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

Sponsor
Genzyme, a Sanofi Company (Industry)
Overall Status
Completed
CT.gov ID
NCT03417245
Collaborator
(none)
120
64
2
40.4
1.9
0

Study Details

Study Description

Brief Summary

Primary Objective:

-To evaluate the efficacy of fitusiran compared to on-demand treatment with factor concentrates, as determined by the frequency of bleeding episodes.

Secondary Objectives:
  • To evaluate the efficacy of fitusiran compared to on-demand treatment with factor concentrates, as determined by:

  • The frequency of spontaneous bleeding episodes.

  • The frequency of joint bleeding episodes.

  • Health-related quality of life (HRQOL) in participants >=17 years of age.

  • To determine the frequency of bleeding episodes during the onset period.

  • To determine the safety and tolerability of fitusiran.

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

The duration of treatment with fitusiran was 9 months. The estimated total time on study, inclusive of screening, was up to 11 months for all participants in the factor on-demand arm and for participants in the fitusiran arm who enrolled in the extension study (LTE15174). The estimated total time on the study was up to 17 months for participants in the fitusiran treatment arm who did not enroll in the extension study due to the requirement for up to an additional 6 months of follow-up monitoring for antithrombin levels.

Participants who completed the study will be eligible for an open-label extension study LTE15174 (NCT03754790).

Study Design

Study Type:
Interventional
Actual Enrollment :
120 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
ATLAS-A/B: A Phase 3 Study to Evaluate the Efficacy and Safety of Fitusiran in Patients With Hemophilia A or B, Without Inhibitory Antibodies to Factor VIII or IX
Actual Study Start Date :
Mar 1, 2018
Actual Primary Completion Date :
Jan 26, 2021
Actual Study Completion Date :
Jul 14, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: 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.

Drug: factor concentrates
by intravenous (IV) injection

Experimental: 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.

Drug: fitusiran
by SC injection

Drug: factor concentrates
by intravenous (IV) injection

Outcome Measures

Primary Outcome Measures

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

    ABR for a participant during efficacy period (EP) was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. Treated Bleeding episode: any occurrence of hemorrhage that required administration of 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).

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

    ABR for a participant during EP was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. ABR= number of bleeding episodes during EP divided by total number of days during EP*365.25. A bleeding episode was defined as any occurrence of hemorrhage that required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections <=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).

Secondary Outcome Measures

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

    ABR for a participant during treatment period (TP) was defined as annualized number of bleeding episodes during TP annualized to a 1-year interval of time. Bleeding episode: any occurrence of hemorrhage that required administration of BPA or factor. It started from first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location or injections <=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).

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

    ABR for a participant during TP was defined as annualized number of bleeding episodes during TP annualized to a 1- year interval of time. ABR= number of bleeding episodes during TP divided by total number of days during TP*365.25. Bleeding episode: any occurrence of hemorrhage that required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at the same location or injections <=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).

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

    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).

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

    ABR for participant during EP was defined as annualized number of spontaneous bleeding episodes during EP annualized to a 1-year interval of time. ABR=number of treated spontaneous bleeding episodes during EP divided by total number of days during EP*365.25. Spontaneous bleeding episode was bleeding event that occurred for no apparent or known reason, into joints, muscles, and soft tissues. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for 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).

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

    Annualized joint bleeding rate for a participant during EP was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. Joint bleeding episode was characterized by an unusual sensation in the joint ("aura") in combination with 1) increasing swelling or warmth over the skin, joint, 2) 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).

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

    Annualized joint bleeding rate for participant during EP was defined as annualized number of joint bleeding episodes during EP annualized to 1-year interval of time. ABR= number of treated joint bleeding episodes during EP divided by total number of days during EP*365.25. A joint bleeding episode was characterized by an unusual sensation in joint ("aura") in combination with 1) increasing swelling or warmth over skin, joint, 2) 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).

  7. 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 [Baseline (Day 1), Month 9]

    Haem-A-QoL: participant-reported questionnaire designed for adult participants (>=17 years of age) with hemophilia; and consisted of 46 items comprising 10 domains (physical health, feelings, view of yourself, sports and leisure, work and school, dealing with hemophilia, treatment, future, family planning, partnership and sexuality). 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.

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

    Haem-A-QoL: participant-reported questionnaire designed for adult participants (>=17 years of age) with hemophilia; and consisted of 46 items comprising 10 domains (physical health, feelings, view of yourself, sports and leisure, work and school, dealing with hemophilia, treatment, future, family planning, partnership and sexuality). 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.

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

    ABR was annualized number of bleeding episodes during onset period per participant annualized to a 1-year interval of time. A treated bleeding episode was defined as any occurrence of hemorrhage that 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).

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

    An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug which did not necessarily have a causal relationship with the treatment. Treatment-emergent AEs were defined as any AE with onset date after first dose of fitusiran in the fitusiran prophylaxis arm or after Day 1 visit in the 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.

Eligibility Criteria

Criteria

Ages Eligible for Study:
12 Years and Older
Sexes Eligible for Study:
Male
Accepts Healthy Volunteers:
No
Inclusion Criteria:
  • Males, >=12 years of age.

  • Severe hemophilia A or B without inhibitors.

  • Severity confirmed by a central laboratory where FVIII level was less than (<) 1 percent (%) or Factor IX (FIX) level was less than or equal to (<=) 2% at Screening.

  • On-demand use of factor concentrate to manage bleeding episodes for at least the last 6 months prior to Screening, and meet each of the following criterion:

  • Nijmegen modified Bethesda assay inhibitor titer of <0.6 Bethesda units per milliliter (BU/mL) at Screening.

  • No use of Bypassing agents to treat bleeding episodes for at least the last 6 months prior to Screening.

  • No history of immune tolerance induction therapy within the last 3 years prior to Screening.

  • A minimum of 6 bleeding episodes requiring factor concentrate treatment within the last 6 months prior to Screening.

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

Exclusion Criteria:
  • Known co-existing bleeding disorders other than hemophilia A or B, i.e., Von Willebrand's disease, additional factor deficiencies, or platelet disorders.

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

  • Co-existing thrombophilic disorder.

  • Clinically significant liver disease.

  • Active hepatitis C virus infection.

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

  • History of arterial or venous thromboembolism.

  • Inadequate renal function.

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

  • History of intolerance to SC injection(s).

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

Contacts and Locations

Locations

Site City State Country Postal Code
1 Investigational Site Number 0140 Little Rock Arkansas United States 72202
2 Investigational Site Number 128 Gainesville Florida United States 32610
3 Investigational Site Number 103 Tampa Florida United States 33607
4 Investigational Site Number 102 Chicago Illinois United States 60612-3833
5 Investigational Site Number 119 New Orleans Louisiana United States 70112
6 Investigational Site Number 125 Ann Arbor Michigan United States 48109
7 Investigational Site Number 111 Las Vegas Nevada United States 89135
8 Investigational Site Number 110 Akron Ohio United States 44308
9 Investigational Site Number 6101 Camperdown Australia 2050
10 Investigational Site Number 6103 Murdoch Australia 6961
11 Investigational Site Number 6104 Prahran Australia 3181
12 Investigational Site Number 8604 Beijing China 100045
13 Investigational Site Number 8602 Guangzhou China 510515
14 Investigational Site Number 8605 Hangzhou China 89147
15 Investigational Site Number 8603 Shanghai China 200025
16 Investigational Site Number 8601 Tianjin China 300020
17 Investigational Site Number 4501 Copenhagen Denmark 2100
18 Investigational Site Number 3303 Lyon France 69677
19 Investigational Site Number 3305 Paris France 75015
20 Investigational Site Number 3301 Rouen France 76038
21 Investigational Site Number 4904 Berlin Germany 10249
22 Investigational Site Number 4905 Frankfurt Am Main Germany 60590
23 Investigational Site Number 4906 Leipzig Germany 4103
24 Investigational Site Number 3602 Budapest Hungary 1134
25 Investigational Site Number 9102 Bangalore India 560034
26 Investigational Site Number 9104 Jaipur India 302017
27 Investigational Site Number 9106 Lucknow India 226003
28 Investigational Site Number 9109 Mumbai India 400012
29 Investigational Site Number 9108 Mumbai India 400022
30 Investigational Site Number 9111 Mumbai India
31 Investigational Site Number 9103 Pune India 411001
32 Investigational Site Number 9105 Vellore India 632004
33 Investigational Site Number 9701 Ramat-Gan Israel 52621
34 Investigational Site Number 3904 Padova Italy 35128
35 Investigational Site Number 8105 Isehara Japan
36 Investigational Site Number 8104 Saitama Japan
37 Investigational Site Number 8201 Busan Korea, Republic of 602-739
38 Investigational Site Number 8202 Daejeon Korea, Republic of 35233
39 Investigational Site Number 8204 Seoul Korea, Republic of 3722
40 Investigational Site Number 6004 Ampang Malaysia 68000
41 Investigational Site Number 6002 Johor Bahru Malaysia 80100
42 Investigational Site Number 6003 Kota Kinabalu Malaysia 88586
43 Investigational Site Number 2701 Parktown South Africa 2193
44 Investigational Site Number 2702 Port Elizabeth South Africa 6001
45 Investigational Site Number 3402 Madrid Spain 28046
46 Investigational Site Number 8807 Taichung Taiwan 40447
47 Investigational Site Number 8805 Taichung Taiwan 40705
48 Investigational Site Number 8804 Taipei Taiwan 100
49 Investigational Site Number 8801 Taipei Taiwan 110
50 Investigational Site Number 8808 Taoyuan Taiwan 33305
51 Investigational Site Number 9002 Adana Turkey ?01130
52 Investigational Site Number 9004 Antalya Turkey 07059
53 Investigational Site Number 9008 Gaziantep Turkey 27100
54 Investigational Site Number 9005 Istanbul Turkey 34093
55 Investigational Site Number 9003 Izmir Turkey TR-35100
56 Investigational Site Number 9009 Kayseri Turkey 38039
57 Investigational Site Number 9006 Samsun Turkey 55200
58 Investigational Site Number 8001 Kyiv Ukraine 04060
59 Investigational Site Number 8003 Kyiv Ukraine ?01135
60 Investigational Site Number 8002 Lviv Ukraine 79044
61 Investigational Site Number 8005 Mykolaiv Ukraine 54058
62 Investigational Site Number 4402 Glasgow United Kingdom G4 0SF
63 Investigational Site Number 4407 London United Kingdom E1 2ES
64 Investigational Site Number 4401 London United Kingdom SE1 9RT

Sponsors and Collaborators

  • Genzyme, a Sanofi Company

Investigators

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

Study Documents (Full-Text)

More Information

Publications

None provided.
Responsible Party:
Genzyme, a Sanofi Company
ClinicalTrials.gov Identifier:
NCT03417245
Other Study ID Numbers:
  • EFC14769
  • ALN-AT3SC-004
  • 2016-001464-11
First Posted:
Jan 31, 2018
Last Update Posted:
Mar 28, 2022
Last Verified:
Mar 1, 2022
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Genzyme, a Sanofi Company
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details 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.
Pre-assignment Detail 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).
Arm/Group Title Factor On-demand Fitusiran 80 mg Prophylaxis
Arm/Group Description 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. 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.
Period Title: Overall Study
STARTED 40 80
Treated 40 79
COMPLETED 37 79
NOT COMPLETED 3 1

Baseline Characteristics

Arm/Group Title Factor On-demand Fitusiran 80 mg Prophylaxis Total Title
Arm/Group Description 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. 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 Participants 40 80 120
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
33.6
(13.6)
33.9
(14.6)
33.8
(14.2)
Sex: Female, Male (Count of Participants)
Female
0
0%
0
0%
0
0%
Male
40
100%
80
100%
120
100%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
0
0%
0
0%
0
0%
Asian
28
70%
43
53.8%
71
59.2%
Native Hawaiian or Other Pacific Islander
0
0%
0
0%
0
0%
Black or African American
0
0%
2
2.5%
2
1.7%
White
12
30%
33
41.3%
45
37.5%
More than one race
0
0%
2
2.5%
2
1.7%
Unknown or Not Reported
0
0%
0
0%
0
0%

Outcome Measures

1. Primary Outcome
Title Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period
Description ABR for a participant during efficacy period (EP) was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. Treated Bleeding episode: any occurrence of hemorrhage that required administration of 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).
Time Frame From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest

Outcome Measure Data

Analysis Population Description
Analysis was performed on ITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.
Arm/Group Title Factor On-demand Fitusiran 80 mg Prophylaxis
Arm/Group Description 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. 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.
Measure Participants 40 79
Number (95% Confidence Interval) [episodes per participant per year]
30.991
3.133
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Factor On-demand, Fitusiran 80 mg Prophylaxis
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments P-value derived from NB regression model during EP, with treatment arm, number of bleeds in 6 months prior to study (<=10, >10) and hemophilia type (A vs B) as fixed effects. Significance threshold was at 0.05.
Method Negative binomial regression mode
Comments
Method of Estimation Estimation Parameter ABR ratio
Estimated Value 0.101
Confidence Interval (2-Sided) 95%
0.064 to 0.159
Parameter Dispersion Type:
Value:
Estimation Comments
2. Primary Outcome
Title Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period
Description ABR for a participant during EP was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. ABR= number of bleeding episodes during EP divided by total number of days during EP*365.25. A bleeding episode was defined as any occurrence of hemorrhage that required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections <=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).
Time Frame From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest

Outcome Measure Data

Analysis Population Description
Analysis was performed on ITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.
Arm/Group Title Factor On-demand Fitusiran 80 mg Prophylaxis
Arm/Group Description 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. 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.
Measure Participants 40 79
Median (Inter-Quartile Range) [episodes per participant per year]
21.8
0.0
3. Secondary Outcome
Title Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period
Description ABR for a participant during treatment period (TP) was defined as annualized number of bleeding episodes during TP annualized to a 1-year interval of time. Bleeding episode: any occurrence of hemorrhage that required administration of BPA or factor. It started from first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location or injections <=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).
Time Frame From Day 1 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest

Outcome Measure Data

Analysis Population Description
Analysis was performed on ITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.
Arm/Group Title Factor On-demand Fitusiran 80 mg Prophylaxis
Arm/Group Description 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. 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.
Measure Participants 40 79
Number (95% Confidence Interval) [episodes per participant per year]
31.444
4.092
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Factor On-demand, Fitusiran 80 mg Prophylaxis
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments P-value derived from NB regression model during TP, with treatment arm, number of bleeds in 6 months prior to study (<=10, >10) and hemophilia type (A vs B) as fixed effects. Significance threshold was at 0.05.
Method Negative binomial regression model
Comments
Method of Estimation Estimation Parameter ABR ratio
Estimated Value 0.130
Confidence Interval (2-Sided) 95%
0.090 to 0.188
Parameter Dispersion Type:
Value:
Estimation Comments
4. Secondary Outcome
Title Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period
Description ABR for a participant during TP was defined as annualized number of bleeding episodes during TP annualized to a 1- year interval of time. ABR= number of bleeding episodes during TP divided by total number of days during TP*365.25. Bleeding episode: any occurrence of hemorrhage that required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at the same location or injections <=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).
Time Frame From Day 1 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest

Outcome Measure Data

Analysis Population Description
Analysis was performed on ITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.
Arm/Group Title Factor On-demand Fitusiran 80 mg Prophylaxis
Arm/Group Description 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. 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.
Measure Participants 40 79
Median (Inter-Quartile Range) [episodes per participant per year]
25.2
1.8
5. Secondary Outcome
Title Estimated Annualized Spontaneous Bleeding Rate for Treated Bleeds During the Efficacy Period
Description Annualized spontaneous bleeding rate for a participant during EP was defined as annualized number of spontaneous bleeding episodes during EP annualized to a 1-year interval of time. Spontaneous bleeding episode was bleeding event that occurred for no apparent or known reason, particularly into joints, muscles, and soft tissues. It started from first sign of a bleed and ended no more than 72 hours after last treatment for the bleed, within which any symptoms of bleeding at the same location or injections <=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).
Time Frame From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest

Outcome Measure Data

Analysis Population Description
Analysis was performed on ITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.
Arm/Group Title Factor On-demand Fitusiran 80 mg Prophylaxis
Arm/Group Description 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. 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.
Measure Participants 40 79
Number (95% Confidence Interval) [episodes per participant per year]
22.036
1.825
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Factor On-demand, Fitusiran 80 mg Prophylaxis
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments P-value derived from NB regression model during EP, with treatment arm, number of bleeds in 6 months prior to study (<=10, >10) and hemophilia type (A vs B) as fixed effects. Significance threshold was at 0.05.
Method Negative binomial regression model
Comments
Method of Estimation Estimation Parameter ABR ratio
Estimated Value 0.083
Confidence Interval (2-Sided) 95%
0.049 to 0.141
Parameter Dispersion Type:
Value:
Estimation Comments
6. Secondary Outcome
Title Observed Annualized Spontaneous Bleeding Rate for Treated Bleeds During the Efficacy Period
Description ABR for participant during EP was defined as annualized number of spontaneous bleeding episodes during EP annualized to a 1-year interval of time. ABR=number of treated spontaneous bleeding episodes during EP divided by total number of days during EP*365.25. Spontaneous bleeding episode was bleeding event that occurred for no apparent or known reason, into joints, muscles, and soft tissues. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for 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).
Time Frame From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest

Outcome Measure Data

Analysis Population Description
Analysis was performed on ITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.
Arm/Group Title Factor On-demand Fitusiran 80 mg Prophylaxis
Arm/Group Description 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. 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.
Measure Participants 40 79
Median (Inter-Quartile Range) [episodes per participant per year]
16.1
0.0
7. Secondary Outcome
Title Estimated Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period
Description Annualized joint bleeding rate for a participant during EP was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. Joint bleeding episode was characterized by an unusual sensation in the joint ("aura") in combination with 1) increasing swelling or warmth over the skin, joint, 2) 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).
Time Frame From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest

Outcome Measure Data

Analysis Population Description
Analysis was performed on ITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.
Arm/Group Title Factor On-demand Fitusiran 80 mg Prophylaxis
Arm/Group Description 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. 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.
Measure Participants 40 79
Number (95% Confidence Interval) [episodes per participant per year]
23.413
2.282
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Factor On-demand, Fitusiran 80 mg Prophylaxis
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments P-value derived from NB regression model during EP, with treatment arm, number of bleeds in 6 months prior to study (<=10, >10) and hemophilia type (A vs B) as fixed effects. Significance threshold was at 0.05.
Method Negative binomial regression model
Comments
Method of Estimation Estimation Parameter ABR ratio
Estimated Value 0.097
Confidence Interval (2-Sided) 95%
0.059 to 0.161
Parameter Dispersion Type:
Value:
Estimation Comments
8. Secondary Outcome
Title Observed Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period
Description Annualized joint bleeding rate for participant during EP was defined as annualized number of joint bleeding episodes during EP annualized to 1-year interval of time. ABR= number of treated joint bleeding episodes during EP divided by total number of days during EP*365.25. A joint bleeding episode was characterized by an unusual sensation in joint ("aura") in combination with 1) increasing swelling or warmth over skin, joint, 2) 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).
Time Frame From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest

Outcome Measure Data

Analysis Population Description
Analysis was performed on ITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.
Arm/Group Title Factor On-demand Fitusiran 80 mg Prophylaxis
Arm/Group Description 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. 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.
Measure Participants 40 79
Median (Inter-Quartile Range) [episodes per participant per year]
15.9
0.0
9. Secondary Outcome
Title Health-related Quality of Life (HRQOL): Change From Baseline in Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) Physical Health Score at Month 9
Description Haem-A-QoL: participant-reported questionnaire designed for adult participants (>=17 years of age) with hemophilia; and consisted of 46 items comprising 10 domains (physical health, feelings, view of yourself, sports and leisure, work and school, dealing with hemophilia, treatment, future, family planning, partnership and sexuality). 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.
Time Frame Baseline (Day 1), Month 9

Outcome Measure Data

Analysis Population Description
Analysis was performed on ITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.
Arm/Group Title Factor On-demand Fitusiran 80 mg Prophylaxis
Arm/Group Description 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. 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.
Measure Participants 34 69
Least Squares Mean (95% Confidence Interval) [scores on a scale]
-3.32
-23.07
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Factor On-demand, Fitusiran 80 mg Prophylaxis
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments Analysis of Covariance (ANCOVA) model included treatment arm, number of bleeds in 6 months prior to study (<=10,>10) and hemophilia type (A vs B) as fixed effects, Baseline score as covariate. Significance threshold was at 0.05.
Method ANCOVA
Comments
Method of Estimation Estimation Parameter Least Square (LS) Mean difference
Estimated Value -19.75
Confidence Interval (2-Sided) 95%
-27.00 to -12.50
Parameter Dispersion Type:
Value:
Estimation Comments
10. Secondary Outcome
Title Health-related Quality of Life (HRQOL): Change From Baseline in Haem-A-QOL Total Score at Month 9
Description Haem-A-QoL: participant-reported questionnaire designed for adult participants (>=17 years of age) with hemophilia; and consisted of 46 items comprising 10 domains (physical health, feelings, view of yourself, sports and leisure, work and school, dealing with hemophilia, treatment, future, family planning, partnership and sexuality). 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.
Time Frame Baseline (Day 1), Month 9

Outcome Measure Data

Analysis Population Description
Analysis was performed on ITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.
Arm/Group Title Factor On-demand Fitusiran 80 mg Prophylaxis
Arm/Group Description 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. 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.
Measure Participants 34 69
Least Squares Mean (95% Confidence Interval) [scores on a scale]
-2.62
-9.68
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Factor On-demand, Fitusiran 80 mg Prophylaxis
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value =0.0011
Comments ANCOVA model included treatment arm, number of bleeds in 6 months prior to study (<=10,>10) and hemophilia type (A vs B) as fixed effects, Baseline score as covariate. Significance threshold was at 0.05.
Method ANCOVA
Comments
Method of Estimation Estimation Parameter LS Mean difference
Estimated Value -7.07
Confidence Interval (2-Sided) 95%
-11.23 to -2.90
Parameter Dispersion Type:
Value:
Estimation Comments
11. Secondary Outcome
Title Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Onset Period
Description ABR was annualized number of bleeding episodes during onset period per participant annualized to a 1-year interval of time. A treated bleeding episode was defined as any occurrence of hemorrhage that 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).
Time Frame From Day 1 up to Day 28 or up to the last day of bleeding follow up (any day up to Day 28), whichever was the earliest

Outcome Measure Data

Analysis Population Description
Analysis was performed on ITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.
Arm/Group Title Factor On-demand Fitusiran 80 mg Prophylaxis
Arm/Group Description 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. 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.
Measure Participants 40 79
Number (95% Confidence Interval) [episodes per participant per year]
33.389
10.805
12. Secondary Outcome
Title Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
Description An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug which did not necessarily have a causal relationship with the treatment. Treatment-emergent AEs were defined as any AE with onset date after first dose of fitusiran in the fitusiran prophylaxis arm or after Day 1 visit in the 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.
Time Frame From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up)

Outcome Measure Data

Analysis Population Description
Analysis was performed on safety analysis set that included all participants who received at least 1 dose of study drug or were randomized to on-demand arm, analyzed according to the actual treatment received.
Arm/Group Title Factor On-demand Fitusiran 80 mg Prophylaxis
Arm/Group Description 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. 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.
Measure Participants 40 79
Any TEAE
18
45%
62
77.5%
Any TESAE
5
12.5%
5
6.3%

Adverse Events

Time Frame From Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-month follow-up).
Adverse Event Reporting Description 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.
Arm/Group Title Factor On-demand Fitusiran 80 mg Prophylaxis
Arm/Group Description 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. 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.
All Cause Mortality
Factor On-demand Fitusiran 80 mg Prophylaxis
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 0/40 (0%) 0/79 (0%)
Serious Adverse Events
Factor On-demand Fitusiran 80 mg Prophylaxis
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 5/40 (12.5%) 5/79 (6.3%)
Eye disorders
Diplopia 1/40 (2.5%) 1 0/79 (0%) 0
Hepatobiliary disorders
Cholecystitis 0/40 (0%) 0 1/79 (1.3%) 1
Cholelithiasis 0/40 (0%) 0 2/79 (2.5%) 2
Infections and infestations
Gastroenteritis 1/40 (2.5%) 1 0/79 (0%) 0
Lower Respiratory Tract Infection 0/40 (0%) 0 1/79 (1.3%) 1
Pneumonia 1/40 (2.5%) 1 0/79 (0%) 0
Injury, poisoning and procedural complications
Epidural Haemorrhage 1/40 (2.5%) 1 0/79 (0%) 0
Humerus Fracture 1/40 (2.5%) 1 0/79 (0%) 0
Subdural Haemorrhage 1/40 (2.5%) 1 0/79 (0%) 0
Tibia Fracture 1/40 (2.5%) 1 0/79 (0%) 0
Musculoskeletal and connective tissue disorders
Osteoarthritis 1/40 (2.5%) 1 0/79 (0%) 0
Psychiatric disorders
Suicidal Ideation 1/40 (2.5%) 1 0/79 (0%) 0
Respiratory, thoracic and mediastinal disorders
Asthma 0/40 (0%) 0 1/79 (1.3%) 1
Other (Not Including Serious) Adverse Events
Factor On-demand Fitusiran 80 mg Prophylaxis
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 8/40 (20%) 45/79 (57%)
Gastrointestinal disorders
Abdominal Pain 1/40 (2.5%) 1 6/79 (7.6%) 6
Abdominal Pain Upper 0/40 (0%) 0 4/79 (5.1%) 5
Gastritis 1/40 (2.5%) 1 5/79 (6.3%) 7
Infections and infestations
Nasopharyngitis 3/40 (7.5%) 3 7/79 (8.9%) 7
Upper Respiratory Tract Infection 0/40 (0%) 0 9/79 (11.4%) 9
Investigations
Alanine Aminotransferase Increased 1/40 (2.5%) 1 18/79 (22.8%) 20
Aspartate Aminotransferase Increased 2/40 (5%) 2 6/79 (7.6%) 7
Blood Bilirubin Increased 0/40 (0%) 0 4/79 (5.1%) 4
Musculoskeletal and connective tissue disorders
Arthralgia 1/40 (2.5%) 1 5/79 (6.3%) 6
Nervous system disorders
Headache 0/40 (0%) 0 5/79 (6.3%) 6
Respiratory, thoracic and mediastinal disorders
Asthma 0/40 (0%) 0 5/79 (6.3%) 5
Cough 0/40 (0%) 0 6/79 (7.6%) 6
Vascular disorders
Hypertension 4/40 (10%) 4 3/79 (3.8%) 3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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

Results Point of Contact

Name/Title Trial Transparency Team
Organization Sanofi aventis recherche & développement
Phone 800-633-1610 ext 6#
Email Contact-US@sanofi.com
Responsible Party:
Genzyme, a Sanofi Company
ClinicalTrials.gov Identifier:
NCT03417245
Other Study ID Numbers:
  • EFC14769
  • ALN-AT3SC-004
  • 2016-001464-11
First Posted:
Jan 31, 2018
Last Update Posted:
Mar 28, 2022
Last Verified:
Mar 1, 2022