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    Clinical Trial Results:
    A Phase II/III Open-label, Multicenter, Safety and Efficacy Study of a Recombinant Coagulation Factor IX Albumin Fusion Protein (rIX-FP) in Subjects with Hemophilia B

    Summary
    EudraCT number
    		 2011-002415-28
    Trial protocol
    		 DE   AT   ES   IT   BG  
    Global end of trial date
    21 Jul 2014

    Results information
    Results version number
    		 v2(current)
    This version publication date
    29 Jul 2016
    First version publication date
    04 Feb 2015
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Minor correction made

    Trial information

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    Trial identification
    Sponsor protocol code
    CSL654_3001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01496274
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    CSL Behring GmbH
    Sponsor organisation address
    Emil-von-Behring-Str. 76, Marburg, Germany, 35041
    Public contact
    Clinical Trial Disclosure Manager, CSL Behring, clinicaltrials@cslbehring.com
    Scientific contact
    Clinical Trial Disclosure Manager, CSL Behring, clinicaltrials@cslbehring.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001107-PIP01-10
    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
    18 Aug 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of the study are to evaluate the efficacy of rIX-FP in preventing bleeding episodes (prophylaxis) and safety of rIX-FP with respect to the development of inhibitors to FIX in patients with severe hemophilia B.
    Protection of trial subjects
    This study was carried out in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice guidelines, and standard operating procedures for clinical research and development at CSL Behring (CSLB). The study protocol and all amendments were approved by the Independent Ethics Committee(s) (IECs) / Institutional Review Board(s) (IRBs) of the participating centers. Before undergoing screening procedures for possible enrollment into the study, subjects were informed, in an understandable form, about the nature, scope, and possible consequences of the study. The investigator was responsible for obtaining a subject’s written informed consent to participate in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Feb 2012
    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
    Spain: 5
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Bulgaria: 6
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Israel: 11
    Country: Number of subjects enrolled
    Japan: 10
    Country: Number of subjects enrolled
    Russian Federation: 1
    Country: Number of subjects enrolled
    United States: 6
    Worldwide total number of subjects
    63
    EEA total number of subjects
    35
    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)
    7
    Adults (18-64 years)
    56
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were enrolled from 30 sites in 10 countries.

    Pre-assignment
    Screening details
    		 A total of 69 subjects provided informed consent and were screened for study participation. Of these, 63 subjects were enrolled and treated with rIX-FP.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Prophylaxis
    Arm description
    		 Routine weekly prophylaxis and episodic treatment for bleeding episodes. An individualized dosing interval may be tested in sub-group subjects during the 2nd part of the trial. Subjects may participate in a surgical 'sub-study' in which rIX-FP may be administered prior to, during and after surgical intervention.
    Arm type
    		 Experimental

    Investigational medicinal product name
    rIX-FP
    Investigational medicinal product code
    CSL654 or rIX-FP
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Recombinant IX-FP (rIX-FP) is a fusion protein linking coagulation factor IX with albumin, and will be administered by intravenous administration.

    Arm title
    		 On-demand
    Arm description
    		 Episodic treatment for bleeding episodes for up to 26 weeks then switch to routine weekly prophylaxis for the remainder of the study. Subjects may participate in a surgical 'sub-study' in which rIX-FP may be administered prior to, during and after surgical intervention.
    Arm type
    		 Experimental

    Investigational medicinal product name
    rIX-FP
    Investigational medicinal product code
    CSL654 or rIX-FP
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Recombinant IX-FP (rIX-FP) is a fusion protein linking coagulation factor IX with albumin, and will be administered by intravenous administration.

    Number of subjects in period 1
    		Prophylaxis On-demand
    Started
    40
    23
    Completed
    37
    18
    Not completed
    3
    5
         Consent withdrawn by subject
    2
    -
         Adverse event, non-fatal
    1
    1
         Protocol violation
    -
    1
         Lost to follow-up
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Prophylaxis
    Reporting group description
    		 Routine weekly prophylaxis and episodic treatment for bleeding episodes. An individualized dosing interval may be tested in sub-group subjects during the 2nd part of the trial. Subjects may participate in a surgical 'sub-study' in which rIX-FP may be administered prior to, during and after surgical intervention.

    Reporting group title
    On-demand
    Reporting group description
    		 Episodic treatment for bleeding episodes for up to 26 weeks then switch to routine weekly prophylaxis for the remainder of the study. Subjects may participate in a surgical 'sub-study' in which rIX-FP may be administered prior to, during and after surgical intervention.

    Reporting group values
    		 Prophylaxis On-demand Total
    Number of subjects
    		 40 23 63
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 7 0 7
        Adults (18-64 years)
    		 33 23 56
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 40 23 63

    End points

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    End points reporting groups
    Reporting group title
    Prophylaxis
    Reporting group description
    		 Routine weekly prophylaxis and episodic treatment for bleeding episodes. An individualized dosing interval may be tested in sub-group subjects during the 2nd part of the trial. Subjects may participate in a surgical 'sub-study' in which rIX-FP may be administered prior to, during and after surgical intervention.

    Reporting group title
    On-demand
    Reporting group description
    		 Episodic treatment for bleeding episodes for up to 26 weeks then switch to routine weekly prophylaxis for the remainder of the study. Subjects may participate in a surgical 'sub-study' in which rIX-FP may be administered prior to, during and after surgical intervention.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The Safety population consisted of subjects who received at least 1 dose of rIX-FP during the study.

    Subject analysis set title
    On-demand Arm, on-demand regimen
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the On-demand Arm, when receiving episodic treatment for bleeding episodes (on-demand regimen).

    Subject analysis set title
    On-demand Arm, prophylaxis regimen
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants in the On-demand Arm, when receiving routine weekly prophylaxis (prophylaxis regimen).

    Subject analysis set title
    Prophylaxis Arm, 7-day regimen
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received prophylactic rIX-FP on a weekly basis.

    Subject analysis set title
    Prophylaxis Arm, 10-day regimen
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received prophylactic rIX-FP every 10 days.

    Subject analysis set title
    Prophylaxis Arm, 14-day regimen
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received prophylactic rIX-FP every 14 days.

    Subject analysis set title
    PK - Prophylaxis Arm
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects included in the Pharmacokinetic (PK) population from the prophylaxis arm who received at least 1 dose of rIX-FP at 50 IU/kg. Data are presented for subjects from the PK population who had a sufficient number of analyzable PK samples for evaluation of the PK profile of rIX-FP.

    Subject analysis set title
    PK - On-demand Arm
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects included in the PK population from the on-demand arm who received at least 1 dose of rIX-FP at 50 IU/kg. Data are presented for subjects from the PK population who had a sufficient number of analyzable PK samples for evaluation of the PK profile of rIX-FP.

    Subject analysis set title
    Surgical population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The Surgical population consisted of 3 subjects in the prophylaxis arm and 1 subject in the on demand arm who received at least 1 dose of rIX FP for a major or minor surgical procedure.

    Primary: Number of subjects developing inhibitors against factor IX (FIX)

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    End point title
    		 Number of subjects developing inhibitors against factor IX (FIX) [1]
    End point description
    The number of participants developing inhibitors against factor IX (FIX) along with the 95% Clopper-Pearson confidence interval, are summarized for subjects with 50 or more exposure days (EDs) to rIX-FP, and for all participants in the study.
    End point type
    Primary
    End point timeframe
    Up to 27.7 months (maximum)
    Notes
    [1] - 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: No statistical analyses were conducted for this end point.
    End point values
    		 Safety Population
    Number of subjects analysed
    63
    Units: Participants
    number (confidence interval 95%)
        Participants with >=50 EDs to rIX-FP (n = 49)
    0 (0 to 7.3)
        All participants (n = 63)
    0 (0 to 5.7)
    No statistical analyses for this end point

    Primary: Change in frequency of spontaneous bleeding events between on-demand and prophylaxis treatments (annualized)

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    End point title
    		 Change in frequency of spontaneous bleeding events between on-demand and prophylaxis treatments (annualized)
    End point description
    Subjects in the on-demand arm received on-demand dosing with rIX-FP for up to 26 weeks (on-demand regimen), and then received weekly prophylaxis with rIX-FP for the remainder of the study (prophylaxis regimen). The effectiveness of prophylaxis in comparison to on-demand therapy was investigated by comparing the same subject's annualized spontaneous bleeding rate (AsBR) during the on-demand regimen and during the prophylaxis regimen.
    End point type
    Primary
    End point timeframe
    Up to 26 weeks for on-demand regimen, and between 1 and 17 months for prophylaxis regimen.
    End point values
    		 On-demand Arm, on-demand regimen On-demand Arm, prophylaxis regimen
    Number of subjects analysed
    19
    19
    Units: bleeds/year/subject
        median (inter-quartile range (Q1-Q3))
    15.43 (7.98 to 17.96)
    0 (0 to 0.96)
    Statistical analysis title
    		 Percent reduction in AsBR
    Statistical analysis description
    Matched pairs design with 19 subjects and 2 observations per subject.
    Comparison groups
    On-demand Arm, prophylaxis regimen v On-demand Arm, on-demand regimen
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.0001 [3]
    Method
    		 Wilcoxon signed-rank test
    Confidence interval
    Notes
    [2] - A test of null hypothesis that the ratio of AsBR (prophylaxis regimen/on-demand regimen) was ≥ 0.50 was conducted at the 1-sided 0.025 level.
    [3] - P value is based on a Wilcoxon signed-rank test of H0: AsBR ratio (prophylaxis regimen/on-demand regimen) ≥ 0.50. The ratio was based on the original scale.

    Secondary: Number of subjects developing antibodies against rIX-FP

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    End point title
    		 Number of subjects developing antibodies against rIX-FP
    End point description
    End point type
    Secondary
    End point timeframe
    For the duration of the study; median 20.27 months.
    End point values
    		 Safety Population
    Number of subjects analysed
    63
    Units: participants
    0
    No statistical analyses for this end point

    Secondary: rIX-FP consumed per month while maintaining assigned prophylactic treatment interval during routine prophylaxis.

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    End point title
    		 rIX-FP consumed per month while maintaining assigned prophylactic treatment interval during routine prophylaxis.
    End point description
    End point type
    Secondary
    End point timeframe
    For Prophylaxis Arm 7-, 10- and 14-day regimens, median 269, 240 and 386 days respectively. For On-demand Arm, prophylaxis regimen, median 316 days.
    End point values
    		 On-demand Arm, prophylaxis regimen Prophylaxis Arm, 7-day regimen Prophylaxis Arm, 10-day regimen Prophylaxis Arm, 14-day regimen
    Number of subjects analysed
    19
    40
    7
    21
    Units: IU/kg/month
        arithmetic mean (standard deviation)
    191.69 ± 36.33
    202.68 ± 47.92
    201.5 ± 42.56
    157.44 ± 16.34
    No statistical analyses for this end point

    Secondary: Incremental recovery of rIX-FP

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    End point title
    		 Incremental recovery of rIX-FP
    End point description
    Pharmacokinetic (PK) data are presented for a single 50 IU/kg dose of rIX-FP.
    End point type
    Secondary
    End point timeframe
    336 hours
    End point values
    		 PK - Prophylaxis Arm PK - On-demand Arm
    Number of subjects analysed
    27
    18
    Units: (IU/dL)/(IU/kg)
        arithmetic mean (standard deviation)
    1.29 ± 0.33
    1.24 ± 0.25
    No statistical analyses for this end point

    Secondary: The frequency of related adverse events

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    End point title
    		 The frequency of related adverse events
    End point description
    The percentage of participants experiencing treatment-related adverse-events (TEAEs).
    End point type
    Secondary
    End point timeframe
    For the duration of the study; median 20.27 months.
    End point values
    		 Prophylaxis On-demand Safety Population
    Number of subjects analysed
    40
    23
    63
    Units: percentage of participants
    number (not applicable)
        Related TEAE
    10
    4.3
    7.9
        Not related TEAE
    87.5
    78.3
    84.1
    No statistical analyses for this end point

    Secondary: Proportion of bleeding episodes requiring one or ≤ two injections of rIX-FP

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    End point title
    		 Proportion of bleeding episodes requiring one or ≤ two injections of rIX-FP [4]
    End point description
    Number of injections required to achieve hemostasis expressed as a percentage of the bleeding episodes requiring treatment. The number of bleeding episodes requiring treatment were 101, 220 and 37 in the Prophylaxis Arm, On-demand Arm (On-demand Regimen) and On-demand Arm (Prophylaxis Regimen), respectively.
    End point type
    Secondary
    End point timeframe
    For the duration of the study; median 20.27 months.
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for the On-demand Arm are provided for the two On-demand sub-group regimens (On-demand regimen and prophylaxis regimen), rather than for the overall On-demand Arm.
    End point values
    		 Prophylaxis On-demand Arm, on-demand regimen On-demand Arm, prophylaxis regimen
    Number of subjects analysed
    40
    23
    19
    Units: percentage of bleeding episodes
    number (not applicable)
        1 injection
    92.1
    94.5
    91.9
        1 or 2 injections
    100
    98.6
    94.6
    No statistical analyses for this end point

    Secondary: Investigator's overall clinical assessment of hemostatic efficacy for treatment of bleeding episodes, based on a four point ordinal scales (excellent, good, moderate, poor/no response)

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    End point title
    		 Investigator's overall clinical assessment of hemostatic efficacy for treatment of bleeding episodes, based on a four point ordinal scales (excellent, good, moderate, poor/no response)
    End point description
    Number of bleeding episodes requiring treatment that resulted in hemostatic efficacy of excellent, good, moderate, poor/no response, according to the Investigator's clinical assessment of hemostatic efficacy, expressed as a percentage of the bleeding episodes requiring treatment. The number of bleeding episodes requiring treatment were 101 and 257 in the Prophylaxis Arm and On-demand Arm, respectively.
    End point type
    Secondary
    End point timeframe
    For the duration of the study; median 20.27 months.
    End point values
    		 Prophylaxis On-demand
    Number of subjects analysed
    40
    23
    Units: percentage of bleeding episodes
    number (not applicable)
        Excellent
    71.3
    87.5
        Good
    20.8
    7.4
        Moderate
    3
    2.3
        Poor/No response
    0
    0.4
        Missing
    5
    2.3
    No statistical analyses for this end point

    Secondary: Half-life (t1/2) of a single dose of rIX-FP

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    End point title
    		 Half-life (t1/2) of a single dose of rIX-FP
    End point description
    PK data are presented for a single 50 IU/kg dose of rIX-FP.
    End point type
    Secondary
    End point timeframe
    336 hours
    End point values
    		 PK - Prophylaxis Arm PK - On-demand Arm
    Number of subjects analysed
    26
    17
    Units: hour
        arithmetic mean (standard deviation)
    104.77 ± 22.73
    96.88 ± 20.94
    No statistical analyses for this end point

    Secondary: Area under the curve (AUC)

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    End point title
    		 Area under the curve (AUC)
    End point description
    AUC to the last sample with quantifiable drug concentration (AUClast) of a single dose of rIX-FP. PK data are presented for a single 50 IU/kg dose of rIX-FP.
    End point type
    Secondary
    End point timeframe
    336 hours
    End point values
    		 PK - Prophylaxis Arm PK - On-demand Arm
    Number of subjects analysed
    27
    18
    Units: IU*hr/dL
        arithmetic mean (standard deviation)
    6534.15 ± 1856.96
    5963.3 ± 1893
    No statistical analyses for this end point

    Secondary: Clearance of a single dose of rIX-FP

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    End point title
    		 Clearance of a single dose of rIX-FP
    End point description
    PK data are presented for a single 50 IU/kg dose of rIX-FP.
    End point type
    Secondary
    End point timeframe
    336 hours
    End point values
    		 PK - Prophylaxis Arm PK - On-demand Arm
    Number of subjects analysed
    26
    17
    Units: mL/hr
        arithmetic mean (standard deviation)
    50.19 ± 12.92
    59 ± 19.37
    No statistical analyses for this end point

    Secondary: Investigator's (or surgeon's) overall clinical assessment of hemostatic efficacy for surgical prophylaxis, based on a four point ordinal scale (excellent, good, moderate, poor/no response

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    End point title
    		 Investigator's (or surgeon's) overall clinical assessment of hemostatic efficacy for surgical prophylaxis, based on a four point ordinal scale (excellent, good, moderate, poor/no response
    End point description
    Number of surgical events treated prophylactically with rIX-FP that resulted in hemostatic efficacy of excellent, good, moderate, poor/no response, according to the Investigator’s (surgeon’s) overall assessment of hemostatic efficacy for surgical prophylaxis. There were six surgical events overall.
    End point type
    Secondary
    End point timeframe
    Up to 14 days after surgery
    End point values
    		 Surgical population
    Number of subjects analysed
    4
    Units: events
        Excellent
    6
        Good
    0
        Moderate
    0
        Poor / No response
    0
    No statistical analyses for this end point

    Secondary: Annualized spontaneous bleeding events compared between 7 day prophylactic and extended regimens

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    End point title
    		 Annualized spontaneous bleeding events compared between 7 day prophylactic and extended regimens
    End point description
    Median number of spontaneous bleeds per year per subject comparing 7-, 10- and 14- day prophylactic regimens.
    End point type
    Secondary
    End point timeframe
    During treatment, between median 240 and 386 days per subject.
    End point values
    		 Prophylaxis Arm, 7-day regimen Prophylaxis Arm, 10-day regimen Prophylaxis Arm, 14-day regimen
    Number of subjects analysed
    38
    7
    21
    Units: bleeds/year/subject
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 1)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For the duration of the study, up to 27.7 months.
    Adverse event reporting additional description
    The Safety analysis population consisted of subjects who received at least 1 dose of rIX-FP during the study. Adverse Event data are treatment-emergent data unless otherwise noted.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Prophylaxis
    Reporting group description
    		 Routine weekly prophylaxis and episodic treatment for bleeding episodes. An individualized dosing interval may be tested in sub-group subjects during the 2nd part of the trial. Subjects may participate in a surgical 'sub-study' in which rIX-FP may be administered prior to, during and after surgical intervention.

    Reporting group title
    On-demand
    Reporting group description
    		 Episodic treatment for bleeding episodes for up to 26 weeks then switch to routine weekly prophylaxis for the remainder of the study. Subjects may participate in a surgical 'sub-study' in which rIX-FP may be administered prior to, during and after surgical intervention.

    Serious adverse events
    		 Prophylaxis On-demand
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 23 (8.70%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    ACQUIRED EPILEPTIC APHASIA
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    SYNOVITIS
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PAIN IN EXTREMITY
    Additional description: This SAE was not treatment-emergent.
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUSCLE HAEMORRHAGE
    Additional description: This SAE was not treatment-emergent.
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Prophylaxis On-demand
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 40 (75.00%)
    14 / 23 (60.87%)
    Injury, poisoning and procedural complications
    LIMB INJURY
         subjects affected / exposed
    5 / 40 (12.50%)
    1 / 23 (4.35%)
         occurrences all number
    5
    1
    CONTUSION
         subjects affected / exposed
    3 / 40 (7.50%)
    1 / 23 (4.35%)
         occurrences all number
    5
    3
    LACERATION
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 23 (8.70%)
         occurrences all number
    1
    2
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    11 / 40 (27.50%)
    4 / 23 (17.39%)
         occurrences all number
    26
    8
    DIZZINESS
         subjects affected / exposed
    4 / 40 (10.00%)
    0 / 23 (0.00%)
         occurrences all number
    5
    0
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    2 / 40 (5.00%)
    3 / 23 (13.04%)
         occurrences all number
    2
    4
    TOOTHACHE
         subjects affected / exposed
    4 / 40 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    4
    1
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 23 (0.00%)
         occurrences all number
    3
    0
    Skin and subcutaneous tissue disorders
    ACNE
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 23 (0.00%)
         occurrences all number
    3
    0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    9 / 40 (22.50%)
    0 / 23 (0.00%)
         occurrences all number
    19
    0
    BACK PAIN
         subjects affected / exposed
    4 / 40 (10.00%)
    2 / 23 (8.70%)
         occurrences all number
    5
    3
    SYNOVITIS
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 23 (0.00%)
         occurrences all number
    6
    0
    PAIN IN EXTREMITY
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 23 (0.00%)
         occurrences all number
    4
    0
    JOINT SWELLING
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 23 (0.00%)
         occurrences all number
    3
    0
    TENDONITIS
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 23 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    NASOPHARYNGITIS
         subjects affected / exposed
    10 / 40 (25.00%)
    6 / 23 (26.09%)
         occurrences all number
    27
    11
    INFLUENZA
         subjects affected / exposed
    4 / 40 (10.00%)
    3 / 23 (13.04%)
         occurrences all number
    7
    3
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    5 / 40 (12.50%)
    0 / 23 (0.00%)
         occurrences all number
    7
    0
    BRONCHITIS
         subjects affected / exposed
    4 / 40 (10.00%)
    1 / 23 (4.35%)
         occurrences all number
    4
    1
    PHARYNGITIS
         subjects affected / exposed
    3 / 40 (7.50%)
    2 / 23 (8.70%)
         occurrences all number
    3
    2
    GASTROENTERITIS
         subjects affected / exposed
    3 / 40 (7.50%)
    0 / 23 (0.00%)
         occurrences all number
    4
    0
    ACUTE TONSILLITIS
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Nov 2011
    Protocol Amendment 1 was issued before the enrollment of the first subject. Key changes to the protocol included: - Re-assigning a secondary endpoint to be a primary endpoint - Adding an efficacy evaluation algorithm for the Investigator rating of bleeding episodes for clarification - Updating treatment groups and assigned doses - Adding the criteria for dose adjustment and treatment regimen switching, as well as an algorithm for the new dose interval - Updating the statistical methodology section
    18 Oct 2012
    Protocol amendment 2 included the following key changes: - Added that, for on-demand treatment (Arm 2), a subject’s prophylaxis dose could only be adjusted during the first 4 weeks, and that the dose prescribed after 4 weeks of prophylaxis treatment was to be maintained for the rest of the study. - Updated the statistical methodology section with analysis population definitions, additional secondary and exploratory endpoints, and additional details on statistical methods - Added the comparison of mean annualized bleeding rates between different prophylaxis regimens as one of the secondary endpoints
    27 Feb 2014
    Protocol Amendment 3 included the following key changes: - The bleeding episodes that occurred during the 4-week run-in period of prophylaxis therapy for subjects in Arm 2 (on-demand) were no longer to be excluded from analyses of the 26-week treatment period, and the total duration of treatment for Arm 2 was reduced from 30 weeks to 26 weeks, but a minimum of 12 weeks - Added additional statistical methods to clarify how missing data were handled during the primary efficacy analysis - Clarified that the test proposed for the comparison between the 7-day and the 10-day or 14-day prophylaxis regimens was referred to as a non-inferiority test

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    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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