Hemophilia
Conditions
Brief summary
Primary Objective: To characterize the frequency of bleeding episodes (BE) while receiving fitusiran treatment, relative to the frequency of bleeding episodes while receiving factor concentrate or bypassing agent (BPA) prophylaxis. Secondary Objectives: * To characterize the following while receiving fitusiran treatment, relative to receiving factor or BPA prophylaxis: * the frequency of spontaneous bleeding episodes * the frequency of joint bleeding episodes * health related quality of life (HRQOL) in participants greater than or equal to (\>=) 17 years of age * To characterize the frequency of bleeding episodes during the onset and treatment periods in participants receiving fitusiran. * To characterize the safety and tolerability of fitusiran. * To characterize the annualized weight-adjusted consumption of factor/BPA while receiving fitusiran treatment, relative to receiving factor or BPA prophylaxis.
Detailed description
The estimated total time on study, inclusive of Screening, for each participant was up to 15 months for participants who were enrolled in the extension study except for participants in the subgroup of Cohort A, for whom it was up to 9 months. The estimated total time on study was up to 21 months (up to 15 months in participants in the subgroup of Cohort A) in participants who did not enroll in the extension study due to the requirement for an additional up to 6 months of follow-up for monitoring of antithrombin (AT) levels.
Interventions
DRUGFitusiran
Pharmaceutical form: solution for injection Route of administration: subcutaneous
DRUGBPA prophylaxis
Pharmaceutical form: solution for injection Route of administration: Intravenous
DRUGFactor (FVIII or FIX) prophylaxis
Pharmaceutical form: solution for injection Route of administration: Intravenous
Sponsors
Genzyme, a Sanofi Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males, \>=12 years of age. * Severe hemophilia A or B (as evidenced by a central laboratory measurement at screening or documented medical record evidence of FVIII less than (\<) 1 percent (%) or FIX level less than or equal to (\<=) 2%). * A minimum of 2 bleeding episodes required BPA treatment within the last 6 months prior to screening for participants with inhibitory antibodies to factor VIII or factor IX (Cohort A). A minimum of 1 bleeding episode required factor treatment within the last 12 months prior to screening for participants without inhibitory antibodies to factor VIII or factor IX (Cohort B). * Met either the definition of inhibitor or non-inhibitor participant as below: * Inhibitor: Use of BPAs for prophylaxis and for any bleeding episodes for at least the last 6 months prior to screening, and met one of the following Nijmegen-modified Bethesda assay results criteria: * Inhibitor titer of \>=0.6 Bethesda Unit per milliliter (BU/mL) at screening, or * Inhibitor titer of \<0.6 BU/mL at screening with medical record evidence of 2 consecutive titers \>=0.6 BU/mL, or * Inhibitor titer of \<0.6 BU/mL at screening with medical record evidence of anamnestic response * The subgroup of participants in Cohort A participants might additionally meet the following criteria to be eligible to start treatment with fitusiran directly after the screening period: * Hemophilia B with inhibitory antibody to Factor IX as defined above * Not responding adequately to BPA treatment (historical ABR \>=20) prior to enrollment * In the opinion of the Investigator, with approval of Sponsor Medical Monitor, 6-month BPA prophylaxis period should be omitted. * Non-inhibitor: Use of factor concentrates for prophylaxis and for any bleeding episodes for at least the last 6 months prior to screening, and met each of the following criterion: * Nijmegen-modified Bethesda assay inhibitor titer of \<0.6 BU/mL at screening and * No use of BPAs to treat bleeding episodes for at least the last 6 months prior to screening and * No history of immune tolerance induction therapy within the past 3 years prior to screening. * Documented prophylactic treatment with factor concentrates or BPAs for the treatment of hemophilia A or B for at least 6 months prior to screening. * Adherent to the prescribed prophylactic therapy for at least 6 months prior to screening per Investigator assessment. * Willed 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. * AT activity \<60% at screening. * Co-existing thrombophilic disorder. * Clinically significant liver disease. * Active Hepatitis C virus infection. * Acute or chronic Hepatitis B virus infection. * HIV positive with a CD4 count of \<200 cells per 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 subcutaneous injection(s). * Any other conditions or comorbidities that made the participant unsuitable for enrollment or could interfere with participation in or completion of the study, per Investigator judgment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Estimated Annualized Bleeding Rate (ABR) | Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest | Bleeding episodes (BE): any occurrence of hemorrhage might require administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location occurred within 72 hours of last injection used to treat BE at that location was considered part of original BE and counted as 1 BE towards ABR. Bleeding began after 72 hours of last injection at that location was considered as a new event. ABR = total number of qualifying BE/total number of days in the respective period\*365.25. Estimated data were derived by using repeated measures negative binomial (NB) regression model. |
| Observed Annualized Bleeding Rate (ABR) | Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest | A bleeding episode (BE): any occurrence of hemorrhage might require administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered a part of original BE and counted as 1 BE towards ABR. Any bleeding that began after 72 hours of last injection at that location was considered as a new event. ABR = total number of qualifying BE/number of days in the respective period \*365.25. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Estimated Annualized Joint Bleeding Rate | Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest | BE: any hemorrhage that required administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection to treat BE at that location was considered part of original BE; counted as 1 BE towards ABR. Bleeding after 72 hours from last injection at that location was considered as a new event. Joint BE: characterized by unusual sensation in joint (aura) + increasing swelling/warmth over joint skin, increasing pain/progressive loss of range of motion/difficulty in limb use compared to Baseline. ABR = total number of qualifying BE/number of days in respective period \*365.25. Estimated data were derived by using repeated measures NB regression model. |
| Observed Annualized Joint Bleeding Rate | Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest | BE: any occurrence of hemorrhage that might require administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered part of original BE and counted as 1 BE towards ABR. Bleeding began after 72 hours from last injection at that location was considered as a new event. Joint BE: characterized by unusual sensation in joint (aura) increasing swelling/warmth over joint skin, increasing pain or progressive loss of range of motion/difficulty in limb use compared to Baseline. ABR = total number of joint BE/number of days in respective period\*365.25. |
| Change in Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) Physical Health Score in the Fitusiran Treatment Period and the Factor or BPA Prophylaxis Period | Month -6 of Factor or BPA prophylaxis period (Baseline), Day 1 (Month 1) and Month 7 of fitusiran treatment period | Haem-A-QoL: participant-reported questionnaire for adults aged \>=17 years with hemophilia and comprised of 46 items covering 10 domains. Physical health domain (PHD) is assessed with 5 items rated on 5-point Likert scale: never, rarely, sometimes, often or all the time. Raw score for PHD were transformed to scale ranged from 0 to 100, where lower scores = better physical health. Least square (LS) mean and 95% confidence interval (CI) by mixed model for repeated measure (MMRM) analysis with robust sandwich covariance matrix: change from Month -6 to Day 1 and to Month 7 as response variable; period (factor/BPA prophylaxis & fitusiran treatment) & Baseline score (Month -6) as fixed effects. |
| Change in Haemophilia Quality of Life Questionnaire for Adults Total Score in the Fitusiran Treatment Period and the Factor or BPA Prophylaxis Period | Month -6 of Factor or BPA prophylaxis period (Baseline), Day 1 (Month 1) and Month 7 of fitusiran treatment period | Haem-A-QoL: questionnaire for adults aged \>= 17 years with hemophilia; and comprised of 46 items covering 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 on 5-point Likert scale: never, rarely, sometimes, often or all time. Domain raw score was transformed to scale ranged from 0 to 100, where lower scores=better health. LS mean & 95% CI by MMRM analysis with robust sandwich covariance matrix: change from Month -6 to Day 1 and to Month 7 as response variable; period (factor/BPA prophylaxis & fitusiran treatment) & Baseline score (Month -6) as fixed effects. |
| Estimated Annualized Bleeding Rate in the Fitusiran Onset Period | Day 1 up to Day 28 or up to the last day of bleeding follow up (any day up to Day 28), whichever was earliest | BE: any occurrence of hemorrhage that might require administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered part of original BE and was counted as 1 BE towards ABR. Bleeding began after 72 hours from last injection at that location was considered as new event. Estimated ABR and 95% CI was derived by using repeated measures NB regression model with logarithm of duration (years) that each participant spends in 1-Month fitusiran onset period matching BE data being analyzed as offset variable. ABR = total number of qualifying BE/number of days in respective period \*365.25. |
| Estimated Annualized Spontaneous Bleeding Rate | Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest | BE: any occurrence of hemorrhage that might require administration of factor/BPA infusion. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered part of original BE and counted as 1 BE towards ABR. Bleeding began after 72 hours of last injection at that location was considered as a new event. Spontaneous BE: BE occurrence for no apparent/known reason, particularly into joints, muscles, and soft tissues. ABR = total number of qualifying BE/number of days in respective period \*365.25. Estimated data was derived using repeated measures NB regression model. |
| Estimated Annualized Bleeding Rate in the Fitusiran Treatment Period | From Day 1 up to Day 190 | BE: defined as any occurrence of hemorrhage that might require administration of factor/BPA. BE start time was time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered a part of original BE and counted as one BE towards ABR. Bleeding began after 72 hours from last injection at that location was considered as new event. Analysis was based on on-treatment strategy which included all treated bleeding events in fitusiran period and excluded any bleeding events in the period of intercurrent events. ABR = total number of qualifying BE/number of days in respective period \*365.25. |
| Observed Annualized Bleeding Rate in the Fitusiran Treatment Period | from Day 1 up to Day 190 | BE: any occurrence of hemorrhage that might require administration of factor/BPA. BE start time was time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered a part of original bleeding event and was counted as one BE towards ABR. Any bleeding that began after 72 hours from last injection at that location was considered as a new event. ABR= total number of qualifying BE/number of days in treatment period \*365.25. Analysis was based on on-treatment strategy which included all treated bleeding events in fitusiran period and excluded any bleeding events in period of intercurrent events. |
| Cohort A: Annualized Weight-adjusted Consumption of BPA (Activated Prothrombin Complex Concentrates) | Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest | Annualized weight-adjusted BPA consumption was calculated for each participant during prophylaxis period as: \[Sum of BPA dose per body weight received during corresponding period/number of days in corresponding period\]\*365.25. In this outcome measure, data of annualized weight-adjusted consumption of BPA agent: aPCC (unit per kilogram \[U/kg\]) were reported. |
| Cohort A: Annualized Weight-adjusted Consumption of BPA (Recombinant Factor VIIa) | Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest | Annualized weight-adjusted BPA consumption was calculated for each participant during prophylaxis period as: (Sum of BPA dose per body weight received during corresponding period/number of days in corresponding period)\*365.25. In this outcome measure, data of annualized weight-adjusted consumption of BPA agents: rFVIIa (unit: micrograms per kg \[mcg/kg\]) were reported. Combined data of annualized weight-adjusted BPA consumption (mcg/kg) for both treated bleeds and prophylaxis purpose were reported in this outcome measure. |
| Cohort B: Annualized Weight-adjusted Consumption of Factor | Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest | Annualized weight-adjusted BPA consumption was calculated for each participant during prophylaxis period as: (Sum of BPA dose per body weight received during corresponding period/number of days in corresponding period)\*365.25. In this outcome measure, data of annualized weight-adjusted consumption of BPA agents: FVIII and FIX (unit: international Units \[IU\] per kg \[IU/kg\]) were reported. |
| Observed Annualized Bleeding Rate in the Fitusiran Onset Period | Day 1 up to Day 28 or up to the last day of bleeding follow up (any day up to Day 28), whichever was earliest | BE: any occurrence of hemorrhage that might require administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered a part of original BE and was counted as one BE towards ABR. Bleeding began after 72 hours from last injection at that location was considered as a new event. ABR= total number of qualifying BE/number of days in the 1-month onset period \*365.25. Analysis was based on on-treatment strategy which included all treated bleeding events in 1-month onset period and excluded any bleeding events in period of intercurrent events. |
| Observed Annualized Spontaneous Bleeding Rate | Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest | BE: any occurrence of hemorrhage that might require administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered part of original BE and was counted as 1 BE towards ABR. Bleeding began after 72 hours from last injection at that location was considered as a new event. Spontaneous BE: bleeding event occurred for no apparent or known reason, particularly into joints, muscles and soft tissues. ABR = total number of qualifying BE/number of days in respective period \*365.25. |
Countries
Australia, China, Denmark, France, Ireland, Israel, Italy, Japan, Malaysia, Mexico, South Korea, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Recruitment details
Study was conducted at 35 active sites in 15 countries. Total of 99 participants were screened from 25 July 2018 to 19 March 2021, of which 19 were screen failure due to not meeting eligibility criteria. Study had 2 main periods: 6-month factor/bypassing agent (BPA) prophylaxis period & 7-month fitusiran treatment period (1-month onset and 6-month fitusiran efficacy period).
Pre-assignment details
Subgroup of Cohort A: Participants with hemophilia B with inhibitors and inadequate response to BPA treatment (historical annualized bleeding rate \[ABR\] greater than or equal to \[\>=\] 20) prior to enrollment did not participate in 6-month prophylaxis period and they entered directly into fitusiran treatment period.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A: Inhibitor Participants with hemophilia A or B and inhibitory antibodies to FVIII or FIX and who were receiving BPA prophylaxis were enrolled in the study and entered into 6-month factor or BPA prophylaxis period in this study and continued their pre-study, regularly scheduled prophylaxis regimen with BPAs (twice weekly \[aPCC\] or every other day \[rFVIIa\]). This period was skipped by a subgroup of Cohort A (hemophilia B with inhibitors and historical ABR \>= 20) and they entered directly in to fitusiran treatment period. Post completion of BPA prophylaxis period, participants entered 7-month fitusiran treatment period (1-month onset period + 6-month efficacy period) and received fitusiran 80 mg QM as SC injection for 7 months until the sponsor initiated a voluntary dose pause. After dose pause and protocol amendment, the fitusiran dose was changed to 50 mg Q2M as SC injection. Participants could continue to receive BPA prophylaxis for up to 7 days after start of fitusiran treatment on Day 1. Throughout the study, participants in fitusiran treatment period could receive on-demand treatment for breakthrough bleeding episodes with BPAs, as appropriate. | 23 |
| Cohort B: Non-inhibitor Participants with hemophilia A or B, without inhibitory antibodies to FVIII or FIX who were receiving factor prophylaxis were enrolled in the study and entered the 6-month factor or BPA prophylaxis period in this study and continued their pre-study, regularly scheduled prophylaxis regimen with factor concentrates (twice weekly \[standard half-life FVIII\], once weekly \[extended half-life FVIII; standard half-life FIX\], and once biweekly \[extended half-life FIX\]). Post completion of factor prophylaxis period, participants entered in to 7-month fitusiran treatment period (1-month onset period + 6-month efficacy period) and received fitusiran 80 mg QM as SC injection until the sponsor initiated a voluntary dose pause. Participants could continue to receive their factor prophylaxis for up to 7 days after start of fitusiran treatment on Day 1. Throughout the study, participants in the fitusiran treatment period could receive on-demand treatment for breakthrough bleeding episodes with factor, as appropriate. | 46 |
| Total Title | 69 |
| Total | 138 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Factor/BPA Prophylaxis: Day -168 to -1 | Adverse Event | 1 | 0 |
| Factor/BPA Prophylaxis: Day -168 to -1 | Did not meet trial eligibility | 0 | 2 |
| Factor/BPA Prophylaxis: Day -168 to -1 | Parent withdrew consent | 1 | 0 |
| Factor/BPA Prophylaxis: Day -168 to -1 | Related to Coronavrus Disease 2019 | 1 | 0 |
| Factor/BPA Prophylaxis: Day -168 to -1 | Switched to treatment not per protocol | 4 | 0 |
| Factor/BPA Prophylaxis: Day -168 to -1 | Withdrawal by Subject | 0 | 2 |
| Fitusiran Treatment: Day 1 to Day 190 | Adverse Event | 0 | 2 |
| Fitusiran Treatment: Day 1 to Day 190 | More than 1 antithrombin (AT) measurement less than 15% | 1 | 0 |
| Fitusiran Treatment: Day 1 to Day 190 | Participant's decision | 0 | 2 |
| Fitusiran Treatment: Day 1 to Day 190 | Study drug on hold | 4 | 5 |
| Fitusiran Treatment: Day 1 to Day 190 | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Cohort B: Non-inhibitor | Total Title | Cohort A: Inhibitor |
|---|---|---|---|
| Age, Continuous | 23.5 years STANDARD_DEVIATION 7.3 | 24.9 years STANDARD_DEVIATION 11 | 27.7 years STANDARD_DEVIATION 15.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 17 Participants | 21 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 27 Participants | 45 Participants | 18 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 46 Participants | 69 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 21 | 0 / 46 | 0 / 46 | 0 / 65 | 0 / 67 | 0 / 2 | 0 / 2 |
| other Total, other adverse events | 10 / 19 | 13 / 21 | 9 / 46 | 28 / 46 | 19 / 65 | 41 / 67 | 1 / 2 | 2 / 2 |
| serious Total, serious adverse events | 5 / 19 | 5 / 21 | 0 / 46 | 4 / 46 | 5 / 65 | 9 / 67 | 1 / 2 | 1 / 2 |
Outcome results
Primary
Estimated Annualized Bleeding Rate (ABR)
Bleeding episodes (BE): any occurrence of hemorrhage might require administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location occurred within 72 hours of last injection used to treat BE at that location was considered part of original BE and counted as 1 BE towards ABR. Bleeding began after 72 hours of last injection at that location was considered as a new event. ABR = total number of qualifying BE/total number of days in the respective period\*365.25. Estimated data were derived by using repeated measures negative binomial (NB) regression model.
Time frame: Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest
Population: Analysis was performed on efficacy analysis set 1 (EAS1) which included participants who received factor/BPA prophylaxis and any dose of fitusiran before dose resumption. Data collection and analysis of combined population of Cohort A and B for each period was planned and performed for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Overall Factor/BPA Prophylaxis Period | Estimated Annualized Bleeding Rate (ABR) | 7.482 episodes per participant per year |
| Overall Fitusiran 80 mg Efficacy Period | Estimated Annualized Bleeding Rate (ABR) | 2.908 episodes per participant per year |
Comparison: Analyzed using repeated measures NB model with fixed effect of treatment period (fitusiran efficacy period or factor/BPA prophylaxis period) and robust sandwich covariance matrix was constructed to account for within participant dependence, logarithm of duration (in years) that each participant spends in each study period matching BE data being analyzed as an offset variable.p-value: =0.000895% CI: [0.224, 0.675]Repeated measures NB regression model
Primary
Observed Annualized Bleeding Rate (ABR)
A bleeding episode (BE): any occurrence of hemorrhage might require administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered a part of original BE and counted as 1 BE towards ABR. Any bleeding that began after 72 hours of last injection at that location was considered as a new event. ABR = total number of qualifying BE/number of days in the respective period \*365.25.
Time frame: Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest
Population: Analysis was performed on EAS1 population. Data collection and analysis of combined population of Cohort A and B for each period was planned and performed for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Overall Factor/BPA Prophylaxis Period | Observed Annualized Bleeding Rate (ABR) | 7.56 episodes per participant per year | Standard Deviation 9.49 |
| Overall Fitusiran 80 mg Efficacy Period | Observed Annualized Bleeding Rate (ABR) | 3.19 episodes per participant per year | Standard Deviation 7.75 |
Secondary
Change in Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) Physical Health Score in the Fitusiran Treatment Period and the Factor or BPA Prophylaxis Period
Haem-A-QoL: participant-reported questionnaire for adults aged \>=17 years with hemophilia and comprised of 46 items covering 10 domains. Physical health domain (PHD) is assessed with 5 items rated on 5-point Likert scale: never, rarely, sometimes, often or all the time. Raw score for PHD were transformed to scale ranged from 0 to 100, where lower scores = better physical health. Least square (LS) mean and 95% confidence interval (CI) by mixed model for repeated measure (MMRM) analysis with robust sandwich covariance matrix: change from Month -6 to Day 1 and to Month 7 as response variable; period (factor/BPA prophylaxis & fitusiran treatment) & Baseline score (Month -6) as fixed effects.
Time frame: Month -6 of Factor or BPA prophylaxis period (Baseline), Day 1 (Month 1) and Month 7 of fitusiran treatment period
Population: Analysis was performed on EAS 1 population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure. Data collection and analysis of combined population of Cohort A and B for each period was planned and performed for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Overall Factor/BPA Prophylaxis Period | Change in Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) Physical Health Score in the Fitusiran Treatment Period and the Factor or BPA Prophylaxis Period | -6.00 score on a scale |
| Overall Fitusiran 80 mg Efficacy Period | Change in Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) Physical Health Score in the Fitusiran Treatment Period and the Factor or BPA Prophylaxis Period | -9.60 score on a scale |
Secondary
Change in Haemophilia Quality of Life Questionnaire for Adults Total Score in the Fitusiran Treatment Period and the Factor or BPA Prophylaxis Period
Haem-A-QoL: questionnaire for adults aged \>= 17 years with hemophilia; and comprised of 46 items covering 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 on 5-point Likert scale: never, rarely, sometimes, often or all time. Domain raw score was transformed to scale ranged from 0 to 100, where lower scores=better health. LS mean & 95% CI by MMRM analysis with robust sandwich covariance matrix: change from Month -6 to Day 1 and to Month 7 as response variable; period (factor/BPA prophylaxis & fitusiran treatment) & Baseline score (Month -6) as fixed effects.
Time frame: Month -6 of Factor or BPA prophylaxis period (Baseline), Day 1 (Month 1) and Month 7 of fitusiran treatment period
Population: Analysis was performed on EAS1 population. Here, 'overall number of participants analyzed = participants with available data for this outcome measure. Data collection and analysis of combined population of Cohort A and B for each period was planned and performed for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Overall Factor/BPA Prophylaxis Period | Change in Haemophilia Quality of Life Questionnaire for Adults Total Score in the Fitusiran Treatment Period and the Factor or BPA Prophylaxis Period | -3.07 score on a scale |
| Overall Fitusiran 80 mg Efficacy Period | Change in Haemophilia Quality of Life Questionnaire for Adults Total Score in the Fitusiran Treatment Period and the Factor or BPA Prophylaxis Period | -7.62 score on a scale |
Secondary
Cohort A: Annualized Weight-adjusted Consumption of BPA (Activated Prothrombin Complex Concentrates)
Annualized weight-adjusted BPA consumption was calculated for each participant during prophylaxis period as: \[Sum of BPA dose per body weight received during corresponding period/number of days in corresponding period\]\*365.25. In this outcome measure, data of annualized weight-adjusted consumption of BPA agent: aPCC (unit per kilogram \[U/kg\]) were reported.
Time frame: Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest
Population: Analysis was performed on EAS 1 population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure. Combined data of annualized weight-adjusted BPA consumption (U/kg) for both treated bleeds and prophylaxis purpose were reported in this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Overall Factor/BPA Prophylaxis Period | Cohort A: Annualized Weight-adjusted Consumption of BPA (Activated Prothrombin Complex Concentrates) | 7912.7 U/kg per participant per year | Standard Deviation 5507.6 |
| Overall Fitusiran 80 mg Efficacy Period | Cohort A: Annualized Weight-adjusted Consumption of BPA (Activated Prothrombin Complex Concentrates) | 39.7 U/kg per participant per year | Standard Deviation 87 |
Secondary
Cohort A: Annualized Weight-adjusted Consumption of BPA (Recombinant Factor VIIa)
Annualized weight-adjusted BPA consumption was calculated for each participant during prophylaxis period as: (Sum of BPA dose per body weight received during corresponding period/number of days in corresponding period)\*365.25. In this outcome measure, data of annualized weight-adjusted consumption of BPA agents: rFVIIa (unit: micrograms per kg \[mcg/kg\]) were reported. Combined data of annualized weight-adjusted BPA consumption (mcg/kg) for both treated bleeds and prophylaxis purpose were reported in this outcome measure.
Time frame: Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest
Population: Analysis was performed on EAS 1 population. Here, 'overall number of participants analyzed' = participants with available data for this outcome measure. Combined data of annualized weight-adjusted BPA consumption (mcg/kg) for both treated bleeds and prophylaxis purpose were reported in this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Overall Factor/BPA Prophylaxis Period | Cohort A: Annualized Weight-adjusted Consumption of BPA (Recombinant Factor VIIa) | 18895.8 mcg/kg per participant per year | Standard Deviation 14081.9 |
| Overall Fitusiran 80 mg Efficacy Period | Cohort A: Annualized Weight-adjusted Consumption of BPA (Recombinant Factor VIIa) | 168.8 mcg/kg per participant per year | Standard Deviation 290.8 |
Secondary
Cohort B: Annualized Weight-adjusted Consumption of Factor
Annualized weight-adjusted BPA consumption was calculated for each participant during prophylaxis period as: (Sum of BPA dose per body weight received during corresponding period/number of days in corresponding period)\*365.25. In this outcome measure, data of annualized weight-adjusted consumption of BPA agents: FVIII and FIX (unit: international Units \[IU\] per kg \[IU/kg\]) were reported.
Time frame: Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest
Population: Analysis was performed on EAS 1 population. Here, 'number analyzed' = participants with available data for each specified category. Combined data of annualized weight-adjusted factor consumption (IU/kg) for both treated bleeds and prophylaxis purpose were reported in this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Overall Factor/BPA Prophylaxis Period | Cohort B: Annualized Weight-adjusted Consumption of Factor | FVIII | 3396.9 IU/kg per participant per year | Standard Deviation 1144.5 |
| Overall Factor/BPA Prophylaxis Period | Cohort B: Annualized Weight-adjusted Consumption of Factor | FIX | 3175.5 IU/kg per participant per year | Standard Deviation 961.3 |
| Overall Fitusiran 80 mg Efficacy Period | Cohort B: Annualized Weight-adjusted Consumption of Factor | FVIII | 60.7 IU/kg per participant per year | Standard Deviation 148.3 |
| Overall Fitusiran 80 mg Efficacy Period | Cohort B: Annualized Weight-adjusted Consumption of Factor | FIX | 17.8 IU/kg per participant per year | Standard Deviation 56.1 |
Secondary
Estimated Annualized Bleeding Rate in the Fitusiran Onset Period
BE: any occurrence of hemorrhage that might require administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered part of original BE and was counted as 1 BE towards ABR. Bleeding began after 72 hours from last injection at that location was considered as new event. Estimated ABR and 95% CI was derived by using repeated measures NB regression model with logarithm of duration (years) that each participant spends in 1-Month fitusiran onset period matching BE data being analyzed as offset variable. ABR = total number of qualifying BE/number of days in respective period \*365.25.
Time frame: Day 1 up to Day 28 or up to the last day of bleeding follow up (any day up to Day 28), whichever was earliest
Population: Analysis was performed on EAS 1 population. Data collection and analysis of combined population of Cohort A and B for fitusiran 1-month onset period was planned and performed for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Overall Factor/BPA Prophylaxis Period | Estimated Annualized Bleeding Rate in the Fitusiran Onset Period | 5.419 episodes per participant per year |
Secondary
Estimated Annualized Bleeding Rate in the Fitusiran Treatment Period
BE: defined as any occurrence of hemorrhage that might require administration of factor/BPA. BE start time was time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered a part of original BE and counted as one BE towards ABR. Bleeding began after 72 hours from last injection at that location was considered as new event. Analysis was based on on-treatment strategy which included all treated bleeding events in fitusiran period and excluded any bleeding events in the period of intercurrent events. ABR = total number of qualifying BE/number of days in respective period \*365.25.
Time frame: From Day 1 up to Day 190
Population: Analysis was performed on EAS 1 population. Data collection and analysis of combined population of Cohort A and B for fitusiran treatment period was planned and performed for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Overall Factor/BPA Prophylaxis Period | Estimated Annualized Bleeding Rate in the Fitusiran Treatment Period | 3.317 episodes per participant per year |
Secondary
Estimated Annualized Joint Bleeding Rate
BE: any hemorrhage that required administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection to treat BE at that location was considered part of original BE; counted as 1 BE towards ABR. Bleeding after 72 hours from last injection at that location was considered as a new event. Joint BE: characterized by unusual sensation in joint (aura) + increasing swelling/warmth over joint skin, increasing pain/progressive loss of range of motion/difficulty in limb use compared to Baseline. ABR = total number of qualifying BE/number of days in respective period \*365.25. Estimated data were derived by using repeated measures NB regression model.
Time frame: Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest
Population: Analysis was performed on EAS 1 population. Data collection and analysis of combined population of Cohort A and B for each period was planned and performed for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Overall Factor/BPA Prophylaxis Period | Estimated Annualized Joint Bleeding Rate | 5.282 episodes per participant per year |
| Overall Fitusiran 80 mg Efficacy Period | Estimated Annualized Joint Bleeding Rate | 2.564 episodes per participant per year |
95% CI: [0.259, 0.91]
Secondary
Estimated Annualized Spontaneous Bleeding Rate
BE: any occurrence of hemorrhage that might require administration of factor/BPA infusion. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered part of original BE and counted as 1 BE towards ABR. Bleeding began after 72 hours of last injection at that location was considered as a new event. Spontaneous BE: BE occurrence for no apparent/known reason, particularly into joints, muscles, and soft tissues. ABR = total number of qualifying BE/number of days in respective period \*365.25. Estimated data was derived using repeated measures NB regression model.
Time frame: Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest
Population: Analysis was performed on EAS 1 population. Data collection and analysis of combined population of Cohort A and B for each period was planned and performed for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Overall Factor/BPA Prophylaxis Period | Estimated Annualized Spontaneous Bleeding Rate | 5.002 episodes per participant per year |
| Overall Fitusiran 80 mg Efficacy Period | Estimated Annualized Spontaneous Bleeding Rate | 2.222 episodes per participant per year |
95% CI: [0.234, 0.842]
Secondary
Observed Annualized Bleeding Rate in the Fitusiran Onset Period
BE: any occurrence of hemorrhage that might require administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered a part of original BE and was counted as one BE towards ABR. Bleeding began after 72 hours from last injection at that location was considered as a new event. ABR= total number of qualifying BE/number of days in the 1-month onset period \*365.25. Analysis was based on on-treatment strategy which included all treated bleeding events in 1-month onset period and excluded any bleeding events in period of intercurrent events.
Time frame: Day 1 up to Day 28 or up to the last day of bleeding follow up (any day up to Day 28), whichever was earliest
Population: Analysis was performed on EAS 1 population. Data collection and analysis of combined population of Cohort A and B for fitusiran 1-month onset period was planned and performed for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Overall Factor/BPA Prophylaxis Period | Observed Annualized Bleeding Rate in the Fitusiran Onset Period | 5.42 episodes per participant per year | Standard Deviation 8.28 |
Secondary
Observed Annualized Bleeding Rate in the Fitusiran Treatment Period
BE: any occurrence of hemorrhage that might require administration of factor/BPA. BE start time was time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered a part of original bleeding event and was counted as one BE towards ABR. Any bleeding that began after 72 hours from last injection at that location was considered as a new event. ABR= total number of qualifying BE/number of days in treatment period \*365.25. Analysis was based on on-treatment strategy which included all treated bleeding events in fitusiran period and excluded any bleeding events in period of intercurrent events.
Time frame: from Day 1 up to Day 190
Population: Analysis was performed on EAS1 population. Data collection and analysis of combined population of Cohort A and B for fitusiran treatment period was planned and performed for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Overall Factor/BPA Prophylaxis Period | Observed Annualized Bleeding Rate in the Fitusiran Treatment Period | 3.48 episodes per participant per year | Standard Deviation 6.98 |
Secondary
Observed Annualized Joint Bleeding Rate
BE: any occurrence of hemorrhage that might require administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered part of original BE and counted as 1 BE towards ABR. Bleeding began after 72 hours from last injection at that location was considered as a new event. Joint BE: characterized by unusual sensation in joint (aura) increasing swelling/warmth over joint skin, increasing pain or progressive loss of range of motion/difficulty in limb use compared to Baseline. ABR = total number of joint BE/number of days in respective period\*365.25.
Time frame: Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest
Population: Analysis was performed on EAS 1 population. Data collection and analysis of combined population of Cohort A and B for each period was planned and performed for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Overall Factor/BPA Prophylaxis Period | Observed Annualized Joint Bleeding Rate | 5.35 episodes per participant per year | Standard Deviation 8.19 |
| Overall Fitusiran 80 mg Efficacy Period | Observed Annualized Joint Bleeding Rate | 2.82 episodes per participant per year | Standard Deviation 7.54 |
Secondary
Observed Annualized Spontaneous Bleeding Rate
BE: any occurrence of hemorrhage that might require administration of factor/BPA. BE start time: time at which 1st BE symptoms develop; bleeding/any symptoms at same location that occurred within 72 hours of last injection used to treat BE at that location was considered part of original BE and was counted as 1 BE towards ABR. Bleeding began after 72 hours from last injection at that location was considered as a new event. Spontaneous BE: bleeding event occurred for no apparent or known reason, particularly into joints, muscles and soft tissues. ABR = total number of qualifying BE/number of days in respective period \*365.25.
Time frame: Factor/BPA prophylaxis period: Day -168 to Day -1 or up to last day of bleeding follow up (any day up to Day -1); 6-month fitusiran efficacy period: Day 29 to Day 190 or up to last day of bleeding follow up (any day up to Day 190), whichever was earliest
Population: Analysis was performed on EAS 1 population. Data collection and analysis of combined population of Cohort A and B for each period was planned and performed for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Overall Factor/BPA Prophylaxis Period | Observed Annualized Spontaneous Bleeding Rate | 5.09 episodes per participant per year | Standard Deviation 7.93 |
| Overall Fitusiran 80 mg Efficacy Period | Observed Annualized Spontaneous Bleeding Rate | 2.51 episodes per participant per year | Standard Deviation 7.33 |