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    Clinical Trial Results:
    ATLAS-PPX trial: An open-label, Multinational, Switching Study to Describe the Efficacy and Safety of Fitusiran Prophylaxis in Hemophilia A and B Patients Previously Receiving Factor or Bypassing Agent Prophylaxis

    Summary
    EudraCT number
    		 2016-004087-19
    Trial protocol
    		 ES   IE   GB   DE   DK   NL   IT   Outside EU/EEA  
    Global end of trial date
    25 Mar 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Oct 2022
    First version publication date
    11 Oct 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC15110
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03549871
    WHO universal trial number (UTN)
    		 U1111-1217-3270
    Other trial identifiers
    		 Alnylam: ALN-AT3SC-009
    Sponsors
    Sponsor organisation name
    Genzyme Corporation, A Sanofi company
    Sponsor organisation address
    50 Binney Street, Cambridge, MA, United States, 02142
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001855-PIP01-15
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Apr 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Mar 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To characterise the frequency of bleeding episodes while receiving fitusiran treatment, relative to the frequency of bleeding episodes while receiving factor or bypassing agent (BPA) prophylaxis.
    Protection of trial subjects
    The study was conducted by investigators experienced in the treatment of adolescent and adult subjects. The parent(s) or guardian(s), as well as the subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in age-appropriate language was provided and explained to the subject. Repeated invasive procedures were minimised. A topical anesthesia might have been used to minimise distress and discomfort. Adult subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    25 Jul 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Ireland: 2
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Malaysia: 5
    Country: Number of subjects enrolled
    Japan: 4
    Country: Number of subjects enrolled
    Korea, Republic of: 12
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    China: 1
    Country: Number of subjects enrolled
    Ukraine: 5
    Country: Number of subjects enrolled
    Turkey: 34
    Country: Number of subjects enrolled
    United States: 1
    Country: Number of subjects enrolled
    Mexico: 4
    Worldwide total number of subjects
    80
    EEA total number of subjects
    7
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    23
    Adults (18-64 years)
    56
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at 35 active sites in 15 countries. Total of 99 subjects 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/BPA prophylaxis period & 7-month fitusiran treatment period (1-month onset and 6-month fitusiran efficacy).

    Pre-assignment
    Screening details
    		 Subjects with inadequate response to BPA treatment (historical annualised 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 and were referred as 'Subgroup of Cohort A' for analysis purpose.

    Period 1
    Period 1 title
    Factor/BPA prophylaxis period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Cohort A: Inhibitor
    Arm description
    		 Subjects with hemophilia A or B, with inhibitory antibodies to coagulation factor VIII (FVIII) or coagulation factor IX (FIX) and who were receiving BPA 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 BPAs. This period was skipped by a subgroup of Cohort A which included subjects with hemophilia B with inhibitory antibodies to FIX who had not responded adequately to BPA prophylaxis prior to study entry (historical ABR >=20).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    BPA prophylaxis
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were to continue to receive BPA prophylaxis on a regimen consistent with recommendations in the approved prescribing information, allowed for adjustment to individual subject response and designed to decrease spontaneous bleeding. The regimen had to have a minimum frequency per protocol: twice weekly (activated prothrombin complex concentrates [aPCC]) or every other day (recombinant factor VIIa [rFVIIa]).

    Arm title
    		 Cohort B: Non-inhibitor
    Arm description
    		 Subjects 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.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Factor (FVIII or FIX) Prophylaxis
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were to continue to receive factor concentrate prophylaxis on a regimen consistent with recommendations in the approved prescribing information, allowed for adjustment to individual subject response and designed to decrease spontaneous bleeding. The regimen had to have a minimum frequency per protocol: twice weekly (standard half-life FVIII), once weekly (extended half-life FVIII; standard half-life FIX), once biweekly (extended half-life FIX).

    Number of subjects in period 1
    		Cohort A: Inhibitor Cohort B: Non-inhibitor
    Started
    28
    50
    Completed
    21
    46
    Not completed
    7
    4
         Consent withdrawn by subject
    1
    2
         Adverse event
    1
    -
         Unspecified
    5
    2
    Period 2
    Period 2 title
    Fitusiran Treatment period
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort A: Inhibitor
    Arm description
    		 Post completion of BPA prophylaxis period, subjects entered into the 7-month fitusiran treatment period (1-month onset period + 6-month efficacy period). Subjects could continue to receive BPA prophylaxis for up to 7 days after start of fitusiran treatment on Day 1. A subgroup of Cohort A (hemophilia B subjects with inhibitory antibodies to Factor IX who were not responding adequately to BPA prophylaxis prior to study entry (historical ABR >=20) entered directly into fitusiran treatment period. Throughout the study, subjects in the fitusiran treatment period could receive on-demand treatment for breakthrough bleeding episodes with BPAs, as appropriate.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fitusiran
    Investigational medicinal product code
    SAR439774
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Fitusiran 80 milligrams (mg) once monthly (QM) as subcutaneous (SC) injection for 7 months until the sponsor initiated a voluntary dose pause. Fitusiran 50 mg once every other month (Q2M) as SC injection after dose pause and protocol amendment.

    Arm title
    		 Cohort B: Non-inhibitor
    Arm description
    		 Post completion of factor prophylaxis period, subjects entered in to 7-month fitusiran treatment period (1-month onset period + 6-month efficacy period). Subjects could continue to receive their factor prophylaxis for up to 7 days after start of fitusiran treatment on Day 1. Throughout the study, subjects in the fitusiran treatment period could receive on-demand treatment for breakthrough bleeding episodes with factor, as appropriate.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fitusiran
    Investigational medicinal product code
    SAR439774
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Fitusiran 80 mg QM as SC injection until the sponsor initiated a voluntary dose pause. Fitusiran 50 mg Q2M as SC injection after dose pause and protocol amendment.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 2 as Baseline period because it included all subjects of efficacy analysis set (included the Cohort A subgroup subjects who entered directly into the fitusiran treatment period).
    Number of subjects in period 2 [2]
    		Cohort A: Inhibitor Cohort B: Non-inhibitor
    Started
    23
    46
    80mg QM & part of safety analysis set 1
    21
    46
    50 mg Q2M & part of safety analysis set2
    2 [3]
    0 [4]
    Efficacy Set 1
    19
    46
    Efficacy Set 2
    2 [5]
    0 [6]
    Completed
    17
    37
    Not completed
    6
    9
         Consent withdrawn by subject
    1
    -
         Study drug on hold
    4
    5
         More than 1 antithrombin measurement less than 15%
    1
    -
         Subject’s decision
    -
    2
         Adverse event
    -
    2
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The baseline period (Period 2) included all completed subjects from BPA/factor prophylaxis period + 2 subjects from Cohort A subgroup who directly enrolled to fitusiran treatment period.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Received fitusiran 50mg Q2M dosing regimen after dose pause and protocol amendment 5, dated 25-Nov-2020. They were considered as safety analysis set 2 (SAS 2) and were subjected only to safety analysis and not to main efficacy analysis.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This milestone is applicable only to arm Cohort A: Inhibitor.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Efficacy Analysis Set 2 (EAS 2) included all subjects in the SAS 2 who received factor or BPA prophylaxis and any dose of fitusiran 50 mg Q2M after dose pause, protocol amendment 5 (dated 25-Nov-2020) and dose resumption.
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This milestone is applicable only to arm Cohort A: Inhibitor.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A: Inhibitor
    Reporting group description
    		 Post completion of BPA prophylaxis period, subjects entered into the 7-month fitusiran treatment period (1-month onset period + 6-month efficacy period). Subjects could continue to receive BPA prophylaxis for up to 7 days after start of fitusiran treatment on Day 1. A subgroup of Cohort A (hemophilia B subjects with inhibitory antibodies to Factor IX who were not responding adequately to BPA prophylaxis prior to study entry (historical ABR >=20) entered directly into fitusiran treatment period. Throughout the study, subjects in the fitusiran treatment period could receive on-demand treatment for breakthrough bleeding episodes with BPAs, as appropriate.

    Reporting group title
    Cohort B: Non-inhibitor
    Reporting group description
    		 Post completion of factor prophylaxis period, subjects entered in to 7-month fitusiran treatment period (1-month onset period + 6-month efficacy period). Subjects could continue to receive their factor prophylaxis for up to 7 days after start of fitusiran treatment on Day 1. Throughout the study, subjects in the fitusiran treatment period could receive on-demand treatment for breakthrough bleeding episodes with factor, as appropriate.

    Reporting group values
    		 Cohort A: Inhibitor Cohort B: Non-inhibitor Total
    Number of subjects
    		 23 46 69
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 27.7 ( 15.9 ) 23.5 ( 7.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 23 46 69
    Race
    Units: Subjects
        White
    		 18 27 45
        Black or African American
    		 1 0 1
        Asian
    		 4 17 21
        Other
    		 0 2 2

    End points

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    End points reporting groups
    Reporting group title
    Cohort A: Inhibitor
    Reporting group description
    		 Subjects with hemophilia A or B, with inhibitory antibodies to coagulation factor VIII (FVIII) or coagulation factor IX (FIX) and who were receiving BPA 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 BPAs. This period was skipped by a subgroup of Cohort A which included subjects with hemophilia B with inhibitory antibodies to FIX who had not responded adequately to BPA prophylaxis prior to study entry (historical ABR >=20).

    Reporting group title
    Cohort B: Non-inhibitor
    Reporting group description
    		 Subjects 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.
    Reporting group title
    Cohort A: Inhibitor
    Reporting group description
    		 Post completion of BPA prophylaxis period, subjects entered into the 7-month fitusiran treatment period (1-month onset period + 6-month efficacy period). Subjects could continue to receive BPA prophylaxis for up to 7 days after start of fitusiran treatment on Day 1. A subgroup of Cohort A (hemophilia B subjects with inhibitory antibodies to Factor IX who were not responding adequately to BPA prophylaxis prior to study entry (historical ABR >=20) entered directly into fitusiran treatment period. Throughout the study, subjects in the fitusiran treatment period could receive on-demand treatment for breakthrough bleeding episodes with BPAs, as appropriate.

    Reporting group title
    Cohort B: Non-inhibitor
    Reporting group description
    		 Post completion of factor prophylaxis period, subjects entered in to 7-month fitusiran treatment period (1-month onset period + 6-month efficacy period). Subjects could continue to receive their factor prophylaxis for up to 7 days after start of fitusiran treatment on Day 1. Throughout the study, subjects in the fitusiran treatment period could receive on-demand treatment for breakthrough bleeding episodes with factor, as appropriate.

    Subject analysis set title
    Overall Factor/BPA Prophylaxis Period
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects, whether with inhibitory antibodies (Cohort A) or without inhibitory antibodies (Cohort B) to FVIII or FIX and who were receiving BPA or 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 BPAs or factors in 6-month factor or BPA prophylaxis period. This period was skipped by a subgroup of Cohort A which included subjects with hemophilia B with inhibitory antibodies to FIX and who had not responded adequately to BPA prophylaxis prior to study entry (historical ABR >=20).

    Subject analysis set title
    Overall Fitusiran 80 mg Efficacy Period
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects who received fitusiran 80 mg QM (either in Cohort A or Cohort B) until sponsor initiated a voluntary dose pause during fitusiran efficacy period (i.e., from Day 29 to Day 190 of fitusiran treatment period) and were considered for efficacy analysis during fitusiran efficacy period.

    Subject analysis set title
    Overall Fitusiran 80 mg Treatment Period
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects who received fitusiran 80 mg QM (either in Cohort A or Cohort B) until sponsor initiated a voluntary dose pause during fitusiran treatment period (i.e., 1-month onset period + 6-month efficacy period) and were considered for efficacy analysis during fitusiran treatment period.

    Subject analysis set title
    Overall Fitusiran 80 mg 1-Month Onset Period
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects who received fitusiran 80 mg QM (either in Cohort A or Cohort B) until sponsor initiated a voluntary dose pause during fitusiran 1-month onset period (i.e., from Day 1 to Day 28 of fitusiran treatment period) and were considered for the efficacy analysis during fitusiran 1-month onset period.

    Subject analysis set title
    BPA Prophylaxis: Cohort: A Inhibitor
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects with hemophilia A or B, with inhibitory antibodies to FVIII or FIX and who were receiving BPA 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 BPAs. This period was skipped by a subgroup of Cohort A which included subjects with hemophilia B with inhibitory antibodies to FIX who had not responded adequately to BPA prophylaxis prior to study entry (historical ABR >=20).

    Subject analysis set title
    Fitusiran 80 mg Prophylaxis: Cohort A: Inhibitor
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Post completion of BPA prophylaxis period, subjects entered into the 7-month fitusiran treatment period (1-month onset period + 6-month efficacy period). Subjects could continue to receive BPA prophylaxis for up to 7 days after start of fitusiran treatment on Day 1. A subgroup of Cohort A (hemophilia B subjects with inhibitory antibodies to Factor IX who were not responding adequately to BPA prophylaxis prior to study entry: historical ABR >=20) entered directly into fitusiran treatment period. Throughout the study, subjects in the fitusiran treatment period could receive on-demand treatment for breakthrough bleeding episodes with BPAs, as appropriate.

    Subject analysis set title
    Factor Prophylaxis: Cohort B: Non-inhibitor
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects 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.

    Subject analysis set title
    Fitusiran 80 mg Prophylaxis: Cohort B: Non-inhibitor
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Post completion of factor prophylaxis period, subjects entered in to 7-month fitusiran treatment period (1-month onset period + 6-month efficacy period). Subjects could continue to receive their factor prophylaxis for up to 7 days after start of fitusiran treatment on Day 1. Throughout the study, subjects in the fitusiran treatment period could receive on-demand treatment for breakthrough bleeding episodes with factor, as appropriate.

    Primary: Estimated Annualised Bleeding Rate (ABR)

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    End point title
    		 Estimated Annualised Bleeding Rate (ABR)
    End point description
    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. Analysis was performed on efficacy analysis set 1 (EAS1) which included subjects who received factor/BPA prophylaxis and any dose of fitusiran before dose resumption. Estimated data were derived by using repeated measures negative (NB) binomial regression model. Data collection and analysis of combined population (Cohort A & B) for each period was planned and performed for this endpoint.
    End point type
    Primary
    End point timeframe
    Factor/BPA prophylaxis period: from Day -168 to Day -1; 6-month fitusiran efficacy period: from Day 29 to Day 190 or up to the last day of bleeding follow up (any day up to Day 190), whichever was the earliest
    End point values
    		 Overall Factor/BPA Prophylaxis Period Overall Fitusiran 80 mg Efficacy Period
    Number of subjects analysed
    65
    65
    Units: episodes per subject per year
        number (confidence interval 95%)
    7.482 (5.520 to 10.141)
    2.908 (1.727 to 4.898)
    Statistical analysis title
    		 Factor/BPA Prophylaxis vs Fitusiran 80 mg Efficacy
    Statistical analysis description
    Analysed 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 subject dependence, logarithm of duration (in years) that each subject spends in each study period matching BE data being analysed as an offset variable. Number of subjects included in this analysis was 65 and not 130.
    Comparison groups
    Overall Fitusiran 80 mg Efficacy Period v Overall Factor/BPA Prophylaxis Period
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0008 [1]
    Method
    		 Repeated measures NB regression model
    Parameter type
    		 ABR ratio
    Point estimate
    0.389
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.224
         upper limit
    		 0.675
    Notes
    [1] - The threshold for significance was <0.05.

    Primary: Observed Annualised Bleeding Rate (ABR)

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    End point title
    		 Observed Annualised Bleeding Rate (ABR) [2]
    End point description
    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. Analysis was performed on EAS1 population. Data collection and analysis of combined population (Cohort A and B) for each period was planned and performed for this endpoint.
    End point type
    Primary
    End point timeframe
    Factor/BPA prophylaxis period: from Day -168 to Day -1; 6-month fitusiran efficacy period: from Day 29 to Day 190 or up to the last day of bleeding follow up (any day up to Day 190), whichever was the earliest
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint was descriptive in nature, no statistical analysis was provided.
    End point values
    		 Overall Factor/BPA Prophylaxis Period Overall Fitusiran 80 mg Efficacy Period
    Number of subjects analysed
    65
    65
    Units: episodes per subject per year
        arithmetic mean (standard deviation)
    7.56 ( 9.49 )
    3.19 ( 7.75 )
    No statistical analyses for this end point

    Secondary: Estimated Annualised Spontaneous Bleeding Rate

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    End point title
    		 Estimated Annualised Spontaneous Bleeding Rate
    End point description
    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. Analysis was performed on EAS 1 population. Estimated data was derived using repeated measures NB regression model. Data collection and combined population (Cohort A and B) analysis of each period was planned and performed for this endpoint.
    End point type
    Secondary
    End point timeframe
    Factor/BPA prophylaxis period: from Day -168 to Day -1; 6-month fitusiran efficacy period: from Day 29 to Day 190 or up to the last day of bleeding follow up (any day up to Day 190), whichever was the earliest
    End point values
    		 Overall Factor/BPA Prophylaxis Period Overall Fitusiran 80 mg Efficacy Period
    Number of subjects analysed
    65
    65
    Units: episodes per subject per year
        number (confidence interval 95%)
    5.002 (3.424 to 7.305)
    2.222 (1.190 to 4.152)
    Statistical analysis title
    		 Factor/BPA Prophylaxis vs Fitusiran 80 mg Efficacy
    Statistical analysis description
    Number of subjects included in this analysis was 65 and not 130.
    Comparison groups
    Overall Factor/BPA Prophylaxis Period v Overall Fitusiran 80 mg Efficacy Period
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 ABR ratio
    Point estimate
    0.444
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.234
         upper limit
    		 0.842

    Secondary: Observed Annualised Spontaneous Bleeding Rate

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    End point title
    		 Observed Annualised Spontaneous Bleeding Rate
    End point description
    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. Analysis was performed on EAS 1 population. Data collection and combined population (Cohort A and B) analysis of each period was planned and performed for this endpoint.
    End point type
    Secondary
    End point timeframe
    Factor/BPA prophylaxis period: from Day -168 to Day -1; 6-month fitusiran efficacy period: from Day 29 to Day 190 or up to the last day of bleeding follow up (any day up to Day 190), whichever was the earliest
    End point values
    		 Overall Factor/BPA Prophylaxis Period Overall Fitusiran 80 mg Efficacy Period
    Number of subjects analysed
    65
    65
    Units: episodes per subject per year
        arithmetic mean (standard deviation)
    5.09 ( 7.93 )
    2.51 ( 7.33 )
    No statistical analyses for this end point

    Secondary: Estimated Annualised Joint Bleeding Rate

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    End point title
    		 Estimated Annualised Joint Bleeding Rate
    End point description
    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: characterised 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. Analysis was performed on EAS 1 population. Data collection and analysis of combined population (Cohort A and B) for each period was planned and performed for this endpoint.
    End point type
    Secondary
    End point timeframe
    Factor/BPA prophylaxis period: from Day -168 to Day -1; 6-month fitusiran efficacy period: from Day 29 to Day 190 or up to the last day of bleeding follow up (any day up to Day 190), whichever was the earliest
    End point values
    		 Overall Factor/BPA Prophylaxis Period Overall Fitusiran 80 mg Efficacy Period
    Number of subjects analysed
    65
    65
    Units: episodes per subject per year
        number (confidence interval 95%)
    5.282 (3.647 to 7.651)
    2.564 (1.440 to 4.566)
    Statistical analysis title
    		 Factor/BPA Prophylaxis vs Fitusiran 80 mg Efficacy
    Statistical analysis description
    Number of subjects included in this analysis was 65 and not 130.
    Comparison groups
    Overall Fitusiran 80 mg Efficacy Period v Overall Factor/BPA Prophylaxis Period
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 ABR ratio
    Point estimate
    0.485
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.259
         upper limit
    		 0.91

    Secondary: Observed Annualised Joint Bleeding Rate

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    End point title
    		 Observed Annualised Joint Bleeding Rate
    End point description
    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: characterised 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. Analysis was performed on EAS 1 population. Data collection and analysis of combined population (Cohort A and B) for each period was planned and performed for this endpoint.
    End point type
    Secondary
    End point timeframe
    Factor/BPA prophylaxis period: from Day -168 to Day -1; 6-month fitusiran efficacy period: from Day 29 to Day 190 or up to the last day of bleeding follow up (any day up to Day 190), whichever was the earliest
    End point values
    		 Overall Factor/BPA Prophylaxis Period Overall Fitusiran 80 mg Efficacy Period
    Number of subjects analysed
    65
    65
    Units: episodes per subject per year
        arithmetic mean (standard deviation)
    5.35 ( 8.19 )
    2.82 ( 7.54 )
    No statistical analyses for this end point

    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

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    End point title
    		 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
    End point description
    Haem-A-QoL: subject-reported questionnaire for adults aged >=17 years with hemophilia and consisted of 46 items comprising 10 domains. Physical health domain (PHD) with 5 items were rated along 5 response options: 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. Analysis was performed on EAS 1 population. Number of subjects analysed = subjects evaluable for endpoint. Least square (LS) mean & 95% confidence interval by mixed model for repeated measure (MMRM) analysis with robust sandwich covariance matrix: change from Baseline in each study period (change from Month -6 to Day 1 and change from Month -6 to Month 7) as response variable; period (factor/BPA prophylaxis & fitusiran treatment) & Baseline score (Month -6) as fixed effects. Data collection and analysis of combined population (Cohort A & B) for each period was planned and performed for this endpoint.
    End point type
    Secondary
    End point timeframe
    Month -6 of prophylaxis period (Baseline), Day 1 (Month 1) and Month 7 of fitusiran treatment period
    End point values
    		 Overall Factor/BPA Prophylaxis Period Overall Fitusiran 80 mg Treatment Period
    Number of subjects analysed
    48
    48
    Units: score on a scale
        least squares mean (confidence interval 95%)
    -6.00 (-10.19 to -1.81)
    -9.60 (-15.35 to -3.84)
    No statistical analyses for this end point

    Secondary: Change in Haemophilia A Quality of Life Questionnaire for Adults Total Score in the Fitusiran Treatment Period and the Factor or BPA Prophylaxis Period

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    End point title
    		 Change in Haemophilia A Quality of Life Questionnaire for Adults Total Score in the Fitusiran Treatment Period and the Factor or BPA Prophylaxis Period
    End point description
    Haem-A-QoL: questionnaire for adults aged >= 17 years with hemophilia; and consisted 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 on 5 response options: never, rarely, sometimes, often or all time. Each domain raw score was transformed to scale ranged from 0 to 100, where lower scores=better health. Haem-A-QoL Total Score: average of all domain scores, ranged from 0 to 100; lower scores=better quality of life. EAS1. Number of subjects analysed=subjects evaluable. LS mean & 95% confidence interval by MMRM analysis with robust sandwich covariance matrix: change from Baseline in each period (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. Data collection and combined analysis (Cohort A&B) performed.
    End point type
    Secondary
    End point timeframe
    Month -6 of prophylaxis period (Baseline), Day 1 (Month 1) and Month 7 of fitusiran treatment period
    End point values
    		 Overall Factor/BPA Prophylaxis Period Overall Fitusiran 80 mg Treatment Period
    Number of subjects analysed
    48
    48
    Units: score on a scale
        least squares mean (confidence interval 95%)
    -3.07 (-5.56 to -0.58)
    -7.62 (-10.26 to -4.98)
    No statistical analyses for this end point

    Secondary: Estimated Annualised Bleeding Rate in the Fitusiran Onset Period

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    End point title
    		 Estimated Annualised Bleeding Rate in the Fitusiran Onset Period
    End point description
    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 subject spends in 1-Month fitusiran onset period matching BE data being analysed as offset variable. ABR = total number of qualifying BE/number of days in respective period *365.25. EAS 1 population. Number of subjects analysed=subjects evaluable. Overall analysis was performed for Fitusiran 80 mg 1-month onset period and reported in this endpoint. Data collection & combined analysis (Cohort A and B) was planned and performed.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 28 or up to the last day of bleeding follow up (any day up to Day 28)
    End point values
    		 Overall Fitusiran 80 mg 1-Month Onset Period
    Number of subjects analysed
    65
    Units: episodes per subject per year
        number (confidence interval 95%)
    5.419 (3.716 to 7.901)
    No statistical analyses for this end point

    Secondary: Observed Annualised Bleeding Rate in the Fitusiran Onset Period

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    End point title
    		 Observed Annualised Bleeding Rate in the Fitusiran Onset Period
    End point description
    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. Analysis was performed on EAS 1 population. Data collection and combined analysis (Cohort A and B) for 1-Month onset period was planned and performed.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 28 or up to the last day of bleeding follow up (any day up to Day 28)
    End point values
    		 Overall Fitusiran 80 mg 1-Month Onset Period
    Number of subjects analysed
    65
    Units: episodes per subject per year
        arithmetic mean (standard deviation)
    5.42 ( 8.28 )
    No statistical analyses for this end point

    Secondary: Estimated Annualised Bleeding Rate in the Fitusiran Treatment Period

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    End point title
    		 Estimated Annualised Bleeding Rate in the Fitusiran Treatment Period
    End point description
    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. Analysis was performed on EAS 1 population. Data collection and analysis of combined population (Cohort A and B) for treatment period was planned and performed.
    End point type
    Secondary
    End point timeframe
    from Day 1 up to Day 190
    End point values
    		 Overall Fitusiran 80 mg Treatment Period
    Number of subjects analysed
    65
    Units: episodes per subject per year
        number (confidence interval 95%)
    3.317 (2.111 to 5.211)
    No statistical analyses for this end point

    Secondary: Observed Annualised Bleeding Rate in the Fitusiran Treatment Period

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    End point title
    		 Observed Annualised Bleeding Rate in the Fitusiran Treatment Period
    End point description
    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. Analysis was performed on EAS1 population. Data collection and analysis of combined population (Cohort A and B) for treatment period was planned and performed.
    End point type
    Secondary
    End point timeframe
    from Day 1 up to Day 190)
    End point values
    		 Overall Fitusiran 80 mg Treatment Period
    Number of subjects analysed
    65
    Units: episodes per subject per year
        arithmetic mean (standard deviation)
    3.48 ( 6.98 )
    No statistical analyses for this end point

    Secondary: Cohort A: Annualised Weight-adjusted Consumption of BPA (Activated Prothrombin Complex Concentrates)

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    End point title
    		 Cohort A: Annualised Weight-adjusted Consumption of BPA (Activated Prothrombin Complex Concentrates)
    End point description
    Annualised weight-adjusted BPA consumption was calculated for each subject 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 endpoint, data of annualised weight-adjusted consumption of BPA agent: aPCC (unit per kilogram [U/kg]) were reported. Combined data of annualised weight-adjusted BPA consumption (U/kg) for both treated bleeds and prophylaxis purpose were reported in this endpoint. Analysis was performed on EAS 1 population. Here, 'number of subjects analysed' = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Day -168 to Day -1 of BPA prophylaxis period; 6-month fitusiran efficacy period: from Day 29 to Day 190 or up to the last day of bleeding follow up (any day up to Day 190), whichever was the earliest
    End point values
    		 BPA Prophylaxis: Cohort: A Inhibitor Fitusiran 80 mg Prophylaxis: Cohort A: Inhibitor
    Number of subjects analysed
    15
    15
    Units: U/kg per subject per year
        arithmetic mean (standard deviation)
    7912.7 ( 5507.6 )
    39.7 ( 87.0 )
    No statistical analyses for this end point

    Secondary: Cohort A: Annualised Weight-adjusted Consumption of BPA (Recombinant Factor VIIa)

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    End point title
    		 Cohort A: Annualised Weight-adjusted Consumption of BPA (Recombinant Factor VIIa)
    End point description
    Annualised weight-adjusted BPA consumption was calculated for each subject 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 endpoint, data of annualised weight-adjusted consumption of BPA agents: rFVIIa (unit: micrograms per kg [mcg/kg]) were reported. Combined data of annualised weight-adjusted BPA consumption (mcg/kg) for both treated bleeds and prophylaxis purpose were reported in this endpoint. Analysis was performed on EAS 1 population. Here, 'number of subjects analysed' = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From Day -168 to Day -1 of BPA prophylaxis period; 6-month fitusiran efficacy period: from Day 29 to Day 190 or up to the last day of bleeding follow up (any day up to Day 190), whichever was the earliest
    End point values
    		 BPA Prophylaxis: Cohort: A Inhibitor Fitusiran 80 mg Prophylaxis: Cohort A: Inhibitor
    Number of subjects analysed
    7
    7
    Units: mcg/kg per subject per year
        arithmetic mean (standard deviation)
    18895.8 ( 14081.9 )
    168.8 ( 290.8 )
    No statistical analyses for this end point

    Secondary: Cohort B: Annualised Weight-adjusted Consumption of Factor

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    End point title
    		 Cohort B: Annualised Weight-adjusted Consumption of Factor
    End point description
    Annualised weight-adjusted BPA consumption was calculated for each subject 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 endpoint, data of annualised weight-adjusted consumption of BPA agents: FVIII and FIX (unit: international Units [IU] per kg [IU/kg]) were reported. Combined data of annualised weight-adjusted BPA consumption (IU/kg) for both treated bleeds and prophylaxis purpose were reported in this endpoint. Analysis was performed on EAS 1 population. Here, ‘n’ = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    From Day -168 to Day -1 of factor prophylaxis period; 6-month fitusiran efficacy period: from Day 29 to Day 190 or up to the last day of bleeding follow up (any day up to Day 190), whichever was the earliest
    End point values
    		 Factor Prophylaxis: Cohort B: Non-inhibitor Fitusiran 80 mg Prophylaxis: Cohort B: Non-inhibitor
    Number of subjects analysed
    46
    46
    Units: IU/kg per subject per year
    arithmetic mean (standard deviation)
        FVIII (n = 36, 36)
    3396.9 ( 1144.5 )
    60.7 ( 148.3 )
        FIX (n = 10, 10)
    3175.5 ( 961.3 )
    17.8 ( 56.1 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Factor/BPA prophylaxis period: from Day -168 to Day -1; Fitusiran 80 mg QM/50 mg Q2M period: from Day 1 of fitusiran treatment period (i.e., 1 month onset+ 6 months efficacy) until antithrombin (AT) follow up (i.e. up to 21 months)
    Adverse event reporting additional description
    An adverse event (AE) was defined as any untoward medical occurrence in a subject who received study drug which did not necessarily have a causal relationship with the treatment. Safety analysis set (SAS): all subjects who were enrolled and received any dose of fitusiran (80 mg, QM before dose pause; SAS 1)/(50 mg, Q2M after dose pause; SAS 2).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Cohort A: SAS 1 - BPA Prophylaxis
    Reporting group description
    		 Subjects with hemophilia A or B, with inhibitory antibodies to FVIII or FIX and who were receiving BPA prophylaxis were enrolled in the study and entered the 6-month BPA prophylaxis period in this study and continued their pre-study, regularly scheduled prophylaxis regimen with BPAs.

    Reporting group title
    Cohort A: SAS 1 - Fitusiran 80 mg QM
    Reporting group description
    		 Post completion of BPA prophylaxis period, subjects entered into the 7-month fitusiran treatment period (1-month onset period + 6-month efficacy period) and received fitusiran 80 mg until sponsor initiated a voluntary dose pause. Subjects could continue to receive BPA prophylaxis for up to 7 days after start of fitusiran treatment on Day 1. A subgroup of Cohort A (hemophilia B subjects with inhibitory antibodies to Factor IX who were not responding adequately to BPA prophylaxis treatment: historical ABR >=20) entered directly into fitusiran treatment period. Throughout the study, subjects in the fitusiran treatment period received could on-demand treatment for breakthrough bleeding episodes with BPAs, as appropriate. Post last fitusiran dose, subjects had a safety follow-up/AT activity level follow-up up to 6 months (monthly monitor until AT activity levels return to approximately 60% or per Investigator discretion).

    Reporting group title
    Cohort B: SAS 1 - Factor Prophylaxis
    Reporting group description
    		 Subjects with hemophilia A or B, without inhibitory antibodies to FVIII or FIX and who were receiving factor prophylaxis were enrolled in the study and entered the 6-month BPA prophylaxis period in this study and continued their pre-study, regularly scheduled prophylaxis regimen with factor concentrates.

    Reporting group title
    Cohort B: SAS 1 - Fitusiran 80 mg QM
    Reporting group description
    		 Post completion of Factor prophylaxis period, subjects entered into the 7-month fitusiran treatment period (1-month onset period + 6-month efficacy period) and received fitusiran 80 mg until sponsor initiated a voluntary dose pause. Subjects could continue to receive BPA prophylaxis for up to 7 days after start of fitusiran treatment on Day 1. Throughout the study, subjects in the fitusiran treatment period received could on-demand treatment for breakthrough bleeding episodes with factor, as appropriate. Post last fitusiran dose, subjects had a safety follow-up/AT activity level follow-up up to 6 months (monthly monitor until AT activity levels return to approximately 60% or per Investigator discretion).

    Reporting group title
    Overall: SAS 1 - Factor/BPA Prophylaxis
    Reporting group description
    		 All subjects whether with inhibitory antibodies (Cohort A) or without inhibitory antibodies (Cohort B) to FVIII or FIX and who were receiving BPA or factor prophylaxis, respectively, 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 BPAs or factors in 6-month factor or BPA prophylaxis period. This period was skipped by a subgroup of Cohort A which included subjects with hemophilia B with inhibitory antibodies to FIX and who had not respond adequately to BPA prophylaxis prior to study entry (historical ABR >=20).

    Reporting group title
    Overall: SAS 1 - Fitusiran 80 mg QM
    Reporting group description
    		 Post completion of BPA prophylaxis period, all subjects who received fitusiran 80 mg QM (either in Cohort A or Cohort B) until sponsor initiated a voluntary dose pause. Subjects could continue to receive BPA/factor prophylaxis for up to 7 days after start of fitusiran treatment on Day 1. A subgroup of Cohort A (hemophilia B subjects with inhibitory antibodies to Factor IX who were not responding adequately to BPA prophylaxis treatment: historical ABR >=20) entered directly into fitusiran treatment period. Throughout the study, subjects in the fitusiran treatment period received could on-demand treatment for breakthrough bleeding episodes with BPAs or factors, as appropriate. Post last fitusiran dose, subjects had a safety follow-up/AT activity level follow-up up to 6 months (monthly monitor until AT activity levels return to approximately 60% or per Investigator discretion).

    Reporting group title
    Cohort A: SAS 2 - BPA Prophylaxis
    Reporting group description
    		 Subjects with hemophilia A or B, with inhibitory antibodies to FVIII or FIX and who were receiving BPA prophylaxis were enrolled in the study and entered the 6-month BPA prophylaxis period in this study and continued their pre-study, regularly scheduled prophylaxis regimen with BPAs.

    Reporting group title
    Cohort A: SAS 2 - Fitusiran 50 mg Q2M
    Reporting group description
    		 Post completion of BPA prophylaxis period, subjects entered into the 7-month fitusiran treatment period (1-month onset period + 6-month efficacy period) and received fitusiran 50 mg Q2M after sponsor initiated a voluntary dose pause. Throughout the study, subjects in the fitusiran treatment period received could on-demand treatment for breakthrough bleeding episodes with BPAs, as appropriate. Post last fitusiran dose, subjects had a safety follow-up/AT activity level follow-up up to 6 months (monthly monitor until AT activity levels return to approximately 60% or per Investigator discretion).

    Serious adverse events
    		 Cohort A: SAS 1 - BPA Prophylaxis Cohort A: SAS 1 - Fitusiran 80 mg QM Cohort B: SAS 1 - Factor Prophylaxis Cohort B: SAS 1 - Fitusiran 80 mg QM Overall: SAS 1 - Factor/BPA Prophylaxis Overall: SAS 1 - Fitusiran 80 mg QM Cohort A: SAS 2 - BPA Prophylaxis Cohort A: SAS 2 - Fitusiran 50 mg Q2M
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 19 (26.32%)
    5 / 21 (23.81%)
    0 / 46 (0.00%)
    4 / 46 (8.70%)
    5 / 65 (7.69%)
    9 / 67 (13.43%)
    1 / 2 (50.00%)
    1 / 2 (50.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Investigations
    C-Reactive Protein Increased
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 65 (0.00%)
    1 / 67 (1.49%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Biliary Neoplasm
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 65 (0.00%)
    1 / 67 (1.49%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 21 (4.76%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    0 / 65 (0.00%)
    1 / 67 (1.49%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 21 (4.76%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    0 / 65 (0.00%)
    1 / 67 (1.49%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Central Venous Catheter Removal
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 21 (4.76%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    0 / 65 (0.00%)
    1 / 67 (1.49%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 65 (0.00%)
    1 / 67 (1.49%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis Acute
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 21 (4.76%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    0 / 65 (0.00%)
    1 / 67 (1.49%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma Late Onset
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 65 (0.00%)
    1 / 67 (1.49%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 21 (4.76%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    0 / 65 (0.00%)
    1 / 67 (1.49%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Stevens-Johnson Syndrome
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 65 (0.00%)
    1 / 67 (1.49%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haemarthrosis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 65 (1.54%)
    0 / 67 (0.00%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemophilic Arthropathy
         subjects affected / exposed
    2 / 19 (10.53%)
    1 / 21 (4.76%)
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    2 / 65 (3.08%)
    2 / 67 (2.99%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 1
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle Haemorrhage
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 65 (1.54%)
    0 / 67 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Covid-19 Pneumonia
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 65 (1.54%)
    0 / 67 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular Device Infection
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 65 (0.00%)
    1 / 67 (1.49%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort A: SAS 1 - BPA Prophylaxis Cohort A: SAS 1 - Fitusiran 80 mg QM Cohort B: SAS 1 - Factor Prophylaxis Cohort B: SAS 1 - Fitusiran 80 mg QM Overall: SAS 1 - Factor/BPA Prophylaxis Overall: SAS 1 - Fitusiran 80 mg QM Cohort A: SAS 2 - BPA Prophylaxis Cohort A: SAS 2 - Fitusiran 50 mg Q2M
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 19 (52.63%)
    13 / 21 (61.90%)
    9 / 46 (19.57%)
    28 / 46 (60.87%)
    19 / 65 (29.23%)
    41 / 67 (61.19%)
    1 / 2 (50.00%)
    2 / 2 (100.00%)
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 19 (5.26%)
    3 / 21 (14.29%)
    0 / 46 (0.00%)
    15 / 46 (32.61%)
    1 / 65 (1.54%)
    18 / 67 (26.87%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    3
    3
    0
    19
    3
    22
    0
    0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 21 (4.76%)
    0 / 46 (0.00%)
    3 / 46 (6.52%)
    1 / 65 (1.54%)
    4 / 67 (5.97%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    3
    0
    4
    1
    7
    0
    0
    Fibrin D Dimer Increased
         subjects affected / exposed
    0 / 19 (0.00%)
    3 / 21 (14.29%)
    0 / 46 (0.00%)
    2 / 46 (4.35%)
    0 / 65 (0.00%)
    5 / 67 (7.46%)
    0 / 2 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    3
    0
    2
    0
    5
    0
    1
    Lymphocyte Count Increased
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Neutrophil Count Decreased
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    White Blood Cell Count Decreased
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Arthropod Bite
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 21 (4.76%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 65 (1.54%)
    1 / 67 (1.49%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    0
    1
    1
    0
    0
    Buttock Injury
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 65 (1.54%)
    0 / 67 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    Fall
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 21 (0.00%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    2 / 65 (3.08%)
    0 / 67 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    2
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 19 (10.53%)
    1 / 21 (4.76%)
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    3 / 65 (4.62%)
    1 / 67 (1.49%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    2
    1
    0
    3
    2
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 21 (0.00%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    2 / 65 (3.08%)
    0 / 67 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    0
    0
    2
    0
    0
    0
    General disorders and administration site conditions
    Injection Site Erythema
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 21 (9.52%)
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 65 (0.00%)
    3 / 67 (4.48%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    2
    0
    4
    0
    0
    Injection Site Pain
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 21 (9.52%)
    0 / 46 (0.00%)
    3 / 46 (6.52%)
    0 / 65 (0.00%)
    5 / 67 (7.46%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    3
    0
    5
    0
    0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 21 (9.52%)
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 65 (0.00%)
    3 / 67 (4.48%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    3
    0
    1
    0
    4
    0
    0
    Dental Caries
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    2 / 65 (3.08%)
    0 / 67 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    2
    0
    1
    0
    3
    0
    0
    0
    Eosinophilic Oesophagitis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 65 (1.54%)
    0 / 67 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    Gastrointestinal Motility Disorder
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 65 (1.54%)
    0 / 67 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 19 (0.00%)
    0 / 21 (0.00%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    0 / 65 (0.00%)
    0 / 67 (0.00%)
    1 / 2 (50.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    Nausea
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 65 (1.54%)
    0 / 67 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    Teething
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 65 (1.54%)
    0 / 67 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    Toothache
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 21 (4.76%)
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    0 / 65 (0.00%)
    2 / 67 (2.99%)
    0 / 2 (0.00%)
    2 / 2 (100.00%)
         occurrences all number
    0
    1
    0
    1
    0
    2
    0
    2
    Vomiting
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 21 (4.76%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 65 (1.54%)
    1 / 67 (1.49%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    0
    1
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 21 (9.52%)
    0 / 46 (0.00%)
    2 / 46 (4.35%)
    0 / 65 (0.00%)
    4 / 67 (5.97%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    3
    0
    2
    0
    5
    0
    0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 21 (9.52%)
    0 / 46 (0.00%)
    2 / 46 (4.35%)
    0 / 65 (0.00%)
    4 / 67 (5.97%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    2
    0
    4
    0
    0
    Cholelithiasis
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 21 (9.52%)
    0 / 46 (0.00%)
    3 / 46 (6.52%)
    0 / 65 (0.00%)
    5 / 67 (7.46%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    0
    3
    0
    5
    0
    0
    Hepatic Steatosis
         subjects affected / exposed
    0 / 19 (0.00%)
    2 / 21 (9.52%)
    1 / 46 (2.17%)
    1 / 46 (2.17%)
    1 / 65 (1.54%)
    3 / 67 (4.48%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    1
    1
    1
    3
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis Allergic
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 65 (1.54%)
    0 / 67 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 65 (1.54%)
    0 / 67 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 21 (4.76%)
    3 / 46 (6.52%)
    4 / 46 (8.70%)
    4 / 65 (6.15%)
    5 / 67 (7.46%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    4
    8
    5
    9
    0
    0
    Joint Swelling
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 46 (0.00%)
    1 / 46 (2.17%)
    1 / 65 (1.54%)
    1 / 67 (1.49%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    1
    1
    1
    0
    0
    Synovitis
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 21 (4.76%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 65 (1.54%)
    1 / 67 (1.49%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    0
    0
    1
    1
    0
    0
    Infections and infestations
    Genital Herpes Simplex
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 65 (1.54%)
    0 / 67 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    Influenza
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 21 (4.76%)
    2 / 46 (4.35%)
    1 / 46 (2.17%)
    3 / 65 (4.62%)
    2 / 67 (2.99%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    1
    2
    1
    3
    2
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 21 (4.76%)
    1 / 46 (2.17%)
    7 / 46 (15.22%)
    1 / 65 (1.54%)
    8 / 67 (11.94%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    1
    9
    1
    10
    0
    0
    Tinea Pedis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    1 / 46 (2.17%)
    0 / 46 (0.00%)
    2 / 65 (3.08%)
    0 / 67 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    1
    0
    2
    0
    0
    0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    3 / 19 (15.79%)
    4 / 21 (19.05%)
    1 / 46 (2.17%)
    2 / 46 (4.35%)
    4 / 65 (6.15%)
    6 / 67 (8.96%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    4
    5
    1
    2
    5
    7
    0
    0
    Metabolism and nutrition disorders
    Iron Deficiency
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 21 (0.00%)
    0 / 46 (0.00%)
    0 / 46 (0.00%)
    1 / 65 (1.54%)
    0 / 67 (0.00%)
    0 / 2 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Nov 2017
    The following changes were done: • One death was reported in a subject with cerebral venous sinus thrombosis (CVST) in another fitusiran study, which was considered possibly related to fitusiran. Accordingly, the primary purpose of this protocol amendment was to implement additional safety measures to mitigate the risk of thrombosis in the lowered-AT setting induced by fitusiran therapy in the context of concomitant use of BPAs (bypassing agents) for bleed management. This included updating the bleed management guidelines, outlining recommendations for the monitoring and management of thrombotic events, clarification on the definitions for bleeding episodes, revising the recommendations for the management of sepsis, and adding additional exploratory laboratory assessments. • Changed the population studied, i.e., the population was only consisted of subjects who had an inhibitory antibody to FVIII or FIX, whereas previously the study design included both subjects with and without inhibitory antibodies to FVIII or FIX; as such, given the known prevalence, the planned sample size had been reduced to N=30. • A list of the primary changes implemented was provided in protocol. Corrections communicated in a previous administrative change letter were applied.
    31 May 2018
    The following changes were done: • Clinical development and commercialisation of fitusiran were granted from Alnylam Pharmaceuticals, Inc. to Genzyme Corporation, a Sanofi Company, which assumed responsibility of the current clinical program. Therefore, the Alnylam logo and reference to Alnylam was changed to “the Sponsor” or “Sanofi Genzyme” as appropriate throughout the protocol. The Sanofi Genzyme study code (EFC15110) was added, and the Alnylam study drug code ALN-AT3SC was also updated to the generic drug name fitusiran. Several sections were created or updated to reflect the Sanofi Genzyme environment. • Expanded to include non-inhibitor subjects under prophylaxis with factor concentrates while inhibitor subjects had higher unmet needs compared to non-inhibitor subjects, there was no known difference in risks between these 2 populations based on the mechanism of action of fitusiran or factor/BPA therapy.
    18 Dec 2018
    The following changes was done: • Extended worldwide the inclusion of a subgroup of Cohort A subjects with hemophilia B (with inhibitory antibodies to Factor IX, who were not responding adequately to BPA prophylaxis (treatment defined as ABR >=20) to start treatment with fitusiran directly after the screening period, limiting however the inclusion to up to 4 subjects. A secondary objective and endpoint were included to further assess fitusiran efficacy.
    25 Nov 2020
    The following changes were done: • Introduction of a risk mitigation strategy for vascular thrombotic events in subjects exposed to fitusiran. To decrease AT lowering with fitusiran dosing regimen was changed from 80 mg QM to 50 mg Q2M. A Schedule of Assessments was added to accommodate the new AT-driven dose regimen and to ensure optimal monitoring during the transition. • Study expanded to include 80 subjects to mitigate for the over enrollment of the non-inhibitor cohort as there were already 79 subjects enrolled at the time of this amendment (i.e., approximately n=30 for Cohort A and approximately n=50 for Cohort B). • Cholecystitis and cholelithiasis had been added to the protocol as adverse events of special interest (AESIs). • Included the addition of new guidance to facilitate the continuation of the study in the event of a regional or national government declared emergency such as the COVID-19 pandemic.
    08 Dec 2020
    The following changes were done - • To minimise the time between two AT measurements if the first AT result was <15%. “Upon the first AT level <15%, the subject must have another AT activity level sample drawn within 1 week of site receipt of the results. If this result is <15%, this will be considered the second AT activity level <15%” had been added to mandate a second AT activity level within 1 week of site receipt of an initial AT level result <15%.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    30 Oct 2020
    A dosing pause period for the original dose regimen (80 mg QM) was implemented on due to thrombotic events observed within the fitusiran clinical study program.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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