ATLAS-INH: A Study of Fitusiran (ALN-AT3SC) in Severe Hemophilia A and B Patients With Inhibitors

• Sponsor: Genzyme, a Sanofi Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03417102
• Collaborator: (none)
• Enrollment: 60
• Locations: 58
• Arms: 2
• Actual Duration (Months): 40.2
• Patients Per Site: 1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study was to determine the frequency of bleeding episodes in participants receiving fitusiran as prophylactic treatment of hemophilia compared to participants who were assigned to continue with their regular medication. In addition, the study assessed safety, quality of life, pharmacodynamics (PD), and pharmacokinetics (PK).

Condition or Disease	Intervention/Treatment	Phase
Hemophilia A; Hemophilia B	Drug: fitusiran; Drug: Bypassing agents	Phase 3

Detailed Description

The duration of treatment with fitusiran was 9 months. The estimated total time on study, inclusive of screening, for each participant was up to 11 months for all participants who enroll in the extension study and participants in the on-demand arm who did not enroll in the extension study. The estimated total time on study was up to 17 months in fitusiran treatment arm participants who did not enroll in the extension study due to the requirement for up to an additional 6 months of follow-up monitoring for antithrombin levels.

Study Design

• Study Type: Interventional
• Actual Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: ATLAS-INH: A Phase 3 Study to Evaluate the Efficacy and Safety of Fitusiran in Patients With Hemophilia A or B, With Inhibitory Antibodies to Factor VIII or IX
• Actual Study Start Date: Feb 14, 2018
• Actual Primary Completion Date: Nov 25, 2020
• Actual Study Completion Date: Jun 23, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Bypassing Agents (BPA) On-demand Participants received On-demand BPAs (use of these agents, as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion from Day 1 for treatment of breakthrough bleeding episodes, up to a total of 9 months.	Drug: Bypassing agents; solution for injection; by intravenous (IV) injection
Experimental: Fitusiran 80 mg Prophylaxis Participants received Fitusiran 80 mg subcutaneously (SC) as prophylaxis once monthly from Day 1, along with the on-demand BPAs (per investigator's discretion and within bleeding dosing guidelines) for treatment of breakthrough bleeding episodes, up to a total of 9 months.	Drug: fitusiran; solution for injection; by subcutaneous (SC) injection

Outcome Measures

Primary Outcome Measures

1. Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period [From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest]

   ABR for a participant during efficacy period (EP) was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. Treated Bleeding episode: any occurrence of hemorrhage that required administration of BPA or factor. It started from first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. EP was defined as time duration starting from Day 29 when antithrombin (AT) lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This outcome measure (OM) represents estimated results (i.e., results received by applying negative binomial [NB] regression model on data collected during EP).

2. Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period [From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest]

   ABR for a participant during EP was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. ABR= number of bleeding episodes during EP divided by total number of days during EP*365.25. A bleeding episode was defined as any occurrence of hemorrhage that required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. EP was defined as time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or the last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This OM represents observed results (i.e., descriptive statistics values based on the data which was collected during EP).

Secondary Outcome Measures

1. Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period [From Day 1 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest]

   ABR for a participant during treatment period (TP) was defined as annualized number of bleeding episodes during TP annualized to a 1-year interval of time. Bleeding episode: any occurrence of hemorrhage that required administration of BPA or factor. It started from first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. TP was sum of onset period (first 28 days after first dose of fitusiran) and EP (starting on Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to earliest of [Day 246 or last day of bleeding follow up])(maximum duration of TP: from Day 1 to Day 246). This OM represents estimated results (i.e., results received by applying NB regression model on data collected during TP).

2. Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period [From Day 1 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest]

   ABR for a participant during TP was defined as annualized number of bleeding episodes during TP annualized to a 1-year interval of time. ABR= number of bleeding episodes during TP divided by total number of days during TP*365.25. Bleeding episode: any occurrence of hemorrhage that required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. TP was sum of onset period (first 28 days after the first dose of fitusiran) and EP (starting on Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of [Day 246 or the last day of bleeding follow up]) (maximum duration of TP: from Day 1 to Day 246). This OM represents observed results (i.e., descriptive statistics values based on data collected during TP).

3. Estimated Annualized Spontaneous Bleeding Rate for Treated Bleeds During Efficacy Period [From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest]

   Annualized spontaneous bleeding rate for a participant during EP was defined as annualized number of spontaneous bleeding episodes during EP annualized to a 1-year interval of time. Spontaneous bleeding episode was bleeding event that occurred for no apparent or known reason, particularly into joints, muscles, and soft tissues. It started from first sign of a bleed and ended no more than 72 hours after last treatment for the bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. EP was defined as time duration starting from Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This OM represents estimated results (i.e., results received by applying NB regression model on data collected during EP).

4. Observed Annualized Spontaneous Bleeding Rate for Treated Bleeds During the Efficacy Period [From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest]

   ABR for participant during EP was defined as annualized number of spontaneous bleeding episodes during EP annualized to a 1-year interval of time. ABR=number of treated spontaneous bleeding episodes during EP divided by total number of days during EP*365.25. Spontaneous bleeding episode was bleeding event that occurred for no apparent or known reason, into joints, muscles, and soft tissues. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. EP: time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to earliest of (Day 246 or the last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This OM represents observed results (i.e., descriptive statistics values based on data collected during EP).

5. Estimated Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period [From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest]

   Annualized joint bleeding rate for a participant during EP was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. Joint bleeding episode was characterized by an unusual sensation in the joint ("aura") in combination with 1) increasing swelling or warmth over the skin, joint, 2) increased pain, or 3) progressive loss of range of motion or difficulty in using the limb as compared with Baseline. It started from first sign of a bleed and ended no more than 72 hours after last treatment for the bleed. EP was defined as time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or the last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This OM presents estimated results (i.e., results received by applying NB regression model on data collected during EP).

6. Observed Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period [From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest]

   Annualized joint bleeding rate for participant during EP was defined as annualized number of joint bleeding episodes during EP annualized to 1-year interval of time. ABR= number of treated joint bleeding episodes during EP divided by total number of days during EP*365.25. A joint bleeding episode was characterized by an unusual sensation in joint ("aura") in combination with 1) increasing swelling or warmth over skin, joint, 2) increased pain, or 3) progressive loss of range of motion or difficulty in using limb as compared with Baseline. It started from first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed. EP: time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This OM presents observed results (i.e., descriptive statistics values based on data collected during EP).

7. Health-related Quality of Life (HRQOL): Change From Baseline in Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) Physical Health Domain Score at Month 9 [Baseline (Day 1), Month 9]

   Haem-A-QoL: participant-reported questionnaire designed for adult participants (>=17 years of age) with hemophilia; and consisted of 46 items comprising 10 domains (physical health, feelings, view of yourself, sports and leisure, work and school, dealing with hemophilia, treatment, future, family planning, partnership and sexuality). Items were rated along five response options: never, rarely, sometimes, often, or all the time. Change from baseline in physical Health domain score was reported in this outcome measure. Raw score for physical health domain were transformed to a scale ranged from 0 to 100, where lower scores denoted better physical health.

8. Health-related Quality of Life (HRQOL): Change From Baseline in Haem-A-QOL Total Score at Month 9 [Baseline (Day 1), Month 9]

   Haem-A-QoL: participant-reported questionnaire designed for adult participants (>=17 years of age) with hemophilia; and consisted of 46 items comprising 10 domains (physical health, feelings, view of yourself, sports and leisure, work and school, dealing with hemophilia, treatment, future, family planning, partnership and sexuality). Items were rated along five response options: never, rarely, sometimes, often, or all the time. Raw score for each domain were transformed to a scale ranged from 0 to 100, where lower scores denoted better health. Haem-A-QoL Total Score was average of all domain scores and ranged from 0 to 100, where lower scores denoted better quality of life.

9. Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Onset Period [From Day 1 up to Day 28 or up to the last day of bleeding follow up (any day up to Day 28), whichever was the earliest]

   ABR was annualized number of bleeding episodes during onset period per participant annualized to a 1-year interval of time. A treated bleeding episode was defined as any occurrence of hemorrhage that may required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. The onset period was defined as time interval from Day 1 to the earlier of Day 28 or the last day of bleeding follow up. This OM represents estimated results (i.e., results received by applying NB regression model on data collected during onset period).

10. Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) [From Baseline (Day 1) up to 15 months (i.e. 9 months treatment period + 6-months follow-up)]

    An adverse Event (AE) was defined as any untoward medical occurrence in a participant who received study drug which did not necessarily have a causal relationship with the treatment. Treatment emergent AEs were defined as any AE with onset date after first dose of fitusiran in the fitusiran prophylaxis arm or after Day 1 visit in the BPA on-demand arm. A Serious AE (SAE) was defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly or birth defect, or was a medically important event.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Males, greater than or equal to (>=) 12 years of age.

• Severe hemophilia A or B with inhibitors.

• (Severity confirmed by a central laboratory where coagulation factor VIII (FVIII) level was less than (<)1% or factor IX (FIX) level was less than or equal to [<=]2% at Screening; Inhibitors defined as inhibitor titer of >=0.6 Bethesda units per milliliter [BU/mL] or as evidenced by medical records).

• A minimum of 6 bleeding episodes requiring BPA treatment within the last 6 months prior to screening.

• Willing and able to comply with the study requirements and to provide written informed consent and assent.

Exclusion Criteria:

• Known co-existing bleeding disorders other than hemophilia A or B.

• Antithrombin (AT) activity <60% at Screening.

• Co-existing thrombophilic disorder.

• Clinically significant liver disease.

• Active hepatitis C virus infection.

• HIV positive with a cluster of differentiation-4 count of <200 cells/microliter.

• History of arterial or venous thromboembolism.

• Inadequate renal function.

• History of multiple drug allergies or history of allergic reaction to an oligonucleotide or N-Acetylgalactosamine.

• History of intolerance to SC injection(s).

• Any other conditions or comorbidities that would make the participant unsuitable for enrollment or could interfere with participation in or completion of the study, per Investigator judgement.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Investigational Site Number 0117	Phoenix	Arizona	United States	85016
2	Investigational Site Number 0139	Los Angeles	California	United States	90027
3	Investigational Site Number 0135	Orange	California	United States	92868
4	Investigational Site Number 0137	San Diego	California	United States	92123
5	Investigational Site Number 0128	Gainesville	Florida	United States	32610
6	Investigational Site Number 0115	Jacksonville	Florida	United States	32207
7	Investigational Site Number 0105	Miami	Florida	United States	33136
8	Investigational Site Number 0103	Tampa	Florida	United States	33607
9	Investigational Site Number 0119	New Orleans	Louisiana	United States	70112
10	Investigational Site Number 0136	Baltimore	Maryland	United States	21205
11	Investigational Site Number 0111	Las Vegas	Nevada	United States	89135
12	Investigational Site Number 0104	Philadelphia	Pennsylvania	United States	19104-5127
13	Investigational Site Number 6101	Camperdown		Australia	2050
14	Investigational Site Number 6104	Clayton		Australia	3168
15	Investigational Site Number 1102	Montreal		Canada	H1T 2M4
16	Investigational Site Number 8604	Beijing		China	100045
17	Investigational Site Number 8602	Guangzhou		China	510515
18	Investigational Site Number 8605	Hangzhou		China	310003
19	Investigational Site Number 8603	Shanghai		China	200025
20	Investigational Site Number 8601	Tianjin		China	300020
21	Investigational Site Number 3303	Lyon		France	69677
22	Investigational Site Number 3301	Rouen		France	76038
23	Investigational Site Number 4905	Frankfurt Am Main		Germany	60590
24	Investigational Site Number 4906	Leipzig		Germany	4103
25	Investigational Site Number 9102	Bangalore		India	560034
26	Investigational Site Number 9108	India		India
27	Investigational Site Number 9104	Jaipur		India	302017
28	Investigational Site Number 9106	Lucknow		India	226003
29	Investigational Site Number 9103	Pune		India	411001
30	Investigational Site Number 9111	Pune		India	411004
31	Investigational Site Number 9105	Vellore		India	632004
32	Investigational Site Number 3901	Florence		Italy	50134
33	Investigational Site Number 3904	Padua		Italy	35128
34	Investigational Site Number 8110	Japan		Japan
35	Investigational Site Number 8103	Kita Kyushu-Shi		Japan
36	Investigational Site Number 8202	Daejeon		Korea, Republic of	35233
37	Investigational Site Number 8203	Seoul		Korea, Republic of	3722
38	Investigational Site Number 8204	Seoul		Korea, Republic of
39	Investigational Site Number 6003	Kota Kinabalu		Malaysia	88586
40	Investigational Site Number 6004	Malaysia		Malaysia
41	Investigational Site Number 2701	Parktown		South Africa	2193
42	Investigational Site Number 2703	Polokwane		South Africa	699
43	Investigational Site Number 2702	Port Elizabeth		South Africa	6001
44	Investigational Site Number 3402	Madrid		Spain	28046
45	Investigational Site Number 8803	Changhua		Taiwan	500
46	Investigational Site Number 8801	Taipei		Taiwan	110
47	Investigational Site Number 8804	Taiwan		Taiwan
48	Investigational Site Number 8805	Taiwan		Taiwan
49	Investigational Site Number 9002	Adana		Turkey	?01130
50	Investigational Site Number 9004	Akdeniz		Turkey	07059
51	Investigational Site Number 9001	Ankara		Turkey	06100
52	Investigational Site Number 9005	Istanbul		Turkey	34093
53	Investigational Site Number 9003	Izmir		Turkey	35100
54	Investigational Site Number 9006	Turkey		Turkey
55	Investigational Site Number 8003	Kyiv		Ukraine	01135
56	Investigational Site Number 8001	Kyiv		Ukraine	04060
57	Investigational Site Number 8002	Lviv		Ukraine	79044
58	Investigational Site Number 4407	London		United Kingdom	E1 2ES

Sponsors and Collaborators

• Genzyme, a Sanofi Company

Investigators

• Study Director: Clinical Sciences & Operations, MD, Sanofi

Study Documents (Full-Text)

• Study Protocol - Jun 27, 2018
• Statistical Analysis Plan - Jul 16, 2020

More Information

Publications

None provided.

• Responsible Party: Genzyme, a Sanofi Company
• ClinicalTrials.gov Identifier: NCT03417102
• Other Study ID Numbers: EFC14768; 2016-001463-36; ALN-AT3SC-003
• First Posted: Jan 31, 2018
• Last Update Posted: Mar 28, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Genzyme, a Sanofi Company: RNAi therapeutic; Hemophilia A; Hemophilia B; Hemophilia A, Severe; Hemophilia B, Severe; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Factor VIII; Factor IX; Inhibitor; Bypassing agents; Coagulants; Fitusiran
• Additional relevant MeSH terms: Hemophilia A; Hemophilia B

Study Results

Participant Flow

Recruitment Details	The study was conducted at 58 centers in 17 countries. A total of 85 participants were screened between 14 February 2018 to 19-Mar-2021, of which 25 participants were screen failure. Screen failures were mainly due to the presence of clinically significant liver disease. A total of 60 participants were enrolled in the study.
Pre-assignment Detail	57 participants randomized in 2:1 ratio to fitusiran prophylaxis and on-demand arms; stratified by number of bleeding episodes prior to Screening (<=10 vs >10). 3 participants from China were treated with fitusiran but not randomized. These participants were considered in fitusiran prophylaxis arm for safety analysis, but not in any other analysis.

Arm/Group Title	Bypassing Agents (BPA) On-demand	Fitusiran 80 mg Prophylaxis
Arm/Group Description	Participants received On-demand BPAs (use of these agents, as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion from Day 1 for treatment of breakthrough bleeding episodes, up to a total of 9 months.	Participants received Fitusiran 80 mg subcutaneously (SC) as prophylaxis once monthly from Day 1, along with the on-demand BPAs (per investigator's discretion and within bleeding dosing guidelines) for treatment of breakthrough bleeding episodes, up to a total of 9 months.
Period Title: Overall Study
STARTED	19	38
Safety Analysis Set	19	41
COMPLETED	19	33
NOT COMPLETED	0	5

Baseline Characteristics

Arm/Group Title	Bypassing Agents (BPA) On-demand	Fitusiran 80 mg Prophylaxis	Total Title
Arm/Group Description	Participants received On-demand BPAs (use of these agents, as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion from Day 1 for treatment of breakthrough bleeding episodes, up to a total of 9 months.	Participants received Fitusiran 80 mg subcutaneously (SC) as prophylaxis once monthly from Day 1, along with the on-demand BPAs (per investigator's discretion and within bleeding dosing guidelines) for treatment of breakthrough bleeding episodes, up to a total of 9 months.
Overall Participants	19	38	57
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	31.5 (13.1)	26.8 (9.8)	28.4 (11.1)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	19 100%	38 100%	57 100%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	13 68.4%	26 68.4%	39 68.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	6 31.6%	10 26.3%	16 28.1%
Other	0 0%	1 2.6%	1 1.8%
Multiple	0 0%	1 2.6%	1 1.8%
Unknown or Not Reported	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period
Description	ABR for a participant during efficacy period (EP) was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. Treated Bleeding episode: any occurrence of hemorrhage that required administration of BPA or factor. It started from first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. EP was defined as time duration starting from Day 29 when antithrombin (AT) lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This outcome measure (OM) represents estimated results (i.e., results received by applying negative binomial [NB] regression model on data collected during EP).
Time Frame	From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population.

Arm/Group Title	Bypassing Agents (BPA) On-demand	Fitusiran 80 mg Prophylaxis
Arm/Group Description	Participants received On-demand BPAs (use of these agents, as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion from Day 1 for treatment of breakthrough bleeding episodes, up to a total of 9 months.	Participants received Fitusiran 80 mg subcutaneously (SC) as prophylaxis once monthly from Day 1, along with the on-demand BPAs (per investigator's discretion and within bleeding dosing guidelines) for treatment of breakthrough bleeding episodes, up to a total of 9 months.
Measure Participants	19	38
Number (95% Confidence Interval) [episodes per participant per year]	18.071	1.666

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bypassing Agents (BPA) On-demand, Fitusiran 80 mg Prophylaxis
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value derived from NB regression model, accounted for different follow-up times during EP, with treatment arm and randomization strata of number of bleeds in 6 months prior to study (<=10,>10) as fixed effects. Significance threshold was 0.05.
	Method	Negative binomial regression model
	Comments
Method of Estimation	Estimation Parameter	ABR ratio
	Estimated Value	0.092
	Confidence Interval	(2-Sided) 95%; 0.044 to 0.192
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period
Description	ABR for a participant during EP was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. ABR= number of bleeding episodes during EP divided by total number of days during EP*365.25. A bleeding episode was defined as any occurrence of hemorrhage that required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. EP was defined as time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or the last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This OM represents observed results (i.e., descriptive statistics values based on the data which was collected during EP).
Time Frame	From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population.

Arm/Group Title	Bypassing Agents (BPA) On-demand	Fitusiran 80 mg Prophylaxis
Arm/Group Description	Participants received On-demand BPAs (use of these agents, as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion from Day 1 for treatment of breakthrough bleeding episodes, up to a total of 9 months.	Participants received Fitusiran 80 mg subcutaneously (SC) as prophylaxis once monthly from Day 1, along with the on-demand BPAs (per investigator's discretion and within bleeding dosing guidelines) for treatment of breakthrough bleeding episodes, up to a total of 9 months.
Measure Participants	19	38
Mean (Standard Deviation) [episodes per participant per year]	18.1 (14.9)	1.7 (3.8)

3. Secondary Outcome

Title	Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period
Description	ABR for a participant during treatment period (TP) was defined as annualized number of bleeding episodes during TP annualized to a 1-year interval of time. Bleeding episode: any occurrence of hemorrhage that required administration of BPA or factor. It started from first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. TP was sum of onset period (first 28 days after first dose of fitusiran) and EP (starting on Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to earliest of [Day 246 or last day of bleeding follow up])(maximum duration of TP: from Day 1 to Day 246). This OM represents estimated results (i.e., results received by applying NB regression model on data collected during TP).
Time Frame	From Day 1 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population.

Arm/Group Title	Bypassing Agents (BPA) On-demand	Fitusiran 80 mg Prophylaxis
Arm/Group Description	Participants received On-demand BPAs (use of these agents, as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion from Day 1 for treatment of breakthrough bleeding episodes, up to a total of 9 months.	Participants received Fitusiran 80 mg subcutaneously (SC) as prophylaxis once monthly from Day 1, along with the on-demand BPAs (per investigator's discretion and within bleeding dosing guidelines) for treatment of breakthrough bleeding episodes, up to a total of 9 months.
Measure Participants	19	38
Number (95% Confidence Interval) [episodes per participant per year]	18.819	2.024

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bypassing Agents (BPA) On-demand, Fitusiran 80 mg Prophylaxis
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value derived from NB regression model, accounted for different follow-up times during TP, with treatment arm and randomization strata of number of bleeds in 6 months prior to study (<=10,>10) as fixed effects. Significance threshold was 0.05.
	Method	Negative binomial regression model
	Comments
Method of Estimation	Estimation Parameter	ABR ratio
	Estimated Value	0.108
	Confidence Interval	(2-Sided) 95%; 0.056 to 0.207
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period
Description	ABR for a participant during TP was defined as annualized number of bleeding episodes during TP annualized to a 1-year interval of time. ABR= number of bleeding episodes during TP divided by total number of days during TP*365.25. Bleeding episode: any occurrence of hemorrhage that required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. TP was sum of onset period (first 28 days after the first dose of fitusiran) and EP (starting on Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of [Day 246 or the last day of bleeding follow up]) (maximum duration of TP: from Day 1 to Day 246). This OM represents observed results (i.e., descriptive statistics values based on data collected during TP).
Time Frame	From Day 1 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population.

Arm/Group Title	Bypassing Agents (BPA) On-demand	Fitusiran 80 mg Prophylaxis
Arm/Group Description	Participants received On-demand BPAs (use of these agents, as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion from Day 1 for treatment of breakthrough bleeding episodes, up to a total of 9 months.	Participants received Fitusiran 80 mg subcutaneously (SC) as prophylaxis once monthly from Day 1, along with the on-demand BPAs (per investigator's discretion and within bleeding dosing guidelines) for treatment of breakthrough bleeding episodes, up to a total of 9 months.
Measure Participants	19	38
Mean (Standard Deviation) [episodes per participant per year]	18.8 (15.4)	2.0 (3.7)

5. Secondary Outcome

Title	Estimated Annualized Spontaneous Bleeding Rate for Treated Bleeds During Efficacy Period
Description	Annualized spontaneous bleeding rate for a participant during EP was defined as annualized number of spontaneous bleeding episodes during EP annualized to a 1-year interval of time. Spontaneous bleeding episode was bleeding event that occurred for no apparent or known reason, particularly into joints, muscles, and soft tissues. It started from first sign of a bleed and ended no more than 72 hours after last treatment for the bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. EP was defined as time duration starting from Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This OM represents estimated results (i.e., results received by applying NB regression model on data collected during EP).
Time Frame	From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population.

Arm/Group Title	Bypassing Agents (BPA) On-demand	Fitusiran 80 mg Prophylaxis
Arm/Group Description	Participants received On-demand BPAs (use of these agents, as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion from Day 1 for treatment of breakthrough bleeding episodes, up to a total of 9 months.	Participants received Fitusiran 80 mg subcutaneously (SC) as prophylaxis once monthly from Day 1, along with the on-demand BPAs (per investigator's discretion and within bleeding dosing guidelines) for treatment of breakthrough bleeding episodes, up to a total of 9 months.
Measure Participants	19	38
Number (95% Confidence Interval) [episodes per participant per year]	15.675	0.872

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bypassing Agents (BPA) On-demand, Fitusiran 80 mg Prophylaxis
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value derived from NB regression model, accounted for different follow-up times during EP, with treatment arm and randomization strata of number of bleeds in 6 months prior to study (<=10,>10) as fixed effects. Significance threshold was 0.05.
	Method	Negative binomial regression model
	Comments
Method of Estimation	Estimation Parameter	ABR ratio
	Estimated Value	0.056
	Confidence Interval	(2-Sided) 95%; 0.026 to 0.121
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Observed Annualized Spontaneous Bleeding Rate for Treated Bleeds During the Efficacy Period
Description	ABR for participant during EP was defined as annualized number of spontaneous bleeding episodes during EP annualized to a 1-year interval of time. ABR=number of treated spontaneous bleeding episodes during EP divided by total number of days during EP*365.25. Spontaneous bleeding episode was bleeding event that occurred for no apparent or known reason, into joints, muscles, and soft tissues. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. EP: time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to earliest of (Day 246 or the last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This OM represents observed results (i.e., descriptive statistics values based on data collected during EP).
Time Frame	From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population.

Arm/Group Title	Bypassing Agents (BPA) On-demand	Fitusiran 80 mg Prophylaxis
Arm/Group Description	Participants received On-demand BPAs (use of these agents, as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion from Day 1 for treatment of breakthrough bleeding episodes, up to a total of 9 months.	Participants received Fitusiran 80 mg subcutaneously (SC) as prophylaxis once monthly from Day 1, along with the on-demand BPAs (per investigator's discretion and within bleeding dosing guidelines) for treatment of breakthrough bleeding episodes, up to a total of 9 months.
Measure Participants	19	38
Mean (Standard Deviation) [episodes per participant per year]	15.6 (14.9)	0.9 (2.0)

7. Secondary Outcome

Title	Estimated Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period
Description	Annualized joint bleeding rate for a participant during EP was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. Joint bleeding episode was characterized by an unusual sensation in the joint ("aura") in combination with 1) increasing swelling or warmth over the skin, joint, 2) increased pain, or 3) progressive loss of range of motion or difficulty in using the limb as compared with Baseline. It started from first sign of a bleed and ended no more than 72 hours after last treatment for the bleed. EP was defined as time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or the last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This OM presents estimated results (i.e., results received by applying NB regression model on data collected during EP).
Time Frame	From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population.

Arm/Group Title	Bypassing Agents (BPA) On-demand	Fitusiran 80 mg Prophylaxis
Arm/Group Description	Participants received On-demand BPAs (use of these agents, as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion from Day 1 for treatment of breakthrough bleeding episodes, up to a total of 9 months.	Participants received Fitusiran 80 mg subcutaneously (SC) as prophylaxis once monthly from Day 1, along with the on-demand BPAs (per investigator's discretion and within bleeding dosing guidelines) for treatment of breakthrough bleeding episodes, up to a total of 9 months.
Measure Participants	19	38
Number (95% Confidence Interval) [episodes per participant per year]	13.759	1.349

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bypassing Agents (BPA) On-demand, Fitusiran 80 mg Prophylaxis
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	P-value derived from NB regression model, accounted for different follow-up times during EP, with treatment arm and randomization strata of number of bleeds in 6 months prior to study (<=10,>10) as fixed effects. Significance threshold was 0.05.
	Method	Negative binomial regression model
	Comments
Method of Estimation	Estimation Parameter	ABR ratio
	Estimated Value	0.098
	Confidence Interval	(2-Sided) 95%; 0.046 to 0.210
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Observed Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period
Description	Annualized joint bleeding rate for participant during EP was defined as annualized number of joint bleeding episodes during EP annualized to 1-year interval of time. ABR= number of treated joint bleeding episodes during EP divided by total number of days during EP*365.25. A joint bleeding episode was characterized by an unusual sensation in joint ("aura") in combination with 1) increasing swelling or warmth over skin, joint, 2) increased pain, or 3) progressive loss of range of motion or difficulty in using limb as compared with Baseline. It started from first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed. EP: time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This OM presents observed results (i.e., descriptive statistics values based on data collected during EP).
Time Frame	From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population.

Arm/Group Title	Bypassing Agents (BPA) On-demand	Fitusiran 80 mg Prophylaxis
Arm/Group Description	Participants received On-demand BPAs (use of these agents, as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion from Day 1 for treatment of breakthrough bleeding episodes, up to a total of 9 months.	Participants received Fitusiran 80 mg subcutaneously (SC) as prophylaxis once monthly from Day 1, along with the on-demand BPAs (per investigator's discretion and within bleeding dosing guidelines) for treatment of breakthrough bleeding episodes, up to a total of 9 months.
Measure Participants	19	38
Mean (Standard Deviation) [episodes per participant per year]	13.8 (12.2)	1.4 (3.4)

9. Secondary Outcome

Title	Health-related Quality of Life (HRQOL): Change From Baseline in Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) Physical Health Domain Score at Month 9
Description	Haem-A-QoL: participant-reported questionnaire designed for adult participants (>=17 years of age) with hemophilia; and consisted of 46 items comprising 10 domains (physical health, feelings, view of yourself, sports and leisure, work and school, dealing with hemophilia, treatment, future, family planning, partnership and sexuality). Items were rated along five response options: never, rarely, sometimes, often, or all the time. Change from baseline in physical Health domain score was reported in this outcome measure. Raw score for physical health domain were transformed to a scale ranged from 0 to 100, where lower scores denoted better physical health.
Time Frame	Baseline (Day 1), Month 9

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

Arm/Group Title	Bypassing Agents (BPA) On-demand	Fitusiran 80 mg Prophylaxis
Arm/Group Description	Participants received On-demand BPAs (use of these agents, as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion from Day 1 for treatment of breakthrough bleeding episodes, up to a total of 9 months.	Participants received Fitusiran 80 mg subcutaneously (SC) as prophylaxis once monthly from Day 1, along with the on-demand BPAs (per investigator's discretion and within bleeding dosing guidelines) for treatment of breakthrough bleeding episodes, up to a total of 9 months.
Measure Participants	17	32
Least Squares Mean (95% Confidence Interval) [score on a scale]	-1.94	-30.67

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bypassing Agents (BPA) On-demand, Fitusiran 80 mg Prophylaxis
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Analysis of Covariance (ANCOVA) model included treatment arm and randomization strata of number of bleeds (<=10, > 10) as fixed effects, Baseline score as a covariate. Significance threshold was at 0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Least Square (LS) Mean difference
	Estimated Value	-28.72
	Confidence Interval	(2-Sided) 95%; -39.07 to -18.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	Health-related Quality of Life (HRQOL): Change From Baseline in Haem-A-QOL Total Score at Month 9
Description	Haem-A-QoL: participant-reported questionnaire designed for adult participants (>=17 years of age) with hemophilia; and consisted of 46 items comprising 10 domains (physical health, feelings, view of yourself, sports and leisure, work and school, dealing with hemophilia, treatment, future, family planning, partnership and sexuality). Items were rated along five response options: never, rarely, sometimes, often, or all the time. Raw score for each domain were transformed to a scale ranged from 0 to 100, where lower scores denoted better health. Haem-A-QoL Total Score was average of all domain scores and ranged from 0 to 100, where lower scores denoted better quality of life.
Time Frame	Baseline (Day 1), Month 9

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

Arm/Group Title	Bypassing Agents (BPA) On-demand	Fitusiran 80 mg Prophylaxis
Arm/Group Description	Participants received On-demand BPAs (use of these agents, as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion from Day 1 for treatment of breakthrough bleeding episodes, up to a total of 9 months.	Participants received Fitusiran 80 mg subcutaneously (SC) as prophylaxis once monthly from Day 1, along with the on-demand BPAs (per investigator's discretion and within bleeding dosing guidelines) for treatment of breakthrough bleeding episodes, up to a total of 9 months.
Measure Participants	17	31
Least Squares Mean (95% Confidence Interval) [score on a scale]	-0.42	-15.27

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bypassing Agents (BPA) On-demand, Fitusiran 80 mg Prophylaxis
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	ANCOVA model included treatment arm and randomization strata of number of bleeds (<=10, > 10) as fixed effects, Baseline score as a covariate. Significance threshold was at 0.05.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	LS Mean difference
	Estimated Value	-14.85
	Confidence Interval	(2-Sided) 95%; -21.37 to -8.33
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Onset Period
Description	ABR was annualized number of bleeding episodes during onset period per participant annualized to a 1-year interval of time. A treated bleeding episode was defined as any occurrence of hemorrhage that may required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. The onset period was defined as time interval from Day 1 to the earlier of Day 28 or the last day of bleeding follow up. This OM represents estimated results (i.e., results received by applying NB regression model on data collected during onset period).
Time Frame	From Day 1 up to Day 28 or up to the last day of bleeding follow up (any day up to Day 28), whichever was the earliest

Outcome Measure Data

Analysis Population Description

Analysis was performed on ITT population.

Arm/Group Title	Bypassing Agents (BPA) On-demand	Fitusiran 80 mg Prophylaxis
Arm/Group Description	Participants received On-demand BPAs (use of these agents, as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion from Day 1 for treatment of breakthrough bleeding episodes, up to a total of 9 months.	Participants received Fitusiran 80 mg subcutaneously (SC) as prophylaxis once monthly from Day 1, along with the on-demand BPAs (per investigator's discretion and within bleeding dosing guidelines) for treatment of breakthrough bleeding episodes, up to a total of 9 months.
Measure Participants	19	38
Number (95% Confidence Interval) [episodes per participant per year]	25.149	4.426

12. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
Description	An adverse Event (AE) was defined as any untoward medical occurrence in a participant who received study drug which did not necessarily have a causal relationship with the treatment. Treatment emergent AEs were defined as any AE with onset date after first dose of fitusiran in the fitusiran prophylaxis arm or after Day 1 visit in the BPA on-demand arm. A Serious AE (SAE) was defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly or birth defect, or was a medically important event.
Time Frame	From Baseline (Day 1) up to 15 months (i.e. 9 months treatment period + 6-months follow-up)

Outcome Measure Data

Analysis Population Description

Analysis was performed on safety analysis set that included all participants who received at least 1 dose of study drug or were randomized to on-demand arm, analyzed according to the actual treatment received.

Arm/Group Title	Bypassing Agents (BPA) On-demand	Fitusiran 80 mg Prophylaxis
Arm/Group Description	Participants received On-demand BPAs (use of these agents, as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion from Day 1 for treatment of breakthrough bleeding episodes, up to a total of 9 months.	Participants received Fitusiran 80 mg subcutaneously (SC) as prophylaxis once monthly from Day 1, along with the on-demand BPAs (per investigator's discretion and within bleeding dosing guidelines) for treatment of breakthrough bleeding episodes, up to a total of 9 months.
Measure Participants	19	41
Any TEAE	11 57.9%	38 100%
Any TESAE	5 26.3%	7 18.4%

Adverse Events

Time Frame	AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up).
Adverse Event Reporting Description	TEAEs: any AE with onset date after first dose of fitusiran in fitusiran prophylaxis arm or after Day 1 visit in the BPA on-demand arm. Analysis done on safety analysis set. Three participants who were treated with fitusiran but not randomized as per protocol addendum for China, were included in safety analysis for the fitusiran prophylaxis arm.
Arm/Group Title	Bypassing Agents (BPA) On-demand		Fitusiran 80 mg Prophylaxis
Arm/Group Description	Participants received On-demand BPAs (use of these agents, as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion from Day 1 for treatment of breakthrough bleeding episodes, up to a total of 9 months.		Participants received Fitusiran 80 mg subcutaneously (SC) as prophylaxis once monthly from Day 1, along with the on-demand BPAs (per investigator's discretion and within bleeding dosing guidelines) for treatment of breakthrough bleeding episodes, up to a total of 9 months.
All Cause Mortality
	Bypassing Agents (BPA) On-demand		Fitusiran 80 mg Prophylaxis
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/19 (0%)		0/41 (0%)
Serious Adverse Events
	Bypassing Agents (BPA) On-demand		Fitusiran 80 mg Prophylaxis
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/19 (26.3%)		7/41 (17.1%)
Blood and lymphatic system disorders
Anaemia	0/19 (0%)	0	1/41 (2.4%)	1
Hepatobiliary disorders
Biliary Colic	0/19 (0%)	0	1/41 (2.4%)	2
Cholecystitis Acute	0/19 (0%)	0	1/41 (2.4%)	1
Cholecystitis Chronic	0/19 (0%)	0	1/41 (2.4%)	1
Infections and infestations
Asymptomatic Covid-19	0/19 (0%)	0	1/41 (2.4%)	1
Device Related Infection	0/19 (0%)	0	1/41 (2.4%)	1
Haematoma Infection	0/19 (0%)	0	1/41 (2.4%)	1
Vascular Device Infection	0/19 (0%)	0	1/41 (2.4%)	1
Injury, poisoning and procedural complications
Tooth Fracture	1/19 (5.3%)	1	0/41 (0%)	0
Traumatic Haemorrhage	1/19 (5.3%)	2	0/41 (0%)	0
Musculoskeletal and connective tissue disorders
Haemarthrosis	1/19 (5.3%)	2	0/41 (0%)	0
Muscle Haemorrhage	1/19 (5.3%)	1	0/41 (0%)	0
Nervous system disorders
Spinal Vascular Disorder	0/19 (0%)	0	1/41 (2.4%)	1
Renal and urinary disorders
Haematuria	1/19 (5.3%)	1	1/41 (2.4%)	1
Vascular disorders
Haemorrhage	1/19 (5.3%)	1	0/41 (0%)	0
Subclavian Vein Thrombosis	0/19 (0%)	0	1/41 (2.4%)	1
Thrombosis	0/19 (0%)	0	1/41 (2.4%)	1
Other (Not Including Serious) Adverse Events
	Bypassing Agents (BPA) On-demand		Fitusiran 80 mg Prophylaxis
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/19 (42.1%)		32/41 (78%)
Gastrointestinal disorders
Abdominal Pain Upper	0/19 (0%)	0	6/41 (14.6%)	7
Constipation	1/19 (5.3%)	1	1/41 (2.4%)	1
Haemorrhoids	1/19 (5.3%)	1	2/41 (4.9%)	2
General disorders
Asthenia	1/19 (5.3%)	1	0/41 (0%)	0
Pyrexia	0/19 (0%)	0	3/41 (7.3%)	3
Infections and infestations
Asymptomatic Covid-19	1/19 (5.3%)	1	0/41 (0%)	0
Cystitis	1/19 (5.3%)	1	1/41 (2.4%)	1
Influenza	0/19 (0%)	0	3/41 (7.3%)	3
Nasopharyngitis	0/19 (0%)	0	3/41 (7.3%)	5
Pharyngotonsillitis	1/19 (5.3%)	1	0/41 (0%)	0
Upper Respiratory Tract Infection	1/19 (5.3%)	1	6/41 (14.6%)	8
Investigations
Alanine Aminotransferase Increased	0/19 (0%)	0	13/41 (31.7%)	23
Aspartate Aminotransferase Increased	0/19 (0%)	0	8/41 (19.5%)	16
Blood Alkaline Phosphatase Increased	0/19 (0%)	0	5/41 (12.2%)	9
Fibrin D Dimer Increased	0/19 (0%)	0	3/41 (7.3%)	6
Gamma-Glutamyltransferase Increased	0/19 (0%)	0	6/41 (14.6%)	9
Prothrombin Fragment 1.2 Increased	0/19 (0%)	0	3/41 (7.3%)	6
Transaminases Increased	0/19 (0%)	0	5/41 (12.2%)	6
Musculoskeletal and connective tissue disorders
Arthralgia	0/19 (0%)	0	5/41 (12.2%)	13
Back Pain	1/19 (5.3%)	1	1/41 (2.4%)	2
Nervous system disorders
Headache	1/19 (5.3%)	1	6/41 (14.6%)	9
Hypoaesthesia	1/19 (5.3%)	1	0/41 (0%)	0
Skin and subcutaneous tissue disorders
Urticaria	1/19 (5.3%)	1	1/41 (2.4%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Sponsor supports publication of clinical trial results but may request that investigators temporarily delay or alter publications in order to protect proprietary information. The Sponsor may also require that the results of multicenter studies be published only in their entirety and not as individual site data.