Trial Outcomes & Findings for A Study of Fitusiran (ALN-AT3SC) in Severe Hemophilia A and B Patients Without Inhibitors (NCT NCT03417245)

NCT ID: NCT03417245

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 by-passing agents (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) presents 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: 120 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 64 centers in 19 countries. A total of 177 participants were screened between 1 March 2018 to 22 May 2020, of which 57 participants were screen failure. Screen failures were mainly due to presence of a co-existing thrombophilic disorder. In total, 120 participants were enrolled in the study.

120 participants were randomized in 2:1 ratio to fitusiran prophylaxis and on-demand arms by interactive response system; stratified by the number of bleeding episodes in the 6 months prior to Screening (less than or equal to [<=10] versus greater than [>]10) and by hemophilia type (hemophilia A or B).

Participant milestones

Measure	Factor On-demand Participants received on-demand factor concentrates (as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion for the treatment of breakthrough bleeding episodes from Day 1 up to a total of 9 months.	Fitusiran 80 mg Prophylaxis Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes.
Overall Study STARTED	40	80
Overall Study Treated	40	79
Overall Study COMPLETED	37	79
Overall Study NOT COMPLETED	3	1

Reasons for withdrawal

Measure	Factor On-demand Participants received on-demand factor concentrates (as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion for the treatment of breakthrough bleeding episodes from Day 1 up to a total of 9 months.	Fitusiran 80 mg Prophylaxis Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes.
Overall Study Adverse Event	1	0
Overall Study Protocol Violation	1	0
Overall Study Withdrawal by Subject	1	1

Baseline Characteristics

A Study of Fitusiran (ALN-AT3SC) in Severe Hemophilia A and B Patients Without Inhibitors

Baseline characteristics by cohort

Measure	Factor On-demand n=40 Participants Participants received on-demand factor concentrates (as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion for the treatment of breakthrough bleeding episodes from Day 1 up to a total of 9 months.	Fitusiran 80 mg Prophylaxis n=80 Participants Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes.	Total Title n=120 Participants
Age, Continuous	33.6 years STANDARD_DEVIATION 13.6 • n=5 Participants	33.9 years STANDARD_DEVIATION 14.6 • n=7 Participants	33.8 years STANDARD_DEVIATION 14.2 • 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	40 Participants n=5 Participants	80 Participants n=7 Participants	120 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	28 Participants n=5 Participants	43 Participants n=7 Participants	71 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) White	12 Participants n=5 Participants	33 Participants n=7 Participants	45 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) 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. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

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 by-passing agents (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) presents estimated results (i.e., results received by applying negative binomial [NB] regression model on data collected during EP).

Outcome measures

Measure	Factor On-demand n=40 Participants Participants received on-demand factor concentrates (as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion for the treatment of breakthrough bleeding episodes from Day 1 up to a total of 9 months.	Fitusiran 80 mg Prophylaxis n=79 Participants Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes.
Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period	30.991 episodes per participant per year Interval 21.114 to 45.487	3.133 episodes per participant per year Interval 2.269 to 4.326

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. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

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 <=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 presents observed results (i.e., descriptive statistics values based on the data collected during EP).

Outcome measures

Measure	Factor On-demand n=40 Participants Participants received on-demand factor concentrates (as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion for the treatment of breakthrough bleeding episodes from Day 1 up to a total of 9 months.	Fitusiran 80 mg Prophylaxis n=79 Participants Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes.
Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period	21.8 episodes per participant per year Interval 8.4 to 41.0	0.0 episodes per participant per year Interval 0.0 to 3.4

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. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

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 <=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 presents estimated results (i.e., results received by applying NB regression model on data collected during TP).

Outcome measures

Measure	Factor On-demand n=40 Participants Participants received on-demand factor concentrates (as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion for the treatment of breakthrough bleeding episodes from Day 1 up to a total of 9 months.	Fitusiran 80 mg Prophylaxis n=79 Participants Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes.
Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period	31.444 episodes per participant per year Interval 22.995 to 42.999	4.092 episodes per participant per year Interval 3.143 to 5.328

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. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

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 <=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 presents observed results (i.e., descriptive statistics values based on data collected during TP).

Outcome measures

Measure	Factor On-demand n=40 Participants Participants received on-demand factor concentrates (as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion for the treatment of breakthrough bleeding episodes from Day 1 up to a total of 9 months.	Fitusiran 80 mg Prophylaxis n=79 Participants Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes.
Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period	25.2 episodes per participant per year Interval 11.9 to 43.8	1.8 episodes per participant per year Interval 0.0 to 4.5

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. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

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 <=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 presents estimated results (i.e., results received by applying NB regression model on data collected during EP).

Outcome measures

Measure	Factor On-demand n=40 Participants Participants received on-demand factor concentrates (as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion for the treatment of breakthrough bleeding episodes from Day 1 up to a total of 9 months.	Fitusiran 80 mg Prophylaxis n=79 Participants Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes.
Estimated Annualized Spontaneous Bleeding Rate for Treated Bleeds During the Efficacy Period	22.036 episodes per participant per year Interval 14.159 to 34.295	1.825 episodes per participant per year Interval 1.237 to 2.692

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. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

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 the bleed, within which any symptoms of bleeding at the same location or injections <=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 presents observed results (i.e., descriptive statistics values based on data collected during EP).

Outcome measures

Measure	Factor On-demand n=40 Participants Participants received on-demand factor concentrates (as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion for the treatment of breakthrough bleeding episodes from Day 1 up to a total of 9 months.	Fitusiran 80 mg Prophylaxis n=79 Participants Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes.
Observed Annualized Spontaneous Bleeding Rate for Treated Bleeds During the Efficacy Period	16.1 episodes per participant per year Interval 3.4 to 27.6	0.0 episodes per participant per year Interval 0.0 to 1.7

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. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

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) increasing 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

Measure	Factor On-demand n=40 Participants Participants received on-demand factor concentrates (as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion for the treatment of breakthrough bleeding episodes from Day 1 up to a total of 9 months.	Fitusiran 80 mg Prophylaxis n=79 Participants Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes.
Estimated Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period	23.413 episodes per participant per year Interval 15.363 to 35.68	2.282 episodes per participant per year Interval 1.594 to 3.268

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. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

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) increasing 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

Measure	Factor On-demand n=40 Participants Participants received on-demand factor concentrates (as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion for the treatment of breakthrough bleeding episodes from Day 1 up to a total of 9 months.	Fitusiran 80 mg Prophylaxis n=79 Participants Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes.
Observed Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period	15.9 episodes per participant per year Interval 4.2 to 33.5	0.0 episodes per participant per year Interval 0.0 to 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). Scoring for each item was based on a 5-point Likert scale (1= never, 2= rarely, 3= sometimes, 4= often, and 5=all the time), and higher scores represented greater impairment. 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 (better health outcome) to 100 (worst health outcome), where lower scores denoted better physical health.

Outcome measures

Measure	Factor On-demand n=34 Participants Participants received on-demand factor concentrates (as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion for the treatment of breakthrough bleeding episodes from Day 1 up to a total of 9 months.	Fitusiran 80 mg Prophylaxis n=69 Participants Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes.
Health-related Quality of Life (HRQOL): Change From Baseline in Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) Physical Health Score at Month 9	-3.32 scores on a scale Interval -9.67 to 3.04	-23.07 scores on a scale Interval -28.0 to -18.14

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). Scoring for each item was based on a 5-point Likert scale (1= never, 2= rarely, 3= sometimes, 4= often, and 5=all the time), and higher scores represent greater impairment. Raw score for each domain were transformed to a scale ranged between 0 and 100, where lower scores denoted better health. Haem-A-QoL total score was average of all domain scores and ranged from 0 (better health outcome) to 100 (worst health outcome), where lower scores denoted better physical health.

Outcome measures

Measure	Factor On-demand n=34 Participants Participants received on-demand factor concentrates (as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion for the treatment of breakthrough bleeding episodes from Day 1 up to a total of 9 months.	Fitusiran 80 mg Prophylaxis n=69 Participants Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes.
Health-related Quality of Life (HRQOL): Change From Baseline in Haem-A-QOL Total Score at Month 9	-2.62 scores on a scale Interval -6.27 to 1.03	-9.68 scores on a scale Interval -12.51 to -6.86

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. Here, overall number of participants analyzed = participants evaluable for this outcome measure.

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 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 <=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 presents estimated results (i.e., results received by applying NB regression model on data collected during onset period).

Outcome measures

Measure	Factor On-demand n=40 Participants Participants received on-demand factor concentrates (as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion for the treatment of breakthrough bleeding episodes from Day 1 up to a total of 9 months.	Fitusiran 80 mg Prophylaxis n=79 Participants Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes.
Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Onset Period	33.389 episodes per participant per year Interval 25.619 to 43.517	10.805 episodes per participant per year Interval 8.143 to 14.337

SECONDARY outcome

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

Measure	Factor On-demand n=40 Participants Participants received on-demand factor concentrates (as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion for the treatment of breakthrough bleeding episodes from Day 1 up to a total of 9 months.	Fitusiran 80 mg Prophylaxis n=79 Participants Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) Any TEAE	18 Participants	62 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) Any TESAE	5 Participants	5 Participants

Adverse Events

Factor On-demand

Serious events: 5 serious events

Other events: 8 other events

Deaths: 0 deaths

Fitusiran 80 mg Prophylaxis

Serious events: 5 serious events

Other events: 45 other events

Deaths: 0 deaths

Serious adverse events

Measure	Factor On-demand n=40 participants at risk Participants received on-demand factor concentrates (as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion for the treatment of breakthrough bleeding episodes from Day 1 up to a total of 9 months.	Fitusiran 80 mg Prophylaxis n=79 participants at risk Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes.
Injury, poisoning and procedural complications Epidural Haemorrhage	2.5% 1/40 • Number of events 1 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.	0.00% 0/79 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.
Injury, poisoning and procedural complications Humerus Fracture	2.5% 1/40 • Number of events 1 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.	0.00% 0/79 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.
Injury, poisoning and procedural complications Subdural Haemorrhage	2.5% 1/40 • Number of events 1 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.	0.00% 0/79 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.
Injury, poisoning and procedural complications Tibia Fracture	2.5% 1/40 • Number of events 1 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.	0.00% 0/79 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.
Eye disorders Diplopia	2.5% 1/40 • Number of events 1 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.	0.00% 0/79 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.
Musculoskeletal and connective tissue disorders Osteoarthritis	2.5% 1/40 • Number of events 1 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.	0.00% 0/79 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.
Infections and infestations Gastroenteritis	2.5% 1/40 • Number of events 1 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.	0.00% 0/79 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.
Infections and infestations Lower Respiratory Tract Infection	0.00% 0/40 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.	1.3% 1/79 • Number of events 1 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.
Infections and infestations Pneumonia	2.5% 1/40 • Number of events 1 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.	0.00% 0/79 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.
Psychiatric disorders Suicidal Ideation	2.5% 1/40 • Number of events 1 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.	0.00% 0/79 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.
Respiratory, thoracic and mediastinal disorders Asthma	0.00% 0/40 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.	1.3% 1/79 • Number of events 1 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.
Hepatobiliary disorders Cholecystitis	0.00% 0/40 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.	1.3% 1/79 • Number of events 1 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.
Hepatobiliary disorders Cholelithiasis	0.00% 0/40 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.	2.5% 2/79 • Number of events 2 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.

Other adverse events

Measure	Factor On-demand n=40 participants at risk Participants received on-demand factor concentrates (as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion for the treatment of breakthrough bleeding episodes from Day 1 up to a total of 9 months.	Fitusiran 80 mg Prophylaxis n=79 participants at risk Participants received open-label fitusiran 80 milligram (mg) administered subcutaneously (SC) as prophylaxis once monthly from Day 1 up to a total of 9 months. Participants received on-demand factor concentrates (per investigator's discretion and within bleeding dosing guidelines) for the treatment of breakthrough bleeding episodes.
Investigations Alanine Aminotransferase Increased	2.5% 1/40 • Number of events 1 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.	22.8% 18/79 • Number of events 20 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.
Investigations Aspartate Aminotransferase Increased	5.0% 2/40 • Number of events 2 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.	7.6% 6/79 • Number of events 7 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.
Investigations Blood Bilirubin Increased	0.00% 0/40 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.	5.1% 4/79 • Number of events 4 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.
Nervous system disorders Headache	0.00% 0/40 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.	6.3% 5/79 • Number of events 6 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.
Gastrointestinal disorders Abdominal Pain	2.5% 1/40 • Number of events 1 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.	7.6% 6/79 • Number of events 6 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.
Gastrointestinal disorders Abdominal Pain Upper	0.00% 0/40 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.	5.1% 4/79 • Number of events 5 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.
Gastrointestinal disorders Gastritis	2.5% 1/40 • Number of events 1 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.	6.3% 5/79 • Number of events 7 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.
Musculoskeletal and connective tissue disorders Arthralgia	2.5% 1/40 • Number of events 1 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.	6.3% 5/79 • Number of events 6 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.
Infections and infestations Nasopharyngitis	7.5% 3/40 • Number of events 3 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.	8.9% 7/79 • Number of events 7 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.
Infections and infestations Upper Respiratory Tract Infection	0.00% 0/40 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.	11.4% 9/79 • Number of events 9 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.
Vascular disorders Hypertension	10.0% 4/40 • Number of events 4 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.	3.8% 3/79 • Number of events 3 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.
Respiratory, thoracic and mediastinal disorders Asthma	0.00% 0/40 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.	6.3% 5/79 • Number of events 5 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/40 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.	7.6% 6/79 • Number of events 6 • From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up). Treatment-emergent AE 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 factor on-demand arm. Analysis was performed on safety analysis set.

Additional Information

Trial Transparency Team

Sanofi aventis recherche & développement

Phone: 800-633-1610

Email: Contact-US@sanofi.com

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