Hemophilia A, Hemophilia B
Conditions
Keywords
RNAi therapeutic, Hemophilia A, Hemophilia B, Hemophilia A, Severe, Hemophilia B, Severe, Blood Coagulation Disorders, Inherited, Blood Coagulation Disorders, Hematologic Diseases, Coagulation Protein Disorders, Hemorrhagic Disorders, Genetic Diseases, Inborn, Genetic Diseases, X-Linked, Factor VIII, Factor IX, Inhibitor, Bypassing agents, Coagulants, Fitusiran
Brief summary
The purpose of this study was to determine the frequency of bleeding episodes in participants receiving fitusiran as prophylactic treatment of hemophilia compared to participants who were assigned to continue with their regular medication. In addition, the study assessed safety, quality of life, pharmacodynamics (PD), and pharmacokinetics (PK).
Detailed description
The duration of treatment with fitusiran was 9 months. The estimated total time on study, inclusive of screening, for each participant was up to 11 months for all participants who enroll in the extension study and participants in the on-demand arm who did not enroll in the extension study. The estimated total time on study was up to 17 months in fitusiran treatment arm participants who did not enroll in the extension study due to the requirement for up to an additional 6 months of follow-up monitoring for antithrombin levels.
Interventions
DRUGfitusiran
solution for injection; by subcutaneous (SC) injection
DRUGBypassing agents
solution for injection; by intravenous (IV) injection
Sponsors
Genzyme, a Sanofi Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males, greater than or equal to (\>=) 12 years of age. * Severe hemophilia A or B with inhibitors. * (Severity confirmed by a central laboratory where coagulation factor VIII (FVIII) level was less than (\<)1% or factor IX (FIX) level was less than or equal to \[\<=\]2% at Screening; Inhibitors defined as inhibitor titer of \>=0.6 Bethesda units per milliliter \[BU/mL\] or as evidenced by medical records). * A minimum of 6 bleeding episodes requiring BPA treatment within the last 6 months prior to screening. * Willing and able to comply with the study requirements and to provide written informed consent and assent.
Exclusion criteria
* Known co-existing bleeding disorders other than hemophilia A or B. * Antithrombin (AT) activity \<60% at Screening. * Co-existing thrombophilic disorder. * Clinically significant liver disease. * Active hepatitis C virus infection. * HIV positive with a cluster of differentiation-4 count of \<200 cells/microliter. * History of arterial or venous thromboembolism. * Inadequate renal function. * History of multiple drug allergies or history of allergic reaction to an oligonucleotide or N-Acetylgalactosamine. * History of intolerance to SC injection(s). * Any other conditions or comorbidities that would make the participant unsuitable for enrollment or could interfere with participation in or completion of the study, per Investigator judgement.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period | From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest | ABR for a participant during efficacy period (EP) was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. Treated Bleeding episode: any occurrence of hemorrhage that required administration of BPA or factor. It started from first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. EP was defined as time duration starting from Day 29 when antithrombin (AT) lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This outcome measure (OM) represents estimated results (i.e., results received by applying negative binomial \[NB\] regression model on data collected during EP). |
| Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period | From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest | ABR for a participant during EP was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. ABR= number of bleeding episodes during EP divided by total number of days during EP\*365.25. A bleeding episode was defined as any occurrence of hemorrhage that required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. EP was defined as time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or the last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This OM represents observed results (i.e., descriptive statistics values based on the data which was collected during EP). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Estimated Annualized Spontaneous Bleeding Rate for Treated Bleeds During Efficacy Period | From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest | Annualized spontaneous bleeding rate for a participant during EP was defined as annualized number of spontaneous bleeding episodes during EP annualized to a 1-year interval of time. Spontaneous bleeding episode was bleeding event that occurred for no apparent or known reason, particularly into joints, muscles, and soft tissues. It started from first sign of a bleed and ended no more than 72 hours after last treatment for the bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. EP was defined as time duration starting from Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This OM represents estimated results (i.e., results received by applying NB regression model on data collected during EP). |
| Observed Annualized Spontaneous Bleeding Rate for Treated Bleeds During the Efficacy Period | From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest | ABR for participant during EP was defined as annualized number of spontaneous bleeding episodes during EP annualized to a 1-year interval of time. ABR=number of treated spontaneous bleeding episodes during EP divided by total number of days during EP\*365.25. Spontaneous bleeding episode was bleeding event that occurred for no apparent or known reason, into joints, muscles, and soft tissues. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. EP: time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to earliest of (Day 246 or the last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This OM represents observed results (i.e., descriptive statistics values based on data collected during EP). |
| Estimated Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period | From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest | Annualized joint bleeding rate for a participant during EP was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. Joint bleeding episode was characterized by an unusual sensation in the joint (aura) in combination with 1) increasing swelling or warmth over the skin, joint, 2) increased pain, or 3) progressive loss of range of motion or difficulty in using the limb as compared with Baseline. It started from first sign of a bleed and ended no more than 72 hours after last treatment for the bleed. EP was defined as time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or the last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This OM presents estimated results (i.e., results received by applying NB regression model on data collected during EP). |
| Observed Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period | From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest | Annualized joint bleeding rate for participant during EP was defined as annualized number of joint bleeding episodes during EP annualized to 1-year interval of time. ABR= number of treated joint bleeding episodes during EP divided by total number of days during EP\*365.25. A joint bleeding episode was characterized by an unusual sensation in joint (aura) in combination with 1) increasing swelling or warmth over skin, joint, 2) increased pain, or 3) progressive loss of range of motion or difficulty in using limb as compared with Baseline. It started from first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed. EP: time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This OM presents observed results (i.e., descriptive statistics values based on data collected during EP). |
| Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period | From Day 1 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest | ABR for a participant during treatment period (TP) was defined as annualized number of bleeding episodes during TP annualized to a 1-year interval of time. Bleeding episode: any occurrence of hemorrhage that required administration of BPA or factor. It started from first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. TP was sum of onset period (first 28 days after first dose of fitusiran) and EP (starting on Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to earliest of \[Day 246 or last day of bleeding follow up\])(maximum duration of TP: from Day 1 to Day 246). This OM represents estimated results (i.e., results received by applying NB regression model on data collected during TP). |
| Health-related Quality of Life (HRQOL): Change From Baseline in Haem-A-QOL Total Score at Month 9 | Baseline (Day 1), Month 9 | Haem-A-QoL: participant-reported questionnaire designed for adult participants (\>=17 years of age) with hemophilia; and consisted of 46 items comprising 10 domains (physical health, feelings, view of yourself, sports and leisure, work and school, dealing with hemophilia, treatment, future, family planning, partnership and sexuality). Items were rated along five response options: never, rarely, sometimes, often, or all the time. Raw score for each domain were transformed to a scale ranged from 0 to 100, where lower scores denoted better health. Haem-A-QoL Total Score was average of all domain scores and ranged from 0 to 100, where lower scores denoted better quality of life. |
| Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Onset Period | From Day 1 up to Day 28 or up to the last day of bleeding follow up (any day up to Day 28), whichever was the earliest | ABR was annualized number of bleeding episodes during onset period per participant annualized to a 1-year interval of time. A treated bleeding episode was defined as any occurrence of hemorrhage that may required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. The onset period was defined as time interval from Day 1 to the earlier of Day 28 or the last day of bleeding follow up. This OM represents estimated results (i.e., results received by applying NB regression model on data collected during onset period). |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | From Baseline (Day 1) up to 15 months (i.e. 9 months treatment period + 6-months follow-up) | An adverse Event (AE) was defined as any untoward medical occurrence in a participant who received study drug which did not necessarily have a causal relationship with the treatment. Treatment emergent AEs were defined as any AE with onset date after first dose of fitusiran in the fitusiran prophylaxis arm or after Day 1 visit in the BPA on-demand arm. A Serious AE (SAE) was defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly or birth defect, or was a medically important event. |
| Health-related Quality of Life (HRQOL): Change From Baseline in Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) Physical Health Domain Score at Month 9 | Baseline (Day 1), Month 9 | Haem-A-QoL: participant-reported questionnaire designed for adult participants (\>=17 years of age) with hemophilia; and consisted of 46 items comprising 10 domains (physical health, feelings, view of yourself, sports and leisure, work and school, dealing with hemophilia, treatment, future, family planning, partnership and sexuality). Items were rated along five response options: never, rarely, sometimes, often, or all the time. Change from baseline in physical Health domain score was reported in this outcome measure. Raw score for physical health domain were transformed to a scale ranged from 0 to 100, where lower scores denoted better physical health. |
| Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period | From Day 1 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest | ABR for a participant during TP was defined as annualized number of bleeding episodes during TP annualized to a 1-year interval of time. ABR= number of bleeding episodes during TP divided by total number of days during TP\*365.25. Bleeding episode: any occurrence of hemorrhage that required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. TP was sum of onset period (first 28 days after the first dose of fitusiran) and EP (starting on Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of \[Day 246 or the last day of bleeding follow up\]) (maximum duration of TP: from Day 1 to Day 246). This OM represents observed results (i.e., descriptive statistics values based on data collected during TP). |
Countries
Australia, Canada, China, France, Germany, India, Italy, Japan, Malaysia, South Africa, South Korea, Spain, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 58 centers in 17 countries. A total of 85 participants were screened between 14 February 2018 to 19-Mar-2021, of which 25 participants were screen failure. Screen failures were mainly due to the presence of clinically significant liver disease. A total of 60 participants were enrolled in the study.
Pre-assignment details
57 participants randomized in 2:1 ratio to fitusiran prophylaxis and on-demand arms; stratified by number of bleeding episodes prior to Screening (\<=10 vs \>10). 3 participants from China were treated with fitusiran but not randomized. These participants were considered in fitusiran prophylaxis arm for safety analysis, but not in any other analysis.
Participants by arm
| Arm | Count |
|---|---|
| Bypassing Agents (BPA) On-demand Participants received On-demand BPAs (use of these agents, as needed, for episodic bleeding episodes, and not on a regular regimen intended to prevent spontaneous bleeding) per Investigator discretion from Day 1 for treatment of breakthrough bleeding episodes, up to a total of 9 months. | 19 |
| Fitusiran 80 mg Prophylaxis Participants received Fitusiran 80 mg subcutaneously (SC) as prophylaxis once monthly from Day 1, along with the on-demand BPAs (per investigator's discretion and within bleeding dosing guidelines) for treatment of breakthrough bleeding episodes, up to a total of 9 months. | 38 |
| Total Title | 57 |
| Total | 114 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Other | 0 | 1 |
| Overall Study | Related to Coronavirus Pandemic (Covid-19) | 0 | 3 |
Baseline characteristics
| Characteristic | Bypassing Agents (BPA) On-demand | Total Title | Fitusiran 80 mg Prophylaxis |
|---|---|---|---|
| Age, Continuous | 31.5 years STANDARD_DEVIATION 13.1 | 28.4 years STANDARD_DEVIATION 11.1 | 26.8 years STANDARD_DEVIATION 9.8 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 13 Participants | 39 Participants | 26 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Multiple | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 6 Participants | 16 Participants | 10 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 19 Participants | 57 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 41 |
| other Total, other adverse events | 8 / 19 | 32 / 41 |
| serious Total, serious adverse events | 5 / 19 | 7 / 41 |
Outcome results
Primary
Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period
ABR for a participant during efficacy period (EP) was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. Treated Bleeding episode: any occurrence of hemorrhage that required administration of BPA or factor. It started from first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. EP was defined as time duration starting from Day 29 when antithrombin (AT) lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This outcome measure (OM) represents estimated results (i.e., results received by applying negative binomial \[NB\] regression model on data collected during EP).
Time frame: From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bypassing Agents (BPA) On-demand | Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period | 18.071 episodes per participant per year |
| Fitusiran 80 mg Prophylaxis | Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period | 1.666 episodes per participant per year |
p-value: <0.000195% CI: [0.044, 0.192]Negative binomial regression model
Primary
Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period
ABR for a participant during EP was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. ABR= number of bleeding episodes during EP divided by total number of days during EP\*365.25. A bleeding episode was defined as any occurrence of hemorrhage that required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. EP was defined as time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or the last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This OM represents observed results (i.e., descriptive statistics values based on the data which was collected during EP).
Time frame: From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bypassing Agents (BPA) On-demand | Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period | 18.1 episodes per participant per year | Standard Deviation 14.9 |
| Fitusiran 80 mg Prophylaxis | Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period | 1.7 episodes per participant per year | Standard Deviation 3.8 |
Secondary
Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Onset Period
ABR was annualized number of bleeding episodes during onset period per participant annualized to a 1-year interval of time. A treated bleeding episode was defined as any occurrence of hemorrhage that may required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. The onset period was defined as time interval from Day 1 to the earlier of Day 28 or the last day of bleeding follow up. This OM represents estimated results (i.e., results received by applying NB regression model on data collected during onset period).
Time frame: From Day 1 up to Day 28 or up to the last day of bleeding follow up (any day up to Day 28), whichever was the earliest
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bypassing Agents (BPA) On-demand | Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Onset Period | 25.149 episodes per participant per year |
| Fitusiran 80 mg Prophylaxis | Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Onset Period | 4.426 episodes per participant per year |
Secondary
Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period
ABR for a participant during treatment period (TP) was defined as annualized number of bleeding episodes during TP annualized to a 1-year interval of time. Bleeding episode: any occurrence of hemorrhage that required administration of BPA or factor. It started from first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. TP was sum of onset period (first 28 days after first dose of fitusiran) and EP (starting on Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to earliest of \[Day 246 or last day of bleeding follow up\])(maximum duration of TP: from Day 1 to Day 246). This OM represents estimated results (i.e., results received by applying NB regression model on data collected during TP).
Time frame: From Day 1 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bypassing Agents (BPA) On-demand | Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period | 18.819 episodes per participant per year |
| Fitusiran 80 mg Prophylaxis | Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period | 2.024 episodes per participant per year |
p-value: <0.000195% CI: [0.056, 0.207]Negative binomial regression model
Secondary
Estimated Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period
Annualized joint bleeding rate for a participant during EP was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. Joint bleeding episode was characterized by an unusual sensation in the joint (aura) in combination with 1) increasing swelling or warmth over the skin, joint, 2) increased pain, or 3) progressive loss of range of motion or difficulty in using the limb as compared with Baseline. It started from first sign of a bleed and ended no more than 72 hours after last treatment for the bleed. EP was defined as time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or the last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This OM presents estimated results (i.e., results received by applying NB regression model on data collected during EP).
Time frame: From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bypassing Agents (BPA) On-demand | Estimated Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period | 13.759 episodes per participant per year |
| Fitusiran 80 mg Prophylaxis | Estimated Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period | 1.349 episodes per participant per year |
p-value: <0.000195% CI: [0.046, 0.21]Negative binomial regression model
Secondary
Estimated Annualized Spontaneous Bleeding Rate for Treated Bleeds During Efficacy Period
Annualized spontaneous bleeding rate for a participant during EP was defined as annualized number of spontaneous bleeding episodes during EP annualized to a 1-year interval of time. Spontaneous bleeding episode was bleeding event that occurred for no apparent or known reason, particularly into joints, muscles, and soft tissues. It started from first sign of a bleed and ended no more than 72 hours after last treatment for the bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. EP was defined as time duration starting from Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This OM represents estimated results (i.e., results received by applying NB regression model on data collected during EP).
Time frame: From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bypassing Agents (BPA) On-demand | Estimated Annualized Spontaneous Bleeding Rate for Treated Bleeds During Efficacy Period | 15.675 episodes per participant per year |
| Fitusiran 80 mg Prophylaxis | Estimated Annualized Spontaneous Bleeding Rate for Treated Bleeds During Efficacy Period | 0.872 episodes per participant per year |
p-value: <0.000195% CI: [0.026, 0.121]Negative binomial regression model
Secondary
Health-related Quality of Life (HRQOL): Change From Baseline in Haem-A-QOL Total Score at Month 9
Haem-A-QoL: participant-reported questionnaire designed for adult participants (\>=17 years of age) with hemophilia; and consisted of 46 items comprising 10 domains (physical health, feelings, view of yourself, sports and leisure, work and school, dealing with hemophilia, treatment, future, family planning, partnership and sexuality). Items were rated along five response options: never, rarely, sometimes, often, or all the time. Raw score for each domain were transformed to a scale ranged from 0 to 100, where lower scores denoted better health. Haem-A-QoL Total Score was average of all domain scores and ranged from 0 to 100, where lower scores denoted better quality of life.
Time frame: Baseline (Day 1), Month 9
Population: Analysis was performed on ITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Bypassing Agents (BPA) On-demand | Health-related Quality of Life (HRQOL): Change From Baseline in Haem-A-QOL Total Score at Month 9 | -0.42 score on a scale |
| Fitusiran 80 mg Prophylaxis | Health-related Quality of Life (HRQOL): Change From Baseline in Haem-A-QOL Total Score at Month 9 | -15.27 score on a scale |
p-value: <0.000195% CI: [-21.37, -8.33]ANCOVA
Secondary
Health-related Quality of Life (HRQOL): Change From Baseline in Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) Physical Health Domain Score at Month 9
Haem-A-QoL: participant-reported questionnaire designed for adult participants (\>=17 years of age) with hemophilia; and consisted of 46 items comprising 10 domains (physical health, feelings, view of yourself, sports and leisure, work and school, dealing with hemophilia, treatment, future, family planning, partnership and sexuality). Items were rated along five response options: never, rarely, sometimes, often, or all the time. Change from baseline in physical Health domain score was reported in this outcome measure. Raw score for physical health domain were transformed to a scale ranged from 0 to 100, where lower scores denoted better physical health.
Time frame: Baseline (Day 1), Month 9
Population: Analysis was performed on ITT population. Here, overall number of participants analyzed = participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Bypassing Agents (BPA) On-demand | Health-related Quality of Life (HRQOL): Change From Baseline in Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) Physical Health Domain Score at Month 9 | -1.94 score on a scale |
| Fitusiran 80 mg Prophylaxis | Health-related Quality of Life (HRQOL): Change From Baseline in Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) Physical Health Domain Score at Month 9 | -30.67 score on a scale |
p-value: <0.000195% CI: [-39.07, -18.37]ANCOVA
Secondary
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
An adverse Event (AE) was defined as any untoward medical occurrence in a participant who received study drug which did not necessarily have a causal relationship with the treatment. Treatment emergent AEs were defined as any AE with onset date after first dose of fitusiran in the fitusiran prophylaxis arm or after Day 1 visit in the BPA on-demand arm. A Serious AE (SAE) was defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly or birth defect, or was a medically important event.
Time frame: From Baseline (Day 1) up to 15 months (i.e. 9 months treatment period + 6-months follow-up)
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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Bypassing Agents (BPA) On-demand | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | Any TEAE | 11 Participants |
| Bypassing Agents (BPA) On-demand | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | Any TESAE | 5 Participants |
| Fitusiran 80 mg Prophylaxis | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | Any TEAE | 38 Participants |
| Fitusiran 80 mg Prophylaxis | Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | Any TESAE | 7 Participants |
Secondary
Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period
ABR for a participant during TP was defined as annualized number of bleeding episodes during TP annualized to a 1-year interval of time. ABR= number of bleeding episodes during TP divided by total number of days during TP\*365.25. Bleeding episode: any occurrence of hemorrhage that required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. TP was sum of onset period (first 28 days after the first dose of fitusiran) and EP (starting on Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of \[Day 246 or the last day of bleeding follow up\]) (maximum duration of TP: from Day 1 to Day 246). This OM represents observed results (i.e., descriptive statistics values based on data collected during TP).
Time frame: From Day 1 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bypassing Agents (BPA) On-demand | Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period | 18.8 episodes per participant per year | Standard Deviation 15.4 |
| Fitusiran 80 mg Prophylaxis | Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period | 2.0 episodes per participant per year | Standard Deviation 3.7 |
Secondary
Observed Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period
Annualized joint bleeding rate for participant during EP was defined as annualized number of joint bleeding episodes during EP annualized to 1-year interval of time. ABR= number of treated joint bleeding episodes during EP divided by total number of days during EP\*365.25. A joint bleeding episode was characterized by an unusual sensation in joint (aura) in combination with 1) increasing swelling or warmth over skin, joint, 2) increased pain, or 3) progressive loss of range of motion or difficulty in using limb as compared with Baseline. It started from first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed. EP: time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This OM presents observed results (i.e., descriptive statistics values based on data collected during EP).
Time frame: From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bypassing Agents (BPA) On-demand | Observed Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period | 13.8 episodes per participant per year | Standard Deviation 12.2 |
| Fitusiran 80 mg Prophylaxis | Observed Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period | 1.4 episodes per participant per year | Standard Deviation 3.4 |
Secondary
Observed Annualized Spontaneous Bleeding Rate for Treated Bleeds During the Efficacy Period
ABR for participant during EP was defined as annualized number of spontaneous bleeding episodes during EP annualized to a 1-year interval of time. ABR=number of treated spontaneous bleeding episodes during EP divided by total number of days during EP\*365.25. Spontaneous bleeding episode was bleeding event that occurred for no apparent or known reason, into joints, muscles, and soft tissues. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. EP: time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to earliest of (Day 246 or the last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This OM represents observed results (i.e., descriptive statistics values based on data collected during EP).
Time frame: From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest
Population: Analysis was performed on ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Bypassing Agents (BPA) On-demand | Observed Annualized Spontaneous Bleeding Rate for Treated Bleeds During the Efficacy Period | 15.6 episodes per participant per year | Standard Deviation 14.9 |
| Fitusiran 80 mg Prophylaxis | Observed Annualized Spontaneous Bleeding Rate for Treated Bleeds During the Efficacy Period | 0.9 episodes per participant per year | Standard Deviation 2 |