Trial Outcomes & Findings for A Study of Fitusiran (ALN-AT3SC) in Severe Hemophilia A and B Patients With Inhibitors (NCT NCT03417102)

Last Updated: 2022-03-28

Results Overview

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).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

60 participants

Primary outcome timeframe

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

Results posted on

2022-03-28

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	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.	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.
Overall Study STARTED	19	38
Overall Study Safety Analysis Set	19	41
Overall Study COMPLETED	19	33
Overall Study NOT COMPLETED	0	5

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.
Overall Study Adverse Event	0	1
Overall Study Related to Coronavirus Pandemic (Covid-19)	0	3
Overall Study Other	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Bypassing Agents (BPA) On-demand n=19 Participants 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.	Fitusiran 80 mg Prophylaxis n=38 Participants 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.	Total Title n=57 Participants
Age, Continuous	31.5 years STANDARD_DEVIATION 13.1 • n=5 Participants	26.8 years STANDARD_DEVIATION 9.8 • n=7 Participants	28.4 years STANDARD_DEVIATION 11.1 • n=5 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Sex: Female, Male Male	19 Participants n=5 Participants	38 Participants n=7 Participants	57 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Asian	13 Participants n=5 Participants	26 Participants n=7 Participants	39 Participants n=5 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized White	6 Participants n=5 Participants	10 Participants n=7 Participants	16 Participants n=5 Participants
Race/Ethnicity, Customized Other	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Multiple	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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

Population: Analysis was performed on ITT population.

Outcome measures

Outcome measures
Measure	Bypassing Agents (BPA) On-demand n=19 Participants 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.	Fitusiran 80 mg Prophylaxis n=38 Participants 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.
Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period	18.071 episodes per participant per year Interval 10.598 to 30.812	1.666 episodes per participant per year Interval 1.014 to 2.736

PRIMARY outcome

Timeframe: 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

Population: Analysis was performed on ITT population.

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).

Outcome measures

Outcome measures
Measure	Bypassing Agents (BPA) On-demand n=19 Participants 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.	Fitusiran 80 mg Prophylaxis n=38 Participants 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.
Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period	18.1 episodes per participant per year Standard Deviation 14.9	1.7 episodes per participant per year Standard Deviation 3.8

SECONDARY outcome

Timeframe: 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

Population: Analysis was performed on ITT population.

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).

Outcome measures

Outcome measures
Measure	Bypassing Agents (BPA) On-demand n=19 Participants 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.	Fitusiran 80 mg Prophylaxis n=38 Participants 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.
Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period	18.819 episodes per participant per year Interval 11.541 to 30.687	2.024 episodes per participant per year Interval 1.306 to 3.138

SECONDARY outcome

Timeframe: 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

Population: Analysis was performed on ITT population.

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).

Outcome measures

Outcome measures
Measure	Bypassing Agents (BPA) On-demand n=19 Participants 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.	Fitusiran 80 mg Prophylaxis n=38 Participants 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.
Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period	18.8 episodes per participant per year Standard Deviation 15.4	2.0 episodes per participant per year Standard Deviation 3.7

SECONDARY outcome

Timeframe: 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

Population: Analysis was performed on ITT population.

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).

Outcome measures

Outcome measures
Measure	Bypassing Agents (BPA) On-demand n=19 Participants 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.	Fitusiran 80 mg Prophylaxis n=38 Participants 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.
Estimated Annualized Spontaneous Bleeding Rate for Treated Bleeds During Efficacy Period	15.675 episodes per participant per year Interval 9.281 to 26.471	0.872 episodes per participant per year Interval 0.491 to 1.551

SECONDARY outcome

Timeframe: 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

Population: Analysis was performed on ITT population.

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).

Outcome measures

Outcome measures
Measure	Bypassing Agents (BPA) On-demand n=19 Participants 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.	Fitusiran 80 mg Prophylaxis n=38 Participants 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.
Observed Annualized Spontaneous Bleeding Rate for Treated Bleeds During the Efficacy Period	15.6 episodes per participant per year Standard Deviation 14.9	0.9 episodes per participant per year Standard Deviation 2.0

SECONDARY outcome

Timeframe: 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

Population: Analysis was performed on ITT population.

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).

Outcome measures

Outcome measures
Measure	Bypassing Agents (BPA) On-demand n=19 Participants 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.	Fitusiran 80 mg Prophylaxis n=38 Participants 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.
Estimated Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period	13.759 episodes per participant per year Interval 7.95 to 23.811	1.349 episodes per participant per year Interval 0.798 to 2.28

SECONDARY outcome

Timeframe: 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

Population: Analysis was performed on ITT population.

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).

Outcome measures

Outcome measures
Measure	Bypassing Agents (BPA) On-demand n=19 Participants 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.	Fitusiran 80 mg Prophylaxis n=38 Participants 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.
Observed Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period	13.8 episodes per participant per year Standard Deviation 12.2	1.4 episodes per participant per year Standard Deviation 3.4

SECONDARY outcome

Timeframe: Baseline (Day 1), Month 9

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

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.

Outcome measures

Outcome measures
Measure	Bypassing Agents (BPA) On-demand n=17 Participants 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.	Fitusiran 80 mg Prophylaxis n=32 Participants 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.
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	-1.94 score on a scale Interval -10.32 to 6.43	-30.67 score on a scale Interval -36.9 to -24.43

SECONDARY outcome

Timeframe: Baseline (Day 1), Month 9

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

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.

Outcome measures

Outcome measures
Measure	Bypassing Agents (BPA) On-demand n=17 Participants 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.	Fitusiran 80 mg Prophylaxis n=31 Participants 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.
Health-related Quality of Life (HRQOL): Change From Baseline in Haem-A-QOL Total Score at Month 9	-0.42 score on a scale Interval -5.65 to 4.8	-15.27 score on a scale Interval -19.3 to -11.24

SECONDARY outcome

Timeframe: 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

Population: Analysis was performed on ITT population.

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).

Outcome measures

Outcome measures
Measure	Bypassing Agents (BPA) On-demand n=19 Participants 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.	Fitusiran 80 mg Prophylaxis n=38 Participants 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.
Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Onset Period	25.149 episodes per participant per year Interval 15.819 to 39.981	4.426 episodes per participant per year Interval 2.439 to 8.03

SECONDARY outcome

Timeframe: From Baseline (Day 1) up to 15 months (i.e. 9 months treatment period + 6-months follow-up)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Bypassing Agents (BPA) On-demand n=19 Participants 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.	Fitusiran 80 mg Prophylaxis n=41 Participants 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.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) Any TEAE	11 Participants	38 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) Any TESAE	5 Participants	7 Participants

Adverse Events

Bypassing Agents (BPA) On-demand

Serious events: 5 serious events

Other events: 8 other events

Deaths: 0 deaths

Fitusiran 80 mg Prophylaxis

Serious events: 7 serious events

Other events: 32 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Trial Transparency Team

Sanofi aventis recherche & développement

Phone: 800-633-1610

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Bypassing Agents (BPA) On-demand n=19 participants at risk 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.	Fitusiran 80 mg Prophylaxis n=41 participants at risk 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.
Infections and infestations Device Related Infection	0.00% 0/19 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.	2.4% 1/41 • Number of events 1 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.
Infections and infestations Haematoma Infection	0.00% 0/19 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.	2.4% 1/41 • Number of events 1 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.
Injury, poisoning and procedural complications Tooth Fracture	5.3% 1/19 • Number of events 1 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.	0.00% 0/41 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.
Injury, poisoning and procedural complications Traumatic Haemorrhage	5.3% 1/19 • Number of events 2 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.	0.00% 0/41 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.
Blood and lymphatic system disorders Anaemia	0.00% 0/19 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.	2.4% 1/41 • Number of events 1 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.
Nervous system disorders Spinal Vascular Disorder	0.00% 0/19 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.	2.4% 1/41 • Number of events 1 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.
Renal and urinary disorders Haematuria	5.3% 1/19 • Number of events 1 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.	2.4% 1/41 • Number of events 1 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.
Musculoskeletal and connective tissue disorders Haemarthrosis	5.3% 1/19 • Number of events 2 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.	0.00% 0/41 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.
Musculoskeletal and connective tissue disorders Muscle Haemorrhage	5.3% 1/19 • Number of events 1 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.	0.00% 0/41 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.
Infections and infestations Asymptomatic Covid-19	0.00% 0/19 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.	2.4% 1/41 • Number of events 1 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.
Infections and infestations Vascular Device Infection	0.00% 0/19 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.	2.4% 1/41 • Number of events 1 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.
Vascular disorders Haemorrhage	5.3% 1/19 • Number of events 1 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.	0.00% 0/41 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.
Vascular disorders Subclavian Vein Thrombosis	0.00% 0/19 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.	2.4% 1/41 • Number of events 1 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.
Vascular disorders Thrombosis	0.00% 0/19 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.	2.4% 1/41 • Number of events 1 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.
Hepatobiliary disorders Biliary Colic	0.00% 0/19 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.	2.4% 1/41 • Number of events 2 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.
Hepatobiliary disorders Cholecystitis Acute	0.00% 0/19 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.	2.4% 1/41 • Number of events 1 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.
Hepatobiliary disorders Cholecystitis Chronic	0.00% 0/19 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.	2.4% 1/41 • Number of events 1 • AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up). 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.