Conditions: Hemophilia A Hemophilia B
Keywords: Hemophilia RNAi therapeutic
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 34
Healthy volunteers: no

Brief summary:
Primary Objective:

To evaluate the long-term safety and tolerability of fitusiran in male patients with moderate or severe hemophilia A or B

Secondary Objectives:

* To investigate the long-term efficacy of fitusiran
* To characterize the safety and efficacy of concomitantly administered Factor VIII (FVIII), Factor IX (FIX) or bypassing agents (BPA) and fitusiran for treatment of bleeding episodes
* To assess changes in health-related quality of life (QOL) over time
* To characterize antithrombin (AT) reduction and thrombin generation (TG) increase
* To characterize the pharmacokinetics (PK) of fitusiran

Detailed description:
It is anticipated that patients in this study will receive treatment with open label fitusiran for approximately 7 years or until fitusiran becomes commercially available, whichever occurs first.

Arms:
arm 1: Patients will be administered subcutaneous (SC) fitusiran once monthly or every 2 months according to the dose selection rules defined in protocol.

Interventions: intervention 1: Fitusiran (SAR439774)
Intervention descriptions: intervention 1: Pharmaceutical form: solution for injection Route of administration : subcutaneous (sc)

Protocol document:
Prot_000.pdf: 
SAR439774 (formerly ALN-AT3SC) (fitusiran) 
Clinical Study Protocol Number ALN-AT3SC-002 
  (Sanofi Genzyme LTE14762) 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential 
1 
ALN-AT3SC-002 (SANOFI GENZYME LTE14762) 
AN OPEN-LABEL EXTENSION STUDY OF SUBCUTANEOUSLY ADMINISTERED 
FITUSIRAN IN PATIENTS WITH MODERATE OR SEVERE HEMOPHILIA A OR B 
WHO HAVE PARTICIPATED IN A PREVIOUS CLINICAL STUDY WITH FITUSIRAN
Final Protocol: 
02 June 2015 
Amendment 1 
30 November 2015 
Amendment 2 
20 October 2016 
Amendment 3 
13 June 2017 
Amendment 4 
09 November 2017 
Amendment 5 
31 May 2018 
Amendment 6 
05 March 2019 
Amendment 7 
25 November 2020 
Amendment 8 
Amendment 9 
08 December 2020 
23 June 2021 
EUDRACT Number: 
2015-001395-21 
NCT number: 
NCT02554773 
IND Number: 
125632 
Sponsor: 
Genzyme Corporation, 
50 Binney Street, 
Cambridge, MA 02142, USA 
Sponsor Contact: 
VV-CLIN-0257058 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
  (Sanofi Genzyme LTE14762) 
 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential  
2 
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. 
 
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 
 
 
 
VV-CLIN-0257058 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
  (Sanofi Genzyme LTE14762) 
 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential  
3 
 
 
PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
 
Document 
Country-specificity 
if applicable 
Date 
Amendment 09 
NA 
23 June 2021 
Amendment 08 
NA 
08 December 2020 
Amendment 07 
NA 
25 November 2020 
Amendment 06 
NA 
05 March 2019 
Amendment 05 
NA 
31 May 2018 
Amendment 04 
NA 
09 November 2017 
Amendment 03 
NA 
13 June 2017 
Amendment 02 
NA 
20 October 2016 
Amendment 01 
NA 
30 November 2015 
Original Protocol 
NA 
02 June 2015 
 
Amendment 09 (23 June 2021) 
This amended protocol 09 (amendment 09) 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  
Antithrombin activity level was recently identified as a modifiable target for risk mitigation of 
vascular thrombosis in patients exposed to fitusiran and the protocol was subsequently amended 
to introduce a revised fitusiran dose and regimen with the aim of lessening AT reduction.   
The overall rationale for the amendment is to extend the study duration for some patients to 
allow all patients currently in the study to have at least an 18 calendar months period after 
introduction of the revised dose and regimen (regardless whether the individual patient changed 
regimen) for purposes of collecting sufficient data for assessment of efficacy and safety of the 
revised dose and regimen. The study duration will be extended for few patients who would 
complete the study as per current schedule before having at least 18 calendar months on study 
after resuming fitusiran under the new dose and regimen. 
VV-CLIN-0257058 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
  (Sanofi Genzyme LTE14762) 
 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential  
4 
The whole study duration (till last patient last visit) will not be impacted and the extension will 
concern only some patients (those who would have completed the study before having this 
additional follow-up). 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Cover page 
Added NCT number and updated amended protocol 
version to 9.0 
Administrative change 
Synopsis 
Introduced the following text “Some patients will 
have an extended treatment duration by a maximum 
of 12 months to ensure all patients will have at least 
an 18-calendar months treatment period after recent 
restart with modified SoA and revised fitusiran dose 
and regimen. This will not affect the whole study 
duration (last patient last visit is unchanged).” 
To extend the study 
duration for few 
patients for purposes 
of collecting sufficient 
data for assessment 
of efficacy and safety 
of the revised dose 
and regimen. 
Table 1 Schedule of assessments (Years 1 
to 4), Table 2 Schedule of assessments 
(Years 5 to 6), Table 3 Modified IMP 
regimen schedule of assessments (Year 1, 
2, 3) 
Updated footnoteS of COVID-19 test with the 
following text:” All study patients that are consenting 
to this procedure are requested to undergo testing 
for SARS-CoV-2 (virus responsible for COVID-19), 
which should include both RT-PCR and antibody 
testing. Note: Rapid test may be used if RT-PCR is 
not available. These tests should be performed as 
early as possible during the study, except for 
patients who have undergone COVID-19 
vaccination, after which antibody testing is no longer 
required.” 
To clarify the 
COVID-19 test 
requirement in the 
context of COVID-19 
vaccine(s) availability 
and to allow rapid-test 
when RT-PCR is not 
available.  
Table 2 Schedule of assessments (Years 5 
to 6) 
Table title updated to “Schedule of Assessments 
(Years 5, 6 and 7)”; introduced new columns (M78, 
M84/EOT) and footnote p for Year 7 assessments. 
To accommodate the 
extension of study 
duration for few 
patients following the 
introduction of revised 
dose and regimen. 
Table 3 Modified IMP regimen schedule of 
assessments (Year 1, 2, 3) 
Added Coagulation assessment in EOS/ET visit. 
To correct an 
omission.  
 
Footnote “a”: updated the study duration in footnote 
with the following text “The duration that the patient 
must continue in the study post modified IMP 
dose/frequency re-start depends on the re-start 
time-point relative to the overall study start for each 
individual patient to ensure an overall duration of 
fitusiran administration of approximately 72 months 
or 18 calendar months after restarting dosing post 
dosing pause (whichever is longer). Thus, when the 
patient reaches the latter of 72 months of study 
participation or 18 calendar months post dosing 
restart, the EOT visit should be performed, followed 
by the EOS and AT follow-up period.” 
To extend the study 
duration for few 
patients for purposes 
of collecting sufficient 
data for assessment 
of efficacy and safety 
of the revised dose 
and regimen. 
VV-CLIN-0257058 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
  (Sanofi Genzyme LTE14762) 
 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential  
5 
Section # and Name 
Description of Change 
Brief Rationale 
Table 4 Perioperative schedule of 
assessments in patients undergoing major 
operative procedures 
Introduced a new row for 
“Hemostatic/Thromboprophylaxis Treatment Plan.” 
To align with eCRF.  
 
Updated row of “Perioperative Questionnaire” to 
“Hemostatic efficacy (Perioperative Questionnaire)” 
and updated “Perioperative questionnaire” to 
“Hemostatic efficacy (by using perioperative 
questionnaire” in footnotes where applicable.  
For clarity. 
 
Added “up to 28 days” following “SDay 28” in the 
column for postoperative Visit 3. 
For clarity.  
 
Updated footnote “k” with the following text “The 
date/time of when perioperative hemostatic 
treatment and thromboprophylaxis (if applicable) 
coverage was completed will be captured. If 
hemostatic treatment and thromboprophylaxis are 
completed at Postoperative Visit 2, the date/time of 
completion should be recorded, and the SDay 28 
visit is not required.” 
For clarity and 
facilitate trial 
operational practice.  
Section 1.3.1 Summary of efficacy  
Added the following text “Consistent with its 
intended pharmacologic effects, fitusiran treatment 
is associated with reductions in AT, increases in 
thrombin generation, and reductions in number of 
bleeding episodes.” 
To update fitusiran 
efficacy data. 
Section 1.3.2 Summary of safety; 
Section 1.6 benefit-risk assessment 
 
 
 
To align with the 
fitusiran safety 
updates. 
Section 1.3.2 Summary of safety 
 
Removed the text “One death has been reported in 
a participant with cerebral venous sinus thrombosis 
(CVST) in ALN-AT3SC-002. In response to this 
event, the bleed management guidelines were 
revised in December 2017.” 
To align with the 
fitusiran safety 
updates. 
Section 1.4 Study design rational  
Introduced the following text “The duration may be 
longer (up to 7 years) for some patients so that they 
continue fitusiran treatment for 18 calendar months 
after introduction of the new dose and regimen into 
the study.” 
To extend the study 
duration for few 
patients for purposes 
of collecting sufficient 
data for assessment 
of efficacy and safety 
of the revised dose 
and regimen. 
Section 1.5 Dose rationale 
Specified in “Protocol Amendment 07” that 
introduced the fitusiran revised dose and regimen. 
For clarity. 
 
Revised the language of patients on fitusiran dose 
“on that dose” to “on either dose, respectively.” 
To reflect the fitusiran 
revised dose and 
regimen.  
VV-CLIN-0257058 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
  (Sanofi Genzyme LTE14762) 
 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential  
6 
Section # and Name 
Description of Change 
Brief Rationale 
 
Updated “pharmacokinetic/pharmacodynamic 
(PK/PD) model” with “population 
pharmacokinetic/pharmacodynamic (popPK/PD) 
model.”  
For clarity. 
Section 1.6 Benefit-risk assessment 
Updated the text on LFT monitoring by including 
“and provides instruction for the potential 
discontinuation of fitusiran.” 
To consider the 
context of fitusiran on 
pause. 
Section 5.2 Concomitant medications  
Included the following text “Use of emicizumab 
(Hemlibra®) during the study is not permitted.“ 
To clarify that the use 
of emicizumab 
(Hemlibra®) during 
the study is prohibited. 
Section 5.3 Management of bleeding 
episodes with factor or bypassing agents 
while on fitusiran 
Updated the subtitle with the following text: “Bleed 
management guidelines for patients with AT 
recovery of ≥60% prior to re-initiation of fitusiran or 
during a potential fitusiran dose pause.” 
To consider the 
context of fitusiran on 
pause.  
 
Introduced the following text “During the study 
period, in case fitusiran is on pause for any reasons 
and AT activity levels return to approximately 60% 
(per the central laboratory), patients can initiate 
regular factor concentrates or BPAs for prophylaxis 
therapy to prevent spontaneous bleeding episodes, 
per Investigator discretion in consultation with the 
study Medical Monitor.” 
For clarity regarding 
the use of factor 
concentrates or BPAs. 
Section 5.11 Alcohol restrictions 
Introduced a new section on alcohol restrictions as 
Section 5.11. 
To provide definition 
and criteria for alcohol 
restriction advise to 
patients during the 
study to add clarity on 
already existing 
criteria for alcohol use 
at study entry. 
Section 6.1 Study drug 
Defined antithrombin (AT) utilized for AT reversal as 
NIMPs and clarified IMP/NIMP accountability.  
To classify AT utilized  
for AT reversal as 
NIMP. 
Section 6.5 Dose and administration  
Removal of fitusiran dosing frequency of "once 
every month". 
To adapt to fitusiran 
new dose and 
regimen.  
Section 6.5.1.1 LFT criteria for withholding, 
monitoring and stopping fitusiran dosing 
Reworded the language of LFT results by central 
laboratory and listed prior to other items: “It is 
preferable that LFT results are to be obtained by 
Central laboratory. If not available, local laboratory 
results may be used; however, if a local assessment 
is drawn, a biochemistry sample must also be drawn 
for analysis at the central laboratory.” 
For readability and 
clarity.  
 
Modified the text on criteria for reduced predose LFT 
monitoring considering the patients on monthly 
dosing schedule following the SoAs or modified IMP 
regimen SoA. 
For clarity. 
VV-CLIN-0257058 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
  (Sanofi Genzyme LTE14762) 
 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential  
7 
Section # and Name 
Description of Change 
Brief Rationale 
 
Modified “2 months” to “2 consecutive months”, 
where applicable.  
For clarity. 
 
Introduced the criteria for reduced predose LFT 
monitoring for patients on a every other month 
dosing schedule. 
For clarity and to 
accommodate every 
other month (Q2M) 
dosing regimen. 
Section 6.5.1.3 Antithrombin level criteria for 
a dose adjustment 
Section been updated.  
To clarify the 
requirements for 
restarting dosing after 
the dosing pause. And 
re-organized the text 
for readability. 
Section 6.5.1.3 Fig 1 
Added a footnote for Fig 1 “Note: Restart following 
dosing pause to occur only once centrally measured 
AT activity levels ≥22%.” 
To clarify the rule of 
dosing restart.  
Section 6.5.1.3 Fig 2 
Added a footnote: “See rules and exceptions as 
described above in Section 6.5.1.3. “. 
For clarity.  
Section 9.1.7.2 Additional Laboratory 
Assessments 
Newly included additional evaluations to be 
performed for participants undergoing 
cholecystectomy.  
To allow for source 
data collection to 
support a better 
interpretation of 
biliary-related events. 
Section 9.2.7 Adverse Events of Special 
Interest 
Added cross reference to Section 9.1.7.2 regarding 
the instructions of additional evaluations if 
participants undergoing cholecystectomy. 
For better 
interpretation/narrative 
if participant undergo 
cholecystectomy. 
Section 10.2.1 Populations to be Analyzed 
Included the following text “All the analysis sets 
before and after the 2020 dose pause will be 
populated separately. Accordingly, the statistical 
analysis will be performed based on each analysis 
set respectively.” 
For clarity and 
consider the context 
of fitusiran on pause 
in the year 2020.  
Section 10.2.3 Efficacy analysis 
Update the efficacy analysis with the following text 
“Bleed free duration will be defined as the maximum 
time intervals between 2 bleeding events and will be 
analyzed descriptively.” 
For clarity.  
Section10.2.8 Interim analysis 
Specified that the interim analysis will be describe in 
the SAP. 
For clarity.  
Section 18.1 Pharmacokinetic assessments 
time points  
In Table 15 and 16, added a footnote regarding the 
ADA sampling timepoint on PR Months 24 and 36. 
For clarity. 
Section 18.2.1 Definitions of minor and 
major surgery 
Updated the definition of major dental surgery by 
including “or any tooth implantation”. 
For clarity. 
Section 18.5 Contingency measures for a 
regional or national emergency that is 
declared by a government agency 
Upgraded the appendix for contingency measures 
for a regional or national emergency as 
Appendix 18.5, which was originally listed as 
Appendix 18.6. Subsequent sections have been 
re-numbered. 
Cosmetic, to follow 
the updated protocol 
template. 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
  (Sanofi Genzyme LTE14762) 
 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential  
8 
Section # and Name 
Description of Change 
Brief Rationale 
Section 18.6.8 Amended protocol 08 
Amendment history of previous version (ie, 
Amended protocol 08) was newly inserted in the 
current document Section 18.6 Protocol amendment 
history.  
Administrative 
change.  
Throughout  
Added “approximately“ prior to “monthly intervals” of 
safety FU visits where applicable.  
To improve flexibility 
of patients and 
facilitate trial operation 
practice. 
Throughout 
Added “major” prior to “operative procedure” in 
perioperative assessment or management where 
applicable.   
For clarity. 
Throughout  
Used “EQ-5D-5L” instead of “EQ-5D”, “QoL” instead 
of “QOL”. Abbreviations been updated accordingly.  
To correct the typo.  
Throughout 
Minor editorial, typo error corrections and document 
formatting revisions. 
Minor, therefore, have 
not been summarized. 
VV-CLIN-0257058 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
  (Sanofi Genzyme LTE14762) 
 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential  
9 
PROTOCOL SYNOPSIS  
Name of Sponsor:  Genzyme Corporation  
Name of Investigational Product:  Fitusiran (formerly Alnylam ALN-AT3SC henceforth referred to 
as fitusiran)  
Name of Active Ingredient:  SAR439774 (formerly ALN-57213) 
Title of Study:  An Open-label Extension Study of Subcutaneously Administered Fitusiran in 
Patients with Moderate or Severe Hemophilia A or B who have Participated in a Previous Clinical 
Study with Fitusiran 
Study center(s):  This study will be conducted at up to 30 clinical study centers worldwide that have 
enrolled patients in a previous clinical study with fitusiran. 
Phase of development:  1/2 
Objectives:  
Primary: 
• 
To evaluate the long-term safety and tolerability of fitusiran in male patients with moderate or 
severe hemophilia A or B 
Secondary: 
• 
To investigate the long-term efficacy of fitusiran 
• 
To characterize the safety and efficacy of concomitantly administered Factor VIII (FVIII), 
Factor IX (FIX) or bypassing agents (BPA) and fitusiran for treatment of bleeding episodes 
• 
To assess changes in health-related quality of life (QoL) over time  
• 
To characterize antithrombin (AT) reduction and thrombin generation (TG) increase 
• 
To characterize the pharmacokinetics (PK) of fitusiran 
Exploratory: 
• 
To assess the safety and hemostatic efficacy rating for major operative procedures conducted in 
patients while on study 
Methodology: This is a 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, 
who previously tolerated dosing in the parent study, ALN-AT3SC-001. ALN-AT3SC-001 is an 
ongoing Phase 1 study evaluating the safety, tolerability, and PK of fitusiran in healthy subjects and 
male patients with hemophilia A or B. ALN-AT3SC-001 is being conducted in 4 parts: Part A, a 
single-ascending dose phase in healthy subjects; Part B, a multiple-ascending dose phase in patients 
with moderate or severe hemophilia A or B; Part C, an exploratory multiple-dose phase in male 
patients with moderate or severe hemophilia A or B; and Part D, a multiple-dose phase in patients 
with moderate or severe hemophilia A or B with inhibitors. 
Patients from Part B may roll over into this study after completing Day 70 in the parent study.  
Patients from Parts C and D are expected to roll over into this study approximately 1 month after 
completing the 3 monthly doses of study drug in the parent study, thereby maintaining their monthly 
dosing schedule. 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
  (Sanofi Genzyme LTE14762) 
 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential  
10 
Screening will occur between Day -60 and Day -1. Eligibility for this study will be confirmed before 
administration of the first dose of study drug.  Administration of fitusiran will occur at the clinical 
study center.  Patients will be monitored for 6 hours postdose for the first dose only. At the discretion 
of the Investigator, contingent upon adequate training after the Month 3 visit, where applicable 
country and local regulations and infrastructure allow, and if the patient has not previously 
experienced any severe AEs or SAEs considered related to the study drug that the Investigator and 
study Medical Monitor believe should preclude the patient from self-administration, 
patients/caregivers may be trained by the Investigator or a healthcare professional in 
self-administration. Patients who experience a severe AE or SAE considered related to the study drug 
that occurs at any time during the study should not self-administer study drug for a 12-week period, 
unless prior approval is obtained from the study Medical Monitor. 
Study assessments will be performed as specified in the Schedule of Assessments (Table 1, Table 2, 
and Table 3). Fitusiran dosing may occur at home in patients who are trained on self-administration.   
For up to 2 years, all fitusiran dosing administered at the study center or at home, LFT results are to 
be obtained within 7 days prior to dosing and results are to be reviewed prior to each dose. From 
Year 3 onwards, the frequency of predose LFT monitoring may be decreased for patients who have 
negative hepatitis C antibody titers and meet the following criteria for reduced predose LFT 
monitoring: 
a) Did not have any ALT elevation >3× ULN persisting for ≥2 months at any time during 
the previous 12 months. 
b) Did not have any fitusiran doses held due to LFT elevations during the study. 
After any modification to the dosing regimen: 
a) Did not have any ALT elevation >3× ULN persisting for ≥2 months at any time during 
the first 12 months under this regimen 
b) Must not have had any fitusiran doses held during the first 12 months under this regimen 
Safety and efficacy assessments will be performed at the clinical study center at each clinic visit and 
during an End of Treatment visit. Patients will return to the clinical study center for an End of Study 
visit 30 days after the last dose of study drug. Separately, follow-up visits to assess AT activity levels 
should occur at approximately monthly intervals until AT activity level returns to approximately 60% 
(per the central laboratory), or per Investigator discretion in consultation with the study Medical 
Monitor (Note: for patients who opt for the commercially available fitusiran, these follow-up visits to 
assess AT activity level are not required). 
Pharmacokinetic assessments will be performed on Day 1, at the Month 12 visit, and at the Month 24 
visit (in a subset of patients).  Patients will also return to the clinical study center on Day 2 and the 
day after the Month 12 and Month 24 (in a subset of patients) visits for further PK sampling.  Pooled 
urine collection will also occur at the Month 24 visit in a subset of patients. 
In addition, where possible, in patients undergoing major operative procedures while on study, 
exploratory safety and hemostatic assessments will be performed preoperatively (SDay -3 to  
SDay -1), intraoperatively (SDay 0), 24 hours postoperatively (SDay 1), and at a postoperative visit 
occurring 2 to 14 days after the procedure (SDay 2 to SDay 14, per type of procedure).  A final 
postoperative visit will occur on SDay 28 (up to + 28 days) to document the date/time when 
perioperative hemostatic treatment and thromboprophylaxis (if applicable) coverage was completed. 
Bleed events and doses of factor or BPAs administered during the conduct of the study will be 
recorded in a conventional or patient diary. Safety, quality of life, pharmacodynamic, and 
pharmacokinetic data will also be collected. 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
  (Sanofi Genzyme LTE14762) 
 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential  
11 
A Safety Review Committee (SRC) will review safety, tolerability, and available PD data, collected 
during the study with the primary purpose of protecting the safety of patients participating in the 
study. 
Number of patients (planned):  Up to 48 patients will be enrolled in this study. 
Diagnosis and eligibility criteria:  To be enrolled in this study, patients must have moderate or 
severe hemophilia A or B, previously participated in study ALN-AT3SC-001, and meet the eligibility 
criteria for this study. 
Inclusion criteria: 
1. Completed and tolerated study drug dosing in study ALN-AT3SC-001 
2. Male aged ≥18 years 
3. Moderate or severe, clinically stable hemophilia A or B as evidenced by a laboratory FVIII or 
FIX level ≤5% at screening.  Patients with a FVIII or FIX level >5% at screening will be 
eligible on provision of a historic laboratory report indicating a trough level ≤5%   
4. <deleted per Amendment 1>  
5. Willing and able to comply with the study requirements and provide written informed consent 
Exclusion criteria: 
1. Liver disease defined as any of the following: 
• 
Clinically significant cirrhosis as determined by the Investigator 
• 
INR >1.5 at Screening 
• 
ALT or AST >3× upper limit of the normal (ULN) of the reference range at Screening 
• 
Platelet count ≤120,000/μL and/or other complete blood count test results that are 
considered clinically significant and unacceptable by the Investigator 
• 
Known hepatitis C virus (HCV) infection currently requiring treatment with ribavirin or 
interferon 
2. Known to be human immunodeficiency virus seropositive and have a CD4 count 
<200 cells/µL at screening (a CD4 result from the previous 6 months may be used to confirm 
eligibility) 
3. History of venous thromboembolism, except for those patients who have a medical history of 
previous thrombotic event related to permanent indwelling venous access 
4. Current serious mental illness that, in the judgment of the Investigator, may compromise 
patient safety, ability to participate in all study assessments, or study integrity 
5. Uncontrolled hypertension (defined as systolic blood pressure ≥160 mmHg and diastolic 
blood pressure ≥100 mmHg)  
6. Corrected QT(QTc) interval ≥450 msec and/or concomitant use of drugs known to prolong 
the QT/QTc interval at screening 
7. Estimated glomerular filtration rate ≤45 mL/min (using the Modification of Diet in Renal 
Disease formula) 
VV-CLIN-0257058 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
  (Sanofi Genzyme LTE14762) 
 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential  
12 
8. Clinically relevant history or presence of cardiovascular, respiratory, gastrointestinal, renal, 
neurological, inflammatory, or other diseases that, in the judgment of the Investigator, 
precludes study participation 
9. If using nonsteroidal anti-inflammatory drugs intermittently or chronically, must tolerate 
them with no previous side effects (eg, gastric distress or bleeding) 
10. Clinically significant alcohol consumption, as assessed by the Investigator 
11. Any condition(s) that, in the opinion of the Investigator, would make the patient unsuitable 
for enrollment or could interfere with patient participation in or completion of the study 
Investigational product, dose and mode of administration: Fitusiran Solution for Injection 
(subcutaneous [SC] use) is comprised of a synthetic, small interfering ribonucleic acid (siRNA) 
targeting AT and bearing a triantennary N-acetylgalactosamine (GalNAc) ligand conjugated to the 
sense strand, formulated in phosphate buffer.   
Fitusiran will be administered as a 50 or 80 mg SC injection once monthly or every 2 months 
according to the dose selection rules in Section 6.5.1 and the SoAs  (Table 1, Table 2 and Table 3). 
Duration of treatment:  It is anticipated that patients in this study will receive treatment with 
open-label fitusiran for approximately 6 years or until fitusiran becomes commercially available, 
whichever occurs first. Some patients will have an extended treatment duration by a maximum of 
12 months to ensure all patients will have at least an 18-calendar months treatment period after recent 
restart with modified SoA and revised fitusiran dose and regimen. This will not affect the whole study 
duration (last patient last visit is unchanged). 
Reference therapy, dosage and mode of administration:  Not applicable. 
Criteria for evaluation: 
Safety:  Safety assessments will include monitoring for AEs (including serious AEs [SAEs]), clinical 
laboratory evaluations (including hematology, biochemistry, urinalysis, and coagulation), vital signs, 
12-lead electrocardiogram (ECG), antidrug antibodies, and physical examinations. 
Efficacy:  The efficacy of fitusiran will be evaluated by the following assessments: 
• 
Annualized bleed rate 
• 
Time intervals between bleeding episodes 
• 
Weight-adjusted consumption of FVIII, FIX, or BPA 
• QoL assessed by an EQ-5D-5L questionnaire and Haem-A-QoL  
• 
AT levels 
• 
TG levels 
Pharmacokinetic Assessments:  Blood and urine samples will be collected to assess levels of 
fitusiran.   
Exploratory: Exploratory assessments will include perioperative assessments of safety and 
hemostatic efficacy rating for major operative procedures conducted while on study. 
Statistical methods:  The size of this study is not determined via power analysis of particular 
hypotheses tests.  Statistical analyses will be primarily descriptive. Results will be presented in 
summary tables by starting dose regimen and then by final dose regimen of fitusiran separately for 
patients with and without inhibitors.   
AE summaries will include tabulations of all treatment-emergent AEs (TEAEs), TEAEs by maximum 
severity, TEAEs by relationship to study medication or underlying hemophilia, SAEs, and AEs 
VV-CLIN-0257058 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
  (Sanofi Genzyme LTE14762) 
 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential  
13 
leading to discontinuation of treatment. By-patient listings will be provided for deaths, SAEs, and 
events leading to discontinuation of treatment.  Laboratory parameter shifts from baseline to worst 
post-baseline values will be presented.  Descriptive statistics will be provided for clinical laboratory 
data and vital signs.  Abnormal physical examination findings, 12-lead ECG data, and antidrug 
antibody results will be listed by patient (antidrug antibody results will also be tabulated). 
Descriptive statistics will be provided for clinical efficacy data. Annualized bleed rate, bleed rate 
reduction, and percentage reduction compared with pretreatment will be calculated. Descriptive 
statistics will be presented for the EQ-5D-5L questionnaire, Haem-A-QoL, plasma AT activity, and 
TG.  The total number of patients in each rating category of hemostatic response in patients 
undergoing operative procedures will be summarized. 
VV-CLIN-0257058 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
(Sanofi Genzyme LTE14762) 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential 
14 
Table 1: 
Schedule of Assessments (Years 1 to 4)         
 
Treatment Period 
Year 1 
Year 2 
Year 3 
Year 4 
Study Month (Visit) 
Screening  
 
 
M1 
M2 
M3 
M4, M5b 
M6 
M7, M8b 
M 9 
M10, M11b 
M12 
M13, M14 
M15 
M16, M17b 
M18 
M19, M20b 
M21 
M22, M23b 
M24 
M25, M26 
M27 
M28, M29b 
M30 
M31, M32b 
M33 
M34, M35b 
M36 
M37, M38 
M39 
M40, M41b 
M42 
M43, M44b 
M45 
M46, M47b 
M48  
Study Day  
(±Visit Window) 
-60 to -1 
1 
2 
31 ±7 
61 ±7 
91 ±7 
121, 151 ±7 
181 ±7 
211, 241 ±7 
271 ±7 
301, 331 ±7 
361 ±7 
362 ±7 
391, 421 ±7 
451 ±7 
481, 511 ±7 
541 ±7 
571, 601 ±7 
631 ±7 
661, 691 ±7 
721 ±7 
722 ±7 
751, 781 ±7 
811 ±7 
841, 871 ±7 
901 ±7 
931, 961 ±7 
991 ±7 
1021, 1051 ±7 
1081 ±7 
1111, 1141 ±7 
1171 ±7 
1201, 1231 ±7 
1261 ±7 
1291, 1321 ±7 
1351 ±7 
1381, 1411 ±7 
1441 ±7 
Informed Consent 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Historya 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
Exclusion Criteria 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FVIII or FIX Levels X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug 
Administrationb 
 X  X X X X X X X X X  
X X X X X X X X  
X X X X X X X X X X X X X X X X 
Directed Physical 
Examc 
X X 
 X X X X X X X X X  
X X X X X X X X  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 X 
Body Weight 
X X  X X X 
 
X 
 
X 
 X  
 
X 
 
X 
 
X 
 
X  
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 X 
Vital Signsd 
X X  X X X 
 
X 
 
X 
 X  
 
X 
 
X 
 
X 
 
X  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 X 
12-Lead ECGe 
X X X  
 
 
 
 
 
 
 X X 
 
 
 
 
 
 
 
X X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 X 
Liver Status Studiesf 
X, must be performed once at any clinic visitf 
Inhibitor Statusg 
 X  
 
 
 
 
 
 
 
 X  
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 X 
Clinical Laboratory 
Assessmenth, k 
X X  X X X X X X X X X  
X X X X X X X X  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 X 
Urinalysisi 
X X  X X X 
 
X 
 
X 
 X  
 
X 
 
X 
 
X 
 
X  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 X 
VV-CLIN-0257058 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
(Sanofi Genzyme LTE14762) 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential 
15 
Table 1: 
Schedule of Assessments (Years 1 to 4)         
 
Treatment Period 
Year 1 
Year 2 
Year 3 
Year 4 
Study Month (Visit) 
Screening  
 
 
M1 
M2 
M3 
M4, M5b 
M6 
M7, M8b 
M 9 
M10, M11b 
M12 
M13, M14 
M15 
M16, M17b 
M18 
M19, M20b 
M21 
M22, M23b 
M24 
M25, M26 
M27 
M28, M29b 
M30 
M31, M32b 
M33 
M34, M35b 
M36 
M37, M38 
M39 
M40, M41b 
M42 
M43, M44b 
M45 
M46, M47b 
M48  
Study Day  
(±Visit Window) 
-60 to -1 
1 
2 
31 ±7 
61 ±7 
91 ±7 
121, 151 ±7 
181 ±7 
211, 241 ±7 
271 ±7 
301, 331 ±7 
361 ±7 
362 ±7 
391, 421 ±7 
451 ±7 
481, 511 ±7 
541 ±7 
571, 601 ±7 
631 ±7 
661, 691 ±7 
721 ±7 
722 ±7 
751, 781 ±7 
811 ±7 
841, 871 ±7 
901 ±7 
931, 961 ±7 
991 ±7 
1021, 1051 ±7 
1081 ±7 
1111, 1141 ±7 
1171 ±7 
1201, 1231 ±7 
1261 ±7 
1291, 1321 ±7 
1351 ±7 
1381, 1411 ±7 
1441 ±7 
Antidrug 
Antibodiesj 
 X  X X X 
 
X 
 
X 
 X  
 
X 
 
X 
 
X 
 
X  
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 X 
Plasma PKl 
 X X  
 
 
 
 
 
 
 X X 
 
 
 
 
 
 
 
X X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine PKm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma AT 
Activityj, k 
 X  X X X X X X X X X  
X X X X X X X X  
 
 
 
X 
 
 
 
X 
  
  
  X 
 
  
 X 
Plasma TGj, k 
 X  X X X X X X X X X  
X X X X X X X X  
 
 
 
X 
 
 
 
X 
  
  
  X 
 
  
 X 
EQ-5D-5L 
Questionnaire and 
Haem-A-QoLn 
 
X  
 
 
X 
 
X 
 
X 
 X  
 
X 
 
X 
 
X 
 
X  
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 X 
Patient Education 
Module Training 
 
To be completed onceo 
Patient Diary 
 
Review with patient at each dosing, and contact every 2 weeks (±4 days) in between fitusiran dosing 
Bleed Management 
Reviewp 
 
Review with patient at each dosing, and contact every 2 weeks (±4 days) in between fitusiran dosing 
Perioperative 
Assessmentq 
 
Continuous 
Adverse Eventsr 
 
Continuous 
Concomitant 
Medicationss 
      Continuous 
VV-CLIN-0257058 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
(Sanofi Genzyme LTE14762) 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential 
16 
Table 1: 
Schedule of Assessments (Years 1 to 4)         
 
Treatment Period 
Year 1 
Year 2 
Year 3 
Year 4 
Study Month (Visit) 
Screening  
 
 
M1 
M2 
M3 
M4, M5b 
M6 
M7, M8b 
M 9 
M10, M11b 
M12 
M13, M14 
M15 
M16, M17b 
M18 
M19, M20b 
M21 
M22, M23b 
M24 
M25, M26 
M27 
M28, M29b 
M30 
M31, M32b 
M33 
M34, M35b 
M36 
M37, M38 
M39 
M40, M41b 
M42 
M43, M44b 
M45 
M46, M47b 
M48  
Study Day  
(±Visit Window) 
-60 to -1 
1 
2 
31 ±7 
61 ±7 
91 ±7 
121, 151 ±7 
181 ±7 
211, 241 ±7 
271 ±7 
301, 331 ±7 
361 ±7 
362 ±7 
391, 421 ±7 
451 ±7 
481, 511 ±7 
541 ±7 
571, 601 ±7 
631 ±7 
661, 691 ±7 
721 ±7 
722 ±7 
751, 781 ±7 
811 ±7 
841, 871 ±7 
901 ±7 
931, 961 ±7 
991 ±7 
1021, 1051 ±7 
1081 ±7 
1111, 1141 ±7 
1171 ±7 
1201, 1231 ±7 
1261 ±7 
1291, 1321 ±7 
1351 ±7 
1381, 1411 ±7 
1441 ±7 
COVID-19 Testing 
Anytime during the studyt 
Abbreviations:  AE=adverse event; APRI=Aspartate aminotransferase to Platelet Ratio Index; AT=antithrombin; BPA=bypassing agent; CD4=cluster of differentiation 4; ECG=electrocardiogram; 
EOS=End of Study; EOT=End of Treatment; EQ-5D-5L=EuroQoL 5-Dimensions, 5-Levels Questionnaire.; ET=Early Termination; exam=examination; FVIII=factor VIII; FIX=factor IX; 
Haem-A-QoL=Haemophilia Quality of Life Questionnaire; HIV=human immunodeficiency virus; LFT=Liver function test; INR=international normalized ratio; M=Month; PK=pharmacokinetics; 
PT=prothrombin time; SC=subcutaneous; TG=thrombin generation; treat=treatment. 
Notes:   
• 
When scheduled at the same time points, assessments of vital signs and 12-lead ECGs should be performed first, before the physical examinations and blood/urine sample collections. 
• 
Where study assessments overlap with the parent study, the assessments only need to be performed once. 
• 
This schedule applies for patients who continue to receive fitusiran under the 50 or 80 mg monthly dose without meeting criteria for adjusted dosing. 
a Any ongoing AEs from the parent study will be captured as medical history.  See Section 9.1.1 for details on the medical history/hemophilia history to be recorded at screening. 
b SC administration of study drug as per Pharmacy Manual.  For up to 2 years, all fitusiran dosing administered at the study center or at home, LFT results are to be obtained within 7 days prior to 
dosing and results are to be reviewed prior to each dose.  From Year 3 onwards, the frequency of predose LFT monitoring may be decreased for patients who have negative hepatitis C antibody 
titers and meet specific criteria defined in Section 6.5.1.1. 
c On Day 1, a directed physical examination will be performed at predose and 6 hours postdose.  On all other dosing days checked in the table, the directed physical examination will be performed 
predose.  See Section 9.1.5 for assessments to be performed during a directed physical examination. 
d Vital signs include blood pressure, heart rate, body temperature (oral, tympanic, or axillary), and respiratory rate.  Vital signs will be measured in the seated or supine position after the patient has 
rested comfortably for 10 minutes.  On Day 1, vital signs will be collected predose and at 6 hours (±30 minutes) postdose.  On all other dosing days checked in the table, vital signs will be 
collected predose. 
e 12-lead ECGs will be performed in the supine position after the patient has rested comfortably for 10 minutes.  12-lead ECGs will be performed at predose; 30 minutes (±10 minutes) postdose; 
and 2, 4, and 24 hours (±30 minutes) postdose in relation to the Day 1 and Month 12 fitusiran doses.  12-lead ECGs will be performed at predose; 30 minutes (±10 minutes) postdose; and 2, 4, 
and 24 hours (±30 minutes) postdose in relation to the Month 24 fitusiran doses.  At remaining visits checked in the table, the predose ECG will be performed before blood sample collection. 
f 
Full Hepatic Tests (Table 10) Sample must be performed in all patients once, at Screening (if newly enrolled) or at next scheduled clinic visit (if patient has already completed a clinic visit) and 
annually thereafter.  FibroScan (or FibroTest with APRI) testing must be performed in all patients found to have positive hepatitis C antibody titers 
g As determined by Nijmegen modified Bethesda assay. 
h Blood samples will be collected predose at visits checked in the table.  Biochemistry, hematology, and coagulation are described in Section 9.1.7.1.  At Screening, only a complete blood count, 
platelet count, INR, and CD4 count in HIV seropositive patients is required; however, a CD4 count from the previous 6 months may be used to confirm eligibility. 
i 
Sample for urinalysis will be collected predose at visits checked in the table. Urinalysis parameters are described in Section 9.1.7.3. 
VV-CLIN-0257058 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
(Sanofi Genzyme LTE14762) 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential 
17 
j 
Blood samples will be collected predose at visits checked in the table.   
k When patients reinitiate the study at their monthly dose (no dose change) they will have their AT, TG, and coagulation measured monthly for 6 months. Upon the first AT level <15%, the patient 
must have another AT activity level sample drawn within 1 week of site receipt of the results. 
l 
Blood samples for PK analysis will be collected at the time points listed in Table 13 (Appendix 18.1).  Samples collected at the Month 24 visit will be in a subset of patients who opt to participate.  
There will be no blood samples collected for PK after Month 24. 
m In a subset of patients who opt to participate, pooled urine collection will occur at the time points listed in Table 14 (Appendix 18.1).  Urine samples for PK will not be collected after Month 24. 
n Assessments will be performed predose at visits checked in the table, where available. 
o To be completed once, following initiation of the amendment to this protocol (Amendment 4), prior to dosing with fitusiran.   
p Will include review of entries, (symptoms of bleed events, bleed causality, bleed severity, factor or BPA doses administered), whether site contact occurred regarding treatment of bleeds, and 
review of patient bleed management plan and recommendations and requirements for site contact regarding dosing.   
q Perioperative assessment of safety and hemostatic efficacy only in patients undergoing major operative procedures while on study (see Table 4). 
r 
AEs including signs and symptoms of thrombosis will be evaluated continuously (see Section 5.5). 
s Medication(s) will be recorded as concomitant if any of the following apply:  1) medication is ongoing from a previous fitusiran clinical trial; 2) medication started between a previous fitusiran 
clinical trial and the present study; or 3) medication started after signing informed consent for the present clinical trial. 
t 
All study patients that are consenting to this procedure are requested to undergo testing for SARS-CoV-2 (virus responsible for COVID-19), which should include both RT-PCR and antibody 
testing. Note: Rapid test may be used if RT-PCR is not available. These tests should be performed as early as possible during the study, except for patients who have undergone COVID-19 
vaccination, after which antibody testing is no longer required. Alternatively, historical test results may be provided under certain circumstances as defined by Sponsor. 
 
Table 2: 
Schedule of Assessments (Years 5, 6 and 7)                           
  
Year 5 
Year 6 
Year 7p 
EOS/ET 
AT 
FU 
Study Month (Visit) 
M54 
M60 
M66 
M72/EOT 
M78 
M84/EOT 
M73 or 
M74-M84p 
Study Day (±Visit Window) 
1621 ±7 
1801 ±7 
1981 ±7 
2161 ±7 
2341 ±7 
2521 ±7 
EOT+30 ±7 
EOT+
60 ±7 
Study Drug Administrationa, b 
X, monthly 
 
 
Directed Physical Examc 
X 
X 
X 
X 
X 
X 
X 
 
Body Weight 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signsd 
X 
X 
X 
X 
X 
X 
X 
 
12-Lead ECGe 
 
X 
 
X 
 
X 
X 
 
Liver Function Testsb 
X, monthlyb 
 
 
Liver Status Studiesf 
X, annually at any clinic visitg 
 
 
VV-CLIN-0257058 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
(Sanofi Genzyme LTE14762) 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential 
18 
Clinical Laboratory Assessmentg, k 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysish 
X 
X 
X 
X 
X 
X 
X 
 
Antidrug Antibodiesi 
 
X 
 
X 
 
X 
 
 
Inhibitor Statusj 
 
X 
 
X 
 
X 
 
 
Plasma AT Activityk 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma TGk 
X 
X 
X 
X 
X 
X 
X 
 
EQ-5D-5L Questionnaire and 
Haem-A-QoL 
 
X 
 
X 
 
X 
 
 
Patient Diary 
Review with patient at each dosing, and contact every 2 weeks (±4 days) in between fitusiran dosing 
Bleed Management Reviewl 
Review with patient at each dosing, and contact every 2 weeks (±4 days) in between fitusiran dosing  
Perioperative Assessmentm 
Continuous 
Adverse Eventsn 
Continuous 
Concomitant Medications 
Continuous 
COVID-19 Testing 
Anytime during the studyo 
Abbreviations:  AE=adverse event; APRI= Aspartate aminotransferase to Platelet Ratio Index; AT=antithrombin; BPA=bypassing agent; ECG=electrocardiogram; EOS=End of Study; EOT=End of 
Treatment; EQ-5D-5L=EuroQoL 5-Dimensions, 5-Levels Questionnaire; ET=Early Termination; exam=examination; FU=Follow-up; Haem-A-QoL=Haemophilia Quality of Life Questionnaire for Adults; 
HIV=human immunodeficiency virus; FVIII=factor VIII; FIX=factor IX; INR=international normalized ratio; LFT=Liver function test; M=Month; PK=pharmacokinetics; PT=prothrombin time; 
SC=subcutaneous; TG=thrombin generation; treat=treatment. 
Notes:  
• 
When scheduled at the same time points, assessments of vital signs and 12-lead ECGs should be performed first, before the physical examinations and blood/urine sample collections. 
• 
This schedule applies for patients who continue to receive fitusiran under the 50 or 80 mg monthly dose without meeting criteria for adjusted dosing. 
a SC administration of study drug as per Pharmacy Manual. 
b For all fitusiran dosing administered at the study center or at home, LFT results are to be obtained within 7 days prior to dosing and results are to be reviewed prior to each dose.  The frequency 
of predose LFT monitoring may be decreased to quarterly for patients who have negative hepatitis C antibody titers and meet specific criteria defined in Section 6.5.1.1. 
c A directed physical examination will be performed predose on dosing days checked in the table.  See Section 9.1.5 for assessments to be performed during a directed physical examination. 
d Vital signs include blood pressure, heart rate, body temperature (oral, tympanic, or axillary), and respiratory rate.  Vital signs will be measured in the seated or supine position after the patient has 
rested comfortably for 10 minutes.  Vital signs will be collected predose on dosing days checked in the table. 
e 12-lead ECGs will be performed in the supine position after the patient has rested comfortably for 10 minutes. ECG will be performed before blood sample collection. 
f 
Full Hepatic Tests (Table 10) must be performed in all patients once annually. FibroScan (or FibroTest with APRI) testing must be performed in all patients found to have positive hepatitis C 
antibody titers. 
g Blood samples will be collected predose on dosing days checked in the table. Biochemistry, hematology, and coagulation are described in Section 9.1.7.1. 
h Sample for urinalysis will be collected predose on dosing days checked in the table. Urinalysis parameters are described in Section 9.1.7.3.   
i 
Blood samples will be collected predose on dosing days checked in the table.   
j 
As determined by Nijmegen modified Bethesda assay. 
VV-CLIN-0257058 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
(Sanofi Genzyme LTE14762) 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential 
19 
k When patients reinitiate the study at their 80 mg or 50 mg monthly dose (no dose change) they will have their AT, TG, and coagulation measured monthly for 6 months. Upon the first AT activity 
level <15%, the patient must have another AT activity level sample drawn within 1 week of site receipt of the results. 
l 
Will include review of entries, (symptoms of bleed events, bleed causality, bleed severity, factor or BPA doses administered), whether site contact occurred regarding treatment of bleeds, and 
review of patient bleed management plan and recommendations and requirements for site contact regarding dosing.   
m Perioperative assessment of safety and hemostatic efficacy only in patients undergoing major operative procedures while on study (see Table 4). 
n AEs including signs and symptoms of thrombosis will be evaluated continuously (see Section 5.5). 
o All study patients that are consenting to this procedure are requested to undergo testing for SARS-CoV-2 (virus responsible for COVID-19), which should include both RT-PCR and antibody 
testing. Note: Rapid test may be used if RT-PCR is not available. These tests should be performed as early as possible during the study, except for patients who have undergone COVID-19 
vaccination, after which antibody testing is no longer required. Alternatively, historical test results may be provided under certain circumstances as defined by Sponsor. 
p Only for patients who would complete the study as per current schedule before having at least 18-calendar months treatment under the new dose and regimen. For patients continuing beyond 
Month 72 for this reason, when 18-calendar months post resuming treatment is reached, the EOT visit should be completed, followed by the EOS and AT follow-up period.  
Table 3:  
Modified IMP Regimen Schedule of Assessments (Year 1, 2, 3)  
 
Treatment Period 
 
 
Year 1 
Year 2 
Year 3 
 
 
Time from modified 
IMP regimen   
re-starta 
Day of dose 
re-start 
PRM1 
PRM2 
PRM3 
PRM4 
PRM5 
PRM6 
PRM7 
PRM8 
PRM 9 
PRM10 
PRM11 
PRM12 
PRM13 
PRM14 
PRM15 
PRM16 
PRM17 
PRM18 
PRM19 
PRM20 
PRM21 
PRM22  
PRM23 
PRM24 
PRM25 
PRM26 
PRM27 
PRM28 
PRM29 
PRM30 
PRM31  
PRM32 
PRM33 
PRM34 
PRM35 
PRM36 
EOS/ET 
AT FU 
PR Study Day  
(±Visit Window) 
1 
 
29 ±7 
57 ±7 
85 ±7 
113 ±7 
141 ±7 
169 ±7 
197 ±7 
225 ±7 
253 ±7 
281 ±7 
309 ±7 
337 ±7 
365 ±7 
393 ±7 
421 ±7 
449 ±7 
477 ±7 
505 ±7 
533 ±7 
561 ±7 
589 ±7 
617 ±7 
645 ±7 
673 ±7 
701 ±7 
729 ±7 
757 ±7 
785 ±7 
813 ±7 
841 ±7 
869 ±7 
897 ±7 
925 ±7 
953 ±7 
981 ±7 
1009 ±7 
 
 
Re-sign Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FVIII or FIX Levels 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug 
Administration Q2Mb 
X 
 
X 
 
X 
 
X 
 
X  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Study Drug 
Administration QMb 
X 
X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X 
X 
 
 
Directed Physical 
Examc 
X 
 
X 
 
X 
 
X 
 
X  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X X 
 
Body Weight 
X 
 
X 
 
X 
 
X 
 
X  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X X  
Vital Signsd 
X 
 
X 
 
X 
 
X 
 
X  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X X  
12-Lead ECGe 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X X  
VV-CLIN-0257058 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
(Sanofi Genzyme LTE14762) 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential 
20 
 
Treatment Period 
 
 
Year 1 
Year 2 
Year 3 
 
 
Time from modified 
IMP regimen   
re-starta 
Day of dose 
re-start 
PRM1 
PRM2 
PRM3 
PRM4 
PRM5 
PRM6 
PRM7 
PRM8 
PRM 9 
PRM10 
PRM11 
PRM12 
PRM13 
PRM14 
PRM15 
PRM16 
PRM17 
PRM18 
PRM19 
PRM20 
PRM21 
PRM22  
PRM23 
PRM24 
PRM25 
PRM26 
PRM27 
PRM28 
PRM29 
PRM30 
PRM31  
PRM32 
PRM33 
PRM34 
PRM35 
PRM36 
EOS/ET 
AT FU 
PR Study Day  
(±Visit Window) 
1 
 
29 ±7 
57 ±7 
85 ±7 
113 ±7 
141 ±7 
169 ±7 
197 ±7 
225 ±7 
253 ±7 
281 ±7 
309 ±7 
337 ±7 
365 ±7 
393 ±7 
421 ±7 
449 ±7 
477 ±7 
505 ±7 
533 ±7 
561 ±7 
589 ±7 
617 ±7 
645 ±7 
673 ±7 
701 ±7 
729 ±7 
757 ±7 
785 ±7 
813 ±7 
841 ±7 
869 ±7 
897 ±7 
925 ±7 
953 ±7 
981 ±7 
1009 ±7 
 
 
Liver Status Studiesf 
X, must be performed once at any clinic visitf 
 
 
Inhibitor Statusg 
X  
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Biochemistry and 
hematology 
Assessmentsh 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X  
Liver function testsh 
X 
X X X X X X X X X X X X Xi X Xi X Xi X Xi X Xi X Xi X Xi X Xi X Xi X Xi X Xi X Xi X X  
Urinalysisj 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X X  
Antidrug Antibodiesk 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Coagulationh  
X 
X X X X X X X X X X X X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X X  
Plasma AT Activityk  
X 
X X X X X X X X X X X X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X X X 
Plasma TGk 
X 
X X X X X X X X X X X X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X X  
EQ-5D-5L 
Questionnaire and 
Haem-A-QoLl 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Patient Education 
Module Training 
To be completed oncem 
 
 
Patient Diary 
Review with patient at each dosing, and contact every 2 weeks (±4 days) in between fitusiran dosing 
Bleed Management 
Reviewn 
Review with patient at each dosing, and contact every 2 weeks (±4 days) in between fitusiran dosing 
Perioperative 
Assessmento 
Continuous 
VV-CLIN-0257058 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
(Sanofi Genzyme LTE14762) 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential 
21 
 
Treatment Period 
 
 
Year 1 
Year 2 
Year 3 
 
 
Time from modified 
IMP regimen   
re-starta 
Day of dose 
re-start 
PRM1 
PRM2 
PRM3 
PRM4 
PRM5 
PRM6 
PRM7 
PRM8 
PRM 9 
PRM10 
PRM11 
PRM12 
PRM13 
PRM14 
PRM15 
PRM16 
PRM17 
PRM18 
PRM19 
PRM20 
PRM21 
PRM22  
PRM23 
PRM24 
PRM25 
PRM26 
PRM27 
PRM28 
PRM29 
PRM30 
PRM31  
PRM32 
PRM33 
PRM34 
PRM35 
PRM36 
EOS/ET 
AT FU 
PR Study Day  
(±Visit Window) 
1 
 
29 ±7 
57 ±7 
85 ±7 
113 ±7 
141 ±7 
169 ±7 
197 ±7 
225 ±7 
253 ±7 
281 ±7 
309 ±7 
337 ±7 
365 ±7 
393 ±7 
421 ±7 
449 ±7 
477 ±7 
505 ±7 
533 ±7 
561 ±7 
589 ±7 
617 ±7 
645 ±7 
673 ±7 
701 ±7 
729 ±7 
757 ±7 
785 ±7 
813 ±7 
841 ±7 
869 ±7 
897 ±7 
925 ±7 
953 ±7 
981 ±7 
1009 ±7 
 
 
Adverse Eventsp 
Continuous 
Concomitant 
Medicationsq 
Continuous 
COVID-19 Testing 
Anytime during the studyr 
Abbreviations:  AE=adverse event; APRI=Aspartate aminotransferase to Platelet Ratio Index; AT=antithrombin; BPA=bypassing agent; CRF=Case Report Form; CD4=cluster of differentiation 4; 
ECG=electrocardiogram; EOS=End of Study; EOT=End of Treatment; EQ-5D-5L=EuroQoL 5-Dimensions, 5-Levels Questionnaire.; ET=Early Termination; exam=examination; FVIII=factor VIII; 
FIX=factor IX; Haem-A-QoL=Haemophilia Quality of Life Questionnaire; HIV=human immunodeficiency virus; LFT=Liver function test; INR=international normalized ratio; M=Month; 
PK=pharmacokinetics; PR=post-restart; PT=prothrombin time; SC=subcutaneous; TG=thrombin generation; treat=treatment. 
Notes:   
• 
When scheduled at the same time points, assessments of vital signs and 12-lead ECGs should be performed first, before the physical examinations and blood/urine sample collections. 
• 
Where study assessments overlap with the parent study, the assessments only need to be performed once. 
a This schedule applies for patients meeting criteria for adjusted dosing regimen.  Upon each dose adjustment, the patient will restart the schedule (For dose adjustment from 50 mg Q2M to 50 mg 
QM, the patient will restart at PR M1 as their Month 6 visit under 50 mg will serves as their PR Study Day 1. For dose adjustment from 50 mg QM to 80 mg QM, the patient will restart at PR Study 
Day 1). The duration that the patient must continue in the study post modified IMP dose/frequency re-start depends on the re-start time-point relative to the overall study start for each individual 
patient to ensure an overall duration of fitusiran administration of approximately 72 months or 18 calendar months after restarting dosing post dosing pause (whichever is longer). Thus, when the 
patient reaches the latter of 72 months of study participation or 18 calendar months post dosing restart, the EOT visit should be performed, followed by the EOS and AT follow-up period. 
b Patients will follow either the Q2M or QM dosing regimen according to the dose adjustment rules; see Section 6.5.1.3. SC administration of study drug as per Pharmacy Manual.  From Year 3 
onwards, the frequency of predose LFT monitoring may be decreased for patients who have negative hepatitis C antibody titers and meet specific criteria defined in Section 6.5.1.1.  
c On Day 1, a directed physical examination will be performed at predose and 6 hours postdose.  On all other dosing days checked in the table, the directed physical examination will be performed 
predose.  See Section 9.1.5 for assessments to be performed during a directed physical examination. 
d Vital signs include blood pressure, heart rate, body temperature (oral, tympanic, or axillary), and respiratory rate.  Vital signs will be measured in the seated or supine position after the patient has 
rested comfortably for 10 minutes.  On Day 1, vital signs will be collected predose and at 6 hours (±30 minutes) postdose.  On all other dosing days checked in the table, vital signs will be 
collected predose. 
e 12-lead ECGs will be performed in the supine position after the patient has rested comfortably for 10 minutes. 12-lead ECGs will be performed before blood sample collection. 
f 
Full Hepatic Tests (Table 9) Sample must be performed in all patients once, at Screening (if newly enrolled) or at next scheduled clinic visit (if patient has already completed a clinic visit) and 
annually thereafter.  FibroScan (or FibroTest with APRI) testing must be performed in all patients found to have positive hepatitis C antibody titers 
g As determined by Nijmegen modified Bethesda assay. 
h Blood samples will be collected predose at visits checked in the table.  Biochemistry, hematology, and coagulation are described in Section 9.1.7.1. 
VV-CLIN-0257058 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
(Sanofi Genzyme LTE14762) 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential 
22 
i 
LFT testing is not required at these visits for patients on the every other month dosing regimen or for patients who meet the criteria for every other month pre-dose LFT monitoring with dosing 
described in Section 6.5.1.1 
j 
Sample for urinalysis will be collected predose at visits checked in the table. Urinalysis parameters are described in Section 9.1.7.3. 
k Blood samples will be collected predose at visits checked in the table. ADA samples will be collected within 240 minutes before dosing according to the schedule in Table 15 and Table 16. At 
each dose level, upon the first AT activity level <15%, the patient must have another AT activity level sample drawn within 1 week of site receipt of the result.  
l 
Assessments will be performed predose at visits checked in the table, where available. 
m To be completed once, prior to dosing with fitusiran.   
n Will include review of entries, (symptoms of bleed events, bleed causality, bleed severity, factor or BPA doses administered), whether site contact occurred regarding treatment of bleeds, and 
review of patient bleed management plan and recommendations and requirements for site contact regarding dosing.   
o Perioperative assessment of safety and hemostatic efficacy only in patients undergoing major operative procedures while on study (see Table 4). 
p AEs including signs and symptoms of thrombosis will be evaluated continuously (see Section 5.5). 
q Medication(s) will be recorded as concomitant if any of the following apply:  1) medication is ongoing from a previous fitusiran clinical trial; 2) medication started between a previous fitusiran 
clinical trial and the present study; or 3) medication started after signing informed consent for the present clinical trial. 
r 
All study patients that are consenting to this procedure are requested to undergo testing for SARS-CoV-2 (virus responsible for COVID-19), which should include both RT-PCR and antibody 
testing. Note: Rapid test may be used if RT-PCR is not available. These tests should be performed as early as possible during the study, except for patients who have undergone COVID-19 
vaccination, after which antibody testing is no longer required. Alternatively, historical test results may be provided under certain circumstance as defined by Sponsor. 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
(Sanofi Genzyme LTE14762) 
 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential  
23 
Table 4: 
Perioperative Schedule of Assessments in Patients Undergoing Major 
Operative Procedures        
 
Perioperative Evaluation Perioda 
Preoperative 
Screening 
Dental/Surgical 
Procedure Visit 
Postoperative 
Visit 1 
Postoperative 
Visit 2 
Postoperative 
Visit 3 
SDay -3 to -1 
SDay 0 
SDay 1b 
SDay 2 to 14c SDay 28 (up to 
28 days)k 
Hemostatic/ 
Thromboprophylaxis 
Treatment Plan 
X 
 
 
 
 
Directed Physical 
Examinationd 
X 
 
 
 
X 
Vital Sign 
Measurementse 
X 
 
 
 
X 
Clinical Laboratory 
Assessmentsf 
X 
Xh 
X 
X 
X 
TG 
X 
X g, h  
Xg 
Xg 
Xg 
AT Activity Level 
X 
Xi, h  
 
 
 
FVIII/IX Levelsg  
X 
Xg, h 
Xg 
Xg 
Xg 
Hemostatic efficacy 
(Perioperative 
Questionnaire) 
 
Xj, h 
X 
X 
 
Completion of 
Hemostatic Treatment 
Coverage 
 
 
 
Xk 
Xk 
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; PF=prothrombin 
fragment; SDay=surgery day; TG=thrombin generation 
a During Perioperative Evaluation Period, adverse events 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 Hemostatic efficacy (by using perioperative questionnaire) for Postoperative Visit 2 
should be completed on the day of the last visit. 
d Directed physical examination (see Section 9.1.5). 
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 10). 
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 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 Hemostatic efficacy (by using 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 The date/time of when perioperative hemostatic treatment and thromboprophylaxis (if applicable) coverage was completed will be captured.  
If hemostatic treatment and thromboprophylaxis are completed at Postoperative Visit 2, the date/time of completion should be recorded, 
and the SDay 28 visit is not required. 
VV-CLIN-0257058 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
(Sanofi Genzyme LTE14762) 
 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential  
24 
 
Table 5: 
Bleeding Episode Assessments – Unscheduled Visit                 
 
Predose 
Postdose 
10 min (±5 min) 
Postdose 
60 min (±5 min) 
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 
Optional Imagingb 
X 
 
 
Abbreviations:  AT=antithrombin; FVIII=factor VIII; FIX=factor IX; TG=thrombin generation 
a See Section 9.1.5 for assessments to be performed during a directed physical examination. 
b 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. 
 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
(Sanofi Genzyme LTE14762) 
 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential  
25 
TABLE OF CONTENTS  
<<PROTOCOL AMENDMENT SUMMARY OF CHANGES .............................................................. 3 
DOCUMENT HISTORY ...................................................................................................................... 3 
OVERALL RATIONALE FOR THE AMENDMENT ........................................................................... 3 
PROTOCOL SYNOPSIS .................................................................................................................... 9 
TABLE OF CONTENTS ................................................................................................................... 25 
LIST OF TABLES ............................................................................................................................. 30 
LIST OF FIGURES ........................................................................................................................... 31 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................................... 32 
1 
INTRODUCTION ............................................................................................................... 35 
1.1 
DISEASE OVERVIEW ....................................................................................................... 35 
1.2 
FITUSIRAN (SAR439774) ................................................................................................. 36 
1.3 
CLINICAL DEVELOPMENT .............................................................................................. 36 
1.3.1 
Summary of Efficacy .......................................................................................................... 36 
1.3.2 
Summary of Safety ............................................................................................................ 36 
1.3.3 
Summary of Pharmacokinetic and Pharmacodynamic Effects in ALN-AT3SC-001 and 
ALN-AT3SC-002 ................................................................................................................ 37 
1.4 
STUDY DESIGN RATIONALE .......................................................................................... 37 
1.5 
DOSE RATIONALE ........................................................................................................... 37 
1.6 
BENEFIT-RISK ASSESSMENT ........................................................................................ 39 
2 
STUDY OBJECTIVES ....................................................................................................... 40 
2.1 
PRIMARY OBJECTIVE ..................................................................................................... 40 
2.2 
SECONDARY OBJECTIVES ............................................................................................ 40 
2.3 
EXPLORATORY OBJECTIVES ........................................................................................ 40 
3 
INVESTIGATIONAL PLAN ............................................................................................... 41 
3.1 
OVERALL STUDY DESIGN .............................................................................................. 41 
3.2 
NUMBER OF PATIENTS................................................................................................... 42 
3.3 
TREATMENT ASSIGNMENT ............................................................................................ 42 
3.4 
SAFETY REVIEW COMMITTEE ....................................................................................... 42 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
(Sanofi Genzyme LTE14762) 
 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential  
26 
3.5 
DOSE ADJUSTMENT CRITERIA ..................................................................................... 42 
3.6 
CRITERIA FOR STUDY TERMINATION .......................................................................... 43 
4 
SELECTION AND WITHDRAWAL OF PATIENTS .......................................................... 44 
4.1 
INCLUSION CRITERIA ..................................................................................................... 44 
4.2 
EXCLUSION CRITERIA .................................................................................................... 44 
4.3 
WITHDRAWAL CRITERIA ................................................................................................ 45 
4.4 
CRITERIA FOR TEMPORARILY DELAYING ADMINISTRATIONS OF STUDY 
INTERVENTION ................................................................................................................ 46 
5 
TREATMENT OF PATIENTS ............................................................................................ 47 
5.1 
DESCRIPTION OF STUDY DRUG ................................................................................... 47 
5.2 
CONCOMITANT MEDICATIONS ...................................................................................... 47 
5.3 
MANAGEMENT OF BLEEDING EPISODES WITH FACTOR OR BYPASSING AGENTS 
WHILE ON FITUSIRAN ..................................................................................................... 48 
5.4 
ASSESSMENT OF COAGULATION PARAMETERS AT THE TIME OF A BLEED ......... 52 
5.5 
MONITORING AND MANAGEMENT OF THROMBOTIC EVENTS ................................. 52 
5.6 
USE OF FACTOR OR BPA FOLLOWING DISCONTINUATION OF FITUSIRAN ........... 52 
5.7 
ELECTIVE AND/OR EMERGENCY SURGERY ............................................................... 53 
5.8 
MANAGEMENT OF SEPSIS ............................................................................................. 54 
5.9 
TREATMENT COMPLIANCE ............................................................................................ 54 
5.10 
RANDOMIZATION AND BLINDING .................................................................................. 54 
5.11 
ALCOHOL RESTRICTIONS .............................................................................................. 54 
6 
STUDY DRUG MATERIALS AND MANAGEMENT ......................................................... 55 
6.1 
STUDY DRUG ................................................................................................................... 55 
6.2 
STUDY DRUG PACKAGING AND LABELING ................................................................. 55 
6.3 
STUDY DRUG STORAGE ................................................................................................ 55 
6.4 
STUDY DRUG PREPARATION ........................................................................................ 56 
6.5 
DOSE AND ADMINISTRATION ........................................................................................ 56 
6.5.1 
Dose Modifications ............................................................................................................ 57 
6.5.1.1 
LFT Criteria for Withholding, Monitoring and Stopping Fitusiran Dosing .......................... 57 
6.5.1.2 
Non-invasive Assessments of Liver Stiffness in Patients with Hepatitis C Infection ......... 60 
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Clinical Study Protocol Number ALN-AT3SC-002 
(Sanofi Genzyme LTE14762) 
 
 
Amendment 9_23 Jun 2021 
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6.5.1.3 
Antithrombin level criteria for a dose adjustment .............................................................. 60 
6.5.1.4 
Temporary discontinuation due to a regional or national emergency ............................... 63 
6.6 
STUDY DRUG ACCOUNTABILITY ................................................................................... 63 
6.7 
STUDY DRUG HANDLING AND DISPOSAL.................................................................... 64 
7 
PHARMACOKINETIC ASSESSMENTS ........................................................................... 65 
7.1 
BLOOD AND SAMPLE COLLECTION .............................................................................. 65 
7.2 
SAMPLE ANALYSIS .......................................................................................................... 65 
7.3 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH .................... 65 
8 
ASSESSMENT OF EFFICACY ......................................................................................... 67 
8.1 
ASSESSMENT OF BLEEDING EVENTS AND ADMINISTRATION OF FACTOR OR 
BYPASSING AGENT USAGE ........................................................................................... 67 
8.2 
PATIENT-REPORTED QUALITY OF LIFE ....................................................................... 68 
8.3 
ASSESSMENT OF PLASMA ANTITHROMBIN ACTIVITY AND PLASMA THROMBIN 
GENERATION ................................................................................................................... 68 
8.4 
EXPLORATORY PERIOPERATIVE ASSESSMENTS OF SAFETY AND HEMOSTATIC 
EFFICACY IN PATIENTS UNDERGOING MAJOR OPERATIVE PROCEDURES .......... 68 
9 
ASSESSMENT OF SAFETY ............................................................................................. 70 
9.1 
SAFETY PARAMETERS ................................................................................................... 70 
9.1.1 
Demographic and Medical History ..................................................................................... 70 
9.1.2 
Patient Education Module .................................................................................................. 70 
9.1.3 
Vital Signs .......................................................................................................................... 70 
9.1.4 
Weight and Height ............................................................................................................. 71 
9.1.5 
Physical Examination ......................................................................................................... 71 
9.1.6 
Electrocardiogram .............................................................................................................. 71 
9.1.7 
Laboratory Assessments ................................................................................................... 71 
9.1.7.1 
Hematology, Biochemistry, and Coagulation..................................................................... 72 
9.1.7.2 
Additional Laboratory Assessments .................................................................................. 74 
9.1.7.3 
Urinalysis ........................................................................................................................... 75 
9.1.7.4 
Antidrug Antibodies ............................................................................................................ 76 
9.1.8 
Inhibitor Status ................................................................................................................... 76 
9.1.9 
FibroScan or FibroTest and APRI ..................................................................................... 76 
9.2 
ADVERSE AND SERIOUS ADVERSE EVENTS .............................................................. 76 
9.2.1 
Adverse Event Definition ................................................................................................... 76 
9.2.2 
Serious Adverse Event Definition ...................................................................................... 76 
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Clinical Study Protocol Number ALN-AT3SC-002 
(Sanofi Genzyme LTE14762) 
 
 
Amendment 9_23 Jun 2021 
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9.2.3 
Eliciting Adverse Event Information ................................................................................... 77 
9.2.4 
Adverse Event Reporting ................................................................................................... 77 
9.2.5 
Assessment of Causality ................................................................................................... 77 
9.2.6 
Assessment of Severity ..................................................................................................... 78 
9.2.7 
Adverse Events of Special Interest .................................................................................... 78 
9.2.7.1 
Recording Adverse Events of Special Interest .................................................................. 79 
9.2.8 
Coding of Adverse Events ................................................................................................. 79 
9.2.9 
Serious Adverse Event and Adverse Events of Special Interest Reporting ...................... 80 
9.2.9.1 
Notifying the Institutional Review Board/Independent Ethics Committee ......................... 80 
9.2.9.2 
Sponsor Reporting:  Notifying Regulatory Authorities ....................................................... 80 
9.2.9.3 
Sponsor Notification of Participating Investigators ............................................................ 81 
9.2.10 
Pregnancy Reporting ......................................................................................................... 81 
9.2.11 
Guidelines for Reporting Product Complaints/Medical Device Incidents (Including 
Malfunctions) ..................................................................................................................... 81 
10 
STATISTICS ...................................................................................................................... 82 
10.1 
NUMBER OF PATIENTS................................................................................................... 82 
10.2 
STATISTICAL METHODOLOGY ...................................................................................... 82 
10.2.1 
Populations to be Analyzed ............................................................................................... 82 
10.2.2 
Baseline Evaluations ......................................................................................................... 83 
10.2.3 
Efficacy Analyses ............................................................................................................... 83 
10.2.4 
Pharmacodynamic Analysis .............................................................................................. 83 
10.2.5 
Exploratory Analyses ......................................................................................................... 83 
10.2.6 
Safety Analyses ................................................................................................................. 83 
10.2.7 
Pharmacokinetic Analysis .................................................................................................. 84 
10.2.8 
Interim Analysis ................................................................................................................. 84 
11 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ................................................... 85 
11.1 
STUDY MONITORING ...................................................................................................... 85 
11.2 
AUDITS AND INSPECTIONS ........................................................................................... 85 
11.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ................... 85 
12 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................... 86 
13 
ETHICS .............................................................................................................................. 87 
13.1 
ETHICS REVIEW .............................................................................................................. 87 
13.2 
ETHICAL CONDUCT OF THE STUDY ............................................................................. 87 
13.3 
WRITTEN INFORMED CONSENT PROCESS ................................................................. 87 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
(Sanofi Genzyme LTE14762) 
 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential  
29 
14 
DATA HANDLING AND RECORD KEEPING .................................................................. 89 
14.1 
INSPECTION OF RECORDS ............................................................................................ 89 
14.2 
STUDY DOCUMENTATION, CONFIDENTIALITY, AND RECORDS RETENTION ......... 89 
15 
PUBLICATION POLICY .................................................................................................... 90 
16 
DISSEMINATION OF CLINICAL STUDY DATA .............................................................. 91 
17 
LIST OF REFERENCES ................................................................................................... 92 
18 
APPENDICES ................................................................................................................... 94 
18.1 
PHARMACOKINETIC ASSESSMENT TIME POINTS ...................................................... 94 
18.2 
PERIOPERATIVE SCHEDULE OF ASSESSMENTS ....................................................... 95 
18.2.1 
Definitions of Minor and Major Surgery ............................................................................. 95 
18.2.2 
Perioperative Assessments of Safety and Hemostatic Efficacy in Patients Undergoing 
Major Operative Procedures .............................................................................................. 96 
18.3 
DATA PROTECTION ......................................................................................................... 98 
18.4 
COUNTRY-SPECIFIC REQUIREMENTS ....................................................................... 100 
18.5 
CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL EMERGENCY THAT 
IS DECLARED BY A GOVERNMENTAL AGENCY ........................................................ 101 
18.6 
PROTOCOL AMENDMENT HISTORY ........................................................................... 102 
18.6.1 
Amended Protocol 01 ...................................................................................................... 102 
18.6.2 
Amended Protocol 02 ...................................................................................................... 103 
18.6.3 
Amended Protocol 03 ...................................................................................................... 103 
18.6.4 
Amended Protocol 04 ...................................................................................................... 104 
18.6.5 
Amended Protocol 05 ...................................................................................................... 105 
18.6.6 
Amended Protocol 06 ...................................................................................................... 107 
18.6.7 
Amended Protocol 07 ...................................................................................................... 115 
18.6.8 
Amended Protocol 08 ...................................................................................................... 122 
 
 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
(Sanofi Genzyme LTE14762) 
 
 
Amendment 9_23 Jun 2021 
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30 
LIST OF TABLES  
Table 1: 
Schedule of Assessments (Years 1 to 4) ................................................................................... 14 
Table 2: 
Schedule of Assessments (Years 5, 6 and 7) ............................................................................ 17 
Table 3:  
Modified IMP Regimen Schedule of Assessments (Year 1, 2, 3) ............................................. 19 
Table 4: 
Perioperative Schedule of Assessments in Patients Undergoing Major Operative Procedures 23 
Table 5: 
Bleeding Episode Assessments – Unscheduled Visit ................................................................ 24 
Table 6:   Simulated AT activity percentiles, for various doses of fitusiran ................................................. 38 
Table 7: 
Investigational Product ............................................................................................................... 47 
Table 8: 
Bleed Management Dosing Guidelines by Specific Product ..................................................... 51 
Table 9: 
Monitoring and Dosing Rules for Patients with Confirmed ALT Elevations >3× ULN or >3× 
Baseline with No Alternative Cause Identified ............................................................................................ 59 
Table 10: 
Clinical Laboratory Assessments ............................................................................................. 73 
Table 11: 
Hepatic Assessments in Patients who Experience LFT Elevations ......................................... 75 
Table 12: 
Urinalysis Parameters .............................................................................................................. 75 
Table 13: 
Pharmacokinetic Time Points .................................................................................................. 94 
Table 14: 
Urine Pharmacokinetic Time Points ......................................................................................... 94 
Table 15:   ADA timepoints in all patients at 50 mg Q2M dose .................................................................. 95 
Table 16:   ADA timepoints with dose escalation to 50 mg QM or 80 mg QM ............................................ 95 
Table 17: 
Hemostatic Efficacy Rating Scale for Major Operative Procedures ........................................ 97 
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LIST OF FIGURES  
 
Figure 1 - Dose modification rules .............................................................................................................. 62 
Figure 2 - Dose escalation process ............................................................................................................ 63 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
Abbreviation 
Definition 
ABR 
annualized bleeding rate 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
aPCC 
Activated prothrombin complex concentrate 
APRI 
Aspartate aminotransferase to Platelet Ratio Index 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AT 
Antithrombin 
AUC 
Area under the concentration-time curve 
BPA 
Bypassing agents 
CAT 
Calibrated automated thrombogram 
CBC 
Complete blood count 
CD4 
cluster of differentiation 4 
CFR 
Code of Federal Regulation 
Cmax 
Maximum plasma concentration 
COVID-19 
Coronavirus Disease-19 
CRO 
Contract Research Organization 
CVST 
Cerebral venous sinus thrombosis 
DAA 
Direct-acting antiviral 
DTP 
Direct-to-Patient 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated glomerular filtration rate 
EQ-5D-5L 
EuroQoL 5-Dimension, 5-Levels Questionnaire 
FIX 
Factor IX 
FVIII 
Factor VIII 
GalNAc 
N-acetylgalactosamine 
GCP 
Good Clinical Practice 
Haem-A-QoL 
Haemophilia Quality of Life Questionnaire 
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Abbreviation 
Definition 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
IARs 
injection associated reactions 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ISR 
Injection site reaction 
ISTH 
International Society on Thrombosis and Haemostasis 
LFTs 
Liver function tests 
MAD 
Multiple-ascending dose 
MD 
Multiple dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MDRD 
Modification of Diet in Renal Disease 
NSAID 
Nonsteroidal anti-inflammatory drug 
NIMP 
Non-investigational Medicinal Product 
PD 
Pharmacodynamic 
PI 
Principal Investigator 
PK 
Pharmacokinetic(s) 
PT 
Prothrombin time 
Q2M 
every 2 months 
QM 
every month 
QoL 
Quality of life 
QTc 
QT interval corrected for heart rate 
rFVIIa 
Recombinant factor VIIa 
RT-PCR 
reverse transcription-polymerase chain reaction 
SAD 
Single-ascending dose 
SAE 
Serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
(Sanofi Genzyme LTE14762) 
 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential  
34 
Abbreviation 
Definition 
SC 
Subcutaneous 
SDay 
Surgery day 
siRNA 
Small interfering ribonucleic acid 
SRC 
Safety Review Committee 
SSC 
scientific and standardization committee 
t½β 
Elimination half-life 
TEAE 
Treatment-emergent adverse event 
TG 
Thrombin generation 
tmax 
Time to maximum plasma concentration 
ULN 
Upper limit of normal 
VTE 
Venous thromboembolism 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
(Sanofi Genzyme LTE14762) 
 
 
Amendment 9_23 Jun 2021 
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1 
INTRODUCTION  
1.1 
DISEASE OVERVIEW  
Hemophilia is an inherited bleeding disorder characterized by a deficiency in blood clotting 
factors leading to increased risk of bleeding in affected patients (1). People with hemophilia have 
missing or decreased levels of clotting factors in the intrinsic pathway of coagulation:  factor 
VIII (FVIII) in the case of hemophilia A, and factor IX (FIX) in the case of hemophilia B.   
The bleeding severity associated with hemophilia generally correlates with the level of clotting 
factor, and hemophilia is classified as mild, moderate, or severe based on clotting factor activity 
relative to normal.  Patients with severe hemophilia (factor level <1%) will typically bleed after 
injury, but also can have frequent spontaneous bleeds, most commonly into muscles and 
joints (2). Recurrent bleeding into a joint can result in a chronic and disabling arthropathy that is 
painful and disfiguring, and can markedly impair a patient’s mobility and quality of life 
(QoL) (3).  
The coagulation system has evolved to balance the need to maintain hemostasis with the need to 
prevent thrombosis.  This balance is achieved through a well-defined cascade of both 
procoagulant (eg, FVIII, FIX) and anticoagulant (eg, antithrombin [AT] and protein C) factors.  
Antithrombin is a liver-expressed natural anticoagulant that is the major endogenous inhibitor of 
thrombin.  Recent studies suggest that the co-inheritance of a deficiency in natural anticoagulants 
may contribute to a milder phenotype in patients with hemophilia (4, 5).  In addition, studies in 
hemophilic mice demonstrate that the coexistence of AT deficiency resulted in enhanced 
thrombin generation (TG) as well as a decreased bleeding phenotype in response to injury (6). 
Therefore, suppression of AT production is being investigated as a potential hemophilia 
treatment. 
Moreover, a proportion of patients treated with replacement factor develop inhibitory antibodies 
(“inhibitors”) to replacement factors that limit effectiveness.  Development of inhibitors to 
infused factor occurs mainly in severe hemophilia, and more frequently in hemophilia A (up to 
39% of patients) (7, 8), than in hemophilia B (1% to 3.5% of patients) (9, 10). Once inhibitors 
are present in high titer (defined as ≥5 Bethesda Units), treatment or prevention of bleeding can 
become more difficult due to the decreased responsiveness to factor concentrates.  In addition, in 
the case of persons with inhibitors to FIX, anaphylactic reactions and nephrotic syndrome can 
occur.  Treatment of persons with inhibitors consists of both controlling active bleeding by 
utilizing “bypassing agents” (BPAs; ie, FVIIa or activated prothrombin complex concentrate 
[aPCC]) as well as attempting to eradicate the inhibitors through immune tolerance induction 
(ITI) therapy (11).  Currently, the treatment of persons with inhibitors with BPA and ITI is both 
costly and suboptimally effective.  The development of inhibitors has been associated with worse 
musculoskeletal outcomes for persons with hemophilia, diminished quality of life, increased risk 
of death as well as a markedly increased cost of care (12).  Thus, there is a significant unmet 
need in hemophilia, especially in patients with inhibitors, for novel and improved therapeutic 
agents that can provide effective prophylactic hemostasis.   
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(Sanofi Genzyme LTE14762) 
 
 
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1.2 
FITUSIRAN (SAR439774)  
Fitusiran (SAR439774 [formerly Alnylam ALN-AT3SC]) is an investigational agent comprising 
a synthetic small interfering ribonucleic acid (siRNA) covalently linked to a triantennary 
N-acetyl galactosamine (GalNAc) ligand, designed to suppress liver production of AT as a 
strategy to rebalance the coagulation cascade, thereby improving TG and hemostasis in 
individuals with hemophilia.   
The initial proposed indication for fitusiran is for the treatment of patients with hemophilia A or 
hemophilia B.  Pharmacology data in mouse models of hemophilia support the therapeutic 
hypothesis for fitusiran.  Specifically, administration of fitusiran has been shown to increase TG 
in both wild type and hemophilia models and to improve hemostasis in models of hemophilia.  
The nonclinical pharmacology, pharmacokinetics (PK), and toxicology of fitusiran were 
evaluated in a series of in vitro and in vivo studies that have enabled chronic dosing in clinical 
studies. 
A summary of the nonclinical data is in the fitusiran Investigator’s Brochure (IB). 
1.3 
CLINICAL DEVELOPMENT  
The Investigator must become familiar with all sections of the fitusiran Investigator’s Brochure 
which will be provided by the Sponsor before the start of the study and during the study, as 
amendments are completed. 
Details of completed and ongoing studies of fitusiran are presented in the Investigator’s 
Brochure. 
1.3.1 Summary of Efficacy  
In Phase 1/2 clinical trials, monthly dosing with fitusiran in patients with hemophilia A and B, 
with or without inhibitors resulted in sustained antithrombin lowering and improved hemostasis 
as measured by reductions in patients’ annualized bleeding rate (ABR) (13, 14). Consistent with 
its intended pharmacologic effects, fitusiran treatment is associated with reductions in AT, 
increases in thrombin generation, and reductions in number of bleeding episodes. 
A complete summary of available clinical efficacy data relevant to fitusiran is presented in the 
Investigator’s Brochure. 
1.3.2 Summary of Safety  
 
 
 
. 
A more detailed summary of available clinical safety data is presented in the Investigator’s 
Brochure. 
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1.3.3 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 this study 
(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. 
1.4 
STUDY DESIGN RATIONALE  
This is a 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, who have 
previously tolerated dosing in a clinical study with fitusiran.  Both nonclinical and clinical data 
support the continuation of fitusiran treatment in this long-term extension study. 
Safety and efficacy assessments will be performed periodically as outlined in the Schedule of 
Assessments (Table 1, Table 2 and Table 3) to continue to assess the effect of fitusiran beyond 
the duration of the ongoing clinical studies, and will enable patients who have completed dosing 
in a prior study with fitusiran (provided eligibility criteria for this study are met) to continue to 
receive fitusiran. This study will allow patients to receive treatment with fitusiran for 
approximately 6 years or until fitusiran becomes commercially available, whichever occurs first.  
The duration may be longer (up to 7 years) for some patients so that they continue fitusiran 
treatment for 18 calendar months after introduction of the new dose and regimen into the study. 
1.5 
DOSE RATIONALE  
Patients enrolled in this study were initially administered subcutaneous (SC) fitusiran once every 
month where 1 month has been defined as 30 days to aid in patient compliance with the 
long-term dosing regimen.  Patients started the study on weight-based doses then transitioned 
early on to a 50 mg- or 80 mg-fixed monthly dose depending on what they received in the parent 
study.  
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(Sanofi Genzyme LTE14762) 
 
 
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A once-monthly dosing regimen is supported by preliminary results from clinical and nonclinical 
studies.  Data from the parent study (ALN-AT3SC-001) suggest that a reduction in AT levels is 
sustained for up to 60 days following a single dose of fitusiran.  Additionally, preliminary data in 
nonhuman primates suggest that steady-state AT suppression can be achieved and maintained 
after monthly doses of fitusiran.   
A change in the fitusiran dosing regimen has been introduced as a risk mitigation measure for 
vascular thrombotic events in Protocol Amendment 07. As the risk of vascular thrombotic events 
is thought to be increased in the setting of low AT activity levels, a reduced dose of 50 mg 
administered SC once every 2 months has been selected to minimize the occurrence of AT 
activity levels below 10%.  At a reduced dose of 50 mg every 2 months, if a patient has more 
than 1 AT level <15%, the patient will be required to permanently discontinue fitusiran. Patients 
previously exposed to fitusiran at a dose of 50 mg monthly or 80 mg monthly with no more than 
1 AT activity level <15% at any time during fitusiran treatment (based on at least 3 months of 
prior AT measurements) may have the option to remain on either dose, respectively.   
If a patient receiving fitusiran 50 mg once every 2 months has 2 steady state AT levels above 
35%, the patient will be dose escalated to fitusiran 50 mg monthly.  In very rare cases, if a 
patient still has 2 steady state AT levels above 35% at the 50 mg monthly dose, the patient will 
escalate to the 80 mg monthly dose. Details are described in Section 6.5.1.3. 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
(Sanofi Genzyme LTE14762) 
 
 
Amendment 9_23 Jun 2021 
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1.6 
BENEFIT-RISK ASSESSMENT  
Based on the available clinical data (see Section 1.3), fitusiran 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.  
 
 
 The risk of vascular thrombotic events 
is thought to be elevated in patients receiving fitusiran with AT activity levels <10%. In addition, 
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 thrombotic 
events. Additional details regarding the benefits and risks of fitusiran are provided in the 
Investigator’s Brochure. 
This clinical protocol has exclusion criteria intended to minimize the risk of thrombosis, 
. With respect to the risk of thrombosis, the protocol includes a 
change in the fitusiran dosing regimen to minimize the occurrence of AT levels <10% 
(Section 6.5.1.3), detailed guidance and oversight on treatment of breakthrough bleeding 
episodes with reduced factor and/or BPA dosing (Section 5.3), and monitoring and management 
of thrombosis while patients are on fitusiran (Section 5.7). The protocol stipulates ongoing 
monitoring for elevated transaminases (Section 6.5.1.1) and provides instruction for the potential 
discontinuation of fitusiran. The safety of trial patients will be overseen by a Safety Review 
Committee (Section 3.4).  
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Clinical Study Protocol Number ALN-AT3SC-002 
(Sanofi Genzyme LTE14762) 
 
 
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2 
STUDY OBJECTIVES  
2.1 
PRIMARY OBJECTIVE  
The primary objective of this study is to evaluate the long-term safety and tolerability of fitusiran 
in male patients with moderate or severe hemophilia A or B. 
2.2 
SECONDARY OBJECTIVES  
The secondary objectives of this study are: 
• To investigate the long-term efficacy of fitusiran 
• To characterize the safety and efficacy of concomitantly administered FVIII, FIX, or 
BPA and fitusiran for treatment of bleeding episodes 
• To assess changes in health-related QoL over time  
• To characterize AT reduction and TG increase 
• To characterize the PK of fitusiran 
2.3 
EXPLORATORY OBJECTIVES  
The exploratory objective of this study is:  
• To assess safety and the hemostatic efficacy rating for operative procedures conducted in 
patients while on study 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
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3 
INVESTIGATIONAL PLAN  
3.1 
OVERALL STUDY DESIGN  
This is a Phase 1/2 multicenter, multinational, open-label extension study, conducted at up to 
30 clinical study centers worldwide, to evaluate the long-term safety and efficacy of fitusiran in 
male patients with moderate or severe hemophilia A or B, who previously tolerated dosing in 
Part B, Part C or Part D of the parent study, ALN-AT3SC-001. 
Patients from Part B may roll over into this study after completing Day 70 in the parent study.  
Patients from Parts C and D are expected to roll over into this study approximately 1 month after 
completing the 3 monthly doses of study drug in the parent study, thereby maintaining their 
monthly dosing schedule.   
Screening will occur between Day -60 and Day -1.  Eligibility for this study will be confirmed 
before administration of the first dose of study drug.  Administrations of fitusiran will occur at 
the clinical study center or may be self-administered at home under the conditions described 
below.  Patients will be monitored for 6 hours postdose for the first dose only.   
At the discretion of the Investigator, contingent upon adequate training after the Month 3 visit, 
where applicable country and local regulations allow, and if the patient has not previously 
experienced any severe AEs or SAEs considered related to the study drug that the Investigator 
and study Medical Monitor believe should preclude the patient from self-administration, the 
patient/caregiver may be trained by the Investigator or healthcare professional in 
self-administration.  For up to 2 years, all fitusiran dosing, liver function test (LFT) results are to 
be obtained within 7 days prior to dosing and results are to be reviewed prior to each dose.  From 
Year 3 onwards, the frequency of predose LFT monitoring may be decreased for patients who 
have negative hepatitis C antibody titers and meet specific criteria defined in Section 6.5.1.1.  
Safety and efficacy assessments will be performed at time points specified in Table 1, Table 2 
and Table 3.  Unscheduled visits for study assessments may occur if deemed necessary by the 
study personnel.  In addition, patients who complete the study or discontinue treatment will 
continue to have safety assessments and AT activity levels monitored at time points specified in 
Table 1, Table 2 and Table 3 following the final fitusiran dose until AT activity levels return to 
approximately 60% (per the central laboratory), or per Investigator discretion in consultation 
with the study Medical Monitor (Note: for patients who opt for the commercially available 
fitusiran, these follow-up visits to assess AT activity level are not required). 
Pharmacokinetic and urine assessments will be performed at clinic visits on Day 1 and 
Month 12, and on Month 24 (in subset of patients).  Patients will also return to the clinical study 
center on Day 2 and the day after Month 12 and Month 24 (in subset of patients) visits for further 
PK sampling.  Also, pooled urine collection will occur on Month 24 in a subset of patients. 
Where possible, in patients undergoing major operative procedures while on study, safety and 
hemostatic efficacy assessments will be performed preoperatively (SDay -3 to SDay -1), 
intraoperatively (SDay 0), 24 hours postoperatively (SDay 1), and a postoperative visit 2 to 
14 days after the procedure (SDay 2 to SDay 14, per type of procedure).  A final postoperative 
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(Sanofi Genzyme LTE14762) 
 
 
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visit will occur on SDay 28 (up to + 28 days) to document the date/time when perioperative 
hemostatic and thromboprophylaxis (if applicable) treatment coverage was completed. 
The end of the study is defined as last patient last visit. 
3.2 
NUMBER OF PATIENTS  
Up to 48 patients with moderate or severe hemophilia A or B who have previously participated 
in the parent study (ALN-AT3SC-001) may be enrolled if they meet the eligibility criteria for 
this study. 
3.3 
TREATMENT ASSIGNMENT  
Patients enrolled in this study will receive open-label fitusiran. 
After confirming eligibility, patients will be assigned a patient number that corresponds to or can 
be mapped to their current patient number on the parent study.   
3.4 
SAFETY REVIEW COMMITTEE  
The SRC will review safety, tolerability, and available PD data, collected during the study with 
the primary purpose of protecting the safety of patients participating in the study.  The SRC will 
be comprised of the PI from each clinical study center with a patient currently in the study (either 
dosed or about to be dosed) or their designee, an independent hematologist with experience 
caring for patients with hemophilia, the study Medical Monitor, and the Contract Research 
Organization (CRO) Medical Monitor.  The SRC will meet at approximately every 3 to 
6 months, and on an ad hoc basis, as required.  Further details will be specified in the SRC 
Charter. 
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 also look to involve the study Medical Monitor. 
3.5 
DOSE ADJUSTMENT CRITERIA  
Following SRC review, the dose may be adjusted (increased or decreased) for the entire study 
population if emerging safety and tolerability data support a more optimal dose.   
Additionally, the SRC, or the treating Principal Investigator (PI), may authorize dose 
adjustments for individual patients based on safety, tolerability, and available PD response data. 
Dose adjustment criteria are detailed in Section 6.5.1.  Study drug administration for individual 
patients may be paused if an SAE reported is considered related to study drug, including venous 
thromboembolism (VTE). The SRC will be consulted before restarting study drug administration 
in individual patients. 
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Clinical Study Protocol Number ALN-AT3SC-002 
(Sanofi Genzyme LTE14762) 
 
 
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Instructions for AT-driven fitusiran regimen modification are provided in Section 6.5.1.3. 
3.6 
CRITERIA FOR STUDY TERMINATION  
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. 
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 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol Number ALN-AT3SC-002 
(Sanofi Genzyme LTE14762) 
 
 
Amendment 9_23 Jun 2021 
Property of the Sanofi Group - strictly confidential  
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4 
SELECTION AND WITHDRAWAL OF PATIENTS  
4.1 
INCLUSION CRITERIA  
To be enrolled in the study, patients must meet the following criteria before administration of the 
first dose of fitusiran: 
1. Completed and tolerated study drug dosing in study ALN-AT3SC-001  
2. Male aged ≥18 years 
3. Moderate or severe, clinically stable hemophilia A or B as evidenced by a laboratory 
FVIII or FIX level ≤5% at screening.  Patients with a FVIII or FIX level >5% at 
screening will be eligible on provision of a historic laboratory report indicating a trough 
level ≤5%   
4. <Removed per Amendment 1> 
5. Willing and able to comply with the study requirements and provide written informed 
consent 
4.2 
EXCLUSION CRITERIA  
1. Liver disease defined as any of the following: 
• Clinically significant cirrhosis as determined by the Investigator 
• International normalized ratio (INR) >1.5 at Screening 
• ALT or AST >3× ULN of the reference range at Screening 
• Platelet count ≤120,000/μL and/or other complete blood count (CBC) test results that are 
considered clinically significant and unacceptable by the Investigator  
• Known hepatitis C virus (HCV) infection currently requiring treatment with ribavirin or 
interferon  
2. Known to be human immunodeficiency virus (HIV) seropositive and have a CD4 count 
<200 cells/µL at screening (a CD4 result from the previous 6 months may be used to 
confirm eligibility) 
3. History of VTE, except for those patients using inhibitors who have a medical history of 
previous thrombotic event related to permanent indwelling venous access. 
4. Current serious mental illness that, in the judgment of the Investigator, may compromise 
patient safety, ability to participate in all study assessments, or study integrity 
5. Uncontrolled hypertension (defined as systolic blood pressure ≥160 mmHg and diastolic 
blood pressure ≥100 mmHg)  
6. Corrected QT (QTc) interval ≥450 msec and/or concomitant use of drugs known to 
prolong the QT/QTc interval at Screening 
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(Sanofi Genzyme LTE14762) 
 
 
Amendment 9_23 Jun 2021 
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7. Estimated glomerular filtration rate [eGFR] ≤45 mL/min (using the Modification of Diet 
in Renal Disease formula [MDRD]) 
8. Clinically relevant history or presence of cardiovascular, respiratory, gastrointestinal, 
renal, neurological, inflammatory, or other diseases that, in the judgment of the 
Investigator, precludes study participation 
9. If using nonsteroidal anti-inflammatory drugs (NSAIDs) intermittently or chronically, 
must tolerate them with no previous side effects (eg, gastric distress or bleeding) 
10. Clinically significant alcohol consumption, as assessed by the Investigator 
11. Any condition(s) that, in the opinion of the Investigator, would make the patient 
unsuitable for enrollment or could interfere with patient participation in or completion of 
the study 
4.3 
WITHDRAWAL CRITERIA  
Patients are free to discontinue from study treatment or withdraw from the study at any time and 
for any reason, without penalty to their continuing medical care.  There will be no replacements 
of patients who withdraw from this study. 
The Investigator may withdraw a patient from the study for any of the following reasons: 
• Protocol violation 
• AE 
• Use of, or need for, a prohibited medication (Note:  Before discontinuation, the 
Investigator should consult with the study Medical Monitor to determine if withdrawal is 
warranted.) 
• Physician decision 
• Patient decision (withdrawal of consent) 
• Patient is considerably noncompliant with the protocol-required fitusiran dosing visits 
The Investigator will also withdraw the patient from the study upon the request of the Sponsor or 
if the Sponsor terminates the study. 
Upon occurrence of a serious or intolerable AE, the Investigator will make every possible 
attempt to confer with the Sponsor before withdrawing the patient. 
Missing an occasional dose of fitusiran will not necessarily result in the patient being withdrawn 
from the study.  However, if a patient misses multiple consecutive doses of fitusiran, the 
Investigator at the clinical study center and the study Medical Monitor will determine whether 
the patient should be withdrawn from the study.   
When a patient withdraws or is withdrawn from the study, an Early Termination visit should 
occur 30 days following the patient’s last dose.  Separately, follow-up visits to assess AT activity 
levels should occur at approximately monthly intervals until AT activity level returns to 
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approximately 60% (per the central laboratory) (Note: for patients who opt for the commercially 
available fitusiran, these follow-up visits to assess AT activity level are not required).  For 
patients who withdraw early, at least 2 attempts will be made to contact the patient to complete 
an Early Termination visit.   
In the event a patient withdraws or is withdrawn from the study, the Investigator will inform the 
Sponsor immediately.   
If the patient withdraws or is withdrawn from the study, the reason will be noted in the patient 
medical record and on the electronic Case Report Form (eCRF). 
4.4 
CRITERIA FOR TEMPORARILY DELAYING ADMINISTRATIONS OF STUDY 
INTERVENTION  
During a regional or national emergency declared by a governmental agency, if the site is unable 
to adequately follow protocol mandated procedures, contingency measures are proposed in 
Section 18.5 for patient visits and/or administration of study intervention. 
 
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5 
TREATMENT OF PATIENTS  
5.1 
DESCRIPTION OF STUDY DRUG  
A description of the investigational product is provided in Table 7. 
Table 7: 
Investigational Product  
 
Investigational Product 
Product Name: 
Fitusiran 
Dosage Form: 
Sterile solution packaged in 2-mL Type I glass vials 
or prefilled syringesa 
Route of Administration 
Subcutaneous 
Physical Description 
Fitusiran Solution for Injection (SC use) is an 
siRNA targeting AT and bearing a triantennary 
GalNAc ligand conjugated to the sense strand, 
formulated in phosphate buffer.   
Abbreviations:  AT = antithrombin; GalNAc = N-acetylgalactosamine; SC = subcutaneous; siRNA = small interfering 
ribonucleic acid. 
a Study drug may be provided in prefilled syringes either at the clinic (healthcare setting) or in a nonhealth care setting (home injection) in 
a subset of patients receiving 80 mg monthly dose of fitusiran. The patient will be trained on prefilled syringe self-administration.  
Patients who have missed more than 6 consecutive fitusiran doses for any reason should utilize the study drug provided as a vial and 
syringe for at least 3 injections prior to utilizing prefilled syringe. 
5.2 
CONCOMITANT MEDICATIONS  
Use of concomitant medications will be recorded on the patient’s eCRF as specified in the 
Schedule of Assessments (Table 1, Table 2 and Table 3).  This includes all prescription 
medications, herbal preparations, over-the-counter medications, vitamins, and minerals.  Any 
changes in medications during the study will also be recorded on the eCRF. 
Treatment for hemophilia must be “on demand.”  Importantly, patients should not use factor 
concentrates as prophylaxis for bleeding episode prevention, including doses related to 
anticipated hemostatic challenges such as physical activity, after Day 7 on fitusiran.  For 
prophylaxis of bleeding episodes in patients who require major operative procedures see 
Section 5.7. 
Concomitant use of drugs known to prolong the QT/QTc interval should be avoided. 
Antifibrinolytics may be used as single agents but may not be used in combination with factor or 
BPA.  Use of FEIBA and rFVIIa as combination therapy is not recommended. Use of 
emicizumab (Hemlibra®) during the study is not permitted. 
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If patients use NSAIDs intermittently or chronically, they must have been able to tolerate them 
with no previous side effects (eg, gastric distress or bleeding). 
Use of >4 g acetaminophen per day is not permitted.   
For patients with known HCV infection, concurrent treatment with ribavirin or interferon is not 
permitted during fitusiran treatment.  In patients without cirrhosis or HBV-coinfection, 
concurrent treatment of HCV with direct-acting antiviral (DAA) therapy may be permitted after 
review and approval of the individual treatment plan by the study Medical Monitor.   
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 administered 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. 
5.3 
MANAGEMENT OF BLEEDING EPISODES WITH FACTOR OR BYPASSING AGENTS 
WHILE ON FITUSIRAN  
Investigators will establish and provide instructions for an individualized bleed management plan 
based on the guidelines in Table 8 for each patient. 
The bleed management plan should be reviewed by the Investigator or designee with the patient 
at each dosing (and via telephone contact every 2 weeks [±4 days] between fitusiran dosing) and 
updated as necessary. 
Initiation of fitusiran treatment results in a progressive lowering of AT levels over 4 weeks.   
Guidelines are provided below for patients newly initiating therapy or re-initiating therapy, and 
during continuous therapy with fitusiran. 
Bleed management guidelines for patients with AT recovery of ≥60% prior to re-initiation 
of fitusiran or during a potential fitusiran dose pause 
AT recovery is defined as AT activity level of approximately 60% or greater (per the central 
laboratory). 
After initiating therapy with fitusiran, it is recommended that patients call the Investigator prior 
to dosing with factor or BPA, and must call for any repeat doses of FVIII, FIX, aPCC, or for the 
third or subsequent dose of rFVIIa.   
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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 participants 
will have AT activity 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/BPA regimens for 
the first week following re-initiation of fitusiran dosing, with institution of the protocol-specific 
bleed management guidelines with reduced factor/BPA starting the second week after 
re-initiation, as described below and in Table 8.   
During the study period, in case fitusiran is on pause for any reason and AT activity levels return 
to approximately 60% (per the central laboratory), patients can initiate regular factor 
concentrates or BPAs for prophylaxis therapy to prevent spontaneous bleeding episodes, per 
Investigator discretion in consultation with the study Medical Monitor. 
Bleed management guidelines for Week 2 and beyond, and for patients with AT recovery of 
<60% prior to re-initiation of fitusiran: 
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 
perform assessments per Section 5.4 and Table 5. 
2. If a determination is made that symptoms require treatment, the recommended treatment 
algorithm for bleeding episodes is described below: 
3. A single dose can be administered according to the guidelines in Table 8. 
4. 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. 
5. 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 contact 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 5.4 and Table 5). 
b) If more than two doses of FVIII, FIX or aPCC or three doses of rFVIIa are needed, 
the patient to be seen at the study center within 48-72 hours. 
6. Doses should not be administered at less than 24-hour intervals (except rFVIIa as 
indicated in Table 8). 
7. Doses should not exceed the protocol maximum recommended dose indicated in Table 8.   
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8. 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 8 
b) Dosing of factor or BPA at decreased intervals than those recommended in Table 8 
c) Multiple or repeated doses of factor or BPA  
9. Antifibrinolytics may not be used in combination with factor or BPA. 
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Table 8: 
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 5.4) 
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 Assessment 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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5.4 
ASSESSMENT OF COAGULATION PARAMETERS AT THE TIME OF A BLEED  
If a patient presents at 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 5. 
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 post-dose assessments in 
Table 5 should be obtained in a single draw at any time during the visit. 
5.5 
MONITORING AND MANAGEMENT OF THROMBOTIC EVENTS  
As serious vascular (arterial and venous) thrombotic events have been reported in patients 
exposed to fitusiran, Investigators should have a low threshold to evaluate signs and symptoms 
potentially consistent with these diagnoses.  Signs and symptoms of vascular thrombotic events 
may include, but are not limited to, severe or persistent headache, headache with nausea and 
vomiting, chest pain and/or tightness, coughing up blood, trouble breathing, abdominal pain, 
fainting or loss of consciousness, swelling or pain in the arms or legs, vision problems, weakness 
and/or sensory deficits, and changes in speech. 
An evaluation of signs and symptoms potentially consistent with vascular thrombosis should 
include appropriate imaging studies as applicable. For the diagnosis of cerebral venous sinus 
thrombosis, magnetic resonance imaging venogram (MRV) or computed tomography venogram 
(CTV) is recommended (15).  
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 9.2.7 for further information regarding Adverse Events of Special 
Interest). 
5.6 
USE OF FACTOR OR BPA FOLLOWING DISCONTINUATION OF FITUSIRAN  
Patients who opt to discontinue fitusiran may resume standard on-demand or prophylactic dosing 
with factor concentrates (FVIII, FIX) or BPAs (aPCC, rFVIIa) 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. 
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5.7 
ELECTIVE AND/OR EMERGENCY SURGERY  
If an urgent need for major 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 18.2 (Section 18.2.1) for definitions of minor and major surgery. 
Perioperative Treatment Plan 
In all patients undergoing major surgery, a written perioperative treatment plan will be reviewed 
with the study Medical Monitor before conducting the procedure, unless clinical circumstances 
do not allow.  The perioperative treatment plan should be developed using the same principles as 
bleed management described in Section 5.3 and the guideline below:    
• If the clinical circumstance is such that the recommended factor or BPA doses and/or 
dose intervals in Table 8 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 18.2 (Section 18.2.1) 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 an 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 Evaluation Period is defined as the day of the 
surgery through 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 major surgery during the 
study as described in Section 8.4, and as scheduled in Table 4. 
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5.8 
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 (16, 17).  If a clinical determination is made that AT correction is desirable for an 
fitusiran-treated patient in the setting of sepsis, this may be initiated per Investigator discretion.   
5.9 
TREATMENT COMPLIANCE  
Compliance with study drug administration will be verified through observation by study staff or 
trained home healthcare professionals.  Patients will be permitted to miss an occasional dose of 
study drug.  However, if a patient misses multiple consecutive doses, the Investigator, in 
consultation with the CRO Medical Monitor, will discuss whether the patient will be able to 
continue on the study.   
5.10 
RANDOMIZATION AND BLINDING  
The study is an open-label, nonrandomized design. 
5.11 
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. 
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6 
STUDY DRUG MATERIALS AND MANAGEMENT  
6.1 
STUDY DRUG  
Investigational Medicinal Product (IMP): 
Fitusiran Solution for Injection (SC use) will be supplied as a sterile solution in vials or prefilled 
syringes. Detailed information describing the preparation, administration, and storage of fitusiran 
is provided in the Pharmacy Manual. 
Non-investigational Medicinal Product (s) (NIMPs): 
For antithrombin reversal refer to Section 5.5. 
The IMP supplied for this study must not be used for any purpose other than the present study 
and must not be administered to any patient not enrolled in this study. The IMP that has been 
dispensed to a patient and returned unused must not be re-dispensed to a different patient. 
All study drug must be dispensed by the Investigator or designee as defined in the Pharmacy 
Manual. The IMP/NIMP may be supplied at the site or from the Investigator/site/Sponsor to the 
patient via a Sponsor-approved courier company where allowed by local regulations and agreed 
upon by the patient. 
In case of a regional or national emergency declared by a governmental agency that results in 
travel restrictions, confinement, or restricted site access, contingency measures are included in 
Section 18.5. 
6.2 
STUDY DRUG PACKAGING AND LABELING  
All packaging, labeling, and production of IMP will be in compliance with Good Manufacturing 
Practice specifications, as described in the Manufacture of Investigational Medicinal Products 
Volume 4 Annex 13, and any other or local applicable regulations. 
The IMP labels and external packaging will include all appropriate information as per local 
labeling requirements. Sample labels will be submitted to health authorities, per local country 
submission requirements. 
6.3 
STUDY DRUG STORAGE  
Study drug will be stored per the labeled instructions. Any deviation from the recommended 
storage conditions should be reported to the Sponsor and use of the study drug halted until 
authorization for its continued use has been provided by the Sponsor or designee. 
No special procedures for the safe handling of fitusiran are required. 
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A Sponsor representative or designee will be permitted, upon request, to audit the supplies, 
storage, dispensing procedures, and records. 
Study drug supplied for this study may not be administered to any person not enrolled in the 
study. 
Additional storage details are provided in the Pharmacy Manual. 
6.4 
STUDY DRUG PREPARATION  
Qualified staff at each clinical study center or the home healthcare professional (where available) 
who may dispense study drug to the patient for self-administration will be responsible for 
preparation of fitusiran doses, according to procedures detailed in the Pharmacy Manual.  
Patients and/or caregivers may also prepare fitusiran doses after receiving proper instruction. 
6.5 
 DOSE AND ADMINISTRATION   
Patients will be administered fitusiran as an SC injection for the duration of the study. Initially, 
based on the parent study dosing paradigm, it is expected that the starting dose administered in 
this study will be 0.225 mg/kg.  Either fixed or weight-based doses may be given, provided that 
the dose is no greater on a weight basis than the highest dose determined to be safe and well 
tolerated in the parent study (ALN-AT3SC-001).  Following review of safety and tolerability 
data, the dose may be modified, for individual patients or for the entire study population, if 
emerging data support a more optimal dose and dosing regimen. 
If the patient has not previously experienced any severe AEs or SAEs considered related to the 
study drug that the Investigator and study Medical Monitor believe should preclude the patient 
from self-administration, the patient/caregiver may be trained by the Investigator or healthcare 
professional in self-administration, permitted to occur from Month 3 forward.   
Patients who experience a severe AE or SAE considered related to the study drug that occurs at 
any time during the study should not self-administer study drug for a 12-week period, unless 
prior approval is obtained from the study Medical Monitor. 
Patients with elevated liver transaminases will be further evaluated at a clinic visit prior to 
permitting self-administration of study drug.  Once considered asymptomatic and if liver 
transaminases are returning towards normal, patients may be permitted to self-administer study 
drug at Investigator discretion.  For up to 2 years, all fitusiran dosing administered at the study 
center or at home, LFT results are to be obtained within 7 days prior to dosing and results are to 
be reviewed prior to each dose.  From Year 3 onwards, the frequency of predose LFT monitoring 
may be decreased for patients who have negative hepatitis C antibody titers and meet specific 
criteria defined in Section 6.5.1.1. 
If a patient does not receive a dose of fitusiran within the specified dosing window, the 
Investigator must contact the study Medical Monitor.  After such consultation, the dose may be 
administered or considered missed and not administered. 
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 Pre-filled Syringe with Safety System: 
Study drug may be provided in prefilled syringes either at the clinic (healthcare setting) or in a 
nonhealth care setting (home injection) in a subset of patients receiving 80 mg SC injection once 
monthly.  The patient will be trained on prefilled syringe self-administration.  The Investigator 
and/or delegated designee will complete a treatment process with the patient and/or patient’s 
caregiver to prepare and administer the injection using the pre-filled syringe with safety system 
for monthly injections.  The first injection is given by the Investigator and/or delegated designee 
while teaching patient and/or caregiver on how to perform the injection.  The second injection is 
performed by patient or caregiver under the supervision of the Investigator and/or delegated 
designee.  Once patient or caregiver has completed the required training and the Investigator 
and/or delegated designee approves, patient or caregiver may prepare and self-administer the 
subsequent injection at home.  Patients who have missed more than 6 consecutive fitusiran dose 
for any reason should utilize the study drug provided as a vial and syringe for at least 3 injections 
prior to utilizing prefilled syringe. 
6.5.1 Dose Modifications  
If a study drug-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, at which time the study Medical Monitor should be contacted. 
6.5.1.1 LFT Criteria for Withholding, Monitoring and Stopping Fitusiran Dosing  
1. It is preferable that LFT results are to be obtained by Central laboratory. If not available, 
local laboratory results may be used; however, if a local assessment is drawn, a 
biochemistry sample must also be drawn for analysis at the central laboratory. 
2. For patients following the SoAs in Table 1 and Table 2: 
a) For up to 2 years, LFT results are to be obtained within 7 days prior to dosing and 
results are to be reviewed prior to each dose of fitusiran.  
b) From Year 3 onwards, the frequency of predose LFT monitoring may be decreased 
for patients who have negative hepatitis C antibody titers and who meet following 
specific criteria: 
- 
Did not have any ALT elevation >3× ULN persisting for ≥2 consecutive months at 
any time during the previous 12 months. 
- 
Did not have any fitusiran doses held due to LFT elevations during the study. 
Note: negative Hep C patients include patients who never met HCV, ie, antibodies are 
negative, but also those with only positive antibodies without any viral load detected 
(ie, patient has cleared the infection, but antibodies still detected as positive). To confirm 
this eligibility, patients who cleared Hep C infection must have documented sustained 
negative virologic load. 
3. For patients on a monthly dosing schedule following the SoA in Table 3 (modified IMP 
regimen SoA), monthly predose LFT testing is not required if the criteria for reduced 
predose LFT monitoring is met as described below:  
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- 
Did not have any ALT elevation >3× ULN persisting for ≥2 consecutive months at 
any time during the first 12 months under this regimen. 
- 
Must not have had any fitusiran doses held during the first 12 months under this 
regimen. 
4. For patients on a every other month dosing schedule following the SoA in Table 3 
(modified IMP regimen SoA), monthly testing is required for the first 12 months under 
the dosing regimen. After the first year, predose LFT testing is only required every other 
month prior to dosing. 
5. For any ALT elevation >3× ULN or >3× Baseline (for those with elevated baseline 
values), central laboratory results should be used to guide subsequent monitoring as 
detailed in Table 9. 
6. For any ALT elevation >3× ULN or >3× Baseline (for those with elevated baseline 
values) (Table 9):  
a) Confirm using central laboratory, as soon as possible, ideally within 2 to 3 days, but 
no later than 7 days. 
a) Perform assessments per Table 10 and Table 11. 
b) If an alternative cause is found, provide appropriate care. 
7. For any ALT elevation >3× ULN or >3× Baseline without alternative cause see Table 9 
below: 
 
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Table 9: Monitoring and Dosing Rules for Patients with Confirmed ALT Elevations >3× ULN or >3× Baseline with No Alternative Cause Identified     
Transaminase 
Level 
HCV RNA Negative Patients 
with Normal Baseline ALT 
HCV RNA Negative Patients with 
Elevated Baseline ALTa 
HCV RNA Positive Patients with 
Normal Baseline ALT 
HCV RNA Positive Patients 
with Elevated Baseline ALTa, b 
>3× to  
5×ULN or 
Baseline 
Discontinue dosing when 
ALT>3×ULN if patient is 
symptomaticc, TBL ≥2×ULN, or 
INR >1.5. 
Otherwise, may continue dosing 
with biweeklyd monitoring 
including hematology, 
biochemistry, LFT, and 
coagulation per Table 10.  If 
elevation persists for ≥2 months, 
must discuss with the study 
Medical Monitor before 
continuing dosing. 
Discontinue dosing when ALT >3× 
Baseline or >300 U/L (whichever 
comes first) if patient is 
symptomaticc, TBL >2×ULN, or 
INR >1.5. 
Otherwise, may continue dosing 
with biweeklyd monitoring 
including hematology, 
biochemistry, LFT, and coagulation 
per Table 10.  If elevation persists 
for ≥2 months, must discuss with 
the study Medical Monitor before 
continuing dosing. 
 
Discontinue dosing when 
ALT >3× Baseline or >300 U/L 
(whichever comes first) if patient 
is symptomaticc,  
TBL >2× ULN, or INR >1.5. 
Otherwise, may continue dosing 
with biweeklyd monitoring 
including hematology, 
biochemistry, LFT, and 
coagulation per Table 10.  If 
elevation persists for ≥2 months, 
must discuss with the study 
Medical Monitor before 
continuing dosing. 
>5× to 8× 
ULN or 
Baseline 
Holde dose if ALT >5×ULN 
until ALT ≤1.5×ULN. 
Monitoring at least weekly until 
ALT declining on two 
consecutive draws, then 
monitoring biweeklyd, including 
hematology, biochemistry, and 
coagulation per Table 10.   
 
Discontinue dosing when ALT 
>5×ULN if patient is symptomaticc, 
TBL >2×ULN or INR >1.5. 
Otherwise, biweeklyd monitoring 
including hematology, biochemistry, 
LFT, and coagulation per Table 10.  
If elevation persists for ≥2 months, 
must discuss with the study Medical 
Monitor before continuing dosing. 
 
>8× ULN or 
Baseline 
Discontinue dosing after 
confirmation if ALT >8×ULN 
Discontinue dosing after 
confirmation if ALT >8×Baseline 
or >500 U/L (whichever comes 
first). 
Discontinue dosing after confirmation 
if ALT >8×ULN. 
Discontinue dosing after 
confirmation if ALT 
>8×Baseline or >500 U/L 
(whichever comes first). 
Abbreviations:  ALT=alanine aminotransferase; INR=international normalized ratio; TBL=total bilirubin; ULN=upper limit of normal 
Note:  In addition to these criteria, other assessments or evaluations may be performed per Investigator discretion, as appropriate. 
a If multiple baseline ALT measurements are available, Baseline ALT will be defined as the average of the 2 most recent ALT measurements prior to first dose administered in parent study  
(ALN-AT3SC-001); if these two measurements differ by >50%, the average of the 3 most recent ALT measurements will be utilized (if available). 
b In HCV RNA positive patients with elevated Baseline ALT whose ALT normalizes after successful DAA treatment (with SVR), Baseline ALT should be considered reset to the new normalized 
value and the stopping rules for HCV RNA negative patients with normal Baseline ALT should be applied going forward. 
c Symptoms of liver injury (eg, nausea, right upper quadrant pain, jaundice). 
d The frequency of laboratory monitoring should be decreased from biweekly to monthly once ALT has decreased to ≤1.5 × ULN or ≤1.5 × Baseline (whichever is higher). 
e After dosing is held, once ALT has decreased to ≤1.5×ULN or ≤1.5×Baseline (whichever is higher), re-dosing may be considered.  In patients with normal Baseline ALT, permanently discontinue 
dosing if ALT increases to >5×ULN following repeat dosing.  In patients with elevated Baseline ALT, permanently discontinue dosing if ALT increases to >5×Baseline or >300 U/L (whichever 
comes first) following repeat dosing. 
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(Sanofi Genzyme LTE14762) 
 
 
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6.5.1.2 Non-invasive Assessments of Liver Stiffness in Patients with Hepatitis C 
Infection  
In patients who are hepatitis C antibody positive, FibroScan (or FibroTest/aspartate 
aminotransferase to Platelet Ratio Index [APRI], if FibroScan is not available) will be assessed.  
If FibroScan, or FibroTest and APRI values indicate possible cirrhosis as defined by the criteria 
below, approval for continued dosing must be obtained following discussion with the study 
Medical Monitor and consideration of overall risk-benefit.  Additional testing and evaluation 
may be required.  Evidence of cirrhosis is defined according to one of the following assessments: 
- 
FibroScan ≥12.5 kPa (where available), or 
- 
FibroTest score ≥0.75 and APRI ≥2 (if FibroScan unavailable) 
6.5.1.3 Antithrombin level criteria for a dose adjustment  
With the introduction of the new dose and regimen with Protocol Amendment 07 following the 
global program dosing pause implemented by Sponsor in 2020, patients will receive fitusiran 
treatment according to the below antithrombin level scenarios and criteria. See the rationale for a 
new dosing justification in Section 1.5. Dose modification rules are detailed in the section below 
and displayed in Figure 1 and Figure 2. 
A) Dose restart 
a) Restart at 50 mg Q2M  
- 
Patients that reach AT activity levels ≥22% (per central laboratory), 
- 
Patients previously exposed to fitusiran at a dose of 50 mg QM or 80 mg QM with 
more than one AT activity level <15% (per central laboratory) at any time during 
fitusiran treatment, 
- 
Patients will resume dosing at a dose of 50 mg Q2M and follow the modified IMP 
regimen SoAs (Table 3). 
b) Restart at 50 mg QM or 80 mg QM (prior dose) 
- 
Patients that reach AT activity levels ≥22% (per central laboratory), 
- 
Patients previously exposed to fitusiran at a dose of 50 mg QM or 80 mg QM with no 
more than one AT activity level <15% (per central laboratory) at any time during 
fitusiran treatment (based on at least 3 months of prior AT measurements), 
- 
Participant may have the option to remain on that dose and follow the SoAs in 
Table 1 and Table 2. 
B) Dose escalation 
a) Dose escalation to 50 mg QM  
- 
After a period of dosing at 50 mg Q2M, 
- 
Based on 2 steady state AT values >35% at the 50 mg Q2M dosing regimen, 
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- 
At least 2 of the 3 AT samples taken pre-dose at PR Month 4, PR Month 5 and PR 
Month 6 must be >35% to meet the escalation rule, 
- 
Patients who previously had more than 1 AT value <15% at the 50 mg QM dose are 
not eligible to re-escalate to this dose level, 
- 
If escalation rules are met, patient will receive the 50 mg dose at PR Month 7 (this 
will be considered the PR Month 1 of 50 mg QM, ie, the second 50 mg QM dose). 
Note: If any of the doses prior to PR Month 6 are missed, then the decision-making for 
escalation must be shifted accordingly. 
b) Dose escalation to 80 mg QM  
- 
After a prior escalation to the 50 mg QM dosing regimen, 
- 
Based on 2 steady state AT values >35% at the 50 mg QM dosing regimen, 
- 
If a patient was dosed with fitusiran at PR Baseline and PR Month 1 visits, the AT 
values taken pre-dose at PR Month 2 and PR Month 3 of 50 mg QM will be used for 
assessment.  If escalation rules are met, patient will receive the 80 mg dose at PR 
Month 4 (this will be considered the PR Day 1 of 80 mg QM), 
- 
Patients who previously had more than 1 AT value <15% at the 80 mg QM dose are 
not eligible to re-escalate to this dose level, 
- 
Patients on 50 mg QM prior to dosing pause are not eligible to escalate to 80 mg QM, 
- 
If escalation rules are met, patient will receive the 80 mg dose at PR Month 4 (this 
will be considered the PR Day 1 of 80 mg QM). 
Note: If any of the doses prior to PR Month 3 are missed, then the decision-making for 
escalation must be shifted accordingly. 
c) In the rare circumstance that a patient does not meet criteria for escalation at this time 
the timepoints as described under sections a) and b) above and later meets criteria 
- 
The investigator may use any of the central AT test results available once the patient 
is on steady state,  
- 
The investigator will consult with the study Medical Monitor prior to any dose 
escalation. 
C) Dose de-escalation 
a) Patient receiving fitusiran at a dose of 50mg Q2M with more than 1 AT activity level 
<15% at any time on this dose and regimen  
Patient must permanently discontinue fitusiran. 
b) Patient having escalated to the 50 mg QM or 80 mg QM dose with now more than 
1 AT activity level <15% after escalation. 
In this unlikely circumstance, the Investigator will consult with the study Medical 
Monitor regarding further treatment with fitusiran, with the possibility of 
de-escalating the dose, if deemed beneficial for the study participant. 
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c) Patients having restarted at 50 mg QM or 80 mg QM dose subsequently having more 
than 1 AT activity level <15%.  
Fitusiran dose must be reduced to 50 mg Q2M.  
The first 50 mg dose should be administered no sooner than 2 months after the last 
50 mg QM or 80 mg QM dose (the protocol-permitted visit windows are permissible) 
and only after the patients AT level reaches again at least 22 %. 
At each dose level, upon the first AT level <15%, the patient must have another AT activity level 
sample drawn within 1 week of site receipt of the results. If the result is <15%, this will be 
considered the second AT activity level <15%. 
Figure 1 - Dose modification rules  
 
Abbreviations: AT = antithrombin; QM = once monthly; Q2M = every second month; ss= steady state 
Note: Restart following dosing pause to occur only once centrally measured AT activity levels ≥22%. 
 
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(Sanofi Genzyme LTE14762) 
 
 
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Figure 2 - Dose escalation process  
 
Abbreviations: AT = antithrombin; BL = baseline; D = Day; M = Month; PR = post-restart; QM = once monthly; Q2M = every second month.   
See rules and exceptions as described above in Section 6.5.1.3.  
6.5.1.4 Temporary discontinuation due to a regional or national emergency  
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs or disruption of the clinical trial due to a regional or national emergency declared 
by a governmental agency (Section 18.5). For all temporary intervention discontinuations, the 
associated reason/emergency should be recorded by the Investigator in the appropriate pages of 
the eCRF.  
Re-initiation of intervention with the IMP will be done under close and appropriate clinical 
and/or laboratory monitoring once the Investigator will have considered according to his/her best 
medical judgment that the responsibility of the IMP in the occurrence of the concerned AE was 
unlikely and if the selection criteria for the study are still met (refer to Section 4). 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 18.5. 
6.6 
STUDY DRUG 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 clinic or as self-
administered by the patient during 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 study drugs.   
Further instructions about IMP accountability are detailed in the Pharmacy Manual. 
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Any quality issue noticed with the receipt or use of an investigational medicinal product 
(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 9.2.11). 
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 
Direct-to- Patient [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. 
6.7 
STUDY DRUG HANDLING AND DISPOSAL  
All used, partially used, and unused vials or prefilled syringes of fitusiran will be returned to the 
Sponsor or its specified designee/depot or destroyed at the site according to applicable 
regulations. 
Study drug supplied for this study must not be used for any purpose other than the present study.  
Study drug which has been dispensed to a patient and returned unused must not be re-dispensed 
to a different patient. 
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7 
PHARMACOKINETIC ASSESSMENTS  
7.1 
BLOOD AND SAMPLE COLLECTION  
Blood and urine samples for PK analysis will be collected at the time points in the Schedule of 
Assessments (Table 1) and according to the detailed schedule presented in Appendix 18.1.  
In a subset of patients who opt to participate, blood samples for PK analysis will be collected for 
additional time points as noted in the Schedule of Assessments (Table 1) and according to the 
detailed schedule presented in Appendix 18.1 (Table 13).  In a separate subset of patients, pooled 
urine samples for PK analysis will be collected over 24 hours according to the time points 
presented in Appendix 18.1, (Table 14), as specified in the Schedule of Assessments (Table 1). 
7.2 
SAMPLE ANALYSIS  
The concentration of fitusiran will be determined for each plasma sample using a validated 
assay.  Details regarding the processing, shipping, and analysis of the samples will be provided 
in the Laboratory Manual. 
7.3 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
Future research may help further the understanding of disease subtypes, disease biology, related 
conditions, drug response and toxicity, and can help identify new drug targets or biomarkers that 
predict patient response to treatment. Therefore, data and biological samples will be stored and 
used for future research when consented to by patients (see Section 13.3) unless prohibited by 
local laws or IRBs/IECs (in such case, consent for future use of sample will not be included in 
the local ICF).  
For patients who consent to the storage and use of their data and remaining and/or extra clinical 
samples, data and samples may be used after the study ends for future research related either to 
the drug, the mechanism of action, and the disease or its associated conditions. Such research 
may include, but is not limited to, performing assessments on DNA, RNA, proteins or 
metabolites.  If future research on genetic material is performed, this will also be limited to the 
purpose of addressing research questions related to the drug, the mechanism of action, the 
disease or its associated conditions. 
In the event future research is conducted for other purposes, the study patients will be informed 
of those purposes and will be given means to object to those research projects. 
Data and samples will be used in compliance with the information provided to patients in the 
ICF. 
All study patient data and samples will be coded such that no patient direct identifiers will be 
linked to them. Coded data and samples may be transferred to a Sponsor site (or a subcontractor 
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site), which may be located outside of the country where the study is conducted. The Sponsor 
adopts safeguards for protecting patient confidentiality and personal data (see Section 18.3). 
The samples will be stored for a maximum of 15 years after the end of the study. Any samples 
remaining at the end of retention period will be destroyed. If a patient requests destruction of 
their samples before the end of the retention period, the Investigator must notify the Sponsor (or 
its contract organization) in writing. In such case, samples will be destroyed and related coded 
data will be anonymized unless otherwise required by applicable laws. 
Study patient coded data will be stored for future research for up to 25 years after the end of the 
study. If data are still considered of important scientific value after this period, coded data 
already available will be anonymized unless otherwise required by applicable laws (the same 
will apply to the data of a study patient who has requested the destruction of his/her samples). 
Patient’s coded data sets provided to researchers for a specific research project will be available 
to the researchers for a maximum of 2 years after the end of their specific project (end of project 
is defined by publication of the results or finalization of the future research project report). 
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Clinical Study Protocol Number ALN-AT3SC-002 
(Sanofi Genzyme LTE14762) 
 
 
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8 
ASSESSMENT OF EFFICACY  
8.1 
ASSESSMENT OF BLEEDING EVENTS AND ADMINISTRATION OF FACTOR OR 
BYPASSING AGENT USAGE  
Patients will be provided take home diaries.  Patients will be trained to complete the diaries on an 
ongoing basis to record episodes of bleeding, administration of factor or BPA, as applicable, and 
response to factor or BPA treatment.  Details will be recorded as specified in the Schedule of 
Assessments (Table 1, Table 2 and Table 3).  Data recorded in the diaries will be reviewed with 
the clinical study center staff or home healthcare professional. 
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 9.2.2.   
The definition of bleeding episode types described below is based on consensus opinion of 
International Society on Thrombosis and Haemostasis (ISTH) as reflected in a recent publication 
(18).  
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 
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. 
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Annualized bleeding rate (ABR) will be calculated as described in Section 10.2.3.  Bleeding 
episodes will be managed according to Section 5.3. 
8.2 
PATIENT-REPORTED QUALITY OF LIFE  
Quality of life will be assessed as specified in the Schedule of Assessments (Table 1, Table 2 and 
Table 3) through the use of the EuroQoL (EQ-5D-5L) questionnaire, a standardized 5-question 
instrument for use as a measure of health outcomes (19), and the Haem-A-QoL (20), where 
available. 
8.3 
ASSESSMENT OF PLASMA ANTITHROMBIN ACTIVITY AND PLASMA THROMBIN 
GENERATION  
Patients will have blood samples collected as specified in the Schedule of Assessments (Table 1, 
Table 2 and Table 3) for the analysis of plasma AT activity and plasma TG. Analysis of plasma 
TG will be as determined by the calibrated automated thrombogram (CAT) assay. Antithrombin 
protein may be measured in a subset of plasma samples for correlation.  Details regarding the 
processing, shipping, and analysis of the samples will be provided in the Laboratory Manual. 
Data and biological samples will be stored and used for future research when consented to by 
patients (Section 7.3). 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 18.5. 
8.4 
EXPLORATORY PERIOPERATIVE ASSESSMENTS OF SAFETY AND HEMOSTATIC 
EFFICACY IN PATIENTS UNDERGOING MAJOR OPERATIVE PROCEDURES  
In patients undergoing elective or emergency major operative procedures during the study, safety 
and hemostatic efficacy assessments will be performed perioperatively according to the Schedule 
of Assessments outlined in Table 1, Table 2 and Table 3, 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 4): 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, prothrombin time (PT)/INR, fibrinogen, 
D-dimer); and hemostatic efficacy assessments (rating scale based on ISTH Scientific and 
Standardization Committee [SSC] definitions (18). 
On day of the procedure and thereafter as specified in the Perioperative Schedule of Assessments 
(Table 4), the following may be assessed: coagulation parameters, TG, AT levels, factor VIII/IX 
levels, and hemostatic efficacy assessments. 
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Hemostatic response will be assessed at the end of the procedure (SDay 0), 24 hours 
postoperatively (SDay 1), and up to 14 days postoperatively (SDay 2-14; day to be determined 
by the Investigator) using the hemostatic efficacy rating scale (Table 17).  A final postoperative 
visit will occur on SDay 28 (up to + 28 days) to document the date/time when perioperative 
hemostatic and thromboprophylaxis (if applicable) treatment was completed.  The perioperative 
hemostatic rating will be collected via questionnaires that will be provided.  The total number of 
patients in each rating category of hemostatic response (“none,” “moderate,” “good,” and 
“excellent”) will be summarized for both the intraoperative and postoperative assessments.   
The end of the Perioperative Evaluation Period for each patient will be defined as the date/time 
when perioperative hemostatic treatment and thromboprophylaxis (if applicable) was completed, 
as documented at the last postoperative visit. 
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9 
ASSESSMENT OF SAFETY  
Safety assessments are performed according to the Schedule of Assessments (Table 1, Table 2 
and Table 3). For a regional or national emergency declared by a governmental agency, 
contingency measures are included in Section 18.5. 
9.1 
SAFETY PARAMETERS  
9.1.1 Demographic and Medical History  
Demographic data, medical history, and hemophilia history will be collected as specified in the 
Schedule of Assessments (Table 1). 
Medical history and hemophilia history will only be collected for clinically relevant events 
occurring between the parent study and before administration of the first dose of study drug in 
this open-label extension study.  Hemophilia history includes bleeding events and any treatment 
administered for bleeding events. 
For all patients in this study, AEs from the parent study that are ongoing will be considered as 
part of the medical history. 
9.1.2 Patient Education Module  
Patients will be educated by Investigators or trained healthcare professionals on coagulation and 
general considerations with regards to managing hemophilia in the clinical setting of 
lowered-AT.  This will be performed as specified in the Schedule of Assessments (Table 1 and 
Table 3). 
9.1.3 Vital Signs  
Vital signs will be measured as specified in the Schedule of Assessments (Table 1, Table 2 and 
Table 3).  When vital signs are scheduled at the same time as a physical examination or 
blood/urine sample collection, the vital signs must be performed first. 
Vital signs will include systolic/diastolic blood pressure, heart rate, respiratory rate, and body 
temperature (oral, tympanic, or axillary), and will be measured in the seated or supine position 
using an automated instrument, or manually, after the patient has rested comfortably for 
10 minutes.  Temperature will be recorded in degrees Celsius.  Heart rate will be counted for a 
full minute and recorded in beats per minute.  Respirations will be counted for a full minute and 
recorded in breaths per minute. 
For the safety of the patient, additional vital signs may be obtained at the discretion of the 
Investigator. 
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9.1.4 Weight and Height  
Height will be measured only if it was not obtained in the parent study. 
Body weight will be measured in kilograms (kg) as specified in the Schedule of Assessments 
(Table 1, Table 2 and Table 3). 
Body weight measurements to be used for the dose calculations will be collected during the 
clinical study center visit.  Where doses are prepared in advance of the visit, the last recorded 
body weight may be used for dose calculation.  If weight changes more than 10% at the predose 
assessment, the dose of study drug will be re calculated. 
9.1.5 Physical Examination  
A directed physical examination will be performed as specified in the Schedule of Assessments 
(Table 1, Table 2 and Table 3).  A directed physical examination will include the 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.  For patients 
undergoing a surgical procedure, a directed physical examination will also be performed as 
specified in the Perioperative Schedule of Assessments (Table 4).   
9.1.6 Electrocardiogram  
The 12-lead electrocardiogram (ECG) recordings will be obtained as specified in the Schedule of 
Assessments (Table 1, Table 2 and Table 3).  When an ECG is scheduled at the same time as a 
physical examination or blood/urine sample collection, the ECG must be performed first. 
Standard 12-lead ECGs will be performed in the supine position after the patient has rested 
comfortably for 10 minutes.  The parameters assessed will be rhythm, ventricular rate, PR 
interval, QRS duration, QT interval, and QTc (Bazett-corrected QT interval and 
Fridericia-corrected QT interval). 
The Investigator or designee is responsible for reviewing the ECGs to assess whether the results 
are within normal limits and to determine the clinical significance of the results.  These 
assessments will be recorded on the eCRF.  For any clinically significant abnormal results, the 
Investigator or designee must contact the CRO Medical Monitor to discuss continued 
participation of the patient in the study. 
9.1.7 Laboratory Assessments  
Where study assessments overlap with the parent study, the assessments only need to be 
performed once. 
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9.1.7.1 Hematology, Biochemistry, and Coagulation  
Blood samples for the assessment of hematology, biochemistry, coagulation, and serology 
parameters will be collected as specified in the Schedule of Assessments (Table 1, Table 2 and 
Table 3).  Additional and repeat testing may be performed at the discretion of the Investigator. 
The specific procedures for the clinical laboratory tests are provided in the Laboratory Manual. 
Details regarding the processing, shipping, and analysis of the samples will also be provided in 
the Laboratory Manual. 
Specific instructions for transaminase elevations are provided in Section 6.5.1.1.  For any other 
unexplained clinically relevant abnormal laboratory test occurring after study drug 
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 10 and 
will be assessed as specified in the Schedule of Assessments (Table 1, Table 2 and Table 3). 
While local laboratory results may be used for dosing decisions and urgent clinical decisions, on 
the day of the clinic visit assessments, all laboratory assessments specified in Table 10 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 with available 
results, central laboratory results will be relied upon for clinical and dosing decisions.
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Table 10: Clinical Laboratory Assessments                           
Hematology 
Complete blood count (CBC)a 
Neutrophils, absolute and % 
White blood cell (WBC) count  
Lymphocytes, absolute and % 
Red blood cell (RBC) count  
Monocytes, absolute and % 
Hemoglobin  
Eosinophils, absolute and % 
Hematocrit  
Basophils, absolute and % 
Mean corpuscular volume 
Plateletsa 
Mean corpuscular hemoglobin 
CD4 in HIV seropositive patientsa 
Mean corpuscular hemoglobin concentration 
 
Biochemistry 
Sodium 
Alanine aminotransferase (ALT) 
Potassium 
Aspartate aminotransferase (AST) 
Blood urea nitrogen (BUN) 
Gamma glutamyl transferase (GGT) 
Creatinine and eGFR (using the MDRD formula) 
Total protein 
Albumin 
Uric acid 
Calcium 
Lactate dehydrogenase 
Phosphate 
Bilirubin (total and direct)  
Glucose 
Chloride 
C-reactive protein (CRP) 
Alkaline phosphatase (ALP) 
Carbon dioxide 
 
Coagulation 
International normalized ratio (INR) 
Antithrombin (AT) activityb 
FVIII for patients with hemophilia A 
(screening and perioperatively) 
Thrombin generation (TG) by calibrated automated 
thrombogram (CAT) assayb 
FIX for patients with hemophilia B (screening 
and perioperatively) 
Prothrombin time (PT) 
Activated partial thromboplastin time (APTT) 
Fibrinogen 
D-dimer 
Prothrombin fragment 1, 2 
Hepatic Tests 
HAV antibody IgM and IgG 
HCV antibodyc 
Hepatitis B surface antigen (HBsAg)  
Hepatitis B core antibody: IgM and IgG anti-HBc 
HCV RNA PCR – qualitative and quantitative 
assaysc 
HEV antibody IgM and IgG 
a At Screening, only a complete blood count, platelet count, and CD4 in HIV seropositive patients is required (a CD4 result from the previous 
6 months may be used to confirm eligibility).   
b Plasma AT and TG by CAT are also listed under the efficacy assessments. 
c In patients with a history of HCV infection, documentation detailing prior treatment prescribed for HCV infection will be collected.  In 
addition, HCV genotyping will be performed in consented patients with positive HCV RNA. 
 
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Clinical laboratory assessments may be collected at the clinical site or at home by a trained 
healthcare professional.  Central laboratory results are preferable.  If not available, local 
laboratory results may be used. 
Please see Section 6.5.1.1 for the LFT monitoring and dosing plan.   
9.1.7.2 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. 
For patients undergoing cholecystectomy due to cholecystitis, cholelithiasis or any other biliary 
pathology, the following should be performed, as possible: histopathological evaluation of the 
resected gallbladder and analyses of gallbladder contents including bile and gallstone 
composition. If performed, results should be included in the SAE and/or AESI report, as 
applicable. 
Additional laboratory assessments will be performed in patients who experience any LFT 
abnormalities as outlined in Section 6.5.1.1.  Following the occurrence of elevated liver 
transaminases or other LFT abnormalities per central laboratory, all assessments in Table 11 will 
be performed, as well as hematology, biochemistry, LFT, and coagulation assessments from 
Table 10, AT levels, and other assessments or evaluations per Investigator discretion, as 
appropriate. 
Monitoring and dose modification will also be performed as outlined in Section 6.5.1.1. 
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Table 11: 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 
HBsAg, 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 
Abbreviations:  CT=computed tomography; HAV=hepatitis A virus; HBc=hepatitis B core; HBsAg=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. 
9.1.7.3 Urinalysis  
Urine samples will be collected as specified in the Schedule of Assessments (Table 1, Table 2 
and Table 3) for evaluation of the following urinalysis parameters: 
Table 12: Urinalysis Parameters                           
Urinalysisa, b 
Leukocytes 
Red blood cells 
Protein 
pH (dipstick) 
Bilirubin 
Nitrite 
Urobilinogen 
Specific gravity 
Ketone 
Glucose 
a Visual or automated inspection for appearance and color will occur. 
b Urine microscopy will be performed if clinically indicated. 
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9.1.7.4 Antidrug Antibodies  
To explore the effect of fitusiran on the induction of antidrug antibodies, blood samples will be 
collected as specified in the Schedule of Assessments (Table 1, Table 2 and Table 3).   
Details regarding the processing, shipping, and analysis of the samples will be provided in the 
Laboratory Manual. 
9.1.8 Inhibitor Status  
Patients inhibitor status will be determined as specified in the Schedule of Assessments (Table 1, 
Table 2 and Table 3) by Nijmegen modified Bethesda assay. 
9.1.9 FibroScan or FibroTest and APRI  
FibroScan will be performed at the clinical study center according to the Schedule of 
Assessments (Table 1, Table 2 and Table 3) to determine cirrhosis status in patients with a 
history of hepatitis C. If FibroScan is unavailable, FibroTest and APRI will be performed at the 
central laboratory according to the Schedule of Assessments (Table 1, Table 2 and Table 3).   
9.2 
ADVERSE AND SERIOUS ADVERSE EVENTS  
9.2.1 Adverse Event Definition  
An AE is any untoward medical occurrence in a patient or clinical investigational subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment.   
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
Bleeding events will not be recorded as AEs but will be recorded on a separate bleeding events 
page of the eCRF.  Data will be captured to classify whether bleeding events are related to 
hemophilia and whether they are spontaneous or traumatic. 
Any medical condition that is present when a patient is screened and does not deteriorate should 
not be reported as an AE; however, if the medical condition does deteriorate at any time after 
administration of the first dose of study drug, it should be reported as an AE. 
9.2.2 Serious Adverse Event Definition  
An SAE is any untoward medical occurrence that at any dose:   
• Results in death 
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• 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 inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital abnormality or birth defect 
• 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). 
9.2.3 Eliciting Adverse Event Information  
The patient should be asked about medically relevant changes in his health since the last visit.  
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 
over-the-counter). 
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. 
9.2.4 Adverse Event Reporting  
The Investigator is responsible for reporting all AEs that are observed or reported from the first 
administration of study drug in this study, regardless of their relationship to study drug, through 
the follow-up visit. 
All AEs must be fully 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 product, action taken, and outcome (including time and date of resolution, if 
applicable). 
9.2.5 Assessment of Causality  
Causal relationship assessment to drug treatments is required for purposes of reporting AEs.  To 
promote consistency, the following guidelines should be taken into consideration along with 
good clinical and scientific judgment when determining the relationship of drug treatments to an 
AE: 
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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. 
9.2.6 Assessment of Severity  
Adverse events are to be graded according to the categories detailed below: 
Mild: 
Mild events are those which are easily tolerated with no disruption of 
normal daily activity. 
Moderate: 
Moderate events are those which cause sufficient discomfort to 
interfere with normal daily activities. 
Severe: 
 
Severe events are those which incapacitate and prevent usual activity. 
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). 
9.2.7 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 
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• Systemic injection associated reactions (IARs), defined as hypersensitivity reactions 
which are related or possibly related to IMP. 
• Cholecystitis*  
• Cholelithiasis* 
*See Section 9.1.7.2 for recommendations on additional evaluations to be performed for 
participants undergoing cholecystectomy. 
9.2.7.1 Recording Adverse Events of Special Interest  
For AEs that are considered AESI, additional clinical, laboratory, and diagnostic information 
may be collected based upon the severity or nature of the event.   
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). 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. 
If a patient has ISRs meeting any of the following criteria, the Investigator, or delegate, should 
contact the study Medical Monitor and submit a supplemental ISR eCRF: 
• ISRs that are recurrent and/or demonstrate a pattern of increasing severity 
• Any ISR that is determined to be severe and/or a cause for study drug discontinuation  
• Any ISR that, in the opinion of the Investigator, requires further medical evaluation or 
treatment 
In some cases, where it is medically appropriate, further evaluation may include photographs, 
referral to a dermatologist, skin biopsy, or other laboratory testing.  If a biopsy is obtained, the 
Sponsor may request that the biopsy also be reviewed by a central dermatopathologist.  To better 
understand the safety profile of the study drug, additional analysis of biopsy tissue may be 
performed according to local regulations. 
For patients with hepatic AEs, local laboratory results may be collected to monitor LFT levels or 
other laboratory parameters. 
Refer to the eCRF completion guidelines for details on reporting events in the supplemental 
AESI eCRF. 
9.2.8 Coding of Adverse Events  
The Medical Dictionary for Regulatory Activities (MedDRA) will be used to code AEs. 
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9.2.9 Serious Adverse Event and Adverse Events of Special Interest Reporting  
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 9.2.2 and any AESI must be 
reported to the CRO within 24 hours from the time that clinical study site personnel first learn of 
the event.  All SAEs and AESI must be reported regardless of the relationship to study drug. 
The initial report of SAEs 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 causality to study drug 
To report the SAE or an AESI, complete the SAE/AESI form.   
Within 24 hours of receipt of relevant follow-up information, the Investigator must update the 
SAE/AESI form.  SAE/AESI forms must be reported using the contact information provided 
below. 
SAE Reporting Contact Information 
PSI CRO 
SafetyDesk@psi-cro.com  
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 study drug, 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. 
9.2.9.1 Notifying the Institutional Review Board/Independent Ethics Committee  
SAEs and/or 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. 
9.2.9.2 Sponsor Reporting:  Notifying Regulatory Authorities  
The Sponsor or its representative is required to report certain study events in an expedited 
manner to the Food and Drug Administration, the European Medicines Agency 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. 
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The following describes the safety reporting timeline requirements for suspected unexpected 
serious adverse reactions and other reportable events: 
Immediately and within 7 calendar days: 
• Any suspected adverse reaction that is:  associated with the use of the study drug, 
unexpected, and fatal or life threatening.  Follow-up information must be reported in the 
following 8 days. 
Immediately and within 15 calendar days: 
• Any suspected adverse reaction that is:  associated with the use of the study drug, 
unexpected, and serious, but not fatal or life threatening, and there is evidence to suggest 
a causal relationship between the study drug and the reaction. 
• Any finding from tests in laboratory animals that:  suggest a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. 
• Any event in connection with the conduct of the study or the development of the study 
drug that may affect the safety of the trial subjects. 
In addition, periodic safety reporting to regulatory authorities will be performed by the Sponsor, 
or its representative, according to national and local regulations. 
9.2.9.3 Sponsor Notification of Participating Investigators  
All Investigators will be informed by the Sponsor, or its representative, of relevant clinical safety 
findings from this or other clinical studies, as well as any new findings from tests in laboratory 
animals that significantly impact the benefit/risk to patients in this study.  All reports should be 
transmitted to the IEC/IRB that approved the study. 
9.2.10 Pregnancy Reporting  
If the female partner of a patient becomes pregnant during the course of this study, the 
Investigator must report the pregnancy to the CRO within 24 hours of being notified of the 
pregnancy.  The pregnancy should be followed by the Investigator until its conclusion. 
9.2.11 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. 
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10 
STATISTICS  
A detailed Statistical Analysis Plan will be written after finalizing the protocol and before 
database lock.  The plan will detail the implementation of all the statistical analyses in 
accordance with the principal features stated in the protocol. 
10.1 
NUMBER OF PATIENTS  
Up to 48 patients with moderate or severe hemophilia A or B who have previously participated 
in a clinical study with fitusiran may be enrolled if they meet the eligibility criteria for this study.  
The size of this study is not determined via power analysis of particular hypotheses tests. 
10.2 
STATISTICAL METHODOLOGY  
All study data will be presented in by-patient data listings.  Statistical analyses will be primarily 
descriptive.  Summary tables will be presented by starting dose level and final dose 
level/frequency of fitusiran separately for patients with and without inhibitors. 
For categorical variables, summary tabulations of the number and percentage of patients within 
each category (with a category for missing data) will be presented.  For continuous variables, the 
number of patients, mean, median, standard deviation, minimum, and maximum values will be 
presented. 
All analyses will be conducted for patients with and without inhibitors separately. 
10.2.1 Populations to be Analyzed  
The following populations (ie, analysis sets) may be evaluated and used for presentation of the 
data: 
• Safety Analysis Set:  All patients who receive at least a partial dose of fitusiran will be 
included in the safety analyses. 
• Per Protocol Set:  All patients in the safety analysis set who have no major protocol 
violations. 
• PK Analysis Set:  All patients who receive at least 1 dose of study drug and have at least 
1 blood sample collection postdose to determine plasma concentrations of fitusiran. 
• PD Analysis Set:  All patients who receive at least 1 dose of fitusiran and have at least 
1 blood sample collection postdose to determine plasma AT and TG levels will be 
included in the PD analyses. 
The Safety Analysis Set will be the primary set for safety assessments.  Both the Safety Analysis 
Set and the Per Protocol Set will be used to assess efficacy endpoints.  The PK Analysis Set will 
be used for PK analysis and the PD Analysis Set will be used for PD analyses. All the analysis 
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sets before and after the 2020 dose pause will be populated separately. Accordingly, the 
statistical analysis will be performed based on each analysis set respectively. 
10.2.2 Baseline Evaluations  
Demographic data will be summarized by dose level and overall. 
Descriptive statistics will be provided for age, height, weight, and body mass index at screening.  
Frequencies and percentages will be tabulated for sex, race, and ethnicity. 
10.2.3 Efficacy Analyses  
Annualized bleed rate estimate will be calculated as the number of bleed events occurring 
4 weeks after the first dose of fitusiran in this study and until the End of Study visit.  Bleed-free 
duration will be defined as the maximum time intervals between 2 bleeding events and will be 
analyzed descriptively.  Bleed rate reduction and percentage reduction compared with 
pretreatment will also be calculated.   
A weight-adjusted consumption of FVIII or FIX or BPA will be assessed. 
Patient-reported QoL will be assessed by descriptive statistics for the EQ-5D-5L questionnaire.  
Descriptive statistics will be provided for observed values and changes from baseline (ie, Day 1, 
predose in the current study).   
10.2.4 Pharmacodynamic Analysis  
The pharmacodynamic evaluation will include an analysis of plasma AT activity and protein 
level and TG (determined by CAT assay).  Descriptive statistics will be presented by study day 
for actual results and change from baseline. 
10.2.5 Exploratory Analyses  
For patients who undergo major operative procedures during the study, the total number of 
patients in each rating category of hemostatic efficacy response (“none,” “moderate,” “good,” 
and “excellent”) will be summarized at each time point for both the intraoperative and 
postoperative assessments. 
10.2.6 Safety Analyses  
Adverse events will be summarized by the MedDRA System Organ Class and Preferred Term.  
Incidence of treatment-emergent adverse events (TEAEs; those events that started after exposure 
to study drug or worsened in severity after dosing) will be presented by dose level and overall.  
Incidence of TEAEs will also be presented by maximum severity and relationship to study 
medication or underlying hemophilia.  The incidence of SAEs and AEs leading to 
discontinuation of treatment will also be tabulated.  By-patient listings will be provided for 
deaths, SAEs, and events leading to discontinuation of treatment.   
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Descriptive statistics will be provided for clinical laboratory data (including biochemistry, 
hematology, urinalysis, and coagulation) and vital signs data, presented as both actual values and 
changes from baseline relative to each on-study evaluation.  Laboratory shift tables from baseline 
to worst values will be presented.  Baseline will be defined as the last observation on or before 
Day 1.  Abnormal physical examination findings, 12-lead ECG data, and antidrug antibody 
results will be presented in a by-patient data listing.  Antidrug antibody results will also be 
tabulated. 
10.2.7 Pharmacokinetic Analysis  
Pharmacokinetic analyses will be conducted using a population PK approach.   
In addition to performing population PK, in a subset of patients, the following PK parameters 
will be evaluated using non-compartmental analysis:  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).  The amount of fitusiran or metabolite excreted in urine will also be estimated using 
non-compartmental analysis.  Other parameters may be calculated, if deemed necessary.   
10.2.8 Interim Analysis  
Interim data examinations may be performed and will generally be descriptive in nature.  As this 
is an open-label, extension study, interim analyses may be performed and will be described in the 
SAP. 
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11 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS  
11.1 
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, 
International Council on Harmonisation (ICH) GCP, and all applicable regulatory requirements. 
Monitoring details describing strategy, methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in separate study documents. 
Records and documents, including signed informed consent forms (ICFs), pertaining to the 
conduct of this study must be retained by the Investigator for 25 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. 
11.2 
AUDITS AND INSPECTIONS  
Authorized representatives of the Sponsor, a regulatory authority, an IEC or an IRB may visit the 
site to perform audits or inspections, including source data verification. The purpose of an audit 
or inspection by the Sponsor is to systematically and independently examine all study-related 
activities 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.  The Investigator should contact the Sponsor, 
or its designee, immediately if contacted by a regulatory agency about an inspection. 
11.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE  
The PI must obtain IRB/IEC approval for the investigation. Initial IRB/IEC approval, and all 
materials approved by the IRB/IEC for this study including the patient consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 
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12 
QUALITY CONTROL AND QUALITY ASSURANCE  
Study personnel are expected to adhere to the following practices, governed by GCP and all 
applicable regulatory requirements. To ensure these practices are in place, the Sponsor may 
conduct a quality assurance audit. 
The Investigator will submit reports of SAEs as outlined in this protocol.  In addition, the 
Investigator agrees to submit progress reports to his/her IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study.  The reports will be made 
available to the Sponsor or designee. 
Deviations from the protocol necessary to protect patient safety should be reported to the CRO 
within 24 hours of knowledge of the event. 
Any communications from regulatory agencies in regard to inspections, other studies that impact 
this protocol or the qualifications of study personnel should be promptly reported to the CRO. 
Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor and the IRB or IEC that approved the 
study.  Amendments to the protocol must be submitted in writing to the Investigator’s IRB or 
IEC and the Regulatory Authority for approval before patients are enrolled under the amended 
protocol. 
Regulatory authorities will receive the protocol, amendments, reports on SAEs, and the 
Integrated Clinical Study Report according to national and any local regulations. 
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13 
ETHICS  
13.1 
ETHICS 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 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, European 
Regulation 536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
13.2 
ETHICAL CONDUCT OF THE STUDY  
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 
13.3 
WRITTEN INFORMED CONSENT PROCESS  
• The Investigator or his/her representative will explain the nature of the study to the 
patient or his 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. 
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• 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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14 
DATA HANDLING AND RECORD KEEPING  
• 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 electronic CRF 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. 
14.1 
INSPECTION OF RECORDS  
The Sponsor, or its designee, will be allowed to conduct site visits to the investigation facilities 
for the purpose of monitoring any aspect of the study.  The Investigator agrees to allow the 
monitor to inspect the drug storage area, study drug stocks, drug accountability records, patient 
charts and study source documents, and other records relative to study conduct. 
14.2 
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 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 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. 
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15 
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. 
 
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16 
DISSEMINATION OF CLINICAL STUDY DATA  
Sanofi shares information about clinical trials and results on publicly 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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17 
LIST OF REFERENCES  
1. Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key NS, Kitchen S, Llinas A, et al.  
Guidelines for the management of hemophilia.  Haemophilia.  2013 Jan;19(1):e1-47. 
2. Ljung R, Petrini P, Nilsson IM.  Diagnostic symptoms of severe and moderate haemophilia A 
and B. A survey of 140 cases.  Acta Paediatr Scand.  1990 Feb;79(2):196-200. 
3. Mannucci PM, Tuddenham EG.  The hemophilias--from royal genes to gene therapy.  N Engl 
J Med. 2001 Jun 07;344(23):1773-9. 
4. Escuriola Ettingshausen C, Halimeh S, Kurnik K, Schobess R, Wermes C, Junker R, et al. 
Symptomatic onset of severe hemophilia A in childhood is dependent on the presence of 
prothrombotic risk factors.  Thromb Haemost.  2001 Feb;85(2):218-20. 
5. Shetty S, Vora S, Kulkarni B, Mota L, Vijapurkar M, Quadros L, et al.  Contribution of 
natural anticoagulant and fibrinolytic factors in modulating the clinical severity of 
haemophilia patients.  Br J Haematol.  2007 Aug;138(4):541-4. 
6. Bolliger D, Szlam F, Suzuki N, Matsushita T, Tanaka KA.  Heterozygous antithrombin 
deficiency improves in vivo haemostasis in factor VIII-deficient mice.  Thromb Haemost.  
2010 Jun;103(6):1233-8. 
7. Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. 
Haemophilia. 2003 Jul;9(4):418-35. 
8. Peyvandi F, Ettingshausen CE, Goudemand J, Jiménez-Yuste V, Santagostino E, Makris M. 
New findings on inhibitor development: from registries to clinical studies. Haemophilia. 
2017 Jan;23 Suppl 1:4-13. 
9. Puetz J, Soucie JM, Kempton CL, Monahan PE; Hemophilia Treatment Center Network 
(HTCN) Investigators. Prevalent inhibitors in haemophilia B subjects enrolled in the 
Universal Data Collection database. Haemophilia. 2014 Jan;20(1):25-31. 
10. Brettler DB. Inhibitors in congenital haemophilia. Baillieres Clin Haematol. 1996 
Jun;9(2):319-29. 
11. Hay CR, Brown S, Collins PW, Keeling DM, Liesner R.  The diagnosis and management of 
factor VIII and IX inhibitors: a guideline from the United Kingdom Haemophilia Centre 
Doctors Organisation.  Br J Haematol.  2006 Jun;133(6):591-605. 
12. Dimichele D, Negrier C.  A retrospective postlicensure survey of FEIBA efficacy and safety.  
Haemophilia.  2006 Jul;12(4):352-62. 
13. Pasi KJ, Rangarajan S, Georgiev P, Mant T, Creagh MD, Lissitchkov T, et al. Targeting of 
Antithrombin in Hemophilia A or B with RNAi Therapy. N Engl J Med. 2017 Aug 
31;377(9):819-828. 
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14. Machin N, Ragni MV. An investigational RNAi therapeutic targeting antithrombin for the 
treatment of hemophilia A and B. J Blood Med. 2018 Aug 22;9:135-140. 
15. 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;42(4):1158-92. 
16. 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;43(3):304-77. 
17. 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;145(1):24-33. 
18. 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;12(11):1935-9. 
19. 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;20(10):1727-36. 
20. 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;21(5):578-84. 
 
 
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18 
APPENDICES  
18.1 
PHARMACOKINETIC ASSESSMENT TIME POINTS  
Detailed collection of schedules for blood (Table 13) and urine (Table 14) samples for PK 
analysis are presented below.   
Table 13: Pharmacokinetic Time Points                           
Study Day 
Protocol Time 
(hh:mm) 
PK Blood 
Day 1, Month 12  
(Day 361 ±7 days) and Month 24 
(Day 721 ±7 days)a 
Predose (within 60 minutes 
before dosing) 
X 
00:30 (±2 min) 
X 
02:00 (±5 min) 
X 
04:00 (±30 min) 
X 
08:00 (±30 min) 
X 
Day 2, Month 12  
(Day 362 ±7 days) and Month 24 
(Day 722 ±7 days)a 
24:00 (±2 hours) 
X 
a Month 24 assessment to be performed in a subset of patients who opt to participate. 
 
Table 14: Urine Pharmacokinetic Time Points                           
Study Day 
Protocol Time 
(hh:mm), Pooled Urine 
Month 24 (Day 721 ±7 days) 
Postdose, 0:00 to 06:00 (±30 min)a 
06:00 (±30 min) to 12:00 (±30 min) 
Month 24 (Day 721 to Day 722 ±7 days) 
12:00 (±30 min) to 24:00 (±2 hours) 
Note:  To be performed in a subset of patients who opt to participate.  Urine volume will be recorded for each urine collection 
interval. 
a Patients must empty bladder before this urine collection interval.   
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Table 15:   ADA timepoints in all patients at 50 mg Q2M dose  
Study Day 
Protocol Time 
(hh:mm) 
ADA 
Day of dose 
re-start  
Predose (within 240 minutes 
before dosing) 
X 
PR Month 6 
Predose (within 240 minutes 
before dosing) 
X 
PR Month 12  
Predose (within 240 minutes 
before dosing) 
X 
PR Month 24 
Predose (within 240 minutes 
before dosing) 
Xa 
PR Month 36 
Predose (within 240 minutes 
before dosing) 
Xa 
a ADA samples collected at PR Months 24 and 36 will only be analyzed if the preceding sample was ADA positive.   
Table 16:   ADA timepoints with dose escalation to 50 mg QM or 80 mg QM  
Study Day 
Protocol Time 
(hh:mm) 
ADA 
Day of new dose 
Predose (within 240 minutes 
before dosing) 
X 
PR Month 6 
Predose (within 240 minutes 
before dosing) 
X 
PR Month 12  
Predose (within 240 minutes 
before dosing) 
X 
PR Month 24 
Predose (within 240 minutes 
before dosing) 
Xa 
PR Month 36  
Predose (within 240 minutes 
before dosing) 
Xa 
a ADA samples collected at PR Months 24 and 36 will only be analyzed if the preceding sample was ADA positive.   
18.2 
PERIOPERATIVE SCHEDULE OF ASSESSMENTS  
18.2.1 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. 
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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 or any tooth implantation 
• Operative alteration of normal anatomy 
• Crossing of a mesenchymal barrier (eg, pleura, peritoneum, dura) 
18.2.2 Perioperative Assessments of Safety and Hemostatic Efficacy in Patients 
Undergoing Major Operative Procedures  
In patients who undergo a major operative procedure while on study, questionnaires will be 
provided to capture the exploratory perioperative assessments of hemostasis.  The questionnaires 
may be completed by the dentist/surgeon/anesthesiologist involved in the procedure, or by the 
Investigator in consultation with the involved dentist/surgeon/anesthesiologist.  The 
questionnaires include the Hemostatic Efficacy Rating Scale for Major Operative Procedures 
(Table 17), based on the ISTH SSC definitions (18).  
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Table 17: Hemostatic Efficacy Rating Scale for Major Operative Procedures                           
Excellent 
Intra-operative and post-operative blood loss similar (approximately within 10%) to the 
non-hemophilic patient 
• 
No extra (unplanned) doses of FVIII/FIX/BPAs needed AND 
• 
Blood component transfusions required are similar to non-hemophilic patient 
Good 
Intra-operative and/or post-operative blood loss slightly increased over expectation for 
the non-hemophilic patient (approximately between 10-25% of expected), but the 
difference is not clinically significant 
• 
No extra (unplanned) doses of FVIII/FIX/BPAs needed AND 
• 
Blood component transfusions required are similar to the non-hemophilic 
patient 
Moderate 
Intra-operative and/or post-operative blood loss increased over expectation 
(approximately 25-50%) for the non-hemophilic patient and additional treatment is 
needed 
• 
Extra (unplanned) dose of FVIII/FIX/BPAs needed OR 
• 
Increased blood component (within 2-fold) of the anticipated transfusion 
None 
Significant intra-operative and/or post-operative blood loss that is substantially 
increased over expectation (approximately >50%) for the non-hemophilic patient, 
requires intervention, and is not explained by a surgical/medical issue other than 
hemophilia 
• 
Unexpected hypotension or unexpected transfer to intensive care unit (ICU) 
due to bleeding OR 
• 
Substantially increased blood component (approximately >2 fold) of the 
anticipated transfusion requirement 
See Section 8.4 for further details regarding major operative procedures while on study.  The 
Perioperative Schedule of Assessments in patients undergoing major operative procedures while 
on study is presented in Table 4. 
 
 
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18.3 
DATA PROTECTION  
All personal data collected and/or processed in relation to this study will be handled in 
compliance with all applicable Privacy & Data Protection laws and regulations, including the 
GDPR (General Data Protection Regulation). The study Sponsor is the Sanofi company 
responsible for ensuring compliance with this matter, when processing data from any individual 
who may be included in the Sanofi databases, including Investigators, nurses, experts, service 
providers, Ethics Committee members, etc.  
When archiving or processing personal data pertaining to the Investigator and/or to the patients, 
the Sponsor takes all appropriate measures to safeguard and prevent access to this data by any 
unauthorized third party. 
Protection of patient data 
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
“Patient race and ethnicity will be collected in this study because they are expected to modify the 
drug response/because they are required by regulatory agencies (eg, on African American 
population for the FDA or on Japanese population for the Pharmaceuticals and Medical Devices 
Agency in Japan)”. They will not be collected in the countries where this is prohibited by local 
regulation. 
• Patients will be assigned a unique identifier by the Sponsor. Any patient records or 
datasets that are transferred to the Sponsor or its service providers will be identifiable 
only by the unique identifier; patient names or any information which would make the 
patient identifiable will not be transferred to the Sponsor.  
• The patient must be informed that his personal study-related data will be used by the 
Sponsor in accordance with applicable data protection laws. The level of disclosure must 
also be explained to the patient as described in the informed consent.  
• The patient must be informed that his 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. 
• Patients must be informed that their study-related data will be used for the whole “drug 
development program”, ie, for this trial as well as for the following steps necessary for 
the development of the investigational product, including to support negotiations with 
payers and publication of results. 
Protection of data related to professionals involved in the study  
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow Sanofi to manage involvement in the study and/or the related contractual or 
pre-contractual relationship. They may be communicated to any company of the Sanofi 
group (“Sanofi”) or to Sanofi service providers, where needed. 
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• Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available 
at Sanofi.com).  
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals 
have already been involved in a Sanofi study, they will not be able to object to the 
processing of their personal data as long as they are required to be processed by 
applicable regulations. The same rule applies in case the professionals are listed on a 
regulatory agency’s disqualification list. 
• Personal data can be communicated to the following recipients:  
- 
Personnel within Sanofi or partners or service providers involved in the study,  
- 
Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research 
transparency. 
• Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering an 
adequate level of protection. Those transfers are safeguarded by Sanofi in accordance 
with the requirement of European law including, notably:  
- 
The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers, 
- 
Sanofi’s Binding Corporate Rules for intra-group transfers.  
• Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory 
Authority, the “Commission Nationale de l’Informatique et des Libertés” (CNIL) or with 
any competent local regulatory authority. 
• Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless 
further retention is required by applicable regulations. 
• In order to facilitate the maintenance of Investigators personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates 
in the Shared Investigator Platform (SIP) and in the TransCelerate Investigator Registry 
(IR) project (https://transceleratebiopharmainc.com/initiatives/investigator-registry/). 
Therefore, personal data will be securely shared by Sanofi with other pharmaceutical 
company members of the TransCelerate project. This sharing allows Investigators to keep 
their data up-to-date once for all across pharmaceutical companies participating in the 
project, with the right to object to the transfer of the data to the TransCelerate project.  
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Professionals have the right to request the access to and the rectification of their personal data, as 
well as their erasure (where applicable) by contacting the Sanofi Data Protection Officer: Sanofi 
DPO - 54 rue La Boétie - 75008 PARIS - France (to contact Sanofi by email, visit 
https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-policy/contact). 
18.4 
COUNTRY-SPECIFIC REQUIREMENTS  
There were no country-specific requirements. 
 
 
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18.5 
CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL EMERGENCY THAT 
IS DECLARED BY A GOVERNMENTAL AGENCY  
A regional or national emergency declared by a governmental agency (eg, public health 
emergency, natural disaster, pandemic, terrorist attack) may prevent access to the clinical trial 
site. 
Clinical supplies and dosing 
The following contingencies may be implemented for the duration of the emergency (after 
Sponsor agreement is obtained) to make clinical supplies available to the patients for the duration 
of the emergency: 
• The Direct-to-Patient (DTP) supply of IMP from the Sponsor where allowed by local 
regulations and agreed upon by the patient.  
• Re-initiation of the IMP can only occur once the Investigator has determined, according 
to his/her best judgement, that the contribution of the IMP to the occurrence of the 
epidemic event (eg, COVID-19) was unlikely. 
Operational measures 
Contingency procedures for continuation of the study in the event of a regional or national 
emergency declared by a governmental agency are suggested below and in Section 4.4, 
Section 6.1, and Section 6.5.1.4. These procedures apply to an emergency that prevents access to 
the study site, to optimize the safety of the patients, to consider continuity of the clinical study 
conduct, protect trial integrity, and assist in maintaining compliance with Good Clinical Practice 
in Conduct of Clinical Trials Guidance. Sponsor agreement MUST be obtained prior to the 
implementation of these procedures for the duration of the emergency.   
Procedures to be considered in the event of a regional or national emergency declared by a 
governmental agency: 
• If onsite visits are not possible, remote visits (eg, with home nurses, home health vendor, 
etc.) may be planned for the collection of possible safety and/or efficacy data. For any 
patients receiving fitusiran, factors and BPAs, Investigator and/or designee should 
contact the patient via regular phone calls at least every two weeks to oversee the 
tolerability of the drugs, to check for AEs, review the bleed management including 
bleeding episodes and patient diary. Depending on the delay of patient on-site visit, PRO 
collection may also be considered via remote visits. 
• If onsite visits are not feasible, visit windows may be extended for assessment of safety 
and/or efficacy data that cannot be obtained remotely. If a visit cannot be completed in its 
entirety, at a minimum the site should maintain contact with patients every 2 weeks, to 
check for AEs, review the bleed management including bleeding episodes. 
• Use of local laboratory may be allowed; Hematology, serum chemistry, coagulation, and 
liver function tests (which are due at certain visits and which cannot be frozen) should be 
prioritized for local lab testing by the study site for continued safety assessment. 
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Contingencies implemented due to emergency will be documented.  
During the emergency, if the site will be unable to adequately follow protocol mandated 
procedures, alternative treatment outside the clinical trial should be proposed, and administration 
of study intervention may be temporarily delayed (see also Section 6.5.1.4).  
Attempts should be made to perform all assessments in accordance with the approved protocol to 
the extent possible.  In case this is not possible due to a temporary disruption caused by an 
emergency, focus should be given to assessments necessary to optimize the safety of patients and 
those important to preserving the main scientific value of the study.   
The patient or their legally authorized representative should be verbally informed prior to 
initiating any changes that are to be implemented for the duration of the emergency (eg, study 
visit delays, treatment extension, use of local labs, etc.). 
18.6 
PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Protocol Synopsis. 
18.6.1 Amended Protocol 01  
Changes to eligibility criteria: 
• Exclusion criterion #3, updated to permit enrollment of patients with inhibitors who have 
a medical history of previous thrombotic event related to permanent indwelling venous 
access 
Other changes: 
• Maximum sample size increased to N=48 and sites increased to 30 
• Bleed management guidelines revised for patients without inhibitors and added for 
patients with inhibitors 
• Patients may resume standard prophylaxis or on-demand dosing with Factor or BPA at 
Investigator discretion after dosing of ALN-AT3SC has been completed and AT levels 
begin returning to Screening levels 
• Removal of contraception language 
• Use of fixed dose, provided that dose is no greater on a weight basis than the highest dose 
determined previously in the parent study (ALN-AT3SC-001) to be safe and well 
tolerated 
• Addition of the Haem-A-QoL to assess QoL 
• Addition of text based on EC feedback 
• Clarification of overlapping study assessments (vs parent study) 
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18.6.2 Amended Protocol 02  
Changes to objectives: 
• Exploratory objective added for assessment of safety and hemostatic efficacy rating for 
operative procedures conducted in patients while on study 
Other changes: 
• Study duration expanded by 2 years to 4 years total 
• Text added to permit self-administration of study drug during non-quarterly visits from 
Month 3 forward 
• Patient activity levels assessment removed 
• Adverse Events of Clinical Interest section added 
• Body temperature method revised to include all types (oral, tympanic, axillary) 
• Other minor corrections 
18.6.3 Amended Protocol 03  
Primary changes: 
• Text and table added for LFT monitoring in patients with elevated ALT 
• Text added to permit direct-acting antiviral treatment for HCV infected patients 
• FibroScan (FibroTest and APRI where FibroScan unavailable) added to assess liver 
fibrosis/cirrhosis in HCV infected patients; added in text and to Schedule of Assessments 
• Clinical development status text updated 
• Risk-benefit text updated 
• New bleed management recommendations added to text and new tables added 
• Surgery table and footnotes updated to align with Phase 3 studies 
• Optional plasma PK visit and optional urine PK visit added at Month 24 
• Schedule of Assessments reformatted and visits adjusted where necessary per above 
changes 
• Other minor corrections applied 
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18.6.4 Amended Protocol 04  
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 this study 
• Additional safety measures were implemented to mitigate risk of thrombosis in the 
lowered-AT setting, including updating bleed management guidelines, adding 
recommendations for monitoring and management of thrombotic events, clarification of 
definitions for bleeding episodes, revised recommendations for management of sepsis, 
and adding additional exploratory laboratory assessments 
• Frequency of visits increased in Schedule of Assessments from quarterly schedule in 
years 2 to 4, to a monthly schedule 
• 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 
• Revision of hepatic tests for hepatitis B 
• 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 
• Addition of monthly AT monitoring visits after the final dose of ALN-AT3SC until 
AT activity level returns to ~60% 
• 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 TG and other coagulation 
parameters 
• Other minor corrections applied 
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18.6.5 Amended Protocol 05  
AMENDMENT 05 (31 May 2018) 
This amended protocol (amendment 05) 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 (LTE14762) 
has been added.  The Alnylam study drug code ALN-AT3SC has also been updated to the 
generic drug name fitusiran.  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. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Throughout 
Name of Sponsor changed from “Alnylam 
Pharmaceuticals, Inc.” to “Genzyme 
Corporation” 
Change of protocol Sponsor 
Throughout 
Name of Sponsor contact changed from 
“Pushkal Garg” to “Olivier Huynh-Ba” 
Change of protocol Sponsor; contact details 
Section 1.3 (only at 
first occurrence) 
“Sanofi Genzyme LTE14762” added to the 
Study number “ALN-AT3SC-002” 
Change of protocol Sponsor; Sanofi Genzyme study 
ID required for administrative purposes on first use 
Throughout 
Name of product “ALN-AT3SC” changed to 
“Fitusiran” 
Change of protocol Sponsor; name of product 
updated 
Title page 
Disclaimer note text changed 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Section 3.6 
Criteria for Study Termination language 
updated for clarity 
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 
“Investigational study drug” changed to 
“Investigational medicinal product” 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 6.6 
“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, etc.) 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Section 9.1.7.1 
(Table 7) 
Hepatitis B surface antibody (anti-HBs) 
deleted 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Section 9.2.7 
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 
Section 9.2.9 
Heading updated from “Serious Adverse Event 
Reporting” to “Serious Adverse Event and 
Adverse Events of Special Interest Reporting” 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Section 9.2.11 
New Section 9.2.11 “Guidelines for Reporting 
Product Complaints/Medical Device Incidents 
(Including Malfunctions)” added with text 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Section 11.1 
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 13.1 
Ethics Review language updated for clarity 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Section 13.2 
Ethical Conduct of the Study language 
updated to provide additional details 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Section 13.3 
Written Informed Consent Process language 
updated to provide additional process details 
and clarity 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Section 14 
Data Handling and Record Keeping language 
updated to provide additional details and 
clarify responsibilities 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Section 14.2 
Retention of Records section heading and text 
updated to include additional details to ensure 
confidentiality of patient data and records 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Section 15 
Publication Policy language updated to 
provide additional process details and some 
text moved into Section 16 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Section 16 
New Section 16 “Dissemination of Clinical 
Study Data” added with text 
Change of protocol Sponsor; text aligned with Sanofi 
Genzyme environment 
Appendix 18 
Appendix 18.3 - appendix for Country-Specific 
Requirements and Appendix 18.4- 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 
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18.6.6 Amended Protocol 06  
AMENDMENT 06 (05 March 2019) 
This amended protocol (amendment 06) 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  
• Study extension beyond 48 months: The ALN-AT3SC-002 (LTE14762) is an open-label 
extension study of the long-term safety and efficacy of fitusiran in patients with 
hemophilia A or B, with or without inhibitory antibodies to factor VIII or factor IX. The 
primary objective of this study is the safety and tolerability assessed by incidence, 
severity, relatedness, and seriousness of adverse events, and laboratory assessments. This 
amendment, as study duration extension, will enable patients who have completed 
48 months study participation to continue to be treated and evaluated for long-term safety 
and efficacy over 24 additional months or until fitusiran becomes commercially available, 
whichever occurs first. 
• Prefilled syringe with safety system (PFS-S): Study drug may be provided in prefilled 
syringes either at the clinic (healthcare setting) or in a nonhealth care setting (home 
injection) in a subset of patients receiving 80 mg monthly dose of fitusiran. The patient 
will be trained on prefilled syringe self-administration. Patients who have missed more 
than 6 consecutive fitusiran dose for any reason should utilize the study drug provided as 
a vial and syringe for at least 3 injections prior to utilizing prefilled syringe. 
• After at least a 2-year period of participation in the study, visits and assessments will be 
adjusted with reducing frequency of routine clinical hematology/biochemistry and 
urinary laboratory evaluations (but must be performed if clinically indicated), coagulation 
testing and exploratory biomarkers. The study duration of all patients has reached 
adequate follow-up to allow this adjustment. Based on gathered cumulative safety data 
during the study without any new safety concern or any new potential risk for fitusiran, 
the Sponsor determined that current visits and assessments frequency does not contribute 
additional information needed to evaluate patient’s safety beyond 2 years. This justifies 
the proposed visits and routine assessments frequency adjustment and will also reduce 
patient burden without compromising safety monitoring. 
Description of visits content and frequency with corresponding assessments during the extended 
period beyond 48 months are detailed in the amended protocol. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
Updated the Sponsor contact from “Olivier Huynh-ba” to 
“Salim Kichou”. 
• 
Administrative 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Protocol synopsis 
exploratory objectives 
Section 2.3 
Deleted following exploratory objective:  To investigate 
in vitro coagulation response to the reduction of AT 
levels. 
• 
There is no longer a consideration 
that some of the exploratory 
assessments would yield critical 
results.  Therefore, it was decided 
to reduce the study burden by 
deleting these assessments and 
related objectives 
Protocol synopsis 
methodology 
Following texts updated from: “Patients will visit the 
clinical study center for monthly assessments, including 
administration of study drug.  Fitusiran dosing may 
occur at home in patients who are trained on self-
administration.  For all fitusiran dosing administered at 
the study center or at home, LFT results are to be 
obtained within 7 days prior to dosing and results are to 
be reviewed prior to each dose.   
Safety and efficacy assessments will be performed at 
the clinical study center at each monthly visit and during 
an End of Treatment visit.  Patients will return to the 
clinical study center for an End of Study visit 30 days 
after the last dose of study drug.  Separately, follow-up 
visits to assess AT activity levels should occur at 
monthly intervals until AT activity level returns to 
approximately 60% (per the central laboratory), or per 
Investigator discretion in consultation with the study 
Medical Monitor. 
• 
Study extension beyond 
48 months. 
• 
There is no longer a consideration 
that some of the routine 
assessments would yield critical 
results.  Therefore, it was decided 
to reduce the study burden by 
deleting these assessments. 
 
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Pharmacokinetic assessments will be performed on 
Day 1, at the Month 12 visit, and at the Month 24 visit (in 
a subset of patients).  Patients will also return to the 
clinical study center on Day 2 and the day after the 
Month 12 and Month 24 (in a subset of patients) visits 
for further PK sampling.  Pooled urine collection will also 
occur at the Month 24 visit in a subset of patients. 
In patients who present to the study site for 
management of bleeding symptoms, samples will be 
collected for exploratory coagulation biomarker 
assessment, including TG.” 
to 
“Patients will visit the clinical study center monthly up to 
the end of Year 2 and then every 6 months up to the 
end of Year 6 for assessments including administration 
of study drug.  Fitusiran dosing may occur at home in 
patients who are trained on self-administration.  For up 
to 2 years, all fitusiran dosing administered at the study 
center or at home, LFT results are to be obtained within 
7 days prior to dosing and results are to be reviewed 
prior to each dose.  From Year 3 onwards, the 
frequency of predose LFT monitoring may be decreased 
to quarterly for patients who have negative hepatitis C 
antibody titers and meet the following criteria for 
quarterly predose LFT monitoring: 
a) 
Did not have any ALT elevation >3× ULN persisting 
for ≥2 months at any time during the previous 12 
months. 
b) 
Did not have any fitusiran doses held due to LFT 
elevations during the study. 
Safety and efficacy assessments will be performed at 
the clinical study center at each clinic visit and during an 
End of Treatment visit.  Patients will return to the clinical 
study center for an End of Study visit 30 days after the 
last dose of study drug.  Separately, follow-up visits to 
assess AT activity levels should occur at monthly 
intervals until AT activity level returns to approximately 
60% (per the central laboratory), or per Investigator 
discretion in consultation with the study Medical Monitor.  
(Note: for patients who opt for the commercially 
available fitusiran, these follow-up visits to assess AT 
activity level are not required). 
Pharmacokinetic assessments will be performed on 
Day 1, at the Month 12 visit, and at the Month 24 visit (in 
a subset of patients).  Patients will also return to the 
clinical study center on Day 2 and the day after the 
Month 12 and Month 24 (in a subset of patients) visits 
for further PK sampling.  Pooled urine collection will also 
occur at the Month 24 visit in a subset of patients.” 
 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Protocol synopsis 
duration of treatment 
Updated following texts from “It is anticipated that 
patients in this study will receive treatment with 
open-label fitusiran for approximately 4 years.” to “It is 
anticipated that patients in this study will receive 
treatment with open-label fitusiran for approximately 
6 years or until fitusiran becomes commercially 
available, whichever occurs first.” 
• 
Study extension beyond 
48 months. 
Protocol synopsis 
exploratory 
assessments 
Deleted following exploratory assessments: modified 
(heparin) activated partial thromboplastin time, plasma 
clot lysis, whole blood clot formation as assessed by 
ROTEM® (where available), evaluation of TG in an ex 
vivo assay with factor/BPA-spiked samples. 
• 
There is no longer a consideration 
that some of the exploratory 
assessments would yield critical 
results.  Therefore, it was decided 
to reduce the study burden by 
deleting these assessments. 
Protocol synopsis 
statistical methods 
Updated following texts from “Descriptive statistics will 
be provided for clinical efficacy and exploratory data” to 
“Descriptive statistics will be provided for clinical efficacy 
data.” 
Updated following texts from “Annualized bleed rate, 
bleed rate reduction, and percentage reduction 
compared with pretreatment will be calculated.  
Descriptive statistics will be presented for the EQ-5D 
questionnaire, plasma AT activity, and TG.” to 
“Annualized bleed rate, bleed rate reduction, and 
percentage reduction compared with pretreatment will 
be calculated.  Descriptive statistics will be presented 
for the EQ-5D questionnaire, Haem-A-QoL, plasma AT 
activity, and TG.” 
• 
Due to updates in assessments. 
Schedule of 
assessments 
Table 1 updated to reflect extension of the study beyond 
4 years and deleted following exploratory assessments 
with the update in related footnotes: modified (heparin) 
APTT sampling, plasma clot lysis, whole blood clot 
formation by ROTEM® (where available), and 
exploratory biochemistry sampling. 
Reduced the frequency of routine clinical 
hematology/biochemistry and urinary laboratory 
evaluations (but must be performed if clinically 
indicated), coagulation testing and exploratory 
biomarkers for Years 3 and 4.   
Newly added Table 2 for schedule of assessments for 
the Years 5 and 6. 
• 
Study extension beyond 
48 months. 
• 
There is no longer a consideration 
that some of the routine and 
exploratory assessments would 
yield critical results. Therefor it 
was decided to reduce the study 
burden by deleting these 
assessments. 
• 
The study duration of all patients 
has reached adequate follow-up to 
allow adjustment for visits and 
routine assessments.  Based on 
gathered cumulative safety data 
during the study without any new 
safety concern or any new 
potential risk for fitusiran, the 
Sponsor determined that current 
visits and assessments frequency 
does not contribute additional 
information needed to evaluate 
patient’s safety beyond 2 years.  
This justifies the proposed visits 
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Section # and Name 
Description of Change 
Brief Rationale 
and assessments frequency 
adjustment and will also reduce 
patient burden without 
compromising safety monitoring. 
Table 3 bleeding 
episode assessments – 
unscheduled visit table 
Table number updated from “Table 3” to “Table 4”. 
Deleted exploratory coagulation assessment and related 
footnote. 
• 
Study extension beyond 
48 months. 
• 
There is no longer a consideration 
that some of the assessments 
would yield critical results.  
Therefore, it was decided to 
reduce the study burden by 
deleting these assessments. 
Throughout 
Wherever applicable, added reference of schedule of 
assessments Table 2.   
• 
Study extension beyond 
48 months. 
Section 1.4 
Updated following texts from “This study will allow 
patients to receive treatment with fitusiran for 
approximately 4 years.” to “This study will allow patients 
to receive treatment with fitusiran for approximately 
6 years or until fitusiran becomes commercially 
available, whichever occurs first.” 
• 
Study extension beyond 
48 months. 
Section 3.1  
Updated following texts from “For all fitusiran dosing, 
liver function test (LFT) results are to be obtained within 
7 days prior to dosing and results are to be reviewed 
prior to each dose.  Safety and efficacy assessments 
will be performed at monthly visits and during an End of 
Treatment visit.  Unscheduled visits for study 
assessments may occur if deemed necessary by the 
study personnel.  In addition, patients who complete the 
study or discontinue treatment will continue to have 
safety assessments and AT activity levels monitored at 
monthly intervals following the final fitusiran dose until 
AT activity levels return to approximately 60% (per the 
central laboratory), or per Investigator discretion in 
consultation with the study Medical Monitor.” 
to 
“For up to 2 years, all fitusiran dosing, liver function test 
(LFT) results are to be obtained within 7 days prior to 
dosing and results are to be reviewed prior to each 
dose.  From Year 3 onwards, the frequency of predose 
LFT monitoring may be decreased to quarterly for 
patients who have negative hepatitis C antibody titers 
and meet specific criteria defined in Section 6.5.1.1.  
Safety and efficacy assessments will be performed at 
time points specified in Table 1 and Table 2.  
Unscheduled visits for study assessments may occur if 
deemed necessary by the study personnel.  In addition, 
patients who complete the study or discontinue 
treatment will continue to have safety assessments and 
AT activity levels monitored at time points specified in 
Table 1 and Table 2 following the final fitusiran dose 
• 
Study extension beyond 
48 months. 
• 
There is no longer a consideration 
that some of the assessments 
would yield critical results.  
Therefore, it was decided to 
reduce the study burden by 
deleting these assessments. 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
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Section # and Name 
Description of Change 
Brief Rationale 
until AT activity levels return to approximately 60% (per 
the central laboratory), or per Investigator discretion in 
consultation with the study Medical Monitor (Note: for 
patients who opt for the commercially available fitusiran, 
these follow-up visits to assess AT activity level are not 
required).” 
Section 4.3 
Updated following texts from “When a patient withdraws 
or is withdrawn from the study, an Early Termination 
visit should occur 30 days following the patient’s last 
dose.  Separately, follow-up visits to assess AT activity 
levels should occur at monthly intervals until AT activity 
level returns to approximately 60% (per the central 
laboratory).  For patients who withdraw early, at least 
2 attempts will be made to contact the patient to 
complete an Early Termination visit.” 
to  
“When a patient withdraws or is withdrawn from the 
study, an Early Termination visit should occur 30 days 
following the patient’s last dose.  Separately, follow-up 
visits to assess AT activity levels should occur at 
monthly intervals until AT activity level returns to 
approximately 60% (per the central laboratory) (Note: 
for patients who opt for the commercially available 
fitusiran, these follow-up visits to assess AT activity 
level are not required).  For patients who withdraw early, 
at least 2 attempts will be made to contact the patient to 
complete an Early Termination visit.” 
• 
Study extension beyond 
48 months. 
• 
There is no longer a consideration 
that some of the assessments 
would yield critical results.  
Therefore, it was decided to 
reduce the study burden by 
deleting these assessments. 
 
Section 5.1 
Dosage form updated from “Sterile solution packaged in 
2-mL Type I glass vials” to “Sterile solution packaged in 
2-mL Type I glass vials or prefilled syringes”, and 
related following footnote added “Study drug may be 
provided in prefilled syringes either at the clinic 
(healthcare setting) or in a nonhealth care setting (home 
injection) in a subset of patients receiving 80 mg 
monthly dose of fitusiran.  The patient will be trained on 
prefilled syringe self-administration.  Patients who have 
missed more than 6 consecutive fitusiran dose for any 
reason should utilize the study drug provided as a vial 
and syringe for at least 3 injections prior to utilizing 
prefilled syringe.” 
• 
To allow use of prefilled syringes 
of fitusiran. 
Section 5.3 
Updated following texts from “The bleed management 
plan should be reviewed by the Investigator with the 
patient at each clinic visit (and via telephone contact 
every 2 weeks [±4 days] between clinic visits) and 
updated as necessary.”  to “The bleed management 
plan should be reviewed by the Investigator or designee 
with the patient at each dosing (and via telephone 
contact every 2 weeks [±4 days] between fitusiran 
dosing) and updated as necessary.” 
• 
Clarification due to change in the 
assessments.  
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.1 
Updated following texts from “Fitusiran Solution for 
Injection (SC use) will be supplied as a sterile solution in 
vials.” to “Fitusiran Solution for Injection (SC use) will be 
supplied as a sterile solution in vials or prefilled 
syringes.” 
• 
To allow use of prefilled syringes 
of fitusiran. 
Section 6.2  
Updated following texts from “Study drug labels will 
include all appropriate local labeling requirements on 
the vials and external packaging.” to “Study drug labels 
and external packaging will include all appropriate 
information as per local labeling requirements.” 
• 
Clarification. 
Section 6.4 
Added following text “Patients and/or caregivers may 
also prepare fitusiran doses after receiving proper 
instruction.” 
• 
Clarification. 
Section 6.5 
Updated following texts from “For all fitusiran dosing 
administered at the study center or at home, LFT results 
are to be obtained within 7 days prior to dosing and 
results are to be reviewed prior to each dose.” 
to  
“For up to 2 years, all fitusiran dosing administered at 
the study center or at home, LFT results are to be 
obtained within 7 days prior to dosing and results are to 
be reviewed prior to each dose.  From Year 3 onwards, 
the frequency of predose LFT monitoring may be 
decreased to quarterly for patients who have negative 
hepatitis C antibody titers and meet specific criteria 
defined in Section 6.5.1.1.” 
Added following texts:  
Pre-filled Syringe with Safety System: 
Study drug may be provided in prefilled syringes either 
at the clinic (healthcare setting) or in a nonhealth care 
setting (home injection) in a subset of patients receiving 
80 mg monthly dose of fitusiran.  The patient will be 
trained on prefilled syringe self-administration.  The 
Investigator and/or delegated designee will complete a 
treatment process with the patient and/or patient’s 
caregiver to prepare and administer the injection using 
the pre-filled syringe with safety system for monthly 
injections.  The first injection is given by the Investigator 
and/or delegated designee while teaching patient and/or 
caregiver on how to perform the injection.  The second 
injection is performed by patient or caregiver under the 
supervision of the Investigator and/or delegated 
designee.  Once patient or caregiver has completed the 
required training and the Investigator and/or delegated 
designee approves, patient or caregiver may prepare 
and self-administer the subsequent injection at home.  
Patients who have missed more than 6 consecutive 
• 
Study extension beyond 
48 months. 
• 
There is no longer a consideration 
that some of the assessments 
would yield critical results.  
Therefore, it was decided to 
reduce the study burden by 
deleting these assessments. 
• 
To allow use of prefilled syringes 
of fitusiran. 
 
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Section # and Name 
Description of Change 
Brief Rationale 
fitusiran dose for any reason should utilize the study 
drug provided as a vial and syringe for at least 
3  njections prior to utilizing prefilled syringe. 
Section 6.5.1.1 
Modified first criteria from “LFT results are to be 
obtained…” to “For up to 2 years, LFT results are to be 
obtained…” 
Added following texts in the first criteria: From Year 3 
onwards, the frequency of predose LFT monitoring may 
be decreased to quarterly for patients who have 
negative hepatitis C antibody titers and meet following 
specific criteria: 
a) Did not have any ALT elevation >3× ULN 
persisting for ≥2 months at any time during 
the previous 12 months. 
b) Did not have any fitusiran doses held due to 
LFT elevations during the study. 
• 
Study extension beyond 
48 months. 
• 
There is no longer a consideration 
that some of the assessments 
would yield critical results.  
Therefore, it was decided to 
reduce the study burden by 
deleting these assessments. 
Section 6.7 
Updated following texts from “All used, partially used, 
and unused vials of fitusiran will be…” to “All used, 
partially used, and unused vials or prefilled syringes of 
fitusiran will be…”. 
• 
To allow use of prefilled syringes 
of fitusiran. 
 
Section 8.3, 
Section 9.1.7.1 
Section 9.1.7.4 
Deleted following sentence: On dosing days, blood 
samples will be collected predose. 
• 
Administrative change to clarify 
the process due to study 
extension beyond 48 months. 
Section 8.4 
Section 8.6 
Section 8.7 
Deleted these sections. 
Subsequent section numberings updated accordingly. 
• 
There is no longer a consideration 
that some of the exploratory 
assessments would yield critical 
results.  Therefore, it was decided 
to reduce the study burden by 
deleting these assessments. 
Section 9.1.3 
Deleted following sentence: On dosing days, vital signs 
will be measured predose.   
• 
Administrative change to clarify 
the process due to study 
extension beyond 48 months. 
Section 9.1.7.1 
Table 8 Clinical 
laboratory assessments 
Deleted following exploratory parameters: modified 
(heparin) APTT, plasma clot lysis test, and whole blood 
clot formation by ROTEM® (where available). 
• 
There is no longer a consideration 
that some of the exploratory 
assessments would yield critical 
results.  Therefore, it was decided 
to reduce the study burden by 
deleting these assessments. 
Section 9.2.9 
Updated following texts from  
“All SAEs must be reported regardless of the 
relationship to study drug. 
The initial report should include at least the following 
information: 
• 
Patient’s study number 
• 
Description and date of onset of the event 
• 
Administrative change to clarify 
the process 
 
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Section # and Name 
Description of Change 
Brief Rationale 
• 
Criterion for serious  
• 
Preliminary assignment of causality to study 
drug 
To report the SAE, complete the SAE form.   
Within 24 hours of receipt of follow-up information, the 
Investigator must update the SAE form.  SAE forms 
must be reported using the contact information provided 
below. 
to  
“All SAEs and AESI must be reported regardless of the 
relationship to study drug. 
The initial report of SAEs 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 causality to study 
drug 
To report the SAE or an AESI, complete the SAE/AESI 
form.   
Within 24 hours of receipt of relevant follow-up 
information, the Investigator must update the SAE/AESI 
form.  SAE/AESI forms must be reported using the 
contact information provided below.” 
Section 10.2.5 
Deleted following texts: For exploratory parameters 
including plasma clot lysis, modified [heparin] APTT, 
and whole blood clot formation (ROTEM), descriptive 
statistics will be presented for each scheduled time 
point. 
• 
There is no longer a consideration 
that some of the exploratory 
assessments would yield critical 
results.  Therefore, it was decided 
to reduce the study burden by 
deleting these assessments. 
18.6.7 Amended Protocol 07  
AMENDMENT 07 (25 November 2020) 
This amended protocol (amendment 07) 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  
• The main purpose of this amendment is to introduce a risk mitigation strategy for 
vascular thrombotic events in patients exposed to fitusiran. This strategy aims to decrease 
the level of antithrombin reduction via a change in the fitusiran dosing regimen. A 
Schedule of Assessments was added to accommodate the new dose regimen and to ensure 
optimal monitoring during the transition. 
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• Cholecystitis and symptomatic cholelithiasis are newly identified risks of fitusiran.  As 
such, cholecystitis and cholelithiasis have been added to the protocol as adverse events of 
special interest (AESIs).   
• The amendment also includes the addition of new guidance to facilitate the continuation 
of the study in the event of a regional or national government declared emergency such as 
the COVID-19 pandemic. The guidance provides instruction on how to ensure continued 
dosing, monitor patients and perform assessments remotely when study patients are 
unable to travel to the site. 
• Other minor editorial changes have been made to improve the clarity and readability of 
the protocol. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Synopsis 
The following sentence added “Study 
assessments will be performed as specified in the 
Schedule of Assessments for monthly dosing 
(Table 1, Table 2 and Table 3) or every other 
month dosing (Table 5).  
Fitusiran dosing regimen changed as a risk 
mitigation measure for vascular thrombotic events, 
added to align with the new SOA.  
 
 
Synopsis, Section 
6.5 and 6.5.1.  
The following sentence modified “From Year 3 
onwards, the frequency of predose LFT 
monitoring may be decreased for patients who 
have negative hepatitis C antibody titers and 
meet the following criteria for quarterly predose 
LFT monitoring:” 
To optimize safety monitoring procedures and 
facilitate the process. 
Synopsis 
The following texts added ” After any modification 
to the dosing regimen: a)Did not have any ALT 
elevation >3× ULN persisting for ≥2 months at 
any time during the first 12 months under this 
regimen; b)Must not have had any fitusiran doses 
held during the first 12 months under this 
regimen” 
To optimize safety monitoring procedures and 
facilitate the process. 
Synopsis 
The following sentence added “Fitusiran will be 
administered as a 50 or 80 mg SC injection once 
monthly or every 2 months according to the dose 
selection rules in Section 6.5.1 and the SoAs in 
Table 1, Table 2 and Table 3.” 
Fitusiran dosing regimen changed as a risk 
mitigation measure for vascular thrombotic events, 
added to align with the new SOA.  
 
Synopsis 
Statistical methods updated: “Results will be 
presented in summary tables by starting dose 
level.” changed to “Results will be presented in 
summary tables by starting regimen and then by 
final dose regimen of fitusiran separately for 
patients with and without inhibitors.”. 
To add statistical analysis by final dose 
level/frequency to accommodate the new dose 
regimen, 
List of 
Abbreviations and 
Definitions of 
Terms 
New abbreviations added “Coronavirus 
Disease-19 (COVID-19), every 2 months (Q2M), 
every month (QM), reverse transcription-
polymerase chain reaction (RT-PCR) and sever 
To clarify.  
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Amendment 9_23 Jun 2021 
 
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117 
Section # and 
Name 
Description of Change 
Brief Rationale 
acute respiratory syndrome coronavirus 2 
(SARS-CoV-2)” 
 
“duties and taxes paid” changed to  
“Direct-to-Patient”. 
To correct typo. 
Table 1 
Plasma AT activity to be assessed at M42. 
Fitusiran dosing regimen changed as a risk 
mitigation measure for vascular thrombotic events. 
Table 1  
Plasma TG to be assessed at M42. 
Fitusiran dosing regimen changed as a risk 
mitigation measure for vascular thrombotic events. 
Table 1, Table 2 
Table updated with COVID-19 Testing to be done 
at any time during the study. 
To include the addition of new guidance to facilitate 
the continuation of the study in the event of a 
regional or national government declared 
emergency such as the COVID-19 pandemic. 
Table 1, 
Section 3.1 
Foot note “b” modified “From Year 3 onwards, the 
frequency of predose LFT monitoring may be 
decreased for patients who have negative 
hepatitis C antibody titers and meet specific 
criteria defined in Section 6.5.1.1.” 
To optimize safety monitoring procedures and 
facilitate the process. 
Table 1 
Foot note “d”: “Vital signs will be measured in the 
position after the patient has rested comfortably 
for 10 minutes.” changed to “Vital signs will be 
measured in the seated or supine position after 
the patient has rested comfortably for 
10 minutes.”  
To clarify. 
Table 1 
Foot note “k” added: “When patients reinitiate the 
study at their monthly dose (no dose change) 
they will have their AT, TG, and coagulation 
measured monthly for 6 months.” 
For clarity as the dosing regimen changed. 
Table 2 
Foot note “k” added: “When patients reinitiate the 
study at their 80mg or 50 mg monthly dose (no 
dose change) they will have their AT and TG 
measured monthly for 6 months.” 
For clarity as the dosing regimen changed. 
Table 1, Table 2 
Foot note “t” in Table 1 and “o” in Table 2 added 
respectively: “All study patients that are 
consenting to this procedure are requested to 
undergo testing for SARS-CoV-2 (virus 
responsible for COVID-19), which should include 
both RT-PCR and antibody testing. These tests 
should be performed as early as possible during 
the study. Alternatively, historical test results may 
be provided under certain circumstances as 
defined by Sponsor” 
To clarify COVID-19 test. 
Schedule of 
assessment, 
Table 3 
New table “Modified IMP Regimen Schedule of 
Assessments (Year 1, 2, 3)” added as Table 3. 
Therefore, numerical order of all tables 
throughout document updated accordingly.  
Fitusiran dosing regimen changed as a risk 
mitigation measure for vascular thrombotic events. 
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118 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 6.6 
“duties and taxes paid” changed to  
“Direct-to-Patient”. 
Typo. 
Section 1.1 
“The development of inhibitors is considered the 
most serious complication today and occurs in up 
to 30% of persons with severe hemophilia A, and 
3-5% of persons with severe hemophilia B.[3]  ” 
updated to “ Development of inhibitors to infused 
factor occurs mainly in severe hemophilia, and 
more frequently in hemophilia A (up to 39% of 
patients), than in hemophilia B (1% to 3.5% of 
patients).”. 
Reference updated. 
Section 1.3 
Paragraphs 1 to 3 removed. Added “The 
Investigator must become familiar with all 
sections of the fitusiran Investigator’s Brochure 
which will be provided by the Sponsor before the 
start of the study and during the study, as 
amendments are completed.”. 
Fitusiran dosing regimen changed as a risk 
mitigation measure for vascular thrombotic events. 
Section 1.3.1 
Paragraphs 1 to 3 removed. Added “Phase 1/2 
clinical trials, monthly dosing with fitusiran in 
patients with hemophilia A and B, with or without 
inhibitors resulted in sustained antithrombin 
lowering and improved hemostasis as measured 
by reductions in patients’ annualized bleeding 
rate (ABR)(13)(14)..” 
Refer to the IB for current updates. 
Section 1.3.2 
 
Refer to the IB for current updates. 
Section 1.5 
Dose rationale text updated. 
Fitusiran dosing regimen changed as a risk 
mitigation measure for vascular thrombotic 
events. 
Section 1.6 
Benefit-risk assessment text updated. 
Fitusiran dosing regimen changed as a risk 
mitigation measure for vascular thrombotic 
events. 
Section 3.5 
The following sentence added “Dose adjustment 
criteria are detailed in Section 6.5.1”. 
To align with instructions for AT-driven fitusiran 
regimen modification 
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119 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 3.5 
The following sentence added: “Instructions for 
AT-driven fitusiran regimen modification are 
provided in Section 6.5.1.3.” 
To align with the new fitusiran dosing regimen. 
Section 4.3 
Adapted the section title to from “Withdrawal 
criteria“ to “Discontinuation of the study 
intervention and patient discontinuation 
/withdrawal) 
To address and clarify the criteria for study 
intervention and patient withdrawal, separately.  
Section 4.3.1 
Added “More than 1 AT measurements <15% if at 
a dose of 50 mg Q2M” as bullet points.  
Risk mitigation measure for vascular thrombotic 
events. 
Section 4.4 
New section added. 
To include the addition of new guidance to 
facilitate the continuation of the study in the event 
of a regional or national government declared 
emergency such as the COVID-19 pandemic. 
Section 5.3 
“After initiating therapy with fitusiran, patients 
should call the Investigator prior to…” changed to 
“After initiating therapy with fitusiran, it is 
recommended patients call the Investigator prior 
to…” 
For clarity. 
Section 5.5 
Monitoring and management of thrombotic events 
text updated. 
Risk mitigation measure for vascular thrombotic 
events. 
Section 5.7 
“surgery” rephrased to major surgery” 
For clarity 
Section 6.1 
The following paragraph added “The IMP may be 
supplied at the site or from the PI/site/Sponsor to 
the patient via a Sponsor-approved courier 
company where allowed by local regulations and 
agreed upon by the patient.  
For a regional or national emergency declared by 
a governmental agency that results in travel 
restrictions, confinement, or restricted site 
access, contingency measures are included in 
Appendix 18.6.” 
To include the addition of new guidance to 
facilitate the continuation of the study in the event 
of a regional or national government declared 
emergency such as the COVID-19 pandemic. 
Section 6.4 
The following sentence removed “The study drug 
will be prepared using aseptic technique.” 
Administrative change to facilitate and clarify the 
process. 
Section 6.5 
The following sentence removed “Additional 
details can be found in the study operations 
manual.” 
Study operations manual not applicable for the 
study. 
Section 6.5  
“…in a subset of patients receiving 80 mg 
monthly dose of fitusiran.” changed to “in a 
subset of patients receiving 80 mg SC injection 
once monthly”. 
Fitusiran dosing regimen changed as a risk 
mitigation measure for vascular thrombotic 
events. 
Section 6.5.1.1 
The following paragraph added “Note: negative 
Hep C patients include patients who never met 
HCV, i.e., antibodies are negative, but also those 
with only positive antibodies without any viral load 
detected (i.e., patient has cleared the infection, 
but antibodies still detected as positive). To 
For clarity. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
confirm this eligibility, patients who cleared Hep C 
infection must have documented sustained 
negative virologic load. 
 
2. 
After any modification to the dosing regimen: 
c) 
Did not have any ALT elevation >3× ULN 
persisting for ≥2 months at any time during the 
first 12 months under this regimen 
d) 
Must not have had any fitusiran doses held 
during the first 12 months under this regimen”. 
 
Section 6.5.1.3 
New section added “Antithrombin level criteria for 
a dose adjustment” 
Fitusiran dosing regimen changed as a risk 
mitigation measure for vascular thrombotic 
events. 
Section 6.5.1.4 
New section added “Temporary discontinuation 
due to a regional or national emergency” 
To include the addition of new guidance to 
facilitate the continuation of the study in the event 
of a regional or national government declared 
emergency such as the COVID-19 pandemic. 
Section 7.3 
New section added “Use of biological samples 
and data for future research” 
To include biological sample and data use 
guidance to optimize operative process.  
Section 8.3 
Added following text ”Data and biological 
samples will be stored and used for future 
research when consented to by participants 
(Section 7.3).” 
To clarify operation process and follow guidance.  
Section 8.3 
The following paragraph added “For a regional or 
national emergency declared by a governmental 
agency, contingency measures are included in 
Appendix 18.6.” 
To include the addition of new guidance to 
facilitate the continuation of the study in the event 
of a regional or national government declared 
emergency such as the COVID-19 pandemic. 
Section 9 
The following paragraph added “Safety 
assessments are performed according to the 
Schedule of Assessments (Table 1, Table 2 and 
Table 3). For a regional or national emergency 
declared by a governmental agency, contingency 
measures are included in Appendix 18.6.” 
To include the addition of new guidance to 
facilitate the continuation of the study in the event 
of a regional or national government declared 
emergency such as the COVID-19 pandemic. 
Section 9.2.7 
ASEI: Cholecystitis and Cholelithiasis added. 
To reflect the updates of fitusiran safety profile 
and to optimize the monitoring process. 
Section 9.2.7.1 
The following paragraph added “For all ISRs, the 
Investigator, or delegate, should submit a 
supplemental ISR eCRF, recording additional 
information (e.g., descriptions, onset and 
resolution date, severity, treatment given, event 
outcome). A systemic reaction which includes the 
injection site, e.g., generalized urticaria, other 
distinct entities or conditions like 
lymphadenopathy that may be near the injection 
site, is not considered an ISR.”. 
For clarity. 
Section 9.2.9 
“Country-specific fax numbers will be included in 
the Study Operations Manual.” removed. 
Study operations manual not applicable for the 
study. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 10.2 
 “Results will be presented in summary tables by 
starting dose level.” changed to “Summary tables 
will be presented by starting dose level and final 
dose level/frequency of fitusiran separately for 
patients with and without inhibitors.”. 
To add statistical analysis by final dose 
level/frequency to accommodate the new dose 
regimen, 
Section 11.1 
The following paragraph added: “Monitoring 
details describing strategy methods, 
responsibilities and requirements, including 
handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site 
monitoring) are provided in separate study 
documents.” 
To include proactive monitoring details. 
 
 
Section 11.1 
“…must be retained by the Investigator for 
15 years after study completion” changed to 
“must be retained by the Investigator for 25 years 
after study completion”. 
To align with the updated requirement. 
Section 14 
“The Investigator must permit study-related 
monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct 
access to source data documents.” changed to 
“The Investigator must permit study-related 
monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct 
access to source data documents (including 
remote access, if possible and authorized).”. 
For clarity. 
Section 18.1 
New tables added “ADA timepoints in all patients 
at 50 mg Q2M dose” and “ADA timepoints with 
dose escalation to 50 mg QM or 80 mg QM”. 
Fitusiran dosing regimen changed as a risk 
mitigation measure for vascular thrombotic 
events. ADA timepoints added to accommodate 
the new dosing regimen. 
Section 18.3 
New section added “Data protection”. 
To harmonize the content of protocol template 
updates and clarify operational process 
Section 18.5.6 
New section added “Amended Protocol 06” 
To document protocol amendments history   
Section 18.6 
New section added “Contingency measures for a 
regional or national emergency that is declared 
by a governmental agency”. . 
To clarify contingency measures for a regional or 
national emergency such the COVID-19 
pandemic. 
Throughout 
Minor editorial, typo error corrections and 
document formatting revisions 
Minor, therefore, have not been summarized 
Throughout 
“CRF/eCRF” changed to “eCRF” 
CRF not applicable for the study 
 
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18.6.8 Amended Protocol 08  
Amendment 08 (08 December 2020) 
This amended protocol 08 (amendment 08) 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  
The main purpose of this amendment is to minimize the time between 2 antithrombin (AT) 
measurements if the first AT result is <15%. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Protocol Synopsis 
Tables 1-3 
 
Sentence added to footnotes “k”: Upon the first 
AT activity level <15%, the patients must have 
another AT activity level sample drawn within 
1 week of site receipt of the results. 
 
To mandate a second AT activity level within 
1 week of site receipt of an initial AT level 
result <15%. 
Tables 1 and 2 
Footnote added: This schedule applies for 
patients who continue to receive fitusiran under 
the 50 or 80 mg monthly dose without meeting 
criteria for adjusted dosing. 
To clarify which Schedule of Assessments patients 
should follow if they continue on the fitusiran 80 mg 
or 50 mg monthly dose. 
Table 3 
Foot note “b” added following sentence “Patients 
will follow either the Q2M or QM dosing regimen 
according to the dose adjustment rules; see 
Section 6.5.1.3.” 
Foot note “k” added the following sentence: “ADA 
samples will be collected within 240 minutes 
before dosing according to the schedule in 
Table 15 and Table 16.”  
For clarity. 
Section 1.5 
Updated the following text “If a patient has 
2 steady state AT levels above 35%, the patient 
will be dose escalated to fitusiran 50 mg 
monthly.“ to “If a patient receiving fitusiran 50 mg 
once every 2 months has 2 steady state AT 
levels above 35%, the patient will be dose 
escalated to fitusiran 50 mg monthly. ” 
For clarity. 
Section 6.5.1.3 
Qualifier added to the bullet “after 50 mg Q2M:”: 
Patients who previously had more than 1 AT level 
<15% at the 50 mg QM dose are not eligible to 
re-escalate to this dose level. 
Qualifier added to the bullet “after 50 mg QM:”: 
Patients who previously had more than 1 AT level 
<15% at the 80 mg QM dose are not eligible to 
re-escalate to this dose level. 
To specify and address dose adjustment based on 
AT activity levels.  
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Amendment 9_23 Jun 2021 
 
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123 
Section # and 
Name 
Description of Change 
Brief Rationale 
The following text was inserted prior “Patients 
receiving fitusiran at a dose of 50 mg Q2M with 
more than 1 AT activity measurement <15% at 
any time on this dose during the study must 
permanently discontinue fitusiran.”: At each dose 
level, upon the first AT level <15%, the patient 
must have another AT activity level sample drawn 
within 1 week of site receipt of the result. If this 
result is <15%, this will be considered the second 
AT activity level <15%. 
Section 18.5.7 
New section added “Amended Protocol 07”. 
To document protocol amendments’ history.   
Throughout 
Minor editorial, typo error corrections and 
document formatting revisions. 
Minor, therefore, have not been summarized. 
 
 
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SAP_001.pdf: 
Statistical Analysis Plan LTE14762 
SAR439774 (formerly ALN-AT3SC) (fitusiran) 
Genzyme Corporation 
Confidential 
Page 1 of 41 
STATISTICAL ANALYSIS PLAN 
An open-label extension study of subcutaneously administered fitusiran (formerly 
ALN-AT3SC) in patients with moderate or severe hemophilia A or B who have 
participated in a previous clinical study with fitusiran 
Protocol Number:  
LTE14762 (formerly ALN-AT3SC-002) 
Protocol Version(s) and Date(s): 
Final Protocol: 
02 June 2015  
Amendment 1 
30 November 2015  
Amendment 2 
20 October 2016  
Amendment 3 
13 June 2017  
Amendment 4 
09 November 2017  
Amendment 5 
31 May 2018  
Amendment 6 
05 March 2019  
Amendment 7 
25 November 2020 
Amendment 8 
08 December 2020 
Amendment 9 
23 June 2021 
Name of Test Drug: 
SAR439774 (formerly ALN-AT3SC) (fitusiran) 
Phase:  
Phase 1/2  
Sponsor:  
Genzyme Corporation  
50 Binney Street  
Cambridge, MA 02142, USA 
Analysis Plan Version and Date: 
1: 20 June 2018  
2: 22 November 2019 
3: 16 March 2023 
Confidentiality Statement 
The concepts and information contained in this document or generated during the study are considered 
proprietary and may not be disclosed in whole or in part without expressed written authorization of 
Genzyme Corporation. 
VV-CLIN-0050037 3.0
NCT02554773


Statistical Analysis Plan LTE14762 
 
SAR439774 (formerly ALN-AT3SC) (fitusiran) 
Genzyme Corporation 
 
Confidential 
Page 2 of 41 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
ABBREVIATIONS ........................................................................................................................................... 5 
1 
INTRODUCTION .............................................................................................................................. 6 
2 
STUDY OVERVIEW......................................................................................................................... 7 
2.1 
SYNOPSIS OF STUDY DESIGN ..................................................................................................... 7 
2.2 
RANDOMIZATION METHODOLOGY ............................................................................................. 8 
2.3 
UNBLINDING ................................................................................................................................... 8 
2.4 
STUDY PROCEDURES .................................................................................................................. 8 
2.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL .................................. 8 
2.6 
OTHER MODIFICATIONS MADE TO THE STATISTICAL ANALYSIS PLAN .............................. 14 
2.7 
MODIFICATION MADE IN SAP TO THE STATISTICAL SECTION IN PROTOCOL ................... 15 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 16 
3.1 
OBJECTIVES ................................................................................................................................. 16 
3.1.1 
Primary objective ............................................................................................................................ 16 
3.1.2 
Secondary objectives ..................................................................................................................... 16 
3.1.3 
Exploratory objectives .................................................................................................................... 16 
3.2 
ENDPOINTS .................................................................................................................................. 16 
3.2.1 
Efficacy endpoints .......................................................................................................................... 16 
3.2.2 
Pharmacokinetic endpoints ............................................................................................................ 16 
3.2.3 
Pharmacodynamic endpoints ......................................................................................................... 17 
3.2.4 
Safety variables .............................................................................................................................. 17 
3.2.5 
Antidrug antibody endpoints .......................................................................................................... 17 
4 
PARTICIPANT POPULATION ...................................................................................................... 18 
5 
GENERAL STATISTICAL METHODS .......................................................................................... 20 
5.1 
SAMPLE SIZE JUSTIFICATION .................................................................................................... 20 
5.2 
GENERAL METHODS ................................................................................................................... 20 
5.3 
COMPUTING ENVIRONMENT ..................................................................................................... 22 
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5.4 
TIMING OF ANALYSES ................................................................................................................ 22 
5.5 
BASELINE DEFINITIONS .............................................................................................................. 22 
5.6 
RANDOMIZATION STRATIFICATION FACTORS ........................................................................ 23 
5.7 
MULTIPLE COMPARISONS/MULTIPLICITY ................................................................................ 23 
5.8 
MISSING DATA ............................................................................................................................. 23 
5.9 
PROTOCOL DEVIATIONS ............................................................................................................ 23 
5.10 
DERIVED ANALYSIS VISIT WINDOWS ....................................................................................... 23 
6 
STATISTICAL ANALYSES ........................................................................................................... 26 
6.1 
PARTICIPANT DISPOSITION ....................................................................................................... 26 
6.2 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ........................................................... 26 
6.3 
EFFICACY ..................................................................................................................................... 26 
6.3.1 
Analysis of long-term durability and efficacy .................................................................................. 29 
6.3.1.1 
Annualized bleeding rate ............................................................................................................... 29 
6.3.1.2 
Bleed-free duration......................................................................................................................... 29 
6.3.2 
Quality of life .................................................................................................................................. 30 
6.3.2.1 
EQ-5D-5L ....................................................................................................................................... 30 
6.3.2.2 
Haem-A-Qol ................................................................................................................................... 30 
6.3.3 
Annualized weight-adjusted consumption of BPA and factor ........................................................ 30 
6.4 
PHARMACODYNAMIC ANALYSIS ............................................................................................... 30 
6.4.1 
AT lowering and peak thrombin ..................................................................................................... 31 
6.5 
ANALYSES DURING DOSE INTERRUPTION ............................................................................. 31 
6.6 
ADDITIONAL EXPLORATORY ANALYSES ................................................................................. 32 
6.7 
PHARMACOKINETIC ANALYSIS ................................................................................................. 32 
6.8 
SAFETY ANALYSES ..................................................................................................................... 32 
6.8.1 
Study drug exposure ...................................................................................................................... 33 
6.8.2 
Adverse events .............................................................................................................................. 33 
6.8.3 
Laboratory data .............................................................................................................................. 35 
6.8.4 
Vital signs and physical examination ............................................................................................. 37 
6.8.5 
Electrocardiogram .......................................................................................................................... 37 
6.8.6 
Medical history ............................................................................................................................... 37 
6.8.7 
Concomitant medications ............................................................................................................... 37 
6.8.8 
Bleed management guidelines ....................................................................................................... 38 
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6.9 
ANTIDRUG ANTIBODY ................................................................................................................. 38 
6.10 
PRE-FILLED SYRINGE ................................................................................................................. 38 
6.11 
SUBGROUP ANALYSIS ................................................................................................................ 38 
7 
REFERENCES ............................................................................................................................... 39 
8 
APPENDIX: QUESTIONNAIRE/SCORING................................................................................... 40 
8.1 
HAEM-A-QOL ................................................................................................................................ 40 
8.2 
EUROQOL-5 DIMENSION 5 LEVEL (EQ-5D-5L) SCORE............................................................ 41 
 
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ABBREVIATIONS  
 
Abbreviation  
Definition  
ABR  
annualized bleeding rate  
ADA  
antidrug antibody  
AE  
adverse event  
ALT  
alanine aminotransferase  
AT  
antithrombin  
AUC  
area under the concentration-time curve  
BFD  
bleed-free duration  
BMI  
body mass index  
BPA  
bypassing agents  
CL/F  
apparent clearance  
Cmax  
maximum plasma concentration  
CSR  
clinical study report  
EQ-5D-5L  
Euro Quality of Life- 5 dimensions 5 levels  
FIX  
factor IX  
FVIII  
factor VIII  
GalNAc  
N-acetylgalactosamine  
HGLT 
Higher level group term 
MD  
multiple-dose  
MAD  
multiple-ascending dose  
OLE  
open-label extension  
PK  
pharmacokinetic  
Q1  
first quartile  
Q3  
third quartile  
QoL  
quality of life  
QTcF  
Fridericia’s corrected QT  
SAD  
single-ascending dose  
SAP  
statistical analysis plan  
SEM  
standard error of the mean  
SI  
international system of units  
siRNA  
small interfering ribonucleic acid  
SOC  
system organ class  
t½β  
elimination half-life  
TG  
thrombin generation  
tmax  
time to maximum plasma concentration  
VAS  
visual analogue scale  
V/F  
volume of distribution  
 
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1 
INTRODUCTION  
Hemophilia A and hemophilia B are X-linked recessive inherited bleeding disorders, 
characterized by deficiency of coagulation factor VIII (FVII) or factor IX (FXI), leading to 
a profound defect in thrombin generation with impaired hemostasis and increased risk of bleeding. 
Antithrombin (AT) is a liver-expressed natural anticoagulant that plays a key role in inhibiting 
thrombin. 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 bleeding episodes. Therefore, suppression of AT 
production is being investigated as a potential hemophilia treatment. 
Fitusiran (SAR439774 [formerly Alnylam ALN-AT3SC]) is an investigational agent, comprising 
a synthetic small interfering RNA (siRNA) covalently linked to a triantennary 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. 
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.  
This statistical analysis plan (SAP) provides a comprehensive description of statistical analyses to 
be implemented to assess the clinical safety and efficacy of Study LTE14762(formerly ALN-
AT3SC-002) protocol amendment 9 dated 23 June 2021. The data analyses will be used for the 
clinical study report (CSR).  
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2 
STUDY OVERVIEW  
2.1 
SYNOPSIS OF STUDY DESIGN  
LTE14762 is an open-label extension (OLE) study to evaluate long-term safety, tolerability, and 
efficacy of subcutaneously administered fitusiran in patients with moderate or severe hemophilia 
A or B, with or without inhibitory antibodies to factor VIII or factor IX, who previously tolerated 
dosing in the parent study, TDR14767(formerly ALN-AT3SC-001). The primary objective of this 
study is to evaluate the long-term safety and tolerability of fitusiran, assessed by incidence, 
severity, relatedness, and seriousness of adverse events, and laboratory assessments.  
TDR14767(ALN-AT3SC-001) was a Phase 1 study that evaluated the safety, tolerability, and PK 
of fitusiran in healthy male volunteers and male patients with hemophilia A or B. 
TDR14767(ALN-AT3SC-001) was conducted in 4 parts:  
Part A: a randomized, placebo-controlled, single-blind single-ascending dose (SAD) phase in 
healthy subjects  
Part B: an open-label, multiple-ascending dose (MAD) phase in patients with moderate to severe 
hemophilia A or B without inhibitors  
Part C: an open-label, exploratory multiple dose (MD) phase in patients with moderate to severe 
hemophilia A or B without inhibitors  
Part D, an open-label MD phase in patients with moderate to severe hemophilia A or B with 
inhibitors.  
Study TDR14767(ALN-AT3SC-001) was completed on 20 July 2017 (last patient last visit).  
Patients who received all 3 doses of study drug in TDR14767(ALN-AT3SC-001) and completed 
required study visits in the parent study were eligible for participation in LTE14762. All enrolled 
participants will initially receive a 50 mg or 80 mg dose of fitusiran once monthly.  
A change in the fitusiran dosing regimen(referred as ‘revised dose and regimen’ throughout this 
SAP) has been introduced as a risk mitigation measure for vascular thrombotic events in Protocol 
Amendment 07. As the risk of vascular thrombotic events is thought to be increased in the setting 
of low AT activity levels, a reduced dose of 50 mg administered SC once every 2 months has 
been selected to minimize the occurrence of AT activity levels below 10%. At a reduced dose of 
50 mg every 2 months, if a patient has more than 1 AT level <15%, the patient will be required to 
permanently discontinue fitusiran. Patients previously exposed to fitusiran at a dose of 50 mg 
monthly or 80 mg monthly with no more than 1 AT activity level <15% at any time during 
fitusiran treatment (based on at least 3 months of prior AT measurements) may have the option to 
remain on either dose, respectively. 
If a patient receiving fitusiran 50 mg once every 2 months has 2 steady state AT levels above 
35%, the patient will be dose escalated to fitusiran 50 mg monthly. In very rare cases, if a patient 
still has 2 steady state AT levels above 35% at the 50 mg monthly dose, the patient will escalate to 
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the 80 mg monthly dose. Detailed dosing adjustment plan can be found in Protocol 
Amendment 09 section 6.5.1.3. 
2.2 
RANDOMIZATION METHODOLOGY  
Not applicable.  
2.3 
UNBLINDING  
Not applicable.  
2.4 
STUDY PROCEDURES  
The schedule of assessments is described in the study protocol (Table 1 for Years 1 to 4, Table 2 
for Years 5,6, and 7 and Table 3 for Modified IMP Regimen Schedule of Assessments).  
2.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
This section summarizes major changes to the protocol statistical section. The statistical analysis 
plan history table below gives the timing, rationale, and key details for major changes to the 
protocol statistical section.  
The first patient was enrolled on 08-Oct-2015.  
Table 1 - Protocol amendment statistical changes  
Amendment 
number 
Date approved 
Rationale 
Description of statistical 
changes 
5 
31-May-2018  
“Adverse events of clinical interest” changed 
to “Adverse events of special interest; and 
Systemic injection associated reactions 
(IARs) added to the criteria of adverse 
events of special interest (to align text with 
Sanofi Genzyme environment).  
AESI (instead of AECI) will be listed 
and summarized as per Section 6.8.2 
of this SAP.  
6  
05-Mar-2019  
Deleted following exploratory objectives:  
i) 
To investigate in vitro coagulation 
response to the reduction of AT 
levels. 
ii) 
Modified (heparin) activated partial 
thromboplastin time,  
iii) Plasma clot lysis,  
iv) Whole blood clot formation as 
assessed by ROTEM®,  
v) 
Evaluation of TG in an ex vivo 
assay with factor/BPA-spiked 
samples. 
Deleted these assessments and 
related objectives from Sections 3.1.3 
and 6.6 of the SAP.  
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Amendment 
number 
Date approved 
Rationale 
Description of statistical 
changes 
7 
25-Nov-2020 
To introduce a risk mitigation strategy for 
vascular thrombotic events in patients 
exposed to fitusiran 
To include the addition of new guidance to 
facilitate the continuation of the study in the 
event of a regional or national government 
declared emergency such as the Covid-19 
pandemic. 
Added revised dose and regimen  
Added AESI: Cholecystitis and 
Cholelithiasis 
Allowed COVID19 test for analysis  
 
8 
08-Dec-2020 
To minimize the time between 2 
antithrombin (AT) measurements if the first 
AT result is <15%. 
NA 
9 
23-Jun-2021 
Administrative change 
Added NCT number and updated 
amended protocol version to 9.0 
9 
23-Jun-2021 
To extend the study duration for few patients 
for purposes of collecting sufficient data for 
assessment of efficacy and safety of the 
revised dose and regimen. 
Introduced the following text “Some 
patients will have an extended 
treatment duration by a maximum of 
12 months to ensure all patients will 
have at least an 18-calendar months 
treatment period after recent restart 
with modified SoA and revised 
fitusiran dose and regimen. This will 
not affect the whole study duration 
(last patient last visit is unchanged).” 
9 
23-Jun-2021 
To clarify the COVID-19 test requirement in 
the context of COVID-19 vaccine(s) 
availability and to allow rapid-test when RT-
PCR is not available.  
Updated footnotes of COVID-19 test 
with the following text:” All study 
patients that are consenting to this 
procedure are requested to undergo 
testing for SARS-CoV-2 (virus 
responsible for COVID-19), which 
should include both RT-PCR and 
antibody testing. Note: Rapid test 
may be used if RT-PCR is not 
available. These tests should be 
performed as early as possible during 
the study, except for patients who 
have undergone COVID-19 
vaccination, after which antibody 
testing is no longer required.” 
9 
23-Jun-2021 
To accommodate the extension of study 
duration for few patients following the 
introduction of revised dose and regimen. 
Table title updated to “Schedule of 
Assessments (Years 5, 6 and 7)”; 
introduced new columns (M78, 
M84/EOT) and footnote p for Year 7 
assessments. 
9 
23-Jun-2021 
To correct an omission.  
Added Coagulation assessment in 
EOS/ET visit. 
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Amendment 
number 
Date approved 
Rationale 
Description of statistical 
changes 
9 
23-Jun-2021 
To extend the study duration for few patients 
for purposes of collecting sufficient data for 
assessment of efficacy and safety of the 
revised dose and regimen. 
Footnote “a”: updated the study 
duration in footnote with the following 
text “The duration that the patient 
must continue in the study post 
modified IMP dose/frequency re-start 
depends on the re-start time-point 
relative to the overall study start for 
each individual patient to ensure an 
overall duration of fitusiran 
administration of approximately 
72 months or 18 calendar months 
after restarting dosing post dosing 
pause (whichever is longer). Thus, 
when the patient reaches the latter of 
72 months of study participation or 
18 calendar months post dosing 
restart, the EOT visit should be 
performed, followed by the EOS and 
AT follow-up period.” 
9 
23-Jun-2021 
To align with eCRF.  
Introduced a new row for 
“Hemostatic/Thromboprophylaxis 
Treatment Plan.” 
9 
23-Jun-2021 
For clarity. 
Updated row of “Perioperative 
Questionnaire” to “Hemostatic 
efficacy (Perioperative 
Questionnaire)” and updated 
“Perioperative questionnaire” to 
“Hemostatic efficacy (by using 
perioperative questionnaire” in 
footnotes where applicable.  
9 
23-Jun-2021 
For clarity.  
Added “up to 28 days” following 
“SDay 28” in the column for 
postoperative Visit 3. 
9 
23-Jun-2021 
For clarity and facilitate trial operational 
practice.  
Updated footnote “k” with the 
following text “The date/time of when 
perioperative hemostatic treatment 
and thromboprophylaxis (if 
applicable) coverage was completed 
will be captured. If hemostatic 
treatment and thromboprophylaxis 
are completed at Postoperative Visit 
2, the date/time of completion should 
be recorded, and the Day 28 visit is 
not required.” 
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Amendment 
number 
Date approved 
Rationale 
Description of statistical 
changes 
9 
23-Jun-2021 
To update fitusiran efficacy data. 
Added the following text “Consistent 
with its intended pharmacologic 
effects, fitusiran treatment is 
associated with reductions in AT, 
increases in thrombin generation, and 
reductions in number of bleeding 
episodes.” 
9 
23-Jun-2021 
To align with the fitusiran safety updates. 
9 
23-Jun-2021 
To align with the fitusiran safety updates. 
Removed the text “One death has 
been reported in a participant with 
cerebral venous sinus thrombosis 
(CVST) in ALN-AT3SC-002. In 
response to this event, the bleed 
management guidelines were revised 
in December 2017.” 
9 
23-Jun-2021 
To extend the study duration for few patients 
for purposes of collecting sufficient data for 
assessment of efficacy and safety of the 
revised dose and regimen. 
Introduced the following text “The 
duration may be longer (up to 
7 years) for some patients so that 
they continue fitusiran treatment for 
18 calendar months after introduction 
of the new dose and regimen into the 
study.” 
9 
23-Jun-2021 
For clarity. 
Specified in “Protocol Amendment 07” 
that introduced the fitusiran revised 
dose and regimen. 
9 
23-Jun-2021 
To reflect the fitusiran revised dose and 
regimen.  
Revised the language of patients on 
fitusiran dose “on that dose” to “on 
either dose, respectively.” 
9 
23-Jun-2021 
For clarity. 
Updated 
“pharmacokinetic/pharmacodynamic 
(PK/PD) model” with “population 
pharmacokinetic/pharmacodynamic 
(pop PK/PD) model.”  
9 
23-Jun-2021 
To consider the context of fitusiran on 
pause. 
Updated the text on LFT monitoring 
by including “and provides instruction 
for the potential discontinuation of 
fitusiran.” 
9 
23-Jun-2021 
To clarify that the use of emicizumab 
(Hemlibra®) during the study is prohibited. 
Included the following text “Use of 
emicizumab (Hemlibra®) during the 
study is not permitted.“ 
9 
23-Jun-2021 
To consider the context of fitusiran on 
pause.  
Updated the subtitle with the following 
text: “Bleed management guidelines 
for patients with AT recovery of ≥60% 
prior to re-initiation of fitusiran or 
during a potential fitusiran dose 
pause.” 
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Amendment 
number 
Date approved 
Rationale 
Description of statistical 
changes 
9 
23-Jun-2021 
For clarity regarding the use of factor 
concentrates or BPAs. 
Introduced the following text “During 
the study period, in case fitusiran is 
on pause for any reasons and AT 
activity levels return to approximately 
60% (per the central laboratory), 
patients can initiate regular factor 
concentrates or BPAs for prophylaxis 
therapy to prevent spontaneous 
bleeding episodes, per Investigator 
discretion in consultation with the 
study Medical Monitor.” 
9 
23-Jun-2021 
To provide definition and criteria for alcohol 
restriction advise to patients during the 
study to add clarity on already existing 
criteria for alcohol use at study entry. 
Introduced a new section on alcohol 
restrictions as Section 5.11. 
 
 
To classify AT utilized for AT reversal as 
NIMP. 
Defined antithrombin (AT) utilized for 
AT reversal as NIMPs and clarified 
IMP/NIMP accountability.  
 
 
To adapt to fitusiran new dose and regimen.  
Removal of fitusiran dosing frequency 
of "once every month". 
 
 
For readability and clarity.  
Reworded the language of LFT 
results by central laboratory and listed 
prior to other items: “It is preferable 
that LFT results are to be obtained by 
Central laboratory. If not available, 
local laboratory results may be used; 
however, if a local assessment is 
drawn, a biochemistry sample must 
also be drawn for analysis at the 
central laboratory.” 
 
 
For clarity. 
Modified the text on criteria for 
reduced predose LFT monitoring 
considering the patients on monthly 
dosing schedule following the SoAs 
or modified IMP regimen SoA. 
 
 
For clarity. 
Modified “2 months” to “2 consecutive 
months”, where applicable.  
 
 
For clarity and to accommodate every other 
month (Q2M) dosing regimen. 
Introduced the criteria for reduced 
predose LFT monitoring for patients 
on a every other month dosing 
schedule. 
 
 
To clarify the requirements for restarting 
dosing after the dosing pause. And re-
organized the text for readability. 
Section been updated.  
 
 
To clarify the rule of dosing restart.  
Added a footnote for Fig 1 “Note: 
Restart following dosing pause to 
occur only once centrally measured 
AT activity levels ≥22%.” 
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Amendment 
number 
Date approved 
Rationale 
Description of statistical 
changes 
 
 
For clarity.  
Added a footnote: “See rules and 
exceptions as described above in 
Section 6.5.1.3. “. 
 
 
To allow for source data collection to 
support a better interpretation of biliary-
related events. 
Newly included additional evaluations 
to be performed for participants 
undergoing cholecystectomy.  
 
 
For better interpretation/narrative if 
participant undergo cholecystectomy. 
Added cross reference to 
Section 9.1.7.2 regarding the 
instructions of additional evaluations if 
participants undergoing 
cholecystectomy. 
 
 
For clarity and consider the context of 
fitusiran on pause in the year 2020.  
Included the following text “All the 
analysis sets before and after the 
2020 dose pause will be populated 
separately. Accordingly, the statistical 
analysis will be performed based on 
each analysis set respectively.” 
 
 
For clarity.  
Update the efficacy analysis with the 
following text “Bleed free duration will 
be defined as the maximum time 
intervals between 2 bleeding events 
and will be analyzed descriptively.” 
 
 
For clarity.  
Specified that the interim analysis will 
be describe in the SAP. 
 
 
For clarity. 
In Table 15 and 16, added a footnote 
regarding the ADA sampling timepoint 
on PR Months 24 and 36. 
 
 
For clarity. 
Updated the definition of major dental 
surgery by including “or any tooth 
implantation”. 
 
 
Cosmetic, to follow the updated protocol 
template. 
Upgraded the appendix for 
contingency measures for a regional 
or national emergency as 
Appendix 18.5, which was originally 
listed as Appendix 18.6. Subsequent 
sections have been re-numbered. 
 
 
Administrative change.  
Amendment history of previous 
version (ie, Amended protocol 08) 
was newly inserted in the current 
document Section 18.6 Protocol 
amendment history.  
 
 
To improve flexibility of patients and 
facilitate trial operation practice. 
Added “approximately“ prior to 
“monthly intervals” of safety FU visits 
where applicable.  
 
 
For clarity. 
Added “major” prior to “operative 
procedure” in perioperative 
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assessment or management where 
applicable.   
Amendment 
number 
Date approved 
Rationale 
Description of statistical 
changes 
 
 
To correct the typo.  
Used “EQ-5D-5L” instead of “EQ-5D”, 
“QoL” instead of “QOL”. Abbreviations 
been updated accordingly.  
 
 
Minor, therefore, have not been 
summarized. 
Minor editorial, typo error corrections 
and document formatting revisions. 
2.6 
OTHER MODIFICATIONS MADE TO THE STATISTICAL ANALYSIS PLAN  
This section summarizes other changes to the SAP during this amendment, based on interpretation 
of the Protocol.  
Other SAP amendment changes 
Description of change to SAP 
Reason for revision 
Kaplan-Meier (Time-to-event) analyses deleted from SAP Section 6.5.  
The protocol specifies only that the times between 
successive bleeds be summarized descriptively. 
Replace lab analysis using CTCAE by PCSA. Lab analysis by NCI 
CTCAE grade and shift tables are removed in Section 6.8.3 since PCSA 
analysis will be performed. Vital sign by PCSA is added in 
Section 6.8.4. 
To be aligned with Sanofi’s standard analysis for Lab 
and vital sign. 
Treatment period is defined to be the onset period plus the efficacy 
period. 
The term “treatment period” is defined in Section 6.3 for 
consistency with other Fitusiran studies. 
The ‘treatment policy strategy’ of analyzing the ABR is added to the 
primary analysis. 
Added in Section 6.3.1 for consistency and comparison 
with other Fitusiran studies. 
In the LTE14762) study we will consider untreated bleeds as well as 
treated bleeds in efficacy analyses. 
Modifications made to Section 6.3 to the effect that 
additional analyses will be performed which will include 
all bleeds, both treated and untreated. 
Concomitant medication was removed from safety variables in 
Section 3.2.4. 
Typo corrected.  
‘Patient’ was replaced by ‘participant’ throughout the document except 
for description of study design. 
Align with company standard. 
Analysis sets are defined for participants receiving original dose and 
regimen and participants receiving revised dose and regimen 
separately. Covid unaffected sets and full analysis sets are described in 
Section 4.  
Treatment regimens are different before and after the 
dosing pause in 2020. Analysis sets are refined 
accordingly. Inclusion of covid unaffected sets to 
evaluate the impact of pandemic on the study. 
Inclusion of full analysis sets for efficacy analysis. 
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Description of change to SAP 
Reason for revision 
Description of intercurrent events is updated in Section 6.3.. 
Inclusion of 2020 voluntary dose pause. Update the 
definition of missing 2 consecutive dose for revised 
dose and regimen. 
An additional baseline defined for safety analysis after the 2020 dosing 
pause. 
Given the duration of voluntary dose pause in 2020, an 
additional baseline for selected safety endpoints is 
added to better evaluate the safety profile of revised 
dose and regimen. 
Imputation rule for AE is updated in Section 5.8. 
Align with Sanofi standard. 
Inclusion of analysis window for revised dose and regimen. 
Describe the analysis window for revised dose and 
regimen. 
Specify analysis in general will be performed under original dose and 
regimen and under revised dose and regimen separately in Section 6. 
Describe planned analysis under revised dose and regimen. 
To better evaluate the safety and long-term efficacy of 
revised dose and regimen.  
Describe analysis for dosing interruption periods in Section 6.5. 
To evaluate the AT recovery and bleeding during 
dosing pause in 2017 clinical hold and 2020 voluntary 
dose pause. 
Describe algorithm of identifying cholecystitis and cholelithiasis in 
Section 6.8.2. 
Align with other studies of fitusiran. 
Describe analysis of liver function in Section 6.8.3 
Additional analysis of liver function. 
Description of subgroups to be analyzed in Section 6.11. 
Inclusion of subgroups to be analyzed. Given the 
extended duration of treatment post TDR14767(ALN-
AT3SC-001), the treatment type before parent study 
entry has limited impact on efficacy evaluation. 
Subgroup analysis of treatment type before enrollment 
into TDR14767(ALN-AT3SC-001) will be removed. 
2.7 
MODIFICATION MADE IN SAP TO THE STATISTICAL SECTION IN PROTOCOL  
Description in SAP 
Rationale 
Description in Protocol 
The analysis periods are defined in 
Section 6.3. The start of analysis 
periods is the date of fitusiran with at 
least 20mg since parent study entry. 
Prior exposure on fitusiran in 
TDR14767(ALN-AT3SC-001) may impact 
the efficacy evaluation in LTE14762. The 
analysis will incorporate the parent study 
data and extension study data for a 
comprehensive assessment of efficacy on 
bleeding. 
Annualized bleed rate estimate will be 
calculated as the number of bleed 
events occurring 4 weeks after the first 
dose of fitusiran in this study and until 
the End of Study visit. 
 
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3 OBJECTIVES AND ENDPOINTS  
3.1 
OBJECTIVES  
3.1.1 Primary objective  
To evaluate the long-term safety and tolerability of fitusiran in male patients with moderate or 
severe hemophilia A or B.  
3.1.2 Secondary objectives  
To investigate the long-term efficacy of fitusiran 
To characterize the safety and efficacy of concomitantly administered factor VIII (FVIII), factor 
IX (FIX), or bypassing agents (BPA) and fitusiran for treatment of bleeding episodes  
To assess changes in health-related quality of life (QoL) over time  
To characterize antithrombin (AT) reduction and thrombin generation (TG) increase  
To characterize the pharmacokinetics (PK) of fitusiran. 
3.1.3 Exploratory objectives  
To assess safety and hemostatic efficacy rating for operative procedures conducted in patients 
while on study. 
3.2 
ENDPOINTS  
3.2.1 Efficacy endpoints  
Annualized bleeding rate (ABR) during the efficacy period  
Annualized spontaneous bleeding rate during the efficacy period  
Annualized joint bleeding rate during the efficacy period  
Time intervals between bleeding events  
Annualized weight-adjusted consumption of FVIII, FIX and BPA  
Quality of life (QoL) measured by EuroQol 5-dimension 5-level (EQ-5D-5L) score  
QoL measured by Haem-A-QoL score. 
3.2.2 Pharmacokinetic endpoints  
Plasma PK parameters of ALN-AT3SC  
Urine PK parameters of ALN-AT3SC. 
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3.2.3 Pharmacodynamic endpoints  
AT activity level over time  
TG over time. 
3.2.4 Safety variables  
Adverse events (AE)  
Clinical laboratory parameters  
Vital signs  
12-lead ECGs  
Physical examinations. 
3.2.5 Antidrug antibody endpoints  
Incidence and titer of antidrug antibodies to fitusiran. 
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4 PARTICIPANT POPULATION  
The following populations/analysis sets may be evaluated and used for presentation of the data.  
Safety analysis set 1: All participants who receive at least a partial dose of study drug during the 
LTE14762 study under the original dose and regimen (ie, before the 2020 voluntary dose pause). 
The analysis set will be the main analysis set for analysis under original dose and regimen except 
for efficacy analysis and pharmacodynamics analysis. 
Safety analysis set 2: All participants who receive at least a partial dose of study drug during the 
LTE14762 study under the revised dose and regimen (ie, after the 2020 voluntary dose pause). 
The analysis set will be used in safety analysis under revised dose and regimen. The analysis set 
will be the main analysis set for analysis under revised dose and regimen except for efficacy 
analysis and pharmacodynamics analysis. 
Full analysis set 1: All participants in safety analysis set 1. The analysis set will be used in 
efficacy analysis and pharmacodynamics analysis under original dose and regimen. 
Full analysis set 2: All participants in safety analysis set 2. The analysis set will be used in 
efficacy analysis and pharmacodynamics analysis under revised dose and regimen. 
Per protocol set 1: All participants in the safety analysis set 1 who have no major protocol 
violations under the original dose and regimen in the following categories 
• 
Failure to meet key eligibility criteria, which will be identified prior to database lock 
• 
Prophylactic use of factor treatment or BPA (except for prophylaxis of bleeding in patients 
who require procedures or surgeries) 
The protocol violation will be manually reviewed and adjudicated prior to database lock. 
Per protocol set 2: All participants in the safety analysis set 2 who have no major protocol 
violations under the revised dose and regimen in the following categories 
• 
Failure to meet key eligibility criteria, which will be identified prior to database lock 
• 
Prophylactic use of factor treatment or BPA(except for prophylaxis of bleeding in patients 
who require procedures or surgeries) 
The protocol violation will be manually reviewed and adjudicated prior to database lock. 
PK analysis set 1: All participants who receive at least one dose of study drug and have at least 
1 blood sample collection post-dose to determine plasma concentrations of study drug during the 
LTE14762 study under the original dose and regimen (ie, before the 2020 voluntary dose pause).  
PK analysis set 2: All participants who receive at least one dose of study drug and have at least 
1 blood sample collection post-dose to determine plasma concentrations of study drug during the 
LTE14762 study under the revised dose and regimen (ie, after the 2020 voluntary dose pause). 
PD analysis set 1: All participants who receive at least one partial dose of study drug and have at 
least 1 blood sample collection post-dose to determine plasma AT and TG levels during the 
LTE14762 study under the original dose and regimen (ie, before the 2020 voluntary dose pause).  
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PD analysis set 2: All participants who receive at least one partial dose of study drug and have at 
least 1 blood sample collection post dose to determine plasma AT and TG levels during the 
LTE14762 study under the revised dose and regimen (ie, after the 2020 voluntary dose pause). 
Operative procedure analysis set 1: All participants who received at least one partial dose of study 
drug and underwent at least 1 operative procedure during the LTE14762 study under the original 
dose and regimen (ie, before the 2020 voluntary dose pause). 
Operative procedure analysis set 2: All participants who received at least one partial dose of study 
drug and underwent at least 1 operative procedure during the LTE14762 study under the revised 
dose and regimen (ie, after the 2020 voluntary dose pause). 
Covid-19 unaffected set 1: All participants who have no major or critical protocol deviations due 
to Covid-19 during the study period under the original dose and regimen (ie, before the 
2020 voluntary dose pause).  
Covid-19 unaffected set 2: All participants who have no major or critical protocol deviations due 
to Covid-19 during the study period under the revised dose and regimen (ie, after the 
2020 voluntary dose pause).  
The Safety Analysis Set 1 and Safety Analysis Set 2 will be the primary sets for safety 
assessments, and for analyses of the efficacy and durability of fitusiran treatment. The PK 
Analysis Set 1 and PK Analysis Set 2 will be used for PK analysis and the PD Analysis Set 1 and 
PD Analysis Set 2 will be used for PD analyses. The PP Analysis set 1 and PP Analysis set 2 will 
also be used to assess the long-term efficacy of fitusiran treatment. The Operative procedure 
analysis set 1 and Operative procedure analysis set 2 will be used to assess safety and hemostatic 
efficacy in participants undergoing operative procedures while on study. 
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5 
GENERAL STATISTICAL METHODS  
5.1 
SAMPLE SIZE JUSTIFICATION  
Sample size was based on the number of participants who enrolled in the parent study and 
subsequently received doses of fitusiran while enrolled in the LTE14762 study, and not on 
statistical considerations.  
5.2 
GENERAL METHODS  
Both efficacy and safety analysis under the original and revised dose regimens will be analyzed 
separately, unless otherwise specified. The data collected during the 2020 voluntary dose pause 
will be analyzed along with the pre-pause data.  
A significant dose is defined as any single dose of fitusiran that is greater than or equal to 20 mg. 
Before the voluntary dose pause, the analysis period for efficacy endpoints starts from the date of 
first significant dose up to the earlier of 2020 voluntary dose pause date or the last day of study 
follow-up. For safety endpoints, the analysis will be performed based on LTE14762 study period 
data only up until the dose restart date. Date of first significant dose in the TDR14767(ALN-
AT3SC-001) and LTE14762 study/studies will be designated as Treatment Day 1; there will be no 
Treatment Day 0. Participants who receive doses (either weight-dependent or weight-
independent) of at least 20 mg but less than 75 mg will be “classified” as “50 mg” participants, 
while participants receiving doses of greater than or equal to 75 mg will be “classified” as 
“80 mg” participants (except PK analysis in which actual dose on Day of PK sample collection 
will be used). However, for purposes of efficacy and safety analyses and summaries in the final 
CSR report for the LTE14762 study, the classification of each participant under the original dose 
and regimen will be according to the fixed dose to which they are eventually taken by the end of 
the LTE14762 study original dose period. For example, participants who received a 50 mg dose in 
TDR14767(ALN-AT3SC-001) or LTE14762 and then were switched to 80 mg dose at some point 
in time during the LTE14762 study, are classified in the LTE14762 study as “80 mg” participants 
(except for PK analyses). Treatment after the volunteer dose pause will be treated as each 
participant’s treatment sequence. 
Treatment Days under the original dose and regimen will be calculated as evaluation date – first 
significant dose date +1 and pre-treatment days will be calculated as evaluation date – first 
significant dose date. (The pre-treatment day formula applies when evaluation date < first 
significant dose date; ie, for example, there will be pre-treatment Days … -3, -2, -1, then 
treatment Day 1, 2, 3, 4, …; there is no “pre-Treatment Day 0” nor is there any “Treatment 
Day 0”). 
We also define Study Days in the LTE14762 study as the number of days from first significant 
dose in LTE14762 and calculate similarly as the Treatment Days. For participants who received 
first significant dose in LTE14762, the Study Days is the same as the Treatment Days.  
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For participants under the revised dose and regimen, both efficacy and safety data will be 
analyzed from the dose re-start Day 1 up until the last day of study follow-up.  
Treatment day after the dose re-start will be calculated as evaluation date – first dose date after 
dose re-start + 1 (days). It should be not applicable for assessments before the dose re-start.  A 
summary of study periods and start day in analysis is outlined in Figure 1 
Figure 1 Study periods and analysis start day summary  
 
 
 
Original dose and 
regimen 
2017 clinical hold/2020 
voluntary dose pause 
Revised dose and 
regimen 
Efficacy analysis 
Starts from first 
significant dose of 
fitusiran in 
TDR14767(ALN-
AT3SC-001) or 
LTE14762 and in terms 
of treatment days.  
Starts from the 29th 
days after last dose date 
before the hold/pause 
Starts from first dose 
date of revised dose 
and regimen and in 
terms of treatment 
days 
Safety analysis 
Starts from first 
significant dose of 
fitusiran in LTE14762 
and in terms of study 
days 
Starts from the day after 
last dose date before the 
hold/pause and in terms 
of study days 
Starts from first dose 
date of revised dose 
and regimen and in 
terms of study days 
Summary statistics will be reported by analysis visits defined in Section 5.10 below. Unless 
otherwise noted, tables under both the original and revised dose regimens will be presented by 
hemophilia type, inhibitor type and overall. Participants who received a significant dose in 
TDR14767(ALN-AT3SC-001) will be considered as a subgroup in the analysis under the original 
dose and regimen. Details will be specified in the Section 6.11. 
Categorical data summary will include the number and percentage of participants within each 
category, with a category for missing data. Continuous data summary will include descriptive 
statistics - the number of participants, mean, median, standard deviation (SD), first quartile (Q1), 
third quartile (Q3), minimum, and maximum. The precision of the measurement for each 
continuous variable will be used to determine the number of decimal places to present in tables, 
figures and derived listings. Minimum and maximum values will be reported with the same 
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precision as the units of measure. The other statistics will be reported with 1 greater decimal 
place. Any values that require transformation to standard units (metric or SI) will be converted 
with the appropriate corresponding precision. 
To be consistent with the compound level wording, ‘revised dose and regimen’ will be shown as 
‘recommended dose and regimen’ in the statistical output. 
5.3 
COMPUTING ENVIRONMENT  
All statistical analyses will be performed using SAS statistical software Version 9.4 (or later), 
unless otherwise noted.  
5.4 
TIMING OF ANALYSES  
Data will be analyzed as needed; the final analyses will be conducted after the last participant 
completes the last study assessment or withdraws from the study.  
5.5 
BASELINE DEFINITIONS  
Baseline demographics and disease characteristics will be the baseline from both the parent study 
TDR14767(ALN-AT3SC-001) and study LTE14762. The following disease characteristics will be 
taken from the parent study: 
• hemophilia type 
• time since diagnosis 
• biological phenotype  
• prior treatment type  
• historical ABR  
• hepatitis C status 
• historical ABR  
• historical hemophilia clinic visit 6 months prior to parent study entry 
Baseline assessment for by-visit analyses is defined as the last non-missing value on or before 
first significant Treatment Day and/or LTE14762 Study Day (ie, baseline on or before the first 
significant treatment day will be considered for all efficacy endpoints while baseline on or before 
the first LTE14762 study day will be considered for all safety endpoints). These baselines will be 
considered in analyses under both original and revised dose and regimen as main analysis.  
An additional baseline under the revised dose and regimen is defined as the non-missing 
assessment on or prior to the revised dose re-start date regardless of dose regimen. It is applicable 
only for participant who consented to the protocol amendment 8. This baseline will be analyzed in 
selected safety endpoints under the revised dose and regimen. Detailed information will be 
specified in Section 6.8.  
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5.6 
RANDOMIZATION STRATIFICATION FACTORS  
Not applicable.  
5.7 
MULTIPLE COMPARISONS/MULTIPLICITY  
Not applicable.  
5.8 
MISSING DATA  
Data will be analyzed as observed. No imputation for missing data will be performed, except in 
the case of missing questionnaire data and adverse event data. Missing questionnaire data will be 
handled according to universally accepted standards. If the assessment of the relationship to 
fitusiran is missing for an AE, this AE will be assumed as related to fitusiran. If the severity is 
missing for one of the treatment-emergent occurrences of an AE, the severity will be imputed with 
the maximal severity of the other occurrences. If the severity is missing for all the occurrences, 
the severity will be left as missing. 
5.9 
PROTOCOL DEVIATIONS  
Major protocol deviations will be identified before final analysis.  
5.10 
DERIVED ANALYSIS VISIT WINDOWS  
For LTE14762 by-visit analyses under the original dose and regimen such as lab and vital sign 
parameters, it is expected that all 002 study visits will occur according to the protocol schedule of 
assessments. Analysis visits will be assigned based on LTE14762 evaluation visits as recorded on 
the CRF even if the assessment is outside of the window for that study visit.  
For TDR14767(ALN-AT3SC-001)/ LTE14762 combined by-visit analyses under the original 
dose and regimen such as PD and QoL endpoints, analysis visits will be defined as follows.  
For participants whose first “significant” dose of fitusiran was administered in TDR14767(ALN-
AT3SC-001) (eg, this could only occur in the MD cohort [Part C and Part D]; other cohorts are 
administered relatively small doses of fitusiran),  
a) Analysis visits for all TDR14767(ALN-AT3SC-001) assessments will be first assigned 
based on TDR14767(ALN-AT3SC-001) evaluation visit as recorded on the CRF and 
will be adjusted, if necessary, so that the window of the TDR14767(ALN-AT3SC-001) 
assessment overlaps as much as possible with the LTE14762 scheduling. 
b) Analysis visits will be derived for the LTE14762 Day 1 assessment based on the 
Treatment Days and will be assigned for subsequent visits based on LTE14762 
evaluation visit as recorded on the CRF. For example, Haem-A-Qol is assessed 
quarterly in the 1st two years and then yearly after in LTE14762. If the Treatment Days 
for Day 1 visit is within 18 months +/-1.5 month, then analysis visit for Day 1 visit 
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will be derived as Month 18, and the subsequent analysis visits will be assigned 
quarterly or yearly after Month 18 accordingly.  
For participants whose first “significant” dose of fitusiran was administered in LTE14762, 
Analysis visits under the original dose and regimen will be assigned based on LTE14762 
evaluation visit as recorded on the CRF.  
For LTE14762 by-visit analyses under the revised dose and regimen, analysis visits for scheduled 
visits will be defined based on CRF reported VISIT, even if the assessment is outside of the 
window for that study visit.  
• For participant who had dose reduction after the dose pause, the analysis visit will be 
assigned based on the CRF reported PR VISIT (PRxx) as following example for the first 
18 months after dose pause for the revised dose regimen scenarios. For unscheduled visit, 
the analysis visit will be populated based on treatment day after dose re-start (ie, Date of 
PR Day 1). The analysis visit window will be derived as the middle-point of the target day 
between the 2 consecutive scheduled visits for each of the assessment. The target day is 
calculated as 28 days of visit interval times corresponding scheduled months plus 1. The 
treatment day after the volunteer dose pause is defined in Section 5.2 
Table 2 – Analysis visit schedule after the 2020 dose pause  
CRF reported VISIT 
Analysis visit 
Target day 
Binning algorithm 
No dose escalation 
after pause 
Dose escalated to 
50QM 
Lower bound 
Upper bound 
50Q2M Day1 
50Q2M Day1 
PR Day 1 
1 
1 
1 
50Q2M PRM1 
50Q2M PRM1 
PR Month 1 
29 
2 
42 
50Q2M PRM2 
50Q2M PRM2 
PR Month 2 
57 
43 
70 
50Q2M PRM3 
50Q2M PRM3 
PR Month 3 
85 
71 
98 
50Q2M PRM4 
50Q2M PRM4 
PR Month 4 
113 
99 
126 
50Q2M PRM5 
50Q2M PRM5 
PR Month 5 
141 
127 
154 
50Q2M PRM6 
50Q2M PRM6 
PR Month 6 
169 
155 
182 
50Q2M PRM7 
50QM PRM1 
PR Month 7 
197 
183 
210 
50Q2M PRM8 
50QM PRM2 
PR Month 8 
225 
211 
238 
50Q2M PRM9 
50QM PRM3 
PR Month 9 
253 
239 
266 
50Q2M PRM10 
50QM PRM4 
PR Month 10 
281 
267 
294 
50Q2M PRM11 
50QM PRM5 
PR Month 11 
309 
295 
322 
50Q2M PRM12 
50QM PRM6 
PR Month 12 
337 
323 
350 
50Q2M PRM13 
50QM PRM7 
PR Month 13 
365 
351 
378 
50Q2M PRM14 
50QM PRM8 
PR Month 14 
393 
379 
406 
50Q2M PRM15 
50QM PRM9 
PR Month 15 
421 
407 
434 
50Q2M PRM16 
50QM PRM10 
PR Month 16 
449 
435 
462 
50Q2M PRM17 
50QM PRM11 
PR Month 17 
477 
463 
490 
50Q2M PRM18 
50QM PRM12 
PR Month 18 
505 
491 
518 
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• For participant who remain the original dose regimen after the dose pause, the analysis 
visit will be derived based on original visit schedule (ie, Month xx), which will be reported 
following the original visit scheme. The first dose date after the dose pause will be 
assigned as Day1. The subsequent visits can be assigned based on the first visit 
accordingly. For example, the first visit after dose re-start is reported as “Month 36”, then 
the next visit is reported as “Month 37”. The Month 36 visit should be assigned as “PR 
Day 1” and the Month 37 should be assigned as “PR Month 1”. For unscheduled visit, the 
analysis visit will be populated based on treatment day after dose re-start. The analysis 
visit window will be derived as the middle-point of the target day between the 
2 consecutive scheduled visits for each of the assessment. The target day is calculated as 
30 days of visit interval times corresponding scheduled months plus 1. The treatment day 
after the volunteer dose pause is defined in Section 5.2. 
 
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6 
STATISTICAL ANALYSES  
6.1 
PARTICIPANT DISPOSITION  
Participant disposition (all participants) will be summarized before and after the 2020 voluntary 
dose pause separately including participants enrolled, participants in each analysis population/set, 
participants who completed the study, participants who discontinue study drug with primary 
reasons for study drug discontinuation, participants who withdraw prior to completing the study 
with primary reason for withdrawal, and period of clinical hold or voluntary dose pause for each 
participant.   
6.2 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS  
Demographics and baseline disease characteristics will be summarized for the safety analysis set 1 
and safety analysis set 2. Demographics will include age, age group, gender, race, ethnicity, 
height, weight, body mass index (BMI), and region. Baseline hemophilia disease characteristics 
will be reported from parent study TDR14767(ALN-AT3SC-001) and will include hemophilia 
type, biological phenotype, historical ABR based on 6-month bleed history prior to parent study 
entry and historical number of hemophilia clinic visits.  
6.3 
EFFICACY  
Bleeding event definitions  
A bleeding episode is defined as any occurrence of hemorrhage that may require administration of 
BPA infusion or factor concentrates. Bleeding episodes sustained during sports and recreation will 
be counted as traumatic bleeding episodes. 
Bleeding or any symptoms of bleeding at the same location that occur within 72 hours of the last 
injection used to treat a bleed or 72 hours after an untreated bleed at that location will be 
considered a part of the original bleeding event and will count as one bleeding episode. Any 
bleeding symptoms that begin more than 72 hours from the last injection used to treat a bleed or 
72 hours after an untreated bleed at that location will constitute a new bleeding event.  
The following definitions of bleeding event types, based on consensus opinion of International 
Society on Thrombosis and Haemostasis (ISTH), will apply:  
Traumatic bleed: caused by a known injury or trauma, including sports and recreation  
Spontaneous bleed: that occurs for no apparent or known reason  
Joint bleed: an unusual sensation in the joint (“aura”) in combination with either of  
- 
increasing swelling/warmth on the skin over the joint  
- 
increasing pain  
- 
progressive loss of range of motion  
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- 
progressive difficulty in using the limb. 
Muscle bleed: 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 events occur within 
a consecutive 6-month period has occurred; if ≤2 bleeding events occur in a joint within a 
consecutive 12-month period the joint will be excluded from target joint.  
Traumatic bleeds that occur in different locations simultaneously (same date/time) in the same 
participant will be considered as one bleeding episode. Spontaneous bleeds that occur 
simultaneously (same date/time) in different locations in the same participant will be considered 
as separate bleeds.  
Efficacy analysis will focus on observed data as collected, unless otherwise specified. Only 
bleeding episodes that are treated with BPA/factor will be include in the primary analysis of 
endpoints evaluating bleeding; however additional analyses will be performed which will include 
all bleeds, both treated and untreated. 
Definition of analysis period  
The analysis periods will be defined separately before and after the volunteer dose pause.  
The original dose and regimen: 
• Onset period: The onset period is defined as the period of time consisting of the first 
28 days: Treatment Day 1 to Treatment Day 28 (of TDR14767(ALN-AT3SC-001) and 
LTE14762) (see above - definition of “Treatment Day”); this is the period of time during 
which the AT lowering capacity of fitusiran is increasing but has not yet reached 
therapeutic levels. 
• Efficacy period 1: The efficacy period 1 is defined as Treatment Day 29 to earlier of End 
of study date before the dose pause or the last fitusiran administration date before the dose 
pause + 28 days, whichever comes first. 
• Treatment period 1: The treatment period 1 is defined to be the onset period plus the 
efficacy period 1. 
The revised dose and regimen: 
• Dose adjustment period: The dose adjustment period is defined as the dose re-start Day 1 
to the earlier of dose re-start Day 168 or the end of study. 
• Efficacy period 2: The efficacy period 2 is defined as the dose re-start Day 169 to the end 
of study visit 
• Treatment period 2: The treatment period 2 is defined to be the dose adjustment period 
plus the efficacy period 2. 
 
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All the analysis periods will exclude the period of following intercurrent events to avoid 
confounding of treatment effect for the primary efficacy analysis based on On-Treatment 
Strategy:  
Intercurrent events: 
I. “Dose interruption periods”: 
a. Gap between TDR14767(ALN-AT3SC-001)/ LTE14762 study >28 days and skips at 
least two doses in the gap: Exclude events occurring on dates starting from the date of 
the last dose in 001 +29 days to the date of first dose in LTE14762 +28 days and gap 
duration >84 days. 
b. Clinical hold/dose pause period during LTE14762 study: Exclude events occurring on 
dates starting from the date of the last dose before dose interruption +29 days to the 
date of dose resumption +28 days and on-hold duration > 84 days. 
- 
Dose hold in 2017: The last dose before dose interruption is defined as the last 
fitusiran administration before 2017
. The first dose after dose resumption is 
defined as the first fitusiran administration after 2017
.  
- 
Voluntary dose pause in 2020: The last dose before dose interruption is defined as 
the last fitusiran administration before 2020
. The first dose after dose 
resumption is defined as the first fitusiran administration after 2021
. 
c. Missing two consecutive doses in LTE14762 (eg, a participant skips at least two 
consecutive scheduled doses): If participant under Q2M regimen before the dose 
interruption, then exclude events occurring on dates starting from the date of the last 
dose before the dose interruption + 57 days to the date of the dose resumption 
+ 56 days. If participant under QM regimen before the dose interruption, then excluded 
events from the date of the last dose before the dose interruption + 29 days to the date 
of the dose resumption + 28 days. The missing two consecutive doses will be 
considered separately before and after the dose pause in 2020.  
d. Fitusiran treatment discontinuation in LTE14762: Exclude events occurring on any 
dates starting from the date of the last dose +29 days if the last dose regimen is QM 
(ie, until the end of the study.) If the last dose regimen is Q2M, then the start date of 
this intercurrent event should be last dose + 57 days. 
II. Perioperative period of major surgery and major trauma is defined as the day of the 
surgery or trauma through the final day on which supplemental hemostatic or 
antithrombotic treatments are administered as part of the perioperative treatment plan.  
III. Perioperative period of minor surgery is defined as the perioperative period of surgery as 
defined for major surgery (see above) or to 72 hours from the end of surgery, whichever is 
later.  
IV. Period of antithrombin treatment defined as the first day of antithrombin treatment through 
the final day on which antithrombin or other anticoagulant therapies are administered 
+5 half-lives. 
V. After treatment with emicizumab. 
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6.3.1 Analysis of long-term durability and efficacy  
6.3.1.1 Annualized bleeding rate  
The ABR efficacy analysis will include all bleeding events occurring in the efficacy period. The 
ABR will be annualized for each participant using the following formula:  
 
The primary efficacy analysis will consist of the ABR results based on the “on-treatment strategy” 
during the efficacy period (efficacy period as strictly defined in Section 6.3 above, excluding the 
periods of intercurrent events). The “on-treatment strategy” analysis will also be performed for the 
onset period and the treatment period. The “treatment policy strategy” analysis, will be performed 
for the treatment period only, and will consist of the ABR calculations applied to all (treated) 
bleeds (even including surgery periods), taking place during the analysis period of interest only 
excluding the gap between TDR14767(ALN-AT3SC-001) and LTE14762 where the bleeds were 
not collected. ABR will be estimated (with 95% CI) using a negative binomial model adjusted by 
TDR14767(ALN-AT3SC-001) study baseline ABR.  No imputations of missing data will be 
performed in the ABR analyses. The ABR analysis under the original dose and regimen will be 
performed for the entire efficacy period 1 and also for the treatment period 1 and onset period (for 
the “on-treatment strategy”), as well as by year for the treatment period 1 (both on-treatment and 
treatment policy strategies) in order to demonstrate the durability of the prophylactic maintenance. 
Model based ABR will be provided when there are at least 3 participants in the group and model 
converges for by-year analysis. Also, additional analyses will be performed including all bleeds, 
both “treated” and “untreated”. 
ABR under the revised dose and regimen after the dose pause for treated bleeding events and all 
bleeding events during the dose adjustment period, efficacy period 2 and treatment period 2 based 
on on-treatment strategy will be analyzed respectively. ABR for treated bleeding events during the 
treatment period 2 will also be summarized based on on-treatment strategy every 6 months. 
Similar ABR analysis during treatment period 2 based on treatment policy (ignoring all 
intercurrent events) will be performed as well.  
The ABR primary analyses described above will be performed again on the PP population to 
support long-term efficacy of fitusiran and robustness of result. If per-protocol population is the 
same set of participants as the safety population, then analysis based on safety population will be 
provided only.   
6.3.1.2 Bleed-free duration  
Bleed-free duration (BFD) for each participant will be calculated as the time interval between 
2 protocol-defined treated bleeding events, excluding bleeding events that occur during the 
intercurrent periods during both of the efficacy periods based on on-treatment strategy 
respectively. If participant don’t have any bleeding event in each of the efficacy period, the 
overall duration of the corresponding efficacy period will be the bleed-free duration. ABR and 
maximum BFD (after 1st significant dose) will be summarized descriptively. A similar calculation 
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of bleed-free duration considering all bleeding events will be performed for clinical hold or 
voluntary dose pause analysis described in Section 6.5.  
6.3.2 Quality of life  
Descriptive summary for QoL questionnaires will be provided before and after the 2020 voluntary 
dose pause respectively. 
6.3.2.1 EQ-5D-5L  
The EQ-5D-5L is a standardized instrument for use as a measure of QoL outcome. Index values 
and visual analogue scale (VAS) scores and their changes from Treatment baseline to each 
post-baseline visit will be summarized descriptively. Numbers and percentages of participant by 
level and dichotomized level (1 = “no problems”, 2 to 5 = “some problems”) of each dimension 
will be reported.  
6.3.2.2 Haem-A-Qol  
The Haem-A-QoL 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. Total score, domain scores, standardized scale scores, and transformed scale scores 
and their changes from treatment baseline to each post-baseline visit will be summarized 
descriptively.  
6.3.3 Annualized weight-adjusted consumption of BPA and factor  
Weight-adjusted factor/BPA usage will be calculated programmatically. Number of factor or BPA 
injections per bleed, weight adjusted total dose per injection and total dose per bleed will be 
summarized descriptively. Additional summary will be provided by bleed location, causality and 
severity. 
6.4 
PHARMACODYNAMIC ANALYSIS  
Pharmacodynamic analyses before the dose pause will be conducted using the PD analysis set 1. 
AT activity, AT lowering (% reduction from Treatment baseline) and peak thrombin values will 
be summarized at each post-baseline visit descriptively. The baseline under the original dose and 
regimen will be the last non-missing assessment before the first significant dose. Only evaluable 
PD result will be included in the analysis. The criteria listed in the Table 3.  
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Table 3 - PD assessment evaluable criteria  
 
Criteria description 
AT 
TG 
Criteria 1 
Assessments collected during any of the dose interruption perioda will be excluded. 
X 
X 
Criteria 2 
Assessments collected during the antithrombin treatmentb period or within 5 half-lives after the 
antithrombin treatment administration will be excluded. 
X 
X 
Criteria 3 
Assessments collected within 48 hours of factor, BPA or antifibrinolytic administration will be excluded. 
 
X 
Criteria 4 
Assessment collected at one visit without AUC assessment available on the same visit will be excluded. 
 
X 
a Refers to section 6.3  intercurrent event definition. 
b The antithrombin treatment includes Heparin, Antithrombin Concentrate and Factor Xa inhibitors. All the other antithrombin treatment will be 
adjudicated by Sanofi medical team. 
Similar pharmacodynamic analyses after the 2020 voluntary dose pause will be performed based 
on the PD analysis set 2 by treatment sequence specified in Section 5.2. 
6.4.1 AT lowering and peak thrombin  
Correlation between AT (actual AT activity and AT lowering) and peak TG will be computed on 
paired assessments, where both parameters are measured on the same day. Log transformation 
may be used.  
6.5 
ANALYSES DURING DOSE INTERRUPTION  
For participants who had clinical hold in 2017, the following exploratory analyses will be 
performed:  
Rate of AT recovery since last dose before interruption will be summarized descriptively. AT 
activity over time since last dose before interruption will plotted.  
AT activity and peak TG over time since last dose before interruption will be plotted.  
ABR before, during and after the interruption period will be summarized descriptively. Similarly, 
maximum bleed free duration for treated bleeding events before and after interruption period will 
be summarized descriptively. ABR and maximum bleed free duration before and after the 
interruption period will be analyzed based on efficacy period and on-treatment strategy 
considering all intercurrent events. Bleeding events during the first 29 days after dose resumption 
will not be considered based on on-treatment strategy for participants whose 2017 dose hold 
period >84 days as outlined in Section 6.3. ABR during the interruption period will consider 
intercurrent events II – V based on on-treatment strategy. The interruption period will start from 
29 days after last dose before interruption till the day before first dose at resumption of treatment.  
ABR before, during and after the interruption period will be summarized descriptively. Similarly, 
maximum bleed free duration for all bleeding events before and after interruption period will be 
summarized descriptively. ABR and maximum bleed free duration before and after the 
interruption period will be analyzed based on efficacy period and on-treatment strategy 
considering all intercurrent events. Bleeding events during the first 29 days after dose resumption 
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will not be considered based on on-treatment strategy for participants whose 2017 dose hold 
period >84 days as outlined in Section 6.3. ABR during the interruption period will consider 
intercurrent events II – V based on on-treatment strategy. The interruption period will start from 
29 days after last dose before interruption till the day before first dose at resumption of treatment. 
For participant who had voluntary dose pause interruption in 2020, similar analysis will be done 
for the AT/TG assessments, ABR and maximum bleed free duration. 
6.6 
ADDITIONAL EXPLORATORY ANALYSES  
For participants who undergo operative procedures during the study, the total number of 
participants in each rating category of hemostatic efficacy response (“none,” “moderate,” “good,” 
and “excellent”) will be summarized at each time point for both the intraoperative and 
postoperative assessments. Other data on surgical cases, including factor/BPA use, may be 
described in narrative form.  
6.7 
PHARMACOKINETIC ANALYSIS  
Pharmacokinetic analyses will be conducted using the PK analysis set 1 and PK analysis set 2. 
Plasma PK parameters will be estimated using a population PK approach. The population PK 
analysis will be described in a separate population PK analysis plan. In addition to performing 
population PK 32onhealt, PK parameters will also be estimated using non-compartmental analysis 
in participants who opted to participate in extensive PK sampling during one or more of the PK 
sampling periods (Day 1, Month 12, Month 24). 
PK parameters to be estimated using non-compartmental analysis will include, but will not be 
limited to: 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). The amount of fitusiran excreted in 0-24 h 
urine from a subset of participants who opted to participate in urine collections, will also be 
estimated using non-compartmental analysis. Other plasma and/or urine PK parameters may also 
be calculated, if considered appropriate. 
6.8 
SAFETY ANALYSES  
Safety analyses will be conducted using the safety analysis set 1 and safety analysis set 2. Only 
the safety data occurred in LTE14762 will be summarized unless specified otherwise. 
Safety analysis under the original dose and regimen (i.e. before the 2020 voluntary dose pause) 
and the revised dose and regimen (i.e. after the 2020 voluntary dose pause) will be analyzed 
separately. The additional baseline prior to the revised dose regimen administration will be 
implemented for data collected under the revised dose and regimen. Similar descriptive 
summaries in reference to the additional baseline will be provided for laboratory, vital sign and 
ECG endpoints. 
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6.8.1 Study drug exposure  
Duration of exposure (years) and the number of study drug doses used from Treatment Day 1 in 
the TDR14767(ALN-AT3SC-001)/LTE14762 under the original dose and regimen will be 
summarized descriptively, where duration of exposure (days) = date of the last dose of study drug 
– the date of the first significant dose of study drug + 28 days excluding the gaps between 
TDR14767(ALN-AT3SC-001)/LTE14762 and dose suspension in LTE14762. Duration of 
exposure and the number of study drug doses in LTE14762 study will be summarized similarly.  
Duration of exposure under the revised dose and regimen will be summarized. If participant had 
the last dose under the Q2M dose frequency, the duration (days) = date of the last dose of fitusiran 
– the date of the first dose of fitusiran under the revised dose and regimen + 56 days. If participant 
had the last dose under the QM dose frequency, the duration (days) = date of the last dose of 
fitusiran – the date of the first dose of fitusiran under the revised dose and regimen + 28 days.  
The overall duration of exposure regardless of revised dose from the first significant dose and/or 
from the first dose in the LTE14762 study until the end of study may also be summarized as 
needed. The planned dose intermittent period (Table 4) will be excluded from the overall duration 
of exposure. 
Table 4 – Definition of planned dose intermittent periods  
 
Start date 
End date 
Note 
Gap between parent 
and extension study 
Last fitusiran dose date in parent 
study + 29 days 
First fitusiran dose date in 
extension study – 1 
If duration < 14 days, then no gap 
between the 2 studies.  
2017 dose suspension 
Last fitusiran dose before 
01SEP2017 + 29 days 
First fitusiran dose after 
01SEP2017 – 1 
If duration < 14 days, then no dose 
suspension period should be excluded. 
2020 dose suspension 
Last fitusiran dose date before 
31Oct2020 + 29 days 
First fitusiran dose after 
26Jan2021 – 1 
If duration < 14 days, then no dose 
suspension period should be excluded 
Note: Duration is calculated as end date – start date +1 for each dose intermittent periods. 
6.8.2 Adverse events  
Adverse events (AE) analysis will include treatment-emergent events, with onset occurring in the 
LTE14762 study. (Note: All AEs collected in LTE14762 are considered TEAE because all 
participants received dose in TDR14767(ALN-AT3SC-001).) 
All AEs will be coded using the MedDRA(version 25.1 or later) coding system and displayed in 
tables and data listings using system organ class (SOC) and preferred term (PT). AEs will be 
summarized by the numbers and percentages of participants reporting at least 1 AE, having at 
least 1 AE by primary SOC and PT. A participant with multiple occurrences of an AE will be 
counted only once in the respective AE category. Participants who report multiple occurrences of 
the same AE (preferred term) will be classified according to the most related or most severe 
occurrence, respectively.  
All AE summaries will be summarized (frequency counts and percentages) by system organ class 
and/or preferred term, unless specified otherwise. The SOC will be presented according to 
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international standards (MedDRA Internationally Agreed Order), and the preferred term will be 
sorted within each SOC in decreasing order of frequency.  
The following events are considered to be AEs of special interest (AESI):  
1. ALT or AST elevations >3 × ULN  
2. Suspected or confirmed thromboembolic events  
3. Severe or serious injection site reactions (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 study drug.  
4. Systemic (injection associated reactions (IARs), defined as hypersensitivity reactions which 
are related or possibly related to IMP. 
5. Cholecystitis 
6. Cholelithiasis 
The identification of cholecystitis and cholelithiasis will be a combination of systematic search of 
higher level group term (HLGT) and AESI collected as it is in CRF. AEs whose HLGT fall into 
the categories listed below will be considered as AESI of cholecystitis and cholelithiasis: 
1. Bile duct disorders,  
2. Gallbladder disorders  
3. Hepatic and hepatobiliary disorders 
An overall summary of TEAEs will include the number and percentage of participants with any 
TEAE, any TEAE assessed by the Investigator as related to study drug (possibly related or 
definitely related),  any serious TEAE (TESAE), any TESAE related to study drug, any TEAE of 
special interest; any AE/SAE leading to permanent study drug discontinuation, any TEAE/TESAE 
leading to study withdrawal, and any deaths. The TEAE onset within any major surgery period 
will be provided in a separate column in the overview summary statistics as well as in the overall 
column. They will be excluded from the rest of by-indication columns in the table.  
Tabulations of TEAEs by SOC and PT excluding those AE onsets within major surgery period 
will be produced for the following:  
1. TEAEs  
2. TEAEs by severity  
3. Treatment emergent SAEs 
4. TEAEs related to study drug  
5. Treatment emergent SAEs related to study drug  
6. TEAEs leading to permanent study drug discontinuation  
7. Treatment emergent SAEs leading to permanent study drug discontinuation  
8. TEAEs leading to study withdrawal  
9. Treatment emergent SAEs leading to study withdrawal  
10. Treatment emergent AESI (Adverse Events of Special Interest) 
11. TEAEs potentially consistent with Covid-19. These AEs will be identified based on SMQ 
group searching.   
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All AEs will be listed along with the information collected on those AEs, eg, AE relationship to 
study drug, AE outcome etc. By-participant listings will also be provided for the following: all 
participant deaths, all SAEs, and all AEs leading to permanent study drug discontinuation or study 
withdrawal, all AEs leading to death. AE onset during the major surgery period will also be 
included in each of the by-participant listing with major surgery flag.   
The incidence rate of severe or serious ISRs will also be summarized. The incidence rate is 
defined as the number of severe or serious ISRs per study drug injection. If multiple ISRs occur 
between two consecutive injections, they will be counted under the first injection as 1 ISR.  
Because of hepatitis C infected participant got enrolled in the TDR14767(ALN-AT3SC-001) 
study, participants with treatment emergent ALT or AST elevations > 3 ULN AESI will be 
analyzed based on their HCV status at the enrollment of LTE14762 study.  
Additional summary of incidence rate for TEAE, SAE, AEs leading to permanent study drug 
discontinuation and AESI before and after the 2020 dose pause by primary SOC and PT will be 
provided. 
6.8.3  Laboratory data  
Clinical laboratory values will be expressed in standard international (SI) units. Laboratory data 
collected and recorded as below the limit of detection will be set equal to the lower limit of 
detection for the calculation of summary statistics.  
For each continuous clinical laboratory parameter (including hematology, serum chemistry, 
coagulation studies and thyroid and liver function tests) from the central laboratory descriptive 
statistics will be presented for the actual values, change from baseline, and percent change from 
baseline by visit. The descriptive statistics under the original dose and regimen will be provided 
from the LTE14762 study baseline up to the last assessment before the 2017 clinical hold. The 
baseline used for this analysis is LTE14762 study baseline. Similar by-visit summary will be 
provided under the revised dose and regimen from the dose resumption after 2020 voluntary dose 
pause up to the end of study. There are 2 baselines considered for this analysis, which are 
LTE14762 study baseline and dose resumption baseline on or before the dose resumption after the 
2020 voluntary dose pause.  
In order to address impact of 2017 and 2020 dose interruption, additional spaghetti plots using 
actual values will be provided for below laboratory parameters:   
4. Alanine Aminotransferase (ALT),  
5. Aspartate Aminotransferase (AST),  
6. Total Bilirubin,  
7. Alkaline Phosphatase,  
8. D-Dimer,  
9. Prothrombin Fragments 1 + 2 and  
10. Fibrinogen.  
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All the assessments from central laboratory, including assessments performed during the 2017 
and 2020 dose interruption periods, will be used for the plot. For those assessments collected 
during the 2017 and 2020 dose interruption periods, a different color will be used to distinguish 
these periods.  
For each continuous laboratory parameter, results will be categorized as low, normal, or high 
based on the laboratory normal ranges (when available).  
Listings will be produced for all participants with abnormal liver function tests defined as an 
ALT >3 × ULN or 3 × Baseline (for those participants with abnormal values at baseline), or AST 
>3 × ULN or 3 × Baseline (for those participants with abnormal values at baseline, at any time 
point. (“Baseline” here means LTE14762 baseline.) These listings will include each of the 
assessments specified in Tables 8 and 9 of the Protocol (Amendment 9).  
Number of participants with at least one occurrence of AST/ALT >3 × ULN and at least 
2 occurrence of AST/ALT >3 × ULN will be summarized descriptively. Time to first onset of 
AST/ALT >3 × ULN will be analyzed using Kaplan-Meier method. Participants who complete the 
study and do not have the event will censor at study completion date. Participants who do not 
complete the study under original dose and regimen will be censor at the earlier of last dose date 
under the original dose and regimen +28 days or the day before dose resumption. Participants who 
do not have the event under revised dose and regimen will be censored at last visit date as of data 
cutoff. If participants experienced the event of after AST/ALT >3 × ULN 2017 clinical hold under 
original dose and regimen, the 2017 clinical hold period will be excluded. 
A table will be produced to summarize the number and percentage of participants in each of 
below categories at any time point during the duration of LTE14762) study.  
1. ALT >1 & ≤3, >3 & ≤5, >5 & ≤10, >10 & ≤20, >20 × ULN  
2. AST >1 & ≤3, >3 & ≤5, >5 & ≤10, >10 & ≤20, >20 × ULN  
3. ALT or AST >1 & ≤3, >3 & ≤5, >5 & ≤10, >10 & ≤20, >20 × ULN  
4. ALP >1.5 × ULN  
5. Total Bilirubin >1.5 & ≤2, >2 & ≤3, >3 & ≤5 and >5×ULN 
6. Total Bilirubin > 2×ULN concurrent with ALT or AST > 3×ULN 
7. INR >1.2×ULN 
eDISH(evaludation of drug-induced serious hepatotoxicity) plots will be provided by indications. 
Number of participants in the following categories will be listed: cholestasis, potential Hy’s law 
case, Temple’s corollary range and normal range.  
For hematology and blood chemistry, summary tables of potentially clinically significant 
abnormalities (PCSA) will be provided. Both data from central laboratory and local laboratory 
will be considered in PCSA analysis. Additional liver function PCSA analysis by HCV status will 
be analyzed as well.  
All the laboratory data analysis will not include assessment taken during the major surgery period.  
All laboratory data will be provided in data listings with identifier of assessment during the major 
surgery period. Out-of-range laboratory results and PCSA will be identified in the listings.  
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While local laboratory results may be used for dosing decisions and urgent clinical decisions, on 
the day of the clinic visit assessments, all laboratory assessments specified in the protocol 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 with available 
results, central laboratory results will be relied upon for clinical and dosing decisions. 
6.8.4 Vital signs and physical examination  
Descriptive statistics will be provided for vital signs, including blood pressure, pulse rate, oral 
body temperature and respiration rate. For data under the original dose and regimen, the 
descriptive summary will be provided from the LTE14762 study baseline up to the 2017 clinical 
dose pause. For data under the revised dose, the summary will be provided from the dose 
resumption up to the end of study. A summary table of PCSA will be provided. Abnormal PE 
results will be listed. All the vital sign and physical examination summary tables will not include 
assessment taken during the major surgery period. These results will be presented in listings with 
identifier of major surgery.   
6.8.5 Electrocardiogram  
Listings for 12-lead ECG will be provided. Additionally, PR, QRS, QT, Bazzett’s (QTcB) and 
Fridericia’s (QTcF) corrected QT and RR intervals will be summarized descriptively, where 
(QTcF) is calculated using the formula  
QTcF (ms) = QT (ms)  3  HR (bpm) 
60 
and where (QTcB) is calculated using the formula  
QTcB (ms) = QT (ms)   HR (bpm) 
60 
For data under the original dose and regimen, the descriptive summary will be provided from the 
LTE14762 study baseline up to the 2017 clinical dose pause. For data under the revised dose, the 
summary will be provided from the dose resumption up to the end of study.  
6.8.6 Medical history  
Medical history will be summarized by MedDRA(version 25.1 or later) coding system SOC and 
PT. A participant contributes only once to the count for a given condition (overall, by SOC, by 
PT).  
6.8.7 Concomitant medications  
Concomitant medication is defined as all medications other than study drug administered to 
a participant during the study. (All AE and CM collected in the study should be included in the 
analyses because all participants received dose in TDR14767(ALN-AT3SC-001).) Concomitant 
medications will be coded using the WHO Drug Dictionary. Results will be tabulated by anatomic 
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therapeutic class (ATC) and preferred term. Concomitant medications excluding the medication 
used during the major surgery period will be summarized. A separate summary of concomitant 
medication administrated during the major surgery period will also be provided. 
6.8.8 Bleed management guidelines  
Compliance and deviations from bleed management guidelines (as presented in Table 8 of the 
Protocol) will be listed and summarized descriptively.  
6.9 
ANTIDRUG ANTIBODY  
ADA will be analyzed similarly as PD after the 1st significant dose. Number of participants testing 
positive for antidrug antibody (ADA) pre-study-drug (before first study drug dose in 
TDR14767(ALN-AT3SC-001) study) and post-study-drug administration will be summarized by 
Hemophilia type (A/B) and incidence of ADA positivity will be presented by frequency and as a 
percent by Hemophilia type and across all participants. In addition, maximum ADA titer and 
range of titer values will be presented by hemophilia type and across all participants, if applicable. 
ADA results will be listed by visit. 
6.10 
PRE-FILLED SYRINGE  
Study drug may be provided in prefilled syringes (PFS) either at the clinic (healthcare setting) or 
in a non-healthcare setting (home injection) in a subset of participants receiving 80 mg monthly 
dose of fitusiran. In order to investigate safety and efficacy during PFS administration, data 
relating to exposure (for example, number of doses administered via PFS), safety (eg, related 
ISRs, etc) as well as ABR will be summarized descriptively for PFS usage period and vial usage 
period respectively under the original dose and regimen.  
6.11 
SUBGROUP ANALYSIS  
Participants who received their significant dose in parent study will be considered as a subgroup 
for below endpoints. These subgroup analyses only appliable for the analyses under the original 
dose and regimen. 
• Annualized bleeding rate (ABR) during the efficacy period for treated bleeds and all 
bleeds 
• Annualized weight-adjusted consumption of FVIII, FIX and BPA  
• Quality of life (QoL) measured by EuroQol 5-dimension 5-level (EQ-5D-5L) score  
• QoL measured by Haem-A-QoL score  
• AT activity level 
• TG level 
 
Negative binomial regression model will be applied only for subgroup that has at least 
3 participants and the model converges. Otherwise, only summary statistics will be presented.  
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7 REFERENCES  
1. Blanchette VS, Key NS, Ljung LR, Manco-Johnson MJ, van den Berg HM, Srivastava A, 
et al. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb 
Haemost. 2014:12(11);1935-9.  
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8 
APPENDIX: QUESTIONNAIRE/SCORING  
8.1 
HAEM-A-QOL  
The Haem-A-QoL questionnaire is psychometrically tested QoL assessment instrument for 
participants with hemophilia 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.  
Basically high score represent low quality of life and the Haem-A-QoL scoring involves the 
following steps:  
1. For negatively worded items, assign numbers to the response scale: 1 = never, 2 = seldom, 
3 = sometimes, 4 = often, 5 = all the time.  
2. For positively worded items, the score has to be reversed: 1 = all the time, 2 = often, 
3 = sometimes, 4 = seldom, 5 = never.  
3. Use the Scoring List to identify which items belong to a subscale.  
4. Summing up the items belonging to a subscale yields the raw score per subscale. Its range 
lies between the lowest possible (number of items (n) x 1) and highest possible (number of 
items (n) x 5) value of the respective scale.  
5. Comparing scores across subscales is possible. If this raw score is divided by the number 
of items in the scale, the resulting standardized scale score can have any (also decimal) 
value between 1 and 5. A value of 1 represents the highest possible quality of life rating 
and a value of 5 the lowest possible quality of life rating of the participant.  
6. Transferring a raw score to a transformed scale score between 0 and 100 makes it possible 
to express the scale score in percent between the lowest (0) and the highest (100) possible 
value. To obtain the transformed scale score (TSS) the following transformation rule has 
to be applied:  
 
Example:  
A raw score of 11 on the “Feelings” Scale is to be transformed:  
- 
Minimal possible raw score = 4 (since there are 4 items and lowest score for each item 
is 1.)  
- 
Possible range of raw scores = maximal possible raw score – minimal possible raw 
score = (4 items x 5 [max score]) – 4 = 20 – 4 
= 16  
TSS = 100 x (11 – 4) / 16 = 43.75 
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7. Producing the Total score involves the addition of the scores of a person using all items 
(instead of the subscale items only) of the questionnaire (again paying attention to the 
recoding procedure - see Steps 1 and 2). Items may be added to form a total raw score 
(according to Step 4, but using all items), a total standardized score (according to Step 5, 
but using all items) or a total transformed score (according to Step 6, but using all items).  
8. If there is missing item score within a domain, the standardized scale score and 
transformed score for that domain will be calculated based on the number of items 
answered if at least 50% of those scores are non-missing and otherwise it is set to missing. 
Of note, participants can answer “Not applicable” to questions in the sports and leisure, 
work and school, and family planning domains. In this case, the domain score will be 
calculated if at least 50% of those scores are non-missing and not responded to “Not 
Applicable”. The raw score for that domain will be set to missing if at least one item score 
is missing. 
Table 1: Haem-A- QoL domains and an example item in each domain 
Haem-A-QoL domains  
Example items  
Physical health (5 items)  
In the past month, it was painful for me to move  
Feelings (4 items)  
In the past month, I was worried because of my haemophilia  
View of yourself (5 items)  
In the past month, I felt different from others because of my haemophilia  
Sports & leisure (5 items)  
In the past month, I had to avoid sports that I like because of my haemophilia  
Work & school (4 items)  
In the past month, my everyday work/school activities were jeopardized by my 
haemophilia  
Dealing with haemophilia (3 items)  
In the past month, I was able to tell whether or not I was bleeding  
Treatment (8 items)  
In the past month, I had problems with how my treatment was administered  
Future (5 items)  
In the past month, I have been thinking that it will be difficult for me to lead a normal life  
Family planning (4 items)  
In the past month, I have been worrying about not being able to raise a family  
Partnership & sexuality (3 items)  
In the past month, I haven’t been able to have a normal relationship because of my 
haemophilia  
8.2 
EUROQOL-5 DIMENSION 5 LEVEL (EQ-5D-5L) SCORE  
The EQ-5D-5L is a standardized instrument for use as a measure of QoL outcome. It consists of 
a descriptive system and a visual analog scale (VAS).  
1. EQ-5D descriptive system: has 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression) with 5 levels (no problems, slight problems, 
moderate problems, severe problems, and extreme problems).  
2. EQ-5D VAS: is a continuous score ranging from 0 to 100. 
3. EQ-5D Valuation index: The information of the 5 dimensions of the descriptive system 
summarized into one index. The EQ-5D-5L index value is calculated using the crosswalk 
link function and the individual responses to the EQ-5D5L descriptive system.  
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