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    Clinical Trial Results:
    An Open-Label Study to Evaluate Prophylaxis Treatment, and to Characterize the Efficacy, Safety, and Pharmacokinetics of B-Domain Deleted Recombinant Factor VIII Albumin Free (Moroctocog Alfa [AF-CC]) in Children With Hemophilia A

    Summary
    EudraCT number
    		 2006-005575-17
    Trial protocol
    		 ES   DE   AT   IT  
    Global end of trial date
    18 Apr 2018

    Results information
    Results version number
    		 v1
    This version publication date
    10 Oct 2018
    First version publication date
    10 Oct 2018
    Other versions
    		 v2

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    3082B2-313
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00543439
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.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
    13 Aug 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Apr 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that moroctocog alfa prophylaxis reduces annualized bleeding rates relative to on-demand (OD) therapy. Enrollment into the OD cohort has been closed.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Dec 2007
    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
    Poland: 15
    Country: Number of subjects enrolled
    Turkey: 11
    Country: Number of subjects enrolled
    Oman: 10
    Country: Number of subjects enrolled
    Jordan: 6
    Country: Number of subjects enrolled
    United States: 6
    Country: Number of subjects enrolled
    Romania: 5
    Country: Number of subjects enrolled
    Mexico: 3
    Country: Number of subjects enrolled
    New Zealand: 3
    Country: Number of subjects enrolled
    Argentina: 2
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Colombia: 1
    Country: Number of subjects enrolled
    Croatia: 1
    Worldwide total number of subjects
    65
    EEA total number of subjects
    23
    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)
    5
    Children (2-11 years)
    59
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects for 1 of the sites, were excluded from efficacy and safety analysis due to data integrity issues, however were reported in subject disposition and baseline. Out of 66 enrolled subjects, 65 were treated (started Period 1). Period 1 and Period 2 both were post-baseline.

    Period 1
    Period 1 title
    Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Moroctocog alfa (AF-CC), OD Cohort: OD Therapy Then RP Therapy
    Arm description
    		 In Period 1 subjects for, on-demand (OD) therapy were treated with intravenous (IV) infusion of moroctocog alfa (AF-CC) for 6 months (Day 1 up to Month 6) as prescribed by investigator based on current recommendations for on demand treatment with licensed product Xyntha (Minor bleeding: repetition of IV infusion of AF-CC, 20-40 international units per kilogram [IU/kg], every 12-24 hours until resolved for at least 1 day, depending upon severity of bleeding episode; Moderate bleeding: repetition of IV infusion of AF-CC, 30-60 IU/kg, every 12-24 hours for 3-4 days or until adequate local hemostasis was achieved; Major bleeding: repetition of IV infusion of AF-CC, 60-100 IU/kg, every 8-24 hours until bleeding was resolved). Period 1 was followed by Period 2 where subjects received IV infusion of AF-CC at 25 IU/kg once in 2 days up to 12 months (Month 7 to Month 18) as routine prophylaxis (RP) therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Moroctocog alfa (AF-CC)
    Investigational medicinal product code
    Other name
    Xyntha
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    First period: Subjects were treated with moroctocog alfa (AF-CC) IV infusion for 6 months as prescribed by investigator based on current recommendations for on demand treatment with licensed product Xyntha.

    Arm title
    		 Moroctocog alfa (AF-CC), RP Cohort: RP 25IU/kg Then RP 45IU/kg
    Arm description
    		 In Period 1 subjects for routine prophylaxis therapy, received IV infusion of moroctocog alfa (AF-CC) at 25 IU/kg once in 2 days up to 12 months (Day 1 up to Month 12). Period 1 was followed by Period 2 where subjects received IV infusion of moroctocog alfa (AF-CC) at 45 IU/kg, twice per week up to 12 months (Month 13 up to Month 24) as routine prophylaxis therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Moroctocog alfa (AF-CC)
    Investigational medicinal product code
    Other name
    Xyntha
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    First period: Subjects received moroctocog alfa (AF-CC) infusion intravenously at 25 IU/kg, once in 2 days up to 12 months.

    Arm title
    		 Moroctocog alfa(AF-CC), RP Cohort: RP 45 IU/kg Then RP 25IU/kg
    Arm description
    		 In Period 1 subjects for routine prophylaxis therapy, received IV infusion of moroctocog alfa (AF-CC) at 45 IU/kg twice per week up to 12 months (Day 1 up to Month 12). Period 1 was followed by Period 2 where subjects received IV infusion of moroctocog alfa (AF-CC) at 25 IU/kg, once in 2 days up to 12 months (Month 13 up to Month 24) as routine prophylaxis therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Moroctocog alfa (AF-CC)
    Investigational medicinal product code
    Other name
    Xyntha
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    First period: Subjects received 45 IU/kg moroctocog alfa (AF-CC) infusion intravenously twice per week up to 12 months.

    Number of subjects in period 1
    		Moroctocog alfa (AF-CC), OD Cohort: OD Therapy Then RP Therapy Moroctocog alfa (AF-CC), RP Cohort: RP 25IU/kg Then RP 45IU/kg Moroctocog alfa(AF-CC), RP Cohort: RP 45 IU/kg Then RP 25IU/kg
    Started
    9
    29
    27
    Completed
    9
    26
    25
    Not completed
    0
    3
    2
         Consent withdrawn by subject
    -
    1
    -
         Physician decision
    -
    -
    1
         Adverse Event
    -
    2
    1
    Period 2
    Period 2 title
    Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Moroctocog alfa (AF-CC), OD Cohort: OD Therapy Then RP Therapy
    Arm description
    		 In Period 1 subjects for, on-demand (OD) therapy were treated with intravenous (IV) infusion of moroctocog alfa (AF-CC) for 6 months (Day 1 up to Month 6) as prescribed by investigator based on current recommendations for on demand treatment with licensed product Xyntha (Minor bleeding: repetition of IV infusion of AF-CC, 20-40 international units per kilogram [IU/kg], every 12-24 hours until resolved for at least 1 day, depending upon severity of bleeding episode; Moderate bleeding: repetition of IV infusion of AF-CC, 30-60 IU/kg, every 12-24 hours for 3-4 days or until adequate local hemostasis was achieved; Major bleeding: repetition of IV infusion of AF-CC, 60-100 IU/kg, every 8-24 hours until bleeding was resolved). Period 1 was followed by Period 2 where subjects received IV infusion of AF-CC at 25 IU/kg once in 2 days up to 12 months (Month 7 to Month 18) as routine prophylaxis (RP) therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Moroctocog alfa (AF-CC)
    Investigational medicinal product code
    Other name
    Xyntha
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Second period: Subjects received 25 IU/kg moroctocog alfa (AF-CC) infusion intravenously once in 2 days up to 12 months.

    Arm title
    		 Moroctocog alfa, RP Cohort: RP 25 IU/kg Then RP 45 IU/kg
    Arm description
    		 In Period 1 subjects for routine prophylaxis therapy, received IV infusion of moroctocog alfa (AF-CC) at 25 IU/kg once in 2 days up to 12 months (Day 1 up to Month 12). Period 1 was followed by Period 2 where subjects received IV infusion of moroctocog alfa (AF-CC) at 45 IU/kg, twice per week up to 12 months (Month 13 up to Month 24) as routine prophylaxis therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Moroctocog alfa (AF-CC)
    Investigational medicinal product code
    Other name
    Xyntha
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Second period: Subjects received 45 IU/kg moroctocog alfa (AF-CC) infusion intravenously twice per week up to 12 months.

    Arm title
    		 Moroctocog alfa(AF-CC), RP Cohort: RP 45 IU/kg Then RP 25IU/kg
    Arm description
    		 In Period 1 subjects for routine prophylaxis therapy, received IV infusion of moroctocog alfa (AF-CC) at 45 IU/kg twice per week up to 12 months (Day 1 up to Month 12). Period 1 was followed by Period 2 where subjects received IV infusion of moroctocog alfa (AF-CC) at 25 IU/kg, once in 2 days up to 12 months (Month 13 up to Month 24) as routine prophylaxis therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Moroctocog alfa (AF-CC)
    Investigational medicinal product code
    Other name
    Xyntha
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Second period: Subjects received 25 IU/kg moroctocog alfa (AF-CC) infusion intravenously once in 2 days up to 12 months.

    Number of subjects in period 2
    		Moroctocog alfa (AF-CC), OD Cohort: OD Therapy Then RP Therapy Moroctocog alfa, RP Cohort: RP 25 IU/kg Then RP 45 IU/kg Moroctocog alfa(AF-CC), RP Cohort: RP 45 IU/kg Then RP 25IU/kg
    Started
    9
    26
    25
    Completed
    8
    25
    23
    Not completed
    1
    1
    2
         Adverse Event
    -
    1
    1
         Protocol deviation
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Moroctocog alfa (AF-CC), OD Cohort: OD Therapy Then RP Therapy
    Reporting group description
    		 In Period 1 subjects for, on-demand (OD) therapy were treated with intravenous (IV) infusion of moroctocog alfa (AF-CC) for 6 months (Day 1 up to Month 6) as prescribed by investigator based on current recommendations for on demand treatment with licensed product Xyntha (Minor bleeding: repetition of IV infusion of AF-CC, 20-40 international units per kilogram [IU/kg], every 12-24 hours until resolved for at least 1 day, depending upon severity of bleeding episode; Moderate bleeding: repetition of IV infusion of AF-CC, 30-60 IU/kg, every 12-24 hours for 3-4 days or until adequate local hemostasis was achieved; Major bleeding: repetition of IV infusion of AF-CC, 60-100 IU/kg, every 8-24 hours until bleeding was resolved). Period 1 was followed by Period 2 where subjects received IV infusion of AF-CC at 25 IU/kg once in 2 days up to 12 months (Month 7 to Month 18) as routine prophylaxis (RP) therapy.

    Reporting group title
    Moroctocog alfa (AF-CC), RP Cohort: RP 25IU/kg Then RP 45IU/kg
    Reporting group description
    		 In Period 1 subjects for routine prophylaxis therapy, received IV infusion of moroctocog alfa (AF-CC) at 25 IU/kg once in 2 days up to 12 months (Day 1 up to Month 12). Period 1 was followed by Period 2 where subjects received IV infusion of moroctocog alfa (AF-CC) at 45 IU/kg, twice per week up to 12 months (Month 13 up to Month 24) as routine prophylaxis therapy.

    Reporting group title
    Moroctocog alfa(AF-CC), RP Cohort: RP 45 IU/kg Then RP 25IU/kg
    Reporting group description
    		 In Period 1 subjects for routine prophylaxis therapy, received IV infusion of moroctocog alfa (AF-CC) at 45 IU/kg twice per week up to 12 months (Day 1 up to Month 12). Period 1 was followed by Period 2 where subjects received IV infusion of moroctocog alfa (AF-CC) at 25 IU/kg, once in 2 days up to 12 months (Month 13 up to Month 24) as routine prophylaxis therapy.

    Reporting group values
    		 Moroctocog alfa (AF-CC), OD Cohort: OD Therapy Then RP Therapy Moroctocog alfa (AF-CC), RP Cohort: RP 25IU/kg Then RP 45IU/kg Moroctocog alfa(AF-CC), RP Cohort: RP 45 IU/kg Then RP 25IU/kg Total
    Number of subjects
    		 9 29 27 65
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 2 3 5
        Children (2-11 years)
    		 9 27 23 59
        Adolescents (12-17 years)
    		 0 0 1 1
        Adults (18-64 years)
    		 0 0 0 0
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 4.7 ( 1.05 ) 4.4 ( 1.84 ) 4.1 ( 2.28 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 0 0 0 0
        Male
    		 9 29 27 65
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 0 0 0 0
        White
    		 8 24 22 54
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 1 5 5 11

    End points

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    End points reporting groups
    Reporting group title
    Moroctocog alfa (AF-CC), OD Cohort: OD Therapy Then RP Therapy
    Reporting group description
    		 In Period 1 subjects for, on-demand (OD) therapy were treated with intravenous (IV) infusion of moroctocog alfa (AF-CC) for 6 months (Day 1 up to Month 6) as prescribed by investigator based on current recommendations for on demand treatment with licensed product Xyntha (Minor bleeding: repetition of IV infusion of AF-CC, 20-40 international units per kilogram [IU/kg], every 12-24 hours until resolved for at least 1 day, depending upon severity of bleeding episode; Moderate bleeding: repetition of IV infusion of AF-CC, 30-60 IU/kg, every 12-24 hours for 3-4 days or until adequate local hemostasis was achieved; Major bleeding: repetition of IV infusion of AF-CC, 60-100 IU/kg, every 8-24 hours until bleeding was resolved). Period 1 was followed by Period 2 where subjects received IV infusion of AF-CC at 25 IU/kg once in 2 days up to 12 months (Month 7 to Month 18) as routine prophylaxis (RP) therapy.

    Reporting group title
    Moroctocog alfa (AF-CC), RP Cohort: RP 25IU/kg Then RP 45IU/kg
    Reporting group description
    		 In Period 1 subjects for routine prophylaxis therapy, received IV infusion of moroctocog alfa (AF-CC) at 25 IU/kg once in 2 days up to 12 months (Day 1 up to Month 12). Period 1 was followed by Period 2 where subjects received IV infusion of moroctocog alfa (AF-CC) at 45 IU/kg, twice per week up to 12 months (Month 13 up to Month 24) as routine prophylaxis therapy.

    Reporting group title
    Moroctocog alfa(AF-CC), RP Cohort: RP 45 IU/kg Then RP 25IU/kg
    Reporting group description
    		 In Period 1 subjects for routine prophylaxis therapy, received IV infusion of moroctocog alfa (AF-CC) at 45 IU/kg twice per week up to 12 months (Day 1 up to Month 12). Period 1 was followed by Period 2 where subjects received IV infusion of moroctocog alfa (AF-CC) at 25 IU/kg, once in 2 days up to 12 months (Month 13 up to Month 24) as routine prophylaxis therapy.
    Reporting group title
    Moroctocog alfa (AF-CC), OD Cohort: OD Therapy Then RP Therapy
    Reporting group description
    		 In Period 1 subjects for, on-demand (OD) therapy were treated with intravenous (IV) infusion of moroctocog alfa (AF-CC) for 6 months (Day 1 up to Month 6) as prescribed by investigator based on current recommendations for on demand treatment with licensed product Xyntha (Minor bleeding: repetition of IV infusion of AF-CC, 20-40 international units per kilogram [IU/kg], every 12-24 hours until resolved for at least 1 day, depending upon severity of bleeding episode; Moderate bleeding: repetition of IV infusion of AF-CC, 30-60 IU/kg, every 12-24 hours for 3-4 days or until adequate local hemostasis was achieved; Major bleeding: repetition of IV infusion of AF-CC, 60-100 IU/kg, every 8-24 hours until bleeding was resolved). Period 1 was followed by Period 2 where subjects received IV infusion of AF-CC at 25 IU/kg once in 2 days up to 12 months (Month 7 to Month 18) as routine prophylaxis (RP) therapy.

    Reporting group title
    Moroctocog alfa, RP Cohort: RP 25 IU/kg Then RP 45 IU/kg
    Reporting group description
    		 In Period 1 subjects for routine prophylaxis therapy, received IV infusion of moroctocog alfa (AF-CC) at 25 IU/kg once in 2 days up to 12 months (Day 1 up to Month 12). Period 1 was followed by Period 2 where subjects received IV infusion of moroctocog alfa (AF-CC) at 45 IU/kg, twice per week up to 12 months (Month 13 up to Month 24) as routine prophylaxis therapy.

    Reporting group title
    Moroctocog alfa(AF-CC), RP Cohort: RP 45 IU/kg Then RP 25IU/kg
    Reporting group description
    		 In Period 1 subjects for routine prophylaxis therapy, received IV infusion of moroctocog alfa (AF-CC) at 45 IU/kg twice per week up to 12 months (Day 1 up to Month 12). Period 1 was followed by Period 2 where subjects received IV infusion of moroctocog alfa (AF-CC) at 25 IU/kg, once in 2 days up to 12 months (Month 13 up to Month 24) as routine prophylaxis therapy.

    Subject analysis set title
    Moroctocog alfa (AF-CC), On Demand Cohort: On Demand Therapy
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    In Period 1, subjects for on-demand therapy were treated with IV infusion of moroctocog alfa (AF-CC) for 6 months (Day 1 up to Month 6) as prescribed by the investigator based on current recommendations for on-demand treatment with licensed product Xyntha (Minor bleeding: repetition of IV infusion of moroctocog alfa (AF-CC), 20-40 IU/kg, every 12-24 hours as necessary until resolved for at least 1 day, depending upon severity of bleeding episode; Moderate bleeding: repetition of IV infusion of Moroctocog alfa, 30-60 IU/kg, every 12-24 hours for 3-4 days or until adequate local hemostasis was achieved; Major bleeding: repetition of IV infusion of moroctocog alfa (AF-CC), 60-100 IU/kg, every 8-24 hours until bleeding was resolved).

    Subject analysis set title
    Moroctocog alfa (AF-CC), On Demand Cohort: RP Therapy 25 IU/kg
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    In Period 2, subjects for on-demand cohort received IV infusion of moroctocog alfa (AF-CC) at 25 IU/kg once in 2 days up to 12 months (Month 7 up to Month 18) as routine prophylaxis therapy.

    Subject analysis set title
    Moroctocog alfa (AF-CC): On Demand Therapy
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects of either on demand cohort or routine prophylaxis cohort were treated for bleeds, as needed on demand, with IV infusion of moroctocog alfa (AF-CC) up to 24 months as prescribed by the investigator based on current recommendations for on-demand treatment with licensed product Xyntha (Minor bleeding: repetition of IV infusion of moroctocog alfa (AF-CC), 20-40 IU/kg, every 12-24 hours as necessary until resolved for at least 1 day, depending upon severity of bleeding episode; Moderate bleeding: repetition of IV infusion of moroctocog alfa (AF-CC), 30-60 IU/kg, every 12-24 hours for 3-4 days or until adequate local hemostasis was achieved; Major bleeding: repetition of IV infusion of moroctocog alfa (AF-CC), 60-100 IU/kg, every 8-24 hours until bleeding was resolved).

    Subject analysis set title
    Moroctocog alfa (AF-CC), RP Cohort: RP Therapy 25 IU/kg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects of routine prophylaxis cohort, as routine prophylaxis therapy received IV infusion of moroctocog alfa (AF-CC) at 25 IU/kg, once in 2 days up to 12 months as routine prophylaxis therapy for either Period 1 (Day 1 up to Month 12) or Period 2 (Month 13 up to Month 24) of the study.

    Subject analysis set title
    Moroctocog alfa (AF-CC): 50 IU/kg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received a single 50 IU/kg infusion of moroctocog alfa (AF-CC) on Day 1 before initiation of moroctocog alfa (AF-CC) study treatment either in on demand cohort or routine prophylaxis cohort.

    Subject analysis set title
    Moroctocog alfa (AF-CC): All Subjects
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects enrolled to receive moroctocog alfa (AF-CC) in on demand cohort as on demand therapy in Period 1 and routine prophylaxis 25 IU/kg therapy in Period 2 or in routine prophylaxis cohort as routine prophylaxis 45 IU/kg therapy each for either in Period 1 or Period 2 and routine prophylaxis 25 IU/kg therapy either in Period 1 or Period 2.

    Subject analysis set title
    Moroctocog alfa (AF-CC) RP Cohort: RP therapy
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects received moroctocog alfa (AF-CC) in routine prophylaxis cohort as RP 45 IU/kg, twice per week up to 12 months either in Period 1 (Day 1 up to Month 12) or Period 2 (Month 13 up to Month 24); and as RP 25 IU/kg, once in 2 days up to 12 months either in Period 1 (Day 1 up to Month 12) or Period 2 (Month 13 up to Month 24).

    Subject analysis set title
    Moroctocog alfa (AF-CC), RP Cohort: RP Therapy 45 IU/kg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects randomized to the routine prophylaxis cohort, in which IV infusion of moroctocog alfa (AF-CC) at 45 IU/kg, twice per week up to 12 months as routine prophylaxis therapy would be assigned for either Period 1 (Day 1 up to Month 12) or Period 2 (Month 13 up to Month 24) of the study.

    Subject analysis set title
    Moroctocog alfa (AF-CC), OD and RP Cohort: RP Therapy 25 IU/kg
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Subjects of routine prophylaxis cohort received IV infusion of moroctocog alfa (AF-CC) at 25 IU/kg, once in 2 days up to 12 months as routine prophylaxis therapy each for either Period 1 (Day 1 up to Month 12) or Period 2 (Month 13 up to Month 24) of the study. And subjects of on demand cohort for Period 2 of the study, received IV infusion of moroctocog alfa (AF-CC) at 25 IU/kg, once in 2 days as routine prophylaxis therapy up to 12 months (Month 7 up to Month 18).

    Subject analysis set title
    Moroctocog alfa (AF-CC), RP Cohort: RP Therapy 45 IU/kg
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Subjects of routine prophylaxis cohort, received IV infusion of moroctocog alfa (AF-CC) at 45 IU/kg, twice per week up to 12 months as routine prophylaxis therapy each for either Period 1 (Day 1 up to Month 12) or Period 2 (Month 13 up to Month 24) of the study.

    Subject analysis set title
    Moroctocog alfa (AF-CC): All Subjects
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects of either on demand cohort or routine prophylaxis cohort who were at risk for developing inhibitor to FVIII, and who received moroctocog alfa (AF-CC) in on demand cohort as on demand therapy in Period 1 and routine prophylaxis 25 IU/kg therapy in Period 2 or in routine prophylaxis cohort as routine prophylaxis 45 IU/kg therapy each for either in Period 1 or Period 2 and routine prophylaxis 25 IU/kg therapy either in Period 1 or Period 2.

    Subject analysis set title
    Moroctocog alfa (AF-CC), OD and RP Cohort: RP Therapy 25 IU/kg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects randomized to routine prophylaxis cohort to receive IV infusion of moroctocog alfa (AF-CC) at 25 IU/kg, once in 2 days up to 12 months as routine prophylaxis therapy for either Period 1 (Day 1 up to Month 12) or Period 2 (Month 13 up to Month 24) of the study. And subjects randomized to on demand cohort for Period 2 of the study, to receive IV infusion of moroctocog alfa (AF-CC) at 25 IU/kg, once in 2 days as routine prophylaxis therapy up to 12 months (Month 7 up to Month 18).

    Primary: Mean Annualized Bleed Rate (ABR) by Treatment: On Demand Cohort

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    End point title
    		 Mean Annualized Bleed Rate (ABR) by Treatment: On Demand Cohort
    End point description
    ABR for each subject was calculated as the number of bleeds requiring administration of moroctocog alfa (AF-CC) divided by the total therapy duration (in days), then multiplied by 365.25 (days in a year). Intent-to-treat (ITT) analysis population included all subjects for whom a legal acceptable representative had signed the informed consent/assent form. Here, "Overall Number of Subjects Analysed" signifies subjects who were evaluable for this end point.
    End point type
    Primary
    End point timeframe
    Day 1 up to Month 6 (OD Cohort, OD Therapy, Period 1); Month 7 up to Month 18 (OD Cohort, RP 25 IU/kg, Period 2)
    End point values
    		 Moroctocog alfa (AF-CC), On Demand Cohort: On Demand Therapy Moroctocog alfa (AF-CC), On Demand Cohort: RP Therapy 25 IU/kg
    Number of subjects analysed
    9
    8
    Units: Bleeds per year
        arithmetic mean (standard deviation)
    47.0 ( 32.2 )
    1.5 ( 2.2 )
    Statistical analysis title
    		 OD Cohort: OD therapy versus RP therapy 25 IU/kg
    Statistical analysis description
    Ratio of the arithmetic means of the ABR for on demand cohort, on demand therapy to routine prophylaxis therapy 25 IU/kg was calculated. One-sided 95% CI for this ratio was reported. Number of subjects contributing to ratio of means and CI =9.
    Comparison groups
    Moroctocog alfa (AF-CC), On Demand Cohort: On Demand Therapy v Moroctocog alfa (AF-CC), On Demand Cohort: RP Therapy 25 IU/kg
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.002 [2]
    Method
    		 Paired t-test
    Parameter type
    		 Ratio of arithmetic means
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 0.08
    Notes
    [1] - Field appearing in later section: "Number of subjects included in analysis", is an auto populated field from database (sum of number of subjects analysed for the reporting arms selected to report statistical data): which may not be the actual number of subjects contributing to statistical analysis.
    [2] - Number of subjects contributing to P-value = 8.

    Secondary: Mean Annualized Bleed Rate (ABR) by Treatment: Routine Prophylaxis Cohort

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    End point title
    		 Mean Annualized Bleed Rate (ABR) by Treatment: Routine Prophylaxis Cohort
    End point description
    ABR for each subject was calculated as the number of bleeds requiring administration of moroctocog alfa (AF-CC) divided by the total therapy duration (in days), then multiplied by 365.25 (days in a year). ITT analysis population included all subjects for whom a legal acceptable representative had signed the informed consent/assent form. Here, "Overall Number of Subjects Analysed" signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Month 24 (RP Cohort, Period 1 and Period 2)
    End point values
    		 Moroctocog alfa (AF-CC), RP Cohort: RP Therapy 25 IU/kg Moroctocog alfa (AF-CC), RP Cohort: RP Therapy 45 IU/kg
    Number of subjects analysed
    38
    38
    Units: Bleeds per year
        arithmetic mean (standard deviation)
    2.2 ( 4.1 )
    3.3 ( 5.3 )
    Statistical analysis title
    		 RP Cohort: RP 45 IU/kg versus RP 25 IU/kg
    Statistical analysis description
    Field appearing in later section: “Number of subjects included in analysis", is auto populated from database (sum of number of subjects analysed for reporting arms selected to report statistical data): which may not be actual number of subjects contributing to statistical analysis. Here, number of subjects contributing to statistical analysis =35.
    Comparison groups
    Moroctocog alfa (AF-CC), RP Cohort: RP Therapy 25 IU/kg v Moroctocog alfa (AF-CC), RP Cohort: RP Therapy 45 IU/kg
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.1
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.03
         upper limit
    		 2.22
    Notes
    [3] - 90% 2-sided CI for the mean difference in ABRs for the 2 prophylaxis regimens for ITT subjects was constructed using the t distribution with n-1 degrees of freedom (n equals the number of subjects) to assess the equivalence of the 2 regimens. Equivalence was demonstrated and the null hypothesis rejected if the limits of the 90% CI fell wholly within the interval of (–4, 4) bleeds per year.

    Secondary: Mean of Moroctocog alfa (AF-CC) Infusions Administered To Treat Bleeding Episode

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    End point title
    		 Mean of Moroctocog alfa (AF-CC) Infusions Administered To Treat Bleeding Episode
    End point description
    In this end point mean of total number of moroctocog alfa (AF-CC) infusions administered to treat each bleeding episode was reported. ITT analysis population included all subjects for whom a legal acceptable representative had signed the informed consent/assent form. Here, "Overall Number of Subjects Analysed" signifies subjects who were evaluable for this endpoint. Number of bleeds analysed: Moroctocog alfa: All Subjects (562)
    End point type
    Secondary
    End point timeframe
    Day 1 up to Month 24
    End point values
    		 Moroctocog alfa (AF-CC): All Subjects
    Number of subjects analysed
    38
    Units: Infusions
        arithmetic mean (standard deviation)
    1.5 ( 1.38 )
    No statistical analyses for this end point

    Secondary: Number of Treated Bleeds Classified on Basis of Response to First Infusion of Moroctocog alfa (AF-CC) as On-Demand Treatment

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    End point title
    		 Number of Treated Bleeds Classified on Basis of Response to First Infusion of Moroctocog alfa (AF-CC) as On-Demand Treatment
    End point description
    Number (no.) of bleeds treated reported on basis of response to first (1st) infusion of study drug, at 4-point scale: excellent, good, moderate, no response. Excellent: definite pain relief and improvement (DPRI) in bleeding signs within 8 hours (hr) after infusion, no additional infusion given; Good: DPRI in bleeding signs within 8 hr after infusion, at least 1 additional infusion given for complete resolution or with no additional infusion given; Moderate: probable or slight improvement starting after 8 hr following infusion, at least 1 additional infusion given for complete resolution; No Response: no improvement at all between infusions or during 24 hr interval following infusion or condition worsen. Bleeds in which response not recorded, reported as: Data Not Recorded. No. of 1st infusions not=total no. of bleeds if bleed was: missing start date/dose information or treated initially with non study FVIII. ITT analysis. Subjects Analysed=subjects evaluable. Bleeds analysed=559.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Month 24
    End point values
    		 Moroctocog alfa (AF-CC): On Demand Therapy
    Number of subjects analysed
    38
    Units: Bleeds
        Excellent
    376
        Good
    150
        Moderate
    27
        No Response
    2
        Data Not Recorded
    4
    No statistical analyses for this end point

    Secondary: Number of Treated Spontaneous Bleeds by Time Interval between Bleed Onset and Prior Moroctocog alfa (AF-CC) Prophylaxis Dose: Routine Prophylaxis Therapy

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    End point title
    		 Number of Treated Spontaneous Bleeds by Time Interval between Bleed Onset and Prior Moroctocog alfa (AF-CC) Prophylaxis Dose: Routine Prophylaxis Therapy
    End point description
    In this end point number of treated spontaneous bleeding episodes for following time intervals between bleed onset and prior moroctocog alfa (AF-CC) prophylaxis dose are reported: lesser than or equal to (<=) 24 hours, greater than (>) 24 hours to <=48 hours, >48 hours to <=72 hours, >72 hours. For reporting arm: routine prophylaxis 25 IU/kg therapy, cumulative data for routine prophylaxis cohort (Day 1 up to Month 24, Period 1 and Period 2) and on demand cohort (Month 7 up to Month 18, Period 2) is reported. Analysis population included all subjects for whom a legal acceptable representative had signed the informed consent/assent form and only subjects who reported a spontaneous bleeding episode following a routine prophylaxis dose. Number of bleeds analysed: Moroctocog alfa, RP Therapy 45 IU/kg (28) and Moroctocog alfa: RP Therapy 25 IU/kg (18).
    End point type
    Secondary
    End point timeframe
    Day 1 up to Month 24 (RP Cohort, RP 25 IU/kg and 45 IU/kg, Period 1 and 2); Month 7 up to Month 18 (OD Cohort, RP 25 IU/kg, Period 2)
    End point values
    		 Moroctocog alfa (AF-CC), OD and RP Cohort: RP Therapy 25 IU/kg Moroctocog alfa (AF-CC), RP Cohort: RP Therapy 45 IU/kg
    Number of subjects analysed
    7
    9
    Units: Bleeds
        <=24 hours
    3
    1
        >24 hours to <=48 hours
    6
    4
        >48 hours to <=72 hours
    2
    10
        >72 hours
    7
    13
    No statistical analyses for this end point

    Secondary: Number of Subjects Requiring Prophylaxis Regimen Escalation: Routine Prophylaxis Therapy

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    End point title
    		 Number of Subjects Requiring Prophylaxis Regimen Escalation: Routine Prophylaxis Therapy
    End point description
    During prophylaxis, criteria for prophylaxis regimen escalation are occurrence, over 4-week duration of (a) 2 or more spontaneous bleeds into a major joint and target joint, or (b) 3 or more spontaneous bleeds (consisting of joint bleeds and significant soft tissue/muscle or other site bleeds). If either criterion was met, subject was escalated to more intense prophylaxis regimen of 45 IU/kg, administered every other day. Subject who met dose escalation criteria while on prophylaxis regimen of 45 IU/kg, were escalated to higher intensity regimen designated by investigator. Significant spontaneous bleeds were those that led to transient or persistent loss of function. For reporting arm: routine prophylaxis 25 IU/kg therapy, cumulative data for RP cohort (Day 1 up to Month 24, Period 1 and Period 2) and OD cohort (Month 7 up to Month 18, Period 2) is reported. ITT analysis set. Overall Number of Subjects Analysed = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Month 24 (RP Cohort, RP 25 IU/kg and 45 IU/kg, Period 1 and 2); Month 7 up to Month 18 (OD Cohort, RP 25 IU/kg, Period 2)
    End point values
    		 Moroctocog alfa (AF-CC), OD and RP Cohort: RP Therapy 25 IU/kg Moroctocog alfa (AF-CC), RP Cohort: RP Therapy 45 IU/kg
    Number of subjects analysed
    48
    39
    Units: Subjects
    1
    2
    No statistical analyses for this end point

    Secondary: Mean Routine Prophylaxis Dose (IU/kg) of Moroctocog alfa (AF-CC) Received: Routine Prophylaxis Therapy

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    End point title
    		 Mean Routine Prophylaxis Dose (IU/kg) of Moroctocog alfa (AF-CC) Received: Routine Prophylaxis Therapy
    End point description
    Mean RP dose (by weight) for each subject was calculated as his total moroctocog alfa (AF-CC) consumption (in IU) divided by weight (in kg). For reporting arm: routine prophylaxis 25 IU/kg therapy, cumulative data for routine prophylaxis cohort (Day 1 up to Month 24, Period 1 and Period 2) and on demand cohort (Month 7 up to Month 18, Period 2) is reported. ITT analysis population included all subjects for whom a legal acceptable representative had signed the informed consent/assent form. Here, "Overall Number of Subjects Analysed" signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Month 24 (RP Cohort, Period 1 and Period 2); Month 7 up to Month 18 (OD Cohort, RP 25 IU/kg, Period 2)
    End point values
    		 Moroctocog alfa (AF-CC), On Demand Cohort: RP Therapy 25 IU/kg Moroctocog alfa (AF-CC), RP Cohort: RP Therapy 25 IU/kg Moroctocog alfa (AF-CC), OD and RP Cohort: RP Therapy 25 IU/kg Moroctocog alfa (AF-CC), RP Cohort: RP Therapy 45 IU/kg
    Number of subjects analysed
    8
    40
    48
    39
    Units: IU/kg
        arithmetic mean (standard deviation)
    25 ( 4.6 )
    26 ( 5.4 )
    26 ( 5.2 )
    46 ( 5.8 )
    No statistical analyses for this end point

    Secondary: Mean of Total Number Moroctocog alfa (AF-CC) Infusions Received: Routine Prophylaxis Therapy

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    End point title
    		 Mean of Total Number Moroctocog alfa (AF-CC) Infusions Received: Routine Prophylaxis Therapy
    End point description
    In this end point mean of total number of infusions of moroctocog alfa (AF-CC) received by subject is reported. For reporting arm: routine prophylaxis 25 IU/kg therapy, cumulative data for routine prophylaxis cohort (Day 1 up to Month 24, Period 1 and Period 2) and on demand cohort (Month 7 up to Month 18, Period 2) is reported. ITT analysis population included all subjects for whom a legal acceptable representative had signed the informed consent/assent form. Here, "Overall Number of Subjects Analysed" signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Month 24 (RP Cohort, Period 1 and Period 2); Month 7 up to Month 18 (OD Cohort, RP 25 IU/kg, Period 2)
    End point values
    		 Moroctocog alfa (AF-CC), On Demand Cohort: RP Therapy 25 IU/kg Moroctocog alfa (AF-CC), RP Cohort: RP Therapy 25 IU/kg Moroctocog alfa (AF-CC), OD and RP Cohort: RP Therapy 25 IU/kg Moroctocog alfa (AF-CC), RP Cohort: RP Therapy 45 IU/kg
    Number of subjects analysed
    8
    40
    48
    39
    Units: Infusions
        arithmetic mean (standard deviation)
    170 ( 31.3 )
    150 ( 37.0 )
    154 ( 36.6 )
    91 ( 22.4 )
    No statistical analyses for this end point

    Secondary: Mean of Total Number of Days Subjects Exposed to Moroctocog alfa (AF-CC): Routine Prophylaxis Therapy

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    End point title
    		 Mean of Total Number of Days Subjects Exposed to Moroctocog alfa (AF-CC): Routine Prophylaxis Therapy
    End point description
    For reporting arm: routine prophylaxis 25 IU/kg therapy, cumulative data for routine prophylaxis cohort (Day 1 up to Month 24, Period 1 and Period 2) and on demand cohort (Month 7 up to Month 18, Period 2) is reported. ITT analysis population included all subjects for whom a legal acceptable representative had signed the informed consent/assent form. Here, "Overall Number of Subjects Analysed" signifies subjects who were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Month 24 (RP Cohort, Period 1 and Period 2); Month 7 up to Month 18 (OD Cohort, RP 25 IU/kg, Period 2)
    End point values
    		 Moroctocog alfa (AF-CC), On Demand Cohort: RP Therapy 25 IU/kg Moroctocog alfa (AF-CC), RP Cohort: RP Therapy 25 IU/kg Moroctocog alfa (AF-CC), OD and RP Cohort: RP Therapy 25 IU/kg Moroctocog alfa (AF-CC), RP Cohort: RP Therapy 45 IU/kg
    Number of subjects analysed
    8
    40
    48
    39
    Units: Days
        arithmetic mean (standard deviation)
    170 ( 31.3 )
    150 ( 37.0 )
    153 ( 36.5 )
    91 ( 22.3 )
    No statistical analyses for this end point

    Secondary: Mean of Total Number of Infusions of Moroctocog alfa (AF-CC) Received per Week to Assess Compliance: Routine Prophylaxis Therapy

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    End point title
    		 Mean of Total Number of Infusions of Moroctocog alfa (AF-CC) Received per Week to Assess Compliance: Routine Prophylaxis Therapy
    End point description
    Subjects' compliance to their assigned prophylaxis regimen was measured by following: a) number of infusions received per week and b) dose received. In this end point mean of total number of infusions of moroctocog alfa (AF-CC) received by subjects per week is reported. For reporting arm: routine prophylaxis 25 IU/kg therapy, cumulative data for routine prophylaxis cohort (Day 1 up to Month 24, Period 1 and Period 2) and on demand cohort (Month 7 up to Month 18, Period 2) is reported. ITT analysis population included all subjects for whom a legal acceptable representative had signed the informed consent/assent form. Here, "Overall Number of Subjects Analysed" signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Month 24 (RP Cohort, RP 25 IU/kg and 45 IU/kg, Period 1 and 2); Month 7 up to Month 18 (OD Cohort, RP 25 IU/kg, Period 2)
    End point values
    		 Moroctocog alfa (AF-CC), OD and RP Cohort: RP Therapy 25 IU/kg Moroctocog alfa (AF-CC), RP Cohort: RP Therapy 45 IU/kg
    Number of subjects analysed
    48
    39
    Units: Infusions per week
        arithmetic mean (standard deviation)
    3.3 ( 0.18 )
    2.1 ( 0.81 )
    No statistical analyses for this end point

    Secondary: Terminal Phase Half Life (t1/2) of Factor VIII (FVIII) Activity

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    End point title
    		 Terminal Phase Half Life (t1/2) of Factor VIII (FVIII) Activity
    End point description
    Plasma decay half-life is the time measured for the FVIII activity to decrease by one half. Analysis population included all subjects for whom a legal acceptable representative had signed the informed consent/assent form, were in a non bleeding state, participated in a single pharmacokinetic (PK) assessment at the start of the study and for whom an adequate PK profile had been obtained.
    End point type
    Secondary
    End point timeframe
    0.5, 8, 24, 28 and 32 hours post dose on Day 1
    End point values
    		 Moroctocog alfa (AF-CC): 50 IU/kg
    Number of subjects analysed
    7
    Units: Hour
        arithmetic mean (standard deviation)
    8.86 ( 2.3513 )
    No statistical analyses for this end point

    Secondary: Clearance (CL) of Factor VIII Activity

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    End point title
    		 Clearance (CL) of Factor VIII Activity
    End point description
    Clearance is a measure of the volume of plasma from which FVIII activity is removed per unit time. It was reported in units milliliter per hour per kilogram (mL/hr/kg). Analysis population included all subjects for whom a legal acceptable representative had signed the informed consent/assent form, were in a non bleeding state, participated in a single PK assessment at the start of the study and for whom an adequate PK profile had been obtained.
    End point type
    Secondary
    End point timeframe
    0.5, 8, 24, 28 and 32 hours post dose on Day 1
    End point values
    		 Moroctocog alfa (AF-CC): 50 IU/kg
    Number of subjects analysed
    7
    Units: mL/hr/kg
        geometric mean (geometric coefficient of variation)
    5.822 ( 59 )
    No statistical analyses for this end point

    Secondary: Incremental Recovery of Factor VIII Activity

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    End point title
    		 Incremental Recovery of Factor VIII Activity
    End point description
    Incremental recovery was the increase in circulating factor VIII (FVIII) activity for every international unit (IU) of moroctocog alfa (AF-CC) administered per kilogram of body weight of subject. It was measured in international units per deciliter per international units per kilogram (IU/dL)/(IU/kg). Analysis population included all subjects for whom legal acceptable representative had signed informed consent/assent form, were in a non-bleeding state, participated in single PK assessment at start of the study and for whom an adequate PK profile had been obtained. Here, “n” signifies number of subjects evaluable at specified time point.
    End point type
    Secondary
    End point timeframe
    Day 1, Month 6
    End point values
    		 Moroctocog alfa (AF-CC): 50 IU/kg
    Number of subjects analysed
    7
    Units: (IU/dL)/(IU/kg)
    arithmetic mean (standard deviation)
        Day 1(n=6)
    1.4438 ( 0.6145 )
        Month 6 (n=2)
    1.4148 ( 0.4046 )
    No statistical analyses for this end point

    Secondary: Maximum Concentration of Factor VIII Activity

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    End point title
    		 Maximum Concentration of Factor VIII Activity
    End point description
    Maximum concentration of FVIII activity was measured in international units per milliliter (IU/mL). Analysis population included all subjects for whom legal acceptable representative had signed informed consent/assent form, were in a non-bleeding state, participated in single PK assessment at start of the study and for whom an adequate PK profile had been obtained.
    End point type
    Secondary
    End point timeframe
    0.5, 8, 24, 28 and 32 hours post dose on Day 1
    End point values
    		 Moroctocog alfa (AF-CC): 50 IU/kg
    Number of subjects analysed
    7
    Units: IU/mL
        geometric mean (geometric coefficient of variation)
    0.7005 ( 60 )
    No statistical analyses for this end point

    Secondary: Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Factor VIII Activity

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    End point title
    		 Area Under the Curve From Time Zero to Extrapolated Infinite Time (AUCinf) of Factor VIII Activity
    End point description
    Area under FVIII activity-time profile from time zero extrapolated to infinite time. AUCinf is reported in units: international units*hour per milliliter (IU*hour/mL). Analysis population included all subjects for whom legal acceptable representative had signed informed consent/assent form, were in a non-bleeding state, participated in single PK assessment at start of the study and for whom an adequate PK profile had been obtained.
    End point type
    Secondary
    End point timeframe
    0.5, 8, 24, 28 and 32 hours post dose on Day 1
    End point values
    		 Moroctocog alfa (AF-CC): 50 IU/kg
    Number of subjects analysed
    7
    Units: IU*hr/mL
        geometric mean (geometric coefficient of variation)
    9.02 ( 50 )
    No statistical analyses for this end point

    Secondary: Area Under the Curve From Time Zero to Last Measurable Concentration (AUClast) of Factor VIII Activity

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    End point title
    		 Area Under the Curve From Time Zero to Last Measurable Concentration (AUClast) of Factor VIII Activity
    End point description
    Area under the FVIII activity-versus-time curve from time zero to the time of the last quantifiable concentration. Analysis population included all subjects for whom legal acceptable representative had signed informed consent/assent form, were in a non-bleeding state, participated in single PK assessment at start of the study and for whom an adequate PK profile had been obtained.
    End point type
    Secondary
    End point timeframe
    0.5, 8, 24, 28 and 32 hours post dose on Day 1
    End point values
    		 Moroctocog alfa (AF-CC): 50 IU/kg
    Number of subjects analysed
    7
    Units: IU*hr/mL
        geometric mean (geometric coefficient of variation)
    8.04 ( 46 )
    No statistical analyses for this end point

    Secondary: Steady-State Volume of Distribution (Vss) of Factor VIII Activity

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    End point title
    		 Steady-State Volume of Distribution (Vss) of Factor VIII Activity
    End point description
    Volume of distribution is defined as the theoretical volume in which the total amount of FVIII would need to be uniformly distributed to produce the observed plasma concentration of FVIII. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state. Analysis population included all subjects for whom legal acceptable representative had signed informed consent/assent form, were in a non-bleeding state, participated in single PK assessment at start of the study and for whom an adequate PK profile had been obtained.
    End point type
    Secondary
    End point timeframe
    0.5, 8, 24, 28 and 32 hours post dose on Day 1
    End point values
    		 Moroctocog alfa (AF-CC): 50 IU/kg
    Number of subjects analysed
    7
    Units: Milliliter per kilogram
        geometric mean (geometric coefficient of variation)
    78.38 ( 50 )
    No statistical analyses for this end point

    Secondary: Mean Residence Time (MRT) of Factor VIII Activity

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    End point title
    		 Mean Residence Time (MRT) of Factor VIII Activity
    End point description
    MRT was calculated as AUMCinf /AUCinf-TI/2, where AUMCinf is the area under the moment curve from time zero to infinity and TI is the duration of infusion. Analysis population included all subjects for whom legal acceptable representative had signed informed consent/assent form, were in a non-bleeding state, participated in single PK assessment at start of the study and for whom an adequate PK profile had been obtained.
    End point type
    Secondary
    End point timeframe
    0.5, 8, 24, 28 and 32 hours post dose on Day 1
    End point values
    		 Moroctocog alfa (AF-CC): 50 IU/kg
    Number of subjects analysed
    7
    Units: Hour
        geometric mean (geometric coefficient of variation)
    13.46 ( 33 )
    No statistical analyses for this end point

    Secondary: Number of Subjects with Treatment Emergent Adverse Events (AEs) According to Severity

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    End point title
    		 Number of Subjects with Treatment Emergent Adverse Events (AEs) According to Severity
    End point description
    An AE is any untoward medical occurrence in a clinical investigation subject administered a product or medical device; the event need not necessarily had a causal relationship with the treatment or usage. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose of study drug (up to 25 months) that were absent before treatment or that worsened relative to pretreatment state. AEs were classified into following on basis of severity: 1) mild = did not interfere with subject’s usual function; 2) moderate = interfered to some extent with subject’s usual function; 3) severe = interfered significantly with subject’s usual function; 4) life threatening = AE required discontinuation of the study drug, subject was at immediate risk of death. Analysis population included all subjects for whom a legal acceptable representative had signed the informed consent/assent form and were analysed for safety. N = number of subjects were evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Month 25
    End point values
    		 Moroctocog alfa (AF-CC): All Subjects
    Number of subjects analysed
    49
    Units: Subjects
        Mild
    12
        Moderate
    29
        Severe
    8
        Life threatening
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Related Adverse Events

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    End point title
    		 Number of Subjects With Treatment-Related Adverse Events
    End point description
    A treatment related AE is any untoward medical occurrence in a clinical investigation subject administered a product or medical device; the event had a causal relationship with the treatment or usage. Analysis population included all subjects for whom a legal acceptable representative had signed the informed consent/assent form and were analysed for safety.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Month 25
    End point values
    		 Moroctocog alfa (AF-CC): All Subjects
    Number of subjects analysed
    51
    Units: Subjects
    49
    No statistical analyses for this end point

    Secondary: Number of Subjects With Confirmed FVIII Inhibitor Development

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    End point title
    		 Number of Subjects With Confirmed FVIII Inhibitor Development
    End point description
    Confirmed FVIII inhibitors were defined as a neutralizing antibody to FVIII with a titer value of greater than or equal to (>=) 0.6 Bethesda units (BU) per millimeter in a sample assayed using the Nijmegen assay at the central laboratory. Modified intent-to-treat (mITT) analysis population included all subjects for whom a legal acceptable representative had signed the informed consent/assent form and who received at least 1 dose of moroctocog alfa (AF-CC). Here, “Overall Number of Subjects Analysed” signifies those subjects who were evaluable for this end point and “n” signifies subjects evaluable at specific time points.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Month 24
    End point values
    		 Moroctocog alfa (AF-CC): All Subjects
    Number of subjects analysed
    49
    Units: Subjects
        OD Cohort (n =8)
    0
        RP Cohort (n = 41)
    3
    No statistical analyses for this end point

    Secondary: Number of Subjects With Incidence of Less than Expected Therapeutic Effect (LETE): On Demand Therapy

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    End point title
    		 Number of Subjects With Incidence of Less than Expected Therapeutic Effect (LETE): On Demand Therapy
    End point description
    LETE occurs in on-demand setting if subject recorded 2 successive “No Response” ratings after 2 successive infusions of study drug. Infusions must have been administered within 24 hours of each other for treatment of same bleeding event in the absence of confounding factors (known presence or subsequent identification of a FVIII inhibitor, known inadequate dose for type and severity of bleed in opinion of investigator, delay of >4 hours between onset of bleed to infusion, delay of >24 hours before administration of a follow-up infusion, known compromised study drug, faulty administration of study drug, subject had an underlying, predisposing condition responsible for bleed in opinion of investigator. For reporting arm: routine prophylaxis 25 IU/kg therapy, cumulative data for RP cohort (Day 1 up to Month 24, Period 1 and Period 2) and OD cohort (Month 7 up to Month 18, Period 2) is reported. ITT analysis population. Number of Subjects Analysed = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Month 24 (RP Cohort, RP 25 IU/kg and 45 IU/kg, Period 1 and 2); Day 1 up to Month 6 (OD Cohort, OD Therapy, Period 1); Month 7 up to Month 18 (OD Cohort, RP 25 IU/kg, Period 2)
    End point values
    		 Moroctocog alfa (AF-CC), On Demand Cohort: On Demand Therapy Moroctocog alfa (AF-CC), RP Cohort: RP Therapy 45 IU/kg Moroctocog alfa (AF-CC), OD and RP Cohort: RP Therapy 25 IU/kg
    Number of subjects analysed
    9
    42
    51
    Units: Subjects
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Incidence of Less than Expected Therapeutic Effect (LETE): Routine Prophylaxis Therapy

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    End point title
    		 Number of Subjects With Incidence of Less than Expected Therapeutic Effect (LETE): Routine Prophylaxis Therapy
    End point description
    LETE in prophylaxis setting if there was spontaneous bleed within 48 hours after regularly scheduled prophylactic dose of study drug in absence of confounding factors (known presence or subsequent identification of a FVIII inhibitor, known inadequate prophylactic dose [a dose less than that prescribed in subject’s regimen], known lack of adherence to the prescribed prophylaxis regimen, bleed occurs in a target joint identified at the start of the study, known compromised study drug, faulty administration of study drug, subject had an underlying, predisposing condition responsible for bleed in opinion of investigator. Therefore, LETE in prophylaxis setting was occurrence of a bleed. For reporting arm: routine prophylaxis 25 IU/kg therapy, cumulative data for RP cohort (Day 1 up to Month 24, Period 1 and Period 2) and OD cohort (Month 7 up to Month 18, Period 2) is reported. ITT analysis population. Number of Subjects Analysed = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Month 24 (RP Cohort, RP 25 IU/kg and 45 IU/kg, Period 1 and 2); Month 7 up to Month 18 (OD Cohort, RP 25 IU/kg, Period 2)
    End point values
    		 Moroctocog alfa (AF-CC), RP Cohort: RP Therapy 45 IU/kg Moroctocog alfa (AF-CC), OD and RP Cohort: RP Therapy 25 IU/kg
    Number of subjects analysed
    42
    51
    Units: Subjects
    3
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 up to Month 25
    Adverse event reporting additional description
    Same event may be as both AE and serious SAE, but distinct events. An event might be as serious in 1 subject and as non-serious in other, or subject may experienced both serious and non-serious event. Analysis population = all subjects for whom legal acceptable representative had signed informed consent/assent form and were analysed for safety.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Moroctocog alfa (AF-CC), OD Cohort: OD Therapy Then RP Therapy
    Reporting group description
    		 In Period 1 subjects for, OD therapy were treated with IV infusion of moroctocog alfa (AF-CC) for 6 months (Day 1 up to Month 6) as prescribed by investigator based on current recommendations for on demand treatment with licensed product Xyntha (Minor bleeding: repetition of IV infusion of AF-CC, 20-40 IU/kg, every 12-24 hours until resolved for at least 1 day, depending upon severity of bleeding episode; Moderate bleeding: repetition of IV infusion of AF-CC, 30-60 IU/kg, every 12-24 hours for 3-4 days or until adequate local hemostasis was achieved; Major bleeding: repetition of IV infusion of AF-CC, 60-100 IU/kg, every 8-24 hours until bleeding was resolved). Period 1 was followed by Period 2 where subjects received IV infusion of AF-CC at 25 IU/kg once in 2 days up to 12 months (Month 7 to Month 18) as RP therapy.

    Reporting group title
    Moroctocog alfa(AF-CC), RP Cohort: RP 45 IU/kg Then RP 25IU/kg
    Reporting group description
    		 In Period 1 subjects for routine prophylaxis therapy, received IV infusion of moroctocog alfa (AF-CC) at 45 IU/kg twice per week up to 12 months (Day 1 up to Month 12). Period 1 was followed by Period 2 where subjects received IV infusion of moroctocog alfa (AF-CC) at 25 IU/kg, once in 2 days up to 12 months (Month 13 up to Month 24) as routine prophylaxis therapy.

    Reporting group title
    Moroctocog alfa (AF-CC), RP Cohort: RP 25IU/kg Then RP 45IU/kg
    Reporting group description
    		 In Period 1 subjects for routine prophylaxis therapy, received IV infusion of moroctocog alfa (AF-CC) at 25 IU/kg once in 2 days up to 12 months (Day 1 up to Month 12). Period 1 was followed by Period 2 where subjects received IV infusion of moroctocog alfa (AF-CC) at 45 IU/kg, twice per week up to 12 months (Month 13 up to Month 24) as routine prophylaxis therapy.

    Serious adverse events
    		 Moroctocog alfa (AF-CC), OD Cohort: OD Therapy Then RP Therapy Moroctocog alfa(AF-CC), RP Cohort: RP 45 IU/kg Then RP 25IU/kg Moroctocog alfa (AF-CC), RP Cohort: RP 25IU/kg Then RP 45IU/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 9 (11.11%)
    5 / 18 (27.78%)
    7 / 24 (29.17%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Limb injury
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Monoplegia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Factor VIII inhibition
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    2 / 24 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter site rash
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haemarthrosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    2 / 24 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Torticollis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Moroctocog alfa (AF-CC), OD Cohort: OD Therapy Then RP Therapy Moroctocog alfa(AF-CC), RP Cohort: RP 45 IU/kg Then RP 25IU/kg Moroctocog alfa (AF-CC), RP Cohort: RP 25IU/kg Then RP 45IU/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 9 (100.00%)
    18 / 18 (100.00%)
    24 / 24 (100.00%)
    Surgical and medical procedures
    Tooth extraction
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 18 (16.67%)
    0 / 24 (0.00%)
         occurrences all number
    0
    4
    0
    Central venous catheterisation
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 9 (44.44%)
    13 / 18 (72.22%)
    7 / 24 (29.17%)
         occurrences all number
    12
    32
    12
    Fatigue
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    4 / 24 (16.67%)
         occurrences all number
    0
    0
    4
    Catheter site discharge
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Catheter site haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Catheter site swelling
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Peripheral swelling
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Immune system disorders
    Allergy to arthropod bite
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 9 (55.56%)
    5 / 18 (27.78%)
    5 / 24 (20.83%)
         occurrences all number
    8
    7
    6
    Rhinorrhoea
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 18 (11.11%)
    4 / 24 (16.67%)
         occurrences all number
    3
    2
    6
    Epistaxis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    2 / 24 (8.33%)
         occurrences all number
    0
    4
    2
    Nasal congestion
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences all number
    0
    4
    0
    Upper respiratory tract congestion
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 18 (5.56%)
    3 / 24 (12.50%)
         occurrences all number
    1
    1
    3
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences all number
    1
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    Body temperature increased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences all number
    0
    3
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Joint injury
         subjects affected / exposed
    0 / 9 (0.00%)
    5 / 18 (27.78%)
    5 / 24 (20.83%)
         occurrences all number
    0
    14
    5
    Limb injury
         subjects affected / exposed
    0 / 9 (0.00%)
    5 / 18 (27.78%)
    5 / 24 (20.83%)
         occurrences all number
    0
    6
    5
    Head injury
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 18 (11.11%)
    5 / 24 (20.83%)
         occurrences all number
    0
    11
    7
    Contusion
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 18 (5.56%)
    3 / 24 (12.50%)
         occurrences all number
    7
    1
    3
    Fall
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 18 (16.67%)
    2 / 24 (8.33%)
         occurrences all number
    0
    5
    3
    Face injury
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    3 / 24 (12.50%)
         occurrences all number
    0
    0
    3
    Laceration
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    2 / 24 (8.33%)
         occurrences all number
    0
    1
    2
    Traumatic haematoma
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 18 (16.67%)
    0 / 24 (0.00%)
         occurrences all number
    0
    4
    0
    Eye injury
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 18 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    0
    2
    0
    Injury
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    1
    Skin abrasion
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    0
    2
    Arthropod bite
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    Arthropod sting
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Foreign body in gastrointestinal tract
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences all number
    0
    2
    0
    Traumatic haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Cyanosis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 9 (0.00%)
    4 / 18 (22.22%)
    3 / 24 (12.50%)
         occurrences all number
    0
    6
    7
    Restless legs syndrome
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Neutropenia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    0
    5
    Tympanic membrane hyperaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    0
    2
    Eye disorders
    Astigmatism
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Ocular hyperaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences all number
    0
    2
    0
    Vitreous floaters
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 9 (11.11%)
    5 / 18 (27.78%)
    4 / 24 (16.67%)
         occurrences all number
    1
    9
    8
    Diarrhoea
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 18 (5.56%)
    5 / 24 (20.83%)
         occurrences all number
    1
    1
    5
    Abdominal pain
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 18 (5.56%)
    3 / 24 (12.50%)
         occurrences all number
    2
    1
    3
    Toothache
         subjects affected / exposed
    1 / 9 (11.11%)
    4 / 18 (22.22%)
    1 / 24 (4.17%)
         occurrences all number
    1
    4
    1
    Abdominal pain upper
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    4 / 24 (16.67%)
         occurrences all number
    0
    2
    6
    Tooth loss
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    3 / 24 (12.50%)
         occurrences all number
    0
    1
    3
    Constipation
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    0
    2
    Dental caries
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    1
    Dyspepsia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    Gingival swelling
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Lip haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Oral disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    2 / 24 (8.33%)
         occurrences all number
    0
    1
    2
    Swelling face
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    1 / 24 (4.17%)
         occurrences all number
    0
    2
    1
    Intertrigo
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    Rash
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    Skin lesion
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Ecchymosis
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 18 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    0
    3
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 18 (11.11%)
    8 / 24 (33.33%)
         occurrences all number
    0
    2
    12
    Pain in extremity
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 18 (11.11%)
    7 / 24 (29.17%)
         occurrences all number
    1
    2
    14
    Back pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    4 / 24 (16.67%)
         occurrences all number
    0
    0
    6
    Haemarthrosis
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 18 (11.11%)
    1 / 24 (4.17%)
         occurrences all number
    1
    2
    1
    Joint swelling
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    2
    Osteochondrosis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 9 (11.11%)
    7 / 18 (38.89%)
    8 / 24 (33.33%)
         occurrences all number
    1
    12
    22
    Nasopharyngitis
         subjects affected / exposed
    2 / 9 (22.22%)
    5 / 18 (27.78%)
    7 / 24 (29.17%)
         occurrences all number
    5
    14
    14
    Influenza
         subjects affected / exposed
    3 / 9 (33.33%)
    1 / 18 (5.56%)
    4 / 24 (16.67%)
         occurrences all number
    6
    2
    4
    Tonsillitis
         subjects affected / exposed
    3 / 9 (33.33%)
    1 / 18 (5.56%)
    3 / 24 (12.50%)
         occurrences all number
    5
    1
    3
    Pharyngitis
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 18 (5.56%)
    2 / 24 (8.33%)
         occurrences all number
    7
    1
    3
    Varicella
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    3 / 24 (12.50%)
         occurrences all number
    1
    0
    3
    Viral infection
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    1
    0
    3
    Device related infection
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    6
    0
    1
    Eye infection
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 18 (11.11%)
    0 / 24 (0.00%)
         occurrences all number
    0
    2
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    0
    Impetigo
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    0
    4
    Laryngitis
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 18 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    4
    0
    0
    Otitis media
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    0
    2
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    0
    2
    Body tinea
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    Bronchitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    Conjunctivitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    Enterobiasis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 18 (5.56%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Infection
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    Pharyngotonsillitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 18 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 18 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    0
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Jun 2007
    Duration of each treatment period (Period 1 and 2) was lengthened from 9 months per treatment period to 12 months per treatment period.
    31 Aug 2011
    Segment 1 for the OD cohort was shortened to 6 months duration from 12 months. Segment 2 for the OD cohort and Segments 1 and 2 for the RP cohort remained at 12 months duration.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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