DCTs, safety reporting forms, source 
documents, detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.
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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.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent 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 the protocol, legal and regulatory 
requirements, and the general principles set forth in the International Ethical Guidelines for 
Biomedical Research Involving Human Subjects (Council for International Organizations of 
Medical Sciences 2002), ICH Guidelines for Good Clinical Practice, and the Declaration of 
Helsinki. 
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. 
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses,  and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study subjects. The investigator
site will maintain a confidential list of subjects who participated in the study, linking each 
subject’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws.
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The informed consent documents and any subject recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The informed consent documents used during the informed consent process and any subject 
recruitment materials must be reviewed and approved by Pfizer, approved by the IRB/EC
before use, and available for inspection.
The investigator must ensure that each study subject is fully informed about the nature and 
objectives of the study and possible risks associated with participation. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject, 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 document.
12.4. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, 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.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in the United States
Last subject last visit (LSLV) is defined as the date the investigator reviews the last subject’s 
final safety data and determines that no further evaluation is required for the subject to 
complete the trial.  
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product 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, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating subjects and the hospital pharmacy 
(if applicable) within 7 days.  As directed by Pfizer, all study materials must be collected and 
all CRFs/DCTs completed to the greatest extent possible.
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15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical study 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 (PCD) 
for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.
PCD 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 PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual patients have 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 supports the exercise of academic freedom and has no objection to publication by a 
principal investigator of the results of the study based on information collected or generated 
by the principal investigator, whether or not the results are favorable to the Pfizer product.
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
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publication or other type of disclosure of the results of the study (collectively, “publication”)
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before it is submitted 
for publication or otherwise disclosed. If any patent action is required to protect intellectual 
property rights, the investigator agrees to delay the disclosure for a period not to exceed an 
additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multi-center study, the investigator agrees that the first publication is 
to be a joint publication covering all investigator sites, and that any subsequent publications 
by the principal investigator will reference that primary publication. 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, the investigator is free to publish separately, 
subject to the other requirements of this section.
For all publications relating to the study, the institution 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 CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.
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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.
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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.
Schubert TT. Hepatobiliary system in sickle cell disease.  Gastroenterology. 
1986;90 :2013-21.
23.
Guidance for Industry: Pharmacokinetics in patients with impaired hepatic 
function - Study design, data analysis, and impact on dosing and labeling. FDA 
Guidance, March 2011.
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Appendix 1. Determination of Encephalopathy for the Calculation of the Child Pugh 
Score
For the calculation of the portosystemic encephalopathy (PSE) index the parameters are 
evaluated or determined as follows:
A = Degree of consciousness
According to the given grading of the table (clinical estimation of the investigating 
physician).
B = Number Connection Test
According to the table
C = Tremor
According to the table
D = Ammonia concentration in venous blood
According to the table normal values: 25-94 g/dL
The weighting is according to the given formula 3×A+B+C+D, and the index calculated by 
multiplication by 100 and division by 24 (see below).
In deviation from the PSE index form, however, a maximum of only 24 score can be attained 
in total (not 25).
The evaluation was then done according to the following grading:
PSE-Index (%)
Normal:

0: no encephalopathy
Moderate:

1-25: encephalopathy grade I

26-50: encephalopathy grade II
Severe:

51-75: encephalopathy grade III

76-100: encephalopathy grade IV grade severe
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Portosystemic Encephalopathy (PSE) Examination
PSE-Index
A 
Grade of consciousness
0 = no abnormality
1= slight absence, phobia, euphoria, shortened attention
2 = lethargy, chronotaraxis, personality change, strange behavior
3 = somnolence, semistupor
4 = coma
B 
Number of Connection test
0 = <30 sec
1 = 31-50 sec
2 = 51-80 sec
3 = 81-120 sec
4 = >120 sec
C 
Tremor (arms and hands, ca 30 sec stretched)
0 = no tremor
1 = rare tremor
2 = occasional tremor, not regularly
3 = frequent tremor
4 = continuous tremor
D
Ammonia Concentration in venous blood 
0 = 10% elevated above ULN
1 = 11 - 60% elevated above ULN
2 = 61 - 86% elevated above ULN
3 = 87 - 123% elevated above ULN
4 = >124% elevated above ULN
PSE-sum = 3×A+B+C+D (max 24 scores) 
PSE-Index (%) = (PSE-sum x 100)/24

26-50: encephalopathy grade II
Severe:

51-75: encephalopathy grade III

76-100: encephalopathy grade IV grade severe
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Appendix 2. Abbreviations 
The following is a list of abbreviations that may be used in the protocol.  
Abbreviation
Term
AE
adverse event
Abs
absolute
ACS
acute chest syndrome
ADR
Adverse Drug Reaction
ALT
alanine transaminase
ANOVA
analysis of variance
AST
aspartate transaminase
AUC
area under the curve
AUCinf
area under the concentration-time curve from time 0 to infinity
AUClast
area under the concentration-time curve from time 0 to the time of the 
last quantifiable concentration
BBS
Biospecimen Banking System
BMI
body mass index
BP
blood pressure
BPM
beats per minute
BUN
blood urea nitrogen
CI
confidence interval
CL/F
apparent oral clearance
CLr
renal clearance
Cmax
peak or maximum observed concentration
CO2
carbon dioxide (bicarbonate)
CRF
case report form
CRU
clinical research unit
CSA
clinical study agreement
CSR
clinical study report
CT
computed tomography
CTA
clinical trial application
DCT
data collection tool
DILI
drug-induced liver injury
EC
ethics committee
ECG
electrocardiogram
EDP
exposure during pregnancy
EDTA
edetic acid (ethylenediaminetetraacetic acid)
eGFR
estimated glomerular filtration rate
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United States)
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
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Abbreviation
Term
GGT
gamma-glutamyl transpeptidase
GMI
Glycomimetics
Hb
hemoglobin
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ID
identification
IND
investigational new drug application
INR
international normalized ratio
IPM
Investigational Product Manual
IRB
institutional review board
IUD
intrauterine device
IV
intravenous
K2EDTA
dipotassium ethylene diamine tetraacetic acid
LFT
liver function test
LSLV
last subject last visit 
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MDRD
Modification of Diet in Renal Disease
MRI
magnetic resonance imaging
N/A
not applicable
PCD
primary completion date
PD
pharmacodynamic
PK
pharmacokinetic(s)
PT
prothrombin time
QTc
QT corrected for heart rate
QTcF
QTc using Fridericia’s formula
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SCD
Sickle Cell Disease
SD
standard deviation
SOP
standard operating procedure
SRSD
single reference study document
t½
terminal half-life
TEAE
treatment-emergent adverse event
TIPS
transjugular intrahepatic portosystemic shunt
Tmax
time to reach maximum concentration
THC
tetrahydrocannabinol
TBili
total bilirubin
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Abbreviation
Term
ULN
upper limit of normal
US
United States
VOC
vaso-occlusive crisis
Vss
volume of distribution at steady state
WBC
white blood cell
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SAP_001.pdf: 
Protocol B5201006 (PF-06460031) Statistical Analysis Plan
Page 1 of 14
         
DMB02-GSOP-RF18 2.0 STATISTICAL ANALYSIS PLAN TEMPLATE FOR HEPATIC IMPAIRMENT 
STUDY 
30-Jun-2015
TMF Doc ID: 98.03
Protocol B5201006
A PHASE 1, NON-RANDOMIZED, OPEN-LABEL, PARALLEL-
GROUP SINGLE-DOSE STUDY TO EVALUATE THE 
PHARMACOKINETICS, SAFETY, AND TOLERABILITY OF 
INTRAVENOUS RIVIPANSEL (PF-06460031) IN SUBJECTS 
WITH MODERATE HEPATIC IMPAIRMENT AND IN 
HEALTHY SUBJECTS WITH NORMAL HEPATIC FUNCTION
Statistical Analysis Plan 
(SAP)
Version:
1.0
SAP Author: 
(Clinical Statistician – Shanghai)
Date:
02 SEP 2016
PPD
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TMF Doc ID: 98.03
Revision History
Version
Date
Author(s)
Summary of Changes/Comments
Version 1.0
Aug 03rd, 2016
This is an initial version based on the final 
protocol dated on 27Jun2016.
List of Reviewers
Role Name
Reviewer’s Name
Clinician
Clin Pharm Clinician
Clinical Lead
Clinical Statistician
Regulatory Lead
Clinical Programming
Clinical Operations Study Team Lead
Data Analysis & Reporting Lead
NOTE: Italicized text within this document has been taken verbatim from the Protocol.
PPD
PPD
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TMF Doc ID: 98.03
TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
APPENDICES ...........................................................................................................................4
1. AMENDMENTS FROM PREVIOUS VERSION(S) ...........................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Design .............................................................................................................5
2.2. Study Objectives .......................................................................................................6
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING..................................7
4. HYPOTHESES AND DECISION RULES...........................................................................7
4.1. Statistical Hypotheses ...............................................................................................7
4.2. Statistical Decision Rules..........................................................................................7
5. ANALYSIS SETS .................................................................................................................7
5.1. Pharmacokinetic (PK) Analysis Set ..........................................................................7
5.1.1. Concentration Analysis Set...........................................................................7
5.1.2. Parameter Analysis Set.................................................................................7
5.2. Pharmacodynamic Analysis Set................................................................................7
5.3. Safety Analysis Set....................................................................................................7
5.4. Other Analysis Sets ...................................................................................................7
5.5. Treatment Misallocations..........................................................................................8
5.6. Protocol Deviations...................................................................................................8
5.6.1. Deviations Assessed Prior to Randomization...............................................8
5.6.2. Deviations Assessed Post-Randomization....................................................8
6. ENDPOINTS AND COVARIATES .....................................................................................8
6.1. Efficacy Endpoint(s) .................................................................................................8
6.2. Safety Endpoints .......................................................................................................8
6.3. Other Endpoints.........................................................................................................9
6.3.1. PK Endpoints................................................................................................9
6.3.2. PD Endpoints................................................................................................9
6.4. Covariates..................................................................................................................9
7. HANDLING OF MISSING VALUES ..................................................................................9
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7.1. Concentrations below the Limit of Quantification....................................................9
7.2. Deviations, Missing Concentrations and Anomalous Values .................................10
7.3. Pharmacokinetic Parameters ...................................................................................10
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES ..........................10
8.1. Statistical Methods ..................................................................................................10
8.2. Statistical Analyses .................................................................................................10
8.3. Safety Analysis........................................................................................................12
8.3.1. Treatment and Disposition of Subjects.......................................................12
8.3.2. Demographic and Clinical Examination Data............................................12
8.3.3. Discontinuation(s).......................................................................................12
8.3.4. Adverse Events...........................................................................................13
8.3.5. Laboratory Data..........................................................................................13
8.3.6. Vital Signs Data..........................................................................................13
8.3.7. ECG Data....................................................................................................13
8.3.8. Other Safety Data .......................................................................................13
8.3.9. Concomitant Treatments.............................................................................13
8.3.10. Screening and Other Special Purpose Data ..............................................13
9. REFERENCES ....................................................................................................................13
10. APPENDICES ...................................................................................................................14
LIST OF TABLES
Table 1.
Child-Pugh Classification.......................................................................................6
Table 2.
Noncompartmental PK Parameters.........................................................................9
Table 3.
PK Parameters to be Summarized Descriptively by Group..................................11
APPENDICES
Appendix 1. SAS CODE FOR ANALYSES...........................................................................14
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1. AMENDMENTS FROM PREVIOUS VERSION(S) 
None.
2. INTRODUCTION
Rivipansel is being developed as a pan-selectin antagonist for the treatment of vaso-
occlusive crisis (VOC) in subjects with Sickle Cell Disease (SCD). Both children and adults 
are affected, and greater mortality is seen in those with more severe disease.
Although rivipansel is known to be primarily eliminated by the kidney (>90% of dose 
excreted in urine based on data from the Single Ascending Dose study GMI-1070-101), 
hepatic function can have an effect on the PK of drugs for which the excretion is primarily 
renal. This study is therefore being conducted to evaluate the effect of hepatic impairment on 
the PK, safety and tolerability of rivipansel. Results from this study will be used in 
conjunction with collective safety, efficacy, and PK/pharmacodynamic (PD) data from other 
rivipansel studies to provide recommendations on dosing for subjects with hepatic 
impairment.
A single 840 mg dose of IV rivipansel will be used in this study as it is the dose selected for 
maintenance dosing in the rivipansel Phase 3 program. IV doses of rivipansel as high as 4 g 
(as a single dose) have been well tolerated in healthy volunteers. In the Phase 2 study 
multiple doses, using a loading dose of 40 mg/kg followed by doses of 20 mg/kg given every 
12 hours for up to 7 days were also well tolerated. Therefore, it is expected that potential 
increases in exposure due to hepatic impairment with a single dose of 840 mg should not 
pose a safety concern. Single-dose administration was chosen because time-independent PK 
of rivipansel have been demonstrated at the anticipated concentrations, and thus single-dose 
PK will be able to adequately predict multiple-dose PK.
2.1. Study Design
This study is a Phase 1 open-label, single-dose, single-treatment, non-randomized study of
rivipansel in subjects with moderate hepatic impairment and healthy subjects with normal
hepatic function. Since rivipansel is primarily eliminated renally, a reduced study design
with two groups (control subjects and subjects with moderate hepatic impairment) was
considered adequate to characterize the PK in subjects with hepatic impairment. The Child-
Pugh Score will be utilized to assess entry criteria and to assign subjects to the appropriate 
hepatic-impairment group. Child-Pugh assessments will be performed within the 14 days 
prior to study medication administration and Day 0 (baseline). Subjects should satisfy the 
criteria for Child-Pugh classification as Moderate Hepatic Impairment (Class B Score 7-9) 
for both assessments in order to be enrolled into the study. The subjects’ hepatic function 
will be ranked based on clinical signs and liver function test results (Table 1).
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DMB02-GSOP-RF18 2.0 STATISTICAL ANALYSIS PLAN TEMPLATE FOR HEPATIC IMPAIRMENT 
STUDY        30-Jun-2015
TMF Doc ID: 98.03
Table 1.
Child-Pugh Classification
Assessment Parameters
Assigned Score for Observed Findings
1 point
2 points
3 points
Encephalopathy Grade a
0
1 or 2
3 or 4
Ascites
Absent
Slight
Moderate
Serum bilirubin (mg/dL)
<2
2 to 3
>3
Serum albumin (g/dL)
>3.5
2.8 to 3.5
<2.8
Prothrombin time 
(seconds prolonged)
<4
4 to 6
>6
Classification of clinical severity:
Mild (Class A): Total score 5-6 points
Moderate (Class B): Total score 7-9 points
Severe (Class C): Total score >9 points
a. Grade 0: Normal consciousness, personality, neurological examination, electroencephalogram.
    Grade 1: Restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps (cycles per sec) 
    waves.
    Grade 2: Lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves.
    Grade 3: Somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slow waves.
    Grade 4: Unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity.
A total of approximately 16 subjects will be enrolled; 8 subjects with moderate hepatic 
impairment and 8 healthy subjects with normal hepatic function. Healthy subjects with 
normal hepatic function will be enrolled after all of the subjects with moderate hepatic 
impairment have completed the in-patient portion of the study and will be matched for age, 
weight, and gender to the mean demographics of subjects in the moderate hepatic 
impairment group. Healthy subjects with normal hepatic function will be enrolled to enable 
comparison of PK parameters between healthy subjects and subjects with moderate hepatic 
impairment.
Subjects who withdraw from the normal hepatic function or moderate hepatic impairment 
groups for non-safety related reasons and who are considered to be non-evaluable with 
respect to the primary PK objective will be replaced at the discretion of the investigator and 
sponsor such that the number of completed subjects in each group equals eight.
2.2. Study Objectives
Primary Objectives

To evaluate the effect of moderate hepatic impairment on the PK of rivipansel 
following a single 840 mg IV dose.
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DMB02-GSOP-RF18 2.0 STATISTICAL ANALYSIS PLAN TEMPLATE FOR HEPATIC IMPAIRMENT 
STUDY        30-Jun-2015
TMF Doc ID: 98.03

To evaluate the safety and tolerability of a single 840 mg IV dose of rivipansel in 
subjects with moderate hepatic impairment and in healthy subjects with normal 
hepatic function.
Secondary Objective

To evaluate the effect of moderate hepatic impairment on additional PK parameters 
for rivipansel following a single 840 mg IV dose.
3. INTERIM ANALYSES, FINAL ANALYSES AND UNBLINDING
No interim analysis is planned.  Final analysis will follow the official database release.  As 
this will be an open-label study, there is no formal unblinding of the randomization code.
4. HYPOTHESES AND DECISION RULES
4.1. Statistical Hypotheses
No hypotheses are required.
4.2. Statistical Decision Rules
No decision rules are required.
5. ANALYSIS SETS
5.1. Pharmacokinetic (PK) Analysis Set
5.1.1. Concentration Analysis Set
The PK concentration population is defined as all subjects treated who have at least 1 
concentration.
5.1.2. Parameter Analysis Set
The PK parameter analysis population is defined as all subjects treated who have at least 1 
of the PK parameters of primary interest.
5.2. Pharmacodynamic Analysis Set
None.
5.3. Safety Analysis Set
All subjects who receive at least 1 dose of study medication will be included in the safety 
analyses and listings.
5.4. Other Analysis Sets
None.
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DMB02-GSOP-RF18 2.0 STATISTICAL ANALYSIS PLAN TEMPLATE FOR HEPATIC IMPAIRMENT 
STUDY        30-Jun-2015
TMF Doc ID: 98.03
5.5. Treatment Misallocations 
All analyses will be performed on an “as-treated” basis and will not include data from 
subjects who are randomized but not treated.
5.6. Protocol Deviations
Subjects who experience events that may affect their PK profile (eg lack of compliance with 
dosing) may be excluded from the PK analysis.  At the discretion of the pharmacokineticist a 
concentration value may also be excluded if the deviation in sampling time is of sufficient 
concern or if the concentration is anomalous for any other reason.
A full list of protocol deviations will be compiled and reviewed to identify major and minor 
deviations prior to database closure.
5.6.1. Deviations Assessed Prior to Randomization
At Screening, the investigator will assess subjects against the inclusion and exclusion criteria 
as set out in Sections 4.1 and 4.2 of the protocol.
5.6.2. Deviations Assessed Post-Randomization
A full list of protocol deviations for the study report will be compiled prior to database 
closure.  Any significant deviation from the protocol will be reviewed prior to database 
closure and a decision taken regarding evaluation for each analysis population.
6. ENDPOINTS AND COVARIATES
6.1. Efficacy Endpoint(s)
None.
6.2. Safety Endpoints
Any events occurring or increasing in severity following start of treatment will be counted as 
treatment emergent.
Events that occur in the Follow-up period will be counted as treatment emergent and 
causality attributed to the treatment taken.
The following data are considered in standard safety summaries (see protocol for collection 
days and list of parameters):

Adverse events,

Laboratory data,

Vital signs data,

ECG results.
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DMB02-GSOP-RF18 2.0 STATISTICAL ANALYSIS PLAN TEMPLATE FOR HEPATIC IMPAIRMENT 
STUDY        30-Jun-2015
TMF Doc ID: 98.03
6.3. Other Endpoints
6.3.1. PK Endpoints
Blood samples for PK analysis of PF-06460031will be collected according to the Schedule of 
Activities given in the protocol.
The following PK parameters will be calculated for PF-06460031 (if possible) from the 
concentration-time data using standard non-compartmental methods:
Table 2.
Noncompartmental PK Parameters
PK Parameter
Analysis 
Scale
PF-06460031
AUCinf
*
ln
A, D
AUClast
ln
A, D
Cmax
ln
A, D
Tmax
R
D
t1/2
*
R
D
CL*
ln
D
Vss
*
ln
D
Key:
A=analyzed using statistical model, D=displayed with descriptive statistics,
ln=natural-log transformed, R=raw (untransformed), *=if data permits
6.3.2. PD Endpoints
None.
6.4. Covariates
None.
7. HANDLING OF MISSING VALUES
For the analysis of safety endpoints, the sponsor data standard rules for imputation will be 
applied.
7.1. Concentrations below the Limit of Quantification
In all data presentations (except listings), concentrations below the limit of quantification 
(BLQ) will be set to zero.  (In listings BLQ values will be reported as “<LLQ”, where LLQ 
will be replaced with the value for the lower limit of quantification).
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DMB02-GSOP-RF18 2.0 STATISTICAL ANALYSIS PLAN TEMPLATE FOR HEPATIC IMPAIRMENT 
STUDY        30-Jun-2015
TMF Doc ID: 98.03
7.2. Deviations, Missing Concentrations and Anomalous Values
In summary tables and plots of median profiles, statistics will be calculated having set 
concentrations to missing if 1 of the following cases is true:
1. A concentration has been recorded as ND (ie not done) or NS (ie no sample),
2. A deviation in sampling time is of sufficient concern or a concentration has been 
flagged anomalous by the pharmacokineticist.
Note that summary statistics will not be presented at a particular time point if more than 50% 
of the data are missing.
7.3. Pharmacokinetic Parameters
Actual PK sampling times will be used in the derivation of PK parameters.
If a PK parameter cannot be derived from a subject’s concentration data, the parameter will 
be coded as NC (ie not calculated). (Note that NC values will not be generated beyond the 
day that a subject discontinues).
In summary tables, statistics will be calculated by setting NC values to missing; and statistics 
will be presented for a particular hepatic function group with ≥3 evaluable measurements.  
For statistical analyses (ie analysis of variance), PK parameters coded as NC will also be set 
to missing and analyses will not be performed for a particular parameter if more than 50% of 
the data are NC.
If an individual subject has a known biased estimate of a PK parameter (due for example to 
an unexpected event such as vomiting before all the compound is adequately absorbed in the 
body), this will be footnoted in summary tables and will not be included in the calculation of 
summary statistics or statistical analyses.
8. STATISTICAL METHODOLOGY AND STATISTICAL ANALYSES
8.1. Statistical Methods
The effect of hepatic impairment on PK parameters will be assessed by constructing 90% 
confidence intervals around the estimated differences between the Test (impaired hepatic 
function group) and the Reference (normal hepatic function group) PK parameters using a 
one-way ANOVA model based on natural log transformed data.
8.2. Statistical Analyses
Analysis of variance (ANOVA) will be used to compare the natural log transformed AUCinf
(if data permit), AUClast and Cmax between normal hepatic function group and the impaired
hepatic function group. Estimates of the adjusted mean differences (Test-Reference) and 
corresponding 90% confidence intervals will be obtained from the model.  The adjusted 
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DMB02-GSOP-RF18 2.0 STATISTICAL ANALYSIS PLAN TEMPLATE FOR HEPATIC IMPAIRMENT 
STUDY        30-Jun-2015
TMF Doc ID: 98.03
mean differences and 90% confidence intervals for the differences will be exponentiated to 
provide estimates of the ratio of adjusted geometric means (Test/Reference) and 90% 
confidence intervals for the ratios. The normal hepatic function group will be the Reference 
group and the impaired hepatic function group will be Test group.
Residuals from the models will be examined for normality and the presence of outliers via 
visual inspection of plots of residuals vs predicted values and normal probability plots of 
residuals, but these will not be included in the clinical study report.  If there are major 
deviations from normality or outliers then the effect of these on the conclusions will be 
investigated through alternative transformations and/or analyses excluding outliers.  
Justification for any alternative to the planned analyses will be provided in the report of the 
study.
The following PK parameters will be summarized by hepatic function group:
Table 3.
PK Parameters to be Summarized Descriptively by Group
Parameter
Summary Statistics
AUClast, AUCinf, 
Cmax, CL and Vss
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum, geometric mean and geometric cv%.
Tmax
N, median, minimum, maximum.
t1/2
N, arithmetic mean, median, cv%, standard deviation, minimum, 
maximum.
Box and whisker plots for individual subject parameters (AUCinf, AUClast and Cmax) will be 
presented by hepatic function group and overlaid with geometric means.
Supporting data from the estimation of t½ and AUCinf will be listed by hepatic function 
group:  terminal phase rate constant (kel); goodness of fit statistic from the log-linear 
regression (r2); the percent of AUCinf based on extrapolation (AUCextrap%); and the first, last, 
and number of time points used in the estimation of kel. This data may be included in the 
clinical study report.
Presentations for PF-06460031 concentrations will include:

A listing of all concentrations sorted by hepatic function group (present in heading), 
subject id and nominal time postdose.  The concentration listing will also include the 
actual times.  Deviations from the nominal time will be provided in a separate listing.

A summary of concentrations by hepatic function group and nominal time postdose, 
where the set of statistics will include n, mean, median, standard deviation, coefficient of 
variation (cv), minimum, maximum and the number of concentrations above the lower 
limit of quantification.
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DMB02-GSOP-RF18 2.0 STATISTICAL ANALYSIS PLAN TEMPLATE FOR HEPATIC IMPAIRMENT 
STUDY        30-Jun-2015
TMF Doc ID: 98.03

Median concentrations time plots (on both linear and semi-log scales) against nominal 
time postdose by hepatic function group (both hepatic function groups on the same plot 
per scale, based on the summary of concentrations by hepatic function group and time 
postdose).

Mean concentrations time plots (on both linear and semi-log scales) against nominal time 
postdose by hepatic function group (both hepatic function groups on the same plot per 
scale, based on the summary of concentrations by hepatic function group and time 
postdose).

Individual concentration time plots by hepatic function group (on both linear and semi-
log scales) against actual time postdose (there will be separate spaghetti plots for each 
hepatic function group per scale).
For summary statistics and median/mean plots by sampling time, the nominal PK sampling 
time will be used. For individual subject plots by time, the actual PK sampling time will be 
used.
8.3. Safety Analysis
A set of summary tables split by hepatic function group will be produced to evaluate any 
potential risk associated with the safety and toleration of administering PF-06460031.
8.3.1. Treatment and Disposition of Subjects
Subject evaluation groups will show end of study subject disposition and will show which 
subjects were analyzed for pharmacokinetics, as well as for safety (adverse events and 
laboratory data).  Frequency counts will be supplied for subject discontinuation(s) by hepatic 
function group.
Data will be reported in accordance with the sponsor reporting standards.
8.3.2. Demographic and Clinical Examination Data
A break-down of demographic data will be provided for age, race, weight, body mass index, 
and height.  Each will be summarized by sex at birth and ‘All Subjects’ in accordance with 
the sponsor reporting standards.
8.3.3. Discontinuation(s)
Subject discontinuations due to adverse events will be detailed and summarized by hepatic 
function group.
Data will be reported in accordance with the sponsor reporting standards.
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DMB02-GSOP-RF18 2.0 STATISTICAL ANALYSIS PLAN TEMPLATE FOR HEPATIC IMPAIRMENT 
STUDY        30-Jun-2015
TMF Doc ID: 98.03
8.3.4. Adverse Events
Adverse events will be reported in accordance with the sponsor reporting standards by 
hepatic function group.
8.3.5. Laboratory Data
Laboratory data will be listed and out of range values will be summarized in accordance with 
the sponsor reporting standards.
8.3.6. Vital Signs Data
The baseline measurement is the last pre-dose measurement.
These data will be listed and out of range values will be summarized in accordance with the 
sponsor reporting standards.
8.3.7. ECG Data
The baseline measurement is the pre-dose measurement.
These data will be listed and out of range values will be summarized in accordance with the 
sponsor reporting standards.
8.3.8. Other Safety Data
None.
8.3.9. Concomitant Treatments
All concomitant medication(s) as well as non-drug treatment(s) will be provided in the 
listings.
8.3.10. Screening and Other Special Purpose Data
Prior medication(s) and non-drug treatment(s), serum FSH concentrations, , reproductive 
status and, and alcohol test will be obtained at Screening.
These data will not be brought in-house, and therefore will not be listed.
9. REFERENCES
None.
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DMB02-GSOP-RF18 2.0 STATISTICAL ANALYSIS PLAN TEMPLATE FOR HEPATIC IMPAIRMENT 
STUDY        30-Jun-2015
TMF Doc ID: 98.03
10. APPENDICES
Appendix 1. SAS CODE FOR ANALYSES
An example of the PROC Mixed code is provided below:
proc mixed data=tab.pk  covtest alpha=0.1;
class group;
model l&var=group/ alpha=0.1 CL DDFM=KR;
lsmeans group;
estimate 'Moderate vs Normal'
group 1 -1;
            ods output lsmeans = lsmeans&var;
ods output solutionf = solution&var;
run;
/* Letter assignments for group within the estimate statement above are as follows;
A = Moderate (Test);
B = Normal (Reference);
*/;
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