Clinical trial NCT03549871
Conditions: Hemophilia
Sponsor: Genzyme, a Sanofi Company
Start date: 2018-07-25; Completion date: 2022-03-25
Enrollment: 80 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Primary Objective:

To characterize the frequency of bleeding episodes (BE) while receiving fitusiran treatment, relative to the frequency of bleeding episodes while receiving factor concentrate or bypassing agent (BPA) prophylaxis.

Secondary Objectives:

* To characterize the following while receiving fitusiran treatment, relative to receiving factor or BPA prophylaxis:
* the frequency of spontaneous bleeding episodes
* the frequency of joint bleeding episodes
* health related quality of life (HRQOL) in participants greater than or equal to (\>=) 17 years of age
* To characterize the frequency of bleeding episodes during the onset and treatment periods in participants receiving fitusiran.
* To characterize the safety and tolerability of fitusiran.
* To characterize the annualized weight-adjusted consumption of factor/BPA while receiving fitusiran treatment, relative to receiving factor or BPA prophylaxis.

Detailed description:
The estimated total time on study, inclusive of Screening, for each participant was up to 15 months for participants who were enrolled in the extension study except for participants in the subgroup of Cohort A, for whom it was up to 9 months. The estimated total time on study was up to 21 months (up to 15 months in participants in the subgroup of Cohort A) in participants who did not enroll in the extension study due to the requirement for an additional up to 6 months of follow-up for monitoring of antithrombin (AT) levels.

Arms: arm 1: Cohort A \[inhibitor\]: participants with severe hemophilia A/B and inhibitory antibodies to coagulation factor VIII (FVIII)/factor IX (FIX) previously received BPA prophylaxis. Cohort B \[non-inhibitor\]: participants with severe hemophilia A/B without inhibitory antibodies to FVIII/FIX previously received factor prophylaxis. Participants from both cohorts was enrolled into 6-month factor/BPA prophylaxis period and continued their pre-study, regularly scheduled prophylaxis regimen with factor/BPAs. This period could be skipped by subgroup of Cohort A (hemophilia B with inhibitors to FIX and historical annualized bleeding rate \[ABR\] \>=20) that started directly with fitusiran. Post completing factor/BPA prophylaxis period, participants entered 7-month fitusiran treatment period (1-month onset+6-month efficacy) followed by AT follow-up/roll-over into LTE15174 (NCT03754790). Throughout study, participants could receive on-demand treatment for breakthrough BE with factor/BPAs, as appropriate.
Interventions: intervention 1: Fitusiran intervention 2: BPA prophylaxis intervention 3: Factor (FVIII or FIX) prophylaxis
Intervention descriptions: intervention 1: Pharmaceutical form: solution for injection Route of administration: subcutaneous intervention 2: Pharmaceutical form: solution for injection Route of administration: Intravenous intervention 3: Pharmaceutical form: solution for injection Route of administration: Intravenous

Protocol documents:
Prot_000.pdf: 


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE  
DOCUMENT HISTORY  
 
Document 
Country-specificity if 
applicable 
Date, version 
Amended protocol 06 
NA 
08 December 2020, version 1 (electronic 4.0) 
Amended protocol 05 
NA 
25 November 2020, version 1 (electronic 3.0) 
Amended protocol 04 
United States, Japan 
18 December 2018, version 1 (electronic 2.0) 
Amended protocol 03 
Republic of Ireland 
24 August 2018, version 1 (electronic 2.0) 
Amended protocol 02 
NA 
31 May 2018, version 1 (electronic 1.0) 
Amended protocol 01 
NA 
28 November 2017, version 1 (electronic 1.0) 
Original protocol 
NA 
23 May 2017, version 1 (electronic 1.0) 
Amended protocol 06 (08 December 2020) 
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  
The main purpose of this amendment is to minimize the time between 2 antithrombin (AT) 
measurements if the first AT result is <15%. 
 
VV-CLIN-0254442 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
3 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Table1: Schedule of 
assessments 
Sentence added to footnotes “n”: For the 
AT assessments, 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. 
To mandate a second AT activity level within 1 
week of site receipt of an initial AT level result 
<15%. 
Section 6.2.3.2: 
Antithrombin level criteria 
for a dose adjustment 
Text changed from “Patients receiving 
fitusiran at a dose of 50 mg Q2M with 
more than 1 AT activity measurement 
<15% at any time during the study must 
permanently discontinue fitusiran.” to 
“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 this result is 
<15%, this will be considered the second 
AT activity level <15%. Patients 
receiving fitusiran at a dose of 50 mg 
Q2M with more than 1 AT activity level 
<15% at any time during the study must 
permanently discontinue fitusiran .” 
To specify and address dose adjustment based on 
AT activity levels. 
Section 11.7.5 Amended 
Protocol 05  
New section added.  
To document protocol amendments history. 
Throughout 
Minor editorial, typo error corrections 
and document formatting revisions. 
Minor, therefore, have not been summarized. 
 
VV-CLIN-0254442 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
4 
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-0254442 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
5 
PROTOCOL SYNOPSIS  
Protocol title 
ATLAS-PPX:  an open-label, multinational, switching study to describe the efficacy and safety of fitusiran prophylaxis in 
patients with hemophilia A and B previously receiving factor or bypassing agent prophylaxis. 
Product name 
Fitusiran (INN); SAR439774 (formerly Alnylam ALN-AT3SC)  
Indication 
Routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and adolescent (≥12 years old) 
hemophilia A or B patients 
Phase 
3  
Study center(s)   
The study will be conducted at approximately 70 clinical study centers worldwide. 
Objectives 
Primary 
• 
To characterize the frequency of bleeding episodes while receiving fitusiran treatment, relative to the frequency of 
bleeding episodes while receiving factor or bypassing agent (BPA) prophylaxis 
Secondary 
• 
To characterize the following while receiving fitusiran treatment, relative to receiving factor or BPA prophylaxis: 
- 
the frequency of spontaneous bleeding episodes 
- 
the frequency of joint bleeding episodes 
- 
health related quality of life (HRQOL) in patients ≥17 years of age 
• 
To characterize the frequency of bleeding episodes during the onset and treatment periods in patients receiving 
fitusiran  
• 
To characterize the safety and tolerability of fitusiran 
• 
To characterize the annualized weight-adjusted consumption of factor/BPA while receiving fitusiran treatment, 
relative to receiving factor or BPA prophylaxis 
Exploratory 
• 
To characterize the effects of fitusiran on the following patient-reported outcomes while receiving fitusiran 
treatment, relative to receiving factor or BPA prophylaxis: 
- 
Patient satisfaction with fitusiran 
- 
Patient activity 
- 
HRQOL in adolescents (≥12 to <17 years of age) 
• 
To characterize the pharmacodynamic (PD) effect, pharmacokinetics (PK), and immunogenicity of fitusiran 
• 
To characterize the effects of fitusiran on joint status while receiving fitusiran treatment, relative to receiving factor 
or BPA prophylaxis 
• 
To characterize the effects of fitusiran on patient resource use, relative to receiving factor or BPA prophylaxis 
VV-CLIN-0254442 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
6 
Endpoints 
Primary 
• 
Annualized Bleeding Rate (ABR) in the fitusiran efficacy period and the factor or BPA prophylaxis period 
Secondary 
• 
Annualized spontaneous bleeding rate in the fitusiran efficacy period and the factor or BPA prophylaxis period 
• 
Annualized joint bleeding rate in the fitusiran efficacy period and the factor or BPA prophylaxis period 
• 
Change in Haem-A-QOL physical health score and total score in the fitusiran treatment period and the factor or 
BPA prophylaxis period 
• 
ABR in the fitusiran onset period 
• 
ABR in fitusiran treatment period 
• 
Annualized weight-adjusted consumption of factor/BPA 
Exploratory 
• 
Change in the following in the fitusiran treatment period: 
- 
Treatment Satisfaction Questionnaire for Medication (TSQM) domain scores 
- 
Haemophilia Activities List (HAL) score 
- 
Paediatric HAL (pedHAL) score 
- 
EuroQol-5 Dimensions (EQ-5D) score 
- 
Haemo-QOL score 
- 
Hemophilia Joint Health Score (HJHS) 
• 
Number of target joint bleeding episodes 
• 
Incidence and titer of antidrug antibodies to fitusiran in the fitusiran treatment period 
• 
Antithrombin (AT) activity level over time 
• 
Thrombin generation over time 
• 
Fitusiran plasma levels 
• 
Change in patient resource use (eg, work/school attendance, visits to doctor/hospital) 
Safety 
• 
Incidence, severity, seriousness, and relatedness of adverse events 
Study design 
The ATLAS-PPX trial (ALN-AT3SC-009 [Sanofi Genzyme EFC15110]) is a multicenter, multinational, open label, Phase 3 
study designed to evaluate the efficacy and safety of fitusiran in male patients, aged ≥12 years, with hemophilia A or B, who 
have switched from prior bypassing agent (BPA, Cohort A) or factor (Cohort B) prophylaxis. A subgroup of Cohort A patients 
will include hemophilia B patients with inhibitory antibodies to Factor IX who are not responding adequately to BPA 
prophylaxis treatment (historical ABR ≥20). 
The study has 3 periods: 
• 
6-Month factor or BPA prophylaxis period in which patients will continue their prestudy, regularly scheduled 
prophylaxis regimen with factor concentrates or BPAs 
The subgroup of Cohort A patients who are not responding adequately to BPA prophylaxis treatment will not 
participate in this 6-month BPA prophylaxis period and will start directly receiving fitusiran (in the 1-month onset 
period described below) after the screening period. 
• 
1-Month onset period in which patients receive their first dose of fitusiran while continuing their factor or BPA 
prophylaxis for up to 7 days 
• 
6-Month fitusiran efficacy period in which patients receive fitusiran as prophylaxis 
Together, the 1-month onset period and the 6-month fitusiran efficacy period constitute the fitusiran treatment period. 
VV-CLIN-0254442 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
7 
Bleeding events and doses of factors or BPAs administered during the conduct of the study will be recorded in an electronic 
Diary (eDiary). Safety, quality of life, pharmacodynamic, and pharmacokinetic data will also be collected. 
Following the screening and prophylaxis periods or following the screening period for the subgroup of Cohort A enrolling 
directly into the fitusiran treatment period, all patients will be treated with fitusiran for a total of 7 months. 
Throughout the study, patients may receive on-demand treatment for breakthrough bleeding episodes with factors or BPAs, 
as appropriate. 
An independent data monitoring committee (DMC) will oversee the safety and overall conduct of this study. The DMC will 
perform periodic reviews of data during the course of the clinical trial, and on an ad hoc basis for review of emergent safety 
data, as defined in the DMC Charter for this clinical trial. 
Patients who complete the study may be eligible for participation in an open-label extension study. For patients who do not 
enroll in the extension study, AT activity level will be monitored at monthly intervals following the final fitusiran dose until 
activity levels return to approximately 60% per the central laboratory, or per Investigator discretion in consultation with the 
study Medical Monitor. 
For the United States specific requirements, see Section 11.6.1.1. 
Number of planned patients 
Approximately 80 patients are planned for enrollment in this study, including approximately 30 patients with inhibitors 
(Cohort A) and approximately 50 patients without inhibitors (Cohort B). Approximately 18 patients with hemophilia B 
(including approximately 7 hemophilia B patients in Cohort A, among which are a subgroup of no more than 4 patients who 
are not responding adequately to BPA prophylaxis, and approximately  11 hemophilia B patients in Cohort B, and 
approximately 7 adolescents (≥12 to <18 years of age) are also planned for enrollment. For the United States specific 
requirements, see Section 11.6.1.1. 
Diagnosis and main eligibility criteria 
This study will include males with severe hemophilia A or B with or without inhibitors, aged ≥12 years, who have been 
prescribed prophylactic treatment with factor concentrates or BPAs for at least 6 months prior to Screening. Diagnosis of 
severe hemophilia A or B will be based on a central laboratory measurement or documented medical record evidence of 
FVIII level <1% or FIX level ≤2%.   
Patients with inhibitors must have used BPAs for prophylaxis for at least the last 6 months prior to Screening and must meet 
one of the following Nijmegen-modified Bethesda assay results criteria:  1) Inhibitor titer of ≥0.6 BU/mL at Screening, OR 2) 
Inhibitor titer of <0.6 BU/mL at Screening with medical record evidence of 2 consecutive titers ≥0.6 BU/mL, OR 3) Inhibitor 
titer of <0.6 BU/mL at Screening with medical record evidence of anamnestic response.  The subgroup of patients in Cohort 
A patients must additionally meet the following criteria to be eligible to start treatment with fitusiran directly after the 
screening period: 1) Hemophilia B with inhibitory antibody to Factor IX as defined above; 2) Not responding adequately to 
BPA treatment (historical ABR ≥20) prior to enrollment; and 3) in the opinion of the Investigator, with approval of Sponsor 
Medical Monitor, 6-month BPA prophylaxis period should be omitted. A minimum of 2 bleeding episodes requiring BPA 
treatment within the last 6 months prior to Screening is required.  
Patients without inhibitors must have used factor concentrates for prophylaxis for at least the last 6 months prior to 
Screening and must meet each of the following criteria: 1) Nijmegen-modified Bethesda assay inhibitor titer of <0.6 BU/mL 
at Screening, AND 2) No use of bypassing agents to treat bleeding episodes for at least the last 6 months prior to 
Screening, AND 3) No history of immune tolerance induction therapy within the last 3 years prior to Screening. A minimum 
of 1 bleeding episode requiring factor treatment within the last 12 months prior to Screening is required. For the United 
States specific requirements, see Section 11.6.1.1. 
Investigational product, dose and mode of administration 
Fitusiran is a subcutaneously (SC) administered GalNAc-conjugated siRNA targeting liver-expressed messenger RNA 
(mRNA) for AT.  
Patients will receive open label fitusiran as an SC injection, for a total of 7 months; dosing will begin on Day 1 of the fitusiran 
treatment period. 
VV-CLIN-0254442 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
8 
Reference therapy, dose and mode of administration 
During the factor or BPA prophylaxis period, patients will continue FVIII, FIX, or BPA prophylaxis as treatment for hemophilia 
on a regimen consistent with recommendations in the approved prescribing information, allowing for adjustment to individual 
patient response, and designed to decrease spontaneous bleeding. Dose and mode of administration will be per Investigator 
discretion; bleeding episode management should be per the local standard practice for episodic use of factors or BPAs and 
as per Investigator discretion. The subgroup of Cohort A patients who are not responding adequately to BPA prophylaxis 
treatment will not participate into this BPA prophylaxis period and will directly start the fitusiran treatment period after the 
screening period. All patients will continue to receive FVIII, FIX, or BPA prophylaxis for the first 7 days of the onset period. 
Subsequently, breakthrough bleeding episodes will be treated with on-demand factor or BPA therapy as necessary per the 
bleeding episode management guidelines. For the United States specific requirements, see Section 11.6.1.1. 
Duration of treatment 
The duration of treatment with fitusiran is 7 months. The estimated total time on study, inclusive of Screening, for each 
patient is up to 15 months for patients who enroll in the extension study except for patients in the subgroup of Cohort A, 
which is up to 9 months. The estimated total time on study may be up to 21 months (up to 15 months in patients in the 
subgroup of Cohort A) in patients who do not enroll in the extension study due to the requirement for an additional 6 months 
of follow-up for monitoring of AT levels.  
Statistical methods 
Sample size is based on clinical considerations. The efficacy analyses will be based on the efficacy analysis set, which 
includes all patients who received both factor or BPA prophylaxis and any dose of fitusiran in the study. The subgroup of 
Cohort A patients who are not responding adequately to BPA prophylaxis treatment will be included in the safety analysis 
set but will not be part of the efficacy analysis set; however, their efficacy data will be presented separately. The primary 
endpoint and the secondary endpoints (spontaneous bleeding episodes and joint bleeding episodes) will be based on the 
bleeding events occurring in the factor or BPA prophylaxis period (Day -162 to Day -1) and the fitusiran efficacy period 
(Day 29 to Day 190). To avoid confounding treatment effect, bleed data following major surgery, antithrombin administration, 
major trauma, or the re-initiation of prophylaxis treatment with factors or BPAs after fitusiran discontinuation will be excluded 
from the primary analysis. 
The number of bleeding episodes will be analyzed using a repeated measures negative binomial model with fixed effect of 
treatment period. The ratio of bleeding rates in the fitusiran efficacy period relative to the factor/BPA prophylaxis period and 
its 95% CI and p-value will be presented. The logarithm of bleeding episode follow-up time in each period for each patient 
will be used as an offset parameter in the model to account for any difference in follow-up duration. The p-value should be 
interpreted with caution. In addition, as a contrast Bayesian analyses will be performed to summarize the point estimates of 
the posterior probability of a clinically significant treatment effect, along with associated measures of uncertainty. In addition, 
estimated mean ABR and its 95% CI during each of the 2 periods and during the fitusiran onset period will be presented. 
The spontaneous bleeding episodes and the joint bleeding episodes will be analyzed using the same model as used in the 
primary analysis. Safety data will be summarized descriptively.  The bleeding episodes in the fitusiran onset period and in 
the fitusiran treatment period will be analyzed using a negative binomial model with logarithm of follow-up time in the period 
as an offset parameter. Change in Haem-A-QOL physical health score and total score in the factor/BPA prophylaxis period 
and fitusiran treatment period will be summarized descriptively. A mixed model for repeated measures analysis may be 
performed as deemed appropriate. The annualized weight-adjusted consumption of factor/BPA injections will be 
summarized using descriptive statistics. For United States specific requirements see Section 11.6.1.1. 
The above analyses will be done for Cohort A and Cohort B separately. A pooled analysis will be performed after all patients 
in the 2 cohorts have either finished the Month 7 visit during the fitusiran treatment period or discontinued from the study. 
VV-CLIN-0254442 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
 
9 
Table 1 - Schedule of assessments                   
Study visit (Month) 
Screening 
Factor or BPA 
prophylaxis perioda 
Fitusiran treatment periodb 
AT 
F/Ud,e  
Onset 
periodb 
Efficacy period 
Month -6 
Month -5 
Month -4 
Month -3 
Month -2 
Month -1 
Baseline 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
EOT 
EOS/ 
ETc,d  
Month 8 
Month 6 
Month 7 
Study day (±Visit Window) 
-228 to -169 
Day -168 
Day -140 ±7 
Day -112 ±7 
Day -84 ±7 
Day -56 ±7 
Day -28 ±7 
Day 1  
Day 15 ±3  
Day 29 ±7 
Day 43 ±3 
Day 57 ±7 
Day 85 ±7 
Day 113 ±7 
Day 141 ±7 
Day 169 ±7 
Day 197 ±7 
Day 225 ±7 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical Historyf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eDiary Trainingg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examinationh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Weight and Heighti 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGj 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
FibroScan OR FibroTest/APRIk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TG Levell 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VV-CLIN-0254442 4.0




SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
 
11 
Table 1 - Schedule of assessments                   
Study visit (Month) 
Screening 
Factor or BPA 
prophylaxis perioda 
Fitusiran treatment periodb 
AT 
F/Ud,e  
Onset 
periodb 
Efficacy period 
Month -6 
Month -5 
Month -4 
Month -3 
Month -2 
Month -1 
Baseline 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
EOT 
EOS/ 
ETc,d  
Month 8 
Month 6 
Month 7 
Study day (±Visit Window) 
-228 to -169 
Day -168 
Day -140 ±7 
Day -112 ±7 
Day -84 ±7 
Day -56 ±7 
Day -28 ±7 
Day 1  
Day 15 ±3  
Day 29 ±7 
Day 43 ±3 
Day 57 ±7 
Day 85 ±7 
Day 113 ±7 
Day 141 ±7 
Day 169 ±7 
Day 197 ±7 
Day 225 ±7 
Exploratory biomarkersl,p  
(Optional) 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Exploratory circulating RNAl, p 
(Optional) 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Exploratory DNA samplel  
(Optional) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma PK (East Asian patients 
only) l, p 
 
 
 
 
 
 
 
X 
 
  
 
X 
  
X 
  
X  
 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urine Collection for Biomarkersl 
(Optional) 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
HJHSq 
 
X 
 
 
 
 
 
Xw 
 
 
 
 
 
 
 
 
Xq 
 
Patient Resource Useq 
 
X 
 
 
 
 
 
Xw 
 
 
 
 
 
 
 
 
Xq 
 
VV-CLIN-0254442 4.0




SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
 
13 
Table 1 - Schedule of assessments                   
Study visit (Month) 
Screening 
Factor or BPA 
prophylaxis perioda 
Fitusiran treatment periodb 
AT 
F/Ud,e  
Onset 
periodb 
Efficacy period 
Month -6 
Month -5 
Month -4 
Month -3 
Month -2 
Month -1 
Baseline 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
EOT 
EOS/ 
ETc,d  
Month 8 
Month 6 
Month 7 
Study day (±Visit Window) 
-228 to -169 
Day -168 
Day -140 ±7 
Day -112 ±7 
Day -84 ±7 
Day -56 ±7 
Day -28 ±7 
Day 1  
Day 15 ±3  
Day 29 ±7 
Day 43 ±3 
Day 57 ±7 
Day 85 ±7 
Day 113 ±7 
Day 141 ±7 
Day 169 ±7 
Day 197 ±7 
Day 225 ±7 
COVID-19 Testing 
Anytime during the study x  
Abbreviations:  APRI = AST to platelet ratio; AT = antithrombin; BPA = bypassing agent; ECG = electrocardiogram; eDiary = electronic diary; EOS = End of Study; EOT = End of Treatment; ET = 
Early Termination; FVIII = Factor VIII; FIX = Factor IX; F/U = follow-up; HAL = Haemophilia Activities List; HJHS = Hemophilia Joint Health Score; Min = minute; pedHAL = paediatric HAL; PK = 
pharmacokinetics; Q2M = every 2 months; SAEs = serious adverse events; TG = thrombin generation; TSQM-9 = treatment satisfaction questionnaire for medication 
Note: 
• 
See Section 7 for study assessment instructions. 
• 
Any Screening assessments performed within 7 days prior to Month -6 do not need to be repeated at the Month -6 visit. In exceptional circumstances, screening may be extended beyond 
the 60 day window after consultation with the sponsor. In this case, some assessments done at the beginning of screening may have to be repeated.  
• 
Rescreening of patients is permitted with consultation of the study Medical Monitor.  
• 
Laboratory parameters are described in Section 7.6.5 and listed in Table 7. 
• 
When scheduled at the same time points, vital signs and 12-lead ECGs will be performed before the physical examinations and blood/urine sample collections. 
• 
Unless otherwise specified, assessments on dosing days are predose. 
a Routine prophylaxis with factor concentrates or BPAs for treatment of hemophilia. The subgroup Cohort A patients who are not responding adequately to BPA prophylaxis treatment will not 
participate in the BPA prophylaxis period and will directly start the fitusiran treatment period after the screening period. For these patients, the screening period will be from Day -60 to Day 0 and 
assessments during the BPA prophylaxis period are not applicable with the exception of the exploratory DNA sample. For the United States specific requirements see Section 11.6.1.1. 
b Fitusiran as prophylaxis treatment and permitted on-demand use of factors or BPAs for treatment of breakthrough bleeding episodes.  Patients may continue their routine factor or BPA 
administration schedule for up to the first 7 days of the onset period. For the United States specific requirements see Section 11.6.1.1. 
c Not required at Early Termination Visit for patients who complete assessment at EOT Visit and subsequently Early Terminate.  
VV-CLIN-0254442 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
 
14 
d Patients who discontinue study drug dosing for any reason and agree to complete the remaining assessments through the EOS/ET and AT FU visits and may receive treatment consistent with 
local standard practice for their disease per Investigator judgement, as applicable.  For patients who withdraw from the study early and do not consent to complete remaining assessments through 
the EOS/ET and AT FU visits, every effort should be made to conduct the assessments performed at the EOS/ET visit. 
e Patients not enrolling in the extension study will complete AT F/U visits at monthly intervals following final fitusiran dose until AT activity level returns to ~60% (per the central laboratory), or per 
Investigator discretion in consultation with the study Medical Monitor. 
f 
The complete medical history/disease history (ie, including bleeding episode and treatment history over the prior 6 months) to be recorded at Screening. 
g eDiary training will be completed at the Clinic at Screening (see Section 7.2.1). 
h A full physical examination will be performed at Screening only; a directed physical exam will be performed at all other visits (see Section 7.6.3). 
i 
Height will be recorded only at Screening for patients > 18 years old. Height for patients < 18 years old and weight for all patients will be recorded at all checked visits (Section 7.6.2).  
j 
12-lead ECGs will be performed in triplicate. On Day 1, 12-lead ECGs will be performed predose and 4 hours (±30 min) postdose (see Section 7.6.4). The Month 7 12-lead ECG will be performed 
only in those patients who are performing the ET visit and may be performed in singlicate.   
k Hepatitis C virus antibody positive patients only. FibroScan where available, otherwise FibroTest and APRI. 
l 
Sample may be used for study of biomarkers related to hemophilia and associated conditions, investigations of emerging safety issues, or the development of fitusiran.  After specified analyses 
are run, residual samples may be stored for up to 15 years from last patient, last visit, or as per local regulations, and used for further study of biomarkers related to hemophilia and associated 
conditions, investigation of emerging safety issues, or the development of fitusiran. Samples drawn from central lines may be excluded from TG analysis. 
m To be performed in all patients, at any clinic visit during their factor or BPA prophylaxis period, with blood drawn before, 10 min (±5 min) after, and 60 min (±5 min) after administration of their 
usual prophylactic dose of factor or BPA.  Laboratory testing pre- and post- factor/BPA include: Coagulation, and TG.  The timing of this visit should coincide with the patient’s usual prophylaxis 
regimen, so that pre-dose thrombin generation is at nadir and the benefit of administered factor or BPA is maintained. For the United States specific requirements see Section 11.6.1.1.  
n On fitusiran dosing days, samples will be collected within 4 hour priors to dosing. For the AT assessments, upon the first AT level <15%, the patients must have another AT activity level sample 
drawn within 1 week of site receipt of the results. 
o Liver function tests (LFTs) and hepatic tests are as listed in Table 7. LFTs may be obtained up to 7 days before the clinic visit on which fitusiran dosing is scheduled.  LFTs performed within 
7 days of Day 1 will only be used to inform dosing on Day 1 and do not need to be used to confirm eligibility.  LFTs can be analyzed locally, but if a local assessment is drawn, a serum chemistry 
sample must also be drawn for analysis at the central laboratory. Under conditions of elevated ALT and/or AST, see Section 6.2.3.1 and Table 8. LFT results will be obtained prior to receiving 
monthly fitusiran dosing.   
p Blood samples for PK analysis will be collected at the time points listed in Table 11 in East Asian patients at East Asian sites.   
q Must be completed at clinic.  Will be collected at EOS visit; not collected at ET visit. 
r 
Perioperative assessment of safety and hemostatic efficacy only in patients undergoing major operative procedures while on study drug (see Table 12). 
s Will include review of entries, (symptoms of bleed events, bleed causality, bleed severity, doses administered), whether appropriate site contact occurred regarding treatment of bleeds, and 
review of patient bleed management plan and recommendations and requirements for site contact regarding dosing. 
t 
It is strongly preferred that factor or BPA administration and bleeding events are entered in the eDiary immediately or within 24 hours. Additional patient follow-up may be required as described in 
Section 7.2.1. Patients in the fitusiran treatment arm who present in the clinic with symptoms characteristic of a potential bleeding episode should have assessments completed per Table 2. For 
the United States specific requirements see Section 11.6.1.1. 
u AEs will be monitored and recorded from date of signed informed consent through Follow-Up.  Signs and symptoms of thrombosis will be evaluated at every visit (see Section 6.5). 
v In addition to recording concomitant medications, documented history of prior medications will be collected during Screening. 
w As per patient and Investigator convenience, these assessments can be completed on a different day within 2 days prior to the Baseline visit.  
x 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. 
VV-CLIN-0254442 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
 
15 
Table 2 - Bleeding episode assessments - unscheduled visit               
 
Predose 
Postdose 
10 min (±5 min)d 
Postdose 
60 min (±5 min) d 
Directed Physical Examinationa 
X 
 
 
Vital Signs 
X 
 
 
AT 
X 
 
 
FVIII/FIX Levels 
(only if treated with FVIII or FIX) 
X 
X 
X 
TG 
X 
X 
X 
Coagulation 
X 
X 
X 
Hematology 
X 
X 
X 
Optional Imagingc 
X 
 
 
Abbreviations:  AT = antithrombin; FVIII = Factor VIII; FIX = Factor IX; TG = thrombin generation 
For the United States specific requirements see Section 11.6.1.1. 
a See Section 7.6.3 for assessments to be performed during a directed physical examination. 
b Removed. 
c Investigator to consider confirmation of bleed via ultrasound or other imaging modality at clinical study centers where appropriate equipment and staff with related expertise is available. 
d If the patient presents following administration of factor or BPAs at home and within 48 hours of the dose, and no further treatment is given at the center, AT and the postdose assessments should 
be obtained in a single draw at any time during the visit. 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
16 
TABLE OF CONTENTS  
CLINICAL STUDY PROTOCOL........................................................................................................ 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................................... 2 
DOCUMENT HISTORY ...................................................................................................................... 2 
OVERALL RATIONALE FOR THE AMENDMENT ........................................................................... 2 
PROTOCOL SYNOPSIS .................................................................................................................... 5 
TABLE OF CONTENTS ................................................................................................................... 16 
LIST OF TABLES ............................................................................................................................. 22 
LIST OF FIGURES ........................................................................................................................... 22 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ......................................................... 23 
1 
INTRODUCTION ............................................................................................................... 26 
1.1 
DISEASE OVERVIEW ....................................................................................................... 26 
1.2 
FITUSIRAN (SAR439774) ................................................................................................. 27 
1.2.1 
Summary of nonclinical data with fitusiran ........................................................................ 27 
1.2.2 
Summary of clinical data with fitusiran .............................................................................. 29 
1.2.2.1 
Summary of efficacy .......................................................................................................... 29 
1.2.2.2 
Summary of safety ............................................................................................................. 29 
1.2.2.3 
Summary of pharmacokinetic and pharmacodynamic effects in ALN-AT3SC-001 and 
ALN-AT3SC-002 ................................................................................................................ 30 
1.3 
STUDY DESIGN RATIONALE .......................................................................................... 30 
1.4 
DOSE RATIONALE ........................................................................................................... 31 
1.5 
BENEFIT-RISK ASSESSMENT ........................................................................................ 32 
2 
OBJECTIVES .................................................................................................................... 34 
2.1 
PRIMARY OBJECTIVE ..................................................................................................... 34 
2.2 
SECONDARY OBJECTIVES ............................................................................................ 34 
2.3 
EXPLORATORY OBJECTIVES ........................................................................................ 34 
3 
ENDPOINTS ...................................................................................................................... 35 
3.1 
PRIMARY ENDPOINT ....................................................................................................... 35 
3.2 
SECONDARY ENDPOINTS .............................................................................................. 35 
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3.3 
EXPLORATORY ENDPOINTS .......................................................................................... 35 
3.4 
SAFETY ENDPOINT ......................................................................................................... 35 
4 
INVESTIGATIONAL PLAN ............................................................................................... 36 
4.1 
SUMMARY OF STUDY DESIGN ...................................................................................... 36 
4.2 
DURATION OF TREATMENT ........................................................................................... 38 
4.3 
NUMBER OF PATIENTS................................................................................................... 38 
4.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUPS................................ 39 
4.5 
BLINDING .......................................................................................................................... 39 
4.6 
STUDY STEERING COMMITTEE .................................................................................... 39 
4.7 
DATA MONITORING COMMITTEE .................................................................................. 39 
5 
SELECTION AND WITHDRAWAL OF PATIENTS .......................................................... 40 
5.1 
INCLUSION CRITERIA ..................................................................................................... 40 
5.2 
EXCLUSION CRITERIA .................................................................................................... 41 
5.3 
REMOVAL FROM THERAPY OR ASSESSMENT ........................................................... 43 
5.3.1 
Discontinuation of study drug ............................................................................................ 44 
5.3.2 
Withdrawal from study ....................................................................................................... 44 
5.3.3 
Criteria for temporarily delaying enrollment or administrations of study intervention ........ 45 
6 
TREATMENTS .................................................................................................................. 46 
6.1 
TREATMENTS ADMINISTERED ...................................................................................... 46 
6.2 
INVESTIGATIONAL MEDICINAL PRODUCT ................................................................... 46 
6.2.1 
Description ......................................................................................................................... 46 
6.2.2 
Dose and administration .................................................................................................... 46 
6.2.3 
Dose modifications ............................................................................................................ 47 
6.2.3.1 
LFT criteria for withholding, monitoring, and stopping fitusiran dosing ............................. 47 
6.2.3.2 
Antithrombin level criteria for a dose adjustment .............................................................. 48 
6.2.3.3 
Temporary discontinuation due to a regional or national emergency ............................... 48 
6.2.4 
Preparation, handling, and storage ................................................................................... 49 
6.2.5 
Packaging and labeling...................................................................................................... 49 
6.2.6 
Accountability ..................................................................................................................... 49 
6.3 
CONCOMITANT MEDICATIONS ...................................................................................... 50 
6.3.1 
Factor concentrates or bypassing agent prophylaxis ........................................................ 50 
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6.3.1.1 
Routine use of factor or bypassing agent prophylaxis in the factor or bypassing agent 
prophylaxis period .............................................................................................................. 50 
6.3.1.2 
Management of factor or bypassing agent prophylaxis during the transition to the fitusiran 
treatment period ................................................................................................................. 51 
6.3.2 
Management of bleeding episodes .................................................................................... 51 
6.3.2.1 
Bleeding episode management recommendations for patients during the factor or 
bypassing agent prophylaxis period (patients not receiving fitusiran) ............................... 51 
6.3.2.2 
Bleeding episode management recommendations for patients during the fitusiran 
treatment period (for the United States specific requirements, see Appendix 11.5.1.2) ... 52 
6.3.2.3 
Use of factor or bypassing agents following discontinuation of fitusiran (for the United 
States specific requirements, see Appendix 11.5.1.2) ...................................................... 54 
6.3.3 
Other concomitant medications ......................................................................................... 54 
6.4 
ASSESSMENT OF COAGULATION PARAMETERS AT THE TIME OF A BLEED ......... 55 
6.5 
MONITORING AND MANAGEMENT OF THROMBOTIC EVENTS ................................. 55 
6.6 
ELECTIVE AND/OR EMERGENCY SURGERY ............................................................... 56 
6.7 
MANAGEMENT OF SEPSIS ............................................................................................. 57 
6.8 
CONTRACEPTIVE REQUIREMENTS .............................................................................. 57 
6.9 
TREATMENT COMPLIANCE ............................................................................................ 57 
6.10 
ALCOHOL RESTRICTIONS .............................................................................................. 57 
7 
STUDY ASSESSMENTS .................................................................................................. 58 
7.1 
SCREENING/BASELINE ASSESSMENTS....................................................................... 58 
7.1.1 
Patient education module .................................................................................................. 58 
7.1.2 
Inhibitor status ................................................................................................................... 58 
7.1.3 
FibroScan or FibroTest/APRI ............................................................................................ 58 
7.2 
EFFICACY ASSESSMENTS ............................................................................................. 59 
7.2.1 
Electronic diary .................................................................................................................. 60 
7.3 
PHARMACODYNAMIC ASSESSMENTS ......................................................................... 60 
7.3.1 
Antithrombin (AT) activity................................................................................................... 61 
7.3.2 
Thrombin generation .......................................................................................................... 61 
7.3.3 
Coagulation/Thrombin generation response assessment in factor or bypassing agent 
prophylaxis period .............................................................................................................. 61 
7.3.4 
Exploratory analyses ......................................................................................................... 61 
7.4 
PHARMACOKINETIC ASSESSMENTS ............................................................................ 62 
7.5 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH .................... 62 
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19 
7.6 
SAFETY ASSESSMENTS ................................................................................................. 63 
7.6.1 
Vital signs .......................................................................................................................... 63 
7.6.2 
Weight and height .............................................................................................................. 63 
7.6.3 
Physical examination ......................................................................................................... 63 
7.6.4 
Electrocardiogram .............................................................................................................. 64 
7.6.5 
Clinical laboratory assessments ........................................................................................ 64 
7.6.5.1 
Additional laboratory assessments .................................................................................... 66 
7.6.5.2 
Immunogenicity .................................................................................................................. 67 
7.6.6 
Adverse events .................................................................................................................. 67 
7.6.6.1 
Definitions .......................................................................................................................... 67 
7.6.6.2 
Eliciting and recording adverse events .............................................................................. 70 
7.6.6.3 
Serious adverse events and adverse events of special interest require immediate 
reporting to Sponsor/Designee .......................................................................................... 71 
7.6.6.4 
Sponsor safety reporting to Regulatory Authorities ........................................................... 71 
7.6.6.5 
Serious adverse event notification to the Institutional Review Board/Independent Ethics 
Committee ......................................................................................................................... 72 
7.6.6.6 
Pregnancy reporting .......................................................................................................... 72 
7.6.6.7 
Overdose reporting ............................................................................................................ 72 
7.6.6.8 
Guidelines for reporting product complaints/medical device incidents (including 
malfunctions) ..................................................................................................................... 72 
7.7 
OTHER ASSESSMENTS .................................................................................................. 73 
7.7.1 
Patient-reported outcomes ................................................................................................ 73 
7.7.1.1 
HRQOL instruments: Haem-A-QOL and Haemo-QOL ...................................................... 73 
7.7.1.2 
TSQM-9 ............................................................................................................................. 73 
7.7.1.3 
HAL .................................................................................................................................... 73 
7.7.1.4 
EQ-5D-5L ........................................................................................................................... 74 
7.7.2 
HJHS.................................................................................................................................. 74 
8 
STATISTICS ...................................................................................................................... 75 
8.1 
DETERMINATION OF SAMPLE SIZE .............................................................................. 75 
8.2 
STATISTICAL METHODOLOGY ...................................................................................... 76 
8.2.1 
Populations to be analyzed ............................................................................................... 76 
8.2.2 
Examination of subgroups ................................................................................................. 77 
8.2.3 
Handling of missing data ................................................................................................... 77 
8.2.4 
Baseline evaluations .......................................................................................................... 77 
8.2.5 
Efficacy analyses ............................................................................................................... 77 
8.2.5.1 
Primary endpoint ................................................................................................................ 77 
8.2.5.2 
Secondary endpoints ......................................................................................................... 78 
8.2.5.3 
Exploratory endpoints ........................................................................................................ 78 
8.2.6 
Pharmacodynamic analysis ............................................................................................... 78 
8.2.7 
Pharmacokinetic analysis .................................................................................................. 78 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
20 
8.2.8 
Safety analyses ................................................................................................................. 79 
8.2.9 
Other analyses ................................................................................................................... 79 
8.2.10 
Interim analysis .................................................................................................................. 79 
9 
STUDY ADMINISTRATION .............................................................................................. 80 
9.1 
ETHICAL AND REGULATORY CONSIDERATIONS ....................................................... 80 
9.1.1 
Informed consent process ................................................................................................. 80 
9.1.2 
Ethical review ..................................................................................................................... 80 
9.1.3 
Study documentation, confidentiality, and records retention ............................................. 81 
9.1.4 
End of the study ................................................................................................................. 81 
9.1.5 
Discontinuation of the clinical study ................................................................................... 81 
9.2 
DATA QUALITY CONTROL AND QUALITY ASSURANCE ............................................. 82 
9.2.1 
Data handling ..................................................................................................................... 82 
9.2.2 
Study monitoring ................................................................................................................ 82 
9.2.3 
Audits and inspections ....................................................................................................... 83 
9.3 
PUBLICATION POLICY..................................................................................................... 83 
9.4 
DISSEMINATION OF CLINICAL STUDY DATA ............................................................... 83 
10 
LIST OF REFERENCES ................................................................................................... 84 
11 
APPENDICES ................................................................................................................... 86 
11.1 
PHARMACOKINETIC ASSESSMENT TIME POINTS ...................................................... 86 
11.2 
PERIOPERATIVE SCHEDULE OF ASSESSMENTS ....................................................... 87 
11.2.1 
Definitions of minor and major surgery .............................................................................. 87 
11.2.2 
Perioperative assessments of safety and hemostatic efficacy in patients undergoing major 
operative procedures ......................................................................................................... 87 
11.3 
ISTH GUIDELINE FOR ASSESSMENT OF TREATMENT RESPONSE ......................... 89 
11.4 
BLEED SEVERITY DEFINITIONS .................................................................................... 89 
11.5 
DATA PROTECTION ......................................................................................................... 89 
11.6 
COUNTRY-SPECIFIC REQUIREMENTS ......................................................................... 91 
11.6.1 
United States ..................................................................................................................... 91 
11.6.1.1 Protocol synopsis ............................................................................................................... 92 
11.6.1.2 Protocol body ..................................................................................................................... 95 
11.6.2 
Japan ............................................................................................................................... 111 
11.7 
PROTOCOL AMENDMENT HISTORY ........................................................................... 112 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
21 
11.7.1 
Amended Protocol 01 ...................................................................................................... 112 
11.7.2 
Amended Protocol 02 ...................................................................................................... 113 
11.7.3 
Amended Protocol 03 ...................................................................................................... 118 
11.7.4 
Amended Protocol 04 ...................................................................................................... 120 
11.7.5 
Amended Protocol 05 ...................................................................................................... 130 
11.8 
CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL EMERGENCY THAT 
IS DECLARED BY A GOVERNMENTAL AGENCY ........................................................ 139 
 
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Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
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22 
LIST OF TABLES  
Table 1 - Schedule of assessments .............................................................................................................. 9 
Table 2 - Bleeding episode assessments - unscheduled visit .................................................................... 15 
Table 3 – Simulated AT activity percentiles, for various doses of fitusiran ................................................. 32 
Table 4 - Monitoring and dosing rules for asymptomatic patients with confirmed isolated elevations of ALT 
and/or AST >3× ULN, with no alternative cause identified ......................................................................... 47 
Table 5 - Factor or bypassing agent prophylaxis requirements .................................................................. 50 
Table 6 - Bleed management dosing guidelines by specific product .......................................................... 53 
Table 7 - Clinical laboratory assessments .................................................................................................. 65 
Table 8 - Hepatic assessments in patients who experience LFT elevations .............................................. 67 
Table 9 - Simulated ratio of rates for Cohort A, with 95% confidence intervals .......................................... 75 
Table 10 - Simulated ratio of rates for Cohort B, with 95% confidence intervals ........................................ 76 
Table 11 - Pharmacokinetic time points in East Asian patients at East Asian sites following fitusiran 
administration at 50 mg Q2M ...................................................................................................................... 86 
Table 12 - Perioperative schedule of assessments in patients undergoing major operative procedures .. 88 
Table 13 - Assessment of treatment of acute joint/muscle bleeding episodes ........................................... 89 
Table 14 - Bleed severity definitions ........................................................................................................... 89 
Table 15 - Factor or Bypassing agent prophylaxis requirements ............................................................. 102 
Table 16 - Bleed management dosing guidelines by specific product ...................................................... 105 
 
LIST OF FIGURES  
Figure 1 - Study design ............................................................................................................................... 37 
Figure 2 - Study design (for subgroup of Cohort A patients enrolling directly into the fitusiran treatment 
period) ......................................................................................................................................................... 38 
 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
23 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
Abbreviation or Specialist Term 
Explanation 
ABR 
annualized bleeding rate 
AE 
adverse event 
ALT 
alanine transaminase 
aPCC 
activated prothrombin complex concentrates 
APRI 
AST to platelet ratio index 
AST 
aspartate transaminase 
AT 
antithrombin 
AUC 
area under the concentration-time curve 
BPA 
bypassing agent 
CFR 
Code of Federal Regulation 
CL/F 
apparent clearance 
Cmax 
maximum plasma concentration 
COVID-19 
Coronavirus Disease 2019  
CYP P450 
cytochrome P450 
DMC 
Data Monitoring Committee 
DTP 
Direct-to-Patient 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eDiary 
electronic diary 
EOS 
end of study 
EOT 
end of treatment 
EQ-5D 
EuroQol- 5 dimension 
FIX 
Factor IX 
FV 
Factor V 
FVIII 
Factor VIII 
FX 
Factor X 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HAL 
Haemophilia Activities List 
Haem-A-QOL 
Haemophilia Quality of Life Questionnaire for Adults 
Haemo-QOL 
Haemophilia Quality of Life Questionnaire for Children and 
Adolescents 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
24 
Abbreviation or Specialist Term 
Explanation 
HRQOL 
health-related quality of life 
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 
IV 
intravenously  
MAD 
multiple-ascending dose 
MD 
multiple dose 
mRNA 
messenger ribonucleic acid 
NHP 
non-human primates 
NOAEL 
no observed adverse effect level 
OTC 
over-the-counter 
pedHAL 
pediatric HAL 
PK 
pharmacokinetics 
PT 
prothrombin time 
Q2M 
every 2 months 
QM 
every month 
QOL 
quality of life 
RT-PCR 
reverse transcription polymerase chain reaction 
rVIIa 
recombinant Factor VIIa 
SAD 
single-ascending dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SC 
subcutaneous 
SDay 
surgery day 
siRNA 
small interfering ribonucleic acid 
tmax 
time to maximum plasma concentration 
TG 
thrombin generation 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
25 
Abbreviation or Specialist Term 
Explanation 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
t½β 
elimination half-life 
ULN 
upper limit of normal 
V/F 
apparent volume of distribution 
VV-CLIN-0254442 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
26 
1 
INTRODUCTION  
1.1 
DISEASE OVERVIEW  
Hemophilia A and hemophilia B are X-linked recessive inherited bleeding disorders, 
characterized by deficiency of coagulation Factors VIII (FVIII) or Factor IX (FIX), leading to a 
profound defect of thrombin generation with impaired hemostasis and increased risk of bleeding.  
Hemophilia A is found in approximately 1 in 4000 males whereas hemophilia B is five times less 
common and seen in approximately 1 in 20,000 males (1). The disease affects all ethnicities and 
the mutation responsible for hemophilia is typically inherited from a carrier parent, although 
spontaneous mutations are responsible for ~30% of all cases (2). 
The disease phenotype presents similarly in hemophilia A and B (3). Hemophilia is classified as 
mild (factor levels 6% to 30%), moderate (factor levels 1% to 5%), or severe (factor levels <1%) 
based on clotting factor activity relative to normal (healthy, non-hemophiliac plasma levels of 
factor are 50% to 150%). Patients with mild hemophilia typically experience bleeding after a 
serious injury or surgery; patients with moderate hemophilia experience bleeding episodes 
associated with injuries, and may have spontaneous bleeding episodes; severe hemophilia 
patients experience substantial bleeding with injury and may have frequent spontaneous bleeding 
episodes resulting in debilitating musculoskeletal damage that can markedly impair a patient’s 
mobility and quality of life (QOL). 
The hemostatic system aims to maintain the integrity of the vasculature by protecting against 
bleeding from vessel lesions combined with multiple options to prevent thrombosis. This 
hemostatic balance is achieved through an orchestrated regulation of both procoagulant 
(eg, Factor V [FV], Factor VII [FVII], FVIII, FIX, Factor X [FX]) and anticoagulant 
(eg, antithrombin, protein C/protein S and tissue factor pathway inhibitor) factors. Recent studies 
have suggested that coinheritance of a deficiency in natural anticoagulants may contribute to a 
milder phenotype in patients with hemophilia. Antithrombin (AT) is a liver-expressed natural 
anticoagulant that plays a key role in inhibiting thrombin. Furthermore, AT acts as an inhibitor of 
FVIIa and FXa, which are typically at normal levels in patients with hemophilia A or B.  
Extensive preclinical in vitro and in vivo studies have described reduction of AT as a potential 
safe and effective way to correct thrombin generation in both hemophilia A and B and control 
against microvascular and macrovascular traumatic bleeding episodes (4). Therefore, 
suppression of AT production is being investigated as a potential hemophilia treatment. 
Replacement with factor concentrates is the current standard of care for hemophilia patients 
without inhibitory antibodies to FVIII or FIX. While the current standard of care of factor 
substitution therapy, administered either episodically or as routine prophylaxis, is well 
established, safe, and efficacious, it is associated with high treatment burden due to requiring 
intravenous (IV) administration on a frequent schedule (2 to 3 times per week or more) to 
prophylactically maintain hemostasis (3). Factor concentrates also can be of limited availability 
in developing nations.  In addition, patients receiving factor concentrates may develop an 
inhibitory antibody to factor, a result that carries a poorer prognosis and requires a change in 
treatment regimen to infusion with BPAs. 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
27 
Hemophilia patients who develop inhibitory antibodies to factor concentrates represent a distinct 
subset of the population; these patients typically experience more difficult-to-treat bleeding 
episodes, leading to increased morbidity and increased mortality (5). Development of inhibitors 
to infused factor occurs mainly in severe hemophilia, and more frequently in hemophilia A (up to 
39% of patients) (6, 7) than in hemophilia B (1% to 3.5% of patients) (8, 9) with the greatest risk 
of development in the early exposure days. These “inhibitor” patients, may be eligible for 
immune tolerance therapy, however in most cases bleeding episodes require hemostatic 
intervention with intravenously (IV)-administered BPAs, ie, recombinant Factor VIIa (rVIIa), or 
activated prothrombin complex concentrates (aPCC), either as prophylaxis or as on-demand 
episodic treatment of bleeding episodes. 
A subcutaneous therapy that can effectively and safely prevent or reduce the frequency of 
bleeding episodes in patients with hemophilia A or B, including those with inhibitors, may 
reduce treatment burden, improve clinical outcomes and enhance quality of life. Fitusiran is 
being developed to address these needs of patients with hemophilia. 
1.2 
FITUSIRAN (SAR439774)  
Fitusiran (SAR439774 [formerly Alnylam ALN-AT3SC]) is an investigational agent comprising 
a synthetic siRNA covalently linked to a triantennary GalNAc ligand, designed to suppress liver 
production of AT as a strategy to rebalance the hemostatic system, thereby improving thrombin 
generation and hemostasis in individuals with hemophilia. 
Fitusiran is a GalNAc-siRNA conjugate that reduces production of AT, leading to lower plasma 
AT levels.  By reducing plasma AT, fitusiran is designed to improve thrombin generation and 
hemostasis in individuals with hemophilia, regardless of hemophilia type or presence of 
inhibitory antibodies to Factor VIII or IX. Because of the durability of the PD effect of fitusiran 
demonstrated in previous nonclinical and clinical studies, the subcutaneous (SC) administration 
required is notably less frequent  than current IV standard of care with factor concentrates or 
BPAs (as frequent as every other day in severe cases), representing potentially improved quality 
of life and lowered treatment burden for patients with hemophilia.  Further, with the durable PD 
effect, it is possible that fitusiran may maintain a patient at a more consistent, robust hemostasis 
than intermittent factor concentrates or BPAs. 
Fitusiran is being developed for the indication of routine prophylaxis to prevent or reduce the 
frequency of bleeding episodes in patients with hemophilia A or B with or without inhibitory 
antibodies to FVIII or FIX. 
1.2.1 Summary of nonclinical data with fitusiran  
Nonclinical pharmacology and exploratory toxicity studies have been conducted in wild-type 
(WT) and hemophilia mouse models, as well as WT rats, WT dogs, hemophilic dogs, and WT 
non-human primates (NHP). The fitusiran siRNA sequence is homologous across all tested 
species; therefore, across multiple studies (single and repeat-dose), fitusiran exhibits potent and 
dose-dependent pharmacologic activity, resulting in reduced tissue AT mRNA levels and 
subsequent reduced circulating AT protein and activity levels, with a single-dose ED50 of 
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28 
~1 mg/kg in multiple species. Exploratory pharmacology studies have also been completed in the 
hemophilia A dog and in an NHP induced hemophilia model. 
A GLP-compliant SC safety pharmacology study in NHP was conducted and there were no 
effects on measured cardiovascular or respiratory parameters after a single SC dose at any dose, 
with a NOEL for cardiovascular effects of 
 (highest dose evaluated). There were no 
neurological effects in the GLP 39-week NHP study with a NOEL of 
 (highest dose 
evaluated with repeat dosing). The pharmacology studies are summarized in greater detail in the 
Investigator’s Brochure. 
Plasma PK and toxicokinetic studies of single and repeated IV and/or SC 
 doses of 
fitusiran were conducted in rats, dogs, and monkeys, and 
 of fitusiran in mice.  
Following SC administration, fitusiran was rapidly absorbed following IV and SC 
administrations of 
 in mice with Cmax occurring within 30 minutes of dose 
administration followed by clearance in a biphasic manner. There were no gender-related 
differences in the PK properties of fitusiran.  After repeat dosing, the plasma PK profiles were 
similar after first and last dose indicating no time dependent changes in the PK of fitusiran. 
In the in vitro studies of rats and NHPs fitusiran did not cause induction of the common P450 
isoforms and was not a substrate for the common cytochrome P450 (CYP P450) isoforms. 
Genetic toxicity studies (bacterial reverse mutation, mammalian chromosome aberration, rat 
micronucleus test) have been completed, and demonstrated that fitusiran is non-genotoxic. GLP 
toxicology (7-weekly doses) studies were conducted with fitusiran in the rat and NHP. A chronic 
26-week study in the rat and a 39-week study in NHP have been completed. The no observed 
adverse effect level (NOAEL) in the 7-week rat toxicology study was 
, and in the 
26-week rat toxicology study was 
.  The NOAEL in the 7-week NHP study was 
, and the NOAEL in the chronic NHP study was 
. The NOAELs in all 
studies were based on toxicity attributable to the exaggerated on-target, pro-coagulant 
pharmacology of fitusiran that is expected in wild type animals (hemorrhage and/or thrombosis 
in various tissues, which led to mortality above a threshold of approximately 
). By 
contrast, in exploratory studies, highly exaggerated doses of fitusiran (exposures in 100-fold 
excess of therapeutic relevance; >95% reduction in AT) were well tolerated in hemophilia A and 
B mice, with no evidence of toxicity or thrombosis. A 26-week GLP chronic toxicity in the 
hemophilia A mouse model was conducted. The top dose of 
 was well tolerated for 
26 weeks, indicating that hemophilic animals are not predisposed to pro-thrombotic effects 
compared to WT animals; a survival benefit was demonstrated in animals dosed with fitusiran vs 
saline controls (40% mortality in saline control vs 6% in fitusiran treated groups [p<0.0001 by 
Log-Rank test]). In addition, 6-month TgRasH2 mouse and 2-year rat carcinogenicity studies are 
currently ongoing. 
In the GLP-compliant 39-week chronic NHP toxicology study, administration of fitusiran by 
once weekly SC injection to peripubertal cynomolgus monkeys at doses of 
 
 was well tolerated (approximately 70% chronic AT suppression at 
).  Based on the absence of fitusiran related effects on the toxicology parameters 
evaluated at all dose levels tested, the NOAEL was considered to be 
. 
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29 
There was no effect of fitusiran on male reproduction in the rat and with repeat dose 
administration of fitusiran to juvenile rats and sexually immature cynomolgus monkeys, growth 
and maturation were unaffected. Overall, fitusiran was well tolerated locally, and non-genotoxic.  
Fitusiran does not activate the immune system. 
Taken together, the results from the nonclinical studies exhibit reduction in AT activity level, 
increase in thrombin generation, and corrective effect on hemostasis, thereby validating the 
therapeutic approach of the clinical studies. These nonclinical studies are summarized in the 
Investigator’s Brochure. 
1.2.2 Summary of clinical data with fitusiran  
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. 
1.2.2.1 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) (10, 11). 
A complete summary of available clinical efficacy data relevant to fitusiran is presented in the 
Investigator’s Brochure. 
1.2.2.2 Summary of safety  
Events of serious vascular thrombosis, liver transaminase abnormalities, cholecystitis, and 
symptomatic cholelithiasis have been reported in the clinical development program and are 
considered identified risks of fitusiran. In addition, serious hypersensitivity reactions, including 
injection site reactions, are considered a potential risk of fitusiran. 
One death has been reported in a patient with cerebral venous thrombosis (CVST) in 
ALN-AT3SC-002. In response to this event, the bleed management guidelines were revised in 
December 2017. 
A more detailed summary of available clinical safety data is presented in the Investigator’s 
Brochure. 
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30 
1.2.2.3 Summary of pharmacokinetic and pharmacodynamic effects in ALN-AT3SC-001 
and ALN-AT3SC-002  
Consistent with the intended pharmacological effects, regardless of inhibitor status, fitusiran 
dose-related reductions in AT activity level have been observed in the clinical studies and have 
been associated with increased thrombin generation. In Part C of the Phase 1 study, the mean 
maximum AT activity level reductions following 3 monthly doses of 0.225, 0.45, 0.9 or 
1.8 mg/kg fitusiran were 70% (N=3), 77% (N=3), 77% (N=3), and 89% (N=3), respectively. A 
fixed dose, 80 mg fitusiran, was also explored in Part C, resulting in a mean maximum AT 
activity level reduction of 87% (N=6).  In Part D of the study, patients with inhibitors were dosed 
with 50 or 80 mg fitusiran and experienced mean maximum AT activity level reduction of 82% 
(N=6) and 87% (N=10), respectively.  AT reduction was maintained in ALN-AT3SC-002, with 
mean maximal AT reduction of 83.6% for 50 mg (N=13) and 85.9% for 80 mg (N=21) as of 
08 August 2017. 
Consistent with the therapeutic hypothesis, increased AT lowering in patients with hemophilia 
resulted in increased thrombin generation when AT lowering was in the highest quartile (>75%) 
compared to when AT lowering was in the lowest quartile (<25%).  Further, the peak thrombin 
generation values achieved with AT lowering of >75% were comparable to those in the lower 
end of the normal range observed in healthy individuals.  None of the thrombin generation 
measurements following >75% AT reduction in hemophilia patients exceeded those seen in 
healthy males. 
1.3 
STUDY DESIGN RATIONALE  
The ATLAS-PPX trial (Alnylam ALN-AT3SC-009 [Sanofi Genzyme EFC15110]) is a 
multicenter, multinational, open-label Phase 3 switching study designed to demonstrate the 
efficacy and safety of fitusiran in patients with hemophilia A or B, who are currently treated with 
prophylactic regimens of factor concentrates or BPAs.   
The switching design allows for an intra-patient control to enable examination of the effect of the 
two treatment methods through comparison of the median ABR during the factor or BPA 
prophylaxis period and the median ABR of the same patient group when receiving fitusiran, 
while limiting confounding effects of different patient bleeding phenotypes and prophylaxis 
therapy variability.  Inhibitor patients with hemophilia B may have a high unmet need despite 
prophylactic BPA therapy, with limited other treatment options. Therefore, a limited number of 
inhibitor patients with hemophilia B who are not adequately responding to prophylactic BPA 
therapy could enroll directly into the fitusiran treatment period, thereby skipping the 6-month 
BPA prophylaxis period. The onset period duration reflects modeling data that estimates it takes 
approximately 28 days to reach the therapeutic target range in the majority of patients. For the 
United States specific requirements, see Section 11.6.1.2. 
Given that the study design employed is a single treatment arm, with a switch from prophylaxis 
to fitusiran for each patient, the study is not blinded. 
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31 
The primary endpoint of the study is ABR in the fitusiran efficacy period and the factor or BPA 
prophylaxis period.  ABR is a well-established endpoint that has been used as the primary 
endpoint in global approvals of factor replacement and BPA products. Secondary endpoints 
characterize annualized spontaneous and joint bleeding rates, change in Haem-A-QoL physical 
health score and total score in patients ≥17 years of age, ABR in the onset period, overall safety 
profile and the consumption of factor/BPA. 
Characterization of bleeding episodes is clinically relevant to assess overall bleeding episode 
protection.  Joint bleeding episodes result in pain and hemarthrosis, leading to progressive joint 
destruction, and hence are important to assess.  The Haem-A-QOL is a hemophilia-specific 
HRQOL survey instrument, has been used in other hemophilia clinical trials, has been validated, 
reviewed by clinicians, and is considered the most appropriate HRQOL tool available for use in 
the study.   
The study population will be comprised of males ≥12 years of age; it is appropriate to study 
fitusiran in adolescents (patients ≥12 to <18 years of age) because the pathophysiology of disease 
progression and bleeding episode management is the same as adults and self-management of 
hemophilia typically begins at 12 years of age (12). 
In the event of a breakthrough bleeding episode, on-demand use of factors or BPAs will be 
permitted throughout the entire study duration (see Section 6.3.2). 
1.4 
DOSE RATIONALE  
Dose selection was guided by the principle of identifying an optimal dose that is both well-
tolerated and efficacious. The fitusiran dose proposed for Phase 3 development was identified 
using both observed data from ongoing clinical studies, as well as extensive clinical simulations 
and modeling. The key pharmacodynamic (PD) and clinical parameters used to support the dose 
selection include decreases in AT activity, the most proximate and direct PD effect of fitusiran, 
as well as increases in thrombin generation and decreases in ABR. 
Observed data from Phase 1 and Phase 1/2 studies in patients with hemophilia A and B with or 
without inhibitors, and pharmacokinetic/pharmacodynamic (PK/PD)-modeled data, supported 
the initial selection of a fixed dose of 80 mg for this study, as subcutaneously administered once-
monthly. 
In observed data from Phase 1 and Phase 1/2 studies, monthly equivalent doses or monthly doses 
ranging from 0.045 mg/kg to 1.8 mg/kg and fixed doses of 50 mg and 80 mg have been 
evaluated.  A clear dose response trend of increased AT lowering was evident, with 
approximately 10% to 20% residual AT activity at a dose of 1.8 mg/kg and at fixed doses of 
50 mg and 80 mg subcutaneously administered once monthly. These data suggested that the 
maximum AT lowering achieved as a function of the dose administered reached an asymptote at 
~90% AT lowering and that it was unlikely higher doses will achieve meaningfully greater AT 
lowering.  In addition, both the 50 mg and 80 mg fixed doses produced substantial increases in 
peak thrombin generation, which approached the lower end of the normal range, but did not 
exceed the normal range. 
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32 
Dose-response modeling analyses are supportive of the observed data. A repeated time to event 
model was used to evaluate the relationship between AT lowering and the anticipated ABR.  
According to the model, the 80 mg fixed, once-monthly dose was anticipated to result in near 
maximal achievable reduction in ABR, in which the majority of patients may achieve >75% AT 
lowering, the therapeutic target. Weight was not a significant covariate in the model, suggesting 
no advantage to weight-based dosing. 
A change in the fitusiran dosing regimen is being introduced as a risk mitigation measure for 
vascular thrombotic events. 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 activity level <15% at 
any time during fitusiran treatment, the patient will be required to permanently discontinue 
fitusiran.  
Dosing Regimen Simulation 
A PK/PD model that describes the dynamics of AT activity for patients treated with fitusiran was 
developed and characterized on AT activity data from Phase 1 and Phase 2 studies. The model 
with the estimated parameters was used to simulate AT activity at steady state for different 
dosing scenarios in a virtual population of 1000 patients. 
The results of the simulations are shown in Table 3. Every 2 months (Q2M) and every month 
(QM) refer to fitusiran dosing every 8 weeks and every 4 weeks respectively; Trough AT and 
Peak AT are trough and peak AT activities; 5th, Median and 95th referring to 5th percentile, 
median and 95th percentile. 
Table 3 – Simulated AT activity percentiles, for various doses of fitusiran  
REGI
MEN 
Min
AT 
TroughAT_
5th_SS 
TroughAT_Me
dian_SS 
TroughAT_
95th_SS 
Max
AT 
PeakAT_5
th_SS 
PeakAT_Me
dian_SS 
PeakAT_9
5th_SS 
50 
Q2M 
10.5 
13.9 
23.3 
39.7 
77.5 
17.87 
32.37 
56.42 
50 QM 
7.96 
10.3 
17.2 
29.6 
58.5 
11.36 
18.23 
31.15 
 
 Based on the simulation results from Table 3, starting all patients on a 50 mg Q2M regimen is 
expected to achieve AT activity above 10% for all patients.      
1.5 
BENEFIT-RISK ASSESSMENT  
Based on the available clinical data (see Section 1.2.2), 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 
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33 
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. 
Identified risks of fitusiran include serious vascular thrombosis, liver transaminase abnormalities, 
cholecystitis, and symptomatic cholelithiasis.  In addition, serious hypersensitivity reactions, 
including injection site reactions, are considered a potential risk of fitusiran. 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, due to 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, liver 
transaminase abnormalities, and serious ISRs. 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 6.2.3.2), detailed guidance and oversight on treatment of breakthrough 
bleeding episodes with reduced factor and/or BPA dosing (Section 6.3.2), and monitoring and 
management of  thrombosis while patients are on fitusiran (Section 6.5). The protocol also 
excludes patients with evidence of liver disease (including active viral hepatitis) and stipulates 
ongoing monitoring for elevated transaminases (Section 6.2.3.1). The safety of trial patients will 
be overseen by an independent DMC (Section 4.7). 
For the United States specific requirements, see Section 11.6.1.2. 
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34 
2 
OBJECTIVES  
2.1 
PRIMARY OBJECTIVE  
• To characterize the frequency of bleeding episodes while receiving fitusiran treatment, 
relative to the frequency of bleeding episodes while receiving factor concentrate or 
bypassing agent (BPA) prophylaxis. For the United States specific requirements, see 
Section 11.6.1.2. 
2.2 
SECONDARY OBJECTIVES  
• To characterize the following while receiving fitusiran treatment, relative to receiving 
factor or BPA prophylaxis (for the United States specific requirements, 
see Section 11.6.1.2): 
- 
the frequency of spontaneous bleeding episodes 
- 
the frequency of joint bleeding episodes 
- 
health related quality of life (HRQOL) in patients ≥17 years of age 
• To characterize the frequency of bleeding episodes during the onset and treatment periods 
in patients receiving fitusiran  
• To characterize safety and tolerability of fitusiran 
• To characterize the annualized weight-adjusted consumption of factor/BPA while 
receiving fitusiran treatment, relative to receiving factor or BPA prophylaxis 
2.3 
EXPLORATORY OBJECTIVES  
• To characterize the effects of fitusiran on the following patient-reported outcomes while 
receiving fitusiran treatment, relative to receiving factor or BPA prophylaxis (for the 
United States specific requirements, see Section 11.6.1.2): 
- 
Patient satisfaction with fitusiran 
- 
Patient activity 
- 
HRQOL in adolescents (≥12 to <17 years of age) 
• To characterize the pharmacodynamic (PD) effect, PK, and immunogenicity of fitusiran 
• To characterize the effects of fitusiran on joint status while receiving fitusiran treatment, 
relative to receiving factor or BPA prophylaxis 
• To characterize the effects of fitusiran on patient resource use, relative to receiving factor 
or BPA prophylaxis 
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35 
3 
ENDPOINTS  
3.1 
PRIMARY ENDPOINT  
• Annualized Bleeding Rate (ABR) in the fitusiran efficacy period and the factor or BPA 
prophylaxis period (for the United States specific requirements, see Section 11.6.1.2) 
3.2 
SECONDARY ENDPOINTS  
• Annualized spontaneous bleeding rate in the fitusiran efficacy period and the factor or 
BPA prophylaxis period (for the United States specific requirements, 
see Section 11.6.1.2) 
• Annualized joint bleeding rate in the fitusiran efficacy period and the factor or BPA 
prophylaxis period (for the United States specific requirements, see Section 11.6.1.2) 
• Change in Haem-A-QOL physical health score and total score in the fitusiran treatment 
period and the factor or BPA prophylaxis period 
• ABR in the onset period 
• ABR in treatment period 
• Annualized weight-adjusted consumption of factor/BPA 
3.3 
EXPLORATORY ENDPOINTS  
• Change in the following in the fitusiran treatment period: 
- 
Treatment Satisfaction Questionnaire for Medication (TSQM) domain scores 
- 
Haemophilia Activities List (HAL) score 
- 
Paediatric HAL (pedHAL) score 
- 
EuroQol-5 Dimensions (EQ-5D) score 
- 
Haemo-QOL score 
- 
Hemophilia Joint Health Score (HJHS)  
• Number of target joint bleeding episodes  
• Incidence and titer of antidrug antibodies to fitusiran in the fitusiran treatment period 
• AT activity level over time 
• Thrombin generation over time 
• Fitusiran plasma levels  
• Change in patient resource use (eg, work/school attendance, visits to doctor/hospital) 
3.4 
SAFETY ENDPOINT  
• Incidence, severity, seriousness, and relatedness of adverse events 
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36 
4 
INVESTIGATIONAL PLAN  
4.1 
SUMMARY OF STUDY DESIGN  
The ATLAS-PPX trial (ALN-AT3SC-009) is a multicenter, multinational, open-label, Phase 3 
study designed to characterize the efficacy and safety of fitusiran in male patients, aged 
≥12 years, with severe hemophilia A or B, previously receiving factor or BPA prophylaxis.  The 
study consists of 2 cohorts: Cohort A will consist of patients with inhibitory antibodies to 
Factor VIII or Factor IX; Cohort B will consist of patients without inhibitor antibodies to 
Factor VIII or Factor IX.  A subgroup of Cohort A patients will include hemophilia B patients 
with inhibitory antibodies to Factor IX who are not responding adequately to BPA prophylaxis 
treatment (historical ABR ≥20) (see Inclusion Criteria in Section 5.1). The study has 3 periods 
defined by type of prophylaxis regimen (for the United States specific requirements, 
see Section 11.6.1.2): 
• 6-Month factor or BPA prophylaxis period in which patients will continue their prestudy, 
regularly scheduled prophylaxis regimen with factors or BPAs 
The subgroup of Cohort A patients who are not responding adequately to BPA 
prophylaxis treatment will not participate in this 6-Month BPA prophylaxis period and 
will start to directly receive fitusiran (in the 1-month onset period described below) after 
the screening period. 
• 1-Month onset period in which patients receive first dose of fitusiran while continuing 
their factor or BPA prophylaxis for up to 7 days 
• 6-Month fitusiran efficacy period in which patients receive fitusiran as prophylaxis. 
Together, the 1-month onset period and the 6-month fitusiran efficacy period constitute the 
fitusiran treatment period. 
Bleeding events and doses of factor concentrates or BPAs administered during the conduct of the 
study will be recorded in an electronic Diary (eDiary), as described in Section 7.2.1. Since 
bleeding episodes are recorded as an efficacy assessment of fitusiran, these will not be treated as 
AEs unless they meet any of the SAE criteria listed in Section 7.6.6.1.  Safety, quality of life, 
pharmacodynamic, and pharmacokinetic data will also be collected. 
On-demand use of factor concentrates or BPAs is defined as the use of these agents, as needed, 
for episodic bleeding, and not on a regular regimen intended to prevent spontaneous bleeding.  
Throughout the study, patients in the fitusiran treatment period may receive on-demand 
treatment for breakthrough bleeding episodes with factors or BPAs, as appropriate. For patients 
in the fitusiran treatment period who have received at least 1 dose of fitusiran and are being 
treated for breakthrough bleeding episodes, it is recommended to follow the guidelines provided 
in Section 6.3.2 per Investigator discretion. 
Following the screening and prophylaxis periods or following the screening period for the 
subgroup of Cohort A enrolling directly into the fitusiran treatment period all patients will be 
treated with fitusiran for a total of 7 months.  Therefore, the overall fitusiran treatment period is 
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37 
defined as the onset period (Day 1-28 after receipt of the first dose, during which the AT 
lowering capacity of fitusiran is increasing but has not yet reached therapeutic levels) plus the 
efficacy period (Day 29 and after, when the AT lowering capacity of fitusiran has achieved 
therapeutic target range). For the United States specific requirements, see Section 11.6.1.2. 
Any current surgery occurring close to the date of the Screening visit must have surgery-related 
hemostatic treatment completed at least 72 hours prior to Screening. Patients may undergo 
unplanned or emergency surgery during the study but must not schedule non-urgent surgery to 
occur during the study. Perioperative guidance should be followed as specified in Section 6.6. 
A study Steering Committee, composed of experts in the field of hemophilia, will advise the 
Sponsor on study design and conduct (Section 4.6). 
An independent data monitoring committee (DMC) will oversee the safety and overall conduct 
of this study as described in Section 4.7. 
The study design schema is presented in Figure 1. Patients who complete the study may be 
eligible for an open-label extension study. 
Figure 1 - Study design  
 
Abbreviations: AT=antithrombin 
Note: For subgroup of Cohort A patients enrolling directly into the fitusiran treatment period, see Figure 2. 
Note: For the United States specific requirements, see Section 11.6.1.2. 
a Patients will continue to receive prescribed factor or BPA prophylaxis for the first 7 days of the onset period.  
b Following final fitusiran dose, AT activity level will be monitored at monthly intervals following the final fitusiran dose until activity levels 
return to approximately 60% (per the central laboratory) or per Investigator discretion in consultation with the study Medical Monitor.  
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38 
Figure 2 - Study design (for subgroup of Cohort A patients enrolling directly into the fitusiran treatment 
period)  
 
Abbreviations: AT=antithrombin 
Note: For the United States specific requirements, see Section 11.6.1.2. 
a Patients will receive prescribed factor or BPA prophylaxis for the first 7 days of the onset period. 
b Following final fitusiran dose, AT activity level will be monitored at monthly intervals following the final fitusiran dose until activity levels 
return to approximately 60% (per the central laboratory) or per Investigator discretion in consultation with the study Medical Monitor. 
4.2 
DURATION OF TREATMENT  
The duration of treatment with fitusiran is 7 months.  The estimated total time on the study, 
inclusive of screening, for each patient is up to 15 months for all patients who enroll in the 
extension study, except for patients in the subgroup of Cohort A, which is up to 9 months. The 
estimated total time on study may be up to 21 months (up to 15 months for patients in the 
subgroup of Cohort A) for patients who do not enroll in the extension study due to the 
requirement for an additional 6 months of follow-up for monitoring of AT levels. 
4.3 
NUMBER OF PATIENTS  
Approximately 80 patients are planned for enrollment in this study, including approximately 
30 patients with inhibitors (Cohort A) and approximately 50 patients without inhibitors 
(Cohort B). Approximately 18 patients with hemophilia B (including approximately 
7 hemophilia B patients in Cohort A, among which are a subgroup of no more than 4 patients 
who are not responding adequately to BPA prophylaxis [see Section 5.1]), approximately 
11 hemophilia B patients in Cohort B, and approximately 7 adolescents (≥12 to <18 years of age) 
are also planned for enrollment. For the United States specific requirements, 
see Section 11.6.1.2. 
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39 
4.4 
METHOD OF ASSIGNING PATIENTS TO TREATMENT GROUPS  
All patients will be assigned to the same treatment sequence (prophylaxis period followed by 
fitusiran period) in this open-label study. 
Each patient will be uniquely identified in the study by a combination of the site number and 
patient identification number.  Upon signing the informed consent form (ICF), the patient will be 
assigned a patient identification number by the interactive response system (IRS). The 
Investigator or his/her delegate will contact the IRS after confirming that the patient fulfills all 
the inclusion criteria and none of the exclusion criteria. A combination of the site number and 
patient identification number will create the unique patient identifier. 
4.5 
BLINDING  
This study is an open-label study so blinding is not applicable; however, performing aggregate 
summaries of efficacy data will be restricted until database lock. 
4.6 
STUDY STEERING COMMITTEE  
A study Steering Committee, composed of experts in the field of hemophilia, will advise the 
Sponsor on study design and conduct.  In collaboration with the Sponsor, the committee will 
provide scientific leadership to the study to ensure that the highest standards are maintained. 
Clinical Advisors who are experts in the care of hemophilia patients and familiar with fitusiran 
will be available to discuss clinical aspects of care with Investigators for surgical cases, cases of 
thrombosis, or other medically complex circumstances that may arise on study, when clinical 
circumstances allow.  Such discussions will also look to involve the study Medical Monitor. 
4.7 
DATA MONITORING COMMITTEE  
An independent DMC will oversee the safety and overall conduct of this study, providing input 
to the Sponsor. The DMC will operate under the rules of a charter that will be reviewed and 
approved at the organizational meeting of the DMC. The DMC has the responsibility for 
reviewing safety data and analyses and making recommendations to the Sponsor. The DMC will 
perform periodic reviews of data during the course of the clinical trial, and on an ad hoc basis for 
review of emergent safety data, as defined in the DMC Charter for this clinical trial. 
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Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
40 
5 
SELECTION AND WITHDRAWAL OF PATIENTS  
5.1 
INCLUSION CRITERIA  
Each patient must meet all of the following inclusion criteria to be eligible for enrollment in the 
study (for the United States specific requirements, see Section 11.6.1.2): 
I 01. Males ≥12 years of age. 
I 02. Severe hemophilia A or B as evidenced by: 
a) A central laboratory measurement at screening or documented medical record 
evidence of FVIII <1% or FIX level ≤2%. 
I 03. A minimum of 2 bleeding episodes requiring BPA treatment within the last 6 months 
prior to Screening for patients with inhibitory antibodies to Factor VIII or Factor IX 
(Cohort A). A minimum of 1 bleeding episode requiring factor treatment within the last 
12 months prior to Screening for patients without inhibitory antibodies to Factor VIII or 
Factor IX (Cohort B). 
I 04. Must meet either the definition of inhibitor or non-inhibitor patient as below: 
Inhibitor: 
Use of BPAs for prophylaxis and for any bleeding episodes for at least the last 6 months 
prior to Screening, and meet one of the following Nijmegen-modified Bethesda assay 
results criteria: 
- 
Inhibitor titer of ≥0.6 BU/mL at Screening, or 
- 
Inhibitor titer of <0.6 BU/mL at Screening with medical record evidence of 
2 consecutive titers ≥0.6 BU/mL, or 
- 
Inhibitor titer of <0.6 BU/mL at Screening with medical record evidence of 
anamnestic response 
- 
The subgroup of patients in Cohort A patients must additionally meet the following 
criteria to be eligible to start treatment with fitusiran directly after the screening 
period: 
- 
Hemophilia B with inhibitory antibody to Factor IX as defined above 
- 
Not responding adequately to BPA treatment (historical ABR ≥20) prior to 
enrollment 
- 
In the opinion of the Investigator, with approval of Sponsor Medical Monitor, 
6-month BPA prophylaxis period should be omitted.  
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
41 
Non-inhibitor: 
Use of factor concentrates for prophylaxis and for any bleeding episodes for at least the 
last 6 months prior to Screening, and meet each of the following criterion: 
- 
Nijmegen-modified Bethesda assay inhibitor titer of <0.6 BU/mL at Screening and 
- 
No use of bypassing agents to treat bleeding episodes for at least the last 6 months 
prior to Screening and 
- 
No history of immune tolerance induction therapy within the past 3 years prior to 
Screening. 
I 05. Prescribed prophylactic treatment (documented in the medical or pharmacy records) of 
hemophilia with factor concentrates or BPAs for at least 6 months prior to Screening; the 
regimen must be consistent with the approved prescribing information for the product or 
local recommendations, allowing for adjustment to individual patient response, and 
designed to decrease spontaneous bleeding.   
I 06. Adherent to the prescribed prophylactic therapy for at least 6 months prior to Screening 
per Investigator assessment. 
I 07. Willing and able to comply with the study requirements and to provide written informed 
consent and assent in the case of patients under the age of legal consent, per local and 
national requirements. 
5.2 
EXCLUSION CRITERIA  
Each patient must not meet any of the following exclusion criteria to be eligible for enrollment in 
the study (for the United States specific requirements, see Section 11.6.1.2): 
E 01. Known co-existing bleeding disorders other than hemophilia A or B, ie, Von 
Willebrand’s disease, additional factor deficiencies, or platelet disorders. 
E 02. Current participation in immune tolerance induction therapy (ITI). 
E 03. AT activity <60% at Screening, as determined by central laboratory measurement. 
E 04. Presence of clinically significant liver disease, or as indicated by any of the conditions 
below:  
a) INR >1.2;  
b) ALT and/or AST >1.5× upper limit of normal reference range (ULN); 
c) Total bilirubin >ULN (>1.5× ULN in patients with Gilbert’s Syndrome); 
d) History of portal hypertension, esophageal varices, or hepatic encephalopathy; 
e) Presence of ascites by physical exam. 
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Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
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42 
E 05. Hepatitis C virus antibody positive, except patients with a history of HCV infection who 
meet both conditions a. and b.: 
a) Completed curative treatment at least 12 weeks prior to enrollment and attained 
sustained virologic response as documented by a negative HCV RNA at screening, or 
they have spontaneously cleared infection as documented by negative HCV RNA at 
Screening. 
b) No evidence of cirrhosis according to one of the following assessments: 
- 
FibroScan <12.5 kPa (where available), or  
- 
FibroTest score <0.75 and APRI <2 (if FibroScan unavailable) 
E 06. Presence of acute hepatitis, ie, hepatitis A, hepatitis E. 
E 07. Presence of acute or chronic hepatitis B infection (IgM anti-HBc antibody positive or 
HBsAg positive). 
E 08. Platelet count ≤100,000/μL. 
E 09. Presence of acute infection at Screening. 
E 10. Known to be HIV positive with CD4 count <200 cells/μL. 
E 11. Estimated glomerular filtration rate ≤45 mL/min/1.73 m2 (using the Modification of Diet 
in Renal Disease [MDRD] formula). 
E 12. Co-existing thrombophilic disorder, as determined by presence of any of the below as 
identified at central laboratory (or via historical results, where available): 
a) FV Leiden mutation (homozygous or heterozygous) 
b) Protein S deficiency 
c) Protein C deficiency 
d) Prothrombin mutation (G20210A; homozygous and heterozygous) 
E 13. History of antiphospholipid antibody syndrome. 
E 14. History of arterial or venous thromboembolism, atrial fibrillation, significant valvular 
disease, myocardial infarction, angina, transient ischemic attack, or stroke. Patients who 
have experienced thrombosis associated with indwelling venous access may be enrolled. 
E 15. Had a malignancy within 2 years, except for basal or squamous cell carcinoma of the skin 
that has been successfully treated. 
E 16. Any condition (eg, medical concern), which in the opinion of the Investigator, would 
make the patient unsuitable for dosing on Day 1 or which could interfere with the study 
compliance, the patient’s safety and/or the patient’s participation in the completion of the 
treatment period of the study. This includes significant active and poorly controlled 
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Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
43 
(unstable) cardiovascular, neurologic, gastrointestinal, endocrine, renal or psychiatric 
disorders unrelated to hemophilia identified by key laboratory abnormalities or medical 
history. 
E 17. At Screening, anticipated need of surgery during the study or planned surgery scheduled 
to occur during the study. 
E 18. Completion of a surgical procedure within 14 days prior to Screening, or currently 
receiving additional factor concentrate or BPA infusion for postoperative hemostasis. 
E 19. History of multiple drug allergies or history of allergic reaction to an oligonucleotide or 
GalNAc. 
E 20. Inadequate venous access, as determined by the Investigator, to allow the blood draws 
required by the study protocol. 
E 21. History of intolerance to SC injection(s). 
E 22. Current or future participation in another clinical study, scheduled to occur during this 
study, involving an investigational product other than fitusiran or an investigational 
device; in order to participate in this study, patient must discontinue the investigational 
product or investigational device at least 30 days (or 5× the investigational product half-
life, whichever is longer) prior to dosing (Day 1). 
E 23. Current or prior participation in a gene therapy trial. 
E 24. History of alcohol abuse within the 12 months before Screening.  Alcohol abuse is 
defined as regular weekly intake of more than 14 units (unit: 1 glass of wine 
[approximately 125 mL] = 1 measure of spirits [approximately 1 fluid ounce] = ½ pint of 
beer [approximately 284 mL]). 
5.3 
REMOVAL FROM THERAPY OR ASSESSMENT  
Patients or their legal guardian (in case patient is a minor) are free to discontinue treatment or 
withdraw from the study at any time and for any reason, without penalty to their continuing 
medical care. Any discontinuation of treatment or withdrawal from the study must be fully 
documented in the electronic case report form (eCRF) and should be followed up by the 
Investigator. The Investigator may withdraw a patient at any time if this is considered to be in the 
patient’s best interest. 
Patients who discontinue their prophylactic treatment or withdraw consent during the factor or 
BPA prophylaxis period (BPA prophylaxis period is not applicable for the subgroup of Cohort A 
patients who are not responding adequately to BPA prophylaxis treatment) will be withdrawn 
from the study. For the United States specific requirements, see Section 11.6.1.2. 
Procedures for discontinuation of study drug and/or withdrawal from the study during the 
fitusiran treatment period are described in Section 5.3.1 and Section 5.3.2, respectively. 
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Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
44 
5.3.1 Discontinuation of study drug  
The Investigator or designee may discontinue dosing in a patient if the patient: 
• Is in significant violation of the protocol 
• Is non-adherent to treatment regimen 
• Experiences a serious or intolerable AE, a life-threatening bleeding episode, eg, any 
gastrointestinal hemorrhage or intracranial hemorrhage, or life-threatening 
thromboembolic event 
• Requires a prohibited medication 
• More than 1 AT measurement <15% if at a dose of 50 mg Q2M 
The Investigator will confer with the Sponsor or study Medical Monitor before discontinuing 
dosing in the patient.  
Patients (or their guardians) may decide to discontinue study drug. 
In general, patients who discontinue study drug dosing for any reason will be encouraged to 
remain on the study to complete the remaining assessments through the end of study so that their 
experiences are captured in the final analyses. If a patient discontinues dosing due to a serious 
adverse event (SAE), the SAE should be followed as described in Section 7.6.6. When a patient 
discontinues study drug dosing, the primary reason must be recorded in the appropriate section 
of the eCRF. Patients who discontinue study drug but who remain on study may receive 
treatment consistent with local standard practice for their disease per Investigator judgement, as 
applicable. Safety will be captured for the entire duration of study for patients who discontinue 
treatment. 
5.3.2 Withdrawal from study  
A patient or guardian may withdraw consent from study participation at any time. The 
Investigator may withdraw a patient at any time if this is considered to be in the patient’s best 
interest. Any withdrawal from the study must be fully documented in the eCRF and should be 
followed-up by the Investigator. 
However, study integrity and interpretation is best maintained if all enrolled patients continue 
study assessments and follow-up even if study treatment is discontinued. Patients considering 
withdrawing from the study should be informed that they can discontinue treatment and still 
remain in the study to complete study assessments and follow-up as specified in the Schedule of 
Assessments (Table 1). If a patient still chooses to discontinue study treatment and withdraw 
from all follow-up, every effort should be made to conduct the EOS/ET assessments within 
4 weeks of the last dose (see Table 1). When a patient withdraws from the study, the withdrawal 
of consent and the reason for withdrawal must be recorded in the appropriate section of the eCRF 
and all efforts will be made to complete and report the observations as thoroughly as possible.  
There will be no replacements of patients who withdraw from this study. 
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Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
45 
5.3.3 Criteria for temporarily delaying enrollment or 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 11.8 for screening, enrollment and/or administration of study intervention. 
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Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
46 
6 
TREATMENTS  
6.1 
TREATMENTS ADMINISTERED  
Study drug supplied for this study must not be used for any purpose other than the present study 
and must not be administered to any person not enrolled in the study. Study drug that has been 
dispensed to a patient and returned unused must not be re-dispensed to a different patient. 
The IMP 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. 
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 
Section 11.8. 
6.2 
INVESTIGATIONAL MEDICINAL PRODUCT  
Detailed information describing the preparation, administration, and storage of fitusiran is 
provided in the Pharmacy Manual. 
6.2.1 Description  
Fitusiran (SAR439774) solution for injection (SC use) will be supplied as a sterile solution (see 
Pharmacy Manual for further details of solution concentration and fill volume). 
6.2.2 Dose and administration  
Patients will receive open-label fitusiran as an SC injection, during the fitusiran treatment period 
for a total of 7 months; dosing will begin on Day 1 of the fitusiran treatment period (Table 1). 
Study drug injection will be administered at the clinic by qualified staff under the supervision of 
the Investigator or designee.  Detailed instructions for study drug administration are found in the 
Pharmacy Manual. 
Study drug will not be blinded as this is an open-label study. See Section 6.2.5 regarding 
packaging and labeling. 
If a patient does not receive a fitusiran dose within the specified dosing window (Table 1), the 
Investigator should contact the study Medical Monitor.  After such consultation, the dose may be 
administered or considered missed and not administered. 
If a patient misses a dose, the Investigator, in consultation with the study Medical Monitor, will 
discuss whether the patient will be able to continue on the study. 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
Property of the Sanofi Group - strictly confidential 
47 
Additional details regarding dosing can be found in the Pharmacy Manual. 
6.2.3 Dose modifications  
Instructions for AT-driven fitusiran regimen modification are provided in Section 6.2.3.2. If an 
IMP-related AE occurs in a patient that the Investigator judges as presenting a potential risk to 
the patient for further dosing, the fitusiran dose may be held at the discretion of the Investigator 
and the study Medical Monitor should be contacted. 
6.2.3.1 LFT criteria for withholding, monitoring, and stopping fitusiran dosing  
1. LFT results are to be obtained within 7 days prior to dosing and results are to be reviewed 
prior to each dose of fitusiran. Central laboratory results are preferable. If not available, 
local laboratory results may be used; however, if a local assessment is drawn, a serum 
chemistry sample must also be drawn for analysis at the central laboratory. 
2. For any ALT or AST elevation >3× ULN central laboratory results should be used to 
guide subsequent monitoring as detailed in Table 4.  
3. For any ALT or AST elevation >3× ULN:  
a) Confirm using central laboratory, as soon as possible, ideally within 2 to 3 days, but 
no later than 7 days. 
b) Perform assessments per Table 4 and Table 7. 
c) If an alternative cause is found, provide appropriate care. 
4. For any ALT or AST elevation >3× ULN without alternative cause that is accompanied 
by clinical symptoms consistent with liver injury (eg, nausea, right upper quadrant 
abdominal pain, jaundice) or elevated bilirubin to ≥2× ULN or INR ≥1.5, permanently 
discontinue dosing. 
5. For confirmed ALT or AST elevations >3× ULN without alternative cause and not 
accompanied by symptoms or elevated bilirubin ≥2× ULN or INR ≥1.5, see Table 4 
below: 
Table 4 - Monitoring and dosing rules for asymptomatic patients with confirmed isolated 
elevations of ALT and/or AST >3× ULN, with no alternative cause identified      
Transaminase Level 
Action 
>3× to 5× ULN 
• 
May continue dosing 
• 
Evaluate the initial elevation in LFT per the following assessments:  
- 
Table 8  (all assessments to be performed once) 
- 
Hematology, serum chemistry, LFT, and coagulation per Table 7   
- 
AT 
• 
Monitor at least every two weeks (hematology, serum chemistry, LFT, and 
coagulation per Table 7 and AT)  
• 
If elevation persists for ≥2 months, must discuss with the study Medical Monitor 
before continuing dosing 
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Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
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48 
Table 4 - Monitoring and dosing rules for asymptomatic patients with confirmed isolated 
elevations of ALT and/or AST >3× ULN, with no alternative cause identified      
Transaminase Level 
Action 
>5× to 8× ULN 
• 
Hold fitusiran dose until recovery to ≤1.5× ULN; may resume dosing after 
discussion with the study Medical Monitor 
• 
Evaluate the initial elevation in LFT per the following assessments:  
- 
Table 8 (all assessments to be performed once) 
- 
Hematology, serum chemistry, LFT, and coagulation per Table 7  
- 
AT 
• 
Monitor at least weekly (hematology, serum chemistry, LFT, and coagulation per 
Table 7 and AT) until ALT and/or AST is declining on two consecutive draws, then 
may decrease monitoring to biweekly 
• 
If ALT or AST rises to >5× ULN following repeat dosing, permanently discontinue 
dosing 
>8× ULN 
• 
Permanently discontinue dosing after confirmation of the transaminase value 
Note: In addition to these criteria, other assessments or evaluations may be performed per 
Investigator discretion, as appropriate. 
6.2.3.2 Antithrombin level criteria for a dose adjustment  
With amendment 6, patients will resume dosing at a dose of 50 mg Q2M (Table 1). Patients 
rolling over from this study to the extension study may have the option for dose escalation in that 
study if dose escalation criteria defined in that protocol are met. 
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%.  Patients receiving fitusiran at a dose of 50 mg Q2M with more 
than 1 AT activity level <15% at any time during the study must permanently discontinue 
fitusiran. 
See the rationale for a new dosing justification in Section 1.4. 
6.2.3.3 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 11.8). For all temporary intervention discontinuations, the 
associated reason/emergency should be recorded by the Investigator (or designee) in the 
appropriate pages of the eCRF.  
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 11.8. 
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49 
6.2.4 Preparation, handling, and storage  
Qualified staff at each clinical study center will be responsible for preparation of fitusiran doses, 
according to procedures detailed in the Pharmacy Manual.  No special procedures for the safe 
handling of study drug are required. 
Study drug will be stored per the Pharmacy Manual and refrigerated at approximately 5±3°C. 
Deviations from the recommended storage conditions should be reported to the Sponsor and use 
of the study drug halted until authorization for its continued use has been provided by the 
Sponsor or designee, as described in the Pharmacy Manual. 
A Sponsor representative or designee will be permitted, upon request, to audit the supplies, 
storage, dispensing procedures, and records. 
Instructions specific to unused study drug and additional storage details are provided in the 
Pharmacy Manual. 
6.2.5 Packaging and labeling  
All packaging, labeling, and production of study drug will be in compliance with current Good 
Manufacturing Practices, or local applicable regulations, where necessary. Study drug labels and 
external packaging will include all appropriate information as per local labeling requirements.  
Additional details will be available in the Pharmacy Manual. 
6.2.6 Accountability  
The Investigator or designee will maintain accurate records of receipt and the condition of the 
study drug supplied for this study, including dates of receipt. In addition, accurate records will be 
kept of when and how much study drug is dispensed and administered to each patient in the 
study. Any reasons for departure from the protocol dispensing regimen must also be recorded. 
At the completion of the study, there will be a final reconciliation of all study drug.   
Further instructions about drug accountability are detailed in the Pharmacy Manual. 
Any quality issue noticed with the receipt or use of an investigational medicinal product (IMP) 
(deficiency in condition, appearance, pertaining documentation, labeling, expiration date, etc.) 
must be promptly notified to the Sponsor. Some deficiencies may be recorded through a 
complaint procedure (see Section 7.6.6.8). 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor.  In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (except for Direct-to- 
Patient [DTP] shipment, for which a courier company has been approved by the Sponsor), allow 
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50 
the IMP to be used other than as directed by this clinical trial protocol, or dispose of IMP in any 
other manner. 
6.3 
CONCOMITANT MEDICATIONS  
Use of concomitant medications will be recorded on the patient’s eCRF as specified in the 
Schedule of Assessments (see Table 1). 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. 
Local standard treatment of hemophilia is considered to be, but not limited to, intravenously (IV) 
infusion of FVIII or FIX concentrates, aPCC, or rFVIIa. Use of these agents will be captured in 
the patient’s eDiary. 
Use of prothrombin complex concentrates for bleeding episode management is not permitted. 
Antifibrinolytics may be used as single agents but may not be used in combination with factor or 
BPA.  Use of aPCC and rFVIIa as combination therapy is not recommended. 
6.3.1 Factor concentrates or bypassing agent prophylaxis  
6.3.1.1 Routine use of factor or bypassing agent prophylaxis in the factor or bypassing 
agent prophylaxis period  
During the factor or BPA prophylaxis period, patients will continue to receive prophylaxis with 
their usual products on a regimen consistent with recommendations in the approved prescribing 
information, allowing for adjustment to individual patient response, and designed to decrease 
spontaneous bleeding. The regimen used during the factor or BPA prophylaxis period must have 
a minimum frequency of administration as presented in Table 5. The subgroup of Cohort A 
patients who are not responding adequately to BPA prophylaxis treatment will not participate in 
this BPA prophylaxis period and will directly start the fitusiran treatment period after the 
screening period. For the United States specific requirements, see Section 11.6.1.2. 
Table 5 - Factor or bypassing agent prophylaxis requirements  
Type of Factor or BPA replacement 
Frequency of administration 
Standard half-life FVIII 
Twice weekly 
Extended half-life FVIII 
Once weekly 
Standard half-life FIX 
Once weekly 
Extended half-life FIX 
Once biweekly 
aPCC 
Twice weekly 
rFVIIa 
Every other day 
Abbreviation:  aPCC= activated prothrombin complex concentrates; BPA=bypassing agent; FVIII = Factor VIII; FIX = Factor IX; 
rFVIIa=recombinant Factor VIIa Note: For the United States specific requirements, see Section 11.6.1.2. 
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Clinical Study Protocol ALN-AT3SC-009 
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08-Dec-2020 
 
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51 
6.3.1.2 Management of factor or bypassing agent prophylaxis during the transition to 
the fitusiran treatment period  
The first 28 days of fitusiran treatment is referred to as the onset period. During the onset period 
AT lowering will be progressing toward therapeutic levels.  Patients will continue factor or BPA 
prophylaxis with minimum frequency as in Table 5, for the first 7 days of the fitusiran onset 
period.  Subsequent to Day 7 of the fitusiran treatment period, factor concentrates or BPAs 
should be administered only for bleeding episodes or if needed in advance of invasive medical 
procedures. For the United States specific requirements, see Section 11.6.1.2. 
6.3.2 Management of bleeding episodes  
The occurrence of bleeding episodes is a typical characteristic of hemophilia (3, 13, 14); 
bleeding episodes will be recorded as efficacy assessments of fitusiran and will not be considered 
as AEs unless the criteria for SAEs are met (see adverse events definitions in Section 7.6.6.1). 
Bleeding episodes will be recorded in the eDiary. For bleeding episodes in which there was no 
factor or BPA infusion or other type of intervention employed, the reason the bleeding episodes 
were untreated will be recorded in the eDiary (see Section 7.2.1). 
Investigators will establish and provide instructions for an individualized bleed management plan 
based on the guidelines in Table 6 for each patient. 
The bleed management plan should be reviewed by the Investigator or designee with the patient 
at each clinic visit (and contact every 2 weeks between clinic visits) and updated as necessary. 
For the United States specific requirements, see Section 11.6.1.2. 
6.3.2.1 Bleeding episode management recommendations for patients during the factor 
or bypassing agent prophylaxis period (patients not receiving fitusiran)  
During the factor or BPA prophylaxis period, bleeding management therapy with factors or 
BPAs will be managed based on the local standard practice for treating hemophilia patients, as 
routinely administered by the physician. The subgroup of Cohort A patients who are not 
responding adequately to BPA prophylaxis treatment will not participate in this BPA prophylaxis 
period and will directly start the fitusiran treatment period after the screening period. Where 
clinical circumstances allow, it is recommended that the patient contact the Investigator for all 
events that may be suspected to be or are characteristic of a bleeding episode. If adequate 
hemostasis does not occur after two doses of factor or BPA, the patient should contact the site for 
further instruction. If the patient feels the need to administer doses higher than the patient’s 
bleeding episode management plan recommends, or at a higher frequency, it is recommended 
that the patient contact the site. See Section 7.2.1 regarding patient use of the eDiary and site 
alerts that will assist in this process. For the United States specific requirements, 
see Section 11.6.1.2. 
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6.3.2.2 Bleeding episode management recommendations for patients during the 
fitusiran treatment period (for the United States specific requirements, see 
Appendix 11.5.1.2)  
Given the mechanism of action and pharmacodynamics profile of fitusiran, the factor or BPA 
dose necessary to safely and effectively treat breakthrough bleeding episodes in patients 
receiving fitusiran during the fitusiran treatment period will be lower than standardly prescribed.  
This is supported by data from the Phase 1 study in which bleed events were managed with 
factor or BPA, as well as additional modeling and ex vivo spiking data.  More detailed 
information on the clinical experience in bleeding episode management in Phase 1 and Phase 1/2 
fitusiran studies, as well as supportive nonclinical studies is provided in the Investigator’s 
Brochure. 
After administration of fitusiran, AT lowering will be progressing toward therapeutic levels.  As 
quickly as 7 days after the initial fitusiran dose, the majority of patients will have AT levels at or 
below 60% residual activity. By 14 days after dosing, it is expected that 94% of patients will 
have AT lowering of >50%, with a median value of 66.8%. Based on these AT kinetics, it is 
recommended that patients continue with their standard factor or BPA regimens for the first 
7 days following initiation of fitusiran dosing, with institution of the protocol-specific bleed 
management guidelines with reduced factor or BPA at Day 8 and beyond (Table 6). 
Patients on fitusiran will be provided a written bleed management plan with appropriate dosing 
of factor or BPA for use during Day 1 through 7, as well as a bleed management plan with 
dosing for Day 8 and beyond. Thereafter the bleed management plan will be reviewed and 
updated at monthly visits, and new written plans provided to the patient if dosing changes. 
Importantly, after Day 7 of the fitusiran treatment period, patients should not use factor, BPA, or 
other hemostatic agents as prophylaxis for bleeding episode prevention, including doses related 
to anticipated hemostatic challenges such as physical activity.  For prophylaxis of bleeding 
episodes in patients who require operative procedures see Section 6.6. 
Bleed Management Guidelines Day 1 to Day 7 of Fitusiran Treatment Period:  
Patients should be instructed to call the site prior to administering factor or BPA for the 
management of bleeding episodes. Patients should continue with their standard factor or BPA 
regimens.  
Bleed Management Guidelines Day 8 and Beyond of Fitusiran Treatment Period: 
When a patient experiences symptom 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 and/or BPA dose to use. This interaction between patient and Investigator is 
recommended prior to the administration of each dose of factor or BPA. Confirmation of 
bleeds at the study center prior to treatment may be considered.  Such visits should 
capture assessments per Section 6.4 and Table 2. 
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2. If a determination is made that symptoms require treatment, the recommended treatment 
algorithm for bleeding episodes is described below: 
1. A single dose can be administered according to the guidelines in Table 6. 
2. The patient should be instructed to re-evaluate symptoms in 24 hours for bleeds treated 
with FVIII, FIX or aPCC and in 2-3 hours for bleeds treated with rFVIIa. 
a) Administration of FIX Extended half-life should not be more frequent than every 5-7 
days. 
3. If a second dose (in the case of FVIII, FIX or aPCC) or a third dose (in the case of 
rFVIIa) is needed, the patient must call the study center before dosing. 
a) Consider evaluation and treatment of the patient at the study center and confirmation 
of bleeds when any repeated doses are needed (See Section 6.4 and Table 2). 
b) If more than two doses of FVIII, FIX or aPCC or three doses of rFVIIa are needed, 
the patient should be seen at the study center within 48-72 hours. 
4. Doses should not be administered at less than 24-hour intervals (except rFVIIa as 
indicated in Table 6). 
5. Doses should not exceed the protocol maximum recommended dose indicated in Table 6. 
6. Consultation with the study Medical Monitor and Clinical Advisor should be considered 
for clinical circumstances below, that may warrant AT replacement: 
a) Doses of factor or BPA higher than those recommended in Table 6 
b) Dosing of factor or BPA at decreased intervals than those recommended in Table 6 
c) Multiple or repeated doses of factor or BPA  
7. Antifibrinolytics may not be used in combination with factor or BPA. 
Table 6 - Bleed management dosing guidelines by specific product      
 
Factor VIII 
Factor IX 
Standard half-
life 
Factor IX 
Extended half-
life 
aPCC 
Recombinant 
Factor VIIa 
Recommende
d single dose 
of 
10 IU/kg 
20 IU/kg 
20 IU/kg 
30 U/kg 
≤45 µg/kg 
Single Dose 
should not 
exceed 
20 IU/kg 
30 IU/kg 
30 IU/kg 
50 U/kg 
45 µg/kg 
Repeat dose 
instructions 
Mandatory to call the clinical study center prior to second dose 
Consider evaluation and treatment at the clinical study center 
 (see Section 6.4) 
Mandatory to call 
site prior to third 
dose 
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Note:  Adjunctive management of bleeding episodes should be carried out per standard of care. For the United States specific requirements, 
see Section 11.6.1.2. For the Japan specific requirements, see Section 11.6.2. 
6.3.2.3 Use of factor or bypassing agents following discontinuation of fitusiran (for the 
United States specific requirements, see Appendix 11.5.1.2)  
Resuming routine prophylaxis following discontinuation of fitusiran 
Patients who opt to discontinue fitusiran may resume standard prophylaxis with factor 
concentrates or BPAs when their AT 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). 
Bleed episode management following discontinuation of fitusiran 
Patients who opt to discontinue fitusiran may resume standard on-demand dosing with factor 
concentrates or BPAs for bleeding episodes 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 (approximately 60% residual activity per the central 
laboratory), AT replacement should be considered. 
6.3.3 Other concomitant medications  
If patients use nonsteroidal anti-inflammatory drugs intermittently or chronically, they must be 
able to tolerate them and have had no previous side effects (eg, gastric distress or bleeding). 
Use of >4 g acetaminophen per day is not permitted. 
Treatment for HIV is permitted and must be recorded as concomitant medication. 
 
Should not repeat 
in less than  
24 hours 
Should not repeat 
in less than 
 24 hours 
Should not 
repeat in less than 
 5-7 days 
Should not 
repeat in less than  
24 hours 
Should not 
repeat in less than  
2 hours 
 
Should be seen at site within 48-72 hours if more than 2 doses are required 
(see Schedule of Assessments Table 1  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. 
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Standard vitamins and topical medications are permitted.  However, topical steroids must not be 
applied anywhere near the injection site(s) unless medically indicated. 
Any concomitant medication that is required for the patient’s welfare may be prescribed by the 
Investigator. However, it is the responsibility of the Investigator to ensure that details regarding 
the medication are recorded on the eCRF. Concomitant medication will be coded using an 
internationally recognized and accepted coding dictionary. 
6.4 
ASSESSMENT OF COAGULATION PARAMETERS AT THE TIME OF A BLEED  
Any patient who presents to the clinical study center for evaluation of symptoms that are 
suspected as characteristic of a bleeding episode, the patient should be assessed by the 
Investigator to determine whether symptom(s) require treatment.  If treatment is required, blood 
samples should be collected predose and postdose and assessments performed as scheduled in 
Table 2. 
If a patient presents following administration of factor or BPAs at home and within 48 hours of 
the dose, and no further treatment is given at the center, AT and the postdose assessments in 
Table 2 should be obtained in a single draw at any time during the visit. 
6.5 
MONITORING AND MANAGEMENT OF THROMBOTIC EVENTS  
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 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 individualize patient doses to target 80-120% AT activity. The use of plasma 
derived AT may be preferable to recombinant AT, given its longer half-life. It is recommended 
that cases of thrombosis are discussed with the study Medical Monitor and Clinical Advisor 
(see Section 7.6.6.1 for further information regarding Adverse Events of Special Interest). For 
the United States specific requirements, see Section 11.6.1.2. For the Japan specific 
requirements, see Section 11.6.2. 
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6.6 
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 a written perioperative treatment plan will be reviewed with the study 
Medical Monitor before conducting the procedure, unless clinical circumstances do not allow. 
It is recommended that, when possible, any elective non-dental major surgery be performed at a 
clinical study center. 
For reference, see Appendix (Section 11.2.1) for definitions of minor and major surgery. 
Perioperative Treatment Plan 
In patients undergoing major surgery during the study, a written perioperative treatment plan will 
be reviewed with the study Medical Monitor before conducting the procedure, unless clinical 
circumstances do not allow.  In patients on fitusiran, the perioperative treatment plan should be 
developed using the same principles as bleed management described in Section 6.3.2 and the 
guideline below: 
• If the clinical circumstance is such that the recommended doses and/or dose intervals in 
Table 6 are deemed insufficient for hemostasis, consider AT replacement and manage 
thrombotic risk as per Investigator practice for a hemophilia patient undergoing that 
particular surgery. 
• Non-pharmacologic methods of thromboprophylaxis should also be employed as 
clinically indicated. 
Fitusiran Treatment During the Perioperative Evaluation Period  
For reference, see Appendix (Section 11.2.1) for definitions of minor and major surgery. 
If the need for a major surgery arises during the trial and the procedure is not an emergency or 
urgent, it is recommended that the procedure be postponed until after completion of the trial. 
For minor operative procedures, dosing with fitusiran may continue uninterrupted. 
If the need for emergency or urgent major surgery arises during the trial, the patient should be 
managed medically according to the guidelines above.  If a fitusiran dose is scheduled to occur 
on or in close proximity to the day of surgery, or anytime during the perioperative period, the 
dose should be withheld. The Perioperative 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 surgery during the study as 
described in Section 11.2.1, and as scheduled in Table 12. 
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6.7 
MANAGEMENT OF SEPSIS  
Formal clinical guidelines do not currently recommend correction of low AT that is seen in the 
setting of sepsis, citing a lack of evidence for improved outcomes and an increased risk of 
bleeding (16, 17). If a clinical determination is made that AT correction is desirable for a 
fitusiran-treated patient in the setting of sepsis, this may be initiated per Investigator discretion. 
6.8 
CONTRACEPTIVE REQUIREMENTS  
All study patients will be male, and there are no contraceptive requirements for this study except 
where required per local regulations. For the Japan specific requirements, see Section 11.6.2. 
Details of fitusiran toxicology studies are presented in the Investigator’s Brochure. 
6.9 
TREATMENT COMPLIANCE  
Compliance with scheduled clinic visits (Table 1), and patient use of eDiary to record data as 
required, will be monitored by study staff over the ~13-months, except for patients in the 
subgroup of Cohort A, which is up to 7 months, of eDiary recording (including both the 6-month 
factor or BPA prophylaxis period [6-month BPA prophylaxis period is not applicable for the 
subgroup of Cohort A patients who are not responding adequately to BPA prophylaxis treatment] 
and 7-month fitusiran treatment period). For the United States specific requirements, 
see Section 11.6.1.2. 
6.10 
ALCOHOL RESTRICTIONS  
Patients will be required to limit alcohol consumption throughout the course of the study.  
Alcohol is limited to no more than 2 units (unit: 1 glass of wine [approximately 
125 mL] = 1 measure of spirits [approximately 1 fluid ounce] = ½ pint of beer [approximately 
284 mL]) per day (no more than 14 units per week) for the duration of the study. 
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7 
STUDY ASSESSMENTS  
The Schedule of Assessments is provided in Table 1. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 11.8. 
7.1 
SCREENING/BASELINE ASSESSMENTS  
An informed consent form (ICF) or assent form that has been approved by the appropriate 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) must be signed by the 
patient (or legal guardian) before the Screening procedures are initiated. All patients (or their 
legal guardians) will be given a copy of the signed and dated ICF and/or assent form. 
Patient demographic and medical history will be obtained at Screening. Medical history must 
include documentation of factor concentrate and/or BPA prescriptions (in the medical or 
pharmacy record) and documentation of reported number of bleeding episodes over the last 
6 months (for inhibitor patients) or 12 months (for non-inhibitor patients). Patients will be 
screened to ensure that they meet all of the inclusion criteria and none of the exclusion criteria.  
Rescreening of patients is permitted with consultation of the study Medical Monitor. 
To complement medical records, information regarding health resource use will be collected as 
specified in the Schedule of Assessments (Table 1), including days missed from work/school (as 
appropriate) and days not able to perform normal activities outside of work/school due to 
hemophilia, physician office visits, hemophilia treatment site visits, emergency room visits 
(reason and number), hospitalizations (reason, dates of hospitalization and associated length of 
stay). 
For the United States specific requirements, see Section 11.6.1.2. 
7.1.1 Patient education module  
Patients will be educated by Investigators or trained healthcare professionals on coagulation and 
general considerations with regard to managing hemophilia in the clinical setting of lowered AT. 
This will be performed as specified in the Schedule of Assessments (Table 1). 
7.1.2 Inhibitor status  
Patients inhibitor status will be determined as specified in the Schedule of Assessments (Table 1) 
by Nijmegen modified Bethesda assay. 
7.1.3 FibroScan or FibroTest/APRI  
A FibroScan or FibroTest/APRI will be performed according to the Schedule of Assessments 
(Table 1) to rule out cirrhosis in patients with a history of Hepatitis C. 
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7.2 
EFFICACY ASSESSMENTS  
Bleeding Episode Definitions 
A bleeding episode is defined as any occurrence of hemorrhage that requires administration of 
factor or BPA infusion, eg, hemarthrosis, muscle, or mucosal bleeding episodes.  Since bleeding 
episodes are recorded as an efficacy assessment of fitusiran, these will not be treated as AEs 
unless they meet any of the SAE criteria listed in Section 7.6.6.1. 
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 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, 
but patients will be asked to indicate in the eDiary that the event occurred during such activities. 
Training will be provided on this and other aspects of eDiary use (see Section 7.2.1). 
Annualized bleeding rate will be calculated as described in Section 8.2.5.1. Bleeding episodes 
will be managed according to Section 6.3.2. 
For the United States specific requirements, see Section 11.6.1.2. 
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7.2.1 Electronic diary  
Patients will be issued an eDiary to record all bleeding events and all doses of factors or BPAs 
administered during the conduct of the study. Entries are to be made in a timely manner, and it is 
preferred that doses are entered immediately upon administration or within 24 hours. Patients 
will be prompted to enter bleeding location, severity, causality (spontaneous or traumatic), doses 
of factors or BPAs, and reasons for dosing (prophylaxis, treatment of a bleeding episode, and 
preventive dose for anticipated activity).  Training of patients should be documented in the 
appropriate source record. 
The Sponsor will review diary entries for data quality to identify issues such as patients who may 
need retraining on eDiary use and timely entry of bleeding episode information. 
Bleeding episodes will be recorded by the patient in the eDiary and reviewed by the Investigator 
(and Sponsor) continuously for the study duration. The site will contact the patient at a minimum 
interval of every 2 weeks (+/- 4 days) per schedule of assessments to review eDiary records and 
ensure that the patient is utilizing the device appropriately. 
Sites will be notified when patients enter initial treatments for bleeding events into their eDiaries. 
If the dose amount exceeds the recommended dose according to the bleeding episode 
management plan, the patient must be contacted as soon as possible, preferably within 
24-48 hours of receiving the alert. At the time of contact the patient’s clinical condition will be 
reviewed along with the dose and efficacy of the treatment given, and the Investigator will 
provide appropriate guidance regarding further management of the bleed.  The site will also 
receive an alert, and must make contact with the patient as soon as possible if a third dose of 
product is administered for a single bleed, to review clinical condition, the need for further 
therapy, and appropriate ongoing management of the bleeding episode required to achieve 
hemostasis. 
In addition, patients will be instructed to contact the site if they feel they need to administer 
factor or BPA at a higher dose level or higher frequency than their bleeding episode management 
plan recommends, or if more than two doses are required to achieve hemostasis. 
For the United States specific requirements, see Section 11.6.1.2. 
7.3 
PHARMACODYNAMIC ASSESSMENTS  
In this study AT activity level and thrombin generation will be collected as measurements of PD 
effect and coagulation assessments are collected for exploratory analyses of PD effect. These 
measurements will be collected and analyzed centrally for research purposes. As interpretation is 
uncertain, thrombin generation results will not be used to adjust dosing of fitusiran or guide other 
elements of study conduct or clinical management and will not be shared with sites until after 
study completion. If clinical circumstances arise for which AT activity levels are required to 
guide patient care, local laboratory assessments may be drawn. 
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7.3.1 Antithrombin (AT) activity  
AT activity level will be assessed according to the Schedule of Assessments (Table 1). On 
dosing days, samples will be collected within 4 hours prior to dosing. Antithrombin levels will 
be determined by validated assay. Antithrombin protein may be measured in a subset of plasma 
samples for correlation. Results will be collected and interpreted centrally. 
Following final fitusiran dose, and in case the patient is not rolled over to the open label 
extension study, AT activity level will be monitored at monthly intervals until returning to an 
activity level of approximately 60% (per the central laboratory) or per Investigator discretion in 
consultation with the study Medical Monitor. 
7.3.2 Thrombin generation  
Thrombin generation will be assessed according to the Schedule of Assessments (Table 1) using 
a functional assay per the laboratory manual and will be collected and interpreted centrally. 
7.3.3 Coagulation/Thrombin generation response assessment in factor or bypassing 
agent prophylaxis period  
During the factor or BPA prophylaxis period (before fitusiran treatment), patients will undergo a 
coagulation and peak thrombin/thrombin generation response assessment with timed blood 
collections both before and following a dose of their routine factor or BPA prophylaxis doses. 
The subgroup of Cohort A patients who are not responding adequately to BPA prophylaxis 
treatment will not participate in this BPA prophylaxis period and will directly start the fitusiran 
treatment period after the screening period. For these patients, the coagulation and peak 
thrombin/thrombin generation response assessment are not applicable. For the United States 
specific requirements, see Section 11.6.1.2. 
These laboratory assessments are collected for research purposes, will be run centrally, and will 
not be released to sites or used to guide study conduct or clinical management. 
7.3.4 Exploratory analyses  
Except where prohibited by local or national regulations, in consented patients (since optional), 
plasma, serum, and urine samples may be archived and used for analyses of exploratory 
biomarkers related to the metabolic profiling or effects of fitusiran and for the development of 
modified thrombin generation assays, and may also be archived for use in other exploratory 
analyses related to hemophilia and its complications. 
In addition, where permitted in consented patients (since optional), serum samples may be used 
for analysis of circulating RNA, including the assessment of cleaved antithrombin RNA, and a 
sample of DNA may be obtained and archived to permit potential confirmation of hemophilia 
mutation or genotyping of hemophilia modifier genes, or genes that may modify the effects of 
fitusiran. 
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7.4 
PHARMACOKINETIC ASSESSMENTS  
Blood samples will be collected for assessment of PK according to the collection schedule 
presented in Table 11, on the days specified in the Schedule of Assessments (Table 1). 
Blood must be aliquoted and processed as plasma for PK analysis.  All plasma concentration data 
(Table 11) will be summarized and analyzed using a population PK approach and 
noncompartmental analysis, as applicable. 
The concentration of fitusiran will be determined using a validated assay.  Full details regarding 
the processing, shipping, and analysis of the samples will be provided in the Laboratory Manual. 
7.5 
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 9.1.1) 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 
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 11.5). 
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. 
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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). 
7.6 
SAFETY ASSESSMENTS  
The assessment of safety during the course of the study will consist of the surveillance and 
recording of AEs including SAEs, recording of concomitant medication and measurements of 
vital signs, weight and height, physical examinations, ECG findings, and laboratory tests. 
Safety data will be periodically reviewed over the course of the study by the DMC as described 
in Section 4.6. 
7.6.1 Vital signs  
Vital signs will be measured as specified in the Schedule of Assessments (Table 1), and will 
include blood pressure, heart rate, body temperature, and respiratory rate. Vital signs will be 
measured predose in the seated or supine position, after the patient has rested comfortably for 
10 minutes. 
Body temperature in degrees Celsius will be obtained via oral, tympanic, or axillary methods. 
Heart rate will be counted for a full minute and recorded in beats per minute, and respiration rate 
will be counted for a full minute and recorded in breaths per minute. 
For the safety of the patient, additional vital sign assessments may be added at the discretion of 
the Investigator. 
Vital signs results will be recorded in the eCRF. 
7.6.2 Weight and height  
Height will be measured in centimeters.  Body weight will be measured in kilograms. Height and 
body weight measurements will be collected as specified in the Schedule of Assessments 
(Table 1) and will be recorded in the eCRF. 
7.6.3 Physical examination  
Full and directed physical examinations will be conducted according to the Schedule of 
Assessments (Table 1); if a physical examination is scheduled for a dosing visit, it should be 
conducted prior to dosing. 
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Full physical examinations will include the examination of the following:  general appearance, 
head, eyes, ears, nose and throat; respiratory, cardiovascular, gastrointestinal, musculoskeletal, 
and dermatological systems; thyroid, lymph nodes, and neurological status. 
Directed physical examinations will include 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. Other organ systems may be evaluated as indicated by patient 
symptoms.  In patients undergoing a surgical procedure, a directed physical examination will 
also be performed as specified in the Perioperative Schedule of Assessments (Table 12). 
Physical examination notes regarding any observed abnormalities will be recorded on the eCRF. 
7.6.4 Electrocardiogram  
Triplicate standard 12-lead ECGs, with readings approximately 1 minute apart, will be recorded 
as specified in the Schedule of Assessments (Table 1). Patients should be supine for at least 
5 minutes before each ECG is obtained.  The electrophysiological parameters assessed will be 
rhythm, ventricular rate, RR interval, PR interval, QRS duration, QT interval, Bazett-corrected 
QT interval (QTcB), and Fridericia corrected QT interval (QTcF). 
When ECG and blood sample collection occur at the same time, ECGs should be performed 
before blood samples are drawn. 
The Investigator or qualified designee will review all ECGs to assess whether the results have 
changed since the Baseline visit and to determine the clinical significance of the results. These 
assessments will be recorded on the eCRF. Additional ECGs may be collected at the discretion 
of the Investigator. Recordings will be archived at sites. 
7.6.5 Clinical laboratory assessments  
The following clinical laboratory tests will be evaluated by a central laboratory. Specific 
instructions for transaminase elevations are provided in Section 6.2.3.1. For any other 
unexplained clinically relevant abnormal laboratory test occurring after 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 7 and will 
be assessed as specified in the Schedule of Assessments (Table 1). 
While local laboratory results may be used for urgent clinical and dosing decisions, on the day of 
the clinic visit assessments, all laboratory assessments specified in Table 7 which are performed 
at the clinic should also be repeated at the central laboratory. In the case of discrepant local and 
central laboratory results on samples drawn on the same day, central laboratory results will be 
relied upon for clinical and dosing decisions. 
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Clinical laboratory assessments may be collected at the clinical site or at home by a trained 
healthcare professional.  It is preferred that clinical laboratory assessments be drawn via 
peripheral draw (ie, fresh stick), however in cases where peripheral access is not possible 
existing indwelling venous access may be utilized. 
Please see Section 6.2.3.1 for the LFT monitoring and dosing plan. 
Table 7 - Clinical laboratory assessments      
Hematology 
Hematocrit 
Neutrophils, absolute and % 
Hemoglobin 
Lymphocytes, absolute and % 
RBC count 
Monocytes, absolute and % 
WBC count 
Eosinophils, absolute and % 
Mean corpuscular volume 
Basophils, absolute and % 
Mean corpuscular hemoglobin 
Platelet count 
Mean corpuscular hemoglobin concentration 
CD4 in HIV-positive patients (At Screening Only) 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Phosphate 
Creatinine and eGFR (using the MDRD formula) 
Albumin 
Glucose 
Calcium 
Chloride 
Carbon dioxide 
Liver Function Tests (LFTs) 
 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
GGT 
 
Coagulation 
Prothrombin time 
Activated partial thromboplastin time 
INR 
Fibrinogen 
 D-dimer 
Prothrombin fragment 1, 2 
Factor Activity 
 
FVIII activity for patients with hemophilia A 
FIX activity for patients with hemophilia B 
Urinalysis 
Visual inspection for appearance and color 
Bilirubin 
pH (dipstick) 
Nitrite 
Specific gravity 
RBCs 
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Table 7 - Clinical laboratory assessments      
Ketones 
Urobilinogen 
Glucose 
Leukocytes 
Protein 
Microscopy (if clinically indicated) 
Thrombophilia Screening 
Protein C deficiency 
Protein S deficiency 
Factor V Leiden (genetic testing) 
Prothrombin mutation (genetic testing) 
Hepatic Tests 
Hepatitis A, including: 
HAV antibody IgM and IgG 
Hepatitis C, including:  
HCV antibody 
HCV RNA PCR – qualitative and quantitative assays 
Hepatitis B, including:  
HBc antibody, IgM and IgG 
Hepatitis E, including: 
HEV antibody IgM and IgG 
Immunogenicity 
Antidrug Antibodies 
Note:  All assessments will be measured in the central laboratory  
Abbreviations:  ALP=alkaline phosphatase; ALT=alanine transaminase; AST=aspartate transaminase; BUN=blood urea nitrogen; 
eGFR=estimated glomerular filtration rate; FIX=Factor IX; FVIII=Factor VIII; GGT= gamma glutamyl transferase; HAV=hepatitis A virus; 
HBsAg=hepatitis B virus surface antigen; HBc=hepatitis B virus core; HCV=hepatitis C virus; HEV= hepatitis E virus; HIV=human 
immunodeficiency virus; IgG=immunoglobulin G antibody; IgM=immunoglobulin M antibody; INR=International normalized ratio; 
MDRD=Modification of Diet in Renal Disease; PCR=polymerase chain reaction; RBC=red blood cell; RNA=ribonucleic acid; WBC=white blood 
cell. 
7.6.5.1 Additional laboratory assessments  
For any safety event or laboratory abnormality, additional laboratory assessments, imaging, and 
consultation may be performed for clinical evaluation and/or in consultation with the study 
Medical Monitor; results may be collected and should be included in the clinical database. 
Additional laboratory assessments will be performed in patients who experience any LFT 
abnormalities during either the factor or BPA prophylaxis period (BPA prophylaxis period is not 
applicable for the subgroup of Cohort A patients who are not responding adequately to BPA 
prophylaxis treatment) or the fitusiran treatment period. Following the occurrence of elevated 
liver transaminases or other LFT abnormalities per the central laboratory, all assessments in 
Table 8 will be performed one time, as well as hematology, serum chemistry, LFT, and 
coagulation assessments from Table 7, AT levels, and other assessments or evaluations per 
Investigator discretion, as appropriate. For the United States specific requirements, 
see Section 11.6.1.2. 
For patients in the fitusiran treatment period, monitoring and dose modification will also be 
performed as outlined in Section 6.2.3.1. 
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Table 8 - Hepatic assessments in patients who experience LFT elevations      
Extended Hepatic Panel 
Herpes Simplex Virus 1 and 2 antibody IgM, IgG 
Herpes Zoster Virus IgM, IgG 
HIV 1 and 2a 
HHV-6 
Cytomegalovirus antibodies, IgM, IgG 
HBs Ag, HBc antibody IgM and IgG 
Anti-nuclear antibodies 
Epstein-Barr Virus antibodies, IgM and IgG 
Anti-smooth muscle antibodies 
Anti-mitochondrial antibodies 
HCV antibody 
HAV antibody IgM 
HCV RNA PCR – qualitative and quantitative 
HEV antibody IgM 
Imaging 
Abdominal ultrasound with Doppler flow (or CT or MRI) including right upper quadrant 
Focused Medical and Travel History 
Use of any potentially hepatotoxic concomitant medications, 
including over the counter medications and herbal remedies 
Alcohol consumption  
Other potentially hepatotoxic agents including any work-related 
exposures 
Recent travels to areas where hepatitis A or E is endemic 
Note:  All assessments will be measured in central laboratory. The full panel of assessments should only be performed once; individual 
assessments may be repeated, as needed 
Abbreviations: CT=computed tomography; HAV=hepatitis A virus; HBc=hepatitis B core; 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. 
7.6.5.2 Immunogenicity  
Blood samples will be collected to evaluate antidrug antibodies (ADAs) to fitusiran. Blood 
samples for ADA testing must be collected within 4 hours before study drug administration as 
specified in the Schedule of Assessments (Table 1). In addition, a blood sample to evaluate 
ADAs will be collected at the ET visit, if applicable. 
Details regarding the processing, shipping, and analysis of the samples are provided in the 
Laboratory Manual. 
7.6.6 Adverse events  
7.6.6.1 Definitions  
Adverse Event 
According to the International Conference on Harmonisation (ICH) E2A guideline Definitions 
and Standards for Expedited Reporting, and 21 Code of Federal Regulations (CFR) 312.32, IND 
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Safety Reporting, an adverse event (AE) is any untoward medical occurrence in a patient or 
clinical investigational subject administered a medicinal product and which does not necessarily 
have a causal relationship with this treatment.  Since bleeding episodes are recorded as an 
efficacy assessment of fitusiran, these will not be treated as AEs unless they meet any of the SAE 
criteria listed in Section 7.6.6.1. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening (an event which places the patient at immediate risk of death from the 
event as it occurred.  It does not include an event that had it occurred in a more severe 
form might have caused death) 
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient and may require intervention to 
prevent one of the other outcomes listed in the definition above (eg, events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias, convulsions, or the development of drug dependency or abuse). 
• Bleeding episodes will be recorded as an efficacy assessment of fitusiran and will not be 
treated as AEs unless they meet any of the above criteria for SAEs. 
Adverse Events of Special Interest 
The following events are considered to be AEs of special interest (AESI):  
• ALT or AST elevations >3× ULN 
• Suspected or confirmed thrombosis 
• Severe or serious ISRs, ISRs that are associated with a recall phenomenon (reaction at the 
site of a prior injection with subsequent injections), or those that lead to temporary dose 
interruption or permanent discontinuation of fitusiran 
• Systemic injection associated reactions (IARs), defined as hypersensitivity reactions 
which are related or possibly related to IMP. 
• Cholecystitis 
• Cholelithiasis 
Adverse Event Severity 
Adverse events are to be graded according to the categories detailed below: 
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Mild: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated  
Moderate: 
Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (eg, preparing meals, 
shopping for groceries or clothes, using the telephone, managing money) 
Severe: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living (ie, bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, and not 
bedridden); OR life-threatening consequences; urgent intervention indicated; 
OR death related to an adverse event 
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). 
AE severity and seriousness are assessed independently.  ‘Severity’ characterizes the intensity of 
an AE.  ‘Serious’ is a regulatory definition and serves as a guide to the Sponsor for defining 
regulatory reporting obligations (see definition for SAE). 
Relationship of the Adverse Event to Study Treatment 
The relationship of each AE to study treatment should be evaluated by the Investigator using the 
following criteria:  
Definitely related: 
A clinical event, including laboratory test abnormality, occurring in a plausible 
time relationship to the medication administration, and which cannot be 
explained by concurrent disease or other drugs or chemicals.  The response to 
withdrawal of the drug should be clinically plausible. 
Possibly related: 
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to the medication administration, but which could also be explained 
by concurrent disease or other drugs or chemicals.  Information on the drug 
withdrawal may be lacking or unclear. 
Unlikely related: 
A clinical event, including laboratory test abnormality, with little or no 
temporal relationship to medication administration, and which other drugs, 
chemicals, or underlying disease provide plausible explanations. 
Not related: 
A clinical event, including laboratory test abnormality that has no temporal 
relationship to the medication or has more likely alternative etiology. 
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7.6.6.2 Eliciting and recording adverse events  
Eliciting Adverse Events 
The patient should be asked about medically relevant changes in his health since the last visit, 
with attention to any signs and symptoms that could be consistent with thrombosis. The patient 
should also be asked if he has been hospitalized, had any accidents, used any new medications, 
or changed concomitant medication routines (both prescription and over the counter [OTC]). In 
addition to patient observations, AEs will be documented from any clinically relevant laboratory 
findings, physical examination findings, ECG changes, or other findings that are relevant to 
patient safety. 
Recording Adverse Events 
The Investigator is responsible for recording non-serious AEs and SAEs that are observed or 
reported by the patient after the time when the informed consent is signed regardless of their 
relationship to study drug through the end of study. Non-serious AEs will be followed until the 
end of study. SAEs will be followed until satisfactory resolution, until baseline level is reached, 
or until the SAE is considered by the Investigator to be chronic or the patient is stable, as 
appropriate. 
All AEs must be recorded in the source records for the clinical study center and in the eCRF for 
the patient, whether or not they are considered to be drug related. Each AE must be described in 
detail:  onset time and date, description of event, severity, relationship to investigational drug, 
action taken, and outcome (including time and date of resolution, if applicable). 
For SAEs, record the event(s) on both the eCRF and the SAE form. 
For AEs that are considered AESI (Section 7.6.6.1), the Sponsor or its designee should be 
notified within 24 hours using a supplemental AESI eCRF. Additional clinical and laboratory 
information may be collected; see Section 6.2.3.1 regarding monitoring for liver abnormalities. 
Refer to the eCRF completion guidelines for details on reporting events in the supplemental 
AESI eCRF. 
Since bleeding episodes are recorded as an efficacy assessment of fitusiran, these will not be 
treated as AEs unless they meet any of the SAE criteria listed in Section 7.6.6.1. The 
manifestation and frequency of bleeding episodes is an efficacy indicator of this study and ABR 
is the focus of the primary and secondary efficacy analyses. 
Recording an ISR 
For all ISRs, the Investigator, or delegate, should submit a supplemental ISR eCRF, recording 
additional information (eg, descriptions, onset and resolution date, severity, treatment given, 
event outcome). An ISR is defined as a local reaction at or near the site of injection. “At or near” 
the injection site includes reactions at the injection site, adjacent to the injection site, or a 
reaction which may shift slightly away from the injection site due to gravity (eg, as may occur 
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with swelling or hematoma). Reactions with onset and resolution within 4 hours of the injection 
eg, transient pain/burning at injection site) do not meet the study definition of ISRs, unless 
immediate treatment is required. A systemic reaction which includes the injection site, 
eg, generalized urticaria, other distinct entities or conditions like lymphadenopathy that may be 
near the injection site is not considered an ISR. 
7.6.6.3 Serious adverse events and adverse events of special interest require immediate 
reporting to Sponsor/Designee  
An assessment of the seriousness of each AE will be made by the Investigator. Any AE and 
laboratory abnormality that meets the SAE criteria in Section 7.6.6.1 and any AESI must be 
reported to the Sponsor or designee within 24 hours from the time that clinical study center staff 
first learns of the event. All SAEs must be reported regardless of the relationship to study drug. 
The initial report should include at least the following information: 
• Patient’s study number 
• Description and date of onset of the event 
• Criterion for serious 
• Preliminary assignment of relationship to study drug, and 
• Investigator/site information 
To report the SAE, complete the SAE form.  Within 24 hours of receipt of follow-up 
information, the Investigator must update the SAE form. 
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. 
7.6.6.4 Sponsor safety reporting to Regulatory Authorities  
The Sponsor or its representative will report certain study events in an expedited manner to the 
Food and Drug Administration, the European Medicines Agency’s EudraVigilance electronic 
system according to Directive 2001/20/EC, and to all country Regulatory Authorities where the 
study is being conducted, according to local applicable regulations. 
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7.6.6.5 Serious adverse event notification to the Institutional Review Board/Independent 
Ethics Committee  
Suspected unexpected serious adverse reactions (SUSARs) will be reported to the IRB/IEC per 
their institutional policy by the Investigator or Sponsor (or Sponsor designee) according to 
country requirements.  Copies of each report and documentation of IRB/IEC notification and 
acknowledgement of receipt will be kept in the Investigator’s study file. 
7.6.6.6 Pregnancy reporting  
There will only be male patients in this study. 
The reporting of any pregnancy outcome for a female partner of a male patient participating in 
this study that results in a postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly should be reported to the Investigator, who will then report this to 
the Sponsor or designee. The pregnancy outcome is to be recorded on the pregnancy reporting 
form. 
7.6.6.7 Overdose reporting  
An overdose is defined as any dose administered to or taken by a patient (accidentally or 
intentionally) that exceeds the highest daily dose, or is at a higher frequency, than included in the 
protocol.  Overdose must be recorded in the eCRF. 
All reports of overdose (with or without an AE) must be reported within 24 hours to the Sponsor 
or designee. 
7.6.6.8 Guidelines for reporting product complaints/medical device incidents (including 
malfunctions)  
Any defect in the IMP must be reported as soon as possible by the Investigator to the monitoring 
team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related 
to product identification and to the potential deficiencies may need to be gathered. The 
Investigator will assess whether or not the quality issue has to be reported together with an AE or 
SAE. 
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7.7 
OTHER ASSESSMENTS  
7.7.1 Patient-reported outcomes  
Patient-reported outcomes will be utilized in this study where available to assess health-related 
quality of life (HRQOL), physical activity, and treatment satisfaction and health utility. The age 
of the patient at Enrollment will determine which age-specific versions of questionnaires will be 
utilized and will be in force for the study duration. All completed questionnaires or instrument 
forms for the patient-reported outcome assessments described below will be collected, entered 
into a database, and archived at study sites. 
The Sponsor or designee will provide the translations for all survey instruments, where 
translations are available. The sites must not translate any survey instruments. 
7.7.1.1 HRQOL instruments: Haem-A-QOL and Haemo-QOL  
The Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) and Haemophilia 
Quality of Life Questionnaire for Children and Adolescents (Haemo-QOL) are psychometrically 
tested QOL assessment instruments for patients with hemophilia (19). The Haem-A-QOL will be 
provided to patients ≥17 years of age, and includes 46 items contributing to 10 QOL domains 
(physical health, feelings, view of yourself, sports and leisure, work and school, dealing with 
hemophilia, treatment, future, family planning, partnership and sexuality). Scoring for each item 
is based on a 5-point Likert scale (never, rarely, sometimes, often, and all the time), and higher 
scores represent greater impairment. 
The Haemo-QOL (Children’s short version for age groups II/III [8-16 years of age]) will be 
provided to patients <17 years of age, to self-complete as specified in the Schedule of 
Assessments (Table 1). The same questionnaire used during the Month 7 visit will be utilized 
throughout the study. 
7.7.1.2 TSQM-9  
The Treatment Satisfaction Questionnaire for Medication (TSQM) will assess patient satisfaction 
with treatment. The TSQM is a validated psychometric tool that provides a general measure of 
patient satisfaction with medication (20). Where available, the TSQM questionnaire will be 
distributed to patients to self-complete as specified in the Schedule of Assessments (Table 1). 
7.7.1.3 HAL  
The Haemophilia Activities List (HAL) and Paediatric HAL (pedHAL) questionnaires will 
assess subjective functional ability to perform activities of daily living (21). The HAL will be 
assessed in patients ≥18 years of age, and the pedHAL will be assessed in patients <18 years of 
age. Where available, the HAL and pedHAL questionnaire will be distributed to patients to self-
complete as specified in the Schedule of Assessments (Table 1). 
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7.7.1.4 EQ-5D-5L  
The EQ-5D-5L is a standardized instrument for use as a measure of QOL outcome (22). It 
consists of a questionnaire pertaining to 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression and a visual analog scale.  Scoring of the questionnaire 
is based on 5 degrees of disability (none, slight, moderate, severe, or extreme). Scoring of the 
visual analog scale is based on a visual scale ranging from 0 (worst imaginable health state) to 
100 (best imaginable health state). Higher scores indicate better health status. The questionnaires 
will be completed by all patients as specified in the Schedule of Assessments (Table 1). 
7.7.2 HJHS  
The HJHS is a tool for assessment of joint health in subjects with hemophilia (23). Joint health 
status will be assessed via the HJHS, as administered by a healthcare professional trained in the 
use of anthropometric measures, as specified in the Schedule of Assessments (Table 1). 
Completed HJHS score forms will be collected and archived at study sites. 
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8 
STATISTICS  
A Statistical Analysis Plan (SAP) will be finalized before database lock. The plan will detail the 
implementation of the statistical analyses in accordance with the principal features stated in the 
protocol. 
The primary efficacy and safety analyses will be done for Cohort A and Cohort B separately. A 
pooled analysis will be performed after all patients have either finished the Month 7 visit during 
the fitusiran treatment period or discontinued from the study. 
8.1 
DETERMINATION OF SAMPLE SIZE  
Sample size is based on clinical considerations. The overall sample size of 80 patients including 
approximately 30 patients with inhibitor (Cohort A) and approximately 50 patients without 
inhibitor (Cohort B) was selected recognizing the limited number of patients with hemophilia, 
and to yield a reasonably robust estimate of the fitusiran bleeding episode rate and address the 
secondary objectives, including characterization of safety and tolerability. The proposed sample 
size is also expected to provide reasonable precision around the ratio of bleeding rate in the 
fitusiran efficacy period to bleeding rate in the factor or BPA prophylaxis period for both 
Cohort A and Cohort B. 
Since patients will participate in multiple periods, within-patient correlation of numbers of 
bleeding episodes is expected between the periods. Having no prior knowledge of this 
correlation, different correlation scenarios were considered and the ratio of the bleeding rate in 
fitusiran efficacy period to the bleeding rate in factor or BPA prophylaxis period along with its 
95% CIs were simulated. For the United States specific requirements see Section 11.6.1.2. 
Table 9 and Table 10 summarizes the results from 10,000 simulated studies along with the ABR 
assumptions. 
Table 9 - Simulated ratio of rates for Cohort A, with 95% confidence intervals                   
Correlation 
Average Ratio (Average 95% CI Bounds), N=30 
Based on 10,000 Simulations 
Fitusiran period ABR: mean=4, SD=6 
Factor/BPA period ABR:  
Mean=16; SD=14 
Factor/BPA period ABR:  
Mean=12; SD=11 
0.25 
0.24 (0.14, 0.42) 
0.32 (0.19, 0.57) 
0.50 
0.24 (0.15, 0.39) 
0.32 (0.20, 0.52) 
0.75 
0.24 (0.17, 0.35) 
0.32 (0.22, 0.47) 
Abbreviation:  ABR=annualized bleeding rate; BPA=bypassing agent; CI=confidence interval; SD=standard deviation 
Note: Correlation = within-patient correlation between bleeding episodes of fitusiran efficacy period and factor or BPA period. BPA period ABR 
per Oldenburg, et al (24). 
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Table 10 - Simulated ratio of rates for Cohort B, with 95% confidence intervals  
Correlation 
Average Ratio (Average 95% CI Bounds), N=40 
Based on 10,000 Simulations 
Fitusiran period ABR: mean=4, SD=6; N=40 
Factor/BPA period ABR:  
Mean=4; SD=5 
Factor/BPA period ABR:  
Mean=6; SD=7 
0.25 
1.04 (0.57, 1.94) 
0.69 (0.39, 1.25) 
0.50 
1.03 (0.63, 1.69) 
0.68 (0.43, 1.09) 
0.75 
1.01 (0.72, 1.41) 
0.67 (0.48, 0.93) 
Abbreviation:  ABR=annualized bleeding rate; BPA=bypassing agent; CI=confidence interval; SD=standard deviation 
Note: Correlation = within-patient correlation between bleeding episodes of fitusiran efficacy period and factor or BPA period. BPA period ABR 
per Oldenburg, et al (24). 
8.2 
STATISTICAL METHODOLOGY  
The statistical and analytical plans presented below are brief summaries of planned analyses.  
The analyses will be done for Cohort A, and Cohort B separately. A pooled analysis will be 
performed after all patients in the 2 cohorts have either finished the Month 7 visit during the 
fitusiran treatment period or discontinued from the study. More complete plans will be described 
in the SAP. Changes to the methods described in the final SAP will be described and justified as 
needed in the clinical study report. 
8.2.1 Populations to be analyzed  
The populations (analysis sets) are defined as follows: 
• Safety Analysis Set:  All patients who enrolled and then received any dose of fitusiran. 
• Efficacy Analysis Set (EAS):  All patients in the safety analysis set who received both 
factor or BPA prophylaxis and any dose of fitusiran (Addressed in more detail in SAP). 
• Per-protocol Analysis Set (PPS):  All patients in the EAS who had no major protocol 
deviations.  Major deviations will be specified in the SAP. 
• PK Analysis Set:  All patients who received any dose of study fitusiran and have at least 
1 postdose blood sample for PK parameters and have evaluable PK data. 
• COVID-19 Unaffected Set: All patients who had no major or critical protocol deviations 
due to COVID-19 at any visit up to the end of study (Month 7). 
• The subgroup of Cohort A patients who are not responding adequately to BPA 
prophylaxis treatment will be included in the safety analysis set but will not be part of the 
efficacy analysis set; however, their efficacy data will be presented separately. 
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8.2.2 Examination of subgroups  
Exploratory subgroup analysis on ABR will be conducted for the primary endpoint.  Description 
of the subgroups will be detailed in the SAP. 
8.2.3 Handling of missing data  
Handling of missing data will be described in the SAP. 
8.2.4 Baseline evaluations  
Demographics and other baseline characteristics will be summarized for the Safety Analysis Set 
and EAS. 
8.2.5 Efficacy analyses  
Primary analyses of the primary and secondary endpoints will be based on the EAS. 
To address the potential impact of COVID-19, the efficacy analyses will be repeated on the 
COVID-19 unaffected set. Additional analyses and methods required to evaluate the impact are 
detailed in the SAP. 
8.2.5.1 Primary endpoint  
The primary analysis will be performed on the EAS and will include all bleeding episodes 
occurring in the factor or BPA prophylaxis period (Day -162 to Day -1) and the fitusiran efficacy 
period (Day 29 to Day 190).  If a patient does not have bleeding episode data collected after 
Day 28 (eg, due to early study discontinuation), the available bleeding episode data starting from 
Day 1 will be used in the primary analysis. To avoid confounding the treatment effect, bleeding 
episode data during and after major surgery, antithrombin administration, major trauma, or 
initiation of prophylaxis treatment with factors or BPAs during the fitusiran treatment period will 
be excluded from the primary analysis. 
The number of bleeding episodes will be analyzed using a repeated measures negative binomial 
model with fixed effect of treatment period.  The logarithm number of days that each patient 
spends in the efficacy period matching the bleeding episode data being analyzed will be included 
as an offset variable to account for unequal follow-up time due to early withdrawal or surgery. 
The ratio of bleeding rates in the fitusiran efficacy period to the factor or BPA prophylaxis 
period and its 95% CI and p-value will be presented. The p-value should be interpreted with 
caution. In addition, as a contrast Bayesian analyses will be performed to summarize the point 
estimates of the posterior probability of a clinically significant treatment effect, along with 
associated measures of uncertainty. The estimated mean ABRs in these 2 periods along with 
their 95% CIs will be presented from this model.  In addition, summary statistics for ABR, 
including the median and interquartile range, will be presented for each treatment arm, where 
ABR is defined as: 
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total number of qualifying bleeding episodes
total number of days in the respective period  × 365.25 
Patients who discontinue treatment during the study will be strongly encouraged to continue 
recording bleeding episode data. 
For the United States specific requirements, see Section 11.6.1.2. 
8.2.5.2 Secondary endpoints  
Spontaneous bleeding episodes and joint bleeding episodes will be analyzed using the same 
method as primary analysis of ABR. Summary statistics, including the median and interquartile 
range, for annualized spontaneous bleeding rate and annualized joint bleeding rate will be 
reported. 
Change in Haem-A-QOL physical health score and total score (in patients ≥17 years of age) in 
the factor or BPA prophylaxis period and fitusiran treatment period will be summarized 
descriptively. A mixed model for repeated measures analysis may be performed as deemed 
appropriate. 
The bleeding episodes in the fitusiran onset period and in the fitusiran treatment period will be 
analyzed using a negative binomial model with logarithm of follow-up time in the period as an 
offset parameter.  Summary statistics, including the median and interquartile range, for the ABR 
in 2 periods will be reported. 
The secondary endpoint of annualized weight-adjusted consumption of factor/BPA injections 
will be summarized using descriptive statistics 
8.2.5.3 Exploratory endpoints  
Details of the analyses for the exploratory endpoints will be described in the SAP. 
8.2.6 Pharmacodynamic analysis  
AT and thrombin levels will be summarized descriptively by scheduled visit.  Mixed models 
repeated measures analyses may be performed as deemed appropriate. Correlation between AT 
and thrombin levels may be explored. 
8.2.7 Pharmacokinetic analysis  
Pharmacokinetic analyses will be conducted using a population PK approach on all patients. The 
details of analysis will be presented in a separated population PK analysis plan. 
In addition to performing population PK analyses, the following PK parameters will be included 
in an analysis of East Asian patients at East Asian sites:  maximum plasma concentration (Cmax), 
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time to maximum plasma concentration (tmax), elimination half-life (t½β), area under the 
concentration-time curve (AUC), apparent clearance (CL/F), and apparent volume of distribution 
(V/F); these parameters will be estimated during the fitusiran treatment period using non-
compartmental analysis.  Other parameters may be calculated, if deemed necessary. 
8.2.8 Safety analyses  
Extent of exposure will be summarized.  Safety results will be based on all AEs having onset 
(start or worsening in severity) within the analysis period and on the Safety Analysis Set. 
Incidence of AEs, AEs by maximum severity, AEs by relationship to study medication, SAEs 
and AEs leading to discontinuation of treatment will be presented. 
Descriptive statistics will be provided for clinical laboratory data, ECG and vital signs.  
Laboratory shift tables from baseline to worst post-baseline values may be presented.  
Other safety summaries will be presented as appropriate. Further details will be provided in the 
SAP. 
Adverse events will be classified according to the MedDRA System Organ Class and Preferred 
Term. Prior and concomitant medications will be classified according to the World Health 
Organization (WHO) drug dictionary. 
8.2.9 Other analyses 
  
Antidrug antibody results will be summarized descriptively. 
8.2.10 Interim analysis  
An interim analysis may be conducted as a part of this study. 
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9 
STUDY ADMINISTRATION  
9.1 
ETHICAL AND REGULATORY CONSIDERATIONS  
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
9.1.1 Informed consent process  
The Investigator or his/her representative will explain the nature of the study to the patient or his 
legally authorized representative (defined as an individual or juridical or other body authorized 
under applicable law to consent, on behalf of a prospective patient, to the patient's participation 
in the clinical trial) and answer all questions regarding the study. 
Patients must be informed that their participation is voluntary. Patients or their legally authorized 
representative will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center. 
The medical record must include a statement that written informed consent was obtained before 
the patient was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
Patients must be re-consented to the most current version of the ICF(s) during their participation 
in the study. 
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorized 
representative. 
9.1.2 Ethical review  
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients. 
The Investigator will be responsible for the following: 
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• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European Regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations 
9.1.3 Study documentation, confidentiality, and records retention  
Patients will be assigned a unique identifier by the Sponsor. Any patient records or datasets that 
are transferred to the Sponsor will contain the identifier only; patient names or any information 
which would make the patient identifiable will not be transferred. 
The patient must be informed that his/her personal study-related data will be used by the Sponsor 
in accordance with local data protection law.  The level of disclosure must also be explained to 
the patient. 
The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
9.1.4 End of the study  
The end of the study is defined as last patient last visit. 
9.1.5 Discontinuation of the clinical study  
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor.  Study sites will be closed upon study 
completion.  A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The Investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
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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9.2 
DATA QUALITY CONTROL AND QUALITY ASSURANCE  
9.2.1 Data handling  
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the Investigator’s site. 
Data reported or entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The Investigator 
may need to request previous medical records or transfer records, depending on the study. Also, 
current medical records must be available. 
All patient data relating to the study will be recorded on eCRF unless transmitted to the Sponsor 
or designee electronically (eg, laboratory data). The Investigator is responsible for verifying that 
data entries are accurate and correct by physically or electronically signing the eCRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
9.2.2 Study monitoring  
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements. 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality such as 
Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 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 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. 
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9.2.3 Audits and inspections  
Periodically, the Sponsor or its authorized representatives audit clinical investigative sites as an 
independent review of core trial processes and documents to determine whether these activities 
were conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, GCP guidelines of the ICH, and any applicable regulatory requirements. A regulatory 
authority, an IEC or an IRB may visit the site to perform audits or inspections, including source 
data verification. The Investigator should contact the Sponsor, or its designee, immediately if 
contacted by a regulatory agency, an IEC or an IRB about an inspection. 
9.3 
PUBLICATION POLICY  
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows the Sponsor to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
9.4 
DISSEMINATION OF CLINICAL STUDY DATA  
Sanofi shares information about clinical trials and results on 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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10 
LIST OF REFERENCES  
1. Iorio A, Stonebraker JS, Chambost H, Makris M, Coffin D, Herr C, Germini F; Data and 
Demographics Committee of the World Federation of Hemophilia. Establishing the 
Prevalence and Prevalence at Birth of Hemophilia in Males: A Meta-analytic Approach 
Using National Registries. Ann Intern Med. 2019 Oct 15;171(8):540-46. 
2. What is hemophilia? Word Federation of Hemophilia [Internet]. 2004 [cited 2020 Aug 17]. 
Available from: http://www1.wfh.org/publications/files/pdf-1324.pdf. 
3. Bauer KA. Current challenges in the management of hemophilia. Am J Manag Care. 
2015;21(6 Suppl):S112-22. 
4. Sehgal A, Barros S, Ivanciu L, Cooley B, Qin J, Racie T, et al. An RNAi therapeutic 
targeting antithrombin to rebalance the coagulation system and promote hemostasis in 
hemophilia. Nat Med. 2015;21(5):492-7. 
5. Walsh CE, Soucie JM, Miller CH. Impact of inhibitors on hemophilia A mortality in the 
United States. Am J Hematol. 2015;90(5):400-5. 
6. Wight J, Paisley S. The epidemiology of inhibitors in haemophilia A: a systematic review. 
Haemophilia. 2003 Jul;9(4):418-35. 
7. 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. 
8. 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. 
9. Brettler DB. Inhibitors in congenital haemophilia. Baillieres Clin Haematol. 1996 
Jun;9(2):319-29. 
10. 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):819-28. 
11. 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. 
12. Schrijvers L, Beijlevelt-Van der Zande M, Peters M, Lock J, Cnossen M, Schuurmans M, et 
al. Achieving self-management of prophylactic treatment in adolescents: The case of 
haemophilia. Patient Educ Couns. 2016. 
13. Makris M, Kasper C. The World Federation of Hemophilia guideline on management of 
haemophilia. Haemophilia. 2013;19(1):1. 
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14. Witkop M, Guelcher C, Forsyth A, Hawk S, Curtis R, Kelley L, et al. Treatment outcomes, 
quality of life, and impact of hemophilia on young adults (aged 18-30 years) with 
hemophilia. Am J Hematol. 2015;90 Suppl 2:S3-10. 
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. 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. 
20. Atkinson MJ, Sinha A, Hass SL, Colman SS, Kumar RN, Brod M, et al. Validation of a 
general measure of treatment satisfaction, the Treatment Satisfaction Questionnaire for 
Medication (TSQM), using a national panel study of chronic disease. Health Qual Life 
Outcomes. 2004;2:12. 
21. van Genderen FR, Westers P, Heijnen L, de Kleijn P, van den Berg HM, Helders PJ, et al. 
Measuring patients' perceptions on their functional abilities: validation of the Haemophilia 
Activities List. Haemophilia. 2006;12(1):36-46. 
22. 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. 
23. Feldman BM, Funk SM, Bergstrom BM, Zourikian N, Hilliard P, van der Net J, et al. 
Validation of a new pediatric joint scoring system from the International Hemophilia 
Prophylaxis Study Group: validity of the hemophilia joint health score. Arthritis Care Res 
(Hoboken). 2011;63(2):223-30. 
24. Oldenburg J, Mahlangu JN, Kim B, Schmitt C, Callaghan MU, Young G, et al. Emicizumab 
Prophylaxis in Hemophilia A with Inhibitors. N Engl J Med. 2017;377(9):809-18. 
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11 
APPENDICES  
11.1 
PHARMACOKINETIC ASSESSMENT TIME POINTS  
Table 11 provides a schedule for the collection of blood samples for PK analysis in East Asian 
patients). 
Table 11 - Pharmacokinetic time points in East Asian patients at East Asian sites following 
fitusiran administration at 50 mg Q2M                   
Study day 
Protocol time (hh:mm) 
PK blood 
Day 1  
Predose 
(within 240 minutes before dosing) a 
X 
00:30 (±5 min) a 
X 
01:00 (±5 min) a 
X 
02:00 (±15 min) a 
X 
04:00 (±30 min) a 
X 
06:00 (±30 min) a 
X 
08:00 (±30 min) a 
X 
12:00 (±30 min) a 
X 
Month 2 
Predose 
(within 240 minutes before dosing) a 
X 
Month 4 
Predose 
(within 240 minutes before dosing) a 
X 
04:00 (±30 min) a 
X 
Month 6 (EOT)  
Predose 
(within 240 minutes before dosing) a 
X 
Abbreviations: hh=hours mm=minutes; PK=pharmacokinetic 
a Timepoint used in population PK analysis 
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11.2 
PERIOPERATIVE SCHEDULE OF ASSESSMENTS  
11.2.1 Definitions of minor and major surgery  
Minor surgery is defined as any invasive operative procedure in which only skin, mucous 
membranes, or superficial connective tissue is manipulated and does not meet the criteria for 
major surgery (eg, dental extraction of <3 non-molar teeth).  Minor surgical procedures may be 
performed at a local health care provider institution. 
Major surgery is defined as any invasive operative procedure that requires any of the following: 
• Opening into a major body cavity (eg, abdomen, thorax, skull) 
• Operation on a joint 
• Removal of an organ 
• Dental extraction of any molar teeth or ≥3 non-molar teeth 
• Operative alteration of normal anatomy 
• Crossing of a mesenchymal barrier (eg, pleura, peritoneum, dura) 
It is strongly recommended that any elective non-dental major surgery be performed at a clinical 
study center, when possible. 
11.2.2 Perioperative assessments of safety and hemostatic efficacy in patients 
undergoing major operative procedures  
In patients undergoing major operative procedures during the fitusiran treatment period, safety 
and hemostatic efficacy assessments will be performed according to the Perioperative Schedule 
of Assessments (described below and outlined in Table 12, 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 12): 
directed physical examination and assessment of vital sign measurements; clinical laboratory 
assessments including hematology (complete blood count, white blood count, red blood cell 
count, hemoglobin, hematocrit, platelets); coagulation (APTT, PT/INR, fibrinogen, D-dimer); 
hepatic assessments; and hemostatic efficacy assessments (rating scale based on ISTH Scientific 
and Standardization Committee [SSC] definitions) (18). 
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11.3 
ISTH GUIDELINE FOR ASSESSMENT OF TREATMENT RESPONSE  
ISTH recommendations (18) are provided in the table below for assessment of treatment 
response (Table 13). 
Table 13 - Assessment of treatment of acute joint/muscle bleeding episodes  
Category 
Response 
Excellent 
Complete pain relief within 8 hours and/or complete resolution of signs of bleeding after the initial injection and 
not requiring any further replacement therapy for relief of persistent symptoms and signs in the same joint 
within 72 hours 
Good 
Significant pain relief and/or improvement in signs of bleeding within approximately 8 hours after a single 
injection, but requiring more than one dose of replacement therapy within 72 hours for complete resolution 
Moderate 
Modest pain relief and/or improvement in signs of bleeding within approximately 8 hours after the initial 
injection and requiring more than one injection within 72 hours but without complete resolution 
None 
No or minimal improvement, or condition worsens, within approximately 8 hours after the initial injection 
11.4 
BLEED SEVERITY DEFINITIONS  
The definitions of bleed severity are shown in Table 14. 
Table 14 - Bleed severity definitions      
Bleed Severity 
Definition 
Minor 
Early joint bleeding; mild muscle bleeding; or mild bleeding (any other location) 
Moderate 
Definite joint bleeding; moderate muscle bleeding; moderate bleeding (any other location); 
known trauma (other than head trauma or fractures) 
Major 
Severe bleeding that is life- or limb-threatening; including fractures and head trauma 
11.5 
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 
participants, the Sponsor takes all appropriate measures to safeguard and prevent access to this 
data by any unauthorized third party. 
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Protection of participant 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. 
“Participant 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. 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor or its service providers will be identifiable 
only by the unique identifier; participant names or any information which would make 
the participant identifiable will not be transferred to the Sponsor. 
• The participant 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 participant as described in the informed consent. 
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
• Participants 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. 
• 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. 
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• 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. 
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). 
11.6 
COUNTRY-SPECIFIC REQUIREMENTS  
11.6.1 United States  
Change to the protocol for the United States only: new texts addition is presented as bold texts 
and deleted text is presented in crossed texts. 
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11.6.1.1 Protocol synopsis  
Study design 
The ATLAS-PPX trial (ALN-AT3SC-009 [Sanofi Genzyme EFC15110]) is a multicenter, 
multinational, open label, Phase 3 study designed to evaluate the efficacy and safety of fitusiran 
in male patients, aged ≥12 years, with hemophilia A or B, who have switched from prior 
bypassing agent (BPA, Cohort A) or factor (Cohort B) prophylaxis. A subgroup of Cohort A 
patients will include hemophilia B patients with inhibitory antibodies to Factor IX who are not 
responding adequately to BPA prophylaxis treatment (historical ABR ≥20). U.S.A. patients can 
only participate in Cohort A. 
The study has 3 periods: 
• 6-Month factor or BPA prophylaxis period in which patients will continue their prestudy, 
regularly scheduled prophylaxis regimen with factor concentrates or BPAs 
- 
The subgroup of Cohort A patients who are not responding adequately to BPA 
prophylaxis treatment will not participate in this 6-month BPA prophylaxis period 
and will start the following period after the screening period. 
• 1-Month onset period in which patients receive their first dose of fitusiran while 
continuing their factor or BPA prophylaxis for up to 7 days 
• 6-Month fitusiran efficacy period in which patients receive fitusiran as prophylaxis 
Together, the 1-month onset period and the 6-month fitusiran efficacy period constitute the 
fitusiran treatment period. 
Bleeding events and doses of factors or BPAs administered during the conduct of the study will 
be recorded in an electronic Diary (eDiary). Safety, quality of life, pharmacodynamic, and 
pharmacokinetic data will also be collected. 
Following the screening and prophylaxis periods or following the screening period for the 
subgroup of Cohort A enrolling directly into the fitusiran treatment period, all patients will be 
treated with fitusiran for a total of 7 months.  Because the full PD effect of fitusiran is not 
achieved until approximately 28 days after receiving the first dose, for the US efficacy will be 
assessed not only during the overall treatment period (Day 1 to Day 190; primary 
endpoint), but also during the efficacy period (Day 29 to Day 190; final 6 months of the 
fitusiran treatment period (Day 29 to Month 7) key secondary endpoint). 
 
Throughout the study, patients may receive on-demand treatment for breakthrough bleeding 
episodes with factors or BPAs, as appropriate. 
Number of planned patients 
Approximately 80 patients are planned for enrollment in this study, including approximately 
30 patients with inhibitors (Cohort A) and approximately 50 patients without inhibitors (Cohort 
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B). Approximately 18 patients with hemophilia B (including approximately 7 hemophilia B 
patients in Cohort A, among which are a subgroup of no more than 4 patients who are not 
responding adequately to BPA prophylaxis), 11 hemophilia B patients in Cohort B, and 
approximately 7 adolescents (≥12 to <18 years of age) are also planned for enrollment. In the 
US, only patients from Cohort A will be included. 
Diagnosis and main eligibility criteria 
Patients without inhibitors must have used factor concentrates for prophylaxis for at least the last 
6 months prior to Screening and must meet each of the following criteria: 1) Nijmegen modified 
Bethesda assay inhibitor titer of <0.6 BU/mL at Screening, AND 2) No use of bypassing agents 
to treat bleeding episodes for at least the last 6 months prior to Screening, AND 3) No history of 
immune tolerance induction therapy within the last 3 years prior to Screening. A minimum of 1 
bleeding episode requiring factor treatment within the last 12 months prior to Screening is 
required. 
Reference therapy, dose and mode of administration 
During the factor or BPA prophylaxis period, patients will continue FVIII, FIX, or BPA 
prophylaxis as treatment for hemophilia on a regimen consistent with recommendations in the 
approved prescribing information, allowing for adjustment to individual patient response, and 
designed to decrease spontaneous bleeding. Dose and mode of administration will be per 
Investigator discretion; bleeding episode management should be per the local standard practice 
for episodic use of factors or BPAs and as per Investigator discretion. The subgroup of Cohort A 
patients who are not responding adequately to BPA prophylaxis treatment will not participate 
into this BPA prophylaxis period and will directly start the fitusiran treatment period after the 
screening period. All patients will continue to receive FVIII, FIX, or BPA prophylaxis for the 
first 7 days of the onset period. Subsequently, breakthrough bleeding episodes will be treated 
with on demand factor or BPA therapy as necessary per the bleeding episode management 
guidelines. 
Statistical methods 
The primary endpoint secondary endpoints (spontaneous bleeding episodes and joint bleeding 
episodes) will be based on the bleeding events occurring in the factor or BPA prophylaxis period 
(Day -162 to Day -1), and the fitusiran treatment period (Day 1 to Day 190). To avoid 
confounding treatment effect, bleed data following major surgery, antithrombin administration, 
major trauma, or the re-initiation of prophylaxis treatment with factors or BPAs after fitusiran 
discontinuation will be excluded from the primary analysis. 
The number of bleeding episodes will be analyzed using a repeated measures negative binomial 
model with fixed effect of treatment period. The logarithm of bleeding episode follow-up time in 
each period for each patient will be used as an offset parameter in the model to account for any 
difference in follow-up duration. The ratio of bleeding rates in the fitusiran efficacy treatment 
period relative to the factor/BPA prophylaxis period and its 95% CI and p-value will be 
presented. The p-value should be interpreted with caution. In addition, as a contrast Bayesian 
analyses will be performed to summarize the point estimates of the posterior probability of a 
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clinically significant treatment effect, along with associated measures of uncertainty. In addition, 
estimated mean ABR and its 95% CI during each of the 2 periods and during the fitusiran onset 
period and efficacy period (key secondary endpoint) will be presented. 
For the secondary endpoints, the spontaneous bleeding episodes and the joint bleeding 
episodes will be analyzed using the same model as used in the primary analysis. Safety data will 
be summarized descriptively. The bleeding episodes in the fitusiran onset period and in the 
fitusiran treatment efficacy period will be analyzed using a negative binomial model with 
logarithm of follow-up time in the period as an offset parameter. Change in Haem-A-QOL 
physical health score and total score in the factor/BPA prophylaxis period and fitusiran treatment 
period will be summarized descriptively. The annualized weight-adjusted consumption of 
factor/BPA injections will be summarized using descriptive statistics. 
Safety data will be summarized descriptively. 
Table 1: 
Schedule of assessments 
Study Visit (Month) 
Screeninga 
Factor or BPA 
Prophylaxis Perioda 
Fitusiran Treatment Periodb 
AT 
F/Ud,e 
Onset 
Periodb 
Efficacy Period 
Month -6a 
Month -5a 
Month -4a 
Month -3a 
Month -2a 
Month -1a 
Baseline 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
EOT 
EOS/E
Tc,d 
Month 8 
Month 6 
Month 7 
Study Day (±Visit 
Window) 
-228 to -169 
Day -168 
Day -140 ±7 
Day -112 ±7 
Day -84 ±7 
Day -56 ±7 
Day -28 ±7 
Day 1  
Day 15 ±3  
Day 29 ±7 
Day 43 ±3 
Day 57 ±7 
Day 85 ±7 
Day 113 ±7 
Day 141 ±7 
Day 169 ±7 
Day 197 ±7 
Day 225 ±7 
Footnote “a”: Routine prophylaxis with factor concentrates or BPAs for treatment of hemophilia. The subgroup of Cohort A patients who are not 
responding adequately to BPA prophylaxis treatment will not participate in the BPA prophylaxis period and will directly start the fitusiran 
treatment period after the screening period. For these patients, the screening period will be from Day -60 to Day 0 and assessments during the 
BPA prophylaxis period are not applicable. 
Footnote "b": Fitusiran as prophylaxis treatment and permitted on-demand use of factors or BPAs for treatment of breakthrough bleeding 
episodes. Patients may continue their routine factor or BPA administration schedule for up to the first 7 days of the onset period. 
Footnote "m": To be performed in all patients, at any clinic visit during their factor or BPA prophylaxis period, with blood drawn before, 10 min 
(±5 min) after, and 60 min (±5 min) after administration of their usual prophylactic dose of factor or BPA. Laboratory testing pre- and post- 
factor/BPA include: Coagulation, and TG. The timing of this visit should coincide with the patient’s usual prophylaxis regimen, so that pre-dose 
thrombin generation is at nadir and the benefit of administered factor or BPA is maintained. 
Footnote "t": It is strongly preferred that factor or BPA administration and bleeding events are entered in the eDiary immediately or within 
24 hours. Additional patient follow-up may be required as described in Section 7.2.1. Patients in the fitusiran treatment arm who present in the 
clinic with symptoms characteristic of a potential bleeding episode should have assessments completed per Table 2. 
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Table 2: 
Bleeding episode assessments - unscheduled visit 
 
Predose 
Postdose 
10 min (±5 min)d 
Postdose 
60 min (±5 min) d 
Directed Physical Examinationa 
X 
 
 
Vital Signs 
X 
 
 
AT 
X 
 
 
FVIII/FIX Levels 
(only if treated with FVIII or FIX) 
X 
X 
X 
TG 
X 
X 
X 
Coagulation 
X 
X 
X 
Hematology 
X 
X 
X 
Optional Imagingc 
X 
 
 
Abbreviations:  AT=antithrombin; FVIII=Factor VIII; FIX=Factor IX; TG=thrombin generation 
a See Section 7.6.3 for assessments to be performed during a directed physical examination. 
b Removed. 
c Investigator to consider confirmation of bleed via ultrasound or other imaging modality at clinical study centers where appropriate 
equipment and staff with related expertise is available. 
d If the patient presents following administration of factor or BPAs at home and within 48 hours of the dose, and no further treatment is given 
at the center, AT and the postdose assessments should be obtained in a single draw at any time during the visit. 
11.6.1.2 Protocol body  
Section 1.3 
Study Design Rationale 
The ATLAS-PPX trial (Alnylam ALN-AT3SC-009 [Sanofi Genzyme EFC15110]) is a 
multicenter, multinational, open-label Phase 3 switching study designed to demonstrate the 
efficacy and safety of fitusiran in patients with hemophilia A or B, who are currently treated with 
prophylactic regimens of factor concentrates or BPAs. 
The switching design allows for an intra-patient control to enable examination of the effect of the 
two treatment methods through comparison of the median ABR during the factor or BPA 
prophylaxis period and the median ABR of the same patient group when receiving fitusiran, 
while limiting confounding effects of different patient bleeding phenotypes and prophylaxis 
therapy variability. Inhibitor patients with hemophilia B may have a high unmet need despite 
prophylactic BPA therapy, with limited other treatment options. Therefore, a limited number of 
inhibitor patients with hemophilia B who are not adequately responding to prophylactic BPA 
therapy could enroll directly into the fitusiran treatment period, thereby skipping the 6-month 
BPA prophylaxis period. The onset period duration reflects modeling data that estimates it takes 
approximately 28 days to reach the therapeutic target range in the majority of patients. 
Given that the study design employed is a single treatment arm, with a switch from prophylaxis 
to fitusiran for each patient, the study is not blinded. The primary endpoint of the study is ABR 
in the fitusiran efficacy period and the factor or BPA prophylaxis period. ABR is a well-
established endpoint that has been used as the primary endpoint in global approvals of factor 
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replacement and BPA products. Secondary endpoints characterize annualized spontaneous and 
joint bleeding rates, change in Haem-A-QoL physical health score and total score in patients 
≥17 years of age, ABR in the onset period, overall safety profile and the consumption of 
factor/BPA. 
Characterization of bleeding episodes is clinically relevant to assess overall bleeding episode 
protection. Joint bleeding episodes result in pain and hemarthrosis, leading to progressive joint 
destruction, and hence are important to assess. The Haem-A-QOL is a hemophilia-specific 
HRQOL survey instrument, has been used in other hemophilia clinical trials, has been validated, 
reviewed by clinicians, and is considered the most appropriate HRQOL tool available for use in 
the study. 
The study population will be comprised of males ≥12 years of age; it is appropriate to study 
fitusiran in adolescents (patients ≥12 to <18 years of age) because the pathophysiology of disease 
progression and bleeding episode management is the same as adults and self-management of 
hemophilia typically begins at 12 years of age (12). 
In the event of a breakthrough bleeding episode, on-demand use of factors or BPAs will be 
permitted throughout the entire study duration (see Section 6.3.2). 
Section 1.5 
Benefit-Risk Assessment 
Identified risks of fitusiran include serious vascular thrombosis, liver transaminase abnormalities, 
cholecystitis, and symptomatic cholelithiasis.  In addition, serious hypersensitivity reactions, 
including injection site reactions, are considered a potential risk of fitusiran.  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, due to 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, liver 
transaminase abnormalities, and serious ISRs. 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 6.2.3.2), detailed guidance and oversight on treatment of breakthrough 
bleeding episodes with reduced factor and/or BPA dosing (Section 6.3.2), and monitoring and 
management of thrombosis while patients are on fitusiran (Section 6.5). The protocol also 
excludes patients with evidence of liver disease (including active viral hepatitis) and stipulates 
ongoing monitoring for elevated transaminases (Section 6.2.3.1). The safety of trial patients will 
be overseen by an independent DMC (Section 4.7). 
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Section 2 Objectives 
2.1. 
Primary Objective 
• To characterize the frequency of bleeding episodes while receiving fitusiran treatment, 
relative to the frequency of bleeding episodes while receiving factor concentrate or 
bypassing agent (BPA) prophylaxis 
2.2. 
Secondary Objectives 
• To characterize the following while receiving fitusiran treatment, relative to receiving 
factor or BPA prophylaxis: 
- 
the frequency of spontaneous bleeding episodes 
- 
the frequency of joint bleeding episodes 
- 
health related quality of life (HRQOL) in patients ≥17 years of age 
- 
the consumption of factor/BPA 
• To characterize the frequency of bleeding episodes during the onset and efficacy periods 
in patients receiving fitusiran  
• To characterize safety and tolerability of fitusiran 
2.3. 
Exploratory Objectives 
• To characterize the effects of fitusiran on the following patient reported outcomes while 
receiving fitusiran treatment, relative to receiving factor or BPA prophylaxis: 
- 
Patient satisfaction with fitusiran 
- 
Patient activity 
- 
HRQOL in adolescents (≥12 to <17 years of age) 
• To characterize the pharmacodynamic (PD) effect, PK, and immunogenicity of fitusiran 
• To characterize the effects of fitusiran on joint status while receiving fitusiran treatment, 
relative to receiving factor or BPA prophylaxis 
• To characterize the effects of fitusiran on patient resource use, relative to receiving factor 
or BPA prophylaxis 
Section 3 Endpoints 
3.1  
Primary Endpoint 
• Annualized Bleeding Rate (ABR) in the fitusiran treatment efficacy period and factor or 
the BPA prophylaxis period 
3.2  
Key secondary endpoint 
• ABR in the fitusiran efficacy period 
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3.3  
Secondary Endpoints 
• Annualized spontaneous bleeding rate in the fitusiran efficacy period and the factor or 
BPA prophylaxis period 
• Annualized joint bleeding rate in the fitusiran efficacy period and the factor or BPA 
prophylaxis period 
• Change in Haem-A-QOL physical health score and total score in the fitusiran treatment 
period 
• ABR in the onset period 
• ABR in treatment efficacy period 
• Annualized weight-adjusted consumption of factor/BPA 
Section 4.1 
Summary of Study Design 
The ATLAS-PPX trial (ALN-AT3SC-009) is a multicenter, multinational, open label, Phase 3 
study designed to characterize the efficacy and safety of fitusiran in male patients, aged 
≥12 years, with severe hemophilia A or B, previously receiving factor or BPA prophylaxis.  The 
study consists of 2 cohorts: Ccohort A will consist of patients with inhibitory antibodies to 
Factor VIII or Factor IX; Cohort B will consist of patients without inhibitor antibodies to 
Factor VIII or Factor IX.  A subgroup of Cohort A patients will include hemophilia B patients 
with inhibitory antibodies to Factor IX who are not responding adequately to BPA prophylaxis 
treatment (historical ABR ≥20) (see Inclusion Criteria in Section 5.1). In the US only Cohort A 
will be enrolled.  The study has 3 periods defined by type of prophylaxis regimen: 
• 6-Month factor or BPA prophylaxis period in which patients will continue their prestudy, 
regularly scheduled prophylaxis regimen with BPAs 
- 
The subgroup of Cohort A patients who are not responding adequately to BPA 
prophylaxis treatment will not participate in this 6-Month BPA prophylaxis period 
and will start the following period after the screening period. 
• 1-Month onset period in which patients receive first dose of fitusiran while continuing 
their factor or BPA prophylaxis for up to 7 days 
• 6-Month fitusiran efficacy period in which patients receive fitusiran as prophylaxis. 
Together, the 1-month onset period and the 6-month fitusiran efficacy period constitute the 
fitusiran treatment period. 
Bleeding events and doses of factor concentrates or BPAs administered during the conduct of the 
study will be recorded in an electronic Diary (eDiary), as described in Section 7.2.1.  Since 
bleeding episodes are recorded as an efficacy assessment of fitusiran, these will not be treated as 
AEs unless they meet any of the SAE criteria listed in Section 7.5.6.1.  Safety, quality of life, 
pharmacodynamic, and pharmacokinetic data will also be collected. 
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On-demand use of factor concentrates or BPAs is defined as the use of these agents, as needed, 
for episodic bleeding, and not on a regular regimen intended to prevent spontaneous bleeding.  
Throughout the study, patients in the fitusiran treatment period may receive on-demand 
treatment for breakthrough bleeding episodes with factors or BPAs, as appropriate.  For patients 
in the fitusiran treatment period who have received at least 1 dose of fitusiran and are being 
treated for breakthrough bleeding episodes, it is recommended to follow the guidelines provided 
in Section 6.3.2 per Investigator discretion.   
Following the screening and prophylaxis period, or following the screening period for the 
subgroup of Cohort A enrolling directly into the fitusiran treatment period, all patients will 
be treated with fitusiran for a total of 7 months.  Because the full PD effect of fitusiran is 
not achieved until approximately 28 days after receiving the first dose, efficacy will be 
assessed during the remaining 6 months of the fitusiran treatment period (Day 29 to Month 
7; key secondary endpoint). Therefore, the overall fitusiran treatment period is defined as 
the onset period (Day 1- Day 28 after receipt of the first dose, during which the AT 
lowering capacity of fitusiran is increasing but has not yet reached therapeutic levels) plus 
the efficacy period (Day 29 and after, when the AT lowering capacity of fitusiran has 
achieved therapeutic target range).  
 
Figure 1: 
Study design 
 
Abbreviations: AT=antithrombin 
Note: For subgroup of Cohort A patients enrolling directly into the fitusiran treatment period, see Figure 2. 
a Patients will continue to receive prescribed factor or BPA prophylaxis for the first 7 days of the onset period.  
b Following final fitusiran dose, AT activity level will be monitored at monthly intervals following the final fitusiran dose until activity levels 
return to approximately 60% (per the central laboratory) or per Investigator discretion in consultation with the study Medical Monitor.  
 
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Figure 2: 
Study design (for subgroup of Cohort A patients enrolling directly into the 
fitusiran treatment period) 
 
Abbreviations: AT=antithrombin 
a Patients will receive prescribed factor or BPA prophylaxis for the first 7 days of the onset period.  
b Following final fitusiran dose, AT activity level will be monitored at monthly intervals following the final fitusiran dose until activity levels 
return to approximately 60% (per the central laboratory) or per Investigator discretion in consultation with the study Medical Monitor.  
Section 4.3 
Number of Patients 
Approximately 80 patients are planned for enrollment in this study, including approximately 
30 patients with inhibitors (Cohort A) and approximately 50 patients without inhibitors 
(Cohort B). Approximately 18 patients with hemophilia B (including approximately 
7 hemophilia B patients in Cohort A, among which are a subgroup of no more than 4 patients 
who are not responding adequately to BPA prophylaxis [see Section 5.1]), and approximately 
7 adolescents (≥12 to <18 years of age) are also planned for enrollment. In the US, only 
patients from Cohort A will be included. 
Section 5.1 
Inclusion Criteria 
I 03. A minimum of 2 bleeding episodes requiring BPA treatment within the last 6 months 
prior to Screening for patients with inhibitory antibodies to Factor VIII or Factor IX 
(Cohort A).  A minimum of 1 bleeding episode requiring factor treatment within the last 
12 months prior to Screening for patients without inhibitory antibodies to Factor VIII or 
Factor IX (Cohort B). 
I 04. Must meet either the definition of inhibitor or non inhibitor patient as below:  
Inhibitor: 
Use of BPAs for prophylaxis and for any bleeding episodes for at least the last 6 months 
prior to Screening, and meet one of the following Nijmegen-modified Bethesda assay 
results criteria: 
- 
Inhibitor titer of ≥0.6 BU/mL at Screening, or 
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- 
Inhibitor titer of <0.6 BU/mL at Screening with medical record evidence of 
2 consecutive titers ≥0.6 BU/mL, or 
- 
Inhibitor titer of <0.6 BU/mL at Screening with medical record evidence of 
anamnestic response 
- 
The subgroup of patients in Cohort A patients must additionally meet the following 
criteria to be eligible to start treatment with fitusiran directly after the screening 
period: 
- 
Hemophilia B with inhibitory antibody to Factor IX as defined above 
- 
Not responding adequately to BPA treatment (historical ABR ≥20) prior to 
enrollment 
- 
In the opinion of the Investigator, with approval of Sponsor Medical Monitor, 
6-month BPA prophylaxis period should be omitted. 
Non inhibitor: 
Use of factor concentrates for prophylaxis and for any bleeding episodes for at least the 
last 6 months prior to Screening, and meet each of the following criterion: 
- Nijmegen modified Bethesda assay inhibitor titer of <0.6 BU/mL at Screening 
and 
- No use of bypassing agents to treat bleeding episodes for at least the last 6 months 
prior to Screening and 
- No history of immune tolerance induction therapy within the past 3 years prior to 
Screening. 
I 05. Prescribed prophylactic treatment (documented in the medical or pharmacy records) of 
hemophilia with factor concentrates or BPAs for at least 6 months prior to Screening; the 
regimen must be consistent with the approved prescribing information for the product or 
local recommendations, allowing for adjustment to individual patient response, and 
designed to decrease spontaneous bleeding. 
Section 5.2 
Exclusion Criteria 
E 18. Completion of a surgical procedure within 14 days prior to Screening, or currently 
receiving additional factor concentrate or BPA infusion for postoperative hemostasis. 
Section 5.3 
Removal from Therapy or Assessment 
Patients or their legal guardian (in case patient is a minor) are free to discontinue treatment or 
withdraw from the study at any time and for any reason, without penalty to their continuing 
medical care.  Any discontinuation of treatment or withdrawal from the study must be fully 
documented in the electronic case report form (eCRF) and should be followed up by the 
Investigator.  The Investigator may withdraw a patient at any time if this is considered to be in 
the patient’s best interest. 
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Patients who discontinue their prophylactic treatment or withdraw consent during the factor or 
BPA prophylaxis period (BPA prophylaxis period is not applicable for the subgroup of Cohort A 
patients who are not responding adequately to BPA prophylaxis treatment) will be withdrawn 
from the study. 
Procedures for discontinuation of study drug and/or withdrawal from the study during the 
fitusiran treatment period are described in Section 5.3.1 and Section 5.3.2, respectively. 
Section 6.3.1 Factor Concentrates or Bypassing agent prophylaxis 
Section 6.3.1.1 
Routine use of factor or bypassing agent prophylaxis in the factor or bypassing 
agent prophylaxis period 
During the factor or BPA prophylaxis period, patients will continue to receive prophylaxis with 
their usual products on a regimen consistent with recommendations in the approved prescribing 
information, allowing for adjustment to individual patient response, and designed to decrease 
spontaneous bleeding. The regimen used during the factor or BPA prophylaxis period must have 
a minimum frequency of administration as presented in Table 4. The subgroup of Cohort A 
patients who are not responding adequately to BPA prophylaxis treatment will not participate in 
this BPA prophylaxis period and will directly start the fitusiran treatment period after the 
screening period. 
Table 15 - Factor or Bypassing agent prophylaxis requirements  
Type of Factor or BPA replacement 
Frequency of administration 
Standard half life FVIII 
Twice weekly 
Extended half life FVIII 
Once weekly 
Standard half life FIX 
Once weekly 
Extended half life FIX 
Once biweekly 
aPCC 
Twice weekly 
rFVIIa 
Every other day 
Abbreviation:  aPCC= activated prothrombin complex concentrates; BPA=bypassing agent; FVIII = Factor VIII; FIX = Factor IX; 
rFVIIa=recombinant Factor VIIa 
Section 6.3.1.2 
Management of factor or bypassing agent prophylaxis during the transition to 
the fitusiran treatment period 
The first 28 days of fitusiran treatment is referred to as the onset period. During the onset period 
AT lowering will be progressing toward therapeutic levels. Patients will continue factor or BPA 
prophylaxis with minimum frequency as in Table 4, for the first 7 days of the fitusiran onset 
period. Subsequent to Day 7 of the fitusiran treatment period, factor concentrates or BPAs should 
be administered only for bleeding episodes or if needed in advance of invasive medical 
procedures. 
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Section 6.3.2 Management of bleeding episodes 
The occurrence of bleeding episodes is a typical characteristic of hemophilia; [2, 7, 8] bleeding 
episodes will be recorded as efficacy assessments of fitusiran and will not be considered as AEs 
unless the criteria for SAEs are met (see adverse events definitions in Section 7.5.6.1). Bleeding 
episodes will be recorded in the eDiary. For bleeding episodes in which there was no factor or 
BPA infusion or other type of intervention employed, the reason the bleeding episodes were 
untreated will be recorded in the eDiary (see Section 7.2.1). 
Investigators will establish and provide instructions for an individualized bleed management plan 
based on the guidelines in Table 5 for each patient. 
The bleed management plan should be reviewed by the Investigator or designee with the patient 
at each clinic visit (and contact every 2 weeks between clinic visits) and updated as necessary. 
Section 6.3.2.1 
Bleeding episode management recommendations for patients during the factor 
or bypassing agent prophylaxis period (patients not receiving fitusiran) 
During the factor or BPA prophylaxis period, bleeding management therapy with factors or 
BPAs will be managed based on the local standard practice for treating hemophilia patients with 
inhibitors, as routinely administered by the physician. The subgroup of Cohort A patients who 
are not responding adequately to BPA prophylaxis treatment will not participate in this BPA 
prophylaxis period and will directly start the fitusiran treatment period after the screening period. 
Where clinical circumstances allow, it is recommended that the patient contact the Investigator 
for all events that may be suspected to be or are characteristic of a bleeding episode. If adequate 
hemostasis does not occur after two doses of factor or BPA, the patient should contact the site for 
further instruction. If the patient feels the need to administer doses higher than the patient’s 
bleeding episode management plan recommends, or at a higher frequency, it is recommended 
that the patient contact the site. See Section 7.2.1 regarding patient use of the eDiary and site 
alerts that will assist in this process. 
Section 6.3.2.2 
Bleeding episode management recommendations for patients during the 
fitusiran treatment period 
Given the mechanism of action and pharmacodynamics profile of fitusiran, the factor or BPA 
dose necessary to safely and effectively treat breakthrough bleeding episodes in patients 
receiving fitusiran during the fitusiran treatment period will be lower than standardly prescribed. 
This is supported by data from the Phase 1 study in which bleed events were managed with 
factor or BPA, as well as additional modeling and ex vivo spiking data. More detailed 
information on the clinical experience in bleeding episode management in Phase 1 and Phase 1/2 
fitusiran studies, as well as supportive nonclinical studies is provided in the Investigator’s 
Brochure.  
After administration of fitusiran, AT lowering will be progressing toward therapeutic levels. As 
quickly as 7 days after the initial fitusiran dose, the majority of patients will have AT levels at or 
below 60% residual activity. By 14 days after dosing, it is expected that 94% of patients will 
have AT lowering of >50%, with a median value of 66.8%. Based on these AT kinetics, it is 
recommended that patients continue with their standard factor or BPA regimens for the 
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first 7 days following initiation of fitusiran dosing, with institution of the protocol-specific bleed 
management guidelines with reduced factor or BPA at Day 8 and beyond (Table 5). 
Patients on fitusiran will be provided a written bleed management plan with appropriate dosing 
of factor or BPA for use during Day 1 through 7, as well as a bleed management plan with 
dosing for Day 8 and beyond.  Thereafter the bleed management plan will be reviewed and 
updated at monthly visits, and new written plans provided to the patient if dosing changes. 
Importantly, after Day 7 of the fitusiran treatment period, patients should not use factor, BPA, or 
other hemostatic agents as prophylaxis for bleeding episode prevention, including doses related 
to anticipated hemostatic challenges such as physical activity. For prophylaxis of bleeding 
episodes in patients who require operative procedures see Section 6.6. 
Bleed Management Guidelines Day 1 to Day 7 of Fitusiran Treatment Period:  
Patients should be instructed to call the site prior to administering factor or BPA for the 
management of bleeding episodes.  Patients should continue with their standard factor or BPA 
regimens. 
Bleed Management Guidelines Day 8 and Beyond of Fitusiran Treatment Period: 
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 and/or BPA dose to use.  This interaction between patient and Investigator is 
recommended prior to the administration of each dose of factor or BPA.  Confirmation of 
bleeds at the study center prior to treatment may be considered.  Such visits should 
capture assessments per Section 6.4 and Table 2. 
2. If a determination is made that symptoms require treatment, the recommended treatment 
algorithm for bleeding episodes is described below: 
1. A single dose can be administered according to the guidelines in Table 5. 
2. The patient should be instructed to re-evaluate symptoms in 24 hours for bleeds 
treated with FVIII, FIX or aPCC and in 2-3 hours for bleeds treated with rFVIIa. 
a) Administration of FIX Extended half-life should not be more frequent than every 
5-7 days. 
3. If a second dose (in the case of FVIII, FIX or aPCC) or a third dose (in the case of 
rFVIIa) is needed, the patient must call the study center before dosing. 
a) Consider evaluation and treatment of the patient at the study center and 
confirmation of bleeds when any repeated doses are needed (See Section 6.4 and 
Table 2). 
b) If more than two doses of FVIII, FIX or aPCC or three doses of rFVIIa are 
needed, the patient should be seen at the study center within 48-72 hours. 
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4. Doses should not be administered at less than 24-hour intervals (except rFVIIa as 
indicated in Table 5). 
5. Doses should not exceed the protocol maximum recommended dose indicated in 
Table 5. 
6. Consultation with the study Medical Monitor and Clinical Advisor should be 
considered for clinical circumstances below, that may warrant AT replacement: 
a) Doses of factor or BPA higher than those recommended in Table 5 
b) Dosing of factor or BPA at decreased intervals than those recommended in 
Table 5 
c) Multiple or repeated doses of factor or BPA  
7. Antifibrinolytics may not be used in combination with factor or BPA. 
Note:  Doses of FVIII and FIX are included for completeness. It is expected that these non-inhibitor patients will be managed with 
factor concentrates and inhibitor patients will be routinely managed with rFVIIa or aPCC for bleeding episodes. Adjunctive 
management of bleeding episodes should be carried out per standard of care. 
Table 16 - Bleed management dosing guidelines by specific product               
 
Factor VIII 
Factor IX 
Standard half-
life 
Factor IX 
Extended half-
life 
aPCC 
Recombinant 
Factor VIIa 
Recommende
d single dose 
of 
10 IU/kg 
20 IU/kg 
20 IU/kg 
30 U/kg 
≤45 µg/kg 
Single Dose 
should not 
exceed 
20 IU/kg 
30 IU/kg 
30 IU/kg 
50 U/kg 
45 µg/kg 
Repeat dose 
instructions 
Mandatory to call the clinical study center prior to second dose 
Consider evaluation and treatment at the clinical study center 
 (see Section 6.4) 
Mandatory to call 
site prior to third 
dose 
 
Should not repeat 
in less than  
24 hours 
Should not repeat 
in less than 
 24 hours 
Should not 
repeat in less than 
 5-7 days 
Should not 
repeat in less than  
24 hours 
Should not 
repeat in less than  
2 hours 
 
Should be seen at site within 48-72 hours if more than 2 doses are required 
(see Schedule of Assessments Table 1 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. 
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Section 6.3.2.3 
Use of Factor or Bypassing agents following discontinuation of fitusiran 
Resuming routine prophylaxis following discontinuation of fitusiran 
Patients who opt to discontinue fitusiran may resume standard prophylaxis with factor 
concentrates or BPAs when their AT 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).   
Bleed episode management following discontinuation of fitusiran 
Patients who opt to discontinue fitusiran may resume standard on-demand dosing with factor 
concentrates or BPAs for bleeding episodes 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 (approximately 60% residual activity per the central 
laboratory), AT replacement should be considered. 
Section 6.5 
Monitoring and Management of Thrombotic Events 
Given safety events observed thus far and the possible thrombotic risk associated with fitusiran’s 
AT lowering mechanism, which may be increased with concurrent use of factor concentrates or 
BPAs, there should be a low threshold to evaluate any signs and symptoms consistent with 
thrombosis, including symptoms consistent with CVST.  Symptoms of thrombosis may include a 
severe or persistent headache, headache with nausea and vomiting, chest pain/tightness, 
coughing up blood, trouble breathing, abdominal pain, fainting or loss of consciousness, vision 
problems, and swelling or pain in the arms or legs. 
If signs and symptoms consistent with thrombosis are present, the Investigator should evaluate 
the patient for thrombosis, including appropriate imaging studies. For the diagnosis of CVST 
magnetic resonance imaging venogram (MRV) or computed tomography venogram (CTV) are 
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 individualize patient doses to target 80-120% AT activity.  
The use of plasma derived AT may be preferable to recombinant AT, given its longer half-life.  
It is recommended that cases of thrombosis are discussed with the study Medical Monitor and 
Clinical Advisor (see Section 7.5.6.1 for further information regarding Adverse Events of 
Special Interest). 
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Section 6.9 
Treatment Compliance 
Compliance with scheduled clinic visits (Table 1), and patient use of eDiary to record data as 
required, will be monitored by study staff over the ~13-months, except for patients in the 
subgroup of Cohort A, which is up to 7 months, of eDiary recording (including both the 6-month 
factor or BPA prophylaxis period [6-month BPA prophylaxis period is not applicable for the 
subgroup of Cohort A patients who are not responding adequately to BPA prophylaxis treatment] 
and 7-month fitusiran treatment period). 
Section 7.1 
Screening/Baseline Assessments 
An informed consent form (ICF) or assent form that has been approved by the appropriate 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) must be signed by the 
patient (or legal guardian) before the Screening procedures are initiated.  All patients (or their 
legal guardians) will be given a copy of the signed and dated ICF and/or assent form. 
Patient demographic and medical history will be obtained at Screening. Medical history must 
include documentation of factor concentrate and/or BPA prescriptions (in the medical or 
pharmacy record) and documentation of reported number of bleeding episodes over the last 
6 months (for inhibitor patients) or 12 months (for non inhibitor patients). Patients will be 
screened to ensure that they meet all of the inclusion criteria and none of the exclusion criteria. 
Rescreening of patients is permitted with consultation of the study Medical Monitor. 
To complement medical records, information regarding health resource use will be collected as 
specified in the Schedule of Assessments (Table 1), including days missed from work/school (as 
appropriate) and days not able to perform normal activities outside of work/school due to 
hemophilia, physician office visits, hemophilia treatment site visits, emergency room visits 
(reason and number), hospitalizations (reason, dates of hospitalization and associated length of 
stay). 
Section 7.2 
Efficacy Assessments 
Bleeding Episode Definitions 
A bleeding episode is defined as any occurrence of hemorrhage that requires administration of 
factor or BPA infusion, eg, hemarthrosis, muscle, or mucosal bleeding episodes. Since bleeding 
episodes are recorded as an efficacy assessment of fitusiran, these will not be treated as AEs 
unless they meet any of the SAE criteria listed in Section 7.5.6.1. 
The definition of bleeding episode types described below is based on consensus opinion of 
International Society on Thrombosis and 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 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 
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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, 
but patients will be asked to indicate in the eDiary that the event occurred during such activities.  
Training will be provided on this and other aspects of eDiary use (see Section 7.2.1). 
Annualized bleeding rate will be calculated as described in Section 8.2.5.1. Bleeding episodes 
will be managed according to Section 6.3.2. 
7.2.1 Electronic Diary  
Patients will be issued an eDiary to record all bleeding events and all doses of factors or BPAs 
administered during the conduct of the study.  Entries are to be made in a timely manner, and it 
is preferred that doses are entered immediately upon administration or within 24 hours.  Patients 
will be prompted to enter bleeding location, severity, causality (spontaneous or traumatic), doses 
of factors or BPAs, and reasons for dosing (prophylaxis, treatment of a bleeding episode, and 
preventive dose for anticipated activity).  Training of patients should be documented in the 
appropriate source record. 
The Sponsor will review diary entries for data quality to identify issues such as patients who may 
need retraining on eDiary use and timely entry of bleeding episode information. 
Bleeding episodes will be recorded by the patient in the eDiary and reviewed by the Investigator 
(and Sponsor) continuously for the study duration. The site will contact the patient at a minimum 
interval of every 2 weeks (± 4 days) per schedule of assessments to review eDiary records and 
ensure that the patient is utilizing the device appropriately. 
Sites will be notified when patients enter initial treatments for bleeding events into their eDiaries. 
If the dose amount exceeds the recommended dose according to the bleeding episode 
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management plan, the patient must be contacted as soon as possible, preferably within 
24-48 hours of receiving the alert. At the time of contact the patient’s clinical condition will be 
reviewed along with the dose and efficacy of the treatment given, and the Investigator will 
provide appropriate guidance regarding further management of the bleed. The site will also 
receive an alert, and must make contact with the patient as soon as possible if a third dose of 
product is administered for a single bleed, to review clinical condition, the need for further 
therapy, and appropriate ongoing management of the bleeding episode required to achieve 
hemostasis. 
In addition, patients will be instructed to contact the site if they feel they need to administer 
factor or BPA at a higher dose level or higher frequency than their bleeding episode management 
plan recommends, or if more than two doses are required to achieve hemostasis. 
Section 7.3.3 Coagulation/Thrombin generation response assessment in factor or bypassing 
agent prophylaxis period 
During the factor or BPA prophylaxis period (before fitusiran treatment), patients will undergo a 
coagulation and peak thrombin/thrombin generation response assessment with timed blood 
collections both before and following a dose of their routine factor or BPA prophylaxis doses. 
The subgroup of Cohort A patients who are not responding adequately to BPA prophylaxis 
treatment will not participate in this BPA prophylaxis period and will directly start the fitusiran 
treatment period after the screening period. For these patients, the coagulation and peak 
thrombin/thrombin generation response assessment are not applicable. 
These laboratory assessments are collected for research purposes, will be run centrally, and will 
not be released to sites or used to guide study conduct or clinical management. 
Section 7.5.5.1 
Additional laboratory assessments 
Additional laboratory assessments will be performed in patients who experience any LFT 
abnormalities during either the factor or BPA prophylaxis period (BPA prophylaxis period is not 
applicable for the subgroup of Cohort A patients who are not responding adequately to BPA 
prophylaxis treatment) or the fitusiran treatment period.  Following the occurrence of elevated 
liver transaminases or other LFT abnormalities per the central laboratory, all assessments in 
Table 7 will be performed one time, as well as hematology, serum chemistry, LFT, and 
coagulation assessments from Table 6, AT levels, and other assessments or evaluations per 
Investigator discretion, as appropriate. 
Section 8.1 Determination of Sample Size 
Sample size is based on clinical considerations. The overall sample size of 80 patients including 
approximately 30 patients with inhibitor (Cohort A) and approximately 50 patients without 
inhibitor (Cohort B) was selected recognizing the limited number of patients with hemophilia, 
and to yield a reasonably robust estimate of the fitusiran bleeding episode rate and address the 
secondary objectives, including characterization of safety and tolerability. The proposed sample 
size is also expected to provide reasonable precision around the ratio of bleeding rate in the 
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fitusiran efficacy treatment period to bleeding rate in the factor or BPA prophylaxis period for 
both Cohort A and Cohort B. In the US, only patients from Cohort A will be included.  
Section 8.2.5.1 Primary endpoint 
The primary analysis will be performed on the EAS and will include all bleeding episodes 
occurring in the factor or BPA prophylaxis period (Day -162 to Day -1) and the fitusiran 
treatment period (Day 1 to Day 190). If a patient does not have bleeding episode data collected 
after Day 28 (eg due to early study discontinuation), the available bleeding episode data starting 
from Day 1 will be used in the primary analysis. To avoid confounding the treatment effect, 
bleeding episode data during and after major surgery, antithrombin administration, major trauma, 
or initiation of prophylaxis treatment with factors or BPAs during the fitusiran treatment period 
will be excluded from the primary analysis. 
The number of bleeding episodes will be analyzed using a repeated measures negative binomial 
model with fixed effect of treatment period. The logarithm number of days that each patient 
spends in the treatment period matching the bleeding episode data being analyzed will be 
included as an offset variable to account for unequal follow-up time due to early withdrawal or 
surgery. The ratio of bleeding rates in the fitusiran treatment period to the factor or BPA 
prophylaxis period and its 95% CI and p-value will be presented. The p-value should be 
interpreted with caution. In addition, as a contrast Bayesian analyses will be performed to 
summarize the point estimates of the posterior probability of a clinically significant treatment 
effect, along with associated measures of uncertainty. The estimated mean ABRs in these 
2 periods along with their 95% CIs will be presented from this model. In addition estimated 
mean ABR and its 95% CI during the fitusiran onset period and efficacy period (key secondary 
endpoint) will be presented. 
Section 8.2.5.2 Secondary endpoint 
Spontaneous bleeding episodes and joint bleeding episodes will be analyzed using the same 
method as primary analysis of ABR.  Summary statistics, including the median and interquartile 
range, for annualized spontaneous bleeding rate and annualized joint bleeding rate will be 
reported. 
Change in Haem-A-QOL physical health score and total score (in patients ≥17 years of age) in 
the factor or BPA prophylaxis period and fitusiran treatment period will be summarized 
descriptively. A mixed model for repeated measures analysis may be performed as deemed 
appropriate.  
The bleeding episodes in the fitusiran onset period and in the fitusiran treatment period will be 
analyzed using a negative binomial model with logarithm of follow-up time in the period as an 
offset parameter.  Summary statistics, including the median and interquartile range, for the ABR 
in 2 periods will be reported. 
The secondary endpoint of annualized weight-adjusted consumption of factor/BPA injections 
will be summarized using descriptive statistics. 
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11.6.2 Japan  
As recommended by the PMDA, the following sections are modified for Japan: 
6.3.2.2  
Bleeding episode management recommendations for patients during the 
fitusiran treatment period 
Table 5 - Bleed management dosing guidelines by specific product 
Footnote Additions 
The half-life of standard Factor VIII and Factor IX replacement therapies are approximately 
12 hours and approximately 16-18 hours, respectively (16). The improvement in half-life of 
extended Factor VIII therapies are approximately 1.2- to 1.5-fold, whereas the improvement in 
half-life of extended Factor IX therapies are much greater at approximately 3 to 5 fold (17). 
Thus, given the shorter half life of standard Factor VIII therapies and the limited improvement in 
half life of extended Factor VIII replacement therapies, the product-specific recommendations 
for dosing frequency of Factor VIII apply to all standard half-life and extended half-life Factor 
VIII products. 
Time periods indicated in the repeat dose instructions section of Table 6 of the protocol start at 
the time of the first injection. 
Should AT reversal be considered, it is strongly recommended that cases be discussed with the 
study Medical Monitor and Clinical Advisor. Dosing of AT replacement therapies in Japan 
should follow locally available AT replacement therapies for the treatment of thrombogenicity 
tendency based on congenital AT deficiency targeting peak levels of 80-120% AT activity level. 
Timing of AT replacement should be determined by the clinical circumstances with avoidance of 
delays in standard treatment as dictated by clinical scenario. Antithrombin level should be 
monitored per AT label during dosing adjustments. Resumption of fitusiran following AT 
reversal will follow clinical circumstances and may include guidance from the Medial Monitor, 
Clinical Advisors and/or the Data Monitoring Committee (see Section 4.1 and Section 10.1.5). 
6.5  
Monitoring and Management of Thrombotic Events  
If a patient develops thrombosis while on fitusiran, AT reversal is recommended in combination 
with factor or BPA replacement and appropriate anticoagulation. Antithrombin reversal should 
follow labeled product recommendations of locally available AT replacement therapy for 
treatment of thrombogenicity tendency based on congenital AT deficiency, and patient doses 
individualized to target 80-120% AT activity level. It is recommended that cases of thrombosis 
are discussed with the study Medical Monitor and Clinical Advisor (see Section 8.4 for further 
information regarding AEs of Specific Interest). 
6.8  
Contraceptive Requirements 
Patients in this study upon consultation with their Investigators must agree to use appropriate 
contraceptive method(s) for 72 hours after each administration of the study drug. 
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6.11 
Management of AT and rFVIIa in Japan (new section) 
In Japan, relationship between AE/SAE and ATs administration for AT replacement is to be 
collected. Antithrombins will be supplied by the Sponsor. The supplied ATs will be stored 
appropriately, and the storage condition, date of administration, usage amount etc. will be 
recorded at study sites in the same manner as IMP. 
In addition, relationship between AE/SAE and rFVIIa is also to be collected when rFVIIa is 
administrated on top of fitusiran. Nevertheless, rFVIIa will not be supplied by the Sponsor. 
11.7 
PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
11.7.1 Amended Protocol 01  
Primary changes: 
• Change to the type of population studied, to only patients with inhibitors; planned sample 
size reduced to N=30; eligibility criteria updated to only include patients who have an 
inhibitory antibody to FVIII or FIX and must have an ABR of at least 4 (ie, 2 bleeds 
within past 6 months) 
• Updated clinical development status text to account for a patient death, which was 
reported in a patient with cerebral venous sinus thrombosis (CVST) in the 
ALN-AT3SC-002 study (Phase 1/2 open-label extension study) 
• Additional safety measures were implemented to mitigate risk of thrombosis in the 
lowered-AT setting, including: revised bleed management guidelines to allow standard 
BPA prophylactic and bleed management regimens only up to the first 7 days following 
fitusiran dosing; added recommendations for monitoring and management of thrombotic 
events; added clarification of definitions for bleeding episodes; revised recommendations 
for management of sepsis, and adding additional exploratory laboratory assessments 
• Frequency of directed physical exams to monthly 
• Updated Benefit-Risk Assessment section accordingly with respect to the above new 
safety monitoring 
• Added Patient Education Module training to Schedule of Assessments 
• Clarification added that Adverse Events should include review for signs and symptoms of 
thrombosis at each visit 
• Clarifications added to the Perioperative Schedule of Assessments 
• Addition of acetaminophen restriction to <4 grams per day 
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• Stipulation added that antifibrinolytics may be used as single agents, but may not be used 
in combination with factor or BPA 
• Revised bleed management recommendations following discontinuation of fitusiran; 
standard on-demand dosing with BPAs is permitted when AT residual activity level 
returns to ~60% (per the central laboratory) 
• Addition of prothrombin activation fragment 1,2 to the coagulation panel, as exploratory 
marker of hemostasis 
• Addition of new stipulation for patients who present to the study site for management of 
bleed symptoms, samples will be collected pre-treatment and post-treatment with factor 
or BPA for the exploratory purposes of characterizing thrombin generation and other 
coagulation parameters 
• Other minor corrections applied 
11.7.2 Amended Protocol 02  
AMENDMENT 02 (31 May 2018) 
This amended protocol (amendment 02) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
Clinical development and commercialization of fitusiran were granted from Alnylam 
Pharmaceuticals, Inc. to Genzyme Corporation, a Sanofi Company that will be assuming 
responsibility of the current clinical program. Therefore, the Alnylam logo and reference to 
Alnylam within the confidentiality statement were deleted from the title page. Throughout all 
sections of the protocol including the page headers and appendices, Alnylam has been changed 
to “the Sponsor” or “Sanofi Genzyme” as appropriate. In addition to change in Sponsor name, 
address and contact details were also updated. The Sanofi Genzyme study code (EFC15110) 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. The study is expanded to include non-inhibitor patients 
under prophylaxis with factor concentrates: while inhibitor patients have higher unmet needs 
compared to non-inhibitor patients, there is no known difference in risks between these 
2 populations based on the mechanism of action of fitusiran or factor/BPA therapy. 
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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 
Title of the study (also 
relevant text updated 
throughout) 
Changed from “ATLAS-PPX:  an open-
label, multinational, switching study to 
describe the efficacy and safety of 
fitusiran prophylaxis in patients with 
hemophilia A and B with inhibitory 
antibodies to factor VIII or IX previously 
receiving bypassing agent prophylaxis.” 
to “ATLAS-PPX:  an open-label, 
multinational, switching study to describe 
the efficacy and safety of fitusiran 
prophylaxis in patients with hemophilia A 
and B previously receiving factor or 
bypassing agent prophylaxis” 
Study expanded to include patients without 
inhibitory antibodies to factor VIII or factor IX in 
addition to patients with inhibitory antibodies to 
factor VIII or factor IX 
Title page 
IND number 125632 added 
Study to be conducted at US sites 
Title page 
Disclaimer note text changed 
Change of protocol Sponsor; text aligned with 
Sanofi Genzyme environment 
Title page 
Name of Sponsor contact changed from 
“Pushkal Garg” to “Olivier Huynh-Ba” 
Change of protocol Sponsor; contact details 
Throughout 
Name of product “ALN-AT3SC” changed 
to “Fitusiran” 
Change of protocol Sponsor; name of product 
updated 
Synopsis  
Number of study centers updated from 
“60” to “70” 
Study expanded to include patients without 
inhibitory antibodies to factor VIII or factor IX in 
addition to patients with inhibitory antibodies to 
factor VIII or factor IX 
Synopsis and Section 3.2 
(Secondary Endpoints) 
and throughout relevant 
text 
“Change in Haem-A-QOL score in the 
treatment period” changed to “Change in 
Haem-A-QOL physical health score and 
total score in the treatment period” 
Change of protocol Sponsor; text aligned with 
Sanofi Genzyme environment 
Synopsis and Section 4.3 
Number of planned patients: Text 
updated from “Approximately 30 patients 
are planned for enrollment in this study, 
all with inhibitors, including 
approximately 7 patients with hemophilia 
B, and approximately 3 adolescents 
(≥12 to <18 years of age)” to 
“Approximately 70 patients are planned 
for enrollment in this study, including 
approximately 30 patients with inhibitors 
(Cohort A) and approximately 40 
patients without inhibitors (Cohort B). 
Approximately 18 patients with 
hemophilia B, and approximately 7 
adolescents (≥12 to <18 years of age) 
are also planned for enrollment” 
Study expanded to include patients without 
inhibitory antibodies to factor VIII or factor IX in 
addition to patients with inhibitory antibodies to 
factor VIII or factor IX 
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Section # and Name 
Description of Change 
Brief Rationale 
Synopsis 
Diagnosis and main eligibility criteria: 
Text added as “Patients without 
inhibitors must have used factor 
concentrates for prophylaxis for at least 
the last 6 months prior to Screening and 
must meet each of the following criteria: 
1) Nijmegen-modified Bethesda assay 
inhibitor titer of <0.6 BU/mL at 
Screening, AND 2) No use of bypassing 
agents to treat bleeding episodes for at 
least the last 6 months prior to 
Screening, AND 3) No history of immune 
tolerance induction therapy within the 
last 3 years prior to Screening. A 
minimum of 1 bleeding episode requiring 
factor treatment within the last 
12 months prior to Screening is 
required.” 
Eligibility criteria amended to encompass patients 
without inhibitory antibodies to factor VIII or factor 
IX in addition to patients with inhibitory antibodies 
to factor VIII or factor IX 
Table 1 
Footnote “W” changed from: “Non-
serious AEs will be monitored and 
recorded from date of Day 1 visit through 
Follow-Up. SAEs will be monitored and 
recorded from date of signed informed 
consent through Follow-Up.  Signs and 
symptoms of thrombosis will be 
evaluated at every visit (see Section 
6.5)” to “AEs will be monitored and 
recorded from date of signed informed 
consent through Follow-Up.  Signs and 
symptoms of thrombosis will be 
evaluated at every visit (see Section 
6.5).” 
For consistency throughout the protocol 
Table 2 
Table updated with FVIII and/or FIX level 
to be checked at 10 minutes and 
60 minutes postdose. 
Study expanded to include patients without 
inhibitory antibodies to factor VIII or factor IX in 
addition to patients with inhibitory antibodies to 
factor VIII or factor IX  
Throughout 
“Investigational study drug” changed to 
“Investigational medicinal product” 
Change of protocol Sponsor; text aligned with 
Sanofi Genzyme environment 
Section 1.3 (only at first 
occurrence) 
“Sanofi Genzyme EFC15110” added to 
the Study number “ALN-AT3SC-009” 
Change of protocol Sponsor; Sanofi Genzyme 
study ID required for administrative purposes on 
first use 
Section 4.1 
Text added as “… previously receiving 
factor or BPA prophylaxis. The study 
consists of 2 cohorts: Cohort A will 
consist of patients with inhibitory 
antibodies to factor VIII or factor IX; 
Cohort B will consist of patients without 
inhibitor antibodies to factor VIII or factor 
IX.” 
Study expanded to include patients without 
inhibitory antibodies to factor VIII or factor IX in 
addition to patients with inhibitory antibodies to 
factor VIII or factor IX 
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(Sanofi Genzyme EFC15110) 
 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 4.1 (Figure 1) 
Study design updated to reflect the 
inclusion of non-inhibitor patients. 
Study expanded to include patients without 
inhibitory antibodies to factor VIII or factor IX in 
addition to patients with inhibitory antibodies to 
factor VIII or factor IX 
Synopsis and Section 4.2 
Duration of treatment language updated 
For clarity 
Section 5.1 
Inclusion criterion #3 updated from “A 
minimum of 2 bleeding episodes 
requiring BPA treatment within the last 
6 months prior to Screening” to “A 
minimum of 2 bleeding episodes 
requiring BPA treatment within the last 
6 months prior to Screening for patients 
with inhibitory antibodies to factor VIII or 
factor IX (Cohort A).  A minimum of 
1 bleeding episode requiring factor 
treatment within the last 12 months prior 
to Screening for patients without 
inhibitory antibodies to factor VIII or 
factor IX (Cohort B).” 
Study expanded to include patients without 
inhibitory antibodies to factor VIII or factor IX in 
addition to patients with inhibitory antibodies to 
factor VIII or factor IX  
Section 5.1 
Inclusion criterion #4 updated with 
definition of non-inhibitor patients. 
Study expanded to include patients without 
inhibitory antibodies to factor VIII or factor IX in 
addition to patients with inhibitory antibodies to 
factor VIII or factor IX 
Section 6.2.6 
“Accountability” section updated with 
reporting procedure to follow with 
regards to any quality issue noticed with 
the receipt or use of an IMP (deficiency 
in condition, appearance, pertaining 
documentation, labeling, expiration date, 
etc.) 
Change of protocol Sponsor; text aligned with 
Sanofi Genzyme environment 
Section 6.3.1.1 (Table 4) 
Table updated with details of standard 
and extended half-life of factor VIII and 
factor IX 
Study expanded to include patients without 
inhibitory antibodies to factor VIII or factor IX in 
addition to patients with inhibitory antibodies to 
factor VIII or factor IX  
Section 6.3.2.2 (Table 5) 
Footnote updated 
Study expanded to include patients without 
inhibitory antibodies to factor VIII or factor IX in 
addition to patients with inhibitory antibodies to 
factor VIII or factor IX  
Throughout 
“Adverse events of clinical interest” 
changed to “Adverse events of special 
interest” 
Change of protocol Sponsor; text aligned with 
Sanofi Genzyme environment 
Section 7.5.6.1 
Systemic injection associated reactions 
(IARs) added to the criteria of adverse 
events of special interest 
Change of protocol Sponsor; text aligned with 
Sanofi Genzyme environment 
Section 7.5.6.2 
“Recording adverse events” section 
updated 
Change of protocol Sponsor; text aligned with 
Sanofi Genzyme environment 
Section 7.5.6.3 
Heading updated from “Serious Adverse 
Events Require Immediate Reporting to 
Change of protocol Sponsor; text aligned with 
Sanofi Genzyme environment 
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Section # and Name 
Description of Change 
Brief Rationale 
Sponsor/Designee” to “Serious Adverse 
Events and Adverse Events of Special 
Interest Require Immediate Reporting to 
Sponsor/Designee” 
Section 7.5.6.7 
Overdose reporting text updated 
Change of protocol Sponsor; text aligned with 
Sanofi Genzyme environment 
Section 7.5.6.8 
New Section 7.5.6.8 “Guidelines for 
Reporting Product Complaints/Medical 
Device Incidents (Including 
Malfunctions)” added with text 
Change of protocol Sponsor; text aligned with 
Sanofi Genzyme environment 
Section 8.1 
Text updated for sample size with new 
Table 9 added for simulated ratio of 
rates for Cohort A, with 95% confidence 
intervals 
Change of protocol Sponsor; text aligned with 
Sanofi Genzyme environment 
Synopsis and Section 8.2 
Text added “These analyses will be done 
for Cohort A and Cohort B separately.  A 
pooled analysis will be performed after 
all patients in the 2 cohorts have either 
finished the Month 7 visit during the 
fitusiran treatment period or discontinued 
from the study”. 
Change of protocol Sponsor; text aligned with 
Sanofi Genzyme environment 
Section 8.2.5.1 
Text changed from “The primary analysis 
will be performed on the EAS and will 
include all bleeding episodes occurring 
in the factor or bypass agent prophylaxis 
period (Day -162 to Day -1) and the 
fitusiran efficacy period (Day 29 to 
Day 190) including bleeding episode 
data collected after discontinuation of 
study drug” to “The primary analysis will 
be performed on the EAS and will 
include all bleeding episodes occurring 
in the factor or bypass agent prophylaxis 
period (Day -162 to Day -1) and the 
fitusiran efficacy period (Day 29 to Day 
190)”. 
Change of protocol Sponsor; text aligned with 
Sanofi Genzyme environment 
Section 8.2.10 
Text changed from “No interim analysis 
is planned” to “An Interim Analysis may 
be conducted as a part of this study”. 
An interim analysis may be conducted as a part of 
this study to support regulatory filings. 
Section 9.1 
Ethical and Regulatory Considerations 
language updated to provide additional 
details 
Change of protocol Sponsor; text aligned with 
Sanofi Genzyme environment 
Section 9.1.1 
Informed Consent Process language 
updated to provide additional process 
details and clarity 
Change of protocol Sponsor; text aligned with 
Sanofi Genzyme environment 
Section 9.1.2 
Ethical Review language updated for 
clarity 
Change of protocol Sponsor; text aligned with 
Sanofi Genzyme environment 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 9.1.3 
Study Documentation, Confidentiality, 
and Records Retention language 
updated 
Change of protocol Sponsor; text aligned with 
Sanofi Genzyme environment 
Section 9.1.5 
Discontinuation of the Clinical Study 
language updated 
Change of protocol Sponsor; text aligned with 
Sanofi Genzyme environment 
Section 9.2.1 
Data Handling language updated to 
provide additional details and clarify 
responsibilities 
Change of protocol Sponsor; text aligned with 
Sanofi Genzyme environment 
Section 9.2.2 
Study Monitoring language updated to 
provide more detail regarding source 
data verification and record retention 
Change of protocol Sponsor; text aligned with 
Sanofi Genzyme environment 
Section 9.3 
Publication Policy language updated to 
provide additional process details and 
some text moved into Section 9.4 
Change of protocol Sponsor; text aligned with 
Sanofi Genzyme environment 
Section 9.4 
New Section 9.4 “Dissemination of 
Clinical Study Data” added with text 
Change of protocol Sponsor; text aligned with 
Sanofi Genzyme environment 
Appendix 11 
Appendix 11.5 - appendix for 
Country-Specific Requirements and 
Appendix 11.6 - appendix for protocol 
amendment history added 
Change of protocol Sponsor; text aligned with 
Sanofi Genzyme environment 
Throughout 
Minor editorial, typo error corrections 
and document formatting revisions 
Minor, therefore have not been summarized 
11.7.3 Amended Protocol 03  
AMENDMENT 03 (24 August 2018) 
This amended protocol (amendment 03) 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 
This is the Republic of Ireland-specific protocol amendment to allow a subgroup of Cohort A 
patients with hemophilia B with inhibitory antibodies to Factor IX who are not responding 
adequately to bypassing agent (BPA) prophylaxis treatment (defined as annualized bleeding 
rate ≥20) to start treatment with fitusiran directly after the screening period. 
Inhibitor patients with hemophilia B may have a high unmet need despite prophylactic BPA 
therapy, with limited other treatment options. Therefore, a limited number of inhibitor patients 
with hemophilia B who are not adequately responding to prophylactic BPA therapy could enroll 
in the ALN-AT3SC-009 (Sanofi Genzyme EFC15110) study directly into the fitusiran treatment 
period, thereby skipping the 6-month bypassing agent treatment period. 
 
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Clinical Study Protocol ALN-AT3SC-009 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
Added WHO number: U1111-1217-3270 
Administrative change 
Synopsis (Study Design) 
Changed from “……who have switched 
from factor (Cohort A) or bypassing 
agent (BPA, Cohort B) prophylaxis.” to 
“.... who have switched from prior 
bypassing agent (BPA, Cohort A) or 
factor (Cohort B) prophylaxis.” 
Corrected the typographical 
error. 
Synopsis (Study Design, Number of Planned 
Patients, Diagnosis and Main Eligibility Criteria, 
Reference Therapy, Dose and Mode of 
Administration, Duration of Treatment) 
Following sentence added at 
appropriate location of these sections: 
“For the Republic of Ireland specific 
requirements, see Appendix 11.5.1.1” 
This is the Republic of 
Ireland-specific protocol 
amendment to allow a 
subgroup of Cohort A 
patients to start treatment 
with fitusiran directly after 
the screening period. 
Table 1: Schedule of Assessments 
Following sentence added at the end of 
footnote “a”: “For the Republic of Ireland 
specific requirements, see 
Appendix 11.5.1.1” 
This is the Republic of 
Ireland-specific protocol 
amendment to allow a 
subgroup of Cohort A 
patients to start treatment 
with fitusiran directly after 
the screening period. 
Section 1.3 Study Design Rationale 
Section 4.1 Summary of Study Design 
Section 4.2 Duration of Treatment 
Section 4.3 Number of Patients 
Section 5.1 Inclusion Criteria (criterion 4) 
Section 5.3 Removal from Therapy or Assessment 
Section 6.3.1.1 Routine Use of Factor or 
Bypassing Agent Prophylaxis in the Factor or 
Bypassing Agent Prophylaxis Period 
Section 6.3.2.1 Bleeding Episode Management 
Recommendations for Patients during the Factor 
or Bypassing Agent Prophylaxis Period (Patients 
Not Receiving Fitusiran) 
Section 6.9 Treatment Compliance 
Section 7.3.3 Coagulation/Thrombin Generation 
Response Assessment in Factor or Bypassing 
Agent Prophylaxis Period 
Section 7.5.5.1 Additional Laboratory 
Assessments 
Following sentence added at 
appropriate location of these sections: 
“For the Republic of Ireland specific 
requirements, see Appendix 11.5.1.2” 
This is the Republic of 
Ireland-specific protocol 
amendment to allow a 
subgroup of Cohort A 
patients to start treatment 
with fitusiran directly after 
the screening period. 
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Section # and Name 
Description of Change 
Brief Rationale 
Appendix 11.5 
Republic of Ireland-specific 
requirements have been added. The 
changes are identified in the Appendix 
11.5.1. 
This is the Republic of 
Ireland-specific protocol 
amendment to allow a 
subgroup of Cohort A 
patients to start treatment 
with fitusiran directly after 
the screening period. 
Appendix 11.6.2 
Newly added appendix. Texts from the 
“Document History” page have been 
moved to this appendix. 
Due to change in the 
amendment number, overall 
rationale and summary of 
changes of protocol 
amendment 02 have been 
moved to Appendix 11.6.2. 
11.7.4 Amended Protocol 04  
AMENDMENT 04 (18 December 2018) 
This amended protocol (amendment 04) 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 
Global changes: 
Inhibitor patients with hemophilia B may have a high unmet need despite prophylactic BPA 
therapy with limited other treatment options. Therefore, a limited number of inhibitor subjects 
with hemophilia B, who are not adequately responding to prophylactic BPA therapy could enroll 
directly into the fitusiran treatment period of the ALN-AT3SC-009 STUDY (Sanofi Genzyme 
EFC15110), thereby skipping the 6-month bypassing agent treatment period. 
In the Republic of Ireland, Amendment 03 of the protocol includes a subgroup of Cohort A 
subjects with hemophilia B (with inhibitory antibodies to Factor IX, who are not responding 
adequately to BPA prophylaxis (treatment defined as ABR ≥20) to start treatment with fitusiran 
directly after the screening period. The purpose of this global amendment, is to extend 
worldwide the inclusion of this subgroup, limiting however the inclusion to up to 4 patients. 
A secondary objective and endpoint are included to further assess fitusiran efficacy. 
United Stated specific requirement: Primary rationale for amendment: 
In order to address the regulatory requirement from the US Food and Drug Administration 
(FDA), the US population for this study will be limited to patients with inhibitory antibodies to 
Factor VIII or Factor IX with more than 2 bleeding episodes requiring BPA treatment within the 
last 6 months prior to Screening. 
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Japan specific requirements: 
Specific requirements for Japan who were previously managed through protocol addendum and 
administrative changes are now included in the protocol. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis (Study Design, Number of Planned 
Patients, Diagnosis and Main Eligibility Criteria, 
Reference Therapy, Dose and Mode of 
Administration, Duration of Treatment) 
Following sentence removed: "For the 
Republic of Ireland specific 
requirements, see Appendix 11.5.1.1” 
Since the Republic of 
Ireland amendment is 
extended to the global 
protocol, it is no longer 
specific to the Republic of 
Ireland. 
Synopsis (Study Design, Number of Planned 
Patients, Diagnosis and Main Eligibility Criteria, 
Reference Therapy, Dose and Mode of 
Administration, Statistical Methods) 
Following sentence added at 
appropriate location of these sections: 
“For the United States specific 
requirements, see Appendix 11.5.1.1” 
This is the United States 
specific protocol amendment 
to limit the enrollment to 
patients with inhibitory 
antibodies to Factor VIII or 
Factor IX. 
Synopsis: Objectives 
“To characterize the annualized weight-
adjusted consumption of 
factor/BPA while receiving fitusiran 
treatment, relative to receiving 
factor or BPA prophylaxis” is added as a 
secondary objective 
A secondary objective and 
endpoint are included to 
further assess fitusiran 
efficacy. 
Synopsis: Endpoints 
Secondary endpoint “Change in Haem-
A-QOL physical health score and total 
score in the fitusiran treatment period” is 
changed to “Change in Haem-A-QOL 
physical health score and total score in 
the fitusiran treatment period and the 
factor or BPA prophylaxis period” 
Correction of a discrepancy 
with the corresponding study 
objective. 
Synopsis: Endpoints 
“Annualized weight-adjusted 
consumption of factor/BPA” is added as 
a secondary endpoint 
A secondary objective and 
endpoint are included to 
further assess fitusiran 
efficacy. 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Synopsis: Study Design  
Following sentences added at 
appropriate location: "A subgroup of 
Cohort A patients will include hemophilia 
B patients with inhibitory antibodies to 
Factor IX who are not responding 
adequately to BPA prophylaxis 
treatment (historical ABR ≥20)." and 
"The subgroup of Cohort A patients who 
are not responding adequately to BPA 
prophylaxis treatment will not participate 
in this 6-month BPA prophylaxis period 
and will start directly receiving fitusiran 
(in the 1-month onset period described 
below) after the screening period. 
The following sentence "Following the 
screening and prophylaxis periods, all 
patients will be treated with fitusiran for 
a total of 7 months and will receive 7 SC 
injections of fitusiran." is changed to 
"Following the screening and 
prophylaxis periods, or following the 
screening period for the subgroup of 
Cohort A enrolling directly into the 
fitusiran treatment period, all patients 
will be treated with fitusiran for a total of 
7 months and will receive 7 SC 
injections of fitusiran." 
Study expanded to enroll a 
subgroup of hemophilia B 
patients with inhibitors who 
are not responding 
adequately to BPA 
prophylaxis treatment. 
Synopsis: Number of Planned Patients 
Following sentence "30 patients with 
inhibitors (Cohort A) and approximately 
40 patients without inhibitors (Cohort B). 
Approximately 18 patients with 
hemophilia B and approximately 
7 adolescents (≥12 to <18 years of age) 
are also planned for enrollment." 
changed to "30 patients with inhibitors 
(Cohort A) and approximately 40 
patients without inhibitors (Cohort B). 
Approximately 18 patients with 
hemophilia B (including approximately 
7 hemophilia B patients in Cohort A, 
among which are a subgroup of no more 
than 4 patients who are not responding 
adequately to BPA prophylaxis and 
approximately 11 hemophilia B patients 
in Cohort B), and approximately 
7 adolescents (≥12 to <18 years of age) 
are also planned for enrollment." 
Study expanded to enroll a 
subgroup of hemophilia B 
patients with inhibitors who 
are not responding 
adequately to BPA 
prophylaxis treatment. 
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SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
08-Dec-2020 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Synopsis: Diagnosis and Main Eligibility Criteria 
Following sentence added at 
appropriate location: " The subgroup of 
patients in Cohort A patients must 
additionally meet the following criteria to 
be eligible to start treatment with 
fitusiran directly after the screening 
period: 1) Hemophilia B with inhibitory 
antibody to Factor IX as defined above; 
2) Not responding adequately to BPA 
treatment (historical ABR ≥20) prior to 
enrollment; and 3) in the opinion of the 
Investigator, with approval of Sponsor 
Medical Monitor, 6-month BPA 
prophylaxis period should be omitted." 
Study expanded to enroll a 
subgroup of hemophilia B 
patients with inhibitors who 
are not responding 
adequately to BPA 
prophylaxis treatment. 
Synopsis: Reference Therapy, Dose and Mode of 
Administration 
Following sentence added at 
appropriate location: "The subgroup of 
Cohort A patients who are not 
responding adequately to BPA 
prophylaxis treatment will not participate 
into this BPA prophylaxis period and will 
directly start the fitusiran treatment 
period after the screening period." 
Study expanded to enroll a 
subgroup of hemophilia B 
patients with inhibitors who 
are not responding 
adequately to BPA 
prophylaxis treatment. 
Synopsis: Duration of Treatment 
Following sentences "The estimated 
total time on study, inclusive of 
Screening, for each patient is up to 
15 months for patients who enroll in the 
extension study. The estimated total 
time on study may be up to 21 months 
in patients who do not enroll in the 
extension study due to the requirement 
for an additional 6 months of follow-up 
for monitoring of AT levels." changed to 
"The estimated total time on study, 
inclusive of Screening, for each patient 
is up to 15 months for patients who 
enroll in the extension study except for 
patients in the subgroup of Cohort A, 
which is up to 9 months. The estimated 
total time on study may be up to 21 
months (up to 15 months in patients in 
the subgroup of Cohort A) in patients 
who do not enroll in the extension study 
due to the requirement for an additional 
6 months of follow-up for monitoring of 
AT levels." 
Study expanded to enroll a 
subgroup of hemophilia B 
patients with inhibitors who 
are not responding 
adequately to BPA 
prophylaxis treatment. 
VV-CLIN-0254442 4.0


SAR439774 (formerly ALN-AT3SC) (fitusiran) 
 
Clinical Study Protocol ALN-AT3SC-009 
(Sanofi Genzyme EFC15110) 
 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Synopsis: Statistical Methods 
Following sentence “The subgroup of 
Cohort A patients who are not 
responding adequately to BPA 
prophylaxis treatment will not be part of 
the efficacy analysis set; however their 
efficacy data will be presented 
separately.” is added in first paragraph. 
Following sentence “The p-value should 
be interpreted with caution.” is added in 
second paragraph before “In addition, 
as a contrast Bayesian analyses will be 
performed to summarize the point 
estimates of the posterior probability of 
a clinically significant treatment effect, 
along with associated measures of 
uncertainty.” 
Following sentence: “Change in Haem-
A-QOL physical health score and total 
score in the factor/BPA prophylaxis 
period and fitusiran treatment period will 
be summarized descriptively.” is 
changed to “Change in Haem-A-QOL 
physical health score and total score in 
the factor/BPA prophylaxis period and 
fitusiran treatment period will be 
summarized descriptively. A mixed 
model for repeated measures analysis 
may be performed as deemed 
appropriate. The annualized weight-
adjusted consumption of factor/BPA 
injections will be summarized using 
descriptive statistics.” 
Study expanded to enroll a 
subgroup of hemophilia B 
patients with inhibitors who 
are not responding 
adequately to BPA 
prophylaxis treatment. 
Table 1: Schedule of Assessments 
The following tests: 
“Exploratory biomarkers m, r” 
“Urine Collection for Biomarkers m” are 
now: 
“Exploratory biomarkers m, r (optional)” 
“Urine Collection for Biomarkers m 
(optional)” 
These samples are now 
optional. 
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Section # and Name 
Description of Change 
Brief Rationale 
Table 1: Schedule of Assessments 
Following sentence added in footnote 
"a": "The subgroup Cohort A patients 
who are not responding adequately to 
BPA prophylaxis treatment will not 
participate in the BPA prophylaxis 
period and will directly start the fitusiran 
treatment period after the screening 
period. For these patients, the screening 
period will be from Day -60 to Day 0 and 
assessments during the BPA 
prophylaxis period are not applicable 
with the exception of the exploratory 
DNA sample." 
Study expanded to enroll a 
subgroup of hemophilia B 
patients with inhibitors who 
are not responding 
adequately to BPA 
prophylaxis treatment. 
Table 1: Schedule of Assessments 
Following sentence removed at the end 
of footnote "a": "For the Republic of 
Ireland specific requirements, see 
Appendix 11.5.1.1” 
Since the Republic of 
Ireland amendment is 
extended to the global 
protocol, it is no more 
specific to the Republic of 
Ireland. 
Table 1: Schedule of Assessments 
Following sentence added at the end of 
footnote “a, b, n & v”: “For the United 
States specific requirements, see 
Appendix 11.5.1.1” 
This is the United States 
specific protocol amendment 
to limit the enrollment to 
patients with inhibitory 
antibodies to Factor VIII or 
Factor IX. 
Table 1: Schedule of Assessments 
Following sentence in footnote n “The 
pre-dose TG draw should be a volume 
of 15 ml.”' is changed to “The pre-dose 
TG draw should be a volume of 
13.5 mL.” 
Typo correction. 
Table 1: Schedule of Assessments 
Footnote i "Height will be recorded at 
Screening only. Weight will be recorded 
at all other visits (Section 7.5.2)." is 
changed to "Height will be recorded only 
at Screening for patients >18 years old. 
Height for patients <18 years old and 
weight for all patients will be recorded at 
all checked visits (Section 7.5.2)." 
Typo correction. 
Table 2: Bleeding Episode Assessments – 
Unscheduled Visit 
The following row is deleted 
“Exploratory Coagulation” 
These samples are no 
longer collected. 
Table 2: Bleeding Episode Assessments – 
Unscheduled Visit 
Footnote b is removed 
These samples are no 
longer collected. 
Table 2: Bleeding Episode Assessments – 
Unscheduled Visit 
Following sentence added under the 
Table: “For the United States specific 
requirements, see Appendix 11.5.1.1” 
This is the United States 
specific protocol amendment 
to limit the enrollment to 
patients with inhibitory 
antibodies to Factor VIII or 
Factor IX. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 Study Design Rationale 
Following sentence “Secondary 
endpoints characterize annualized 
spontaneous and joint bleeding rates, 
change in Haem A QoL physical health 
score and total score in patients 
≥17 years of age, ABR in the onset 
period, and overall safety profile.” 
Changed to “Secondary endpoints 
characterize annualized spontaneous 
and joint bleeding rates, change in 
Haem A QoL physical health score and 
total score in patients ≥17 years of age, 
ABR in the onset period, overall safety 
profile and the consumption of 
factor/BPA.” 
A secondary objective and 
endpoint are included to 
further assess fitusiran 
efficacy. 
Section 2.2. Secondary Objectives 
“To characterize the annualized weight-
adjusted consumption of factor/BPA 
while receiving fitusiran treatment, 
relative to receiving factor or BPA 
prophylaxis” is added as a secondary 
objective 
A secondary objective and 
endpoint are included to 
further assess fitusiran 
efficacy. 
Section 3.2. Secondary Endpoints 
“Annualized weight-adjusted 
consumption of factor/BPA” is added as 
a secondary endpoint 
A secondary objective and 
endpoint are included to 
further assess fitusiran 
efficacy. 
Section 7.3.4. Exploratory Analyses 
Following sentence “Except where 
prohibited by local or national 
regulations, in consented patients, 
plasma, serum, and urine samples may 
be archived and used for analyses of 
exploratory biomarkers related to the 
metabolic profiling or effects of fitusiran 
and for the development of modified 
thrombin generation assays, and may 
also be archived for use in other 
exploratory analyses related to 
hemophilia and its complications.” is 
changed to “Except where prohibited by 
local or national regulations, in 
consented patients (since optional), 
plasma, serum, and urine samples may 
be archived and used for analyses of 
exploratory biomarkers related to the 
metabolic profiling or effects of fitusiran 
and for the development of modified 
thrombin generation assays, and may 
also be archived for use in other 
exploratory analyses related to 
hemophilia and its complications.” 
These samples are now 
optional. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 7.3.4. Exploratory Analyses 
Following sentence “In addition, where 
permitted in consented patients, serum 
samples may be used for analysis of 
circulating RNA, including the 
assessment of cleaved antithrombin 
RNA, and a sample of DNA may be 
obtained and archived to permit 
potential confirmation of hemophilia 
mutation or genotyping of hemophilia 
modifier genes, or genes that may 
modify the effects of fitusiran.” is 
changed to “In addition, where permitted 
in consented patients (since optional), 
serum samples may be used for 
analysis of circulating RNA, including 
the assessment of cleaved antithrombin 
RNA, and a sample of DNA may be 
obtained and archived to permit 
potential confirmation of hemophilia 
mutation or genotyping of hemophilia 
modifier genes, or genes that may 
modify the effects of fitusiran.” 
Clarification that these tests 
are optional is made. 
Section 8.2.5.2. Secondary Endpoints 
Following sentence is added “The 
secondary endpoint of annualized 
weight-adjusted consumption of 
factor/BPA injections will be 
summarized using descriptive statistics” 
A secondary objective and 
endpoint are included to 
further assess fitusiran 
efficacy. 
Section 1.3 Study Design Rationale 
Section 4.1 Summary of Study Design 
Section 4.2 Duration of Treatment 
Section 4.3 Number of Patients 
Section 5.1 Inclusion Criteria (criterion 4) 
Section 5.3 Removal from Therapy or Assessment 
Section 6.3.1.1 Routine Use of Factor or 
Bypassing Agent Prophylaxis in the Factor or 
Bypassing Agent Prophylaxis Period 
Section 6.3.2.1 Bleeding Episode Management 
Recommendations for Patients during the Factor 
or Bypassing Agent Prophylaxis Period (Patients 
Not Receiving Fitusiran) 
Table 5: Bleed Management Dosing Guidelines by 
Specific Product 
Section 6.9 Treatment Compliance 
Section 7.2.1 Electronic diary 
Section 7.3.3 Coagulation/Thrombin Generation 
Response Assessment in Factor or Bypassing 
Agent Prophylaxis Period 
Section 7.5.5.1 Additional Laboratory 
Assessments 
Following sentence removed: “For the 
Republic of Ireland specific 
requirements, see Appendix 11.5.1.2” 
Since the Republic of 
Ireland amendment is 
extended to the global 
protocol, it is no more 
specific to the Republic of 
Ireland. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 Study Design Rationale 
Section 1.5 Benefit-Risk Assessment  
Section 2 Objectives  
Section 3 Endpoints 
Section 4.1 Summary of Study Design 
Figure 1: Study Design 
Figure 2: Study Design (for Subgroup of Cohort A 
Patients Enrolling Directly In to the Fitusiran 
Treatment Period) 
Section 4.3 Number of Patients 
Section 5.1 Inclusion Criteria 
Section 5.2. Exclusion Criteria 
Section 5.3 Removal from Therapy or Assessment 
Section 6.3.1 
Section 6.3.1.1 Routine Use of Factor or 
Bypassing Agent Prophylaxis in the Factor or 
Bypassing Agent Prophylaxis Period 
Table 4 
Section 6.3.1.2. Management of Factor or 
Bypassing Agent Prophylaxis During the 
Transition to the Fitusiran Treatment Period 
Section 6.3.2 (subsections 6.3.2.1, 6.3.2.2, 
6.3.2.3) Management of Bleeding Episodes 
Table 5: Bleed Management Dosing Guidelines by 
Specific Product 
Section 6.5.Monitoring and Management of 
Thrombotic Events 
Section 6.9 Treatment Compliance 
Section 7.1. Screening/Baseline Assessments 
Section 7.2. Efficacy Assessments 
Section 7.2.1 Electronic diary 
Section 7.3.3 Coagulation/Thrombin Generation 
Response Assessment in Factor or Bypassing 
Agent Prophylaxis Period 
Section 7.5.5.1 Additional Laboratory 
Assessments 
Section 8.1 Determination of sample size 
Section 8.2.5.1 Primary Endpoint 
Following sentence added at 
appropriate location of these sections: 
“For the United States specific 
requirements, see Appendix 11.5.1.2” 
This is the United States 
specific protocol amendment 
to limit the enrollment to 
patients with inhibitory 
antibodies to Factor VIII or 
Factor IX. 
Section 3.2: Secondary Endpoints 
Secondary endpoint “Change in Haem-
A-QOL physical health score and total 
score in the fitusiran treatment period” 
completed to “Change in Haem-A-QOL 
physical health score and total score in 
the fitusiran treatment period and the 
factor or BPA prophylaxis period” 
Correction of a discrepancy 
with the corresponding study 
objective. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.3.2.2. Bleeding Episode Management 
Recommendations for Patients during the 
Fitusiran Treatment Period 
Table 5: Bleed Management Dosing Guidelines by 
Specific Product 
Section 6.5. Monitoring and Management of 
Thrombotic Events 
Section 6.8 Contraceptive Requirements 
Following sentence added at 
appropriate location of these sections: 
“For the Japan specific requirements, 
see Appendix 11.5.2” 
This is the Japan specific 
protocol amendment to 
include previous PMDA 
recommendations previously 
managed as protocol 
addendum administrative 
changes. 
Section 8.2.1 Populations to be Analyzed 
The whole section is changed to: 
The populations (analysis sets) are 
defined as follows: 
Safety Analysis Set: All patients who 
enrolled and then received any dose of 
fitusiran.  
Efficacy Analysis Set (EAS): All patients 
in the safety analysis set who received 
both factor or BPA prophylaxis and any 
dose of fitusiran (Addressed in more 
details in SAP). 
Per-protocol Analysis Set (PPS): All 
patients In the EAS who had no major 
protocol deviations. Major deviations will 
be specified in the SAP.  
PK Analysis Set: All patients who 
received any dose of fitusiran and have 
at least 1 post dose blood sample for PK 
parameters and have evaluable PK 
data. 
The subgroup of Cohort A patients who 
are not responding adequately to BPA 
prophylaxis treatment will be included in 
the safety analysis set. They will not be 
part of the efficacy analysis set. 
However, their efficacy data will be 
presented separately. 
Study expanded to enroll a 
subgroup of hemophilia B 
patients with inhibitors who 
are not responding 
adequately to BPA 
prophylaxis treatment. 
Appendix 11.5 
Republic of Ireland-specific 
requirements have been removed. 
Since the Republic of 
Ireland amendment is 
extended to the global 
protocol, it is no more 
specific to the Republic of 
Ireland. 
Appendix 11.5 
United States specific requirements 
have been added. The changes are 
identified in the Appendix 11.5.1. 
This is the United States 
specific protocol amendment 
to limit the enrollment to 
patients with inhibitory 
antibodies to Factor VIII or 
Factor IX. 
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Section # and Name 
Description of Change 
Brief Rationale 
Appendix 11.5 
Japan specific requirements have been 
added. The changes are identified in the 
Appendix 11.5.2. 
This is the Japan specific 
protocol amendment to 
include previous PMDA 
recommendations previously 
managed as protocol 
addendum administrative 
changes 
Appendix 11.6.3 
Newly added appendix. Texts from the 
“Document History” page have been 
moved to this appendix. 
Due to change in the 
amendment number, overall 
rationale and summary of 
changes of protocol 
amendment 03 have been 
moved to Appendix 11.6.3. 
11.7.5 Amended Protocol 05  
AMENDMENT 05 (25 November 2020) 
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  
• 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. 
• Cholecystitis and symptomatic cholelithiasis are newly identified risk 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. 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis: Study design 
Section 4.1: Summary of 
study design 
Section 11.6.1.1: Protocol 
synopsis  
Text changed from “…receive their first 
dose of 80 mg fitusiran” to “…receive 
their first dose of fitusiran” 
Fitusiran dosing regimen changed as a risk 
mitigation measure for vascular thrombotic events.   
Synopsis: Study design  
Section 4.1: Summary of 
study design 
Section 11.6.1.1: Protocol 
synopsis 
Text changed from “…receive 80 mg 
fitusiran as a once monthly prophylaxis” 
to “…receive fitusiran as prophylaxis” 
Fitusiran dosing regimen changed as a risk 
mitigation measure for vascular thrombotic events. 
Synopsis: Study design 
Section 4.1: Summary of 
study design 
Section 11.6.1.1: Protocol 
synopsis 
Text changed from “…with fitusiran for a 
total of 7 months and will receive 7 SC 
injections of fitusiran.” to “…with fitusiran 
for a total of 7 months.” 
Fitusiran dosing regimen changed as a risk 
mitigation measure for vascular thrombotic events. 
Synopsis: Number of 
planned patients 
Section 4.3: Number of 
patients  
Section 11.6.1.1: Protocol 
synopsis 
Text updated from “Approximately 
70 patients are planned for enrollment in 
this study, including approximately 
30 patients with inhibitors (Cohort A) and 
approximately 40 patients without 
inhibitors (Cohort B).” to “Approximately 
80 patients are planned for enrollment in 
this study, including approximately 
30 patients with inhibitors (Cohort A) and 
approximately 50 patients without 
inhibitors (Cohort B).” 
Study expanded to include patients to mitigate for 
the over enrollment of the non-inhibitor cohort as 
there were already 79 patients enrolled at the time 
of this amendment. 
Synopsis: Investigational 
product, dose and mode of 
administration 
Section 6.2.2: Dose and 
administration 
Text changed from “Patients will receive 
open-label fitusiran 80 mg as an SC 
injection once monthly injection” to 
“Patients will receive open-label fitusiran 
as an SC injection”. 
Fitusiran dosing regimen changed as a risk 
mitigation measure for vascular thrombotic events. 
Table 1: Schedule of 
assessments 
Table updated with 12-Lead ECG not to 
be checked at Month 5. 
ECG is expected to be performed pre and post 
dose of fitusiran, so deleted with the change of 
dose frequency. 
Table 1: Schedule of 
assessments 
Table updated with Antidrug Antibodies 
samples to be collected at Day 1, Month 
2, Month 4, Month 6, and Month 7. 
Fitusiran dosing regimen changed as a risk 
mitigation measure for vascular thrombotic events. 
Table 1: Schedule of 
assessments 
Table updated with Plasma PK samples 
to be collected at Day 1, Month 2, Month 
4, Month 6, and clarified “Plasma PK 
(East Asian patients only)”. 
Fitusiran dosing regimen changed as a risk 
mitigation measure for vascular thrombotic events. 
Table 1: Schedule of 
assessments 
Table updated with Fitusiran 
Administration Q2M schedule to be 
injected at Day 1, Month 2, Month 4, and 
Month 6. 
Fitusiran dosing regimen changed as a risk 
mitigation measure for vascular thrombotic events. 
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Section # and Name 
Description of Change 
Brief Rationale 
Table 1: Schedule of 
assessments 
Text changed from “Review with patient 
at each visit and contact every 2 weeks 
between visits” to “Review with patient at 
each visit and contact every 2 weeks 
(±4 days) between visits” for Bleed 
Management Review and Bleeding 
Episodes/eDiary. 
Window added for flexibility. 
Table 1: Schedule of 
assessments 
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: Schedule of 
assessments 
Note “AT and factor results will be 
provided at screening for confirmation of 
eligibility.  AT results will be provided at 
AT follow-up visits for monitoring.” from 
previous amended protocol 04 removed. 
AT results and Factor results during the study will 
be provided 
Table 1: Schedule of 
assessments 
Foot note “j” changed from: “…On Day 1 
and Month 5, …” to “…On Day 1, …” 
ECG is expected to be performed pre and post 
dose of fitusiran, so deleted with the change of 
dose frequency. 
Table 1: Schedule of 
assessments 
Foot note “n”, the flowing sentence was 
removed: “The pre-dose TG draw should 
be a volume of 13.5 mL.” 
Usually volume is not mentioned in the protocols 
but rather in lab manuals only. 
Table 1: Schedule of 
assessments 
Foot note “o” in previous amended 
protocol 4 “Only for patients who do not 
enroll in the open-label extension study” 
removed 
Both “Nijmegen-Modified Bethesda Assay (Inhibitor 
Status)” and “antidrug antibody test” are required 
for patients who roll over to the OLE study. 
Table 1: Schedule of 
assessments 
Foot note “p” changed from “East Asian 
patients at East Asian sites, blood 
samples for PK analysis will be collected 
at the time points listed in (which 
includes all those time points listed in), 
and pooled urine samples will be 
collected for PK analysis at the time 
points listed in …” to “Pooled urine 
samples will be collected for PK analysis 
at the time points listed in...” 
Draws will now be the same for all patients whether 
East Asian or not.   
Table 1: Schedule of 
assessments 
Foot note “r” changed from “…in patients 
undergoing operative procedures while 
on study” to “…in patients undergoing 
major operative procedures while on 
study drug”. 
For clarity. 
Table 1: Schedule of 
assessments 
New foot note “x” added: “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. 
To clarify COVID-19 test. 
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Section # and Name 
Description of Change 
Brief Rationale 
Alternatively, historical test results may 
be provided under certain circumstances 
as defined by the Sponsor.” 
List of abbreviations 
Section 6.2.6: 
Accountability 
Abbreviation for DTP changed from 
“duties and taxes paid” to “Direct-to-
Patient”. 
Typo. 
Section 1.1: Disease 
overview 
Text updated from “Hemophilia A is 
found in approximately 1 in 5000 males 
whereas hemophilia B is five times less 
common and seen in approximately 1 in 
25,000 males” to “Hemophilia A is found 
in approximately 1 in 4000 males 
whereas hemophilia B is five times less 
common and seen in approximately 1 in 
20,000 males”. 
Reference updated. 
Section 1.1: Disease 
overview 
Text updated from “In 20% to 33% of 
patients with hemophilia A, inhibitory 
antibodies form to FVIII; in hemophilia B, 
1% to 6% of patients develop inhibitory 
antibodies to FIX” to “Development of 
inhibitors to infused factor occurs mainly 
in severe hemophilia, and more 
frequently in hemophilia A (up to 39% of 
patients) (5,6) than in hemophilia B (1% 
to 3.5% of patients) (7,8) with the 
greatest risk of development in the early 
exposure days.”. 
Reference updated. 
Section 1.1: Disease 
overview 
Text changed from “A fixed-dose 
subcutaneous therapy…” to “A 
subcutaneous therapy…”. 
Fitusiran dosing regimen changed as a risk 
mitigation measure for vascular thrombotic events. 
Section 1.2: Fitusiran 
(SAR439774) 
Text changed from “, the subcutaneous 
(SC) administration required is notably 
less frequent (once monthly) than…” to “, 
the subcutaneous (SC) administration 
required is notably less frequent than…”. 
Fitusiran dosing regimen changed as a risk 
mitigation measure for vascular thrombotic events. 
Section 1.2.2: Summary of 
clinical data section 
Simplified. 
Refer to the IB for current updates. 
Section 1.2.2.1: Summary 
of efficacy 
Paragraphs 1 to 3 from previous 
amended protocol 04 removed, the 
following paragraph 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) (9, 10).”. 
Refer to the IB for current updates. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.2.2.2: Summary 
of safety 
Paragraphs 1 to 6 from previous 
amended protocol 04 removed, the 
following paragraph added: “Events of 
serious vascular thrombosis, liver 
transaminase abnormalities, 
cholecystitis, and symptomatic 
cholelithiasis have been reported in the 
clinical development program and are 
considered identified risks of fitusiran.  In 
addition, serious hypersensitivity 
reactions, including injection site 
reactions, are considered a potential risk 
of fitusiran. One death has been 
reported in a patient with cerebral 
venous thrombosis (CVST) in ALN-
AT3SC-002. In response to this event, 
the bleed management guidelines were 
revised in December 2017.  ” 
Refer to the IB for current updates. 
Section 1.4: Dose 
rationale 
Dose rationale text updated, dosing 
regimen simulation added, Table 3 
added. 
Fitusiran dosing regimen changed as a risk 
mitigation measure for vascular thrombotic events. 
Section 1.5: Benefit-risk 
assessment 
Section 11.6.1.2: Protocol 
body 
Benefit-risk assessment text updated. 
Fitusiran dosing regimen changed as a risk 
mitigation measure for vascular thrombotic events. 
Section 4.4: Summary of 
study design 
Text changed from “All patients will be 
assigned to the same treatment 
sequence in this open-label study.” to 
“All patients will be assigned to the same 
treatment sequence (prophylaxis period 
followed by fitusiran period) in this open-
label study.”. 
For clarity. 
Section 5.3.1: 
Discontinuation of study 
drug  
New bullet added “More than 1 AT 
measurements <15% if at a dose of 
50 mg Q2M”. 
To align with instructions for AT-driven fitusiran 
regimen modification 
Section 5.3.3: Criteria for 
temporarily delaying 
enrollment or 
administrations of study 
intervention 
New section “Criteria for temporarily 
delaying enrollment or administrations of 
study intervention” 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 6.1: Treatments 
administered 
The following paragraphs added: “The 
IMP 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.  
For a regional or national emergency 
declared by a governmental agency that 
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. 
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Section # and Name 
Description of Change 
Brief Rationale 
results in travel restrictions, confinement, 
or restricted site access, contingency 
measures are included in Section 11.8.  
Section 6.2.3: Dose 
modifications 
The following sentence added: 
“Instructions for AT-driven fitusiran 
regimen modification are provided in 
Section 6.2.3.1.” 
To align with the new fitusiran dosing regimen. 
Section 6.2.3.2: 
Antithrombin level criteria 
for a dose adjustment 
New section added. 
Fitusiran dosing regimen changed as a risk 
mitigation measure for vascular thrombotic events. 
Section 6.2.3.3: 
Temporary discontinuation 
due to a regional or 
national emergency 
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 6.5: Monitoring 
and management of 
thrombotic events 
Monitoring and management of 
thrombotic events text updated. 
Risk mitigation measure for vascular thrombotic 
events. 
Section 6.6: Elective 
and/or emergency surgery 
Text changed from “If an urgent need for 
surgery arises during…” to “If an urgent 
need for major surgery arises during…”. 
“In patients undergoing surgery during 
the study, …” changed to “In patients 
undergoing major surgery during the 
study, …”. 
For clarity. 
Section 7: Study 
assessment 
The following sentence from previous 
amended protocol 04 removed 
“Additional information on the collection 
of study assessments will be detailed in 
the Study Manual.” 
It was an error as no study manual provided for this 
study. 
Section 7: Study 
assessment 
The following sentence added “For a 
regional or national emergency declared 
by a governmental agency, contingency 
measures are included in Section 11.8.” 
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 7.1: 
Screening/baseline 
assessments 
Section 11.6.1.2: Protocol 
body 
Text changed from “…must be signed by 
the patient (or legal guardian) before the 
Screening/Baseline procedures are 
initiated” to “…must be signed by the 
patient (or legal guardian) before the 
Screening procedures are initiated” 
For clarity. 
Section 7.2.1: Electronic 
diary 
Section 11.6.1.2: Protocol 
body 
Text changed from “The site will contact 
the patient at a minimum interval of 
every 2 weeks per schedule of 
assessments…” to “The site will contact 
the patient at a minimum interval of 
every 2 weeks (+/- 4 days) per schedule 
of assessments…”. 
Window added for flexibility 
Section 7.2.1: Electronic 
diary 
Text changed from “Sponsor or an 
independent delegate” to “Sponsor”. 
No independent reviewer of eDiary data 
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Section # and Name 
Description of Change 
Brief Rationale 
Section11.6.1.2: Protocol 
body 
Section 7.2.1: Electronic 
diary 
Section 11.6.1.2: Protocol 
body 
The following sentence removed 
“Complete instructions will be provided in 
the Study Manual.” 
It was an error as no study manual provided for this 
study. 
Section 7.3.1: 
Antithrombin (AT) activity 
Text changed from “Samples will be 
collected within 4 hours prior to dosing.” 
to “On dosing days, samples will be 
collected within 4 hours prior to dosing.” 
For clarity. 
Section 7.3.1: 
Antithrombin (AT) activity 
Text changed from “Following final 
fitusiran dose, AT activity level will be 
monitored” to “Following final fitusiran 
dose, and in case the patient is not rolled 
over to the open label extension study, 
AT activity level will be monitored”. 
For clarity. 
Section 7.4: 
Pharmacokinetic 
assessments 
Text changed from “All plasma 
concentration data (Table 11) will be 
summarized and analyzed using a 
population PK” to “All plasma 
concentration data (Table 11) will be 
summarized and analyzed using a 
population PK approach and 
noncompartmental analysis, as 
applicable.” 
For clarity. 
Section 7.4: 
Pharmacokinetic 
assessments  
Text changed from “In addition, plasma 
PK (Table 11, which includes all time 
points in Table 10) will be evaluated in 
East Asian patients at East Asian sites 
(defined as patients from sites in China, 
Japan, South Korea, and Taiwan), and 
there will be pooled urine collection for 
urine PK analysis also in these patients” 
to “In addition,  there will be pooled urine 
collection for urine PK analysis also in 
patients from East Asian sites (defined 
as patients from sites in China, Japan, 
South Korea, and Taiwan). This does not 
apply to patients on the 50 mg Q2M 
dosing regimen.”. 
Need to collect any urine data from any patients 
after dose switch to 50 mg Q2M regimen. 
Section 7.5: Use of 
biological samples and 
data for future research 
New section added. 
To align with new template mandatory text. 
Section 7.6.4: 
Electrocardiogram 
Text changed from “Recordings will be 
archived according to the Study Manual.” 
to “Recordings will be archived at sites.” 
It was an error as no study manual provided for this 
study. 
Section 7.6.6.1: Definitions 
ASEI: Cholecystitis and Cholelithiasis 
added. 
To reflect the updates of fitusiran safety profile and 
to optimize the monitoring process. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 7.6.6.3: Serious 
adverse events and 
adverse events of special 
interest require immediate 
reporting to 
Sponsor/Designee 
The following sentence removed: “SAEs 
must be reported using the contact 
information provided in the Study 
Manual.” 
It was an error as no study manual provided for this 
study. 
Section 7.7.1: Patient-
reported outcomes 
Text changed from “All completed 
questionnaires or instrument forms for 
the patient-reported outcome 
assessments described below will be 
collected, entered into a database, and 
archived according to the Study Manual.” 
to “All completed questionnaires or 
instrument forms for the patient-reported 
outcome assessments described below 
will be collected, entered into a 
database, and archived at study sites.” 
It was an error as no study manual provided for this 
study. 
Section 7.7.2: HJHS 
Text changed from “Completed HJHS 
score forms will be collected and 
archived according to the Study Manual.” 
to “Completed HJHS score forms will be 
collected and archived at study sites.” 
It was an error as no study manual provided for this 
study. 
Section 8.1: Determination 
of sample size 
Text changed from “The overall sample 
size of 70 patients including 
approximately 30 patients with inhibitor 
(Cohort A) and approximately 
40 patients without inhibitor (Cohort B) 
was selected” to “The overall sample 
size of 80 patients including 
approximately 30 patients with inhibitor 
(Cohort A) and approximately 
50 patients without inhibitor (Cohort B) 
was selected”. 
Study expanded to include patients to mitigate for 
the over enrollment of the non-inhibitor cohort as 
there were already 79 patients enrolled at the time 
of this amendment. 
Section 8.2.1: Populations 
to be analyzed 
COVID-19 Unaffected Set added: All 
patients who had no major or critical 
protocol deviations due to COVID-19 at 
any visit up to the end of study 
(Month 7). 
To define Covid-19 Unaffected Set. 
Section 8.2.5: Efficacy 
analyses 
The following paragraph added: “To 
address the potential impact of 
COVID-19, the efficacy analyses will be 
repeated on the COVID-19 unaffected 
set. Additional analyses and methods 
required to evaluate the impact are 
detailed in the SAP”. 
To add the efficacy analyses due to Covid-19 
impact to address the potential impact. 
Section 9.2.1: Data 
handling 
Text changed from “The Investigator 
must permit study-related monitoring, 
audits, IRB/IEC review, and regulatory 
agency inspections and provide direct 
access to source data documents.” to 
For clarity. 
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Section # and Name 
Description of Change 
Brief Rationale 
“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).”. 
Section 9.2.2: Study 
monitoring 
The following paragraph added: 
“Monitoring details describing strategy 
(eg, risk-based initiatives in operations 
and quality such as Risk Management 
and Mitigation Strategies and Analytical 
Risk-Based Monitoring), 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 9.2.2: Study 
monitoring 
Text changed from “…must be retained 
by the Investigator for 15 years after 
study completion” to “must be retained 
by the Investigator for 25 years after 
study completion”. 
To align with the updated requirement. 
List of Reference  
Reference list updated.  
New references were added 
Table 11: Pharmacokinetic 
time points in East Asian 
patients following fitusiran 
administration at 50 mg 
Q2M 
Updated. 
Fitusiran dosing regimen changed as a risk 
mitigation measure for vascular thrombotic events. 
Table 11 and Table 12 
from previous amended 
protocol 04 
Removed. 
Sampling updated. 
Appendices Section 
11.2.2: Perioperative 
assessments of safety and 
hemostatic efficacy in 
patients undergoing 
operative procedures 
Text changed from “In patients 
undergoing operative procedures during 
the fitusiran treatment period…” to “In 
patients undergoing major operative 
procedures during the fitusiran treatment 
period…”. 
For clarity. 
Appendices Section 11.5: 
Data protection” 
New section added. 
To align with new template mandatory text. 
Appendices Section 11.8 
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 
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11.8 
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 participant for the 
duration of the emergency: 
• The Direct-to-Patient (DTP) supply of IMP via Investigator or Sponsor approved courier 
where allowed by local regulations and agreed upon by the participant.  
• 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 5.3.3, 
Section 6.1, Section 6.2.3.3, and Section 7. These procedures apply to an emergency that 
prevents access to the study site, to optimize the safety of the study 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. Home 
injection with IMP can be performed as per Investigator’s judgement. For any patient 
receiving fitusiran, BPAs, Investigator or designee should contact the patient via regular 
phone calls at least every two weeks to oversee the tolerability of the drugs, check for 
AEs, review bleed management including bleeding episodes and eDiary. Depending on 
the delay of patient on-site visit, Patient Reported Outcomes (PRO) ie, questionnaires) 
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 and eDiary. 
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• Use of a 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. 
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 
screening/enrollment/administration of study intervention may be temporarily delayed (see also 
Section 7). 
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). 
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Statistical Analysis Plan  
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 4 
LIST OF FIGURES .......................................................................................................................................... 4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................ 7 
1.1 
STUDY DESIGN .............................................................................................................................. 7 
1.2 
OBJECTIVES ................................................................................................................................... 8 
1.2.1 
Primary objectives ............................................................................................................................ 8 
1.2.2 
Secondary objectives ....................................................................................................................... 8 
1.2.3 
Exploratory objectives ...................................................................................................................... 8 
1.3 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 8 
1.4 
GRAPHIC STUDY PLAN ................................................................................................................. 9 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL ................................ 10 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN ..................... 12 
2 
STATISTICAL AND ANALYTICAL PROCEDURES .................................................................... 17 
2.1 
ANALYSIS ENDPOINTS ............................................................................................................... 17 
2.1.1 
Demographic and baseline characteristics .................................................................................... 17 
2.1.2 
Prior or concomitant medications ................................................................................................... 18 
2.1.3 
Efficacy endpoints .......................................................................................................................... 18 
2.1.3.1 
Primary efficacy endpoint ............................................................................................................... 18 
2.1.3.2 
Secondary efficacy endpoints ........................................................................................................ 20 
2.1.4 
Safety endpoints ............................................................................................................................ 21 
2.1.4.1 
Adverse events variables ............................................................................................................... 21 
2.1.4.2 
Deaths ............................................................................................................................................ 22 
2.1.4.3 
Laboratory safety variables ............................................................................................................ 22 
2.1.4.4 
Physical examination and vital signs variables .............................................................................. 23 
2.1.4.5 
Electrocardiogram variables .......................................................................................................... 24 
2.1.5 
Pharmacokinetic variables ............................................................................................................. 25 
2.1.6 
Pharmacodynamic endpoints ......................................................................................................... 25 
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2.1.7 
Exploratory endpoints .................................................................................................................... 25 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 26 
2.3 
ANALYSIS POPULATIONS ........................................................................................................... 27 
2.4 
STATISTICAL METHODS ............................................................................................................. 30 
2.4.1 
Demographics and baseline characteristics .................................................................................. 30 
2.4.2 
Prior or concomitant medications ................................................................................................... 31 
2.4.3 
Study duration, extent of study treatment exposure and compliance ............................................ 31 
2.4.4 
Analyses of efficacy endpoints ....................................................................................................... 32 
2.4.4.1 
Analysis of primary efficacy endpoint(s) ........................................................................................ 32 
2.4.4.2 
Analyses of secondary efficacy endpoints ..................................................................................... 38 
2.4.4.3 
Multiplicity issues ........................................................................................................................... 40 
2.4.5 
Analyses of safety data .................................................................................................................. 40 
2.4.5.1 
Analyses of adverse events ........................................................................................................... 41 
2.4.5.2 
Analyses of laboratory variables .................................................................................................... 43 
2.4.5.3 
Analyses of physical examination and vital sign variables ............................................................ 44 
2.4.5.4 
Analyses of electrocardiogram variables ....................................................................................... 44 
2.4.6 
Analyses of pharmacokinetic and pharmacodynamic variables .................................................... 44 
2.4.6.1 
Analyses of pharmacodynamic variables....................................................................................... 44 
2.4.6.2 
Analyses of pharmacokinetic variables .......................................................................................... 45 
2.4.7 
Analyses of exploratory endpoints ................................................................................................. 45 
2.4.7.1 
TSQM-9 .......................................................................................................................................... 45 
2.4.7.2 
HAL and pedHAL ........................................................................................................................... 45 
2.4.7.3 
EQ-5D-5L ....................................................................................................................................... 45 
2.4.7.4 
Haemo-QOL ................................................................................................................................... 46 
2.4.7.5 
HJHS .............................................................................................................................................. 46 
2.4.7.6 
Number of target joint bleeding episodes ...................................................................................... 46 
2.4.7.7 
Incidence and titer of antidrug antibodies to fitusiran in the fitusiran treatment period ................. 46 
2.4.7.8 
AT activity level over time .............................................................................................................. 46 
2.4.7.9 
Thrombin generation over time ...................................................................................................... 46 
2.4.7.10 Fitusiran plasma levels .................................................................................................................. 47 
2.4.7.11 Change in patient resource use (eg, work/school attendance, visits to doctor/hospital) ............... 47 
2.5 
DATA HANDLING CONVENTIONS .............................................................................................. 47 
2.5.1 
General conventions ...................................................................................................................... 47 
2.5.2 
Data handling conventions for secondary efficacy variables ......................................................... 47 
2.5.3 
Missing data ................................................................................................................................... 47 
2.5.4 
Windows for time points ................................................................................................................. 49 
2.5.5 
Unscheduled visits ......................................................................................................................... 50 
2.5.6 
Pooling of centers for statistical analyses ...................................................................................... 50 
2.5.7 
Statistical technical issues ............................................................................................................. 50 
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Statistical Analysis Plan  
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Page 4 
3 
INTERIM ANALYSIS ..................................................................................................................... 51 
4 
DATABASE LOCK ........................................................................................................................ 52 
5 
SOFTWARE DOCUMENTATION ................................................................................................. 53 
6 
REFERENCES ............................................................................................................................... 54 
7 
LIST OF APPENDICES ................................................................................................................. 55 
APPENDIX A 
SUMMARY OF STATISTICAL ANALYSES ........................................................................ 56 
APPENDIX B 
QUESTIONNAIRE/SCORING: HAEM-A-QOL AND HAEMO-QOL .................................... 58 
APPENDIX C 
QUESTIONNAIRE/SCORING: TREATMENT SATISFACTION QUESTIONNAIRE 
FOR MEDICATION (TSQM) DOMAIN SCORES ................................................................ 60 
APPENDIX D 
QUESTIONNAIRE/SCORING: HAEMOPHILIA ACTIVITIES LIST 
(HAL)/PAEDIATRIC HAL (PEDHAL) SCORE ..................................................................... 61 
APPENDIX E 
QUESTIONNAIRE/SCORING: EUROQOL-5 DIMENSION 5 LEVEL (EQ-5D-5L) 
SCORE ................................................................................................................................ 63 
APPENDIX F 
POSITION PAPER ............................................................................................................... 64 
 
LIST OF TABLES  
Table 1 - Simulated ratio of rates for Cohort A, with 95% confidence intervals .............................................. 9 
Table 2 - Simulated ratio of rates for Cohort B, with 95% confidence intervals .............................................. 9 
Table 3 - Protocol amendment statistical changes ....................................................................................... 11 
Table 4 - Statistical analysis plan statistical changes ................................................................................... 12 
LIST OF FIGURES  
Figure 1 - Study design ................................................................................................................................. 10 
Figure 2 - Study design (for subgroup of Cohort A patients enrolling directly into the fitusiran treatment 
period)............................................................................................................................................................ 10 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
ABR: 
annualized bleeding rate 
ADA: 
antidrug antibody formulation 
AE: 
adverse event 
AESI: 
adverse events of special interest 
ALP: 
alkaline phosphatase  
ALT: 
alanine aminotransferase 
AST: 
aspartate aminotransferase 
AT: 
antithrombin 
ATC: 
anatomic therapeutic class 
AUC: 
area under the concentration-time curve 
BMI: 
body mass index 
BPA: 
bypassing agent 
BUN: 
blood urea nitrogen 
CL/F: 
apparent clearance 
Cmax: 
maximum plasma concentration 
CR: 
copy reference 
CRF: 
case report form 
ECG: 
electrocardiogram 
EQ-5D: 
EuroQoL - 5 Dimensions 
GGT: 
gamma-glutamyl transpeptidase 
Haem-A-QOL: Haemophilia Quality of Life Questionnarire for Adults 
Haemo-QOL: 
Haemophilia Quality of Life Questionnaire for Children and Adolescents 
HAL: 
Haemophilia Activities List 
HJHS: 
Hemophilia Joint Health Score 
HLGT: 
high-level group term 
HLT: 
high-level term 
HRQOL: 
health related quality of life 
IARs: 
injection associated reactions 
ICF: 
informed consent form 
ISRs: 
injection systematic reactions 
LLT: 
lower-level term 
MAR: 
missing at random 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MI: 
multiple imputation 
PCSA: 
potentially clinically significant abnormality 
PD: 
pharmacodynamic 
pedHAL: 
Paediatric HAL 
PK: 
pharmacokinetics 
PT: 
preferred term 
SAE: 
serious adverse event 
SD: 
standard deviation 
SOC: 
system organ class 
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t½β: 
elimination half-life 
TG: 
thrombin generation 
tmax: 
time to maximum plasma concentration 
TSQM: 
Treatment Satisfaction Questionnaire for Medication 
ULN: 
upper limit of normal 
V/F: 
apparent volume of distribution 
WBC: 
white blood cell 
WHO-DD: 
World Heath Organization_Drug Dictionary 
 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN  
1.1 
STUDY DESIGN  
This is a multicenter, multinational, open label, Phase 3 switching study designed to characterize 
the efficacy and safety of fitusiran in male patients, aged ≥12 years, with severe hemophilia A or 
B, previously receiving factor or bypassing agent (BPA) prophylaxis. 
The study consists of 2 cohorts: Cohort A consists of patients with inhibitory antibodies to factor 
VIII or factor IX. Cohort B consists of patients without inhibitory antibodies to factor VIII or 
factor IX. A subgroup of Cohort A patients includes hemophilia B patients with inhibitory 
antibodies to factor IX who are not responding adequately to BPA prophylaxis treatment 
(historical annualized bleeding rate (ABR) ≥20) (see Inclusion Criteria in Section 5.1 of the study 
protocol). 
The study has 3 periods defined by type of prophylaxis regimen: 
• 6-month factor/BPA prophylaxis period in which patients continue their prestudy, 
regularly scheduled prophylaxis regimen with factor/BPAs. 
The subgroup of Cohort A patients who are not responding adequately to BPA prophylaxis 
treatment do not participate in this 6-month BPA prophylaxis period and start to directly 
receive fitusiran (in the 1-month onset period described below) after the screening period. 
• 1-month onset period in which patients receive first dose of fitusiran while continuing 
their factor/BPA prophylaxis for up to 7 days. 
• 6-month fitusiran efficacy period in which patients receive fitusiran prophylaxis. 
Together, the 1-month onset period and the 6-month fitusiran efficacy period constitute the 
fitusiran treatment period. An additional 6 months follow-up period for monitoring of AT levels is 
required for patients who do not enroll in the extension study after the fitusiran treatment period. 
Given that the study design employed is a single treatment arm, with a switch from factor/BPA 
prophylaxis to fitusiran prophylaxis for each patient, the study is not blinded and no 
randomization is performed. 
Approximately 80 patients are planned for enrollment in this study, including approximately 
30 patients with inhibitors (Cohort A) and approximately 50 patients without inhibitors 
(Cohort B). Approximately 18 patients with hemophilia B (including approximately 7 hemophilia 
B patients in Cohort A, among which are a subgroup of no more than 4 patients who are not 
responding adequately to BPA prophylaxis), and approximately 7 adolescents (≥12 to <18 years 
of age) are also planned for enrollment. In the US, only patients from Cohort A are included. 
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1.2 
OBJECTIVES  
1.2.1 Primary objectives  
• To characterize the frequency of bleeding episodes while receiving fitusiran treatment, 
relative to the frequency of bleeding episodes while receiving factor concentrate or 
bypassing agent (BPA) prophylaxis. 
1.2.2 Secondary objectives  
• To characterize the following while receiving fitusiran treatment, relative to receiving 
factor or BPA prophylaxis: 
- 
The frequency of spontaneous bleeding episodes 
- 
The frequency of joint bleeding episodes  
- 
Health related quality of life (HRQOL)in patients ≥17 years of age 
• To characterize the frequency of bleeding episodes during the onset and treatment periods 
in patients receiving fitusiran 
• To characterize safety and tolerability of fitusiran 
• To characterize the annualized weight-adjusted consumption of factor/BPA while 
receiving fitusiran treatment, relative to receiving factor or BPA prophylaxis 
1.2.3 Exploratory objectives  
• To characterize the effects of fitusiran on the following patient-reported outcomes while 
receiving fitusiran treatment, relative to receiving factor or BPA prophylaxis: 
- 
Patient satisfaction with fitusiran 
- 
Patient activity 
- 
HRQOL in adolescents (≥12 to <17 years of age) 
• To characterize the pharmacodynamic (PD) effect, PK, and immunogenicity of fitusiran 
• To characterize the effects of fitusiran on joint status while receiving fitusiran treatment, 
relative to receiving factor or BPA prophylaxis 
• To characterize the effects of fitusiran on patient resource use, relative to receiving factor 
or BPA prophylaxis 
1.3 
DETERMINATION OF SAMPLE SIZE  
Sample size is based on clinical considerations. The overall sample size of 80 patients including 
approximately 30 patients with inhibitor (Cohort A) and approximately 50 patients without 
inhibitor (Cohort B) was selected recognizing the limited number of patients with hemophilia, and 
to yield a reasonably robust estimate of the fitusiran bleeding episode rate and address the 
secondary objectives, including characterization of safety and tolerability. The proposed sample 
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size is also expected to provide reasonable precision around the ratio of bleeding rate in the 
fitusiran efficacy period to bleeding rate in the factor/BPA period for both Cohort A and Cohort B. 
Since patients participate in multiple periods, within-patient correlation of numbers of bleeding 
episodes is expected between the periods. Having no prior knowledge of this correlation, different 
correlation scenarios were considered and the ratio of the bleeding rate in fitusiran efficacy period 
to the bleeding rate in factor/BPA period along with its 95% CIs were simulated. Below tables 
summarize the results from 10 000 simulated studies along with the ABR assumptions. 
Table 1 - Simulated ratio of rates for Cohort A, with 95% confidence intervals  
Correlation 
Average Ratio (Average 95% CI Bounds), N=30 
Based on 10 000 Simulations 
Fitusiran period ABR: mean = 4, SD = 6 
Factor/BPA period ABR:  
Mean = 16; SD = 14 
Factor/BPA period ABR:  
Mean = 12; SD = 11 
0.25 
0.24 (0.14, 0.42) 
0.32 (0.19, 0.57) 
0.50 
0.24 (0.15, 0.39) 
0.32 (0.20, 0.52) 
0.75 
0.24 (0.17, 0.35) 
0.32 (0.22, 0.47) 
Abbreviation: ABR=annualized bleeding rate; BPA=bypassing agent; CI=confidence interval; SD=standard deviation 
Note: Correlation = within-patient correlation between bleeding episodes of fitusiran efficacy period and factor or BPA period. 
Table 2 - Simulated ratio of rates for Cohort B, with 95% confidence intervals  
Correlation 
Average Ratio (Average 95% CI Bounds), N=40 
Based on 10 000 Simulations 
Fitusiran period ABR: mean = 4, SD = 6 
Factor/BPA period ABR:  
Mean = 4; SD = 5 
Factor/BPA period ABR:  
Mean = 6; SD = 7 
0.25 
1.04 (0.57,1.94) 
0.69 (0.39,1.25) 
0.50 
1.03 (0.63,1.69) 
0.68 (0.43,1.09) 
0.75 
1.01 (0.72,1.41) 
0.67 (0.48,0.93) 
Abbreviation: ABR=annualized bleeding rate; BPA=bypassing agent; CI=confidence interval; SD=standard deviation 
Note: Correlation = within-patient correlation between bleeding episodes of fitusiran efficacy period and factor or BPA period. 
To maintain the previously planned safety database size of at least 244 patients from ATLAS 
studies, the planned sample size for this study has increased from approximately 70 patients to 
approximately 80 patients. The detailed rationale for the sample size increase is documented in the 
position paper in Appendix F. 
1.4 
GRAPHIC STUDY PLAN  
The study design schema is presented in Figure 1. Patients who complete the study may be 
eligible for an open-label extension study. 
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Figure 1 - Study design  
 
Abbreviations: AT=antithrombin 
Note: For subgroup of Cohort A patients enrolling directly into the fitusiran treatment period, see Figure 2. 
a Patients will continue to receive prescribed factor concentrate or BPA prophylaxis for the first 7 days of the onset period.  
b Following final fitusiran dose, AT activity level will be monitored at monthly intervals following the final fitusiran dose until activity levels return 
to approximately 60% (per the central laboratory) or per Investigator discretion in consultation with the study Medical Monitor.  
Figure 2 - Study design (for subgroup of Cohort A patients enrolling directly into the fitusiran 
treatment period)  
 
Abbreviations: AT= antithrombin 
a Patients will continue to receive prescribed factor concentrate or BPA prophylaxis for the first 7 days of the onset period.  
b Following final fitusiran dose, AT activity level will be monitored at monthly intervals following the final fitusiran dose until activity levels return 
to approximately 60% (per the central laboratory) or per Investigator discretion in consultation with the study Medical Monitor. 
Please refer to table 1 of the study protocol for the detailed study flow chart. 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
This section summarizes major changes to the protocol statistical section with emphasis on 
changes after the first patient was enrolled. The protocol history table below gives the timing, 
rationale, and key details of major changes to the protocol statistical section.  
The first patient was enrolled on Sep 21st, 2018. An interim analysis may be conducted as a part of 
this study. 
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Table 3 - Protocol amendment statistical changes  
Amendment 
number 
Date 
approved 
Rationale 
Description of statistical changes 
2 
31-May-2018 
Study expanded to include patients 
without inhibitory antibodies to factor 
VIII or factor IX in addition to 
patients with inhibitory antibodies to 
factor VIII or factor IX 
Text updated for sample size with new Table 9 
added for simulated ratio of rates for Cohort A, 
with 95% confidence intervals 
 
Text added “These analyses will be done for 
Cohort A and Cohort B separately. A pooled 
analysis will be performed after all patients in 
the 2 cohorts have either finished the Month 7 
visit during the fitusiran treatment period or 
discontinued from the study”. 
2 
31-May-2018 
On-treatment strategy is used for the 
primary analysis of primary endpoint 
in assessing the primary objective of 
the study (ICH E9 (R1)). 
Text changed from “The primary analysis will 
be performed on the EAS and will include all 
bleeding episodes occurring in the factor or 
bypass agent prophylaxis period (Day -162 to 
Day -1) and the fitusiran efficacy period (Day 
29 to Day 190) including bleeding episode data 
collected after discontinuation of study drug” to 
“The primary analysis will be performed on the 
EAS and will include all bleeding episodes 
occurring in the factor or bypass agent 
prophylaxis period (Day -162 to Day -1) and the 
fitusiran efficacy period (Day 29 to Day 190)”. 
2 
31-May-2018 
An interim analysis may be 
conducted as a part of this study to 
support regulatory filings. 
Text changed from “No interim analysis is 
planned” to “An Interim Analysis may be 
conducted as a part of this study”. 
4 
18-Dec-2018 
Study expanded to enroll a subgroup 
of hemophilia B patients with 
inhibitors who are not responding 
adequately to BPA prophylaxis 
treatment 
Analysis population is updated in Section 8.2.1 
of the study protocol. 
4 
18-Dec-2018 
Since the study is not designed as a 
superiority study and is not powered 
to detect a statistically significant 
difference, Bayesian analyses will be 
added to help interpret the p-value. 
The below sentence is added to primary 
efficacy analysis: 
The p-value should be interpreted with caution. 
In addition, as a contrast Bayesian analyses 
will be performed to summarize the point 
estimates of the posterior probability of a 
clinically significant treatment effect, along with 
associated measures of uncertainty. 
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Amendment 
number 
Date 
approved 
Rationale 
Description of statistical changes 
4 
18-Dec-2018 
Correction of a discrepancy with the 
corresponding secondary study 
objective 
Secondary endpoint 'Change in Haem-AQOL 
physical health score and total score in the 
fitusiran treatment period' is changed to 
'Change in Haem-A-QOL physical health score 
and total score in the fitusiran treatment period 
and the factor or BPA prophylaxis period' 
The below sentence is added to secondary 
efficacy analysis: 
Change in Haem-A-QOL physical health score 
and total score (in patients ≥17 years of age) in 
the factor or BPA prophylaxis period and 
fitusiran treatment period will be summarized 
descriptively. A mixed model for repeated 
measures analysis may be performed as 
deemed appropriate. 
4 
18-Dec-2018 
A secondary objective and endpoint 
are included to further assess 
fitusiran efficacy. 
“To characterize the annualized weight-
adjusted consumption of factor/BPA while 
receiving fitusiran treatment, relative to 
receiving factor or BPA prophylaxis” is added 
as a secondary objective. 
“Annualized weight-adjusted consumption of 
factor/BPA” is added as a secondary endpoint 
 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN  
This section summarizes major changes in statistical analysis plan to the protocol statistical 
section, with emphasis on changes after the first patient is enrolled. 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 Sep 21st, 2018. An interim analysis may be conducted as a part of 
this study.  
Table 4 - Statistical analysis plan statistical changes  
SAP version 
number 
Date 
approved 
Rationale 
Description of statistical changes 
1 
02-Jan-2020 
Revised the definition of efficacy period 
based on on-treatment strategy for the 
primary analysis of primary endpoint in 
assessing the primary objective of the 
study (ICH 
E9 (R1)). 
Efficacy period (Day 29 to Day 190) defined 
in the protocol is changed to (Day 29, earliest 
of (Day 190, or the last day of bleeding follow 
up), excluding the period for each 
intercurrent event. 
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SAP version 
number 
Date 
approved 
Rationale 
Description of statistical changes 
 
 
Added exclusion periods due to 
fitusiran treatment discontinuation, 
major or minor surgery, prophylaxis 
treatment with emicizumab or factor 
since including bleeding events in 
these periods in the primary analysis 
would bias fitusiran treatment effect. 
Exclusion period for each intercurrent event 
is described in details in Section 2.1.3.1 
 
 
To clarify how to calculate domain 
score when item scores are missing for 
Haem-A-QOL and Haemo-QOL 
assessments. 
The method to calculate domain score when 
item scores are missing for Haem-A-QOL 
and Haemo-QOL assessments is added in 
Appendix B. 
 
 
To maintain the regulatory agency 
agreed upon safety database size of at 
least 244 patients from ATLAS studies 
The planned sample size for this study has 
increased from approximately 70 patients to 
approximately 80 patients. 
2 
04-Sep-2020  To clarify the definition of number of 
bleeding episodes prior to screening 
“Number of bleeds reported in the last 
6 months prior to screening” was modified to 
“number of bleeding episodes prior to 
screening (ie, number of bleeds reported in 
the last 6 months prior to screening for 
Cohort A and number of bleeds reported in 
the last 12 months prior to screening for 
Cohort B) in Section 2.1.1. 
 
 
To add patient disposition category for 
Covid-19 impact summary 
Patients discontinue the treatment due to 
Covid-19 and patient discontinue the study 
due to Covid-19 are added in Section 2.2. 
 
 
To update Per-protocol Analysis Set 
definition 
The detail deviations are included in the Per-
protocol analysis set definition in Section 2.3. 
 
 
To define Covid-19 Unaffected Set 
Covid-19 Unaffected Set is defined in 
Section 2.3. 
 
 
To add statistical analysis by 
hemophilia type 
By hemophilia type and overall summary is 
added in Section 2.4.1, 2.4.2 and 2.4.3. 
By hemophilia type summary is added for 
key AE tables in Section 2.4.5.1. 
 
 
To clarify the baseline definition for 
efficacy analysis 
The baseline definition for efficacy analysis is 
modified from “the last non-missing value 
before first dose of fitusiran/enrollment date” 
to “the last non-missing value on or before 
the first dose date of fitusiran/enrollment 
date” in Section 2.4.4. 
 
 
To add the efficacy analyses for ABR 
endpoints due to Covid-19 impact 
For ABR, the sensitivity analyses on Covid-
19 unaffected set is added in Section 2.4.4.1. 
In addition, a sensitivity analysis to exclude 
the bleeds during the period of missing at 
least 2 consecutive fitusiran doses due to 
Covid-19 event and the period from 6 
months after enrollment to the date of 
delayed first fitusiran dose due to Covid-19 is 
added in Section 2.4.4.1. 
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SAP version 
number 
Date 
approved 
Rationale 
Description of statistical changes 
 
 
To add the analyses for Haem-A-QoL 
due to Covid-19 impact 
For sensitivity analyses, MMRM model will 
be run on Covid-19 unaffected set, on the set 
excluding data collected with Covid-19 
impact, on the set of patients whose 
responses level to EQ-5D dimensions 
“anxiety/depression” is no change or 
improved from prophylaxis baseline in 
Section 2.4.4.2.4. 
 
 
To add the sensitivity analysis for 
Haem-A-QoL baseline assessments 
For sensitivity analyses, the same analysis 
as main but excluding values of those who 
completed Haem-A-QOL at baseline on the 
same day but after first dose of fitusiran in 
Section 2.4.4.2.4. 
 
 
To be consistent with the statistical 
model of primary analysis  
The covariate “Number of bleeding episodes 
prior to screening” was removed from the 
statistical model of exploratory analysis and 
secondary efficacy analysis in 
Section 2.4.4.1.3 and Section 2.4.4.2.4.  
 
 
To clarify the analysis of the annualized 
weight-adjusted consumption of 
factor/BPA 
The parameters to be summarized for the 
consumption of factor/BPA is modified to: 
annualized weight-adjusted factor/BPA 
consumption for both treating bleeds and 
prophylaxis purpose, number of factor/BPA 
injections per bleed/per subject, weight 
adjusted total dose per bleed/per subject. 
The summary of compliance to the bleed 
management guideline is added. 
 
 
To add the AE summary related to 
Covid-19 infection 
AE potentially consistent with COVID-19 will 
be summarized by SOC and PT and list will 
also be provided. The search term list is 
added in the Appendix G. 
 
 
To add AE summary by hemophilia 
type 
By hemophilia type summary is added to key 
AE tables. 
 
 
Due to the exclusion criteria 5, the 
analysis of fibroscan/fibrotest result at 
baseline against worst post-baseline 
ALT elevation is not necessary 
The related analysis is removed in 
Section 2.4.5.2. 
 
 
Appendix A Potentially clinically 
significant abnormalities criteria is not 
applicable to this study 
Appendix A Potentially clinically significant 
abnormalities criteria is removed  
3 
This version    Removed 80mg for fitusiran dosing and 
fitusiran prophylaxis period 
To accommodate the new dose regimen of 
50mg Q2M per protocol V6.0. 
 
 
Added safety analysis set 1, safety 
analysis set 2, efficacy analysis set 1, 
and efficacy analysis set 2 
To accommodate the new dose regimen of 
50mg Q2M per protocol V6.0. 
 
 
Removed pharmacokinetics analysis 
set 
No PK analysis planned in this SAP 
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SAP version 
number 
Date 
approved 
Rationale 
Description of statistical changes 
 
 
Added one more major pd which will 
lead to PPS exclusion: The participant 
did not administer prophylaxis therapy 
with minimum frequency as per 
protocol (table 5) during the prophylaxis 
period 
To exclude patient with poor compliance 
during prophylaxis period. 
 
 
Clarified Covid-19 Unaffected Set is a 
subset of EAS 1 
To add clarification.  
 
 
Updated the intercurrent event of 
fitusiran treatment discontinuation  
To accommodate the new dose regimen of 
50mg Q2M per protocol V6.0. 
 
 
Updated the intercurrent event of 
prophylaxis treatment 
Prophylaxis BPA and Factor are prohibited. 
 
 
Added AESI of Cholecystitis and 
Cholelithiasis 
Added AESI per protocol V6.0. 
 
 
Clarified the patients with 80mg QM 
and participants with 50mg Q2M will be 
analyzed separately and relevant 
scope 
To accommodate the new dose regimen of 
50mg Q2M per protocol V6.0. 
 
 
Clarified the treatment duration will be 
calculated for patients with 80mg QM 
To accommodate the new dose regimen of 
50mg Q2M per protocol V6.0. 
 
 
Removed “covariates as in the primary 
analysis” in bayesian negative binomial 
model 
To correct the wording due to no covariates 
will be considered. 
 
 
Added one more sensitivity analysis 
with Bayesian model with prior mean of 
1 for ABR ratio and clarified the MCMC 
procedure in SAS  
To add sensitivity analysis and clarify the 
SAS procedure. 
 
 
Clarified period of missing at least two 
fitusiran doses for participants with 
50mg Q2M 
To accommodate the new dose regimen of 
50mg Q2M per protocol V6.0. 
 
 
Clarified the impact of intercurrent 
event on time to first bleeding event 
analysis for on-treatment strategy 
To add clarifications. 
 
 
Added study drug related AE/SAE of 
special interest in the AE overview 
tables 
To add more information in AE overview 
table. 
 
 
Removed three redundant AESI tables 
To Remove redundant tables.   
 
 
Added plots for  liver function 
parameters: The mean of ALT, AST, 
and total bilirubin will be plotted over 
time. The Kaplan-Meier curve for the 
time to first onset of ALT>3ULN, 
AST>3ULN and AST/AST >3ULN  
To add plots and better visualize the liver 
function changes. 
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SAP version 
number 
Date 
approved 
Rationale 
Description of statistical changes 
 
 
Updated COVID-19 infection be based 
on appendix G to a search on MedDRA 
SMQ COVID-19 (narrow) 
MedDRA SMQ COVID-19 (narrow) is 
released. 
 
 
Defined the ADA endpoint and analysis 
in the section of exploratory endpoint, 
rather than the section of safety 
Removed redundant wordings in the section 
of safety. 
 
 
Replaced subject with participant  
To standardize the wording. 
 
 
Administrative and editorial changes 
 
 
 
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2 
STATISTICAL AND ANALYTICAL PROCEDURES  
2.1 
ANALYSIS ENDPOINTS  
2.1.1 Demographic and baseline characteristics  
Demographic characteristics  
Demographic variables are: 
• Age in years (quantitative and qualitative variable: ≥12 to <18, ≥18 to <65 and ≥65 years) 
• Sex (Male) 
• Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Other)  
• Ethnicity (Hispanic or Latino, not Hispanic or Latino, not available/not reported) 
• Weight in kg 
• Height in cm 
• Body Mass Index (BMI) in kg/m2  
• Geographic Region (Defined in Section 2.5.6) 
Medical or surgical history 
Medical (or surgical) history includes all the relevant medical (or surgical) history during the 
lifetime of the patient. 
This information will be coded using the version of Medical Dictionary for Regulatory Activities 
(MedDRA) currently in effect at Sanofi at the time of database lock. 
Disease characteristics 
The following disease characteristics are summarized 
• Hemophilia type 
• Inhibitor status  
• Number of bleeding episodes prior to screening (ie, number of bleeds reported in the last 
6 months prior to screening for Cohort A and number of bleeds reported in the last 
12 months prior to screening for Cohort B) 
• Age at diagnosis 
• Time from diagnosis to screening  
Any technical details related to computation, dates, and imputation for missing dates are described 
in Section 2.5. 
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2.1.2 Prior or concomitant medications  
Concomitant medications are defined as all medications other than study drug administered to a 
patient from the study enrollment until the end of the study. 
Local standard treatment of hemophilia, which is considered to be, but not limited to, IV infusion 
of FVIII or FIX concentrates, aPCC or rFVIIa are used for Factor/BPA Prophylaxis and bleeding 
episode management. Use of these agents will be captured in the patient’s eDiary. 
Other concomitant medications including all prescription medications, herbal preparations, over 
the counter medications, vitamins, and minerals are to be reported in the case report form (CRF) 
pages. 
Prior medications for HCV treatment before study enrollment are also collected at screening visit.  
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5. 
2.1.3 Efficacy endpoints  
2.1.3.1 Primary efficacy endpoint  
Global protocol: The primary efficacy endpoint of the study is annualized bleeding rate (ABR) in 
the fitusiran efficacy period and the factor/BPA prophylaxis period. 
US protocol: The primary efficacy endpoint of the study is annualized bleeding rate (ABR) in the 
fitusiran treatment period and the BPA prophylaxis period. 
Bleeding Episode Definitions 
The primary source of bleeding data is the eDiary. Additional bleeding data may be captured from 
the bleeding diary pages of the CRF, if not reported in the eDiary. Any other sources of bleeding 
data will be discussed in the CSR. 
A bleeding episode is defined as any occurrence of hemorrhage that may require administration of 
factor or BPA infusion, eg, hemarthrosis, muscle, or mucosal bleeding episodes. 
The start time of a bleeding episode will be considered the time at which symptoms of 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 bleed or 72 hours after the start of an untreated 
bleed 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 bleed or 72 hours after the start of an untreated bleed 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. 
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Bleeding episodes sustained during sports and recreation will be counted as traumatic bleeding 
episodes. 
Traumatic bleeds that occur in different locations simultaneously (same date/time) in the same 
patient will be considered as one bleeding episode. Spontaneous bleeds that occur simultaneously 
(same date/time) in different locations in the same patient will be considered as separate bleeds. 
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 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 has been ≤2 bleeding episodes in 
the joint within a consecutive 12-month period the joint is no longer considered a target joint. 
Efficacy analysis will focus on observed data as collected, unless otherwise specified. Patients 
who discontinue study drug during the study will be strongly encouraged to continue study 
participation including the recording of bleeding episode data. Only bleeding episodes that are 
treated with BPA/factor will be included in the primary analysis of endpoints evaluating bleeding. 
Annualized bleeding rate will be calculated as described in Section 2.4.4.1.1. 
Efficacy Period and factor/BPA prophylaxis Period 
In the protocol, for the purpose of ABR calculation, the factor/BPA prophylaxis period and 
fitusiran “Onset Period”, “Efficacy Period” and “Treatment Period” are defined. The factor/BPA 
prophylaxis period is defined as the 6 months period before the first dose of fitusiran, during 
which patients continue their pre-study, regularly scheduled prophylaxis regimen with factor 
concentrates or BPAs. The Onset Period is defined as the first 28 days after the first dose of 
fitusiran, during which the AT lowering capacity of fitusiran is increasing but has not yet reached 
therapeutic levels. The Efficacy Period is defined as starting on Day 29 when the AT lowering 
capacity of fitusiran has achieved therapeutic target range. The Treatment Period is defined as the 
onset period plus the efficacy period. The window for each period is summarized in the table 
below. 
 
Period 
Definition 
Factor/BPA prophylaxis period 
Day -168 to the earlier of Day -1 or the last day of bleeding follow up 
Fitusiran onset period 
Day 1 to the earlier of Day 28 or the last day of bleeding follow up 
Fitusiran efficacy period 
Day 29 to the earlier of Day 190 or the last day of bleeding follow up 
Fitusiran treatment period 
Onset period plus the efficacy period 
The last day of bleeding follow up is defined as the deactivation date captured in eDiary. 
If a patient does not have bleeding episode data collected after Day 28 due to early study 
discontinuation in the fitusiran treatment period, the efficacy period will be from Day 1 to the 
earlier of date of study discontinuation and the last day of bleeding follow up. 
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The factor/BPA prophylaxis period, fitusiran onset period, efficacy period and treatment period 
also exclude the period of following intercurrent events to avoid confounding of treatment effect 
for the primary efficacy analysis based on On-Treatment Strategy. 
• Permanent fitusiran treatment discontinuation during treatment period: Exclude events 
occurring on any dates starting from the date of the last dose within treatment period 
+29 days. For patients whose last dose is on 50 mg/20 mg Q2M regimen, the “29 days” 
adjustment will be replaced with 57 days. 
• Perioperative period of major surgery. The perioperative 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. 
• Period of minor surgery is defined as the perioperative period of surgery above or to 
72 hours from the end of surgery, whichever is later. 
• Period of antithrombin treatment is defined as the first day of antithrombin treatment 
through the final day on which antithrombin or other anticoagulant therapies are 
administered plus 5 half-lives of that specific product. 
• After prophylactic treatment with emicizumab. 
The summary statistics for number of patients who are lost-to-follow-up and who had each 
intercurrent event will be provided. 
2.1.3.2 Secondary efficacy endpoints  
 
 
Global protocol 
US protocol 
Key secondary 
endpoint 
 
ABR in the fitusiran efficacy period 
Secondary 
endpoints 
ABR in the treatment period 
 
Annualized spontaneous bleeding rate in the 
fitusiran efficacy period and the factor/BPA 
prophylaxis period 
Annualized spontaneous bleeding rate in the 
fitusiran efficacy period and the BPA prophylaxis 
period 
Annualized joint bleeding rate in the fitusiran 
efficacy period and the factor/BPA prophylaxis 
period 
Annualized joint bleeding rate in the fitusiran 
efficacy period and the BPA prophylaxis period 
Change in Haem-A-QOL physical health score 
and total score in the fitusiran treatment period 
and the factor or BPA prophylaxis period 
Change in Haem-A-QOL physical health score 
and total score in the fitusiran treatment period 
ABR in the onset period 
ABR in the onset period 
Annualized weight-adjusted consumption of 
factor/BPA 
Annualized weight-adjusted consumption of BPA 
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2.1.3.2.1 HRQOL Instruments: Haem-A-QOL and Haemo-QOL  
The Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) and Haemophilia 
Quality of Life Questionnaire for Children and Adolescents (Haemo-QOL) are psychometrically 
tested QOL assessment instruments for patients with hemophilia. The Haem-A-QOL are provided 
to patients ≥17 years of age, and includes 46 items contributing to 10 QOL domains (physical 
health, feelings, view of yourself, sports and leisure, work and school, dealing with hemophilia, 
treatment, future, family planning, partnership and sexuality). Scoring for each item is based on a 
5-point Likert scale (never, rarely, sometimes, often, and all the time), and higher scores represent 
greater impairment. 
The Haemo-QOL (Children’s short version for age groups II/III [8-16 years of age]) are provided 
to patients <17 years of age. 
Both Haem-A-QOL and Haemo-QOL test are assessed at Month -6, Day 1 and Month 7 visit. 
2.1.4 Safety endpoints  
The safety analysis will be based on the reported adverse events (AEs) including SAEs and other 
safety information, such as clinical laboratory data, vital signs, weight and height, physical 
examination, ECG findings, and ADA detection/assessment. 
Observation period: 
• Factor/BPA prophylaxis period is defined as the time from enrollment (Month-6 visit) up 
to the 1st dose of fitusiran. 
• Fitusiran prophylaxis period is defined as the time after the 1st dose of fitusiran up to the 
end of the study (defined as last protocol planned visit). It includes the following 
2 periods: 
- 
Fitusiran treatment period is defined as the time after the 1st dose of fitusiran to the 
EOS/ET visit, 
- 
Follow up period is defined as the time after Fitusiran treatment period up to the end of 
the study. 
The treatment-emergent adverse event period equals fitusiran prophylaxis period. 
On-study observation period includes both factor/BPA prophylaxis period and fitusiran 
prophylaxis period. 
2.1.4.1 Adverse events variables  
AE observation period: 
• Pretreatment AEs are defined as those AEs that developed or worsened during factor/BPA 
prophylaxis period. 
• Treatment emergent AEs are defined as those AEs that developed or worsened during 
treatment-emergent adverse event period. 
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All adverse events (including serious adverse events [SAEs] and adverse events of special 
interests [AESI]) will be coded to a lower-level term (LLT), preferred term (PT), high-level term 
(HLT), high-level group term (HLGT), and associated primary system organ class (SOC) using 
the version of Medical Dictionary for Regulatory Activities (MedDRA) in effect at the time of 
database lock. 
Record the occurrence of adverse events (including serious adverse events and adverse events of 
special interest) from the time of signed informed consent until the end of the study. 
Adverse events of special interest include the following terms: 
• ALT or AST elevations >3 × ULN, 
• Suspected or confirmed thrombosis, 
• Severe or serious ISRs, ISRs that are associated with a recall phenomenon (reaction at the 
site of a prior injection with subsequent injections), or those that lead to temporary dose 
interruption or permanent discontinuation of fitusiran, 
• Systemic IARs (injection associated reactions), defined as hypersensitivity reactions which 
are related or possibly related to IMP. 
• Cholecystitis  
• Cholelithiasis 
The cholecystitis and cholelithiasis will be identified by medical adjudication on a listing of 
adverse event searched with SMQ Biliary disorders (broad) and SMQ Acute pancreatitis 
(narrow), since these two AESIs were added in protocol V6.0 near the end of study. 
2.1.4.2 Deaths  
The deaths observation periods are per the observation periods defined above. 
• Death on-study: deaths occurring during the on-study period, 
• Death on factor/BPA prophylaxis: deaths occurring during the factor/BPA prophylaxis 
period, 
• Death on fitusiran treatment: deaths occurring during the fitusiran treatment period, 
• Death on follow up: death occurring during the follow up period. 
2.1.4.3 Laboratory safety variables  
Clinical laboratory data consists of blood analysis, including hematology, clinical chemistry, and 
urinalysis. Clinical laboratory values after conversion are analyzed in standard international units 
and international units are used in listings and tables. 
Blood samples for clinical laboratories are taken at screening visit, every month in factor/BPA 
prophylaxis period, every half month in the first two months of fitusiran treatment period and then 
every month in the remaining study period. 
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The laboratory parameters are classified as follows: 
• Hematology 
- 
Red blood cells and platelets: hemoglobin, hematocrit, mean corpuscular volume, 
mean corpuscular hemoglobin concentration, mean corpuscular hemoglobin, red blood 
cell count, platelet count 
- 
White blood cells: white blood cell (WBC) count, neutrophils, lymphocytes, 
monocytes, basophils, eosinophils, CD4 in HIV-positive patients (at screening only) 
- 
Coagulation: Prothrombin time, Activated partial thromboplastin time, INR, 
Fibrinogen, D-dimer, Prothrombin fragment 1, 2  
• Clinical chemistry  
- 
Metabolism: glucose, albumin 
- 
Electrolytes: sodium, potassium, chloride, calcium, phosphate, Carbon dioxide 
- 
Renal function: creatinine and eGFR (using the MDRD formula), blood urea nitrogen 
(BUN) 
- 
Liver function: aspartate aminotransferase (AST), ALT, ALP, GGT, bilirubin (total 
and direct) 
• Factor Activity (are assessed at screening only): FVIII activity for patients with 
hemophilia A, FIX activity for patients with hemophilia B  
• Hepatic tests (are assessed at screening and Day 1 visit):  
- 
Hepatitis A, including: HAV antibody IgM and IgG 
- 
Hepatitis B, including: HBc antibody IgM and IgG 
- 
Hepatitis C, including: HCV antibody and HCV RNA PCR - qualitative and 
quantitative assays  
- 
Hepatitis E, including: HEV antibody IgM and IgG 
• Thrombophilia Screening (are assessed at screening only): Protein C deficiency, Protein S 
deficiency, Factor V Leiden (genetic testing), Prothrombin mutation (genetic testing) 
Urine samples are collected as follows: 
• Urinalysis (assessed at screening, Month -6 and Month 7 visit): Visual inspection for 
appearance and color, pH (dipstick), ketones, protein, glucose, RBCs, urobilinogen, 
bilirubin, Nitrite, microscopic (if clinically indicated), Leukocytes, specific gravity. 
2.1.4.4 Physical examination and vital signs variables  
Physical examination and vital signs are done at screening visit, every month in factor/BPA 
prophylaxis period, every half month in the first two months of fitusiran treatment period and then 
every month in the remaining study period. 
Physical examination may be full or directed. 
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Full physical examinations include general appearance, head, eyes, ears, nose and throat; 
respiratory, cardiovascular, gastrointestinal, musculoskeletal, and dermatological systems; 
thyroid, lymph nodes, and neurological status. 
Directed physical examinations include systems associated or common for signs and symptoms of 
thrombosis, bleeding, and arthropathy: neurologic, chest/respiratory, heart/cardiovascular, 
dermatological/skin, gastrointestinal/liver, and musculoskeletal/extremities. Other organ systems 
may be evaluated as indicated by patient symptoms. In patients undergoing a surgical procedure, a 
directed physical examination will also be performed as specified in the Perioperative Schedule of 
Assessments in the protocol. 
A full physical examination is done at screening only; a directed physical exam is done at all other 
visits. 
Physical examination notes regarding any observed abnormalities are recorded on the eCRF. 
Vital signs include blood pressure, heart rate, body temperature, and respiratory rate. Vital signs 
are measured predose in the seated or supine position, after the patient has rested comfortably for 
10 minutes. 
Body temperature is recorded in degrees Celsius. Heart rate is counted for a full minute and 
recorded in beats per minute, and respiration rate is counted for a full minute and recorded in 
breaths per minute. 
For the safety of the patient, additional vital sign assessments may be added at the discretion of 
the Investigator. 
Vital signs results are recorded in the eCRF. 
Measurements of weight and height are also collected at above scheduled visits for physical 
examination and vital signs. 
2.1.4.5 Electrocardiogram variables  
Triplicate standard 12-lead ECGs, with readings approximately 1 minute apart, are recorded at 
screening, Month -6, Day 1, Month 5 and Month 7 visits. 
The electrophysiological parameters assessed are rhythm, ventricular rate, RR interval, PR 
interval, QRS duration, QT interval, Bazett-corrected QT interval (QTcB), and Fridericia 
corrected QT interval (QTcF). 
The Investigator or qualified designees review all ECGs to assess whether the results have 
changed since the Day 1 visit and to determine the clinical significance of the results. These 
assessments are recorded on the eCRF. Additional ECGs may be collected at the discretion of the 
Investigator. Recordings are archived according to the Study Manual. 
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2.1.5 Pharmacokinetic variables  
For all patients 
• Plasma PK parameters are estimated using a population PK approach. The population PK 
analysis is described in a separate population PK analysis plan 
For patients from East Asian sites only 
• In addition to population PK analysis, plasma PK parameters for the patients from the East 
Asian sites only are also estimated using non-compartmental analysis. The plasma PK 
parameters include, but may 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) 
- 
Apparent volume of distribution (V/F) 
• Fitusiran levels in 0-24 h urine are reported as cumulative amount of drug excreted 
unchanged in urine (Ae) 
• Additional PK parameters for plasma and/or urine may also be calculated, if considered 
appropriate 
2.1.6 Pharmacodynamic endpoints  
In this study AT activity level and thrombin generation (TG) over time are collected as 
measurements of PD effect and coagulation assessments are collected for exploratory analyses of 
PD effect. 
AT activity level and TG are assessed at screening, Day 1 and then every half month in the first 
two months of fitusiran treatment period and then every month in the remaining study period. 
During the factor/BPA prophylaxis period (before fitusiran treatment), patients undergo a 
coagulation and peak thrombin/thrombin generation response assessment with timed blood 
collections both before and following a dose of their routine factor/BPA prophylaxis doses. 
2.1.7 Exploratory endpoints  
Exploratory endpoints include:  
• Change in the following in the fitusiran treatment period: 
- 
Treatment Satisfaction Questionnaire for Medication (TSQM) domain scores 
- 
Haemophilia Activities List (HAL) score 
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- 
Paediatric HAL (pedHAL) score 
- 
EuroQol -5 Dimensions (EQ-5D) score 
- 
Haemo-QOL score 
- 
Hemophilia Joint Health Score (HJHS) 
• Number of target joint bleeding episodes 
• Incidence and titer of antidrug antibodies to fitusiran in the fitusiran treatment period 
• AT activity level over time 
• TG over time 
• Fitusiran plasma levels  
• Change in patient resource use (eg, work/school attendance, visits to doctor/hospital) 
2.2 
DISPOSITION OF PATIENTS  
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Screened patients are defined as any patient who signed the informed consent. 
Enrolled patients are defined as any patient with a signed informed consent form (ICF) who met 
all the inclusion criteria and none of the exclusion criteria. 
This is an open-label, single-arm, before and after switch study without randomization. 
For patient study status, the total number of patients in each of the following categories is 
presented in the clinical study report using a flowchart diagram or summary table: 
• Screened patients 
• Screened failure patients and reasons for screen failure (if data are available) 
• Enrolled patients 
• Patients treated without entering factor/BPA prophylaxis period 
• Patients who entered factor/BPA prophylaxis period (run-in) 
• Patients who completed the factor/BPA prophylaxis period 
• Patients who did not complete factor/BPA prophylaxis period, with corresponding reasons 
• Patients who did not complete factor/BPA prophylaxis period, with corresponding reasons 
due to Covid-19 
• Patients treated after factor/BPA prophylaxis period 
• Patients who completed the study treatment (7-month treatment period) 
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• Patients who discontinued study treatment by main reason for permanent treatment 
discontinuation 
• Patients who discontinued study treatment by main reason for permanent treatment 
discontinuation due to Covid-19 
• Patients who completed the study 
• Patients who did not complete the study but complete the 7-month treatment period 
• Patients who did not complete the study, with corresponding reasons. 
• Patients who did not complete the study, with corresponding reasons due to Covid-19. 
For all categories of patients (except for the screened categories), percentages are calculated using 
the number of enrolled patients as the denominator. Reasons for treatment discontinuation are 
supplied in tables giving numbers and percentages. 
All critical or major deviations potentially impacting efficacy analyses, and other major or critical 
deviations are summarized in tables giving numbers and percentages. 
Additionally, the analysis populations (analysis sets) for safety and efficacy are summarized in a 
table. 
• Efficacy Analysis Set 1 
• Efficacy Analysis Set 2 
• Per-protocol Analysis Set  
• Safety Analysis Set 1 
• Safety Analysis Set 2 
• Operative Procedure Analysis Set 
• Covid-19 Unaffected Set 
2.3 
ANALYSIS POPULATIONS  
The populations (analysis sets) are defined as follows: 
• Safety Analysis Set 1 (SAS 1) : All patients who enrolled and then received any dose of 
fitusiran before dose resumption. Safety Analyses for patients who were treated with 
fitusiran in 80mg QM dose regimen before dose resumption will be conducted using the 
Safety Analysis Set 1 unless otherwise specified. 
• Safety Analysis Set 2 (SAS 2) : All patients who enrolled and then received any dose of 
Fitusiran after dose resumption. Safety Analyses for patients who were treated with 
fitusiran in 50mg Q2M after dose resumption will be conducted using the Safety Analysis 
Set 2 unless otherwise specified. 
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• Efficacy Analysis Set 1 (EAS1) 1: All patients in the safety analysis set 1 who received 
factor or BPA prophylaxis and any dose of fitusiran before dose resumption. Efficacy 
Analyses before dose resumption will be conducted using EAS 1 unless otherwise 
specified. 
• Efficacy Analysis Set 2 (EAS 2) : All patients in the safety analysis set 2 who received 
factor or BPA prophylaxis and any dose of fitusiran. Efficacy Analyses after dose 
resumption will be conducted using EAS 2 unless otherwise specified. 
• Per-protocol Analysis Set (PPS): All patients in the EAS 1 who do not have protocol 
deviations in the following categories:  
- 
Failure to meet key Eligibility criteria, which will be identified prior to database lock, 
- 
Other protocol deviations that might significantly affect the completeness, accuracy, 
and/or reliability of the bleeding data. 
The major or critical deviations to be considered are as follows. 
• The participant is not male and/or is younger than 12 years, but the participant was 
enrolled. 
• The participant does not have severe hemophilia A or B as evidenced by a laboratory 
FVIII level <1% or FIX level ≤2% at Screening or by documented medical record, but 
the participant was enrolled. 
• The participant does not have a minimum of: 
- 
2 bleeding episodes requiring bypassing agent treatment within the last 6 months 
prior to Screening for participants with inhibitory antibodies to FVIII or FIX 
(Cohort A), 
- 
1 bleeding episode requiring factor treatment within the last 12 months prior to 
Screening for patients without inhibitory antibodies to FVIII or FIX (Cohort B), 
but the participant was enrolled. 
• The participant was enrolled, but does not meet either the definition of inhibitor or 
non-inhibitor as below: 
Inhibitor, as evidenced by: 
- 
Use of bypassing agents for prophylaxis and for any bleeding episodes for at least 
the last 6 months prior to Screening, 
- 
Meeting one of the following Nijmegen-modified Bethesda assay results criteria: 
- 
Inhibitor titer of ≥0.6 BU/mL at Screening, or 
- 
Inhibitor titer of <0.6 BU/mL at Screening with medical record evidence of 
2 consecutive titers ≥0.6 BU/mL, or 
- 
Inhibitor titer of <0.6 BU/mL at Screening with medical record evidence of 
anamnestic response, 
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- 
The subgroup of patients in Cohort A patients must additionally meet the following 
criteria to be eligible to start treatment with fitusiran directly after the screening 
period: 
- 
Hemophilia B with inhibitory antibody to FIX as defined above and 
- 
Not responding adequately to BPA treatment (historical ABR ≥20) prior to 
enrollment and 
- 
In the opinion of the Investigator, with approval of sponsor medical monitor, 
6-month BPA prophylaxis period should be omitted. 
Non-inhibitor, as evidenced by: 
- 
Use of factor concentrates for prophylaxis and for any bleeding episodes for at 
least the last 6 months prior to Screening,  
- 
Meeting each of the following criteria: 
- 
Nijmegen-modified Bethesda assay inhibitor titer of <0.6 BU/mL at Screening 
and 
- 
No use of bypassing agents to treat bleeding episodes for at least the last 
6 months prior to Screening and 
- 
No history of immune tolerance induction therapy (ITI) within the past 3 years 
prior to Screening, 
• The participant did not receive prescribed prophylactic treatment of hemophilia with factor 
concentrates or bypassing agents for at least 6 months prior to Screening, or did not 
receive a prophylactic regimen consistent with the approved prescribing information for 
the product or local recommendations, allowing for adjustment to individual patient 
response, and designed to decrease spontaneous bleeding, but the participant was enrolled. 
• The participant has known co-existing bleeding disorders other than hemophilia A or B, 
but the participant was enrolled 
• The participant discontinued prophylactic treatment or withdrew consent during the 
factor/bypassing agent prophylaxis period, but participant was not withdrawn from the 
study. 
• The participant continued or reinitiated use of factor concentrates or bypassing agents as 
prophylaxis for bleeding episode prevention, during the fitusiran prophylaxis treatment 
period but the study drug was not discontinued. 
• The participant did not administer prophylaxis therapy with minimum frequency as per 
protocol (table 5) during the prophylaxis period:  
- 
Standard half-life FVIII (Twice weekly)  
- 
Extended half-life FVIII (Once weekly)  
- 
Standard half-life FIX (Once weekly)  
- 
Extended half-life FIX (Once biweekly)  
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- 
aPPC (Twice weekly)  
- 
rFVIIa (Every other day) 
• Operative Procedure Analysis Set: All SAS 1 patients underwent at least 1 operative 
procedure during the study. 
• Covid-19 Unaffected Set: All EAS 1 patients who had no major or critical protocol 
deviations due to Covid-19 at any visits up to end of study (Month 7). 
In addition:  
Patients treated without entering factor/BPA prophylaxis period are included in the safety analysis 
set, but are not part of the efficacy analysis set; however, their efficacy data are presented 
separately. 
Patients who entered factor/BPA prophylaxis period but not treated with fitusiran are not included 
in either safety analysis set or efficacy analysis set, however, their safety data are reported 
separately. 
2.4 
STATISTICAL METHODS  
All the below statistical analyses are done for Cohort A and Cohort B separately. A pooled 
analysis is performed after all patients in the 2 cohorts have either finished the Month 7 visit 
during the fitusiran treatment period or discontinued from the study. Participants treated with 
fitusiran of 80mg QM and participants treated with fitusiran of 50mg Q2M will be analyzed 
separately. All the analysis will mainly focus on the participants treated with fitusiran of 80mg 
QM. The key efficacy, pharmacodynamic and safety data from participants treated with fitusiran 
of 50mg Q2M will mainly be listed due to the small sample size (only 2 participants). When 
safety analysis are mentioned in this doc, it refers to SAS1 and/or SAS 2 in this SAP. 
2.4.1 Demographics and baseline characteristics  
Continuous data are summarized using the number of patients (n), mean, standard deviation (SD), 
median, minimum, Q1, Q3, and maximum. Categorical and ordinal data are summarized using the 
number and percentage of patients. 
Parameters are summarized by hemophilia type and overall on the EAS and Per-protocol analysis 
set. Analyses for the safety analysis set are included in the appendices if the size of the safety 
analysis set is different (>10%) from the size of EAS. 
Medical and surgical history are summarized by system organ class (SOC) and preferred term 
(PT) sorted by internationally agreed order of SOC and by the decreasing frequency of PT within 
SOC. 
No statistical testing on demographic and baseline characteristic data are performed. 
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No specific description of the safety parameters are provided at baseline. If relevant, the baseline 
values are described along with each safety analysis. 
2.4.2 Prior or concomitant medications  
The prior and concomitant medications are summarized by hemophilia type and overall for the 
safety analysis set. 
Prior and concomitant medications are coded using the World Health Organization-Drug 
Dictionary (WHO-DD) currently in effect at Sanofi at the time of database lock. Results will be 
tabulated by anatomic therapeutic class (ATC) and preferred term. 
Concomitant medications are tabulated by observation period (factor/BPA prophylaxis period and 
fitusiran prophylaxis period) and summarized separately for Factor/BPA prophylaxis medications, 
bleeding treatment medications and other concomitant medications. Any medications that did not 
end prior to first visit of the study are included. If an end date is missing or the medication is 
ongoing, the medication is included. 
2.4.3 Study duration, extent of study treatment exposure and compliance  
Fitusiran is the study treatment which is administrated by SC injection during the fitusiran 
treatment period for a total of 7 months. 
Study duration, extent of study treatment exposure and compliance are assessed and summarized 
by hemophilia type and overall in the safety population. 
Study duration in factor/BPA prophylaxis period in days is calculated as first dose date of 
fitusiran - enrollment date. Study duration in fitusiran treatment period in days is calculated as 
EOS/ET visit date -first dose date of fitusiran +1. Total study duration including AT follow-up in 
days is calculated as date of last follow up - enrollment date +1. The number of patients in each 
2 months interval and summary statistics for the study duration are presented. 
The extent of study treatment exposure is assessed by duration of treatment exposure in days and 
total number of fitusiran administrations received. Both of them will be summarized for fitusiran 
treatment period only. 
For participants treated with fitusiran 80mg QM dose regimen, duration of treatment exposure in 
days is calculated as date of the last dose of fitusiran − the date of the first dose of fitusiran + 28. 
The number 28 is the number of days between two scheduled doses of fitusiran. For example, if 
the last dose of fitusiran is taken on day 31, the treatment exposure would be calculated as (31−1) 
+ 28 = 58 days. 
Dose interruptions and compliance are not taken into account for duration of exposure. 
Fitusiran treatment compliance is calculated as the total mg dose received as the percentage of 
total mg dose expected to receive. Fitusiran treatment compliance is summarized.  
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2.4.4 Analyses of efficacy endpoints  
Analyses for all the primary and secondary efficacy endpoints are conducted using EAS 1 as 
defined in Section 2.3. Listings of ABR will be provided for participants in EAS 2. 
Baseline for fitusiran treatment period is defined as the last non-missing value on or before the 
date of first dose of fitusiran. Baseline for factor/BPA prophylaxis period is defined as the last 
non-missing value on or before the enrollment date (Month -6 visit date). 
2.4.4.1 Analysis of primary efficacy endpoint(s)  
2.4.4.1.1 Primary efficacy analysis based on on-treatment strategy  
The primary objective of this study is to characterize the frequency of bleeding episodes while 
receiving fitusiran treatment, relative to the frequency of bleeding episodes while receiving 
factor/BPA prophylaxis. Including bleeding events in the period of intercurrent events such as use 
of prophylactic medication during fitusiran treatment period or surgery or after fitusiran treatment 
discontinuation could significantly bias fitusiran effect and make the comparisons difficult to 
interpret. The on-treatment strategy is considered of greatest relevance in assessing this primary 
objective (ICH E9 (R1), 2018 (1)). 
Global protocol 
The number of bleeding episodes is annualized for each patient using the following formula: 
 
The primary analysis includes all bleeding episodes occurring in the factor/BPA prophylaxis 
period and the fitusiran efficacy period.  
Let λF represent the ABR during fitusiran efficacy period and λO represent the ABR during 
factor/BPA prophylaxis period. The null and alternative hypotheses of the primary analysis, 
respectively, can be written as follows: 
 
An estimated ABR ratio λF/λO <1
 and two-sided p-value <0.05 from the significance test 
lead to the rejection of H0 in favor of HA; it is concluded that prophylactic use of fitusiran reduces 
the frequency of bleeding episodes compared to the factor/BPA prophylaxis therapy. 
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The ABR ratio λF/λO is estimated using a repeated measures negative binomial model: 
 
The number of bleeding episodes is the response variable. The study period (fitusiran efficacy 
period or factor/BPA prophylaxis period) is treated as a fixed effect and a robust sandwich 
covariance matrix is constructed to account for the within participant dependence. The logarithm 
of the duration (in years) that each patient spends in each study period matching the bleeding 
episode data being analyzed is included as an offset variable to account for unequal follow-up 
time due to early withdrawal, surgery, etc. The ratio of ABR in the fitusiran efficacy period to the 
factor/BPA prophylaxis period, its 95% CI and p-value will be presented. The p-value should be 
interpreted with caution. In addition, as a contrast Bayesian analysis is performed to summarize 
the point estimates of the posterior probability of a clinically significant treatment effect, along 
with associated measures of uncertainty. The estimated mean ABRs in these 2 periods along with 
their 95% CIs are presented from this model. In addition, median and interquartile range (Q1, Q3) 
for the observed ABR are summarized descriptively for each study periods. 
For patients who don’t have bleeding episode data collected after Day 28 (eg, due to early study 
discontinuation), the available bleeding episode data starting from Day 1 visit is used in the 
primary analysis.  
US protocol 
The number of bleeding episodes is annualized for each patient using the following formula: 
 
The primary analysis includes all bleeding episodes occurring in the BPA prophylaxis period and 
the fitusiran treatment period.  
Let λF represent the ABR during fitusiran treatment period and λO represent the ABR during BPA 
prophylaxis period. The null and alternative hypotheses of the primary analysis, respectively, can 
be written as follows: 
 
An estimated ABR ratio λF/λO <1
 and two-sided p-value <0.05 from the significance test 
lead to the rejection of H0 in favor of HA; it is concluded that prophylactic use of fitusiran reduces 
the frequency of bleeding episodes compared to the BPA prophylaxis therapy. 
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The ABR ratio λF/λO is estimated using a repeated measures negative binomial model: 
 
The number of bleeding episodes is the response variable. The study period (fitusiran treatment 
period or BPA prophylaxis period) is treated as a fixed effect and a robust sandwich covariance 
matrix is constructed to account for the within participant dependence. The logarithm of the 
duration (in years) that each patient spends in each study period matching the bleeding episode 
data being analyzed is included as an offset variable to account for unequal follow-up time due to 
early withdrawal, surgery, etc.  
The ratio of ABR in the fitusiran treatment period to the BPA prophylaxis period, its 95% CI and 
p-value are presented. The p-value should be interpreted with caution. In addition, as a contrast 
Bayesian analyses are performed to summarize the point estimates of the posterior probability of a 
clinically significant treatment effect, along with associated measures of uncertainty. The 
estimated mean ABRs in these 2 periods along with their 95% CIs are presented from this model. 
In addition, median and interquartile range (Q1, Q3) for the observed ABR are summarized 
descriptively for each study periods. 
Given that the primary analysis is based on on-treatment strategy, primary and secondary 
bleeding-related data during the efficacy and treatment periods are expected to be complete. No 
sensitivity analysis about the missing data mechanism is performed. 
2.4.4.1.2 Efficacy analysis based on treatment policy strategy  
A supportive efficacy analysis is performed by including all bleeding episodes collected through 
the end of the study, regardless of any premature treatment discontinuation, excluding only events 
due to major or minor surgeries based on EAS as in the primary analysis. The same repeated 
measures negative binomial model as in the primary analysis is used. It assesses the benefits of 
the fitusiran treatment policy strategy relative to factor/BPA prophylaxis treatment. 
A sensitivity analysis to the above treatment policy analysis is performed by including all 
bleeding events (ie, not excluding bleeding events due to surgeries). 
Missing data sensitivity analyses using controlled imputation 
The above efficacy analysis assumes the uncollected bleeding events after study discontinuation 
are missing at random (MAR). Sensitivity analyses are performed to assess the robustness of this 
treatment policy analysis by imputing the missing data based on different missing data 
mechanism. The missing data is imputed using multiple imputation (MI) methods for recurrent 
event data based on pattern mixture models (Keene et al, 2014(2)) to assess the impact of different 
assumptions about the statistical behavior of post-withdrawal outcomes. The post-withdrawal part 
of each pattern-specific distribution is modelled using MAR and Copy Reference (CR) 
approaches. No missing data imputation is done for factor/BPA prophylaxis period since all the 
patients in EAS 1 complete factor/BPA prophylaxis period. 
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The MI is carried out in the following steps: 
1. Fit a Bayesian negative binomial model with a noninformative prior to the observed data and 
obtain the posterior distributions of the event rate for both study periods. 
2. Draw 100 independent samples from the conditional distribution of missing counts given the 
observed count and duration of each patient with missing data based on different post-
withdrawal imputation models, described below, for fitusiran efficacy period (fitusiran 
treatment period for US protocol). The conditional distribution is also negative binomial. 
3. The observed counts and imputed counts for each patient with missing data are summed. 
4. Each 100 imputed datasets are then analyzed using the same repeated measure negative 
binomial regression model as in the primary analysis. Estimates from the model such as least 
square means and standard errors are then combined across imputation datasets using Rubin’s 
formula, as implemented in the MIANALYZE procedure. These and their 95% confidence 
interval limits are then exponentiated to obtain the estimate of ABR for each study period and 
the estimate of the ABR ratio. 
MAR and CR approaches are described below: 
1. Missing at Random (MAR) Approach: Post-withdrawal missing bleeding events in fitusiran 
efficacy period (fitusiran treatment period for US protocol) are imputed using only the 
observed data during that period. 
2. Copy Reference (CR) Approach: The expected ABR for a patient in the fitusiran efficacy 
period (fitusiran treatment period for US protocol) both pre- and post-withdrawal is assumed 
to be the same as that in the factor/BPA prophylaxis period. This accounts for a gradual loss of 
fitusiran effectiveness post-withdrawal. If a patient in fitusiran efficacy period (fitusiran 
treatment period for US protocol) has more events pre-withdrawal than expected if this patient 
had been in the factor/BPA prophylaxis period, then this “positive residual” feeds through into 
a higher than expected ABR in the post-withdrawal period. This is because this patient’s 
earlier observed ABR higher than mean event rate suggests the patient has a higher propensity 
to have events.  
The efficacy analysis based on treatment policy strategy may serve as sensitivity analyses for the 
primary efficacy analysis based on on-treatment strategy. It is important to note that the estimand 
based on on-treatment strategy (the primary efficacy analysis) is considered most relevant and 
applicable in characterizing the frequency of bleeding episodes while receiving fitusiran 
treatment, relative to bypassing agent (BPA) prophylaxis.  
Per-protocol analysis 
Efficacy analysis will be repeated on the per-protocol analysis set as defined in Section 2.3. 
Zero-inflated negative binomial model 
To address the concern of potential excessive zero bleeding events, the above on-treatment and 
treatment policy efficacy analyses are repeated using the zero-inflated negative binomial model, 
and the results will be presented if model converges.  
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Bayesian analysis 
A supportive efficacy analysis will be performed for the primary endpoint by using the Bayesian 
repeated measure Negative Binomial regression model. The informative prior distributions of the 
model parameters (eg, treatment effect, random effect, dispersion) may be used in the model. The 
ratio of ABR in the fitusiran efficacy period (fitusiran treatment period for US protocol) to the 
factor/BPA prophylaxis period, its 95% CI and the posterior probability of clinically significant 
treatment effect will be estimated. To assess sensitivity of the posterior distribution to this 
informative prior, an additional analysis will be performed using a neutral prior assuming mean 
ABR ratio of 1. 
This Bayesian analysis will be implemented via PROC MCMC in SAS. 
Covid-19 related sensitivity analysis 
To address the impact of Covid-19, the above on-treatment and treatment policy efficacy analyses 
will be repeated on the Covid-19 unaffected set as defined in Section 2.3. In addition, a sensitivity 
analysis based on on-treatment strategy will be performed by excluding the additional following 
intercurrent events: 
• Period of missing at least two fitusiran doses in consecutive scheduled visits due to Covid-
19 which is defined as one month after last dose (ie, last dose date + 29 days) before 
missing doses due to Covid-19 to one month after starting of re-dosing (ie, first re-dose 
date + 28 days). For participants treated with fitusiran 50mg Q2M dose regimen, replace 
the number of 28 with 56. 
• Period from 6 months after enrollment of factor/BPA prophylaxis period to the date of first 
fitusiran dose if the date of first fitusiran dose was delayed due to Covid-19 
The same negative binomial model as in the primary analysis will be used. 
2.4.4.1.3 Exploratory analysis  
All bleeding episodes (treated or untreated) 
The on-treatment and treatment policy efficacy analyses are performed by including all bleeding 
episodes, regardless of administration of factor concentrates or bypassing agent infusion using the 
same negative binomial model as used for the primary analysis, which only includes treated 
bleeding episodes. 
Time to first bleeding event 
The time to first treated bleeding event in the factor or BPA prophylaxis period is calculated as 
the number of days between Day -168 and the onset date of the first treated bleeding event during 
the factor or BPA prophylaxis period. The patient is censored at the earlier of Day -1 if no treated 
bleeding event has occurred. The time to first treated bleeding event in the fitusiran treatment 
period is calculated as the number of days between Day 1 and the onset date of the first treated 
bleeding event during the treatment period. The patient is censored at the earlier of Day 190 if no 
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treated bleeding event has occurred. The time to first treated bleeding event in the efficacy period 
is calculated similarly from Day 29 as the start of efficacy period. If a patient does not have 
bleeding episode data collected after Day 28 due to early study discontinuation, the time to first 
treated bleeding event in the efficacy period is imputed from Day 1 as in the treatment period. 
The time to first treated spontaneous bleeding event is calculated similarly. 
For on-treatment analysis, time to first treated bleeding episode will be adjusted by intercurrent 
events. 
The proportion of patients who are bleeding free in fitusiran treatment period and factor or BPA 
prophylaxis period will be estimated using the Kaplan-Meier method and compared using a Cox 
proportional hazards (PH) regression model with a robust sandwich covariance matrix to account 
for the within participant dependence, and the study period as a fixed effect. Plots of cumulative 
mean functions for the number of treated bleeds in the fitusiran treatment period and factor or 
BPA prophylaxis period will be provided. 
Symptoms related to bleeding 
Descriptive statistics are provided for symptoms related to bleeding events by each study period. 
2.4.4.1.4 Subgroup analysis  
Based on the mechanism of action of fitusiran, there should not be difference in the safety or 
efficacy of fitusiran between hemophilia A or B, either with or without inhibitors. Nevertheless, 
the subgroup efficacy analysis based on hemophilia type and inhibitor status will be part of 
subgroup analyses specified below without formal statistical testing due to exploratory nature of 
these analyses.  
The on-treatment and treatment policy efficacy analyses for the primary endpoint and the 
secondary endpoints based on bleeding episodes are repeated for the following subgroups: 
• Hemophilia type (Type A vs B) 
• Number of bleeding episodes prior to screening (<=10 vs >10) 
• Age group, years (<18, 18-64, ≥65) 
• Cohort A vs Cohort B 
In addition, region- and/or country-specific analyses are performed to support regulatory 
submission as needed. 
Negative binomial regression model will be applied only for subgroups that have at least 
3 patients and the model converges. Otherwise, only summary statistics are presented.  
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2.4.4.2 Analyses of secondary efficacy endpoints  
2.4.4.2.1 ABR in the fitusiran efficacy period (Key secondary endpoint for US protocol)  
Analysis includes all bleeding episodes occurring in the fitusiran efficacy period. The 
on-treatment and treatment policy efficacy analysis are repeated with this endpoint. Estimated 
mean ABR and its 95% CI will be presented. No formal hypothesis testing will be performed. 
2.4.4.2.2 Annualized spontaneous bleeding rate in the fitusiran efficacy period and the 
factor/BPA prophylaxis period  
Analysis includes spontaneous bleeding episodes occurring in the factor/BPA prophylaxis period 
and the fitusiran efficacy period. The on-treatment and treatment policy efficacy analyses are 
repeated with this endpoint. 
2.4.4.2.3 Annualized joint bleeding rate in the fitusiran efficacy period and the factor/BPA 
prophylaxis period  
Analysis includes joint bleeding episodes occurring in the factor/BPA prophylaxis period and the 
fitusiran efficacy period. The on-treatment and treatment policy efficacy analyses are repeated 
with this endpoint. 
2.4.4.2.4 Change in Haem-A-QOL physical health score and total score in the fitusiran treatment 
period and the factor or BPA prophylaxis period  
Change from baseline in Haem-A-QOL physical health score and total score (in patients 
≥17 years of age) in the factor or BPA prophylaxis period and fitusiran treatment period are 
analyzed using a mixed model for repeated measure analysis (MMRM) with robust sandwich 
covariance matrix, with fixed effects of study period (factor or BPA prophylaxis period and 
fitusiran treatment period), baseline Haem-A-QoL physical health score and total score for each 
study period as covariates. Least square means of the physical health score and total score in each 
treatment period and the difference of the least square means of the physical health score and total 
score in the two periods (along with the 95% CI and p-value) are presented. The normality 
assumption based on MMRM model is examined and a sensitivity analysis based on the non-
parametric Wilcoxon signed-rank test is performed. For patient with missing assessment due to 
early withdrawal, a sensitivity analysis is performed by imputing the domain score and total score 
as the worst score if the reason of withdrawal is treatment-related in the fitusiran treatment period, 
and as the average score for other reasons of withdrawal that are not treatment related in the 
fitusiran treatment period. The same analysis as main will be performed as a sensitivity analysis 
by excluding values of those who completed Haem-A-QoL at baseline after first dose of fitusiran. 
To evaluate the impact of Covid-19, the same MMRM model will also be repeated on Covid-19 
unaffected set. In addition, a sensitivity analysis using same MMRM model will be performed 
excluding the data impacted by Covid-19 major/critical protocol deviation. A supportive analysis 
will be repeated on the patients whose responses level to EQ-5D dimensions “anxiety/depression” 
is no change or improved from baseline of factor or BPA prophylaxis period. 
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Change from baseline in Haem-A-QOL physical health score and total score in the factor or BPA 
prophylaxis period and fitusiran treatment period are also summarized descriptively by study 
period. 
Domain scores, standardized scale scores, and transformed scale scores for Haem-A-QoL and 
their changes from baseline in the factor or BPA prophylaxis period and fitusiran treatment period 
are summarized by study period. 
To evaluate the association between the change in Haem-A-QoL and other clinical measures, the 
analysis of change from baseline in the Haem-A-QOL physical health score and total score are 
stratified by ABR level (0, 1-5, >5) and concomitant pain medication use (Y, N). The ABR level 
is based on on-treatment strategy during the fitusiran treatment period and factor or BPA 
prophylaxis period. 
The summary of adherence with Haem-A-QOL measurement is also provided. 
2.4.4.2.5 ABR in the onset period  
Analysis includes all bleeding episodes occurring in the onset period. The on-treatment and 
treatment policy efficacy analysis are repeated with this endpoint. Estimated mean ABR and its 
95% CI are presented. No formal hypothesis testing is performed.  
2.4.4.2.6 ABR in treatment period (Global protocol)  
Analysis includes all bleeding episodes occurring in the fitusiran treatment period. The on-
treatment and treatment policy efficacy analysis are repeated with this endpoint. Estimated mean 
ABR and its 95% CI are presented. No formal hypothesis testing is performed.  
2.4.4.2.7 Annualized weight-adjusted consumption of factor/BPA  
Factor/BPA dose will be recorded by the patient in the eDiary and reviewed by the Investigator 
(and Sponsor or delegate) for the study duration to assess on-demand factor/BPA usage, as 
treatment of breakthrough bleeding episodes as well as prophylaxis factor/BPA usage. Weight-
adjusted factor/BPA usage will be calculated programmatically.  
The annualized weight-adjusted factor/BPA consumption for both treating bleeds and prophylaxis 
purpose, number of factor/BPA injections per bleed/per participant, weight adjusted total dose per 
bleed/per participant, and results of patient-reported evaluation of effectiveness of treatment for 
each bleed (excellent, good, moderate or none) as assessed by both patient and caregiver 
(Blanchette, 2014) will be summarized for both factor/BPA prophylaxis period and fitusiran 
treatment period. Additional summary will be provided by bleed location, causality and severity. 
The compliance to the bleed management guideline will be summarized after Day 8 to the end of 
study. 
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2.4.4.3 Multiplicity issues  
No multiplicity control is provided for this study 
2.4.5 Analyses of safety data  
General common rules 
All safety analyses will be performed on the safety analysis set (SAS1 or SAS 2) as defined in 
Section 2.3, unless otherwise specified, using the following common rules: 
• Safety data in patients who do not belong to the safety analysis set (eg, entered factor or 
BPA prophylaxis period and not treated with fitusiran) are listed separately 
• The baseline value for fitusiran prophylaxis period is defined as the last non-missing value 
before the first dose of fitusiran. The baseline value for factor or BPA prophylaxis period 
is defined as the last non-missing value before the enrollment date. 
• For ECG measurements, which are taken in triplicate, the average of the last triplicate 
readings before first dose of fitusiran/enrollment date is used as baseline for fitusiran 
prophylaxis period/factor or BPA prophylaxis period. 
• The potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests and vital signs  
• PCSA criteria determines which patients had at least 1 PCSA during each observation 
period (factor or BPA prophylaxis period and fitusiran prophylaxis period), taking into 
account all evaluations performed during each observation period, including nonscheduled 
or repeated evaluations. The number of all such patients is the numerator for the PCSA 
percentage in each observation period. 
• The PCSA denominator for a given parameter is based on the number of patients assessed 
for that given parameter in each observation period on the safety analysis set. Number (%) 
of patients with at least 1 PCSA is summarized regardless of baseline PCSA status and 
also by baseline PCSA status by observation period. 
• For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics are used to summarize results and change from baseline values by 
visit and observation period. Summaries include the endpoint value which is defined as the 
last non-missing post-baseline assessment on or before EOS/ET visit for fitusiran 
prophylaxis period and on or before the day before first dose date of fitusiran for 
factor/BPA prophylaxis period. 
• The analysis of the safety variables is essentially descriptive and no systematic testing is 
planned. 
• All safety values including unscheduled measurements are assigned to the appropriate 
safety analysis visit window defined in Section 2.5.4. 
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2.4.5.1 Analyses of adverse events  
Generalities 
The focus of adverse event reporting is on treatment-emergent adverse events and pre-treatment 
adverse events. Adverse events occurring in the screening period are analyzed separately. 
If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is incomplete 
(missing time, day, month or year), an imputation algorithm is used to classify the adverse event 
as pretreatment and treatment-emergent. The algorithm for imputing date/time of onset is 
conservative and classifies an adverse event as treatment emergent unless there is definitive 
information to determine it is pretreatment or posttreatment. Details on classification of adverse 
events with missing or partial onset dates are provided in Section 2.5.3. 
AEs are summarized by observation period (factor/BPA prophylaxis period and fitusiran 
prophylaxis period) and by the numbers and percentages of patients reporting at least one AE, 
having at least one AE by primary System Organ Class (SOC) and Preferred Term (PT). A patient 
with multiple occurrences of an AE is counted only once in the respective AE category. Patients 
who report multiple occurrences of the same AE (preferred term) are classified according to the 
most related or most severe occurrence, respectively. 
All AE summaries are presented (frequency counts and percentages) by system organ class and/or 
preferred term, unless specified otherwise. The SOC is presented by internationally agreed order 
and the preferred term is sorted within each SOC in decreasing order of frequency in fitusiran 
prophylaxis period. 
Analysis of all adverse events 
An overall summary of AEs includes the number and percentage of patients with any:  
• AE 
• AE assessed by the Investigator as related to study drug (fitusiran only, possibly related or 
definitely related) 
• severe AE 
• severe AE related to study drug 
• serious AE (SAE) 
• SAE related to study drug 
• AE/SAE of special interest 
• Study drug related AE/SAE of special interest 
• AE/SAE leading to study drug discontinuation 
• Study drug related AE/SAE leading to study drug discontinuation 
• AE/SAE leading to study withdrawal 
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• Study drug related AE/SAE leading to study withdrawal 
• SAE with a fatal outcome. 
• AEs potentially consistent with COVID-19 
The overall summary of AEs will also be provided by hemophilia type. 
Tabulations by SOC and PT are produced for the following: 
• AEs 
• AEs by severity 
• AEs by hemophilia type 
• SAEs 
• AEs related to study drug (fitusiran prophylaxis period only) 
• AEs related to study drug by hemophilia type (fitusiran prophylaxis period only) 
• SAEs related to study drug (fitusiran prophylaxis period only) 
• SAEs related to study drug by hemophilia type (fitusiran prophylaxis period only) 
• AESI 
• AESI by hemophilia type 
• AEs leading to study drug discontinuation (fitusiran prophylaxis period only) 
• SAEs leading to study drug discontinuation (fitusiran prophylaxis period only) 
• AESIs leading to study drug discontinuation (fitusiran prophylaxis period only) 
• AEs leading to study withdrawal 
• SAEs leading to study withdrawal 
• AEs potentially consistent with COVID-19 
COVID-19 infection will be identified based on the search on MedDRA SMQ COVID-19 
(narrow). 
Tabulations by PT in decreasing order of frequency in the fitusiran prophylaxis period are 
produced for the following: 
• AEs 
• AEs by hemophilia type 
• SAEs 
• AEs related to study drug (fitusiran prophylaxis period only) 
• SAEs related to study drug (fitusiran prophylaxis period only) 
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All AEs collected are listed along with the information collected on those AEs, eg, AE 
relationship to study drug, AE outcome etc. AEs that are not treatment-emergent are flagged in 
the listings. By-patient listings will also be provided for the following: all patient deaths, all 
SAEs, and all AEs leading to study drug discontinuation or study withdrawal, all AEs leading to 
death, AEs potentially consistent with COVID-19. 
2.4.5.2 Analyses of laboratory variables  
Clinical laboratory values are expressed in Standard International (SI) units. Laboratory data 
collected and recorded as below the limit of detection are set equal to the lower limit of detection 
for the calculation of summary statistics. 
Summary data for each laboratory parameter are presented for each continuous clinical laboratory 
parameter (including hematology, serum chemistry, coagulation studies and liver function tests). 
Descriptive statistics are presented for the actual values, change from baseline, and percent change 
from baseline by visit and observation period. 
For each continuous laboratory parameter, results are categorized as low, normal, or high based 
on the laboratory normal ranges. 
A listing is produced for all patients with abnormal liver function tests defined as an 
ALT >3 × ULN, AST >3 × ULN, and/or total bilirubin >2 × ULN at any time point. 
A table is produced to summarize the number and percentage of patients in each of below 
categories at any post-baseline time point by observation period. 
• ALT >1 & ≤3, >3 & ≤5, >5 & ≤10, >10 & ≤20, >20 × ULN, 
• AST >1 & ≤3, >3 & ≤5, >5 & ≤10, >10 & ≤20, >20 × ULN, 
• ALT or AST >1 & ≤3, >3 & ≤5, >5 & ≤10, >10 & ≤20, >20 × ULN, 
• ALP >1.5 × ULN, 
• Total Bilirubin >1.5 & ≤2, >2 & ≤3, >3 & ≤5 and >5 × ULN, 
• Total Bilirubin >2 × ULN concurrent with ALT or AST >3 × ULN, 
• INR >1.2. 
In separate figures, the peak total bilirubin (at any time post-baseline) is plotted against the peak 
AST, the peak ALT, and the peak AST or ALT levels at any time post-baseline by observation 
period. The mean of ALT, AST, and total bilirubin will be plotted over time. The Kaplan-Meier 
curve for the time to first onset of ALT>3ULN, AST>3ULN and AST/AST >3ULN will be 
provided. 
For hematology and blood chemistry, summary tables of potentially clinically significant 
abnormalities (PCSA) are provided by observation period. 
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Laboratory data will be provided in data listings as appropriate. Values that meet a PCSA criterion 
or out-of-range laboratory values when no PCSA criterion is defined will be identified in the 
listings. 
2.4.5.3 Analyses of physical examination and vital sign variables  
The summary statistics (including number, mean, median, Q1, Q3, standard deviation, minimum 
and maximum) of all vital sign variables are calculated for each visit or study assessment in factor 
or BPA prophylaxis period and fitusiran prophylaxis period. Summary table of potentially 
clinically significant abnormalities (PCSA) are provided by observation period. 
Vital sign measurements are presented for each patient in a data listing as appropriate, with 
abnormal vital signs flagged. 
All physical examination findings are presented in a by-patient data listing.  
2.4.5.4 Analyses of electrocardiogram variables  
PR, QRS, QT, QTc and RR intervals and their change from baseline values are summarized by 
scheduled visit for each observation period. Besides, their change from time-matched and pre-
dose baseline are also summarized in fitusiran prophylaxis period by scheduled visit. Participants 
are categorized into ≤450, >450 - 480, >480 - 500, or >500 ms per their maximum post-baseline 
absolute QTc interval and ≤30, >30 - 60, or >60 ms per their maximum change from baseline QTc 
interval. The number and percentage of participants in each category are summarized. 
For post-baseline assessments where ECG is performed in triplicate, the average of the 3 (or all 
available) readings is used for analysis.  
2.4.6 Analyses of pharmacokinetic and pharmacodynamic variables  
2.4.6.1 Analyses of pharmacodynamic variables  
2.4.6.1.1 Antithrombin  
AT levels and AT lowering (% lowering from baseline) in the fitusiran prophylaxis period are 
summarized descriptively.  
2.4.6.1.2 Peak thrombin  
Peak thrombin values collected within 48 hours of factor, BPA or antifibrinolytic administration 
are excluded from all analysis. Peak thrombin values in the fitusiran prophylaxis period are 
summarized descriptively.  
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2.4.6.1.3 AT lowering and peak thrombin  
Correlation between AT (actual AT levels and AT lowering) and thrombin is computed on paired 
assessments, where both parameters are measured on the same day. Log transformation may be 
used. 
2.4.6.2 Analyses of pharmacokinetic variables  
Non-compartmental analysis for PK parameter estimation in East Asian patients from East Asian 
sites is described in this analysis plan. Population PK analysis is planned for all patients in the 
study and will be described in a separate population PK analysis plan. 
Pharmacokinetic parameters to be estimated using noncompartmental analysis 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). Other parameters may be calculated, 
if deemed necessary. PK analysis is not in the scope of this SAP and would be reported 
separately.  
2.4.7 Analyses of exploratory endpoints  
2.4.7.1 TSQM-9  
The Treatment Satisfaction Questionnaire for Medication (TSQM) version 9 assesses patient 
satisfaction with treatment. The TSQM Scale scores, and their changes from baseline in the factor 
or BPA prophylaxis period and fitusiran treatment period are summarized descriptively. 
2.4.7.2 HAL and pedHAL  
The Haemophilia Activities List (HAL, in patients ≥18 years of age) and pediatric HAL 
(pedHAL, in patients <18 years of age) questionnaires assess subjective functional ability to 
perform activities of daily living. Overall score, component scores, domain scores, and their 
changes from baseline in the factor or BPA prophylaxis period and fitusiran treatment period are 
summarized descriptively. 
2.4.7.3 EQ-5D-5L  
The EQ-5D-5L is a standardized instrument for use as a measure of QOL outcome. Index value 
and visual analogue scale (VAS) score and their changes from baseline in the factor or BPA 
prophylaxis period and fitusiran treatment period are summarized descriptively. Numbers and 
percentages of patient by level and dichotomized level (1 = no problems, 2 to 5 = “problems”) of 
each dimension are reported. 
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2.4.7.4  Haemo-QOL   
The Haemo-QOL will be provided to patients<17 years of age. The change from baseline in total 
score of Haemo-QOL in the factor or BPA prophylaxis period and fitusiran treatment period are 
analyzed using a mixed model for repeated measure analysis (MMRM) with a robust sandwich 
covariance matrix, with fixed effects of study period (factor or BPA prophylaxis period and 
fitusiran treatment period), baseline Haemo-QOL total score for each treatment period as 
covariates. Domain scores for Haemo-QOL and their changes from baseline are summarized 
descriptively. Only the descriptive statistics are provided if MMRM model does not converge due 
to the small sample size. 
2.4.7.5 HJHS  
Joint health status is assessed via the HJHS, as administered by a healthcare professional trained 
in the use of anthropometric measures. Response is summarized. If the joint score is evaluated 
within 2 weeks after a joint or adjacent muscle bleeding episode or a surgery is performed on a 
joint and the joint score is evaluated from start date of surgery to the end of perioperative 
procedure period + 7 days, then the data for that joint will be excluded. A sensitivity analysis 
excluding the non-evaluable results will be performed. 
2.4.7.6 Number of target joint bleeding episodes  
An exploratory analysis of the number of target joint bleeding episodes may be performed using 
the same negative binominal model as the primary analysis. 
2.4.7.7 Incidence and titer of antidrug antibodies to fitusiran in the fitusiran treatment 
period  
The ADA analysis will be based on all patients in the safety analysis set with at least one post 
baseline ADA result in fitusiran prophylaxis period. Number of patients testing positive for ADA 
pre-study-drug (baseline positive) and post-study-drug administration are summarized by 
Hemophilia type (A/B) and incidence of ADA positivity is presented by frequency and as a 
percent by Hemophilia type and across all patients. In addition, maximum ADA titer and range of 
titer values are presented by Hemophilia type and across all patients. 
2.4.7.8 AT activity level over time  
Please refer to Section 2.4.6.1.1. 
2.4.7.9 Thrombin generation over time  
Please refer to Section 2.4.6.1.2. 
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2.4.7.10 Fitusiran plasma levels  
Fitusiran plasma concentrations and PK parameters including but not limited to Cmax, tmax, t½β, 
AUC, CL/F, and V/F will be summarized descriptively.  
2.4.7.11 Change in patient resource use (eg, work/school attendance, visits to 
doctor/hospital)  
Change in patient resource use (eg, work/school attendance, visits to doctor/hospital) from 
baseline in the factor or BPA prophylaxis period and fitusiran treatment period are summarized 
descriptively. 
2.5 
DATA HANDLING CONVENTIONS  
2.5.1 General conventions  
All data listings that contain an evaluation date will contain a study day relative to the first dose 
date of fitusiran, which is designated as Day 1. Study days after first dose date of fitusiran will be 
calculated as evaluation date - first dose date +1 and study days before first dose date of fitusiran 
will be calculated as evaluation date -first dose date. For example, the day prior to first dose date 
of fitusiran will be Day -1 and the day after first dose date of fitusiran will be Day 2, etc. There 
will be no Study Day 0. 
Categorical variables will be summarized using counts and percentages. Continuous variables will 
be summarized using the number of patients (n), mean, SD, median, interquartile range (Q1, Q3), 
minimum value (min), and maximum value (max). 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 
precision as the units of measure. The other statistics mean, median and SD will be reported to 
1 greater decimal place. Any values that require transformation to standard units (metric or SI) 
will be converted with the appropriate corresponding precision. 
2.5.2 Data handling conventions for secondary efficacy variables  
Not Applicable. 
2.5.3 Missing data  
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified. When relevant, the number of patients with missing data 
is presented. 
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Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed. If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered as a concomitant medication. 
Handling of adverse events with missing or partial date/time of onset 
Missing or partial adverse event onset dates and times will be imputed so that if the partial 
adverse event onset date/time information does not indicate that the adverse event started prior to 
treatment or after the treatment-emergent adverse event period, the adverse event will be 
classified as treatment-emergent. No imputation of adverse event end dates/times will be 
performed. These data imputations are for categorization purpose only and will not be used in 
listings. No imputation is planned for date/time of adverse event resolution. 
Handling of adverse events when date and time of first investigational medicinal product 
administration is missing 
When the date and time of the first dose of fitusiran is missing, all adverse events that occurred on 
or after the first day of fitusiran treatment period (M0/D1) should be considered as treatment-
emergent adverse events. The exposure duration should be kept as missing. 
Handling of missing assessment of relationship of adverse events to investigational medicinal 
product  
If the assessment of the relationship to fitusiran is missing, then the relationship to fitusiran has to 
be assumed and the adverse event considered as such in the frequency tables of possibly related 
adverse events, but no imputation should be done at the data level. 
Handling of missing severity of adverse events 
If the severity is missing for 1 of the treatment-emergent occurrences of an adverse event, the 
maximal severity on the remaining occurrences will be considered. If the severity is missing for 
all the occurrences, a “missing” category will be added in the summary table. 
Handling of potentially clinically significant abnormalities  
If a patient has a missing baseline he will be grouped in the category “normal/missing at 
baseline.” 
For PCSAs with 2 conditions, one based on a change from baseline value or a normal range and 
the other on a threshold value, with the first condition being missing, the PCSA will be based only 
on the second condition. 
For a PCSA defined on a threshold and/or a normal range, this PCSA will be derived using this 
threshold if the normal range is missing; eg, for eosinophils the PCSA is >0.5 GIGA/L or > upper 
limit of normal (ULN) if ULN ≥0.5 GIGA/L. When ULN is missing, the value 0.5 should be used. 
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Measurements flagged as invalid by the laboratory will not be summarized or taken into account 
in the computation of PCSA values. 
Handling of bleeding events with missing bleed/treatment time  
On the eDiary device, it is not possible to leave questions unanswered or to enter partial date for 
bleeds or bleeding treatments.  
In the bleeding diary pages of the CRF, it is possible to have missing time of a treatment or a 
bleed. In that case, it is assumed that the bleeds and treatments with missing time occurred at 
12:00 am. 
2.5.4 Windows for time points  
A scheduled measurement will be used if it is available. Otherwise, derived analysis visit window 
will apply to data collected on unscheduled visits and early withdrawal visits (such as PD, clinical 
laboratory parameter, vital signs, etc.) to re-allocate a post-baseline unscheduled measurement to a 
scheduled measurement, except for PK and ECG, using Study Day (defined in Section 2.5.1), 
according to the following allocation table: 
 
Analysis visit label 
Target study day 
Derived Window in study days 
Lower bound 
Upper bound 
Baseline for factor/BPA 
prophylaxis period 
The last non-missing 
assessment before 
enrollment date 
-INF 
Enrollment date 
Day -168 
-168 
1 day after 
enrollment date 
-155 
Day -140 
-140 
-154 
-127 
Day -112 
-112 
-126 
-99 
Day -84 
-84 
-98 
-71 
Day -56 
-56 
-70 
-43 
Day -28 
-28 
-42 
-1 
Baseline for fitusiran 
prophylaxis period 
1 
1 
1 
Day 15 
15 
2  
21 
Day 29 
29 
22 
35 
Day 43 
43 
36 
49 
Day 57 
57 
50 
70 
Day 85 
85 
71 
98 
Day 113 
113 
99 
126 
Day 141 
141 
127 
154 
Day 169 
169 
155 
182 
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Analysis visit label 
Target study day 
Derived Window in study days 
Lower bound 
Upper bound 
Day 197 
197 
≥183 
EOS/ET visit date if EOS/ET 
visit is ≥183 
Day 225 
28 days after EOS/ET for 
patients who complete the 
AT F/U visits 
1 day after EOS/ET 
visit 
999 
Endpoint 
Last non-missing post-baseline assessment on or before EOS/ET visit 
If more than one data point is within a window the visit closest to the target study day will be 
selected. If there are multiple visits with the same distance from the scheduled visit day, the last 
value will be selected. 
2.5.5 Unscheduled visits  
Unscheduled visit measurements of laboratory data and vital signs will be included in the by-visit 
summaries, computation of baseline, and PCSAs. 
Unscheduled visit measurements of efficacy endpoints will be included in the efficacy analysis 
and computation of baseline. 
2.5.6 Pooling of centers for statistical analyses  
Geographic region will consist of the following categories: North America, Europe, Asia, Other. 
The countries in each region are the following: 
• North America (United States, Canada) 
• Europe (Bulgaria, Denmark, France, Germany, Hungary, Italy, Netherlands, Portugal, 
Russia, Spain, Turkey, Ukraine, United Kingdom, Ireland) 
• Asia (China, India, Japan, Korea, Malaysia, Taiwan) 
• Other (Australia, Israel, South Africa) 
2.5.7 Statistical technical issues  
Not Applicable. 
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3 
INTERIM ANALYSIS  
An interim analysis may be conducted as a part of this study. 
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4 
DATABASE LOCK  
The database is planned to be locked at 28 days after last patient last visit. 
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5 
SOFTWARE DOCUMENTATION  
All summaries and statistical analyses will be generated using SAS version 9.4 or higher. 
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6 
REFERENCES  
1. European Medicines Agency. ICH E9 (R1) addendum on estimands and sensitivity analysis in 
clinical trials to the guideline on statistical principles for clinical trials. 2020. 
2. Keene ON, Roger JH, Hartley BF, Kenward MG. Missing data sensitivity analysis for 
recurrent event data using controlled imputation. Pharm Stat. 2014;13(4):258-64. 
 
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7 
LIST OF APPENDICES  
 
Appendix A: 
Summary of statistical analysis 
Appendix B: 
Questionnaire/scoring: Haem-A-QOL and Haemo-QOL 
Appendix C: 
Questionnaire/scoring: Treatment Satisfaction Questionnaire for Medication 
(TSQM) domain scores 
Appendix D: 
Questionnaire/scoring: Haemophilia Activities List (HAL)/Paediatric HAL 
(pedHAL) score 
Appendix E: 
Questionnaire/scoring: EuroQol-5 dimension 5 level (EQ-5D-5L) score 
Appendix F: 
Position paper  
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Appendix A 
Summary of statistical analyses  
Efficacy Analyses 
 
Endpoint 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
Primary endpoint 
Annualized 
bleeding rate (ABR) 
in the fitusiran 
efficacy period 
(fitusiran treatment 
period for US 
protocol) and the 
factor/BPA 
prophylaxis period. 
EAS 1 
Repeated 
measures 
negative binomial 
regression model 
with On-
Treatment 
Strategy 
Yes. Repeated 
measures 
negative binomial 
regression model 
with Treatment 
Policy Strategy 
Yes. Subgroups are 
hemophilia type, 
number of bleeding 
episodes during the 
6 months prior to 
study, age group, 
Cohort A vs B, 
region- and/or 
country- 
Per-protocol 
analysis 
Exploratory 
analysis  
Zero-inflated 
negative binomial 
model 
Bayesian analysis 
MI for treatment 
policy strategy 
Secondary endpoints 
Annualized 
spontaneous 
bleeding rate in the 
fitusiran efficacy 
period and the 
factor/BPA 
prophylaxis period 
EAS 1 
Repeated 
measures 
negative binomial 
regression model 
with On-
Treatment 
Strategy 
Yes. Repeated 
measures 
negative binomial 
regression model 
with Treatment 
Policy Strategy 
Subgroup analysis 
will be performed if 
deemed necessary 
No 
Annualized joint 
bleeding rate in the 
fitusiran efficacy 
period and the 
factor/BPA 
prophylaxis period 
EAS 1 
Repeated 
measures 
negative binomial 
regression model 
with On-
Treatment 
Strategy 
Yes. Repeated 
measures 
negative binomial 
regression model 
with Treatment 
Policy Strategy 
Subgroup analysis 
will be performed if 
deemed necessary 
No 
Change in Haem-A-
QOL physical 
health score and 
total score in the 
fitusiran treatment 
period 
EAS 1 
Descriptive 
statistics and 
Mixed Model with 
repeated 
measures 
(MMRM) 
Non-parametric 
Wilcoxon signed-
rank test 
Subgroup analysis 
will be performed if 
deemed necessary 
No 
ABR in the onset 
period 
 
EAS 1 
negative binomial 
regression model 
with On-
Treatment 
Strategy 
Yes. negative 
binomial 
regression model 
with Treatment 
Policy Strategy  
Subgroup analysis 
will be performed if 
deemed necessary 
No 
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Endpoint 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
ABR in the 
treatment period 
(ABR in the efficacy 
period for US 
protocol) 
 
EAS 1 
negative binomial 
regression model 
with On-
Treatment 
Strategy 
 Yes. negative 
binomial 
regression model 
with Treatment 
Policy Strategy 
Subgroup analysis 
will be performed if 
deemed necessary 
No 
Annualized weight-
adjusted 
consumption of 
factor/BPA 
EAS 1 
Descriptive 
statistics 
 
Subgroup analysis 
will be performed if 
deemed necessary 
 
Other endpoints 
Exploratory 
variables  
EAS 1 
Descriptive 
statistics, 
MMRM, 
Repeated 
measures 
negative binomial 
regression model 
with On-
Treatment 
Strategy 
No 
No 
No 
Note: Listings of ABR will be provided for participants in EAS 2. 
Safety analyses 
 
Endpoint 
Analysis 
population 
Primary analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
Adverse events 
Safety analysis 
set 1 
Follow safety 
guidelines 
No 
No 
No 
Laboratory 
variables 
Safety analysis 
set 1 
Descriptive statistics 
and Incidence of 
PCSAs 
No 
No 
Listings of out-of-
range laboratory 
results or values met 
PCSA criterion 
Vital sign and 
physical 
examination 
variables 
Safety analysis 
set 1 
Descriptive statistics 
and Incidence of 
PCSAs 
No 
No 
Listings of abnormal 
findings/values  
ECG variables 
Safety analysis 
set 1 
Descriptive statistics 
and incidence of 
PCSAs 
No 
No 
Listings of abnormal 
findings/values  
Antidrug antibody 
formation (ADA) 
Safety analysis 
set 1 
Descriptive statistics  
No 
No 
No 
pharmacodynamic 
variables 
Safety analysis 
set 1 
Descriptive statistics, 
MMRM  
No 
No 
No 
Note: Listings of safety data will be provided for participants in safety analysis set 2. 
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Appendix B 
Questionnaire/scoring: Haem-A-QOL and Haemo-QOL  
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Appendix C 
Questionnaire/scoring: Treatment Satisfaction Questionnaire for 
Medication (TSQM) domain scores  
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Appendix D 
Questionnaire/scoring: Haemophilia Activities List (HAL)/Paediatric 
HAL (pedHAL) score  
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Appendix E 
Questionnaire/scoring: EuroQol-5 dimension 5 level (EQ-5D-5L) 
score  
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Appendix F 
Position paper  
 
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