A Phase 2 Randomized, Double-blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Ciraparantag for Reversal of Anticoagulation in Healthy Adults
Phase: PHASE2
Conditions: Healthy
Sponsor: AMAG Pharmaceuticals, Inc.

Clinical Trial Protocol: AMAG-977-213 
Study Title: A Phase 2 Randomized, Double-blind, Placebo-Controlled Study to 
Assess the Efficacy and Safety of Ciraparantag for Reversal of Anticoagulation in 
Healthy Adults 
Document: Protocol
Document Date: Version 4, 14 Oct 2022 
NCT: NCT04593784

Ciraparanta.g 
Clinical Trial Protocol: AMAG-977-213 v4.0 
AMAG Pharmaceuticals, Inc. 
14 Oct 2022 
A Phase 2 Randomized, Double-blind, Placebo-Controlled 
Study to Assess the Efficacy and Safety of Ciraparantag 
for Reversal of Anticoagulation in Healthy Adults 
Sponsor: 
Perosphere Phannaceuticals, fuc. * 
a wholl owned subsidiaiy of AMAG Phannaceuticals, fuc. 
Drug Product: 
Cirapai·antag 
Protocol Number: 
AMAG-977-213 
Phase: 
2 
Protocol Version: 
Version 4.0 
Version Date: 
14 Oct 2022 
*Note: AMAG Phaimaceuticals, fuc. was acquired by Covis Phaima GmbH in November
2020. To prevent confusion at the site/investigator level, the Sponsor name will remain as
above so long as there ai·e active protocols listing AMAG/Perosphere as the Sponsor.
This study will be conducted in accordance with the Protocol and in compliance with Good 
Clinical Practice (GCP), the Declaration of Helsinki, and any other applicable regulato1y 
requirements. Perosphere Phaimaceuticals, fuc., a wholly owned subsidiaiy of AMAG 
Phaimaceuticals, fuc., will also continue to suppo1i the principles of the Declaration of 
Helsinki. 
CONFIDENTIAL 
The confidential information in the following document is provided to you as an 
Investigator, potential Investigator, or consultant for review by you, your staff, and 
applicable Institutional Review Board (IRB)/Independent Ethics Committee (EC) or 
regulatory Health Authority. The information contained herein should not be disclosed to 
others, without written authorization from Perosphere Pharmaceuticals, Inc., a wholly 
owned subsidiary of AMAG Pharmaceuticals, Inc. 

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Clinical Trial Protocol: AMAG-977-213 v4.0 
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CONTACTS 
Emergency Contacts 
Emergency contacts will be listed in the Procedures Manual 

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Clinical Trial Protocol: AMAG-977-213 v4.0 
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INVESTIGATOR PROTOCOL AGREEMENT 
 
Protocol Title: A Phase 2 Randomized, Double-blind, Placebo-Controlled Study to Assess 
the Efficacy and Safety of Ciraparantag for Reversal of Anticoagulation in Healthy Adults 
 
Protocol Number: AMAG-977-213 
___________________________________________________________________________ 
I will provide copies of the study protocol and access to all study-related information to the 
study personnel at my site who are involved with this protocol. I will discuss with them this 
material and the material in the Investigator’s Brochure to ensure that they are fully informed 
about the investigational drug and understand the protocol. All documents will be kept in the 
strictest confidence. 
I confirm that my staff and I have carefully read and understand this protocol. I agree to 
conduct this study according to the attached protocol. I also agree to conduct this study in 
compliance with Good Clinical Practice and all applicable national and local laws and 
regulations, as well as with the requirements of the appropriate Institutional Review Board or 
Independent Ethics Committee (IRB/EC) and any other institutional requirements. No 
changes will be made to the study protocol without prior written approval of the Sponsor and 
the IRB/EC.  
I have read, understand, and agree to abide by all conditions and instructions contained in 
this protocol. 
 
 
______________________________________________                     ____________ 
Principal Investigator’s Signature  
 
 
 
 
 
 
 
 
 
Date 
 
Name (print): _________________________________________ 
 
Clinical Site/Institution: _________________________________ 
 
Address: ______________________________________________ 
   ______________________________________________ 
 
   ______________________________________________ 

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PROTOCOL VERSION HISTORY 
Version 4.0 – 14 Oct 2022 
This amendment consists of two changes:  
• This amendment allows for subjects to be assessed for sufficient anticoagulation on 
either Day 3 or Day 4 of anticoagulant dosing (prior versions indicated assessment 
only on Day 4). Because of the intensity of testing and number of site personnel 
required on the day of ciraparantag/placebo dosing, this Day 3/Day 4 option is 
provided to allow for flexibility in scheduling the day of the week on which this visit 
will occur. For the anticoagulant dosing regimens used in this study, the 
anticoagulants are expected to be at steady state by Day 3, and, per the study design, 
subjects are only randomized if they achieve sufficient anticoagulation, so providing 
this option is not expected to impact subject safety or study findings. All subjects will 
continue to be followed for 5 days following ciraparantag/PBO dosing. The 
associated changes apply predominantly to the Synopsis, Section 3.1, Section 6.6.2, 
Section 6.11.3, and the Schedule of Events in Appendix A. 
• Individual subjects who do not achieve sufficient anticoagulation in one cohort (and 
are not randomized), will now be allowed to be re-screened for potential enrollment 
in a different cohort. This change is being implemented because of challenges with 
identifying volunteers that meet all entry criteria, and because subjects who do not 
achieve the threshold for sufficient anticoagulation with one anticoagulant drug may 
achieve it with a different anticoagulant drug. As before, a subject may only be 
randomized and treated with ciraparantag/placebo once.  This change applies to 
Section 3.1 and Section 6.1. 
 
Version 3.0 – 12 APR 2021 
This amendment provided for evaluation of an additional cohort of subjects to evaluate 
ciraparantag for reversal of edoxaban, which has been inserted as Cohort 1. Key changes 
made to the protocol are described below. 
• Changes were made throughout the protocol to indicate the addition of the edoxaban 
cohort, most notably in the Synopsis, Section 3.1 , and Section 5.4.1 . 
• Study procedures for the edoxaban cohort (Cohort 1) are nearly identical to those of 
other cohorts, except for Cohort 1 the time interval between the last dose of edoxaban 
and the single dose of ciraparantag/placebo is 3 hours, whereas this interval is 4 hours 
for the apixaban and rivaroxaban cohorts. This is because maximum plasma 
concentrations of edoxaban are achieved more rapidly. This timing for each cohort is 
detailed in the Synopsis and Section 3.1, and the timing for associated blood draws is 
detailed in the Schedule of Events in Appendix A.  
• Assuming full enrollment of all cohorts/groups as outlined in the protocol below, the 
maximum number of subjects randomized will increase to 108 (Synopsis and 
Section 3.1 ). 
• Final results for two recently completed clinical studies (Studies 02-011 and 02-012) 
were added. This update was made to Section 1.2.2. 

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Version 2.0 – 11 DEC 2020 
This amendment consisted primarily of additions to blood testing requirements, in 
accordance with discussions between the sponsor and the United States Food and Drug 
Administration (FDA). Key changes made to the protocol are described below. 
• Per FDA feedback, subjects with serum total cholesterol outside the normal range are 
to be excluded. This change was made to Exclusion criterion 1 in the Synopsis and 
Section 4.2 . In addition, total cholesterol was added to the laboratory testing list in 
Section 6.6 and to the Schedule of Events in Appendix A. 
• Per FDA feedback, blood testing for anti-fXa activity was added to the study at 
selected timepoints, and hematology and fibrinogen testing was expanded to 
additional study days. These changes are detailed in Schedule of Events in  
Appendix A, and anti-fXa activity was added to the laboratory testing list in  
Section 6.6 . 
• To further assess the duration of effect of ciraparantag after a single IV dose, a 
WBCT test was added at 8 hours after the end of study drug infusion. This change 
was made in the Synopsis, Section 6.6.2, and in Schedule of Events in Appendix A. 
• The total estimated blood volume to be collected per subject was updated in 
Section 6.8. 
 
Version 1.0 – 04 MAY 2020 
Original 

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SYNOPSIS 
Protocol Title 
A Phase 2 Randomized, Double-blind, Placebo-Controlled Study to Assess 
the Efficacy and Safety of Ciraparantag for Reversal of Anticoagulation in 
Healthy Adults 
Protocol 
Number 
AMAG-977-213 
Study Agent  
Ciraparantag 
Phase of 
Development 
2 
Study Center(s) 
2 to 4 
Study Objectives Primary Objective: 
• 
To demonstrate that a single IV administration of ciraparantag is 
superior to placebo (PBO) in the reversal of anticoagulation 
induced by each of the evaluated anticoagulant drugs (edoxaban, 
apixaban, or rivaroxaban) in healthy adults, as assessed by 
whole blood clotting time (WBCT) measured with Perosphere 
Technologies’ Point-of-Care (PoC) Coagulometer. 
Secondary Objectives: 
• 
To evaluate the safety and tolerability of ciraparantag in this 
population. 
• 
To evaluate the pharmacokinetics (PK) of ciraparantag and the 
evaluated anticoagulant drugs in this population. 
• 
To describe the correlation between WBCT measured with 
Perosphere Technologies’ POC Coagulometer and with a 
manual testing method. 
Study Design 
This is a randomized, double-blind, PBO-controlled study to evaluate the 
efficacy and safety of ciraparantag for reversal of anticoagulation induced by 
different anticoagulant drugs (edoxaban, apixaban, or rivaroxaban) in 
generally healthy adults. Coagulation status will be determined by WBCT, 
which will be measured primarily by the Perosphere Technologies’ PoC 
Coagulometer, and at selected timepoints using a manual testing method.  
The study will be conducted in three separate cohorts; each cohort will 
evaluate the reversal of a different anticoagulant drug. Within each cohort, 
an initial group of subjects (Group 1) will be enrolled for evaluation of a 
target dose of ciraparantag (180 mg IV). Depending on the efficacy and 
safety results from Group 1, a second group (Group 2) may be enrolled to 

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evaluate a different dose of ciraparantag for that cohort, as determined by a 
data review team.  
The Screening period is the same for all cohorts. Eligible subjects will be 
admitted to the clinical study unit on Day -1. The next day (Day 1), a 
baseline (BL) WBCT will be determined prior to receiving the anticoagulant 
based on the cohort to which they were enrolled (Table 1). 
Table 1: 
Anticoagulation Regimen by Cohort 
Cohort 
Anticoagulant 
Regimen 
1 
Edoxaban 
60 mg orally (PO) once daily in the morning from 
Day 1 to Day 3 or Day 4 
2 
Apixaban 
10 mg PO every 12 hours from Day 1 to the morning 
of Day 3 or Day 4 
3 
Rivaroxaban 
20 mg PO once daily in the morning from Day 1 to 
Day 3 or Day 4 
Within each cohort, subjects will be assessed for sufficient anticoagulation 
on Day 3 or Day 4 before proceeding further in the study. The Day 3/Day 4 
option is provided to allow for flexibility in scheduling the day of the week 
on which this visit will occur. WBCT will be determined following the 
morning dose of anticoagulant at the approximate timepoint specified 
(Table 2) for purposes of determining sufficient anticoagulation. If this 
WBCT result is ≥130% of BL (based on the coagulometer), the subject will 
proceed in the study. If testing occurs on Day 3 and does not meet WBCT 
criteria for sufficient anticoagulation, the subject can continue anticoagulant 
dosing and be assessed again on Day 4, at the discretion of the Investigator. 
If testing occurs on Day 4 and does not meet WBCT criteria for sufficient 
anticoagulation, the subject will be discontinued from the study. Subjects 
who proceed in the study will be randomized to a single IV dose of 
ciraparantag or PBO in a 2:1 ratio. Randomization will be stratified by age 
(18 to <50 years vs. ≥50 to 75 years). Within each cohort, between 50% to 
70% of randomized subjects will be ≥50 to 75 years of age, and there will be 
approximately equal numbers of male and female subjects. The 
ciraparantag/PBO dose will be administered starting at the approximate 
timepoint specified in Table 2 followed by multiple WBCT and PK 
measurements. 
Table 2: Timepoints for Assessing Sufficient Anticoagulation and for 
Ciraparantag/Placebo Dosing (Day 3 or Day 4) 
Cohort 
Anticoagulant 
Timepoint for 
assessing sufficient 
anticoagulation 
For sufficiently 
anticoagulated 
subjects, timepoint for 
ciraparantag/PBO dose 

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1 
Edoxaban 
2.75 hours after Day 3 
or Day 4 edoxaban 
dose 
3 hours after the last 
edoxaban dose 
2 
Apixaban 
3.75 hours after Day 3 
or Day 4 apixaban 
dose 
4 hours after the last 
apixaban dose 
3 
Rivaroxaban 
3.75 hours after Day 3 
or Day 4 rivaroxaban 
dose 
4 hours after the last 
rivaroxaban dose 
Subjects in all cohorts who receive ciraparantag/PBO will remain domiciled 
in the clinical study unit for 5 days after dosing (i.e., through Day 8 or Day 
9). Evaluations on the day following ciraparantag/PBO dosing will include 
WBCT, PK, and safety assessments (including testing for prothrombotic 
markers). On subsequent days, follow-up safety assessments (including 
testing for prothrombotic markers) will continue. Any subject with WBCT 
on the day following ciraparantag/PBO dosing that is >120% of BL (based 
on the coagulometer) or >110% of BL (based on the manual method) will 
have both WBCT repeated on subsequent days as required until WBCT is 
≤120% of BL (based on the coagulometer) and ≤110% of BL (based on the 
manual method). The differences in these thresholds is based on the 
differences in assay sensitivity between the two testing methods. Five days 
after ciraparantag/PBO dosing (Day 8 or Day 9), subjects may be discharged 
from the study unit, provided that WBCT results are ≤120% of BL (based on 
the coagulometer) and ≤110% of BL (based on manual WBCT), and the 
Investigator determines that no additional safety monitoring is required. 
Otherwise the subject will remain domiciled until these criteria are met. 
Subjects who remain eligible after the Day -1 assessments and who are 
admitted to the study unit will be considered enrolled in the study. As 
described above, only those subjects who achieve sufficient anticoagulation 
on Day 3 or Day 4 will be randomized. The randomization target is 18 
subjects (12 ciraparantag: 6 PBO) in each group of each cohort. 
The study will be conducted at a minimum of two and up to four study sites. 
For a given cohort, at least two sites will contribute subjects to each group of 
that cohort, and no site will contribute more than 70% of the subjects 
randomized to any group of that cohort. 
Planned 
Number of 
Subjects 
Up to 108 
Duration of 
Subject 
Participation 
Up to approximately 6 weeks, including a Screening period (up to 30 days) 
and a domiciled period in the study unit (10 days). 

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Subject 
Population 
Healthy adult volunteers 
Inclusion 
Criteria 
Eligible subjects must: 
1. Be informed of the nature of the study and provide written informed 
consent before any study-specific procedures are performed. 
2. Be 18 to 75 years of age, inclusive, at time of consent. 
3. Be in good health, in the opinion of the Investigator, based on 
medical history, physical examination, vital signs, electrocardiogram 
(ECG) and laboratory testing (ie, absence of any clinically relevant 
abnormality) during Screening. 
4. Have a body mass index 18 to 32 kg/m2, inclusive, at Screening. 
5. If female, be surgically sterile or post-menopausal (no menses for at 
least 12 months), or if of child-bearing potential, must be using an 
acceptable method of contraception (other than a combination 
estrogen/progestin hormonal contraceptive) for at least 1 month prior 
to Day 1, such as an intrauterine device (IUD), implant, or two 
forms of the following: diaphragm, cervical cap, patch, condom, 
spermicide, or sponge. In addition, females of child-bearing 
potential must agree to continue to use their method of birth control 
for the duration of the study and 12 weeks following discharge from 
the study. 
6. If male, be surgically sterile, or agree to use appropriate 
contraception (latex condom with spermicide) when engaging in 
sexual activity and agree to not donate sperm for the duration of the 
study and 12 weeks following discharge from the study 
7. Have suitable venous access for multiple venipunctures. 
Exclusion 
Criteria 
Eligible subjects must not: 
1. Have any of the following findings at Screening: 
a. Hemoglobin or hematocrit value outside the normal range 
b. Platelet count outside the normal range 
c. Prothrombin time or activated partial thromboplastin time 
outside the normal range 
d. Plasma fibrinogen outside the normal range 
e. Serum triglycerides or total cholesterol outside the normal range 
f. Serum creatinine >1.5 mg/dL (133 µmol/L) or known renal 
disease 
g. Aspartate aminotransferase or alanine aminotransferase >2 x the 
upper limit of normal, or known liver disease 
h. Total bilirubin outside the normal range 
i. 
Positive viral screen for hepatitis B virus, hepatitis C virus, or 
human immunodeficiency virus 

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j. 
Positive pregnancy test (females) 
k. Positive drug, tobacco or alcohol screen 
l. 
Any clinically significant findings on 12-lead ECG or urinalysis 
2. Have a personal or family history of clotting disorder or hematologic 
abnormality, such as excessive bleeding, joint hematoma, 
thrombovascular disease, thrombocytopenia, or any chronic 
condition requiring treatment with transfusions. 
3. Have a history of unexplained syncope. 
4. Have a history within 6 months prior to Screening of major bleeding, 
trauma, surgical procedure of any type, or vaginal delivery. 
5. Have a history within 6 months prior to Screening of peptic ulcer or 
gastrointestinal bleeding (including hematemesis, melena, or rectal 
bleeding). 
6. Have received any blood product or anticoagulant within 3 months 
prior to Screening. 
7. Have donated blood or blood products within 3 months prior to 
Screening. 
8. Have a history of minor bleeding episodes (eg, epistaxis, bruising or 
gingival bleeding) within 1 month prior to Screening, or a long-
standing history of such bleeding. 
9. If female, have a history of excessive or dysfunctional uterine 
bleeding (unless the subject had a subsequent hysterectomy). 
10. Have used any tobacco or nicotine-containing products within 
3 months prior to Screening. 
11. Have used any systemic prescription or non‐prescription drugs 
(including vitamins, supplements, and herbal products) within 
14 days prior to Day 1 (except for permitted contraceptives). NOTE: 
subjects should be asked specifically about use of aspirin and other 
non-steroidal anti-inflammatory drugs. 
12. If female, be pregnant, breastfeeding, or planning to become 
pregnant during the study. 
13. Have received ciraparantag in any prior clinical study. 
14. Have received another investigational drug within 5 half-lives or 30 
days, whichever is longer, prior to Day 1. 
15. Known allergy to edoxaban, apixaban or rivaroxaban. 
16. Have any other condition that, in the opinion of the Investigator, 
would interfere with a subject’s ability to adhere to the protocol, 
interfere with assessment of the investigational product, or 
compromise the safety of the subject or the quality of the data. 

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Study Product 
Ciraparantag: 6 mg/mL solution in single use vials 
Comparator 
Placebo (Sterile 0.9% Sodium Chloride Injection, USP) 
Dose, Route, 
Regimen, 
Duration of 
Administration 
Edoxaban: 60 mg PO once daily (qd) in the morning from Day 1 to Day 3 
or Day 4. 
Apixaban: 10 mg PO every 12 hours (q 12 h) from Day 1 to the morning of 
Day 3 or Day 4. 
Rivaroxaban: 20 mg PO once daily (qd) in the morning from Day 1 to Day 
3 or Day 4. 
Ciraparantag/PBO: Single IV dose on Day 3 or Day 4 
Group 1 of each cohort: 180 mg 
Group 2 of each cohort: a dose from 120 to 360 mg (decision to enroll this 
cohort and dose to be determined by the data review team)  
Efficacy  
Assessments 
Coagulation status will be determined by WBCT, which will be measured at 
the study site immediately after blood collection. WBCT Testing will be 
performed using the Perosphere Technologies’ PoC Coagulometer at all 
planned WBCT timepoints: Day 1 prior to first dose of anticoagulant*; 
ciraparantag/PBO dosing day as follows: after anticoagulant but before 
ciraparantag/PBO*, and 0.25, 0.5, 1*, 3, 6, and 8 hours after 
ciraparantag/PBO; the following day at 24 hours after ciraparantag/PBO*, 
and on subsequent study days* as needed until protocol threshold criteria are 
met.  At the selected timepoints designated with the asterisk (*), WBCT also 
will be tested simultaneously using the manual method.   
Pharmacokinetic  
Assessments 
Blood samples for PK assessments (for ciraparantag/metabolite[s] and 
anticoagulant) will be obtained starting on the ciraparantag/PBO dosing day 
as follows: prior to anticoagulant, prior to ciraparantag/PBO, and 0.25, 0.5, 
0.75, 1, 1.5, 3, 6, and 24 hours after ciraparantag/PBO. 
Study Endpoints 
For all efficacy endpoints listed below, analyses will be based on WBCT 
results obtained with the coagulometer unless otherwise specified. 
Primary Efficacy Endpoint: Achieving a WBCT ≤120% of BL within 
1 hour after administration of ciraparantag/PBO, which is subsequently 
sustained after 1 hour through at least 6 hours after ciraparantag/PBO 
dosing. 
Secondary Efficacy Endpoints:  
The secondary efficacy endpoints are as follows: 

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1. Achieving WBCT ≤115% of BL within 1 hour after administration 
of ciraparantag/PBO, which is subsequently sustained after 1 hour 
through at least 6 hours after ciraparantag/PBO dosing.  
2. Achieving WBCT ≤110% of BL within 1 hour after administration 
of ciraparantag/PBO, which is subsequently sustained after 1 hour 
through at least 6 hours after ciraparantag/PBO dosing.  
3. Achieving WBCT ≤120% of BL within 30 minutes after 
administration of ciraparantag/PBO, which is subsequently sustained 
after 30 minutes through at least 6 hours after ciraparantag/PBO 
dosing. 
4. Achieving WBCT ≤115% of BL within 30 minutes after 
administration of ciraparantag/PBO, which is subsequently sustained 
after 30 minutes through at least 6 hours after ciraparantag/PBO 
dosing.  
5. Achieving WBCT ≤110% of BL within 30 minutes after 
administration of ciraparantag/PBO, which is subsequently sustained 
after 30 minutes through at least 6 hours after ciraparantag/PBO 
dosing. 
6. Achieving a WBCT ≤120% of BL within 15 minutes after 
administration of ciraparantag/PBO, which is subsequently sustained 
after 15 minutes through at least 6 hours after ciraparantag/PBO 
dosing. 
7. Achieving a WBCT ≤115% of BL within 15 minutes after 
administration of ciraparantag/PBO, which is subsequently sustained 
after 15 minutes through at least 6 hours after ciraparantag/PBO 
dosing.  
8. Achieving a WBCT ≤110% of BL within 15 minutes after 
administration of ciraparantag/PBO, which is subsequently sustained 
after 15 minutes through at least 6 hours after ciraparantag/PBO 
dosing. 
Tertiary Efficacy Endpoints: 
The tertiary efficacy endpoints are as follows: 
• 
Achieving a WBCT ≤120% of BL at each of the planned WBCT 
assessment timepoints: 15 minutes, 30 minutes, 1 hour, 3 hours, 
6 hours, 8 hours and 24 hours after administration of 
ciraparantag/PBO (7 endpoints). 
• 
Achieving a WBCT ≤115% of BL at each of the planned WBCT 
assessment timepoints: 15 minutes, 30 minutes, 1 hour, 3 hours, 
6 hours, 8 hours and 24 hours after administration of 
ciraparantag/PBO (7 endpoints). 

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• 
Achieving a WBCT ≤110% of BL at each of the planned WBCT 
assessment timepoints: 15 minutes, 30 minutes, 1 hour, 3 hours, 
6 hours, 8 hours and 24 hours after administration of 
ciraparantag/PBO (7 endpoints). 
• 
Achieving a WBCT ≤120%, ≤115%, or ≤110% of BL at 1 hour 
after administration of ciraparantag/PBO by the manual method 
• 
WBCT (as a percentage of BL) at each of the planned WBCT 
assessment timepoints: 15 minutes, 30 minutes, 1 hour, 3 hours, 
6 hours, 8 hours and 24 hours after administration of 
ciraparantag/PBO (7 endpoints). 
• 
Change from Day 3/Day 4 pre-ciraparantag/PBO WBCT (as a 
percentage of BL) to each of the planned WBCT assessment 
timepoints: 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 8 
hours and 24 hours after administration of ciraparantag/PBO (7 
endpoints). 
Safety Endpoints: 
• 
Treatment-emergent adverse events (TEAEs) 
• 
Treatment-emergent serious adverse events (SAEs) 
• 
Change from BL in vital signs 
• 
Change from BL in clinical laboratory evaluations 
Statistical 
Methods 
The analysis of both efficacy and safety parameters will be conducted for 
each cohort (i.e., for each anticoagulant drug) separately. Each cohort 
consists of up to three treatment groups, i.e., one or two active doses, and 
one PBO group including all subjects randomized to PBO. 
Efficacy Analyses: The primary efficacy parameter is the proportion of 
subjects that achieve a WBCT ≤120% of BL within 1 hour after the 
administration of the study drug which is subsequently sustained after 1 hour 
through at least 6 hours after the administration of the study drug. Summary 
statistics (n, %) will be provided for each treatment group, and 95% 
confidence interval (CI) will be constructed by the Clopper-Pearson method. 
Each active dose will be compared with the PBO group by Boschloo’s test at 
0.05 two-sided significance level. A 95% CI for the difference in 
percentages will be constructed by the Miettinen and Nurminen method. In 
addition, the Cochran-Mantel-Haenszel Test, with stratification by age 
group, will be used to compare each active dose with placebo as a sensitivity 
analysis.  
Safety Analyses: The safety parameters include AEs, clinical laboratory 
parameters (including prothrombotic markers), vital sign measurements, and 
ECG parameters. All safety parameters will be analyzed descriptively. The 
number and percentage of subjects with at least one TEAE, at least one 

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serious TEAE, at least one study drug related TEAE, and at least one TEAE 
leading to study withdrawal will be presented for each treatment group.  
Sample Size Justification: Assuming true response rates for the primary 
efficacy endpoint of 78% and 5% in the first active dose group and the PBO 
group, respectively, 18 subjects with a 2:1 randomization ratio will have 
91% power at 0.05 two-sided significance level based on Boschloo’s test. 
Assuming a response rate of 66% and 5% in the second active dose group 
and the PBO group, respectively, 12 subjects in each group will have 94% 
power. 
 
 

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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................... 1 
CONTACTS ................................................................................................................ 2 
PROTOCOL APPROVAL SIGNATURE PAGE ....................................................... 3 
INVESTIGATOR PROTOCOL AGREEMENT ........................................................ 4 
SYNOPSIS .................................................................................................................. 7 
TABLE OF CONTENTS ........................................................................................... 16 
LIST OF TABLES ..................................................................................................... 20 
LIST OF FIGURES ................................................................................................... 20 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ............................ 21 
1. 
INTRODUCTION .................................................................................. 23 
1.1. 
Background ............................................................................................. 23 
1.2. 
Ciraparantag ............................................................................................ 24 
1.2.1. 
Non-clinical Studies ................................................................................ 25 
1.2.2. 
Clinical Studies ....................................................................................... 26 
1.3. 
Dosing Nomenclature ............................................................................. 29 
2. 
STUDY OBJECTIVES .......................................................................... 29 
2.1. 
Primary Objective ................................................................................... 29 
2.2. 
Secondary Objectives ............................................................................. 29 
3. 
STUDY DESIGN ................................................................................... 30 
3.1. 
Overview ................................................................................................. 30 
3.2. 
Rationale for Key Study Design Elements ............................................. 33 
3.2.1. 
General Design Elements ....................................................................... 33 
3.2.2. 
Use of WBCT Testing ............................................................................ 33 
3.2.3. 
Determination of Sufficient Anticoagulation and Efficacy Endpoints ... 34 
3.3. 
Duration of Subject Participation ........................................................... 35 
4. 
STUDY POPULATION ......................................................................... 36 
4.1. 
Inclusion Criteria .................................................................................... 36 
4.2. 
Exclusion Criteria ................................................................................... 36 
5. 
STUDY DRUG ADMINISTRATION ................................................... 37 
5.1. 
Randomization ........................................................................................ 37 
5.2. 
Selection of Doses .................................................................................. 38 

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5.2.1. 
Anticoagulants ........................................................................................ 38 
5.2.2. 
Ciraparantag ............................................................................................ 38 
5.3. 
Blinding .................................................................................................. 39 
5.3.1. 
Unblinding of Therapy Assignments ...................................................... 39 
5.4. 
Timing of Doses and Dose Administration ............................................ 39 
5.4.1. 
Anticoagulants ........................................................................................ 39 
5.4.2. 
Ciraparantag ............................................................................................ 40 
5.5. 
Duration of Dosing ................................................................................. 40 
5.6. 
Adherence ............................................................................................... 40 
6. 
STUDY PROCEDURES ........................................................................ 41 
6.1. 
Screening ................................................................................................ 41 
6.2. 
Medical History ...................................................................................... 41 
6.3. 
Physical Examination ............................................................................. 41 
6.4. 
Vital Signs .............................................................................................. 42 
6.5. 
Electrocardiograms ................................................................................. 42 
6.6. 
Clinical Laboratory Tests ....................................................................... 42 
6.6.1. 
Fecal Occult Blood Testing .................................................................... 43 
6.6.2. 
Whole Blood Clotting Time Assessments .............................................. 43 
6.7. 
Pharmacokinetic Assessments ................................................................ 44 
6.8. 
Blood Volume Collected ........................................................................ 45 
6.9. 
Prior and Concomitant Medications and Therapies ................................ 45 
6.9.1. 
Prior Medications .................................................................................... 45 
6.9.2. 
Concomitant Medications and Therapies ............................................... 45 
6.9.3. 
Prohibited Medications ........................................................................... 45 
6.10. 
Restrictions ............................................................................................. 46 
6.10.1. 
Dietary Guidelines .................................................................................. 46 
6.10.2. 
Activity Guidelines ................................................................................. 47 
6.11. 
Discontinuation from Treatment or Study .............................................. 47 
6.11.1. 
Discontinuation from Study Drug Treatment ......................................... 47 
6.11.2. 
Discontinuation from Study .................................................................... 47 
6.11.3. 
Data Collection and Follow-up for Withdrawn Subjects ....................... 48 
6.11.4. 
Subject Replacement .............................................................................. 48 
7. 
ADVERSE EVENTS.............................................................................. 49 

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7.1. 
Definitions .............................................................................................. 49 
7.1.1. 
Adverse Event ......................................................................................... 49 
7.1.2. 
Serious Adverse Event ............................................................................ 49 
7.2. 
Adverse Event Evaluation and Classification ......................................... 50 
7.2.1. 
Intensity (Severity) ................................................................................. 50 
7.2.2. 
Causality ................................................................................................. 50 
7.2.3. 
Adverse Event Recording Guidelines ..................................................... 51 
7.3. 
Serious Adverse Event Reporting ........................................................... 52 
7.3.1. 
Study Sponsor Notification by Investigator ........................................... 52 
7.3.2. 
Institutional Review Board/Ethics Committee Notification ................... 52 
7.3.3. 
Serious Adverse Event Follow-up .......................................................... 52 
7.4. 
Pregnancy Reporting .............................................................................. 52 
8. 
CLINICAL TRIAL MATERIALS ......................................................... 53 
8.1. 
Study Drug Supplies ............................................................................... 53 
8.1.1. 
Ciraparantag and Placebo ....................................................................... 53 
8.1.2. 
Anticoagulants ........................................................................................ 53 
8.2. 
Packaging and Labeling .......................................................................... 53 
8.2.1. 
Ciraparantag ............................................................................................ 53 
8.2.2. 
Placebo .................................................................................................... 54 
8.2.3. 
Anticoagulants ........................................................................................ 54 
8.3. 
Storage and Accountability ..................................................................... 54 
8.3.1. 
Storage .................................................................................................... 54 
8.3.2. 
Study Drug Accountability ..................................................................... 54 
8.4. 
Preparation of Study Drug ...................................................................... 54 
8.5. 
Point-of-Care Coagulometer ................................................................... 55 
9. 
STATISTICAL PLAN............................................................................ 55 
9.1. 
Analysis Populations .............................................................................. 55 
9.2. 
Study Endpoints ...................................................................................... 56 
9.2.1. 
Efficacy Endpoints .................................................................................. 56 
9.2.2. 
Safety Endpoints ..................................................................................... 57 
9.2.3. 
Pharmacokinetic Parameters ................................................................... 57 
9.3. 
Statistical Methods .................................................................................. 59 
9.3.1. 
General Considerations ........................................................................... 59 

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9.3.2. 
Efficacy Analyses ................................................................................... 59 
9.3.3. 
Safety Analyses ...................................................................................... 60 
9.3.4. 
Laboratory Tests ..................................................................................... 61 
9.3.5. 
Definition of Baseline Measurements .................................................... 61 
9.3.6. 
Handling of Missing Data ....................................................................... 61 
9.3.7. 
Sensitivity Analyses ................................................................................ 61 
9.3.8. 
Adjustment for Multiple Comparisons ................................................... 61 
9.3.9. 
Sample Size Justification ........................................................................ 62 
10. 
QUALITY ASSURANCE ...................................................................... 62 
10.1. 
Data Handling, Record Keeping, and Direct Access to Data ................. 63 
10.1.1. 
Case Report Forms ................................................................................. 63 
10.2. 
Monitoring, Auditing, and Inspecting .................................................... 63 
10.2.1. 
Study Monitoring .................................................................................... 63 
10.2.2. 
Data Review Team ................................................................................. 64 
10.2.3. 
Criteria for Stopping Enrollment ............................................................ 64 
10.2.4. 
Auditing and Inspecting .......................................................................... 64 
10.2.5. 
Records Retention ................................................................................... 65 
11. 
ETHICAL CONSIDERATIONS............................................................ 65 
11.1. 
Ethics ...................................................................................................... 65 
11.2. 
Review .................................................................................................... 65 
11.3. 
Investigator Responsibilities ................................................................... 66 
11.3.1. 
General Responsibilities ......................................................................... 66 
11.3.2. 
Protocol Compliance .............................................................................. 66 
11.3.3. 
Protocol Amendments ............................................................................ 66 
11.3.4. 
Subject Informed Consent ...................................................................... 67 
11.3.5. 
Confidentiality Regarding Study Subjects .............................................. 67 
11.3.6. 
Laboratory Accreditation ........................................................................ 67 
11.3.7. 
Discontinuation of Study ........................................................................ 67 
12. 
PUBLICATION POLICY ...................................................................... 68 
13. 
REFERENCE LIST ................................................................................ 69 
APPENDIX A SCHEDULE OF EVENTS................................................................ 71 
 

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LIST OF TABLES 
Table 1: 
Anticoagulation Regimen by Cohort ........................................................ 8 
Table 2: 
Timepoints for Assessing Sufficient Anticoagulation and for 
Ciraparantag/Placebo Dosing (Day 3 or Day 4) ....................................... 8 
Table 3: 
Selected Anticoagulants and Reversal Agents ....................................... 24 
Table 4: 
Clinical Studies of Ciraparantag ............................................................. 27 
Table 5: 
Ciraparantag Dosing Conversion ............................................................ 29 
Table 6: 
Anticoagulation Regimen by Cohort ...................................................... 30 
Table 7: 
Timepoints for Assessing Sufficient Anticoagulation and for 
Ciraparantag/Placebo Dosing (Day 3 or Day 4) ..................................... 31 
Table 8: 
Administration Specifications for Anticoagulant Dosing....................... 40 
Table 9: 
Blood Sample Collection Timepoints for WBCT .................................. 44 
Table 10: Identity of Investigational Product ......................................................... 53 
Table 11: PK Parameters ........................................................................................ 58 
Table 12: Hypothesis Testing Paradigm of The Secondary Efficacy Endpoints  For 
Each Dose Group Within Each Cohort ................................................... 62 
Table 13: Schedule of Events .................................................................................... 71 
 
 
LIST OF FIGURES 
Figure 1: Study Design for AMAG-977-213 ....................................................... 32 
 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
AME 
Absorption, metabolism, and excretion 
ANCOVA 
Analysis of covariance 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase  
AUC 
Area under the plasma concentration-time curve 
BAP 
1,4-bis (3- aminopropyl) piperazine 
BL 
baseline 
CI 
confidence interval 
CL 
Total plasma clearance (IV administration) 
CL/F 
Total plasma clearance uncorrected for bioavailability (F)  
Cmax 
Maximum plasma concentration 
C24 
Concentration 24 hours after dosing 
CRF 
Case Report Form 
EC 
Ethics Committee 
ECG 
electrocardiogram 
F 
Bioavailability 
FDA 
US Food and Drug Administration 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
Informed Consent Form 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IV 
intravenous 
IWRS 
Interactive Web Response System 

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Abbreviation 
Definition 
LMWH 
low molecular weight heparin 
MRCmax 
Metabolite to parent ratio of Cmax 
MRAUC(0-last) 
Metabolite to parent ratio of AUC(0-last) 
MRAUC(0-inf) 
Metabolite to parent ratio of AUC(0-inf) 
λz 
Elimination rate constant 
NOACs 
non-vitamin K oral anticoagulants 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
PO 
Oral(ly) 
PoC 
Point-of-Care 
PF 1.2 
prothrombin fragment 1.2 
PT 
prothrombin time 
q 
every 
qd 
once a day (daily) 
SAE 
serious adverse event 
SOC 
System Organ Class 
TAP 
Test Article Preparer 
TEAE 
treatment-emergent adverse event 
TFPI 
tissue factor pathway inhibitor 
UFH 
unfractionated heparin 
Vz 
Apparent volume of distribution 
Vz/F 
Apparent volume of distribution uncorrected for bioavailability (F) 
WBCT 
whole blood clotting time 
 
 

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1. 
INTRODUCTION 
1.1. 
Background 
Anticoagulant medications remain the cornerstone of therapy for the prevention and 
treatment of thrombosis. Anticoagulants have been approved for indications such as 
prevention of stroke in patients with nonvalvular atrial fibrillation, prevention and treatment 
of deep vein thrombosis and pulmonary embolism, and reduction in the risk of myocardial 
infarction or other cardiovascular events in certain patients (Boehringer Ingelheim 
Pharmaceuticals, 2018a; Bristol-Myers Squibb Company, 2016; Daiichi Sankyo, 2017; 
Janssen Pharmaceuticals, 2016; Sanofi-Aventis U.S., 2018). Newer anticoagulants are being 
evaluated for additional indications that could substantially broaden their use. 
The traditional anticoagulants (heparin and warfarin) have a long history of successful 
clinical use, although the dosing and monitoring of these drugs can be time consuming and 
problematic for both physicians and patients. Challenges associated with these traditional 
anticoagulants include the need for parenteral administration of heparin, variable efficacy of 
warfarin that can be affected by diet, and the need for close monitoring of coagulation status. 
More recently, non-vitamin K oral anticoagulants (NOACs) have been developed that have 
several advantages, including rapid therapeutic effectiveness, ease of dosing, and lack of 
monitoring requirements (Alquwaizani, 2013). However, despite the advantages of NOACs, 
all anticoagulants are associated with some risk of major bleeding (Lip, 2016).  
Across the various indications of the currently available anticoagulant medications, the risk 
of major bleeding typically ranges from 1% to 5% annually, although individual patient risk 
can vary substantially based on numerous factors including age, co-morbidities, and 
concomitant medications (Bristol-Myers Squibb Company, 2016; Daiichi Sankyo, 2017; 
Janssen Pharmaceuticals, 2016; Lip, 2016; Tepper, 2018; Yao, 2016). A study from the US 
Centers for Disease Control and Prevention evaluated emergency department visits 
associated with adverse drug events from 2013 to 2014. This study showed that 
anticoagulants accounted for 17.6% of all emergency department visits for outpatient adverse 
drug effects, more than any other class of drugs. These anticoagulant events occurred almost 
exclusively among adults, with increasing risk in successively older age groups. Further, 
these events were mostly severe, with nearly half requiring hospitalization (Shehab, 2016).  
Based on adverse drug event reports submitted to the US Food and Drug Administration 
(FDA) Adverse Event Reporting System during 2016, the US Institute for Safe Medication 
Practices ranked harm from oral anticoagulant drugs as one of the highest priority drug safety 
problems in 2016. Practically all reported anticoagulant-associated injuries or deaths were 
from hemorrhage (ISMP, 2017). Therefore, a major concern regarding the use of any 
anticoagulant, including the NOACs, is how to manage major bleeding in patients who are 
receiving anticoagulant therapy. In some cases, discontinuation of the anticoagulant, 
transfusion, and/or other supportive care measures may be sufficient. However, the 
availability of an anticoagulant reversal agent that is safe, effective and convenient to use 
may be critical in cases such as serious/life-threating bleeding, prior to urgent or emergency 
surgery, after major trauma, or in cases of anticoagulant overdose.  

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Various anticoagulant drugs and the respective reversal agents that are currently available are 
shown in Table 3, along with the limitations of the reversal agents.  
Table 3: Selected Anticoagulants and Reversal Agents 
Anticoagulant 
Reversal Agent a 
Name 
Class 
Initial 
Approval 
(US) 
Name 
Use and Limitations 
UFH 
Heparin 
1939 
Protamine 
Dosing is based on timing and dose 
of last UFH/LMWH administration. 
Reversal potency is lower for 
LMWH vs UFH. Hypotension, 
bradycardia or allergic reactions can 
occur. 
Warfarin 
Vitamin K 
antagonist 
1954 
Vitamin K 
Must decide upon IV or oral dosing 
based on INR and bleeding risk. 
Excessive dosing may lead to 
inability to re-anticoagulate with 
warfarin for several days. 
Dabigatran 
FIIa inhibitor 2010 
Idarucizumab 
(Praxibind®), a 
monoclonal Fab 
that binds to 
dabigatran 
Store refrigerated (beyond 48 hours). 
Adult regimen = two sequential IV 
doses. (Initial US approval 2015) 
Rivaroxaban 
FXa inhibitor 2011 
Coagulation 
factor Xa 
(recombinant) 
(Andexxa®) 
Store refrigerated. Requires 
reconstitution and IV preparation 
time. Adult regimen = 30 minute IV 
bolus then 2 hour infusion. Dosing is 
based on timing and dose of each 
FXa inhibitor. Activity requires 
continuous infusion and wanes 
quickly after end of infusion. Black 
box warning for thromboembolic 
risks. (Initial US approval 2018) 
Apixaban 
FXa inhibitor 2012 
Source: (Alquwaizani, 2013; Boehringer Ingelheim Pharmaceuticals, 2018b; Macdonald, 2018; Portola 
Pharmaceuticals, 2018).  
Abbreviations:  Fab=antibody fragment; FIIa=factor IIa (thrombin); FFP=fresh frozen plasma; FXa=factor Xa; 
INR=international normalized ratio; IV=intravenous; LMWH=low molecular weight heparin; 
PCC=prothrombin complex concentrate; UFH=unfractionated heparin. 
a Shown are anticoagulant-specific reversal agents. Non-specific reversal therapies may include PCC, FFP, or 
recombinant factor VIIa; for oral anticoagulants, activated charcoal also may be used.  
 
1.2. 
Ciraparantag  
Ciraparantag (previously known as PER977, now known as AMAG-977) is a small, 
synthetic, cationic, water-soluble molecule composed of amino acid derivatives with short-
linking elements that physically associate with certain anticoagulant drugs and reverses their 

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effect in order to re-establish a normal blood coagulation state. This is mediated through 
direct non-covalent binding to the anticoagulant molecule, with no binding to blood 
coagulation factors or proteins in the blood. Based on available preclinical and clinical data, 
ciraparantag has the potential to reverse anticoagulation caused by edoxaban, apixaban, 
rivaroxaban, dabigatran, and heparins, with: 
• A single IV dose (administered over approximately 10 minutes) that provides a 
sustained effect through at least 6 hours 
• A ready-to-use solution 
• A favorable safety profile and no prothrombotic signal to date 
1.2.1. 
Non-clinical Studies 
In vivo (in rat models) and/or ex vivo (in human plasma), ciraparantag was shown to reverse 
the anticoagulant effect of edoxaban, apixaban, rivaroxaban, dabigatran, low molecular 
weight heparin (LMWH), and fondaparinux. Ciraparantag did not reverse the anticoagulant 
effect of warfarin in vivo. In a rat tail transection model, intravenous (IV) administration of 
ciraparantag reversed the anticoagulant effect of edoxaban, apixaban, rivaroxaban, 
dabigatran, unfractionated heparin (UFH), and enoxaparin, a LMWH.  
In dynamic light scattering studies, ciraparantag was shown to physically associate with the 
anticoagulants that were tested (i.e., edoxaban, apixaban, rivaroxaban, LMWH, UFH and 
fondaparinux). Ciraparantag showed no self-association, or interaction with fXa, fIIa, 
antithrombin III, or commonly used cardiac drugs (aspirin, clopidogrel, digoxin, 
propafenone, hydrochlorothiazide, triamterene, lisinopril, diltiazem, propranolol), 
antiepileptic drugs (carbamazepine, gabapentin, lamotrigine, phenytoin sodium, valproate 
sodium), or other drugs (metformin, atorvastatin, azithromycin, streptokinase) by the same 
measure.  
In human plasma containing all coagulation factors and albumin, ciraparantag displayed no 
plasma protein binding. In citrated human whole blood, ciraparantag had no effect on platelet 
aggregation. 
Ciraparantag displayed no concentration-dependent inhibition of hepatic cytochromes and 
displayed no concentration-independent inhibition of hERG in vitro. 
With respect to safety, in 14-day repeat IV dosing studies in Sprague Dawley rats and in 
beagle dogs, there were no signs of systemic toxicity at ciraparantag acetate doses up to 
20 mg/kg/day (the highest dose tested). The NOAEL was determined to be 20 mg/kg/day 
ciraparantag acetate. Further, this dose had no consistent dose-related effects on heart rate, 
blood pressure, cardiac rhythm or electrocardiogram parameters including QTc in beagle 
dogs.  
The primary metabolite of ciraparantag, 1,4-bis (3- aminopropyl) piperazine (BAP), was 
estimated to have 1/34th the potency of ciraparantag on a molar basis with respect to pre-
clinical edoxaban reversal. In vivo testing of BAP in rats and dogs at IV doses up to 
20 mg/kg/day ciraparantag acetate showed no treatment related findings. 

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1.2.2. 
Clinical Studies 
Ciraparantag has been evaluated in more than 270 healthy adult volunteers across 
seven completed clinical trials (Table 4). To date, 6 completed clinical studies have evaluated 
single IV doses of ciraparantag following administration of edoxaban, UFH, enoxaparin, 
apixaban or rivaroxaban. A separate completed study evaluated the absorption, metabolism, 
and excretion (AME) of radiolabeled ciraparantag. 
Early clinical studies originally presented doses expressed as the drug substance ciraparantag 
acetate. In accordance with new guidelines, dosing is now expressed as the active moiety 
(ciraparantag) (Section 1.3). In the presentation of data from previous clinical studies, dosing 
is expressed as the active moiety unless otherwise specified. 
Monitoring of coagulation status in clinical studies initially was attempted using traditional 
assays such as prothrombin time (PT), activated partial thromboplastin time (aPTT) or 
thromboelastography reaction time. However, ciraparantag is cationic and binds to the 
anionic substances (citrate, ethylenediaminetetraacetic acid, and oxalate) in standard blood 
collection tubes used for coagulation testing. Ciraparantag also binds to the colloidal 
activators (eg, kaolin or Celite) used in some coagulation assays. Therefore, such assays are 
not appropriate markers for measuring ciraparantag effect because of reagent interference 
and assay insensitivity. 
Despite the challenges with traditional assays, reversal of anticoagulant effect was visually 
observed by the study personnel who were handling blood samples in the first clinical study. 
Whole blood clotting time (WBCT) was performed manually on several blood samples in 
that study and was found to be a good measure of coagulation status (ie, showing an increase 
in clotting time following edoxaban administration, with agreement between independent 
observers). WBCT is a direct measure of the time required for blood clot formation ex vivo 
and uses blood drawn into reagent-free collection tubes; the test uses only glass as the 
activating agent. Therefore, WBCT became the key measure of coagulation status in clinical 
studies of ciraparantag. 
WBCT testing in prior clinical studies was performed manually. In order to reduce the 
possibility of inter-operator differences in testing and technique, a handheld point-of-care 
coagulometer device was developed for automated WBCT testing. In this study, WBCT 
testing will be performed with the coagulometer device (Perosphere Technologies’ PoC 
Coagulometer) and the manual testing method. 
 
 

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Table 4: 
Clinical Studies of Ciraparantag 
Study 
# 
Status 
Study 
Type 
Ciraparantag 
Treatment a 
Key Pharmacodynamic Findings b 
N 
IV Dose 
Range 
 
01-
001 
completed PK/PD – 
reversal of 
edoxaban 
66 
3–180 mg 
Period 1: administered alone, ciraparantag 
displayed no pro-coagulant activity. 
Period 2: when administered 3 hours following 
edoxaban 60 mg PO, ciraparantag demonstrated 
dose-related reversal of anticoagulation (WBCT 
return to ≤120% of baseline), with significant effect 
compared to PBO at most or all timepoints within 1 
hour post-dose for doses ≥60 mg. The effect 
typically started 10–30 minutes post-dose and was 
sustained through 24 hours. 
01-
002 
completed PK/PD – 
reversal of 
UFH 
48 
60–360 mg 
UFH was given as a 5000 u IV bolus then 3 hours 
infusion. When administered within 30 minutes 
after the end of UFH infusion, ciraparantag did not 
demonstrate significant reversal of anticoagulation 
compared to PBO at the doses tested. Higher doses 
were considered but the study was closed early for 
business reasons (there were no safety concerns 
regarding higher dosing). The findings were not 
unexpected due to the much higher binding ability 
of UFH for ciraparantag compared to smaller 
enoxaparin molecules and NOACs. In addition, the 
anticoagulant effect of UFH naturally reverses 
quickly after the end of infusion given its short 
half-life. 
01-
003 
completed PK/PD – 
reversal of 
enoxaparin 
32 
15–180 mg 
When administered 4 hours following enoxaparin 
1.5 mg/kg SC, reversal of WBCT (to ≤120% of 
baseline within 1 hour post-dose and sustained in 
the 1 to 6-hour interval) was observed in 100% of 
subjects receiving ciraparantag doses ≥60 mg and 
no subject in the PBO group.  The effect typically 
started within 20 minutes post-dose and was 
sustained through 24 hours (with notable difference 
from PBO through ~6-8 hours after dosing). 
Those in the 15 mg group received 15 mg IV every 
30 minutes x 4 doses. In this group 71% had 
WBCT reversal to ≤120% of baseline at 1 hour 
post-dose and sustained in the 1 to 6-hour interval. 
However mean WBCT was notably slower to 
decline compared to the other active dose groups. 
01-
004 
completed Mass 
balance, 
metabolic 
disposition 
6 
120 mg 
Subjects received a single IV dose of 14C-labeled 
ciraparantag. Ciraparantag is primarily cleared by 
hydrolysis; it is rapidly enzymatically hydrolyzed to 
MAP, which is converted to BAP; these are the 
major metabolites observed in serum. 

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Study 
# 
Status 
Study 
Type 
Ciraparantag 
Treatment a 
Key Pharmacodynamic Findings b 
N 
IV Dose 
Range 
 
Full recovery of radioactivity was suboptimal 
because elimination continued longer than 
expected.  
02-
001 
completed PK/PD – 
reversal of 
edoxaban 
41 
15–360 mg 
Day 3: when administered 3 hours following 
edoxaban 60 mg PO, reversal of WBCT (to ≤120% 
of baseline within 1 hour post-dose and sustained in 
the 1 to 6-hour interval) was observed in 89-100% 
of subjects receiving ciraparantag doses ≥60 mg vs 
60% for PBO. 
Day 4: administration of another dose of edoxaban 
60 mg PO resulted in successful re-anticoagulation, 
with WBCT results similar to those observed pre-
ciraparantag on Day 3. Administration of 
ciraparantag 3 hours following edoxaban on Day 4 
demonstrated reversal of WBCT with results 
comparable to Day 3. 
Ciraparantag at all doses administered in this study 
had no apparent impact on the PK of edoxaban. 
02-
011 
completed PK/PD – 
reversal of 
apixaban 
36 
30–120 mg 
Day 4: when administered 3 hours following 
apixaban 10 mg PO, reversal of WBCT (to ≤110% 
of baseline within 1 hour post-dose and sustained 
through 5 hours) was observed in 67%, 100% and 
100% of subjects receiving ciraparantag 30, 60 and 
120 mg, respectively, vs 17% for PBO. 
02-
012 
completed PK/PD – 
reversal of 
rivaroxaban 
48 
30–180 mg 
Day 3: when administered 4 hours following 
rivaroxaban 20 mg PO, reversal of WBCT (to 
≤110% of baseline within 1 hour post-dose and 
sustained through 6 hours) was observed in 
58%, 75%, 67% and 100% of subjects 
receiving ciraparantag 30, 60, 120 and 180 mg, 
respectively, vs 13% for PBO. 
Abbreviations:  BAP=1,4-bis (3-aminopropyl) piperazine; IV=intravenous; NOAC=non-vitamin K oral 
anticoagulant; MAP=mono-arginine piperazine; PBO=placebo; PD=pharmacodynamics, PK=pharmacokinetics; 
SC=subcutaneously; UFH=unfractionated heparin; WBCT=whole blood clotting time. 
a N shown for subjects who received ciraparantag. Doses are expressed as the active moiety (ciraparantag); 
unless otherwise specified, these were single IV doses administered over ~10 minutes.  
b Unless otherwise specified, findings are based on manual WBCT results. 
Ciraparantag exhibits linear pharmacokinetics. Across the range of doses that have been 
evaluated, the mean half-life of ciraparantag ranged from 12 to 19 minutes. 
Ciraparantag was well tolerated across the range of doses that were evaluated. The most 
common adverse events (AEs) related to ciraparantag were mild, transient sensations of 
warmth (typically reported as hot flashes or flushing), paresthesia, and alterations in taste. 
There were no clinically significant adverse trends in laboratory values, vital signs, or 
electrocardiogram (ECG) parameters.  

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Additional details of the results of prior studies of ciraparantag are available in the 
Investigator’s Brochure.  
1.3. 
Dosing Nomenclature 
It should be noted that in previously completed non-clinical and clinical studies, the doses of 
study drug (mg) referred to the salt form (ciraparantag acetate). These ciraparantag acetate 
doses have been used in various publications and presentations for these studies; however, 
regulatory preference is now to quantify dosing using the active drug moiety (ciraparantag). 
The conversion factor is as follows: 
ciraparantag (mg) = ciraparantag acetate (mg) x 0.6 
For reference, the equivalent amounts of each drug form are given in Table 5. 
Table 5: 
Ciraparantag Dosing Conversion 
Ciraparantag Acetate 
Ciraparantag 
25 mg 
15 mg 
50 mg 
30 mg 
100 mg 
60 mg 
200 mg 
120 mg 
300 mg 
180 mg 
600 mg 
360 mg 
Throughout this protocol, active study drug doses are expressed as ciraparantag moiety alone, 
without the associated acetate counter-ion. 
2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
• To demonstrate that a single IV administration of ciraparantag is superior to PBO 
in the reversal of anticoagulation induced by each of the evaluated anticoagulant 
drugs (edoxaban, apixaban, or rivaroxaban) in healthy adults, as assessed by 
WBCT measured with Perosphere Technologies’ POC Coagulometer. 
2.2. 
Secondary Objectives 
• To evaluate the safety and tolerability of ciraparantag in this population. 
• To evaluate the pharmacokinetics (PK) of ciraparantag and the evaluated 
anticoagulant drugs in this population. 
• To describe the correlation between WBCT measured with Perosphere 
Technologies’ POC Coagulometer and with a manual testing method. 

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3. 
STUDY DESIGN 
3.1. 
Overview 
This is a randomized, double-blind, PBO-controlled study to evaluate the efficacy and safety 
of ciraparantag for reversal of anticoagulation induced by different anticoagulant drugs 
(edoxaban, apixaban, or rivaroxaban) in generally healthy adults. Throughout the study, 
coagulation status will be determined by WBCT, which will be measured primarily by the 
Perosphere Technologies’ PoC Coagulometer (hereafter referred to as the “coagulometer”) 
and at selected timepoints using a manual testing method (Section 6.6.2).  
The study will be conducted in three separate cohorts; each cohort will evaluate the reversal 
of a different anticoagulant drug. Within each cohort, an initial group of subjects (Group 1) 
will be enrolled for evaluation of a target dose of ciraparantag (180 mg IV). Depending on 
the efficacy and safety results from Group 1, a second group (Group 2) may be enrolled to 
evaluate a different dose of ciraparantag for that cohort. The selection of the ciraparantag 
dose(s) to be evaluated is discussed in Section 5.2.2. 
During the Screening period, which is the same for all cohorts, subjects will be assessed for 
eligibility, and as part of informed consent, they will receive activity and dietary guidelines 
appropriate for a study involving an anticoagulant. Eligible subjects will be admitted to the 
clinical study unit on Day -1. Fecal occult blood test results must be negative for a subject to 
participate (Section 6.6.1). The next day (Day 1), baseline (BL) WBCT will be determined 
prior to receiving the anticoagulant based on the cohort to which they were enrolled 
(Table 6). 
Table 6: 
Anticoagulation Regimen by Cohort 
Cohort Anticoagulant Regimen 
1 
Edoxaban 
60 mg PO once daily in the morning from Day 1 to Day 3 or Day 4 
2 
Apixaban 
10 mg PO every 12 hours from Day 1 to the morning of Day 3 or Day 4 
3 
Rivaroxaban 
20 mg PO once daily in the morning from Day 1 to Day 3 or Day 4 
 PO=orally 
Within each cohort, subjects will be assessed for sufficient anticoagulation on Day 3 or 
Day 4 before proceeding further in the study. The Day 3/Day 4 option is provided to allow 
for flexibility in scheduling the day of the week on which this visit will occur. WBCT will be 
determined following the morning dose of anticoagulant at the approximate timepoint 
specified (Table 7) for purposes of determining sufficient anticoagulation. If this WBCT 
result is ≥130% of BL (based on the coagulometer), the subject will proceed in the study. If 
testing occurs on Day 3 and does not meet WBCT criteria for sufficient anticoagulation, the 
subject can continue anticoagulant dosing and be assessed again on Day 4, at the discretion 
of the Investigator. If testing occurs on Day 4 and does not meet WBCT criteria for sufficient 
anticoagulation, the subject will be discontinued from the study (Section 6.11.3). 
Subjects who proceed in the study will be randomized to a single IV dose of ciraparantag or 
PBO in a 2:1 ratio. Randomization will be stratified by age (18 to <50 years vs. ≥50 to 75 
years). Within each cohort, between 50% and 70% of randomized subjects will be ≥50 to 75 
years of age, and there will be approximately equal numbers of male and female subjects. 

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The ciraparantag/PBO dose will be administered starting at the approximate timepoint 
specified in Table 7, followed by multiple WBCT and PK measurements. 
Table 7: 
Timepoints for Assessing Sufficient Anticoagulation and for 
Ciraparantag/Placebo Dosing (Day 3 or Day 4) 
Cohort 
Anticoagulant 
Timepoint for assessing 
sufficient anticoagulation 
For sufficiently anticoagulated 
subjects, timepoint for 
ciraparantag/placebo dose 
1 
Edoxaban 
2.75 hours after Day 3 or Day 
4 edoxaban dose 
3 hours after the last edoxaban 
dose 
2 
Apixaban 
3.75 hours after Day 3 or Day 
4 apixaban dose 
4 hours after the last apixaban 
dose 
3 
Rivaroxaban 
3.75 hours after Day 3 or Day 
4 rivaroxaban dose 
4 hours after the last rivaroxaban 
dose 
Subjects in all cohorts who receive ciraparantag/PBO will remain domiciled in the clinical 
study unit for 5 days after dosing (i.e., through Day 8 or Day 9). Evaluations on the day 
following ciraparantag/PBO dosing will include WBCT, PK, and safety assessments 
(including testing for prothrombotic markers). On subsequent days, follow-up safety 
assessments (including testing for prothrombotic markers) will continue. Any subject with 
WBCT on the day following ciraparantag/PBO dosing that is >120% of BL (based on the 
coagulometer) or >110% of BL (based on the manual method) will have both WBCT 
measurements repeated on subsequent days as required until WBCT is ≤120% of BL (based 
on the coagulometer) and ≤110% of BL (based on the manual method). Note that the 
differences in these thresholds is based on the differences in assay sensitivity between the 
two testing methods (Section 3.2.2). Once both WBCT thresholds have been met, no further 
WBCT testing is required.  
Five days after ciraparantag/PBO dosing (Day 8 or Day 9), subjects may be discharged from 
the study unit, provided that the last (final) WBCT results are ≤120% of BL (based on the 
coagulometer) and ≤110% of BL (based on manual WBCT), and the Investigator determines 
that no additional safety monitoring is required. Otherwise the subject will remain domiciled 
until these criteria are met. The detailed schedule of study assessments is provided in 
Appendix A. 
An overview of the study design is provided in Figure 1. 
 
 
 
 
 
 
 

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Figure 1: Study Design for AMAG-977-213 
 
An Interactive Web Response System (IWRS) will determine the cohort into which a subject 
is enrolled. Enrollment will begin with Cohort 1, but cohorts may be enrolled in parallel, 
depending on the availability of qualified subjects (eg, if the stratum of younger subjects is 
fully enrolled in Cohort 1, further eligible subjects in that stratum may be enrolled in 
Cohort 2). Within a cohort, subjects will be enrolled in only one group at a time. Individual 
subjects may only be randomized in one cohort or group in this study. If a subject is enrolled 
but does not achieve sufficient anticoagulation in one cohort (and is not randomized), the 
subject may be re-screened for potential enrollment in a different cohort (i.e., a different 
anticoagulant drug). For a given cohort, study treatments and assessments through discharge 
(Day 8 or 9) will be completed for all subjects in Group 1 before deciding to proceed with 
Group 2. This determination, and the ciraparantag dose to be evaluated in Group 2, will be 
made by a data review team as described in Section 10.2.2. Criteria for stopping dosing in a 
cohort are described in Section 10.2.3. 
Subjects who remain eligible after the Day -1 assessments and who are admitted to the study 
unit will be considered enrolled in the study. As described above, only those subjects who 
achieve sufficient anticoagulation on Day 3 or Day 4 will be randomized. The randomization 
target is 18 subjects (12 ciraparantag: 6 PBO) in each group of each cohort. Assuming full 
enrollment of two dose groups for each of the three cohorts, a total of approximately 108 
subjects will be randomized in the study. 
The study will be conducted at a minimum of two and up to four study sites. For a given 
cohort, at least two sites will contribute subjects to each group of that cohort, and no site will 
contribute more than 70% of the subjects randomized to any group of that cohort. 

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3.2. 
Rationale for Key Study Design Elements 
3.2.1. 
General Design Elements 
This study will be conducted in double-blind fashion in conjunction with a PBO control in an 
effort to remove evaluation biased by the expected effects of study drug. A PBO control 
group is considered appropriate because it will provide the comparative data on the “natural” 
time course of return to normal coagulation status following anticoagulant dosing based on 
WBCT. 
Adult subjects will be stratified into two groups (18 to <50 years vs. ≥50 to 75 years), and 
between 50% and 70% of randomized subjects will be ≥50 to 75 years of age, in order to 
evaluate ciraparantag across a range of ages that reflect its potential use in clinical practice. 
For example, reversal of anticoagulation is likely to be needed in relatively younger patients 
in cases of severe bleeding from trauma, and in relatively older patients in cases of 
spontaneous internal bleeding.  
Evaluation of reversal of anticoagulation will be performed on Day 3 or Day 4 of 
anticoagulant dosing to ensure that subjects are at clinically relevant concentrations of the 
anticoagulant when they receive ciraparantag/PBO. Per prescribing information and 
literature, steady state concentrations for each of the anticoagulants are achieved within 3 
days or less with the regimens administered in this study (Daiichi Sankyo, 2017; Frost, 2014; 
Sanofi-Aventis U.S., 2018). 
Ciraparantag/PBO will be administered 3 or 4 hours after the anticoagulant dose on Day 3 or 
Day 4, in order to evaluate study drug treatment administered near the time of maximum 
concentration and effect of the anticoagulant. 
3.2.2. 
Use of WBCT Testing  
WBCT is the key clinical efficacy measurement because ciraparantag is cationic and binds to 
the anionic substances in standard blood collection tubes used for coagulation testing, and 
also binds to anionic, colloidal activators used in the traditional coagulation assays such as 
PT or aPTT (Section 1.2.2). Therefore, such assays are not appropriate markers for 
measuring ciraparantag effect because of reagent interference and assay insensitivity. WBCT 
is a direct measure of the time required for blood clot formation ex vivo and uses blood 
drawn into reagent-free collection equipment; the test uses only glass as the activating agent.  
WBCT testing can be performed with different methods. In this study, WBCT will be tested 
with both the Perosphere Technologies’ PoC Coagulometer and with a manual testing 
method. The Perosphere Technologies’ PoC Coagulometer uses near infrared (IR) 
spectroscopy to detect fibrin assembly; it was developed specifically to provide an objective, 
sensitive and consistent method to measure anticoagulant effects with high precision. Manual 
WBCT testing is simply a visual determination of time to gross clot formation in a test tube; 
it is an old method that is more prone to variability and depends on operator consistency in 
technique and interpretation. While impractical for larger studies across many sites, manual 
WBCT can be performed acceptably under the controlled conditions of a small number of 
dedicated study units.  

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Extensive validation studies have shown that coagulometer results showed a high degree of 
linear correlation with blood concentrations of anticoagulants over a broad range of 
concentrations, as well as a high degree of linear correlation with manual WBCT results. 
However, it is important to note that the results of the coagulometer and manual WBCT are 
not interchangeable. The coagulometer yields clotting times that are approximately half as 
long as manual WBCT results. For example, a typical “normal” blood sample from a healthy 
individual may show a manual WBCT result of approximately 500 seconds, while this same 
sample may show a coagulometer WBCT result of approximately 250 seconds. Similarly, the 
sensitivity of the assay to the effect of anticoagulation is greater with the coagulometer – ie, 
the proportionate increase in clotting time relative to the baseline in response to a given 
anticoagulant concentration is approximately double in comparison to manual WBCT. 
In this study, the coagulometer will provide the primary WBCT assessments for efficacy 
analyses and will be performed at all planned WBCT timepoints. Manual WBCT testing also 
will be performed at selected timepoints in order to further describe the correlation between 
results obtained with the two methods, and to ensure certainty that a subject’s WBCT has 
returned to near baseline after the study drug treatment period and before discharge from the 
study unit. 
3.2.3. 
Determination of Sufficient Anticoagulation and Efficacy Endpoints 
The thresholds for relevant changes from baseline in WBCT as measured by the 
coagulometer are based on multiple factors including: 
• known ranges for plasma concentrations of anticoagulants at therapeutic doses, 
and their associated bleeding risk 
• results of manual WBCT testing following anticoagulant dosing in ciraparantag 
clinical studies conducted to date 
• correlation between anticoagulant concentrations, manual WBCT testing, and 
coagulometer WBCT testing in a methods comparison study conducted as part of 
coagulometer validation 
Rationale for sufficient anticoagulation 
Subjects will be considered sufficiently anticoagulated if the WBCT measurement obtained 
just prior to the planned ciraparantag/PBO dose shows an increase in WBCT to ≥130% of BL 
(based on the coagulometer). 
This threshold was selected for the following reasons: 
• In most prior clinical studies of ciraparantag using manual WBCT testing, the 
threshold for sufficient anticoagulation was WBCT ≥120% of baseline, and in 
those studies the proportion of subjects who reached this threshold following 
therapeutic doses of anticoagulants was high (eg, 85% with apixaban and 100% 
with rivaroxaban [unpublished data on file from Studies 977-02-011 and 977-02-
012]).  
• In a methods comparison study, manual WBCT changes to 120% of baseline 
corresponded to NOAC concentrations of approximately 150 ng/mL. In that 

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study, NOAC concentrations of 150 ng/mL corresponded to WBCT changes of 
approximately 130% of baseline as measured by the coagulometer [unpublished 
data from validation studies for Perosphere Technologies’ POC Coagulometer]. 
• Therefore, the WBCT threshold of ≥130% of BL (based on the coagulometer, 
which is the primary WBCT assessment method for study) represents a degree of 
anticoagulation that is expected to be achievable for the therapeutic anticoagulant 
dosing regimens to be administered and provides a sufficient level from which a 
meaningful improvement can be measured after administration of 
ciraparantag/placebo. 
Rationale for efficacy endpoint 
In this study, the coagulometer will provide the primary WBCT assessments for efficacy 
analyses, because the coagulometer is expected to provide greater sensitivity and precision 
compared to the manual method (Section 3.2.2).  The primary efficacy endpoint is based on 
achieving a WBCT ≤120% of baseline based on the coagulometer. This threshold was 
selected for the following reasons: 
• Available published guidance and clinical study precedent indicates that the 
threshold for clinically relevant anticoagulation with NOACs lies within the range 
of 30 to 75 ng/mL (Connolly, 2019; Levy, 2016; Pernod, 2013). 
• In a methods comparison study, NOAC concentrations of 75 ng/mL corresponded 
to manual WBCT changes of approximately 110% of baseline [unpublished data 
from validation studies for Perosphere Technologies’ POC Coagulometer]. 
Accordingly, among subjects who have been anticoagulated, achievement of 
manual WBCT ≤110% of baseline within a given time period (eg, within 1 hour 
after administration of study drug) has been utilized as an efficacy endpoint in 
some prior clinical studies of ciraparantag, and those studies have shown 
significant differences between ciraparantag and placebo (Section 1.2.2). 
• When tested with the coagulometer (in the methods comparison study), NOAC 
concentrations of 75 ng/mL correspond to WBCT changes of approximately 
120% of baseline.  
• Therefore, the coagulometer WBCT threshold of ≤120% of baseline was selected 
as the primary target for demonstration of reversal of anticoagulation. 
• As described in Section 9.2.1, other WBCT thresholds for reversal of 
anticoagulation will also be examined. 
3.3. 
Duration of Subject Participation 
Subjects will participate in the study for up to approximately 6 weeks. This will consist of a 
Screening period (up to 30 days) and a domiciled period in the study unit (up to 10 days). 

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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
Eligible subjects must: 
1. Be informed of the nature of the study and provide written informed consent before 
any study-specific procedures are performed. 
2. Be 18 to 75 years of age, inclusive, at time of consent. 
3. Be in good health, in the opinion of the Investigator, based on medical history, 
physical examination, vital signs, ECG and laboratory testing (ie, absence of any 
clinically relevant abnormality) during Screening. 
4. Have a body mass index 18 to 32 kg/m2, inclusive, at Screening. 
5. If female, be surgically sterile or post-menopausal (no menses for at least 12 months), 
or if of child-bearing potential, must be using an acceptable method of contraception 
(other than a combination estrogen/progestin hormonal contraceptive) for at least 1 
month prior to Day 1, such as an intrauterine device (IUD), implant, or two forms of 
the following: diaphragm, cervical cap, patch, condom, spermicide, or sponge. In 
addition, females of child-bearing potential must agree to continue to use their 
method of birth control for the duration of the study and 12 weeks following 
discharge from the study. 
6. If male, be surgically sterile, or agree to use appropriate contraception (latex condom 
with spermicide) when engaging in sexual activity and agree to not donate sperm for 
the duration of the study and 12 weeks following discharge from the study. 
7. Have suitable venous access for multiple venipunctures. 
4.2. 
Exclusion Criteria 
Eligible subjects must not: 
1. Have any of the following findings at Screening: 
a. Hemoglobin or hematocrit value outside the normal range 
b. Platelet count outside the normal range 
c. PT or aPTT outside the normal range 
d. Plasma fibrinogen outside the normal range 
e. Serum triglycerides or total cholesterol outside the normal range 
f. Serum creatinine >1.5 mg/dL (133 µmol/L) or known renal disease 
g. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2 x the 
upper limit of normal, or known liver disease 
h. Total bilirubin outside the normal range 
i. Positive viral screen for hepatitis B virus, hepatitis C virus (HCV), or human 
immunodeficiency virus (HIV) 
j. Positive pregnancy test (females) 
k. Positive drug, tobacco or alcohol screen 
l. Any clinically significant findings on 12-lead ECG or urinalysis 

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2. Have a personal or family history of clotting disorder or hematologic abnormality, 
such as excessive bleeding, joint hematoma, thrombovascular disease, 
thrombocytopenia, or any chronic condition requiring treatment with transfusions. 
3. Have a history of unexplained syncope. 
4. Have a history within 6 months prior to Screening of major bleeding, trauma, surgical 
procedure of any type, or vaginal delivery. 
5. Have a history within 6 months prior to Screening of peptic ulcer or gastrointestinal 
bleeding (including hematemesis, melena, or rectal bleeding). 
6. Have received any blood product or anticoagulant within 3 months prior to Screening. 
7. Have donated blood or blood products within 3 months prior to Screening. 
8. Have a history of minor bleeding episodes (eg, epistaxis, bruising or gingival 
bleeding) within 1 month prior to Screening, or a long-standing history of such 
bleeding. 
9. If female, have a history of excessive or dysfunctional uterine bleeding (unless the 
subject had a subsequent hysterectomy). 
10. Have used any tobacco or nicotine-containing products within 3 months prior to 
Screening. 
11. Have used any systemic prescription or non‐prescription drugs (including vitamins, 
supplements, and herbal products) within 14 days prior to Day 1 (except for permitted 
contraceptives). NOTE: subjects should be asked specifically about use of aspirin and 
other non-steroidal anti-inflammatory drugs. 
12. If female, be pregnant, breastfeeding, or planning to become pregnant during the 
study. 
13. Have received ciraparantag in any prior clinical study. 
14. Have received another investigational drug within 5 half-lives or 30 days, whichever 
is longer, prior to Day 1. 
15. Known allergy to edoxaban, apixaban or rivaroxaban. 
16. Have any other condition that, in the opinion of the Investigator, would interfere with 
a subject’s ability to adhere to the protocol, interfere with assessment of the 
investigational product, or compromise the safety of the subject or the quality of the 
data. 
5. 
STUDY DRUG ADMINISTRATION 
5.1. 
Randomization 
Subjects will be randomized via Interactive Web Response System (IWRS) to study 
treatment in a 2:1 ratio (ciraparantag vs. PBO). Randomization will be stratified by age (18 to 
<50 years vs. ≥50 to 75 years) within each dose group of each cohort. 

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5.2. 
Selection of Doses 
5.2.1. 
Anticoagulants 
For each of the anticoagulants (edoxaban, apixaban, or rivaroxaban), the dosing regimens 
administered in this study (Table 6) represent a recommended dose for subjects with normal 
renal function, as per prescribing information. 
5.2.2. 
Ciraparantag 
5.2.2.1. 
Group 1 
For each cohort, the Group 1 target dose of ciraparantag is 180 mg. This dose was selected 
based on the following considerations:  
• Prior clinical studies have evaluated single IV doses of ciraparantag ranging 
between 3 and 360 mg. In general, ciraparantag exhibited dose-related reversal of 
anticoagulation, with the most notable effects at doses ≥60 mg based on manual 
WBCT (Table 4). 
• The most recent clinical studies (Studies 02-011 and 02-012) provide data for 
subjects anticoagulated with apixaban or rivaroxaban (Table 4). Following 
apixaban administration, reversal of manual WBCT (to ≤110% of baseline within 
1 hour post-dose and sustained through 5-6 hours) was observed in 100% of 
subjects receiving ciraparantag 60 or 120 mg. Following rivaroxaban 
administration, such reversal was observed in 75%, 67% and 100% of subjects 
receiving ciraparantag 60, 120 and 180 mg, respectively. Thus, reversal of 
anticoagulation was achieved in high proportions of subjects with doses of 120-
180 mg. To maximize the chances that a single ciraparantag dose can be identified 
for reversal of all anticoagulants of interest, the high end of this dose range (i.e., 
180 mg) was favored. 
• In prior clinical studies, ciraparantag was well tolerated across the range of doses 
that were evaluated (i.e., up to 360 mg). In the completed clinical studies, there 
were no serious adverse events (SAEs) related to study drug. Adverse events that 
appeared to be dose-related were sensations of warmth (e.g., hot flashes or 
flushing) and paresthesia; however, to date these events have been mild and did 
not lead to study discontinuation. 
• Therefore, the data from prior clinical studies indicate that a ciraparantag dose of 
180 mg should be well tolerated and has a high likelihood of reversing 
anticoagulation in a high proportion of subjects, for multiple different 
anticoagulant medications. 
5.2.2.2. 
Group 2 
If it is determined that a second ciraparantag dose group will be evaluated in a given cohort, 
that dose for Group 2 will be within the range of 120 to 360 mg. Based on prior clinical 
studies, ciraparantag doses below 120 mg are not expected to provide high success rates in 

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reversal of all anticoagulants of interest, and doses up to 360 mg (the highest dose tested to 
date) were well tolerated with no dose-limiting toxicity.  
5.3. 
Blinding 
Anticoagulant drugs will be administered in an open-label manner. 
Ciraparantag or PBO will be administered in a double-blind manner. Subjects and all study 
site personnel (except the Test Article Preparer [TAP], Section 8.3) will be blinded to 
individual subject treatment assignment (ciraparantag or PBO). In particular, study site 
personnel who perform or record safety assessments and WBCT testing must be blinded to 
individual treatment assignment. The Sponsor will be unblinded to individual treatment 
assignments in order to monitor efficacy and safety data and compile results for the data 
review team (Section 10.2.2). 
At the conclusion of each dose group in each cohort (i.e., after study treatments and 
assessments through Day 8 or 9 are completed for subjects in that group), available data for 
that group will be reviewed as follows: 
• Investigators will receive results that are unblinded at group level (not individual 
subject level) as part of data review for Group 2 dose determinations 
(Section 5.2.2.2). 
• Subjects and study site personnel (except the TAP) will remain blinded to 
individual subject treatment assignment throughout the study. 
5.3.1. 
Unblinding of Therapy Assignments 
The blind is to be strictly maintained as described in this protocol. However, in the event of a 
medical emergency for which the treatment assignment needs to be known in order to 
manage a subject, the study blind may be broken by the Investigator or designee through the 
IWRS system. Whenever possible, the Investigator should contact the Medical Monitor prior 
to unblinding a subject, unless the emergent nature of the situation precludes this 
communication. In the latter situation, the Investigator must notify the Medical Monitor as 
soon as possible if the blind is broken for any reason. The IWRS will record the date of any 
unblinding of individual therapy assignments. The Investigator will document the details of 
the circumstances surrounding the unblinding. 
If expedited regulatory reporting is required, the report will identify the individual subject’s 
treatment assignment. When applicable, a copy of the regulatory report will be sent to 
Investigators, IRBs and Ethics Committees (ECs) in accordance with relevant regulations. 
Clinical study personnel will not be unblinded to treatment assignment when they are 
involved with these reporting responsibilities. 
5.4. 
Timing of Doses and Dose Administration 
5.4.1. 
Anticoagulants 
For use in the respective cohorts, the anticoagulant drugs will be administered as specified in 
Table 8. Each morning dose after Day 1 will be administered at a time of day ±1 hour of the 
time of administration of the morning dose on Day 1. Oral anticoagulant drugs will be 

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administered under the supervision of clinical site personnel. Additional information 
regarding dietary guidelines during the study is provided in Section 6.10.1.  
The date and time of administration of each dose of anticoagulant will be recorded in the 
Case Report Form (CRF). 
 
Table 8: 
Administration Specifications for Anticoagulant Dosing 
Cohort 
Anticoagulant 
Administration 
Amount per dose 
Dosing Specifications 
1 
Edoxaban 
60 mg (1 x 60 mg tablet) 
PO per dose 
Administer with 240 mL of water in the 
morning within 15 minutes after 
completion of breakfast 
2 
Apixaban 
10 mg (2 x 5 mg tablets) 
PO per dose 
Administer each dose with 240 mL of 
water. Morning doses will be 
administered within 15 minutes after 
completion of breakfast. Evening doses 
will follow a q 12 hour schedule, with 
no restrictions relative to food. 
3 
Rivaroxaban 
20 mg (1 x 20 mg tablet) 
PO per dose 
Administer with 240 mL of water in the 
morning within 15 minutes after 
completion of breakfast. 
5.4.2. 
Ciraparantag 
For subjects who are successfully anticoagulated (as per Section 3.1), a single IV dose of 
ciraparantag/PBO will be administered starting at the timepoint specified in Table 7 (±5 
minutes). Each dose of ciraparantag/PBO will be administered over 10 minutes (±1 minute). 
Ciraparantag/PBO will be infused into an indwelling catheter that is not attached to any other 
IV solution and will not result in dilution of the study drug. The indwelling catheter will be 
flushed with 5 mL of sterile 0.9% Sodium Chloride Injection, USP before and after 
administration of study drug. 
The date and the exact start time and stop time of the ciraparantag/PBO infusion will be 
recorded in the CRF. 
5.5. 
Duration of Dosing 
Subjects will receive doses of anticoagulant for 3 or 4 days. Each randomized subject will 
receive only a single IV dose of ciraparantag/PBO on Day 3 or Day 4. 
5.6. 
Adherence 
All study treatments (i.e., anticoagulant and ciraparantag/PBO) will be administered in the 
study unit by clinical site personnel. 
The ingestion of oral anticoagulant doses will be witnessed and verified by clinical site 
personnel. 

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6. 
STUDY PROCEDURES 
6.1. 
Screening 
The Investigator or designee will obtain written informed consent from all subjects prior to 
initiation of any study-related procedures. Screening procedures will be performed as 
specified in the Schedule of Events (Appendix A).  
As part of informed consent subjects will receive activity and dietary guidelines appropriate 
for a study involving an anticoagulant (Section 6.10). Fecal occult blood kits will be given to 
subjects at Screening (Section 6.6.1). 
For subjects who are screen failures and do not receive any doses of anticoagulant or 
ciraparantag/PBO, demographics and the reason for Screening failure will be recorded. The 
same is true for those who pass Screening, but for any reason do not subsequently receive 
any doses of anticoagulant or ciraparantag/PBO. 
Subjects who are Screen failures may be rescreened with Sponsor approval.  
Per Section 3.1, if a subject is enrolled but does not achieve sufficient anticoagulation in one 
cohort (and is not randomized), the subject may be re-screened for potential enrollment in a 
different cohort (i.e., a different anticoagulant drug). 
6.2. 
Medical History 
A medical history will be taken during the Screening period and updated on Day -1 as 
specified in the Schedule of Events (Appendix A). All medical history findings that have 
been present/active within the 5 years prior to enrollment will be recorded regardless of 
clinical relevance or presence at study start. Medical history findings that have not been 
present/active within the 5 years prior to enrollment will be recorded if deemed clinically 
relevant by the Investigator to the conduct of the study. The medical history should include 
any history of allergic reactions to drugs. 
6.3. 
Physical Examination 
The Investigator or qualified designee will perform physical examinations and measure body 
weight and height at the time points specified in the Schedule of Events (Appendix A). 
The complete physical examination will consist of the following: 
• General appearance, skin, eyes, ears, nose, throat, neck, heart, lungs, abdomen, 
extremities, vascular, and brief neurological examination (including testing of 
cranial nerves, sensation strength, deep tendon reflexes, coordination and gait). 
• If indicated based on medical history or symptoms, additional examination 
(eg, breast, external genitalia, etc.) may be performed. 
The abbreviated physical examination will consist of the following: 
• General appearance, skin, heart, lungs, and abdomen. 
Additional symptom-oriented physical examinations may be conducted at any time during 
the study if clinically indicated. Clinically relevant abnormalities prior to the first dose of 

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anticoagulant will be recorded as medical history; new or worsened clinically relevant 
abnormalities after the first dose of anticoagulant will be recorded as AEs. 
6.4. 
Vital Signs 
Subjects will have vital signs measured at the timepoints specified in the Schedule of Events 
(Appendix A). Whenever possible, vital signs will be taken using a standard procedure that 
maintains consistency in the position of each subject and method of measurement during the 
study. Subjects should be in a seated or supine position a minimum of 5 minutes prior to 
obtaining vital signs. Additional vital sign measurements may be performed at any time 
during the study if clinically indicated. 
Clinically relevant abnormalities prior to the first dose of anticoagulant will be recorded as 
medical history. New or worsened clinically relevant findings after the first dose of 
anticoagulant will be recorded as AEs. 
6.5. 
Electrocardiograms 
A 12-lead ECG will be performed at the timepoints specified in the Schedule of Events 
(Appendix A). Subjects should be in a supine or semi-reclining position a minimum of 5 
minutes prior to obtaining ECGs. Additional ECGs may be performed at any time during the 
study if clinically indicated. 
Parameters assessed will include ventricular rate (beats per minute), RR interval (msec), PR 
interval (msec), QRS duration (msec), QT interval (msec), and QTc interval (msec), as well 
as any other observed abnormalities. 
Clinically relevant abnormalities prior to the first dose of anticoagulant will be recorded as 
medical history. New or worsened clinically relevant findings after the first dose of 
anticoagulant will be recorded as AEs. 
6.6. 
Clinical Laboratory Tests 
Samples for clinical laboratory testing will be obtained at the timepoints specified in the 
Schedule of Events (Appendix A). Additional safety laboratory tests may be performed at 
any time during the study if clinically indicated. 
Laboratory parameters to be evaluated are listed below. Testing will be performed at the 
local laboratory unless otherwise specified. 
• Hematology: hematocrit, hemoglobin, platelet count, red blood cells, white blood 
cells with differential, 
• PT/international normalized ratio (INR) and aPTT. 
• Fibrinogen activity 
• Anti-fXa activity [local or central laboratory] 
• Prothrombotic markers [central laboratory]: D-dimer, prothrombin fragment 
1.2 (PF 1.2), and tissue factor pathway inhibitor (TFPI). 

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• Chemistry: ALT, albumin, AST, bilirubin (total, indirect and direct), blood urea 
nitrogen, calcium, chloride, carbon dioxide, creatinine, glucose, magnesium, 
potassium, sodium, and total protein. 
• Triglycerides and Total cholesterol (fasting will be required for collection of 
these blood samples) 
• Pregnancy Testing: serum pregnancy test; (urine pregnancy test also permitted 
on Day -1). 
• Urinalysis: dipstick (blood, glucose, ketones, protein) and microscopic 
examination if dipstick positive.  
• Viral Screen: hepatitis B surface antigen, HCV antibody test, and HIV antibody 
test. 
• Drug/Tobacco/Alcohol Screen: urine drug screen (minimum screening: opiates, 
amphetamines, methamphetamines, cocaine, cannabinoids, barbiturates, and 
nicotine/cotinine); breath or saliva test for alcohol. 
6.6.1. 
Fecal Occult Blood Testing 
Fecal occult blood kits will be given to subjects at Screening with instructions on their use 
(also see dietary guidance in Section 6.10.1). The subject should obtain a stool sample within 
2 days prior to Day -1 (preferably at a time as close as possible prior to the Day -1 visit) and 
return the kit to the study site on Day -1. If a kit is not returned, on Day -1 at the study site 
the subject must provide a stool sample, or a rectal exam for a stool sample will be required. 
Fecal occult blood test results must be negative for a subject to continue study participation 
and proceed to Study Day 1. 
Additional fecal occult blood testing may be performed at any time during the study if 
clinically indicated. 
6.6.2. 
Whole Blood Clotting Time Assessments 
WBCT Testing will be performed using the Perosphere Technologies’ PoC Coagulometer at 
all planned WBCT timepoints. At selected timepoints, WBCT also will be assessed 
simultaneously using the manual WBCT method. Blood sample collection timepoints are 
shown below (Table 9), and also in the Schedule of Events (Appendix A). 

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Table 9: 
Blood Sample Collection Timepoints for WBCT 
WBCT 
Method 
Day 1c 
Day of CIRA/PBO dose  
(time relative to CIRA/PBO dose) a 
Day after 
CIRA/ 
PBO dose  
Subsequent 
days until 
criteria met 
Pre-
dosed 
0.25 
h 
0.5 
h 
1 h 
3 h 
6 h 
8 h 
24 h 
 
Coagulometer 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X b  
Manual 
X 
X 
 
 
X 
 
 
 
X 
X b 
a Day 3 or Day 4, as per Section 3.1. Timing for samples collected after ciraparantag/PBO are determined 
relative to the end of study drug infusion. 
b WBCT testing to continue daily as needed until protocol threshold criteria are met (Section 3.1). 
c WBCT testing on Day 1 to occur prior to first dose of anticoagulant.  
d Pre-dose WBCT testing on day of ciraparantag/PBO dosing to occur at 2.75 hrs after anticoagulant for Cohort 
1 and 3.75 hrs after anticoagulant for Cohorts 2 and 3.   
Phlebotomy is an important consideration in this study because for each timepoint, blood 
samples for WBCT will be collected from a “fresh” venipuncture. These samples are not to 
be collected from any indwelling vascular catheter, because fibrin and other blood proteins 
can adsorb to and deposit on catheter walls, which may alter WBCT results. Further, each 
venipuncture should be performed at a site separate from recent venipunctures, so that the 
blood being drawn does not pass through a thrombus or recently damaged blood vessel wall.  
WBCT testing will be performed at the study site immediately after blood sample collection. 
The individual(s) performing WBCT testing at a study site must be blinded to treatment 
assignment and will not be involved in the assessment or recording of safety data. In 
addition, whenever possible the same person should perform a given WBCT test method for 
all timepoints for a given subject. 
6.6.2.1. 
WBCT Testing – Perosphere Technologies’ PoC Coagulometer 
The coagulometer is a handheld device that requires only one drop of blood and will provide 
an automated measurement of WBCT. Additional information about the coagulometer is 
provided in Section 8.5. Full details for collection of blood and the process for WBCT testing 
at the study site will be provided in a separate Procedures Manual. 
6.6.2.2. 
WBCT Testing – Manual Method 
The manual WBCT testing method involves placing a small quantity of blood in the bottom 
of reagent-free glass test tubes, which are then placed in a 37°C water bath. The evaluator 
then gently tilts the tubes at 30 second intervals until blood does not flow freely in the tube 
and a clot has visibly established. Full details for collection of blood and the process for 
WBCT testing at the study site will be provided in a separate Procedures Manual. 
6.7. 
Pharmacokinetic Assessments 
Blood samples for PK testing will be collected at the timepoints specified in the Schedule of 
Events (Appendix A). Unlike samples for WBCT testing, PK blood samples can be collected 
from an indwelling vascular catheter. Thus, in this study, the IV catheter that is used for 

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infusion of ciraparantag/PBO will be maintained whenever possible to allow for subsequent 
PK sampling through 1.5 hours after the end of ciraparantag/PBO infusion. If for any reason 
the IV catheter cannot be maintained in this time period, blood samples for PK testing can be 
taken from the venipunctures performed for WBCT testing. For the timepoints at which only 
PK blood samples are planned (i.e., 45 minutes and 1.5 hours after the end of 
ciraparantag/PBO infusion), if the IV catheter cannot be maintained, those particular PK 
samples can be omitted for that subject, in order to preserve venipuncture sites. 
PK blood samples will be sent to a central laboratory and tested for concentrations of 
ciraparantag, ciraparantag metabolite(s), and the anticoagulant being evaluated in a given 
cohort. 
Details for collection and processing, and shipping of PK samples will be provided in a 
separate Procedures Manual.  
6.8. 
Blood Volume Collected 
Over the course of the study, the total estimated volume of blood to be collected from each 
subject who completes all scheduled assessments (i.e., safety, WBCT and PK) is 
approximately 390 mL. 
6.9. 
Prior and Concomitant Medications and Therapies 
6.9.1. 
Prior Medications 
The Investigator or qualified designee will review prior medication use with the subject and 
record the use of any prescription or non-prescription drugs taken by the subject within 
14 days before Day 1. 
Note: Except for permitted contraceptives, systemic medications are prohibited within 
14 days prior to Day 1 (Section 4). Subjects should be asked specifically about use of aspirin 
and other non-steroidal anti-inflammatory drugs that could create a safety issue if used in 
conjunction with an anticoagulant. 
6.9.2. 
Concomitant Medications and Therapies 
Concomitant medication usage for a subject will be recorded for the period starting on Day 1 
and continuing throughout the study, including medications administered for management of 
any AEs. 
Concomitant medications to be recorded include prescription and non-prescription drugs, 
including vaccines, vitamins, herbal supplements, and recreational drugs. 
Non-pharmacologic therapies should be recorded if relevant to a reported AE. 
6.9.3. 
Prohibited Medications 
Non-study systemic prescription and non‐prescription drugs, including vaccines, vitamins, 
herbal supplements, recreational drugs, and other investigational drugs, are prohibited from 
Day -1 through discharge (Day 8 or 9), with the following exceptions: 
• Contraceptive therapy, other than a combination estrogen/progestin, is permitted.  

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− Note: Combination estrogen/progestin hormonal contraceptives are prohibited 
because they can increase the risk of thrombotic vascular events. 
• Acetaminophen up to 1 g every 24 hours may be administered if needed for 
management of AEs, at the discretion of the Investigator. 
If there is a clinical indication for any prohibited therapy, such as management of an 
AE/SAE, the Investigator should contact the Medical Monitor to discuss the situation and 
determine if the subject should be discontinued from study treatment and/or the study. The 
final decision on any supportive therapy rests with the Investigator and/or the subject's 
primary physician. However, the decision to continue the subject in the study requires the 
mutual agreement of the Investigator, the Sponsor, and the subject. 
6.10. 
Restrictions 
6.10.1. 
Dietary Guidelines 
Prior to Check-in on Day -1: The following instructions will be provided to subjects at 
Screening regarding their diet prior to admission to the study unit. The purpose of the 
required diet is to prevent a false positive reading for the fecal blood test. 
• Beginning Day -3 (i.e., two days before Day -1), the following foods and 
beverages should not be consumed: red or rare meat, horseradish, cantaloupe, raw 
turnips, broccoli, cauliflower, red radishes, parsnips, or alcohol (beer, wine, or 
liquor). 
• The following foods and beverages are suggested for consumption during the two 
days prior to Day -1: pasta, rice, potatoes, dairy, vegetables, and non-alcoholic 
beverages (e.g., non-alcoholic sparkling cider, ginger-ale, Sprite, Crystal-light 
with no caffeine, and whole milk [cow, goat, or soy]). 
During the Study: Meals and snacks will be provided by the study site during the domiciled 
period. Among the anticoagulant drugs (edoxaban, apixaban, or rivaroxaban), only 
rivaroxaban has a requirement to be administered with food as per prescribing information 
(Janssen Pharmaceuticals, 2016). Apixaban and edoxaban do not have dosing restrictions 
with respect to food. However, for consistency across cohorts and to minimize the chance for 
interruption of the strict schedule of blood draws, the doses of anticoagulants in all cohorts 
will follow the following schedule: 
• All morning doses of anticoagulant (edoxaban, apixaban, or rivaroxaban) will be 
administered within 15 minutes after completion of breakfast.  
• On study days other than the ciraparantag/PBO dosing day, meals after breakfast 
will follow a standardized schedule for the study unit. For the apixaban cohort, 
the evening doses of apixaban will be administered according to the q 12 hour 
schedule, with no restrictions relative to food. 
• On the ciraparantag/PBO dosing day following the anticoagulant dose, subjects 
will fast (except for water ad libitum) until completion of the blood draw at 1 hour 
post-ciraparantag/PBO (an estimated fasting period of no more than 6 hours). 
Otherwise, meals will follow a standardized schedule for the study unit. 

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• The calories from fat for each day during the domiciled period will not exceed 
30% per day. 
• No alcohol may be consumed for the duration of the domiciled period. 
6.10.2. 
Activity Guidelines 
While domiciled, subjects will be encouraged to engage in regular, low level exercise (such 
as walking laps within the study unit). During this time, subjects will be advised against 
using manual razors and dental flosses; electric razors and soft toothbrushes will be allowed. 
Throughout the study (from Screening through study completion) subjects will be advised 
against performing any activities that are strenuous or outside of their normal living 
activities. No tobacco or nicotine products may be used for the duration of the study. 
6.11. 
Discontinuation from Treatment or Study 
A subject may choose to discontinue study treatment and/or withdraw from the study at any 
time. Subjects who become pregnant or develop a condition which contraindicates the use of 
anticoagulant during the course of the study are to be withdrawn from study treatment. In the 
absence of a medical contraindication, every effort should be made by the Investigator to 
encourage subjects who prematurely discontinue treatment to remain in the study as 
appropriate and, at a minimum, follow the subject for safety data collection. 
6.11.1. 
Discontinuation from Study Drug Treatment 
A subject may be discontinued prematurely from study drug treatment (either anticoagulant 
or ciraparantag/PBO) for the following reasons: 
• AE 
• Withdrawal by subject (specify reason in the Case Report Form [CRF]) 
• Lost to Follow-up 
• Pregnancy 
• Physician decision (i.e., Investigator decision – specify reason in the CRF) 
• Sponsor decision (specify reason in the CRF) 
• Other (specify reason in the CRF) 
6.11.2. 
Discontinuation from Study 
A subject may be discontinued prematurely from the study (in its entirety) for the following 
reasons: 
• Insufficient anticoagulation (Section 3.1) 
• AE 
• Withdrawal by subject (specify reason in the CRF) 
• Lost to Follow-up 

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• Death 
• Physician decision (i.e., Investigator decision – specify reason in the CRF) 
• Sponsor decision (specify reason in the CRF) 
• Other (specify reason in the CRF) 
6.11.3. 
Data Collection and Follow-up for Withdrawn Subjects 
If a subject is discontinued prematurely from treatment or from the study, the reason for 
discontinuation will be collected in the CRF. 
For subjects who discontinue from the study on Day 3 or Day 4 because of insufficient 
anticoagulation, subjects should have a physical examination performed and the Investigator 
should review results of local safety laboratory results for that day. These subjects may be 
discharged from the study unit later that day provided that WBCT results are ≤120% of BL 
(based on the coagulometer) and ≤110% of BL (based on manual WBCT), and the 
Investigator determines that no additional safety monitoring is required. Otherwise, the 
subject will remain domiciled and on subsequent days will have procedures performed for 
the follow-up days as specified in the Schedule of Events (Appendix A) until these criteria 
are met. 
For subjects who discontinue from the study for reasons other than insufficient 
anticoagulation, withdrawal of consent, lost to Follow-up, or death, a reasonable effort 
should be made to complete certain study procedures at or near the time of discontinuation, 
as follows: 
• Complete any remaining procedures (not already performed on that day) as 
specified for the final follow-up day (i.e., Day “FU-5”) in the Schedule of Events 
(Appendix A).  
Any AEs that are present at the time of discontinuation/withdrawal should be followed in 
accordance with the safety requirements. 
If a subject is lost to Follow-up, every reasonable effort must be made by the study site 
personnel to contact the subject and determine the reason for discontinuation/withdrawal. 
6.11.4. 
Subject Replacement 
Given the study objectives of characterizing the efficacy and safety of ciraparantag in 
generally healthy subjects in a tightly controlled setting, additional subjects will be enrolled 
as described below in order to achieve a full target dataset for each cohort. 
For the following situations (i.e., subjects who are not randomized), an additional subject will 
be enrolled as needed to reach target randomization numbers, and each will receive a new 
subject identification number: 
• Any subject who discontinues prior to completion of anticoagulant dosing  
• Any subject who completes anticoagulant dosing, but does not achieve a 
sufficient level of anticoagulation prior to ciraparantag/PBO dosing (Section 3.1) 

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For any subject who is randomized, but does not receive ciraparantag/PBO, an additional 
subject will be enrolled. This subject will receive a new subject identification number and, if 
eligibility requirements are met, will be randomized. 
7. 
ADVERSE EVENTS 
The Investigator is responsible for monitoring of subjects for AEs/SAEs over the assessment 
period as specified in the Schedule of Events (Appendix A). Each AE/SAE will be evaluated 
as described in Section 7.2. Treatment of any AE/SAE will be managed by a physician. If 
any aspect of evaluation or treatment of an AE/SAE is performed by a physician who is not 
part of the study team (e.g., either at the study site or an external medical facility) the 
Investigator will ensure that the appropriate party is contacted as promptly as possible to 
collect the relevant information and documentation to complete the protocol-required 
assessment of each AE/SAE. 
7.1. 
Definitions 
7.1.1. 
Adverse Event  
As per GCP guidelines, an AE is any untoward medical occurrence in a patient 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), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether 
or not related to the medicinal (investigational) product. 
AEs will include (1) any new medical condition (sign/symptom/disease) that occurs during 
the AE reporting period, or (2) any preexisting condition that worsens in severity or 
frequency or changes in character during the AE reporting period. 
7.1.2. 
Serious Adverse Event 
An SAE is defined as an AE that, in the view of either the Investigator or Sponsor, meets any 
of the following criteria: 
• Results in death 
• Is a life-threatening AE 
− A life-threatening AE is defined as an AE that in the view of either the 
Investigator or Sponsor, places the patient or subject at immediate risk of 
death. It does not include an AE that, had it occurred in a more severe form, 
might have caused death. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
(except hospitalization for elective procedures for a pre-existing condition that has 
not worsened, admission to a nursing home or rehabilitation facility, or social 
admissions) 
• Results in persistent or significant disability or incapacity (substantial disruption 
of the ability to conduct normal life functions; it does not include experiences of 

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relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, or accidental trauma [e.g., sprained ankle] that may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption) 
• Is a congenital anomaly or birth defect (i.e., an adverse outcome in a child or fetus 
of a female subject exposed to the study product) 
• Important medical events that do not meet any of the above criteria may be 
considered serious when, based upon appropriate medical judgment, they 
jeopardize the subject and may require intervention to prevent one of the other 
outcomes listed in this definition 
7.2. 
Adverse Event Evaluation and Classification 
All AEs will be assessed by the Investigator. Information to be recorded in the CRF will 
include a description of the event, date and time of onset, date and time of resolution, and 
classification of AEs by intensity (severity), causality (relationship to the study drug[s]), 
seriousness, outcome, and action taken. Subjects with AEs will be followed until the event(s) 
are either resolved or assessed as stable, or until it is determined that no further information 
will become available, or the subject is lost to follow-up. 
7.2.1. 
Intensity (Severity) 
The intensity (severity) of each AE will be assessed using the guidelines below: 
• Mild: Does not interfere with usual activities, easily tolerated, requires no 
treatment. 
• Moderate: Somewhat interferes with usual activities, may cause discomfort, may 
require treatment. 
• Severe: Significantly interferes with usual daily activities, may be incapacitating, 
may require treatment. 
Severity of an event is not the same as seriousness. Regardless of severity rating, an AE is 
considered serious if it meets the criteria for an SAE (Section 7.1.2). 
7.2.2. 
Causality 
The relationship between the AE and study drugs (i.e., separate assessments for relationship 
to ciraparantag/PBO and to anticoagulant) will be determined as one of the following:  
• Related 
• Possibly Related 
• Unlikely Related 
• Not Related 
For analysis purposes, AEs assessed as Related or Possibly Related by the Investigator will 
be considered as "Related" events, while those assessed as Unlikely Related or Not Related 
will be considered as "Not related" events.  

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Causality will be determined based on clinical judgment and the following guidelines: 
Related: 
There is a reasonable possibility that the study product caused or contributed to the AE (e.g., 
the AE follows a reasonable temporal sequence from the study product administration, and 
cannot be reasonably explained by other factors such as the disease under study, concurrent 
diseases, or concomitant medications) or the AE follows a reasonable temporal sequence 
from the study product administration and represents a known reaction to the product, others 
products in its class, or is predicted by the known pharmacological properties of the product. 
Further, the AE resolves with discontinuation of the study product and/or recurs with 
rechallenge, if applicable. 
Possibly Related: 
There is a reasonable possibility that the study product caused or contributed to the AE (i.e. 
there is some evidence to suggest a causal relationship, such as the AE occurred within a 
reasonable time after study product administration). However, the influence of other factors 
may have contributed to the event (e.g., the disease under study, concurrent diseases, or 
concomitant medications). 
Unlikely Related: 
The AE’s temporal relationship to study product administration makes a causal relationship 
improbable (e.g., the AE did not occur within a reasonable time after study product 
administration), and/or other factors (e.g., the disease under study, concurrent diseases, or 
concomitant medications) provide a plausible explanation. 
Not Related: 
There is no reasonable possibility that the study product caused or contributed to the AE 
(e.g., the AE does not follow a reasonable temporal sequence from study product 
administration), or can be reasonably explained by other factors (e.g., the disease under 
study, concurrent diseases, or concomitant medications). 
7.2.3. 
Adverse Event Recording Guidelines 
To improve the quality and consistency of safety data, recording of AEs/SAEs in the CRF 
should follow these general guidelines: 
• Standard English medical terminology should be used rather than colloquial 
expressions or abbreviations. 
• Whenever possible, the AE should be evaluated and reported as a diagnosis rather 
than as individual signs or symptoms.  If a definitive diagnosis is not possible, the 
individual signs and symptoms should be recorded. 
• If an AE requires a surgical or diagnostic procedure, the illness leading to the 
procedure should be recorded as the AE, not the procedure itself. 
• For deaths, whenever possible, the underlying or immediate cause of death should 
be reported as an SAE. Death should be recorded as an outcome of an SAE, not 
an SAE in itself. 

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7.3. 
Serious Adverse Event Reporting 
The Investigator and Sponsor are responsible for determining whether an event should be 
classified as serious. If in the opinion of the Investigator, the AE meets the criteria of an 
SAE, the SAE is to be reported to the Sponsor or Sponsor’s designee. All SAEs, regardless 
of causality, must be reported. SAEs must be reported from the time the Informed Consent 
Form (ICF) is signed until 30 days after the last dose of study drug. SAEs considered related 
to study drug that occur after the specified Follow-up period should also be reported.  
For expedited reporting purposes, SAEs assessed as Related or Possibly Related by the 
Investigator will be considered as "Related" events, while those assessed as Unlikely Related 
or Not Related will be considered as "Not related" events. 
7.3.1. 
Study Sponsor Notification by Investigator 
Any SAEs, regardless of causality, must be reported to the Sponsor or Sponsor’s designee 
within 24 hours of the Investigator or any site staff’s knowledge of the event.  
Within 24 hours after receipt of additional relevant information, the Investigator must 
provide Follow-up information on the SAE along with any additional relevant documentation 
(e.g., test results, physician narrative, discharge summary, autopsy findings) that will assist in 
the understanding of the event.  
7.3.2. 
Institutional Review Board/Ethics Committee Notification 
The Investigator must report all SAEs (including Follow-up information) to the IRB/EC in 
accordance with IRB/EC requirements. Copies of each report and documentation of IRB/EC 
notification and receipt will be kept in the site’s Regulatory Binder. 
7.3.3. 
Serious Adverse Event Follow-up 
The Investigator must respond to all queries received from the Sponsor and must submit 
Follow-up reports for all SAEs to the Sponsor or Sponsor’s designee regarding the subject’s 
subsequent course. All SAEs must be followed until: 
• The SAE is Resolved, or 
• Stabilized (e.g., in the case of persistent impairment), or 
• Subject death, or 
• Subject is lost to follow-up 
SAE Follow-up information should be recorded in the source documents and SAE/CRF 
forms as applicable. 
7.4. 
Pregnancy Reporting 
Should a female subject or female partner of a male subject become pregnant at any time 
during the study, the Investigator must notify the Sponsor within 24 hours after learning 
about the pregnancy. The Sponsor will request Follow-up information regarding the course 
of the pregnancy and its outcome. Voluntary consent must be obtained from a female subject 
or female partner of a male subject (and/or legally authorized representative if the subject is 

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mentally incompetent or physically incapacitated) before any pregnancy-related Follow-up is 
obtained. 
Pregnancy, in and of itself, is not considered an AE, unless there is suspicion that the study 
product may have interfered with the effectiveness of a contraceptive medication or method. 
However, any pregnancy complication or elective termination of a pregnancy for medical 
reasons will be recorded as an AE or SAE and will be followed accordingly. A spontaneous 
abortion is considered to be an SAE. 
8. 
CLINICAL TRIAL MATERIALS 
8.1. 
Study Drug Supplies 
8.1.1. 
Ciraparantag and Placebo 
Supplies of IV ciraparantag and the PBO comparator are described in Table 10. 
Table 10: 
Identity of Investigational Product 
Study Drug 
Formulation 
Ciraparantag for IV injection (supplied by the 
sponsor) 
Each single-use clear vial contains 30.5 mL of 
sterile, isotonic, pH neutral solution for 
injection containing 6 mg/mL ciraparantag (10 
mg/mL ciraparantag acetate) + 6.8 mg/mL 
sodium chloride.  
Placebo for IV injection (supplied by the study 
site) 
Sterile 0.9% Sodium Chloride Injection, USP. 
8.1.2. 
Anticoagulants 
All anticoagulant drugs will be supplied by the sponsor. For use in the respective cohorts, the 
anticoagulant drugs will be provided as follows: 
• Savaysa® (edoxaban; Daiichi Sankyo, Inc.): 60 mg tablets for oral administration 
• Eliquis® (apixaban; Bristol-Myers Squibb): 5 mg tablets for oral administration 
• Xarelto® (rivaroxaban; Janssen Pharmaceuticals, Inc): 20 mg tablets for oral 
administration 
8.2. 
Packaging and Labeling 
8.2.1. 
Ciraparantag 
Vials will be labeled for clinical study use with identifying information such as the lot 
number, storage conditions, and other details as appropriate.   

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8.2.2. 
Placebo 
The PBO in this study is sterile 0.9% Sodium Chloride Injection, USP, which will be 
provided by the study site in amounts needed to match the administered volume of 
ciraparantag at any given dose level. 
8.2.3. 
Anticoagulants 
Each of the commercially available anticoagulant drugs (edoxaban, apixaban, or rivaroxaban) 
will be provided by the Sponsor for the respective cohort. 
8.3. 
Storage and Accountability 
Study drugs provided to participating clinical sites will be stored, dispensed, and recorded in 
accordance with this protocol and the Pharmacy Manual. Only subjects enrolled in the study 
may receive study drug. 
8.3.1. 
Storage  
Ciraparantag will be stored refrigerated at 2 to 8°C (36 to 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 to 8°C (36 to 46°F) until prior to 
administration. 
PBO (sterile 0.9% Sodium Chloride Injection, USP) will be provided by the study site and 
stored at room temperature prior to administration. 
Anticoagulant drugs should be stored according to their prescribing information (i.e., product 
labels).   
Drug supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label. Refer to the Pharmacy Manual for additional guidance on study drug 
storage. 
8.3.2. 
Study Drug Accountability  
The Investigator or his/her designee will maintain accurate records of the receipt of all study 
drugs. In addition, accurate records will be kept regarding when and how much of each study 
drug is dispensed, used and unused by each study subject. Study center personnel should not 
dispose of any used or unused study drug until drug accountability is performed by the 
Sponsor or its designee. At the conclusion of the study, any unused study drug will be 
returned to the Sponsor or destroyed by the site pursuant to written authorization by the 
Sponsor and applicable federal and state regulations. 
8.4. 
Preparation of Study Drug 
The study drugs must be prepared by qualified individuals, assigned by the Investigator. 
The anticoagulant drugs will be administered in open-label fashion. Anticoagulant drug 
supplies can be handled by members of the study team who are qualified to store and 
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An unblinded TAP will prepare the IV ciraparantag/PBO for each subject. The TAP must not 
be involved in the enrollment of subjects or in the performance or recording of any safety or 
efficacy assessments (including performance of any WBCT testing). Qualifications of the 
TAP and detailed instructions for the storage, handling, and preparation of study drugs will 
be provided in the Pharmacy Manual. 
8.5. 
Point-of-Care Coagulometer 
The coagulometers to be used in this study are handheld devices supplied by Perosphere 
Technologies, Inc. that will provide an automated measurement of WBCT (Section 6.6.2). 
Each device uses single-use glass cuvettes onto which a small drop of blood is placed before 
insertion into the device. WBCT (based on fibrin clot formation) is measured using an 
infrared light beam; results are displayed on the device. 
Instructions for use and maintenance of coagulometers are provided in a separate Procedures 
Manual. Study coagulometers will be returned to the Sponsor at the completion of the study. 
Specific instructions regarding return of coagulometers will be provided separately. 
9. 
STATISTICAL PLAN 
9.1. 
Analysis Populations 
The Enrolled Population will include all subjects who remain eligible after the Day -1 
assessments (ie, are not Screen failures) and are admitted to the study unit for the domiciled 
study period. 
The Safety Population will include all randomized subjects who receive at least one dose of 
ciraparantag/PBO. Subjects will be analyzed based on the actual treatment they received. Full 
safety analyses will be performed on this population. 
The Anticoagulant Population will include all subjects in the Enrolled Population who 
receive at least one dose of anticoagulant (edoxaban, apixaban, or rivaroxaban). Limited 
safety analyses will be performed on this population. 
The Efficacy Population will include those randomized subjects who receive the planned 
single dose of ciraparantag/PBO and have at least one subsequent WBCT measurement. 
Subjects will be analyzed based on their randomized treatment assignment. Efficacy analyses 
will be performed on this population. 
The PK Populations (separately for ciraparantag and each anticoagulant) will include all 
subjects who receive at least one administration of ciraparantag or anticoagulant, 
respectively, and provide sufficient data to estimate at least one PK parameter without any 
protocol deviations with the potential to affect these measurements. These populations will 
be used for PK analyses. 

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9.2. 
Study Endpoints 
9.2.1. 
Efficacy Endpoints 
For all endpoints listed below, analyses will be based on WBCT results obtained with the 
coagulometer unless otherwise specified.  
9.2.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is achieving a WBCT ≤120% of BL within 1 hour after 
administration of ciraparantag/PBO, which is subsequently sustained after 1 hour through at 
least 6 hours after ciraparantag/PBO dosing. 
9.2.1.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 
1. Achieving WBCT ≤115% of BL within 1 hour after administration of 
ciraparantag/PBO, which is subsequently sustained after 1 hour through at least 6 
hours after ciraparantag/PBO dosing.  
2. Achieving WBCT ≤110% of BL within 1 hour after administration of 
ciraparantag/PBO, which is subsequently sustained after 1 hour through at least 6 
hours after ciraparantag/PBO dosing.  
3. Achieving WBCT ≤120% of BL within 30 minutes after administration of 
ciraparantag/PBO, which is subsequently sustained after 30 minutes through at least 6 
hours after ciraparantag/PBO dosing. 
4. Achieving WBCT ≤115% of BL within 30 minutes after administration of 
ciraparantag/PBO, which is subsequently sustained after 30 minutes through at least 6 
hours after ciraparantag/PBO dosing. 
5. Achieving WBCT ≤110% of BL within 30 minutes after administration of 
ciraparantag/PBO, which is subsequently sustained after 30 minutes through at least 6 
hours after ciraparantag/PBO dosing. 
6. Achieving a WBCT ≤120% of BL within 15 minutes after administration of 
ciraparantag/PBO, which is subsequently sustained after 15 minutes through at least 6 
hours after ciraparantag/PBO dosing.  
7. Achieving a WBCT ≤115 of BL within 15 minutes after administration of 
ciraparantag/PBO, which is subsequently sustained after 15 minutes through at least 6 
hours after ciraparantag/PBO dosing.  
8. Achieving a WBCT ≤110% of BL within 15 minutes after administration of 
ciraparantag/PBO, which is subsequently sustained after 15 minutes through at least 6 
hours after ciraparantag/PBO dosing. 
9.2.1.3. 
Tertiary Efficacy Endpoints 
The tertiary efficacy endpoints are as follows: 

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• Achieving a WBCT ≤120% of BL at each of the planned WBCT assessment 
timepoints: 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 8 hours and 24 hours 
after administration of ciraparantag/PBO (7 endpoints). 
• Achieving a WBCT ≤115% of BL at each of the planned WBCT assessment 
timepoints: 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 8 hours and 24 hours 
after administration of ciraparantag/PBO (7 endpoints). 
• Achieving a WBCT ≤110% of BL at each of the planned WBCT assessment 
timepoints: 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 8 hours and 24 hours 
after administration of ciraparantag/PBO (7 endpoints). 
• Achieving a WBCT ≤120%, ≤115%, or ≤110% of BL at 1 hour after 
administration of ciraparantag/PBO by the manual method. 
• WBCT (as a percentage of BL) at each of the planned WBCT assessment 
timepoints: 15 minutes, 30 minutes, 1 hour, 3 hours, 6 hours, 8 hours and 24 hours 
after administration of ciraparantag/PBO (7 endpoints). 
• Change from Day 3/Day 4 pre-ciraparantag/PBO WBCT (as a percentage of BL) 
to each of the planned WBCT assessment timepoints: 15 minutes, 30 minutes, 
1 hour, 3 hours, 6 hours, 8 hours and 24 hours after administration of 
ciraparantag/PBO (7 endpoints). 
9.2.2. 
Safety Endpoints 
• Treatment-emergent AEs (TEAEs) 
• Treatment-emergent SAEs 
• Changes from BL in vital signs 
• Changes from BL in clinical laboratory evaluations 
AEs with onset during the anticoagulant administration period also will be summarized. 
9.2.3. 
Pharmacokinetic Parameters 
Individual subject plasma concentrations of ciraparantag and its primary metabolite (BAP) 
and each anticoagulant (edoxaban, apixaban, or rivaroxaban) will be listed and summarized 
using descriptive statistics (N, arithmetic mean, standard deviation, coefficient of variation, 
geometric mean, and geometric coefficient of variation) for each time point. The PK 
parameters (Table 11) will be computed using non-compartmental analysis using appropriate 
software and summarized using descriptive statistics (N, arithmetic mean, standard deviation, 
coefficient of variation, minimum, median, maximum, geometric mean, and geometric 
coefficient of variation). The relationships between PK parameters and dose will be 
evaluated and summarized. 
 
 

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Table 11: 
PK Parameters  
Parameter Units 
Description 
Ciraparantag/ 
BAP 
Anticoagulant 
Cmax 
ng/mL 
Maximum concentration in sampled 
matrix, obtained directly from 
observed concentration vs time data 
X 
X 
C24 
ng/mL 
Observed quantifiable analyte 
concentration in the sampled matrix at 
24-hour time point 
 
X 
tmax 
H 
Time of Cmax, obtained directly from 
the observed concentration vs time 
data 
X 
X 
AUC(0-last) 
ng⋅h/mL Area under the concentration-time 
curve, from time zero to the last 
quantifiable concentration (Clast) 
X 
 
AUC(0-inf)  
ng⋅h/mL Area under the concentration-time 
curve in sampled matrix from time 
zero (predose) extrapolated to infinite 
time by addition of the last quantifiable 
concentration divided by the 
elimination rate constant: 
AUC(0-last) + Clast/λz 
X 
 
AUC(0-24) 
ng⋅h/mL Area under the concentration-time 
curve in sampled matrix over a 24-
hour dosing interval 
 
X 
AUC(0-12) 
ng⋅h/mL Area under the concentration-time 
curve in sampled matrix over a 12-
hour dosing interval 
 
X 
λz 
1/h 
Apparent terminal rate constant 
X 
 
t1/2 
H 
Apparent terminal half-life, determined 
as ln(2)/λz 
X 
 
CL 
L/h 
Systemic clearance after IV dosing 
X 
 
CL/F 
L/h 
Systemic clearance after oral dosing 
 
X 
Vz 
L 
Volume of distribution after IV dosing 
X 
 
MRCmax 
 
Metabolite to parent ratio of Cmax 
X 
 
MRAUC(0-
last) 
 
Metabolite to parent ratio of AUC(0-last) 
X 
 
MRAUC(0-
inf) 
 
Metabolite to parent ratio of AUC(0-inf) 
X 
 

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9.3. 
Statistical Methods  
9.3.1. 
General Considerations 
A detailed statistical analysis plan will be developed separately and finalized prior to 
randomization of the first subject. Deviations from the protocol-planned analyses will be 
noted.  
The statistical analysis of the data obtained from this study will be performed using SAS® 
Version 9.4 or higher. All statistical tests will be performed at the 0.05 (two-sided) 
significance level, unless otherwise noted. 
The data collected in this study will be documented using summary tables and subject data 
listings. Continuous variables will be summarized using descriptive statistics, specifically the 
number of observations, mean, median, standard deviation, minimum and maximum. PK 
parameters will be summarized using these same statistics, plus the coefficient of variation, 
the geometric mean, and the geometric coefficient of variation. Categorical variables will be 
summarized by frequencies and percentages. The analysis of both efficacy and safety 
parameters will be conducted for each cohort (i.e., each anticoagulant drug) separately. Each 
cohort consists of up to three treatment groups, i.e., one or two active doses, and one placebo 
group including all subjects randomized to placebo. Each active dose will be compared 
against placebo. 
 
Baseline characteristics will be summarized using descriptive statistics or frequencies and 
percentages, as appropriate. No statistical hypothesis tests will be performed on these 
characteristics. 
9.3.2. 
Efficacy Analyses 
9.3.2.1. 
Primary Efficacy Endpoint Analyses 
The primary efficacy endpoint is achieving WBCT ≤120% of BL within 1 hour after 
administration of ciraparantag/PBO, which is subsequently sustained after 1 hour through at 
least 6 hours after ciraparantag/PBO dosing.  
The null hypothesis for this endpoint is that the true (success) proportions of subjects meeting 
the primary efficacy endpoint are equal for the two treatments, and the alternative hypothesis 
is that they are unequal. The statistical hypotheses are as follows: 
H0: π1= π2  
 
and 
 
H1: π1≠ π2, 
where π1 and π2 are the true success proportions for ciraparantag and PBO, respectively. 
This endpoint will be summarized by cohort and treatment group (ciraparantag dose vs. 
PBO) using frequencies and percentages and an exact (Clopper-Pearson) 95% confidence 
interval (CI) for the true percentage based on the binomial distribution. The difference in 
percentages between treatments (ciraparantag dose vs. PBO) will be tested using the 

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Boschloo’s test (Boschloo, 1970). A 95% CI for the difference in percentages will be 
constructed by the Miettinen and Nurminen method (Newcombe, 1998). 
 
In addition, the Cochran-Mantel-Haenszel Test, with stratification by age group, will be used 
to compare each active dose with placebo as a sensitivity analysis.  
9.3.2.2. 
Secondary Efficacy Endpoint Analyses 
The secondary efficacy endpoints are as stated in Section 9.2.1.2. These endpoints will be 
analyzed in the same manner as the primary efficacy endpoint.  
9.3.2.3. 
Tertiary Efficacy Endpoint Analyses 
The tertiary efficacy endpoints are as stated in Section 9.2.1.3. These endpoints are 
exploratory in nature and are intended to characterize effects at each of the specified WBCT 
assessment timepoints.  
The first four sets of tertiary efficacy endpoints, achieving a WBCT ≤120%, ≤115% or 
≤110% of BL at each of the planned post-BL WBCT assessment timepoints by coagulometer 
or the manual method will be analyzed in the same manner as the primary efficacy endpoint.  
The fifth and the sixth sets of tertiary efficacy endpoints will be summarized by cohort and 
treatment using descriptive statistics. In addition, the differences between ciraparantag doses 
and PBO will be evaluated using an Analysis of Covariance (ANCOVA) model.  The 
ANCOVA model will include treatment as fixed effects, and baseline value and the 
stratification factor as covariates. A summary of the results of the ANCOVA, and pairwise 
differences in means and the corresponding 95% CI will be presented. 
9.3.2.4. 
Correlation of WBCT Results Between Coagulometer and Manual Method  
Correlation between WBCT as percent of BL obtained with coagulometer and manual 
method will be analyzed by fitting a simple linear regression model between these two sets of 
results. The value of R2 will be presented. Scatter plot of coagulometer results vs. manual 
method results will be provided along with the regression line. In addition, the agreement 
between these two methods with respect to the efficacy endpoints at 1 hour after 
administration of ciraparantag/PBO will be assessed.   
9.3.3. 
Safety Analyses 
All safety summaries will be presented by cohort and treatment (i.e., ciraparantag and PBO), 
and also by pooled ciraparantag vs. pooled PBO across cohorts. 
9.3.3.1. 
Adverse Events 
All AEs and SAEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 23.0 or later. TEAEs will be defined as those AEs that begin or worsen 
on or after the start of double-blind study drug administration (ciraparantag or PBO). 
The number and percentage of subjects with at least one TEAE, at least one serious TEAE, at 
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be presented by cohort and treatment group. AEs that are related or possibly related to study 
drug, or for which the relationship is missing, will be considered study drug related. 
The numbers and percentages of subjects having a non-treatment-emergent AE and a non-
treatment-emergent SAE in each System Organ Class (SOC) and having each individual type 
of non-treatment-emergent AE and SAE (Preferred Term) will be presented by cohort and 
treatment group. 
The number and percentage of subjects having a TEAE in each System Organ Class (SOC) 
and having each individual type of TEAE (Preferred Term) will be presented by cohort and 
treatment group. TEAEs will also be summarized at the event level by SOC/Preferred Term 
and severity and by SOC/Preferred Term and relationship. 
All of these AE analyses will be performed on the Safety Population. 
In addition, the number and percentage of subjects having an AE in each SOC and having 
each individual type of AE (Preferred Term) will be presented for the Anticoagulant 
Population prior to the treatment of ciraparantag/PBO. 
9.3.3.2. 
Vital Signs 
Vital signs, including systolic and diastolic blood pressure, heart rate, and respiration rate 
will be summarized using descriptive statistics by cohort and treatment group at each time 
point for subjects in the Safety Population. The change from BL to each post-
ciraparantag/PBO dose time point also will be summarized.  
9.3.4. 
Laboratory Tests 
All quantitative laboratory test results, including serum chemistry, hematology, 
prothrombotic markers, and urinalysis, will be summarized by cohort, treatment, test and 
time point using descriptive statistics for subjects in the Safety Population. Changes from BL 
to post-BL timepoints also will be summarized. 
9.3.5. 
Definition of Baseline Measurements 
Unless otherwise specified, BL values will be defined as the last assessment prior to 
administration of ciraparantag/PBO. However, BL WBCT will be defined as the Day 1 value 
(obtained prior to the first dose of anticoagulant). 
9.3.6. 
Handling of Missing Data 
For the binary efficacy endpoints, missing outcome will be imputed as non-responder.  
9.3.7. 
Sensitivity Analyses  
For the binary efficacy endpoints, the Cochran-Mantel-Haenszel Test, with stratification by 
age group, will be used to compare each active dose with placebo as a sensitivity analysis.  
9.3.8. 
Adjustment for Multiple Comparisons 
Each group in each cohort will be treated as a standalone sub-study and analyzed separately. 
Within each group in each cohort, if the primary efficacy endpoint is positive, i.e., p-value < 

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0.05, the study will be declared positive, and we will test the secondary efficacy endpoints in 
three reversal target clusters in parallel as shown in Table 12. Because a goal of the study is 
to verify the dose and the endpoints for future evaluations of ciraparantag, we don’t plan to 
control the multiplicity for the entire set of 8 secondary endpoints. Instead, the testing 
approach controls the multiplicity for each reversal target cluster separately.   
Table 12: 
Hypothesis Testing Paradigm of The Secondary Efficacy Endpoints  
For Each Dose Group Within Each Cohort 
<120% Reversal Target 
Cluster 
<115% Reversal Target 
Cluster 
<110% Reversal Target 
Cluster 
 
 
Achieved within 30 minutes 
and subsequently sustained 
from 30 minutes to 6 hours 
Achieved within 1 hour and 
subsequently sustained from 1 
hour to 6 hours 
Achieved within 1 hour and 
subsequently sustained from 1 
hour to 6 hours 
if p-value <0.05 
↓ 
if p-value <0.05 
↓ 
Achieved within 30 minutes 
and subsequently sustained 
from 30 minutes to 6 hours 
Achieved within 30 minutes 
and subsequently sustained 
from 30 minutes to 6 hours 
if p-value <0.05 
↓ 
if p-value <0.05 
↓ 
if p-value <0.05 
↓ 
Achieved within 15 minutes 
and subsequently sustained 
from 15 minutes to 6 hours 
Achieved within 15 minutes 
and subsequently sustained 
from 15 minutes to 6 hours 
Achieved within 15 minutes 
and subsequently sustained 
from 15 minutes to 6 hours 
9.3.9. 
Sample Size Justification 
Assuming true response rates for the primary efficacy endpoint of 78% and 5% in the first 
active dose group and the placebo group, respectively, 18 subjects with a 2:1 randomization 
ratio will have 91% power at 0.05 two-sided significance level based on Boschloo’s test. 
Assuming true response rates of 66% and 5% in the second active dose group and the 
placebo group, respectively, 12 subjects in each group will have 94% power. Note: For the 
second active dose group, the treatment allocation ratio will be 2:1 (ciraparantag:placebo), 
but placebo subjects will be pooled within each cohort, so the analyses will be comparisons 
of two groups of 12 subjects each. 
10. 
QUALITY ASSURANCE 
To assure quality and consistent study data, procedures will only be carried out by the 
Principal Investigator or trained staff under the direction of the Principal Investigator. Study 
related procedures will be exercised in accordance with written materials (e.g., Procedures 

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Manual, Laboratory Manual, Pharmacy [study drug preparation] Manual, and CRF 
completion guidelines). 
10.1. 
Data Handling, Record Keeping, and Direct Access to Data 
The Investigator is responsible for maintaining the following: 
• Site Staff Responsibility Log showing the signatures and handwritten initials of 
authorized study staff and responsibilities. 
• A Screening Log with all subjects who were screened for the study. 
• A Subject Identification Log with subject identification numbers, names, and 
dates of birth to positively identify each subject enrolled in the study. 
• Accurate, complete, and up-to-date source documentation related to the study, 
including any hospital records, films, tracings, computer or electronic source data 
or documents. Source data includes all information, original records of clinical 
findings, or other activities in a clinical study necessary for the reconstruction and 
evaluation of the study and are contained in source documents. 
• Accurate, complete, and up-to-date CRFs. 
10.1.1. 
Case Report Forms 
All CRFs will be completed according to CRF completion guidelines. The Principal 
Investigator must electronically sign and date a declaration on the CRF attesting to his/her 
responsibility for the quality of all data recorded and that the data represent a complete and 
accurate record of each subject’s participation in the study. An electronic copy of the 
completed CRF will then be sent to the Investigator to be retained for their records. 
10.2. 
Monitoring, Auditing, and Inspecting 
10.2.1. 
Study Monitoring  
Study Monitors representing the Sponsor will visit study sites during the study. The 
Investigator will allocate adequate time for such monitoring activities. The Investigator will 
also ensure that the Study Monitor, or other compliance or quality assurance reviewer, is 
given access to all study-related documents and study related facilities (e.g., pharmacy, 
diagnostic laboratory, medical records, etc.), and has adequate space to conduct the 
monitoring visit. 
The Study Monitor will review ICFs and CRFs and compare them with source documents to 
verify adherence to the protocol, and to ensure complete, accurate, consistent, and timely 
collection of data. The Investigator will be asked to provide any missing information or to 
clarify any discrepancies found by the Study Monitor. 
In addition to source document verification of CRFs and ICFs, the Study Monitor will review 
the Clinical Site Regulatory Binder that is to be maintained by the Principal Investigator. 

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10.2.2. 
Data Review Team 
At the conclusion of each dose group in each cohort (i.e., after study treatments and 
assessment are completed for subjects in that group), available efficacy data (i.e., WBCT 
results) and safety data for that group will be analyzed by a data review team, which will 
consist of the Principal Investigator (or a co-investigator designee) from each study site for 
that cohort, and Sponsor team members including but not limited to the Medical Monitor and 
the study statistician. As discussed in Section 5.3, Investigators will receive results that are 
unblinded at group level (not individual subject level) as part of these data reviews. 
Specifically following analyses of Group 1 data for a given cohort, the data review team will 
determine: 
1. whether or not a second ciraparantag dose will be evaluated for that cohort 
2. if so, the ciraparantag dose to be evaluated in Group 2 for that cohort (within the dose 
range described in Section 5.2.2). 
A summary and the conclusions of each data review team meeting will be documented with 
minutes. The data review team conclusions will be forwarded in writing to the participating 
study sites before proceeding to the next group in a given cohort. Study sites may forward 
this information to their respective IRB/EC in accordance with local policies. 
10.2.3. 
Criteria for Stopping Enrollment 
Enrollment will be stopped for a cohort if any of the following occur: 
• Any subject experiences bleeding that is reported as severe or requires 
intervention with medications, blood products or a non-bedside procedure  
• Any subject experiences a serious AE (SAE)  
• Two or more subjects develop either of the following laboratory abnormalities: 
− Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 x the 
upper limit of normal 
− Total bilirubin >2 x the upper limit of normal 
If enrollment in a cohort is stopped based on findings as noted above (or any other safety 
concern identified by the Sponsor), subjects who are in the study at that time should 
discontinue study treatment (if still ongoing), but should complete other required study 
procedures including safety follow-up. The Sponsor will review all available safety data. If 
further dosing in that cohort is proposed, the findings will be presented to the Investigators 
and US FDA regulators; all must agree on the proposed dosing regimen if further dosing is to 
proceed.  
10.2.4. 
Auditing and Inspecting 
The study may be evaluated by representatives of the US FDA, and where applicable, other 
government agencies, national health agencies, and national health authorities, who also will 
be allowed access to study documents. The Investigator should promptly notify the Sponsor 

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when any inspections are scheduled, as well as providing the results of any unscheduled 
investigations performed by any regulatory authorities. 
The Investigator will permit study related monitoring, audits, and inspections by the IRB/EC, 
the Sponsor, government regulatory bodies, and compliance and quality assurance groups of 
all study related documents (e.g., source documents, regulatory documents, data collection 
instruments, study data, etc.). The Investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g., pharmacy, diagnostic laboratory, etc.). All authorized 
personnel, including health authority inspector(s), Sponsor and designees, Study/Medical 
Monitor(s), and auditor(s) will be given direct access to source data and documentation 
(e.g., medical records, laboratory results, etc.) for source data verification, provided that 
subject confidentiality is maintained in accordance with local requirements. 
Participation as an Investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance and quality assurance offices. 
10.2.5. 
Records Retention 
The Principal Investigator shall retain all study related documentation, including source data, 
source documents, CRFs, protocol and amendments, regulatory documentation and 
correspondence, ICFs, subject identification lists, and correspondence. 
It is the Investigator’s responsibility to retain essential study documents for at least 2 years 
after the last approval of a marketing application in their country and until there are no 
pending or contemplated marketing applications in their country, or at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product. These documents should be retained for a longer period if required by an agreement 
with the Sponsor. In such a case, it is the responsibility of the Sponsor to inform the 
Investigator/institution as to when these documents no longer need to be retained. 
If the Investigator leaves the institution, the records shall be transferred to an appropriate 
designee who accepts the responsibility for record retention. Written notice of transfer of 
documentation shall be provided to the Sponsor. 
11. 
ETHICAL CONSIDERATIONS 
11.1. 
Ethics  
This study will be conducted according to the Declaration of Helsinki, international standards 
of GCP, US FDA regulations, International Council for Harmonisation guidelines, and other 
applicable government regulations, and institutional research policies and procedures. 
Perosphere Pharmaceuticals, Inc. will also continue to support the principles of the 
Declaration of Helsinki. 
11.2. 
Review 
This protocol and any amendments will be submitted to an appropriate IRB/EC, in agreement 
with local legal prescriptions, for formal approval of the study conduct. The decision of the 
IRB/EC concerning the conduct of the study will be made in writing to the Investigator, and 

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a copy of this decision will be provided to the Sponsor before commencement of this study. 
The Investigator should provide a list of IRB/EC members and their affiliates to the Sponsor. 
The IRB/EC must also approve all protocol amendments prior to implementation, as well as 
changes in study status (i.e., completion or termination of a study). 
11.3. 
Investigator Responsibilities 
11.3.1. 
General Responsibilities 
All Investigators are responsible for performing the study in accordance with the protocol 
and the above guidelines and regulations, and for collecting, documenting, and reporting the 
data accurately. 
All Investigators must be familiar with the background and requirements of the study and 
with the properties of the study products as described in the current version of the 
Investigator’s Brochure or Package Insert. 
The Principal Investigator is responsible for distributing study information and 
documentation to all appropriate staff members prior to and during the course of the study as 
updated information becomes available. 
The Principal Investigator is responsible for ensuring the privacy, health, and welfare of the 
subjects during and after the clinical study and must ensure that fully functional resuscitation 
equipment and personnel trained in its use are immediately available in the event of an 
emergency. 
The Principal Investigator has the overall responsibility for the conduct and administration of 
the study at the clinical site and for contacts with the Sponsor, the IRB/EC, and local 
authorities. 
11.3.2. 
Protocol Compliance 
Except for a change intended to eliminate an immediate hazard to a study subject, the 
protocol shall be conducted as described without any changes or deviations. Any change 
must be reported immediately to the Sponsor and to the IRB/EC and/or regulatory authority 
as required by guidelines or regulation. Sites that fail to comply may be terminated. 
11.3.3. 
Protocol Amendments 
Protocol amendments will be prepared and approved by the Sponsor or designee and sent to 
the appropriate IRB/EC for review and approval. For each amendment to the protocol, the 
Investigator Protocol Agreement page will be signed by the Principal Investigator. 
Documentation of IRB/EC approval must be forwarded to the Sponsor or designee. 
If an amendment significantly alters the study design, increases potential risk to the subject, 
or otherwise affects statements in the ICF, the ICF must be revised accordingly and 
submitted to the IRB/EC for review and approval. The approved ICF must be used to obtain 
informed consent from new subjects prior to registration (unless there is a significant safety 
risk) and must be used to re-obtain informed consent from subjects already registered if they 
are affected by the amendment. 

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11.3.4. 
Subject Informed Consent  
Each subject will be provided a written ICF, describing this study and providing sufficient 
information to make an informed decision about participation in this study. 
A copy of the proposed ICF must be submitted to the Sponsor and/or designee for review 
prior to submission to the reviewing IRB/EC. The ICF must be approved by the IRB/EC and 
must contain all elements required by federal, state, local, and institutional regulations or 
requirements. Institutions in the US must be in compliance with Health Insurance Portability 
and Accountability Act of 1996 with regard to obtaining authorizations for use and disclosure 
of Protected Health Information. In countries outside the US, local privacy regulations must 
be followed. 
The study, including its goals, methods, expected benefits, and potential hazards will be 
completely explained to each prospective study subject. It will also be explained to subjects 
that they are free to refuse entry or to withdraw from the study at any time without prejudice 
to future treatment. Voluntary informed consent must be obtained from each eligible subject 
(and/or legally authorized representative if the subject is mentally incompetent or physically 
incapacitated) before any protocol-defined procedures are performed. 
The subject’s willingness to participate in this study will be documented on the IRB/EC 
approved ICF which must be signed and dated by the subject or legally acceptable surrogate, 
and the physician Investigator (Principal or sub-Investigator). The Investigator will keep the 
original ICF and a copy will be given to the subject. The process for obtaining informed 
consent should also be noted in the subject’s source documentation. 
11.3.5. 
Confidentiality Regarding Study Subjects 
The Investigator must assure that the privacy of the subjects, including their identity and all 
personal medical information, will be maintained at all times. In the CRFs and other 
documents (e.g., laboratory reports, etc.) submitted to the Sponsor, subjects will not be 
identified by name, but by an identification code (e.g., subject identification numbers). 
Personal medical information may be reviewed for the purpose of verifying data recorded in 
the CRF by the Study/Medical Monitor, Sponsor or designee, or regulatory authorities. 
Personal medical information will always be treated as confidential. 
11.3.6. 
Laboratory Accreditation 
Analyses of blood tests will be performed by the local site laboratory as appropriate. The 
laboratory facilities used for analysis of clinical laboratory samples obtained under this 
protocol will have adequate licensure and accreditation. 
11.3.7. 
Discontinuation of Study 
The Sponsor reserves the right to discontinue or terminate the study for any reason at any 
time. In addition, the study may be stopped at any time if, in the opinion of the Sponsor or 
Medical Monitor, the medical safety of subjects is being compromised. In the event of a 
discontinuation or termination, all investigative sites will immediately be notified, and in 
turn, sites must immediately notify their subjects and respective IRB/EC. 

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12. 
PUBLICATION POLICY 
The publication policy, including authorship, is in accordance with that described in the 
Clinical Trial Agreement.

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13. 
REFERENCE LIST 
Alquwaizani, M., L. Buckley, C. Adams, and J. Fanikos. 2013. 'Anticoagulants: A Review of 
the Pharmacology, Dosing, and Complications', Curr Emerg Hosp Med Rep, 1: 83-
97. 
Boehringer Ingelheim Pharmaceuticals, Inc. 2018a. "PRADAXA® (dabigatran etexilate 
mesylate), US Prescribing Information." Ridgefield, CT. 
Boehringer Ingelheim Pharmaceuticals, Inc. 2018b. "PRAXBIND® (idarucizumab) 
injection, US Prescribing Information." Ridgefield, CT, USA. 
Boschloo, R. D. . 1970. 'Raised conditional level of significance for the 2 x 2-table when 
testing the equality of two probabilities', Statistica Neerlandica, 24: 1-9. 
Bristol-Myers Squibb Company. 2016. "ELIQUIS® (apixaban), US Prescribing 
Information." Princeton, NJ. 
Connolly, S. J., M. Crowther, J. W. Eikelboom, et al. 2019. 'Full Study Report of Andexanet 
Alfa for Bleeding Associated with Factor Xa Inhibitors', N Engl J Med, 380: 1326-35. 
Daiichi Sankyo, Inc. 2017. "SAVAYSA® (edoxaban),US Prescribing Information." 
Parsippany, NJ, USA. 
Frost, C., Y. Song, Y. C. Barrett, et al. 2014. 'A randomized direct comparison of the 
pharmacokinetics and pharmacodynamics of apixaban and rivaroxaban', Clin 
Pharmacol, 6: 179-87. 
ISMP. 2017. 'QuarterWatch™ (2016 Annual Report) Part II: Oral Anticoagulants—The 
Nation’s Top Risk of Acute Injury from Drugs'. 
https://www.ismp.org/resources/quarterwatchtm-2016-annual-report-part-ii-oral-
anticoagulants-nations-top-risk-acute. 
Janssen Pharmaceuticals, Inc. 2016. "XARELTO® (rivaroxaban), US Prescribing 
Information." Titusville, NJ, USA. 
Levy, J. H., W. Ageno, N. C. Chan, et al. 2016. 'When and how to use antidotes for the 
reversal of direct oral anticoagulants: guidance from the SSC of the ISTH', J Thromb 
Haemost, 14: 623-7. 
Lip, G. Y., A. Keshishian, S. Kamble, et al. 2016. 'Real-world comparison of major bleeding 
risk among non-valvular atrial fibrillation patients initiated on apixaban, dabigatran, 
rivaroxaban, or warfarin. A propensity score matched analysis', Thromb Haemost, 
116: 975-86. 
Macdonald, R. L. 2018. 'Management of Intracranial Hemorrhage in the Anticoagulated 
Patient', Neurosurg Clin N Am, 29: 605-13. 
Newcombe, R. G. 1998. 'Interval estimation for the difference between independent 
proportions: comparison of eleven methods', Stat Med, 17: 873-90. 
Pernod, G., P. Albaladejo, A. Godier, et al. 2013. '[Management of major bleeding 
complications and emergency surgery in patients on long-term treatment with direct 
oral anticoagulants, thrombin or factor-Xa inhibitors. Proposals of the Working 
Group on Perioperative Haemostasis (GIHP) - March 2013]', Ann Fr Anesth Reanim, 
32: 691-700. 
Portola Pharmaceuticals, Inc. 2018. "ANDEXXA® (coagulation factor Xa (recombinant), 
inactivated-zhzo), US Prescribing Information." South San Francisco, CA, USA. 
Sanofi-Aventis U.S. 2018. "LOVENOX® (enoxaparin sodium injection), US Prescribing 
Information." Bridgewater, NJ, USA. 

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Shehab, N., M. C. Lovegrove, A. I. Geller, et al. 2016. 'US Emergency Department Visits for 
Outpatient Adverse Drug Events, 2013-2014', J A M A, 316: 2115-25. 
Tepper, P. G., J. Mardekian, C. Masseria, et al. 2018. 'Real-world comparison of bleeding 
risks among non-valvular atrial fibrillation patients prescribed apixaban, dabigatran, 
or rivaroxaban', PLoS One, 13: e0205989. 
Yao, X., N. S. Abraham, L. R. Sangaralingham, et al. 2016. 'Effectiveness and Safety of 
Dabigatran, Rivaroxaban, and Apixaban Versus Warfarin in Nonvalvular Atrial 
Fibrillation', J Am Heart Assoc, 5. 
 
 

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a. Informed consent must be obtained before any study-specific procedure is performed. All Screening procedures are to be performed between Day -30 and Day -3 (inclusive), 
with Screening test results available no later than Day -1 to determine eligibility. Subjects will be provided with lifestyle and dietary guidelines appropriate for an anticoagulant 
study and for fecal occult blood testing. 
b. After completion of all Day -1 assessments, subjects who remain eligible per entry criteria will begin their domiciled period in the study unit. 
c. Subject may be discharged from the study unit after completion of all procedures if WBCT results meet protocol threshold requirements (Section 3.1) and the Investigator 
determines that no additional safety monitoring is required. Otherwise the subject will remain domiciled until these criteria are met. 
d. When timing for assessments coincide, WBCT testing (coagulometer and manual) will be performed first, followed by PK and safety laboratory samples, then other safety 
assessments (physical examinations, vital signs, and ECG). 
e. A complete physical examination will be performed at Screening. An abbreviated physical examination will be performed on the subsequent designated days. 
f. Temperature will be measured at Screening and Day -1. Blood pressure, heart rate, and respiration rate will be measured at Screening, Day -1 and subsequently as follows: on 
all anticoagulant dosing days within 30 minutes prior to anticoagulant dosing; the ciraparantag/PBO dosing day within 30 minutes prior to anticoagulant dosing, within 30 
minutes prior to ciraparantag/PBO dosing and at 1 hour (±10 minutes), 4 hours (±10 minutes), and 8 hours (±10 minutes) after the end of ciraparantag/PBO infusion; Day FU-1 
at 24 hours (±1 hour) after the end of ciraparantag/PBO infusion; Day FU-5 prior to discharge from the study unit. Additional vital sign measurements may be performed 
during the study if clinically indicated. 
g. Additional ECGs may be performed during the study if clinically indicated. 
h. For Cohort 1 these blood samples will be collected on coagulation assessment day(s) at 2.75 hours (±10 minutes) after anticoagulant, and for Cohorts 2 and 3 these blood 
samples will be collected at 3.75 hours (±10 minutes) after anticoagulant.  Urinalysis may be performed at any time of day prior to dose of ciraparantag/PBO. 
i. Blood samples for triglycerides & cholesterol will be collected after at least 8 hours of fasting (except water ad libitum). 
j. Prothrombotic marker (D-dimer, prothrombin fragment 1.2, and tissue factor pathway inhibitor) blood samples will be collected on Day -1, coagulation assessment day(s) at 
2.75 hours (±10 minutes) after anticoagulant for Cohort 1 and 3.75 hours (±10 minutes) after anticoagulant for Cohorts 2 and 3, ciraparantag/PBO dosing day at 6 hours 
(±10 minutes) after the end of ciraparantag/PBO infusion, Day FU-1 at 24 hours (±30 minutes) after the end of ciraparantag/PBO infusion, and on Days FU-2 through FU-5  
(blood draws at a time of day ±2 hours of the time of day of the end of ciraparantag/PBO infusion). Testing for these markers will be performed at a central laboratory. 
k. For female subjects, serum pregnancy tests will be performed, except a urine pregnancy test also may be performed at the study site on Day -1 to ensure that results will be 
available before Day 1. 
l. A urine sample will be taken for drug and tobacco screening. Alcohol screening will be performed via breath or saliva testing performed at the study site. 
m. Fecal occult blood kits will be given to subjects at Screening with instructions on their use. A sample should be obtained at a time as close as possible prior to the Day -1 visit, 
and the kit returned to the study site on Day -1. If a kit is not returned, on Day -1 at the study site the subject must provide a stool sample, or a rectal exam for a stool sample 
will be required. Fecal occult blood test results must be negative for a subject to continue study participation and proceed to Study Day 1. 
n. Anticoagulant morning doses after Day 1 will be administered at a time of day within ±1 hour of the time of morning dose on Day 1. 
o. For sufficiently anticoagulated subjects, ciraparantag/PBO IV dose will be administered at 3 hours (±5 minutes) after the anticoagulant dose for Cohort 1 and 4 hours (±5 
minutes) after the anticoagulant dose for Cohorts 2 and 3 (Section 3.1). 
p. Blood samples for WBCT for coagulometer assessment will be collected as follows: Day 1 prior to the first dose of anticoagulant*; coagulation assessment day(s) at 2.75 hours 
(±10 minutes) after anticoagulant for Cohort 1* and 3.75 hours (±10 minutes) after anticoagulant for Cohorts 2 and 3*.  For sufficiently anticoagulated subjects, blood samples 
for WBCT will be collected at 15 minutes (±5 minutes), 30 minutes (±5 minutes), 1 hour (±5 minutes)*, 3 hours (±10 minutes), 6 hours (±10 minutes) and 8 hours 
(±10 minutes) after the end of ciraparantag/PBO infusion; Day FU-1 at 24 hours (±30 minutes)* after the end of ciraparantag/PBO infusion, and on subsequent study days* as 
needed until protocol threshold criteria are met (Section 3.1). Blood samples for simultaneous testing using the manual method also will be collected at the timepoints 
designated with the asterisk (*). 
q. Any subject with WBCT >120% of BL on Day FU-1 (based on the coagulometer) or >110% of BL (based on the manual method) will have both WBCT measurements 
repeated on subsequent days as required until WBCT protocol threshold requirements are met. 
r. Blood samples for PK assessment for ciraparantag, ciraparantag metabolite(s) and anticoagulant will be collected on the ciraparantag/PBO dosing day and Day FU-1 at the 
same timepoints as WBCT blood collections (for coagulometer assessment), with the following exceptions: PK also will be assessed on coagulation assessment day(s) prior to 

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anticoagulant (within 30 minutes) and for sufficiently anticoagulated subjects at 45 minutes (±5 minutes) and 1.5 hours (±5 minutes) after the end of ciraparantag/PBO 
infusion; PK will not be assessed at 8 hours after the end of ciraparantag/PBO infusion. 
s. AEs will be monitored from the time the informed consent is signed through Day FU-5 (or the day the subject is discharged from the study unit, whichever is later. SAEs will 
be reported through 30 days after the last dose of study drug. 
t. On Day 1, these blood samples will be collected prior to the first dose of anticoagulant. 
u. These assessments will be performed only if the subject will NOT be assessed for sufficient anticoagulation on Day 3. 
v. The coagulation assessment visit (CAV) may occur on Day 3 and/or Day 4 as described below (to allow for flexibility in scheduling the day of the week on which this visit will 
occur). The post-randomization procedures shown are for subjects who are sufficiently anticoagulated and are randomized, and will occur on the calendar day of the CAV. 
• For CAV on Day 3, if subject does not meet WBCT criteria for sufficient anticoagulation, one of the following will occur: 
─ At the discretion of the Investigator the subject can continue anticoagulant dosing and repeat the CAV again on Day 4 (all CAV pre-randomization procedures will be 
repeated on Day 4); or 
─ The subject will be discontinued (CAV post-randomization procedures will not occur); see Section 6.11.3 for discontinuation instructions 
• For CAV on Day 4, if subject does not meet WBCT criteria for sufficient anticoagulation, the subject will be discontinued (CAV post-randomization procedures will not 
occur); see Section 6.11.3 for discontinuation instructions.