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    Clinical Trial Results:
    Randomized, controlled, parallel, prospective trial to evaluate the effect of secondary prophylaxis with rFVIII therapy in severe hemophilia A adult and/or adolescent subjects, as applicable, compared to that of episodic treatment (SPINART)

    Summary
    EudraCT number
    		 2008-000985-21
    Trial protocol
    		 BG  
    Global end of trial date
    22 Nov 2013

    Results information
    Results version number
    		 v1
    This version publication date
    12 Jul 2016
    First version publication date
    03 May 2015
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY14-2222/12800
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00623480
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer HealthCare AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer HealthCare AG, clinical-trials-contact@bayerhealthcare.com
    Scientific contact
    Therapeutic Area Head, Bayer HealthCare AG, clinical-trials-contact@bayerhealthcare.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Nov 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Nov 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of secondary prophylaxis on bleeding frequency (number of all bleeds per year) compared to on-demand (episodic) treatment.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Only after the subject voluntarily signed the informed consent form was he able to enter the study. In case of participation of adolescent subjects (12-17 years, in applicable countries), parents/legal representatives were informed first and upon their agreement, the information was presented to the subject. If the subject agreed, the formal consent was collected from parents/legal representatives and the subject.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Mar 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 31
    Country: Number of subjects enrolled
    Romania: 14
    Country: Number of subjects enrolled
    United States: 54
    Country: Number of subjects enrolled
    Argentina: 7
    Worldwide total number of subjects
    106
    EEA total number of subjects
    45
    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)
    3
    Adults (18-64 years)
    103
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted between 27 March 2008 (first subject first visit) and 22 November 2013 (last subject last visit) at 31 investigational centers in 4 countries.

    Pre-assignment
    Screening details
    		 Out of a total of 106 screened subjects and 84 subjects were randomized to either prophylaxis treatment with Kogenate formulated with sucrose (FS) or on-demand treatment with Kogenate FS using a 1:1 assignment ratio.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Recombinant Factor VIII Prophylaxis treatment
    Arm description
    		 Subjects received 25 international units per kilogram (IU/kg) of Recombinant Factor VIII (Kogenate FS, BAY14-2222) intravenously (IV), 3 times per week. Dose escalation steps by 5 IU/kg (to 30 IU/kg or 35 IU/kg maximum) for subjects exhibiting a bleeding frequency of 12 bleeding episodes per year or greater.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant Factor VIII
    Investigational medicinal product code
    BAY14-2222
    Other name
    Kogenate FS
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received 25 IU/kg of Recombinant Factor VIII (Kogenate FS, BAY14-2222) IV, 3 times per week. Dose escalation steps by 5 IU/kg (to 30 IU/kg or 35 IU/kg maximum) for subjects exhibiting a bleeding frequency of 12 bleeding episodes per year or greater.

    Arm title
    		 Recombinant Factor VIII On-demand Treatment
    Arm description
    		 Subjects received Recombinant Factor VIII (Kogenate FS, BAY14-2222) IV for bleeds in accordance with package insert instructions and study physician recommendations.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant Factor VIII
    Investigational medicinal product code
    BAY14-2222
    Other name
    Kogenate FS
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Recombinant Factor VIII (Kogenate FS, BAY14-2222) IV for bleeds in accordance with package insert instructions and study physician recommendations.

    Number of subjects in period 1 [1]
    		Recombinant Factor VIII Prophylaxis treatment Recombinant Factor VIII On-demand Treatment
    Started
    42
    42
    Completed
    35
    35
    Not completed
    7
    7
         Consent withdrawn by subject
    2
    4
         Site closed by sponsor
    -
    1
         Protocol violation
    -
    1
         'Non-compliant with study medication '
    4
    -
         Lost to follow-up
    -
    1
         Lack of efficacy
    1
    -
    Notes
    [1] - 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: All enrolled subjects were not treated with study drugs. As baseline included only treated subjects, the worldwide number enrolled in the trial differs with the number of subjects reported in the baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Recombinant Factor VIII Prophylaxis treatment
    Reporting group description
    		 Subjects received 25 international units per kilogram (IU/kg) of Recombinant Factor VIII (Kogenate FS, BAY14-2222) intravenously (IV), 3 times per week. Dose escalation steps by 5 IU/kg (to 30 IU/kg or 35 IU/kg maximum) for subjects exhibiting a bleeding frequency of 12 bleeding episodes per year or greater.

    Reporting group title
    Recombinant Factor VIII On-demand Treatment
    Reporting group description
    		 Subjects received Recombinant Factor VIII (Kogenate FS, BAY14-2222) IV for bleeds in accordance with package insert instructions and study physician recommendations.

    Reporting group values
    		 Recombinant Factor VIII Prophylaxis treatment Recombinant Factor VIII On-demand Treatment Total
    Number of subjects
    		 42 42 84
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 30.6 ( 8.8 ) 30.7 ( 9.7 ) -
    Gender categorical
    Units: Subjects
        Male
    		 42 42 84
    Number of subjects with target joints
    A ‘target joint’ is a particular joint that has experienced repeated bleeds or at least four bleeds into one joint within a six month period.
    Units: Subjects
        Yes
    		 28 31 59
        No
    		 14 11 25
    Number of bleeds during last 6 months
    Units: Bleeds
        arithmetic mean (standard deviation)
    		 10 ( 4.4 ) 12.2 ( 5.1 ) -

    End points

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    End points reporting groups
    Reporting group title
    Recombinant Factor VIII Prophylaxis treatment
    Reporting group description
    		 Subjects received 25 international units per kilogram (IU/kg) of Recombinant Factor VIII (Kogenate FS, BAY14-2222) intravenously (IV), 3 times per week. Dose escalation steps by 5 IU/kg (to 30 IU/kg or 35 IU/kg maximum) for subjects exhibiting a bleeding frequency of 12 bleeding episodes per year or greater.

    Reporting group title
    Recombinant Factor VIII On-demand Treatment
    Reporting group description
    		 Subjects received Recombinant Factor VIII (Kogenate FS, BAY14-2222) IV for bleeds in accordance with package insert instructions and study physician recommendations.

    Primary: Bleeding Frequency (Number of Total Bleeds)

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    End point title
    		 Bleeding Frequency (Number of Total Bleeds)
    End point description
    End point type
    Primary
    End point timeframe
    After the last enrolled subject has been in the study for 1 year. At the cut-off, the median follow-up duration was 616 days (minimum was 111 days and maximum was 1109 days)
    End point values
    		 Recombinant Factor VIII Prophylaxis treatment Recombinant Factor VIII On-demand Treatment
    Number of subjects analysed
    42 [1]
    42 [2]
    Units: bleeds
        median (full range (min-max))
    0 (0 to 57)
    54.5 (0 to 149)
    Notes
    [1] - The intent-to-treat (ITT) population included all randomized subjects who received any study drug
    [2] - The ITT population included all randomized subjects who received any study drug
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Recombinant Factor VIII On-demand Treatment v Recombinant Factor VIII Prophylaxis treatment
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 Negative Binomial Regression Model
    Parameter type
    		 Ratio
    Point estimate
    14.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.1
         upper limit
    		 26.5
    Notes
    [3] - Adjusted for time of follow-up.

    Secondary: Change From Baseline to 3 Years in the MRI (Magnetic Resonance Imaging) Scale

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    End point title
    		 Change From Baseline to 3 Years in the MRI (Magnetic Resonance Imaging) Scale
    End point description
    The Extended MRI Scale total score had a range between 0 (normal unaffected joint) to 45 (maximal joint damage) points. It was composed of 2 domains, the soft tissue domain with a maximum of 9 points and the osteochondral domain with a maximum of 36 points. A single score for each subject was to be calculated from the sum of both domains and the average over all joints for the Extended MRI endpoint. Higher MRI score denotes greater joint structure damage thus a positive change from baseline means worsening.
    End point type
    Secondary
    End point timeframe
    Baseline and 3 years
    End point values
    		 Recombinant Factor VIII Prophylaxis treatment Recombinant Factor VIII On-demand Treatment
    Number of subjects analysed
    41 [4]
    38 [5]
    Units: scores on a scale
        least squares mean (confidence interval 95%)
    0.79 (0.27 to 1.32)
    0.96 (0.34 to 1.58)
    Notes
    [4] - Full analysis set (FAS): all randomized subjects who had a baseline and/or post-baseline measurement
    [5] - FAS: all randomized subjects who had a baseline and/or post-baseline measurement
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Recombinant Factor VIII Prophylaxis treatment v Recombinant Factor VIII On-demand Treatment
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6614 [6]
    Method
    		 cLDA model
    Parameter type
    		 Estimated difference
    Point estimate
    -0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.92
         upper limit
    		 0.59
    Notes
    [6] - Adjusted for presence/absence of target joint and prior 6 month bleeding frequency

    Secondary: Change From Baseline to 3 Years in the Colorado Adult Joint Assessment Scale (CAJAS)

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    End point title
    		 Change From Baseline to 3 Years in the Colorado Adult Joint Assessment Scale (CAJAS)
    End point description
    The total joint score was derived for each of six joints: left and right sides for knees (score: 0-25), ankles (score: 0-25), and elbows (score: 0-21). Higher CAJAS score denotes greater joint structure damage thus a positive change from baseline means worsening. CAJAS total score is the sum of all 6 joints, ranging from 0 (best possible outcome) to 142 (worst possible outcome).
    End point type
    Secondary
    End point timeframe
    Baseline and 3 years
    End point values
    		 Recombinant Factor VIII Prophylaxis treatment Recombinant Factor VIII On-demand Treatment
    Number of subjects analysed
    42 [7]
    42 [8]
    Units: scores on a scale
        least squares mean (confidence interval 95%)
    -0.31 (-0.79 to 0.18)
    0.63 (0.08 to 1.18)
    Notes
    [7] - FAS: all randomized subjects who had a baseline and/or post-baseline measurement
    [8] - FAS: all randomized subjects who had a baseline and/or post-baseline measurement
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Recombinant Factor VIII Prophylaxis treatment v Recombinant Factor VIII On-demand Treatment
    Number of subjects included in analysis
    84
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0072 [9]
    Method
    		 cLDA model
    Parameter type
    		 Estimated difference
    Point estimate
    -0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.61
         upper limit
    		 -0.26
    Notes
    [9] - Adjusted for presence/absence of target joint and prior 6 month bleeding frequency.

    Other pre-specified: Change From Baseline to 3 Years in the Physical Functioning Domain of the Haemo-Quality of Life (QoL)-A

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    End point title
    		 Change From Baseline to 3 Years in the Physical Functioning Domain of the Haemo-Quality of Life (QoL)-A
    End point description
    The Haemo-QoL-A total score as well as each of its domains have a range between 0 (worst QoL) and 100 (best QoL) points. Therefore, a higher Haemo-QoL-A score denotes greater QoL.
    End point type
    Other pre-specified
    End point timeframe
    Baseline and 3 years
    End point values
    		 Recombinant Factor VIII Prophylaxis treatment Recombinant Factor VIII On-demand Treatment
    Number of subjects analysed
    41 [10]
    42 [11]
    Units: scores on a scale
        least squares mean (confidence interval 95%)
    7.86 (1.79 to 13.92)
    -5.3 (-11.97 to 1.37)
    Notes
    [10] - FAS: all randomized subjects who had a baseline and/or post-baseline measurement
    [11] - FAS: all randomized subjects who had a baseline and/or post-baseline measurement
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Recombinant Factor VIII Prophylaxis treatment v Recombinant Factor VIII On-demand Treatment
    Number of subjects included in analysis
    83
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 cLDA model
    Parameter type
    		 Estimated difference
    Point estimate
    13.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 5.23
         upper limit
    		 21.08

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomization until Month 37
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Recombinant Factor VIII Prophylaxis treatment
    Reporting group description
    		 Subjects received 25 international units per kilogram (IU/kg) of Recombinant Factor VIII (Kogenate FS, BAY14-2222) intravenously (IV), 3 times per week. Dose escalation steps by 5 IU/kg (to 30 IU/kg or 35 IU/kg maximum) for subjects exhibiting a bleeding frequency of 12 bleeding episodes per year or greater.

    Reporting group title
    Recombinant Factor VIII On-demand Treatment
    Reporting group description
    		 Subjects received Recombinant Factor VIII (Kogenate FS, BAY14-2222) IV for bleeds in accordance with package insert instructions and study physician recommendations.

    Serious adverse events
    		 Recombinant Factor VIII Prophylaxis treatment Recombinant Factor VIII On-demand Treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 42 (21.43%)
    10 / 42 (23.81%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus injury
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stab wound
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Phimosis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Migraine
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Peritoneal haemorrhage
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth impacted
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Balanitis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haemarthrosis
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 42 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint contracture
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint lock
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint range of motion decreased
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Recombinant Factor VIII Prophylaxis treatment Recombinant Factor VIII On-demand Treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 42 (30.95%)
    27 / 42 (64.29%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 42 (4.76%)
    7 / 42 (16.67%)
         occurrences all number
    2
    12
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 42 (2.38%)
    5 / 42 (11.90%)
         occurrences all number
    2
    6
    Gastrointestinal disorders
    Dental caries
         subjects affected / exposed
    0 / 42 (0.00%)
    4 / 42 (9.52%)
         occurrences all number
    0
    4
    Toothache
         subjects affected / exposed
    3 / 42 (7.14%)
    2 / 42 (4.76%)
         occurrences all number
    3
    3
    Dyspepsia
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 42 (11.90%)
    5 / 42 (11.90%)
         occurrences all number
    7
    5
    Back pain
         subjects affected / exposed
    1 / 42 (2.38%)
    4 / 42 (9.52%)
         occurrences all number
    1
    5
    Myalgia
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 42 (2.38%)
         occurrences all number
    3
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    2 / 42 (4.76%)
    7 / 42 (16.67%)
         occurrences all number
    2
    7
    Pharyngitis
         subjects affected / exposed
    0 / 42 (0.00%)
    4 / 42 (9.52%)
         occurrences all number
    0
    5
    Nasopharyngitis
         subjects affected / exposed
    2 / 42 (4.76%)
    9 / 42 (21.43%)
         occurrences all number
    2
    10
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 42 (4.76%)
    3 / 42 (7.14%)
         occurrences all number
    2
    4
    Metabolism and nutrition disorders
    Vitamin D deficiency
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 42 (7.14%)
         occurrences all number
    0
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Sep 2008
    Age listed on inclusion criteria changed from 25-50 to 20-50 years. Requirements for some study procedures were clarified, including joint assessment and timing of MRIs.
    09 Jan 2009
    Added countries and increased the number of investigational centers. Exclusion criteria for poor joint status was clarified. Data Monitoring Committee description was added.
    05 Nov 2009
    Allowed for changes in Inlcusion/Exclusion criteria: subjects were included who experienced more frequent bleeding events, more severe joint damage, as well as the existence of a single transient FVIII inhibitor more than 10 years prior to enrollment into the trial. Maximum limit of 12 subjects per site was removed. Elimination of the dose adjustment for subjects with a body mass index of greater than 30 in order to prevent suboptimal dosing resulting in a trough level that may fall below the target level of 1 percent for effective prophylaxis of spontaneous bleeding. Elimination of the requirement of a follow-up MRI for those subjects who discontinued the study prior to 18 months from the time of their enrollment.
    22 Nov 2011
    Changes in the primary and secondary objectives and inclusion and exclusion criteria. Requirement of recruitment limit per site was removed. Details of assessments were revised and endpoints were clarified. Elimination of the requirement of a follow-up MRI for those subjects who discontinued the study prior to 18 months from the time of their enrollment. Quality of life measurements were updated. Two new instruments for assessments of hypersensitivity and lack of drug effect were added.

    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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