ATLAS-A/B: A Phase 3 Study to Evaluate the Efficacy and Safety of Fitusiran in Patients With Hemophilia A or B, Without Inhibitory Antibodies to Factor VIII or IX
Phase: PHASE3
Conditions: Hemophilia A, Hemophilia B
Sponsor: Genzyme, a Sanofi Company

SAR439774 (formerly ALN-AT3SC) (fitusiran) 
Clinical Study Protocol ALN-AT3SC-004 
(Sanofi Genzyme EFC14769) 
27 Jun 2018 
Property of the Sanofi Group - strictly confidential 
1 
CLINICAL STUDY PROTOCOL 
ALN-AT3SC-004 (Sanofi Genzyme EFC14769) 
Protocol Title: 
ATLAS-A/B:  A Phase 3 Study to Evaluate the 
Efficacy and Safety of Fitusiran in Patients With 
Hemophilia A or B, Without Inhibitory Antibodies 
to Factor VIII or IX 
Investigational Drug: 
Fitusiran (SAR439774 [formerly Alnylam 
ALN-AT3SC]) 
EudraCT Number: 
2016-001464-11 
Protocol Date: 
Original protocol, 19 May 2017 
Amendment 1, 16 Nov 2017 
Amendment 2, 27 Jun 2018 
Sponsor: 
Genzyme Corporation, 
50 Binney Street, 
Cambridge, MA 02142, USA 
Sponsor Contact:  
 
Clinical Study Director 
Any and all information presented in this document shall be treated as confidential and shall remain the 
exclusive property of Sanofi (or any of its affiliated companies). The use of such confidential information 
must be restricted to the recipient for the agreed purpose and must not be disclosed, published, or 
otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the 
prior written consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any 
corporation, partnership, or other entity which at the date of communication or afterwards (i) controls 
directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, 
partnership or other entity 
(electronic 1.0)
NCT03417245

SAR439774 (formerly ALN-AT3SC) (fitusiran)  
Clinical Study Protocol ALN-AT3SC-004 
(Sanofi Genzyme EFC14769) 
 
27 Jun 2018 
 
Property of the Sanofi Group - strictly confidential 
 
2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
DOCUMENT HISTORY 
 
Document 
Country-specificity if 
applicable 
Date 
Amendment 02 
NA 
27 Jun 2018 
Amendment 01 
NA 
16 Nov 2017 
Original Protocol 
NA 
19 May 2017 
 
AMENDMENT 02 (27 Jun 2018) 
This amended protocol (amendment 02) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
Clinical development and commercialization of fitusiran were granted from Alnylam 
Pharmaceuticals, Inc. to Genzyme Corporation, a Sanofi Company that will be assuming 
responsibility of the current clinical program. Therefore, the Alnylam logo and reference to 
Alnylam within the confidentiality statement were deleted from the title page. Throughout all 
sections of the protocol including the page headers and appendices, Alnylam has been changed 
to “the Sponsor” or “Sanofi Genzyme” as appropriate. In addition to change in Sponsor name, 
address, and contact details were also updated. The Sanofi Genzyme study code (EFC14769) has 
been added. The Alnylam study drug code ALN-AT3SC has also been updated to the generic 
drug name fitusiran (SAR439774). Sections regarding ‘Criteria for Study Termination’, ‘Study 
Drug Accountability’, ‘Guidelines for Reporting Product Complaints/Medical Device Incidents 
(including malfunctions)’, ‘Study Monitoring’, ‘Ethics’, ‘Data Handling and Record Keeping’, 
‘Publication Policy’ and ‘Dissemination of Clinical Study Data’ have been created or updated to 
reflect the Sanofi Genzyme environment. 
 
 
(electronic 
 
 
 
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SAR439774 (formerly ALN-AT3SC) (fitusiran)  
Clinical Study Protocol ALN-AT3SC-004 
(Sanofi Genzyme EFC14769) 
 
27 Jun 2018 
 
Property of the Sanofi Group - strictly confidential 
 
3 
Protocol amendment summary of changes table 
Section 
Description of Change 
Brief Rationale 
Throughout 
Sponsor changed from “Alnylam 
Pharmaceuticals, Inc.” to “Genzyme 
Corporation” 
Change of protocol Sponsor 
Throughout 
Name of product “ALN-AT3SC” changed 
to “SAR439774 Fitusiran” 
Change of protocol Sponsor; name of product 
updated 
Title page 
Name of Sponsor contact changed from 
“
” to “
” 
Change of protocol Sponsor; contact details 
Title page 
Disclaimer note text changed 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Protocol synopsis, 
document header, title 
page, and Section 1.3 (only 
at first occurrence) 
“Sanofi Genzyme EFC14769” added to 
the Study number “ALN-AT3SC-004” 
Change of protocol Sponsor; Sanofi Genzyme study 
ID required for administrative purposes on first use 
Protocol synopsis and 
Section 3.2 and throughout 
relevant text 
“Change in Haem-A-QOL score in the 
treatment period” changed to “Change in 
Haem-A-QOL physical health score and 
total score in the treatment period” 
Change in statistical plan; text aligned with Sanofi 
Genzyme environment 
Table 1 
Footnote “W” changed from: “Non-serious 
AEs will be monitored and recorded from 
date of Day 1 visit through Follow-Up. 
SAEs will be monitored and recorded 
from date of signed informed consent 
through Follow-Up.  Signs and symptoms 
of thrombosis will be evaluated at every 
visit (see Section 6.5)” to “AEs will be 
monitored and recorded from date of 
signed informed consent through Follow-
Up.  Signs and symptoms of thrombosis 
will be evaluated at every visit (see 
Section 6.5).” 
For consistency throughout the protocol 
Protocol synopsis and 
Section 4.2 
Duration of treatment language updated 
For clarity 
Section 6.2.6 
“Accountability” section updated with 
reporting procedure to follow with regards 
to any quality issue noticed with the 
receipt or use of an IMP (deficiency in 
condition, appearance, pertaining 
documentation, labeling, expiration date, 
defect in quality of IMP reporting, recall 
procedure, restriction of use and dispose 
of IMP etc.) 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Throughout 
“Adverse events of clinical interest” 
changed to “Adverse events of special 
interest” 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Throughout 
“Study drug” changed to “Investigational 
medicinal product” 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
(electronic 
 
 
 
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SAR439774 (formerly ALN-AT3SC) (fitusiran)  
Clinical Study Protocol ALN-AT3SC-004 
(Sanofi Genzyme EFC14769) 
 
27 Jun 2018 
 
Property of the Sanofi Group - strictly confidential 
 
4 
Section 
Description of Change 
Brief Rationale 
Section 7.3.1 
Text added as “Antithrombin protein may 
be measured in a subset of plasma 
samples for correlation”. 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment, and scientific rationale for 
the change 
Section 7.5.5 (Table 5) 
Hepatitis B surface antibody (anti-HBs) 
deleted 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment, and scientific rationale for 
the change 
Section 7.5.6.1 
Systemic injection associated reactions 
(IARs) added to the criteria of adverse 
events of special interest 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment, and to provide scientific 
rationale for inclusion of IARs to AESI 
Section 7.5.6.2 
“Recording adverse events” section 
updated 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Section 7.5.6.3 
Heading updated from “Serious Adverse 
Event Reporting Require Immediate 
Reporting to Sponsor/Designee” to 
“Serious Adverse Events and Adverse 
Events of Special Interest Require 
Immediate Reporting to 
Sponsor/Designee” 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Section 7.5.6.7 
Overdose reporting section updated 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Section 7.5.6.8 
New Section 7.5.6.8 “Guidelines for 
Reporting Product Complaints/Medical 
Device Incidents (Including Malfunctions)” 
added with text “Any defect in the IMP 
must be reported as soon as possible by 
the Investigator to the monitoring team 
that will complete a product complaint 
form within required timelines. 
Appropriate information (eg, samples, 
labels, or documents like pictures or 
photocopies) related to product 
identification and to the potential 
deficiencies may need to be gathered. 
The Investigator will assess whether or 
not the quality issue has to be reported 
together with an AE or SAE.” 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Section 8.2.5.1 
Text related to “Sensitivity Analysis” is 
added 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Section 9.1 
Ethical and Regulatory Considerations 
language updated to provide additional 
details 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Section 9.1.1 
Informed Consent Process language 
updated to provide additional process 
details and clarity 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Section 9.1.2 
Ethical Review language updated for 
clarity 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Section 9.1.3 
Study Documentation, Confidentiality, and 
Change of protocol Sponsor; text aligned with Sanofi 
(electronic 
 
 
 
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SAR439774 (formerly ALN-AT3SC) (fitusiran)  
Clinical Study Protocol ALN-AT3SC-004 
(Sanofi Genzyme EFC14769) 
 
27 Jun 2018 
 
Property of the Sanofi Group - strictly confidential 
 
5 
Section 
Description of Change 
Brief Rationale 
Records Retention language updated 
Genzyme environment 
Section 9.1.5 
Discontinuation of the Clinical Study 
language updated 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Section 9.2.1 
Data Handling language updated to 
provide additional details and clarify 
responsibilities 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Section 9.2.2 
Study Monitoring language updated to 
provide more detail regarding source data 
verification and record retention 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Section 9.3 
Publication Policy language updated to 
provide additional process details and 
some text moved into Section 9.4 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Section 9.4 
New Section 9.4 “Dissemination of 
Clinical Study Data” added with text 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Appendix 11 
Appendix 11.5 - appendix for 
Country-Specific Requirements and 
Appendix 11.6 - appendix for protocol 
amendment history added 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Throughout 
Minor editorial, typo error corrections and 
document formatting revisions 
Minor, therefore have not been summarized 
 
 
 
NAMES AND ADRESSES OF:  
MONITORING TEAM’S REPRESENTATIVE 
Name: 
Address: 
Tel: 
Fax: 
E-mail 
 
SPONSOR  
Name: 
Address: 
Genzyme Corporation 
50 Binney Street 
Cambridge, MA 02142, USA 
 
 
(electronic 
 
 
 
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SAR439774 (formerly ALN-AT3SC) (fitusiran)  
Clinical Study Protocol ALN-AT3SC-004 
(Sanofi Genzyme EFC14769) 
 
27 Jun 2018 
 
Property of the Sanofi Group - strictly confidential 
 
6 
PROTOCOL SYNOPSIS 
Protocol Title 
ATLAS-A/B:  A Phase 3 Study to Evaluate the Efficacy and Safety of Fitusiran in Patients With 
Hemophilia A or B, Without Inhibitory Antibodies to Factor VIII or IX 
Product Name 
Fitusiran (INN); SAR439774 (formerly Alnylam ALN-AT3SC)  
Indication 
Routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and adolescent 
(≥12 years old) hemophilia A or B patients 
Phase 
3 
Study Centers 
The study will be conducted at approximately 100 clinical study centers worldwide. 
Objectives 
Primary 
 
To evaluate the efficacy of fitusiran compared to on-demand treatment with factor 
concentrates, as determined by the frequency of bleeding episodes 
Secondary 
 
To evaluate the efficacy of fitusiran compared to on-demand treatment with factor 
concentrates, as determined by: 
 
The frequency of spontaneous bleeding episodes 
 
The frequency of joint bleeding episodes 
 
Health-related quality of life (HRQOL) in patients ≥17 years of age 
 
To determine the frequency of bleeding episodes during the onset period 
 
To determine the safety and tolerability of fitusiran 
Exploratory 
 
To evaluate the effects of fitusiran as compared to on-demand treatment with factor 
concentrates on the following patient-reported outcomes: 
 
Patient satisfaction with treatment 
 
Patient activity 
 
HRQOL in adolescents (≥12 to <17 years of age) 
 
To characterize the pharmacodynamic (PD) effect, pharmacokinetics (PK), and 
immunogenicity of fitusiran 
 
To evaluate the effects of fitusiran as compared to on-demand treatment with factor 
(electronic 
 
 
 
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SAR439774 (formerly ALN-AT3SC) (fitusiran)  
Clinical Study Protocol ALN-AT3SC-004 
(Sanofi Genzyme EFC14769) 
 
27 Jun 2018 
 
Property of the Sanofi Group - strictly confidential 
 
7 
concentrates on the total weight-adjusted consumption of factor concentrates 
 
To evaluate the effects of fitusiran as compared to on-demand treatment with factor 
concentrates on joint status 
 
To evaluate the effects of fitusiran as compared to on-demand treatment with factor 
concentrates on patient resource use  
Endpoints 
Primary 
 
Annualized Bleeding Rate (ABR) in the efficacy period 
Secondary 
 
ABR in the treatment period 
 
Annualized spontaneous bleeding rate in the efficacy period  
 
Annualized joint bleeding rate in the efficacy period 
 
Change in Hemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) physical 
health score and total score in the treatment period 
 
ABR in the onset period 
Exploratory 
 
Change in the following in the treatment period: 
 
Treatment Satisfaction Questionnaire for Medication (TSQM) domain scores 
 
Hemophilia Activities List (HAL) score 
 
Pediatric HAL (pedHAL) score 
 
EuroQol-5 dimension (EQ-5D) score 
 
Hemophilia Quality of Life Questionnaire for children and adolescents (Haemo-QOL) 
score 
 
Hemophilia Joint Health Score (HJHS) 
 
Number of target joint bleeding episodes 
 
Incidence and titer of antidrug antibodies to fitusiran in the fitusiran treatment arm 
 
Antithrombin (AT) activity level over time  
 
Thrombin generation over time 
 
Fitusiran plasma levels 
 
Annualized weight-adjusted use of factor concentrates 
 
Change in patient resource use (eg, work/school attendance, visits to doctor/hospital) 
 
 
(electronic 
 
 
 
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SAR439774 (formerly ALN-AT3SC) (fitusiran)  
Clinical Study Protocol ALN-AT3SC-004 
(Sanofi Genzyme EFC14769) 
 
27 Jun 2018 
 
Property of the Sanofi Group - strictly confidential 
 
8 
Safety 
 
Incidence, severity, seriousness, and relatedness of adverse events (AEs) 
Study Design 
The ATLAS-A/B trial (ALN-AT3SC-004 [Sanofi Genzyme EFC14769]) is a multicenter, 
multinational, randomized, open-label Phase 3 study designed to evaluate the efficacy and safety of 
fitusiran in male patients aged ≥12 years, with hemophilia A or B without inhibitory antibodies to 
factor VIII (FVIII) or factor IX (FIX), who are not receiving prophylactic therapy. 
Eligible patients will be randomized in a 2:1 ratio to: 
 
Fitusiran treatment arm:  Fitusiran 80 mg administered subcutaneously (SC) as 
prophylaxis once monthly, with use of on-demand factor concentrates for treatment of 
breakthrough bleeding episodes 
 
On-demand arm:  On-demand factor concentrates for treatment of breakthrough bleeding 
episodes 
On-demand use of factor concentrates is defined as the use of these agents, as needed, for episodic 
bleeding, and not on a regular regimen intended to prevent spontaneous bleeding.  Throughout the 
study, patients in the fitusiran treatment arm may receive on-demand treatment for breakthrough 
bleeding episodes with factor concentrates, as appropriate. 
Bleeding events and doses of factor concentrates administered during the conduct of the study will be 
recorded in an electronic Diary (eDiary).  Safety, quality of life, pharmacodynamic, and 
pharmacokinetic data will also be collected. 
All patients will be treated for a total of 9 months; patients randomized to the fitusiran treatment arm 
will receive a total of 9 SC injections of fitusiran.  Because the full PD effect of fitusiran is not 
achieved until approximately 28 days after receiving the first dose, efficacy will be assessed during the 
remaining 8 months on study (Day 29 to Month 9).  
An independent data monitoring committee (DMC) will oversee the safety and overall conduct of this 
study.  The DMC will perform periodic reviews of data during the course of the clinical trial, and on an 
ad hoc basis for review of emergent safety data, as defined in the DMC Charter for this clinical trial. 
Patients from both the fitusiran and on-demand treatment arms who complete the study may be eligible 
for participation in an open-label extension study. Following final fitusiran dose, for patients in the 
fitusiran treatment arm patients who do not enroll in the extension study, AT activity level will be 
monitored at monthly intervals until returning to an activity level of approximately 60% (per the central 
laboratory) or per Investigator discretion in consultation with the study Medical Monitor. 
Number of Planned Patients 
Approximately 120 patients will be randomized, including approximately 26 patients with 
hemophilia B and approximately 10 adolescents (≥12 to <18 years of age).  
(electronic 
 
 
 
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SAR439774 (formerly ALN-AT3SC) (fitusiran)  
Clinical Study Protocol ALN-AT3SC-004 
(Sanofi Genzyme EFC14769) 
 
27 Jun 2018 
 
Property of the Sanofi Group - strictly confidential 
 
9 
Diagnosis and Main Eligibility Criteria 
This study will include males with severe hemophilia A or B without inhibitors (defined as Nijmegen 
modified Bethesda assay inhibitor titer of <0.6 BU/mL at Screening), aged ≥12 years, who have had a 
minimum of 6 bleeding episodes requiring on-demand treatment with factor concentrates within the 
last 6 months prior to Screening.  Diagnosis of severe hemophilia A or B will be based on a central 
laboratory measurement or documented medical record evidence of FVIII level <1% or FIX level ≤2%. 
Investigational Product, Dose and Mode of Administration 
Fitusiran is an SC administered N-Acetylgalactosamine (GalNAc)-conjugated siRNA targeting liver-
expressed messenger RNA (mRNA) for AT. 
Patients randomized to the fitusiran treatment arm will receive open-label fitusiran 80 mg as an SC 
injection once monthly for a total of 9 months; dosing will begin on Day 1 of the treatment period. 
Reference Therapy, Dose and Mode of Administration 
Patients in the on-demand arm will receive on-demand factor concentrate therapy per Investigator 
discretion to treat bleeding episodes from Day 1 through end of study.  The protocol will recommend 
guidance for patients in the fitusiran treatment arm to use reduced initial doses of factor concentrates 
for breakthrough bleeding episodes during the fitusiran efficacy period. 
Duration of Treatment 
The duration of treatment with fitusiran is 9 months. The estimated total time on study, inclusive of 
screening, for each patient is up to 11 months for all patients who enroll in the extension study and 
patients in the on-demand arm who do not enroll in the extension study.  The estimated total time on 
study may be up to 17 months in fitusiran treatment arm patients who do not enroll in the extension 
study due to the requirement for an additional 6 months of follow-up for monitoring of AT levels. 
Statistical Methods 
Sample Size Calculation 
Assuming a mean ABR of 18 with standard deviation (SD) = 14 in the on-demand arm (patients 
randomized to receive only factor concentrates) and a mean ABR of no more than 4 with SD = 6 in the 
fitusiran treatment arm (patients randomized to receive fitusiran) in either the efficacy period or 
treatment period, with a sample size of 32 evaluable patients in the on-demand arm and approximately 
64 evaluable patients in the fitusiran treatment arm, it is projected that the study will have greater than 
90% power for detecting treatment difference in mean ABRs.  This power estimation was based on a 
negative binomial regression model with a 2-sided type I error rate of 0.05.  
The planned sample size is 120 randomized patients assuming a 20% drop-out rate. 
Analyses 
The primary analysis will be performed on the intent-to-treat (ITT) analysis set which includes all 
randomized patients.  The primary endpoint will be based on the bleeding episodes occurring in the 
efficacy period (Day 29 to Day 246) including the data collected after discontinuation of 
investigational medicinal product (IMP). To avoid confounding the treatment effect, bleeding data 
during and after major surgery, antithrombin (AT) administration, major trauma, or after initiation of 
prophylaxis treatment with factor concentrates will be excluded from the primary analysis. 
The number of bleeding episodes will be analyzed using a negative binomial model with fixed effects 
of treatment arm, the number of bleeding episodes in the 6 months prior to study entry (≤10 vs >10), 
and hemophilia type (hemophilia A or B).  The logarithm number of days that each patient spends in 
the efficacy period matching the bleeding episode data being analyzed will be included as an offset 
(electronic 
 
 
 
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SAR439774 (formerly ALN-AT3SC) (fitusiran)  
Clinical Study Protocol ALN-AT3SC-004 
(Sanofi Genzyme EFC14769) 
 
27 Jun 2018 
 
Property of the Sanofi Group - strictly confidential 
 
10 
variable to account for unequal follow-up time due to early withdrawal or surgery. The ratio of the 
bleeding rate on the fitusiran treatment arm relative to the bleeding rate on the on-demand arm and its 
95% confidence interval will be presented.  Sensitivity analyses will be performed to evaluate the 
impact of missing data under different missing data mechanisms and details will be specified in the 
statistical analysis plan. 
The bleeding episodes in the treatment period (Day 1 to Day 246), spontaneous bleeding episodes in 
the efficacy period, joint bleeding episodes in efficacy period, and bleeding episodes in the onset period 
will be analyzed and compared using the same model as used in the primary analysis. The change from 
baseline in physical health score and total score of Haem-A-QOL will be analyzed using an analysis of 
covariance (ANCOVA) model with fixed effects of treatment arm, baseline Haem-A-QOL physical 
health score and total score, the number of bleeding episodes in the 6 months prior to study entry (≤10 
vs >10), and hemophilia type (hemophilia A or B) as covariates. 
Familywise error rate will be strongly controlled for the primary endpoint and selected secondary 
endpoints using a fixed sequence testing procedure. 
Safety results will be summarized descriptively. 
 
(electronic 
 
 
 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-004 
(Sanofi Genzyme EFC14769) 
 
 
 
27 Jun 2018 
Property of the Sanofi Group - strictly confidential 
 
11 
Table 1: 
Schedule of Assessments 
 
 
 
 
 
Study Visit (Month) 
 
 
 
 
Study Day (±Visit Window) 
 Screening 
Treatment Period 
AT 
F/Ub,c 
Onset 
Period 
Efficacy Period 
Baseline 
  
Month 1 
 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 
Month 7 
EOT 
EOS/
ETa,b 
 
Month 8 
Month 9 
-60 to -1 
Day 1 
15 ±3 
29 ±7 
43 ±3  
57 ±7 
85 ±7 
113 ±7 
141 ±7 
169 ±7 
197±7 
225±7 
253 ±7 
281 ±7 
Informed Consent/Assent 
X 
 
 
Medical Historyd 
X 
 
Demographics 
X 
 
Inclusion/Exclusion Criteria 
X 
 
Randomizatione 
X 
 
eDiary Trainingf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationg 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Weight and Heighth 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGi 
X 
X 
 
X 
X 
FibroScan OR FibroTest/APRIj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
TG Levelk,l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Nijmegen-Modified Bethesda 
Assay (Inhibitor Status)  
X 
 
 
 
 
 
 
 
 
 
 
X 
Xm 
 
AT Activity Levelk,n,l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII / FIX Levelsk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(electronic 
 
 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-004 
(Sanofi Genzyme EFC14769) 
 
 
 
27 Jun 2018 
Property of the Sanofi Group - strictly confidential 
 
12 
Table 1: 
Schedule of Assessments 
 
 
 
 
 
Study Visit (Month) 
 
 
 
 
Study Day (±Visit Window) 
 Screening 
Treatment Period 
AT 
F/Ub,c 
Onset 
Period 
Efficacy Period 
Baseline 
  
Month 1 
 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 
Month 7 
EOT 
EOS/
ETa,b 
 
Month 8 
Month 9 
-60 to -1 
Day 1 
15 ±3 
29 ±7 
43 ±3  
57 ±7 
85 ±7 
113 ±7 
141 ±7 
169 ±7 
197±7 
225±7 
253 ±7 
281 ±7 
Thrombophilia Screening  
X 
 
Serum Chemistryo 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Liver Function Testsp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-Drug Antibodiesk,n,q 
X 
X 
X 
 
X 
X 
Xm 
Hematologyo 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hepatic Testsp 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exploratory Biomarkersk 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
Exploratory Circulating RNA 
(Optional)k 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
Exploratory DNA Sample 
(Optional)k 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PKk,r 
X 
X 
 
X 
X 
X 
 
Urinalysis  
X 
X 
 
X 
Urine Collection for 
Biomarkersk 
 
X 
 
 
 
 
X 
 
 
 
 
 
X 
 
HJHSs 
 
X 
 
 
 
 
 
 
 
 
 
 
Xs 
 
Patient Resource Uses 
X 
 
 
 
 
 
 
 
 
 
Xs 
EQ-5Ds 
 
X 
 
 
Xs 
(electronic 
 
 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-004 
(Sanofi Genzyme EFC14769) 
 
 
 
27 Jun 2018 
Property of the Sanofi Group - strictly confidential 
 
13 
Table 1: 
Schedule of Assessments 
 
 
 
 
 
Study Visit (Month) 
 
 
 
 
Study Day (±Visit Window) 
 Screening 
Treatment Period 
AT 
F/Ub,c 
Onset 
Period 
Efficacy Period 
Baseline 
  
Month 1 
 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6 
Month 7 
EOT 
EOS/
ETa,b 
 
Month 8 
Month 9 
-60 to -1 
Day 1 
15 ±3 
29 ±7 
43 ±3  
57 ±7 
85 ±7 
113 ±7 
141 ±7 
169 ±7 
197±7 
225±7 
253 ±7 
281 ±7 
Haem-A-QOL / Haemo-QOLs 
 
X 
 
 
Xs 
HAL / pedHALs 
 
X 
 
Xs 
TSQM-9s 
 
X 
 
Xs 
Fitusiran Administration 
(Fitusiran arm only) 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Patient Education Module 
Training 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Bleed Management Reviewt 
 
Review with patient at each visit and contact every 2 weeks between visits 
Bleeding Episodes/eDiaryu 
 
Review with patient at each visit and contact every 2 weeks between visits 
Perioperative Assessmentv 
 
Continuous 
Adverse Eventsw 
Continuous 
Concomitant Medicationsx 
Continuous 
Abbreviations:  AEs = adverse events; AT = antithrombin; ECG = electrocardiogram; eDiary = electronic diary; EOS = end of study; EOT = end of treatment; ET = early-
termination; FVIII = factor VIII; FIX = factor IX; F/U = follow-up; Haem-A-QOL = Hemophilia Quality of Life Questionnaire for Adults; Haemo-QOL = Hemophilia Quality of 
Life Questionnaire for children and adolescents; HAL = Hemophilia Activities List; HJHS = Hemophilia Joint Health Score; IMP = Investigational medicinal product; Min = 
minute; pedHAL = pediatric HAL; PK = pharmacokinetics; TG = thrombin generation; TSQM-9 = Treatment Satisfaction Questionnaire for Medication 
 
Note: 
 
See Section 7 for study assessment instructions. 
 
Any Screening assessments performed within 7 days prior to baseline do not need to be repeated at the Baseline visit. 
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 
Rescreening of patients is permitted with consultation of the study Medical Monitor. 
 
Laboratory parameters are described in Section 7.5.5 and listed in Table 5. 
 
As clinical research parameters TG, D-dimer, and all other non-safety laboratory parameter results will not be communicated to sites.  AT and factor results will be 
provided at screening for confirmation of eligibility.  AT results will be provided at AT F/U visits for monitoring. 
 
When scheduled at the same time points, vital signs and 12-lead ECGs will be performed before the physical examinations and blood/urine sample collections. 
 
Unless otherwise specified, assessments on dosing days are predose. 
 
a Not required at Early Termination Visit for patients who complete assessment at EOT Visit and subsequently Early Terminate. 
b Patients in the fitusiran treatment arm who discontinue IMP dosing for any reason and agree to complete the remaining assessments through the EOS/ET and AT FU visits may 
receive treatment consistent with local standard practice for their disease per Investigator judgment once AT activity levels return to ~60% (per the central laboratory) or per 
Investigator discretion in conjunction with consultation with the study Medical Monitor. For patients who withdraw from the study early and do not consent to complete 
remaining assessments through the EOS/ET and AT FU visits, every effort should be made to conduct the assessments performed at the EOS/ET visit.  
c Patients in the fitusiran treatment arm not enrolling in the extension study will complete AT F/U visits at monthly intervals following final fitusiran dose until AT activity level 
returns to ~60% (per the central laboratory) or per Investigator discretion in consultation with the study Medical Monitor. 
d The complete medical history/disease history (ie, including bleeding episode and treatment history over the prior 6 months) to be recorded at Screening. 
e Randomization may occur within 3 days prior to Day 1. 
f eDiary training will be completed at the Clinic at Screening (see Section 7.2.1).  
g A full physical exam will be performed at Screening only; a directed physical exam will be performed at all other visits (see Section 7.5.3).  
h Height will be recorded at Screening only. Weight will be recorded at all other visits (see Section 7.5.2).   
I 12-lead ECGs will be performed in triplicate. For patients on Fitusiran: On Day 1 and Month 7, 12-lead ECG will be performed predose and 4 hours (±30 min) postdose 
(see Section 7.5.4). The Month 9 12-lead ECGs will be performed only in those patients who are performing the ET visit and may be performed in singlicate. For patients in 
the on-demand arm: On Day 1 and Month 7, two ECG measurements should be performed approximately 4 hours (±30 min) apart.   
j Hepatitis C virus antibody positive patients only. FibroScan where available, otherwise FibroTest and APRI. 
k Sample may be used for study of biomarkers related to hemophilia and associated conditions, investigations of emerging safety issues, or the development of fitusiran. After 
specified analyses are run, residual samples may be stored for up to 15 years from last patient last visit, or as per local regulations, and used for further study of biomarkers 
related to hemophilia and associated conditions, investigation of emerging safety issues, or the development of fitusiran.  Samples drawn from central lines may be excluded 
from TG analysis.  
l In addition to the specified time points, TG levels and AT levels will also be performed in East Asian patients at East Asian sites (defined as patients from sites in China, Japan, 
South Korea, and Taiwan) on Day 2 and Day 8. 
m Only for patients who do not enroll in the open-label extension study. 
n For patients on the fitusiran arm, samples will be collected within 4 hours prior to dosing on dosing days.  
o Serum chemistry and hematology laboratory parameters will be collected as listed in Table 5.  
p Liver function tests (LFTs) and hepatic tests are as listed in Table 5. LFTs may be obtained up to 7 days before the clinic visit on which fitusiran dosing is scheduled.  LFTs 
performed within 7 days of Day 1 will only be used to inform dosing on Day 1 and do not need to be used to confirm eligibility. LFTs can be analyzed locally, but if a local 
assessment is drawn, a serum chemistry sample must also be drawn for analysis at the central laboratory. Under conditions of elevated ALT and/or AST see Table 6 and 
Section 6.2.3.1.  LFT results will be obtained prior to receiving monthly fitusiran dosing.   
q All patients will be tested for antibodies to fitusiran at the Screening visit. After randomization, testing for antibodies to fitusiran will be performed in the fitusiran treatment arm 
only.  
r Blood samples for PK analysis will be collected at the timepoints listed in Table 7 in all fitusiran arm patients.  In East Asian patients in the fitusiran arm at East Asian sites, 
blood samples for PK analysis will be collected at the time points listed in Table 8 (which includes those time points listed in Table 7), and pooled urine for PK analysis will 
be collected at the time points listed in Table 9.   
s Must be completed at the clinic. Will be collected at EOS visit, not be collected at ET visit. 
t Will include review of entries, (symptoms of bleed events, bleed causality, bleed severity, doses administered), whether appropriate site contact occurred regarding treatment of 
bleeds, and review of patient bleed management plan and recommendations and requirements for site contact regarding dosing. 
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u It is preferred that factor concentrate administration and bleeding events are entered in the eDiary immediately or within 24 hours. Additional patient follow-up may be required 
as described in Section 7.2.1. Patients in the fitusiran treatment arm who present in the clinic with symptoms characteristic of a potential bleeding episode should have 
assessments completed per Table 2.  
v Perioperative assessment of safety and hemostatic efficacy only in patients undergoing operative procedures while on study (see Table 10). 
w AEs will be monitored and recorded from date of signed informed consent through Follow-Up. Signs and symptoms of thrombosis will be evaluated at every visit (see 
Section 6.5). 
x In addition to recording concomitant medications, documented history of prior medications will be collected during Screening. 
 
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Table 2: 
Bleeding Episode Assessments – Unscheduled Visit 
 
Predose 
Postdose 
10 min (±5 min)d 
Postdose 
60 min (±5 min)d 
Directed Physical 
Examinationa 
X 
 
 
Vital Signs 
X 
 
 
AT 
X 
 
 
FVIII/IX Levels 
X 
X 
X 
TG 
X 
X 
X 
Coagulation 
X 
X 
X 
Hematology 
X 
X 
X 
Exploratory 
Coagulationb 
X 
 
X 
Optional Imagingc 
X 
 
 
Abbreviations:  AT=antithrombin; BPAs=bypassing agents; FVIII=factor VIII; FIX=factor IX; TG=thrombin generation 
a See Section 7.5.3 for assessments to be performed during a directed physical examination. 
b After specified analyses are run, residual samples may be stored for up to 15 years from last patient last visit, or as per local 
regulations, and used for further study of biomarkers related to hemophilia and associated conditions, investigation of emerging 
safety issues, or the development of fitusiran. 
c Investigator to consider confirmation of bleed via ultrasound or other imaging modality at clinical study centers where 
appropriate equipment and staff with related expertise is available. 
d If the patient presents following administration of factor or BPAs at home and within 48 hours of the dose, and no further 
treatment is given at the center, AT and the postdose assessments should be obtained in a single draw at any time during the 
visit. 
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TABLE OF CONTENTS 
DOCUMENT HISTORY.................................................................................................................2 
OVERALL RATIONALE FOR THE AMENDMENT ..................................................................2 
PROTOCOL SYNOPSIS ................................................................................................................6 
TABLE OF CONTENTS ...............................................................................................................17 
LIST OF TABLES .........................................................................................................................22 
LIST OF FIGURES .......................................................................................................................22 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................23 
1. 
INTRODUCTION ......................................................................................................26 
1.1. 
Disease Overview .......................................................................................................26 
1.2. 
Fitusiran (SAR439774) ...............................................................................................27 
1.2.1. 
Summary of Nonclinical Data With Fitusiran ............................................................27 
1.2.2. 
Summary of Clinical Data With Fitusiran ..................................................................28 
1.2.2.1. 
Summary of Efficacy ..................................................................................................29 
1.2.2.2. 
Summary of Safety .....................................................................................................30 
1.2.2.3. 
Summary of Pharmacokinetic and Pharmacodynamic Effects in 
ALN-AT3SC-001 and ALN-AT3SC-002 ..................................................................31 
1.3. 
Study Design Rationale ..............................................................................................31 
1.4. 
Dose Rationale ............................................................................................................32 
1.5. 
Benefit-Risk Assessment ............................................................................................33 
2. 
OBJECTIVES .............................................................................................................33 
2.1. 
Primary Objective .......................................................................................................33 
2.2. 
Secondary Objectives .................................................................................................34 
2.3. 
Exploratory Objectives ...............................................................................................34 
3. 
ENDPOINTS ..............................................................................................................34 
3.1. 
Primary Endpoint ........................................................................................................34 
3.2. 
Secondary Endpoints ..................................................................................................34 
3.3. 
Exploratory Endpoints ................................................................................................35 
3.4. 
Safety Endpoint ..........................................................................................................35 
4. 
INVESTIGATIONAL PLAN .....................................................................................35 
4.1. 
Summary of Study Design ..........................................................................................35 
4.2. 
Duration of Treatment ................................................................................................37 
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4.3. 
Number of Patients .....................................................................................................37 
4.4. 
Method of Assigning Patients to Treatment Groups ..................................................37 
4.5. 
Blinding ......................................................................................................................38 
4.6. 
Study Steering Committee ..........................................................................................38 
4.7. 
Data Monitoring Committee .......................................................................................38 
5. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................38 
5.1. 
Inclusion Criteria ........................................................................................................38 
5.2. 
Exclusion Criteria .......................................................................................................39 
5.3. 
Removal from Therapy or Assessment.......................................................................40 
5.3.1. 
Discontinuation of Investigational Medicinal Product ...............................................41 
5.3.2. 
Withdrawal From Study .............................................................................................41 
6. 
TREATMENTS ..........................................................................................................42 
6.1. 
Treatments Administered ............................................................................................42 
6.2. 
Investigational Medicinal Product ..............................................................................42 
6.2.1. 
Description ..................................................................................................................42 
6.2.2. 
Dose and Administration ............................................................................................42 
6.2.3. 
Dose Modifications .....................................................................................................42 
6.2.3.1. 
LFT Criteria for Withholding, Monitoring and Stopping Fitusiran Dosing ...............42 
6.2.4. 
Preparation, Handling, and Storage ............................................................................45 
6.2.5. 
Packaging and Labeling ..............................................................................................45 
6.2.6. 
Accountability .............................................................................................................45 
6.3. 
Concomitant Medications ...........................................................................................45 
6.3.1. 
Management of Bleeding Episodes ............................................................................46 
6.3.1.1. 
Bleeding Episode Management Recommendations for Patients in the On-
Demand Treatment Arm (Patients Not Receiving Fitusiran) .....................................46 
6.3.1.2. 
Bleeding Episode Management Recommendations for Patients in the 
Fitusiran Treatment Arm ............................................................................................46 
6.3.1.3. 
Bleeding Episode Management Following Discontinuation of Fitusiran...................50 
6.3.2. 
Other Concomitant Medications .................................................................................50 
6.4. 
Assessment of Coagulation Parameters at the Time of a Bleed .................................50 
6.5. 
Monitoring and Management of Thrombotic Events .................................................50 
6.6. 
Elective and/or Emergency Surgery ...........................................................................51 
6.7. 
Management of Sepsis ................................................................................................52 
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6.8. 
Contraceptive Requirements .......................................................................................52 
6.9. 
Treatment Compliance ................................................................................................52 
6.10. 
Alcohol Restrictions ...................................................................................................52 
7. 
STUDY ASSESSMENTS ..........................................................................................52 
7.1. 
Screening/Baseline Assessments ................................................................................52 
7.1.1. 
Patient Education Module ...........................................................................................53 
7.1.2. 
Inhibitor Status ............................................................................................................53 
7.1.3. 
FibroScan or FibroTest/APRI .....................................................................................53 
7.2. 
Efficacy Assessments .................................................................................................53 
7.2.1. 
Electronic Diary ..........................................................................................................54 
7.3. 
Pharmacodynamic Assessments .................................................................................55 
7.3.1. 
Antithrombin Activity ................................................................................................55 
7.3.2. 
Thrombin Generation ..................................................................................................55 
7.3.3. 
Exploratory Analyses ..................................................................................................55 
7.4. 
Pharmacokinetic Assessments ....................................................................................55 
7.5. 
Safety Assessments .....................................................................................................56 
7.5.1. 
Vital Signs ..................................................................................................................56 
7.5.2. 
Weight and Height ......................................................................................................56 
7.5.3. 
Physical Examination .................................................................................................56 
7.5.4. 
Electrocardiogram .......................................................................................................57 
7.5.5. 
Clinical Laboratory Assessments ...............................................................................57 
7.5.5.1. 
Additional Laboratory Assessments ...........................................................................59 
7.5.5.2. 
Immunogenicity ..........................................................................................................60 
7.5.6. 
Adverse Events ...........................................................................................................60 
7.5.6.1. 
Definitions ..................................................................................................................60 
7.5.6.2. 
Eliciting and Recording Adverse Events ....................................................................63 
7.5.6.3. 
Serious Adverse Events and Adverse Events of Special Interest Require 
Immediate Reporting to Sponsor/Designee ................................................................64 
7.5.6.4. 
Sponsor Safety Reporting to Regulatory Authorities .................................................64 
7.5.6.5. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ........................................................................64 
7.5.6.6. 
Pregnancy Reporting ..................................................................................................64 
7.5.6.7. 
Overdose Reporting ....................................................................................................65 
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7.5.6.8. 
Guidelines for Reporting Product Complaints/Medical Device Incidents 
(Including Malfunctions) ............................................................................................65 
7.6. 
Other Assessments ......................................................................................................65 
7.6.1. 
Patient-reported Outcomes .........................................................................................65 
7.6.1.1. 
HRQOL Instruments: Haem-A-QOL and Haemo-QOL ............................................65 
7.6.1.2. 
TSQM-9 ......................................................................................................................66 
7.6.1.3. 
HAL ............................................................................................................................66 
7.6.1.4. 
EQ-5D-5L ...................................................................................................................66 
7.6.2. 
Weight-adjusted Consumption of Factor Concentrates ..............................................66 
7.6.3. 
HJHS ...........................................................................................................................66 
8. 
STATISTICS ..............................................................................................................66 
8.1. 
Determination of Sample Size ....................................................................................67 
8.2. 
Statistical Methodology ..............................................................................................67 
8.2.1. 
Populations to be Analyzed ........................................................................................67 
8.2.2. 
Examination of Subgroups .........................................................................................67 
8.2.3. 
Handling of Missing Data ...........................................................................................67 
8.2.4. 
Baseline Evaluations ...................................................................................................68 
8.2.5. 
Efficacy Analyses .......................................................................................................68 
8.2.5.1. 
Primary Endpoint ........................................................................................................68 
8.2.5.2. 
Secondary Endpoints ..................................................................................................69 
8.2.5.3. 
Exploratory Endpoints ................................................................................................69 
8.2.6. 
Pharmacodynamic Analysis........................................................................................69 
8.2.7. 
Pharmacokinetic Analysis ..........................................................................................69 
8.2.8. 
Safety Analyses ..........................................................................................................69 
8.2.9. 
Immunogenicity Analysis ...........................................................................................70 
8.2.10. 
Interim Analysis ..........................................................................................................70 
9. 
STUDY ADMINISTRATION ...................................................................................70 
9.1. 
Ethical and Regulatory Considerations ......................................................................70 
9.1.1. 
Informed Consent Process ..........................................................................................70 
9.1.2. 
Ethical Review ............................................................................................................71 
9.1.3. 
Study Documentation, Confidentiality, and Records Retention .................................71 
9.1.4. 
End of the Study .........................................................................................................71 
9.1.5. 
Discontinuation of the Clinical Study.........................................................................71 
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9.2. 
Data Quality Control and Quality Assurance .............................................................72 
9.2.1. 
Data Handling .............................................................................................................72 
9.2.2. 
Study Monitoring ........................................................................................................72 
9.2.3. 
Audits and Inspections ................................................................................................73 
9.3. 
Publication Policy .......................................................................................................73 
9.4. 
Dissemination of Clinical Study Data ........................................................................73 
10. 
LIST OF REFERENCES ............................................................................................74 
11. 
APPENDICES ............................................................................................................76 
11.1. 
Pharmacokinetic Assessment Time Points .................................................................76 
11.2. 
Perioperative Schedule of Assessments ......................................................................78 
11.2.1. 
Definitions of Minor and Major Surgery ....................................................................78 
11.2.2. 
Perioperative Assessments of Safety and Hemostatic Efficacy in Patients 
Undergoing Operative Procedures ..............................................................................78 
11.3. 
International Society on Thrombosis and Hemostasis Guideline for 
Assessment of Treatment Response ...........................................................................80 
11.4. 
Bleed Severity Definitions ..........................................................................................80 
11.5. 
Country-Specific Requirements ..................................................................................80 
11.6. 
Protocol Amendment History .....................................................................................81 
11.6.1. 
Amended Protocol 01 .................................................................................................81 
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LIST OF TABLES 
Table 1: 
Schedule of Assessments ............................................................................................11 
Table 2: 
Bleeding Episode Assessments – Unscheduled Visit .................................................16 
Table 3: 
Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative 
Cause Identified ..........................................................................................................44 
Table 4: 
Bleed Management Dosing Guidelines by Specific Product ......................................49 
Table 5: 
Clinical Laboratory Assessments ...............................................................................58 
Table 6: 
Hepatic Assessments in Patients who Experience LFT Elevations ............................60 
Table 7: 
Pharmacokinetic Time Points for All Fitusiran Arm Patients ....................................76 
Table 8: 
Pharmacokinetic (Fitusiran Arm), AT, and TG Time Points for East Asian 
Patients at East Asian Sites .........................................................................................77 
Table 9:   Urine Pharmacokinetic Time Points for East Asian Patients in the Fitusiran 
Arm from East Asian sites ..........................................................................................77 
Table 10: Perioperative Schedule of Assessments in Patients Undergoing Operative 
Procedures ...................................................................................................................79 
Table 11: Assessment of Treatment of Acute Joint/Muscle Bleeding Episodes ........................80 
Table 12 
Bleed Severity Definitions ..........................................................................................80 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................37 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Specialist Term 
Explanation 
ABR 
Annualized bleeding rate 
ADA 
Antidrug antibody 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
aPCC 
Activated prothrombin complex concentrates 
AST 
Aspartate aminotransferase 
AT 
Antithrombin 
AUC 
Area under the concentration-time curve 
BPA 
Bypassing agent 
BU 
Bethesda units 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CFR 
Code of Federal Regulation 
CI 
Confidence interval 
CL/F 
Apparent clearance 
Cmax 
Maximum plasma concentration 
CRF 
Case report form 
CRP 
C-reactive protein 
CT 
Computed tomography 
CVST 
Cerebral venous sinus thrombosis 
CYP P450 
Cytochrome P450 
DMC 
Data Monitoring Committee 
DTP 
Duties and taxes paid 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eDiary 
Electronic diary 
EE 
Efficacy-evaluable 
EQ-5D 
EuroQol-5 dimension 
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Abbreviation or Specialist Term 
Explanation 
ET 
Early termination 
FIX 
Factor IX 
FV 
Factor V 
FVII 
Factor VII 
FVIII 
Factor VIII 
FX 
Factor X 
GalNAc 
N-Acetylgalactosamine 
GCP 
Good Clinical Practice 
GGT 
Gamma glutamyl transferase 
GLP 
Good Laboratory Practice 
Haem-A-QOL 
Hemophilia Quality of Life Questionnaire for Adults 
Haemo-QOL 
Hemophilia Quality of Life Questionnaire for Children and 
Adolescents 
HAL 
Hemophilia Activities List 
HBc Ab 
Hepatitis B core antibody 
HBs Ag 
Hepatitis B surface antigen 
HIV 
Human immunodeficiency virus 
HRQOL 
Health-related quality of life 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IP 
Investigational product 
IRB 
Institutional Review Board 
IRS 
Interactive response system 
ISR 
Injection site reaction 
ISTH 
International Society on Thrombosis and Haemostasis 
ITI 
Immune tolerance induction 
ITT 
Intent-to-treat 
IV 
Intravenous 
LFT 
Liver function test 
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Abbreviation or Specialist Term 
Explanation 
MAD 
Multiple ascending dose 
MDRD 
Modification of Diet in Renal Disease 
MMRM 
Mixed effect repeated measures 
mRNA 
Messenger ribonucleic acid 
NHP 
Non-human primate 
NOAEL 
No observed adverse effect level 
PCC 
Prothrombin complex concentrate 
PD 
Pharmacodynamics  
pedHAL 
Pediatric HAL 
PK 
Pharmacokinetics 
PP 
Per-protocol 
PT 
Prothrombin time 
QOL 
Quality of life 
RNAi 
Ribonucleic acid interference 
rVIIa 
Recombinant factor VIIa 
SAD 
Single ascending dose 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SDay 
Surgery day 
siRNA 
Small interfering ribonucleic acid 
SSC 
Scientific Standardization Committee 
SUSAR 
Suspected unexpected serious adverse reactions 
t1/2β 
Elimination half-life 
tmax 
Time to maximum plasma concentration 
TG 
Thrombin generation 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
ULN 
Upper limit of normal 
V/F 
Apparent volume of distribution 
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1. 
INTRODUCTION 
1.1. 
Disease Overview 
Hemophilia A and hemophilia B are X-linked recessive inherited bleeding disorders, 
characterized by deficiency of coagulation factor VIII (FVIII) or factor IX (FIX), leading to a 
profound defect of thrombin generation with impaired hemostasis and increased risk of bleeding.  
Hemophilia A is found in approximately 1 in 5000 males whereas hemophilia B is five times less 
common and seen in approximately 1 in 25,000 males.[1]  The disease affects all ethnicities and 
the mutation responsible for hemophilia is typically inherited from a carrier parent, although 
spontaneous mutations are responsible for ~30% of all cases.[1]  
The disease phenotype presents similarly in hemophilia A and B.[2]  Hemophilia is classified as 
mild (factor levels 6% to 30%), moderate (factor levels 1% to 5%), or severe (factor levels <1%) 
based on clotting factor activity relative to normal (healthy, non-hemophiliac plasma levels of 
factor are 50% to 150%).  Patients with mild hemophilia typically experience bleeding after a 
serious injury or surgery; patients with moderate hemophilia experience bleeding episodes 
associated with injuries, and may have spontaneous bleeding episodes; severe hemophilia 
patients experience substantial bleeding with injury and may have frequent spontaneous bleeding 
episodes resulting in debilitating musculoskeletal damage that can markedly impair a patient’s 
mobility and quality of life (QOL). 
The hemostatic system aims to maintain the integrity of the vasculature by protecting against 
bleeding from vessel lesions combined with multiple options to prevent thrombosis.  This 
hemostatic balance is achieved through an orchestrated regulation of both procoagulant (eg, 
factor V [FV], factor VII [FVII], FVIII, FIX, factor X [FX]) and anticoagulant (eg, antithrombin 
(AT), protein C/protein S and tissue factor pathway inhibitor) factors.  Recent studies have 
suggested that coinheritance of a deficiency in natural anticoagulants may contribute to a milder 
phenotype in patients with hemophilia.  Antithrombin is a liver-expressed natural anticoagulant 
that plays a key role in inhibiting thrombin.  Furthermore, AT acts as an inhibitor of FVIIa and 
FXa, which are typically at normal levels in patients with hemophilia A or B.  Extensive 
preclinical in vitro and in vivo studies have described reduction of AT as a potential safe and 
effective way to correct thrombin generation in both hemophilia A and B and control against 
microvascular and macrovascular traumatic bleeding episodes.[3]  Therefore, suppression of AT 
production is being investigated as a potential hemophilia treatment. 
Replacement with factor concentrates is the current standard of care for hemophilia patients 
without inhibitory antibodies to FVIII or FIX.  While the current standard of care of factor 
substitution therapy, administered either episodically or as routine prophylaxis, is well 
established, safe, and efficacious, it is associated with high treatment burden due to requiring 
intravenous (IV) administration on a frequent schedule (2 to 3 times per week or more) to 
prophylactically maintain hemostasis.[2]  Factor concentrates also can be of limited availability 
in developing nations.  In addition, patients receiving factor concentrates may develop an 
inhibitory antibody to factor, a result that carries a poorer prognosis and requires a change in 
treatment regimen to infusion with bypassing agents (BPAs). 
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A fixed-dose subcutaneous therapy that can effectively and safely prevent or reduce the 
frequency of bleeding episodes in patients with hemophilia A or B, may reduce treatment 
burden, improve clinical outcomes and enhance quality of life.  Fitusiran is being developed to 
address these needs of patients with hemophilia. 
1.2. 
Fitusiran (SAR439774) 
Fitusiran (SAR439774 [formerly Alnylam ALN-AT3SC]) is an investigational agent comprising 
a synthetic siRNA covalently linked to a triantennary N-Acetylgalactosamine (GalNAc) ligand, 
designed to suppress liver production of AT as a strategy to rebalance the hemostatic system, 
thereby improving thrombin generation and hemostasis in individuals with hemophilia. 
Fitusiran is a GalNAc-siRNA conjugate that reduces production of AT, leading to lower plasma 
AT levels.  By reducing plasma AT, fitusiran is designed to improve thrombin generation and 
hemostasis in individuals with hemophilia, regardless of hemophilia type or presence of 
inhibitory antibodies to factor VIII or IX.  Because of the durability of the PD effect of fitusiran 
demonstrated in previous nonclinical and clinical studies, the subcutaneous (SC) administration 
required is notably less frequent (once monthly) than current IV standard of care with factor 
concentrates or BPAs (as frequent as every other day in severe cases), representing potentially 
improved quality of life and lowered treatment burden for patients with hemophilia.  Further, 
with the durable PD effect, it is possible that fitusiran may maintain a patient at a more 
consistent, robust hemostasis than intermittent factor or BPAs.  
Fitusiran is being developed for the indication of routine prophylaxis to prevent or reduce the 
frequency of bleeding episodes in patients with hemophilia A or B with or without inhibitory 
antibodies to FVIII or FIX.   
1.2.1. 
Summary of Nonclinical Data With Fitusiran 
Nonclinical pharmacology and exploratory toxicity studies have been conducted in wild-type 
(WT) and hemophilia mouse models, as well as WT rats, WT dogs, hemophilic dogs, and WT 
non-human primates (NHP).  The fitusiran siRNA sequence is homologous across all tested 
species; therefore, across multiple studies (single and repeat-dose), fitusiran exhibits potent and 
dose-dependent pharmacologic activity, resulting in reduced tissue AT mRNA levels and 
subsequent reduced circulating AT protein and activity levels, with a single-dose ED50 of 
~1 mg/kg in multiple species.  Exploratory pharmacology studies have also been completed in 
the hemophilia A dog and in an NHP induced hemophilia model. 
A GLP-compliant SC safety pharmacology study in NHP was conducted and there were no 
effects on measured cardiovascular or respiratory parameters after a single SC dose at any dose, 
with a NOEL for cardiovascular effects of 
 (highest dose evaluated).  There were no 
neurological effects in the GLP 39-week NHP study with a NOEL of 
 (highest dose 
evaluated with repeat dosing).  The pharmacology studies are summarized in greater detail in the 
Investigator’s Brochure. 
Plasma PK and toxicokinetic studies of single and repeated IV and/or SC 
 doses of 
fitusiran were conducted in rats, dogs, and monkeys, and 
 of fitusiran in mice.  
Following SC administration, fitusiran was rapidly absorbed following IV and SC 
administrations of 
 in mice with Cmax occurring within 30 minutes of dose 
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administration followed by clearance in a biphasic manner.  There were no gender-related 
differences in the PK properties of fitusiran.  After repeat dosing, the plasma PK profiles were 
similar after first and last dose indicating no time dependent changes in the PK of fitusiran. 
In the in vitro studies of rats and NHPs fitusiran did not cause induction of the common P450 
isoforms and was not a substrate for the common cytochrome P450 (CYP P450) isoforms. 
Genetic toxicity studies (bacterial reverse mutation, mammalian chromosome aberration, rat 
micronucleus test) have been completed, and demonstrated that fitusiran is non-genotoxic.  GLP 
toxicology (7 weekly doses) studies were conducted with fitusiran in the rat and NHP.  A chronic 
26-week study in the rat and a 39-week study in NHP have been completed.  The no observed 
adverse effect level (NOAEL) in the 7-week rat toxicology study was 
, and in the 
26-week rat toxicology study was 
.  The NOAEL in the 7-week NHP study was 
, and the NOAEL in the chronic NHP study was 
.  The NOAELs in all 
studies were based on toxicity attributable to the exaggerated on-target, pro-coagulant 
pharmacology of fitusiran that is expected in wild type animals (hemorrhage and/or thrombosis 
in various tissues, which led to mortality above a threshold of approximately 
).  By 
contrast, in exploratory studies, highly exaggerated doses of fitusiran (exposures in 100-fold 
excess of therapeutic relevance; >95% reduction in AT) were well tolerated in hemophilia A and 
B mice, with no evidence of toxicity or thrombosis.  A 26-week GLP chronic toxicity in the 
hemophilia A mouse model was conducted.  The top dose of 
 was well tolerated for 26 
weeks, indicating that hemophilic animals are not predisposed to pro-thrombotic effects 
compared to WT animals; a survival benefit was demonstrated in animals dosed with fitusiran vs 
saline controls (40% mortality in saline control vs 6% in fitusiran treated groups [p<0.0001 by 
Log-Rank test]).  In addition, 6 month TgRasH2 mouse and 2-year rat carcinogenicity studies are 
currently ongoing. 
In the GLP-compliant 39-week chronic NHP toxicology study, administration of fitusiran by 
once weekly SC injection to peripubertal cynomolgus monkeys at doses of 
, 
 was well tolerated (approximately 70% chronic AT suppression at 
).  Based on the absence of fitusiran related effects on the toxicology parameters 
evaluated at all dose levels tested, the NOAEL was considered to be 
. 
There was no effect of fitusiran on male reproduction in the rat and with repeat dose 
administration of fitusiran to juvenile rats and sexually immature cynomolgus monkeys, growth 
and maturation were unaffected.  Overall, fitusiran was well tolerated locally, and non-genotoxic.  
Fitusiran does not activate the immune system.  
Taken together, the results from the nonclinical studies exhibit reduction in AT activity level, 
increase in thrombin generation, and corrective effect on hemostasis, thereby validating the 
therapeutic approach of the clinical studies.  These nonclinical studies are summarized in the 
Investigator’s Brochure.  
1.2.2. 
Summary of Clinical Data With Fitusiran 
Overview Status of Completed and Ongoing Clinical Studies of Fitusiran 
Study ALN-AT3SC-001 was a Phase 1 study investigating the safety, tolerability and 
pharmacokinetics of subcutaneously administered fitusiran in adult male healthy volunteers and 
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hemophilia A and B adult male patients with moderate or severe hemophilia.  The study was 
conducted in 4 parts: 
 Part A (N=4):  randomized, placebo-controlled, single-blind single ascending dose (SAD) 
phase in healthy subjects (0.03 mg/kg SC single dose) 
 Part B (N=12): open-label, multiple ascending dose (MAD) phase in patients with 
moderate to severe hemophilia A or B without inhibitors (0.015 to 0.075 mg/kg SC once 
weekly) 
 Part C (N=18):  open-label, exploratory multiple dose (MD) phase in patients with 
moderate to severe hemophilia A or B without inhibitors (0.225 to 1.8 mg/kg or 80 mg 
fixed dose SC once monthly) 
 Part D (N=17):  open-label MD phase in patients with moderate to severe hemophilia A 
or B with inhibitors (50 or 80 mg fixed dose SC once monthly) 
Study ALN-AT3SC-001 was completed on 20 July 2017 (last patient last visit). 
Study ALN-AT3SC-002 is a Phase 1/2 multicenter, multinational, open-label extension study to 
evaluate the long-term safety and efficacy of fitusiran in male patients with moderate or severe 
hemophilia A or B, with or without inhibitors, who previously tolerated dosing in Study 
ALN-AT3SC-001.  Study ALN-AT3SC-002 is currently ongoing.  A total of 34 patients who 
previously participated in Study ALN-AT3SC-001 and received at least 1 dose of SC fitusiran 
ranging from 0.225 to 1.8 mg/kg or 50 mg or 80 mg fixed doses have enrolled in the extension 
study.  These 34 patients include 19 non-inhibitor patients (14 with hemophilia A and 5 with 
hemophilia B) and 15 inhibitor patients (13 with hemophilia A and 2 with hemophilia B).  Three 
patients began the extension study on weight-based doses (0.225, 0.9 or 1.8 mg/kg) reflecting 
their original Phase 1 dose.  All patients were transitioned to either 50 mg monthly (N=13) or 
80 mg monthly (N=21) after no more than 4 doses.  Patients are currently receiving either 50 mg 
(N=13) or 80 mg (N=21) fixed doses in this extension study, which is ongoing. 
For a more complete summary and the most recent available pharmacokinetic, 
pharmacodynamic, safety, and efficacy data see the Investigator’s Brochure. 
1.2.2.1. 
Summary of Efficacy 
Preliminary efficacy for pooled ALN-AT3SC-001 and ALN-AT3SC-002 data include analysis of 
annualized bleeding rate (ABR).  For the purpose of ABR calculation, fitusiran “Onset Period” 
and an “Efficacy Period” were defined.  The Onset Period was defined as the first 28 days after 
the first dose of fitusiran, during which the target pharmacodynamic effect is reached.  The 
Efficacy Period, during which bleeds were counted for the purpose of ABR calculation, was 
defined as starting on Day 29.  For patients who did not have an interruption in treatment 
>56 days between the Phase 1 study (ALN-AT3SC-001) and this Phase 1/2 extension study 
(ALN-AT3SC-002), bleed data from ALN-AT3SC-001 were included and the Efficacy Period 
was defined as starting on Day 29 of that study.  As of 8 August 2017, 33 of 34 patients enrolled 
in the extension study met criteria for inclusion in this analysis, with one patient not yet having 
completed 28 days on study. 
Patients entering the extension study all received fitusiran as a once monthly injection.  Initial 
doses ranged from 0.225 mg/kg to 1.8 mg/kg in 3 patients, but all patients were transitioned to 
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30 
either 50 mg (N=13) or 80 mg (N=21) fixed doses after ≤4 doses.  No prophylactic use of factor 
concentrates or BPAs were allowed after the first dose of fitusiran, with only on-demand use of 
these agents for the treatment of any breakthrough bleeding events. 
The ABR was determined for non-inhibitor and inhibitor patients receiving 50 mg or 80 mg.  
The prestudy ABR was reported at ALN-AT3SC-001 study entry, prior to beginning treatment 
with fitusiran.  The ABR of patients from combined data from studies ALN-AT3SC-001 and 
ALN-AT3SC-002 reflects efficacy across hemophilia subtypes in both inhibitor and 
non-inhibitor patients.  In patients on 80 mg monthly, the dose selected for Phase 3 studies, the 
median ABR during the Efficacy Period (Day 29 to the data cut-off [8 August 2017]) is 1.46 and 
0 in non-inhibitor (N=9) and inhibitor (N=11) patients, respectively.  The median ABR on 50 mg 
monthly was 1.57 for non-inhibitor (N=10) and 6.84 for inhibitor (N=3) patients.  All of the 
non-inhibitor patients on prophylactic therapy (N=7) pre-study either maintained low ABR, or 
demonstrated improved ABR on fitusiran, and the median ABR for this group was 1.7. 
A complete summary of available clinical efficacy data relevant to fitusiran is presented in the 
Investigator’s Brochure. 
1.2.2.2. 
Summary of Safety 
As of 31 August 2017, 42 male patients with severe or moderate hemophilia A or B, with or 
without inhibitors, have received fitusiran in clinical studies.  Single and multiple doses of 
fitusiran have been generally well tolerated.  Most patients have reported at least 1 AE, the 
majority of which were assessed as mild or moderate in intensity and unrelated to investigational 
medicinal product (IMP).  The most common AEs reported were injection site reactions, which 
were all mild and generally transient. 
Elevations of liver transaminases occurred in 13 of 42 patients dosed with fitusiran.  None of the 
liver transaminase elevations were associated with elevations of total serum bilirubin >2 × the 
upper limit of normal (ULN).  Except in one patient, these elevations were asymptomatic, and 
occurred in patients with a documented history of prior HCV infection.   
Eleven of 42 patients reported a total of 14 SAEs.  Out of these, 3 SAEs (elevated alanine 
aminotransferase [ALT] and aspartate aminotransferase [AST], seizures, and cerebral venous 
sinus thrombosis [CVST]) were assessed as possibly related to fitusiran.   
Two patients discontinued fitusiran due to AEs (1 due to a non-serious AE of non-cardiac chest 
pain and another due to SAEs of elevated ALT and AST.  
One death has been reported in a patient with CVST in ALN-AT3SC-002, which was considered 
possibly related to fitusiran.  This occurred in a 27-year old patient who had been on study for 
15 months.  The patient was hospitalized for headache several days after treating hip pain with 
31 IU/kg to 46 IU/kg factor VIII.  While the patient was initially suspected of having viral 
meningitis, he was subsequently diagnosed with subarachnoid hemorrhage on the basis of 
computed tomography (CT) imaging, and treated with full dose Factor VIII concentrate two to 
three times daily.  Over a 14-day hospitalization, the patient’s medical condition worsened 
despite the administration of FVIII concentrate and he died from subsequent cerebral edema.  
Post mortem review of images by independent neuro-radiologists confirmed that the initiating 
event was a CVST, and not a subarachnoid hemorrhage.  The event is thus categorized as 
possibly related to fitusiran.  No other thromboembolic events have been observed. 
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No dose-related trend was observed in any of the laboratory, physical exam or EKG results.  No 
consistent dose relationship or clear difference between the 50 mg and 80 mg dose groups was 
observed with respect to incidence of AEs, SAEs or laboratory tests. 
A more detailed summary of clinical safety data is presented in the Investigator’s Brochure. 
1.2.2.3. 
Summary of Pharmacokinetic and Pharmacodynamic Effects in 
ALN-AT3SC-001 and ALN-AT3SC-002  
Consistent with the intended pharmacological effects, regardless of inhibitor status, fitusiran 
dose-related reductions in AT activity level have been observed in the clinical studies, and have 
been associated with increased thrombin generation.  In Part C of the Phase 1 study, the mean 
maximum AT activity level reductions following 3 monthly doses of 0.225, 0.45, 0.9 or 
1.8 mg/kg fitusiran were 70% (N=3), 77% (N=3), 77% (N=3), and 89% (N=3), respectively.  A 
fixed dose, 80 mg fitusiran, was also explored in Part C, resulting in a mean maximum AT 
activity level reduction of 87% (N=6).  In Part D of the study, patients with inhibitors were dosed 
with 50 or 80 mg fitusiran and experienced mean maximum AT activity level reduction of 82% 
(N=6) and 87% (N=11), respectively.  AT reduction was maintained in ALN-AT3SC-002, with 
mean maximal AT reduction of 83.6% for 50 mg (N=13) and 85.9% for 80 mg (N=21) as of 
08 August 2017.   
Consistent with the therapeutic hypothesis, increased AT lowering in patients with hemophilia 
resulted in increased thrombin generation when AT lowering was in the highest quartile (>75%) 
compared to when AT lowering was in the lowest quartile (<25%).  Further, the peak thrombin 
generation values achieved with AT lowering of >75% were comparable to those in the lower 
end of the normal range observed in healthy individuals.  None of the thrombin generation 
measurements following >75% AT reduction in hemophilia patients exceeded those seen in 
healthy males.  
1.3. 
Study Design Rationale 
The ATLAS-A/B trial (ALN-AT3SC-004 [Sanofi Genzyme EFC14769]) is a multicenter, 
multinational, randomized, open-label Phase 3 study designed to demonstrate the efficacy and 
safety of fitusiran in patients with hemophilia A or B without inhibitory antibodies to FVIII or 
FIX who are currently treated with on-demand factor concentrates. 
The primary objective is to assess the efficacy of fitusiran on prevention or reduction of bleeding 
episodes.  Secondary objectives are to assess the efficacy of fitusiran on:  the number and type of 
bleeding episodes; HRQOL; and to determine the safety and tolerability of fitusiran.   
Blinding is not considered feasible for this study since the differences in treatment for each study 
arm cannot be blinded.  The open-label, randomized study design is justified because safety 
monitoring of theoretical risks such as transaminitis or thrombosis can be objectively verified by 
laboratory monitoring or objective visualization, eg, ultrasound or CT.  Therefore, the safety 
monitoring of the studied population does not require blinding. 
The primary endpoint of the study is ABR in the fitusiran efficacy period (Day 29 to EOS).  
ABR is a well-established endpoint that has been used as the primary endpoint in global 
approvals of factor replacement and BPA products.  Secondary endpoints characterize ABR in 
the treatment period, annualized spontaneous and joint bleeding rates, change in Hemophilia 
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Quality of Life Questionnaire for Adults (Haem-A-QOL) physical health score and total score in 
patients ≥17 years of age, ABR in the onset period, and the overall safety profile. 
Characterization of bleeding episodes is clinically relevant to assess overall bleeding episode 
protection.  Joint bleeding episodes result in pain and hemarthrosis, leading to progressive joint 
destruction, and hence are important to assess.  The Haem-A-QOL is a hemophilia-specific 
HRQOL survey instrument that has been validated in other hemophilia clinical trials and is 
considered the most appropriate HRQOL tool for this study.   
The study population will be comprised of males ≥12 years of age; it is appropriate to study 
fitusiran in adolescents (patients ≥12 to <18 years of age) because the pathophysiology of disease 
progression and bleeding episode management is the same as adults and self-management of 
hemophilia typically begins at 12 years of age.[4]  A similar study in hemophilia patients with 
inhibitors (ALN-AT3SC-003) is being conducted concurrently to this study. 
To protect against bias, patients will be assigned to fitusiran (fitusiran treatment arm; N=80) or 
on-demand factor concentrate therapy (on-demand arm; N=40) by stratified randomization.  
The onset period duration reflects modeling data that estimates it takes approximately 28 days to 
reach the therapeutic target range in the majority of patients.  Efficacy of fitusiran will be 
assessed over the remaining 8 months of the study (Day 29 to Month 9). 
In the event of a breakthrough bleeding episode, on-demand use of factor concentrates will be 
permitted throughout the entire study duration (see Section 6.3.1). 
1.4. 
Dose Rationale 
Dose selection was guided by the principle of identifying an optimal dose that is both well-
tolerated and efficacious.  The fitusiran dose proposed for Phase 3 development was identified 
using both observed data from ongoing clinical studies, as well as extensive clinical simulations 
and modeling.  The key PD and clinical parameters used to support the dose selection include 
decreases in AT activity, the most proximate and direct PD effect of fitusiran, as well as 
increases in thrombin generation and decreases in ABR. 
Observed data from Phase 1 and Phase 1/2 studies in patients with hemophilia A and B with or 
without inhibitors, and PK/PD-modeled data, support selection of a fixed dose of 80 mg for this 
study, as subcutaneously administered once-monthly. 
In observed data from Phase 1 and Phase 1/2 studies, monthly equivalent doses or monthly doses 
ranging from 0.045 mg/kg to 1.8 mg/kg and fixed doses of 50 mg and 80 mg have been 
evaluated.  A clear dose response trend of increased AT lowering is evident, with approximately 
10% to 20% residual AT activity at a dose of 1.8 mg/kg and at fixed doses of 50 mg and 80 mg 
subcutaneously administered once monthly.  These data suggest that the maximum AT lowering 
achieved as a function of the dose administered reaches an asymptote at ~90% AT lowering and 
that it is unlikely higher doses will achieve meaningfully greater AT lowering.  In addition, both 
the 50 mg and 80 mg fixed doses produced substantial increases in peak thrombin generation, 
which approach the lower end of the normal range, but do not exceed the normal range. 
Dose-response modeling analyses are supportive of the observed data.  A repeated time to event 
model was used to evaluate the relationship between AT lowering and the anticipated ABR.  
According to the model, the 80 mg, fixed, once-monthly dose is anticipated to result in near 
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maximal achievable reduction in ABR, in which the majority of patients may achieve >75% AT 
lowering, the therapeutic target.  Weight was not a significant covariate in the model, suggesting 
no advantage to weight-based dosing.   
The safety of fitusiran has been evaluated in healthy volunteers and patients with moderate to 
severe hemophilia A and in patients with moderate to severe hemophilia B in the ongoing 
Phase 1 and Phase 1/2 studies, and overall supports monthly administration of the 80 mg dose in 
this study.  Full details of the safety findings from the Phase 1 and Phase 1/2 studies are 
presented in the Investigator’s Brochure. 
1.5. 
Benefit-Risk Assessment 
Based on the available clinical data (see Section 1.2.2), fitusiran administered subcutaneously as 
a once-monthly fixed-dose regimen, may be able to offer potentially reduced bleeding rates for 
patients receiving factor concentrate or BPA treatment prophylactically or on-demand.  Further, 
the pharmacodynamic profile of fitusiran results in consistent reduction of AT and therefore may 
provide more consistent increase in thrombin generation and hemostatic protection throughout 
the dosing interval.  The clinical experience to date suggests that in hemophilia A or B patients, 
with or without inhibitors, fitusiran treatment is associated with reductions in AT, increases in 
thrombin generation, and reduction of the number of bleeding episodes. 
Given the mechanism of action of fitusiran, mode of administration, and available safety data, 
the possible risks associated with the use of fitusiran include thrombosis, liver transaminase 
abnormalities, and injection site reactions (ISRs).  Due to the underlying pro-hemostatic effect of 
fitusiran, the concomitant treatment of breakthrough bleeding episodes with factor or BPA 
particularly at doses higher than recommended in the protocol may confer an increased risk of 
thrombosis.  For summary of the completed Phase 1 study, and preliminary interim results from 
the Phase 1/2 extension study, see Section 1.2.2; further details of fitusiran studies are presented 
in the Investigator’s Brochure. 
This clinical protocol has exclusion criteria intended to minimize the risk of thrombosis, liver 
transaminase abnormalities, and serious ISRs.  With respect to the risk of thrombosis, the 
protocol includes detailed guidance and oversight on treatment of breakthrough bleeding 
episodes with reduced factor/BPA dosing (Section 6.3.1), and management of operative 
procedures that occur while patients are on fitusiran (Section 6.6).  The protocol also excludes 
patients with evidence of liver disease (including active viral hepatitis) and stipulates ongoing 
monitoring for elevated transaminases (Section 6.2.3.1).  The safety of trial patients will be 
overseen by an independent DMC (Section 4.7). 
2. 
OBJECTIVES 
2.1. 
Primary Objective 
 To evaluate the efficacy of fitusiran compared to on-demand treatment with factor 
concentrates, as determined by the frequency of bleeding episodes 
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2.2. 
Secondary Objectives 
 To evaluate the efficacy of fitusiran compared to on-demand treatment with factor 
concentrates, as determined by: 
o The frequency of spontaneous bleeding episodes 
o The frequency of joint bleeding episodes 
o Health-related quality of life (HRQOL) in patients ≥17 years of age 
 To determine the frequency of bleeding episodes during the onset period 
 To determine the safety and tolerability of fitusiran 
2.3. 
Exploratory Objectives 
 To evaluate the effects of fitusiran as compared to on-demand treatment with factor 
concentrates on the following patient-reported outcomes: 
o Patient satisfaction with treatment 
o Patient activity 
o HRQOL in adolescents (≥12 to <17 years of age) 
 To characterize the pharmacodynamic (PD) effect, pharmacokinetics (PK), and 
immunogenicity of fitusiran 
 To evaluate the effects of fitusiran as compared to on-demand treatment with factor 
concentrates on the total weight-adjusted consumption of factor concentrates  
 To evaluate the effects of fitusiran as compared to on-demand treatment with factor 
concentrates on joint status  
 To evaluate the effects of fitusiran as compared to on-demand treatment with factor 
concentrates on patient resource use  
3. 
ENDPOINTS 
3.1. 
Primary Endpoint 
 Annualized Bleeding Rate (ABR) in the efficacy period 
3.2. 
Secondary Endpoints 
 ABR in the treatment period 
 Annualized spontaneous bleeding rate in the efficacy period  
 Annualized joint bleeding rate in the efficacy period 
 Change in Haem-A-QOL physical health score and total score in the treatment period 
 ABR in the onset period 
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3.3. 
Exploratory Endpoints 
 Change in the following in the treatment period: 
o Treatment Satisfaction Questionnaire for Medication (TSQM) domain scores 
o Hemophilia Activities List (HAL) score 
o Pediatric HAL (pedHAL) score 
o EuroQol-5 dimension (EQ-5D) score 
o Hemophilia Quality of Life Questionnaire for children and adolescents 
(Haemo-QOL) score 
o Hemophilia Joint Health Score (HJHS) 
 Number of target joint bleeding episodes 
 Incidence and titer of antidrug antibodies to fitusiran in the fitusiran treatment arm 
 AT activity level over time 
 Thrombin generation over time 
 Fitusiran plasma levels 
 Annualized weight-adjusted use of factor concentrates 
 Change in patient resource use (eg, work/school attendance, visits to doctor/hospital) 
3.4. 
Safety Endpoint 
 Incidence, severity, seriousness, and relatedness of adverse events (AEs) 
4. 
INVESTIGATIONAL PLAN 
4.1. 
Summary of Study Design 
The ATLAS A/B trial (ALN-AT3SC-004) is a multicenter, multinational, randomized, 
open-label Phase 3 study designed to evaluate the efficacy and safety of fitusiran in male patients 
aged ≥12 years with hemophilia A or B, without inhibitory antibodies to FVIII or FIX, who are 
not receiving prophylactic therapy. 
The study will be conducted at approximately 100 clinical study centers worldwide. 
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Eligible patients will be randomized in a 2:1 ratio to: 
 Fitusiran treatment arm: Fitusiran 80 mg administered SC as prophylaxis once 
monthly, with use of on-demand factor concentrates for treatment of breakthrough 
bleeding episodes 
 On-demand arm: On-demand factor concentrates for treatment of breakthrough 
bleeding episodes 
On-demand use of factor concentrates is defined as the use of these agents, as needed, for 
episodic bleeding, and not on a regular regimen intended to prevent spontaneous bleeding.  
Throughout the study, patients in the fitusiran treatment arm may receive on-demand treatment 
for breakthrough bleeding episodes with factor concentrates, as appropriate.  For patients in the 
fitusiran treatment arm who have received at least 1 dose of fitusiran and are being treated for 
breakthrough bleeding episodes, it is recommended to follow the guidelines provided in 
Section 6.3.1 per Investigator discretion. 
Bleeding events and doses of factor concentrates administered during the conduct of the study 
will be recorded in an electronic Diary (eDiary), as described in Section 7.2.1.  Since bleeding 
episodes are recorded as an efficacy assessment of fitusiran, these will not be treated as AEs 
unless they meet any of the SAE criteria listed in Section 7.5.6.1.  Safety, quality of life, 
pharmacodynamic, and pharmacokinetic data will also be collected. 
All patients will be treated for a total of 9 months; patients randomized to the fitusiran treatment 
arm will receive a total of 9 SC injections of fitusiran.  Because the full PD effect of fitusiran is 
not achieved until approximately 28 days after receiving the first dose, efficacy will be assessed 
during the final 8 months on study (Day 29 to Month 9).  Therefore, the overall fitusiran 
treatment period is defined as the onset period (Day 1 to Day 28 after receipt of the first dose, 
during which the AT lowering capacity of fitusiran is increasing but has not yet reached 
therapeutic levels) plus the efficacy period (Day 29 and after, when the AT lowering capacity of 
fitusiran has achieved therapeutic target range). 
Patients may undergo unplanned or emergency surgery during the study, but must not schedule 
non-urgent surgery to occur during the study.  Perioperative guidance should be followed as 
specified in Section 6.6. 
A Study Steering Committee, composed of experts in the field of hemophilia, will advise the 
Sponsor on study design and conduct (see Section 4.6). 
An independent data monitoring committee (DMC) will oversee the safety and overall conduct 
of this study as described in Section 4.7. 
The study design schema is presented in Figure 1.  Patients who complete the study may be 
eligible for an open-label extension study in which patients coming from both the fitusiran and 
the on-demand arms will be administered monthly SC doses of fitusiran.  
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Figure 1: 
Study Design 
 
Abbreviations:  HA/HB = hemophilia type A / hemophilia type B; R = randomized 
a On-demand factor concentrates as routinely prescribed by physician per local standard practice. 
b Fitusiran treatment arm patients who do not enroll in the extension study:  AT activity level will be monitored at monthly 
intervals following the final fitusiran dose until activity levels return to approximately 60% (per the central laboratory) or per 
Investigator discretion in consultation with the study Medical Monitor.  
4.2. 
Duration of Treatment 
The duration of treatment with fitusiran is 9 months.  The estimated total time on study, inclusive 
of Screening, for each patient is up to 11 months for all patients who enroll in the extension 
study and patients in the on-demand arm who do not enroll in the extension study.  The estimated 
total time on study may be up to 17 months in fitusiran treatment arm patients who do not enroll 
in the extension study due to the requirement for an additional 6 months of follow-up for 
monitoring of AT levels. 
4.3. 
Number of Patients 
Approximately 120 patients will be randomized, including approximately 26 with patients 
hemophilia B, and approximately 10 adolescents (≥12 to <18 years of age). 
4.4. 
Method of Assigning Patients to Treatment Groups 
Patients will be randomized 2:1 to the fitusiran treatment arm and the on-demand arm.  
Randomization will be stratified by the number of bleeding episodes in the 6 months prior to 
Screening (≤10 vs >10) and hemophilia type (hemophilia A or B).  
Each patient will be uniquely identified in the study by a combination of the site number and 
patient identification number.  Upon signing the informed consent form (ICF), the patient will be 
assigned a patient identification number by the interactive response system (IRS).  The 
Investigator or his/her delegate will contact the IRS after confirming that the patient fulfills all 
the inclusion criteria and none of the exclusion criteria.  A combination of the site number and 
patient identification number will create the unique patient identifier. 
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4.5. 
Blinding 
This study is an open-label study so blinding is not applicable; however, performing aggregate 
summaries of efficacy data by treatment arm will be restricted until database lock.  
4.6. 
Study Steering Committee 
A Study Steering Committee, composed of experts in the field of hemophilia, will advise the 
Sponsor on study design and conduct.  In collaboration with the Sponsor, the committee will 
provide scientific leadership to the study to ensure that the highest standards are maintained.  
Clinical Advisors who are experts in the care of hemophilia patients and familiar with fitusiran 
will be available to discuss clinical aspects of care with Investigators for surgical cases, cases of 
thrombosis, or other medically complex circumstances that may arise on study, when clinical 
circumstances allow.  Such discussions will involve the study Medical Monitor.  
4.7. 
Data Monitoring Committee 
An independent DMC will oversee the safety and overall conduct of this study, providing input 
to the Sponsor.  The DMC will operate under the rules of a charter that will be reviewed and 
approved at the organizational meeting of the DMC.  The DMC has the responsibility for 
reviewing safety data and analyses and making recommendations to the Sponsor.  The DMC will 
perform periodic reviews of data during the course of the clinical trial, and on an ad hoc basis for 
review of emergent safety data, as defined in the DMC Charter for this clinical trial. 
5. 
SELECTION AND WITHDRAWAL OF PATIENTS 
5.1. 
Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be eligible for enrollment in the 
study: 
1. Males ≥12 years of age. 
2. Severe hemophilia A or B without inhibitors evidenced by: 
a. A central laboratory measurement or documented medical record evidence of 
FVIII <1% or FIX level ≤2% at Screening. 
b. On-demand use of factor concentrate to manage bleeding episodes for at least the last 
6 months prior to Screening, and meet each of the following criterion: 
 Nijmegen modified Bethesda assay inhibitor titer of <0.6 BU/mL at Screening 
 No use of BPAs to treat bleeding episodes for at least the last 6 months prior to 
Screening 
 No history of immune tolerance induction therapy within the last 3 years prior to 
Screening 
3. A minimum of 6 bleeding episodes requiring factor concentrate treatment within the last 
6 months prior to Screening. 
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4. Willing and able to comply with the study requirements and to provide written informed 
consent and assent in the case of patients under the age of legal consent, per local and 
national requirements. 
5.2. 
Exclusion Criteria 
Each patient must not meet any of the following exclusion criteria to be eligible for enrollment in 
the study: 
1. Known co-existing bleeding disorders other than hemophilia A or B, ie, Von 
Willebrand’s disease, additional factor deficiencies, or platelet disorders.  
2. Current use of factor concentrates as regularly administered prophylaxis designed to 
prevent spontaneous bleeding episodes. 
3. AT activity <60% at Screening as determined by central laboratory measurement. 
4. Presence of clinically significant liver disease, or as indicated by any of the conditions 
below:  
a. INR >1.2; 
b. ALT and/or AST >1.5× upper limit of normal reference range (ULN); 
c. Total bilirubin >ULN (>1.5× ULN in patients with Gilbert’s Syndrome); 
d. History of portal hypertension, esophageal varices, or hepatic encephalopathy; 
e. Presence of ascites by physical exam 
5. Hepatitis C virus antibody positive, except patients with a history of HCV infection who 
meet both conditions a. and b.: 
a. Completed curative treatment at least 12 weeks prior to enrollment and attained 
sustained virologic response as documented by a negative HCV RNA at screening, or 
they have spontaneously cleared infection as documented by negative HCV RNA at 
Screening. 
b. No evidence of cirrhosis according to one of the following assessments: 
 FibroScan <12.5 kPa (where available), or  
 FibroTest score <0.75 and APRI <2 (if FibroScan unavailable) 
6. Presence of acute hepatitis, ie, hepatitis A, hepatitis E.  
7. Presence of acute or chronic hepatitis B infection (IgM anti-HBc antibody positive or 
HBs Ag positive).   
8. Platelet count ≤100,000/μL.  
9. Presence of acute infection at Screening. 
10. Known to be HIV positive with CD4 count <200 cells/μL. 
11. Estimated glomerular filtration rate ≤45 mL/min/1.73 m2 (using the Modification of Diet 
in Renal Disease [MDRD] formula). 
12. Co-existing thrombophilic disorder, as determined by presence of any of the below as 
identified at central laboratory (or via historical results, where available):  
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a. FV Leiden (homozygous or heterozygous) 
b. Protein S deficiency 
c. Protein C deficiency 
d. Prothrombin mutation (G20210A; homozygous or heterozygous) 
13. History of antiphospholipid antibody syndrome. 
14. History of arterial or venous thromboembolism, atrial fibrillation, significant valvular 
disease, myocardial infarction, angina, transient ischemic attack, or stroke.  Patients who 
have experienced thrombosis associated with indwelling venous access may be enrolled.  
15. Had a malignancy within 2 years, except for basal or squamous cell carcinoma of the skin 
that has been successfully treated.  
16. Any condition (eg, medical concern), which in the opinion of the Investigator, would 
make the patient unsuitable for dosing on Day 1 or which could interfere with the study 
compliance, the patient’s safety and/or the patient’s participation in the completion of the 
treatment period of the study.  This includes significant active and poorly controlled 
(unstable) cardiovascular, neurologic, gastrointestinal, endocrine, renal or psychiatric 
disorders unrelated to hemophilia identified by key laboratory abnormalities or medical 
history. 
17. At Screening, anticipated need of surgery during the study or planned surgery scheduled 
to occur during the study.  
18. Completion of a surgical procedure within 14 days prior to Screening, or currently 
receiving additional factor infusion for postoperative hemostasis.  
19. History of multiple drug allergies or history of allergic reaction to an oligonucleotide or 
GalNAc. 
20. Inadequate venous access, as determined by the Investigator, to allow the blood draws 
required by the study protocol. 
21. History of intolerance to SC injection(s). 
22. Current or future participation in another clinical study, scheduled to occur during this 
study, involving an investigational product other than fitusiran or investigational device; 
in order to participate in this study, patient must discontinue the investigational product at 
least 30 days (or 5× the investigational product half-life, whichever is longer) prior to 
dosing (Day 1). 
23. Current or prior participation in a gene therapy trial. 
24. History of alcohol abuse within the 12 months before Screening.  Alcohol abuse is 
defined as regular weekly intake of more than 14 units (unit: 1 glass of wine 
[approximately 125 mL] = 1 measure of spirits (approximately 1 fluid ounce) = ½ pint of 
beer [approximately 284 mL]). 
5.3. 
Removal from Therapy or Assessment 
Patients or their legal guardian (in case patient is a minor) are free to discontinue treatment or 
withdraw from the study at any time and for any reason, without penalty to their continuing 
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medical care.  Any discontinuation of treatment or withdrawal from the study must be fully 
documented in the electronic case report form (eCRF), and should be followed up by the 
Investigator.  The Investigator may withdraw a patient at any time if this is considered to be in 
the patient’s best interest. 
Procedures for discontinuation of IMP and withdrawal from the study are described in Section 
5.3.1 and Section 5.3.2, respectively. 
5.3.1. 
Discontinuation of Investigational Medicinal Product 
The Investigator or designee may discontinue dosing in a patient if the patient: 
 Is in significant violation of the protocol 
 Is non-adherent to treatment regimen 
 Experiences a serious or intolerable AE, a life-threatening bleeding episode, eg, any 
gastrointestinal hemorrhage or intracranial hemorrhage, or life-threatening 
thromboembolic event 
 Requires a prohibited medication. 
The Investigator will confer with the Sponsor or study Medical Monitor before discontinuing 
dosing in the patient.  
Patients (or their guardians) may decide to discontinue IMP. 
In general, patients who discontinue IMP dosing for any reason will be encouraged to remain on 
the study to complete the remaining assessments through the end of study so that their 
experience is captured in the final analyses.  If a patient discontinues dosing due to a serious 
adverse event (SAE), the SAE should be followed as described in Section 7.5.6.  When a patient 
discontinues IMP dosing, the primary reason must be recorded in the appropriate section of the 
eCRF.  Patients who discontinue IMP but who remain on study may receive treatment consistent 
with local standard practice for their disease per Investigator judgment, as applicable.  Safety 
will be captured for the entire duration of study for patients who discontinue treatment. 
5.3.2. 
Withdrawal From Study 
A patient or guardian may withdraw consent from study participation at any time.  The 
Investigator may withdraw a patient at any time if this is considered to be in the patient’s best 
interest.  Any withdrawal from the study must be fully documented in the eCRF, and should be 
followed-up by the Investigator.   
However, study integrity and interpretation is best maintained if all enrolled patients continue 
study assessments and follow-up even if study treatment is discontinued.  Patients considering 
withdrawing from the study should be informed that they can discontinue treatment and still 
remain in the study to complete study assessments and follow-up as specified in the Schedule of 
Assessments (Table 1).  If a patient still chooses to discontinue study treatment and withdraw 
from all follow-up, every effort should be made to conduct the EOS/ET assessments within 
4 weeks of the last dose (see Table 1).  When a patient withdraws from the study, the withdrawal 
of consent and the reason for withdrawal must be recorded in the appropriate section of the eCRF 
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and all efforts will be made to complete and report the observations as thoroughly as possible.  
There will be no replacements of patients who withdraw from this study. 
6. 
TREATMENTS 
6.1. 
Treatments Administered 
Investigational medicinal product supplied for this study must not be used for any purpose other 
than the present study and must not be administered to any person not enrolled in the study.  
Investigational medicinal product that has been dispensed to a patient and returned unused must 
not be re-dispensed to a different patient. 
6.2. 
Investigational Medicinal Product 
Detailed information describing the preparation, administration, and storage of fitusiran is 
provided in the Pharmacy Manual. 
6.2.1. 
Description 
Fitusiran (SAR439774) solution for injection (SC use) will be supplied as a sterile solution (see 
the Pharmacy Manual for further details of solution concentration and fill volume). 
6.2.2. 
Dose and Administration 
Patients randomized to the fitusiran treatment arm receive open-label 80 mg fitusiran as an SC 
injection once monthly, for a total of 9 months; dosing will begin on Day 1 of the treatment 
period.   
Investigational medicinal product injection will be administered at the clinic by qualified staff 
under the supervision of the Investigator or designee.  Detailed instructions for IMP 
administration are found in the Pharmacy Manual.  
Investigational medicinal product will not be blinded as this is an open-label study.  See 
Section 6.2.5 regarding packaging and labeling. 
If a patient does not receive a fitusiran dose within the specified dosing window (Table 1), the 
Investigator should contact the study Medical Monitor.  After such consultation, the dose may be 
administered or considered missed and not administered. 
If a patient misses a dose, the Investigator, in consultation with the study Medical Monitor, will 
discuss whether the patient will be able to continue on the study.  
Additional details regarding dosing can be found in the Pharmacy Manual. 
6.2.3. 
Dose Modifications 
No fitusiran dose modifications will be allowed.  If a IMP-related AE occurs in a patient that the 
Investigator judges as presenting a potential risk to the patient for further dosing, the fitusiran 
dose may be held at the discretion of the Investigator and the study Medical Monitor should be 
contacted. 
6.2.3.1. 
LFT Criteria for Withholding, Monitoring and Stopping Fitusiran Dosing 
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1. LFT results are to be obtained within 7 days prior to dosing and results are to be reviewed 
prior to each dose of fitusiran.  Central laboratory results are preferable.  If not available, 
local laboratory results may be used; however, if a local assessment is drawn, a serum 
chemistry sample must also be drawn for analysis at the central laboratory.  
2. For any ALT or AST elevation >3× ULN central laboratory results should be used to 
guide subsequent monitoring as detailed in Table 3.  
3. For any ALT or AST elevation >3× ULN:  
a. Confirm using central laboratory, as soon as possible, ideally within 2 to 3 days, but 
no later than 7 days. 
b. Perform assessments per Table 3 and Table 6. 
c. If an alternative cause is found, provide appropriate care. 
4. For any ALT or AST elevation >3× ULN without alternative cause that is accompanied 
by clinical symptoms consistent with liver injury (eg nausea, right upper quadrant 
abdominal pain, jaundice) or elevated bilirubin to ≥2× ULN or INR ≥1.5, permanently 
discontinue dosing. 
5. For confirmed ALT or AST elevations >3× ULN without alternative cause and not 
accompanied by symptoms or elevated bilirubin ≥2× ULN or INR ≥1.5, see Table 3 
below:
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Table 3: Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative Cause Identified 
Transaminase Level 
Action 
>3× to 5× ULN 
• 
May continue dosing 
• 
Evaluate the initial elevation in LFT per the following 
assessments: 
• 
Table 6 (all assessments to be performed once) 
• 
Hematology, serum chemistry, LFT, and coagulation per  
Table 5 
• 
AT 
• 
Monitor at least every two weeks (hematology, serum chemistry, 
LFT, and coagulation per Table 5 and AT)  
• 
If elevation persists for ≥2 months, must discuss with the study 
Medical Monitor before continuing dosing 
>5× to 8× ULN 
• 
Hold fitusiran dose until recovery to ≤1.5× ULN; may resume 
dosing after discussion with the study Medical Monitor 
• 
Evaluate the initial elevation in LFT per the following assessments 
• 
Table 6 (all assessments to be performed once) 
• 
Hematology, serum chemistry, LFT, and coagulation per  
Table 5 
• 
AT 
• 
Monitor at least weekly (hematology, serum chemistry, LFT, and 
coagulation per Table 5 and AT) until ALT and/or AST is 
declining on two consecutive draws, then may decrease monitoring 
to biweekly 
• 
If ALT or AST rises to >5× ULN following repeat dosing, 
permanently discontinue dosing 
>8× ULN 
Permanently discontinue dosing after confirmation of the transaminase 
value 
Note:  In addition to these criteria, other assessments or evaluations may be performed per 
Investigator discretion, as appropriate. 
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6.2.4. 
Preparation, Handling, and Storage 
Qualified staff at each clinical study center will be responsible for preparation of fitusiran doses, 
according to procedures detailed in the Pharmacy Manual.  No special procedures for the safe 
handling of IMP are required. 
Investigational medicinal product will be stored per the Pharmacy Manual and refrigerated at 
approximately 5±3°C.  Deviations from the recommended storage conditions should be reported 
to the Sponsor and use of the IMP halted until authorization for its continued use has been 
provided by the Sponsor or designee, as described in the Pharmacy Manual. 
A Sponsor representative or designee will be permitted, upon request, to audit the supplies, 
storage, dispensing procedures, and records. 
Instructions specific to unused IMP and additional storage details are provided in the Pharmacy 
Manual. 
6.2.5. 
Packaging and Labeling 
All packaging, labeling, and production of IMP will be in compliance with current Good 
Manufacturing Practices, or local applicable regulations, where necessary.  Investigational 
medicinal product labels and external packaging will include all appropriate information as per 
local labeling requirements.  Additional details will be available in the Pharmacy Manual. 
6.2.6. 
Accountability 
The Investigator or designee will maintain accurate records of receipt and the condition of the 
IMP supplied for this study, including dates of receipt.  In addition, accurate records will be kept 
of when and how much IMP is dispensed and administered to each patient in the study.  Any 
reasons for departure from the protocol dispensing regimen must also be recorded. 
At the completion of the study, there will be a final reconciliation of all IMP. 
Further instructions about drug accountability are detailed in the Pharmacy Manual. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the 
Sponsor.  Some deficiencies may be recorded through a complaint procedure (see Section 
7.5.6.8). 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor.  In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (except for duties and 
taxes paid [DTP] shipment, for which a courier company has been approved by the Sponsor), 
allow the IMP to be used other than as directed by this clinical trial protocol, or dispose of IMP 
in any other manner. 
6.3. 
Concomitant Medications 
Use of concomitant medications will be recorded on the patient’s eCRF as specified in the 
Schedule of Assessments (Table 1).  This includes all prescription medications, herbal 
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preparations, over-the-counter medications, vitamins, and minerals.  Any changes in medications 
during the study will also be recorded on the eCRF. 
Local standard treatment of hemophilia is considered to be, but not limited to, IV infusion of 
FVIII or FIX concentrates.  Use of these concentrates will be captured in the patient’s eDiary. 
Use of prothrombin complex concentrates for bleeding episode management is not permitted. 
Antifibrinolytics may be used as single agents, but may not be used in combination with factor 
concentrates or BPA. 
6.3.1. 
Management of Bleeding Episodes 
The occurrence of bleeding episodes is a typical characteristic of hemophilia; [2, 5, 6] bleeding 
episodes will be recorded as an efficacy assessment of fitusiran and will not be considered as 
AEs unless the criteria for SAEs are met (see AEs definitions in Section 7.5.6.1).  Bleeding 
episodes will be recorded in the eDiary.  For bleeding episodes in which there was no factor 
concentrate infusion or other type of intervention employed, the reason the bleeding episodes 
were untreated will be recorded in the eDiary (see Section 7.2.1). 
Investigators will establish and provide instructions for an individualized bleed management plan 
based on the guidelines in Table 4 for each patient.   
The bleed management plan should be reviewed by the Investigator or designee with the patient 
at each clinic visit (and via telephone contact every 2 weeks between clinic visits) and updated as 
necessary. 
Doses of rFVIIa and aPCC are included for completeness.  It is expected that these non-inhibitor 
patients will be routinely managed with FVIII and FIX. 
6.3.1.1. 
Bleeding Episode Management Recommendations for Patients in the On-
Demand Treatment Arm (Patients Not Receiving Fitusiran) 
For patients not receiving fitusiran (on-demand arm), bleeding management therapy with factor 
concentrate will be managed based on the local standard practice for treating hemophilia patients 
without inhibitors, as routinely administered by the physician.  Where clinical circumstances 
allow, it is recommended that the patient contact the Investigator for all events that may be 
suspected to be or characteristic of a bleeding episode.  If adequate hemostasis does not occur 
after two doses of factor concentrate, the patient should contact the site for further instruction.  If 
the patient feels the need to administer doses higher than the patient’s bleeding episode 
management plan recommends, or at a higher frequency, it is recommended that the patient 
contact the site.  See Section 7.2.1 regarding patient use of the eDiary and site alerts that will 
assist in this process. 
6.3.1.2. 
Bleeding Episode Management Recommendations for Patients in the Fitusiran 
Treatment Arm 
Given the mechanism of action and pharmacodynamic profile of fitusiran, the factor concentrate 
dose necessary to safely and effectively treat breakthrough bleeding episodes will be lower than 
standardly prescribed.  This is supported by data from the Phase 1 study in which bleed events 
were managed with factor and BPA, as well as additional modeling and ex vivo spiking data.  
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More detailed information on the clinical experience in bleeding episode management in Phase 1 
and Phase 1/2 fitusiran studies, as well as supportive nonclinical studies is provided in the 
Investigator’s Brochure. 
After administration of fitusiran, AT lowering will be progressing toward therapeutic levels.  As 
quickly as 7 days after the initial fitusiran dose, the majority of patients will have AT levels at or 
below 60% residual activity.  By 14 days after dosing, it is expected that 94% of patients will 
have AT lowering of >50%, with a median value of 66.8 %.  Based on these AT kinetics, it is 
recommended that patients continue with their standard factor regimens for the first 7 days 
following initiation of fitusiran dosing, with institution of the protocol-specific bleed 
management guidelines with reduced factor or BPA at Day 8 and beyond (Table 4).  
Patients on fitusiran, will be provided a bleed management plan with appropriate dosing of factor 
concentrates for use during Day 1 through 7, as well as a bleed management plan with dosing for 
Day 8 and beyond.  Thereafter the bleed management plan will be reviewed and updated at 
monthly visits, and new written plans provided to the patient if dosing changes. 
Importantly, during the treatment period, patients should not use factor concentrates or other 
hemostatic agents as prophylaxis for bleeding episode prevention, including doses related to 
anticipated hemostatic challenges such as physical activity.  For prophylaxis of bleeding 
episodes in patients who require operative procedures see Section 6.6. 
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Bleed Management Guidelines Day 1 to Day 7: 
Patients should be instructed to call the site prior to administering factor or BPA.  Patients should 
continue with their standard factor/BPA regimens.  
Bleed Management Guidelines Day 8 and Beyond: 
When a patient experiences symptoms that may be consistent with bleeding episodes, the 
following steps should be followed: 
1. Patient should be instructed to call the study center to discuss symptoms to determine 
whether or not they are consistent with a bleeding event and to discuss the appropriate 
factor/BPA dose to use.  This interaction between patient and Investigator is 
recommended prior to the administration of each dose of factor or BPA.  Confirmation of 
bleeds at the study center prior to treatment may be considered.  Such visits should 
capture assessments per Section 6.4 and Table 2. 
2. If a determination is made that symptoms require treatment, the recommended treatment 
algorithm for bleeding episodes is described below: 
1. A single dose can be administered according to the guidelines in Table 4. 
2. The patient should be instructed to re-evaluate symptoms in 24 hours for bleeds 
treated with FVIII, FIX or aPCC and in 2-3 hours for bleeds treated with rFVIIa. 
a. Administration of FIX Extended half-life should not be more frequent than 
every 5-7 days. 
3. If a second dose (in the case of FVIII, FIX or aPCC) or a third dose (in the case of 
rFVIIa) is needed, the patient must call the study center before dosing. 
a. Consider evaluation and treatment of the patient at the study center and 
confirmation of bleeds when any repeated doses are needed (See Section 6.4 
and Table 2). 
b. If more than two doses of FVIII, FIX or aPCC or three doses of rFVIIa are 
needed, the patient should be seen at the study center within 48-72 hours. 
4. Doses should not be administered at less than 24-hour intervals (except rFVIIa as 
indicated in Table 4). 
5. Doses should not exceed the protocol maximum recommended dose indicated in 
Table 4. 
6. Consultation with the study Medical Monitor and Clinical Advisor should be 
considered for clinical circumstances below, that may warrant AT replacement: 
a. Doses of factor or BPA higher than those recommended in Table 4 
b. Dosing of factor or BPA at decreased intervals than those recommended in 
Table 4 
c. Multiple or repeated doses of factor or BPA  
7. Antifibrinolytics may not be used in combination with factor or BPA. 
 
 
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Table 4: 
Bleed Management Dosing Guidelines by Specific Product 
 
Factor VIII 
Factor IX 
Standard 
half-life 
Factor IX 
Extended 
half-life 
aPCC 
Recombinant 
Factor VIIa 
Recommended 
single dose of 
10 IU/kg 
20 IU/kg 
20 IU/kg 
30 U/kg 
≤45 µg/kg 
Single dose 
should not 
exceed 
20 IU/kg 
30 IU/kg 
30 IU/kg 
50 U/kg 
45 µg/kg 
Repeat dose 
instructions 
Mandatory to call the clinical study center prior to second dose 
Consider evaluation and treatment at the clinical study center 
 (see Section 6.4) 
Mandatory to 
call site prior 
to third dose 
 
Should not 
repeat in less 
than  
24 hours 
Should not 
repeat in less 
than 
24 hours 
Should not 
repeat in less 
than 
5-7 days 
Should not 
repeat in less 
than  
24 hours 
Should not 
repeat in less 
than  
2 hours 
 
Should be seen at site within 48-72 hours if more  
than 2 doses are required 
(see Schedule of Assessments for assessments) 
Should be seen 
at site within 
48-72 hours if 
more than 3 
doses are 
required 
For situations requiring higher doses, more frequent administration, multiple repeated doses, 
discussion with study Medical Monitor and Clinical Advisor is recommended, and AT replacement 
should be considered. 
 
Do not use antifibrinolytics in combination with factor or BPA. 
Note:  Doses of rFVIIa and aPCC are included for completeness.  Adjunctive management of bleeding episodes 
should be carried out per standard of care.  It is expected that these non-inhibitor patients will be routinely 
managed with FVIII and FIX. 
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6.3.1.3. 
Bleeding Episode Management Following Discontinuation of Fitusiran 
Patients who opt to discontinue fitusiran may resume standard on-demand dosing with factor 
concentrates (FVIII, FIX) when their AT residual activity level returns to approximately 60% 
(per the central laboratory).  An earlier restart of standard treatment may be considered in 
conjunction with consultation from the study Medical Monitor, if a strong medical need arises 
(eg, increased frequency of bleeding).  If full doses of factor or BPA are required to achieve 
hemostasis prior to AT recovery of approximately 60% residual activity per the central 
laboratory, AT replacement should be considered. 
6.3.2. 
Other Concomitant Medications 
If patients use nonsteroidal anti-inflammatory drugs intermittently or chronically, they must be 
able to tolerate them and have had no previous side effects (eg, gastric distress or bleeding).   
Use of >4 g acetaminophen per day is not permitted.  
Treatment for HIV is permitted and must be recorded as concomitant medication. 
Standard vitamins and topical medications are permitted.  However, topical steroids must not be 
applied anywhere near the injection site(s) unless medically indicated. 
Any concomitant medication that is required for the patient’s welfare may be prescribed by the 
Investigator.  However, it is the responsibility of the Investigator to ensure that details regarding 
the medication are recorded on the eCRF.  Concomitant medication will be coded using an 
internationally recognized and accepted coding dictionary. 
6.4. 
Assessment of Coagulation Parameters at the Time of a Bleed 
Any patient who presents to the clinical study center for evaluation of symptoms that are 
suspected as characteristic of a bleeding episode, the patient should be assessed by the 
Investigator to determine whether symptom(s) require treatment.  If treatment is required, blood 
samples should be collected predose and postdose and assessments performed as scheduled in 
Table 2. 
If a patient presents following administration of factor or BPAs at home and within 48 hours of 
the dose, and no further treatment is given at the center, AT and the postdose assessments in 
Table 2 should be obtained in a single draw at any time during the visit. 
6.5. 
Monitoring and Management of Thrombotic Events 
Given safety events observed thus far and the possible thrombotic risk associated with fitusiran’s 
AT lowering mechanism, which may be increased with concurrent use of factor replacement 
products or BPAs, there should be a low threshold to evaluate any signs and symptoms 
consistent with thrombosis, including symptoms consistent with CVST.  Symptoms of 
thrombosis may include a severe or persistent headache, headache with nausea and vomiting, 
chest pain/tightness, coughing up blood, trouble breathing, abdominal pain, fainting or loss of 
consciousness, vision problems, and swelling or pain in the arms or legs. 
If signs and symptoms consistent with thrombosis are present, the Investigator should evaluate 
the patient for thrombosis, including appropriate imaging studies.  For the diagnosis of CVST 
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magnetic resonance imaging venogram (MRV) or computed tomography venogram (CTV) are 
recommended.[7] 
If a patient develops a thrombosis while on fitusiran, AT reversal is recommended in 
combination with factor or BPA replacement and appropriate anticoagulation.  AT reversal 
should follow labeled product recommendations for the prevention of perioperative thrombosis 
in patients with AT deficiency, and patient doses individualized to target 80-120% AT activity.  
The use of plasma derived AT may be preferable to recombinant AT, given its longer half-life.  
It is recommended that cases of thrombosis are discussed with the study Medical Monitor and 
Clinical Advisor (see Section 7.5.6.1 for further information regarding Adverse Events of 
Special Interest). 
6.6. 
Elective and/or Emergency Surgery 
If an urgent need for surgery arises during the study period, the study Medical Monitor will be 
informed and the perioperative hemostatic treatment plan will be communicated to the study 
Medical Monitor unless clinical circumstances do not allow. 
It is recommended that, when possible, any elective non-dental major surgery be performed at a 
clinical study center. 
For reference, see Appendix (Section 11.2.1) for definitions of minor and major surgery. 
Perioperative Treatment Plan 
In patients in both the on-demand arm and the fitusiran treatment arm undergoing surgery, a 
written perioperative treatment plan will be reviewed with the study Medical Monitor before 
conducting the procedure, unless clinical circumstances do not allow.  In patients on fitusiran, 
the perioperative treatment plan should be developed using the same principles as bleed 
management described in Section 6.3.1 and the guideline below:   
 If the clinical circumstance is such that the recommended doses and/or dose intervals in 
Table 4 are deemed insufficient for hemostasis, consider AT replacement and manage 
thrombotic risk as per Investigator practice for a hemophilia patient undergoing that 
particular surgery.  
 Non-pharmacologic methods of thromboprophylaxis should also be employed as 
clinically indicated. 
Fitusiran Treatment During the Perioperative Evaluation Period  
For reference, see Appendix (Section 11.2.1) for definitions of minor and major surgery. 
If the need for a major surgery arises during the trial and the procedure is not an emergency or 
urgent, it is recommended that the procedure be postponed until after completion of the trial.   
For minor operative procedures, dosing with fitusiran may continue uninterrupted. 
If the need for emergency or urgent major surgery arises during the trial, the patient should be 
managed medically according to the guidelines above.  If a fitusiran dose is scheduled to occur 
on or in close proximity to the day of surgery, or anytime during the perioperative period, the 
dose should be withheld.  The Perioperative Period is defined as the day of the surgery through 
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the final day on which supplemental hemostatic or antithrombotic treatments are administered as 
part of the perioperative treatment plan.  Fitusiran dosing may be resumed at the next scheduled 
visit following the Perioperative Evaluation Period at the discretion of the Investigator.  If 
multiple consecutive doses of fitusiran are withheld, the Investigator will consult with the study 
Medical Monitor, who will determine if the patient may continue on study. 
Perioperative assessments will be performed in patients undergoing surgery during the study as 
described in Appendix (Section 11.2.2) and as scheduled in Table 10. 
6.7. 
Management of Sepsis 
 Formal clinical guidelines do not currently recommend correction of low AT that is seen in the 
setting of sepsis, citing a lack of evidence for improved outcomes and an increased risk of 
bleeding.[8, 9].  If a clinical determination is made that AT correction is desirable for a fitusiran-
treated patient in the setting of sepsis, this may be initiated per Investigator discretion. 
6.8. 
Contraceptive Requirements 
All study patients will be male and there are no contraceptive requirements for this study except 
where required per local regulations. 
Details of fitusiran toxicology studies are presented in the Investigator’s Brochure. 
6.9. 
Treatment Compliance 
Compliance with scheduled clinic visits (Table 1), and patient use of eDiary to record data as 
required, will be monitored by study staff over the 9-month treatment duration. 
6.10. 
Alcohol Restrictions 
Patients will be required to limit alcohol consumption throughout the course of the study.  Alcohol is 
limited to no more than 2 units (unit:  1 glass of wine [approximately 125 mL] = 1 measure of spirits 
(approximately 1 fluid ounce) = ½ pint of beer [approximately 284 mL]) per day (no more than 
14 units per week) for the duration of the study. 
7. 
STUDY ASSESSMENTS 
The Schedule of Assessments is provided in Table 1.  Additional information on the collection of 
study assessments will be detailed in the Study Manual. 
7.1. 
Screening/Baseline Assessments 
An informed consent form (ICF) or assent form that has been approved by the appropriate 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) must be signed by the 
patient (or legal guardian) before the Screening/Baseline procedures are initiated.  All patients 
(or their legal guardians) will be given a copy of the signed and dated ICF and/or assent form. 
Patient demographic and medical history will be obtained at Screening.  Medical history must 
include documentation of factor concentrate prescriptions (in the medical or pharmacy record) 
and documentation of reported number of bleeding episodes over the last 6 months.  Patients will 
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be screened to ensure that they meet all of the inclusion criteria and none of the exclusion 
criteria.  Rescreening of patients is permitted with consultation of the study Medical Monitor. 
To complement medical records, information regarding health resource use will be collected as 
specified in the Schedule of Assessments (Table 1), including days missed from work/school (as 
appropriate) and days not able to perform normal activities outside of work/school due to 
hemophilia, physician office visits, hemophilia treatment site visits, emergency room visits 
(reason and number), hospitalizations (reason, dates of hospitalization and associated length of 
stay). 
7.1.1. 
Patient Education Module 
Patients will be educated by Investigators or trained healthcare professionals on coagulation and 
general considerations with regard to managing hemophilia in the clinical setting of lowered-AT.  
This will be performed as specified in the Schedule of Assessments (Table 1). 
7.1.2. 
Inhibitor Status 
Patients inhibitor status will be determined as specified in the Schedule of Assessments (Table 1) 
by Nijmegen modified Bethesda assay.   
7.1.3. 
FibroScan or FibroTest/APRI 
A FibroScan or FibroTest/APRI will be performed according to the Schedule of Assessments 
(Table 1) to rule out cirrhosis in patients with a history of Hepatitis C. 
7.2. 
Efficacy Assessments 
Bleeding Episode Definitions 
A bleeding episode is defined as any occurrence of hemorrhage that requires administration of 
factor concentrates or BPA infusion, eg, hemarthrosis, muscle, or mucosal bleeding episodes.  
Since bleeding episodes are recorded as an efficacy assessment of fitusiran, these will not be 
treated as AEs unless they meet any of the SAE criteria listed in Section 7.5.6.1. 
The definition of bleeding episode types described below is based on consensus opinion of 
International Society on Thrombosis and Hemostasis (ISTH) as reflected in a recent 
publication.[10] 
The start time of a bleeding episode will be considered the time at which symptoms of a bleeding 
episode first develop.  Bleeding, or any symptoms of bleeding at the same location, that occurs 
within 72 hours of the last injection used to treat a bleeding episode at that location will be 
considered a part of the original bleeding event, and will count as one bleeding episode towards 
the ABR.  Any bleeding symptoms that begin more than 72 hours from the last injection used to 
treat a bleeding episode at that location will constitute a new bleeding event. 
A spontaneous bleeding episode is a bleeding event that occurs for no apparent or known reason, 
particularly into the joints, muscles, and soft tissues. 
A joint bleeding episode is characterized by an unusual sensation in the joint (“aura”) in 
combination with 1) increasing swelling, or warmth over the skin over the joint, 2) increasing 
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pain, or 3) progressive loss of range of motion or difficulty in using the limb as compared with 
baseline. 
A muscle bleed may be characterized by pain, swelling and loss of movement over the affected 
muscle group. 
A target joint is defined as a joint where 3 or more spontaneous bleeding episodes in a single 
joint within a consecutive 6-month period has occurred; where there have been ≤2 bleeding 
episodes in the joint within a consecutive 12-month period the joint is no longer considered a 
target joint. 
A traumatic bleeding episode is one that is caused by a known injury or trauma.  Bleeding 
episodes sustained during sports and recreation will be counted as traumatic bleeding episodes, 
but patients will be asked to indicate in the eDiary that the event occurred during such activities.  
Training will be provided on this and other aspects of eDiary use (see Section 7.2.1). 
Annualized bleeding rate will be calculated as described in Section 8.2.5.1.  Bleeding episodes 
will be managed according to Section 6.3.1. 
7.2.1. 
Electronic Diary  
Patients will be issued an eDiary to record all bleeding events and all doses of factor concentrates 
administered during the conduct of the study.  Entries are to be made in a timely manner, and it 
is preferred that doses are entered immediately upon administration or within 24 hours.  Patients 
will be prompted to enter bleeding location, severity, causality (spontaneous or traumatic), doses 
of factor concentrates, and reasons for dosing (prophylaxis, treatment of a bleed, and preventive 
dose for anticipated activity).  Training of patients should be documented in the appropriate 
source record. 
The Sponsor or an independent delegate will review diary entries for data quality to identify 
issues such as subjects who may need retraining on diary use and timely entry of bleeding 
episode information. 
Bleeding episodes will be recorded by the patient in the eDiary, and reviewed by the Investigator 
(and Sponsor or independent delegate) continuously for the study duration.  The site will contact 
the patient at a minimum interval of every 2 weeks per schedule of assessments to review diary 
records and ensure that the patient is utilizing the device appropriately.   
Sites will be notified when patients enter initial treatments for bleeding events into their eDiaries.  
If the dose amount exceeds the recommended dose according to the bleeding management plan, 
the patient must be contacted as soon as possible, preferably within 24-48 hours of receiving the 
alert.  At the time of contact the patient’s clinical condition will be reviewed along with the dose 
and efficacy of the treatment given, and the Investigator will provide appropriate guidance 
regarding further management of the bleeding episode.  The site will also receive an alert, and 
must make contact with the patient as soon as possible if a third dose of product is administered 
for a single bleed, to review clinical condition, the need for further therapy, and appropriate 
ongoing management of the bleeding episode required to achieve hemostasis.   
In addition, patients will be instructed to contact the site if they feel they need to administer 
factor concentrates at a higher dose level or higher frequency than their bleeding management 
plan recommends, or if more than two doses are required to achieve hemostasis. 
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Complete instructions will be provided in the Study Manual. 
7.3. 
Pharmacodynamic Assessments 
In this study AT activity level and thrombin generation will be collected as measurements of PD 
effect.  These measurements will be collected and analyzed centrally for research purposes.  As 
interpretation is uncertain, TG thrombin generation results will not be used to adjust dosing of 
fitusiran or guide other elements of study conduct or clinical management and will not be shared 
with sites until after study completion.  If clinical circumstances arise for which AT activity 
levels are required to guide patient care, local laboratory assessments may be drawn. 
7.3.1. 
Antithrombin Activity 
AT activity level will be assessed according to the Schedule of Assessments (Table 1); samples 
will be collected within 4 hours prior to dosing.  Antithrombin levels will be determined by 
validated assay.  Antithrombin protein may be measured in a subset of plasma samples for 
correlation.  Results will be collected and interpreted centrally.   
In the fitusiran treatment arm patients who do not enroll in the extension study, following final 
fitusiran dose, AT activity level will be monitored at monthly intervals until returning to an 
activity level of approximately 60% (per the central laboratory) or per Investigator discretion in 
consultation with the study Medical Monitor. 
7.3.2. 
Thrombin Generation 
Thrombin generation will be assessed according to the Schedule of Assessments (Table 1) using 
a functional assay per the Laboratory Manual, and will be collected and interpreted centrally. 
7.3.3. 
Exploratory Analyses 
Except where prohibited by local or national regulations, in consented patients, plasma, serum, 
and urine samples may be archived and used for analyses of exploratory biomarkers related to 
the metabolic profiling or effects of fitusiran and for the development of modified thrombin 
generation assays, and may also be archived for use in other exploratory analyses related to 
hemophilia and its complications. 
In addition, where permitted in consented patients, serum samples may be used for analysis of 
circulating RNA, including the assessment of cleaved AT RNA, and a sample of DNA may be 
obtained and archived to permit potential confirmation of hemophilia mutation or genotyping of 
hemophilia modifier genes or genes that may modify the effects of fitusiran. 
7.4. 
Pharmacokinetic Assessments 
Blood samples will be collected for assessment of PK including metabolites (as necessary) in all 
fitusiran arm patients according to the collection schedule presented in Table 7 on the days 
specified in the Schedule of Assessments (Table 1).   
Blood must be aliquoted and processed as plasma for PK analysis.  All plasma concentration data 
(Table 7 and Table 8) will be summarized and analyzed using a population PK approach. 
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In addition, plasma PK (Table 8, which includes those time points in Table 7) will be evaluated 
in East Asian patients in the fitusiran arm at East Asian sites (defined as patients from sites in 
China, Japan, South Korea, and Taiwan), and there will be pooled urine collection for urine PK 
analysis also in these patients (Table 9).   
The concentration of fitusiran will be determined using a validated assay.  Full details regarding 
the processing, shipping, and analysis of the samples will be provided in the Laboratory Manual. 
7.5. 
Safety Assessments 
The assessment of safety during the course of the study will consist of the surveillance and 
recording of AEs, including SAEs, recording of concomitant medication and measurements of 
vital signs, weight and height, physical examinations, ECG findings, and laboratory tests. 
Safety data will be periodically reviewed over the course of the study by the DMC as described 
in Section 4.7. 
7.5.1. 
Vital Signs 
Vital signs will be measured as specified in the Schedule of Assessments (Table 1) and will 
include blood pressure, heart rate, body temperature, and respiratory rate.  Vital signs will be 
measured predose in the seated or supine position, after the patient has rested comfortably for 
10 minutes.   
Body temperature in degrees Celsius will be obtained via oral, tympanic, or axillary methods.  
Heart rate will be counted for a full minute and recorded in beats per minute, and respiration rate 
will be counted for a full minute and recorded in breaths per minute. 
For the safety of the patient, additional vital sign assessments may be added at the discretion of 
the Investigator. 
Vital signs results will be recorded in the eCRF. 
7.5.2. 
Weight and Height 
Height will be measured in centimeters.  Body weight will be measured in kilograms.  Height 
and body weight measurements will be collected as specified in the Schedule of Assessments 
(Table 1) and will be recorded in the eCRF. 
7.5.3. 
Physical Examination 
Full and directed physical examinations will be conducted according to the Schedule of 
Assessments (Table 1); if a physical examination is scheduled for a dosing visit, it should be 
conducted prior to dosing. 
Full physical examinations will include the examination of the following:  general appearance; 
head, eyes, ears, nose, and throat; respiratory, cardiovascular, gastrointestinal, musculoskeletal, 
and dermatological systems; thyroid; lymph nodes; and neurological status.   
Directed physical examinations will include examination of the following systems with attention 
to evaluation for signs and symptoms of thrombosis, bleeding, and arthropathy:  neurologic, 
chest/respiratory, heart/cardiovascular, dermatological/skin, gastrointestinal/liver, and 
musculoskeletal/extremities.  Other organ systems may be evaluated as indicated by patient 
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symptoms.  In patients undergoing a surgical procedure, a directed physical examination will 
also be performed as specified in the Perioperative Schedule of Assessments (Table 10). 
Physical examination notes regarding any observed abnormalities will be recorded on the eCRF. 
7.5.4. 
Electrocardiogram 
Triplicate standard 12-lead ECGs, with readings approximately 1 minute apart, will be recorded 
as specified in the Schedule of Assessments (Table 1).  Patients should be supine for at least 5 
minutes before each ECG is obtained.  The electrophysiological parameters assessed will be 
rhythm, ventricular rate, RR interval, PR interval, QRS duration, QT interval, Bazett-corrected 
QT interval (QTcB), and Fridericia corrected QT interval (QTcF). 
When ECG and blood sample collection occur at the same time, ECGs should be performed 
before blood samples are drawn. 
The Investigator or qualified designee will review all ECGs to assess whether the results have 
changed since the Baseline visit and to determine the clinical significance of the results.  These 
assessments will be recorded on the eCRF.  Additional ECGs may be collected at the discretion 
of the Investigator.  Recordings will be archived according to the Study Manual. 
7.5.5. 
Clinical Laboratory Assessments 
The following clinical laboratory tests will be evaluated by a central laboratory.  Specific 
instructions for transaminase elevations are provided in Section 6.2.3.1.  For any other 
unexplained clinically relevant abnormal laboratory test occurring after IMP administration, the 
test should be repeated and followed up at the discretion of the Investigator until it has returned 
to the normal range or stabilized, and/or a diagnosis is made to adequately explain the 
abnormality.  Additional safety laboratories and assessments as indicated by the clinical situation 
may be requested.  Clinical laboratory assessments are listed in Table 5 and assessments will be 
assessed as specified in the Schedule of Assessments (Table 1). 
While local laboratory results may be used for urgent clinical and dosing decisions, on the day of 
the clinic visit assessments, all laboratory assessments specified in Table 5 which are performed 
at the clinic should also be sent in parallel to the central laboratory.  In the case of discrepant 
local and central laboratory results on samples drawn on the same day, central laboratory results 
will be relied upon for clinical and dosing decisions. 
Clinical laboratory assessments may be collected at the clinical site or at home by a trained 
healthcare professional.  It is preferred that clinical laboratory assessments be drawn via 
peripheral draw (ie, fresh stick), however in cases where peripheral access is not possible 
existing indwelling venous access may be utilized. 
Please see Section 6.2.3.1 for the LFT monitoring and dosing plan. 
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Table 5: 
Clinical Laboratory Assessments 
Hematology 
Hematocrit 
Neutrophils, absolute and % 
Hemoglobin 
Lymphocytes, absolute and % 
RBC count 
Monocytes, absolute and % 
WBC count 
Eosinophils, absolute and % 
Mean corpuscular volume 
Basophils, absolute and % 
Mean corpuscular hemoglobin 
Platelet count 
Mean corpuscular hemoglobin concentration 
CD4 in HIV-positive patients 
(at Screening only) 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Phosphate 
Creatinine and eGFR (using the MDRD formula) 
Albumin 
 Glucose 
Calcium 
 Chloride 
Carbon dioxide 
Liver Function Tests (LFTs) 
 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
GGT 
 
Coagulation 
Prothrombin time 
Activated partial thromboplastin time 
INR 
Fibrinogen 
D-dimera 
Prothrombin fragment 1, 2 
Factor Activity 
FVIII activity for patients with hemophilia A 
FIX activity for patients with hemophilia B 
Urinalysis 
Visual inspection for appearance and color 
Bilirubin 
pH (dipstick) 
Nitrite 
Specific gravity 
RBCs 
Ketones 
Urobilinogen 
Glucose 
Leukocytes 
Protein 
Microscopy (if clinically indicated) 
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Table 5: 
Clinical Laboratory Assessments 
Thrombophilia Screening 
Protein C deficiency 
Protein S deficiency 
Factor V Leiden (genetic testing) 
Prothrombin mutation (genetic testing) 
Hepatic Tests 
Hepatitis A, including: 
HAV antibody IgM and IgG 
Hepatitis C, including:  
HCV antibody 
HCV RNA PCR – qualitative and quantitative 
assays 
Hepatitis B, including:  
HBs Ag, anti-HBc antibody, IgM and IgG 
Hepatitis E, including: 
HEV antibody IgM and IgG 
Immunogenicity 
Antidrug Antibodies 
Note:  All assessments will be measured in the central laboratory. 
Abbreviations:  ALP=alkaline phosphatase; ALT=alanine transaminase; AST=aspartate transaminase; BUN=blood 
urea nitrogen; CD4=cluster of differentiation 4; eGFR=estimated glomerular filtration rate; FIX=factor IX; 
FVIII=factor VIII; GGT= gamma glutamyl transferase; HAV=hepatitis A virus; HBs Ag=hepatitis B virus surface 
antigen; HBc=hepatitis B virus core; HCV=hepatitis C virus; HEV=hepatitis E virus; HIV=human 
immunodeficiency virus; IgG=immunoglobulin G antibody; IgM=immunoglobulin M antibody; INR=International 
normalized ratio; MDRD=Modification of Diet in Renal Disease; PCR=polymerase chain reaction; RBC=red 
blood cell; RNA=ribonucleic acid; WBC=white blood cell. 
a Will not be communicated to investigational sites. 
7.5.5.1. 
Additional Laboratory Assessments 
For any safety event or laboratory abnormality, additional laboratory assessments, imaging, and 
consultation may be performed for clinical evaluation and/or in consultation with the study 
Medical Monitor; results may be collected and should be included in the clinical database. 
Additional laboratory assessments will be performed in patients who experience any LFT 
abnormalities as outlined in Section 6.2.3.1.  Following the occurrence of elevated liver 
transaminases or other LFT abnormalities per central laboratory, all assessments in Table 6 will 
be performed one time, as well as hematology, serum chemistry, LFT, and coagulation 
assessments from Table 5, AT levels, and other assessments or evaluations per Investigator 
discretion, as appropriate. 
Monitoring and dose modification will also be performed as outlined in Section 6.2.3.1.  
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Table 6: 
Hepatic Assessments in Patients who Experience LFT Elevations 
Extended Hepatic Panel 
Herpes Simplex Virus 1 and 2 antibody IgM, IgG 
Herpes Zoster Virus IgM, IgG 
HIV 1 and 2a 
HHV-6  
Cytomegalovirus antibodies, IgM, IgG 
HBs Ag, HBc antibody IgM and IgG 
Anti-nuclear antibodies 
Epstein-Barr Virus antibodies, IgM and IgG 
Anti-smooth muscle antibodies 
Anti-mitochondrial antibodies 
HCV antibody 
HAV antibody IgM 
HCV RNA PCR – qualitative and quantitative 
HEV antibody IgM 
Imaging 
Abdominal ultrasound with Doppler flow (or CT or MRI) including right upper quadrant 
Focused Medical and Travel History 
Use of any potentially hepatotoxic concomitant 
medications, including over the counter medications 
and herbal remedies 
Alcohol consumption  
Other potentially hepatotoxic agents including any 
work-related exposures 
Recent travels to areas where hepatitis A or E is 
endemic 
Note:  All assessments will be measured in central laboratory. The full panel of assessments should only be performed once; 
individual assessments may be repeated, as needed.  
Abbreviations:  CT=computed tomography; HAV=hepatitis A virus; HBc=hepatitis B core; HBs Ag=hepatitis B 
virus surface antigen; HCV=hepatitis C virus; HEV=hepatitis E virus; HHV-6=human herpesvirus 6; HIV=human 
immunodeficiency virus; IgG=immunoglobulin G antibody; IgM=immunoglobulin M antibody; MRI=magnetic 
resonance imagery; PCR=polymerase chain reaction; PT=prothrombin time; RNA=ribonucleic acid 
a HIV testing will not be performed where prohibited by local regulations. 
7.5.5.2. 
Immunogenicity 
Blood samples will be collected to evaluate antidrug antibodies (ADAs) to fitusiran.  Blood 
samples for ADA testing must be collected within 4 hours before IMP administration as 
specified in the Schedule of Assessments (Table 1).  In addition, a blood sample to evaluate 
ADAs will be collected at the ET visit, if applicable. 
Details regarding the processing, shipping, and analysis of the samples are provided in the 
Laboratory Manual. 
7.5.6. 
Adverse Events 
7.5.6.1. 
Definitions 
Adverse Event 
According to the International Conference on Harmonisation (ICH) E2A guideline Definitions 
and Standards for Expedited Reporting, and 21 Code of Federal Regulations (CFR) 312.32, IND 
Safety Reporting, an AE is any untoward medical occurrence in a patient or clinical 
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investigational subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment.  Since bleeding episodes are recorded as an efficacy 
assessment of fitusiran, these will not be treated as AEs unless they meet any of the SAE criteria 
listed in Section 7.5.6.1. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death 
 Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred.  It does not include an event that had it occurred in a more 
severe form might have caused death.) 
 Requires in-patient hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability or incapacity 
 Is a congenital anomaly or birth defect 
 Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient and may require 
intervention to prevent one of the other outcomes listed in the definition above (eg, 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias, convulsions, or the development of drug 
dependency or abuse) 
 Bleeding episodes will be recorded as an efficacy assessment of fitusiran and will not 
be treated as AEs unless they meet any of the above criteria for SAEs. 
Adverse Events of Special Interest  
The following events are considered to be AEs of special interest (AESI):  
 ALT or AST elevations >3× ULN 
 Suspected or confirmed thrombosis 
 Severe or serious ISRs; ISRs that are associated with a recall phenomenon (reaction 
at the site of a prior injection with subsequent injections), or those that lead to 
temporary dose interruption or permanent discontinuation of fitusiran 
 Systemic injection associated reactions (IARs), defined as hypersensitivity reactions 
which are related or possibly related to IMP.  
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Adverse Event Severity 
Adverse events are to be graded according to the categories detailed below: 
Mild: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated  
Moderate: 
Moderate; minimal, local, or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (eg, preparing meals, 
shopping for groceries or clothes, using the telephone, managing money)   
Severe: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living (ie, bathing, dressing and undressing, feeding 
self, using the toilet, taking medications, and not bedridden); OR life-
threatening consequences; urgent intervention indicated; OR death related to 
an AE 
Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity.  Adverse events characterized as intermittent 
require documentation of the start and stop of each incidence.  When changes in the severity of 
an AE occur more frequently than once a day, the maximum severity for the experience that day 
should be noted.  If the severity category changes over a number of days, then those changes 
should be recorded separately (with distinct onset dates). 
Adverse event severity and seriousness are assessed independently.  ‘Severity’ characterizes the 
intensity of an AE.  ‘Serious’ is a regulatory definition and serves as a guide to the Sponsor for 
defining regulatory reporting obligations (see definition for SAE). 
Relationship of the Adverse Event to Study Treatment 
The relationship of each AE to study treatment should be evaluated by the Investigator using the 
following criteria:  
Definitely related: 
A clinical event, including laboratory test abnormality, occurring in a plausible 
time relationship to the medication administration, and which cannot be 
explained by concurrent disease or other drugs or chemicals.  The response to 
withdrawal of the drug should be clinically plausible. 
Possibly related: 
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to the medication administration, but which could also be explained 
by concurrent disease or other drugs or chemicals.  Information on the drug 
withdrawal may be lacking or unclear. 
Unlikely related: 
A clinical event, including laboratory test abnormality, with little or no 
temporal relationship to medication administration, and which other drugs, 
chemicals, or underlying disease provide plausible explanations. 
Not related: 
A clinical event, including laboratory test abnormality that has no temporal 
relationship to the medication or has more likely alternative etiology. 
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7.5.6.2. 
Eliciting and Recording Adverse Events 
Eliciting Adverse Events 
The patient should be asked about medically relevant changes in his health since the last visit, 
with attention to any signs and symptoms that could be consistent with thrombosis.  The patient 
should also be asked if he has been hospitalized, had any accidents, used any new medications, 
or changed concomitant medication routines (both prescription and OTC).  In addition to patient 
observations, AEs will be documented from any clinically relevant laboratory findings, physical 
examination findings, ECG changes, or other findings that are relevant to patient safety. 
Recording Adverse Events 
The Investigator is responsible for recording non-serious AEs and SAEs that are observed or 
reported by the patient after the time when the informed consent is signed regardless of their 
relationship to IMP through the end of study.  Non-serious AEs will be followed until the end of 
study.  SAEs will be followed until satisfactory resolution, until baseline level is reached, or until 
the SAE is considered by the Investigator to be chronic or the patient is stable, as appropriate. 
All AEs must be recorded in the source records for the clinical study center and in the eCRF for 
the patient, whether or not they are considered to be drug-related.  Each AE must be described in 
detail:  onset time and date, description of event, severity, relationship to investigational drug, 
action taken, and outcome (including time and date of resolution, if applicable). 
For SAEs, record the event(s) on both the eCRF and the SAE form. 
For AEs that are considered AESI (Section 7.5.6.1), the Sponsor or its designee should be 
notified within 24 hours using a supplemental AESI eCRF.  Additional clinical and laboratory 
information may be collected; see Section 6.2.3.1 regarding monitoring for liver abnormalities.   
Refer to eCRF completion guidelines for details on reporting events in the supplemental AESI 
eCRF. 
Since bleeding episodes are recorded as an efficacy assessment of fitusiran, these will not be 
treated as AEs unless they meet any of the SAE criteria listed in Section 7.5.6.1.  The 
manifestation and frequency of bleeding episodes is an efficacy indicator of this study and ABR 
is the focus of the primary and secondary efficacy analyses. 
Recording an ISR 
For all ISRs, the Investigator, or delegate, should submit a supplemental ISR eCRF, recording 
additional information (eg, descriptions, onset and resolution date, severity, treatment given, 
event outcome).  An ISR is defined as a local reaction at or near the site of injection.  “At or 
near” the injection site includes reactions at the injection site, adjacent to the injection site, or a 
reaction which may shift slightly away from the injection site due to gravity (eg, as may occur 
with swelling or hematoma).  Reactions with onset and resolution within 4 hours of the injection 
(eg, transient pain/burning at injection site) do not meet the study definition of ISRs, unless 
immediate treatment is required.  A systemic reaction which includes the injection site, eg, 
generalized urticaria, other distinct entities, or conditions like lymphadenopathy that may be near 
the injection site is not considered an ISR. 
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7.5.6.3. 
Serious Adverse Events and Adverse Events of Special Interest Require 
Immediate Reporting to Sponsor/Designee 
An assessment of the seriousness of each AE will be made by the Investigator.  Any AE and 
laboratory abnormality that meets the SAE criteria in Section 7.5.6.1 and any AESI must be 
reported to the Sponsor or designee within 24 hours from the time that clinical study center staff 
first learns of the event.  All SAEs must be reported regardless of the relationship to IMP. 
The initial report should include at least the following information: 
 Patient’s study number 
 Description and date of onset of the event 
 Criterion for serious 
 Preliminary assignment of relationship to IMP, and 
 Investigator/site information 
To report the SAE, complete the SAE form.  Within 24 hours of receipt of follow-up 
information, the Investigator must update the SAE form.  Serious AEs must be reported using the 
contact information provided in the Study Manual. 
Appropriate remedial measures should be taken by the Investigator using his/her best medical 
judgment to treat the SAE.  These measures and the patient’s response to these measures should 
be recorded.  All SAEs, regardless of relationship to IMP, will be followed by the Investigator 
until satisfactory resolution or the Investigator deems the SAE to be chronic or stable.  Clinical, 
laboratory, and diagnostic measures should be employed by the Investigator as needed to 
adequately determine the etiology of the event. 
7.5.6.4. 
Sponsor Safety Reporting to Regulatory Authorities 
The Sponsor or its representative will report certain study events in an expedited manner to the 
Food and Drug Administration, the European Medicines Agency’s EudraVigilance electronic 
system according to Directive 2001/20/EC, and to all country Regulatory Authorities where the 
study is being conducted, according to local applicable regulations. 
7.5.6.5. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee 
Suspected unexpected serious adverse reactions (SUSARs) will be reported to the IRB/IEC per 
their institutional policy by the Investigator or Sponsor (or Sponsor designee) according to 
country requirements.  Copies of each report and documentation of IRB/IEC notification and 
acknowledgement of receipt will be kept in the Investigator’s study file. 
7.5.6.6. 
Pregnancy Reporting 
There will only be male patients in this study. 
The reporting of any pregnancy outcome for a female partner of a male patient participating in 
this study that results in a postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly should be reported to the Investigator, who will then report this to 
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the Sponsor or designee.  The pregnancy outcome is to be recorded on the pregnancy reporting 
form. 
7.5.6.7. 
Overdose Reporting 
An overdose is defined as any dose administered to or taken by a patient (accidentally or 
intentionally) that exceeds the highest daily dose, or is at a higher frequency than included in the 
protocol.  Overdose must be recorded in the eCRF. 
All reports of overdose (with or without an AE) must be reported within 24 hours to the Sponsor 
or designee.   
7.5.6.8. 
Guidelines for Reporting Product Complaints/Medical Device Incidents 
(Including Malfunctions) 
Any defect in the IMP must be reported as soon as possible by the Investigator to the monitoring 
team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels, or documents like pictures or photocopies) related 
to product identification and to the potential deficiencies may need to be gathered.  The 
Investigator will assess whether or not the quality issue has to be reported together with an AE or 
SAE. 
7.6. 
Other Assessments 
7.6.1. 
Patient-reported Outcomes 
Patient-reported outcomes will be utilized in this study where available to assess health-related 
quality of life (HRQOL), physical activity, and treatment satisfaction and health utility.  The age 
of the patient at randomization will determine which age-specific questionnaires will be utilized, 
and will be in force for the study duration.  All completed questionnaires or instrument forms for 
the patient-reported outcome assessments described below will be collected, entered into a 
database, and archived according to the Study Manual. 
The Sponsor or designee will provide the translations for all survey instruments, where 
translations are available.  The sites must not translate any survey instruments. 
7.6.1.1. 
HRQOL Instruments: Haem-A-QOL and Haemo-QOL 
The Hemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) and Hemophilia 
Quality of Life Questionnaire for Children and Adolescents (Haemo-QOL) are psychometrically 
tested QOL assessment instruments for patients with hemophilia.[11]  The Haem-A-QOL will be 
provided to patients ≥17 years of age, and includes 46 items contributing to 10 QOL domains 
(physical health, feelings, view of yourself, sports and leisure, work and school, dealing with 
hemophilia, treatment, future, family planning, partnership and sexuality).  Scoring for each item 
is based on a 5-point Likert scale (never, rarely, sometimes, often, and all the time), and higher 
scores represent greater impairment. 
The Haemo-QOL (Children’s short version for age groups II/III [8-16 years of age]) will be 
provided to patients <17 years of age, to self-complete as specified in the Schedule of 
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Assessments (Table 1).  The same questionnaire used during the Baseline visit will be utilized 
throughout the study. 
7.6.1.2. 
TSQM-9 
The Treatment Satisfaction Questionnaire for Medication (TSQM) will assess patient satisfaction 
with treatment.  The TSQM is a validated psychometric tool that provides a general measure of 
patient satisfaction with medication.[12]  Where available, the TSQM questionnaire will be 
distributed to patients to self-complete as specified in the Schedule of Assessments (Table 1). 
7.6.1.3. 
HAL 
The Hemophilia Activities List (HAL) and the Pediatric HAL (pedHAL) questionnaires will 
assess subjective functional ability to perform activities of daily living.[13]  The HAL will be 
assessed in patients ≥18 years of age and the pedHAL will be assessed in patients <18 years of 
age.  Where available, the HAL questionnaire will be distributed to patients to self-complete as 
specified in the Schedule of Assessments (Table 1). 
7.6.1.4. 
EQ-5D-5L 
The EQ-5D-5L is a standardized instrument for use as a measure of QOL outcome.[14]  It 
consists of a questionnaire pertaining to 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression) and a visual analog scale.  Scoring of the questionnaire 
is based on 5 degrees of disability (none, slight, moderate, severe, or extreme).  Scoring of the 
visual analog scale is based on a visual scale ranging from 0 (worst imaginable health state) to 
100 (best imaginable health state).  Higher scores indicate better health status.  The 
questionnaires will be completed by all patients as specified in the Schedule of Assessments 
(Table 1). 
7.6.2. 
Weight-adjusted Consumption of Factor Concentrates 
Factor concentrate dose will be recorded by the patient in the eDiary and reviewed by the 
Investigator (and Sponsor or delegate) for the study duration to assess on-demand factor 
concentrate use as treatment of breakthrough bleeding episodes.  Weight adjustment will be 
calculated programmatically. 
7.6.3. 
HJHS 
The HJHS is a tool for assessment of joint health in subjects with hemophilia.[15]  Joint health 
status will be assessed via the HJHS, as administered by a healthcare professional trained in the 
use of anthropometric measures, as specified in the Schedule of Assessments (Table 1).  
Completed HJHS score forms will be collected and archived according to the Study Manual. 
8. 
STATISTICS 
A Statistical Analysis Plan (SAP) will be finalized before database lock.  The plan will detail the 
implementation of the statistical analyses in accordance with the principal features stated in the 
protocol.  
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The primary efficacy and safety analyses will be performed after all patients have either finished 
the 9-month treatment period or discontinued from the study. 
8.1. 
Determination of Sample Size 
Assuming a mean ABR of 18 with standard deviation (SD) = 14 in the on-demand arm (patients 
randomized to receive on-demand factor concentrates) and a mean ABR of no more than 4 with 
SD = 6 in the fitusiran treatment arm (patients randomized to receive fitusiran) in either the 
efficacy period or treatment period, with a sample size of 32 evaluable patients in on-demand 
arm and approximately 64 evaluable patients in the fitusiran treatment arm, it is projected that 
the study will have greater than 90% power for testing treatment difference in mean ABRs.  This 
power estimation was based on a negative binomial regression model with a 2-sided type I error 
rate of 0.05.  
The planned sample size is 120 randomized patients assuming a 20% drop-out rate. 
8.2. 
Statistical Methodology 
The statistical and analytical plans presented below are brief summaries of planned analyses.  
More complete plans will be detailed in the SAP.  Changes to the methods described in the final 
SAP will be described and justified as needed in the clinical study report. 
8.2.1. 
Populations to be Analyzed 
The populations (analysis sets) are defined as follows:  
 Intent-to-treat (ITT) Analysis Set: All randomized patients.  All by-treatment analyses 
based on the ITT analysis set will be according to the randomized treatment arm.  
 Safety Analysis Set: All patients who received at least 1 dose of fitusiran or were 
randomized to on-demand arm.  All by-treatment analyses based on the safety 
analysis set will be according to the actual treatment received. 
 Per-protocol Analysis Set:  All patients in the ITT set who had no major protocol 
deviations.  Major deviations will be specified in the SAP. 
 PK Analysis Set:  All patients who receive at least 1 dose of fitusiran and have at 
least one postdose blood sample for PK parameters and who have evaluable PK data. 
 Operative Procedure Analysis Set:  All patients who received at least 1 dose of 
fitusiran and underwent at least 1 operative procedure during the study. 
8.2.2. 
Examination of Subgroups 
Exploratory subgroup analysis on ABR will be conducted for the primary endpoint and selected 
secondary endpoints.  Description of the subgroups will be specified in the SAP. 
8.2.3. 
Handling of Missing Data 
Handling of missing data will be described in the SAP. 
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8.2.4. 
Baseline Evaluations 
Demographics and other disease-specific baseline characteristics will be summarized for the ITT 
Analysis Set and Safety Analysis Set. 
8.2.5. 
Efficacy Analyses 
Primary analyses of the primary and secondary endpoints will be based on the ITT Analysis Set.  
To control for the familywise error rate in the testing of primary and secondary endpoints, a 
hierarchical testing approach will be used in the following order: 
1. ABR in efficacy period (2-sided alpha = 0.05) 
2. ABR in treatment period (2-sided alpha = 0.05) 
3. Annualized spontaneous bleeding rate in efficacy period (2-sided alpha = 0.05) 
4. Annualized joint bleeding rate in efficacy period (2-sided alpha = 0.05) 
5. Change in physical health score and total score of Haem-A-QOL in treatment period 
(2-sided alpha = 0.05) 
If testing of any of the endpoints is not statistically significant, testing of subsequent endpoints 
will stop and the null hypotheses for the subsequent tests will not be rejected.  The testing of 
secondary endpoint ABR in the onset period will not be included in this hierarchical testing 
procedure. 
8.2.5.1. 
Primary Endpoint 
The primary analysis will be performed on the ITT Analysis Set and will include all bleeding 
episodes occurring in the efficacy period (Day 29 to Day 246) including bleeding episode data 
collected after discontinuation of IMP.  If a patient does not have bleeding episode data collected 
after Day 28 (eg, due to early study discontinuation), the available bleeding episode data starting 
from Day 1 will be used as bleeding episode data of the fitusiran period in the primary analysis.  
To avoid confounding the treatment effect, bleeding episode data during and after major surgery, 
AT administration, major trauma, or initiation of prophylaxis treatment with factor concentrates 
will be excluded from the primary analysis. 
The number of bleeding episodes will be analyzed using a negative binomial model with fixed 
effects of treatment arm and the number of bleeding episodes in the 6 months prior to study entry 
(≤10 vs >10) and hemophilia type (hemophilia A or B).  The logarithm number of days that each 
patient spends in the efficacy period matching the bleeding episode data being analyzed will be 
included as an offset variable to account for unequal follow-up time due to early withdrawal or 
surgery.  The p-value comparing bleeding rates in the 2 treatment arms and the ratio of bleeding 
rates in the fitusiran treatment arm to the on-demand arm along with its 95% CI will be 
presented.  The estimated mean ABRs in each of the 2 treatment arms along with their 95% Cis 
will be presented from this model.  In addition, summary statistics for ABR, including median 
and interquartile range, will be presented for each treatment arm, where ABR is defined as: 
total number of qualifying bleeding episodes
total number of days in the respective period ×  365.25 
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Patients who discontinue treatment during the study will be encouraged to continue recording 
bleeding episode data.  
Sensitivity analyses will be performed to evaluate the impact of missing data under different 
missing data mechanisms and details will be specified in the statistical analysis plan. 
8.2.5.2. 
Secondary Endpoints 
The bleeding episodes in the treatment period (Day 1 to Day 246), spontaneous bleeding 
episodes in the efficacy period, joint bleeding episodes in the efficacy period, and bleeding 
episodes in the onset period will be analyzed using the same method as primary analysis of ABR.  
Summary statistics, including median and interquartile range, for annualized rates of these 
endpoints will be reported. 
The change from baseline in physical health score and total score of Haem-A-QOL will be 
analyzed using an analysis of covariance (ANCOVA) model with fixed effects of treatment arm, 
baseline Haem-A-QOL physical health score and total score, the number of bleeding episodes in 
the 6 months prior to study entry (≤10 vs >10), and hemophilia type (hemophilia A or B) as 
covariates.  Domain scores for Haem-A-QOL and their changes from baseline will be 
summarized descriptively by scheduled visit. 
8.2.5.3. 
Exploratory Endpoints 
Details of the analyses for the exploratory endpoints will be described in the SAP. 
8.2.6. 
Pharmacodynamic Analysis 
AT and thrombin levels will be summarized descriptively by scheduled visit.  Mixed models 
repeated measures analyses may be performed as deemed appropriate.  Correlation between AT 
and thrombin levels may be explored. 
8.2.7. 
Pharmacokinetic Analysis 
Pharmacokinetic analyses will be conducted using a population PK approach on patients in the 
fitusiran arm.  The details of the analysis will be presented in a separated population PK analysis 
plan. 
In addition to performing population PK analyses, the following PK parameters will be included 
in an analysis of East Asian patients in the fitusiran arm at East Asian sites: maximum plasma 
concentration (Cmax), time to maximum plasma concentration (tmax), elimination half-life (t½β), 
area under the concentration-time curve (AUC), apparent clearance (CL/F), and apparent volume 
of distribution (V/F); these parameters will be estimated during the fitusiran treatment period 
using non-compartmental analysis.  Other parameters may be calculated, if deemed necessary. 
8.2.8. 
Safety Analyses 
Extent of exposure will be summarized.  Safety will be based on all AEs having onset (start or 
worsening in severity) within the study and on the Safety Analysis Set.  Incidence of AEs, AEs 
by maximum severity, AEs by relationship to study medication, SAEs and AEs leading to 
discontinuation of treatment will be presented.  
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Descriptive statistics will be provided for clinical laboratory data, ECG and vital signs.  
Laboratory shift tables from baseline to worst post-baseline values may be presented.  
Other safety summaries will be presented as appropriate.  Further details will be specified in the 
SAP.  
Adverse events will be classified according to the MedDRA System Organ Class and Preferred 
Term.  Prior and concomitant medications will be classified according to the World Health 
Organization (WHO) drug dictionary.  
8.2.9. 
Immunogenicity Analysis 
Antidrug antibody results will be summarized descriptively. 
8.2.10. 
Interim Analysis 
No interim analysis is planned. 
9. 
STUDY ADMINISTRATION 
9.1. 
Ethical and Regulatory Considerations 
This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
 Applicable ICH Good Clinical Practice (GCP) Guidelines 
 Applicable laws and regulations 
9.1.1. 
Informed Consent Process 
The Investigator or his/her representative will explain the nature of the study to the patient or 
his/her legally authorized representative (defined as an individual or juridical or other body 
authorized under applicable law to consent, on behalf of a prospective patient, to the patient's 
participation in the clinical trial) and answer all questions regarding the study.  
Patients must be informed that their participation is voluntary. Patients or their legally authorized 
representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center.  
The medical record must include a statement that written informed consent was obtained before 
the patient was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Patients must be re-consented to the most current version of the ICF(s) during their participation 
in the study. 
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorized 
representative. 
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9.1.2. 
Ethical Review 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.  
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients.  
The Investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
 Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
 Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European Regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations 
9.1.3. 
Study Documentation, Confidentiality, and Records Retention 
Patients will be assigned a unique identifier by the Sponsor.  Any patient records or datasets that 
are transferred to the Sponsor will contain the identifier only; patient names or any information 
which would make the patient identifiable will not be transferred.  
The patient must be informed that his/her personal study-related data will be used by the Sponsor 
in accordance with local data protection law.  The level of disclosure must also be explained to 
the patient.  
The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
9.1.4. 
End of the Study 
The end of the study is defined as the last patient last visit. 
9.1.5. 
Discontinuation of the Clinical Study 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
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Reasons for the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
 Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor’s procedures, or GCP guidelines 
 Inadequate recruitment of patients by the Investigator 
 Discontinuation of further study intervention development 
9.2. 
Data Quality Control and Quality Assurance 
9.2.1. 
Data Handling 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the Investigator’s site. 
Data reported or entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained.  The Investigator 
may need to request previous medical records or transfer records, depending on the study.  Also, 
current medical records must be available. 
All patient data relating to the study will be recorded on printed or eCRF unless transmitted to 
the Sponsor or designee electronically (eg, laboratory data).  The Investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF.  
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents.  
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
9.2.2. 
Study Monitoring 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements.  
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during the 
retention period without the written approval of the Sponsor.  No records may be transferred to 
another location or party without written notification to the Sponsor. 
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9.2.3. 
Audits and Inspections 
Periodically, the Sponsor or its authorized representatives audit clinical investigative sites as an 
independent review of core trial processes and documents to determine whether these activities 
were conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, GCP guidelines of the ICH, and any applicable regulatory requirements.  A regulatory 
authority, an IEC, or an IRB may visit the site to perform audits or inspections, including source 
data verification.  The Investigator should contact the Sponsor, or its designee, immediately if 
contacted by a regulatory agency, an IEC or an IRB about an inspection. 
9.3. 
Publication Policy 
The results of this study may be published or presented at scientific meetings.  If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission.  
This allows the Sponsor to protect proprietary information and to provide comments.  
The Sponsor will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data.  In this case, a 
coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
9.4. 
Dissemination of Clinical Study Data 
Sanofi shares information about clinical trials and results on publically accessible websites, 
based on company commitments, international and local legal and regulatory requirements, and 
other clinical trial disclosure commitments established by pharmaceutical industry associations.  
These websites include www.clinicaltrials.gov, www.clinicaltrialregister.eu, and 
www.sanofi.com as well as some national registries. 
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance and intellectual property.  
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to 
www.clinicalstudydatarequest.com. 
Individual patient data and supporting clinical documents are available for request at 
www.clinicalstudydatarequest.com.  While making information available we continue to protect 
the privacy of patients in our clinical trials.  Details on data sharing criteria and process for 
requesting access can be found at this web address: www.clinicalstudydatarequest.com. 
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10. 
LIST OF REFERENCES 
1. WFH. What is Hemophilia?  World Federation of Hemophilia. 2004. 
2. Bauer KA. Current challenges in the management of hemophilia. Am J Manag Care. 2015 
Mar;21(6 Suppl):S112-22. 
3. Sehgal A, Barros S, Ivanciu L, Cooley B, Qin J, Racie T, et al. An RNAi therapeutic 
targeting antithrombin to rebalance the coagulation system and promote hemostasis in 
hemophilia. Nat Med. 2015 May;21(5):492-7. 
4. Schrijvers L, Beijlevelt-Van der Zande M, Peters M, Lock J, Cnossen M, Schuurmans M, et 
al. Achieving self-management of prophylactic treatment in adolescents: The case of 
haemophilia. Patient Educ Couns. 2016 Jan 25. 
5. Makris M, Kasper C. The World Federation of Hemophilia guideline on management of 
haemophilia. Haemophilia. 2013 Jan;19(1):1. 
6. Witkop M, Guelcher C, Forsyth A, Hawk S, Curtis R, Kelley L, et al. Treatment outcomes, 
quality of life, and impact of hemophilia on young adults (aged 18-30 years) with hemophilia. 
Am J Hematol. 2015 Dec;90 Suppl 2:S3-10. 
7. Saposnik G, Barinagarrementeria F, Brown RD, Jr., Bushnell CD, Cucchiara B, Cushman M, 
et al. Diagnosis and management of cerebral venous thrombosis: a statement for healthcare 
professionals from the American Heart Association/American Stroke Association. Stroke. 2011 
Apr;42(4):1158-92. 
8. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis 
Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive 
Care Med. 2017 Mar;43(3):304-77. 
9. Levi M, Toh CH, Thachil J, Watson HG. Guidelines for the diagnosis and management of 
disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J 
Haematol. 2009 Apr;145(1):24-33. 
10. Blanchette VS, Key NS, Ljung LR, Manco-Johnson MJ, van den Berg HM, Srivastava A. 
Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost. 2014 
Nov;12(11):1935-9. 
11. Wyrwich KW, Krishnan S, Poon JL, Auguste P, von Maltzahn R, Yu R, et al. Interpreting 
important health-related quality of life change using the Haem-A-QoL. Haemophilia. 2015 
Sep;21(5):578-84. 
12. Atkinson MJ, Sinha A, Hass SL, Colman SS, Kumar RN, Brod M, et al. Validation of a 
general measure of treatment satisfaction, the Treatment Satisfaction Questionnaire for 
Medication (TSQM), using a national panel study of chronic disease. Health Qual Life 
Outcomes. 2004 Feb 26;2:12. 
13. van Genderen FR, Westers P, Heijnen L, de Kleijn P, van den Berg HM, Helders PJ, et al. 
Measuring patients' perceptions on their functional abilities: validation of the Haemophilia 
Activities List. Haemophilia. 2006 Jan;12(1):36-46. 
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14. Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and 
preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011 
Dec;20(10):1727-36. 
15. Feldman BM, Funk SM, Bergstrom BM, Zourikian N, Hilliard P, van der Net J, et al. 
Validation of a new pediatric joint scoring system from the International Hemophilia Prophylaxis 
Study Group: validity of the hemophilia joint health score. Arthritis Care Res (Hoboken). 2011 
Feb;63(2):223-30. 
 
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11. 
APPENDICES 
11.1. 
Pharmacokinetic Assessment Time Points 
Table 7 provides a schedule for the collection of blood samples for PK analysis in all fitusiran 
arm patients. 
Table 7: Pharmacokinetic Time Points for All Fitusiran Arm Patients 
Study Day 
Protocol Time (hh:mm) 
PK Blood 
Day 1 
Predose 
(within 240 minutes before dosing)a 
X 
04:00 (±30 min)a 
X 
Day 29 (±7 days) 
Predose 
(within 240 minutes before dosing)a 
X 
Day 85 (±7 days) 
Predose 
(within 240 minutes before dosing)a 
X 
Day 197 (±7 days) 
Predose 
(within 240 minutes before dosing)a 
X 
04:00 (±30 min)a 
X 
Day 225 (±7 days) 
Predose 
(within 240 minutes before dosing)a 
X 
a Time point used in population PK analysis. 
Table 8 provides a schedule for the collection of blood samples for PK (fitusiran arm), AT, and 
thrombin generation analysis in East Asian patients at East Asian sites. 
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Table 8: 
Pharmacokinetic (Fitusiran Arm), AT, and TG Time Points for East Asian Patients at 
East Asian Sites 
Study Day 
Protocol Time 
(hh:mm) 
PK Blood 
AT 
TG 
Day 1 
Predose (within 240 minutes before 
dosing)a 
X 
 
 
00:30  (±5 min)  
X 
 
 
01:00 (±5 min) 
X 
 
 
02:00 (±15 min) 
X 
 
 
04:00 (±30 min)a 
X 
 
 
06:00 (±30 min) 
X 
 
 
08:00 (±30 min) 
X 
 
 
12:00 (±30 min) 
X 
 
 
Day 2 
24:00 (±2 hours) 
X 
X 
X 
Day 8 
168 h  
 
X 
X 
Day 29 (±7 days)  
Predose (within 240 minutes before 
dosing)a 
X 
 
 
Day 85 (±7 days)  
Predose (within 240 minutes before 
dosing)a 
X 
 
 
Day 197 (±7 days) 
Predose (within 240 minutes before 
dosing)a 
X 
 
 
04:00 (±30 min)a 
X 
 
 
Day 225 (±7 days)  
Predose (within 240 minutes before 
dosing)a 
X 
 
 
Abbreviations: AT=antithrombin; h=hours; min=minutes; PK=pharmacokinetics; TG=thrombin generation 
a Time point used in population PK analysis. 
Table 9 provides a schedule for the collection of pooled urine samples for PK analysis in East 
Asian patients in the fitusiran arm at East Asian sites.  Volume must be recorded. 
Table 9:   Urine Pharmacokinetic Time Points for East Asian Patients in the Fitusiran Arm 
from East Asian sites 
Study Day 
Protocol Time 
(hh:mm), Pooled Urine 
Day 1 
Postdose (0:00) to 06:00 (±30 min) 
06:00 (±30 min) to 12:00 (±30 min) 
Day 2 
12:00 (±30 min) to 24:00 (±2 hours) 
 
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11.2. 
Perioperative Schedule of Assessments 
11.2.1. 
Definitions of Minor and Major Surgery 
Minor surgery is defined as any invasive operative procedure in which only skin, mucous 
membranes, or superficial connective tissue is manipulated and does not meet the criteria for 
major surgery (eg, dental extraction of <3 non-molar teeth).  Minor surgical procedures may be 
performed at a local health care provider institution. 
Major surgery is defined as any invasive operative procedure that requires any of the following: 
 Opening into a major body cavity (eg, abdomen, thorax, skull) 
 Operation on a joint 
 Removal of an organ 
 Dental extraction of any molar teeth or ≥3 non-molar teeth 
 Operative alteration of normal anatomy 
 Crossing of a mesenchymal barrier (eg, pleura, peritoneum, dura) 
It is recommended that any elective non-dental major surgery be performed at a clinical study 
center, when possible. 
11.2.2. 
Perioperative Assessments of Safety and Hemostatic Efficacy in Patients 
Undergoing Operative Procedures 
In patients undergoing operative procedures during the treatment period, safety and hemostatic 
efficacy assessments will be performed according to the Perioperative Schedule of Assessments 
(described below and outlined in Table 10), where possible. 
After a review of medical and surgery history has been completed, patients will have the 
following assessed as specified in the Perioperative Schedule of Assessments (Table 10):  
directed physical examination and assessment of vital sign measurements; clinical laboratory 
assessments including hematology (complete blood count, white blood count, red blood cell 
count, hemoglobin, hematocrit, platelets); coagulation (APTT, PT/INR, fibrinogen, D-dimer); 
hepatic assessments; and hemostatic efficacy assessments (rating scale based on ISTH Scientific 
and Standardization Committee [SSC] definitions).[10]  
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Table 10: 
Perioperative Schedule of Assessments in Patients Undergoing Operative 
Procedures 
 
Perioperative Evaluation Perioda 
Preoperative 
Screening 
Dental/Surgical 
Procedure 
Visit 
Postoperative 
Visit 1 
Postoperative 
Visit 2 
Postoperative 
Visit 3 
SDay -3 to 
SDay -1 
SDay 0 
SDay 1b 
SDay 2 to 14c 
SDay 28d 
Directed Physical 
Examinationd 
X 
 
 
 
X 
Vital Sign 
Measurementse 
X 
 
 
 
X 
Clinical Laboratory 
Assessmentsf 
X 
Xh 
X 
X 
X 
TG 
X 
Xg,h  
Xk 
Xk 
Xk 
AT Activity Level 
X 
Xi 
 
 
 
FVIII/IX Levelsg  
X 
Xg,h 
Xk 
Xk 
Xk 
Perioperative 
Questionnaire 
 
Xj 
X 
X 
 
Completion of 
Hemostatic 
Treatment Coverage 
 
 
 
Xl 
Xl 
Note:  Any operative procedure dates (SDay -3 to SDay 28) may overlap with the study Schedule of Assessments (Table 1) 
Abbreviations:  APTT=activated partial thromboplastin time; AT=antithrombin; BPA=bypassing agent; SDay=surgery day; 
TG=thrombin generation 
a During the Perioperative Evaluation Period, AEs and concomitant medications will be collected continuously per study 
Schedule of Assessments (Table 1). 
b Assessments to be completed within 24 hours (±12 hours) from the time of end of the procedure. 
c Visit may occur anytime between SDay 2 to SDay 14, postoperatively, on a day to be determined by the Investigator. If multiple 
visits are planned between Days 2-14 after the procedure, the perioperative questionnaire for Postoperative Visit 2 should be 
completed on the day of the last visit. 
d Directed physical examination (see Section 7.5.3). 
e Vital signs will be the same as conducted in the clinical study protocol Schedule of Assessments (Table 1).  
f Clinical laboratory assessments will include coagulation, hematology, and biochemistry (Table 5). 
g If factor or BPA administration and the surgical procedure occur at the study center visit, one sample should be collected pre- 
factor/BPA administration and two samples should be collected post- factor/BPA administration on the day of the procedure.  
The pre- factor/BPA sample may be collected any time before factor or BPA administration.  The post- factor/BPA samples 
should optimally be collected at 10 min (±5 min) and 60 min (±10 min) after factor or BPA administration.  The actual times of 
collections should be recorded. 
h If the operative procedure is not performed at a study center, the assessment is recommended.  
i Not necessary if captured at preoperative screening. 
j Hemostatic efficacy is to be assessed intraoperatively with the perioperative questionnaire on the day of the procedure (SDay 0); 
assessment may be completed up to 8 hours postoperatively.  The perioperative questionnaire will also be completed at 
Postoperative Visit 1 and Visit 2. It is recommended that the Investigator complete this assessment in consultation with the 
surgeon or dentist who performed the operative procedure. 
k If factor or BPA administration occurs at the study center visit, then assessments should be collected at the following time 
points:  pre- factor/BPA administration; 10 min (±5 min) post-factor/BPA administration; and 60 minutes (±10 min) post- 
factor/BPA administration.  The actual times of collection should be recorded. 
l The date/time of when perioperative hemostatic treatment and thromboprophylaxis (if applicable) coverage was completed will 
be captured.  If completed at Postoperative Visit 2, the date/time of completion should be recorded and the SDay 28 visit is not 
required. 
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11.3. 
International Society on Thrombosis and Hemostasis Guideline for 
Assessment of Treatment Response 
ISTH recommendations [10] are provided in the table below for assessment of treatment 
response (Table 11). 
Table 11: 
Assessment of Treatment of Acute Joint/Muscle Bleeding Episodes 
Category 
Response 
Excellent 
Complete pain relief within 8 hours and/or complete resolution of signs of bleeding 
after the initial injection and not requiring any further replacement therapy for relief 
of persistent symptoms and signs in the same joint within 72 hours 
Good 
Significant pain relief and/or improvement in signs of bleeding within 
approximately 8 hours after a single injection, but requiring more than one dose of 
replacement therapy within 72 hours for complete resolution 
Moderate 
Modest pain relief and/or improvement in signs of bleeding within approximately 
8 hours after the initial injection and requiring more than one injection within 
72 hours but without complete resolution 
None 
No or minimal improvement, or condition worsens, within approximately 8 hours 
after the initial injection 
11.4. 
Bleed Severity Definitions 
The definitions of bleed severity are shown in Table 12. 
Table 12 
Bleed Severity Definitions 
Bleed Severity 
Definition 
Minor 
Early joint bleeding; mild muscle bleeding; or mild bleeding (any other 
location) 
Moderate 
Definite joint bleeding; moderate muscle bleeding; moderate bleeding 
(any other location); known trauma (other than head trauma or fractures) 
Major 
Severe bleeding that is life- or limb-threatening; including fractures and 
head trauma 
11.5. 
Country-Specific Requirements 
Country-specific requirements are provided in separate country-specific protocol. 
 
 
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11.6. 
Protocol Amendment History 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
11.6.1. 
Amended Protocol 01 
Primary changes: 
 Updated clinical development status text to account for a patient death, which was 
reported in a patient with cerebral venous sinus thrombosis (CVST) in the 
ALN-AT3SC-002 study (Phase 1/2 open-label extension study) 
 Additional safety measures were implemented to mitigate risk of thrombosis in the 
lowered-AT setting, including: revised bleed management guidelines to allow standard 
BPA regimens only up to the first 7 days following fitusiran dosing; added 
recommendations for monitoring and management of thrombotic events; added 
clarification of definitions for bleeding episodes; revised recommendations for 
management of sepsis, and adding additional exploratory laboratory assessments 
 Frequency of directed physical exams to monthly 
 Updated Benefit-Risk Assessment section accordingly with respect to the above new 
safety monitoring 
 Added Patient Education Module training to Schedule of Assessments 
 Clarification added that Adverse Events should include review for signs and symptoms of 
thrombosis at each visit 
 Clarifications added to the Perioperative Schedule of Assessments 
 Addition of acetaminophen restriction to <4 grams per day 
 Stipulation added that antifibrinolytics may be used as single agents, but may not be used 
in combination with factor or BPA 
 Revised bleed management recommendations following discontinuation of fitusiran; 
standard on-demand dosing with BPAs is permitted when AT residual activity level 
returns to ~60% (per the central laboratory) 
 Addition of prothrombin activation fragment 1,2 to the coagulation panel, as exploratory 
marker of hemostasis 
 Addition of new stipulation for patients who present to the study site for management of 
bleed symptoms, samples will be collected pre-treatment and post-treatment with factor 
or BPA for the exploratory purposes of characterizing thrombin generation and other 
coagulation parameters 
 Other minor corrections applied. 
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ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EFC14769 Amended Protocol02
Clinical Approval
Clinical Approval