Phase 2 Placebo-Controlled, Single-Site, Single-Blind Study of Rivaroxaban Reversal by Ciraparantag as Measured by WBCT
Phase: PHASE2
Conditions: Healthy
Sponsor: Perosphere Pharmaceuticals Inc, a wholly owned subsidiary of AMAG Pharmaceuticals, Inc.

Clinical Trial Protocol: PER977-02-012
Study Title: Phase 2 Placebo-Controlled, Single-Site, Single-
Blind Study of Rivaroxaban Reversal by Ciraparantag as 
Measured by WBCT
Document Date: Version 6, 02May2019
NCT: NCT03172910

Ciraparantag 
Perosphere Inc. 
Clinical Trial Protocol: PER977-02-012 
02May2019 
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Page 1 of 97 
Clinical Trial Protocol: PER977-02-012 
Study Title: 
Phase 2 Placebo-Controlled, Single-Site, Single-Blind Study of 
Rivaroxaban Reversal by Ciraparantag as Measured by WBCT  
Study Number: 
PER977-02-012 
Study Phase: 
2 
Product Name: 
Ciraparantag 
IND Number: 
117,224 
Indication: 
Reversal of edoxaban, rivaroxaban, apixaban, dabigatran, or 
enoxaparin-induced anticoagulation when medically indicated.  
Investigators: 
Sponsor: 
Perosphere Inc., a wholly-owned subsidiary of AMAG 
Pharmaceutical 
Sponsor Contact: 
Medical Monitor: 
Protocol Version: 
6 
Date 
Version 6: 
02May2019 
Confidentiality Statement 
Acceptance of this document constitutes the agreement by the recipient that no unpublished information 
contained herein will be published or disclosed without prior written approval of Perosphere Inc. except that 
this document may be disclosed to appropriate Institutional Review Boards/Institutional Ethics Committee so 
long as they and anyone else to whom this Protocol may be made available are informed that this is considered 
confidential information within the meaning of the Federal Food, Drug, and Cosmetic Act [21 U.S.C. 331 (j)], 
the Freedom of Information Act (5 U.S.C. 552) or the Trade Secrets Act (18 U.S.C. 1905), and may not be 
revealed or disclosed without prior written authorization of Perosphere Inc., Danbury CT 06810.  Any 
secondary recipients to whom the original recipient entrusts this documents thereby acknowledges that this is a 
confidential communication and agree to keep it confidential in the same manner in which the recipient has 
agreed to do so.  

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Item 
Revision in Version 6.0  
Page 1, 
Investigator, 
Sponsor, Sponsor 
Contact, Medical 
Monitor, Protocol 
Version Number 
Sponsor Name 
change- page 18 
Change from: 
Investigators: 
 
Sponsor: Perosphere, Inc 
Sponsor Contact: 
 
Medical Monitor: 
 
Protocol Version: 5 
To: 
Investigators: 
 
Sponsor: Perosphere Inc., a wholly owned subsidiary of AMAG 
Pharmaceutical 
Sponsor Contact: 
 
Medical Monitor: 
 
Protocol Version: 6 
Date of Final Document 
Summary of Main Changes Made in Version 4.0 to Generate Version 5.0 
Item 
Revision in Version 5.0  
Inclusion criteria 
#6  
 
In synopsis on 
page 17 and 18.  
 
In section 4.3 on 
page 48 and 49 
To clarify and modify pregnancy screen procedure. 
Changed from “Female subjects must have a negative urine pregnancy 
test at screening AND: be surgically sterile (with documentation of 
hysterectomy, bilateral oophorectomy, bilateral salpingectomy, bilateral 
tubal ligation/tubal occlusion) OR post-menopausal (no menstruation for a 
minimum of 12 months and confirmed by follicle stimulating hormone 
[FSH] of ≥ 40 mIU/ml) OR, if of child-bearing potential, must be using an 
acceptable method of contraception such as an IUD, implant or 
contraceptive injection, or two forms of the following (e.g., diaphragm, 
cervical cap, patch or vaginal hormonal contraceptive, condom, 
spermicide, or sponge) for the last three months, OR in a  monogamous 
relation with a male partner who has undergone a documented vasectomy 
a minimum of 6 months prior to study commencement. All females must 
agree to continue to use their method of birth control for the duration of 
the study and for a minimum of one complete menstrual cycle or 28 days 
following discharge from the study” 
To “Female subjects must have negative pregnancy tests at screening and 
check-in AND: be surgically sterile at least 6 months before the first dose 
(with documentation of hysterectomy, bilateral oophorectomy, bilateral 
salpingectomy, bilateral tubal ligation/tubal occlusion) OR post-

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Item 
Revision in Version 5.0  
Section 6.5.2 
Laboratory 
Parameters on 
page 59 
To modify pregnancy screen procedures. 
Changed Pregnancy Screen part of the table from 
PREGNANCY SCREEN** (to be performed at screening, check-in, and 
discharge) 
Urine pregnancy test (females only) 
FSH will be done on post-menopausal females 
**the pregnancy tests may be performed in-clinic using CLIA-waived 
marketed kits. 
To  
PREGNANCY SCREEN** (females only)  
Urine pregnancy test will be done at screening and discharge.  Serum 
pregnancy test will be done at check-in on Day -1. 
Serum FSH and estradiol tests will be done on post-menopausal females at 
screening and check-in on Day -1 
**the urine pregnancy tests may be performed in-clinic using CLIA-waived 
marketed kits.  
 
Section 7.1 
Screening Visit 
on page 71 
To modify pregnancy screen procedures 
Added “FSH and estradiol tests for post-menopausal female” 
Section 7.2.1 
Check-in (Day -1) 
Procedures on 
page 72 
To modify pregnancy screen procedures. 
Changed from “Urine pregnancy in all female subjects” to “serum and 
urine pregnancy test in all female subjects” 
Added: “FSH and estradiol tests for post-menopausal female” 
Section 9.7 
Pharmacodynami
c Analyses on 
page 84 
To correct and clarify criteria for rivaroxaban non-responder. 
Changed from “The anticoagulant effect of rivaroxaban will be evaluated 
by comparing WBCT measured at pre PER977 (four hours) versus 
baseline (pre-rivaroxaban at four hours pre-dose on Day 3).  For the 
purposes of the PD analyses, subjects with percent-of-baseline WBCT at 
pre-PER977 ≤125% (i.e., ≤25% increase) will be considered as 
rivaroxaban in non-responders and excluded from all PD summaries and 
assessments.” 
To “The anticoagulant effect of rivaroxaban will be evaluated by 
comparing WBCT measured at pre PER977 (about four hours post-
rivaroxaban on Day 3) versus baseline (pre-rivaroxaban on Day 3).  For 
the purposes of the PD analyses, subjects with percent-of-baseline WBCT 
at pre-PER977 <125% (i.e., <25% increase) will be considered as 

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Item 
Revision in Version 5.0  
rivaroxaban in non-responders and excluded from all PD summaries and 
assessments.” 
Section 9.8 
Analysis of the 
Primary PD 
Endpoint 
(WBCT) on page 
85 
To clarify the definition of reversal of anticoagulation. 
Deleted “Categorical” from section title  
Changed from “Complete reversal is defined as mean WBCT to ≤110% of 
baseline up to and including 1 hour following test article administration.”  
To “Complete reversal is achieved for a treatment group if the mean 
WBCT is ≤ 110% of baseline at any post-baseline time point up to and 
including 1 hour following test article administration. Complete reversal 
is achieved for a subject if WBCT is ≤110% of baseline at any post-
baseline time point up to and including 1 hour following test article 
administration.” 
Changed from “Complete and sustained reversal of anti-coagulation is 
defined as a return of mean WBCT to ≤115% of baseline at all time points 
between 1 and 8 hours (inclusive) following test article administration. 
Dose escalation or de-escalation will be determined by this criterion.”  
To “Complete and sustained reversal of anti-coagulation is achieved for a 
treatment group if the mean WBCT is ≤ 115% of baseline at all time 
points between 1 and 8 hours (inclusive) following test article 
administration. Complete and sustained reversal of anti-coagulation is 
achieved for a subject if WBCT is ≤ 115% of baseline at all time points 
between 1 and 8 hours (inclusive) following test article administration.” 
Summary of Main Changes Made in Version 3.0 to Generate Version 4.0 
Item 
Revision in Version 4.0  
Dose Schema:  
In synopsis and 
section 3.1  
Dosing schema was revised.  The version 3.0 dosing schema was 
replaced with following dosing schema. 
 
Study Design: In 
synopsis  
Add Cohort 4:  
From “A complete schedule of events for Cohort 1-3 is provided.” 
To “A complete schedule of events for Cohort 1-4 is provided.” 
Dose Rationale: 
In synopsis on and 
section 3.2 
Add Cohort 4: 
From “A total of three dosing cohorts (Cohorts 1-3) are planned.”   
To “A total of four dosing cohorts (Cohorts 1-4) are planned.” 

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Item 
Revision in Version 4.0  
Primary Objectives: 
In synopsis and 
section 2  
Modified Primary Objectives: 
From “To evaluate the safety and tolerability of ciraparantag 60 mg 
(100 mg) , 120 mg (200 mg), and 30 mg (50 mg), and additional 
cohorts if necessary administered 4 hours after 20 mg rivaroxaban 
administration at steady state.” 
To  “To evaluate the safety and tolerability of ciraparantag 60 mg (100 
mg) , 120 mg (200 mg), 180 mg (300 mg), and 30 mg (50 mg), and 
additional cohorts if necessary administered 4 hours after 20 mg 
rivaroxaban administration at steady state” 
Study Population: 
In synopsis and in 
section 4.2 
 
Increased study population: 
From “Estimated number of subjects screened: 120 
Planned number of subjects randomized: 48 
Planned number of evaluable subjects: 
48” 
 
To     “Estimated number of subjects screened: 160 
   Planned number of subjects randomized: 64 
   Planned number of evaluable subjects:      64” 
Overall Study 
Design and Plan: 
In section 3.1  
Add Cohort 4: 
From “Subjects will be enrolled sequentially into up to three cohorts.” 
To “Subjects will be enrolled sequentially into up to four cohorts.” 
Dietary Guidelines 
Prior to Check-in: 
In section 5.7.1  
Clarify the minimum duration of dietary restriction prior check-in: 
From “Begin 2 days before check-in at the clinical site for overnight 
visits.” 
To “Begin at least 2 days before check-in at the clinical site for 
overnight visits.” 
Determination of 
Sample Size: In 
section 9.2 
Clarify the determination of sample size: 
From “A one-sided Fisher's z test at the 5% significance level of the 
null hypothesis that the Pearson correlation coefficient r = 0.900, will 
have 90% power to detect a correlation of 0.700 when the sample size 
is 27.   Twenty-three (23) subjects will yield 85% power for the same 
test.” 
To    “The study population will consist of healthy male and female 
adults, age 50-75 years (inclusive). No formal sample size calculations 
were performed for this study; sixteen (16) subjects enrolled in each 
cohort (3:1; active: placebo) is considered an adequate number of 
subjects to achieve the objectives of the study.” 
Method Assigning 
Patients to 
Treatment Groups: 
In section 5.4  
Add Cohort 4: 
From “This method of assignment will continue through all three 
cohorts.” 
To “This method of assignment will continue through all four 
cohorts.” 

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Summary of Main Changes Made in Version 2.0 to Generate Version 3.0 
 
Item 
Revision in Version 3.0  
Dose Schema:  
In synopsis and 
section 3.1 
 
 
 
 
Dosing schema was revised.  The original dosing schema was replaced 
with following dosing schema. 
 
Dose Escalation / 
De-escalation:  
In synopsis and 
section 5.9  
Explaining the escalation and de-escalation in the dosing schema 
Addition: 
The goal of the study is to explore the dose range of ciraparantag that 
reverses the anticoagulation induced by therapeutic doses of 
rivaroxaban at steady state. The study is intended to establish a dose of 
ciraparantag that fully reverses steady-state rivaroxaban, to evaluate at 
least one dose above the reversal dose to establish a therapeutic index, 
and at least one partial or no effect dose. 
Study Objectives: 
In synopsis and 
section 2  
 
Clarify study objectives 
From:  
To evaluate the safety and tolerability of ciraparantag 60 mg (100 mg) 
and either 30 mg (50 mg) or 180 mg (300 mg) and 15 mg (25 mg) or 
120 mg (200 mg) or 360 mg (600 mg), and additional cohorts if 
necessary administered 4 hours after 20 mg rivaroxaban administration 
at steady state. 
To: 
To evaluate the safety and tolerability of ciraparantag 60 mg (100 mg), 
120 mg (200 mg), and 30 mg (50 mg), and additional cohorts if 
necessary administered 4 hours after 20 mg rivaroxaban administration 
at steady state. 
Safety Review 
Between Cohorts: 
In synopsis and in 
section 3.1  
To remove the requirement of a 2-day interval between cohorts 
From:  
There will be a minimum of 2 days between after completion of 
treatment in one cohort and the initiation of treatment in the 
subsequent cohort. 
To:  
There will be a safety review after completion of treatment in one 
cohort and the initiation of treatment in the subsequent cohort. 

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Item 
Revision in Version 3.0  
Screening and 
Checking 
Procedures:  
In synopsis, study 
procedure, and 
section 3.1 
 
To expand the window for PI to modify check-in procedures based the 
on screening results 
From:  
If the Screening visit takes place within 1 weeks prior to check-in, the 
check-in procedures may be modified to exclude redundant procedures 
(safety laboratory tests, ECG, and physical examination) at the 
discretion of the Investigator. 
To: 
If the Screening visit takes place within 3 weeks prior to check-in, the 
check-in procedures may be modified to exclude redundant procedures 
(safety laboratory tests, ECG, and physical examination) at the 
discretion of the Investigator. 
Summary of Main Changes Made in Version 1.0 to Generate Version 2.0 
Item 
Revision in Version 2.0  
Study Design 
Clarification of the redundant check-in procedures: 
Safety laboratory tests, ECG, and physical examination may be 
omitted at the discretion of the PI if the screening visit is within 1 
week of the check-in visit.  
Section 4.4 
Exclusion Criteria 
#1 
 
Clarification of exclusion criteria on hepatic and renal function test: 
Change from “History or current evidence of liver function tests or 
renal function tests (serum creatinine) greater than the upper limit of 
normal (ULN). History or current evidence of QTc (QTcF) greater 
than normal (440±10 msec for males or 460±10 msec for females; 
median of three measurements)” to “History or current evidence of 
liver function tests greater than 50% of the upper limit of normal 
(ULN) or renal function tests (serum creatinine) greater than 1.5 
mg/dl and based on PI discretion. History or current evidence of 
QTc (QTcF) greater than normal (450 msec for males or 470 
msec for females)” 
Section 4.4 
Exclusion Criteria 
#12 
 
Clarification for prohibiting oral contraceptive use: 
Change from “use of hormonal contraceptives is acceptable” to 
“use of hormonal contraceptives is acceptable except for oral 
contraceptives”  
 
PK/PD Time Points 
Ease the stress of blood sampling on subjects: All PK and PD 
sampling time points on day 1 are removed.  The PK and PD 
time points at 2 hour post-rivaroxaban dosing are also removed.  

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Item 
Revision in Version 2.0  
The total volume of blood collection is decreased from 349 to 
225 mL. 
Section 5.5 Blinding To clarify this is a single-blind study: only the subjects and study 
personnel assigned to conduct the WBCT will be blinded 
Section 6.4  
Vital Signs 
To clarify that vital signs will assessed after 5 minutes in supine 
position 
Section 6.7.1 
Ciraparantag 
To specify that ciraparantag needs to be prepared on the day of 
dosing and stored at room temperature at least 1 hour prior to 
use 
Section 6.8 
Efficacy 
Assessments 
Re-prioritized of PK, PD, and safety assessments:  Where timing 
for assessments coincide, PD assessment(s) should be performed 
first, followed by PK assessment(s), and then ECGs, and vital 
signs will be performed. 
 
Broaden window for PK/PD sampling to avoid conflict with 
dosing procedure:  PK/PD Tolerance Window for >0 hour – 12 
hour will be “-10 minutes to +10 minutes” instead of “-5 
minutes to +5 minutes”. 
Section 6.11.1 
Withdraw 
Procedures 
Removed fecal occult test from the withdraw procedures 
Section 7 
Study Activities 
Clarification for time points: Time 0 for PK and PD assessments 
and post-study drug procedures will be the end of the study drug 
injection. 
Section 7.2.4.1 
Pre-study Drug 
Provide a tolerance window to schedule lunch time on day 3: 
+90 minutes tolerance window to avoid conflict with intensive 
PK/PD assessment 
 

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TABLE OF CONTENTS 
TABLE OF CONTENTS .............................................................................................13 
SYNOPSIS ...................................................................................................................20 
STUDY PROCEDURES: ............................................................................................27 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..............................29 
1 
INTRODUCTION ...............................................................................................32 
1.1 
Clinical Problem ........................................................................................32 
1.2 
Clinical Development of Ciraparantag ......................................................33 
1.2.1 
PER977-01-001................................................................................33 
1.2.2 
PER977-01-002................................................................................37 
1.2.3 
PER977-01-003................................................................................39 
1.2.4 
PER977-02-001................................................................................42 
1.2.5 
Pharmacokinetics .............................................................................46 
2 
STUDY OBJECTIVES ........................................................................................49 
3 
INVESTIGATIONAL PLAN ..............................................................................50 
3.1 
Overall Study Design and Plan ..................................................................50 
3.2 
Dose Rationale ...........................................................................................51 
3.3 
Study Duration and Dates ..........................................................................51 
4 
STUDY POPULATION ......................................................................................52 
4.1 
Screening and Enrollment ..........................................................................52 
4.2 
Study Population ........................................................................................52 
4.3 
Inclusion Criteria .......................................................................................52 
4.4 
Exclusion Criteria ......................................................................................53 
5 
STUDY TREATMENT(S) ..................................................................................55 
5.1 
Description of Treatment(s) .......................................................................55 
5.2 
Treatments Administered ...........................................................................55 
5.2.1 
Ciraparantag .....................................................................................55 
5.2.2 
Placebo .............................................................................................55 
5.2.3 
Rivaroxaban .....................................................................................55 
5.3 
Selection and Timing of Dose for Each Volunteer Subject .......................56 
5.4 
Method of Assigning Patients to Treatment Groups..................................56 
5.5 
Blinding......................................................................................................56 
5.6 
Concomitant Therapy.................................................................................56 
5.7 
Meals and Study Restrictions.....................................................................57 
5.7.1 
Dietary Guidelines Prior to Check-in ..............................................57 

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5.7.2 
Dietary Guidelines during the Study................................................57 
5.7.3 
Lifestyle Restrictions .......................................................................57 
5.8 
Treatment Compliance ...............................................................................58 
5.9 
Dose Escalation/De-Escalation ..................................................................58 
5.10 
Packaging and Labeling .............................................................................58 
5.10.1 
Ciraparantag .....................................................................................58 
5.10.2 
Rivaroxaban .....................................................................................58 
5.11 
Storage and Accountability ........................................................................59 
5.11.1 
Ciraparantag .....................................................................................59 
5.11.2 
Placebo .............................................................................................59 
5.11.3 
Rivaroxaban .....................................................................................59 
5.12 
Investigational Product Retention at Study Site ........................................59 
6 
STUDY PROCEDURES .....................................................................................60 
6.1 
Informed Consent.......................................................................................60 
6.2 
Medical History .........................................................................................60 
6.3 
Physical Examination.................................................................................60 
6.4 
Vital Signs ..................................................................................................60 
6.5 
Clinical Laboratory Tests ...........................................................................61 
6.5.1 
Fecal Occult Blood Tests .................................................................61 
6.5.2 
Laboratory Parameters .....................................................................63 
6.5.3 
Experimental Safety Biomarker Assessment ...................................64 
6.6 
Electrocardiograms ....................................................................................64 
6.7 
Dispensing Study Drug ..............................................................................64 
6.7.1 
Ciraparantag .....................................................................................64 
6.7.2 
Placebo .............................................................................................65 
6.7.3 
Rivaroxaban .....................................................................................65 
6.8 
Efficacy Assessments.................................................................................65 
6.8.1 
Pharmacokinetic Assessment ...........................................................65 
6.8.2 
Pharmacodynamic Assessment ........................................................66 
6.9 
Adverse Events Assessments .....................................................................66 
6.9.1 
Clinical Laboratory Abnormalities and Other Abnormal 
Assessments as Adverse Events or Serious Adverse Events ...........67 
6.9.2 
Toxicity Management ......................................................................67 
6.9.3 
Adverse Event (AE) .........................................................................68 
6.9.4 
Serious Adverse Event (SAE) ..........................................................68 
6.9.5 
AE Severity ......................................................................................69 

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6.9.6 
Causality Assessment.......................................................................69 
6.9.7 
Action Taken Regarding the Study Drug.........................................69 
6.9.8 
Adverse Event Outcome ..................................................................70 
6.9.9 
Other Action Taken for Event ..........................................................70 
6.9.10 
Serious Adverse Event Reporting–Procedure for Investigators ......71 
6.9.11 
Notifying Regulatory Authorities, Investigators, and IRB/IEC.......71 
6.9.12 
Pregnancy .........................................................................................72 
6.10 
Concomitant Medication Assessments ......................................................72 
6.11 
Removal of Patients from the Trial or Study Drug ....................................72 
6.11.1 
Withdrawal Procedures ....................................................................73 
6.11.2 
Subject Replacement ........................................................................74 
7 
STUDY ACTIVITIES .........................................................................................75 
7.1 
Screening Visit (Days -36 to -1) ................................................................75 
7.2 
Treatment Period (Day -1 to Day 4) ..........................................................75 
7.2.1 
Check-in (Day -1) Procedures .........................................................75 
7.2.2 
Day 1 Procedures .............................................................................76 
7.2.3 
Day 2 Procedures .............................................................................76 
7.2.4 
Day 3 Procedures .............................................................................76 
7.2.5 
Day 4 or Early Termination Procedures ..........................................79 
7.3 
Follow-up (Day 7-10) ................................................................................80 
8 
QUALITY CONTROL AND ASSURANCE .....................................................81 
8.1 
Monitoring and Inspections .......................................................................81 
8.2 
Data Collection ..........................................................................................81 
8.3 
Data Management ......................................................................................82 
8.4 
Study Documentation and Storage .............................................................82 
8.5 
Record Keeping .........................................................................................83 
8.6 
Document Retention ..................................................................................83 
9 
PLANNED STATISTICAL METHODS ............................................................84 
9.1 
General Considerations ..............................................................................84 
9.2 
Determination of Sample Size ...................................................................84 
9.3 
Analysis Populations ..................................................................................84 
9.4 
Pharmacokinetics of PER977 and Metabolite (BAP) ................................85 
9.5 
Plasma Rivaroxaban Pharmacokinetics .....................................................86 
9.6 
Dose Proportionality ..................................................................................86 
9.7 
Pharmacodynamic Analyses ......................................................................87 
9.8 
Categorical Analysis of the Primary PD Endpoint (WBCT) .....................88 

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9.9 
Pharmacodynamic Parameters ...................................................................88 
9.10 
Demographics and Baseline Characteristics ..............................................89 
9.11 
Safety Endpoints ........................................................................................89 
9.12 
Interim Analysis .........................................................................................89 
10 ADMINISTRATIVE CONSIDERATIONS ........................................................90 
10.1 
Investigators and Study Administrative Structure .....................................90 
10.1.1 
Sponsor ............................................................................................90 
10.1.2 
Clinical Research Organization .......................................................90 
10.1.3 
Clinical Study Drug Supplies...........................................................91 
10.1.4 
Drug Safety ......................................................................................91 
10.1.5 
Pharmacokinetics .............................................................................91 
10.2 
Protocol Amendments ................................................................................91 
10.3 
Institutional Review Board Approval ........................................................91 
10.4 
Ethical Conduct of the Study .....................................................................92 
10.5 
Patient Information and Consent ...............................................................92 
10.6 
Patient Confidentiality ...............................................................................93 
10.7 
Regulatory Compliance .............................................................................93 
10.8 
Case Report Forms and Study Records .....................................................94 
10.9 
Protocol Violations/Deviations ..................................................................94 
10.10 Financial Disclosure...................................................................................94 
10.11 Publication and Disclosure Policy .............................................................94 
10.12 Reimbursement, Indemnity, and Insurance ...............................................94 
11 REFERENCE LIST .............................................................................................95 
 

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LIST OF APPENDICES 
Appendix 1 Sponsor and Investigator Signatures .................................................96 
 

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LIST OF TABLES 
Table 1:  Number of Subjects with Return to Within 20% of Baseline WBCT by 
Dose Cohort and Time Point............................................................................37 
Table 2:  Summary of TEAEs by SOC and Preferred Term for Each Treatment .40 
Table 3:  Parameters for Serum PER977 and BAP ................................................85 
 

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LIST OF FIGURES 
Figure 1:  
WBCT Following a Single IV Dose of Ciraparantag Acetate 
(PER977) Versus Pooled Placebo Data in Subjects Administered a 
Single Oral Dose of Edoxaban 60 mg .............................................36 
Figure 2:  
Percent of Baseline (A-B) WBCT for All Treatments.....................41 
Figure 3:  
Ciraparantag* Serum Concentration Profile ....................................46 
Figure 4:  
BAP Serum Concentration Profile* .................................................47 
Figure 5:  
Ciraparantag* Urinary Excretion Profile as BAP ............................47 
Figure 6:  
Study Schema...................................................................................50 
 
 

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SYNOPSIS 
Sponsor: 
Perosphere Inc., a wholly-owned subsidiary of AMAG Pharmaceutical 
Name of Active Therapeutic Product: 
Ciraparantag, PER977 
Study Title: 
Phase 2 Placebo-Controlled, Single-Site, Single-Blind Study of Rivaroxaban Reversal 
by Ciraparantag as Measured by WBCT 
Study Number: 
PER977-02-012 
Study Phase: 2 
Study Design: 
This study is a randomized, single-blind, placebo-controlled study to assess the 
efficacy and safety of ciraparantag administered to healthy volunteers anticoagulated 
with rivaroxaban measuring clotting times using Whole Blood Clotting Time (WBCT).  
All subjects will undergo screening up to 36 days prior to enrollment.  Randomization 
will take place on Day 3. 
Subjects will be enrolled sequentially.  If the Screening visit takes place within 3 week 
prior to check-in, the check-in procedures may be modified to exclude redundant 
procedures (safety laboratory tests, ECG, and physical examination) at the discretion of 
the Investigator.  There will be a safety review after completion of treatment in one 
cohort and the initiation of treatment in the subsequent cohort. 
Subjects (n=16 per cohort) will be randomized in a 3:1 ratio to receive ciraparantag or 
placebo (saline for injection).  For dosing scheme, please refer to the figure below.  
All subjects will receive a single dose of 20 mg rivaroxaban QD in the morning on 
Days 1-3. Study drug will be administered only to those subjects who have a minimum 
increase in clotting time of 25% (as measured by WBCT) above baseline at the pre-
study drug (i.e., 3.75 hours post rivaroxaban) time point on Day 3.  Any subject who 
does not have a minimum increase in clotting time of 25% above baseline at the pre-
study drug time point on Day 3 will be discontinued from the study and replaced.  At 4 
hours following rivaroxaban a single intravenous (IV) dose of study drug (ciraparantag 
or placebo) will be administered.   
Individual subjects may participate in one dose cohort of this study.  Any subject who 
discontinues prior to completion for reasons other than an adverse event (AE) will be 
replaced and the replacement subject will receive the same treatment as the original 
subject.  Subjects who discontinue due to an AE that precedes administration of study 

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drug may be replaced at the discretion of the Sponsor.  Subjects who discontinue due to 
AEs that follow administration of study drug will not be replaced.  
A complete schedule of events for Cohort 1-4 is provided. 
Throughout this protocol, the active study drug doses are expressed as active drug 
moiety (ciraparantag) (as opposed to previously used ciraparantag acetate salt).  The 
administered dose is based on a concentration of 6 mg/mL ciraparantag (active moiety) 
and translates to the following dose conversions from previously used dose 
identifications:  
Ciraparantag Acetate 
Ciraparantag 
Dose Volume 
600 mg 
360 mg 
60 mL 
300 mg 
180 mg 
30 mL 
100 mg 
60 mg 
10 mL 
50 mg 
30 mg 
5 mL 
25 mg 
15 mg 
2.5 mL 
Dose Schema 
 
The goal of the study is to explore the dose range of ciraparantag that reverses the 
anticoagulation induced by therapeutic doses of rivaroxaban at steady state. The study 
is intended to establish a dose of ciraparantag that fully reverses steady-state 
rivaroxaban, to evaluate at least one dose above the reversal dose to establish a 
therapeutic index, and at least one partial or no effect dose. 
Dose Rationale 
A total of four dosing cohorts (Cohorts 1-4) are planned.  The planned doses of 
ciraparantag or placebo (administered as a volume equivalent of ciraparantag) have 
been evaluated as single and repeat IV doses from 5 mg ciraparantag acetate (3 mg 
ciraparantag) up to 600 mg ciraparantag acetate (360 mg ciraparantag) in previous 
protocols (PER977-01-001, PER977-01-002, PER977-01-003, and PER977-02-001).   
Primary Objective(s): 
The primary objectives of this study are: 
• To evaluate the efficacy of ciraparantag in the reversal of anticoagulation 
induced by rivaroxaban 20 mg administered orally once daily for three days as 
assessed by WBCT. 

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• To evaluate the safety and tolerability of ciraparantag 60 mg (100 mg)1, 120 mg 
(200 mg), 180 mg (300 mg), and 30 mg (50 mg), and additional cohorts if 
necessary administered 4 hours after 20 mg rivaroxaban administration at steady 
state. 
• To assess the PK characteristics of rivaroxaban and of ciraparantag and its 
primary metabolite, 1,4-Bis(3-aminopropyl) piperazine (BAP). 
Eligibility 
Inclusion Criteria 
• Adults age 50 to 75 years, inclusive 
• Laboratory tests (chemistry, hematology and coagulation assessments) and 
urinalysis performed during screening up to 36 days prior to administration of 
study treatment deemed not clinically significant by the principal investigator. 
• No clinically significant findings on 12-lead electrocardiogram (ECG) 
performed during screening 
• Body mass index (BMI) 18 to ≤ 32 kg/m2, inclusive 
• Male subjects agree to use appropriate contraception (i.e., latex condom with 
spermicide) in addition to their partner using an acceptable form of 
contraception (e.g., diaphragm, cervical cap, intrauterine device, hormonal 
contraceptives, surgical sterilization or post-menopausal), when engaging in 
sexual activity during the course of the study. Moreover, male subjects should 
not donate sperm or attempt to impregnate a partner during the course of the 
study and for a period of 12 weeks following discharge from the study. 
• Female subjects must have negative pregnancy tests at screening and check-in 
AND: be surgically sterile at least 6 months before the first dose (with 
documentation of hysterectomy, bilateral oophorectomy, bilateral 
salpingectomy, bilateral tubal ligation/tubal occlusion) OR post-menopausal (no 
menstruation for a minimum of 12 months and confirmed by serum follicle 
stimulating hormone [FSH] of ≥ 40 mIU/ml and estradiol < 30 pg/ml at 
screening and check-in) OR, if of child-bearing potential, must be using an 
acceptable method of contraception such as an IUD, implant or contraceptive 
injection, or two forms of the following (e.g., diaphragm, cervical cap, patch or 
vaginal hormonal contraceptive, condom, spermicide, or sponge) for the last 
three months. All females must agree to continue to use their method of birth 
control for the duration of the study and for a minimum of one complete 
menstrual cycle following discharge from the study 
                                                 
1 Previously used ciraparantag acetate salt dose based on 10 mg/mL.  The active study drug doses in this 
protocol is now expressed as active drug moiety (ciraparantag) based on 6 mg/mL (See conversion table). 

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•
Subjects who have participated in a prior study of ciraparantag must have been
discharged from the study a minimum of 1 month prior to the planned treatment.
•
Subjects must understand and agree to comply with the requirements of the
study and they must be willing to sign the informed consent form indicating
voluntary consent to participate in the study prior to initiation of screening or
study-related activities
Exclusion Criteria 
•
History or current evidence of clinically significant cardiac, hepatic, renal,
pulmonary, endocrine, neurologic, infectious, gastrointestinal, hematologic, or
oncologic disease as determined by screening history, physical examination,
laboratory test results or 12-lead ECG assessment.  History or current evidence
of liver function tests greater than 50% of the upper limit of normal (ULN) or
renal function tests (serum creatinine) greater than 1.5 mg/dl and based on PI
discretion. History or current evidence of QTc (QTcF) greater than normal (450
msec for males or 470 msec for females).
•
History of unexplained syncope
•
History of major bleeding, trauma, surgical procedure of any type, or vaginal
delivery within six months prior to screening
•
History of peptic ulcer, gastrointestinal bleeding (including hematemesis,
melena, rectal bleeding) within one year prior to screening
•
Long standing history of bleeding episodes such as epistaxis, bruising or
gingival bleeding or if not long standing, within 1 month prior to screening
•
Personal or family history of clotting disorder or abnormality, excessive
bleeding, joint hematoma, thrombovascular disease or any hematologic disorder
involving platelets or clotting abnormalities or any condition requiring treatment
with transfusions, or history of thrombocytopenia
•
Females with a history of dysfunctional uterine bleeding who have not
undergone hysterectomy, including history of menorrhagia (heavy menstrual
bleeding), menometrorrhagia or polymenorrhea
•
Smokers or use of tobacco and/or nicotine containing products within 3 months
prior to dosing as determined by the subject’s verbal history
•
Pregnant or breast-feeding
•
Males with a history of hormone therapy within 3 months prior to screening
•
Administration of any blood product or anticoagulant within 3 months prior to
study entry or any non-steroidal anti-inflammatory drug or cyclooxygenase
inhibitor within 2 weeks prior to dosing
•
Taking any type of chronic medication (including vitamin, nutritional and herbal
supplements) for more than 14 consecutive days within the 4 weeks prior to
study entry (use of hormonal contraceptives is acceptable except for oral
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• Positive serologic test for human immunodeficiency virus (HIV), Hepatitis C 
virus antibody (HCV-Ab), or Hepatitis B surface antigen (HBsAg) 
• Donation of blood or blood products within 56 days prior to screening 
• Participation in any study with an investigational compound or device within 30 
days prior to signing informed consent  
• Active drug or alcohol dependence within the prior 12 months or any condition 
that, in the opinion of the Investigator, would interfere with adherence to study 
protocol 
Study Population: 
The sample size is determined empirically, but is considered adequate to achieve the 
objectives of the study.  Sixteen subjects will be enrolled in each cohort (3:1; active: 
placebo). 
Estimated number of subjects screened: 
160 
Planned number of subjects randomized: 
64 
Planned number of evaluable subjects: 
64 
Test Product, Dose, and Mode of Administration: 
The following dosage forms will be provided for this study: 
• Ciraparantag for IV injection 
• Placebo saline for IV injection 
• Rivaroxaban 20 mg tablets (commercial formulation) for oral administration  
All doses of study drug (ciraparantag or placebo) will be administered by IV injection 
(over a minimum of 10 minutes) into an indwelling catheter. The indwelling catheter 
will be flushed with 5.0 mL of sterile 0.9% Sodium Chloride Injection, USP before and 
after administration of study drug. All doses of study drug will be administered in a 
single-blinded-fashion.  
Duration of Treatment: 
Expectation of the total duration of the study is up to approximately 3 months.  
Individual subject participation is approximately 50 days inclusive of screening and 
follow-up.  Subjects enrolled will spend up to four nights admitted to an in-patient 
facility.   

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Concomitant Medications: 
Use of concomitant medications (including vitamin, nutritional and herbal 
supplements) is prohibited as per Exclusion criteria, during screening and for the 
course of the study. Acetaminophen up to 1 gram/24 hours may be administered as 
needed for treatment at the discretion of the Investigator.  As needed use of over-the-
counter antihistamines during screening, prior to admission on Day -1, and following 
discharge from the clinic site on Day 4 is permitted. Use of hormonal contraceptives is 
acceptable except for oral contraceptives 
Pharmacokinetic Assessment: 
Rivaroxaban PK time points: 
Day 3: pre-rivaroxaban (within 1 hr. prior to dosing), post-rivaroxaban at 3.75, 4.25, 
4.5, 4.75, 5, 6, 8, 10, 12, and 28 hrs. 
Ciraparantag and BAP PK time points: 
Day 3: pre-study drug (within 1 hr. prior to dosing of ciraparantag or placebo), post-
study drug at 0.25, 0.5, 0.75, 1, 2, 4, 6, 8 and 24 hrs.  
Pharmacodynamic Assessments: 
WBCT time points: 
Day 3: pre-rivaroxaban (within 1 hr. prior to dosing) and post-rivaroxaban at 3.75 and 
post-study drug at 0.25, 0.5, 0.75, 1, 2, 4, 6, 8 and 24 hrs. (Only subjects with at least 
25% increase of clotting time from pre-rivaroxaban level on day 3 will be randomized). 
Safety Assessments: 
The following parameters will be assessed:  
• Physical examination  
• Vital signs 
• Electrocardiograms (ECGs)  
• Blood and urine safety laboratories  
• Fecal occult blood 
• Experimental safety biomarker assessment 
Citrated plasma for experimental safety biomarker assessment will be collected at pre-
rivaroxaban (within 1 hr. prior to dosing) on Day 1, and at 3.75 and 8 hrs. post-
rivaroxaban on Day 3. Experimental safety biomarker assessment will be done at the 
PI’s discretion. 

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Subjects will be observed for a minimum of 24 hours following the final study drug 
administration.  If, in the opinion of the Investigator, all potentially occurring AEs have 
resolved, coagulation parameters (WBCT) are not clinically significant, and no further 
observation is necessary, the subject will be discharged from the facility on Day 4.  
On Day 7-10, subjects will be followed-up by telephone call.  Subjects will be 
discharged from the study after the telephone call if all AEs have resolved to the 
satisfaction of the Investigator.  
Over the course of the study, the total estimated volume of blood to be sampled for the 
combined PK, PD and safety evaluations is approximately 225 mL per subject. 
Statistical Methods:  
All data collected will be presented in data listings.  Data from subjects excluded from 
an analysis set will be presented in the data listings, but not included in the calculation 
of summary statistics.  For categorical variables, frequencies, and percentages will be 
presented.  Continuous variables will be summarized using descriptive statistics 
(number of subjects, mean, median, standard deviation, minimum, and maximum).  
Data will be tabulated by treatment, across active treatment groups when applicable, 
with all placebo subjects pooled into a single group. 
All evaluable data from subjects in the analysis sets will be included in the analyses.  
No adjustment or imputation will be utilized for missing values or for subjects who 
withdraw prior to completing the study. 
Baseline values will be defined as the last assessment prior to investigational product 
administration and per period if applicable. 
Definition of Reversal of Anticoagulation – Clotting Time by WBCT  
• Complete reversal is defined as a return of mean WBCT to ≤110% of baseline 
up to and including 1 hour following test article administration. 
• Complete and sustained reversal of anti-coagulation is defined as a return of 
mean WBCT to ≤115% of baseline at all time points between 1 and 8 hours 
following test article administration. Dose escalation or de-escalation will be 
determined by this criterion.  
Details of all statistical analyses will be specified in a separate statistical analysis plan 
(SAP) that will be finalized prior to data base lock. 
Date of Original Protocol:   
Prepared in:  Microsoft Word 2013 
 
 

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sample may be performed at the discretion of the Investigator. Following the treatment period, coagulation parameters (WBCT 
result) must be not clinically significant prior to discharge. 
g. Urine drug and saliva alcohol tests will be performed at screening and at check-in. A blood sample will be taken to assess the 
presence of HbsAg, HCV-Ab and HIV at screening. 
h. Electrocardiograms (12-lead) will be performed at screening, check-in, after receiving rivaroxaban on day 1-3, and prior to 
discharge. Additional ECG may be performed at PI discretion. 
i. 
Urine pregnancy testing will be performed for all women at screening and at discharge.  Serum pregnancy test will be done for all 
women at check-in on Day -1.  
j. 
Subjects will be admitted to the clinical site on Day -1 for baseline assessments and will remain confined until 24 hours after the 
study drug administration provided that, in the opinion of the Investigator, it is safe to be discharged. 
k. Rivaroxaban will be administered as a single 20 mg oral tablet after meal on Days 1-3 and followed 4 hours later by study drug 
injection on Day 3. 
l. 
Blood samples for WBCT will be collected on Day 3 pre-rivaroxaban dosing and post-rivaroxaban at 3.75 hrs. and post-study 
drug at 15, 30, and 45 minutes, 1, 2, 4, 6, 8, and 24 hours.  Only subjects with at least 25% increase of clotting time from pre-
rivaroxaban level on day 3 will be randomized  
m. Blood samples for PK assessment of rivaroxaban and ciraparantag and its metabolite will be collected on Day 3 pre-rivaroxaban 
dosing and post-rivaroxaban at 3.75 and post-study drug at 15, 30, and 45 minutes, 1, 2, 4, 6, 8, and 24 hours.   
n. Follow-up will be performed by telephone on Day 7-10. Subjects may be discharged from the study after the telephone call if all 
AEs have resolved to the satisfaction of the Investigator.  
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ABBREVIATION 
DEFINITION 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANOVA 
analysis of variance 
aPTT 
activated partial thromboplastin time  
AST 
aspartate aminotransferase  
AUC 
area under the concentration versus time curve 
AV 
Atrioventricular 
BAP 
1,4-Bis(3-aminopropyl)piperazine 
BMI 
body mass index 
BP 
blood pressure 
bpm 
beats per minute 
CFR 
Code of Federal Regulations 
CI 
confidence interval  
Cmax 
maximal concentration 
C24 
Observed quantifiable analyte concentration in the sampled 
matrix at the 24-hour time point 
Clast 
Last observed quantifiable analyte concentration in the sampled 
matrix 
CRF 
case report form 
CRO 
contract research organization 
ECG 
Electrocardiogram 
EDC 
electronic data capture 
EDTA 
ethylenediaminetetraacetic acid 
Emax 
maximum effect 
Emin 
minimum effect 
FIIa 
factor IIa 

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ABBREVIATION 
DEFINITION 
FXa 
factor Xa 
F1.2 
prothrombin fragments F1 and 2 
FDA 
Food and Drug Administration 
FSH 
follicle stimulating hormone 
GCP 
good clinical practice (refers to ICH and CFR) 
HBsAg 
hepatitis B surface antigen 
HCV-Ab 
hepatitis C virus antibody  
HDPE 
high density polyethylene  
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HR 
heart rate 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
independent ethics committee 
IMPD 
Investigational Medicinal Product Dossier 
IND 
Investigational New Drug 
IRB 
institutional review board 
IV 
Intravenous 
LMWH 
low molecular weight heparin 
LLOQ 
lower limit of quantification 
LOQ 
limit of quantification 
NOAC 
new oral anticoagulants 
NS 
normal saline 
MedDRA 
Medical Dictionary for Regulatory Activities  
PD 
pharmacodynamics 
PK 
Pharmacokinetic 

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ABBREVIATION 
DEFINITION 
PoC 
point-of-care 
PT 
prothrombin Time 
QTcF 
QTc Fridericia  
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SOC 
System Organ Class 
SOP 
standard operating procedures 
SUSAR 
serious unexpected serious adverse reaction 
t1/2 
half-life 
tlast 
time of Clast, obtained directly from the observed concentration 
versus time data 
TEAE 
treatment-emergent adverse event 
TEG-R 
thromboelastography reaction time 
Temp 
Temperature 
TFPI 
tissue factor pathway inhibitor  
Tmax 
time of the maximum observed activity value  
TMF 
trial master file 
UFH 
unfractionated heparin 
ULN 
upper limit of normal 
WBCT 
whole blood clotting time 
WHO 
World Health Organization  

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1 
INTRODUCTION 
Ciraparantag (PER977) is a small, synthetic water-soluble new molecular entity that 
physically associates with heparins and related anticoagulant drugs (i.e., direct factor Xa 
[FXa] and factor IIa [FIIa] inhibitors) allowing rapid re-establishment of a normal blood 
coagulation state.  This reversal effect is due to direct non-covalent binding to the 
anticoagulant molecule with no binding to blood coagulation factors or proteins in the 
blood. 
1.1 Clinical Problem 
In the United States, the number of patients requiring anticoagulation annually numbers 
in the millions; upwards of 600,000 patients with thromboembolic events or pulmonary 
embolism, (CDC Fast Stats 2012) and over 1 million joint replacement procedures (knee 
and hip), (CDC Statistics 2010) necessitate prophylactic post-operative anticoagulation, 
and most of the 2.66 million patients with atrial fibrillation will also be prophylactically 
anticoagulated. (CDC Atrial Fibrillation Fact Sheet)  
Anticoagulation is time consuming and problematic for both physicians and patients.  
The traditional anticoagulants (heparin and warfarin) have a long history of successful 
clinical use, with an accepted risk of substantial bleeding. (Palareti G 2011, FDA Safety 
Alert 2012) Due to the incidence of major bleeding associated with the traditional 
anticoagulants, demand for new therapeutic anticoagulants has been met with the 
introduction of low molecular weight heparin (LMWH) products and selective oral 
inhibitors of clotting factor IIa and Xa.  Although the new oral anticoagulants (NOACs) 
have several advantages including rapid therapeutic effectiveness, ease of dosing, and 
lack of monitoring requirements, each is associated with risk of major bleeding. (ISMP 
2012)  
A significant obstacle to adoption of the new FXa and FIIa inhibitors is clinical concern 
regarding the lack of an effective reversal agent (e.g., vitamin K for warfarin, protamine 
for heparin and LMWH [partial reversal]).  This is germane in cases of overdose, trauma, 
need for emergency or urgent surgery, and in patients undergoing elective procedures 
(cardiac ablations, endoscopies with biopsies, extensive dental surgery) that may require 
discontinuation, changing, or bridging of anticoagulation.  Current recommendations call 
for termination of anticoagulants between 2 – 4 days prior to the elective procedures and 
cautiously keeping a patient off anticoagulation for some period of time after the 
procedure, especially if a biopsy or invasive procedure has been used. (McLean 2012) In 
emergency surgeries, where it is desirable to wait until at least 3 half-lives have passed 
before surgical intervention, if possible, patients are at risk of significant bleeding. 
An efficacious reversal agent for the LMWHs and oral FXa and FIIa inhibitors would 
permit rapid reversal of anticoagulation for emergency purposes, minimize the time 

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patients are off their anticoagulant pre-procedure, and provide a level of confidence 
regarding restarting the anticoagulant therapy post-procedure.   
Equally germane is the issue of identification of biomarkers for both efficacy and safety 
monitoring for pro-coagulation signals for drugs under development for reversal of 
anticoagulants.  Many of the commonly used biomarkers (prothrombin time [PT], 
activated partial thromboplastin time [aPTT], anti-factor Xa [anti-FXa], etc.) show 
significant disparity between the biomarker’s indication of a reversal and the lack of 
bleeding cessation, if there is reagent interference.  The primary goal of reversing an 
anticoagulant is simply to return the ability of the blood to clot; historical biomarkers 
have been used for this purpose but they remain surrogate biomarkers. This problem is 
addressed by WBCT, which measures clotting time in fresh whole blood samples. 
1.2 Clinical Development of Ciraparantag  
As of August 15, 2016, ciraparantag (PER977; previously, aripazine) has been evaluated 
in four clinical studies of single escalating doses of ciraparantag following administration 
edoxaban (PER977-01-001; NCT01826266), unfractionated heparin (PER977-01-002; 
NCT02206087), and enoxaparin (PER977-01-003; NCT02206100), and following 
anticoagulation and re-anticoagulation with edoxaban (PER977-02-001; NCT02207257).  
In this protocol, all doses are listed as the ciraparantag base equivalent.  Both dosing 
formats are utilized in the presentation of clinical data from previous studies.   
In each of the protocols the dosing of active study drug was described based on the drug 
substance ciraparantag acetate (salt).  In accordance with new guidelines, the drug 
substance content is now labeled as active moiety (ciraparantag).  Throughout this 
document, the active study drug doses are expressed according to the new convention. 
Completed safety and efficacy data from PER977-01-001, PER977-01-003, and PER977-
02-001 are presented. 
1.2.1 
PER977-01-001 
PER977-01-001 was a phase 1, first in human, double-blind, placebo-controlled, 
sequential group, two-period, ascending ciraparantag dose study administered alone and 
in combination with edoxaban in healthy volunteers.  The study consisted of two periods: 
a single intravenous IV injection of 3 mg, 9 mg, 15 mg, 30 mg, 60 mg, 120 mg or 180 mg 
ciraparantag, respectively (ciraparantag acetate 5, mg, 15, mg, 25 mg, 50 mg, 100 mg, 
200 mg, or 300 mg) alone or placebo with serial pharmacokinetic (PK), 
pharmacodynamic (PD), and safety monitoring.  After a one-week washout, a single dose 
of edoxaban 60 mg was administered followed 3 hours later by a single dose of 
ciraparantag or placebo at the same dosage as was administered in the first period, and 
with serial PK, PD, and safety monitoring. 

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The highest incidence of treatment emergent adverse events (TEAEs) in Period 1 
(ciraparantag monotherapy) were in the system organ class (SOC) of general disorders 
and administration-site conditions (feeling hot; n=14, 24.1%), and in nervous system 
disorders (dysgeusia; n=8, 13.8%).  Adverse events in placebo subjects comprised feeling 
cold, headache, infusion related reaction and peripheral coldness reported in one subject 
each. 
The highest incidence of TEAEs in Period 2 was in the SOC of general disorders and 
administration-site conditions (feeling hot n=11, 17.2%), nervous system disorders 
(dysgeusia n=8, 12.5%), and in injury, poisonings, and procedural complications 
(contusion n=7, 10.9%).  Adverse events in placebo subjects comprised feeling cold chest 
discomfort, infusion site coldness, vessel puncture site pain, dysgeusia, headache, 
contusion, infusion related reaction, peripheral coldness, and hematoma reported in one 
subject each. 
No serious AEs were reported during the conduct of the study, no laboratory results were 
reported as AEs and there were no clinically significant changes in vital signs.  There 
were no clinically significant AEs and no dose-related findings occurred with regard to 
interval prolongations in median of triplicate ECG tracings with regard to HR, P-R, QRS, 
QTcF or R-R intervals. 
The protocol initially designated prothrombin time (PT) and thromboelastography 
reaction time (TEG-R) as the primary PD efficacy variables based on their use in in vitro 
studies.  One of the objectives of the protocol was to assess which biomarkers were the 
best endpoints for future clinical trials.  In seeking a biomarker for ciraparantag reversal 
effect on anticoagulants, the fact that cationic ciraparantag exhibits strong binding to 
anionic citrate, ethylene diaminetetra acetic acid (EDTA), and oxalate due to charge 
interaction became problematic.  Plasma tubes contain a large molar excess of anions that 
overwhelm and disrupt the ciraparantag-anticoagulant complex rendering the results of 
plasma-based assays non-representative of physiologic conditions.  Findings in Cohorts 
1-4 of the study indicated that PT and TEG-R would not be acceptable biomarkers in 
clinical trials due to their insensitivity and high variability.  Whole blood collected in 
tubes and transported to the laboratory for TEG-R testing were observed to be clotting 
clinically faster as study drug dose increased, and yet the PT values showed no change 
and TEG-R showed a high degree of variability between time points and between 
subjects.  Mean PT and TEG-R showed no change over time within cohorts and across 
escalating dose cohorts. 
Enhanced clotting of anticoagulated blood was observed beginning in Cohort 2 (30 mg 
ciraparantag [ciraparantag acetate 50 mg]).  Whole blood clotting time (WBCT; referred 
to as ‘venous clotting time’ or ‘VCT’ in the protocol or Lee-White clotting time where-in 
glass is the only activating agent) was performed on discarded blood samples from a few 
patients.  This was done in order to assess whether blood was clotting slower than 
baseline with edoxaban administration (e.g., anticoagulation) and possibly returning to 

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baseline after administration of study drug (i.e., reversal of anticoagulation by 
ciraparantag).  Data from the pilot subjects showed a significant increase in clotting time 
with edoxaban and agreement between independent observers.  As a result of these 
observations, measurement of clotting, glass bead activated clotting time and WBCT 
were added to the study as additional exploratory biomarkers for Cohorts 6-7 (120 mg 
ciraparantag [ciraparantag acetate 200 mg] and 180 mg ciraparantag [300 mg 
ciraparantag acetate], respectively). 
Ciraparantag acetate displayed no pro-coagulant activity as demonstrated by lack of 
effect on WBCT, D-dimer, prothrombin fragments 1 and 2 (F1.2), or tissue factor 
pathway inhibitor (TFPI) when administered alone in doses ranging from 3 to 180 mg 
ciraparantag (5 to 300 mg ciraparantag acetate). 
When administered following edoxaban, a single IV dose of ciraparantag acetate 30 mg, 
60 mg, 120 mg, and 180 mg ciraparantag (50 mg, 100 mg, 200 mg and 300 mg 
ciraparantag acetate) demonstrated reversal of edoxaban-induced anticoagulation versus 
placebo for the full testing period of 24 hours following study drug administration.  
Evidence of reversal of anticoagulation was noted 10 - 30 minutes post-study drug 
administration in subjects administered 30 mg to 180 mg ciraparantag (50 to 300 mg 
ciraparantag acetate).  Initial signs of reversal were noted in Cohort 4 (30 mg 
ciraparantag [50 mg ciraparantag acetate]) and full reversal was confirmed with 
subsequent increasing dose in Cohorts 5 to 7 (60 to 180 mg ciraparantag [100 mg to 300 
mg ciraparantag acetate]).  There was no evidence of significant reversal of WBCT in 
subjects who received 15 mg ciraparantag (25 mg ciraparantag acetate) in a repeat cohort 
of new subjects. 

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Figure 1:  WBCT Following a Single IV Dose of Ciraparantag Acetate (PER977) Versus Pooled 
Placebo Data in Subjects Administered a Single Oral Dose of Edoxaban 60 mg 
 
(Ansell NEJM 2014) 
Ciraparantag 
Dose 
Ciraparantag 
Acetate Dose 
Onset of 
Reversal 
(min) 
Duration of 
Reversal 
(hr) 
15 mg 
(25 mg) 
NOED 
NOED 
30 mg 
(50 mg) 
30 
24 
60 mg 
(100 mg) 
30 
24 
120 mg 
(200 mg) 
10 
24  
180 mg 
(300 mg) 
10 
24 
NOED- no observed effect dose 
A dose of 15 mg ciraparantag (equivalent to 25 mg ciraparantag acetate; see conversion 
table above) administered after a single dose of edoxaban 60 mg did not yield a 
statistically significantly improvement in change in WBCT (percent change from 
baseline).  The administration of 30 mg ciraparantag (50 mg ciraparantag acetate) 
(4 subjects) resulted in numerical and statistically significant differences from placebo at 
10 minutes and 60 minutes.  The 60 mg ciraparantag (100 mg ciraparantag acetate) dose 
group showed statistically significant percentage change from baseline compared to 
placebo at all time points but the 10-minute group.  Average WBCT in subjects who 
received 120 mg and 180 mg ciraparantag (200 mg and 300 mg ciraparantag acetate) 
showed significantly different percentage changes from baseline compared to placebo at 

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all time points.  Based on these results, 60 mg ciraparantag (100 mg ciraparantag acetate) 
was selected as the effective reversal dose. 
Table 1:  Number of Subjects with Return to Within 20% of Baseline WBCT by Dose Cohort and 
Time Point 
Time after 
Ciraparantag 
Number of Ciraparantag Treated Subjects with WBCT within 20% 
of Baseline 
15 mg  
(25 mg) 
30 mg  
(50 mg) 
60 mg  
(100 mg) 
120 mg 
(200 mg)  
180 mg  
(300 mg) 
10 min 
6/10 
3/4* 
4/6 
7/8* 
7/8* 
30 min 
8/10 
4/4 
6/7* 
7/8* 
8/8* 
45 min 
6/10 
ND 
7/7* 
8/8* 
8/8* 
60 min 
4/10 
4/4* 
7/7* 
8/8* 
8/8* 
*p<0.05 between ciraparantag and placebo groups. 
ND = No data for time point. 
The designated biomarkers in the protocol (PT and TEG-R) were found to be insensitive 
and too variable for clinical study use.  Whole blood clotting time was identified as the 
most sensitive and clinically relevant biomarker in a subset of the cohorts and was 
targeted for use as the primary efficacy variable in all subsequent studies. 
1.2.2 
PER977-01-002 
This was a single-blind, placebo-controlled, sequential group, ascending ciraparantag 
dose study in healthy volunteers.  Ten subjects were enrolled in each dose cohort and 
randomized in an 8:2 ratio to ciraparantag: placebo.  All subjects in all cohorts received 
UFH 5000u by IV bolus injection followed immediately by 5000u administered by IV 
infusion over 3 hours (~1667u/hour).   
Six cohorts of 10 subjects had been enrolled and had received 60 mg, 120 mg, 180 mg, 
240 mg, 300 mg, and 360 mg ciraparantag, respectively.  Cohort 4 (240 mg) only was 
performed as a two-period treatment where each subject received a single dose of 
ciraparantag alone during Period 1 and during Period 2, each subject received UFH 
followed by a single dose of ciraparantag. 
Perosphere had planned to advance dosing to 480 mg ciraparantag, but the study was 
closed early for business reasons.  Current clinical study plans involve a return to a 
protocol investigating the reversal of unfractionated heparin by ciraparantag following 
completion of studies with edoxaban and enoxaparin.  There were no safety concerns that 
lead to the early termination. No dose limiting toxicities or TEAEs of concern were 
observed.   
Following ciraparantag dosing, over the 60 mg to 360 mg dose levels administered in the 
study, there were no apparent differences in WBCT for the active treatments compared to 
placebo. 

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Complete, partial, and no reversal for WBCT were observed at the same rate for all 
PER977 doses combined and placebo group. There were no apparent dose-related 
relationships for any of the reversal categories. There were no statistically significant 
differences between geometric least-squares means in ciraparantag treatments compared 
to placebo group for percent of baseline WBCT at most time points and for PD 
parameters. The WBCT return to baseline was achieved at similar times, two-hour or 
four-hour time points, across active treatments and placebo group. 
For the secondary endpoints, there were no statistically significant differences for active 
ciraparantag treatments versus placebo in most comparisons for PoC-aPTT and the 
procoagulant biomarkers TEG-R, D-dimer, F1.2, and TFPI. 
Across the 60 mg to 360 mg ciraparantag dose levels, assessments of relationship 
between dosage and reversal of anticoagulation (complete reversal versus partial or 
reversal) and exposure response showed no statistically significant correlations. 
The lack of reversal of unfractionated heparin at the ciraparantag doses utilized in the 
protocol was not unexpected due to the much higher binding ability of unfractionated 
heparin for ciraparantag compared to the newer oral anticoagulants and the smaller 
enoxaparin molecules. 
No deaths, serious adverse events (SAEs), or discontinuations due to AEs were reported. 
At least one TEAE was reported for 35 (72.9%) of the subjects who received ciraparantag 
following UFH:  three subjects (37.5%) who received 60 mg ciraparantag, six subjects 
(75.0%) who received 120 mg ciraparantag, six subjects (75.0%) who received 180 mg 
ciraparantag, six subjects (75.0%) who received 240 mg ciraparantag following UFH, six 
subjects (75.0%) who received 300 mg ciraparantag, all eight subjects (100.0%) who 
received 360 mg ciraparantag and these were all considered related to the study drug by 
the investigator; and seven subjects (87.5%) who received 240 mg ciraparantag without 
UFH.  At least one TEAE was reported for two subjects (16.7%) who received placebo 
following UFH – one of them was considered related to the study drug, and 
one subject (50.0%) who received placebo without UFH (not related). 
The most common TEAE, feeling hot, was reported for a total of 20 subjects (41.7%) 
who received ciraparantag following UFH and for two subjects (25.0%) who received 
240 mg ciraparantag without UFH.  All of these events were transient and considered to 
be mild and related to ciraparantag by the Investigator.  No event of feeling hot was 
reported for subjects who received placebo. 
All TEAEs were considered to be mild in severity by the Investigator. 
No safety concerns or notable differences were observed in safety laboratory, vital signs, 
pulse oximetry, ECG, telemetry, and fecal occult blood assessments, when comparing 
active treated cohorts or comparing active treated cohorts and placebo. 

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1.2.3 
PER977-01-003 
PER977-01-003 was a single-blind, placebo-controlled, sequential group, ascending 
ciraparantag repeating-dose study in healthy volunteers who received a single 
subcutaneous (sc) injection of enoxaparin 1.5 mg/kg.  Four dose cohorts of ciraparantag 
(60 mg, 120 mg, 180 mg, and 4 x 15 mg ciraparantag, respectively [100 mg, 200 mg, 300 
mg and 4 x 25 mg ciraparantag acetate, respectively]) were tested.  In Cohort 1 to 3, 
additional doses of study drug were allowed in subjects randomized to ciraparantag if PD 
assessments (WBCT and aPTT) were >120% of baseline value following evaluation of 
the 60 minute post study drug WBCT assessment.  For the purposes of analysis, subjects 
with percent of baseline WBCT at the pre-study drug time point ≤120% (i.e.≤20% 
increase following enoxaparin) were considered enoxaparin non-responders and were 
excluded from PD assessments. 
A total of 40 subjects were enrolled (32 to ciraparantag and 8 to placebo) and completed 
the study.  In Cohorts 1-3 (ciraparantag 60 mg, 120 mg, and 180 mg [ciraparantag acetate 
100 mg, 200 mg, and 300 mg]) the most commonly AE was flushing, reported in 10 
subjects:2 subjects (25%) who received 60 mg ciraparantag (100 mg ciraparantag 
acetate), 3 subjects (37.5%) who received 120 mg ciraparantag (200 mg ciraparantag 
acetate), and 5 subjects (50%) who received 180 mg ciraparantag (300 mg ciraparantag 
acetate).  Flushing was considered study drug-related in 1 subject (12.5%) who received 
60 mg ciraparantag (100 mg ciraparantag acetate) and in all of the subjects who received 
120 mg and 180 mg ciraparantag (200 mg and 300 mg ciraparantag acetate) who reported 
flushing.  Other TEAEs reported by the investigator as study drug related were feeling 
hot and throat tightness (ciraparantag 60 mg [ciraparantag acetate 100 mg]), chills and 
facial pain (ciraparantag 120 mg [ciraparantag acetate 200 mg]), and chills and dysgeusia 
(ciraparantag 180 mg [ciraparantag acetate 300 mg]). 
 
 

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Table 2:  Summary of TEAEs by SOC and Preferred Term for Each Treatment 
 
Ciraparantag 
 
 
60 mg 
(100 mg)  
n=8 
120 mg 
(200 mg)  
n=8 
180 mg 
(300 mg)  
n=8 
15 mg 
(25 mg) 
x 4 
n=8 
All Doses 
n=32 
Placebo 
n=8 
All related TEAEs, n (%) 
2 (25) 
4 (50) 
7 (87.5) 
0 
13 (40.6) 
0 
General disorders and 
Administration Site Conditions 
 
Chills 
 
Facial Pain 
 
Feeling Hot 
 
1 (12.5) 
0 
0 
1 (12.5) 
 
2(25) 
1 (12.5) 
1 (12.5) 
0 
 
1 (12.5) 
1 (12.5) 
0 
0 
 
0 
0 
0 
0 
 
4 (12.5) 
2 (6.3) 
1 93.1) 
1 (3.1) 
 
0 
0 
0 
0 
Nervous System Disorders 
 
Dysgeusia 
0 
0 
0 
0 
1 (12.5) 
1 (12.5) 
0 
0 
1 (3.1) 
1 (3.1) 
0 
0 
Respiratory, Thoracic, and 
Mediastinal Disorders 
 
Epistaxis 
 
Throat Tightness 
 
1 (12.5) 
0 
1 (12.5) 
 
0 
0 
0 
 
0 
0 
0 
 
0 
0 
0 
 
1 (3.1) 
0 
1 (3.1) 
 
0 
0 
0 
Vascular Disorders 
 
Flushing 
1 (12.5) 
1 (12.5) 
3 (37.5) 
3 (37.5) 
5 (62.5) 
5 (62.5) 
0 
0 
9 (28.1) 
9 (28.1) 
0 
0 
 
A total of 30 subjects (75%) were included in the PD population.  Across the three active 
treatments (ciraparantag 60 mg, 120 mg, and 180 mg [ciraparantag 100 mg, 200 mg, and 
300 mg] in Cohorts 1-3), the mean percent-of-baseline WBCT dropped to ≤120% by 
20 minutes after the end of the ciraparantag injection and remained below 120% for the 
remainder of the 24-hour period.  The maximum effect (Emax) was consistently observed 
at 2 minutes after the completion of the 10-minute injection.  The mean percent-of-
baseline WBCT maximum effect (Emax ) were comparable across the active ciraparantag 
60 mg, 120 mg and 180 mg (ciraparantag acetate 100 mg, 200 mg, and 300 mg) 
treatments (120.77%, 119.57%, and 127.08%, respectively) versus 144.02% in the 
ciraparantag 15 mg (ciraparantag acetate 25 mg) x 4 dose cohort and 140.63% in the 
placebo group.  
 
 

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Figure 2:  Percent of Baseline (A-B) WBCT for All Treatments 
A.  Percent of Baseline Full Interval 
 
B.  Percent of Baseline Partial Interval (pre-study drug to 6 hour post final dose) 
 

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*All doses expressed as ciraparantag acetate  
Complete reversal (WBCT ≤120% at the 1-hour post study drug administration and 
remaining ≤120% for the 1 to 6-hour interval) was observed in 100% of subjects in 
Cohorts 1, 2, and 3 (60 mg, 120 mg, and 180 mg ciraparantag [100 mg, 200 mg, 300 mg 
ciraparantag acetate], respectively), 71.4% in Cohort 4 (ciraparantag 4 x 15 mg [25 mg 
ciraparantag acetate]) and no subject in the placebo group.  Partial reversal (120% to 
≤190% at the 1-hour post-study drug administration and for the 1 to 6-hour interval) was 
observed in 28.6% in Cohort 4 (ciraparantag 4 x 15 mg [25 mg ciraparantag acetate]) and 
100% in the placebo group.  
Statistical assessments comparing ciraparantag treatment versus placebo from all cohorts 
showed no significant differences in F1.2 percent of baseline maximal effect (Emax), 
minimum effect (Emin) or Emin from 0 to 6 hours.  Decreases compared to placebo in TFPI 
percent of baseline Emin (0-6h) were observed with single dose ciraparantag 160 mg to 
180 mg (ciraparantag acetate 100 mg to 300 mg).  There were no significant differences 
between doses in the time to reach minimum effect.  There were no significant changes 
compared to placebo in any of the secondary pharmacodynamic endpoints following 
ciraparantag 15 mg (ciraparantag acetate 25 mg) x 4 treatments. 
Complete reversal of enoxaparin anticoagulation, measured as WBCT response, was 
achieved at a single-dose level of 60 mg ciraparantag (100 mg ciraparantag acetate) or 
higher.  Administration of a single-dose of 60 mg ciraparantag (100 mg ciraparantag 
acetate) or above had better reversal of enoxaparin anticoagulation effect than the 15 mg 
ciraparantag (25 mg ciraparantag acetate) x 4 treatments. 
1.2.4 
PER977-02-001 
PER977-02-001 was a randomized single-blind sequential group ascending ciraparantag 
reversal dose study in healthy volunteers who received a single dose of 60 mg edoxaban 
in the morning on Days 1-4 followed on Day 3 and Day 4 by a single IV dose of study 
drug.  Five dose cohorts of 15 mg, 30 mg, 60 mg, 180 mg, and 360 mg ciraparantag (25 
mg, 50 mg, 100 mg, 300 mg, and 600 mg ciraparantag acetate), respectively were 
planned and completed.  Any subject who did not have a minimum increase in WBCT of 
25% above baseline at the pre-study drug time point on Day 3 was discontinued from the 
study and replaced.   
The pharmacokinetic results show that following 10-minute IV injection of ciraparantag 
on Day 3 and Day 4, serum PER977 Cmax were typically observed at 0.25 hour (i.e., at the 
first postdose time point measured five minutes after the end of the 10-minute injection).  
Ciraparantag was then rapidly eliminated, with mean half-life (t1/2) ranging from 0.207 to 
0.336 hour (12.4 to 20.2 minutes).  Clearance and volumes of distribution remained 
relatively constant across most doses and on both Days 3 and 4.  Over the 24-fold dose 
range from 15 mg to 360 mg, ciraparantag Cmax and total exposures (AUC(0-inf) and 
AUC(0-last)) increased approximately proportionally to the dose increase.  However, the 

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90% confidence interval (CI) of the slope for Day 4 AUC(0-last) were completely above the 
predefined (0.9298, 1.0702) critical region; and the upper bounds of the 90% CI of the 
slopes for other exposure parameters on Day 3 and Day 4 were just above the upper limit 
of the critical region.  Dose-proportionality thus could not be statistically concluded. 
Quantifiable concentrations of BAP were measured in serum as early as at the first time 
point, five minutes after the end of ciraparantag 10-minute injection, and Cmax was 
reached between 0.42 hour to 0.92 hour after the start of injection.  Elimination of BAP 
was slower than that of ciraparantag and, the mean t1/2 of BAP ranged from 0.527 to 1.76 
hours.  Available data on Day 3 suggested an increase in t1/2 at the 360 mg dose level 
compared to lower ciraparantag doses.  Molar ratios of BAP/ciraparantag exposures 
ranged from 0.279 to 0.414 for Cmax and from 0.538 to 2.49 for total exposures.  With 
ciraparantag administration over the 24-fold dose range, more than proportional increases 
in serum BAP Cmax and total exposures were observed.  The slope estimates for Cmax and 
total exposures over the 24-fold dose range were 12% to 48.3% higher than unity and the 
corresponding 90% CIs were completely above the predefined critical region for dose 
proportionality.   
Urine recovery of ciraparantag dose as unchanged ciraparantag was negligible.  Over the 
12-hour collection interval, the mean overall fraction of dose excreted in urine for analyte 
over a 12-hour collection (fe(0-12)) was 0.0377% or less of administered dose.   
The metabolite BAP was excreted in the urine within the first zero to four hour collection 
interval in most subjects; and overall, mean fe(0-12) ranged from 0.886% to 17.7%.  More 
than dose proportional amount of BAP was recovered in the urine.  The mean renal 
clearance (CLr) increased with escalating doses, and ranged from 1.38 L/h at the 15 mg 
dose level to 9.02 L/h at the 360 mg dose level.  The mean CLr at the 360 mg dose level 
(9.41 L/h) was comparable to the 180 mg dose level.   
Administration of ciraparantag at doses from 15 mg to 360 mg 3 hours after edoxaban 
dosing had no apparent impact on the PK of edoxaban and D21-2393.  Serum profiles 
and exposures of edoxaban and D21-2393 and recovery of edoxaban in the urine across 
all PER977 treatments were similar to the placebo group. 
The pharmacodynamics results show that at pre-study drug on Day 3, mean observed 
WBCT after edoxaban dosing increased to similar levels in the placebo group and 
ciraparantag treatments.  Over the one to six hours postdose interval (inclusive) after the 
first ciraparantag dose, complete reversal for WBCT was achieved in a higher percentage 
of subjects in the active treatments (82.9% for all doses) compared to the placebo group 
(60.0%).  Across the 30 mg ciraparantag to 360 mg PER977 treatments, the rate of 
complete reversal at 30 mg was slightly lower (62.5%) while the rate was similar for 60 
mg or higher dose levels (88.9% to 100%).  Both evaluable subjects (100%) in the 15 mg 
PER977 treatment had partial reversal.  None of the subjects in any of the placebo or 
active treatments had percent-of-baseline WBCT >190% at any time point (i.e., no 
reversal). 

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Results of statistical comparisons showed ciraparantag had no impact on re-
anticoagulation with edoxaban as measured by WBCT at pre-study drug on Day 4 versus 
pre-study drug on Day 3.  Over the 1 to 6 hour postdose interval (inclusive) after the 
second ciraparantag dose on Day 4, the rates of complete reversal were comparable to 
Day 3.  Overall, 88.6% of the subjects in the active ciraparantag treatments and 53.3% of 
subjects in the placebo group had complete reversal.  Across the 30 mg to 360 mg active 
treatments, the rate of complete reversal was slightly lower (66.7%) for 180 mg while the 
rate was similar for all other dose levels (87.5% to 100%).  None of the subjects in any of 
the placebo or active treatments had percent-of-baseline WBCT >190% at any time point 
(i.e., no reversal). 
Treatment comparisons of percent-of-baseline WBCT showed lower values compared to 
placebo following 60 mg to 360 mg ciraparantag on Day 3 that were statistically 
significant at most time points between five minutes to three hours after the end of 
injection (geometric least-squares [LS] ratios ranged from 86.52% to 93.70%); and 
following 30 mg to 360 mg ciraparantag on Day 4 at most time points between five 
minutes to six hours after the end of injection (geometric LS ratios ranged from 84.91% 
to 95.71%).  On both study days, WBCT at different dose levels in the active ciraparantag 
treatments returned to baseline within the 0.083-hour to 0.75-hour time points.  
Post-baseline WBCT in placebo-treated subjects did not decrease to baseline level until 
the 1-hour (Day 4) to 1.5-hour (Day 3) post-study drug time point. 
Secondary evaluations of ciraparantag effects on whole blood PoC-PT compared to 
placebo were performed for both Day 3 and Day 4.  On both days, none of the subjects in 
the placebo or ciraparantag treatments had complete reversal.  The rates of partial 
reversal across all ciraparantag treatments were lower than placebo on Day 3 (25.7% 
versus 40.0%), and higher than placebo on Day 4 (45.7% versus 26.7%).  There were no 
statistically significant differences between ciraparantag treatments and placebo for 
maximum and minimum percent-of-baseline PoC-PT (maximum value [Emax], minimum 
value [Emin], and Emin over the partial six-hour interval post study drug [ciraparantag or 
placebo] [Emin(0-6h)]), except for Emax of 100 mg ciraparantag on Day 4 (LS ratio of 
85.19%).  A trend for time to reach minimum value achieved earlier in the ciraparantag 
treatments compared to placebo was observed; in which the differences were statistically 
significant for the time of the minimum value (tEmin) at 360 mg ciraparantag dose level 
on Day 3 (LS difference of -0.7500 h) and tEmin at 30 mg PER977 dose level on Day 4 
(LS difference of -3.705 hours).   
For other secondary endpoints, there were no statistically significant differences versus 
placebo in most comparisons for observed and percent-of-baseline values D-dimer, F1.2, 
and TFPI. 
Results of exposure-response assessments showed statistically significant differences for 
tEmin achieved earlier with increasing ciraparantag Cmax (i.e., negative slopes) on Day 3.  

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There were no statistically significant correlations on Day 4.  Similar results were seen 
for BAP. 
Safety analyses showed no deaths or serious AEs were reported during the study.  One 
subject with an AE leading to study discontinuation (due to migraine) was reported 
There was an increase in the number of subjects who reported at least one 
treatment emergent AE with an increase in the dose of ciraparantag administered 
No relevant trends were observed over time in the mean and median laboratory values 
between active-treated cohorts and between active-treated cohorts and placebo 
No notable differences were noted in pulse oximetry, ECGs, telemetry, or fecal occult 
blood assessments, when comparing active treatment groups or comparing active 
treatment groups and placebo. 
In summary, PER977-02-001 concluded the following: 
• Serum ciraparantag Cmax and total exposures increased in an approximately 
proportional manner for escalating doses from 15 mg to 360 mg; with no dose 
dependent changes in systemic clearance and volume of distribution. 
• BAP is a major metabolite of ciraparantag that exhibits elimination rate limited 
kinetics. 
• Serum BAP Cmax and total exposures increased more than proportionally to 
ciraparantag doses over the 15 mg to 360 mg range. 
• Fractions of the ciraparantag dose recovered in the urine as BAP and CLr increased 
with escalating doses. 
• Administration of ciraparantag three hours after edoxaban dosing had no apparent 
impact on the PK of edoxaban and D21-2393. 
• The integrated PD results suggest an anticoagulation reversal effect, as measured 
by WBCT, at 60 mg ciraparantag dose or above. 
• Single-dose administration of ciraparantag had no impact on re-anticoagulation 
with edoxaban. 
• There were no statistically significant differences versus placebo for any of the 
analytes (D-dimer, F1.2, and TFPI) measured to detect procoagulation signal. 
• Escalating IV doses of ciraparantag (15 mg, 30 mg, 60 mg, 180 mg, and 360 mg) 
administered three hours after a 60 mg edoxaban administration were considered 
well tolerated in the study population. 

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1.2.5 
Pharmacokinetics 
In PER977-01-001, ciraparantag and its primary metabolite, 1,4-Bis(3-aminopropyl) 
piperazine (BAP), demonstrate dose-proportional response both with respect to maximal 
concentration (Cmax) and half-life (t½).  When administered alone, at the lowest dose of 
ciraparantag administered, 3 mg (5 mg ciraparantag acetate), the average Cmax was 
approximately 172 ng/mL ciraparantag in serum and the average t½ was approximately 
12 minutes.  At the highest ciraparantag dose analyzed, 180 mg (300 mg ciraparantag 
acetate), the average Cmax was approximately 10704 ng/mL in serum and the average t½ 
was approximately 17 minutes (Figure 3). 
Figure 3:  Ciraparantag* Serum Concentration Profile 
* All doses expressed as ciraparantag acetate
BAP reaches Tmax 20-30 minutes after ciraparantag administration, and Cmax ranged from 
~ 90 ng BAP/mL serum at a 15 mg ciraparantag (25 mg ciraparantag acetate) dose to 700 
ng BAP/mL serum at a 180 mg ciraparantag (300 mg ciraparantag acetate) dose.  
Ciraparantag was found almost exclusively as BAP in 24-hour pooled urine samples 
indicating full metabolism prior to urinary excretion in keeping with the findings from 
the rat 14C-PER977 study (Figure 4).  

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Figure 4:  BAP Serum Concentration Profile* 
 
* All doses expressed as ciraparantag acetate  
Ciraparantag was found almost exclusively as BAP in pooled urine samples (Figure 5) 
indicating full metabolism prior to excretion as was observed in the nonclinical study.  
Figure 5:  Ciraparantag* Urinary Excretion Profile as BAP 
 
* All doses expressed as ciraparantag acetate  
In PER977-01-003, the full 24-hour mean profiles of WBCT generally mirrored 
enoxaparin mean concentration-time profiles, suggesting enoxaparin anticoagulation was 
well reflected by WBCT.  The PK of ciraparantag and its metabolite, BAP, in serum and 
urinary excretion of plasma enoxaparin following administration of 15 mg ciraparantag 
(25 mg ciraparantag acetate) x 4 or single doses ranging from 20 mg to 180 mg 

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ciraparantag (100 mg to 300 mg ciraparantag acetate), or placebo (enoxaparin only; 
placebo group) were well characterized.  Administration of ciraparantag four hours after 
enoxaparin did not appear to alter the PK profile of enoxaparin in plasma. 

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2 
STUDY OBJECTIVES 
The objectives of Phase 2 of this study are: 
• To evaluate the efficacy of ciraparantag in the reversal of anticoagulation induced 
by rivaroxaban 20 mg administered orally once daily for three days as assessed by 
WBCT 
• To evaluate the safety and tolerability of ciraparantag 60 mg (100 mg)2, 120 mg (200 
mg), 180 mg (300mg), and 30 mg (50 mg), and additional cohorts if necessary 
administered 4 hours after 20 mg rivaroxaban administration at steady state 
• To assess the PK characteristics of rivaroxaban and ciraparantag and its primary 
metabolite 
                                                 
2 Previously used ciraparantag acetate salt dose based on 10 mg/mL.  The active study drug doses in this 
protocol is now expressed as active drug moiety (ciraparantag) based on 6 mg/mL (See conversion table). 

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3 
INVESTIGATIONAL PLAN 
3.1 Overall Study Design and Plan 
This is a randomized, single-blind, placebo-controlled assessment of the efficacy and 
safety of ciraparantag administered to healthy volunteers measuring clotting times using 
WBCT.  All subjects will undergo screening up to 36 days prior to enrollment.  
Randomization will take place on Day 3 after administration of rivaroxaban.  Subjects 
will be enrolled sequentially into up to four cohorts. 
If the Screening visit takes place within 3 week prior to check-in, the check-in procedures 
may be modified to exclude redundant procedures at the discretion of the Investigator.  
There will be a safety review after completion of treatment in one cohort and initiation of 
treatment in the subsequent cohort. 
Subjects (n=16 per cohort) will be randomized in a 3:1 ratio to receive ciraparantag or 
placebo (saline for injection). Figure 6 depicts the experimental design. 
Figure 6:  Study Schema 
 
Throughout the protocol, “study drug” will refer to randomized treatment with 
ciraparantag or placebo.  The active study drug doses are expressed as active drug 
substance (ciraparantag).   
The administered dose is based on a concentration of 6 mg/mL ciraparantag and 
translates to the following dose conversions:  
Ciraparantag Acetate 
Ciraparantag 
Dose Volume 
600 mg 
360 mg 
60 mL 
300 mg 
180 mg 
30 mL 
100 mg 
60 mg 
10 mL 
50 mg 
30 mg 
5 mL 
25 mg 
15 mg 
2.5 mL 
All subjects will receive a single dose of 20 mg rivaroxaban in the morning on Days 1-3.  
Study drug will be administered only to those subjects who have a minimum increase in 
clotting time of 25% (as measured by WBCT) above Day 3 pre-rivaroxaban levels at the 
pre-study drug time point on Day 3 (i.e., 3.75 hours post rivaroxaban).  Any subject who 
does not have a minimum increase in clotting time of 25% above Day 3 pre-rivaroxaban 
levels at the pre-study drug time point on Day 3 will be discontinued from the study and 
replaced.  At 4 hours following rivaroxaban a single IV dose of study drug (ciraparantag 
or placebo) will be administered.   

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Individual subjects may only participate in one dose cohort of this study.  Any subject 
who discontinues prior to completion for reasons other than an AE will be replaced and 
the replacement subject will receive the same treatment as the original subject.  Subjects 
who discontinue due to an AE that precedes administration of study drug may be replaced 
at the discretion of the Sponsor.  Only those subjects who discontinue due to AEs that 
follow administration of study drug (ciraparantag or placebo) will not be replaced.  
3.2 Dose Rationale 
A total of four dosing cohorts (Cohorts 1-4) are planned.  The planned doses of 
ciraparantag or placebo (administered as a volume equivalent of ciraparantag) have been 
evaluated as single and repeat IV doses from 5 mg ciraparantag acetate (3 mg 
ciraparantag) up to 600 mg ciraparantag acetate (360 mg ciraparantag) in previous 
protocols (PER977-01-001, PER977-01-002, PER977-01-003, and PER977-02-001).  All 
doses of study drug will be administered by IV injection over a minimum of 10 minutes. 
3.3 Study Duration and Dates 
Expectation of the total duration of the study is approximately 3 months.  Individual 
subject participation is approximately 50 days inclusive of screening and follow-up.  
Subjects enrolled will spend up to four nights admitted to an in-patient facility.   

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4 
STUDY POPULATION 
4.1 Screening and Enrollment 
The Investigator will maintain a confidential screening log of all potential study 
candidates that includes limited information of the subjects (age, sex), date and outcome 
of screening process (e.g., enrolled in the study, reason for ineligibility, refused to 
participate). 
The Investigator will be expected to maintain an Enrollment Log of all subjects enrolled 
in the study indicating their assigned study number. 
The Investigator will maintain a confidential subject identification code list.  This 
confidential list of names of all subjects allocated to study numbers upon enrolling in the 
study, allows the Investigator to reveal the identity of any subject when necessary. 
Each subject will sign an Informed Consent Form (ICF) prior to any study assessments.   
Subjects should conform to the inclusion/exclusion criteria for the duration of the study.  
If a subject violates an inclusion or exclusion criterion at any point during the study, 
he/she may be removed from the study and replaced. 
4.2 Study Population 
The study population will consist of healthy male and female adults, age 50-75 years 
(inclusive).  
The sample size is determined empirically, but is considered adequate to achieve the 
objectives of the study.  Sixteen subjects will be enrolled in each cohort (3:1; active: 
placebo). 
Estimated number of subjects screened: 
160 
Planned number of subjects randomized/dosed: 
64 
Planned number of evaluable subjects: 
64 
4.3 Inclusion Criteria 
Each patient must meet the following criteria to be enrolled in this study. 
1. Adults age 50 to 75 years, inclusive 
2. Laboratory tests (chemistry, hematology and coagulation assessments) and 
urinalysis performed during screening up to 36 days prior to administration of 
study treatment deemed not clinically significant by the principal investigator. 

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3. No clinically significant findings on 12-lead electrocardiogram (ECG) performed 
during screening 
4. Body mass index (BMI) 18 to ≤ 32 kg/m2, inclusive 
5. Male subjects agree to use appropriate contraception (i.e., latex condom with 
spermicide) in addition to their partner using an acceptable form of contraception 
(e.g., diaphragm, cervical cap, intrauterine device, hormonal contraceptives, 
surgical sterilization or post-menopausal), when engaging in sexual activity during 
the course of the study. Moreover, male subjects should not donate sperm or 
attempt to impregnate a partner during the course of the study and for a period of 
12 weeks following discharge from the study. 
6. Female subjects must have negative pregnancy tests at screening and check-in 
AND: be surgically sterile (with documentation of hysterectomy, bilateral 
oophorectomy, bilateral salpingectomy, bilateral tubal ligation/tubal occlusion) OR 
post-menopausal (no menstruation for a minimum of 12 months and confirmed by 
serum follicle stimulating hormone [FSH] of ≥ 40 mIU/ml and estradiol < 30 pg at 
screening and check-in) OR, if of child-bearing potential,  must be using an 
acceptable method of contraception such as an IUD, implant or contraceptive 
injection, or two forms of the following (e.g., diaphragm, cervical cap, patch or 
vaginal hormonal contraceptive, condom, spermicide, or sponge) for the last three 
months. All females must agree to continue to use their method of birth control for 
the duration of the study and for a minimum of one complete menstrual cycle. 
7. Subjects who have participated in a prior study of ciraparantag must have been 
discharged from the study a minimum of 1 month prior to the planned treatment.  
8. Subjects must understand and agree to comply with the requirements of the study 
and they must be willing to sign the informed consent form indicating voluntary 
consent to participate in the study prior to initiation of screening or study-related 
activities 
4.4 Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from the study. 
1. History or current evidence of clinically significant cardiac, hepatic, renal, 
pulmonary, endocrine, neurologic, infectious, gastrointestinal, hematologic, or 
oncologic disease as determined by screening history, physical examination, 
laboratory test results or 12-lead ECG assessment.  History or current evidence of 
liver function tests greater than 50% of the upper limit of normal (ULN) or renal 
function tests (serum creatinine) greater than 1.5 mg/dl and based on PI 
discretion. History or current evidence of QTc (QTcF) greater than normal (450 
msec for males or 470 msec for females). 
2. History of unexplained syncope 

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3. History of major bleeding, trauma, surgical procedure of any type, or vaginal 
delivery within six months prior to screening  
4. History of peptic ulcer, gastrointestinal bleeding (including hematemesis, melena, 
rectal bleeding) within one year prior to screening  
5. Long standing history of bleeding episodes such as epistaxis, bruising or gingival 
bleeding or if not long standing, within 1 month prior to screening  
6. Personal or family history of clotting disorder or abnormality, excessive bleeding, 
joint hematoma, thrombovascular disease or any hematologic disorder involving 
platelets or clotting abnormalities or any condition requiring treatment with 
transfusions, or history of thrombocytopenia 
7. Females with a history of dysfunctional uterine bleeding who have not undergone 
hysterectomy, including history of menorrhagia (heavy menstrual bleeding), 
menometrorrhagia or polymenorrhea  
8. Smokers or use of tobacco and/or nicotine containing products within 3 months 
prior to dosing as determined by the subject’s verbal history 
9. Pregnant or breast-feeding 
10. Males with a history of hormone therapy within 3 months prior to screening 
11. Administration of any blood product or anticoagulant within 3 months prior to 
study entry or any non-steroidal anti-inflammatory drug or cyclooxygenase 
inhibitor within 2 weeks prior to dosing 
12. Taking any type of chronic medication (including vitamin, nutritional and herbal 
supplements) for more than 14 consecutive days within the 4 weeks prior to study 
entry (use of hormonal contraceptives is acceptable except for oral contraceptives)  
13. Positive serologic test for human immunodeficiency virus (HIV), Hepatitis C 
virus antibody (HCV-Ab), or Hepatitis B surface antigen (HBsAg) 
14. Donation of blood or blood products within 56 days prior to screening 
15. Participation in any study with an investigational compound or device within 30 
days prior to signing informed consent  
16. Active drug or alcohol dependence within the prior 12 months or any condition 
that, in the opinion of the Investigator, would interfere with adherence to study 
protocol 

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5 
STUDY TREATMENT(S) 
5.1 Description of Treatment(s) 
The following dosage forms will be provided for this study: 
• Ciraparantag for IV injection 
• Placebo for IV injection 
• Rivaroxaban 20 mg tablets (commercial formulation Xarelto®, Bayer/Janssen) for 
oral administration  
All doses of study drug (ciraparantag or placebo) will be administered by IV injection 
(over a minimum of 10 minutes) e.g. 60 mg ciraparantag (10 ml) will be administered at a 
rate of approximately 1 mL/min and 360 mg (60 ml) will be administered at a rate of 
approximately 6 mL/min into an indwelling catheter that is not attached to an IV solution 
and will not result in dilution of the study drug.  The indwelling catheter will be flushed 
with 5.0 mL of sterile 0.9% Sodium Chloride Injection, USP before and after 
administration of study drug.  All doses of study drug will be administered in a single-
blinded-fashion. 
5.2 Treatments Administered 
5.2.1 
Ciraparantag 
The investigational drug product is a sterile, isotonic, pH neutral solution for injection 
containing 6 mg/mL ciraparantag (10 mg/mL ciraparantag acetate) + 6.4 mg/mL sodium 
chloride to be administered by IV injection. 
(See the Ciraparantag Investigator Brochure for complete description of the chemical 
structure) 
5.2.2 
Placebo 
Sterile 0.9% Sodium Chloride Injection, USP will be administered as the placebo in the 
same method as ciraparantag. 
5.2.3 
Rivaroxaban 
All doses of rivaroxaban (trade name Xarelto®; Bayer/Janssen) will be administered in an 
open-label manner. The ingestion of rivaroxaban tablets will be witnessed by clinical site 
personnel. Rivaroxaban 20 mg administered once daily as a single oral tablet for three 
consecutive days is a standard, FDA approved dose and is considered safe and well-
tolerated in this population.  

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5.3 Selection and Timing of Dose for Each Volunteer Subject 
The doses of ciraparantag utilized in this study were selected based on the clinical 
findings in PER977-01-001.   
The 20 mg dose for rivaroxaban is the most common and FDA approved dose considered 
safe and well-tolerated in this population. 
All doses of rivaroxaban will be administered in an open-label manner.  All doses of 
study drugs (ciraparantag or placebo) will be administered in a single-blind manner 
(study site personnel performing coagulation testing and subjects will be blinded).   
5.4 Method of Assigning Patients to Treatment Groups 
The Investigator will identify all subjects who will meet all inclusion/exclusion criteria 
and who will be enrolled in the study.  Subjects will be enrolled in cohorts of 16 subjects 
each and will be sequentially assigned Randomization Numbers 1001 to 1016 prior to 
dosing of study drug on Day 3, after confirmation of eligibility.  The next 16 such 
subjects will be enrolled in Cohort 2, and will be sequentially assigned Randomization 
Numbers 2001 to 2016.  This method of assignment will continue through all four 
cohorts.  Replacement subjects, if applicable will be assigned the same treatment, using 
the number of the withdrawing subject +100 (e.g. if subject 1001 withdraws, the 
replacement subject would be 1101).  
The assignment of treatment will be based on Randomization Schedules to be generated 
by the CRO.  Each cohort will have a different, independently generated randomization 
schedule. 
5.5 Blinding 
This is a single-blind study in which the subjects will be blinded to treatment of the study 
drug (ciraparantag or placebo) and the study personnel assigned to conducting 
coagulation testing must be blinded as well.  
5.6 Concomitant Therapy 
Use of concomitant medications (including vitamin, nutritional and herbal supplements) 
is prohibited as per Exclusion criteria, during screening and for the course of the study.  
Acetaminophen up to 1 gram/24 hours may be administered for management of AEs at 
the discretion of the Investigator. As needed use of over-the-counter antihistamines is 
permitted following screening and prior to admission on Day -1 and following discharge 
from the clinical site on Day 4.  Use of hormonal contraceptives is acceptable except for 
oral contraceptives. 

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5.7 Meals and Study Restrictions 
5.7.1 
Dietary Guidelines Prior to Check-in 
The purpose of the required diet is to prevent a false positive reading for the fecal blood 
test. 
Begin at least 2 days before check-in at the clinical site for overnight visits. 
When to begin 
diet restriction? 
Do not eat and 
drink 
What are some suggested foods that are 
ok to eat and drink? 
At least 2 days 
before check-in 
Any red or rare 
meat. Horseradish, 
cantaloupe, raw 
turnips, broccoli, 
cauliflower, red 
radishes, and 
parsnips. 
NO alcohol (beer, 
wine or liquor) 
Pasta, rice, potato, dairy, and vegetables 
Non-alcoholic beverages like sparkling 
cider, ginger-ale, Sprite, Crystal-light with 
no caffeine, whole milk (cow, goat, soy) 
 
5.7.2 
Dietary Guidelines during the Study 
Meals and an evening snack will be provided for each overnight stay. Subjects will be 
instructed on when to fast, what times to eat meals and snacks, and when water may be 
consumed. Identical meals will be served for each treatment.  The calorie content, as well 
as the percent of calories from protein, carbohydrate, and fat, will be uniform for each 
meal during the study (i.e., breakfast uniform to breakfast, lunch uniform to lunch).  
Substitutions of food are not allowed.  The calories from fat for the day will not exceed 
30% per day.  
5.7.3 
Lifestyle Restrictions 
During the study, subjects will be advised against using manual razors and dental flosses.  
Electric razors and soft toothbrushes will be allowed.  
Subjects will not perform any physical activity outside of their normal living activities 
and will not engage in strenuous activity from screening to study completion. 
Except when ECGs must be taken in supine position, subjects will remain in the semi-
erect or upright position with minimal ambulation (i.e. only to and from the washroom or 
for study procedures) for the first 8 hours after study drug dosing on Day 3. 

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5.8 Treatment Compliance 
All study drug will be administered by clinical site personnel by IV injection over a 
minimum of 10 minutes into an indwelling catheter that is not attached to an IV solution 
and will not result in dilution of the study drug.  Following administration of the study 
drug, the indwelling catheter will be flushed with 5.0 mL of sterile 0.9% Sodium 
Chloride Injection, USP. 
All doses of rivaroxaban will be administered after breakfast with 240 ml of water under 
the supervision of clinical site personnel.  The ingestion of all doses of rivaroxaban will 
be witnessed by clinical site staff. A mouth and hand check of all subjects will be carried 
out to ensure that the tablets have been swallowed. 
5.9 Dose Escalation/De-Escalation 
Review of pharmacodynamic, AEs, clinical laboratory tests, and ECG data will be 
conducted by a group that includes the Principal Investigator, Medical Monitor(s), and 
representative(s) of the Sponsor.  The group will be responsible for the decision to 
expand a given dose cohort, escalate (or de-escalate) to a different dose from the planned 
dose, or stop the study. All meetings will be documented with minutes.   
The goal of the study is to explore the dose range of ciraparantag that reverses the 
anticoagulation induced by therapeutic doses of rivaroxaban at steady state. The study is 
intended to establish a dose of ciraparantag that fully reverses steady-state rivaroxaban, to 
evaluate at least one dose above the reversal dose to establish a therapeutic index, and at 
least one partial or no effect dose. 
5.10 Packaging and Labeling 
5.10.1 
Ciraparantag 
Ciraparantag Injection will be supplied as a sterile solution for IV injection containing 6 
mg/ml ciraparantag (10 mg/mL ciraparantag acetate) and supplied in 30 clear vials (5 mL 
each).  Vials will be labeled for clinical study use including study number, contents, 
quantity, lot number, date of manufacture and stability retest date, and storage conditions 
as well as a caution statement according to 21CFR 312.6(a). 
5.10.2 
Rivaroxaban 
Rivaroxaban will be provided in high density polyethylene (HDPE) bottles with child-
resistant closure containing 30 tablets per bottle.  Bottles will be labeled for clinical study 
use including study number, contents, quantity, lot number, directions, and storage as 
well as a caution statement.  

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5.11 Storage and Accountability 
Drug supplies must be stored in a secure, limited access storage area under the 
recommended storage conditions. 
5.11.1 
Ciraparantag 
Ciraparantag will be stored refrigerated at 2-8°C (36-46°F) and shipped on cold packs to 
the clinical test site.  Temperature will be monitored during shipping for excursions.  
After arrival at the clinical study site, it will be refrigerated at 2-8°C (36-46°F) until prior 
to administration. 
5.11.2 
Placebo 
Placebo solution will be provided by the CRO and stored at room temperature prior to 
preparation. 
5.11.3 
Rivaroxaban 
Rivaroxaban tablets must be stored at 20-25°C (68-77°F) with excursions permitted to 
15-30°C (59-86°F). Temperature measurements will be recorded.  
5.12 Investigational Product Retention at Study Site 
Investigational study drug will be labeled with the following statement – Caution: New 
Drug--Limited by Federal (or United States) law to investigational use. The Principal 
Investigator will maintain accurate records of receipt of all test articles, including dates of 
receipt. In addition, accurate records will be kept regarding when and how much of each 
test article is dispensed to and used by each individual subject in the study. Reasons for 
deviation from the expected dispensing regimen must also be recorded. A Drug 
Dispensing Form will be provided for this purpose and will be signed by the Principal 
Investigator at the conclusion of the study. To satisfy regulatory requirements regarding 
drug accountability and destruction, following instruction from the Sponsor, the Principal 
Investigator will arrange for return or destruction of all used, unused, empty and partially 
used study drug and containers to the Sponsor for final accountability and disposal. 
 
 

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6 
STUDY PROCEDURES 
6.1 Informed Consent 
The Investigator or designee will obtain written informed consent from all subjects prior 
to initiation of any study-related procedures as per Section 10.5.   
6.2 Medical History 
The Investigator or designee will obtain a complete medical history including medication 
and surgical history will be obtained at the screening visit.  To ensure subject safety, the 
Investigator may ask the subject to sign a medical release form allowing him to contact 
the subject's doctor for more information about subject's medical history 
6.3 Physical Examination 
The Investigator will perform a complete physical examination at screening and 
abbreviated physical examination will be performed on check-in and prior to discharge. 
The full physical examination will consist of the following: 
•
General physical well-being will be assessed by evaluation of the head, eyes, ears,
nose, throat, neck, heart, chest, lungs, abdomen, extremities, neurological
status (including, but not limited to, consciousness, facial symmetry,
strength/sensation symmetry, gait), skin, and other conditions of note
•
Measurement of height in street clothes and without shoes (to the nearest 0.5 cm)
at screening only
•
Measurement of weight in street clothes and without shoes (to the nearest 0.1 kg).
Weight will be assessed by standard objective means (e.g., weight scale). There
are no adjustments in dose if changes in weight should occur
•
Body mass index is based on height and weight calculated at screening and first
check-in for eligibility purposes using the following formula:
BMI = 
Weight in kilograms
Height in meters2 
The abbreviated physical examination will consist of the following: 
•
General appearance, heart, lungs, abdomen.
•
Additional physical examinations may be conducted at any time throughout the
study, if deemed necessary by the Investigator.
6.4 Vital Signs 
All vital sign measurements will be taken after the subject is supine for 5 minutes. 

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Vital signs (including blood pressure and pulse [radial or brachial to be measured over 
30 seconds if performed manually], respiration rate, and body temperature (oral). 
Vital signs, respiration rate, and body temperature will be measured at screening. Vital 
signs will be measured on Day -1, prior to administration of rivaroxaban on Days 1-3, 30 
minutes prior to study drug, at 1, 4, 8 and 24 hours post-study drug. Please see below for 
tolerance window to perform vital sign assessments: 
Vital Signs Tolerance Window 
Vital Sign Time Point 
Tolerance Window 
Pre-dose 
-60 minutes to 0 hour 
>0 hour - 4 hour 
-10 minutes to +10 minutes 
>4 hour - 12 hour 
-20 minutes to +20 minutes 
>12 hour - 24 hour 
-30 minutes to +30 minutes 
Study Exit/Early Termination 
-30 minutes to +30 minutes 
Vital signs, respiratory rate, and body temperature will be re-assessed at the discretion of 
the investigator if warranted by the subject’s condition and/or in the following situations: 
• Systolic blood pressure less than 90 mmHg or greater than 180 mmHg 
• Diastolic blood pressure less than 50 mmHg or greater than 100 mmHg 
• Pulse less than 40 beats per minute or greater than 110 beats per minute 
• Respiratory rate less than 10 breaths per minute or greater than 30 breaths per 
minute  
• Body temperature less than 36.1°C (97.0°F) or greater than 37.3°C (99.2°F) 
An abnormal vital sign that is considered clinically significant by the Investigator will be 
recorded as an adverse event. Additional vital sign measurements may be conducted at 
any time throughout the study, if deemed necessary by the Investigator. 
 
6.5 Clinical Laboratory Tests 
Blood and urine samples for safety laboratory tests will be collected at screening, at 
check-in, and prior to discharge from the clinical site.  Safety laboratory tests may also be 
done at any time during the study at the discretion of the Investigator to monitor AEs. 
Subjects will be in a seated or supine position during blood collection. 
6.5.1 
Fecal Occult Blood Tests 
Fecal occult blood tests will be done at check-in.  Fecal occult blood kits will be given to 
all subjects at screening to provide stool samples for testing at check-in. In the event 
occult blood kits are not returned, a rectal exam for stool sample may be performed at the 

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discretion of the Investigator. Occult blood test results must be negative during check-in 
to continue study participation.   
Additional fecal occult blood testing may be conducted at any time throughout the study, 
if deemed necessary by the Investigator. 

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6.5.2 
Laboratory Parameters 
Values for the clinical laboratory tests listed below will be determined by accredited 
laboratory facility(ies).   
CLINICAL CHEMISTRY 
HEMATOLOGY 
The following clinical chemistry tests will be 
performed at screening, check-in, and discharge 
from the study: 
The following hematology tests will be 
performed at screening, check-in, and discharge 
from the study: 
Alanine aminotransferase (ALT) 
Hematocrit 
Albumin(ALB) 
Hemoglobin 
Aspartate aminotransferase (AST) 
Platelet count 
Blood urea nitrogen (BUN) 
RBC 
Calcium 
WBC / with differential 
Chloride 
PT-PTT 
CO2 
 
Creatinine(CR) 
URINALYSIS 
Direct bilirubin (DBIL) 
The following urinalysis tests will be performed 
at screening, check-in, and discharge from the 
study: 
Glucose 
Indirect bilirubin (IBIL) 
Appearance 
Lactose dehydrogenase (LDH) 
Bilirubin 
Magnesium 
Blood 
Potassium 
Color 
Sodium 
Creatinine 
Total bilirubin (TBIL) 
Glucose 
Total Protein 
Ketones 
 
Microscopic examination 
 
Occult Blood 
 
pH 
 
Protein 
 
Specific gravity 
  
  
PREGNANCY SCREEN** (females only)  
VIRAL SCREEN*** (to be performed at 
screening only): 
Urine pregnancy test will be done at screening 
and discharge.  Serum pregnancy test will be 
done at check-in on Day -1. 
Serum FSH and estradiol tests will be done on 
post-menopausal females at screening and check-
in on Day -1 
**the urine pregnancy tests may be performed in-
clinic using CLIA-waived marketed kits.  
HBsAg 
HIV antibody test 
HCV antibody test 
 
 
 
Saliva Alcohol Test -(to be performed at 
screening and at check-in using CLIA –waived 
marketed kits) 
Urine Drug Screen – (to be performed at 
screening and check-in using CLIA –waived 
marketed kits) 

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6.5.3 
Experimental Safety Biomarker Assessment 
Two aliquots of citrated plasma (1 ml each) for experimental safety biomarker 
assessments (e.g. D-Dimer, F1.2 tests) will be collected at pre-rivaroxaban (within 1 hr. 
prior to dosing) on Day 1, and at 3.75 and 8 hrs. post-rivaroxaban on Day 3. 
Experimental safety biomarker assessment will only be performed at the discretion of the 
Principal Investigator. 
6.6 Electrocardiograms 
A resting 12-lead electrocardiogram will be performed at screening, check-in, after 
administration of rivaroxaban, and prior to discharge from the clinic site. Parameters 
assessed will include ventricular rate (bpm), PR interval (msec), QRS duration (msec), 
QT interval (msec) and QTc interval (msec). Additional ECGs may be performed at the 
discretion of the Principal Investigator.  
6.7 Dispensing Study Drug 
All study drugs will be prepared by the CRO pharmacy or designated personnel.   
6.7.1 
Ciraparantag  
The study pharmacist or designated personnel will calculate the final volume of 
ciraparantag.  Ciraparantag should be prepared on the day of dosing and stored at room 
temperature at least 1 hour before administration. The appropriate volume of 
Ciraparantag Injection will be withdrawn from the supplied vials. 
Throughout this protocol, the active study drug doses are expressed as active drug 
substance (ciraparantag) (previously study drug doses were expressed as ciraparantag 
acetate with a content of 10 mg/mL).  The administered dose is based on a concentration 
of 6 mg/mL ciraparantag and translates to the following dose conversions:  
Ciraparantag Acetate 
Ciraparantag 
Dose Volume 
600 mg 
360 mg 
60 mL 
300 mg 
180 mg 
30 mL 
100 mg 
60 mg 
10 mL 
50 mg 
25 mg 
30 mg 
15 mg 
5 mL 
2.5 mL 
 
Ciraparantag will be prepared and administered by IV injection over a minimum of 10 
minutes. 
All ciraparantag doses must be labeled with the study number and date. 

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Study drug may be prepared on the day of dosing and will have an expiration of 4 hours 
at room temperature or will be refrigerated at 2-8°C (36-46°F) until use.  All prepared 
solutions must be used within 24 hours.  All unused drugs will be returned to the 
pharmacy.  A record must be kept of all discarded solutions.  
6.7.2 
Placebo 
An equivalent volume of sterile 0.9% Sodium Chloride Injection, USP will be utilized as 
the placebo.   
All placebo doses must be labeled with the study number and date.  
Placebo may be prepared on the day of dosing and will have an expiration of 4 hours at 
room temperature or will be refrigerated at 2-8°C (36-46°F) until use.  All prepared 
solutions must be used within 24 hours.  A record must be kept of all discarded solutions.  
6.7.3 
Rivaroxaban 
Rivaroxaban will be dispensed as one tablet in a container labeled with the study number, 
subject number and date.  All unused tablets will be returned to the pharmacy.   
6.8 Efficacy Assessments 
Time 0 for all PK and PD assessments will be the end of the study drug injection.  Where 
timing for assessments coincide, PD assessment(s) should be performed first, followed by 
PK assessment(s), and then ECGs, and vital signs will be performed. The tolerance window 
to complete PK and PD draws is as follow: 
PK/PD Draw Tolerance Window 
Sampling Time Point 
Tolerance Window 
Pre-dose 
-60 minutes to 0 hour 
>0 hour - 24 hour 
-10 minutes to +10 minutes 
 
Over the course of the study, the total estimated volume of blood to be sampled from 
each subjects for the combined PK, PD and safety evaluations is approximately 225 mL. 
6.8.1 
Pharmacokinetic Assessment 
Blood samples for PK assessment of ciraparantag and its metabolite, and rivaroxaban, 
will be analyzed using LC/MS assay methodology. 
Rivaroxaban PK time points: 
A 4 mL blood sample in potassium EDTA will be collected for each PK assessment of 
rivaroxaban.  

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Day 3: pre-rivaroxaban (within 1 hr. prior to dosing), post-rivaroxaban at 3.75, 4.25, 4.5, 
4.75, 5, 6, 8, 10, 12, and 28 hrs. 
Ciraparantag PK time points: 
Ciraparantag or placebo is administered 4 hrs. after the rivaroxaban dosing on day 3. 
A 3 mL blood sample with no additive (i.e. serum sample) will be collected for each PK 
assessment of ciraparantag and its metabolite.  
Day 3: pre-study drug (within 1 hr. prior to dosing of ciraparantag or placebo), post-study 
drug at 0.25, 0.5, 0.75, 1, 2, 4, 6, 8 and 24 hrs.  
6.8.2 
Pharmacodynamic Assessment 
Blood samples (2 ml) for measuring of clotting time by WBCT will be collected at the 
following time points: 
Day 3: pre-rivaroxaban (within 1 hr. prior to dosing) and post-rivaroxaban at 3.75 and 
post-study drug at 0.25, 0.5, 0.75, 1, 2, 4, 6, 8 and 24 hrs. (Only subjects with at least 
25% increase of clotting time from pre-rivaroxaban level on day 3 will be randomized). 
Triplicate WBCT will be done pre-rivaroxaban, post-rivaroxaban at 3.75 hrs. and post-
study drug at 1 hr. 
6.9 Adverse Events Assessments 
All AEs and SAEs will be captured by electronic data capture (EDC). 
All AEs occurring after the subject signs the ICF up to the time of the Follow-up phone 
call, whether observed by the Investigator or reported by the subject, will be captured.  If 
in the opinion of the Investigator or the sponsor, an AE meets the criteria of an SAE it is 
to be reported. SAEs occurring up to 30 calendar days post treatment should be reported. 
Any AEs and SAEs that occur after the specified reporting period should also be reported 
if in the opinion of the investigator, there is a reasonable possibility for a causal 
association with the study product.  
Medical conditions (including laboratory values/vital signs that are out of range) that 
were diagnosed or known to exist prior to Informed Consent will be recorded as part of 
medical history.  All SAEs are to be reported according to the procedures in Section 
6.9.10 SAE Reporting-Procedure for Investigators.  Report diagnosis as the AE or SAE 
term; when the diagnosis is unavailable, report signs and symptoms as individual entries 
of AE or SAE until the diagnosis becomes available.  For events that are serious due to 
hospitalization, the reason for hospitalization must be reported as the serious adverse 
event (diagnosis or symptom requiring hospitalization).  A procedure is not an AE or 

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SAE, but the reason for the procedure may be an AE or SAE.  Pre-planned (prior to 
signing the Informed Consent Form) procedure or treatment requiring hospitalization for 
pre-existing conditions which do not worsen in severity should not be reported as SAEs.  
For deaths, the underlying or immediate cause of death should always be reported as an 
SAE.  In addition, any serious, untoward event that may occur subsequent to the 
reporting period that the Investigator assesses as related to study drug should also be 
reported and managed as an SAE. 
At each visit, the Investigator will determine whether any AEs have occurred by 
evaluating the subject.  Adverse events may be directly observed, reported spontaneously 
by the subject or by questioning the subject at each study visit.  Subjects should be 
questioned in a general way, without asking about the occurrence of any specific 
symptoms.  All abnormal laboratory values must be appraised by the Investigator as to 
clinical significance.  All abnormal laboratory values considered clinically significant by 
the Investigator must be recorded as an AE on the CRF, and if serious, reported as an 
SAE following the procedures in Section 6.9.10. 
Investigator should follow subjects with AEs until the event has resolved or the condition 
has stabilized.  In case of unresolved AEs including significant abnormal laboratory 
values at the end of study assessment, these events will be followed until resolution or 
until they become clinically not relevant. 
6.9.1 
Clinical Laboratory Abnormalities and Other Abnormal Assessments as 
Adverse Events or Serious Adverse Events 
Laboratory abnormalities are usually not recorded as AEs or SAEs.  However, laboratory 
abnormalities (e.g., clinical chemistry, hematology, and urinalysis) that require medical 
or surgical intervention or lead to study drug discontinuation must be recorded as an AE, 
as well as an SAE, if applicable.  In addition, laboratory or other abnormal assessments 
(e.g., ECG or vital signs) that are associated with signs and/or symptoms must be 
recorded as an AE or SAE if they meet the definition of an AE (or SAE) as described in 
Section 6.9.3 and Section 6.9.4, respectively.  For AEs associated with laboratory 
abnormalities, the event should be graded on the basis of the clinical severity in the 
context of the underlying conditions; this may or may not be in agreement with the 
grading of the laboratory abnormality. 
6.9.2 
Toxicity Management 
Subject safety will be monitored closely. All clinically significant treatment-emergent 
AEs (TEAEs) denoted by the Investigator will be brought to the attention of the 
Perosphere medical monitor. All subjects experiencing a TEAE must be monitored 
periodically until symptoms subside or until there is a satisfactory explanation for the AE. 
Additionally, treatment-emergent abnormal laboratory values should be monitored 
periodically until the abnormality resolves, returns to baseline levels, or is otherwise 
explained.  At the discretion of the Investigator, assessments and/or clinic visits in 

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addition to those scheduled for routine study conduct may be warranted to properly 
monitor the AE or laboratory abnormality. All questions regarding toxicity management 
should be directed to the Perosphere medical monitor. 
6.9.3 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product (ICH E2A Guideline, Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting, Oct 1994). 
It is the responsibility of Investigators, based on their knowledge and experience, to 
determine, those circumstances or abnormal lab findings which should be considered 
adverse events. 
6.9.4 
Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose: 
•
Results in death,
•
Is life-threatening,
•
Requires inpatient hospitalization or prolongation of existing hospitalization,
•
Results in persistent or significant disability/incapacity,
•
Is a congenital anomaly/birth defect, or
•
Is an important medical event
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe (ICH E2A Guideline, 
Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, 
Oct 1994). 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require intervention to prevent one of the other outcomes listed in the 
definition above.  Examples include allergic bronchospasm, convulsions, and blood 
dyscrasias or development of drug dependency or drug abuse. 

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6.9.5 
AE Severity 
The following definitions should be used to assess intensity of adverse events: 
Mild: Awareness of sign or symptom, but easily tolerated, i.e., does not interfere with 
subject’s usual function. 
Moderate: Discomfort enough to cause interference with usual activity. 
Severe: Incapacitating with inability to work or do usual activity, i.e., interferes 
significantly with subject’s usual function. 
Severity should be distinguished from seriousness. Severity is a measure of intensity 
whereas seriousness is classified by the criteria based on the regulatory definitions. 
An AE of severe intensity need not necessarily be classified as serious. 
6.9.6 
Causality Assessment 
The Investigator should assess causal relationship between an AE and ciraparantag and/or 
rivaroxaban (if administered) on the basis or his/her clinical judgment and the following 
definitions.  The causality assessment should be made based on the available information 
and can be updated as new information becomes available. 
1 = Related: 
The AE follows a reasonable temporal sequence from study drug administration, 
and cannot be reasonably explained by the subject’s clinical state or other factors 
(e.g., disease under study, concurrent diseases, and concomitant medications). 
The AE follows a reasonable temporal sequence from study drug administration, 
and is a known reaction to the drug under study or its chemical group, or is 
predicted by known pharmacology. 
2 = Not Related: 
The AE does not follow a reasonable sequence from study product administration, 
or can be reasonably explained by the subject’s clinical state or other factors (e.g., 
disease under study, concurrent diseases, and concomitant medications). 
6.9.7 
Action Taken Regarding the Study Drug 
The following definitions will be used to describe action taken regarding study drug: 
1 = Dose Not Changed: No change in study drug dosage was made. 
2 = Drug Withdrawn: The study product was permanently stopped. 
3 = Dose Reduced: The dosage of study product was reduced. 

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4 = Drug Interrupted: The study product was temporarily stopped. 
5 =Dose Increased: The dosage of study product was increased. 
6.9.8 
Adverse Event Outcome 
The following definitions will be used to describe AE outcomes: 
1 = Recovered/Resolved 
The subject fully recovered from the AE with no residual effect observed. 
2 = Recovered/Resolved with Sequelae 
The residual effects of the AE are still present and observable. 
Include sequelae/residual effects. 
3 = Not Recovered/Not Resolved 
The AE itself is still present and observable. 
4 = Fatal 
5 = Unknown 
6.9.9 
Other Action Taken for Event 
The following definitions will be used to describe other actions taken for an AE:  
1 = None. 
No treatment was required. 
2 = Medication required. 
Prescription and/or OTC medication was required to treat the adverse event. 
3 = Hospitalization or prolongation of hospitalization required. 
Hospitalization was required or prolonged due to the adverse event, whether or 
not medication was required. 
4 = Other. 

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6.9.12 
Pregnancy 
Pregnancy test will be performed at screening and at visits specified in the protocol. 
Subjects with a positive test at screening or during the study period will be excluded from 
the study. Women of child-bearing potential will be instructed to practice an acceptable 
method of birth control for the duration of the study. However, if subject becomes 
pregnant during the study, the pregnancy, in and of itself, is not considered an AE unless 
there is suspicion that the study medication may have interfered with the effectiveness of 
a contraceptive medication or method. 
Any pregnancy diagnosed during the study, or that the Investigator becomes aware of 
within 30 days after stopping study medication, must be reported by the Investigator to 
the Sponsor using the 
 Initial Pregnancy Report Form within 24 hours of 
awareness. The pregnancy should be followed to term by the Investigator and the 
outcome of all such pregnancies, i.e., spontaneous miscarriage, elective termination, 
normal birth, or congenital abnormality, should be reported to the Sponsor using the 
 Pregnancy Outcome Report Form.  
All live births must be followed for a minimum of 8 weeks or to the first well-baby visit 
and information reported using the 
 Pregnancy Follow-Up Report Form. All 
reports of congenital abnormalities/birth defects and spontaneous abortions/miscarriages 
should be reported as an SAE for the study.  
Elective abortion procedures, without complications, will not be considered as AEs. 
6.10 Concomitant Medication Assessments 
Concomitant medication is defined as any medication other than the trial product that is 
taken during the trial including the screening period. 
Details of all medications must be recorded at trial entry.  Any changes in concomitant 
medications must be recorded at each visit. 
The information collected for each concomitant medication includes dosage, route, start 
date, stop date or continuing and indication.  Concomitant medications will be 
summarized and tabulated. 
6.11 Removal of Patients from the Trial or Study Drug 
Any subject who discontinues from the study treatment for any reason will have their 
study treatment discontinuation recorded. 

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Subjects may be withdrawn from the study after signing informed consent for the 
following reasons: 
• Adverse Event 
• Lost to Follow-up 
• Withdrawal of Consent by Subject 
• Investigator decision 
• Death 
• Pregnancy 
• Study terminated by Sponsor  
• Other (any other reason) 
If a subject withdraws from the study, the Investigator will complete and report the 
observations as thoroughly as possible up to the date of withdrawal including the date of 
last treatment and the reason for withdrawal. 
If the subject is withdrawn due to an AE, the Investigator will follow the subject until the 
AE has resolved or stabilized. 
All subjects who are withdrawn from the study should complete protocol specified 
withdrawal procedures. 
6.11.1 
Withdrawal Procedures 
The subject may withdraw from the study at any time.  Subjects who become pregnant or 
who develop a condition which contraindicates the use of rivaroxaban during the course 
of the study will be withdrawn.  The subject may be withdrawn from the study at the 
discretion of the Investigator or Sponsor, if judged non-compliant with study procedures 
or due to safety concerns.  These criteria include: 
• Unwillingness to continue with the study, or because of unwanted effects due to 
study drug  
• Ingestion of interfering substances at times other than those specified in the 
protocol during the course of the study or,  
• Intercurrent illness or concomitant medication that, in the Investigator’s judgment, 
may interfere with the conduct of the study. 
• Study drug will be administered only to those subjects who have a minimum 
increase in WBCT of 25% from pre-rivaroxaban level on day 3 at the pre-study 
drug (i.e., 3.75 hours post rivaroxaban) time point on Day 3.  Any subject who 
does not have a minimum increase in WBCT of 25% from pre-rivaroxaban level 
on day 3 at the pre-study drug time point on Day 3 will be discontinued from the 
study and replaced. 

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Subjects who withdraw from the study prior to completion will undergo abbreviated 
physical exam, vital signs, ECG, and safety laboratories prior to release from the study 
center.  An additional 2 mL blood sample will be collected for confirmatory coagulation 
testing (WBCT).  All subjects who discontinue from the study prior to completion will 
receive a telephone call as follow-up for AEs 3-7 days after discharge. 
6.11.2 
Subject Replacement 
Individual subjects may only participate in one dose-cohort of this study.  Any subject 
who discontinues prior to completion of the dose cohort will be replaced and the 
replacement subject will receive the same treatment as the original subject.  Subjects who 
discontinue due to an AE that precedes administration of study drug may be replaced at 
the discretion of the Sponsor.  Only those subjects who discontinue due to AEs that 
follow administration of study drug (ciraparantag or placebo) will not be replaced.  

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7 
STUDY ACTIVITIES 
A complete schedule of events is provided in the Synopsis.   
Where timing for assessments coincide, PD assessments should be performed first, 
followed by PK assessment(s) as indicated, and then safety measurements.   
Time 0 for PK and PD assessments and post-study drug procedures will be the end of the 
study drug injection. 
7.1 Screening Visit (Days -36 to -1) 
The following activities and/or assessments will be performed at/during Screening in all 
cohorts: 
• Written Informed Consent 
• Review of Inclusion/Exclusion criteria 
• Recording of demographic data, medical/surgical history, medication history 
• Vital signs (including RR and temp), ECG, and safety laboratory tests 
(hematology, chemistry and urinalysis) 
• Complete physical examination 
• Height and weight measurement, and BMI calculation 
• Blood draw for HIV, HBsAg, HCV-Ab 
• Urine pregnancy test for all female subjects 
• FSH and serum estradiol tests for post-menopausal female 
• Saliva alcohol test and urine drug screen 
• Each subject will be given an occult blood kit to be returned at the check-in  
• Subjects will be provided with a lifestyle and dietary guide 
• Adverse events and concomitant medications will be recorded 
7.2 Treatment Period (Day -1 to Day 4) 
7.2.1 
Check-in (Day -1) Procedures 
The following activities and/or assessments will be performed on Day -1 in all subjects: 
• Check-in to the clinical site 
• Review of Inclusion/Exclusion criteria 
• An ECG, vital signs (including RR and temp), and safety laboratory tests 
(hematology, chemistry and urinalysis) 

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• Saliva alcohol and urine drug screen  
• Serum pregnancy tests in all female subjects 
• FSH and serum estradiol tests for post-menopausal female 
• Fecal occult blood analysis 
In the event the occult blood kit is not returned, a rectal exam for stool sample may be 
performed at the discretion of the Investigator.  
• Abbreviated physical examination 
• AEs and concomitant medications will be recorded 
• If the screening visit for the subject is within 3 weeks of check-in, redundant 
procedures (ECG, safety laboratory tests, and physical examination) may be 
omitted at the discretion of the PI. 
7.2.2 
Day 1 Procedures 
The following activities and/or assessments will be performed on Day 1 in all subjects: 
• Administration of a single 20 mg dose of rivaroxaban after breakfast; Maintain fast 
for 4 hours after the rivaroxaban dosing; water allowed ad libitum 
• An ECG and vital signs  
• Blood draw for experimental safety biomarker assessment 
• AEs and concomitant medications will be recorded 
7.2.3 
Day 2 Procedures  
The following activities and/or assessments will be performed on Day 2 in all subjects: 
• An ECG and vital signs  
• Administration of a single 20 mg dose of rivaroxaban after breakfast; Maintain fast 
for 4 hours after the rivaroxaban dosing; water allowed ad libitum 
• AEs and concomitant medications will be recorded 
7.2.4 
Day 3 Procedures 
7.2.4.1 
Pre-study drug 
The following activities and/or assessments will be performed on Day 3 before 
administration of study drug in all subjects: 

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• Administration of a single 20 mg dose of rivaroxaban after breakfast; Maintain fast 
for 4 hours after the rivaroxaban dosing (+90 minutes tolerance window to avoid 
conflict with intensive PK/PD assessment); Water allowed ad libitum 
• An ECG and vital signs  
• Blood draw for PK assessment of rivaroxaban and pre-study drug baseline 
• Blood draw for WBCT measurement (triplicates at pre-rivaroxaban and post-
rivaroxaban at 3.75 hrs.) 
• Blood draw for experimental safety biomarker assessment 
• Randomization 
• AEs and concomitant medications will be recorded 
7.2.4.2 
Study Drug Administration: Time 0 
The following activities and/or assessments will be performed in the order listed on Day 
3 in all subjects: 
• Vital signs 
• I.V. administration of study drug (ciraparantag or placebo) 
• AEs and concomitant medications will be recorded 
7.2.4.3 
Post-study Drug: 15 minutes 
The following activities and/or assessments will be performed on Day 3 at 15 minutes 
post administration of study drug in all subjects: 
• Blood draw for WBCT 
• Blood draw for PK samples for ciraparantag/metabolite and rivaroxaban  
• AEs and concomitant medications will be recorded 
7.2.4.4 
Post-study Drug: 30 minutes 
The following activities and/or assessments will be performed on Day 3 at 30 minutes 
post administration of study drug in all subjects: 
• Blood draw for WBCT 
• Blood draw for PK samples for ciraparantag/metabolite and rivaroxaban  
• AEs and concomitant medications will be recorded 

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7.2.4.5 
Post-study Drug: 45 minutes 
The following activities and/or assessments will be performed on Day 3 at 45 minutes 
post administration of study drug in all subjects: 
• Blood draw for WBCT 
• Blood draw for PK samples for ciraparantag/metabolite and rivaroxaban  
• AEs and concomitant medications will be recorded 
7.2.4.6 
Post-study Drug: 1 hour 
The following activities and/or assessments will be performed on Day 3 at 1 hour post 
administration of study drug in all subjects: 
• Blood draw for WBCT (triplicates) 
• Blood draw for PK samples for ciraparantag/metabolite and rivaroxaban  
• Vital signs 
• AEs and concomitant medications will be recorded 
7.2.4.7 
Post-study Drug: 2 hours 
The following activities and/or assessments will be performed on Day 3 at 2 hours post 
administration of study drug in all subjects: 
• Blood draw for WBCT 
• Blood draw for PK samples for ciraparantag/metabolite and rivaroxaban  
• AEs and concomitant medications will be recorded 
7.2.4.8 
Post-study Drug: 4 hours 
The following activities and/or assessments will be performed on Day 3 at 4 hours post 
administration of study drug in all subjects: 
• Blood draw for WBCT 
• Blood draw for PK samples for ciraparantag/metabolite and rivaroxaban  
• Blood draw for experimental safety biomarker assessment 
• Vital signs 
• AEs and concomitant medications will be recorded 

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7.2.4.9 
Post-study Drug: 6 hours 
The following activities and/or assessments will be performed on Day 3 at 6 hours post 
administration of study drug in all subjects: 
• Blood draw for WBCT 
• Blood draw for PK samples for ciraparantag/metabolite and rivaroxaban  
• AEs and concomitant medications will be recorded 
7.2.4.10 
Post-study Drug: 8 hours 
The following activities and/or assessments will be performed on Day 3 at 8 hours post 
administration of study drug in all subjects: 
• Blood draw for WBCT 
• Blood draw for PK samples for ciraparantag/metabolite and rivaroxaban  
• Vital signs 
• AEs and concomitant medications will be recorded 
7.2.4.11 
Post-study Drug: 24 hours 
The following activities and/or assessments will be performed on Day 4 at 24 hours post 
administration of study drug in all subjects: 
• Blood draw for WBCT 
• Blood draw for PK samples for ciraparantag/metabolite and rivaroxaban  
• Vital signs 
• AEs and concomitant medications will be recorded 
7.2.5 
Day 4 or Early Termination Procedures 
The following activities and/or assessments will be performed on Day 4 prior to 
discharge in all subjects: 
• An ECG and safety laboratory tests (hematology, chemistry and urinalysis) 
• Vital signs (the vital sign assessment at 24 hr. post-study drug may be used for 
discharge) 
• Urine pregnancy test for female 
• AEs and concomitant medications will be recorded  
• Abbreviated physical examination 

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• Discharge from the clinical site if coagulation parameter (WBCT) are not 
clinically significant.  If there is an abnormal laboratory test result or AE, the 
subject may need to return for repeat testing.  
7.3 Follow-up (Day 7-10) 
The following activities and/or assessments will be performed during the follow-up in all 
subjects:  
• Telephone follow-up  
• AEs and concomitant medications will be recorded  
• Discharge from the study 
Subjects may be asked to return to the clinical site at the discretion of the Investigator.  
 
 

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8 
QUALITY CONTROL AND ASSURANCE 
The Investigator/investigational site will permit study-related monitoring, audits, 
IRB/IEC review and regulatory inspections by providing direct access to source 
data/documents.  Direct access includes permission to examine, analyze, verify, and 
reproduce any records and reports that are important to the evaluation of a clinical study. 
8.1 Monitoring and Inspections 
The study monitor or delegate and regulatory authority inspectors are responsible for 
contacting and visiting the Investigator for the purpose of inspecting the facilities and, 
upon request, inspecting the various records of the study (e.g., case report forms, source 
data, and other pertinent documents). 
The monitor is responsible for visiting site(s) at regular intervals throughout the study to 
verify adherence to the protocol; completeness, accuracy, and consistency of the data; 
and adherence to ICH/GCP and local regulations on the conduct of clinical research.  The 
monitor is responsible for inspecting the case report forms and ensuring completeness of 
the study essential documents.  The monitor should have access to subject medical 
records and other study-related records needed to verify the entries on the case report 
forms. 
The monitor will communicate deviations from the protocol, Standard Operating 
Procedures (SOPs), GCP and applicable regulations to the Investigator and the Sponsor 
and will ensure that appropriate action designed to prevent recurrence of the detected 
deviations is taken and documented. 
The Investigator agrees to cooperate with the monitor to ensure that any problems 
detected in the course of these monitoring visits are addressed and documented. 
In accordance with ICH/GCP and the Sponsor’s audit plans, this study may be selected 
for audit by representatives from Perosphere.  Inspection of site facilities (e.g., pharmacy, 
drug storage areas, laboratories etc.) and review of study related records will occur in 
order to evaluate the study conduct and compliance with the protocol, ICH/GCP, and 
applicable regulatory requirements. 
In the event Perosphere elects to conduct an audit onsite, the CRO will be notified in 
advance, will be given sufficient time to prepare, and will be given an opportunity to 
participate in the audit.  
8.2 Data Collection 
Case Report Form (CRF) completion should be kept current to enable the monitor to 
review the subject’s status throughout the course of the study.  Case Report Form will be 
completed, reviewed and signed off or e-signed by the Investigator. 

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If the study employs paper CRFs, the Investigator will sign and date the indicated places 
on the case report form.  These signatures will indicate that the Investigator inspected or 
reviewed the data on the case report form, the data queries, and the site notifications, and 
agrees with the content. 
If the study employs EDC, the Investigator e-signs according to the study data flow. 
8.3 Data Management 
All data recorded during the study will be available for audit against source data and for 
compliance with GCP and specific protocol requirements. Monitoring of the study 
progress and conduct will be ongoing.  
 
The Principal Investigator will be responsible for the following: 
1. 
Monitoring study conduct to ensure that the rights of subjects are protected; 
2. 
Monitoring study conduct to ensure trial compliance with GCP guidelines; and 
3. 
Monitoring accuracy, completion and verification from source documents of 
study data. 
8.4 Study Documentation and Storage 
The Investigator will maintain a Signature List of appropriately qualified persons to 
whom he/she has delegated study duties.  All persons authorized to make entries and/or 
corrections on case report forms will be included on the Signature List. 
Source documents are original documents, data, and records from which the subject’s 
case report form data are obtained.  These include but are not limited to hospital records, 
clinical and office charts, laboratory and pharmacy records, diaries, microfiches, X-rays, 
and correspondence. 
Case Report Form entries may be considered source data if the CRF is the site of the 
original recording (i.e., there is no other written or electronic record of data).  In this 
study, CRF pages may be used as source documents. 
The Investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system (Trial Master File [TMF]) of all study-related (essential) 
documentation, suitable for inspection at any time by representatives from Perosphere 
and/or applicable regulatory authorities.  Essential documents include: 
• Subject files containing completed CRFs, ICFs, and supporting copies of source 
documentation (if kept) 

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• Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of relevant essential documents required prior to commencing a clinical 
study, and all correspondence to and from the IRB/IEC and Perosphere. 
• Records related to the Investigational Product(s) including acknowledgment of 
receipt at site, accountability records and final reconciliation and applicable 
correspondence 
• In addition, all original source documents supporting entries in the case report 
forms must be maintained and be readily available. 
8.5 Record Keeping 
Records of subjects, source documents, monitoring visit logs, data correction forms, 
CRFs, inventory of study product, regulatory documents (e.g., protocol and amendments, 
IRB/EC correspondence and approvals, approved and signed informed consent forms, 
Investigator’s Agreement, clinical supplies receipts, distribution and return records), and 
other sponsor correspondence pertaining to the study must be kept in appropriate study 
files at the site.  Source documents include all recordings and observations or notations of 
clinical activities and all reports and records necessary for the evaluation and 
reconstruction of the clinical study.  These records will be retained in a secure file for the 
period required by the institution or site policy.  Prior to transfer or destruction of these 
records Perosphere must be notified in writing and be given the opportunity to further 
store such records. 
8.6 Document Retention 
All essential documentation will be retained by the Investigator until at least 2 years after 
the last approval of a marketing application in an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region or at least 2 years have 
lapsed since the formal discontinuation of clinical development of the investigational 
product.  These documents should be retained for a longer period, however, if required by 
the applicable regulatory requirements or by an agreement with the sponsor.  It is the 
responsibility of the sponsor to inform the Investigator/institution as to when these 
documents no longer need to be retained. 
No study document should be destroyed without prior written agreement between 
Perosphere and the Investigator.  Should the Investigator wish to assign the study records 
to another party or move them to another location, he/she must notify Perosphere in 
writing of the new responsible person and/or the new location. 

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9 
PLANNED STATISTICAL METHODS 
9.1 General Considerations 
All data collected will be presented in data listings.  Data from subjects excluded from an 
analysis set will be presented in the data listings, but not included in the calculation of 
summary statistics.  For categorical variables, frequencies, and percentages will be 
presented.  Continuous variables will be summarized using descriptive statistics (number 
of subjects, mean, median, standard deviation, minimum, and maximum).  Data will be 
tabulated by treatment, across active treatment groups when applicable, with all placebo 
subjects pooled into a single group. 
All evaluable data from subjects in the analysis sets will be included in the analyses.  No 
adjustment or imputation will be utilized for missing values or for subjects who withdraw 
prior to completing the study, neither will analyses be restricted to subjects with complete 
data. 
Baseline values will be defined as the last assessment prior to investigational product 
administration and per period if applicable. 
Details of all statistical analyses will be specified in a separate statistical analysis plan 
(SAP) that will be finalized prior to database lock. 
9.2 Determination of Sample Size 
The study population will consist of healthy male and female adults, age 50-75 years 
(inclusive).  
No formal sample size calculations were performed for this study; sixteen (16) subjects 
enrolled in each cohort (3:1; active: placebo) is considered an adequate number of 
subjects to achieve the objectives of the study. 
9.3 Analysis Populations  
The safety analysis set will include all subjects who receive at least 1 administration of 
investigational product.  This set will be used for all safety, demographic, subject and 
disposition summaries. 
The PD analysis set will include all subjects who receive at least 1 administration of 
investigational product, and provide at least one on-treatment WBCT measurement 
without protocol deviations with potential to affect these measurements. This set will be 
used for all PD analyses. 
The PK analysis set will include all subjects who receive at least 1 administration of 
study drug, and provide sufficient data to estimate at least one PK parameter without 
protocol deviations with potential to affect these measurements. This set will be used for 
all PK analyses. 

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9.4 Pharmacokinetics of PER977 and Metabolite (BAP) 
PER977 and BAP serum concentration values will be summarized in terms of arithmetic 
means, standard deviations, and geometric means for each time point. The PK parameters 
will be computed using WinNonlin (Version 6.3, Princeton, NJ) or other appropriate 
software. The relationship between each of these PK parameters and dosage will be 
evaluated and summarized.
Table 3:  Parameters for Serum PER977 and BAP 
Parameter 
Units 
Description 
Cmax 
ng/mL 
Maximum concentration in the sampled matrix, obtained 
directly from the observed concentration versus time data 
C24 
ng/mL 
Observed quantifiable analyte concentration in the sampled 
matrix at the 24-hour time point 
Clast 
ng/mL 
Last observed quantifiable analyte concentration in the sampled 
matrix 
tlast 
h 
Time of Clast, obtained directly from the observed concentration 
versus time data 
tmax 
h 
Time of Cmax, obtained directly from the observed concentration 
versus time data 
AUC(0-last) 
ng⋅h/mL 
The area under the concentration-time curve, from time zero to 
the last quantifiable concentration (Clast) 
AUC(0-inf) 
ng⋅h/mL 
Area under the concentration-time curve in the sampled matrix 
λz 
1/h 
t1/2 
h 
CL 
L/h 
Vz 
L 
Vss 
L 
MRCmax 
MRAUC(0-last) 
MRAUC(0-inf) 
from zero (predose) extrapolated to infinite time by addition of 
the last quantifiable concentration divided by the elimination 
rate constant: 
AUC(0-last) + Clast/λz 
Apparent terminal rate constant 
Apparent terminal half-life, determined as ln(2)/λz 
Systemic clearance after IV dosing, calculated for PER977 only 
Volume of distribution after IV dosing, calculated for PER977 
only 
Steady-state volume of distribution after IV dosing, calculated 
for PER977 only 
Metabolite to parent (BAP/PER977) ratio of Cmax 
Metabolite to parent (BAP/PER977) ratio of AUC(0-last) 
Metabolite to parent (BAP/PER977) ratio of AUC(0-inf) 

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Supporting Pharmacokinetic Parameters 
The following PK parameters for PER977 and its metabolite, BAP, will be calculated for 
diagnostic purposes and listed, but will not be summarized.  
T1/2, Interval 
The time interval (h) of the log-linear regression to determine t1/2 
t1/2, N 
Number of data points included in the log-linear regression analysis 
Rsq 
Goodness-of-fit statistic for calculation of λz (regression coefficient) 
%AUCex 
Percentage of AUC(0-inf) that is extrapolated from tlast to infinity, 
calculated as: 100 x [1 – (AUClast/AUC0-inf)], where tlast is the time of 
the last measurable plasma drug concentration 
 
9.5 Plasma Rivaroxaban Pharmacokinetics 
Blood samples for determination of rivaroxaban plasma concentrations will be obtained 
at specified times before and up to 28 hours following dose administration of 
rivaroxaban. PK parameters will include Cmax, Tmax, AUC(0-last), t½, Kel, CL/F and Vz/F, 
if data allow. Rivaroxaban pharmacokinetics will be evaluated by comparison of main 
pharmacokinetic parameters on Day 1 and Day 3. 
9.6 Dose Proportionality  
The dose proportionality of exposure PK parameters for PER977 and BAP (AUC(0-inf),  
AUC(0-last), and Cmax), over the administered dose range will be investigated using the 
following power model:  
log (PK parameter) = a + b * log (dose)  
where ‘a’ is the intercept and ‘b’ is the slope. 
Dose proportionality will be assessed graphically and statistically using the above power 
model approach with the logarithm of PK parameters as the dependent variables and the 
logarithm of the dose as the independent variable for subjects who receive one dose at a 
given dose interval. The intercept (a) and the slope (b) together with their 90% CI will be 
estimated and presented for each PK parameter. Parameters ‘a’ and ‘b’ will be estimated 
using an ordinary least-squares approach or the equivalent. Dose proportionality will be 
declared if the 90% CI for the slope parameter ‘b’ lies entirely within the critical region 
(0.7968, 1.203) using the maximal dose ratio I = 3 (highest dose/lowest dose), a lower 
equivalence limit of 0.80, and an upper equivalence limit of 1.25. 
Additionally, the geometric means for the primary PK parameters between adjacent dose 
levels will be compared using an analysis of covariance (ANCOVA) model including 
dose, gender and weight as fixed effects for subjects who receive one administration at a 
given dose interval. Geometric mean ratios for adjacent administrations (higher 

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dose/lower dose) and corresponding 90% CI will be presented. PER977 and BAP 
exposure parameters (Cmax, AUC(0-inf), and AUC(0-last)) will be plotted versus dose on 
linear and log-log scales for subjects who receive one administration at a given dose level 
using a scatterplot with individual exposures, regression line and corresponding 
confidence bands. 
9.7 Pharmacodynamic Analyses 
The contract research organization’s (
.) SOPs and Work 
Instructions will be used as the default methodology if not otherwise specified.  All PD 
computations will be performed using Phoenix® WinNonlin® 6.3, or SAS® Version 9.2 
(SAS Institute, Inc., Cary, North Carolina).  Graphics will be prepared with SAS® 
Version 9.2 or SigmaPlot® 12.5.  Actual times will be used in the PD analyses. 
The PD endpoint will be WBCT.   
PD endpoint will be summarized at observed time points and change and/or ratio from 
baseline values using descriptive statistics and graphical presentations.  
Data handling for PD measurements below the limit of quantitation (BLQ) will be 
specified in the SAP.  In the actual analysis, BLQ values will be set to the lower limit of 
quantitation (LLOQ) for PD data summaries and calculations.   
Change-from-baseline and percent-of-baseline will be calculated for all PD endpoints.  
Baseline for all PD endpoints will be defined as the pre-rivaroxaban sample 
(approximately four hours before PER977 or placebo administration on Day 3). 
The anticoagulant effect of rivaroxaban will be evaluated by comparing WBCT measured 
at pre-PER977 (about four hours post-rivaroxaban on Day 3) versus baseline (pre-
rivaroxaban on Day 3).  For the purposes of the PD analyses, subjects with percent-of-
baseline WBCT at pre-PER977 <125% (i.e., <25% increase) will be considered as 
rivaroxaban in non-responders and excluded from all PD summaries and assessments. 
Listings of individual PD variable collection times, as well as derived sampling time 
deviations (where applicable), will be provided. 
Individual observed and baseline-adjusted values at scheduled time points and PD 
parameters will be listed and summarized by treatment. In addition, the nature of reversal 
of anticoagulation (no effect, partial reversal, complete or complete and sustained) based 
on the definition of reversal of anticoagulation below using WBCT will be listed for each 
subject and summarized. 

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9.8 Analysis of the Primary PD Endpoint (WBCT) 
Definition of Reversal of Anticoagulation 
• Complete reversal is achieved for a treatment group if the mean WBCT is ≤ 110% 
of baseline at any post-baseline time point up to and including 1 hour following 
test article administration. Complete reversal is achieved for a subject if WBCT is 
≤110% of baseline at any post-baseline time point up to and including 1 hour 
following test article administration. 
• Complete and sustained reversal of anti-coagulation is achieved for a treatment 
group if the mean WBCT is ≤ 115% of baseline at all time points between 1 and 8 
hours (inclusive) following test article administration. Complete and sustained 
reversal of anti-coagulation is achieved for a subject if WBCT is ≤ 115% of 
baseline at all time points between 1 and 8 hours (inclusive) following test article 
administration. 
 
Statistically Significant Complete Reversal 
• Statistically significant complete reversal, relative to mean placebo WBCT, is 
defined as p< 0.05, (one tailed) from the comparison of means between treatment 
and placebo at 15, 30, 45 minutes or 1 hour post study drug administration as 
measured by one-way Analysis of Variance at study completion.  Distribution 
diagnostics will be performed to assure assumptions associated with using 
ANOVA are met. Analysis of Means (ANOM) methods will be used to compare 
means and variances across groups. These methods will be appropriate to test if 
any of the group means are statistically different from the overall mean or if the 
group standard deviations are statistically different from the root mean square error 
(RMSE). Tukey HSD multiple comparison procedure will be used to test for all 
pairwise differences among the means (Tukey 1953, Kramer 1956). This test is an 
exact alpha-level test if the sample sizes are the same, and conservative if the 
sample sizes are different (Hayter 1984). 
 
9.9 Pharmacodynamic Parameters 
Pharmacodynamic parameters will be calculated for observed and percent-of-baseline 
values using actual times relative to the start of injection of first study drug (PER977 or 
placebo) dose using Phoenix® WinNonlin® 6.3 or SAS® Version 9.2 (SAS Institute, Inc., 
Cary, North Carolina).  All PD parameters will be derived over the time window from the 
first study drug administration (zero hour) to the last collection (i.e., 24 hours after the 
final administration of the study drug). 

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The following PD parameters will be determined for the endpoint WBCT: 
• Emin: minimum value over the two minute to 24 hour interval 
• tEmin: time of Emin 
• Emin(0-6h): minimum value over the two minute to six hour interval post-final dose 
• tEmin(0-6h): time of Emin(0-6h) 
• Emax: maximum value over the two minute to 24 hour interval 
• tEmax: time of Emax 
• ΔEmax: maximum value minus the baseline value (observed only) 
9.10 Demographics and Baseline Characteristics 
Subject disposition, demographics, and baseline characteristics will be listed and 
summarized.  Screening assessments and concomitant mediations used during study 
conduct will be listed. 
9.11 Safety Endpoints 
Individual vital signs, ECG parameters, and clinical laboratory data will be listed and 
tabulated with descriptive statistics.  For the laboratory safety data, out of range values 
will be tabulated in shift tables.  Abnormal and clinically noteworthy ECGs will be 
tabulated. 
Treatment-emergent AEs will be tabulated by MedDRA system organ class and preferred 
term, and further by severity and relatedness to study drug.  SAEs and adverse events that 
lead to discontinuation will be listed.  
Physical examination results will be listed.  New onset abnormalities after dosing will be 
recorded as adverse events. 
9.12 Interim Analysis 
No formal interim analyses are planned. 

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10.4 Ethical Conduct of the Study 
This study will be conducted in compliance with the protocol, the ethical principles that 
have their origin in the Declaration of Helsinki, the ICH consolidated Guideline E6 for 
GCP (CPMP/ICH/135/95), and applicable regulatory requirement(s) and FDA GCP 
Regulations: Code of Federal Regulations (CFR) Title 21, parts 11, 50, 54, 56 and 312 as 
appropriate  
10.5 Patient Information and Consent 
Before a subject’s participation in the study, it is the Investigator or designee’s 
responsibility to obtain freely given consent, in writing, from the subject after adequate 
explanation of the aims, methods, anticipated benefits, and potential hazards of the study 
and before any protocol-specific screening procedures or any study drugs are 
administered.  The written ICF must be prepared in the local language(s) of the potential 
subject population. 
In obtaining and documenting informed consent, the Investigator or designee must 
comply with the applicable regulatory requirements, and must adhere to GCP and to the 
ethical principles that have their origin in the Declaration of Helsinki.  The consent form 
and any revision(s) must be approved by the IRB/IEC prior to being provided to potential 
subjects. 
The subject’s written informed consent must be obtained prior to his/her participation in 
the study, and must be documented in the subject’s medical records, as required by 21 
CFR Part 312.62.  The ICF should be signed and personally dated by the subject, and by 
the person who conducted the informed consent discussion (not necessarily the 
Investigator).  The original signed ICF must be retained in accordance with institutional 
policy, and a copy of the signed consent form must be provided to the subject or legal 
representative.  The date and time (if applicable) that informed consent was given must 
be recorded on the CRF. 
If the subject cannot read, then according to ICH/GCP Guideline, Section 4.8.9, an 
impartial witness should be present during the entire informed consent discussion.  This 
witness should sign the ICF after the subject or the legally acceptable representative has 
orally consented to the subject’s participation and, if possible, signed the ICF.  By 
signing the ICF, the witness attests that the information in the ICF and any other written 
information was adequately explained to and apparently understood by the subject or the 
legally acceptable representative and that informed consent was freely given by the 
subject or the legally acceptable representative. 
Additional consent is required for the Health Insurance Portability and Accountability 
Act (HIPAA). 

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10.6 Patient Confidentiality 
The Investigators, the Clinical Research Organization (CRO) and the Sponsor 
(Perosphere) will preserve the confidentiality of all subjects taking part in the study, in 
accordance with GCP and local regulations. 
The Investigator must ensure that the subject’s anonymity is maintained.  On the CRFs or 
other documents submitted by the CRO or Sponsor subjects should be identified by a 
unique subject identifier as defined by the sponsor.  Documents that are not for 
submission to other entities (e.g., signed ICFs) should be kept in strict confidence by the 
Investigator. 
In compliance with US Federal regulations and ICH/GCP Guidelines, it is required that 
the Investigator and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IRB/IEC direct access to review the subject’s original 
medical records for verification of study-related procedures and data.  The Investigator is 
obligated to inform the subject that his/her study-related records will be reviewed by the 
above named representatives without violating the confidentiality of the subject. 
10.7 Regulatory Compliance 
The study protocol, subject information and ICF, the Investigator Brochure, any subject 
diary card or written instructions to be given to the subject, available safety information, 
subject recruitment procedures (e.g., advertisements), information about payments and 
compensation available to the subjects and documentation evidencing the Investigator’s 
qualifications should be submitted to the IRB/IEC for ethical review and approval 
according to local regulations, prior to the study start.  The written approval should 
identify all documents reviewed by name and version. 
Changes in the conduct of the study or planned analysis will be documented in a protocol 
amendment and/or the SAP. 
The Investigator must submit and, where necessary, obtain approval from the IRB/IEC 
and/or Sponsor for all subsequent protocol amendments and changes to the informed 
consent document or changes of the investigational site, facilities or personnel.  The 
Investigator should notify the IRB/IEC of deviations from the protocol or SAEs occurring 
at the site and other AE reports received from the CRO, in accordance with local 
procedures. 
As required by local regulations, the Sponsor’s local Regulatory Affairs group will insure 
all legal aspects are provided, and approval of the appropriate regulatory bodies obtained, 
prior to study initiation, and that implementation of changes to the initial protocol and 
other relevant study documents happen only after the appropriate notification of or 
approval by the relevant regulatory bodies. 

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10.8 Case Report Forms and Study Records 
Study data will be recorded using electronic data capture (EDC).   
10.9 Protocol Violations/Deviations 
The Investigator should conduct the study in compliance with the protocol agreed to by 
Perosphere and, if required, by the regulatory authority(ies), and which was given 
approval/favorable opinion by the IRB/IEC. 
A deviation to any protocol procedure or waiver to any stated criteria will not be allowed 
in this study except where necessary to eliminate immediate hazard(s) to the subject.  
Perosphere must be notified of all intended or unintended deviations to the protocol (e.g., 
inclusion/exclusion criteria, dosing, missed study visits) on an expedited basis. 
The Investigator, or person designated by the Investigator, should document and explain 
any deviation from the approved protocol. 
If a subject was ineligible or received the incorrect dose or investigational treatment, and 
had at least one administration of investigational product, data should be collected for 
safety purposes. 
The Investigator should notify the IRB/IEC of deviations from the protocol in accordance 
with local procedures. 
10.10 Financial Disclosure 
Prior to starting the study, the Principal Investigator and/or institution will sign a clinical 
study agreement with Perosphere.  This agreement will include financial information 
agreed upon by the parties and full financial disclosure (if applicable) and conflict of 
interest on the part of the clinical investigator, sub-investigator, their spouses and 
dependent children.  
10.11 Publication and Disclosure Policy 
A study site may not publish results of a study without the written permission of 
Perosphere and provided that Perosphere has had the opportunity to review and approve 
the study site’s proposed publication prior to its being submitted. 
10.12 Reimbursement, Indemnity, and Insurance 
Reimbursement, indemnity and insurance shall be addressed in a separate agreement on 
terms agreed upon by the parties. 

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11 REFERENCE LIST 
Ansell J, Bakhru SH, Laulicht BE, et al.  Use of PER977 to Reverse the Anticoagulant 
Effect of Edoxaban.  New Eng J Med. 2014, 371:2141-2142. Epub. November 5.  
DOI:10.1056/NEJMc1411800 
Centers for Disease Control and Prevention.  Venous thromboembolism: A public health 
concern.  Available at: http://www.cdc.gov/NCBDDD/dvt/data.html  Accessed on 
January 13, 2014. 
Department of Health and Human Services.  Centers for Disease Control. Atrial 
Fibrillation Fact Sheet.  
http://www.cdc.gov/dhdsp/data_statistics/fact_sheets/docs/fs_atrial_fibrillation.pdf 
Accessed January 13, 2014. 
Institute List of High-Alert Medications.  Available at: 
http://www.ismp.org/Tools/highalertmedications.pdf.  Accessed January 13, 2014. 
Number, rate and standard error of all listed surgical and nonsurgical procedures for 
discharges from short-stay hospitals by selected procedure categories, United States 
2010.  Available at:  
http://www.cdc.gov/nchs/data/nhds/4procedures/2010pro4_numberrate.pdf  Accessed on 
January 13, 2014 . 
MacLean S, Mulla S, Aki EA, et al.  Patient values and preferences in decision making 
for antithrombotic therapy: a systematic review: Antithrombotic therapy and prevention 
of thrombosis, 9th ed.  American College of Chest Physicians Evidence-Based Clinical 
Practice Guidelines. Chest. 2012;141 (2 suppl):e1S-e23S. 
Palareti G.  Bleeding with anticoagulant treatments.  Hamostaseologie.  2011;Vol 4.  
Safety Alerts for Human Medical Products. Pradaxa (dabigatran etexilate mesylate): 
Drug Safety Communication - Safety Review of Post-Market Reports of Serious 
Bleeding Events.  
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedical
Products/ucm282820.htm?source=govdelivery