A Randomized, Placebo-controlled, Dose-range Finding Study to Assess the Pharmacokinetic and Pharmacodynamic Parameters, Safety, Tolerability, and Immunogenicity of MAA868 in Patients With Atrial Fibrillation
Phase: PHASE2
Conditions: Atrial Fibrillation
Sponsor: Anthos Therapeutics, Inc.

Document Type:  
Final Protocols 
Document Dates: 
Version 01 – Initial Protocol: 27 September 2019 
Version 02 – Amendment 1: 01 November 2019 
Version 03 – Amendment 2: 10 May 2020 
Study Title: 
A Multicenter, Randomized, Subject- and Investigator-blinded,  
Placebo-controlled, Parallel-group, Dose-range Finding Study to  
Assess the Pharmacokinetic and Pharmacodynamic Parameters, Safety, 
Tolerability, and Immunogenicity of MAA868 in Patients with Atrial 
Fibrillation 
Protocol Reference Number: ANT-004 
NCT Number:  
NCT04213807 
Page 1 of 212

Anthos Therapeutics
AFib Protocol Amendment 2
Page 1 
Protocol No. ANT-004
PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Protocol Number:
ANT-004
Protocol Title:
A Multicenter, Randomized, Subject- and Investigator-blinded, Placebo- 
controlled, Parallel group, Dose-range Finding Study to Assess the 
Pharmacokinetic and Pharmacodynamic Parameters, Safety, Tolerability, 
and Immunogenicity of MAA868 in Patients with Atrial Fibrillation
Principal Investigator’s Statement and Signature:
I, the undersigned, have read protocol ANT-004 (including all appendices). I agree to 
conduct the clinical study as described and in compliance with International Conference on 
Harmonisation (ICH) Guidelines for Good Clinical Practice (GCP) and applicable 
regulatory requirements. I agree to inform all who assist me in the conduct of this study of
  their responsibilities and obligations. 
Signature of Principal Investigator
Date
Name of Principal Investigator (printed)
Investigative Site Name, Address and Telephone Number:
Sponsor CMO (or Designee) Approval 
Signature:
Name / Title:
Date:
Page 4 of 212

This is a representation of an electronic record that was signed
electronically.
This page is the manifestation of the electronic signature(s).
Page 5 of 212

Anthos Therapeutics 
Page 3 
AFib Protocol Amendment 2 
Protocol No. ANT-004 
NOTIFICATION OF SERIOUS ADVERSE EVENTS 
Dear Investigator, 
You must report a serious adverse event (SAE) (initial or follow-up) to Covance as summarized 
below. Refer to Section 7.6.2 of the protocol for SAE criteria and additional requirements. See 
also the Safety Management Plan for further details on the method of reporting a SAE. 
•
Complete SAE report
•
Submit SAE report to Covance safety within 24 hours after awareness of the SAE
•
Notify the Covance Medical Lead
•
The fax number(s) and email address(es) are located in the Safety Management Plan.
Page 11 of 212

Anthos Therapeutics 
 
Page 4 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
 
TABLE OF CONTENTS 
 
NOTIFICATION OF SERIOUS ADVERSE EVENTS ........................................................... 3 
LIST OF ABBREVIATIONS ................................................................................................... 8 
PHARMACOKINETIC DEFINITIONS AND SYMBOLS .................................................. 10 
GLOSSARY OF TERMS ....................................................................................................... 11 
AMENDMENT #2.................................................................................................................. 12 
AMENDMENT #1.................................................................................................................. 13 
PROTOCOL SYNOPSIS........................................................................................................ 14 
1. 
Introduction ................................................................................................................. 17 
1.1. 
Background ................................................................................................................. 17 
1.2. 
Study Rationale ........................................................................................................... 19 
1.3. 
Benefit-risk Assessment.............................................................................................. 19 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................ 21 
2.1. 
Primary objective and endpoint .................................................................................. 21 
2.2. 
Secondary objectives and endpoints ........................................................................... 21 
2.3. 
Exploratory objectives and endpoint .......................................................................... 21 
3. 
INVESTIGATION PLAN .......................................................................................... 23 
3.1. 
Overall Study Design and Plan Description ............................................................... 23 
3.2. 
Discussion of Study Design, Including the Choice of Control Groups ...................... 24 
3.3. 
Selection of Doses in the Study .................................................................................. 24 
4. 
SELECTION OF STUDY POPULATION ................................................................ 25 
4.1. 
Inclusion Criteria ........................................................................................................ 25 
4.2. 
Exclusion Criteria ....................................................................................................... 25 
4.3. 
Discontinuation Criteria .............................................................................................. 27 
4.3.1. Screen Failures ................................................................................................ 27 
4.3.2. Withdrawal of informed consent .................................................................... 27 
4.3.3. Lost to Follow-up ............................................................................................ 27 
4.4. 
Stopping Rules ............................................................................................................ 27 
5. 
Study Treatments ........................................................................................................ 29 
5.1. 
Treatments Administered ............................................................................................ 29 
5.2. 
Preparation, Storage, Handling, and Accountability .................................................. 29 
5.3. 
Method of Treatment Assignment .............................................................................. 30 
5.4. 
Blinding....................................................................................................................... 30 
Page 12 of 212

Anthos Therapeutics 
 
Page 5 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
5.5. 
Treating the subject ..................................................................................................... 31 
5.6. 
Permitted dose adjustments and interruptions of study treatment .............................. 32 
5.7. 
Study Completion and Post-study Treatment ............................................................. 32 
5.8. 
Discontinuation of Study Treatment ........................................................................... 32 
5.9. 
Study Termination ...................................................................................................... 32 
5.10. Emergency breaking of assigned treatment code........................................................ 33 
6. 
CONCOMITANT THERAPIES ................................................................................ 34 
6.1. 
Concomitant therapy ................................................................................................... 34 
6.2. 
Study restrictions ........................................................................................................ 35 
6.3. 
Reversal medication .................................................................................................... 36 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...................................................... 37 
7.1. 
Assessment schedule ................................................................................................... 37 
7.2. 
Informed consent procedures ...................................................................................... 37 
7.3 
Subject screening ........................................................................................................ 37 
7.4 
Subject demographics/other baseline characteristics .................................................. 37 
7.5 
Efficacy Assessments.................................................................................................. 38 
7.5.1 Free FXI .......................................................................................................... 38 
7.5.2 aPTT ................................................................................................................ 38 
7.5.3 Total FXI ......................................................................................................... 38 
7.5.4 FXI coagulation activity (FXI:C).................................................................... 38 
7.6 
Safety Assessments ..................................................................................................... 38 
7.6.1 Adverse Events ............................................................................................... 39 
7 6 2 Reporting Serious Adverse Events 
 41 
7.7 
Liver safety monitoring............................................................................................... 42 
7.8 
Renal safety monitoring .............................................................................................. 43 
7.9 
Pregnancy .................................................................................................................... 43 
7.10 
Clinical Laboratory Evaluations ................................................................................. 44 
7.11 
Vital Signs, Physical Examination, and Other Safety Evaluations ............................. 45 
7.12 
Electrocardiogram (ECG) ........................................................................................... 45 
7.13Pharmacokinetic Analysis ................................................................................................ 46 
7.14 
Other assessments ....................................................................................................... 46 
7.14.1 Exploratory Biomarker assessments ............................................................... 46 
7.14.2 Immunogenicity (IG) ...................................................................................... 46 
7.15 
Use of residual biological samples ............................................................................. 47 
Page 13 of 212

Anthos Therapeutics 
 
Page 6 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
8. 
SAMPLE SIZE AND DATA ANALYSES ................................................................ 48 
8.1. 
Determination of Sample Size .................................................................................... 48 
8.2. 
Analysis Populations ................................................................................................... 48 
8.3. 
General Considerations ............................................................................................... 48 
8.4. 
Demographics and Baseline characteristics ................................................................ 48 
8.5. 
Efficacy Analysis ........................................................................................................ 49 
8.5.1. Primary Efficacy Outcome Measures ............................................................. 49 
8.5.2. Secondary Efficacy Outcome Measures ......................................................... 49 
8.6. 
Safety Analysis ........................................................................................................... 49 
8.6.1. Adverse Events ............................................................................................... 49 
8.6.2. Bleeding Events .............................................................................................. 50 
8.6.3. Major cardiovascular, cerebrovascular, and venous thromboembolic events 51 
8.6.4. Clinical Laboratory Evaluations ..................................................................... 51 
8.6.5. Vital Sign Measurements ................................................................................ 51 
8.6.6. ECG Parameters .............................................................................................. 51 
8.7. 
Pharmacokinetic Analysis ........................................................................................... 52 
8.8. 
Biomarkers .................................................................................................................. 52 
8.9. 
Interim Analysis (IA) .................................................................................................. 52 
8.10. Data Quality Assurance .............................................................................................. 52 
9. 
Ethical Considerations ................................................................................................ 55 
9.1. 
Regulatory and ethical compliance ............................................................................. 55 
9.2. 
Responsibilities of the Investigator and IRB .............................................................. 55 
9 3  
Publication of study protocol and results 
 55 
10. 
PROTOCOL ADHERENCE ...................................................................................... 56 
10.1. Protocol Amendments ................................................................................................. 56 
11. 
References ................................................................................................................... 57 
12. 
Appendices .................................................................................................................. 59 
12.1. Appendix 1 - Liver Event Definitions and Follow-up Requirements ......................... 60 
12.2. Appendix 2 - Specific Renal Alert Criteria and Actions ............................................ 62 
12.3. Appendix 3 - Clinical notable laboratory values ........................................................ 64 
12.4. Appendix 4 - Schedule of Assessments ...................................................................... 65 
12.5. Appendix 5 – Definition of bleeding events ............................................................... 67 
 
 
 
Page 14 of 212

Anthos Therapeutics 
 
Page 7 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
 
List of Tables 
Table 1: 
Overview of Study Medication ................................................................................... 29 
Table 2: 
Randomization Assignment Numbering ..................................................................... 30 
Table 3: 
Summary of reporting requirements for medication errors ........................................ 35 
Table 4: 
Liver Event and Liver-Related Laboratory Alert Definition ...................................... 60 
Table 5: 
Action required for Liver Events and Liver-Related Laboratory Alerts..................... 60 
Table 6: 
Exclusion of underlying Liver Disease ....................................................................... 61 
Table 7: 
Specific Renal Alert Criteria and Actions .................................................................. 62 
Table 8: 
Follow-up renal events ................................................................................................ 63 
Table 9: 
Schedule of Assessments ............................................................................................ 65 
 
 
List of Figures 
Figure 1: 
Overall study design ....................................................................................... 23 
 
 
 
Page 15 of 212

Anthos Therapeutics 
 
Page 8 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
LIST OF ABBREVIATIONS 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
Adverse event of special interest 
AF 
Atrial fibrillation 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CIAC 
central independent adjudication committee 
CK 
creatine kinase 
CI 
confidence interval 
CRF 
case report form 
CRNM 
clinically relevant non-major 
CRO 
contract research organization 
CSR 
clinical study report 
DOAC 
direct oral anticoagulant 
DSS 
Drug Safety Services 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
FIH 
first-in-human  
FXI 
Factor XI 
FXI:C 
FXI coagulation activity 
GCP 
Good Clinical Practice 
γGT 
gamma glutamyl transferase 
GLP 
Good Laboratory Practice 
IA 
interim analysis 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
Page 16 of 212

Anthos Therapeutics 
 
Page 9 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
IRB 
institutional review board 
ISTH 
International Society of Thrombosis and Haemostasis 
IN 
investigator notification 
MedDRA 
Medical Dictionary for Regulatory Activities 
PAF 
paroxysmal atrial fibrillation 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
QTcF 
QT interval corrected by Fridericia formula 
RBC 
red blood cells 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
s.c. 
subcutaneous 
sCr 
serum creatinine 
sCT 
spiral computed tomography 
SD 
standard deviation 
SOC 
system organ class (MedDRA classification) 
SUSAR 
suspected unexpected serious adverse reaction  
TEAE 
treatment-emergent adverse event 
VTE 
venous thromboembolism 
WBC 
white blood cells 
WHO 
World Health Organization 
 
 
 
Page 17 of 212

Anthos Therapeutics 
 
Page 10 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
PHARMACOKINETIC DEFINITIONS AND SYMBOLS 
AUC0-t 
The area under the plasma concentration-time curve from time zero to time ‘t’ 
where t is a defined time point after administration [mass x time / volume] 
AUCinf 
The area under the plasma concentration-time curve from time zero to infinity 
[mass x time / volume] 
AUClast 
The area under the plasma concentration-time curve from time zero to the time 
of the last quantifiable concentration [mass x time / volume]  
C0 
The initial concentration at the end of an intravenous infusion 
CL 
The systemic clearance following intravenous administration 
Cmax 
The observed maximum plasma concentration following subcutaneous drug 
administration [mass / volume] 
F 
Bioavailability 
T1/2 
The terminal elimination half-life [time] 
Tmax 
The time to reach the maximum concentration after drug administration [time] 
Vss 
The steady state volume of distribution following intravenous administration 
 
Page 18 of 212

Anthos Therapeutics 
 
Page 11 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
GLOSSARY OF TERMS 
Assessment 
A procedure used to generate data required by the study 
Cohort 
A specific group of subjects fulfilling certain criteria 
Dosage 
Dose of the study treatment given to the subject in a time unit  
Enrollment 
Point/time of subject entry into the study at which informed 
consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol) 
Healthy volunteer 
A person with no known significant health problems who 
volunteers to be a study participant  
Investigational drug 
The study drug whose properties are being tested in the study; 
this definition is consistent with US CFR 21 Section 312.3 and 
Directive 
2001/20/EC 
and 
is 
synonymous 
with 
“investigational new drug” or “test substance” 
Screen Failure 
A subject who is screened but is not treated or randomized 
Subject 
A trial participant 
Subject number 
A unique number assigned to each subject upon signing the 
informed consent. This number is the definitive, unique 
identifier for the subject and should be used to identify the 
subject throughout the study for all data collected, sample 
labels, etc. 
Randomization number 
A unique identifier assigned to each randomized subject, 
corresponding to a specific treatment arm assignment 
Study treatment 
Any drug administered to the study participants as part of the 
required study procedures; includes investigational drug (s), 
control(s) or non-investigational medicinal product(s) 
Study treatment 
discontinuation 
When the subject permanently stops taking study treatment 
prior to the defined study treatment completion date 
Study treatment period 
Interval of time in the planned conduct of a study. A treatment 
period is associated with a purpose (e.g. screening, 
randomization, treatment, follow-up), which applies across all 
arms of a study 
Variable 
A measured value or assessed response that is determined in 
specific assessments and used in data analysis to evaluate the 
drug being tested in the study  
Withdrawal of consent  
Withdrawal of consent from the study is defined as when a 
subject does not want to participate in the study any longer, 
and does not want any further visits or assessments, and does 
not want any further study related contact, and does not allow 
analysis of already obtained biologic material 
 
Page 19 of 212

Anthos Therapeutics 
 
Page 12 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
AMENDMENT #2  
 
Amendment rationale 
This protocol is being amended to provide clarification and guidance to sites around changes to 
the protocol in response to COVID-19 travel restrictions. The sponsor is also using this 
opportunity to correct inconsistencies and address minor editorial issues. 
 
Changes to the protocol 
• Section 2.2 – The primary safety endpoint was clarified to refer to the occurrence of AEs 
and SAEs which may include clinically significant findings derived from safety 
assessments such as physical examinations, safety laboratories, assessments of the 
injection site and others. 
• Section 2.3 – Exploratory objective added to include the possibility of assessing the 
effects of MAA868 on aPTT collected via a point-of-care device. 
• Section 3.1 – Language included to enable an earlier assessment of safety in Cohort 1 and 
in the event the Sponsor and Covance Lead Physician agree there is sufficient data to 
proceed to Cohort 2 after half of Cohort 1 has been randomized.     
• Section 5.6 – Guidance provided in the event of unavoidable study drug interruptions that 
are unrelated to the study or study drug such as travel-restrictions related to COVID-19 
and guidance on study drug resumption. 
• Section 7.6 – Further details of the central independent adjudication of bleeding events 
and major cardiovascular, cerebrovascular, and venous thromboembolic events are 
provided. 
• Section 7.6 – Bleeding event definitions are moved to Appendix 5. 
• Section 8.10 – Corrections and clarifications made to how data management and quality 
control will be handled by the clinical research organization (Covance). 
 
Administrative corrections or clarifications are also made throughout the protocol. 
 
 
 
 
Page 20 of 212

Anthos Therapeutics 
 
Page 13 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
AMENDMENT #1 
 
Amendment Rationale 
This protocol is being amended, prior to submission to any Health Authority, to address male 
contraception requirements, correct inconsistencies and to provide greater clarity. 
 
Changes to the Protocol 
• 4.2 (Exclusion criteria) and 6.2 (Study restrictions) – added eligibility criteria and study 
requirement that male study participants use condoms during intercourse throughout the 
study. 
• 5.4 (Blinding) – added clarity regarding activities for which some associates may have 
access to the full randomization list prior to database lock in order to fulfill their 
functions. 
Page 21 of 212

Anthos Therapeutics 
 
Page 14 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
PROTOCOL SYNOPSIS 
Title of study: A Multicenter, Randomized, Subject- and Investigator-blinded, Placebo-
controlled, Parallel-group, Dose-range Finding Study to Assess the Pharmacokinetic and 
Pharmacodynamic Parameters, Safety, Tolerability, and Immunogenicity of MAA868 in Patients 
with Atrial Fibrillation  
Indication: Atrial fibrillation 
Number of Investigators and study centers: 
The study is planned to be conducted in approximately 7 sites. 
Development phase: Phase 2a 
Objectives: 
Primary 
• 
To evaluate the proportion of patients that achieve ≥50%, ≥80%, or ≥90% Factor XI 
(FXI) inhibition at trough after the third dose (Day 91) at different dose levels of 
MAA868. 
Secondary 
• 
To evaluate the proportion of patients achieving FXI inhibition ≥ 50%, ≥80%, and ≥90% 
at trough after the first and second dose (Day 31 and Day 61) at different dose levels of 
MAA868. 
• 
To evaluate the safety and tolerability following multiple s.c. administration of MAA868 
compared to placebo to patients with AF. 
• 
To evaluate the incidence of major bleeding events, clinically relevant non-major 
(CRNM) bleeding events and total bleeding with MAA868 relative to placebo during 
the treatment period. 
• 
To evaluate the immunogenicity of MAA868 compared to placebo. 
Study design: 
This is a randomized, subject- and investigator-blinded, placebo controlled, dose-ranging study 
in patients with atrial fibrillation (AF) or atrial flutter who are at low risk for stroke. Patients will 
be enrolled in up to 3 cohorts of approximately 16 patients each. After a Screening Period of up 
to 28 days4 weeks, patients in will be randomized in a 3:1 ratio (MAA868:placebo) to receive 3 
monthly subcutaneous (s.c.) injections and followed for pharmacokinetics, pharmacodynamic 
efficacy as well as  safety events over the 90-day Treatment Period. Patients will then be followed 
up to Day 170 during the Washout/Follow-up period.  
Number of patients: 
Approximately 48 patients will be randomized into the study. 
Diagnosis and main criteria for inclusion and exclusion: 
Inclusion Criteria 
• 
Male and female patients ≥ 18 and < 85 years old 
• 
Current AF or atrial flutter on 12 lead electrocardiography at Screening  
or 
a history of paroxysmal AF (PAF) or atrial flutter as documented by prior telemetry, 12 
lead electrocardiography or ambulatory (e.g. Holter or patch) monitor which is not due 
to a reversible condition (e.g. alcohol binge drinking) 
• 
A CHA2DS2-VASc risk score of 0-1 for men and 1-2 for women and in whom, in the 
investigator’s judgment, the use of an anticoagulant for stroke prevention is not indicated 
• 
Body weight between 50 and 130 kg, inclusive 
Exclusion criteria 
Page 22 of 212

Anthos Therapeutics 
 
Page 15 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
• 
History of stroke, transient ischemic attack or systemic embolism 
• 
History of major bleeding during treatment with an anticoagulant or antiplatelet therapy. 
(Patients who have had major bleeding on anticoagulants or antiplatelet therapy more 
than a year ago can be enrolled only if the bleeding was due to a reversible cause, e.g. 
gastro-duodenal ulcer, that was successfully treated) 
• 
History of traumatic or non-traumatic intracranial, intraspinal or intraocular bleeding.  
• 
Known bleeding diathesis or any known active bleeding at screening or baseline 
• 
Family history of bleeding disorder  
• 
Known active GI lesions predisposing to bleeding events 
• 
Myocardial infarction, unstable angina pectoris or coronary artery bypass graft (CABG) 
surgery within 12 months prior to the screening period 
• 
Clinically significant moderate or greater mitral stenosis severity (valve area <1.5 cm2)  
• 
Prosthetic heart valve  
• 
Uncontrolled hypertension defined as SBP/DBP ≥ 160/100 mmHg at the screening visit 
• 
NYHA class III-IV heart failure  
• 
Currently being treated with anticoagulant therapy or have been on anticoagulants in the 
previous 12 months. Potential patients who have been on anticoagulation more than 12 
months ago requires discussion with the sponsor before enrolling.   
• 
Currently being treated with antiplatelet therapy such as a P2Y12 inhibitor or aspirin. 
Low dose aspirin (≤ 100 mg/d) is allowed  
• 
Severe renal impairment as defined as an estimated glomerular filtration rate ≤45 
mL/min/1.73m2 by the MDRD equation at the screening visit 
• 
Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
Test products, dose, and mode of administration: 
MAA868 with a dose of 120 mg or 180 mg or placebo s.c. monthly 
Reference therapy, dose, dose form, and mode of administration:   
Matching placebo to MAA868 s.c. monthly 
Page 23 of 212

Anthos Therapeutics 
 
Page 16 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
Duration of patient participation in study: 
Planned Screening duration: Up to 28 days 
Planned treatment duration: Day 1-91: 90 days 
Planned follow-up duration: Day 91 to Day 170: 79 days 
Study populations:  
Approximately 48 male and female patients age ≥ 18 to < 85 with AF or flutter, as defined above, 
will be randomized into the study. 
Evaluation: Efficacy  
• 
Free FXI concentrations at Days 31, 61 and 91 
Evaluation: Safety 
• 
Confirmed major bleeding events, clinically relevant non-major (CRNM) bleeding events 
and total bleeding events 
• 
Adverse and serious adverse events 
• 
Occurrence of major cardiovascular, cerebrovascular, systemic arterial, and  
• 
Physical examinations  
• 
Monitoring of laboratory parameters in blood 
• 
ECGs 
• 
Hypersensitivity reactions 
• 
Injection site reactions 
Evaluation: Other assessments 
• 
Factor XI coagulation activity 
• 
Activated partial thromboplastin time 
• 
Pharmacokinetics 
• 
Development of anti-drug antibodies 
• 
Venous thromboembolic events  
Statistical methods: 
The patients will be enrolled into cohorts of approximately 16 patients with each cohort 
evaluating a different dose level of MAA868. Within each cohort, patients will be randomized 
3:1 to active drug or placebo. 
The primary analysis variable is whether a subject will achieve pre-defined degrees of FXI 
inhibition at trough (Day 91). The dose regimens and targeted FXI inhibition achievement are as 
follows:  
Low-dose cohort (MAA868 120 mg monthly or placebo): Targeted to achieve ≥ 50% FXI 
inhibition in 90% of subjects at trough (Day 91).  
High dose cohort (MAA868 180 mg monthly or placebo): Targeted to achieve ≥ 90% FXI 
inhibition in 90% of subjects at trough (Day 91). 
The “on treatment” trough FXI levels will be used for the primary analysis, where “on treatment” 
FXI level is defined as a value which is collected within 30 (±5) days after the last administration 
of MAA868. The response rate per treatment group will be calculated by number of subjects 
who achieve targeted FXI inhibition rate divided by the total number of subjects in the treatment 
group. The estimate of the responder rate (%) at Day 91 will be presented for each dose regimens 
of MAA868 together with 2-sided 90% confidence intervals. 
The secondary efficacy analysis is to evaluate the proportion of subjects achieving FXI inhibition 
≥ 50%, ≥80%, and ≥90% at trough after the first and second dose (Day 31 and Day 61) at multiple 
dose levels of MAA868. The analyses described for the primary endpoint will be repeated for 
the secondary efficacy variables. 
Safety data including adverse events (AEs), bleeding events, ECG, vital signs, thromboembolic 
events and laboratory results will be reported by count and incidence rate. 
Page 24 of 212

Anthos Therapeutics 
 
Page 17 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
1. 
INTRODUCTION 
1.1. 
Background 
AF is the most common cardiac arrhythmia, accounting for approximately one third of 
hospitalizations for cardiac dysrhythmias. Currently, it is estimated to affect more than 6 million 
patients in Europe and approximately 2.3 million in the United States, and this number continues 
to grow rapidly because of the increasing proportion of the aging population with associated co-
morbidities. As such, the prevalence of AF is expected to increase 2- to 3-fold over the following 
3 decades in western populations (Kannel and Benjamin 2008). 
AF is associated with a 4- to 5-fold increase in embolic stroke. The risk for stroke associated with 
AF increases steeply with age to 23.5% for patients aged 80 to 89 years (Kannel and Benjamin 
2008). Most patients with AF require life-long anticoagulation therapy to prevent cardioembolic 
stroke and systemic embolism. It is estimated that 85 to 90% of AF patients will require 
anticoagulation therapy (Camm et al 2012). 
Vitamin K antagonists (VKA), such as warfarin, are effective in reducing stroke and systemic 
thromboembolism; a highly significant relative risk reduction in stroke incidence by 67% was 
observed in a meta-analysis combining six studies (Hart et al 1999). All-cause mortality was 
reduced (26%) significantly by VKA vs. control (Hart et al 1999). In recent years, direct oral 
anticoagulant (DOACs) medications have been approved and introduced to clinical practice. These 
drugs are at least as effective as warfarin in preventing stroke or systemic embolism and may be 
superior to warfarin in the risk of hemorrhagic stroke and intracranial hemorrhage (Connolly et al 
2009, Granger et al 2011, Patel et al 2011). The incidence of major bleeding events with DOACs 
was similar or slightly lower than the incidence observed with well-conducted warfarin therapy. 
Nonetheless, the overall bleeding risk continues to be high with the use of DOACs. For instance, 
the annual incidence of major and clinically relevant non-major (CRNM) bleeding was 14.9% and 
the annual incidence of major bleeding events was 3.6% in patients treated with rivaroxaban in the 
ROCKET AF study (Patel et al 2011). It is notable that the occurrence of major bleeding was 
strongly associated with mortality. In the same study, the rate of all-cause mortality over the 2-
month period following a major bleeding event was 20.4% in the rivaroxaban group and 26.1% in 
the warfarin group (Piccini et al 2014). Thus, there is a high unmet medical need for an 
anticoagulant therapy that can effectively reduce the risk of AF-related thromboembolic 
complications such as stroke but with a lower risk of bleeding than currently employed 
anticoagulants. 
FXI is an emerging target for potentially safer and more effective anticoagulant medications. FXI 
holds important roles in both the intrinsic and extrinsic coagulation pathways and in bridging the 
initiation and amplification phases of plasmatic hemostasis (Gailani and Renné 2007). Both Factor 
XII and thrombin can activate FXI, resulting in a sustained thrombin generation and fibrinolysis 
inhibition. FXI plays a minor role in normal hemostasis in a high tissue factor environment “after 
vessel injury” whereas it appears to play a key role in thrombosis. Severe FXI deficiency is 
associated with a lower incidence of ischemic stroke and venous thromboembolic events (Salomon 
et al 2008, Salomon et al 2011, Preis et al 2017). Nevertheless, bleeding manifestations in subjects 
with severe FXI deficiency are infrequent and usually mild. Bleeding events that occur are 
typically injury-related and preferentially affect tissues known to have increased fibrinolytic 
Page 25 of 212

Anthos Therapeutics 
 
Page 18 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
activity such as the oral and nasal mucosa, and urinary tract (Bolton-Maggs 2000). Bleeding in 
vital organs is extremely rare or non-existent. 
MAA868 
MAA868 is a human antibody that binds to the catalytic domain of FXI. MAA868 binds to both 
the zymogen (FXI) and activated factor XI (FXIa) with high potency. MAA868 dose-dependently 
prolonged activated partial thromboplastin time (aPTT) in in-vitro and in-vivo studies. After a 
single subcutaneous (s.c.) administration of MAA868 at a 3 mg/kg dose, sustained anticoagulant 
activity lasting for more than one month was observed in cynomolgus monkeys. Moreover, 
MAA868 prevented experimental carotid artery thrombosis induced by FeCl3 and resulted in a 
prolongation in aPTT in FXI-/- mice reconstituted with human FXI. No significant toxicity 
findings were observed in single dose and in the 13-week Good Laboratory Practice (GLP)-
compliant toxicity study conducted in cynomolgus monkeys. The highest s.c. dose administered 
in the 13-week study was defined as no observed adverse effect level NOAEL (100 mg/kg/week 
s.c.). 
MAA868 was evaluated in a first-in-human (FIH) study (CMAA868X2101) to characterize its 
safety/tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) in healthy subjects 
following single s.c. administration. In total, 6 cohorts with 10 subjects each (8 MAA868: 2 
Placebo) were enrolled. The doses of MAA868 administered in Cohorts 1 to 5 ranged from 5 mg 
to 240 mg. In a sixth cohort, 240 mg of MAA868 was administered to subjects with body mass 
index (BMI ≥ 35 kg/m2). 
In the FIH study, MAA868 appeared to be safe and well tolerated, and the incidence of AEs were 
comparable across dose groups and placebo. No bleeding events, hypersensitivity reactions or 
injection site reactions were reported. Exposure increased with increasing dose of s.c. MAA868; 
the median maximum observed concentration (Cmax) occurred on Day 7 to 21 and the mean 
terminal elimination half-life ranged from 20 to 28 days. A dose and time-dependent prolongation 
of aPTT occurred with MAA868 after single s.c. administration; the 150 mg dose resulted in a 
mean aPTT prolongation ≥ 2-fold at Day 29. Doses greater than 150 mg extended the duration of 
aPTT prolongation but did not produce a greater prolongation of aPTT. Robust and sustained 
reductions of free FXI ≥ 90% were observed with 150 mg MAA868 at Day 29 and up to Day 43 
with 240 mg. A high BMI was associated with a lower MAA868 exposure and slightly shorter 
duration of aPTT prolongation. Robust reductions in free FXI and in FXI coagulation activity and 
relevant aPTT prolongation are predicted to occur within 12 to 24 hours after MAA868 s.c. 
administration with relevant clinical doses. 
MAA868 was also studied in healthy Japanese subjects in a single ascending dose, randomized, 
subject- and investigator-blinded, placebo-controlled, non-confirmatory study to assess safety, 
tolerability, PK and PD. Three cohorts (MAA868 dose levels: 15, 50 and 150 mg) were enrolled 
in this study and received a single s.c. dose of MAA868 or matching placebo (8 subjects received 
MAA868 and 2 subjects received placebo in each cohort). Assessments and assessment schedules 
were generally similar to the FIH study. No SAE or study discontinuation due to AEs were reported 
in this study. All AEs were mild in intensity and the distribution of AEs was well balanced between 
the MAA868 dose groups and placebo. No bleeding event, hypersensitivity or injection site 
reactions were reported in the study. PK analysis suggested that there was no indication of an 
impact of the Japanese ethnicity on exposure or PD parameters of MAA868 in healthy subjects. 
Page 26 of 212

Anthos Therapeutics 
Page 19 
AFib Protocol Amendment 2 
Protocol No. ANT-004 
Taken together, the results from both completed studies of MAA868 suggest that the 
administration of MAA868 is safe and well-tolerated. Subcutaneous administration of MAA868 
leads to robust and sustained effects on aPTT, free FXI, and FXI coagulation activity (FXI:C) up 
to/through Day 29 with the 150 mg dose and Day 43 with the 240 mg dose in subjects with normal 
body weight or class 1 obesity (BMI <35 kg/m2). In subjects with class 2 or 3 obesity (BMI ≥35 
kg/m2), exposures of MAA868 may be lower and the duration of aPTT prolongation is shorter. 
1.2. 
Study Rationale 
This study is a multicenter, randomized, subject and Investigator-blinded, placebo-controlled, 
parallel-group, multiple ascending dose-ranging study to evaluate the safety, tolerability, PK, and 
PD effects of MAA868 in patients with AF or flutter at low risk of thromboembolic stroke or 
peripheral embolism. The trial will evaluate the effects of up to three different doses of MAA868 
on FXI inhibition, indices of coagulation, and thrombogenesis biomarkers compared to placebo. 
The incidence of injection site reactions, bleeding events, immunogenicity, and systemic arterial 
and venous thromboembolic events will also be assessed. Results from this study will assist with 
dose-selection of MAA868 for a phase 3 trial in patients with AF. 
1.3. 
Benefit-risk Assessment 
AF is associated with a 4- to 5-fold increase in embolic stroke. MAA868, a fully human 
monoclonal antibody targeting Factor XI, is being considered for development as a novel 
anticoagulant for patients with AF or flutter. FXI is an emerging target as a novel anticoagulant. 
Several lines of evidence suggest that FXI inhibition has the potential to prevent thrombosis with 
minimal risk of bleeding. For example, individuals with an inherited deficiency of FXI have been 
reported to have a lower risk of VTE even though their bleeding phenotype is variable and often 
quite mild. Further support of the safety of inhibiting FXI comes from clinical studies using an 
investigational FXI antisense oligonucleotide (FXI-ASO) where administration of FXI-ASOs in 
healthy subjects and in patients undergoing total knee arthroplasty was demonstrated to be safe 
and well-tolerated (Buller et al 2015). 
Results from the first-in-human (FIH) study of MAA868 (CMAA868X2101) demonstrated that a 
single s.c. administration of MAA868 at increasing doses up to 240 mg in healthy subjects were 
safe and well-tolerated. These doses of MAA868 resulted in a robust and sustained FXI inhibition 
and prolongation of aPTT. The safety and pharmacodynamic efficacy of MAA868 was further 
supported by preliminary data from the study CMAA868A1101, which showed a good safety 
profile of MAA868 in Japanese heathy male subjects. 
This study is designed to evaluate the efficacy and safety of achieving different levels of FXI 
inhibition with different dose levels of s.c. MAA868 in patients with AF or flutter. This study will 
recruit patients with AF or flutter who are judged by their physician to be at low risk for stroke 
based on clinical guidelines. In each case, patients will only be enrolled if their physician has 
determined that the patient does not merit anticoagulation based on the guidelines and the 
physician’s assessment of the benefit-risk profile for that patient. The guidelines state that the 
benefits of anticoagulation in AF patients at low risk of embolic stroke are uncertain given the 
concomitant risks of bleeding with anticoagulant therapy. Accordingly, the guidelines recommend 
individualized shared physician-patient decision-making with regards to the decision to 
initiate anticoagulant therapy in this population (January et al 2019).  Patients with PAF will be 
enrolled who have a CHA2DS2-VASc risk score of 0-1 for men or 1-2 for women, in whom the 
guidelines 
Page 27 of 212

Anthos Therapeutics 
 
Page 20 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
are equivocal regarding the recommendation to initiate anticoagulation and advise an 
individualized assessment of the benefit-risk of anticoagulation (January et al 2019).  
Overall, the nonclinical and clinical data to date support the investigation of MAA868 in the 
prevention of thromboembolic diseases in patients with AF. The risk-benefit relationship appears 
to be acceptable. 
Page 28 of 212

Anthos Therapeutics 
 
Page 21 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
2. 
OBJECTIVES AND ENDPOINTS 
2.1. 
Primary objective and endpoint 
Objective 
Endpoint 
• To evaluate the proportion of patients that 
achieve ≥50%, ≥80%, or ≥90% FXI 
inhibition at trough after the third dose 
(Day 91) at different dose levels of 
MAA868 
• Occurrence of achieving ≥50%, ≥80%, or 
≥90% inhibition of FXI (<50%, <20%, or 
<10% free FXI) at trough on Day 91 at 
different dose levels of MAA868 
2.2. 
Secondary objectives and endpoints 
Objective 
Endpoint 
• To evaluate the proportion of patients 
achieving FXI inhibition ≥50%, ≥80%, and 
≥90% at trough after the first and second 
dose (Day 31 and Day 61) at different dose 
levels of MAA868 
• Occurrence of achieving ≥50%, ≥ 80%, 
and ≥90% inhibition of FXI (<50%, <20%, 
or <10% free FXI) at trough on Day 31 and 
Day 61 at different dose levels of MAA868 
• To evaluate the safety and tolerability 
following multiple s.c. administration of 
MAA868 compared to placebo in patients 
with AF 
•  Occurrence of adverse events (AEs), 
including serious AEs (SAEs) during the 
Treatment Period and through EoS 
• To evaluate the incidence of major 
bleeding events, clinically relevant non-
major (CRNM) bleeding events and total 
bleeding with MAA868 relative to placebo 
during the treatment period 
• Occurrence of confirmed major bleeding 
events, CRNM bleeding events and total 
bleeding events during the treatment 
period 
• To evaluate the immunogenicity of 
MAA868 compared to placebo. 
• Screening and confirmation for anti-drug 
(MAA868) antibodies (ADA) 
2.3. 
Exploratory objectives and endpoint 
Objective 
Endpoint 
• To evaluate the effect of MAA868 
compared to placebo on the incidence of 
major cardiovascular, cerebrovascular, and 
venous thromboembolic events (as defined 
to the right) 
• Occurrence 
of 
major 
cardiovascular, 
cerebrovascular, systemic arterial, and 
venous thromboembolic events (VTEs)  
Page 29 of 212

Anthos Therapeutics 
 
Page 22 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
• To evaluate the change from baseline in D-
dimer and other thrombogenesis markers 
with MAA868 relative to placebo during 
the treatment period 
• Concentrations of D-dimer and other 
exploratory 
thrombogenesis 
markers 
during the treatment period 
• To evaluate the effect of MAA868 
compared to placebo on aPTT as assessed 
by a point-of-care device 
• aPTT measurements collected on a point-
of-care device 
 
Page 30 of 212

Anthos Therapeutics 
 
Page 23 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
3. 
INVESTIGATION PLAN 
3.1. 
Overall Study Design and Plan Description 
This is a phase 2a, randomized, subject- and investigator-blinded, placebo-controlled, multiple 
ascending dose-ranging study to assess the PK/PD, safety, tolerability, and immunogenicity of 
MAA868 in patients with AF or flutter.  
Patients will be enrolled in at least 2 and up to 3 cohorts of approximately 16 patients each for a 
total of up to 48 subjects (Figure 1A). Patients in cohort 1 will be randomized 3:1 to receive a 120 
mg dose of MAA868 or placebo, respectively on Day 1 with two subsequent monthly injections.  
After approximately 10 of the patients in cohort 1 have been randomized, a safety review of 
emerging safety and PK data from cohort 1 will take place. Cohort 2  may be initiated after it is 
confirmed by the Sponsor’s Medical Monitor and the Covance Lead Project Physician that the 
cohort 1 dose was safe and well tolerated after at least half of the patients in cohort 1 have been 
randomized. Likewise, after approximately 10 of the patients in cohort 2 have received their second 
dose and have been followed for at least an additional 14 days, interim safety, tolerability, and 
other analyses will be evaluated by the Sponsor. Based on emerging data, the Sponsor may elect 
to: 
• Enroll cohort 3 to evaluate a higher, lower, or a previously studied dose of MAA868 
• Terminate the study 
The study is comprised of 3 periods:  
(1) Screening period of up to 28 days 
(2) Treatment period with MAA868 administered s.c. monthly (or matching placebo) 
(randomized 3:1) for 90 days 
(3) Follow-up period up to end of study (Day 170). 
Following the screening period of up to28 days, all patients that meet the study eligibility criteria 
(Section 4.1 and Section 4.2) will have baseline efficacy and safety assessments performed on Day 
1 and then randomized to active or placebo (Figure 1B). 
Figure 1: 
Overall study design 
 
The first dose of study drug will be administered at the study center on Day 1. The second and 
third doses of study drug will also be administered at the study center to patients on the Day 31 
visit and Day 61 visit, respectively. 
Page 31 of 212

Anthos Therapeutics 
 
Page 24 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
During the treatment period, patients will return to the study center on Day 11, Day 31, Day 41, 
Day 61, Day 71, and Day 91 for safety assessments such as vital signs, AE assessments, laboratory 
tests, PK, PD, thrombogenesis biomarkers, and other study assessments according to the 
assessment schedule shown in Table 9. 
During the follow-up period, patients will continue to be followed for PK, PD, thrombogenesis, 
and other study assessments. Patients will return to the study center on Day 101, Day 121 and Day 
170 (end of study; EoS) for the evaluations described in the assessment schedule (Table 9). 
3.2. 
Discussion of Study Design, Including the Choice of Control Groups 
Rationale for route of administration and treatment duration. The s.c. route of administration 
was chosen because it is the route of administration anticipated for subsequent studies in patients 
with AF. In the FIH study of MAA868, the half-life of MAA868 ranged from 20-28 days following 
s.c. administration. Furthermore, a sustained PD effect of >2-fold mean activated partial 
thromboplastin time [aPTT] prolongation was observed for ~30 days and returned to the baseline 
level by ~60 days post-dose after a single 150 mg s.c. dose administration in study X2101. These 
data support monthly administration of MAA868. Furthermore, assessment of the exposure-
response relationship of MAA868 in healthy subjects demonstrated a nearly flat exposure-response 
for relevant PD parameters (aPTT, FXI coagulation activity and free FXI) at concentrations above 
4 μg/mL which is consistent with the Day 29 total MAA868 concentrations achieved with the 150 
mg single dose administration in healthy subjects (CMAA868X2101). 
Given the half-life of MAA868 and the observed time to return to baseline aPTT levels, a 
prolonged washout/follow-up period of approximately 110 days from the last dose of MAA868 
should be a sufficient monitoring period for patients. 
3.3. 
Selection of Doses in the Study 
In the FIH study, single s.c. doses of MAA868 up to 240 mg was safe and well-tolerated. Up to 
the 150 mg dose, MAA868 produced robust and sustained dose-dependent inhibition of FXI and 
relevant prolongation of aPTT for approximately 4 weeks. MAA868 doses greater than 150 mg 
s.c. produced a sustained ~2-fold prolongation of aPTT for greater than 4 weeks.  
The precise level of FXI inhibition to achieve a clinically meaningful anticoagulant effect remains 
unknown. The primary efficacy endpoint of this study will be the number of patients who achieve 
≥ 50%, ≥ 80%, or ≥ 90% FXI inhibition [<50%, <20%, or 10% free FXI] at trough on Day 91 
following s.c. administration of MAA868. Based on preliminary PK/PD modeling, the doses 
selected for cohorts 1 and 2 are projected to target the following levels of FXI inhibition: 
• Cohort 1 (120 mg dose group). Targeted to achieve ≥ 50% FXI inhibition in 90% of 
subjects at trough (Day 91).  
• Cohort 2 (180 mg dose group). Targeted to achieve ≥ 90% FXI inhibition in 90% of 
subjects at trough (Day 91). 
Based on interim data, an optional cohort 3 may be dosed to add further data to the PK/PD model 
which will inform dose selection of MAA868 for subsequent studies.  
The dosing regimens selected for evaluation in this study are projected to result in exposure (Cmax) 
below the Cmax achieved with a single dose of 240 mg s.c. in healthy subjects in the FIH study. 
Page 32 of 212

Anthos Therapeutics 
 
Page 25 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
4. 
SELECTION OF STUDY POPULATION 
4.1. 
Inclusion Criteria 
1. Written informed consent must be obtained before any assessment is performed 
2. Male and female patients ≥ 18 and < 85 years old with paroxysmal atrial fibrillation (PAF) 
or atrial flutter on 12 lead electrocardiography at Screening Or 
3. Patients with a history of PAF or atrial flutter, as documented by (telemetry, 12 lead 
electrocardiography or ambulatory [e.g. Holter] monitor) and not due to a reversible 
condition (e.g. alcohol binge drinking) can be entered even if they do not have PAF at 
Screening. There is not time-limit for this. 
4. Patients with a CHA2DS2-VASc risk score (tool as a predictor for estimating the risk of 
stroke in patients with AF; Lip et al 2010) of 0-1 for men and 1-2 for women and in whom, 
in the investigator’s judgment, the use of an anticoagulant for stroke prevention is not 
indicated  
5. Body weight between 50 and 130 kg inclusive 
4.2. 
Exclusion Criteria 
1. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of 
enrollment, or until the expected PD effect has returned to baseline, whichever is longer; 
or longer if required by local regulations. 
2. History of stroke, transient ischemic attack or systemic embolism 
3. History of major bleeding during treatment with an anticoagulant or antiplatelet therapy. 
(Patients who have had major bleeding on anticoagulants or antiplatelet therapy more than 
a year ago can be enrolled only if the bleeding was due to a reversible cause, e.g. gastro-
duodenal ulcer that was successfully treated.) 
4. History of traumatic or non-traumatic intracranial, intraspinal or intraocular bleeding 
5. Known bleeding diathesis or any known active bleeding site at screening or baseline 
6. Family history of bleeding disorder  
7. Known active GI lesions predisposing to bleeding events 
8. Myocardial infarction, unstable angina pectoris or coronary artery bypass graft (CABG) 
surgery within 12 months prior to the Screening period 
9. Known clinically significant valvular heart disease including moderate or severe mitral 
stenosis (valve area <1.5 cm2).  
10. Patients with a prosthetic heart valve 
11. Uncontrolled hypertension defined as SBP/DBP ≥ 160/100 mmHg at the Screening visit 
12. Patients with NYHA Class III- IV heart failure 
13. Currently being treated with anticoagulant therapy or have been on anticoagulants in the 
previous 12 months. Potential patients who have been on anticoagulation more than 12 
months ago requires discussion with the sponsor before enrolling.   
14. Treatment with antiplatelet therapy such as either a P2Y12 inhibitor or aspirin. (Low dose 
aspirin ≤ 100 mg/d) is allowed.) 
15. Severe renal impairment as defined as an estimated glomerular filtration rate ≤45 
mL/min/1.73m2 by the MDRD equation at the Screening Visit 
Page 33 of 212

Anthos Therapeutics 
 
Page 26 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
16. Positive test for human immunodeficiency virus (HIV), positive hepatitis B (hepatitis B 
surface antigen [HBsAg]) or hepatitis C (anti-hepatitis C antibody [Anti-HCV]) at 
Screening 
17. Significant illness, per Investigator judgement, which has not resolved within four (4) 
weeks prior to dosing   
18. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
their time in the study. Highly effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow-up hormone level assessment 
• Male sterilization of sexual partner (at least 6 months prior to screening). For female 
subjects on the study, the vasectomized male partner should be the sole partner for that 
subject 
• Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) 
or other forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception 
In case of use of oral contraception, women should have been stable on the same pill for a 
minimum of 3 months before taking investigational drug. 
Women are considered post-menopausal and not of child-bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., 
age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow-up hormone level assessment with FSH is she 
considered not of child-bearing potential.  
Male subjects must also agree to use highly effective methods of contraception during their 
time in the study and should not father a child or donate sperm in this period.  
19. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test. 
20. Patients with either a psychiatric disease or substance abuse history, which in the opinion 
of the Investigator could interfere with protocol compliance.  
21. Any surgical or medical condition, which in the opinion of the Investigator, may place the 
patient at higher risk from his/her participation in the study, or is likely to prevent the 
patient from complying with the requirements of the study or completing the study. 
Page 34 of 212

Anthos Therapeutics 
 
Page 27 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
4.3. 
Discontinuation Criteria 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure patients to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
serious adverse events (SAEs). 
Patients who do not meet the criteria for participation in this study may be rescreened; however, 
each case must be discussed and agreed with the Sponsor on a case-by-case basis. 
Withdrawal of informed consent 
Subjects may voluntarily withdraw from the study for any reason at any time. 
Withdrawal from the study can occur when a subject chooses to do one or more of the following: 
• Does not want to participate in the study anymore  
• Does not want any further visits or assessments  
• Does not want any further study-related contacts  
• Does not allow analysis of already obtained biologic material. 
If a subject who has received one or more doses of the study drug determines that they no longer 
want to participate the Investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason(s) for the subject’s decision to withdraw his/her consent, record this 
information and conduct any assessments and visits still allowed. 
In the event the subject withdraws consent prior to beginning dosing, the study treatment will not 
be administered. The data that would have been collected at subsequent visits will be considered 
missing. Further attempts to contact the subject are allowed when safety findings require follow-
up. 
Lost to Follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating an 
intention to discontinue or withdraw, the Investigator should show "due diligence" by documenting 
in the source documents steps taken to contact the subject, e.g. dates of telephone calls, registered 
letters, etc. A subject cannot be formally considered lost to follow-up until his/her scheduled end 
of study visit would have occurred. 
4.4. 
Stopping Rules 
Overall study stopping rules: 
Enrollment in the study will be placed on hold if the Sponsor considers that the number and/or 
severity of AEs, abnormal safety monitoring tests or abnormal laboratory findings justify putting 
the study on hold. 
Page 35 of 212

Anthos Therapeutics 
 
Page 28 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
The study may resume following the safety review, if the Investigator and Sponsor’s Medical 
Monitor agree it is safe to proceed. 
Page 36 of 212

Anthos Therapeutics 
 
Page 30 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
5.3. 
Method of Treatment Assignment 
Subjects in each cohort will be randomized to MAA868 or placebo in a ratio of 12: 4 as follows. 
• 
Cohort 1 = 120 mg MAA868 monthly s.c. or placebo 
• 
Cohort 2 = 180 mg MAA868 monthly s.c. or placebo 
• 
Cohort 3 (if necessary) = TBD mg MAA868 monthly s.c. or placebo 
Randomization numbers will be assigned in ascending, sequential order to eligible subjects. The 
Investigator will enter the randomization number on the CRF. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A 
randomization list will be produced by or under the responsibility of Covance statistician using a 
validated system that automates the random assignment of treatment arms to randomization 
numbers in the specified ratio. The randomization scheme for subjects will be reviewed and 
approved by a member of the Covance Randomization Group. 
Patients will be replaced at the Sponsor’s discretion. Replacement subjects will be assigned 
randomization numbers 6101-6316 If a subject requires a replacement, the replacement subject 
will be assigned a randomization number corresponding to the original subject (e.g., Subject 6103 
would replace Subject 1103). 
The table below provides the general details of the numbering of the subjects for randomization: 
Table 2: 
Randomization Assignment Numbering 
Cohort 
Randomization numbers 
Replacement randomization numbers 
I 
1101-1116 
6101-6116 
II 
1201-1216 
6201-6216 
III 
1301-1316 
6301-6316 
5.4. 
Blinding 
This is a subject- and investigator-blinded study. Subjects will remain blinded to study treatment 
throughout the study, except where indicated below. 
The identity of the treatments will be concealed by the use of study drugs that are all identical in 
packaging, labeling, schedule of administration, appearance, and odor. 
Site staff 
With the exception of any unblinded pharmacist or pharmacy designee, all site staff (including 
study investigator and study nurse(s)) will be blinded to study treatment during treatment 
allocation and subject dosing. Appropriate measures must be taken by any unblinded pharmacist 
or pharmacy designee to ensure that the treatment assignments are concealed from the rest of the 
site staff. 
Unblinding a single subject at the site for safety reasons (necessary for subject management) will 
occur via an emergency system in place at the site (see Section 5.10). 
Site staff may also be unblinded to the treatment assignment of one or more subjects (within a 
single cohort or across cohorts as necessary), or an entire cohort at the initial cohort safety 
Page 38 of 212

Anthos Therapeutics 
 
Page 31 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
evaluation timepoint if deemed appropriate to aid decision-making. The decision to un-blind site 
staff will be determined by the clinical trial team based on need or review of the entire study group 
will be performed at a pre-selected time. 
Sponsor staff 
The following unblinded Sponsor roles (or designee) are required for this study: 
• Field monitor(s) (evaluation of drug dispensing and reconciliation) 
• Physician not directly involved in study conduct  
• Sample analyst(s) (PK blood) 
• Study statistician 
• Programmers and other personnel involved in study data analysis 
An unblinded Covance Physician not directly involved in study conduct may receive a copy of the 
randomization schedule (via request to the Randomization Office), to facilitate analysis of aPTT 
safety labs that would otherwise unblind study Investigators. The unblinded Medical Monitor will 
alert the Investigator and Sponsor of any safety concerns. 
The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office), to facilitate analysis of the samples. The sample analysts will provide the 
sample data to the study team under blinded conditions unless otherwise allowed. 
The study statistician will be able to access the full randomization list from the start of the study 
and is allowed to share unblinded information with the rest of the clinical trial team as appropriate 
for internal decision purposes. For example, unblinded summaries and unblinded individual data 
can be shared with the team whenever necessary.  
Study programmers and other personnel involved in study data analysis (e.g. biomarker expert, 
pharmacometrician, modeler(s)) are allowed to access treatment assignment information from the 
start of the study for the purpose of data analysis. 
The clinical trial team is allowed to share unblinded results with other Sponsor staff (e.g. decision 
boards) as required for internal decision making on the study or the project while the study is 
ongoing.  
All unblinded personnel will otherwise keep randomization lists and data or information that could 
un-blind other study team members confidential and secure except as described above.  
Following final database lock all roles may be considered unblinded. 
5.5. 
Treating the subject 
MAA868 will be administered to the subject by study staff via s.c. administration. See the 
Pharmacy Manual for further details. 
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
Page 39 of 212

Anthos Therapeutics 
Page 32 
AFib Protocol Amendment 2 
Protocol No. ANT-004 
5.6. 
Permitted dose adjustments and interruptions of study treatment 
Dosing interruptions are permitted in the case of logistical reasons not related to study therapy, 
e.g., an unrelated event such as a COVID-19-related travel restriction or any other restriction or
safety concern with the subject traveling to the study site. The reason for interruption should be
documented in the patient's study record.
Once the restriction(s) leading to study drug interruption have been lifted and the Sponsor and 
Investigator agree that it is safe for the subject to resume study participation, the subject may be 
resumed on study therapy on a case-by-case basis upon discussion with the Sponsor. Subjects who 
received only 1 dose of study drug before interruption may either resume study drug with the 
second dose or may restart with the first dose of study drug if a sufficient amount of time has 
elapsed such that the expected PD effect has returned to baseline. 
5.7. 
Study Completion and Post-study Treatment 
Each subject will be required to complete the study in its entirety and thereafter no further study 
treatment will be made available to them. 
Study completion is defined as when the last subject completes their EoS visit, and any repeat 
assessments associated with this visit have been documented and followed-up appropriately by the 
Investigator, or in the event of an early study termination decision, the date of that decision. 
All subjects will be required to attend the EoS visit and have related assessments collected as per 
the Schedule of assessments (Table 9). All SAEs reported during this time period must be 
reported as described in Section 7.6.2. and the Safety Management Plan. Documentation of 
attempts to contact the subject should be recorded in the source documentation. 
5.8. 
Discontinuation of Study Treatment 
The Investigator may decide to suspend the s.c. administration of the study drug if symptoms or 
signs consistent with an injection site reaction or hypersensitivity reaction occur.  
Subjects who decide they do not wish to participate in the study further should NOT be 
considered withdrawn from the study UNLESS they withdraw their consent (see Section 4.3,
Withdraw of Informed Consent). Where possible, they should return for the EoS assessments 
indicated in the assessment table. If they fail to return for these assessments for unknown 
reasons, every effort (e.g. telephone, e-mail, letter) should be made to contact the subject/pre-
designated contact as specified in Section 4.3 (Lost to follow-up). This contact should
preferably be done according to the study visit schedule. 
5.9. 
Study Termination 
The study can be terminated by Anthos at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. Should this be necessary, subjects must be 
seen as soon as possible and treated as a prematurely withdrawn subject and followed until the 
aPTT has returned to baseline. The Investigator may be informed of additional procedures to be 
followed in order to ensure that adequate consideration is given to the protection of the subject’s 
interests. The Investigator will be responsible for informing the Institutional Review Board (IRB) 
of the early termination of the trial. 
Page 40 of 212

Anthos Therapeutics 
 
Page 33 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
5.10. 
Emergency breaking of assigned treatment code 
Emergency unblinding must only be undertaken when it is essential to treat the subject safely and 
efficaciously, such as in the event of clinically significant bleeding events. Most often, knowledge 
of the possible treatment assignments is sufficient to treat a study subject who presents with an 
emergency condition. A complete set of emergency code break cards will be provided to the 
Investigator site(s) and a complete set will be available at Anthos and Covance. All code break 
cards must be retained until the end of the study and retained by the site as a source document. 
They must be stored in a secure place but be accessible to the Investigator 24 hours per day in case 
of emergency. The Investigator will receive a blinded code break card for each subject. In an 
emergency, the code break may be opened to determine the treatment. There is no known reversal 
agent for MAA868 (see Section 6.2).  
The code break should not be opened for any reason other than an emergency. If the Investigator 
opened the code break, he/she must note the date, time, and reason for removing it and retain this 
information with the case report form documentation. The unblinded treatment code must not be 
recorded on the CRF. The Investigator must also immediately inform the study monitor that the 
code has been broken.  
It is the Investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the code break cards at any time in case of emergency. The Investigator will need 
to provide: 
• Protocol number  
• Study drug name (if available)  
• Subject number. 
In addition, the Investigator must provide oral and written information to inform the subject how 
to contact his/her backup in cases of emergency when he/she is unavailable to ensure that un 
blinding can be performed at any time. 
Page 41 of 212

Anthos Therapeutics 
 
Page 34 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
6. 
CONCOMITANT THERAPIES 
6.1. 
Concomitant therapy 
The Investigator must instruct the subject to notify the study staff of any new medications 
(including nutritional supplements and herbal medications) that he/she takes after being enrolled 
into the study. 
All prescription medications, OTC drugs and significant non-drug therapies (including physical 
therapy and blood transfusions) administered or taken within the timeframe defined in the entry 
criteria prior to the start of the study and during the study, must be recorded on the Concomitant 
medications/Significant non-drug therapies CRF. 
Medication entries should be specific to trade name, the single dose and unit, the frequency and 
route of administration, the start and discontinuation date and the reason for therapy. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the Investigator should contact Covance before randomizing a subject or, 
if the subject is already enrolled, to determine if the subject should continue participation in the 
study. 
During the study, in the event the Investigator elects to start the patient on chronic antithrombotic 
therapy, anticoagulation or antiplatelet therapy should not be started until the patient’s aPTT has 
returned to baseline. 
Reporting medication errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient/subject or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
All study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the Dose Administration Record CRF. Study treatment errors are only to be reported to Covance 
DSS department if the treatment error is associated with an SAE. 
All instances of misuse or abuse must be documented in the AE CRF irrespective of the 
misuse/abuse being associated with an AE/SAE. In addition, all instances of misuse or abuse must 
be reported to the Covance DSS department. As such, instances of misuse or abuse are also to be 
reported using the SAE form/CRF. Table 3 summarizes the reporting requirements. 
 
 
 
Page 42 of 212

Anthos Therapeutics 
Page 35 
AFib Protocol Amendment 2 
Protocol No. ANT-004 
Table 3: 
Summary of reporting requirements for medication errors 
Treatment error type 
Document in Dose 
Administration CRF 
Document in AE CRF 
Complete SAE 
form/CRF 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see Section 7.6.1 and 
Section 7.6.2, respectively. 
6.2. 
Study restrictions 
Pregnancy and contraception 
Women of child-bearing potential are not permitted to participate in this study, unless they agree 
to use highly effective methods of contraception during their time in the study. 
During their time in the study, sexually active male subjects must agree to use highly effective 
methods of contraception and should not father a child or donate sperm in this period.  
Prohibited treatment 
Use of the following medications is not allowed during the course of the study from screening 
(Visit 1) through the EoS. Patients who are receiving such medication(s) will be excluded, or if 
ethically and clinically justified, the medication(s) should be gradually withdrawn at least seven 
days before the baseline visit: 
•
Use of chronic antiplatelet agents such as clopidogrel or ticagrelor is prohibited; however,
use of low-dose aspirin (≤100 mg per day) is permitted.
•
Use of chronic systemic anticoagulants such as warfarin, low molecular weight heparin or
heparinoids, or direct oral anticoagulants such as apixaban or dabigatran. Patients may be
started on chronic anticoagulation during the Washout/Follow-up period once their aPTT
has returned to baseline, at the Investigator’s discretion.
•
Use of any therapeutic monoclonal antibody regardless of the indication during the study.
Dietary restrictions 
•
No alcohol for 48 hours before each clinic visit (from Screening through the EoS visit).
During the study, alcohol consumption will be restricted to no more than 2 drinks/day for
males and 1 drink/day for females.
•
Patients should not make significant alterations in their diet (e.g., going on weight loss diet)
while in the study.
•
During the study, caffeinated beverages will be restricted to no more than 3 cups/day.
Other restrictions 
No strenuous physical exercise or activities which have an increased risk of injury or falling should 
be undertaken until after the EoS visit. 
Page 43 of 212

Anthos Therapeutics 
 
Page 36 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
6.3. 
Reversal medication 
There is currently no specific antidote for MAA868. FXI concentrates (not marketed in the US) 
are unlikely to be effective as the excess in free MAA868 concentrations in the circulation is 
expected to quickly neutralize the exogenous FXI. 
Recombinant FVIIa can bypass the hypocoagulopathy and restore hemostasis in patients with 
severe FXI deficiency. Administration of intermediate to high doses of rFVIIa (40 to 90 μg/kg) 
resulted in supra-physiological levels of FVII and thromboembolic complications in patients with 
severe FXI deficiency (Riddell et al 2011). Low doses of rFVIIa are associated with lower 
prothrombotic risk. Riddell et al reported their experience in 4 patients with severe FXI deficiency 
undergoing surgery (Riddell et al 2011); patients were administered rFVIIa 30 μg/kg and 
tranexamic acid 1 g i.v. at induction of anesthesia. Subsequent bolus doses of rFVIIa 15–30 μg/kg 
were administered at 2 to 4 hourly intervals as guided by rotational thromboelastometry for 24 48 
hours and tranexamic acid 1 g every 6 hourly for 5 days. Low doses of rFVIIa and tranexamic acid 
were safe and effective in restoring hemostasis in severe FXI deficiency in this study. In another 
study comprising 4 patients with severe FXI deficiency with inhibitor who experienced 5 surgeries 
(Livnat et al 2009), 1 g of tranexamic acid was given 2 hours before surgery, immediately prior to 
the interventions then every 6 hour for at least 7 days; moreover, rFVIIa was administered at doses 
ranging from 15 to 30 μg/kg at the completion of surgery. This protocol secured normal hemostasis 
in patients with severe FXI deficiency with inhibitor. 
Based on the above, rFVIIa can be recommended as a preferred therapeutic option to restore 
hemostasis in subjects with active, non-accessible bleeding site and in subjects requiring 
immediate reversal of the MAA868 PD effects prior to an urgent surgery.  Please see the 
Investigator’s Brochure - Summary of the data and guidance for the investigator for a more 
complete discussion. 
Page 44 of 212

Anthos Therapeutics 
 
Page 37 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
7. 
STUDY ASSESSMENTS AND PROCEDURES 
7.1. 
Assessment schedule 
Subjects should be seen for all visits/assessments as outlined in the assessment schedule (Table 9).  
Missed or rescheduled visits should not lead to automatic discontinuation. Subjects who 
prematurely discontinue the study for any reason should be scheduled for a visit as soon as 
possible, at which time all of the assessments listed for the study treatment discontinuation (TD) 
visit will be performed.  
7.2. 
Informed consent procedures 
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB-approved informed consent. 
The Sponsor, or Sponsor designee, will provide to investigators a proposed informed consent form 
that complies with the ICHE6 Good Clinical Practice (GCP) guideline and regulatory requirements 
and is considered appropriate for this study. The informed consent form will also include a section 
related to optional future research which will require a separate consent checkbox if the subject 
agrees to future research. Any changes to the proposed consent form suggested by the Investigator 
must be agreed to by the Sponsor before submission to the IRB. 
Information about common side effects already known about the investigational drug can be found 
in the IB. This information will be included in the subject informed consent and should be 
discussed with the subject during the study as needed. Any new information regarding the safety 
profile of the investigational drug that is identified between IB updates will be communicated as 
appropriate, for example, via an Investigator Notification or an Aggregate Safety Finding. New 
information might require an update to the informed consent and then must be discussed with the 
subject. 
Ensure subjects are informed of the contraception requirements outlined in the Section 4.2 
(Exclusion criteria). 
A copy of the approved version of all consent forms must be provided to the Covance monitor 
after IRB approval. 
7.3 
Subject screening 
In general, it is permissible to re-screen a subject if s/he fails the initial Screening or falls out of 
the screening window timelines; however, each case must be discussed and agreed with the 
Sponsor Medical Monitor on a case-by-case basis. A new screening number will be assigned to a 
subject who is re screened, thus no screening number will be used twice. 
Reasons for screen failure will be documented in the site log. 
7.4 
Subject demographics/other baseline characteristics 
Subject demographic and baseline characteristic data will be collected on all subjects. Relevant 
medical history/current medical conditions data will also be collected until signature of informed 
consent.  
Page 45 of 212

Anthos Therapeutics 
Page 38 
AFib Protocol Amendment 2 
Protocol No. ANT-004 
Investigators have the discretion to record abnormal test findings on the medical history CRF, if 
in their judgment, the test abnormality occurred prior to the informed consent signature. 
Hepatitis screen, HIV screen 
All subjects will be screened for HIV, Hepatitis B and C. 
Alcohol test and drug screening 
All subjects will be screened for alcohol and substances of abuse. 
7.5 
Efficacy Assessments 
The PD samples will be collected at the timepoints defined in the Assessment schedule (Table 9). 
Follow instructions outlined in the Central Laboratory Manual regarding sample collection, 
numbering, processing and shipment. 
In order to better define the PD profile, the timing of the sample collection may be altered based 
on emergent data. The number of samples/blood draws and total blood volume collected will not 
exceed those stated in the Laboratory Manual. 
PD samples will be obtained and evaluated in all subjects at all dose levels. 
7.5.1 Free FXI 
Free FXI concentrations (FXI that is not bound to MAA868) will be measured in plasma. A 
detailed description of the assay methods will be included in the Bioanalytical Data Report. 
7.5.2 aPTT 
aPTT, calibrated for FXI deficiency, and aPTT using a standard laboratory protocol and/or point 
of care device will be measured at all timepoints indicated in the Assessment schedule (Table 9). 
aPTT will be determined in plasma. The detailed method descriptions of the assay will be included 
in the Bioanalytical Data Report. 
7.5.3 Total FXI 
Total FXI concentrations (FXI that is either bound to MAA868 or free) will be measured in plasma. 
A detailed description of the assay methods will be included in the Bioanalytical Data Report. 
7.5.4 FXI coagulation activity (FXI:C) 
FXI:C will be measured in plasma. A detailed description of the assay methods will be included 
in the Bioanalytical Data Report. 
7.6 
Safety Assessments 
Safety assessments are specified below; assessments will be collected as specified in the 
Assessment Schedule (Table 9). 
Bleeding 
All suspected bleeding events will be documented by the Investigator in the appropriate CRF. All 
documentation regarding suspected bleeding events will be forwarded for adjudication. The central 
Page 46 of 212

Anthos Therapeutics 
Page 39 
AFib Protocol Amendment 2 
Protocol No. ANT-004 
independent adjudication committee (CIAC) will classify the bleeding events as major bleeding, 
CRNM bleeding, nuisance bleeding, or no bleeding. For definition of major bleeding the criteria 
of the International Society of Thrombosis and Haemostasis (ISTH) for non-surgical patients 
(Schulman et al 2005) is referred to. Further definitions can be found in the CIAC charter.  
The members of the CIAC will be blinded to treatment assignment. Further details and procedures 
surrounding adjudication of bleeding events are in the CIAC charter.  
The population is those who have received at least one dose of the study drug.  
Major cardiovascular, cerebrovascular, and venous thromboembolic events 
All suspected major cardiovascular, cerebrovascular, and VTE events will be documented by the 
Investigator in the appropriate CRF including any diagnostic imaging that was used to confirm the 
event. For instance, any suspected episodes of DVT (i.e., swelling, localized pain, redness, heat, 
localized warmth) must be documented by compression ultrasound (CUS) or venography.  
Any suspected episodes of PE (i.e., shortness of breath, chest pain, coughing, tachycardia, 
hemoptysis, hemodynamic compromise, unexplained death) must be documented by 
ventilation/perfusion lung scintigraphy, spiral computed tomography (sCT), or pulmonary 
angiography. 
All major cardiovascular, cerebrovascular, systemic arterial, and venous thromboembolic events 
(VTEs) including deaths for which a major cardiovascular, cerebrovascular, or VTE event could 
not be ruled out will be adjudicated by experienced medical personnel that is blinded to treatment 
assignment. 
The adjudicated outcome will be the basis for any interim and final safety evaluations. 
7.6.1 
Adverse Events 
An AE is any untoward medical occurrence [i.e., any unfavorable and unintended sign (including 
abnormal laboratory findings), symptom or disease] in a subject or clinical investigation subject 
after providing written informed consent for participation in the study until the EoS visit. 
Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal 
(investigational) product. 
In addition, all reports of intentional misuse and abuse of the study treatment are also considered 
an AE irrespective if a clinical event has occurred. See Section 7.6.2 for an overview of the
reporting requirements. 
The occurrence of AEs must be sought by non-directive questioning of the subject at each visit 
during the study. AEs also may be detected when they are volunteered by the subject during or 
between visits or through physical examination finding, laboratory test finding, or other 
assessments. 
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria: 
•
they induce clinical signs or symptoms,
•
they are considered clinically significant,
•
they require therapy.
Page 47 of 212

Anthos Therapeutics 
Page 40 
AFib Protocol Amendment 2 
Protocol No. ANT-004 
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in healthy subjects. 
Investigators have the responsibility for managing the safety of individual subject and identifying 
AEs. Alert ranges for liver and kidney related events are included in Appendix 1 and Appendix 2, 
respectively. Additional clinically notable laboratory values are included in Appendix 3. 
AEs must be recorded on the AE CRF under the signs, symptoms or diagnosis associated with 
them, and accompanied by the following information: 
1. Severity grade
•
mild: usually transient in nature and generally not interfering with normal activities
•
moderate: sufficiently discomforting to interfere with normal activities
•
severe: prevents normal activities
2. Relationship to the study treatment
•
Related
•
Possibly related
•
Not related
3. Duration (start and end dates) or if the event is ongoing an outcome of not recovered/not resolved 
must be reported.
4. Whether it constitutes a SAE (see Section 7.6.2 for definition of SAE) and which seriousness 
criteria have been met
5. Action taken regarding investigational treatment.
All AEs must be treated appropriately. Treatment may include one or more of the following: 
•
no action taken (e.g. further observation only)
•
concomitant medication or non-drug therapy given
•
hospitalization/prolonged hospitalization (see Section 7.6.2 for definition of SAE)
6.
Outcome 
(not 
recovered/not 
resolved; 
recovered/resolved; 
recovering/resolving,
recovered/resolved with sequelae; fatal; or unknown).
Information about common side effects already known about the investigational drug can be found 
in the IB. Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent, and assessment should be made at each visit (or more frequently, if necessary) of any 
changes in severity, the suspected relationship to the investigational drug, the interventions 
required to treat it, and the outcome. 
The Investigator must also instruct each subject to report any new AE (beyond the protocol 
observation period) that the subject, or the subject’s personal physician, believes might reasonably 
be related to study treatment. This information must be recorded in the Investigator’s source 
documents; however, if the AE meets the criteria of an SAE, it must be reported to Covance. 
Page 48 of 212

Anthos Therapeutics 
Page 41 
AFib Protocol Amendment 2 
Protocol No. ANT-004 
7.6.2 
Reporting Serious Adverse Events 
Definition of SAE 
An SAE is defined as any AE [appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s) or medical conditions(s)] which meets any one of the following criteria: 
•
is fatal or life-threatening
•
results in persistent or significant disability/incapacity
•
constitutes a congenital anomaly/birth defect
•
requires inpatient hospitalization or prolongation of existing hospitalization, unless
hospitalization is for:
o
elective or pre-planned treatment for a pre-existing condition and has not worsened
since the start of study drug
o
treatment on an emergency outpatient basis for an event not fulfilling any of the
definitions of a SAE given above and not resulting in hospital admission
o
social reasons and respite care in the absence of any deterioration in the subject’s
general condition
o
is medically significant, e.g. defined as an event that jeopardizes the subject or may
require medical or surgical intervention
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (see Annex IV, ICH-E2D Guideline). 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse (see Annex IV, ICH-E2D Guideline). 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All AEs (serious and non-serious) are captured on the CRF; SAEs also require individual reporting 
to Covance Drug Safety & Epidemiology (DS&E). 
SAE Reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last planned study assessment, must be 
reported to Covance within 24 hours of learning of its occurrence as described below. Any SAEs 
Page 49 of 212

Anthos Therapeutics 
Page 42 
AFib Protocol Amendment 2 
Protocol No. ANT-004 
experienced after this period should only be reported to Covance if the Investigator suspects a 
causal relationship to study treatment. 
Note: SAEs reported by subjects deemed to be screen failures must be reported to Covance as 
outlined here with appropriate information also captured in the CRFs. 
All follow-up information for the SAE including information on complications, progression of the 
initial SAE and recurrent episodes must be reported as follow-up to the original episode within 24 
hours of the Investigator receiving the follow-up information. An SAE occurring at a different 
time interval or otherwise considered completely unrelated to a previously reported one must be 
reported separately as a new event. 
Follow- up information provided must describe whether the event has resolved or continues, if and 
how it was treated, whether the blind was broken or not (if applicable) and whether the subject 
continued or withdrew from study participation. Each re-occurrence, complication, or progression 
of the original event must be reported as a follow-up to that event regardless of when it occurs. 
If the SAE is not previously documented in the IB (new occurrence) and is thought to be related 
to the study treatment a Covance DS&E associate may urgently require further information from 
the Investigator for Health Authority reporting. Covance may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will 
be collected and reported to the competent authorities and relevant ethics committees in 
accordance with EU Guidance 2011/C 172/01 or as per national regulatory requirements in 
participating countries. 
Follow the detailed instructions outlined in the Safety Management Plan regarding the submission 
process for reporting SAEs to Covance. Note: SAEs must be reported to Covance within 24 hours 
of the Investigator learning of its occurrence/receiving follow-up information. 
7.7 
Liver safety monitoring 
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of liver 
events must be followed. 
Please refer to Appendix 1 for complete definitions of liver events. 
Follow-up of liver events 
Every liver event defined in Appendix 1  should be followed up by the Investigator or designated 
personnel at the trial site, as summarized below. Additional details on actions required in case of 
liver events are outlined in Table 4 of Appendix 1. 
•
Repeating liver chemistry tests (ALT, AST, total bilirubin (TBL), PT/INR, ALP and γGT)
to confirm elevation as soon as possible
These liver chemistry repeats should always be performed using the central laboratory,
with the results provided via the standard electronic transfer. If results are needed quickly
then the repeats can also be performed at a local laboratory to monitor the safety of the
subject. If a liver event is subsequently reported, any local liver chemistry tests previously
Page 50 of 212

Anthos Therapeutics 
Page 43 
AFib Protocol Amendment 2 
Protocol No. ANT-004 
conducted that are associated with this event should be available to Covance and the 
Sponsor. 
•
If the initial elevation is confirmed, close observation of the subject will be initiated, 
including consideration of treatment interruption if deemed appropriate.
•
Discontinuation of the investigational drug (refer to Section 4.3 (Discontinuation of study 
treatment), if appropriate
•
Hospitalization of the subject if appropriate
•
Causality assessment of the liver event
•
Thorough follow-up of the liver event should include
o
Repeating liver chemistry tests two or three times weekly. Testing should include 
ALT, AST, ALP, PT/INR, and γGT. If total bilirubin is elevated > 2 x ULN, 
fractionation into direct and indirect bilirubin is required. To rule out muscular 
origin of transaminase elevations, CPK should be measured along with liver 
chemistry tests. Frequency of retesting can decrease to once a week or less if 
abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic. Retesting should be continued up to resolution.
o
Obtaining a more detailed history of symptoms and prior or concurrent diseases.
o
Obtaining a history of concomitant drug use (including non-prescription 
medications and herbal and dietary supplement preparations), alcohol use, 
recreational drug use, and special diets.
o
Exclusion of underlying liver disease, as specified in Table 6.
o
Imaging such as abdominal US, CT or MRI, as appropriate
o
Obtaining a history of exposure to environmental chemical agents.
o
Considering gastroenterology or hepatology consultations.
All follow up information, and the procedures performed must be recorded as appropriate in the 
CRF. 
7.8 
Renal safety monitoring 
Renal laboratory alerts and renal events must be followed up by the Investigator or designated 
personnel at the trial site. Recommended follow-up assessments are listed in Appendix 2. 
7.9 
Pregnancy 
All female study participants, regardless of the requirement to be of non-child-bearing potential to 
be enrolled into this study, will have pregnancy testing. See the Assessment Schedule (Table 9), 
for timing of the protocol required pregnancy testing; additional pregnancy testing may be 
performed to meet local requirements*. Subjects will not receive study medication in case of a 
positive urine or serum pregnancy test. 
*If additional pregnancy testing is needed per local requirements, those additional results will be
kept as source documentation only.
Page 51 of 212

Anthos Therapeutics 
Page 44 
AFib Protocol Amendment 2 
Protocol No. ANT-004 
Pregnancy reporting 
Reproductive toxicity and teratogenicity data are not available for this antibody at this time, 
therefore no guidelines on therapeutic recommendations in case of pregnancy are available. This 
study enrolls women who are considered to be of non-child-bearing potential, thus pregnancy is 
not an expected outcome for any female study participant. However, in the case that a pregnancy 
in a female study participant should occur please follow the below reporting guidelines. The 
follow-up for this subject and for the fetus is at the discretion of the Investigator. 
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Covance within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of the 
birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications. 
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
Investigator to the local Covance DSS department. Pregnancy follow-up should be recorded on 
the same form and should include an assessment of the possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported on a 
SAE form. 
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes should 
be obtained from the mother. 
All assessments that are considered as a risk during pregnancy must not be performed. The subject 
may continue all other protocol assessments. 
7.10 
Clinical Laboratory Evaluations 
Clinically relevant deviations of laboratory test results occurring during or at completion of the 
study must be reported and discussed with Covance personnel. The results should be evaluated for 
criteria defining an AE and reported as such if the criteria are met. Repeated evaluations are 
mandatory until normalization of the result(s) or until the change is no longer clinically relevant. 
In case of doubt, Covance personnel should be contacted. 
Safety labs (hematology, clinical chemistry and urinalysis) do not need to be repeated at baseline 
if the Baseline visit is taking place within 48 hours of the screening labs being collected from an 
individual subject. 
Subjects should be instructed to fast for at least 8 hours prior to scheduled safety lab collections. 
Clinically notable laboratory findings are defined in Appendix 3. 
Hematology 
Hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell (WBC) count with 
differentials and platelet count will be measured. 
Clinical chemistry 
Sodium, potassium, creatinine, BUN/urea, uric acid, chloride, albumin, calcium, alkaline 
phosphatase, total bilirubin, bicarbonate/HCO3, LDH, GGT, AST, ALT, CK, glucose, total 
Page 52 of 212

Anthos Therapeutics 
Page 45 
AFib Protocol Amendment 2 
Protocol No. ANT-004 
cholesterol, triglycerides. If the total bilirubin concentration is increased above 1.5 times the upper 
limit of normal, direct and indirect reacting bilirubin should be differentiated. 
Urinalysis 
 Measurements for specific gravity, protein, glucose and blood will be performed. Microscopy, 
WBC, RBC and sediments will also be assessed in case of an abnormal  test result. 
Special clinical laboratory evaluations 
Stool samples will be collected to check for occult blood at screening and baseline. Screening fecal 
samples can be collected at any time during the Screening period, and baseline fecal samples must 
be collected within 72 hours of Day 1. If fecal screening samples are collected within 72 hours of 
Day 1, then they do not need to be repeated for the Baseline visit. In the event that a subject is 
unable to produce a stool sample for sampling, the site medical staff may elect to produce a sample 
via digital extraction from the rectum. 
Details regarding collection methods and processing are outlined in the Central Laboratory 
Manual. 
7.11 
Vital Signs, Physical Examination, and Other Safety Evaluations 
Vital signs will include the collection of oral body temperature (recorded in °C), blood pressure 
(BP)–sitting and standing –and pulse measurements. At Screening, for eligibility determination, 
three sets of systolic and diastolic BP and pulse rate measurements will be collected after the 
subject has been sitting for 3 minutes, with back supported and both feet placed on the floor and 
the mean will be used to determine eligibility. A single set of BP and pulse rate measurements will 
then be collected after three minutes in the standing position.  
A single set of sitting BP measurements will be collected at subsequent visits. 
Physical exams will include assessment of general appearance, skin, lymph nodes, HEENT, neck, 
thorax/lungs, cardiovascular, abdomen, musculoskeletal, and neurological systems. 
Height in centimeters (cm) and body weight [to the nearest 0.1 kilogram (kg) in indoor clothing, 
but without shoes] will be measured. Body mass index (BMI) will be calculated using the 
following formula: 
BMI = Body weight (kg) / [Height (m)]2. BMI results will be documented in the CRF to 2 decimal 
places. 
7.12 
Electrocardiogram (ECG) 
The ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable baseline. 
PR interval, QRS duration, heart rate, RR interval, QT, QT corrected by the Fridericia correction 
formula (QTcF) will be collected. The QTcF should be used for clinical decision-making. ECGs 
must be collected, analyzed and appropriately signed and archived at the study site; the site will 
also store all ECG readings digitally (if possible). For any ECGs with subject safety concerns, 
duplicate ECGs must be performed to confirm the safety finding. Clinically significant ECG 
findings at baseline must be discussed with the Sponsor before administration of study treatment. 
Clinically significant abnormalities must be reported in the AE CRF. 
Page 53 of 212

Anthos Therapeutics 
Page 46 
AFib Protocol Amendment 2 
Protocol No. ANT-004 
7.13Pharmacokinetic Analysis 
The PK samples will be collected at the timepoints defined in the Assessment schedule (Table 9). 
Follow instructions outlined in the Central Laboratory Manual regarding sample collection, 
numbering, processing and shipment. See Section 7.15 regarding the potential use of residual 
samples. 
In order to better define the PK profile, the timing of the PK sample collection may be altered 
based on emergent data. The number of samples/blood draws and total blood volume collected 
will not exceed those stated in the Laboratory Manual. Changes to the PK Assessment schedule, 
if any, will be communicated to the sites in the dose adjustment minutes. 
The PK samples will be obtained and evaluated in all subjects at all dose levels. Untreated 
(placebo) samples will not be analyzed. 
Concentrations of plasma total MAA868 (i.e. MAA868 that is bound to FXI or not bound to FXI) 
will be determined by a validated LC-MS/MS method. A detailed description of the method used 
to quantify the concentration of total MAA868 will be included in the bioanalytical raw data and 
in the Bioanalytical Data Report. 
All concentrations below the LLOQ or missing data will be labeled as such in the concentration 
data listings. 
For standard PK abbreviations and definitions see the list provided at the beginning of this 
protocol. 
The following PK parameters will be determined, where data permit, using the actual recorded 
sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 6.2 or 
higher): C0 (the concentration at the end of infusion), AUClast, AUCinf, C0/D, and AUC/D, based 
on the plasma concentration data.  
The linear trapezoidal rule will be used for AUC calculation. The terminal half-life of MAA868 
(T1/2), volume of distribution (Vss) and clearance (CL) will also be estimated, if feasible, based on 
the data. 
7.14 
Other assessments 
7.14.1 
Exploratory Biomarker assessments 
Biomarkers including, but not limited to, D-Dimer and biomarkers of thrombogenesis and 
coagulation may also be studied. 
The list may be changed or expanded further, as it is recognized that more relevant or novel 
biomarkers may be discovered during the conduct of the study. 
Sample(s) will be collected at the timepoint(s) defined in the Assessment schedule (Table 9). 
Follow instructions for sample collection, numbering, processing and shipment provided in the 
central lab manual. Detailed descriptions of the assays will be included in the Bioanalytical Data 
Reports. 
7.14.2 
Immunogenicity (IG) 
The IG samples will be collected at the timepoints defined in the Assessment schedule (Table 9). 
Page 54 of 212

Anthos Therapeutics 
Page 47 
AFib Protocol Amendment 2 
Protocol No. ANT-004 
Follow instructions outlined in the Central Laboratory Manual regarding sample collection, 
numbering, processing, and shipment. See Section 7.15egarding the potential use of residual 
samples. 
Immunogenicity analytical method(s) 
A ligand-binding assay will be used to detect anti-MAA868 antibodies. The analytical method will 
be described in detail in the IG Bioanalytical Data Report. 
7.15 
Use of residual biological samples 
Residual blood samples may be used for another protocol specified endpoint. 
Any residual samples remaining after the protocol-defined analysis has been performed may be 
used for additional exploratory analysis. This may include but is not limited to using residual 
samples for protein binding, metabolite profiling, biomarkers of transporters or metabolic enzyme 
activity (such as 4-beta-hydroxycholesterol levels) or other bioanalytical purposes (e.g. cross 
check between different sites and/or stability assessment). Given the exploratory nature of the 
work, the analytical method used for those assessments may not be validated. As such, the results 
from this exploratory analysis will not be included in the clinical study report. 
Page 55 of 212

Anthos Therapeutics 
Page 48 
AFib Protocol Amendment 2 
Protocol No. ANT-004 
8.
SAMPLE SIZE AND DATA ANALYSES
8.1. 
Determination of Sample Size
A sample size of 16 subjects per treatment dose cohort with a ratio of 3:1 for MAA868 and placebo 
treatment assignment is based on historic data considerations. For example, if the observed 
proportion of patients in a cohort achieving target levels of inhibition is 11/12, the 90% confidence 
interval would be 0.66 to 0.996. 
8.2. 
Analysis Populations 
All Randomized Set will include all subjects who are randomized 
Full Analysis Set will include randomized subjects excluding those subjects who are randomized 
into the study in error and did not receive study drug. Subjects will be analyzed based on the 
assigned treatment at the randomization.  
Per Protocol Set will include subjects in Full Analysis Set and those subjects have no major 
protocol deviation after randomization.  
Safety Set will include randomized subjects who at least received one dose of study drug. Subjects 
will be analyzed based on the actual treatment taken. 
PK/PD Analysis Set will comprise all subjects who received at least one dose of study drug and 
have at least one PK/PD assessment. Subjects will be analyzed based on the actual treatment taken. 
8.3. 
General Considerations 
All efficacy analysis will be based on the Full Analysis Set or Per Protocol Set and will be 
performed based on the assigned treatment arm at the randomization. Only descriptive statistics 
will be summarized, no statistical inference will be calculated in efficacy.  
Safety analysis will be performed using Safety Set. Subjects will be analyzed based on the actual 
treatment taken. 
PK and PD analysis will be based on PK/PD Analysis Set. 
Continuous variables will be summarized by number of subjects [n], mean, standard deviation 
[SD], median, minimum [min], and maximum [max]. Categorical variable will be summarized 
using frequency [N] and percentage [%]. 
8.4. 
Demographics and Baseline characteristics 
All baseline summaries will be based on the All Randomized Set and Full Analysis Set 
populations. 
Gender, race and ethnicity will be summarized using counts and percentages. Age, height (cm), 
and weight (kg) will be summarized with descriptive statistics (number of subjects [n], mean, SD, 
median, minimum [min], and maximum [max]). Age may be summarized by decades using N and 
%. 
The listing of subjects with abnormal physical examination findings at screening will be presented. 
The number and percent of subjects with medical history events will be summarized. Vital signs 
Page 56 of 212

Anthos Therapeutics 
Page 49 
AFib Protocol Amendment 2 
Protocol No. ANT-004 
collected at screening (sitting diastolic and systolic blood pressure, pulse, temperature and body 
weight) will be summarized with descriptive statistics (n, mean, SD, median, min, and max). 
8.5. 
Efficacy Analysis 
Primary Efficacy Outcome Measures 
Within each treatment cohort patients will be randomized 3:1 to active drug or placebo. 
The primary analysis variable is whether a subject will achieve a certain percentage FXI inhibition 
at trough (Day 91). The response rate per treatment group will be calculated by number of subjects 
who achieve targeted FXI inhibition rate divided by the total number of subjects in the treatment 
group. The dose regimens and targeted FXI inhibition achievement for Cohorts 1 and 2 are as 
follows  
Cohort 1 (MAA868 120 mg monthly or placebo): Targeted to achieve ≥ 50% FXI inhibition in 
90% of subjects at trough (Day 91).  
Cohort 2 (MAA868 180 mg monthly or placebo): Targeted to achieve ≥ 90% FXI inhibition in 
90% of subjects at trough (Day 91). 
The “on treatment” trough FXI levels will be used for the primary analysis, where “on treatment” 
FXI level is defined as a value which is collected within 30 (±5) days after the last administration 
of MAA868. The estimate of the responder rate (%) at Day 91 will be presented for each dose 
regimens of MAA868 together with 2-sided 90% confidence intervals (CI) computed via the 
Clopper-Pearson exact binomial method. 
Secondary Efficacy Outcome Measures 
The secondary efficacy analysis is to evaluate the proportion of subjects achieving FXI inhibition 
≥ 50%, ≥80%, and ≥90% at trough after the first and second dose (Day 31 and Day 61) at 3 dose 
levels of MAA868. The analyses described for the primary endpoint will be repeated for the 
secondary efficacy variables as follows: 
•
Cohort 1 (MAA868 120 mg monthly or placebo): at Day 31 and 61.
•
Cohort 2 (MAA868 180 mg monthly or placebo):  at Day 31 and 61
•
Cohort 3 (MAA868 TBD mg monthly or placebo): at Day 31 and 61
8.6. 
Safety Analysis 
The safety evaluation includes the analysis of bleeding events, AEs, major cardiovascular, 
cerebrovascular, systemic arterial, and venous thromboembolism events, laboratory data, ECG, 
vital signs, hypersensitivity reactions, injection site reactions, and development of anti-drug 
antibodies. All safety analysis will be performed using the Safety Set. 
Adverse Events 
The Investigator’s verbatim term of each AE will be mapped to system organ class (SOC) and 
preferred term (PT) using the MedDRA dictionary. 
Page 57 of 212

Anthos Therapeutics 
Page 50 
AFib Protocol Amendment 2 
Protocol No. ANT-004 
Treatment-emergent Adverse Events (TEAEs) will be of primary interest. The TEAEs will be 
summarized by SOC and PT; a subject will only be counted once per SOC and once per PT within 
a treatment. If a subject reports more than one AE with the same PT, the AE with the maximum 
severity will be presented. Subject counts and percentages and event counts will be presented for 
each treatment and totaled for all treatments for the following summaries: 
•
All TEAEs
•
Serious TEAEs
•
All TEAEs by severity
•
All TEAEs by relationship to study drug
•
TEAEs potentially related to study drug
•
TEAEs potentially related to study drug by severity
•
TEAEs leading to discontinuation of study drug
•
TEAEs leading to withdrawal from the study
Adverse events of special interest (AESI) will be reported for a selection of interested AE terms 
that are specific to Sponsor’s product and program, for which ongoing monitoring and rapid 
communication by the Investigator to the Sponsor can be appropriate. 
The AESIs for this study are defined as follows: 
1.
TERM 1
2.
TERM 2
Similarly, to the TEAE summary, the AESI will be summarized in the following: 
1.
All AESIs
2.
Serious AESIs
3.
All AESIs by severity
4.
All AESIs by relationship to study drug
5.
AESIs leading to discontinuation of study drug
6.
AESIs leading to withdrawal from the study
No statistical inference between the treatments will be performed on AEs. 
Listings will be presented by subject for all TEAEs, AESIs, as well as for SAEs, TEAEs associated 
with outcome of death, and TEAEs leading to discontinuation from the study. 
Bleeding Events 
An analysis will be performed for the composite safety endpoint of major and CRNM bleeding 
events which occur on-treatment from the first dose of the study drug to the last dose of the study 
drug + 30 days if the subject permanently discontinues the study drug prior to the third dose on 
Day 91. The number of events and the incidence of adjudicated bleeding events will be tabulated 
Page 58 of 212

Anthos Therapeutics 
Page 51 
AFib Protocol Amendment 2 
Protocol No. ANT-004 
based on ISTH definition by treatment including the composite endpoint of major bleeding events 
and/or CRNM bleedings.  
Major bleeding events (Yes/No) 
CRNM bleeding events (Yes/No) 
Total bleeding events (Yes/No) 
If a subject has more than one bleeding event in each above category, the subject will be counted 
only once in the tabulation. 
The adjudicated outcome by the CIAC will be the basis for any interim and final analysis. 
Major cardiovascular, cerebrovascular, and venous thromboembolic events 
An analysis will be performed for the composite safety endpoint of major cardiovascular, 
cerebrovascular, and venous thromboembolic events which occur on-treatment from the first dose 
of the study drug to the last dose of the study drug + 30 days if the subject permanently discontinues 
the study drug prior to the third dose on Day 91.   
The number of events and the incidence of adjudicated events will be tabulated based on the 
outcomes adjudicated by experienced medical personnel, and the adjudicated outcome will be the 
basis for any interim and final analysis. 
Clinical Laboratory Evaluations 
Clinical laboratory results in continuous values at each timepoint and for change from baseline 
will be displayed using summary statistics (n, mean, median, SD, minimum and maximum values). 
A laboratory value that is within the central laboratory’s reference range will be considered normal. 
A laboratory value that is outside the central laboratory’s normal range will be considered 
abnormal and will be flagged as either high (H) or low (L). The number and percentage of subjects 
with abnormal laboratory values will be summarized for each scheduled visit. In addition, shift 
tables will be presented to display the shift in the normal range categories (L, normal [N], H) from 
baseline to specified timepoint. Laboratory results in clinical significance will also be summarized 
in tabulation. 
All clinical laboratory data will be presented in listings. Baseline is defined as the result obtained 
prior to first administration of study medication. Laboratory data will be summarized in SI units. 
Vital Sign Measurements 
Pre-dose values, post-dose values, and the change from baseline in vital sign measurements (sitting 
diastolic and systolic blood pressure, pulse, temperature and body weight) will be summarized 
with descriptive statistics (n, mean, SD, median, min, and max) at each timepoint by treatment. 
The baseline value will be value just prior to first administration of study medication. 
ECG Parameters 
The ECG measures ( QTc-F, QT, RR, ventricular rate, PR, and QRS) will be listed and summarized 
with descriptive statistics (n, mean, SD, median, min, and max) at each timepoint by treatment. 
Page 59 of 212

Anthos Therapeutics 
Page 52 
AFib Protocol Amendment 2 
Protocol No. ANT-004 
The listings of subjects with abnormal ECG results, as judged by the Investigator, will be displayed 
and will be calculated. The baseline will be the value just prior to first administration of study 
medication. 
8.7. 
Pharmacokinetic Analysis 
Descriptive summary statistics will be provided by treatment and visit/sampling timepoint with 
descriptive statistics (n, mean, SD, median, min, and max) at each timepoint by treatment. An 
exception to this is Tmax where median, minimum and maximum will be presented. 
Concentrations below the lower limit of quantitation (LLOQ) will be treated as zero in summary 
statistics and for PK parameter calculations. A geometric mean will not be reported if the dataset 
includes zero values. 
Individual total MAA868 plasma concentration data will be listed by treatment (MAA868 arms 
only), subject, and visit/sampling timepoint. PK parameters will also be listed by treatment and 
subject. 
8.8. 
Biomarkers 
Coagulation parameters, including free and total FXI, FXI:C, and immunogenicity will be 
summarized by timepoint and treatment. 
8.9. 
Interim Analysis (IA) 
Safety and tolerability data (AEs, laboratory assessments, vital signs and ECG data) will be 
evaluated from Cohort 1 by the Sponsor's Medical Monitor  and Covance Lead Project Physician 
after approximately 10 of the patients in cohort 1 have received their second dose of study drug 
and have been followed for at least an additional 14 days. The decision to proceed to cohort 2 will 
be made only after it is confirmed that the cohort 1 dose was safe and well tolerated. and the 
Sponsor determines there is adequate data to proceed to cohort 2. If notable AEs or safety concerns 
are found in cohort 1, the study may be terminated.  
Likewise, after approximately 10 of the patients in cohort 2 have received their second dose of 
study drug and have been followed for at least an additional 14 days, safety, tolerability, and other 
analyses will be evaluated.  
Additional IAs may be conducted to support decision making at any time concerning the current 
clinical study, the Sponsor’s clinical development projects in general or in case of any emergent 
safety concerns. The Investigator(s) may be included for decisions with regards to any unplanned 
IAs that address questions of subject safety. 
Unblinded IA results will be reviewed by the Sponsor (or their designees). 
No further dissemination of interim results should occur, in particular not with individuals 
involved in treating the study’s subjects or assessing clinical data (e.g. ECGs, symptoms) obtained 
in the study. 
8.10. 
Data Quality Assurance 
Site monitoring 
Page 60 of 212

Anthos Therapeutics 
Page 53 
AFib Protocol Amendment 2 
Protocol No. ANT-004 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Covance 
representative will review the protocol and CRFs with the Investigator(s) and their staff. During 
the study Covance employs several methods of ensuring protocol and GCP compliance and the 
quality/integrity of the sites’ data. The monitor will visit the site to check the completeness of 
subject records, the accuracy of entries on the CRFs, the adherence to the protocol and to GCP, 
the progress of enrollment, and ensure that study drug is being stored, dispensed, and accounted 
for according to specifications. Key study personnel must be available to assist the monitor during 
these visits. 
The Investigator must maintain source documents for each subject in the study, consisting of case 
and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or assessments. 
All information on CRFs must be traceable to these source documents in the subject's file. The 
Investigator must also keep the original informed consent form signed by the subject (a signed 
copy is given to the subject). 
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Covance monitoring standards require full verification for the 
presence of informed consent, adherence to the eligibility criteria, documentation of SAEs, and 
the recording of data that will be used for all primary and safety variables. Additional checks of 
the consistency of the source data with the CRFs are performed according to the study-specific 
monitoring plan. No information in source documents about the identity of the subjects will be 
disclosed. 
Data collection 
Designated Investigator staff will enter the data required by the protocol into the Electronic Case 
Report Forms using fully validated software that conforms to 21 CFR Part 11 requirements. 
Designated investigator site staff will not be given access to the electronic data capture (EDC) 
system until they have been trained. Automatic validation programs check for data discrepancies 
and, by generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to Covance working on behalf of Anthos. The Investigator must certify that the 
data entered into the Electronic Case Report Forms are complete and accurate. After database lock, 
the Investigator will receive copies of the subject data for archiving at the investigational site. 
Data not requiring a separate written record are noted on the Assessment schedule (Table 9) and 
can be recorded directly on the CRF. All other data captured for this study will have an external 
originating source (either written or electronic) with the CRF not being considered as source. 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 
Database management and quality control 
Covance will review the data entered into the eCRFs by investigational staff for completeness and 
accuracy and instruct  the site personnel to make any required corrections or additions. System 
queries are sent to the investigational site using an electronic data query which will appear in eCRF 
once data have been entered and saved. Manual queries will be raised by Data Management in 
eCRF based ongoing manual review. Designated investigator site staff is required to respond to 
the query in the eCRF and confirm or correct the data. 
Page 61 of 212

Anthos Therapeutics 
Page 54 
AFib Protocol Amendment 2 
Protocol No. ANT-004 
Concomitant medications entered into the database will be coded using the WHO Drug Reference 
List, which employs the Anatomical Therapeutic Chemical classification system. Medical 
history/current medical conditions and adverse events will be coded using the Medical dictionary 
for regulatory activities (MedDRA) terminology. 
Laboratory samples will be processed centrally, and the results will be sent electronically to 
Covance. 
At the conclusion of the study, the occurrence of any emergency code breaks will be determined 
after return of all code break reports and unused drug supplies to Covance. 
The occurrence of any protocol deviations will be determined. After these actions have been 
completed and the database has been declared to be complete and accurate, it will be locked, and 
the treatment codes will be unblinded and made available for data analysis. Any changes to the 
database after that time can only be made by joint written agreement between the Anthos Head of 
Regulatory and the Chief Medical Officer. 
Page 62 of 212

Anthos Therapeutics 
Page 55 
AFib Protocol Amendment 2 
Protocol No. ANT-004 
9.
ETHICAL CONSIDERATIONS
9.1. 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for GCP, with applicable local regulations 
(including European Directive 2001/20/EC, US Code of Federal Regulations Title 21, and 
Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in the 
Declaration of Helsinki. 
9.2. 
Responsibilities of the Investigator and IRB 
Before initiating a trial, the Investigator/institution must obtain approval/favorable opinion from 
the IRB for the trial protocol, written informed consent form, consent form updates, subject 
recruitment procedures (e.g. advertisements) and any other written information to be provided to 
subjects. Prior to study start, the Investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents and all of 
the instructions and procedures found in this protocol and to give access to all relevant data and 
records to Covance monitors, auditors, Covance Quality Assurance representatives, designated 
agents of Anthos, IRBs, and regulatory authorities as required. If an inspection of the clinical site 
is requested by a regulatory authority, the Investigator must inform Anthos immediately that this 
request has been made. 
For multi-center trials, a Coordinating Investigator will be selected by Anthos around the time of 
Last Patient Last Visit to be a reviewer and signatory for the CSR. 
9.3. 
Publication of study protocol and results 
The key design elements of this protocol will be posted in a publicly accessible database such as 
clinicaltrials.gov. Upon study completion and finalization of the study report the results of this 
trial will be posted in a publicly accessible database of clinical trial results in accordance with local 
regulations. 
No publication or disclosure of study results will be permitted except under the terms and 
conditions of a separate written agreement between the Sponsor and the investigator and/or the 
investigator's institution.  
The information developed from this clinical study will be used by the Sponsor in connection with 
the development of MAA868 and other drugs and diagnostics, and thus may be disclosed as 
required to other clinical investigators, business partners, or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the Sponsor with all data obtained in the study. 
Page 63 of 212

Anthos Therapeutics 
Page 56 
AFib Protocol Amendment 2 
Protocol No. ANT-004 
10.
PROTOCOL ADHERENCE
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
Investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.  
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an Investigator 
feels a protocol deviation would improve the conduct of the study this must be considered a 
protocol amendment, and unless such an amendment is agreed upon by Anthos and approved by 
the IRB and health authorities, where required, it cannot be implemented. 
10.1. 
Protocol Amendments 
Any change to the protocol can only be made in a written protocol amendment that must be 
approved by Anthos, Health Authorities where required, and the IRB prior to implementation.  
Amendments that are intended to eliminate an apparent immediate hazard to subjects may be 
implemented immediately, provided the Health Authorities are subsequently notified by protocol 
amendment and the reviewing IRB is notified.  
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any subject included in this study, 
even if this action represents a deviation from the protocol. In such cases, the 
reporting requirements identified in Section 7.6.2 (Safety Monitoring) must be followed and 
the Study Lead informed. 
Page 64 of 212

Anthos Therapeutics 
 
Page 57 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
11. 
REFERENCES 
1. Bolton-Maggs (2000) Factor XI deficiency and its management. Haemophilia; 6(S1):100-9. 
2. Buller H, Bethune C, Bhanot S, et al (2015) Factor XI Antisense Oligonucleotide for 
prevention of Venous Thrombosis. N Engl J Med; 372; 3:232-240. 
3. Camm AJ, Lip GY, De Caterina R, et al (2012) 2012 focused update of the ESC Guidelines 
for the management of atrial fibrillation. Eur Heart J; 33:719-47. 
4. Connolly SJ, Ezekowitz MD, Yusuf S, et al (2009) Dabigatran versus warfarin in patients with 
atrial fibrillation. N Engl J Med; 361:1139-51. 
5. Gailani D, Renné T (2007) Intrinsic pathway of coagulation and arterial thrombosis. 
Arterioscler Thromb Vasc Biol; 27:2507-13. 
6. Granger C, Alexander J, McMurray J, et al (2011) Apixaban versus warfarin in patients with 
atrial fibrillation. N Engl J Med; 365:981-92. 
7. Hart RG, Benavente O, McBride R, et al (1999) Antithrombotic therapy to prevent stroke in 
patients with atrial fibrillation: a meta-analysis. Ann Intern Med; 131:492-501. 
8. January CT, Wann LS, Alpert JS, et al (2014) AHA/ACC/HRS guideline for the management 
of patients with atrial fibrillation: a report of the American College of Cardiology/American 
Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll 
Cardiol; 64:e1–76. 
9. Kannel WB, Benjamin EJ (2008) Status of the epidemiology of atrial fibrillation. Med Clin 
North Am; 92:17-40. 
10. Lip GY, Nieuwlaat R, Pisters R, et al (2010) Refining clinical risk stratification for predicting 
stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the 
euro heart survey on atrial fibrillation. Chest; 137(2):263-72. 
11. Livnat T, Tamarin I, Mor Y, et al (2009) Recombinant activated factor VII and tranexamic 
acid are haemostatically effective during major surgery in factor XI-deficient patients with 
inhibitor antibodies. Thromb Haemost; 102:487–92. 
12. Patel MR, Mahaffey KW, Garg J, et al (2011) Rivaroxaban versus warfarin in nonvalvular 
atrial fibrillation. N Engl J Med; 365:883-91. 
13. Piccini JP, Garg J, Patel MR, et al (2014) Management of major bleeding events in patients 
treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. Eur Heart J; 
35:1873-80. 
14. Preis M, Hirsch J, Kotler A et al (2017) Factor XI deficiency is associated with lower risk for 
cardiovascular and venous thromboembolism events. Blood; 129(9):1210-5. 
15. Riddell A, Abdul-Kadir R, Pollard D, et al (2011) Monitoring low dose recombinant factor 
VIIa therapy in patients with severe factor XI deficiency undergoing surgery. Thromb 
Haemost; 106:521-7. 
16. Salomon O, Steinberg DM, Koren-Morag N, et al (2008) Reduced incidence of ischemic stroke 
in patients with severe factor XI deficiency. Blood; 111:4113-7. 
17. Salomon O, Steinberg DM, Zucker M, et al (2011) Patients with severe factor XI deficiency 
have a reduced incidence of deep-vein thrombosis. Thromb Haemost; 105:269-73. 
Page 65 of 212

Anthos Therapeutics 
 
Page 58 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
18. Schulman S, et al (2005) Definition of major bleeding in clinical investigations of 
antihemostatic medicinal products in non-surgical patients.  J Thromb Haemost. 2005 
Apr;3(4):692-4. 
 
Page 66 of 212

Anthos Therapeutics 
 
Page 59 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
12. 
APPENDICES 
 
 
 
Page 67 of 212

Anthos Therapeutics 
 
Page 60 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
12.1. 
Appendix 1 - Liver Event Definitions and Follow-up Requirements 
Table 4: 
Liver Event and Liver-Related Laboratory Alert Definition 
Definition 
Thresholds 
Potential Hy’s law cases 
• 
ALT or AST > 3 X ULN and TBL > 2 × ULN without initial 
increase in ALP to > 2 × ULN 
ALT or AST elevation with 
coagulopathy 
• 
ALT or AST > 3 × ULN and INR > 1.5 (in the absence of 
anticoagulation) 
ALT or AST elevation 
accompanied by symptoms 
• 
ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash, or 
eosinophilia 
Isolated ALT or AST elevation 
• 
ALT or AST > 8 × ULN 
• 
5 x ULN < ALT/AST ≤ 8 x ULN 
• 
3 x ULN  ALT/AST  5 x ULN 
Isolated ALP elevation 
• 
ALP > 2 × ULN (in the absence of known bone pathology) 
Others 
• 
Any clinical event of jaundice (or equivalent term) Any 
adverse event potentially indicative of liver toxicity 
 
 
Table 5: 
Action required for Liver Events and Liver-Related Laboratory Alerts 
Criteria 
Action required 
Potential Hy’s law cases 
ALT or AST elevation with 
coagulopathy 
ALT or AST elevation 
accompanied by symptoms 
Isolated ALT or AST elevation > 
8 X ULN Jaundice 
 
 
• 
Hospitalize, if clinically appropriate 
• 
Establish causality 
• 
Complete CRFs per liver event guidance 
Isolated ALT or AST elevation > 
5 to ≤ 8 X ULN 
• 
Establish causality 
• 
Complete CRFs per liver event guidance 
Isolated ALT or AST elevation > 
3 to ≤ 5 × ULN (patient is 
asymptomatic)  
• 
Monitor liver chemistry tests two or three times weekly 
Isolated ALP elevation 
• 
Repeat liver chemistry tests within 48-72 hours 
• 
If elevation is confirmed, measure fractionated ALP; if 
>50% is of liver origin, establish hepatic causality 
• 
Complete CRFs per liver event guidance 
Any AE potentially indicative of 
liver toxicity 
• 
Hospitalize if clinically appropriate 
• 
Complete CRFs per liver event guidance 
Page 68 of 212

Anthos Therapeutics 
 
Page 61 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
 
 
Table 6: 
Exclusion of underlying Liver Disease 
Disease 
Assessment 
Hepatitis A, B, C, E 
• 
IgM anti-HAV; HBSAg, IgM anti-HBc, HBV DNA; anti-
HCV, HCV RNA, IgM & IgG anti-HEV, HEV RNA 
CMV, HSV, EBV infection 
• 
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG 
anti-EBV 
Autoimmune hepatitis 
• 
ANA & ASMA titers, total IgM, IgG, IgE, IgA 
Alcoholic hepatitis 
• 
Ethanol history, γGT, MCV, CD-transferrin 
Nonalcoholic steatohepatitis 
• 
Ultrasound or MRI 
Hypoxic/ischemic hepatopathy 
• 
Medical history: acute or chronic CHF, hypotension, 
hypoxia, hepatic venous occlusion. Ultrasound or MRI 
Biliary tract disease 
• 
Ultrasound or MRI, ERCP as appropriate 
Wilson disease 
• 
Caeruloplasmin 
Hemochromatosis 
• 
Ferritin, transferrin 
Alpha-1-antitrypsin deficiency 
• 
Alpha-1-anitrypsin 
 
 
Page 69 of 212

Anthos Therapeutics 
 
Page 62 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
12.2. 
Appendix 2 - Specific Renal Alert Criteria and Actions 
Table 7: 
Specific Renal Alert Criteria and Actions 
Criteria 
Action required 
Serum creatinine (sCr) increase 
25 – 49% compared to baseline 
• 
Consider causes and possible interventions 
• 
Follow up within 2-5 days 
Serum creatinine increase ≥ 50% 
• 
Consider causes and possible interventions 
• 
Repeat assessment within 24-48 hours if possible 
• 
Consider hospitalization and specialized treatment 
Protein-creatinine or albumin-
creatinine ratio increase ≥ 2-fold, 
or 
new onset  proteinuria ≥ 1+ , or 
Albumin-creatinine ratio (ACR) ≥ 
30 mg/g or ≥ 3 mg/mmol, or 
Protein-creatinine ratio (PCR) ≥ 
150 mg/g or >15 mg/mmol 
 
• 
Consider causes and possible interventions 
 
• 
Assess serum albumin and serum protein 
 
• 
Repeat assessment to confirm 
New onset glucosuria on urine 
exam (unless related to 
concomitant treatment, diabetes) 
Assess and document: 
• 
Blood glucose (fasting) 
• 
Serum creatinine 
• 
Urine albumin-creatinine ratio 
New hematuria on urine exam 
Assess and document 
• 
Urine sediment microscopy 
• 
Assess sCr and urine albumin-creatinine ratio 
• 
Exclude infection, trauma, bleeding from the distal urinary 
tract/bladder, menstruation 
 
• 
Consider bleeding disorder 
 
 
Additional specialized assessments are available to assess renal function or renal pathology.  
(Note: In exceptional cases when a nephrologist considers a renal biopsy, it is strongly recommended to 
make specimen slides available for evaluation by Anthos to potentially identify project-wide patterns of 
nephrotoxicity.) 
Whenever a renal event is identified, a detailed subject history and examination are indicated to identify, 
document and potentially eliminate risk factors that may have initiated or contributed to the event: 
• 
Blood pressure assessment (after 5 min rest, with an appropriate cuff size) 
• 
Signs and symptoms such as fever, headache, shortness of breath, back or abdominal pain, dysuria, 
hematuria, dependent or periorbital edema 
• 
Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output 
• 
Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic failure, 
contrast media or other known nephrotoxin administration, or other potential causes of renal 
dysfunction, e.g., dehydration, hemorrhage, tumor lysis 
 
Page 70 of 212

Anthos Therapeutics 
 
Page 63 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
 
Table 8: 
Follow-up renal events 
Action 
Follow up 
Assess*, document and record in the CRF or via 
electronic data load. Review and record possible 
contributing factors to the renal event 
(co-medications, other co-morbid conditions) 
and additional diagnostic procedures (MRI etc.) 
in the CRF 
• 
Urine exam and sediment microscopy 
• 
Blood pressure and body weight 
• 
Serum creatinine, electrolytes (sodium, 
potassium, 
phosphate, 
calcium), 
bicarbonate, and uric acid 
• 
Urine output 
Monitor subject regularly (frequency at 
Investigator’s discretion) until: 
• 
Event resolution: (sCr within 10% of 
baseline or protein-creatinine ratio within 
50% of baseline) OR 
• 
Event stabilization: sCr level with ±10% 
variability over last 6 months or protein-
creatinine ratio stabilization at a new level 
with ±50% variability over last 6 months. 
*Urine osmolality: in the absence of diuretics or chronic kidney disease this can be a very sensitive 
metric for integrated kidney function that requires excellent tubular function. A high urinary 
osmolality in the setting of an increase in sCr will point toward a “pre-renal” cause rather than tubular 
toxicity. 
 
 
Page 71 of 212

Anthos Therapeutics 
Page 64 
AFib Protocol Amendment 2 
Protocol No. ANT-004 
12.3. 
Appendix 3 - Clinical notable laboratory values 
Clinical notable laboratory values: 
The definition, the specific alert criteria and the corresponding actions for hepatic and renal notable 
laboratory abnormalities are respectively provided in Appendix 1 and Appendix 2. 
The following laboratory values are considered clinically notable and should be forwarded to 
Covance at the same time that they are sent to Investigators: 
•
A change from baseline in hemoglobin ≥ 2 g/dL
•
A decrease from baseline in platelets count ≥ 50% or < 100 x 109/L
•
A positive fecal occult blood test
•
Macroscopic hematuria
Whenever a clinically notable laboratory value is identified, a detailed subject history and 
examination are indicated to identify, document and potentially eliminate a bleeding event: 
•
Blood pressure assessment (after 5 min rest, with an appropriate cuff size);
•
Signs and symptoms such as shortness of breath, tiredness, abdominal pain, hematemesis,
rectorrhagia, melena, gingival or nose bleeding, bruising and hematoma;
•
Concomitant events or procedures such as trauma, surgical procedures.
When one of the above occurs the action plan is as follows: 
•
Confirm the value, assess and document the clinically notable laboratory value in the CRF
or via electronic data load;
•
Investigate the underlying causes such as clinical or subclinical bleeding event and the
contributing factors such as intake of prohibited medications;
•
Monitor subject regularly (frequency at Investigator’s discretion) until resolution or
stabilization. Hospital admission, additional laboratory tests, endoscopy, volume
replacement, transfusion, etc. should be performed at the Investigator’s discretion and
according to the medical needs (see Section 6.3 for reversal therapy).
Page 72 of 212

Anthos Therapeutics 
 
Page 67 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
12.5. 
Appendix 5 – Definition of bleeding events 
Major bleeding event: 
A major bleeding event will be confirmed when it is a clinically overt bleeding event that meets at 
least one of the following: 
a) Fatal bleeding 
b) Bleeding in a critical area or organ such as: 
o Retroperitoneal 
o Intracranial 
 Intracranial bleeding will be further classified as either 
• Subdural 
• Epidural 
• Subarachnoidal 
• Intra-cerebral  
• Undetermined. 
o Intraocular 
o Intraspinal 
o Intra-articular 
o Pericardial 
o Intramuscular with compartment syndrome 
c) A clinically overt bleeding event    
o that is associated with a fall in hemoglobin of 2.0 g/dL (>1.24 mMol/L) or more, 
or  
o leading to a transfusion of  ≥ 2 units of packed red blood cells or whole  blood.  
Note: The (temporal) relationship of the hemoglobin drop (and or the need for transfusion) with 
the overt bleeding will be carefully evaluated since a gradual decrease of hemoglobin and need for 
transfusions may occur without direct association with an overt bleeding and then would not lead 
to classification major. In the case of surgical procedure related bleeding, the bleeding must be in 
excess of that normally associated with the surgery/procedure. 
Clinically relevant non-major bleeding event 
A bleeding event will be classified as a clinically relevant non-major (CRNM) bleeding event if it 
is overt not meeting the criteria for major bleeding, requires medical attention or is associated with 
discomfort for the subject such as pain, or impairment of activities of daily life. Examples of 
bleeding requiring medical attention include, but are not limited to, bleeding events that result in 
the following diagnostic or therapeutic measures: 
 Requires or prolongs hospitalization; 
Page 75 of 212

Anthos Therapeutics 
 
Page 68 
AFib Protocol Amendment 2 
 
Protocol No. ANT-004 
 
 Diagnostic tests: laboratory evaluations, imaging studies, endoscopy, colonoscopy, 
cystoscopy, or bronchoscopy; 
 Therapeutic intervention such as: nasal packing, ultrasound guided closure of an aneurysm, 
coil embolization, surgery. 
 
Clinical examples that might classify as CRNM:  
 
Intramuscular hematoma or subcutaneous (skin) hematoma if the size is larger than 25 cm2, or 100 
cm2 if provoked, or 
 
epistaxis (profuse) lasting longer than 5 minutes, if it is repetitive (i.e. 2 or more episodes of true 
bleeding, i.e. not spots on a handkerchief, within 24 hours), or lead to an intervention (packing, 
electrocoagulation etc.), or 
 
hematuria if it is macroscopic, and either spontaneous or lasts for more than 24 hours after 
instrumentation (e.g. catheter placement or surgery) of the urogenital tract, or 
 
macroscopic gastro-intestinal hemorrhage: at least one episode of melena/hematemesis, if clinically 
apparent, or rectal blood loss, if more than a few spots on toilet paper, or 
 
hemoptysis, if more than a few speckles in the sputum and not occurring within the context of PE  
Nuisance (not clinically relevant) bleeding events 
Other overt bleeding events that do not fulfill the criteria of a major bleeding event or a clinically 
relevant non-major bleeding event will be classified as a nuisance bleeding event. 
 
Note: All other suspected bleeding events (e.g., decline in hemoglobin with no overt bleeding) will 
be classified as “no bleeding event.” 
 
Page 76 of 212

Anthos Therapeutics 
Page 1 
AFib Protocol v02 
Protocol No. ANT-004 
ANTHOS THERAPEUTICS, INC. 
MAA868 
Clinical Trial Protocol ANT-004 
A Multicenter, Randomized, Subject- and Investigator-blinded, 
Placebo-controlled, Parallel-group, Dose-range Finding Study to 
Assess the Pharmacokinetic and Pharmacodynamic Parameters, 
Safety, Tolerability, and Immunogenicity of MAA868 in Patients 
with Atrial Fibrillation 
Property of Anthos Therapeutics 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Anthos Therapeutics 
Document type: 
Protocol  
IND number: 
129008 
EUDRACT number: 
N/A 
Version number: 
V02 - Amendment 1 
Clinical Trial Phase: 
IIa 
Release date: 
1-November-2019
Sponsor: 
Anthos Therapeutics 
55 Cambridge Pkwy, Ste. 103 
Cambridge, MA 02142 
Tel:  617-430-6940  
Chief Medical Officer (CMO) 
 
 
 
 
Page 77 of 212

Anthos Therapeutics 
 
Page 3 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
NOTIFICATION OF SERIOUS ADVERSE EVENTS 
Dear Investigator, 
You must report a serious adverse event (SAE) (initial or follow-up) to Covance as summarized 
below. Refer to Section 7.6.2 of the protocol for SAE criteria and additional requirements. See 
also the Safety Management Plan for further details on the method of reporting a SAE. 
• Complete SAE report  
• Submit SAE report to Covance safety within 24 hours after awareness of the SAE  
• Notify the Covance Medical Lead 
• The fax number(s) and email address(es) are located in the Safety Management Plan.  
 
 
 
 
 
Page 85 of 212

Anthos Therapeutics 
 
Page 4 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
 
TABLE OF CONTENTS 
 
NOTIFICATION OF SERIOUS ADVERSE EVENTS ........................................................... 3 
LIST OF ABBREVIATIONS ................................................................................................... 8 
PHARMACOKINETIC DEFINITIONS AND SYMBOLS .................................................. 10 
GLOSSARY OF TERMS ....................................................................................................... 11 
PROTOCOL SYNOPSIS........................................................................................................ 13 
1. 
Introduction ................................................................................................................. 16 
1.1. 
Background ................................................................................................................. 16 
1.2. 
Study Rationale ........................................................................................................... 18 
1.3. 
Benefit-risk Assessment.............................................................................................. 18 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................ 20 
2.1. 
Primary objective and endpoint .................................................................................. 20 
2.2. 
Secondary objectives and endpoints ........................................................................... 20 
2.3. 
Exploratory objectives and endpoint .......................................................................... 20 
3. 
INVESTIGATION PLAN .......................................................................................... 22 
3.1. 
Overall Study Design and Plan Description ............................................................... 22 
3.2. 
Discussion of Study Design, Including the Choice of Control Groups ...................... 23 
3.3. 
Selection of Doses in the Study .................................................................................. 23 
4. 
SELECTION OF STUDY POPULATION ................................................................ 24 
4.1. 
Inclusion Criteria ........................................................................................................ 24 
4.2. 
Exclusion Criteria ....................................................................................................... 24 
4.3. 
Discontinuation Criteria .............................................................................................. 26 
4.3.1. Screen Failures ................................................................................................ 26 
4.3.2. Withdrawal of informed consent .................................................................... 26 
4.3.3. Lost to Follow-up ............................................................................................ 26 
4.4. 
Stopping Rules ............................................................................................................ 26 
5. 
Study Treatments ........................................................................................................ 28 
5.1. 
Treatments Administered ............................................................................................ 28 
5.2. 
Preparation, Storage, Handling, and Accountability .................................................. 28 
5.3. 
Method of Treatment Assignment .............................................................................. 29 
5.4. 
Blinding....................................................................................................................... 29 
5.5. 
Treating the subject ..................................................................................................... 30 
5.6. 
Permitted dose adjustments and interruptions of study treatment .............................. 31 
Page 86 of 212

Anthos Therapeutics 
 
Page 5 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
5.7. 
Study Completion and Post-study Treatment ............................................................. 31 
5.8. 
Discontinuation of Study Treatment ........................................................................... 31 
5.9. 
Study Termination ...................................................................................................... 31 
5.10. Emergency breaking of assigned treatment code........................................................ 31 
6. 
CONCOMITANT THERAPIES ................................................................................ 33 
6.1. 
Concomitant therapy ................................................................................................... 33 
6.2. 
Study restrictions ........................................................................................................ 34 
6.3. 
Reversal medication .................................................................................................... 35 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...................................................... 36 
7.1. 
Assessment schedule ................................................................................................... 36 
7.2. 
Informed consent procedures ...................................................................................... 36 
7.3. 
Subject screening ........................................................................................................ 36 
7.4. 
Subject demographics/other baseline characteristics .................................................. 36 
7.5. 
Efficacy Assessments.................................................................................................. 37 
7.5.1. Free FXI .......................................................................................................... 37 
7.5.2. aPTT ................................................................................................................ 37 
7.5.3. Total FXI ......................................................................................................... 37 
7.5.4. FXI coagulation activity (FXI:C).................................................................... 37 
7.6. 
Safety Assessments ..................................................................................................... 37 
7.6.1. Adverse Events ............................................................................................... 39 
7.6.2. Reporting Serious Adverse Events ................................................................. 40 
7.7. 
Liver safety monitoring............................................................................................... 42 
7 8  
Renal safety monitoring 
 43 
7.9. 
Pregnancy .................................................................................................................... 43 
7.10. Clinical Laboratory Evaluations ................................................................................. 44 
7.11. Vital Signs, Physical Examination, and Other Safety Evaluations ............................. 44 
7.12. Electrocardiogram (ECG) ........................................................................................... 45 
7.13. Pharmacokinetic Analysis ........................................................................................... 45 
7.14. Other assessments ....................................................................................................... 46 
7.14.1. Exploratory Biomarker assessments ............................................................... 46 
7.14.2. Immunogenicity (IG) ...................................................................................... 46 
7.15. Use of residual biological samples ............................................................................. 46 
8. 
SAMPLE SIZE AND DATA ANALYSES ................................................................ 47 
8.1. 
Determination of Sample Size .................................................................................... 47 
Page 87 of 212

Anthos Therapeutics 
 
Page 6 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
8.2. 
Analysis Populations ................................................................................................... 47 
8.3. 
General Considerations ............................................................................................... 47 
8.4. 
Demographics and Baseline characteristics ................................................................ 47 
8.5. 
Efficacy Analysis ........................................................................................................ 48 
8.5.1. Primary Efficacy Outcome Measures ............................................................. 48 
8.5.2. Secondary Efficacy Outcome Measures ......................................................... 48 
8.6. 
Safety Analysis ........................................................................................................... 48 
8.6.1. Adverse Events ............................................................................................... 48 
8.6.2. Bleeding Events .............................................................................................. 49 
8.6.3. Major cardiovascular, cerebrovascular, and venous thromboembolic events 50 
8.6.4. Clinical Laboratory Evaluations ..................................................................... 50 
8.6.5. Vital Sign Measurements ................................................................................ 50 
8.6.6. ECG Parameters .............................................................................................. 50 
8.7. 
Pharmacokinetic Analysis ........................................................................................... 51 
8.8. 
Biomarkers .................................................................................................................. 51 
8.9. 
Interim Analysis .......................................................................................................... 51 
8.10. Data Quality Assurance .............................................................................................. 51 
9. 
Ethical Considerations ................................................................................................ 54 
9.1. 
Regulatory and ethical compliance ............................................................................. 54 
9.2. 
Responsibilities of the Investigator and IRB .............................................................. 54 
9.3. 
Publication of study protocol and results .................................................................... 54 
10. 
PROTOCOL ADHERENCE ...................................................................................... 55 
10 1  Protocol Amendments 
 55 
11. 
References ................................................................................................................... 56 
12. 
Appendices .................................................................................................................. 58 
12.1. Appendix 1 - Liver Event Definitions and Follow-up Requirements ......................... 59 
12.2. Appendix 2 - Specific Renal Alert Criteria and Actions ............................................ 61 
12.3. Appendix 3 - Clinical notable laboratory values ........................................................ 63 
12.4. Appendix 4 - Schedule of Assessments ...................................................................... 64 
 
 
 
Page 88 of 212

Anthos Therapeutics 
 
Page 7 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
 
List of Tables 
Table 1: 
Overview of Study Medication ................................................................................... 28 
Table 2: 
Randomization Assignment Numbering ..................................................................... 29 
Table 3: 
Summary of reporting requirements for medication errors ........................................ 34 
Table 4: 
Liver Event Definition ................................................................................................ 59 
Table 5: 
Action required for Liver Events ................................................................................ 59 
Table 6: 
Exclusion of underlying Liver Disease ....................................................................... 60 
Table 7: 
Specific Renal Alert Criteria and Actions .................................................................. 61 
Table 8: 
Follow-up renal events ................................................................................................ 62 
Table 9: 
Schedule of Assessments ............................................................................................ 64 
 
 
List of Figures 
Figure 1: 
Overall study design ....................................................................................... 22 
 
 
 
Page 89 of 212

Anthos Therapeutics 
 
Page 8 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
LIST OF ABBREVIATIONS 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
Adverse event of special interest 
AF 
Atrial fibrillation 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CK 
creatine kinase 
CI 
confidence interval 
CRF 
case report form 
CRNM 
clinically relevant non-major 
CRO 
contract research organization 
CSR 
clinical study report 
DOAC 
direct oral anticoagulant 
DSS 
Drug Safety Services 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
FIH 
first-in-human  
FXI 
Factor XI 
FXI:C 
FXI coagulation activity 
GCP 
Good Clinical Practice 
γGT 
gamma glutamyl transferase 
GLP 
Good Laboratory Practice 
IA 
interim analysis 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IRB 
institutional review board 
Page 90 of 212

Anthos Therapeutics 
 
Page 9 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
IN 
investigator notification 
MedDRA 
Medical Dictionary for Regulatory Activities 
PAF 
paroxysmal atrial fibrillation 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
QTcF 
QT interval corrected by Fridericia formula 
RBC 
red blood cells 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
s.c. 
subcutaneous 
sCr 
serum creatinine 
sCT 
spiral computed tomography 
SD 
standard deviation 
SOC 
system organ class (MedDRA classification) 
SUSAR 
suspected unexpected serious adverse reaction  
TEAE 
treatment-emergent adverse event 
VTE 
venous thromboembolism 
WBC 
white blood cells 
 
 
 
 
 
Page 91 of 212

Anthos Therapeutics 
 
Page 10 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
PHARMACOKINETIC DEFINITIONS AND SYMBOLS 
AUC0-t 
The area under the plasma concentration-time curve from time zero to time ‘t’ 
where t is a defined time point after administration [mass x time / volume] 
AUCinf 
The area under the plasma concentration-time curve from time zero to infinity 
[mass x time / volume] 
AUClast 
The area under the plasma concentration-time curve from time zero to the time 
of the last quantifiable concentration [mass x time / volume]  
C0 
The initial concentration at the end of an intravenous infusion 
CL 
The systemic clearance following intravenous administration 
Cmax 
The observed maximum plasma concentration following subcutaneous drug 
administration [mass / volume] 
F 
Bioavailability 
T1/2 
The terminal elimination half-life [time] 
Tmax 
The time to reach the maximum concentration after drug administration [time] 
Vss 
The steady state volume of distribution following intravenous administration 
 
Page 92 of 212

Anthos Therapeutics 
 
Page 11 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
GLOSSARY OF TERMS 
Assessment 
A procedure used to generate data required by the study 
Cohort 
A specific group of subjects fulfilling certain criteria 
Dosage 
Dose of the study treatment given to the subject in a time unit  
Enrollment 
Point/time of subject entry into the study at which informed 
consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol) 
Healthy volunteer 
A person with no known significant health problems who 
volunteers to be a study participant  
Investigational drug 
The study drug whose properties are being tested in the study; 
this definition is consistent with US CFR 21 Section 312.3 and 
Directive 
2001/20/EC 
and 
is 
synonymous 
with 
“investigational new drug” or “test substance” 
Screen Failure 
A subject who is screened but is not treated or randomized 
Subject 
A trial participant 
Subject number 
A unique number assigned to each subject upon signing the 
informed consent. This number is the definitive, unique 
identifier for the subject and should be used to identify the 
subject throughout the study for all data collected, sample 
labels, etc. 
Randomization number 
A unique identifier assigned to each randomized subject, 
corresponding to a specific treatment arm assignment 
Study treatment 
Any drug administered to the study participants as part of the 
required study procedures; includes investigational drug (s), 
control(s) or non-investigational medicinal product(s) 
Study treatment 
discontinuation 
When the subject permanently stops taking study treatment 
prior to the defined study treatment completion date 
Study treatment period 
Interval of time in the planned conduct of a study. A treatment 
period is associated with a purpose (e.g. screening, 
randomization, treatment, follow-up), which applies across all 
arms of a study 
Variable 
A measured value or assessed response that is determined in 
specific assessments and used in data analysis to evaluate the 
drug being tested in the study  
Withdrawal of consent  
Withdrawal of consent from the study is defined as when a 
subject does not want to participate in the study any longer, 
and does not want any further visits or assessments, and does 
not want any further study related contact, and does not allow 
analysis of already obtained biologic material 
 
Page 93 of 212

Anthos Therapeutics 
 
Page 12 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
AMENDMENT #1 
 
Amendment Rationale 
This protocol is being amended, prior to submission to any Health Authority, to address male 
contraception requirements, correct inconsistencies and to provide greater clarity. 
 
Changes to the Protocol 
• 4.2 (Exclusion criteria) and 6.2 (Study restrictions) – added eligibility criteria and study 
requirement that male study participants use condoms during intercourse throughout the 
study. 
• 5.4 (Blinding) – added clarity regarding activities for which some associates may have 
access to the full randomization list prior to database lock in order to fulfill their 
functions. 
 
 
Page 94 of 212

Anthos Therapeutics 
 
Page 13 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
PROTOCOL SYNOPSIS 
Title of study: A Multicenter, Randomized, Subject- and Investigator-blinded, Placebo-
controlled, Parallel-group, Dose-range Finding Study to Assess the Pharmacokinetic and 
Pharmacodynamic Parameters, Safety, Tolerability, and Immunogenicity of MAA868 in Patients 
with Atrial Fibrillation  
Indication: Atrial fibrillation 
Number of Investigators and study centers: 
The study is planned to be conducted in approximately 6 sites. 
Development phase: Phase 2a 
Objectives: 
Primary 
• 
To evaluate the proportion of patients that achieve ≥50%, ≥80%, or ≥90% Factor XI 
(FXI) inhibition at trough after the third dose (Day 91) at different dose levels of 
MAA868. 
Secondary 
• 
To evaluate the proportion of patients achieving FXI inhibition ≥ 50%, ≥80%, and ≥90% 
at trough after the first and second dose (Day 31 and Day 61) at different dose levels of 
MAA868. 
• 
To evaluate the safety and tolerability following multiple s.c. administration of MAA868 
compared to placebo to patients with AF. 
• 
To evaluate the incidence of major bleeding events, clinically relevant non-major 
(CRNM) bleeding events and total bleeding with MAA868 relative to placebo during 
the treatment period. 
• 
To evaluate the immunogenicity of MAA868 compared to placebo. 
Study design: 
This is a randomized, subject- and investigator-blinded, placebo controlled, dose-ranging study 
in patients with atrial fibrillation (AF) or atrial flutter who are at low risk for stroke. Patients will 
be enrolled in up to 3 cohorts of approximately 16 patients each. After a Screening Period of up 
to 4 weeks, patients in will be randomized  in a 3:1 ratio (MAA868:placebo) to receive 3 monthly 
subcutaneous (s.c.) injections and followed for pharmacokinetics, pharmacodynamic efficacy as 
well as  safety events over the 90-day Treatment Period. Patients will then be followed up to Day 
170 during the Washout/Follow-up period.  
Number of patients: 
Approximately 48 patients will be randomized into the study. 
Diagnosis and main criteria for inclusion and exclusion: 
Inclusion Criteria 
• 
Male and female patients ≥ 18 and < 85 years old 
• 
Current AF or atrial flutter on 12 lead electrocardiography at Screening  
or 
a history of paroxysmal AF (PAF) or atrial flutter as documented by prior telemetry, 12 
lead electrocardiography or ambulatory (e.g. Holter or patch) monitor which is not due 
to a reversible condition (e.g. alcohol binge drinking) 
• 
A CHA2DS2-VASc risk score of 0-1 for men and 1-2 for women and in whom, in the 
investigator’s judgment, the use of an anticoagulant for stroke prevention is not indicated 
• 
Body weight between 50 and 130 kg, inclusive 
Exclusion criteria 
Page 95 of 212

Anthos Therapeutics 
 
Page 14 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
• 
History of stroke, transient ischemic attack or systemic embolism 
• 
History of major bleeding during treatment with an anticoagulant or antiplatelet therapy. 
(Patients who have had major bleeding on anticoagulants or antiplatelet therapy more 
than a year ago can be enrolled only if the bleeding was due to a reversible cause, e.g. 
gastro-duodenal ulcer, that was successfully treated) 
• 
History of traumatic or non-traumatic intracranial, intraspinal or intraocular bleeding.  
• 
Known bleeding diathesis or any known active bleeding at screening or baseline 
• 
Family history of bleeding disorder  
• 
Known active GI lesions predisposing to bleeding events 
• 
Myocardial infarction, unstable angina pectoris or coronary artery bypass graft (CABG) 
surgery within 12 months prior to the screening period 
• 
Clinically significant moderate or greater mitral stenosis severity (valve area <1.5 cm2)  
• 
Prosthetic heart valve  
• 
Uncontrolled hypertension defined as SBP/DBP ≥ 160/100 mmHg at the screening visit 
• 
NYHA class III-IV heart failure  
• 
Currently being treated with anticoagulant therapy or have been on anticoagulants in the 
previous 12 months. Potential patients who have been on anticoagulation more than 12 
months ago requires discussion with the sponsor before enrolling.   
• 
Currently being treated with antiplatelet therapy such as a P2Y12 inhibitor or aspirin. 
Low dose aspirin (≤ 100 mg/d) is allowed  
• 
Severe renal impairment as defined as an estimated glomerular filtration rate ≤45 
mL/min/1.73m2 by the MDRD equation at the screening visit 
• 
Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
Test products, dose, and mode of administration: 
MAA868 with a dose of 120 mg or 180 mg or placebo s.c. monthly 
Reference therapy, dose, dose form, and mode of administration:   
Matching placebo to MAA868 s.c. monthly 
Page 96 of 212

Anthos Therapeutics 
 
Page 15 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
Duration of patient participation in study: 
Planned Screening duration: Up to 4 weeks 
Planned treatment duration: Day 0-91: 91 days 
Planned follow-up duration: Day 91 to Day 170: 79 days 
Study populations:  
Approximately 48 male and female patients age ≥ 18 to < 85 with AF or flutter, as defined above, 
will be randomized into the study. 
Evaluation: Efficacy  
• 
Free FXI concentrations at Days 31, 61 and 91 
Evaluation: Safety 
• 
Confirmed major bleeding events, clinically relevant non-major (CRNM) bleeding events 
and total bleeding events 
• 
Adverse and serious adverse events 
• 
Occurrence of major cardiovascular, cerebrovascular, systemic arterial, and  
• 
Physical examinations  
• 
Monitoring of laboratory parameters in blood 
• 
ECGs 
• 
Hypersensitivity reactions 
• 
Injection site reactions 
Evaluation: Other assessments 
• 
Factor XI coagulation activity 
• 
Activated partial thromboplastin time 
• 
Pharmacokinetics 
• 
Development of anti-drug antibodies 
• 
Venous thromboembolic events  
Statistical methods: 
The patients will be enrolled into cohorts of approximately 16 patients with each cohort 
evaluating a different dose level of MAA868. Within each cohort, patients will be randomized 
3:1 to active drug or placebo. 
The primary analysis variable is whether a subject will achieve pre-defined degrees of FXI 
inhibition at trough (Day 91). The dose regimens and targeted FXI inhibition achievement are as 
follows:  
Low-dose cohort (MAA868 120 mg monthly or placebo): Targeted to achieve ≥ 50% FXI 
inhibition in 90% of subjects at trough (Day 91).  
High dose cohort (MAA868 180 mg monthly or placebo): Targeted to achieve ≥ 90% FXI 
inhibition in 90% of subjects at trough (Day 91). 
The “on treatment” trough FXI levels will be used for the primary analysis, where “on treatment” 
FXI level is defined as a value which is collected within 30 (±5) days after the last administration 
of MAA868. The response rate per treatment group will be calculated by number of subjects 
who achieve targeted FXI inhibition rate divided by the total number of subjects in the treatment 
group. The estimate of the responder rate (%) at Day 91 will be presented for each dose regimens 
of MAA868 together with 2-sided 90% confidence intervals. 
The secondary efficacy analysis is to evaluate the proportion of subjects achieving FXI inhibition 
≥ 50%, ≥80%, and ≥90% at trough after the first and second dose (Day 31 and Day 61) at multiple 
dose levels of MAA868. The analyses described for the primary endpoint will be repeated for 
the secondary efficacy variables. 
Safety data including adverse events (AEs), bleeding events, ECG, vital signs, thromboembolic 
events and laboratory results will be reported by count and incidence rate. 
Page 97 of 212

Anthos Therapeutics 
 
Page 16 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
1. 
INTRODUCTION 
1.1. 
Background 
AF is the most common cardiac arrhythmia, accounting for approximately one third of 
hospitalizations for cardiac dysrhythmias. Currently, it is estimated to affect more than 6 million 
patients in Europe and approximately 2.3 million in the United States, and this number continues 
to grow rapidly because of the increasing proportion of the aging population with associated co-
morbidities. As such, the prevalence of AF is expected to increase 2- to 3-fold over the following 
3 decades in western populations (Kannel and Benjamin 2008). 
AF is associated with a 4- to 5-fold increase in embolic stroke. The risk for stroke associated with 
AF increases steeply with age to 23.5% for patients aged 80 to 89 years (Kannel and Benjamin 
2008). Most patients with AF require life-long anticoagulation therapy to prevent cardioembolic 
stroke and systemic embolism. It is estimated that 85 to 90% of AF patients will require 
anticoagulation therapy (Camm et al 2012). 
Vitamin K antagonists (VKA), such as warfarin, are effective in reducing stroke and systemic 
thromboembolism; a highly significant relative risk reduction in stroke incidence by 67% was 
observed in a meta-analysis combining six studies (Hart et al 1999). All-cause mortality was 
reduced (26%) significantly by VKA vs. control (Hart et al 1999). In recent years, direct oral 
anticoagulant (DOACs) medications have been approved and introduced to clinical practice. These 
drugs are at least as effective as warfarin in preventing stroke or systemic embolism and may be 
superior to warfarin in the risk of hemorrhagic stroke and intracranial hemorrhage (Connolly et al 
2009, Granger et al 2011, Patel et al 2011). The incidence of major bleeding events with DOACs 
was similar or slightly lower than the incidence observed with well-conducted warfarin therapy. 
Nonetheless, the overall bleeding risk continues to be high with the use of DOACs. For instance, 
the annual incidence of major and clinically relevant non-major (CRNM) bleeding was 14.9% and 
the annual incidence of major bleeding events was 3.6% in patients treated with rivaroxaban in the 
ROCKET AF study (Patel et al 2011). It is notable that the occurrence of major bleeding was 
strongly associated with mortality. In the same study, the rate of all-cause mortality over the 2-
month period following a major bleeding event was 20.4% in the rivaroxaban group and 26.1% in 
the warfarin group (Piccini et al 2014). Thus, there is a high unmet medical need for an 
anticoagulant therapy that can effectively reduce the risk of AF-related thromboembolic 
complications such as stroke but with a lower risk of bleeding than currently employed 
anticoagulants. 
FXI is an emerging target for potentially safer and more effective anticoagulant medications. FXI 
holds important roles in both the intrinsic and extrinsic coagulation pathways and in bridging the 
initiation and amplification phases of plasmatic hemostasis (Gailani and Renné 2007). Both Factor 
XII and thrombin can activate FXI, resulting in a sustained thrombin generation and fibrinolysis 
inhibition. FXI plays a minor role in normal hemostasis in a high tissue factor environment “after 
vessel injury” whereas it appears to play a key role in thrombosis. Severe FXI deficiency is 
associated with a lower incidence of ischemic stroke and venous thromboembolic events (Salomon 
et al 2008, Salomon et al 2011, Preis et al 2017). Nevertheless, bleeding manifestations in subjects 
with severe FXI deficiency are infrequent and usually mild. Bleeding events that occur are 
typically injury-related and preferentially affect tissues known to have increased fibrinolytic 
Page 98 of 212

Anthos Therapeutics 
 
Page 17 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
activity such as the oral and nasal mucosa, and urinary tract (Bolton-Maggs 2000). Bleeding in 
vital organs is extremely rare or non-existent. 
MAA868 
MAA868 is a human antibody that binds to the catalytic domain of FXI. MAA868 binds to both 
the zymogen (FXI) and activated factor XI (FXIa) with high potency. MAA868 dose-dependently 
prolonged activated partial thromboplastin time (aPTT) in in-vitro and in-vivo studies. After a 
single subcutaneous (s.c.) administration of MAA868 at a 3 mg/kg dose, sustained anticoagulant 
activity lasting for more than one month was observed in cynomolgus monkeys. Moreover, 
MAA868 prevented experimental carotid artery thrombosis induced by FeCl3 and resulted in a 
prolongation in aPTT in FXI-/- mice reconstituted with human FXI. No significant toxicity 
findings were observed in single dose and in the 13-week Good Laboratory Practice (GLP)-
compliant toxicity study conducted in cynomolgus monkeys. The highest s.c. dose administered 
in the 13-week study was defined as no observed adverse effect level NOAEL (100 mg/kg/week 
s.c.). 
MAA868 was evaluated in a first-in-human (FIH) study (CMAA868X2101) to characterize its 
safety/tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) in healthy subjects 
following single s.c. administration. In total, 6 cohorts with 10 subjects each (8 MAA868: 2 
Placebo) were enrolled. The doses of MAA868 administered in Cohorts 1 to 5 ranged from 5 mg 
to 240 mg. In a sixth cohort, 240 mg of MAA868 was administered to subjects with body mass 
index (BMI ≥ 35 kg/m2). 
In the FIH study, MAA868 appeared to be safe and well tolerated, and the incidence of AEs were 
comparable across dose groups and placebo. No bleeding events, hypersensitivity reactions or 
injection site reactions were reported. Exposure increased with increasing dose of s.c. MAA868; 
the median maximum observed concentration (Cmax) occurred on Day 7 to 21 and the mean 
terminal elimination half-life ranged from 20 to 28 days. A dose and time-dependent prolongation 
of aPTT occurred with MAA868 after single s.c. administration; the 150 mg dose resulted in a 
mean aPTT prolongation ≥ 2-fold at Day 29. Doses greater than 150 mg extended the duration of 
aPTT prolongation but did not produce a greater prolongation of aPTT. Robust and sustained 
reductions of free FXI ≥ 90% were observed with 150 mg MAA868 at Day 29 and up to Day 43 
with 240 mg. A high BMI was associated with a lower MAA868 exposure and slightly shorter 
duration of aPTT prolongation. Robust reductions in free FXI and in FXI coagulation activity and 
relevant aPTT prolongation are predicted to occur within 12 to 24 hours after MAA868 s.c. 
administration with relevant clinical doses. 
MAA868 was also studied in healthy Japanese subjects in a single ascending dose, randomized, 
subject- and investigator-blinded, placebo-controlled, non-confirmatory study to assess safety, 
tolerability, PK and PD. Three cohorts (MAA868 dose levels: 15, 50 and 150 mg) were enrolled 
in this study and received a single s.c. dose of MAA868 or matching placebo (8 subjects received 
MAA868 and 2 subjects received placebo in each cohort). Assessments and assessment schedules 
were generally similar to the FIH study. No SAE or study discontinuation due to AEs were reported 
in this study. All AEs were mild in intensity and the distribution of AEs was well balanced between 
the MAA868 dose groups and placebo. No bleeding event, hypersensitivity or injection site 
reactions were reported in the study. PK analysis suggested that there was no indication of an 
impact of the Japanese ethnicity on exposure or PD parameters of MAA868 in healthy subjects. 
Page 99 of 212

Anthos Therapeutics 
 
Page 18 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
Taken together, the results from both completed studies of MAA868 suggest that the 
administration of MAA868 is safe and well-tolerated. Subcutaneous administration of MAA868 
leads to robust and sustained effects on aPTT, free FXI, and FXI coagulation activity (FXI:C) up 
to/through Day 29 with the 150 mg dose and Day 43 with the 240 mg dose in subjects with normal 
body weight or class 1 obesity (BMI <35 kg/m2). In subjects with class 2 or 3 obesity (BMI ≥35 
kg/m2), exposures of MAA868 may be lower and the duration of aPTT prolongation is shorter. 
1.2. 
Study Rationale 
This study is a multicenter, randomized, subject and Investigator-blinded, placebo-controlled, 
parallel-group, multiple ascending dose-ranging study to evaluate the safety, tolerability, PK, and 
PD effects of MAA868 in patients with AF or flutter at low risk of thromboembolic stroke or 
peripheral embolism. The trial will evaluate the effects of up to three different doses of MAA868 
on FXI inhibition, indices of coagulation, and thrombogenesis biomarkers compared to placebo. 
The incidence of injection site reactions, bleeding events, immunogenicity, and systemic arterial 
and venous thromboembolic events will also be assessed. Results from this study will assist with 
dose-selection of MAA868 for a phase 3 trial in patients with AF. 
1.3. 
Benefit-risk Assessment 
AF is associated with a 4- to 5-fold increase in embolic stroke. MAA868, a fully human 
monoclonal antibody targeting Factor XI, is being considered for development as a novel 
anticoagulant for patients with AF or flutter. FXI is an emerging target as a novel anticoagulant. 
Several lines of evidence suggest that FXI inhibition has the potential to prevent thrombosis with 
minimal risk of bleeding. For example, individuals with an inherited deficiency of FXI have been 
reported to have a lower risk of VTE even though their bleeding phenotype is variable and often 
quite mild. Further support of the safety of inhibiting FXI comes from clinical studies using an 
investigational FXI antisense oligonucleotide (FXI-ASO) where administration of FXI-ASOs in 
healthy subjects and in patients undergoing total knee arthroplasty was demonstrated to be safe 
and well-tolerated (Buller et al 2015). 
Results from the first-in-human (FIH) study of MAA868 (CMAA868X2101) demonstrated that a 
single s.c. administration of MAA868 at increasing doses up to 240 mg in healthy subjects were 
safe and well-tolerated. These doses of MAA868 resulted in a robust and sustained FXI inhibition 
and prolongation of aPTT. The safety and pharmacodynamic efficacy of MAA868 was further 
supported by preliminary data from the study CMAA868A1101, which showed a good safety 
profile of MAA868 in Japanese heathy male subjects. 
This study is designed to evaluate the efficacy and safety of achieving different levels of FXI 
inhibition with different dose levels of s.c. MAA868 in patients with AF or flutter. This study will 
recruit patients with AF or flutter who are judged by their physician to be at low risk for stroke 
based on clinical guidelines. In each case, patients will only be enrolled if their physician has 
determined that the patient does not merit anticoagulation based on the guidelines and the 
physician’s assessment of the benefit-risk profile for that patient. The guidelines state that the 
benefits of anticoagulation in AF patients at low risk of embolic stroke are uncertain given the 
concomitant risks of bleeding with anticoagulant therapy. Accordingly, the guidelines recommend 
individualized shared physician-patient decision-making with regards to the decision to initiate 
anticoagulant therapy in this population (January et al 2019).  Patients with PAF will be enrolled 
who have a CHA2DS2-VASc risk score of 0-1 for men or 1-2 for women, in whom the guidelines 
Page 100 of 212

Anthos Therapeutics 
 
Page 19 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
are equivocal regarding the recommendation to initiate anticoagulation and advise an 
individualized assessment of the benefit-risk of anticoagulation (January et al 2019).  
Overall, the nonclinical and clinical data to date support the investigation of MAA868 in the 
prevention of thromboembolic diseases in patients with AF. The risk-benefit relationship appears 
to be acceptable. 
Page 101 of 212

Anthos Therapeutics 
 
Page 20 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
2. 
OBJECTIVES AND ENDPOINTS 
2.1. 
Primary objective and endpoint 
Objective 
Endpoint 
• To evaluate the proportion of patients that 
achieve ≥50%, ≥80%, or ≥90% FXI 
inhibition at trough after the third dose 
(Day 91) at different dose levels of 
MAA868 
• Occurrence of achieving ≥50%, ≥80%, or 
≥90% inhibition of FXI (<50%, <20%, or 
<10% free FXI) at trough on Day 91 at 
different dose levels of MAA868 
2.2. 
Secondary objectives and endpoints 
Objective 
Endpoint 
• To evaluate the proportion of patients 
achieving FXI inhibition ≥50%, ≥80%, and 
≥90% at trough after the first and second 
dose (Day 31 and Day 61) at different dose 
levels of MAA868 
• Occurrence of achieving ≥50%, ≥ 80%, 
and ≥90% inhibition of FXI (<50%, <20%, 
or <10% free FXI) at trough on Day 31 and 
Day 61 at different dose levels of MAA868 
• To evaluate the safety and tolerability 
following multiple s.c. administration of 
MAA868 compared to placebo in patients 
with AF 
• All safety endpoints [i.e., physical exam, 
vital signs, electrocardiogram (ECG), 
safety 
laboratories, 
hypersensitivity 
reactions, injection site reactions, and 
adverse events (AEs), including serious 
AEs (SAEs)] during the Treatment Period 
and through EoS 
• To evaluate the incidence of major 
bleeding events, clinically relevant non-
major (CRNM) bleeding events and total 
bleeding with MAA868 relative to placebo 
during the treatment period 
• Occurrence of confirmed major bleeding 
events, CRNM bleeding events and total 
bleeding events during the treatment 
period 
• To evaluate the immunogenicity of 
MAA868 compared to placebo. 
• Screening and confirmation for anti-drug 
(MAA868) antibodies (ADA) 
2.3. 
Exploratory objectives and endpoint 
Objective 
Endpoint 
• To evaluate the effect of MAA868 
compared to placebo on the incidence of 
major cardiovascular, cerebrovascular, and 
venous thromboembolic events (as defined 
to the right) 
• Occurrence 
of 
major 
cardiovascular, 
cerebrovascular, systemic arterial, and 
venous thromboembolic events (VTEs)  
Page 102 of 212

Anthos Therapeutics 
 
Page 21 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
• To evaluate the change from baseline in D-
dimer and other thrombogenesis markers 
with MAA868 relative to placebo during 
the treatment period 
• Concentrations of D-dimer and other 
exploratory 
thrombogenesis 
markers 
during the treatment period 
 
Page 103 of 212

Anthos Therapeutics 
 
Page 22 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
3. 
INVESTIGATION PLAN 
3.1. 
Overall Study Design and Plan Description 
This is a phase 2a, randomized, subject- and investigator-blinded, placebo-controlled, multiple 
ascending dose-ranging study to assess the PK/PD, safety, tolerability, and immunogenicity of 
MAA868 in patients with AF or flutter.  
Patients will be enrolled in at least 2 and up to 3 cohorts of approximately 16 patients each for a 
total of up to 48 subjects (Figure 1A). Patients in cohort 1 will be randomized 3:1 to receive a 120 
mg dose of MAA868 or placebo, respectively on Day 1 with two subsequent monthly injections.  
After approximately 10 of the patients in cohort 1 have received their second dose of study drug 
and have been followed for at least an additional 14 days, a safety review of emerging safety and 
PK data from cohort 1 will take place. Cohort 2 will be initiated after it is confirmed by the 
Sponsor’s Medical Monitor and the Covance Lead Project Physician that the cohort 1 dose was 
safe and tolerated and all cohort 1 patients have been randomized. Likewise, after 10 of the patients 
in cohort 2 have received their second dose and have been followed for at least an additional 14 
days, interim safety, tolerability, and other analyses will be evaluated by the Sponsor. Based on 
emerging data, the Sponsor may elect to: 
• Enroll cohort 3 to evaluate a higher, lower, or a previously studied dose of MAA868 
• Terminate the study 
The study is comprised of 3 periods:  
(1) Screening period of up to 4 weeks 
(2) Treatment period with MAA868 administered s.c. monthly (or matching placebo) 
(randomized 3:1) for 90 days 
(3) Follow-up period up to end of study (Day 170). 
Following the screening period of up to 4 weeks, all patients that meet the study eligibility criteria 
(Section 4.1 and Section 4.2) will have baseline efficacy and safety assessments performed on Day 
1 and then randomized to active or placebo (Figure 1B). 
Figure 1: 
Overall study design 
 
The first dose of study drug will be administered at the study center on Day 1. The second and 
third doses of study drug will also be administered at the study center to patients on the Day 31 
visit and Day 61 visit, respectively. 
Page 104 of 212

Anthos Therapeutics 
 
Page 23 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
During the treatment period, patients will return to the study center on Day 11, Day 31, Day 41, 
Day 61, Day 71, and Day 91 for safety assessments such as vital signs, AE assessments, laboratory 
tests, PK, PD, thrombogenesis biomarkers, and other study assessments according to the 
assessment schedule shown in Table 9. 
During the follow-up period, patients will continue to be followed for PK, PD, thrombogenesis, 
and other study assessments. Patients will return to the study center on Day 101, Day 121 and Day 
170 (end of study; EoS) for the evaluations described in the assessment schedule (Table 9). 
3.2. 
Discussion of Study Design, Including the Choice of Control Groups 
Rationale for route of administration and treatment duration. The s.c. route of administration 
was chosen because it is the route of administration anticipated for subsequent studies in patients 
with AF. In the FIH study of MAA868, the half-life of MAA868 ranged from 20-28 days following 
s.c. administration. Furthermore, a sustained PD effect of >2-fold mean activated partial 
thromboplastin time [aPTT] prolongation was observed for ~30 days and returned to the baseline 
level by ~60 days post-dose after a single 150 mg s.c. dose administration in study X2101. These 
data support monthly administration of MAA868. Furthermore, assessment of the exposure-
response relationship of MAA868 in healthy subjects demonstrated a nearly flat exposure-response 
for relevant PD parameters (aPTT, FXI coagulation activity and free FXI) at concentrations above 
4 μg/mL which is consistent with the Day 29 total MAA868 concentrations achieved with the 150 
mg single dose administration in healthy subjects (CMAA868X2101). 
Given the half-life of MAA868 and the observed time to return to baseline aPTT levels, a 
prolonged washout/follow-up period of approximately 110 days from the last dose of MAA868 
should be a sufficient monitoring period for patients. 
3.3. 
Selection of Doses in the Study 
In the FIH study, single s.c. doses of MAA868 up to 240 mg was safe and well-tolerated. Up to 
the 150 mg dose, MAA868 produced robust and sustained dose-dependent inhibition of FXI and 
relevant prolongation of aPTT for approximately 4 weeks. MAA868 doses greater than 150 mg 
s.c. produced a sustained ~2-fold prolongation of aPTT for greater than 4 weeks.  
The precise level of FXI inhibition to achieve a clinically meaningful anticoagulant effect remains 
unknown. The primary efficacy endpoint of this study will be the number of patients who achieve 
≥ 50%, ≥ 80%, or ≥ 90% FXI inhibition [<50%, <20%, or 10% free FXI] at trough on Day 91 
following s.c. administration of MAA868. Based on preliminary PK/PD modeling, the doses 
selected for cohorts 1 and 2 are projected to target the following levels of FXI inhibition: 
• Cohort 1 (120 mg dose group). Targeted to achieve ≥ 50% FXI inhibition in 90% of 
subjects at trough (Day 91).  
• Cohort 2 (180 mg dose group). Targeted to achieve ≥ 90% FXI inhibition in 90% of 
subjects at trough (Day 91). 
Based on interim data, an optional cohort 3 may be dosed to add further data to the PK/PD model 
which will inform dose selection of MAA868 for subsequent studies.  
The dosing regimens selected for evaluation in this study are projected to result in exposure (Cmax) 
below the Cmax achieved with a single dose of 240 mg s.c. in healthy subjects in the FIH study. 
Page 105 of 212

Anthos Therapeutics 
 
Page 24 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
4. 
SELECTION OF STUDY POPULATION 
4.1. 
Inclusion Criteria 
1. Written informed consent must be obtained before any assessment is performed 
2. Male and female patients ≥ 18 and < 85 years old with paroxysmal atrial fibrillation (PAF) 
or atrial flutter on 12 lead electrocardiography at Screening Or 
3. Patients with a history of PAF or atrial flutter, as documented by (telemetry, 12 lead 
electrocardiography or ambulatory [e.g. Holter] monitor) and not due to a reversible 
condition (e.g. alcohol binge drinking) can be entered even if they do not have PAF at 
Screening. There is not time-limit for this. 
4. Patients with a CHA2DS2-VASc risk score (tool as a predictor for estimating the risk of 
stroke in patients with AF; Lip et al 2010) of 0-1 for men and 1-2 for women and in whom, 
in the investigator’s judgment, the use of an anticoagulant for stroke prevention is not 
indicated  
5. Body weight between 50 and 130 kg inclusive 
4.2. 
Exclusion Criteria 
1. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of 
enrollment, or until the expected PD effect has returned to baseline, whichever is longer; 
or longer if required by local regulations. 
2. History of stroke, transient ischemic attack or systemic embolism 
3. History of major bleeding during treatment with an anticoagulant or antiplatelet therapy. 
(Patients who have had major bleeding on anticoagulants or antiplatelet therapy more than 
a year ago can be enrolled only if the bleeding was due to a reversible cause, e.g. gastro-
duodenal ulcer that was successfully treated.) 
4. History of traumatic or non-traumatic intracranial, intraspinal or intraocular bleeding 
5. Known bleeding diathesis or any known active bleeding site at screening or baseline 
6. Family history of bleeding disorder  
7. Known active GI lesions predisposing to bleeding events 
8. Myocardial infarction, unstable angina pectoris or coronary artery bypass graft (CABG) 
surgery within 12 months prior to the Screening period 
9. Known clinically significant valvular heart disease including moderate or severe mitral 
stenosis (valve area <1.5 cm2).  
10. Patients with a prosthetic heart valve 
11. Uncontrolled hypertension defined as SBP/DBP ≥ 160/100 mmHg at the Screening visit 
12. Patients with NYHA Class III- IV heart failure 
13. Currently being treated with anticoagulant therapy or have been on anticoagulants in the 
previous 12 months. Potential patients who have been on anticoagulation more than 12 
months ago requires discussion with the sponsor before enrolling.   
14. Treatment with antiplatelet therapy such as either a P2Y12 inhibitor or aspirin. (Low dose 
aspirin ≤ 100 mg/d) is allowed.) 
15. Severe renal impairment as defined as an estimated glomerular filtration rate ≤45 
mL/min/1.73m2 by the MDRD equation at the Screening Visit 
Page 106 of 212

Anthos Therapeutics 
 
Page 25 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
16. Positive test for human immunodeficiency virus (HIV), positive hepatitis B (hepatitis B 
surface antigen [HBsAg]) or hepatitis C (anti-hepatitis C antibody [Anti-HCV]) at 
Screening 
17. Significant illness, per Investigator judgement, which has not resolved within four (4) 
weeks prior to dosing   
18. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
their time in the study. Highly effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow-up hormone level assessment 
• Male sterilization of sexual partner (at least 6 months prior to screening). For female 
subjects on the study, the vasectomized male partner should be the sole partner for that 
subject 
• Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) 
or other forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception 
In case of use of oral contraception, women should have been stable on the same pill for a 
minimum of 3 months before taking investigational drug. 
Women are considered post-menopausal and not of child-bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g., 
age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the 
woman has been confirmed by follow-up hormone level assessment with FSH is she 
considered not of child-bearing potential. Male subjects must also agree to use highly 
effective methods of contraception during their time in the study and should not father a 
child or donate sperm in this period.  
19. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test. 
20. Patients with either a psychiatric disease or substance abuse history, which in the opinion 
of the Investigator could interfere with protocol compliance.  
21. Any surgical or medical condition, which in the opinion of the Investigator, may place the 
patient at higher risk from his/her participation in the study, or is likely to prevent the 
patient from complying with the requirements of the study or completing the study. 
Page 107 of 212

Anthos Therapeutics 
 
Page 26 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
4.3. 
Discontinuation Criteria 
4.3.1. 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure patients to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
serious adverse events (SAEs). 
Patients who do not meet the criteria for participation in this study may be rescreened. 
4.3.2. 
Withdrawal of informed consent 
Subjects may voluntarily withdraw from the study for any reason at any time. 
Withdrawal from the study can occur when a subject chooses to do one or more of the following: 
• Does not want to participate in the study anymore  
• Does not want any further visits or assessments  
• Does not want any further study-related contacts  
• Does not allow analysis of already obtained biologic material. 
If a subject who has received one or more doses of the study drug determines that they no longer 
want to participate the Investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason(s) for the subject’s decision to withdraw his/her consent, record this 
information and conduct any assessments and visits still allowed. 
In the event the subject withdraws consent prior to beginning dosing, the study treatment will not 
be administered. The data that would have been collected at subsequent visits will be considered 
missing. Further attempts to contact the subject are allowed when safety findings require follow-
up. 
4.3.3. 
Lost to Follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating an 
intention to discontinue or withdraw, the Investigator should show "due diligence" by documenting 
in the source documents steps taken to contact the subject, e.g. dates of telephone calls, registered 
letters, etc. A subject cannot be formally considered lost to follow-up until his/her scheduled end 
of study visit would have occurred. 
4.4. 
Stopping Rules 
Overall study stopping rules: 
Enrollment in the study will be placed on hold if the Sponsor considers that the number and/or 
severity of AEs, abnormal safety monitoring tests or abnormal laboratory findings justify putting 
the study on hold. 
Page 108 of 212

Anthos Therapeutics 
 
Page 27 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
The study may resume following the safety review, if the Investigator and Sponsor’s Medical 
Monitor agree it is safe to proceed. 
Page 109 of 212

Anthos Therapeutics 
 
Page 28 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
5. 
STUDY TREATMENTS 
5.1. 
Treatments Administered 
MAA868 drug product is a sterile, preservative-free liquid in vial for subcutaneous (s.c.) or 
intravenous (i.v.) administration. Each drug product vial contains 150 mg of MAA868 active 
ingredient per 1 mL plus 20% (0.2 mL) overfill which allows for complete withdrawal of the 
labeled dose (150 mg). 
 
 The excipients utilized are standard pharmacopoeial excipients that are commonly used in 
parenteral products. MAA868 will be provided as a 150 mg/mL solution in 6 mL single-use vials 
(with 1.2 mL fill). The 180 mg dose will require 2 vials. 0.8 and 1.2 mL should be withdrawn into 
a syringe and administered subcutaneously for the 120 mg and 180 mg doses, respectively. 
Table 1: 
Overview of Study Medication 
Study Treatment Name: 
 
MAA868 
Placebo 
Dosage Formulation: 
 
Liquid (in vial) 
Liquid (in vial) 
Unit Dose 
Strength(s)/Dosage 
Level(s): 
150 mg/mL 
Placebo to MAA868 
Route of Administration:  
SC injection 
SC injection 
Packaging and Labeling: 
 
Study Treatment will be 
provided in vials. Each vial will 
be labeled as required per 
country requirement.  
Placebo will be provided in 
vials. Each vial will be labeled 
as required per country 
requirement. 
Provided by: 
Anthos 
Anthos 
5.2. 
Preparation, Storage, Handling, and Accountability 
Details on the requirements for storage and management of study treatment, and instructions to be 
followed for subject numbering, prescribing/dispensing and administering study treatment are 
outlined in the Pharmacy Manual. 
MAA868 drug product vials should be stored refrigerated at 2°- 8°C and protected from light. A 
disposable syringe will be used to administer the s.c. injection. 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment. Only patients enrolled in the study may receive study 
treatment and only authorized site staff may supply or administer study treatment. The 
Investigator, institution, or the head of the medical institution (where applicable) is responsible for 
study treatment accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, 
and final disposition records). 
Further guidance and information for the final disposition of unused study treatment are provided 
in the Pharmacy Manual. 
Page 110 of 212

Anthos Therapeutics 
 
Page 29 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
5.3. 
Method of Treatment Assignment 
Subjects in each cohort will be randomized to MAA868 or placebo in a ratio of 12: 4 as follows. 
• 
Cohort 1 = 120 mg MAA868 monthly s.c. or placebo 
• 
Cohort 2 = 180 mg MAA868 monthly s.c. or placebo 
• 
Cohort 3 (if necessary) = TBD mg MAA868 monthly s.c. or placebo 
Randomization numbers will be assigned in ascending, sequential order to eligible subjects. The 
Investigator will enter the randomization number on the CRF. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A 
randomization list will be produced by or under the responsibility of Covance Drug Supply 
Management using a validated system that automates the random assignment of treatment arms to 
randomization numbers in the specified ratio. The randomization scheme for subjects will be 
reviewed and approved by a member of the Covance IIS Randomization Group. 
Patients will be replaced at the Sponsor’s discretion. Replacement subjects will be assigned 
randomization numbers 6101-6316 If a subject requires a replacement, the replacement subject 
will be assigned a randomization number corresponding to the original subject (e.g., Subject 6103 
would replace Subject 1103). 
The table below provides the general details of the numbering of the subjects for randomization: 
Table 2: 
Randomization Assignment Numbering 
Cohort 
Randomization numbers 
Replacement randomization numbers 
I 
1101-1116 
6101-6116 
II 
1201-1216 
6201-6216 
III 
1301-1316 
6301-6316 
5.4. 
Blinding 
This is a subject- and investigator-blinded study. Subjects will remain blinded to study treatment 
throughout the study, except where indicated below. 
The identity of the treatments will be concealed by the use of study drugs that are all identical in 
packaging, labeling, schedule of administration, appearance, and odor. 
Site staff 
With the exception of any unblinded pharmacist or pharmacy designee, all site staff (including 
study investigator and study nurse(s)) will be blinded to study treatment during treatment 
allocation and subject dosing. Appropriate measures must be taken by any unblinded pharmacist 
or pharmacy designee to ensure that the treatment assignments are concealed from the rest of the 
site staff. 
Unblinding a single subject at the site for safety reasons (necessary for subject management) will 
occur via an emergency system in place at the site (see Section 5.10). 
Site staff may also be unblinded to the treatment assignment of one or more subjects (within a 
single cohort or across cohorts as necessary), or an entire cohort at the initial cohort safety 
Page 111 of 212

Anthos Therapeutics 
 
Page 30 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
evaluation timepoint if deemed appropriate to aid decision-making. The decision to un-blind site 
staff will be determined by the clinical trial team based on need or review of the entire study group 
will be performed at a pre-selected time. 
Sponsor staff 
The following unblinded Sponsor roles (or designee) are required for this study: 
• Field monitor(s) (evaluation of drug dispensing and reconciliation) 
• Physician not directly involved in study conduct  
• Sample analyst(s) (PK blood) 
• Study statistician 
• Programmers and other personnel involved in study data analysis 
An unblinded Covance Physician not directly involved in study conduct may receive a copy of the 
randomization schedule (via request to the Randomization Office), to facilitate analysis of aPTT 
safety labs that would otherwise unblind study Investigators. The unblinded Medical Monitor will 
alert the Investigator and Sponsor of any safety concerns. 
The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office), to facilitate analysis of the samples. The sample analysts will provide the 
sample data to the study team under blinded conditions unless otherwise allowed. 
The study statistician will be able to access the full randomization list from the start of the study 
and is allowed to share unblinded information with the rest of the clinical trial team as appropriate 
for internal decision purposes. For example, unblinded summaries and unblinded individual data 
can be shared with the team whenever necessary.  
Study programmers and other personnel involved in study data analysis (e.g. biomarker expert, 
pharmacometrician, modeler(s)) are allowed to access treatment assignment information from the 
start of the study for the purpose of data analysis. 
The clinical trial team is allowed to share unblinded results with other Sponsor staff (e.g. decision 
boards) as required for internal decision making on the study or the project while the study is 
ongoing.  
All unblinded personnel will otherwise keep randomization lists and data or information that could 
un-blind other study team members confidential and secure except as described above.  
Following final database lock all roles may be considered unblinded. 
5.5. 
Treating the subject 
MAA868 will be administered to the subject by study staff via s.c. administration. See the 
Pharmacy Manual for further details. 
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
Page 112 of 212

Anthos Therapeutics 
 
Page 31 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
5.6. 
Permitted dose adjustments and interruptions of study treatment 
Study treatment dose adjustments are not permitted. Any study drug administration that occurs 
outside of study visit windows must be approved by the study medical monitor. 
5.7. 
Study Completion and Post-study Treatment 
Each subject will be required to complete the study in its entirety and thereafter no further study 
treatment will be made available to them. 
Study completion is defined as when the last subject completes their EoS visit, and any repeat 
assessments associated with this visit have been documented and followed-up appropriately by the 
Investigator, or in the event of an early study termination decision, the date of that decision. 
All subjects will be required to attend the EoS visit and have related assessments collected as per 
the Schedule of assessments (Table 9). All SAEs reported during this time period must be reported 
as described in Section 7.6.2 and the Safety Management Plan. Documentation of attempts to 
contact the subject should be recorded in the source documentation. 
5.8. 
Discontinuation of Study Treatment 
The Investigator may decide to suspend the s.c. administration of the study drug if symptoms or 
signs consistent with an injection site reaction or hypersensitivity reaction occur.  
Subjects who decide they do not wish to participate in the study further should NOT be considered 
withdrawn from the study UNLESS they withdraw their consent (see Section 4.3.2, Withdraw of 
Informed Consent). Where possible, they should return for the EoS assessments indicated in the 
assessment table. If they fail to return for these assessments for unknown reasons, every effort (e.g. 
telephone, e-mail, letter) should be made to contact the subject/pre-designated contact as specified 
in Section 4.3.3 (Lost to follow-up). This contact should preferably be done according to the study 
visit schedule. 
5.9. 
Study Termination 
The study can be terminated by Anthos at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. Should this be necessary, subjects must be 
seen as soon as possible and treated as a prematurely withdrawn subject and followed until the 
aPTT has returned to baseline. The Investigator may be informed of additional procedures to be 
followed in order to ensure that adequate consideration is given to the protection of the subject’s 
interests. The Investigator will be responsible for informing the Institutional Review Board (IRB) 
of the early termination of the trial. 
5.10. 
Emergency breaking of assigned treatment code 
Emergency unblinding must only be undertaken when it is essential to treat the subject safely and 
efficaciously, such as in the event of clinically significant bleeding events. Most often, knowledge 
of the possible treatment assignments is sufficient to treat a study subject who presents with an 
emergency condition. A complete set of emergency code break cards will be provided to the 
Investigator site(s) and a complete set will be available at Anthos and Covance. All code break 
cards must be retained until the end of the study and retained by the site as a source document. 
Page 113 of 212

Anthos Therapeutics 
 
Page 32 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
They must be stored in a secure place but be accessible to the Investigator 24 hours per day in case 
of emergency. The Investigator will receive a blinded code break card for each subject. In an 
emergency, the code break may be opened to determine the treatment. There is no known reversal 
agent for MAA868 (see Section 6.2).  
The code break should not be opened for any reason other than an emergency. If the Investigator 
opened the code break, he/she must note the date, time, and reason for removing it and retain this 
information with the case report form documentation. The unblinded treatment code must not be 
recorded on the CRF. The Investigator must also immediately inform the study monitor that the 
code has been broken.  
It is the Investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the code break cards at any time in case of emergency. The Investigator will need 
to provide: 
• Protocol number  
• Study drug name (if available)  
• Subject number. 
In addition, the Investigator must provide oral and written information to inform the subject how 
to contact his/her backup in cases of emergency when he/she is unavailable to ensure that un 
blinding can be performed at any time. 
Page 114 of 212

Anthos Therapeutics 
 
Page 33 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
6. 
CONCOMITANT THERAPIES 
6.1. 
Concomitant therapy 
The Investigator must instruct the subject to notify the study staff of any new medications 
(including nutritional supplements and herbal medications) that he/she takes after being enrolled 
into the study. 
All prescription medications, OTC drugs and significant non-drug therapies (including physical 
therapy and blood transfusions) administered or taken within the timeframe defined in the entry 
criteria prior to the start of the study and during the study, must be recorded on the Concomitant 
medications/Significant non-drug therapies CRF. 
Medication entries should be specific to trade name, the single dose and unit, the frequency and 
route of administration, the start and discontinuation date and the reason for therapy. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the Investigator should contact Covance before randomizing a subject or, 
if the subject is already enrolled, to determine if the subject should continue participation in the 
study. 
During the study, in the event the Investigator elects to start the patient on chronic antithrombotic 
therapy, anticoagulation or antiplatelet therapy should not be started until the patient’s aPTT has 
returned to baseline. 
Reporting medication errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient/subject or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
All study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the Dose Administration Record CRF. Study treatment errors are only to be reported to Covance 
DSS department if the treatment error is associated with an SAE. 
All instances of misuse or abuse must be documented in the AE CRF irrespective of the 
misuse/abuse being associated with an AE/SAE. In addition, all instances of misuse or abuse must 
be reported to the Covance DSS department. As such, instances of misuse or abuse are also to be 
reported using the SAE form/CRF. Table 3 summarizes the reporting requirements. 
 
 
 
Page 115 of 212

Anthos Therapeutics 
 
Page 34 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
Table 3: 
Summary of reporting requirements for medication errors 
Treatment error type 
Document in Dose 
Administration CRF 
Document in AE CRF 
Complete SAE 
form/CRF 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see Section 7.6.1 and 
Section 7.6.2, respectively. 
6.2. 
Study restrictions 
Pregnancy and contraception 
Women of child-bearing potential are not permitted to participate in this study, unless they agree 
to use highly effective methods of contraception during their time in the study. 
During their time in the study, sexually active male subjects must agree to use highly effective 
methods of contraception and should not father a child or donate sperm in this period. Prohibited 
treatment 
Use of the following medications is not allowed during the course of the study from screening 
(Visit 1) through the EoS. Patients who are receiving such medication(s) will be excluded, or if 
ethically and clinically justified, the medication(s) should be gradually withdrawn at least seven 
days before the baseline visit: 
• Use of chronic antiplatelet agents such as clopidogrel or ticagrelor is prohibited; however, 
use of low-dose aspirin (≤100 mg per day) is permitted. 
• Use of chronic systemic anticoagulants such as warfarin, low molecular weight heparin or 
heparinoids, or direct oral anticoagulants such as apixaban or dabigatran. Patients may be 
started on chronic anticoagulation during the Washout/Follow-up period once their aPTT 
has returned to baseline, at the Investigator’s discretion. 
• Use of any therapeutic monoclonal antibody regardless of the indication during the study. 
Dietary restrictions  
• No alcohol for 48 hours before each clinic visit (from Screening through the EoS visit). 
During the study, alcohol consumption will be restricted to no more than 2 drinks/day for 
males and 1 drink/day for females. 
• Patients should not make significant alterations in their diet (e.g., going on weight loss diet) 
while in the study. 
• During the study, caffeinated beverages will be restricted to no more than 3 cups/day. 
Other restrictions 
No strenuous physical exercise or activities which have an increased risk of injury or falling should 
be undertaken until after the EoS visit. 
Page 116 of 212

Anthos Therapeutics 
 
Page 35 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
6.3. 
Reversal medication 
There is currently no specific antidote for MAA868. FXI concentrates (not marketed in the US) 
are unlikely to be effective as the excess in free MAA868 concentrations in the circulation is 
expected to quickly neutralize the exogenous FXI. 
Recombinant FVIIa can bypass the hypocoagulopathy and restore hemostasis in patients with 
severe FXI deficiency. Administration of intermediate to high doses of rFVIIa (40 to 90 μg/kg) 
resulted in supra-physiological levels of FVII and thromboembolic complications in patients with 
severe FXI deficiency (Riddell et al 2011). Low doses of rFVIIa are associated with lower 
prothrombotic risk. Riddell et al reported their experience in 4 patients with severe FXI deficiency 
undergoing surgery (Riddell et al 2011); patients were administered rFVIIa 30 μg/kg and 
tranexamic acid 1 g i.v. at induction of anesthesia. Subsequent bolus doses of rFVIIa 15–30 μg/kg 
were administered at 2 to 4 hourly intervals as guided by rotational thromboelastometry for 24 48 
hours and tranexamic acid 1 g every 6 hourly for 5 days. Low doses of rFVIIa and tranexamic acid 
were safe and effective in restoring hemostasis in severe FXI deficiency in this study. In another 
study comprising 4 patients with severe FXI deficiency with inhibitor who experienced 5 surgeries 
(Livnat et al 2009), 1 g of tranexamic acid was given 2 hours before surgery, immediately prior to 
the interventions then every 6 hour for at least 7 days; moreover, rFVIIa was administered at doses 
ranging from 15 to 30 μg/kg at the completion of surgery. This protocol secured normal hemostasis 
in patients with severe FXI deficiency with inhibitor. 
Based on the above, rFVIIa can be recommended as a preferred therapeutic option to restore 
hemostasis in subjects with active, non-accessible bleeding site and in subjects requiring 
immediate reversal of the MAA868 PD effects prior to an urgent surgery.  Please see the 
Investigator’s Brochure - Summary of the data and guidance for the investigator for a more 
complete discussion. 
Page 117 of 212

Anthos Therapeutics 
 
Page 36 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
7. 
STUDY ASSESSMENTS AND PROCEDURES 
7.1. 
Assessment schedule 
Subjects should be seen for all visits/assessments as outlined in the assessment schedule (Table 9).  
Missed or rescheduled visits should not lead to automatic discontinuation. Subjects who 
prematurely discontinue the study for any reason should be scheduled for a visit as soon as 
possible, at which time all of the assessments listed for the study treatment discontinuation (TD) 
visit will be performed. At the TD visit, all dispensed investigational product should be reconciled, 
and the AE and concomitant medications recorded on the CRF. 
7.2. 
Informed consent procedures 
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB-approved informed consent. 
The Sponsor, or Sponsor designee, will provide to investigators a proposed informed consent form 
that complies with the ICHE6 Good Clinical Practice (GCP) guideline and regulatory requirements 
and is considered appropriate for this study. The informed consent form will also include a section 
related to optional future research which will require a separate signature if the subject agrees to 
future research. Any changes to the proposed consent form suggested by the Investigator must be 
agreed to by the Sponsor before submission to the IRB. 
Information about common side effects already known about the investigational drug can be found 
in the IB. This information will be included in the subject informed consent and should be 
discussed with the subject during the study as needed. Any new information regarding the safety 
profile of the investigational drug that is identified between IB updates will be communicated as 
appropriate, for example, via an Investigator Notification or an Aggregate Safety Finding. New 
information might require an update to the informed consent and then must be discussed with the 
subject. 
Ensure subjects are informed of the contraception requirements outlined in the Section 4.2 
(Exclusion criteria). 
A copy of the approved version of all consent forms must be provided to the Covance monitor 
after IRB approval. 
7.3. 
Subject screening 
In general, it is permissible to re-screen a subject if s/he fails the initial Screening or falls out of 
the screening window timelines; however, each case must be discussed and agreed with the 
Sponsor Medical Monitor on a case-by-case basis. A new screening number will be assigned to a 
subject who is re screened, thus no screening number will be used twice. 
Reasons for screen failure will be documented in the site log. 
7.4. 
Subject demographics/other baseline characteristics 
Subject demographic and baseline characteristic data will be collected on all subjects. Relevant 
medical history/current medical conditions data will also be collected until signature of informed 
consent.  
Page 118 of 212

Anthos Therapeutics 
 
Page 37 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
Investigators have the discretion to record abnormal test findings on the medical history CRF, if 
in their judgment, the test abnormality occurred prior to the informed consent signature. 
Hepatitis screen, HIV screen 
All subjects will be screened for HIV, Hepatitis B and C. 
Alcohol test and drug screening 
All subjects will be screened for alcohol and substances of abuse. 
7.5. 
Efficacy Assessments 
The PD samples will be collected at the timepoints defined in the Assessment schedule (Table 9). 
Follow instructions outlined in the Central Laboratory Manual regarding sample collection, 
numbering, processing and shipment. 
In order to better define the PD profile, the timing of the sample collection may be altered based 
on emergent data. The number of samples/blood draws and total blood volume collected will not 
exceed those stated in the Laboratory Manual. 
PD samples will be obtained and evaluated in all subjects at all dose levels. 
7.5.1. 
Free FXI 
Free FXI concentrations (FXI that is not bound to MAA868) will be measured in plasma. A 
detailed description of the assay methods will be included in the Bioanalytical Data Report. 
7.5.2. 
aPTT 
aPTT, calibrated for FXI deficiency, and aPTT using a standard laboratory protocol will be 
measured at all timepoints indicated in the Assessment schedule (Table 9). 
aPTT will be determined in plasma. The detailed method descriptions of the assay will be included 
in the Bioanalytical Data Report. 
7.5.3. 
Total FXI 
Total FXI concentrations (FXI that is either bound to MAA868 or free) will be measured in plasma. 
A detailed description of the assay methods will be included in the Bioanalytical Data Report. 
7.5.4. 
FXI coagulation activity (FXI:C) 
FXI:C will be measured in plasma. A detailed description of the assay methods will be included 
in the Bioanalytical Data Report. 
7.6. 
Safety Assessments 
Safety assessments are specified below; assessments will be collected as specified in the 
Assessment Schedule (Table 9). 
Bleeding 
All suspected bleeding events will be documented by the Investigator in the appropriate CRF. All 
suspected bleeding events will be adjudicated by experienced medical personnel that is blinded to 
Page 119 of 212

Anthos Therapeutics 
 
Page 38 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
treatment assignment. Adjudication of bleeding events will be performed in accordance with the 
International Society of Thrombosis and Haemostasis (ISTH) definition of a major bleeding in 
non-surgical patients (Schulman et al 2005) and criteria for clinically-relevant non-major bleeding 
(CRNM) events. The definitions of bleedings are as follows: 
Major bleeding events include: 
• Fatal bleeding, and/or 
• Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intra‐articular or pericardial, or intramuscular with 
compartment syndrome, and/or 
• Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more or leading to 
transfusion of two or more units of whole blood or red cells. 
CRNMs (clinically relevant non-major) bleeding events will be defined as clinically overt bleeding 
that did not satisfy the criteria for major bleeding and that led to: 
• hospital admission, or 
• physician-guided medical treatment, or 
• surgical treatment or 
• change in antithrombotic therapy 
In addition to the ISTH definition of bleeding events other definitions such as TIMI, BARC, 
GUSTO, etc. can be used as supportive for exploratory safety analyses. 
The population is those who have received at least one dose of the study drug. 
 
Major cardiovascular, cerebrovascular, and venous thromboembolic events 
All suspected major cardiovascular, cerebrovascular, and VTE events will be documented by the 
Investigator in the appropriate CRF including any diagnostic imaging that was used to confirm the 
event. For instance, any suspected episodes of DVT (i.e., swelling, localized pain, redness, heat, 
localized warmth) must be documented by compression ultrasound (CUS) or venography.  
Any suspected episodes of PE (i.e., shortness of breath, chest pain, coughing, tachycardia, 
hemoptysis, hemodynamic compromise, unexplained death) must be documented by 
ventilation/perfusion lung scintigraphy, spiral computed tomography (sCT), or pulmonary 
angiography. 
All major cardiovascular, cerebrovascular, systemic arterial, and venous thromboembolic events 
(VTEs) including deaths for which a major cardiovascular, cerebrovascular, or VTE event could 
not be ruled out will be adjudicated by experienced medical personnel that is blinded to treatment 
assignment. 
The adjudicated outcome will be the basis for any interim and final safety evaluations. 
Page 120 of 212

Anthos Therapeutics 
 
Page 39 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
7.6.1. 
Adverse Events 
An AE is any untoward medical occurrence [i.e., any unfavorable and unintended sign (including 
abnormal laboratory findings), symptom or disease] in a subject or clinical investigation subject 
after providing written informed consent for participation in the study until the EoS visit. 
Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal 
(investigational) product. 
In addition, all reports of intentional misuse and abuse of the study treatment are also considered 
an AE irrespective if a clinical event has occurred. See Section 7.6.2 for an overview of the 
reporting requirements. 
The occurrence of AEs must be sought by non-directive questioning of the subject at each visit 
during the study. AEs also may be detected when they are volunteered by the subject during or 
between visits or through physical examination finding, laboratory test finding, or other 
assessments. 
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria: 
• they induce clinical signs or symptoms, 
• they are considered clinically significant, 
• they require therapy. 
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in healthy subjects. 
Investigators have the responsibility for managing the safety of individual subject and identifying 
AEs. Alert ranges for liver and kidney related events are included in Appendix 1 and Appendix 2, 
respectively. Additional clinically notable laboratory values are included in Appendix 3. 
AEs must be recorded on the AE CRF under the signs, symptoms or diagnosis associated with 
them, and accompanied by the following information: 
1. Severity grade 
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
2. Relationship to the study treatment 
• Related 
• Possibly related 
• Not related 
3. Duration (start and end dates) or if the event is ongoing an outcome of not recovered/not resolved 
must be reported. 
Page 121 of 212

Anthos Therapeutics 
 
Page 40 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
4. Whether it constitutes a SAE (see Section 7.6.2 for definition of SAE) and which seriousness 
criteria have been met 
5. Action taken regarding investigational treatment. 
All AEs must be treated appropriately. Treatment may include one or more of the following: 
• no action taken (e.g. further observation only) 
• concomitant medication or non-drug therapy given 
• hospitalization/prolonged hospitalization (see Section 7.6.2 for definition of SAE) 
6. 
Outcome 
(not 
recovered/not 
resolved; 
recovered/resolved; 
recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown). 
Information about common side effects already known about the investigational drug can be found 
in the IB. Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent, and assessment should be made at each visit (or more frequently, if necessary) of any 
changes in severity, the suspected relationship to the investigational drug, the interventions 
required to treat it, and the outcome. 
The Investigator must also instruct each subject to report any new AE (beyond the protocol 
observation period) that the subject, or the subject’s personal physician, believes might reasonably 
be related to study treatment. This information must be recorded in the Investigator’s source 
documents; however, if the AE meets the criteria of an SAE, it must be reported to Covance. 
7.6.2. 
Reporting Serious Adverse Events 
Definition of SAE 
An SAE is defined as any AE [appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s) or medical conditions(s)] which meets any one of the following criteria: 
• is fatal or life-threatening 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
o elective or pre-planned treatment for a pre-existing condition and has not worsened 
since the start of study drug 
o treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
o social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
o is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention 
Page 122 of 212

Anthos Therapeutics 
 
Page 41 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (see Annex IV, ICH-E2D Guideline). 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse (see Annex IV, ICH-E2D Guideline). 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All AEs (serious and non-serious) are captured on the CRF; SAEs also require individual reporting 
to Covance Drug Safety & Epidemiology (DS&E). 
SAE Reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last planned study assessment, must be 
reported to Covance within 24 hours of learning of its occurrence as described below. Any SAEs 
experienced after this period should only be reported to Covance if the Investigator suspects a 
causal relationship to study treatment. 
Note: SAEs reported by subjects deemed to be screen failures must be reported to Covance as 
outlined here with appropriate information also captured in the CRFs. 
All follow-up information for the SAE including information on complications, progression of the 
initial SAE and recurrent episodes must be reported as follow-up to the original episode within 24 
hours of the Investigator receiving the follow-up information. An SAE occurring at a different 
time interval or otherwise considered completely unrelated to a previously reported one must be 
reported separately as a new event. 
Follow- up information provided must describe whether the event has resolved or continues, if and 
how it was treated, whether the blind was broken or not (if applicable) and whether the subject 
continued or withdrew from study participation. Each re-occurrence, complication, or progression 
of the original event must be reported as a follow-up to that event regardless of when it occurs. 
If the SAE is not previously documented in the IB (new occurrence) and is thought to be related 
to the study treatment a Covance DS&E associate may urgently require further information from 
the Investigator for Health Authority reporting. Covance may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will 
be collected and reported to the competent authorities and relevant ethics committees in 
accordance with EU Guidance 2011/C 172/01 or as per national regulatory requirements in 
participating countries. 
Page 123 of 212

Anthos Therapeutics 
 
Page 42 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
Follow the detailed instructions outlined in the Safety Management Plan regarding the submission 
process for reporting SAEs to Covance. Note: SAEs must be reported to Covance within 24 hours 
of the Investigator learning of its occurrence/receiving follow-up information. 
7.7. 
Liver safety monitoring 
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of liver 
events must be followed. 
Please refer to Appendix 1 for complete definitions of liver events. 
Follow-up of liver events 
Every liver event defined in Appendix 1  should be followed up by the Investigator or designated 
personnel at the trial site, as summarized below. Additional details on actions required in case of 
liver events are outlined in Table 4 of Appendix 1. 
• Repeating liver chemistry tests (ALT, AST, total bilirubin (TBL), PT/INR, ALP and γGT) 
to confirm elevation within 48-72 hours. 
These liver chemistry repeats should always be performed using the central laboratory, 
with the results provided via the standard electronic transfer. If results will not be available 
from the central laboratory within 24 hours, then the repeats can also be performed at a 
local laboratory to monitor the safety of the subject. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with this 
event should have results reported on the unscheduled local laboratory CRF. 
• If the initial elevation is confirmed, close observation of the subject will be initiated, 
including consideration of treatment interruption if deemed appropriate. 
• Discontinuation of the investigational drug (refer to Section 4.3 (Discontinuation of study 
treatment), if appropriate 
• Hospitalization of the subject if appropriate 
• Causality assessment of the liver event 
• Thorough follow-up of the liver event should include  
o Repeating liver chemistry tests two or three times weekly. Testing should include 
ALT, AST, ALP, PT/INR, and γGT. If total bilirubin is elevated > 2 x ULN, 
fractionation into direct and indirect bilirubin is required. To rule out muscular 
origin of transaminase elevations, CPK should be measured along with liver 
chemistry tests. Frequency of retesting can decrease to once a week or less if 
abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic. Retesting should be continued up to resolution. 
o Obtaining a more detailed history of symptoms and prior or concurrent diseases. 
o Obtaining a history of concomitant drug use (including non-prescription 
medications and herbal and dietary supplement preparations), alcohol use, 
recreational drug use, and special diets. 
Page 124 of 212

Anthos Therapeutics 
Page 43 
AFib Protocol v02 
Protocol No. ANT-004 
o
Exclusion of underlying liver disease, as specified in Table 6.
o
Imaging such as abdominal US, CT or MRI, as appropriate
o
Obtaining a history of exposure to environmental chemical agents.
o
Considering gastroenterology or hepatology consultations.
All follow-up information, and the procedures performed must be recorded as appropriate in the 
CRF. 
7.8. 
Renal safety monitoring 
Every renal laboratory trigger or renal event must be followed up by the Investigator or designated 
personnel at the trial site. Recommended follow-up assessments are listed in Appendix 2. 
7.9. 
Pregnancy 
All female study participants, regardless of the requirement to be of non-child-bearing potential to 
be enrolled into this study, will have pregnancy testing. See the Assessment Schedule (Table 9), 
for timing of the protocol required pregnancy testing; additional pregnancy testing may be 
performed to meet local requirements*. Subjects will not receive study medication in case of a 
positive urine or serum pregnancy test. 
*If additional pregnancy testing is needed per local requirements, those additional results will be
kept as source documentation only.
Pregnancy reporting 
Reproductive toxicity and teratogenicity data are not available for this antibody at this time, 
therefore no guidelines on therapeutic recommendations in case of pregnancy are available. This 
study enrolls women who are considered to be of non-child-bearing potential, thus pregnancy is 
not an expected outcome for any female study participant. However, in the case that a pregnancy 
in a female study participant should occur please follow the below reporting guidelines. The 
follow-up for this subject and for the fetus is at the discretion of the Investigator. 
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Covance within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of the 
birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications. 
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
Investigator to the local Covance DSS department. Pregnancy follow-up should be recorded on 
the same form and should include an assessment of the possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported on a 
SAE form. 
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes should 
be obtained from the mother. 
Page 125 of 212

Anthos Therapeutics 
 
Page 44 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
All assessments that are considered as a risk during pregnancy must not be performed. The subject 
may continue all other protocol assessments. 
7.10. 
Clinical Laboratory Evaluations 
Clinically relevant deviations of laboratory test results occurring during or at completion of the 
study must be reported and discussed with Covance personnel. The results should be evaluated for 
criteria defining an AE and reported as such if the criteria are met. Repeated evaluations are 
mandatory until normalization of the result(s) or until the change is no longer clinically relevant. 
In case of doubt, Covance personnel should be contacted. 
Safety labs (hematology, clinical chemistry and urinalysis) do not need to be repeated at baseline 
if the Baseline visit is taking place within 48 hours of the screening labs being collected from an 
individual subject. 
Subjects should be instructed to fast for at least 8 hours prior to scheduled safety lab collections. 
Clinically notable laboratory findings are defined in Appendix 3. 
Hematology 
Hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell (WBC) count with 
differentials and platelet count will be measured. 
Clinical chemistry 
Sodium, potassium, creatinine, BUN/urea, uric acid, chloride, albumin, calcium, alkaline 
phosphatase, total bilirubin, bicarbonate/HCO3, LDH, GGT, AST, ALT, CK, glucose, total 
cholesterol, triglycerides. If the total bilirubin concentration is increased above 1.5 times the upper 
limit of normal, direct and indirect reacting bilirubin should be differentiated. 
Urinalysis 
Dipstick measurements for specific gravity, protein, glucose and blood will be performed. 
Microscopy, WBC, RBC and sediments will also be assessed in case of an abnormal dipstick test. 
Special clinical laboratory evaluations 
Stool samples will be collected to check for occult blood at screening and baseline. Screening fecal 
samples can be collected at any time during the Screening period, and baseline fecal samples must 
be collected within 72 hours of Day 1. If fecal screening samples are collected within 72 hours of 
Day 1, then they do not need to be repeated for the Baseline visit. In the event that a subject is 
unable to produce a stool sample for sampling, the site medical staff may elect to produce a sample 
via digital extraction from the rectum. 
Details regarding collection methods and processing are outlined in the Central Laboratory 
Manual. 
7.11. 
Vital Signs, Physical Examination, and Other Safety Evaluations 
Vital signs will include the collection of oral body temperature (recorded in °C), blood pressure 
(BP)–sitting and standing –and pulse measurements. At Screening, for eligibility determination, 
three sets of systolic and diastolic BP and pulse rate measurements will be collected after the 
subject has been sitting for 3 minutes, with back supported and both feet placed on the floor and 
Page 126 of 212

Anthos Therapeutics 
Page 45 
AFib Protocol v02 
Protocol No. ANT-004 
the mean will be used to determine eligibility. A single set of BP and pulse rate measurements will 
then be collected after three minutes in the standing position.  
A single set of sitting BP measurements will be collected at subsequent visits. 
Physical exams will include assessment of general appearance, skin, lymph nodes, HEENT, neck, 
thorax/lungs, cardiovascular, abdomen, musculoskeletal, and neurological systems. 
Height in centimeters (cm) and body weight [to the nearest 0.1 kilogram (kg) in indoor clothing, 
but without shoes] will be measured. Body mass index (BMI) will be calculated using the 
following formula: 
BMI = Body weight (kg) / [Height (m)]2. BMI results will be documented in the CRF to 2 decimal 
places. 
7.12. 
Electrocardiogram (ECG) 
The ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable baseline. 
PR interval, QRS duration, heart rate, RR interval, QT, QT corrected by the Fridericia correction 
formula (QTcF) will be collected. The QTcF should be used for clinical decision-making. ECGs 
must be collected, analyzed and appropriately signed and archived at the study site; the site will 
also store all ECG readings digitally (if possible). For any ECGs with subject safety concerns, 
duplicate ECGs must be performed to confirm the safety finding. Clinically significant ECG 
findings at baseline must be discussed with the Sponsor before administration of study treatment. 
Clinically significant abnormalities must be reported in the AE CRF. 
7.13. 
Pharmacokinetic Analysis 
The PK samples will be collected at the timepoints defined in the Assessment schedule (Table 9). 
Follow instructions outlined in the Central Laboratory Manual regarding sample collection, 
numbering, processing and shipment. See Section 7.15 regarding the potential use of residual 
samples. 
In order to better define the PK profile, the timing of the PK sample collection may be altered 
based on emergent data. The number of samples/blood draws and total blood volume collected 
will not exceed those stated in the Laboratory Manual. Changes to the PK Assessment schedule, 
if any, will be communicated to the sites in the dose adjustment minutes. 
The PK samples will be obtained and evaluated in all subjects at all dose levels. Untreated 
(placebo) samples will not be analyzed. 
Concentrations of plasma total MAA868 (i.e. MAA868 that is bound to FXI or not bound to FXI) 
will be determined by a validated LC-MS/MS method. A detailed description of the method used 
to quantify the concentration of total MAA868 will be included in the bioanalytical raw data and 
in the Bioanalytical Data Report. 
All concentrations below the LLOQ or missing data will be labeled as such in the concentration 
data listings. 
For standard PK abbreviations and definitions see the list provided at the beginning of this 
protocol. 
Page 127 of 212

Anthos Therapeutics 
 
Page 46 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
The following PK parameters will be determined, where data permit, using the actual recorded 
sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 6.2 or 
higher): C0 (the concentration at the end of infusion), AUClast, AUCinf, C0/D, and AUC/D, based 
on the plasma concentration data.  
The linear trapezoidal rule will be used for AUC calculation. The terminal half-life of MAA868 
(T1/2), volume of distribution (Vss) and clearance (CL) will also be estimated, if feasible, based on 
the data. 
7.14. 
Other assessments 
7.14.1. 
Exploratory Biomarker assessments 
Biomarkers including, but not limited to, D-Dimer and biomarkers of thrombogenesis and 
coagulation may also be studied. 
The list may be changed or expanded further, as it is recognized that more relevant or novel 
biomarkers may be discovered during the conduct of the study. 
Sample(s) will be collected at the timepoint(s) defined in the Assessment schedule (Table 9). 
Follow instructions for sample collection, numbering, processing and shipment provided in the 
central lab manual. Detailed descriptions of the assays will be included in the Bioanalytical Data 
Reports. 
7.14.2. 
Immunogenicity (IG) 
The IG samples will be collected at the timepoints defined in the Assessment schedule (Table 9). 
Follow instructions outlined in the Central Laboratory Manual regarding sample collection, 
numbering, processing, and shipment. See Section 7.15 regarding the potential use of residual 
samples. 
Immunogenicity analytical method(s) 
A ligand-binding assay will be used to detect anti-MAA868 antibodies. The analytical method will 
be described in detail in the IG Bioanalytical Data Report. 
7.15. 
Use of residual biological samples 
Residual blood samples may be used for another protocol specified endpoint. 
Any residual samples remaining after the protocol-defined analysis has been performed may be 
used for additional exploratory analysis. This may include but is not limited to using residual 
samples for protein binding, metabolite profiling, biomarkers of transporters or metabolic enzyme 
activity (such as 4-beta-hydroxycholesterol levels) or other bioanalytical purposes (e.g. cross 
check between different sites and/or stability assessment). Given the exploratory nature of the 
work, the analytical method used for those assessments may not be validated. As such, the results 
from this exploratory analysis will not be included in the clinical study report. 
Page 128 of 212

Anthos Therapeutics 
 
Page 47 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
8. 
SAMPLE SIZE AND DATA ANALYSES 
8.1. 
Determination of Sample Size 
A sample size of 16 subjects per treatment dose cohort with a ratio of 3:1 for MAA868 and placebo 
treatment assignment is based on historic data considerations. For example, if the observed 
proportion of patients in a cohort achieving target levels of inhibition is 11/12, the 90% confidence 
interval would be 0.66 to 0.996. 
8.2. 
Analysis Populations 
All Randomized Set will include all subjects who are randomized  
Full Analysis Set will include randomized subjects excluding those subjects who are randomized 
into the study in error and did not receive study drug. Subjects will be analyzed based on the 
assigned treatment at the randomization.  
Per Protocol Set will include subjects in Full Analysis Set and those subjects have no major 
protocol deviation after randomization.  
Safety Set will include randomized subjects who at least received one dose of study drug. Subjects 
will be analyzed based on the actual treatment taken. 
PK/PD Analysis Set will comprise all subjects who received at least one dose of study drug and 
have at least one PK/PD assessment. Subjects will be analyzed based on the actual treatment taken. 
8.3. 
General Considerations 
All efficacy analysis will be based on the Full Analysis Set or Per Protocol Set and will be 
performed based on the assigned treatment arm at the randomization. Only descriptive statistics 
will be summarized, no statistical inference will be calculated in efficacy.  
Safety analysis will be performed using Safety Set. Subjects will be analyzed based on the actual 
treatment taken. 
PK and PD analysis will be based on PK/PD Analysis Set. 
Continuous variables will be summarized by number of subjects [n], mean, standard deviation 
[SD], median, minimum [min], and maximum [max]. Categorical variable will be summarized 
using frequency [N] and percentage [%]. 
8.4. 
Demographics and Baseline characteristics 
All baseline summaries will be based on the All Randomized Set and Full Analysis Set 
populations. 
Gender, race and ethnicity will be summarized using counts and percentages. Age, height (cm), 
and weight (kg) will be summarized with descriptive statistics (number of subjects [n], mean, SD, 
median, minimum [min], and maximum [max]). Age may be summarized by decades using N and 
%. 
The listing of subjects with abnormal physical examination findings at screening will be presented. 
The number and percent of subjects with medical history events will be summarized. Vital signs 
Page 129 of 212

Anthos Therapeutics 
 
Page 48 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
collected at screening (sitting diastolic and systolic blood pressure, pulse, temperature and body 
weight) will be summarized with descriptive statistics (n, mean, SD, median, min, and max). 
8.5. 
Efficacy Analysis 
8.5.1. 
Primary Efficacy Outcome Measures 
Within each treatment cohort patients will be randomized 3:1 to active drug or placebo. 
The primary analysis variable is whether a subject will achieve a certain percentage FXI inhibition 
at trough (Day 91). The response rate per treatment group will be calculated by number of subjects 
who achieve targeted FXI inhibition rate divided by the total number of subjects in the treatment 
group. The dose regimens and targeted FXI inhibition achievement for Cohorts 1 and 2 are as 
follows  
Cohort 1 (MAA868 120 mg monthly or placebo): Targeted to achieve ≥ 50% FXI inhibition in 
90% of subjects at trough (Day 91).  
Cohort 2 (MAA868 180 mg monthly or placebo): Targeted to achieve ≥ 90% FXI inhibition in 
90% of subjects at trough (Day 91). 
The “on treatment” trough FXI levels will be used for the primary analysis, where “on treatment” 
FXI level is defined as a value which is collected within 30 (±5) days after the last administration 
of MAA868. The estimate of the responder rate (%) at Day 91 will be presented for each dose 
regimens of MAA868 together with 2-sided 90% confidence intervals (CI) computed via the 
Clopper-Pearson exact binomial method. 
8.5.2. 
Secondary Efficacy Outcome Measures 
The secondary efficacy analysis is to evaluate the proportion of subjects achieving FXI inhibition 
≥ 50%, ≥80%, and ≥90% at trough after the first and second dose (Day 31 and Day 61) at 3 dose 
levels of MAA868. The analyses described for the primary endpoint will be repeated for the 
secondary efficacy variables as follows: 
• Cohort 1 (MAA868 120 mg monthly or placebo): at Day 31 and 61.  
• Cohort 2 (MAA868 180 mg monthly or placebo):  at Day 31 and 61 
• Cohort 3 (MAA868 TBD mg monthly or placebo): at Day 31 and 61 
8.6. 
Safety Analysis 
The safety evaluation includes the analysis of bleeding events, AEs, major cardiovascular, 
cerebrovascular, systemic arterial, and venous thromboembolism events, laboratory data, ECG, 
vital signs, hypersensitivity reactions, injection site reactions, and development of anti-drug 
antibodies. All safety analysis will be performed using the Safety Set. 
8.6.1. 
Adverse Events 
The Investigator’s verbatim term of each AE will be mapped to system organ class (SOC) and 
preferred term (PT) using the MedDRA dictionary. 
Page 130 of 212

Anthos Therapeutics 
 
Page 49 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
Treatment-emergent Adverse Events (TEAEs) will be of primary interest. The TEAEs will be 
summarized by SOC and PT; a subject will only be counted once per SOC and once per PT within 
a treatment. If a subject reports more than one AE with the same PT, the AE with the maximum 
severity will be presented. Subject counts and percentages and event counts will be presented for 
each treatment and totaled for all treatments for the following summaries: 
• All TEAEs 
• Serious TEAEs  
• All TEAEs by severity 
• All TEAEs by relationship to study drug 
• TEAEs potentially related to study drug 
• TEAEs potentially related to study drug by severity 
• TEAEs leading to discontinuation of study drug 
• TEAEs leading to withdrawal from the study 
Adverse events of special interest (AESI) will be reported for a selection of interested AE terms 
that are specific to Sponsor’s product and program, for which ongoing monitoring and rapid 
communication by the Investigator to the Sponsor can be appropriate. 
The AESIs for this study are defined as follows: 
1. 
TERM 1 
2. 
TERM 2 
Similarly, to the TEAE summary, the AESI will be summarized in the following: 
1. 
All AESIs 
2. 
Serious AESIs 
3. 
All AESIs by severity 
4. 
All AESIs by relationship to study drug 
5. 
AESIs leading to discontinuation of study drug 
6. 
AESIs leading to withdrawal from the study 
No statistical inference between the treatments will be performed on AEs. 
Listings will be presented by subject for all TEAEs, AESIs, as well as for SAEs, TEAEs associated 
with outcome of death, and TEAEs leading to discontinuation from the study. 
8.6.2. 
Bleeding Events 
An analysis will be performed for the composite safety endpoint of major and CRNM bleeding 
events which occur on-treatment from the first dose of the study drug to the last dose of the study 
drug + 30 days if the subject permanently discontinues the study drug prior to the third dose on 
Day 91. The number of events and the incidence of adjudicated bleeding events will be tabulated 
Page 131 of 212

Anthos Therapeutics 
 
Page 50 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
based on ISTH definition by treatment including the composite endpoint of major bleeding events 
and/or CRNM bleedings.  
Major bleeding events (Yes/No) 
CRNM bleeding events (Yes/No) 
Total bleeding events (Yes/No) 
If a subject has more than one bleeding event in each above category, the subject will be counted 
only once in the tabulation. 
The adjudicated outcome will be the basis for any interim and final analysis. 
8.6.3. 
Major cardiovascular, cerebrovascular, and venous thromboembolic events 
An analysis will be performed for the composite safety endpoint of major cardiovascular, 
cerebrovascular, and venous thromboembolic events which occur on-treatment from the first dose 
of the study drug to the last dose of the study drug + 30 days if the subject permanently discontinues 
the study drug prior to the third dose on Day 91.   
The number of events and the incidence of adjudicated events will be tabulated based on the 
outcomes adjudicated by experienced medical personnel, and the adjudicated outcome will be the 
basis for any interim and final analysis. 
8.6.4. 
Clinical Laboratory Evaluations 
Clinical laboratory results in continuous values at each timepoint and for change from baseline 
will be displayed using summary statistics (n, mean, median, SD, minimum and maximum values). 
A laboratory value that is within the central laboratory’s reference range will be considered normal. 
A laboratory value that is outside the central laboratory’s normal range will be considered 
abnormal and will be flagged as either high (H) or low (L). The number and percentage of subjects 
with abnormal laboratory values will be summarized for each scheduled visit. In addition, shift 
tables will be presented to display the shift in the normal range categories (L, normal [N], H) from 
baseline to specified timepoint. Laboratory results in clinical significance will also be summarized 
in tabulation. 
All clinical laboratory data will be presented in listings. Baseline is defined as the result obtained 
prior to first administration of study medication. Laboratory data will be summarized in SI units. 
8.6.5. 
Vital Sign Measurements 
Pre-dose values, post-dose values, and the change from baseline in vital sign measurements (sitting 
diastolic and systolic blood pressure, pulse, temperature and body weight) will be summarized 
with descriptive statistics (n, mean, SD, median, min, and max) at each timepoint by treatment. 
The baseline value will be value just prior to first administration of study medication. 
8.6.6. 
ECG Parameters 
The ECG measures (QTc-B, QTc-F, QT, RR, ventricular rate, PR, and QRS) will be listed and 
summarized with descriptive statistics (n, mean, SD, median, min, and max) at each timepoint by 
treatment. 
Page 132 of 212

Anthos Therapeutics 
 
Page 51 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
The listings of subjects with abnormal ECG results, as judged by the Investigator, will be displayed 
and will be calculated. The baseline will be the value just prior to first administration of study 
medication. 
8.7. 
Pharmacokinetic Analysis 
Descriptive summary statistics will be provided by treatment and visit/sampling timepoint with 
descriptive statistics (n, mean, SD, median, min, and max) at each timepoint by treatment. An 
exception to this is Tmax where median, minimum and maximum will be presented. 
Concentrations below the lower limit of quantitation (LLOQ) will be treated as zero in summary 
statistics and for PK parameter calculations. A geometric mean will not be reported if the dataset 
includes zero values. 
Individual total MAA868 plasma concentration data will be listed by treatment (MAA868 arms 
only), subject, and visit/sampling timepoint. PK parameters will also be listed by treatment and 
subject. 
8.8. 
Biomarkers 
Coagulation parameters, including free and total FXI, FXI:C, and immunogenicity will be 
summarized by timepoint and treatment. 
8.9. 
Interim Analysis 
Safety and tolerability data (AEs, laboratory assessments, vital signs and ECG data) will be 
evaluated from Cohort 1 by the Sponsor's Medical Monitor  and Covance Lead Project Physician 
after approximately 10 of the patients in cohort 1 have received their second dose of study drug 
and have been followed for at least an additional 14 days. The decision to proceed to cohort 2 will 
be made only after it is confirmed that the cohort 1 dose was safe and tolerated and all planned 
subjects in cohort 1 have been randomized. If notable AEs or safety concerns are found in cohort 
1, the study may be terminated.  
Likewise, after approximately 10 of the patients in cohort 2 have received their second dose of 
study drug and have been followed for at least an additional 14 days, safety, tolerability, and other 
analyses will be evaluated.  
Additional IAs may be conducted to support decision making concerning the current clinical study, 
the Sponsor’s clinical development projects in general or in case of any emergent safety concerns. 
The Investigator(s) may be included for decisions with regards to any unplanned IAs that address 
questions of subject safety. 
Unblinded IA results will be reviewed by the Sponsor (or their designees).  
No further dissemination of interim results should occur, in particular not with individuals 
involved in treating the study’s subjects or assessing clinical data (e.g. ECGs, symptoms) obtained 
in the study. 
8.10. 
Data Quality Assurance 
Site monitoring 
Page 133 of 212

Anthos Therapeutics 
 
Page 52 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Covance 
representative will review the protocol and CRFs with the Investigator(s) and their staff. During 
the study Covance employs several methods of ensuring protocol and GCP compliance and the 
quality/integrity of the sites’ data. The monitor will visit the site to check the completeness of 
subject records, the accuracy of entries on the CRFs, the adherence to the protocol and to GCP, 
the progress of enrollment, and ensure that study drug is being stored, dispensed, and accounted 
for according to specifications. Key study personnel must be available to assist the monitor during 
these visits. 
The Investigator must maintain source documents for each subject in the study, consisting of case 
and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or assessments. 
All information on CRFs must be traceable to these source documents in the subject's file. The 
Investigator must also keep the original informed consent form signed by the subject (a signed 
copy is given to the subject). 
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Covance monitoring standards require full verification for the 
presence of informed consent, adherence to the eligibility criteria, documentation of SAEs, and 
the recording of data that will be used for all primary and safety variables. Additional checks of 
the consistency of the source data with the CRFs are performed according to the study-specific 
monitoring plan. No information in source documents about the identity of the subjects will be 
disclosed. 
Data collection 
Designated Investigator staff will enter the data required by the protocol into the Electronic Case 
Report Forms using fully validated software that conforms to 21 CFR Part 11 requirements. 
Designated investigator site staff will not be given access to the electronic data capture (EDC) 
system until they have been trained. Automatic validation programs check for data discrepancies 
and, by generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to Covance working on behalf of Anthos. The Investigator must certify that the 
data entered into the Electronic Case Report Forms are complete and accurate. After database lock, 
the Investigator will receive copies of the subject data for archiving at the investigational site. 
Data not requiring a separate written record are noted on the Assessment schedule (Table 9) and 
can be recorded directly on the CRF. All other data captured for this study will have an external 
originating source (either written or electronic) with the CRF not being considered as source. 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 
Database management and quality control 
Covance will review the data entered into the CRFs by investigational staff for completeness and 
accuracy and instruct the site personnel to make any required corrections or additions. Queries are 
sent to the investigational site using an electronic data query. Designated investigator site staff is 
required to respond to the query and confirm or correct the data. Site personnel will complete and 
sign the faxed copy and fax it back to Covance who will make the correction to the database. The 
signed copy of the Data Query Form is kept at the investigator site. 
Page 134 of 212

Anthos Therapeutics 
 
Page 53 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
Concomitant medications entered into the database will be coded using the WHO Drug Reference 
List, which employs the Anatomical Therapeutic Chemical classification system. Medical 
history/current medical conditions and adverse events will be coded using the Medical dictionary 
for regulatory activities (MedDRA) terminology. 
Laboratory samples will be processed centrally, and the results will be sent electronically to 
Covance. 
At the conclusion of the study, the occurrence of any emergency code breaks will be determined 
after return of all code break reports and unused drug supplies to Covance. 
The occurrence of any protocol deviations will be determined. After these actions have been 
completed and the database has been declared to be complete and accurate, it will be locked, and 
the treatment codes will be unblinded and made available for data analysis. Any changes to the 
database after that time can only be made by joint written agreement between the Anthos Head of 
Regulatory and the Chief Medical Officer. 
Page 135 of 212

Anthos Therapeutics 
 
Page 54 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
9. 
ETHICAL CONSIDERATIONS 
9.1. 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for GCP, with applicable local regulations 
(including European Directive 2001/20/EC, US Code of Federal Regulations Title 21, and 
Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in the 
Declaration of Helsinki. 
9.2. 
Responsibilities of the Investigator and IRB 
Before initiating a trial, the Investigator/institution must obtain approval/favorable opinion from 
the IRB for the trial protocol, written informed consent form, consent form updates, subject 
recruitment procedures (e.g. advertisements) and any other written information to be provided to 
subjects. Prior to study start, the Investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents and all of 
the instructions and procedures found in this protocol and to give access to all relevant data and 
records to Covance monitors, auditors, Covance Quality Assurance representatives, designated 
agents of Anthos, IRBs, and regulatory authorities as required. If an inspection of the clinical site 
is requested by a regulatory authority, the Investigator must inform Anthos immediately that this 
request has been made. 
For multi-center trials, a Coordinating Investigator will be selected by Anthos around the time of 
Last Patient Last Visit to be a reviewer and signatory for the CSR. 
9.3. 
Publication of study protocol and results 
The key design elements of this protocol will be posted in a publicly accessible database such as 
clinicaltrials.gov. Upon study completion and finalization of the study report the results of this 
trial will be posted in a publicly accessible database of clinical trial results in accordance with local 
regulations. 
No publication or disclosure of study results will be permitted except under the terms and 
conditions of a separate written agreement between the Sponsor and the investigator and/or the 
investigator's institution.  
The information developed from this clinical study will be used by the Sponsor in connection with 
the development of MAA868 and other drugs and diagnostics, and thus may be disclosed as 
required to other clinical investigators, business partners, or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the Sponsor with all data obtained in the study. 
Page 136 of 212

Anthos Therapeutics 
 
Page 55 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
10. 
PROTOCOL ADHERENCE 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
Investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.  
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an Investigator 
feels a protocol deviation would improve the conduct of the study this must be considered a 
protocol amendment, and unless such an amendment is agreed upon by Anthos and approved by 
the IRB and health authorities, where required, it cannot be implemented. 
10.1. 
Protocol Amendments 
Any change to the protocol can only be made in a written protocol amendment that must be 
approved by Anthos, Health Authorities where required, and the IRB prior to implementation.  
Amendments that are intended to eliminate an apparent immediate hazard to subjects may be 
implemented immediately, provided the Health Authorities are subsequently notified by protocol 
amendment and the reviewing IRB is notified.  
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any subject included in this study, 
even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7.6.2 (Safety Monitoring) must be followed and the Study Lead 
informed. 
Page 137 of 212

Anthos Therapeutics 
 
Page 56 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
11. 
REFERENCES 
1. Bolton-Maggs (2000) Factor XI deficiency and its management. Haemophilia; 6(S1):100-9. 
2. Buller H, Bethune C, Bhanot S, et al (2015) Factor XI Antisense Oligonucleotide for 
prevention of Venous Thrombosis. N Engl J Med; 372; 3:232-240. 
3. Camm AJ, Lip GY, De Caterina R, et al (2012) 2012 focused update of the ESC Guidelines 
for the management of atrial fibrillation. Eur Heart J; 33:719-47. 
4. Connolly SJ, Ezekowitz MD, Yusuf S, et al (2009) Dabigatran versus warfarin in patients with 
atrial fibrillation. N Engl J Med; 361:1139-51. 
5. Gailani D, Renné T (2007) Intrinsic pathway of coagulation and arterial thrombosis. 
Arterioscler Thromb Vasc Biol; 27:2507-13. 
6. Granger C, Alexander J, McMurray J, et al (2011) Apixaban versus warfarin in patients with 
atrial fibrillation. N Engl J Med; 365:981-92. 
7. Hart RG, Benavente O, McBride R, et al (1999) Antithrombotic therapy to prevent stroke in 
patients with atrial fibrillation: a meta-analysis. Ann Intern Med; 131:492-501. 
8. January CT, Wann LS, Alpert JS, et al (2014) AHA/ACC/HRS guideline for the management 
of patients with atrial fibrillation: a report of the American College of Cardiology/American 
Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll 
Cardiol; 64:e1–76. 
9. Kannel WB, Benjamin EJ (2008) Status of the epidemiology of atrial fibrillation. Med Clin 
North Am; 92:17-40. 
10. Lip GY, Nieuwlaat R, Pisters R, et al (2010) Refining clinical risk stratification for predicting 
stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the 
euro heart survey on atrial fibrillation. Chest; 137(2):263-72. 
11. Livnat T, Tamarin I, Mor Y, et al (2009) Recombinant activated factor VII and tranexamic 
acid are haemostatically effective during major surgery in factor XI-deficient patients with 
inhibitor antibodies. Thromb Haemost; 102:487–92. 
12. Patel MR, Mahaffey KW, Garg J, et al (2011) Rivaroxaban versus warfarin in nonvalvular 
atrial fibrillation. N Engl J Med; 365:883-91. 
13. Piccini JP, Garg J, Patel MR, et al (2014) Management of major bleeding events in patients 
treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. Eur Heart J; 
35:1873-80. 
14. Preis M, Hirsch J, Kotler A et al (2017) Factor XI deficiency is associated with lower risk for 
cardiovascular and venous thromboembolism events. Blood; 129(9):1210-5. 
15. Riddell A, Abdul-Kadir R, Pollard D, et al (2011) Monitoring low dose recombinant factor 
VIIa therapy in patients with severe factor XI deficiency undergoing surgery. Thromb 
Haemost; 106:521-7. 
16. Salomon O, Steinberg DM, Koren-Morag N, et al (2008) Reduced incidence of ischemic stroke 
in patients with severe factor XI deficiency. Blood; 111:4113-7. 
17. Salomon O, Steinberg DM, Zucker M, et al (2011) Patients with severe factor XI deficiency 
have a reduced incidence of deep-vein thrombosis. Thromb Haemost; 105:269-73. 
Page 138 of 212

Anthos Therapeutics 
 
Page 57 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
18. Schulman S, et al (2005) Definition of major bleeding in clinical investigations of 
antihemostatic medicinal products in non-surgical patients.  J Thromb Haemost. 2005 
Apr;3(4):692-4. 
 
Page 139 of 212

Anthos Therapeutics 
 
Page 58 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
12. 
APPENDICES 
 
 
 
Page 140 of 212

Anthos Therapeutics 
 
Page 59 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
12.1. 
Appendix 1 - Liver Event Definitions and Follow-up Requirements 
Table 4: 
Liver Event Definition 
Definition 
Thresholds 
Potential Hy’s law cases 
• 
ALT or AST > 3 X ULN and TBL > 2 × ULN without initial 
increase in ALP to > 2 × ULN 
ALT or AST elevation with 
coagulopathy 
• 
ALT or AST > 3 × ULN and INR > 1.5 (in the absence of 
anticoagulation) 
ALT or AST elevation 
accompanied by symptoms 
• 
ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash, or 
eosinophilia 
Isolated ALT or AST elevation 
• 
ALT or AST > 8 × ULN 
• 
5 x ULN < ALT/AST ≤ 8 x ULN 
• 
3 x ULN  ALT/AST  5 x ULN 
Isolated ALP elevation 
• 
ALP > 2 × ULN (in the absence of known bone pathology) 
Others 
• 
Any clinical event of jaundice (or equivalent term) Any 
adverse event potentially indicative of liver toxicity 
 
 
Table 5: 
Action required for Liver Events 
Criteria 
Action required 
Potential Hy’s law cases 
ALT or AST elevation with 
coagulopathy 
ALT or AST elevation 
accompanied by symptoms 
Isolated ALT or AST elevation > 
8 X ULN Jaundice 
 
 
• 
Hospitalize, if clinically appropriate 
• 
Establish causality 
• 
Complete CRFs per liver event guidance 
Isolated ALT or AST elevation > 
5 to ≤ 8 X ULN 
• 
Establish causality 
• 
Complete CRFs per liver event guidance 
Isolated ALT or AST elevation > 
3 to ≤ 5 × ULN (patient is 
asymptomatic)  
• 
Monitor liver chemistry tests two or three times weekly 
Isolated ALP elevation 
• 
Repeat liver chemistry tests within 48-72 hours 
• 
If elevation is confirmed, measure fractionated ALP; if 
>50% is of liver origin, establish hepatic causality 
• 
Complete CRFs per liver event guidance 
Any AE potentially indicative of 
liver toxicity 
• 
Hospitalize if clinically appropriate 
• 
Complete CRFs per liver event guidance 
Page 141 of 212

Anthos Therapeutics 
 
Page 60 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
 
 
Table 6: 
Exclusion of underlying Liver Disease 
Disease 
Assessment 
Hepatitis A, B, C, E 
• 
IgM anti-HAV; HBSAg, IgM anti-HBc, HBV DNA; anti-
HCV, HCV RNA, IgM & IgG anti-HEV, HEV RNA 
CMV, HSV, EBV infection 
• 
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG 
anti-EBV 
Autoimmune hepatitis 
• 
ANA & ASMA titers, total IgM, IgG, IgE, IgA 
Alcoholic hepatitis 
• 
Ethanol history, γGT, MCV, CD-transferrin 
Nonalcoholic steatohepatitis 
• 
Ultrasound or MRI 
Hypoxic/ischemic hepatopathy 
• 
Medical history: acute or chronic CHF, hypotension, 
hypoxia, hepatic venous occlusion. Ultrasound or MRI 
Biliary tract disease 
• 
Ultrasound or MRI, ERCP as appropriate 
Wilson disease 
• 
Caeruloplasmin 
Hemochromatosis 
• 
Ferritin, transferrin 
Alpha-1-antitrypsin deficiency 
• 
Alpha-1-anitrypsin 
 
 
Page 142 of 212

Anthos Therapeutics 
 
Page 61 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
12.2. 
Appendix 2 - Specific Renal Alert Criteria and Actions 
Table 7: 
Specific Renal Alert Criteria and Actions 
Criteria 
Action required 
Serum creatinine (sCr) increase 
25 – 49% compared to baseline 
• 
Consider causes and possible interventions 
• 
Follow up within 2-5 days 
Serum creatinine increase ≥ 50% 
• 
Consider causes and possible interventions 
• 
Repeat assessment within 24-48 hours if possible 
• 
Consider hospitalization and specialized treatment 
Protein-creatinine or albumin-
creatinine ratio increase ≥ 2-fold, 
or 
new onset dipstick proteinuria ≥ 
1+ , or 
Albumin-creatinine ratio (ACR) ≥ 
30 mg/g or ≥ 3 mg/mmol, or 
Protein-creatinine ratio (PCR) ≥ 
150 mg/g or >15 mg/mmol 
 
• 
Consider causes and possible interventions 
 
• 
Assess serum albumin and serum protein 
 
• 
Repeat assessment to confirm 
New onset glucosuria on urine 
dipstick (unless related to 
concomitant treatment, diabetes) 
Assess and document: 
• 
Blood glucose (fasting) 
• 
Serum creatinine 
• 
Urine albumin-creatinine ratio 
New hematuria on dipstick 
Assess and document 
• 
Urine sediment microscopy 
• 
Assess sCr and urine albumin-creatinine ratio 
• 
Exclude infection, trauma, bleeding from the distal urinary 
tract/bladder, menstruation 
 
• 
Consider bleeding disorder 
 
 
Additional specialized assessments are available to assess renal function or renal pathology.  
(Note: In exceptional cases when a nephrologist considers a renal biopsy, it is strongly recommended to 
make specimen slides available for evaluation by Anthos to potentially identify project-wide patterns of 
nephrotoxicity.) 
Whenever a renal event is identified, a detailed subject history and examination are indicated to identify, 
document and potentially eliminate risk factors that may have initiated or contributed to the event: 
• 
Blood pressure assessment (after 5 min rest, with an appropriate cuff size) 
• 
Signs and symptoms such as fever, headache, shortness of breath, back or abdominal pain, dysuria, 
hematuria, dependent or periorbital edema 
• 
Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output 
• 
Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic failure, 
contrast media or other known nephrotoxin administration, or other potential causes of renal 
dysfunction, e.g., dehydration, hemorrhage, tumor lysis 
Page 143 of 212

Anthos Therapeutics 
 
Page 62 
AFib Protocol v02 
 
Protocol No. ANT-004 
 
 
 
Table 8: 
Follow-up renal events 
Action 
Follow up 
Assess*, document and record in the CRF or via 
electronic data load. Review and record possible 
contributing factors to the renal event 
(co-medications, other co-morbid conditions) 
and additional diagnostic procedures (MRI etc.) 
in the CRF 
• 
Urine dipstick and sediment microscopy 
• 
Blood pressure and body weight 
• 
Serum creatinine, electrolytes (sodium, 
potassium, 
phosphate, 
calcium), 
bicarbonate, and uric acid 
• 
Urine output 
Monitor subject regularly (frequency at 
Investigator’s discretion) until: 
• 
Event resolution: (sCr within 10% of 
baseline or protein-creatinine ratio within 
50% of baseline) OR 
• 
Event stabilization: sCr level with ±10% 
variability over last 6 months or protein-
creatinine ratio stabilization at a new level 
with ±50% variability over last 6 months. 
*Urine osmolality: in the absence of diuretics or chronic kidney disease this can be a very sensitive 
metric for integrated kidney function that requires excellent tubular function. A high urinary 
osmolality in the setting of an increase in sCr will point toward a “pre-renal” cause rather than tubular 
toxicity. 
 
 
Page 144 of 212

Anthos Therapeutics 
Page 63 
AFib Protocol v02 
Protocol No. ANT-004 
12.3. 
Appendix 3 - Clinical notable laboratory values 
Clinical notable laboratory values: 
The definition, the specific alert criteria and the corresponding actions for hepatic and renal notable 
laboratory abnormalities are respectively provided in Appendix 1 and Appendix 2. 
The following laboratory values are considered clinically notable and should be forwarded to 
Covance at the same time that they are sent to Investigators: 
•
A change from baseline in hemoglobin ≥ 2 g/dL
•
A decrease from baseline in platelets count ≥ 50% or < 100 x 109/L
•
A positive fecal occult blood test
•
Macroscopic hematuria
Whenever a clinically notable laboratory value is identified, a detailed subject history and 
examination are indicated to identify, document and potentially eliminate a bleeding event: 
•
Blood pressure assessment (after 5 min rest, with an appropriate cuff size);
•
Signs and symptoms such as shortness of breath, tiredness, abdominal pain, hematemesis,
rectorrhagia, melena, gingival or nose bleeding, bruising and hematoma;
•
Concomitant events or procedures such as trauma, surgical procedures.
When one of the above occurs the action plan is as follows: 
•
Confirm the value, assess and document the clinically notable laboratory value in the CRF 
or via electronic data load;
•
Investigate the underlying causes such as clinical or subclinical bleeding event and the 
contributing factors such as intake of prohibited medications;
•
Monitor subject regularly (frequency at Investigator’s discretion) until resolution or 
stabilization. Hospital admission, additional laboratory tests, endoscopy, volume 
replacement, transfusion, etc. should be performed at the Investigator’s discretion and 
according to the medical needs (see Section 6.3 for reversal therapy).
Page 145 of 212

Anthos Therapeutics 
Page 1 
AFib Protocol v01 
Protocol No. ANT-004 
ANTHOS THERAPEUTICS, INC. 
MAA868 
Clinical Trial Protocol ANT-004 
A Multicenter, Randomized, Subject- and Investigator-blinded, 
Placebo-controlled, Parallel-group, Dose-range Finding Study to 
Assess the Pharmacokinetic and Pharmacodynamic Parameters, 
Safety, Tolerability, and Immunogenicity of MAA868 in Patients 
with Atrial Fibrillation 
Property of Anthos Therapeutics 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Anthos Therapeutics 
Document type: 
Protocol  
IND number: 
129008 
EUDRACT number: 
N/A 
Version number: 
V01 - Initial Protocol 
Clinical Trial Phase: 
IIa 
Release date: 
27-September-2019
Sponsor: 
Anthos Therapeutics 
55 Cambridge Pkwy, Ste. 103 
Cambridge, MA 02142 
Tel:  617-430-6940  
Chief Medical Officer (CMO) 
 
 
 
 
Page 148 of 212

Anthos Therapeutics 
 
Page 2 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
Protocol Number: 
ANT-004 
Protocol Title:  
A Multicenter, Randomized, Subject- and Investigator-blinded, Placebo-
controlled, Parallel group, Dose-range Finding Study to Assess the 
Pharmacokinetic and Pharmacodynamic Parameters, Safety, Tolerability, 
and Immunogenicity of MAA868 in Patients with Atrial Fibrillation 
Principal Investigator’s Statement and Signature: 
I, the undersigned, have read protocol ANT-004 (including all appendices). I agree to 
conduct the clinical study as described and in compliance with International Conference on 
Harmonisation (ICH) Guidelines for Good Clinical Practice (GCP) and applicable 
regulatory requirements. I agree to inform all who assist me in the conduct of this study of 
their responsibilities and obligations.  
 
 
 
____________________________________________ 
___________________________ 
Signature of Principal Investigator 
Date 
 
 
 
____________________________________________ 
Name of Principal Investigator (printed) 
 
 
 
Investigative Site Name, Address and Telephone Number: 
 
____________________________________________ 
 
____________________________________________ 
 
____________________________________________ 
 
____________________________________________ 
 
 
Sponsor CMO Signature 
 
CMO Approval: 
 
_______________________________________________________ 
 
Date: 
 
_______________________________________________________ 
 
 
Page 149 of 212

Anthos Therapeutics 
 
Page 3 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
NOTIFICATION OF SERIOUS ADVERSE EVENTS 
Dear Investigator, 
You must report a serious adverse event (SAE) (initial or follow-up) to Covance as summarized 
below. Refer to Section 7.6.2 of the protocol for SAE criteria and additional requirements. See 
also the Safety Management Plan for further details on the method of reporting a SAE. 
• Complete SAE report  
• Submit SAE report to Covance safety within 24 hours after awareness of the SAE  
• Notify the Covance Medical Lead 
• The fax number(s) and email address(es) are located in the Safety Management Plan.  
 
 
 
 
 
Page 150 of 212

Anthos Therapeutics 
 
Page 4 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
 
TABLE OF CONTENTS 
 
NOTIFICATION OF SERIOUS ADVERSE EVENTS ........................................................... 3 
LIST OF ABBREVIATIONS ................................................................................................... 8 
PHARMACOKINETIC DEFINITIONS AND SYMBOLS .................................................. 10 
GLOSSARY OF TERMS ....................................................................................................... 11 
PROTOCOL SYNOPSIS........................................................................................................ 12 
1. 
Introduction ................................................................................................................. 15 
1.1. 
Background ................................................................................................................. 15 
1.2. 
Study Rationale ........................................................................................................... 17 
1.3. 
Benefit-risk Assessment.............................................................................................. 17 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................ 19 
2.1. 
Primary objective and endpoint .................................................................................. 19 
2.2. 
Secondary objectives and endpoints ........................................................................... 19 
2.3. 
Exploratory objectives and endpoint .......................................................................... 19 
3. 
INVESTIGATION PLAN .......................................................................................... 21 
3.1. 
Overall Study Design and Plan Description ............................................................... 21 
3.2. 
Discussion of Study Design, Including the Choice of Control Groups ...................... 22 
3.3. 
Selection of Doses in the Study .................................................................................. 22 
4. 
SELECTION OF STUDY POPULATION ................................................................ 23 
4.1. 
Inclusion Criteria ........................................................................................................ 23 
4.2. 
Exclusion Criteria ....................................................................................................... 23 
4.3. 
Discontinuation Criteria .............................................................................................. 25 
4.3.1. Screen Failures ................................................................................................ 25 
4.3.2. Withdrawal of informed consent .................................................................... 25 
4.3.3. Lost to Follow-up ............................................................................................ 25 
4.4. 
Stopping Rules ............................................................................................................ 25 
5. 
Study Treatments ........................................................................................................ 27 
5.1. 
Treatments Administered ............................................................................................ 27 
5.2. 
Preparation, Storage, Handling, and Accountability .................................................. 27 
5.3. 
Method of Treatment Assignment .............................................................................. 28 
5.4. 
Blinding....................................................................................................................... 28 
5.5. 
Treating the subject ..................................................................................................... 29 
5.6. 
Permitted dose adjustments and interruptions of study treatment .............................. 30 
Page 151 of 212

Anthos Therapeutics 
 
Page 5 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
5.7. 
Study Completion and Post-study Treatment ............................................................. 30 
5.8. 
Discontinuation of Study Treatment ........................................................................... 30 
5.9. 
Study Termination ...................................................................................................... 30 
5.10. Emergency breaking of assigned treatment code........................................................ 30 
6. 
CONCOMITANT THERAPIES ................................................................................ 32 
6.1. 
Concomitant therapy ................................................................................................... 32 
6.2. 
Study restrictions ........................................................................................................ 33 
6.3. 
Reversal medication .................................................................................................... 34 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...................................................... 35 
7.1. 
Assessment schedule ................................................................................................... 35 
7.2. 
Informed consent procedures ...................................................................................... 35 
7.3. 
Subject screening ........................................................................................................ 35 
7.4. 
Subject demographics/other baseline characteristics .................................................. 35 
7.5. 
Efficacy Assessments.................................................................................................. 36 
7.5.1. Free FXI .......................................................................................................... 36 
7.5.2. aPTT ................................................................................................................ 36 
7.5.3. Total FXI ......................................................................................................... 36 
7.5.4. FXI coagulation activity (FXI:C).................................................................... 36 
7.6. 
Safety Assessments ..................................................................................................... 36 
7.6.1. Adverse Events ............................................................................................... 38 
7.6.2. Reporting Serious Adverse Events ................................................................. 39 
7.7. 
Liver safety monitoring............................................................................................... 41 
7 8  
Renal safety monitoring 
 42 
7.9. 
Pregnancy .................................................................................................................... 42 
7.10. Clinical Laboratory Evaluations ................................................................................. 43 
7.11. Vital Signs, Physical Examination, and Other Safety Evaluations ............................. 43 
7.12. Electrocardiogram (ECG) ........................................................................................... 44 
7.13. Pharmacokinetic Analysis ........................................................................................... 44 
7.14. Other assessments ....................................................................................................... 45 
7.14.1. Exploratory Biomarker assessments ............................................................... 45 
7.14.2. Immunogenicity (IG) ...................................................................................... 45 
7.15. Use of residual biological samples ............................................................................. 45 
8. 
SAMPLE SIZE AND DATA ANALYSES ................................................................ 46 
8.1. 
Determination of Sample Size .................................................................................... 46 
Page 152 of 212

Anthos Therapeutics 
 
Page 6 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
8.2. 
Analysis Populations ................................................................................................... 46 
8.3. 
General Considerations ............................................................................................... 46 
8.4. 
Demographics and Baseline characteristics ................................................................ 46 
8.5. 
Efficacy Analysis ........................................................................................................ 47 
8.5.1. Primary Efficacy Outcome Measures ............................................................. 47 
8.5.2. Secondary Efficacy Outcome Measures ......................................................... 47 
8.6. 
Safety Analysis ........................................................................................................... 47 
8.6.1. Adverse Events ............................................................................................... 47 
8.6.2. Bleeding Events .............................................................................................. 48 
8.6.3. Major cardiovascular, cerebrovascular, and venous thromboembolic events 49 
8.6.4. Clinical Laboratory Evaluations ..................................................................... 49 
8.6.5. Vital Sign Measurements ................................................................................ 49 
8.6.6. ECG Parameters .............................................................................................. 49 
8.7. 
Pharmacokinetic Analysis ........................................................................................... 50 
8.8. 
Biomarkers .................................................................................................................. 50 
8.9. 
Interim Analysis .......................................................................................................... 50 
8.10. Data Quality Assurance .............................................................................................. 50 
9. 
Ethical Considerations ................................................................................................ 53 
9.1. 
Regulatory and ethical compliance ............................................................................. 53 
9.2. 
Responsibilities of the Investigator and IRB .............................................................. 53 
9.3. 
Publication of study protocol and results .................................................................... 53 
10. 
PROTOCOL ADHERENCE ...................................................................................... 54 
10 1  Protocol Amendments 
 54 
11. 
References ................................................................................................................... 55 
12. 
Appendices .................................................................................................................. 57 
12.1. Appendix 1 - Liver Event Definitions and Follow-up Requirements ......................... 58 
12.2. Appendix 2 - Specific Renal Alert Criteria and Actions ............................................ 60 
12.3. Appendix 3 - Clinical notable laboratory values ........................................................ 62 
12.4. Appendix 4 - Schedule of Assessments ...................................................................... 63 
 
 
 
Page 153 of 212

Anthos Therapeutics 
 
Page 7 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
 
List of Tables 
Table 1: 
Overview of Study Medication ................................................................................... 27 
Table 2: 
Randomization Assignment Numbering ..................................................................... 28 
Table 3: 
Summary of reporting requirements for medication errors ........................................ 33 
Table 4: 
Liver Event Definition ................................................................................................ 58 
Table 5: 
Action required for Liver Events ................................................................................ 58 
Table 6: 
Exclusion of underlying Liver Disease ....................................................................... 59 
Table 7: 
Specific Renal Alert Criteria and Actions .................................................................. 60 
Table 8: 
Follow-up renal events ................................................................................................ 61 
Table 9: 
Schedule of Assessments ............................................................................................ 63 
 
 
List of Figures 
Figure 1: 
Overall study design ....................................................................................... 21 
 
 
 
Page 154 of 212

Anthos Therapeutics 
 
Page 8 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
LIST OF ABBREVIATIONS 
ADA 
anti-drug antibody 
AE 
adverse event 
AESI 
Adverse event of special interest 
AF 
Atrial fibrillation 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
Code of Federal Regulations 
CK 
creatine kinase 
CI 
confidence interval 
CRF 
case report form 
CRNM 
clinically relevant non-major 
CRO 
contract research organization 
CSR 
clinical study report 
DOAC 
direct oral anticoagulant 
DSS 
Drug Safety Services 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
FIH 
first-in-human  
FXI 
Factor XI 
FXI:C 
FXI coagulation activity 
GCP 
Good Clinical Practice 
γGT 
gamma glutamyl transferase 
GLP 
Good Laboratory Practice 
IA 
interim analysis 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IRB 
institutional review board 
Page 155 of 212

Anthos Therapeutics 
 
Page 9 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
IN 
investigator notification 
MedDRA 
Medical Dictionary for Regulatory Activities 
PAF 
paroxysmal atrial fibrillation 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
QTcF 
QT interval corrected by Fridericia formula 
RBC 
red blood cells 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
s.c. 
subcutaneous 
sCr 
serum creatinine 
sCT 
spiral computed tomography 
SD 
standard deviation 
SOC 
system organ class (MedDRA classification) 
SUSAR 
suspected unexpected serious adverse reaction  
TEAE 
treatment-emergent adverse event 
VTE 
venous thromboembolism 
WBC 
white blood cells 
 
 
 
 
 
Page 156 of 212

Anthos Therapeutics 
 
Page 10 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
PHARMACOKINETIC DEFINITIONS AND SYMBOLS 
AUC0-t 
The area under the plasma concentration-time curve from time zero to time ‘t’ 
where t is a defined time point after administration [mass x time / volume] 
AUCinf 
The area under the plasma concentration-time curve from time zero to infinity 
[mass x time / volume] 
AUClast 
The area under the plasma concentration-time curve from time zero to the time 
of the last quantifiable concentration [mass x time / volume]  
C0 
The initial concentration at the end of an intravenous infusion 
CL 
The systemic clearance following intravenous administration 
Cmax 
The observed maximum plasma concentration following subcutaneous drug 
administration [mass / volume] 
F 
Bioavailability 
T1/2 
The terminal elimination half-life [time] 
Tmax 
The time to reach the maximum concentration after drug administration [time] 
Vss 
The steady state volume of distribution following intravenous administration 
 
 
Page 157 of 212

Anthos Therapeutics 
 
Page 11 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
GLOSSARY OF TERMS 
Assessment 
A procedure used to generate data required by the study 
Cohort 
A specific group of subjects fulfilling certain criteria 
Dosage 
Dose of the study treatment given to the subject in a time unit  
Enrollment 
Point/time of subject entry into the study at which informed 
consent must be obtained (i.e. prior to starting any of the 
procedures described in the protocol) 
Healthy volunteer 
A person with no known significant health problems who 
volunteers to be a study participant  
Investigational drug 
The study drug whose properties are being tested in the study; 
this definition is consistent with US CFR 21 Section 312.3 and 
Directive 
2001/20/EC 
and 
is 
synonymous 
with 
“investigational new drug” or “test substance” 
Screen Failure 
A subject who is screened but is not treated or randomized 
Subject 
A trial participant 
Subject number 
A unique number assigned to each subject upon signing the 
informed consent. This number is the definitive, unique 
identifier for the subject and should be used to identify the 
subject throughout the study for all data collected, sample 
labels, etc. 
Randomization number 
A unique identifier assigned to each randomized subject, 
corresponding to a specific treatment arm assignment 
Study treatment 
Any drug administered to the study participants as part of the 
required study procedures; includes investigational drug (s), 
control(s) or non-investigational medicinal product(s) 
Study treatment 
discontinuation 
When the subject permanently stops taking study treatment 
prior to the defined study treatment completion date 
Study treatment period 
Interval of time in the planned conduct of a study. A treatment 
period is associated with a purpose (e.g. screening, 
randomization, treatment, follow-up), which applies across all 
arms of a study 
Variable 
A measured value or assessed response that is determined in 
specific assessments and used in data analysis to evaluate the 
drug being tested in the study  
Withdrawal of consent  
Withdrawal of consent from the study is defined as when a 
subject does not want to participate in the study any longer, 
and does not want any further visits or assessments, and does 
not want any further study related contact, and does not allow 
analysis of already obtained biologic material 
 
Page 158 of 212

Anthos Therapeutics 
 
Page 12 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
PROTOCOL SYNOPSIS 
Title of study: A Multicenter, Randomized, Subject- and Investigator-blinded, Placebo-
controlled, Parallel-group, Dose-range Finding Study to Assess the Pharmacokinetic and 
Pharmacodynamic Parameters, Safety, Tolerability, and Immunogenicity of MAA868 in Patients 
with Atrial Fibrillation  
Indication: Atrial fibrillation 
Number of Investigators and study centers: 
The study is planned to be conducted in approximately 6 sites. 
Development phase: Phase 2a 
Objectives: 
Primary 
• 
To evaluate the proportion of patients that achieve ≥50%, ≥80%, or ≥90% Factor XI 
(FXI) inhibition at trough after the third dose (Day 91) at different dose levels of 
MAA868. 
Secondary 
• 
To evaluate the proportion of patients achieving FXI inhibition ≥ 50%, ≥80%, and ≥90% 
at trough after the first and second dose (Day 31 and Day 61) at different dose levels of 
MAA868. 
• 
To evaluate the safety and tolerability following multiple s.c. administration of MAA868 
compared to placebo to patients with AF. 
• 
To evaluate the incidence of major bleeding events, clinically relevant non-major 
(CRNM) bleeding events and total bleeding with MAA868 relative to placebo during 
the treatment period. 
• 
To evaluate the immunogenicity of MAA868 compared to placebo. 
Study design: 
This is a randomized, subject- and investigator-blinded, placebo controlled, dose-ranging study 
in patients with atrial fibrillation (AF) or atrial flutter who are at low risk for stroke. Patients will 
be enrolled in up to 3 cohorts of approximately 16 patients each. After a Screening Period of up 
to 4 weeks, patients in will be randomized  in a 3:1 ratio (MAA868:placebo) to receive 3 monthly 
subcutaneous (s.c.) injections and followed for pharmacokinetics, pharmacodynamic efficacy as 
well as  safety events over the 90-day Treatment Period. Patients will then be followed up to Day 
170 during the Washout/Follow-up period.  
Number of patients: 
Approximately 48 patients will be randomized into the study. 
Diagnosis and main criteria for inclusion and exclusion: 
Inclusion Criteria 
• 
Male and female patients ≥ 18 and < 85 years old 
• 
Current AF or atrial flutter on 12 lead electrocardiography at Screening  
or 
a history of paroxysmal AF (PAF) or atrial flutter as documented by prior telemetry, 12 
lead electrocardiography or ambulatory (e.g. Holter or patch) monitor which is not due 
to a reversible condition (e.g. alcohol binge drinking) 
• 
A CHA2DS2-VASc risk score of 0-1 for men and 1-2 for women and in whom, in the 
investigator’s judgment, the use of an anticoagulant for stroke prevention is not indicated 
• 
Body weight between 50 and 130 kg, inclusive 
Exclusion criteria 
Page 159 of 212

Anthos Therapeutics 
 
Page 13 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
• 
History of stroke, transient ischemic attack or systemic embolism 
• 
History of major bleeding during treatment with an anticoagulant or antiplatelet therapy. 
(Patients who have had major bleeding on anticoagulants or antiplatelet therapy more 
than a year ago can be enrolled only if the bleeding was due to a reversible cause, e.g. 
gastro-duodenal ulcer, that was successfully treated) 
• 
History of traumatic or non-traumatic intracranial, intraspinal or intraocular bleeding.  
• 
Known bleeding diathesis or any known active bleeding at screening or baseline 
• 
Family history of bleeding disorder  
• 
Known active GI lesions predisposing to bleeding events 
• 
Myocardial infarction, unstable angina pectoris or coronary artery bypass graft (CABG) 
surgery within 12 months prior to the screening period 
• 
Clinically significant moderate or greater mitral stenosis severity (valve area <1.5 cm2)  
• 
Prosthetic heart valve  
• 
Uncontrolled hypertension defined as SBP/DBP ≥ 160/100 mmHg at the screening visit 
• 
NYHA class III-IV heart failure  
• 
Currently being treated with anticoagulant therapy or have been on anticoagulants in the 
previous 12 months. Potential patients who have been on anticoagulation more than 12 
months ago requires discussion with the sponsor before enrolling.   
• 
Currently being treated with antiplatelet therapy such as a P2Y12 inhibitor or aspirin. 
Low dose aspirin (≤ 100 mg/d) is allowed  
• 
Severe renal impairment as defined as an estimated glomerular filtration rate ≤45 
mL/min/1.73m2 by the MDRD equation at the screening visit 
• 
Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
Test products, dose, and mode of administration: 
MAA868 with a dose of 120 mg or 180 mg or placebo s.c. monthly 
Reference therapy, dose, dose form, and mode of administration:   
Matching placebo to MAA868 s.c. monthly 
Page 160 of 212

Anthos Therapeutics 
 
Page 14 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
Duration of patient participation in study: 
Planned Screening duration: Up to 4 weeks 
Planned treatment duration: Day 0-91: 91 days 
Planned follow-up duration: Day 91 to Day 170: 79 days 
Study populations:  
Approximately 48 male and female patients age ≥ 18 to < 85 with AF or flutter, as defined above, 
will be randomized into the study. 
Evaluation: Efficacy  
• 
Free FXI concentrations at Days 31, 61 and 91 
Evaluation: Safety 
• 
Confirmed major bleeding events, clinically relevant non-major (CRNM) bleeding events 
and total bleeding events 
• 
Adverse and serious adverse events 
• 
Occurrence of major cardiovascular, cerebrovascular, systemic arterial, and  
• 
Physical examinations  
• 
Monitoring of laboratory parameters in blood 
• 
ECGs 
• 
Hypersensitivity reactions 
• 
Injection site reactions 
Evaluation: Other assessments 
• 
Factor XI coagulation activity 
• 
Activated partial thromboplastin time 
• 
Pharmacokinetics 
• 
Development of anti-drug antibodies 
• 
Venous thromboembolic events  
Statistical methods: 
The patients will be enrolled into cohorts of approximately 16 patients with each cohort 
evaluating a different dose level of MAA868. Within each cohort, patients will be randomized 
3:1 to active drug or placebo. 
The primary analysis variable is whether a subject will achieve pre-defined degrees of FXI 
inhibition at trough (Day 91). The dose regimens and targeted FXI inhibition achievement are as 
follows:  
Low-dose cohort (MAA868 120 mg monthly or placebo): Targeted to achieve ≥ 50% FXI 
inhibition in 90% of subjects at trough (Day 91).  
High dose cohort (MAA868 180 mg monthly or placebo): Targeted to achieve ≥ 90% FXI 
inhibition in 90% of subjects at trough (Day 91). 
The “on treatment” trough FXI levels will be used for the primary analysis, where “on treatment” 
FXI level is defined as a value which is collected within 30 (±5) days after the last administration 
of MAA868. The response rate per treatment group will be calculated by number of subjects 
who achieve targeted FXI inhibition rate divided by the total number of subjects in the treatment 
group. The estimate of the responder rate (%) at Day 91 will be presented for each dose regimens 
of MAA868 together with 2-sided 90% confidence intervals. 
The secondary efficacy analysis is to evaluate the proportion of subjects achieving FXI inhibition 
≥ 50%, ≥80%, and ≥90% at trough after the first and second dose (Day 31 and Day 61) at multiple 
dose levels of MAA868. The analyses described for the primary endpoint will be repeated for 
the secondary efficacy variables. 
Safety data including adverse events (AEs), bleeding events, ECG, vital signs, thromboembolic 
events and laboratory results will be reported by count and incidence rate. 
Page 161 of 212

Anthos Therapeutics 
 
Page 15 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
1. 
INTRODUCTION 
1.1. 
Background 
AF is the most common cardiac arrhythmia, accounting for approximately one third of 
hospitalizations for cardiac dysrhythmias. Currently, it is estimated to affect more than 6 million 
patients in Europe and approximately 2.3 million in the United States, and this number continues 
to grow rapidly because of the increasing proportion of the aging population with associated co-
morbidities. As such, the prevalence of AF is expected to increase 2- to 3-fold over the following 
3 decades in western populations (Kannel and Benjamin 2008). 
AF is associated with a 4- to 5-fold increase in embolic stroke. The risk for stroke associated with 
AF increases steeply with age to 23.5% for patients aged 80 to 89 years (Kannel and Benjamin 
2008). Most patients with AF require life-long anticoagulation therapy to prevent cardioembolic 
stroke and systemic embolism. It is estimated that 85 to 90% of AF patients will require 
anticoagulation therapy (Camm et al 2012). 
Vitamin K antagonists (VKA), such as warfarin, are effective in reducing stroke and systemic 
thromboembolism; a highly significant relative risk reduction in stroke incidence by 67% was 
observed in a meta-analysis combining six studies (Hart et al 1999). All-cause mortality was 
reduced (26%) significantly by VKA vs. control (Hart et al 1999). In recent years, direct oral 
anticoagulant (DOACs) medications have been approved and introduced to clinical practice. These 
drugs are at least as effective as warfarin in preventing stroke or systemic embolism and may be 
superior to warfarin in the risk of hemorrhagic stroke and intracranial hemorrhage (Connolly et al 
2009, Granger et al 2011, Patel et al 2011). The incidence of major bleeding events with DOACs 
was similar or slightly lower than the incidence observed with well-conducted warfarin therapy. 
Nonetheless, the overall bleeding risk continues to be high with the use of DOACs. For instance, 
the annual incidence of major and clinically relevant non-major (CRNM) bleeding was 14.9% and 
the annual incidence of major bleeding events was 3.6% in patients treated with rivaroxaban in the 
ROCKET AF study (Patel et al 2011). It is notable that the occurrence of major bleeding was 
strongly associated with mortality. In the same study, the rate of all-cause mortality over the 2-
month period following a major bleeding event was 20.4% in the rivaroxaban group and 26.1% in 
the warfarin group (Piccini et al 2014). Thus, there is a high unmet medical need for an 
anticoagulant therapy that can effectively reduce the risk of AF-related thromboembolic 
complications such as stroke but with a lower risk of bleeding than currently employed 
anticoagulants. 
FXI is an emerging target for potentially safer and more effective anticoagulant medications. FXI 
holds important roles in both the intrinsic and extrinsic coagulation pathways and in bridging the 
initiation and amplification phases of plasmatic hemostasis (Gailani and Renné 2007). Both Factor 
XII and thrombin can activate FXI, resulting in a sustained thrombin generation and fibrinolysis 
inhibition. FXI plays a minor role in normal hemostasis in a high tissue factor environment “after 
vessel injury” whereas it appears to play a key role in thrombosis. Severe FXI deficiency is 
associated with a lower incidence of ischemic stroke and venous thromboembolic events (Salomon 
et al 2008, Salomon et al 2011, Preis et al 2017). Nevertheless, bleeding manifestations in subjects 
with severe FXI deficiency are infrequent and usually mild. Bleeding events that occur are 
typically injury-related and preferentially affect tissues known to have increased fibrinolytic 
Page 162 of 212

Anthos Therapeutics 
 
Page 16 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
activity such as the oral and nasal mucosa, and urinary tract (Bolton-Maggs 2000). Bleeding in 
vital organs is extremely rare or non-existent. 
MAA868 
MAA868 is a human antibody that binds to the catalytic domain of FXI. MAA868 binds to both 
the zymogen (FXI) and activated factor XI (FXIa) with high potency. MAA868 dose-dependently 
prolonged activated partial thromboplastin time (aPTT) in in-vitro and in-vivo studies. After a 
single subcutaneous (s.c.) administration of MAA868 at a 3 mg/kg dose, sustained anticoagulant 
activity lasting for more than one month was observed in cynomolgus monkeys. Moreover, 
MAA868 prevented experimental carotid artery thrombosis induced by FeCl3 and resulted in a 
prolongation in aPTT in FXI-/- mice reconstituted with human FXI. No significant toxicity 
findings were observed in single dose and in the 13-week Good Laboratory Practice (GLP)-
compliant toxicity study conducted in cynomolgus monkeys. The highest s.c. dose administered 
in the 13-week study was defined as no observed adverse effect level NOAEL (100 mg/kg/week 
s.c.). 
MAA868 was evaluated in a first-in-human (FIH) study (CMAA868X2101) to characterize its 
safety/tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) in healthy subjects 
following single s.c. administration. In total, 6 cohorts with 10 subjects each (8 MAA868: 2 
Placebo) were enrolled. The doses of MAA868 administered in Cohorts 1 to 5 ranged from 5 mg 
to 240 mg. In a sixth cohort, 240 mg of MAA868 was administered to subjects with body mass 
index (BMI ≥ 35 kg/m2). 
In the FIH study, MAA868 appeared to be safe and well tolerated, and the incidence of AEs were 
comparable across dose groups and placebo. No bleeding events, hypersensitivity reactions or 
injection site reactions were reported. Exposure increased with increasing dose of s.c. MAA868; 
the median maximum observed concentration (Cmax) occurred on Day 7 to 21 and the mean 
terminal elimination half-life ranged from 20 to 28 days. A dose and time-dependent prolongation 
of aPTT occurred with MAA868 after single s.c. administration; the 150 mg dose resulted in a 
mean aPTT prolongation ≥ 2-fold at Day 29. Doses greater than 150 mg extended the duration of 
aPTT prolongation but did not produce a greater prolongation of aPTT. Robust and sustained 
reductions of free FXI ≥ 90% were observed with 150 mg MAA868 at Day 29 and up to Day 43 
with 240 mg. A high BMI was associated with a lower MAA868 exposure and slightly shorter 
duration of aPTT prolongation. Robust reductions in free FXI and in FXI coagulation activity and 
relevant aPTT prolongation are predicted to occur within 12 to 24 hours after MAA868 s.c. 
administration with relevant clinical doses. 
MAA868 was also studied in healthy Japanese subjects in a single ascending dose, randomized, 
subject- and investigator-blinded, placebo-controlled, non-confirmatory study to assess safety, 
tolerability, PK and PD. Three cohorts (MAA868 dose levels: 15, 50 and 150 mg) were enrolled 
in this study and received a single s.c. dose of MAA868 or matching placebo (8 subjects received 
MAA868 and 2 subjects received placebo in each cohort). Assessments and assessment schedules 
were generally similar to the FIH study. No SAE or study discontinuation due to AEs were reported 
in this study. All AEs were mild in intensity and the distribution of AEs was well balanced between 
the MAA868 dose groups and placebo. No bleeding event, hypersensitivity or injection site 
reactions were reported in the study. PK analysis suggested that there was no indication of an 
impact of the Japanese ethnicity on exposure or PD parameters of MAA868 in healthy subjects. 
Page 163 of 212

Anthos Therapeutics 
Page 17 
AFib Protocol v01 
Protocol No. ANT-004 
Taken together, the results from both completed studies of MAA868 suggest that the 
administration of MAA868 is safe and well-tolerated. Subcutaneous administration of MAA868 
leads to robust and sustained effects on aPTT, free FXI, and FXI coagulation activity (FXI:C) up 
to/through Day 29 with the 150 mg dose and Day 43 with the 240 mg dose in subjects with normal 
body weight or class 1 obesity (BMI <35 kg/m2). In subjects with class 2 or 3 obesity (BMI ≥35 
kg/m2), exposures of MAA868 may be lower and the duration of aPTT prolongation is shorter. 
1.2. 
Study Rationale 
This study is a multicenter, randomized, subject and Investigator-blinded, placebo-controlled, 
parallel-group, multiple ascending dose-ranging study to evaluate the safety, tolerability, PK, and 
PD effects of MAA868 in patients with AF or flutter at low risk of thromboembolic stroke or 
peripheral embolism. The trial will evaluate the effects of up to three different doses of MAA868 
on FXI inhibition, indices of coagulation, and thrombogenesis biomarkers compared to placebo. 
The incidence of injection site reactions, bleeding events, immunogenicity, and systemic arterial 
and venous thromboembolic events will also be assessed. Results from this study will assist with 
dose-selection of MAA868 for a phase 3 trial in patients with AF. 
1.3. 
Benefit-risk Assessment 
AF is associated with a 4- to 5-fold increase in embolic stroke. MAA868, a fully human 
monoclonal antibody targeting Factor XI, is being considered for development as a novel 
anticoagulant for patients with AF or flutter. FXI is an emerging target as a novel anticoagulant. 
Several lines of evidence suggest that FXI inhibition has the potential to prevent thrombosis with 
minimal risk of bleeding. For example, individuals with an inherited deficiency of FXI have been 
reported to have a lower risk of VTE even though their bleeding phenotype is variable and often 
quite mild. Further support of the safety of inhibiting FXI comes from clinical studies using an 
investigational FXI antisense oligonucleotide (FXI-ASO) where administration of FXI-ASOs in 
healthy subjects and in patients undergoing total knee arthroplasty was demonstrated to be safe 
and well-tolerated (Buller et al 2015). 
Results from the first-in-human (FIH) study of MAA868 (CMAA868X2101) demonstrated that a 
single s.c. administration of MAA868 at increasing doses up to 240 mg in healthy subjects were 
safe and well-tolerated. These doses of MAA868 resulted in a robust and sustained FXI inhibition 
and prolongation of aPTT. The safety and pharmacodynamic efficacy of MAA868 was further 
supported by preliminary data from the study CMAA868A1101, which showed a good safety 
profile of MAA868 in Japanese heathy male subjects. 
This study is designed to evaluate the efficacy and safety of achieving different levels of FXI 
inhibition with different dose levels of s.c. MAA868 in patients with AF or flutter. This study will 
recruit patients with AF or flutter who are judged by their physician to be at low risk for stroke 
based on clinical guidelines. In each case, patients will only be enrolled if their physician has 
determined that the patient does not merit anticoagulation based on the guidelines and the 
physician’s assessment of the benefit-risk profile for that patient. The guidelines state that the 
benefits of anticoagulation in AF patients at low risk of embolic stroke are uncertain given the 
concomitant risks of bleeding with anticoagulant therapy. Accordingly, the guidelines recommend 
individualized shared physician-patient decision-making with regards to the decision to initiate 
anticoagulant therapy in this population (January et al 2019).  Patients with PAF will be enrolled 
who have a CHA2DS2-VASc risk score of 0-1 for men or 1-2 for women, in whom the guidelines 
Page 164 of 212

Anthos Therapeutics 
 
Page 18 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
are equivocal regarding the recommendation to initiate anticoagulation and advise an 
individualized assessment of the benefit-risk of anticoagulation (January et al 2019).  
Overall, the nonclinical and clinical data to date support the investigation of MAA868 in the 
prevention of thromboembolic diseases in patients with AF. The risk-benefit relationship appears 
to be acceptable. 
Page 165 of 212

Anthos Therapeutics 
 
Page 19 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
2. 
OBJECTIVES AND ENDPOINTS 
2.1. 
Primary objective and endpoint 
Objective 
Endpoint 
• To evaluate the proportion of patients that 
achieve ≥50%, ≥80%, or ≥90% FXI 
inhibition at trough after the third dose 
(Day 91) at different dose levels of 
MAA868 
• Occurrence of achieving ≥50%, ≥80%, or 
≥90% inhibition of FXI (<50%, <20%, or 
<10% free FXI) at trough on Day 91 at 
different dose levels of MAA868 
2.2. 
Secondary objectives and endpoints 
Objective 
Endpoint 
• To evaluate the proportion of patients 
achieving FXI inhibition ≥50%, ≥80%, and 
≥90% at trough after the first and second 
dose (Day 31 and Day 61) at different dose 
levels of MAA868 
• Occurrence of achieving ≥50%, ≥ 80%, 
and ≥90% inhibition of FXI (<50%, <20%, 
or <10% free FXI) at trough on Day 31 and 
Day 61 at different dose levels of MAA868 
• To evaluate the safety and tolerability 
following multiple s.c. administration of 
MAA868 compared to placebo in patients 
with AF 
• All safety endpoints [i.e., physical exam, 
vital signs, electrocardiogram (ECG), 
safety 
laboratories, 
hypersensitivity 
reactions, injection site reactions, and 
adverse events (AEs), including serious 
AEs (SAEs)] during the Treatment Period 
and through EoS 
• To evaluate the incidence of major 
bleeding events, clinically relevant non-
major (CRNM) bleeding events and total 
bleeding with MAA868 relative to placebo 
during the treatment period 
• Occurrence of confirmed major bleeding 
events, CRNM bleeding events and total 
bleeding events during the treatment 
period 
• To evaluate the immunogenicity of 
MAA868 compared to placebo. 
• Screening and confirmation for anti-drug 
(MAA868) antibodies (ADA) 
2.3. 
Exploratory objectives and endpoint 
Objective 
Endpoint 
• To evaluate the effect of MAA868 
compared to placebo on the incidence of 
major cardiovascular, cerebrovascular, and 
venous thromboembolic events (as defined 
to the right) 
• Occurrence 
of 
major 
cardiovascular, 
cerebrovascular, systemic arterial, and 
venous thromboembolic events (VTEs)  
Page 166 of 212

Anthos Therapeutics 
 
Page 20 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
• To evaluate the change from baseline in D-
dimer and other thrombogenesis markers 
with MAA868 relative to placebo during 
the treatment period 
• Concentrations of D-dimer and other 
exploratory 
thrombogenesis 
markers 
during the treatment period 
 
Page 167 of 212

Anthos Therapeutics 
 
Page 21 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
3. 
INVESTIGATION PLAN 
3.1. 
Overall Study Design and Plan Description 
This is a phase 2a, randomized, subject- and investigator-blinded, placebo-controlled, multiple 
ascending dose-ranging study to assess the PK/PD, safety, tolerability, and immunogenicity of 
MAA868 in patients with AF or flutter.  
Patients will be enrolled in at least 2 and up to 3 cohorts of approximately 16 patients each for a 
total of up to 48 subjects (Figure 1A). Patients in cohort 1 will be randomized 3:1 to receive a 120 
mg dose of MAA868 or placebo, respectively on Day 1 with two subsequent monthly injections.  
After approximately 10 of the patients in cohort 1 have received their second dose of study drug 
and have been followed for at least an additional 14 days, a safety review of emerging safety and 
PK data from cohort 1 will take place. Cohort 2 will be initiated after it is confirmed by the 
Sponsor’s Medical Monitor and the Covance Lead Project Physician that the cohort 1 dose was 
safe and tolerated and all cohort 1 patients have been randomized. Likewise, after 10 of the patients 
in cohort 2 have received their second dose and have been followed for at least an additional 14 
days, interim safety, tolerability, and other analyses will be evaluated by the Sponsor. Based on 
emerging data, the Sponsor may elect to: 
• Enroll cohort 3 to evaluate a higher, lower, or a previously studied dose of MAA868 
• Terminate the study 
The study is comprised of 3 periods:  
(1) Screening period of up to 4 weeks 
(2) Treatment period with MAA868 administered s.c. monthly (or matching placebo) 
(randomized 3:1) for 90 days 
(3) Follow-up period up to end of study (Day 170). 
Following the screening period of up to 4 weeks, all patients that meet the study eligibility criteria 
(Section 4.1 and Section 4.2) will have baseline efficacy and safety assessments performed on Day 
1 and then randomized to active or placebo (Figure 1B). 
Figure 1: 
Overall study design 
 
The first dose of study drug will be administered at the study center on Day 1. The second and 
third doses of study drug will also be administered at the study center to patients on the Day 31 
visit and Day 61 visit, respectively. 
Page 168 of 212

Anthos Therapeutics 
 
Page 22 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
During the treatment period, patients will return to the study center on Day 11, Day 31, Day 41, 
Day 61, Day 71, and Day 91 for safety assessments such as vital signs, AE assessments, laboratory 
tests, PK, PD, thrombogenesis biomarkers, and other study assessments according to the 
assessment schedule shown in Table 9. 
During the follow-up period, patients will continue to be followed for PK, PD, thrombogenesis, 
and other study assessments. Patients will return to the study center on Day 101, Day 121 and Day 
170 (end of study; EoS) for the evaluations described in the assessment schedule (Table 9). 
3.2. 
Discussion of Study Design, Including the Choice of Control Groups 
Rationale for route of administration and treatment duration. The s.c. route of administration 
was chosen because it is the route of administration anticipated for subsequent studies in patients 
with AF. In the FIH study of MAA868, the half-life of MAA868 ranged from 20-28 days following 
s.c. administration. Furthermore, a sustained PD effect of >2-fold mean activated partial 
thromboplastin time [aPTT] prolongation was observed for ~30 days and returned to the baseline 
level by ~60 days post-dose after a single 150 mg s.c. dose administration in study X2101. These 
data support monthly administration of MAA868. Furthermore, assessment of the exposure-
response relationship of MAA868 in healthy subjects demonstrated a nearly flat exposure-response 
for relevant PD parameters (aPTT, FXI coagulation activity and free FXI) at concentrations above 
4 μg/mL which is consistent with the Day 29 total MAA868 concentrations achieved with the 150 
mg single dose administration in healthy subjects (CMAA868X2101). 
Given the half-life of MAA868 and the observed time to return to baseline aPTT levels, a 
prolonged washout/follow-up period of approximately 110 days from the last dose of MAA868 
should be a sufficient monitoring period for patients. 
3.3. 
Selection of Doses in the Study 
In the FIH study, single s.c. doses of MAA868 up to 240 mg was safe and well-tolerated. Up to 
the 150 mg dose, MAA868 produced robust and sustained dose-dependent inhibition of FXI and 
relevant prolongation of aPTT for approximately 4 weeks. MAA868 doses greater than 150 mg 
s.c. produced a sustained ~2-fold prolongation of aPTT for greater than 4 weeks.  
The precise level of FXI inhibition to achieve a clinically meaningful anticoagulant effect remains 
unknown. The primary efficacy endpoint of this study will be the number of patients who achieve 
≥ 50%, ≥ 80%, or ≥ 90% FXI inhibition [<50%, <20%, or 10% free FXI] at trough on Day 91 
following s.c. administration of MAA868. Based on preliminary PK/PD modeling, the doses 
selected for cohorts 1 and 2 are projected to target the following levels of FXI inhibition: 
• Cohort 1 (120 mg dose group). Targeted to achieve ≥ 50% FXI inhibition in 90% of 
subjects at trough (Day 91).  
• Cohort 2 (180 mg dose group). Targeted to achieve ≥ 90% FXI inhibition in 90% of 
subjects at trough (Day 91). 
Based on interim data, an optional cohort 3 may be dosed to add further data to the PK/PD model 
which will inform dose selection of MAA868 for subsequent studies.  
The dosing regimens selected for evaluation in this study are projected to result in exposure (Cmax) 
below the Cmax achieved with a single dose of 240 mg s.c. in healthy subjects in the FIH study. 
Page 169 of 212

Anthos Therapeutics 
 
Page 23 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
4. 
SELECTION OF STUDY POPULATION 
4.1. 
Inclusion Criteria 
1. Written informed consent must be obtained before any assessment is performed 
2. Male and female patients ≥ 18 and < 85 years old with paroxysmal atrial fibrillation (PAF) 
or atrial flutter on 12 lead electrocardiography at Screening 
3. Patients with a history of PAF or atrial flutter, as documented by (telemetry, 12 lead 
electrocardiography or ambulatory [e.g. Holter] monitor) and not due to a reversible 
condition (e.g. alcohol binge drinking) can be entered even if they do not have PAF at 
Screening. There is not time-limit for this. 
4. Patients with a CHA2DS2-VASc risk score (tool as a predictor for estimating the risk of 
stroke in patients with AF; Lip et al 2010) of 0-1 for men and 1-2 for women and in whom, 
in the investigator’s judgment, the use of an anticoagulant for stroke prevention is not 
indicated  
5. Body weight between 50 and 130 kg inclusive 
4.2. 
Exclusion Criteria 
1. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of 
enrollment, or until the expected PD effect has returned to baseline, whichever is longer; 
or longer if required by local regulations. 
2. History of stroke, transient ischemic attack or systemic embolism 
3. History of major bleeding during treatment with an anticoagulant or antiplatelet therapy. 
(Patients who have had major bleeding on anticoagulants or antiplatelet therapy more than 
a year ago can be enrolled only if the bleeding was due to a reversible cause, e.g. gastro-
duodenal ulcer that was successfully treated.) 
4. History of traumatic or non-traumatic intracranial, intraspinal or intraocular bleeding 
5. Known bleeding diathesis or any known active bleeding site at screening or baseline 
6. Family history of bleeding disorder  
7. Known active GI lesions predisposing to bleeding events 
8. Myocardial infarction, unstable angina pectoris or coronary artery bypass graft (CABG) 
surgery within 12 months prior to the Screening period 
9. Known clinically significant valvular heart disease including moderate or severe mitral 
stenosis (valve area <1.5 cm2).  
10. Patients with a prosthetic heart valve 
11. Uncontrolled hypertension defined as SBP/DBP ≥ 160/100 mmHg at the Screening visit 
12. Patients with NYHA Class III- IV heart failure 
13. Currently being treated with anticoagulant therapy or have been on anticoagulants in the 
previous 12 months. Potential patients who have been on anticoagulation more than 12 
months ago requires discussion with the sponsor before enrolling.   
14. Treatment with antiplatelet therapy such as either a P2Y12 inhibitor or aspirin. (Low dose 
aspirin ≤ 100 mg/d) is allowed.) 
15. Severe renal impairment as defined as an estimated glomerular filtration rate ≤45 
mL/min/1.73m2 by the MDRD equation at the Screening Visit 
Page 170 of 212

Anthos Therapeutics 
 
Page 24 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
16. Positive test for human immunodeficiency virus (HIV), positive hepatitis B (hepatitis B 
surface antigen [HBsAg]) or hepatitis C (anti-hepatitis C antibody [Anti-HCV]) at 
Screening 
17. Significant illness, per Investigator judgement, which has not resolved within four (4) 
weeks prior to dosing   
18. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
their time in the study. Highly effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive status 
of the woman has been confirmed by follow-up hormone level assessment 
• Male sterilization of sexual partner (at least 6 months prior to screening). For female 
subjects on the study, the vasectomized male partner should be the sole partner for that 
subject 
• Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS) 
or other forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception 
In case of use of oral contraception, women should have been stable on the same pill 
for a minimum of 3 months before taking investigational drug. 
Women are considered post-menopausal and not of child-bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at 
least six weeks ago. In the case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow-up hormone level assessment with 
FSH is she considered not of child-bearing potential.  
19. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive hCG 
laboratory test. 
20. Patients with either a psychiatric disease or substance abuse history, which in the opinion 
of the Investigator could interfere with protocol compliance.  
21. Any surgical or medical condition, which in the opinion of the Investigator, may place the 
patient at higher risk from his/her participation in the study, or is likely to prevent the 
patient from complying with the requirements of the study or completing the study. 
Page 171 of 212

Anthos Therapeutics 
 
Page 25 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
4.3. 
Discontinuation Criteria 
4.3.1. 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure patients to meet the Consolidated Standards of Reporting 
Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
serious adverse events (SAEs). 
Patients who do not meet the criteria for participation in this study may be rescreened. 
4.3.2. 
Withdrawal of informed consent 
Subjects may voluntarily withdraw from the study for any reason at any time. 
Withdrawal from the study can occur when a subject chooses to do one or more of the following: 
• Does not want to participate in the study anymore  
• Does not want any further visits or assessments  
• Does not want any further study-related contacts  
• Does not allow analysis of already obtained biologic material. 
If a subject who has received one or more doses or the study drug determines that they no longer 
want to participate the Investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason(s) for the subject’s decision to withdraw his/her consent, record this 
information and conduct any assessments and visits still allowed. 
In the event the subject withdraws consent prior to beginning dosing, the study treatment will not 
be administered. The data that would have been collected at subsequent visits will be considered 
missing. Further attempts to contact the subject are allowed when safety findings require follow-
up. 
4.3.3. 
Lost to Follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating an 
intention to discontinue or withdraw, the Investigator should show "due diligence" by documenting 
in the source documents steps taken to contact the subject, e.g. dates of telephone calls, registered 
letters, etc. A subject cannot be formally considered lost to follow-up until his/her scheduled end 
of study visit would have occurred. 
4.4. 
Stopping Rules 
Overall study stopping rules: 
Enrollment in the study will be placed on hold if the Sponsor considers that the number and/or 
severity of AEs, abnormal safety monitoring tests or abnormal laboratory findings justify putting 
the study on hold. 
Page 172 of 212

Anthos Therapeutics 
 
Page 26 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
The study may resume following the safety review, if the Investigator and Sponsor’s Medical 
Monitor agree it is safe to proceed. 
Page 173 of 212

Anthos Therapeutics 
 
Page 27 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
5. 
STUDY TREATMENTS 
5.1. 
Treatments Administered 
MAA868 drug product is a sterile, preservative-free liquid in vial for subcutaneous (s.c.) or 
intravenous (i.v.) administration. Each drug product vial contains 150 mg of MAA868 active 
ingredient per 1 mL plus 20% (0.2 mL) overfill which allows for complete withdrawal of the 
labeled dose (150 mg). 
 
The excipients utilized are standard pharmacopoeial excipients that are commonly used in 
parenteral products. MAA868 will be provided as a 150 mg/mL solution in 6 mL single-use vials 
(with 1.2 mL fill). The 180 mg dose will require 2 vials. 0.8 and 1.2 mL should be withdrawn into 
a syringe and administered subcutaneously for the 120 mg and 180 mg doses, respectively. 
Table 1: 
Overview of Study Medication 
Study Treatment Name: 
 
MAA868 
Placebo 
Dosage Formulation: 
 
Liquid (in vial) 
Liquid (in vial) 
Unit Dose 
Strength(s)/Dosage 
Level(s): 
150 mg/mL 
Placebo to MAA868 
Route of Administration:  
SC injection 
SC injection 
Packaging and Labeling: 
 
Study Treatment will be 
provided in vials. Each vial will 
be labeled as required per 
country requirement.  
Placebo will be provided in 
vials. Each vial will be labeled 
as required per country 
requirement. 
Provided by: 
Anthos 
Anthos 
5.2. 
Preparation, Storage, Handling, and Accountability 
Details on the requirements for storage and management of study treatment, and instructions to be 
followed for subject numbering, prescribing/dispensing and administering study treatment are 
outlined in the Pharmacy Manual. 
MAA868 drug product vials should be stored refrigerated at 2°- 8°C and protected from light. A 
disposable syringe will be used to administer the s.c. injection. 
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment. Only patients enrolled in the study may receive study 
treatment and only authorized site staff may supply or administer study treatment. The 
Investigator, institution, or the head of the medical institution (where applicable) is responsible for 
study treatment accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, 
and final disposition records). 
Further guidance and information for the final disposition of unused study treatment are provided 
in the Pharmacy Manual. 
Page 174 of 212

Anthos Therapeutics 
 
Page 28 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
5.3. 
Method of Treatment Assignment 
Subjects in each cohort will be randomized to MAA868 or placebo in a ratio of 12: 4 as follows. 
• 
Cohort 1 = 120 mg MAA868 monthly s.c. or placebo 
• 
Cohort 2 = 180 mg MAA868 monthly s.c. or placebo 
• 
Cohort 3 (if necessary) = TBD mg MAA868 monthly s.c. or placebo 
Randomization numbers will be assigned in ascending, sequential order to eligible subjects. The 
Investigator will enter the randomization number on the CRF. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A 
randomization list will be produced by or under the responsibility of Covance Drug Supply 
Management using a validated system that automates the random assignment of treatment arms to 
randomization numbers in the specified ratio. The randomization scheme for subjects will be 
reviewed and approved by a member of the Covance IIS Randomization Group. 
Patients will be replaced at the Sponsor’s discretion. Replacement subjects will be assigned 
randomization numbers 6101-6316 If a subject requires a replacement, the replacement subject 
will be assigned a randomization number corresponding to the original subject (e.g., Subject 6103 
would replace Subject 1103). 
The table below provides the general details of the numbering of the subjects for randomization: 
Table 2: 
Randomization Assignment Numbering 
Cohort 
Randomization numbers 
Replacement randomization numbers 
I 
1101-1116 
6101-6116 
II 
1201-1216 
6201-6216 
III 
1301-1316 
6301-6316 
5.4. 
Blinding 
This is a subject- and investigator-blinded study. Subjects will remain blinded to study treatment 
throughout the study, except where indicated below. 
The identity of the treatments will be concealed by the use of study drugs that are all identical in 
packaging, labeling, schedule of administration, appearance, and odor. 
Site staff 
With the exception of any unblinded pharmacist or pharmacy designee, all site staff (including 
study investigator and study nurse(s)) will be blinded to study treatment during treatment 
allocation and subject dosing. Appropriate measures must be taken by any unblinded pharmacist 
or pharmacy designee to ensure that the treatment assignments are concealed from the rest of the 
site staff. 
Unblinding a single subject at the site for safety reasons (necessary for subject management) will 
occur via an emergency system in place at the site (see Section 5.10). 
Site staff may also be unblinded to the treatment assignment of one or more subjects (within a 
single cohort or across cohorts as necessary), or an entire cohort at the initial cohort safety 
Page 175 of 212

Anthos Therapeutics 
 
Page 29 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
evaluation timepoint if deemed appropriate to aid decision-making. The decision to un-blind site 
staff will be determined by the clinical trial team based on need or review of the entire study group 
will be performed at a pre-selected time. 
Sponsor staff 
The following unblinded Sponsor roles (or designee) are required for this study: 
• Field monitor(s) 
• Physician not directly involved study conduct  
• Sample analyst(s) (PK blood) 
• Study statistician 
• Programmers and other personnel involved in study data analysis 
An unblinded Covance Physician not directly involved in study conduct may receive a copy of the 
randomization schedule (via request to the Randomization Office), to facilitate analysis of aPTT 
safety labs that would otherwise unblind study Investigators. The unblinded Medical Monitor will 
alert the Investigator and Sponsor of any safety concerns. 
The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office), to facilitate analysis of the samples. The sample analysts will provide the 
sample data to the study team under blinded conditions unless otherwise allowed. 
The study statistician will be able to access the full randomization list from the start of the study 
and is allowed to share unblinded information with the rest of the clinical trial team as appropriate 
for internal decision purposes. For example, unblinded summaries and unblinded individual data 
can be shared with the team whenever necessary.  
Study programmers and other personnel involved in study data analysis (e.g. biomarker expert, 
pharmacometrician, modeler(s)) are allowed to access treatment assignment information from the 
start of the study for the purpose of data analysis. 
The clinical trial team is allowed to share unblinded results with other Sponsor staff (e.g. decision 
boards) as required for internal decision making on the study or the project while the study is 
ongoing.  
All unblinded personnel will otherwise keep randomization lists and data or information that could 
un-blind other study team members confidential and secure except as described above.  
Following final database lock all roles may be considered unblinded. 
5.5. 
Treating the subject 
MAA868 will be administered to the subject by study staff via s.c. administration. See the 
Pharmacy Manual for further details. 
Sponsor qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
Page 176 of 212

Anthos Therapeutics 
 
Page 30 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
5.6. 
Permitted dose adjustments and interruptions of study treatment 
Study treatment dose adjustments are not permitted. Any study drug administration that occurs 
outside of study visit windows must be approved by the study medical monitor. 
5.7. 
Study Completion and Post-study Treatment 
Each subject will be required to complete the study in its entirety and thereafter no further study 
treatment will be made available to them. 
Study completion is defined as when the last subject completes their EoS visit, and any repeat 
assessments associated with this visit have been documented and followed-up appropriately by the 
Investigator, or in the event of an early study termination decision, the date of that decision. 
All subjects will be required to attend the EoS visit and have related assessments collected as per 
the Schedule of assessments (Table 9). All SAEs reported during this time period must be reported 
as described in Section 7.6.2 and the Safety Management Plan. Documentation of attempts to 
contact the subject should be recorded in the source documentation. 
5.8. 
Discontinuation of Study Treatment 
The Investigator may decide to suspend the s.c. administration of the study drug if symptoms or 
signs consistent with an injection site reaction or hypersensitivity reaction occur.  
Subjects who decide they do not wish to participate in the study further should NOT be considered 
withdrawn from the study UNLESS they withdraw their consent (see Section 4.3.2, Withdraw of 
Informed Consent). Where possible, they should return for the EoS assessments indicated in the 
assessment table. If they fail to return for these assessments for unknown reasons, every effort (e.g. 
telephone, e-mail, letter) should be made to contact the subject/pre-designated contact as specified 
in Section 4.3.3 (Lost to follow-up). This contact should preferably be done according to the study 
visit schedule. 
5.9. 
Study Termination 
The study can be terminated by Anthos at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. Should this be necessary, subjects must be 
seen as soon as possible and treated as a prematurely withdrawn subject and followed until the 
aPTT has returned to baseline. The Investigator may be informed of additional procedures to be 
followed in order to ensure that adequate consideration is given to the protection of the subject’s 
interests. The Investigator will be responsible for informing the Institutional Review Board (IRB) 
of the early termination of the trial. 
5.10. 
Emergency breaking of assigned treatment code 
Emergency unblinding must only be undertaken when it is essential to treat the subject safely and 
efficaciously, such as in the event of clinically significant bleeding events. Most often, knowledge 
of the possible treatment assignments is sufficient to treat a study subject who presents with an 
emergency condition. A complete set of emergency code break cards will be provided to the 
Investigator site(s) and a complete set will be available at Anthos and Covance. All code break 
cards must be retained until the end of the study and retained by the site as a source document. 
Page 177 of 212

Anthos Therapeutics 
 
Page 31 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
They must be stored in a secure place but be accessible to the Investigator 24 hours per day in case 
of emergency. The Investigator will receive a blinded code break card for each subject. In an 
emergency, the code break may be opened to determine the treatment. There is no known reversal 
agent for MAA868 (see Section 6.2).  
The code break should not be opened for any reason other than an emergency. If the Investigator 
opened the code break, he/she must note the date, time, and reason for removing it and retain this 
information with the case report form documentation. The unblinded treatment code must not be 
recorded on the CRF. The Investigator must also immediately inform the study monitor that the 
code has been broken.  
It is the Investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the code break cards at any time in case of emergency. The Investigator will need 
to provide: 
• Protocol number  
• Study drug name (if available)  
• Subject number. 
In addition, the Investigator must provide oral and written information to inform the subject how 
to contact his/her backup in cases of emergency when he/she is unavailable to ensure that un 
blinding can be performed at any time. 
Page 178 of 212

Anthos Therapeutics 
 
Page 32 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
6. 
CONCOMITANT THERAPIES 
6.1. 
Concomitant therapy 
The Investigator must instruct the subject to notify the study staff of any new medications 
(including nutritional supplements and herbal medications) that he/she takes after being enrolled 
into the study. 
All prescription medications, OTC drugs and significant non-drug therapies (including physical 
therapy and blood transfusions) administered or taken within the timeframe defined in the entry 
criteria prior to the start of the study and during the study, must be recorded on the Concomitant 
medications/Significant non-drug therapies CRF. 
Medication entries should be specific to trade name, the single dose and unit, the frequency and 
route of administration, the start and discontinuation date and the reason for therapy. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the Investigator should contact Covance before randomizing a subject or, 
if the subject is already enrolled, to determine if the subject should continue participation in the 
study. 
During the study, in the event the Investigator elects to start the patient on chronic antithrombotic 
therapy, anticoagulation or antiplatelet therapy should not be started until the patient’s aPTT has 
returned to baseline. 
Reporting medication errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient/subject or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
All study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the Dose Administration Record CRF. Study treatment errors are only to be reported to Covance 
DSS department if the treatment error is associated with an SAE. 
All instances of misuse or abuse must be documented in the AE CRF irrespective of the 
misuse/abuse being associated with an AE/SAE. In addition, all instances of misuse or abuse must 
be reported to the Covance DSS department. As such, instances of misuse or abuse are also to be 
reported using the SAE form/CRF.  
 
Page 179 of 212

Anthos Therapeutics 
 
Page 33 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
Table 3 summarizes the reporting requirements. 
 
 
 
Page 180 of 212

Anthos Therapeutics 
Page 34 
AFib Protocol v01 
Protocol No. ANT-004 
Table 3: 
Summary of reporting requirements for medication errors 
Treatment error type 
Document in Dose 
Administration CRF 
Document in AE CRF 
Complete SAE 
form/CRF 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see Section 7.6.1 and 
Section 7.6.2, respectively. 
6.2. 
Study restrictions 
Women of child-bearing potential 
Women of child-bearing potential are not permitted to participate in this study, unless they agree 
to use highly effective methods of contraception during their time in the study. 
Prohibited treatment 
Use of the following medications is not allowed during the course of the study from screening 
(Visit 1) through the EoS. Patients who are receiving such medication(s) will be excluded, or if 
ethically and clinically justified, the medication(s) should be gradually withdrawn at least seven 
days before the baseline visit: 
•
Use of chronic antiplatelet agents such as clopidogrel or ticagrelor is prohibited; however,
use of low-dose aspirin (≤100 mg per day) is permitted.
•
Use of chronic systemic anticoagulants such as warfarin, low molecular weight heparin or
heparinoids, or direct oral anticoagulants such as apixaban or dabigatran. Patients may be
started on chronic anticoagulation during the Washout/Follow-up period once their aPTT
has returned to baseline, at the Investigator’s discretion.
•
Use of any therapeutic monoclonal antibody regardless of the indication during the study.
Dietary restrictions 
•
No alcohol for 48 hours before each clinic visit (from Screening through the EoS visit).
During the study, alcohol consumption will be restricted to no more than 2 drinks/day for
males and 1 drink/day for females.
•
Patients should not make significant alterations in their diet (e.g., going on weight loss diet)
while in the study.
•
During the study, caffeinated beverages will be restricted to no more than 3 cups/day.
Other restrictions 
No strenuous physical exercise or activities which have an increased risk of injury or falling should 
be undertaken until after the EoS visit. 
Page 181 of 212

Anthos Therapeutics 
 
Page 35 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
6.3. 
Reversal medication 
There is currently no specific antidote for MAA868. FXI concentrates (not marketed in the US) 
are unlikely to be effective as the excess in free MAA868 concentrations in the circulation is 
expected to quickly neutralize the exogenous FXI. 
Recombinant FVIIa can bypass the hypocoagulopathy and restore hemostasis in patients with 
severe FXI deficiency. Administration of intermediate to high doses of rFVIIa (40 to 90 μg/kg) 
resulted in supra-physiological levels of FVII and thromboembolic complications in patients with 
severe FXI deficiency (Riddell et al 2011). Low doses of rFVIIa are associated with lower 
prothrombotic risk. Riddell et al reported their experience in 4 patients with severe FXI deficiency 
undergoing surgery (Riddell et al 2011); patients were administered rFVIIa 30 μg/kg and 
tranexamic acid 1 g i.v. at induction of anesthesia. Subsequent bolus doses of rFVIIa 15–30 μg/kg 
were administered at 2 to 4 hourly intervals as guided by rotational thromboelastometry for 24 48 
hours and tranexamic acid 1 g every 6 hourly for 5 days. Low doses of rFVIIa and tranexamic acid 
were safe and effective in restoring hemostasis in severe FXI deficiency in this study. In another 
study comprising 4 patients with severe FXI deficiency with inhibitor who experienced 5 surgeries 
(Livnat et al 2009), 1 g of tranexamic acid was given 2 hours before surgery, immediately prior to 
the interventions then every 6 hour for at least 7 days; moreover, rFVIIa was administered at doses 
ranging from 15 to 30 μg/kg at the completion of surgery. This protocol secured normal hemostasis 
in patients with severe FXI deficiency with inhibitor. 
Based on the above, rFVIIa can be recommended as a preferred therapeutic option to restore 
hemostasis in subjects with active, non-accessible bleeding site and in subjects requiring 
immediate reversal of the MAA868 PD effects prior to an urgent surgery.  Please see the 
Investigator’s Brochure - Summary of the data and guidance for the investigator for a more 
complete discussion. 
Page 182 of 212

Anthos Therapeutics 
 
Page 36 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
7. 
STUDY ASSESSMENTS AND PROCEDURES 
7.1. 
Assessment schedule 
Subjects should be seen for all visits/assessments as outlined in the assessment schedule (Table 9).  
Missed or rescheduled visits should not lead to automatic discontinuation. Subjects who 
prematurely discontinue the study for any reason should be scheduled for a visit as soon as 
possible, at which time all of the assessments listed for the study treatment discontinuation (TD) 
visit will be performed. At the TD visit, all dispensed investigational product should be reconciled, 
and the AE and concomitant medications recorded on the CRF. 
7.2. 
Informed consent procedures 
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB-approved informed consent. 
The Sponsor, or Sponsor designee, will provide to investigators a proposed informed consent form 
that complies with the ICHE6 Good Clinical Practice (GCP) guideline and regulatory requirements 
and is considered appropriate for this study. The informed consent form will also include a section 
related to optional future research which will require a separate signature if the subject agrees to 
future research. Any changes to the proposed consent form suggested by the Investigator must be 
agreed to by the Sponsor before submission to the IRB. 
Information about common side effects already known about the investigational drug can be found 
in the IB. This information will be included in the subject informed consent and should be 
discussed with the subject during the study as needed. Any new information regarding the safety 
profile of the investigational drug that is identified between IB updates will be communicated as 
appropriate, for example, via an Investigator Notification or an Aggregate Safety Finding. New 
information might require an update to the informed consent and then must be discussed with the 
subject. 
Ensure subjects are informed of the contraception requirements outlined in the Section 4.2 
(Exclusion criteria). 
A copy of the approved version of all consent forms must be provided to the Covance monitor 
after IRB approval. 
7.3. 
Subject screening 
In general, it is permissible to re-screen a subject if s/he fails the initial Screening or falls out of 
the screening window timelines; however, each case must be discussed and agreed with the 
Sponsor Medical Monitor on a case-by-case basis. A new screening number will be assigned to a 
subject who is re screened, thus no screening number will be used twice. 
Reasons for screen failure will be documented in the site log. 
7.4. 
Subject demographics/other baseline characteristics 
Subject demographic and baseline characteristic data will be collected on all subjects. Relevant 
medical history/current medical conditions data will also be collected until signature of informed 
consent.  
Page 183 of 212

Anthos Therapeutics 
 
Page 37 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
Investigators have the discretion to record abnormal test findings on the medical history CRF, if 
in their judgment, the test abnormality occurred prior to the informed consent signature. 
Hepatitis screen, HIV screen 
All subjects will be screened for HIV, Hepatitis B and C. 
Alcohol test and drug screening 
All subjects will be screened for alcohol and substances of abuse. 
7.5. 
Efficacy Assessments 
The PD samples will be collected at the timepoints defined in the Assessment schedule (Table 9). 
Follow instructions outlined in the Central Laboratory Manual regarding sample collection, 
numbering, processing and shipment. 
In order to better define the PD profile, the timing of the sample collection may be altered based 
on emergent data. The number of samples/blood draws and total blood volume collected will not 
exceed those stated in the protocol. 
PD samples will be obtained and evaluated in all subjects at all dose levels. 
7.5.1. 
Free FXI 
Free FXI concentrations (FXI that is not bound to MAA868) will be measured in plasma. A 
detailed description of the assay methods will be included in the Bioanalytical Data Report. 
7.5.2. 
aPTT 
aPTT, calibrated for FXI deficiency, and aPTT using a standard laboratory protocol will be 
measured at all timepoints indicated in the Assessment schedule (Table 9). 
aPTT will be determined in plasma. The detailed method descriptions of the assay will be included 
in the Bioanalytical Data Report. 
7.5.3. 
Total FXI 
Total FXI concentrations (FXI that is either bound to MAA868 or free) will be measured in plasma. 
A detailed description of the assay methods will be included in the Bioanalytical Data Report. 
7.5.4. 
FXI coagulation activity (FXI:C) 
FXI:C will be measured in plasma. A detailed description of the assay methods will be included 
in the Bioanalytical Data Report. 
7.6. 
Safety Assessments 
Safety assessments are specified below; assessments will be collected as specified in the 
Assessment Schedule (Table 9). 
Bleeding 
All suspected bleeding events will be documented by the Investigator in the appropriate CRF. All 
suspected bleeding events will be adjudicated by experienced medical personnel that is blinded to 
Page 184 of 212

Anthos Therapeutics 
 
Page 38 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
treatment assignment. Adjudication of bleeding events will be performed in accordance with the 
International Society of Thrombosis and Haemostasis (ISTH) definition of a major bleeding in 
non-surgical patients (Schulman et al 2005) and criteria for clinically-relevant non-major bleeding 
(CRNM) events. The definitions of bleedings are as follows: 
Major bleeding events include: 
• Fatal bleeding, and/or 
• Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intra‐articular or pericardial, or intramuscular with 
compartment syndrome, and/or 
• Bleeding causing a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more or leading to 
transfusion of two or more units of whole blood or red cells. 
CRNMs (clinically relevant non-major) bleeding events will be defined as clinically overt bleeding 
that did not satisfy the criteria for major bleeding and that led to: 
• hospital admission, or 
• physician-guided medical treatment, or 
• surgical treatment or 
• change in antithrombotic therapy 
In addition to the ISTH definition of bleeding events other definitions such as TIMI, BARC, 
GUSTO, etc. can be used as supportive for exploratory safety analyses. 
The population is those who have received at least one dose of the study drug. 
 
Major cardiovascular, cerebrovascular, and venous thromboembolic events 
All suspected major cardiovascular, cerebrovascular, and VTE events will be documented by the 
Investigator in the appropriate CRF including any diagnostic imaging that was used to confirm the 
event. For instance, any suspected episodes of DVT (i.e., swelling, localized pain, redness, heat, 
localized warmth) must be documented by compression ultrasound (CUS) or venography.  
Any suspected episodes of PE (i.e., shortness of breath, chest pain, coughing, tachycardia, 
hemoptysis, hemodynamic compromise, unexplained death) must be documented by 
ventilation/perfusion lung scintigraphy, spiral computed tomography (sCT), or pulmonary 
angiography. 
All major cardiovascular, cerebrovascular, systemic arterial, and venous thromboembolic events 
(VTEs) including deaths for which a major cardiovascular, cerebrovascular, or VTE event could 
not be ruled out will be adjudicated by experienced medical personnel that is blinded to treatment 
assignment. 
The adjudicated outcome will be the basis for any interim and final safety evaluations. 
Page 185 of 212

Anthos Therapeutics 
 
Page 39 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
7.6.1. 
Adverse Events 
An AE is any untoward medical occurrence [i.e., any unfavorable and unintended sign (including 
abnormal laboratory findings), symptom or disease] in a subject or clinical investigation subject 
after providing written informed consent for participation in the study until the EoS visit. 
Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal 
(investigational) product. 
In addition, all reports of intentional misuse and abuse of the study treatment are also considered 
an AE irrespective if a clinical event has occurred. See Section 7.6.2 for an overview of the 
reporting requirements. 
The occurrence of AEs must be sought by non-directive questioning of the subject at each visit 
during the study. AEs also may be detected when they are volunteered by the subject during or 
between visits or through physical examination finding, laboratory test finding, or other 
assessments. 
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria: 
• they induce clinical signs or symptoms, 
• they are considered clinically significant, 
• they require therapy. 
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in healthy subjects. 
Investigators have the responsibility for managing the safety of individual subject and identifying 
AEs. Alert ranges for liver and kidney related events are included in Appendix 1 and Appendix 2, 
respectively. Additional clinically notable laboratory values are included in Appendix 3. 
AEs must be recorded on the AE CRF under the signs, symptoms or diagnosis associated with 
them, and accompanied by the following information: 
1. Severity grade 
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
2. Relationship to the study treatment 
• Related 
• Possibly related 
• Not related 
3. Duration (start and end dates) or if the event is ongoing an outcome of not recovered/not resolved 
must be reported. 
Page 186 of 212

Anthos Therapeutics 
 
Page 40 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
4. Whether it constitutes a SAE (see Section 7.6.2 for definition of SAE) and which seriousness 
criteria have been met 
5. Action taken regarding investigational treatment. 
All AEs must be treated appropriately. Treatment may include one or more of the following: 
• no action taken (e.g. further observation only) 
• concomitant medication or non-drug therapy given 
• hospitalization/prolonged hospitalization (see Section 7.6.2 for definition of SAE) 
6. 
Outcome 
(not 
recovered/not 
resolved; 
recovered/resolved; 
recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown). 
Information about common side effects already known about the investigational drug can be found 
in the IB. Once an AE is detected, it must be followed until its resolution or until it is judged to be 
permanent, and assessment should be made at each visit (or more frequently, if necessary) of any 
changes in severity, the suspected relationship to the investigational drug, the interventions 
required to treat it, and the outcome. 
The Investigator must also instruct each subject to report any new AE (beyond the protocol 
observation period) that the subject, or the subject’s personal physician, believes might reasonably 
be related to study treatment. This information must be recorded in the Investigator’s source 
documents; however, if the AE meets the criteria of an SAE, it must be reported to Covance. 
7.6.2. 
Reporting Serious Adverse Events 
Definition of SAE 
An SAE is defined as any AE [appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s) or medical conditions(s)] which meets any one of the following criteria: 
• is fatal or life-threatening 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
o elective or pre-planned treatment for a pre-existing condition and has not worsened 
since the start of study drug 
o treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
o social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
o is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention 
Page 187 of 212

Anthos Therapeutics 
Page 41 
AFib Protocol v01 
Protocol No. ANT-004 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (see Annex IV, ICH-E2D Guideline). 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Examples of such events 
are intensive treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization or development of dependency or 
abuse (see Annex IV, ICH-E2D Guideline). 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All AEs (serious and non-serious) are captured on the CRF; SAEs also require individual 
reporting to Covance Drug Safety & Epidemiology (DS&E) as per Section 0. 
SAE Reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last planned study assessment, must be 
reported to Covance within 24 hours of learning of its occurrence as described below. Any SAEs 
experienced after this period should only be reported to Covance if the Investigator suspects a 
causal relationship to study treatment. 
Note: SAEs reported by subjects deemed to be screen failures must be reported to Covance as 
outlined here with appropriate information also captured in the CRFs. 
All follow-up information for the SAE including information on complications, progression of the 
initial SAE and recurrent episodes must be reported as follow-up to the original episode within 24 
hours of the Investigator receiving the follow-up information. An SAE occurring at a different 
time interval or otherwise considered completely unrelated to a previously reported one must be 
reported separately as a new event. 
Follow- up information provided must describe whether the event has resolved or continues, if and 
how it was treated, whether the blind was broken or not (if applicable) and whether the subject 
continued or withdrew from study participation. Each re-occurrence, complication, or progression 
of the original event must be reported as a follow-up to that event regardless of when it occurs. 
If the SAE is not previously documented in the IB (new occurrence) and is thought to be related 
to the study treatment a Covance DS&E associate may urgently require further information from 
the Investigator for Health Authority reporting. Covance may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will 
be collected and reported to the competent authorities and relevant ethics committees in 
accordance with EU Guidance 2011/C 172/01 or as per national regulatory requirements in 
participating countries. 
Page 188 of 212

Anthos Therapeutics 
Page 42 
AFib Protocol v01 
Protocol No. ANT-004 
Follow the detailed instructions outlined in the Safety Management Plan regarding the submission 
process for reporting SAEs to Covance. Note: SAEs must be reported to Covance within 24 hours 
of the Investigator learning of its occurrence/receiving follow-up information. 
7.7. 
Liver safety monitoring 
To ensure subject safety and enhance reliability in determining the hepatotoxic potential of an 
investigational drug, a standardized process for identification, monitoring and evaluation of liver 
events must be followed. 
Please refer to Appendix 1 for complete definitions of liver events. 
Follow-up of liver events 
Every liver event defined in Appendix 1  should be followed up by the Investigator or designated 
personnel at the trial site, as summarized below. Additional details on actions required in case of 
liver events are outlined in Table 4 of Appendix 1. 
•
Repeating liver chemistry tests (ALT, AST, total bilirubin (TBL), PT/INR, ALP and γGT)
to confirm elevation within 48-72 hours.
These liver chemistry repeats should always be performed using the central laboratory,
with the results provided via the standard electronic transfer. If results will not be available
from the central laboratory within 24 hours, then the repeats can also be performed at a
local laboratory to monitor the safety of the subject. If a liver event is subsequently
reported, any local liver chemistry tests previously conducted that are associated with this
event should have results reported on the unscheduled local laboratory CRF.
•
If the initial elevation is confirmed, close observation of the subject will be initiated,
including consideration of treatment interruption if deemed appropriate.
•
Discontinuation of the investigational drug (refer to Section 4.3 (Discontinuation of study
treatment), if appropriate
•
Hospitalization of the subject if appropriate
•
Causality assessment of the liver event
•
Thorough follow-up of the liver event should include
o
Repeating liver chemistry tests two or three times weekly. Testing should include
ALT, AST, ALP, PT/INR, and γGT. If total bilirubin is elevated > 2 x ULN,
fractionation into direct and indirect bilirubin is required. To rule out muscular
origin of transaminase elevations, CPK should be measured along with liver
chemistry tests. Frequency of retesting can decrease to once a week or less if
abnormalities stabilize or the study drug has been discontinued and the subject is
asymptomatic. Retesting should be continued up to resolution.
o
Obtaining a more detailed history of symptoms and prior or concurrent diseases.
o
Obtaining a history of concomitant drug use (including non-prescription
medications and herbal and dietary supplement preparations), alcohol use,
recreational drug use, and special diets.
Page 189 of 212

Anthos Therapeutics 
Page 43 
AFib Protocol v01 
Protocol No. ANT-004 
o
Exclusion of underlying liver disease, as specified in Table 6.
o
Imaging such as abdominal US, CT or MRI, as appropriate
o
Obtaining a history of exposure to environmental chemical agents.
o
Considering gastroenterology or hepatology consultations.
All follow-up information, and the procedures performed must be recorded as appropriate in the 
CRF. 
7.8. 
Renal safety monitoring 
Every renal laboratory trigger or renal event must be followed up by the Investigator or designated 
personnel at the trial site. Recommended follow-up assessments are listed in Appendix 2. 
7.9. 
Pregnancy 
All female study participants, regardless of the requirement to be of non-child-bearing potential to 
be enrolled into this study, will have pregnancy testing. See the Assessment Schedule (Table 9), 
for timing of the protocol required pregnancy testing; additional pregnancy testing may be 
performed to meet local requirements*. Subjects will not receive study medication in case of a 
positive urine or serum pregnancy test. 
*If additional pregnancy testing is needed per local requirements, those additional results will be
kept as source documentation only.
Pregnancy reporting 
Reproductive toxicity and teratogenicity data are not available for this antibody at this time, 
therefore no guidelines on therapeutic recommendations in case of pregnancy are available. This 
study enrolls women who are considered to be of non-child-bearing potential, thus pregnancy is 
not an expected outcome for any female study participant. However, in the case that a pregnancy 
in a female study participant should occur please follow the below reporting guidelines. The 
follow-up for this subject and for the fetus is at the discretion of the Investigator. 
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Covance within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of the 
birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or 
newborn complications. 
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
Investigator to the local Covance DSS department. Pregnancy follow-up should be recorded on 
the same form and should include an assessment of the possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported on a 
SAE form. 
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes should 
be obtained from the mother. 
Page 190 of 212

Anthos Therapeutics 
 
Page 44 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
All assessments that are considered as a risk during pregnancy must not be performed. The subject 
may continue all other protocol assessments. 
7.10. 
Clinical Laboratory Evaluations 
Clinically relevant deviations of laboratory test results occurring during or at completion of the 
study must be reported and discussed with Covance personnel. The results should be evaluated for 
criteria defining an AE and reported as such if the criteria are met. Repeated evaluations are 
mandatory until normalization of the result(s) or until the change is no longer clinically relevant. 
In case of doubt, Covance personnel should be contacted. 
Safety labs (hematology, clinical chemistry and urinalysis) do not need to be repeated at baseline 
if the Baseline visit is taking place within 48 hours of the screening labs being collected from an 
individual subject. 
Subjects should be instructed to fast for at least 8 hours prior to scheduled safety lab collections. 
Clinically notable laboratory findings are defined in Appendix 3. 
Hematology 
Hemoglobin, hematocrit, red blood cell (RBC) count, white blood cell (WBC) count with 
differentials and platelet count will be measured. 
Clinical chemistry 
Sodium, potassium, creatinine, BUN/urea, uric acid, chloride, albumin, calcium, alkaline 
phosphatase, total bilirubin, bicarbonate/HCO3, LDH, GGT, AST, ALT, CK, glucose, total 
cholesterol, triglycerides. If the total bilirubin concentration is increased above 1.5 times the upper 
limit of normal, direct and indirect reacting bilirubin should be differentiated. 
Urinalysis 
Dipstick measurements for specific gravity, protein, glucose and blood will be performed. 
Microscopy, WBC, RBC and sediments will also be assessed in case of an abnormal dipstick test. 
Special clinical laboratory evaluations 
Stool samples will be collected to check for occult blood at screening and baseline. Screening fecal 
samples can be collected at any time during the Screening period, and baseline fecal samples must 
be collected within 72 hours of Day 1. If fecal screening samples are collected within 72 hours of 
Day 1, then they do not need to be repeated for the Baseline visit. In the event that a subject is 
unable to produce a stool sample for sampling, the site medical staff may elect to produce a sample 
via digital extraction from the rectum. 
Details regarding collection methods and processing are outlined in the Central Laboratory 
Manual. 
7.11. 
Vital Signs, Physical Examination, and Other Safety Evaluations 
Vital signs will include the collection of oral body temperature (recorded in °C), blood pressure 
(BP)–sitting and standing –and pulse measurements. At Screening, for eligibility determination, 
three sets of systolic and diastolic BP and pulse rate measurements will be collected after the 
subject has been sitting for 3 minutes, with back supported and both feet placed on the floor and 
Page 191 of 212

Anthos Therapeutics 
 
Page 45 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
the mean will be used to determine eligibility. A single set of BP and pulse rate measurements will 
then be collected after three minutes in the standing position.  
A single set of sitting BP measurements will be collected at subsequent visits. 
Physical exams will include assessment of general appearance, skin, lymph nodes, HEENT, neck, 
thorax/lungs, cardiovascular, abdomen, musculoskeletal, and neurological systems. 
Height in centimeters (cm) and body weight [to the nearest 0.1 kilogram (kg) in indoor clothing, 
but without shoes] will be measured. Body mass index (BMI) will be calculated using the 
following formula: 
BMI = Body weight (kg) / [Height (m)]2. BMI results will be documented in the CRF to 2 decimal 
places. 
7.12. 
Electrocardiogram (ECG) 
The ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable baseline. 
PR interval, QRS duration, heart rate, RR interval, QT, QT corrected by the Fridericia correction 
formula (QTcF) will be collected. The QTcF should be used for clinical decision-making. ECGs 
must be collected, analyzed and appropriately signed and archived at the study site; the site will 
also store all ECG readings digitally (if possible). For any ECGs with subject safety concerns, 
duplicate ECGs must be performed to confirm the safety finding. Clinically significant ECG 
findings at baseline must be discussed with the Sponsor before administration of study treatment. 
Clinically significant abnormalities must be reported in the AE CRF. 
7.13. 
Pharmacokinetic Analysis 
The PK samples will be collected at the timepoints defined in the Assessment schedule (Table 9). 
Follow instructions outlined in the Central Laboratory Manual regarding sample collection, 
numbering, processing and shipment. See Section 7.13 regarding the potential use of residual 
samples. 
In order to better define the PK profile, the timing of the PK sample collection may be altered 
based on emergent data. The number of samples/blood draws and total blood volume collected 
will not exceed those stated in the protocol. Changes to the PK Assessment schedule, if any, will 
be communicated to the sites in the dose adjustment minutes. 
The PK samples will be obtained and evaluated in all subjects at all dose levels. Untreated 
(placebo) samples will not be analyzed. 
Concentrations of plasma total MAA868 (i.e. MAA868 that is bound to FXI or not bound to FXI) 
will be determined by a validated LC-MS/MS method. A detailed description of the method used 
to quantify the concentration of total MAA868 will be included in the bioanalytical raw data and 
in the Bioanalytical Data Report. 
All concentrations below the LLOQ or missing data will be labeled as such in the concentration 
data listings. 
For standard PK abbreviations and definitions see the list provided at the beginning of this 
protocol. 
Page 192 of 212

Anthos Therapeutics 
 
Page 46 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
The following PK parameters will be determined, where data permit, using the actual recorded 
sampling times and non-compartmental method(s) with Phoenix WinNonlin (Version 6.2 or 
higher): C0 (the concentration at the end of infusion), AUClast, AUCinf, C0/D, and AUC/D, based 
on the plasma concentration data.  
The linear trapezoidal rule will be used for AUC calculation. The terminal half-life of MAA868 
(T1/2), volume of distribution (Vss) and clearance (CL) will also be estimated, if feasible, based on 
the data. 
7.14. 
Other assessments 
7.14.1. 
Exploratory Biomarker assessments 
Biomarkers including, but not limited to, D-Dimer and biomarkers of thrombogenesis and 
coagulation may also be studied. 
The list may be changed or expanded further, as it is recognized that more relevant or novel 
biomarkers may be discovered during the conduct of the study. 
Sample(s) will be collected at the timepoint(s) defined in the Assessment schedule (Table 9). 
Follow instructions for sample collection, numbering, processing and shipment provided in the 
central lab manual. Detailed descriptions of the assays will be included in the Bioanalytical Data 
Reports. 
7.14.2. 
Immunogenicity (IG) 
The IG samples will be collected at the timepoints defined in the Assessment schedule (Table 9). 
Follow instructions outlined in the Central Laboratory Manual regarding sample collection, 
numbering, processing, and shipment. See Section 7.13 regarding the potential use of residual 
samples. 
Immunogenicity analytical method(s) 
A ligand-binding assay will be used to detect anti-MAA868 antibodies. The analytical method will 
be described in detail in the IG Bioanalytical Data Report. 
7.15. 
Use of residual biological samples 
Residual blood samples may be used for another protocol specified endpoint. 
Any residual samples remaining after the protocol-defined analysis has been performed may be 
used for additional exploratory analysis. This may include but is not limited to using residual 
samples for protein binding, metabolite profiling, biomarkers of transporters or metabolic enzyme 
activity (such as 4-beta-hydroxycholesterol levels) or other bioanalytical purposes (e.g. cross 
check between different sites and/or stability assessment). Given the exploratory nature of the 
work, the analytical method used for those assessments may not be validated. As such, the results 
from this exploratory analysis will not be included in the clinical study report. 
Page 193 of 212

Anthos Therapeutics 
 
Page 47 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
8. 
SAMPLE SIZE AND DATA ANALYSES 
8.1. 
Determination of Sample Size 
A sample size of 16 subjects per treatment dose cohort with a ratio of 3:1 for MAA868 and placebo 
treatment assignment is based on historic data considerations. For example, if the observed 
proportion of patients in a cohort achieving target levels of inhibition is 11/12, the 90% confidence 
interval would be 0.66 to 0.996. 
8.2. 
Analysis Populations 
All Randomized Set will include all subjects who are randomized  
Full Analysis Set will include randomized subjects excluding those subjects who are randomized 
into the study in error and did not receive study drug. Subjects will be analyzed based on the 
assigned treatment at the randomization.  
Per Protocol Set will include subjects in Full Analysis Set and those subjects have no major 
protocol deviation after randomization.  
Safety Set will include randomized subjects who at least received one dose of study drug. Subjects 
will be analyzed based on the actual treatment taken. 
PK/PD Analysis Set will comprise all subjects who received at least one dose of study drug and 
have at least one PK/PD assessment. Subjects will be analyzed based on the actual treatment taken. 
8.3. 
General Considerations 
All efficacy analysis will be based on the Full Analysis Set or Per Protocol Set and will be 
performed based on the assigned treatment arm at the randomization. Only descriptive statistics 
will be summarized, no statistical inference will be calculated in efficacy.  
Safety analysis will be performed using Safety Set. Subjects will be analyzed based on the actual 
treatment taken. 
PK and PD analysis will be based on PK/PD Analysis Set. 
Continuous variables will be summarized by number of subjects [n], mean, standard deviation 
[SD], median, minimum [min], and maximum [max]. Categorical variable will be summarized 
using frequency [N] and percentage [%]. 
8.4. 
Demographics and Baseline characteristics 
All baseline summaries will be based on the All Randomized Set and Full Analysis Set 
populations. 
Gender, race and ethnicity will be summarized using counts and percentages. Age, height (cm), 
and weight (kg) will be summarized with descriptive statistics (number of subjects [n], mean, SD, 
median, minimum [min], and maximum [max]). Age may be summarized by decades using N and 
%. 
The listing of subjects with abnormal physical examination findings at screening will be presented. 
The number and percent of subjects with medical history events will be summarized. Vital signs 
Page 194 of 212

Anthos Therapeutics 
 
Page 48 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
collected at screening (sitting diastolic and systolic blood pressure, pulse, temperature and body 
weight) will be summarized with descriptive statistics (n, mean, SD, median, min, and max). 
8.5. 
Efficacy Analysis 
8.5.1. 
Primary Efficacy Outcome Measures 
Within each treatment cohort patients will be randomized 3:1 to active drug or placebo. 
The primary analysis variable is whether a subject will achieve a certain percentage FXI inhibition 
at trough (Day 91). The response rate per treatment group will be calculated by number of subjects 
who achieve targeted FXI inhibition rate divided by the total number of subjects in the treatment 
group. The dose regimens and targeted FXI inhibition achievement for Cohorts 1 and 2 are as 
follows  
Cohort 1 (MAA868 120 mg monthly or placebo): Targeted to achieve ≥ 50% FXI inhibition in 
90% of subjects at trough (Day 91).  
Cohort 2 (MAA868 180 mg monthly or placebo): Targeted to achieve ≥ 90% FXI inhibition in 
90% of subjects at trough (Day 91). 
The “on treatment” trough FXI levels will be used for the primary analysis, where “on treatment” 
FXI level is defined as a value which is collected within 30 (±5) days after the last administration 
of MAA868. The estimate of the responder rate (%) at Day 91 will be presented for each dose 
regimens of MAA868 together with 2-sided 90% confidence intervals (CI) computed via the 
Clopper-Pearson exact binomial method. 
8.5.2. 
Secondary Efficacy Outcome Measures 
The secondary efficacy analysis is to evaluate the proportion of subjects achieving FXI inhibition 
≥ 50%, ≥80%, and ≥90% at trough after the first and second dose (Day 31 and Day 61) at 3 dose 
levels of MAA868. The analyses described for the primary endpoint will be repeated for the 
secondary efficacy variables as follows: 
• Cohort 1 (MAA868 120 mg monthly or placebo): at Day 31 and 61.  
• Cohort 2 (MAA868 180 mg monthly or placebo):  at Day 31 and 61 
• Cohort 3 (MAA868 TBD mg monthly or placebo): at Day 31 and 61 
8.6. 
Safety Analysis 
The safety evaluation includes the analysis of bleeding events, AEs, major cardiovascular, 
cerebrovascular, systemic arterial, and venous thromboembolism events, laboratory data, ECG, 
vital signs, hypersensitivity reactions, injection site reactions, and development of anti-drug 
antibodies. All safety analysis will be performed using the Safety Set. 
8.6.1. 
Adverse Events 
The Investigator’s verbatim term of each AE will be mapped to system organ class (SOC) and 
preferred term (PT) using the MedDRA dictionary. 
Page 195 of 212

Anthos Therapeutics 
 
Page 49 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
Treatment-emergent Adverse Events (TEAEs) will be of primary interest. The TEAEs will be 
summarized by SOC and PT; a subject will only be counted once per SOC and once per PT within 
a treatment. If a subject reports more than one AE with the same PT, the AE with the maximum 
severity will be presented. Subject counts and percentages and event counts will be presented for 
each treatment and totaled for all treatments for the following summaries: 
• All TEAEs 
• Serious TEAEs  
• All TEAEs by severity 
• All TEAEs by relationship to study drug 
• TEAEs potentially related to study drug 
• TEAEs potentially related to study drug by severity 
• TEAEs leading to discontinuation of study drug 
• TEAEs leading to withdrawal from the study 
Adverse events of special interest (AESI) will be reported for a selection of interested AE terms 
that are specific to Sponsor’s product and program, for which ongoing monitoring and rapid 
communication by the Investigator to the Sponsor can be appropriate. 
The AESIs for this study are defined as follows: 
1. 
TERM 1 
2. 
TERM 2 
Similarly, to the TEAE summary, the AESI will be summarized in the following: 
1. 
All AESIs 
2. 
Serious AESIs 
3. 
All AESIs by severity 
4. 
All AESIs by relationship to study drug 
5. 
AESIs leading to discontinuation of study drug 
6. 
AESIs leading to withdrawal from the study 
No statistical inference between the treatments will be performed on AEs. 
Listings will be presented by subject for all TEAEs, AESIs, as well as for SAEs, TEAEs associated 
with outcome of death, and TEAEs leading to discontinuation from the study. 
8.6.2. 
Bleeding Events 
An analysis will be performed for the composite safety endpoint of major and CRNM bleeding 
events which occur on-treatment from the first dose of the study drug to the last dose of the study 
drug + 30 days if the subject permanently discontinues the study drug prior to the third dose on 
Day 91. The number of events and the incidence of adjudicated bleeding events will be tabulated 
Page 196 of 212

Anthos Therapeutics 
 
Page 50 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
based on ISTH definition by treatment including the composite endpoint of major bleeding events 
and/or CRNM bleedings.  
Major bleeding events (Yes/No) 
CRNM bleeding events (Yes/No) 
Total bleeding events (Yes/No) 
If a subject has more than one bleeding event in each above category, the subject will be counted 
only once in the tabulation. 
The adjudicated outcome will be the basis for any interim and final analysis. 
8.6.3. 
Major cardiovascular, cerebrovascular, and venous thromboembolic events 
An analysis will be performed for the composite safety endpoint of major cardiovascular, 
cerebrovascular, and venous thromboembolic events which occur on-treatment from the first dose 
of the study drug to the last dose of the study drug + 30 days if the subject permanently discontinues 
the study drug prior to the third dose on Day 91.   
The number of events and the incidence of adjudicated events will be tabulated based on the 
outcomes adjudicated by experienced medical personnel, and the adjudicated outcome will be the 
basis for any interim and final analysis. 
8.6.4. 
Clinical Laboratory Evaluations 
Clinical laboratory results in continuous values at each timepoint and for change from baseline 
will be displayed using summary statistics (n, mean, median, SD, minimum and maximum values). 
A laboratory value that is within the central laboratory’s reference range will be considered normal. 
A laboratory value that is outside the central laboratory’s normal range will be considered 
abnormal and will be flagged as either high (H) or low (L). The number and percentage of subjects 
with abnormal laboratory values will be summarized for each scheduled visit. In addition, shift 
tables will be presented to display the shift in the normal range categories (L, normal [N], H) from 
baseline to specified timepoint. Laboratory results in clinical significance will also be summarized 
in tabulation. 
All clinical laboratory data will be presented in listings. Baseline is defined as the result obtained 
prior to first administration of study medication. Laboratory data will be summarized in SI units. 
8.6.5. 
Vital Sign Measurements 
Pre-dose values, post-dose values, and the change from baseline in vital sign measurements (sitting 
diastolic and systolic blood pressure, pulse, temperature and body weight) will be summarized 
with descriptive statistics (n, mean, SD, median, min, and max) at each timepoint by treatment. 
The baseline value will be value just prior to first administration of study medication. 
8.6.6. 
ECG Parameters 
The ECG measures (QTc-B, QTc-F, QT, RR, ventricular rate, PR, and QRS) will be listed and 
summarized with descriptive statistics (n, mean, SD, median, min, and max) at each timepoint by 
treatment. 
Page 197 of 212

Anthos Therapeutics 
 
Page 51 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
The listings of subjects with abnormal ECG results, as judged by the Investigator, will be displayed 
and will be calculated. The baseline will be the value just prior to first administration of study 
medication. 
8.7. 
Pharmacokinetic Analysis 
Descriptive summary statistics will be provided by treatment and visit/sampling timepoint with 
descriptive statistics (n, mean, SD, median, min, and max) at each timepoint by treatment. An 
exception to this is Tmax where median, minimum and maximum will be presented. 
Concentrations below the lower limit of quantitation (LLOQ) will be treated as zero in summary 
statistics and for PK parameter calculations. A geometric mean will not be reported if the dataset 
includes zero values. 
Individual total MAA868 plasma concentration data will be listed by treatment (MAA868 arms 
only), subject, and visit/sampling timepoint. PK parameters will also be listed by treatment and 
subject. 
8.8. 
Biomarkers 
Coagulation parameters, including free and total FXI, FXI:C, and immunogenicity will be 
summarized by timepoint and treatment. 
8.9. 
Interim Analysis 
Safety and tolerability data (AEs, laboratory assessments, vital signs and ECG data) will be 
evaluated from Cohort 1 by the Sponsor's Medical Monitor  and Covance Lead Project Physician 
after approximately 10 of the patients in cohort 1 have received their second dose of study drug 
and have been followed for at least an additional 14 days. The decision to proceed to cohort 2 will 
be made only after it is confirmed that the cohort 1 dose was safe and tolerated and all planned 
subjects in cohort 1 have been randomized. If notable AEs or safety concerns are found in cohort 
1, the study may be terminated.  
Likewise, after approximately 10 of the patients in cohort 2 have received their second dose of 
study drug and have been followed for at least an additional 14 days, safety, tolerability, and other 
analyses will be evaluated.  
Additional IAs may be conducted to support decision making concerning the current clinical study, 
the Sponsor’s clinical development projects in general or in case of any emergent safety concerns. 
The Investigator(s) may be included for decisions with regards to any unplanned IAs that address 
questions of subject safety. 
Unblinded IA results will be reviewed by the Sponsor (or their designees).  
No further dissemination of interim results should occur, in particular not with individuals 
involved in treating the study’s subjects or assessing clinical data (e.g. ECGs, symptoms) obtained 
in the study. 
8.10. 
Data Quality Assurance 
Site monitoring 
Page 198 of 212

Anthos Therapeutics 
 
Page 52 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Covance 
representative will review the protocol and CRFs with the Investigator(s) and their staff. During 
the study Covance employs several methods of ensuring protocol and GCP compliance and the 
quality/integrity of the sites’ data. The monitor will visit the site to check the completeness of 
subject records, the accuracy of entries on the CRFs, the adherence to the protocol and to GCP, 
the progress of enrollment, and ensure that study drug is being stored, dispensed, and accounted 
for according to specifications. Key study personnel must be available to assist the monitor during 
these visits. 
The Investigator must maintain source documents for each subject in the study, consisting of case 
and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or assessments. 
All information on CRFs must be traceable to these source documents in the subject's file. The 
Investigator must also keep the original informed consent form signed by the subject (a signed 
copy is given to the subject). 
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Covance monitoring standards require full verification for the 
presence of informed consent, adherence to the eligibility criteria, documentation of SAEs, and 
the recording of data that will be used for all primary and safety variables. Additional checks of 
the consistency of the source data with the CRFs are performed according to the study-specific 
monitoring plan. No information in source documents about the identity of the subjects will be 
disclosed. 
Data collection 
Designated Investigator staff will enter the data required by the protocol into the Electronic Case 
Report Forms using fully validated software that conforms to 21 CFR Part 11 requirements. 
Designated investigator site staff will not be given access to the electronic data capture (EDC) 
system until they have been trained. Automatic validation programs check for data discrepancies 
and, by generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to Covance working on behalf of Anthos. The Investigator must certify that the 
data entered into the Electronic Case Report Forms are complete and accurate. After database lock, 
the Investigator will receive copies of the subject data for archiving at the investigational site. 
Data not requiring a separate written record are noted on the Assessment schedule (Table 9) and 
can be recorded directly on the CRF. All other data captured for this study will have an external 
originating source (either written or electronic) with the CRF not being considered as source. 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 
Database management and quality control 
Covance will review the data entered into the CRFs by investigational staff for completeness and 
accuracy and instruct the site personnel to make any required corrections or additions. Queries are 
sent to the investigational site using an electronic data query. Designated investigator site staff is 
required to respond to the query and confirm or correct the data. Site personnel will complete and 
sign the faxed copy and fax it back to Covance who will make the correction to the database. The 
signed copy of the Data Query Form is kept at the investigator site. 
Page 199 of 212

Anthos Therapeutics 
 
Page 53 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
Concomitant medications entered into the database will be coded using the WHO Drug Reference 
List, which employs the Anatomical Therapeutic Chemical classification system. Medical 
history/current medical conditions and adverse events will be coded using the Medical dictionary 
for regulatory activities (MedDRA) terminology. 
Laboratory samples will be processed centrally, and the results will be sent electronically to 
Covance. 
At the conclusion of the study, the occurrence of any emergency code breaks will be determined 
after return of all code break reports and unused drug supplies to Covance. 
The occurrence of any protocol deviations will be determined. After these actions have been 
completed and the database has been declared to be complete and accurate, it will be locked, and 
the treatment codes will be unblinded and made available for data analysis. Any changes to the 
database after that time can only be made by joint written agreement between the Anthos Head of 
Regulatory and the Chief Medical Officer. 
Page 200 of 212

Anthos Therapeutics 
 
Page 54 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
9. 
ETHICAL CONSIDERATIONS 
9.1. 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for GCP, with applicable local regulations 
(including European Directive 2001/20/EC, US Code of Federal Regulations Title 21, and 
Japanese Ministry of Health, Labor, and Welfare), and with the ethical principles laid down in the 
Declaration of Helsinki. 
9.2. 
Responsibilities of the Investigator and IRB 
Before initiating a trial, the Investigator/institution must obtain approval/favorable opinion from 
the IRB for the trial protocol, written informed consent form, consent form updates, subject 
recruitment procedures (e.g. advertisements) and any other written information to be provided to 
subjects. Prior to study start, the Investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents and all of 
the instructions and procedures found in this protocol and to give access to all relevant data and 
records to Covance monitors, auditors, Covance Quality Assurance representatives, designated 
agents of Anthos, IRBs, and regulatory authorities as required. If an inspection of the clinical site 
is requested by a regulatory authority, the Investigator must inform Anthos immediately that this 
request has been made. 
For multi-center trials, a Coordinating Investigator will be selected by Anthos around the time of 
Last Patient Last Visit to be a reviewer and signatory for the CSR. 
9.3. 
Publication of study protocol and results 
The key design elements of this protocol will be posted in a publicly accessible database such as 
clinicaltrials.gov. Upon study completion and finalization of the study report the results of this 
trial will be posted in a publicly accessible database of clinical trial results in accordance with local 
regulations. 
No publication or disclosure of study results will be permitted except under the terms and 
conditions of a separate written agreement between the Sponsor and the investigator and/or the 
investigator's institution.  
The information developed from this clinical study will be used by the Sponsor in connection with 
the development of MAA868 and other drugs and diagnostics, and thus may be disclosed as 
required to other clinical investigators, business partners, or regulatory agencies. To permit the 
information derived from the clinical studies to be used, the investigator is obligated to provide 
the Sponsor with all data obtained in the study. 
Page 201 of 212

Anthos Therapeutics 
 
Page 55 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
10. 
PROTOCOL ADHERENCE 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
Investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.  
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an Investigator 
feels a protocol deviation would improve the conduct of the study this must be considered a 
protocol amendment, and unless such an amendment is agreed upon by Anthos and approved by 
the IRB and health authorities, where required, it cannot be implemented. 
10.1. 
Protocol Amendments 
Any change to the protocol can only be made in a written protocol amendment that must be 
approved by Anthos, Health Authorities where required, and the IRB prior to implementation.  
Amendments that are intended to eliminate an apparent immediate hazard to subjects may be 
implemented immediately, provided the Health Authorities are subsequently notified by protocol 
amendment and the reviewing IRB is notified.  
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any subject included in this study, 
even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 7.6.2 (Safety Monitoring) must be followed and the Study Lead 
informed. 
Page 202 of 212

Anthos Therapeutics 
 
Page 56 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
11. 
REFERENCES 
1. Bolton-Maggs (2000) Factor XI deficiency and its management. Haemophilia; 6(S1):100-9. 
2. Buller H, Bethune C, Bhanot S, et al (2015) Factor XI Antisense Oligonucleotide for 
prevention of Venous Thrombosis. N Engl J Med; 372; 3:232-240. 
3. Camm AJ, Lip GY, De Caterina R, et al (2012) 2012 focused update of the ESC Guidelines 
for the management of atrial fibrillation. Eur Heart J; 33:719-47. 
4. Connolly SJ, Ezekowitz MD, Yusuf S, et al (2009) Dabigatran versus warfarin in patients with 
atrial fibrillation. N Engl J Med; 361:1139-51. 
5. Gailani D, Renné T (2007) Intrinsic pathway of coagulation and arterial thrombosis. 
Arterioscler Thromb Vasc Biol; 27:2507-13. 
6. Granger C, Alexander J, McMurray J, et al (2011) Apixaban versus warfarin in patients with 
atrial fibrillation. N Engl J Med; 365:981-92. 
7. Hart RG, Benavente O, McBride R, et al (1999) Antithrombotic therapy to prevent stroke in 
patients with atrial fibrillation: a meta-analysis. Ann Intern Med; 131:492-501. 
8. January CT, Wann LS, Alpert JS, et al (2014) AHA/ACC/HRS guideline for the management 
of patients with atrial fibrillation: a report of the American College of Cardiology/American 
Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll 
Cardiol; 64:e1–76. 
9. Kannel WB, Benjamin EJ (2008) Status of the epidemiology of atrial fibrillation. Med Clin 
North Am; 92:17-40. 
10. Lip GY, Nieuwlaat R, Pisters R, et al (2010) Refining clinical risk stratification for predicting 
stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the 
euro heart survey on atrial fibrillation. Chest; 137(2):263-72. 
11. Livnat T, Tamarin I, Mor Y, et al (2009) Recombinant activated factor VII and tranexamic 
acid are haemostatically effective during major surgery in factor XI-deficient patients with 
inhibitor antibodies. Thromb Haemost; 102:487–92. 
12. Patel MR, Mahaffey KW, Garg J, et al (2011) Rivaroxaban versus warfarin in nonvalvular 
atrial fibrillation. N Engl J Med; 365:883-91. 
13. Piccini JP, Garg J, Patel MR, et al (2014) Management of major bleeding events in patients 
treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. Eur Heart J; 
35:1873-80. 
14. Preis M, Hirsch J, Kotler A et al (2017) Factor XI deficiency is associated with lower risk for 
cardiovascular and venous thromboembolism events. Blood; 129(9):1210-5. 
15. Riddell A, Abdul-Kadir R, Pollard D, et al (2011) Monitoring low dose recombinant factor 
VIIa therapy in patients with severe factor XI deficiency undergoing surgery. Thromb 
Haemost; 106:521-7. 
16. Salomon O, Steinberg DM, Koren-Morag N, et al (2008) Reduced incidence of ischemic stroke 
in patients with severe factor XI deficiency. Blood; 111:4113-7. 
17. Salomon O, Steinberg DM, Zucker M, et al (2011) Patients with severe factor XI deficiency 
have a reduced incidence of deep-vein thrombosis. Thromb Haemost; 105:269-73. 
Page 203 of 212

Anthos Therapeutics 
 
Page 57 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
18. Schulman S, et al (2005) Definition of major bleeding in clinical investigations of 
antihemostatic medicinal products in non-surgical patients.  J Thromb Haemost. 2005 
Apr;3(4):692-4. 
 
Page 204 of 212

Anthos Therapeutics 
 
Page 58 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
12. 
APPENDICES 
 
 
 
Page 205 of 212

Anthos Therapeutics 
 
Page 59 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
12.1. 
Appendix 1 - Liver Event Definitions and Follow-up Requirements 
Table 4: 
Liver Event Definition 
Definition 
Thresholds 
Potential Hy’s law cases 
• 
ALT or AST > 3 X ULN and TBL > 2 × ULN without initial 
increase in ALP to > 2 × ULN 
ALT or AST elevation with 
coagulopathy 
• 
ALT or AST > 3 × ULN and INR > 1.5 (in the absence of 
anticoagulation) 
ALT or AST elevation 
accompanied by symptoms 
• 
ALT or AST > 3 × ULN accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash, or 
eosinophilia 
Isolated ALT or AST elevation 
• 
ALT or AST > 8 × ULN 
• 
5 x ULN < ALT/AST ≤ 8 x ULN 
• 
3 x ULN  ALT/AST  5 x ULN 
Isolated ALP elevation 
• 
ALP > 2 × ULN (in the absence of known bone pathology) 
Others 
• 
Any clinical event of jaundice (or equivalent term) Any 
adverse event potentially indicative of liver toxicity 
 
 
Table 5: 
Action required for Liver Events 
Criteria 
Action required 
Potential Hy’s law cases 
ALT or AST elevation with 
coagulopathy 
ALT or AST elevation 
accompanied by symptoms 
Isolated ALT or AST elevation > 
8 X ULN Jaundice 
 
 
• 
Hospitalize, if clinically appropriate 
• 
Establish causality 
• 
Complete CRFs per liver event guidance 
Isolated ALT or AST elevation > 
5 to ≤ 8 X ULN 
• 
Establish causality 
• 
Complete CRFs per liver event guidance 
Isolated ALT or AST elevation > 
3 to ≤ 5 × ULN (patient is 
asymptomatic)  
• 
Monitor liver chemistry tests two or three times weekly 
Isolated ALP elevation 
• 
Repeat liver chemistry tests within 48-72 hours 
• 
If elevation is confirmed, measure fractionated ALP; if 
>50% is of liver origin, establish hepatic causality 
• 
Complete CRFs per liver event guidance 
Any AE potentially indicative of 
liver toxicity 
• 
Hospitalize if clinically appropriate 
• 
Complete CRFs per liver event guidance 
Page 206 of 212

Anthos Therapeutics 
 
Page 60 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
 
 
Table 6: 
Exclusion of underlying Liver Disease 
Disease 
Assessment 
Hepatitis A, B, C, E 
• 
IgM anti-HAV; HBSAg, IgM anti-HBc, HBV DNA; anti-
HCV, HCV RNA, IgM & IgG anti-HEV, HEV RNA 
CMV, HSV, EBV infection 
• 
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG 
anti-EBV 
Autoimmune hepatitis 
• 
ANA & ASMA titers, total IgM, IgG, IgE, IgA 
Alcoholic hepatitis 
• 
Ethanol history, γGT, MCV, CD-transferrin 
Nonalcoholic steatohepatitis 
• 
Ultrasound or MRI 
Hypoxic/ischemic hepatopathy 
• 
Medical history: acute or chronic CHF, hypotension, 
hypoxia, hepatic venous occlusion. Ultrasound or MRI 
Biliary tract disease 
• 
Ultrasound or MRI, ERCP as appropriate 
Wilson disease 
• 
Caeruloplasmin 
Hemochromatosis 
• 
Ferritin, transferrin 
Alpha-1-antitrypsin deficiency 
• 
Alpha-1-anitrypsin 
 
 
Page 207 of 212

Anthos Therapeutics 
 
Page 61 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
12.2. 
Appendix 2 - Specific Renal Alert Criteria and Actions 
Table 7: 
Specific Renal Alert Criteria and Actions 
Criteria 
Action required 
Serum creatinine (sCr) increase 
25 – 49% compared to baseline 
• 
Consider causes and possible interventions 
• 
Follow up within 2-5 days 
Serum creatinine increase ≥ 50% 
• 
Consider causes and possible interventions 
• 
Repeat assessment within 24-48 hours if possible 
• 
Consider hospitalization and specialized treatment 
Protein-creatinine or albumin-
creatinine ratio increase ≥ 2-fold, 
or 
new onset dipstick proteinuria ≥ 
1+ , or 
Albumin-creatinine ratio (ACR) ≥ 
30 mg/g or ≥ 3 mg/mmol, or 
Protein-creatinine ratio (PCR) ≥ 
150 mg/g or >15 mg/mmol 
 
• 
Consider causes and possible interventions 
 
• 
Assess serum albumin and serum protein 
 
• 
Repeat assessment to confirm 
New onset glucosuria on urine 
dipstick (unless related to 
concomitant treatment, diabetes) 
Assess and document: 
• 
Blood glucose (fasting) 
• 
Serum creatinine 
• 
Urine albumin-creatinine ratio 
New hematuria on dipstick 
Assess and document 
• 
Urine sediment microscopy 
• 
Assess sCr and urine albumin-creatinine ratio 
• 
Exclude infection, trauma, bleeding from the distal urinary 
tract/bladder, menstruation 
 
• 
Consider bleeding disorder 
 
 
Additional specialized assessments are available to assess renal function or renal pathology.  
(Note: In exceptional cases when a nephrologist considers a renal biopsy, it is strongly recommended to 
make specimen slides available for evaluation by Anthos to potentially identify project-wide patterns of 
nephrotoxicity.) 
Whenever a renal event is identified, a detailed subject history and examination are indicated to identify, 
document and potentially eliminate risk factors that may have initiated or contributed to the event: 
• 
Blood pressure assessment (after 5 min rest, with an appropriate cuff size) 
• 
Signs and symptoms such as fever, headache, shortness of breath, back or abdominal pain, dysuria, 
hematuria, dependent or periorbital edema 
• 
Changes in blood pressure, body weight, fluid intake, voiding pattern, or urine output 
• 
Concomitant events or procedures such as trauma, surgical procedures, cardiac or hepatic failure, 
contrast media or other known nephrotoxin administration, or other potential causes of renal 
dysfunction, e.g., dehydration, hemorrhage, tumor lysis 
Page 208 of 212

Anthos Therapeutics 
 
Page 62 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
 
 
Table 8: 
Follow-up renal events 
Action 
Follow up 
Assess*, document and record in the CRF or via 
electronic data load. Review and record possible 
contributing factors to the renal event 
(co-medications, other co-morbid conditions) 
and additional diagnostic procedures (MRI etc.) 
in the CRF 
• 
Urine dipstick and sediment microscopy 
• 
Blood pressure and body weight 
• 
Serum creatinine, electrolytes (sodium, 
potassium, 
phosphate, 
calcium), 
bicarbonate, and uric acid 
• 
Urine output 
Monitor subject regularly (frequency at 
Investigator’s discretion) until: 
• 
Event resolution: (sCr within 10% of 
baseline or protein-creatinine ratio within 
50% of baseline) OR 
• 
Event stabilization: sCr level with ±10% 
variability over last 6 months or protein-
creatinine ratio stabilization at a new level 
with ±50% variability over last 6 months. 
*Urine osmolality: in the absence of diuretics or chronic kidney disease this can be a very sensitive 
metric for integrated kidney function that requires excellent tubular function. A high urinary 
osmolality in the setting of an increase in sCr will point toward a “pre-renal” cause rather than tubular 
toxicity. 
 
 
Page 209 of 212

Anthos Therapeutics 
 
Page 63 
AFib Protocol v01 
 
Protocol No. ANT-004 
 
12.3. 
Appendix 3 - Clinical notable laboratory values 
Clinical notable laboratory values: 
The definition, the specific alert criteria and the corresponding actions for hepatic and renal notable 
laboratory abnormalities are respectively provided in Appendix 1 and Appendix 2. 
The following laboratory values are considered clinically notable and should be forwarded to 
Covance at the same time that they are sent to Investigators: 
• A change from baseline in hemoglobin ≥ 2 g/dL 
• A decrease from baseline in platelets count ≥ 50% or < 100 x 109/L 
• A positive fecal occult blood test 
• Macroscopic hematuria 
Whenever a clinically notable laboratory value is identified, a detailed subject history and 
examination are indicated to identify, document and potentially eliminate a bleeding event: 
• Blood pressure assessment (after 5 min rest, with an appropriate cuff size);  
• Signs and symptoms such as shortness of breath, tiredness, abdominal pain, hematemesis, 
rectorrhagia, melena, gingival or nose bleeding, bruising and hematoma;  
• Concomitant events or procedures such as trauma, surgical procedures.  
When one of the above occurs the action plan is as follows: 
• Confirm the value, assess and document the clinically notable laboratory value in the CRF 
or via electronic data load;  
• Investigate the underlying causes such as clinical or subclinical bleeding event and the 
contributing factors such as intake of prohibited medications;  
• Monitor subject regularly (frequency at Investigator’s discretion) until resolution or 
stabilization. Hospital admission, additional laboratory tests, endoscopy, volume 
replacement, transfusion, etc. should be performed at the Investigator’s discretion and 
according to the medical needs (see Section 6.3 for reversal therapy). 
 
Page 210 of 212