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    Clinical Trial Results:
    A Non-randomized, Open-label Study To Evaluate The Pharmacokinetics, Safety And Efficacy Of Refacto Af In Previously Treated Pediatric Subjects Less Than Twelve Years Of Age With Severe Hemophilia A (Fviii:c <1%)

    Summary
    EudraCT number
    		 2008-008435-29
    Trial protocol
    		 FR   ES   IT   GR   CZ   SE   DK   FI   BG  
    Global end of trial date
    05 Apr 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Sep 2016
    First version publication date
    02 Sep 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    3082B2-4433
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00914459
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Alias: B1831005
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800­-718-­1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800­-718-­1021, 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
    20 Jul 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to evaluate the PK and incremental recovery of ReFacto AF in pediatric subjects less than 12 years of age after a single exposure to ReFacto AF. The secondary objectives of this study are to evaluate the efficacy of ReFacto AF in pediatric subjects less than 12 years of age, including the frequency of less-than-expected therapeutic effect (LETE) and to evaluate the safety of ReFacto AF in these subjects.
    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 Council for Harmonisation (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 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Finland: 1
    Country: Number of subjects enrolled
    Georgia: 1
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Romania: 9
    Country: Number of subjects enrolled
    Serbia: 9
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    Turkey: 5
    Country: Number of subjects enrolled
    Ukraine: 5
    Worldwide total number of subjects
    37
    EEA total number of subjects
    17
    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)
    1
    Children (2-11 years)
    36
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study was started in 11 Dec 2009 and completed on 05 Apr 2016.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ReFacto AF: Less Than 6 Years
    Arm description
    		 Subjects below 6 years of age were treated with IV injections of ReFacto AF at a dose and frequency prescribed by the investigator (minimum dose of 17 international units per kilogram [IU/kg] up to maximum dose of 51 IU/kg) as per local standard of care in accordance with the Summary of Product Characteristics (SmPC).
    Arm type
    		 Experimental

    Investigational medicinal product name
    ReFacto AF
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Refacto AF IV infusion as a single dose (minimum dose of 17 IU/kg up to maximum dose of 51 IU/kg) and frequency prescribed by the investigator as per local standard of care in accordance with the Summary of Product Characteristics (SmPC). A single 50 IU/kg dose was administered for assessment of PK parameters, including recovery.

    Arm title
    		 ReFacto AF: 6 to Less Than 12 Years
    Arm description
    		 Subjects of 6 to 12 years of age were treated with IV injections of ReFacto AF at a dose and frequency prescribed by the investigator (minimum dose of 17 IU/kg up to maximum dose of 51 IU/kg) as per local standard of care in accordance with the SmPC.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ReFacto AF
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received Refacto AF IV infusion as a single dose (minimum dose of 17 IU/kg up to maximum dose of 51 IU/kg) and frequency prescribed by the investigator as per local standard of care in accordance with the Summary of Product Characteristics (SmPC). A single 50 IU/kg dose was administered for assessment of PK parameters, including recovery.

    Number of subjects in period 1
    		ReFacto AF: Less Than 6 Years ReFacto AF: 6 to Less Than 12 Years
    Started
    18
    19
    Completed
    17
    18
    Not completed
    1
    1
         Parent/Legal guardian request
    1
    -
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ReFacto AF: Less Than 6 Years
    Reporting group description
    		 Subjects below 6 years of age were treated with IV injections of ReFacto AF at a dose and frequency prescribed by the investigator (minimum dose of 17 international units per kilogram [IU/kg] up to maximum dose of 51 IU/kg) as per local standard of care in accordance with the Summary of Product Characteristics (SmPC).

    Reporting group title
    ReFacto AF: 6 to Less Than 12 Years
    Reporting group description
    		 Subjects of 6 to 12 years of age were treated with IV injections of ReFacto AF at a dose and frequency prescribed by the investigator (minimum dose of 17 IU/kg up to maximum dose of 51 IU/kg) as per local standard of care in accordance with the SmPC.

    Reporting group values
    		 ReFacto AF: Less Than 6 Years ReFacto AF: 6 to Less Than 12 Years Total
    Number of subjects
    		 18 19 37
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 1 0 1
        Children (2-11 years)
    		 17 19 36
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 3.6 ± 1.42 9.2 ± 1.47 -
    Gender, Male/Female
    Units: participants
        Female
    		 0 0 0
        Male
    		 18 19 37
    Subject analysis sets

    Subject analysis set title
    ReFacto AF: All Subjects
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects (aged less than or equal to [<=] 12 years of age) were treated with IV injections of ReFacto AF at a dose and frequency prescribed by the investigator (minimum dose of 17 IU/kg up to maximum dose of 51 IU/kg) as per local standard of care in accordance with the SmPC.

    Subject analysis sets values
    		 ReFacto AF: All Subjects
    Number of subjects
    37
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    1
        Children (2-11 years)
    36
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    6.5 ± 3.2
    Gender, Male/Female
    Units: participants
        Female
    0
        Male
    37

    End points

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    End points reporting groups
    Reporting group title
    ReFacto AF: Less Than 6 Years
    Reporting group description
    		 Subjects below 6 years of age were treated with IV injections of ReFacto AF at a dose and frequency prescribed by the investigator (minimum dose of 17 international units per kilogram [IU/kg] up to maximum dose of 51 IU/kg) as per local standard of care in accordance with the Summary of Product Characteristics (SmPC).

    Reporting group title
    ReFacto AF: 6 to Less Than 12 Years
    Reporting group description
    		 Subjects of 6 to 12 years of age were treated with IV injections of ReFacto AF at a dose and frequency prescribed by the investigator (minimum dose of 17 IU/kg up to maximum dose of 51 IU/kg) as per local standard of care in accordance with the SmPC.

    Subject analysis set title
    ReFacto AF: All Subjects
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects (aged less than or equal to [<=] 12 years of age) were treated with IV injections of ReFacto AF at a dose and frequency prescribed by the investigator (minimum dose of 17 IU/kg up to maximum dose of 51 IU/kg) as per local standard of care in accordance with the SmPC.

    Primary: Percentage of Subjects With Clinically Significant Factor VIII Inhibitor Development

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    End point title
    		 Percentage of Subjects With Clinically Significant Factor VIII Inhibitor Development [1]
    End point description
    Clinically significant factor VIII (FVIII) inhibitors were defined as a central laboratory confirmed positive inhibitor of greater than or equal to (>=) 0.6 Bethesda units (BU) using the Nijmegen modification of the Bethesda assay present at 2 consecutive blood draws within a 6-week interval and one of the following within 4 weeks before the initial or within 4 weeks following the second positive FVIII inhibitor sample collection: the need for the subject to administer alternative hemostatic products in order to achieve sufficient efficacy, or >=2 events indicating a decrease in the efficacy of the study treatment. Percentage of subjects who developed clinically significant Factor VIII inhibitor after study drug administration were reported. Safety analysis population included all enrolled subjects who received at least 1 dose of ReFacto AF.
    End point type
    Primary
    End point timeframe
    Baseline up to Month 24
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    		 ReFacto AF: Less Than 6 Years ReFacto AF: 6 to Less Than 12 Years
    Number of subjects analysed
    18
    19
    Units: percentage of subjects
        number (confidence interval 95%)
    0 (0 to 18.53)
    0 (0 to 17.65)
    No statistical analyses for this end point

    Primary: Incremental Recovery

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    End point title
    		 Incremental Recovery [2]
    End point description
    Incremental recovery was the increase in circulating FVIII activity for every international unit (IU) of ReFacto AF administered per kilogram of body weight. It was measured in international units per deciliter (IU/dL) per international units per kilogram (IU/kg). The pharmacokinetic (PK) parameter analysis population included all enrolled subjects who received at least 1 dose of ReFacto AF. Here, "n" signifies subjects who were evaluable at the specified time point for each reporting group respectively.
    End point type
    Primary
    End point timeframe
    Days 1, 15, 50, Months 6, 18 and Final visit (up to Month 24)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    		 ReFacto AF: Less Than 6 Years ReFacto AF: 6 to Less Than 12 Years
    Number of subjects analysed
    18
    19
    Units: (IU/dL)/(IU/kg)
    arithmetic mean (standard deviation)
        Day 1 (n= 17, 18)
    1.67 ± 0.361
    1.97 ± 0.437
        Day 15 (n= 18, 17)
    1.23 ± 0.65
    1.91 ± 0.423
        Day 50 (n= 17, 18)
    1.66 ± 0.626
    1.96 ± 0.586
        Month 6 (n= 2, 5)
    1.69 ± 0.21
    2.17 ± 0.379
        Month 18 (n= 4, 5)
    1.81 ± 0.405
    1.8 ± 0.493
        Final Visit (n= 17, 17)
    1.98 ± 1.454
    1.89 ± 0.503
    No statistical analyses for this end point

    Primary: Terminal Elimination Half Life of ReFacto AF (t1/2)

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    End point title
    		 Terminal Elimination Half Life of ReFacto AF (t1/2) [3] [4]
    End point description
    T1/2 was the time for the plasma concentration of drug to decrease by one-half of its original concentration. PK parameter analysis population included all enrolled subjects who received at least 1 dose of ReFacto AF. Here, "number of subjects analysed" signifies subjects who were evaluable for this endpoint. Data was not planned to be collected and analysed for reporting arm “ReFacto AF: Less Than 6 Years”, as pre-specified in protocol.
    End point type
    Primary
    End point timeframe
    Pre-dose, 0.5, 1, 3, 6, 9, 24, 28, 32, 48 hours post-dose on Day 1
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be assessed for "ReFacto AF: 6 to Less Than 12 Years" reporting group only. 
    End point values
    		 ReFacto AF: 6 to Less Than 12 Years
    Number of subjects analysed
    14
    Units: hours
        arithmetic mean (standard deviation)
    9.12 ± 1.9429
    No statistical analyses for this end point

    Primary: Clearance (CL)

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    End point title
    		 Clearance (CL) [5] [6]
    End point description
    Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. PK parameter analysis population included all enrolled subjects who received at least 1 dose of ReFacto AF. Here, "number of subjects analysed" signifies subjects who were evaluable for this endpoint. Data was not planned to be collected and analysed for reporting arm “ReFacto AF: Less Than 6 Years”, as pre-specified in protocol.
    End point type
    Primary
    End point timeframe
    Pre-dose, 0.5, 1, 3, 6, 9, 24, 28, 32, 48 hours post-dose on Day 1
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be assessed for "ReFacto AF: 6 to Less Than 12 Years" reporting group only. 
    End point values
    		 ReFacto AF: 6 to Less Than 12 Years
    Number of subjects analysed
    14
    Units: milliliter per hour per kilogram
        geometric mean (geometric coefficient of variation)
    4.406 ± 30
    No statistical analyses for this end point

    Secondary: Mean Annualized Bleeding Rates (ABRs): All Subjects

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    End point title
    		 Mean Annualized Bleeding Rates (ABRs): All Subjects
    End point description
    ABR for each subject was calculated as the number of bleeds requiring administration of FVIII replacement product (taken from the Infusion Log Diary case report form), divided by the total therapy duration (in days), then multiplied by 365.25. ABR for the participants who reported following a primary or secondary prophylaxis, on-demand regimen or preventive regimen at baseline were reported. Efficacy analysis population included all enrolled subjects who received at least 1 dose of ReFacto AF. Here, "number of subjects analysed" signifies subjects who were evaluable for this endpoint and "n" signifies subjects who were evaluable at the specified time points. Here "99999" for mean and "+/­99999" for standard deviation signifies "not available" as the data was not calculated and reported because none of the subjects were reported at baseline as following a preventive regimen.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 24
    End point values
    		 ReFacto AF: All Subjects
    Number of subjects analysed
    36
    Units: bleeds per year
    arithmetic mean (standard deviation)
        On-demand regimen (n=14)
    27.51 ± 20.387
        Preventive regimen (n=0)
    99999 ± 99999
        Primary or secondary prophylaxis regimen (n=22)
    4.18 ± 3.849
    No statistical analyses for this end point

    Secondary: Response to the First On-Demand Treatment for all New Bleeds: All Subjects

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    End point title
    		 Response to the First On-Demand Treatment for all New Bleeds: All Subjects
    End point description
    Scale for assessment of ‘on-demand’ treatment is defined as: 1.Excellent:Definite pain relief and/or improvement (improve.)in signs of bleeding starting within 8 hours after an infusion (inf.),with no additional inf. Administered (adm.). 2.Good: Definite pain relief and/or improve. in signs of bleeding starting within 8 hours after an inf.,with at least 1 additional inf. adm. for complete resolution of bleeding episode;or,Definite pain relief and/or improve. in signs of bleeding starting after 8 hours following inf.,with no additional inf. adm. 3.Moderate:Probable or slight improve. starting after 8 hours following inf.,with at least 1 additional inf. adm. for complete resolution of bleeding episode. 4.No Response:No improve. at all between inf. or during 24-hour interval following inf.,or condition worsens.Efficacy population.Number of subjects analysed signifies subjects who were evaluable for this endpoint and received at least 1 dose of ReFacto AF for at least 1 bleeding episode.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 24
    End point values
    		 ReFacto AF: All Subjects
    Number of subjects analysed
    30
    Units: responses
        Excellent
    713
        Good
    73
        Moderate
    16
        Data Not Recorded
    2
    No statistical analyses for this end point

    Secondary: Number of On-Demand ReFacto AF Infusions to Treat a New Bleed: All Subjects

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    End point title
    		 Number of On-Demand ReFacto AF Infusions to Treat a New Bleed: All Subjects
    End point description
    The infusion log diary case report form (CRF) was used to determine the number of on-demand (administration of an unscheduled bolus infusion of Refacto-AF to stop bleeding) ReFacto AF infusions administered to treat a new bleed. This was calculated by adding the initial for a new bleed (on-demand) infusion to any subsequent (on-demand) infusions for the same "previously treated bleed" (same bleed with same start date/time). Efficacy analysis population included all enrolled subjects who received at least 1 dose of ReFacto AF. Here, "number of subjects analysed" signifies subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 24
    End point values
    		 ReFacto AF: All Subjects
    Number of subjects analysed
    30
    Units: infusions
        arithmetic mean (standard deviation)
    1.1 ± 0.55
    No statistical analyses for this end point

    Secondary: Number of Breakthrough Bleeds Within 48 Hours of a Prophylaxis Dose of ReFacto AF: All Subjects

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    End point title
    		 Number of Breakthrough Bleeds Within 48 Hours of a Prophylaxis Dose of ReFacto AF: All Subjects
    End point description
    The number of breakthrough bleeds within 48 hours following a prophylaxis dose of ReFacto AF was summarized. The infusion log diary CRF was used to determine the number of infusions administered to treat a new bleed counting only those infusions which were administered less than or equal to (<=) 48 hours after an infusion marked as “prophylaxis” (which had no associated bleed). Efficacy analysis population included all enrolled subjects who received at least 1 dose of ReFacto AF.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 24
    End point values
    		 ReFacto AF: All Subjects
    Number of subjects analysed
    37
    Units: breakthrough bleeds
        arithmetic mean (standard deviation)
    2 ± 1.15
    No statistical analyses for this end point

    Secondary: Average Infusion Dose of ReFacto AF: All Subjects

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    End point title
    		 Average Infusion Dose of ReFacto AF: All Subjects
    End point description
    The average infusion dose (by weight) for each subject was calculated as his total factor FVIII consumption (in IU) divided by weight (in kg) divided by the number of infusions administered in total study duration. Data was reported separately for subjects classified at baseline as following non-prophylaxis regimen (for example: on-demand regimen, preventive, or not specified), and subjects classified at baseline following a primary or secondary prophylaxis regimen. Efficacy analysis population included all enrolled subjects who received at least 1 dose of ReFacto AF. Here, "n" signifies subjects who were evaluable for each specified baseline category.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 24
    End point values
    		 ReFacto AF: All Subjects
    Number of subjects analysed
    37
    Units: IU/kg
    arithmetic mean (standard deviation)
        With prophylaxis regimen at baseline (n= 22)
    37 ± 8.7
        With non-prophylaxis regimen at baseline (n= 15)
    29.5 ± 7.61
    No statistical analyses for this end point

    Secondary: Total Factor VIII Consumption: All Subjects

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    End point title
    		 Total Factor VIII Consumption: All Subjects
    End point description
    Total factor VIII consumption for each subject was calculated by sum of the total amount of ReFacto AF (in IU) infused for each ReFacto AF infusion (recorded in the infusion log diary CRF) divided by the weight (kg) recorded at the previous visit for each subject. Data was reported separately for subjects classified at baseline as following non-prophylaxis regimen (for example: on-demand regimen, preventive, or not specified), and subjects classified at baseline following a primary or secondary prophylaxis regimen. Efficacy analysis population included all enrolled subjects who received at least 1 dose of ReFacto AF. Here, "n" signifies subjects who were evaluable for each specified baseline category.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 24
    End point values
    		 ReFacto AF: All Subjects
    Number of subjects analysed
    37
    Units: IU
    arithmetic mean (standard deviation)
        With Prophylaxis regimen at baseline (n= 22)
    97959.4 ± 48474.09
        With non-prophylaxis regimen at baseline (n= 15)
    84051.7 ± 47362.6
    No statistical analyses for this end point

    Secondary: Number of Less-Than-Expected-Therapeutic Effect (LETE) Bleeds in the On-Demand Setting: All Subjects

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    End point title
    		 Number of Less-Than-Expected-Therapeutic Effect (LETE) Bleeds in the On-Demand Setting: All Subjects
    End point description
    LETE was based on response to treatment of bleeding episode and occurred if subject recorded 2 successive"no response"ratings after 2 ReFacto AF infusions(inf.)which were administered(admin.)at interval of 24 hours for treatment of same bleeding event in absence of confounding factor which included: known presence or identification of a FVIII inhibitor,known inadequate dose for type and/or severity of bleed in opinion of investigator,delay of greater than(>)4 hours between onset of bleed to inf.,delay of >24 hours before admin. of a follow-up inf.,known compromised ReFacto AF,faulty admin. of ReFacto AF,subject had underlying, predisposing condition responsible for bleed in opinion of investigator(kidney stones or medications which impair platelet function like aspirin or NSAIDs),or ongoing trauma responsible for continued bleeding.Efficacy analysis population.“Number of subjects analysed” are subjects who were evaluable for this endpoint and received treatment for at least 1 bleed.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 24
    End point values
    		 ReFacto AF: All Subjects
    Number of subjects analysed
    30
    Units: LETE bleeds
        LETE bleeds
    0
        Bleeding episodes
    804
    No statistical analyses for this end point

    Secondary: Number of Less-Than-Expected-Therapeutic Effect (LETE) Bleeds in the Prophylaxis Setting: All Subjects

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    End point title
    		 Number of Less-Than-Expected-Therapeutic Effect (LETE) Bleeds in the Prophylaxis Setting: All Subjects
    End point description
    LETE in the prophylaxis setting occurred if there was a spontaneous bleed within 48 hours(<=48 hours) after a regularly scheduled prophylactic dose of ReFacto AF(which was not used to treat a bleed) in the absence of confounding factors. Therefore, LETE in the prophylaxis setting is the occurrence of a bleed. Confounding factors include:Known presence or subsequent identification of a FVIII inhibitor, known inadequate prophylactic dose, known lack of adherence to the prescribed prophylaxis regimen, bleed occurs in a target joint identified at the start of the study, known compromised ReFacto AF, faulty administration of ReFacto AF, an underlying, predisposing condition responsible for the bleed in the opinion of the investigator (e.g., kidney stones or use of medications known to impair platelet function, such as aspirin or NSAIDs) or traumatic injury responsible for bleeding. Efficacy analysis population. Subjects who received at least 1 prophylaxis dose of ReFacto AF were reported.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 24
    End point values
    		 ReFacto AF: All Subjects
    Number of subjects analysed
    37
    Units: LETE bleeds
        LETE bleeds
    2
        Prophylaxis infusions
    2457
    No statistical analyses for this end point

    Secondary: Number of Occurrences of Less-Than-Expected-Therapeutic Effect (LETE) in the Low Recovery Setting: All Subjects

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    End point title
    		 Number of Occurrences of Less-Than-Expected-Therapeutic Effect (LETE) in the Low Recovery Setting: All Subjects
    End point description
    LETE in the low recovery setting was defined as lower than expected recovery of FVIII (in the opinion of investigator), following the infusion of ReFacto AF in the absence of confounding factors for the low recovery. The only confounding factors for low recovery are as follows: known presence or subsequent identification of a FVIII inhibitor, known compromised ReFacto AF, faulty administration of ReFacto AF, including inadequate dosing. Efficacy analysis population included all enrolled subjects who received at least 1 dose of ReFacto AF.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 24
    End point values
    		 ReFacto AF: All Subjects
    Number of subjects analysed
    37
    Units: LETE bleeds
    9
    No statistical analyses for this end point

    Secondary: Number of Subjects Requiring Escalated Dose of Prescribed Regimen During the Treatment Period: All Subjects

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    End point title
    		 Number of Subjects Requiring Escalated Dose of Prescribed Regimen During the Treatment Period: All Subjects
    End point description
    Subjects who met the dose escalation criteria were prescribed a higher dose and/or more frequent doses as per the investigator’s discretion. Efficacy analysis population included all enrolled subjects who received at least 1 dose of ReFacto AF. Subjects who used a prophylaxis regimen were analysed for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to Month 24
    End point values
    		 ReFacto AF: All Subjects
    Number of subjects analysed
    37
    Units: subjects
    5
    No statistical analyses for this end point

    Secondary: Plasma Concentration of Factor VIII at 0.5 Hour Post-dose (C0.5)

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    End point title
    		 Plasma Concentration of Factor VIII at 0.5 Hour Post-dose (C0.5)
    End point description
    PK parameter analysis population included all enrolled subjects who received at least 1 dose of ReFacto AF.
    End point type
    Secondary
    End point timeframe
    0.5 hour post-dose on Day 1
    End point values
    		 ReFacto AF: Less Than 6 Years ReFacto AF: 6 to Less Than 12 Years
    Number of subjects analysed
    18
    19
    Units: IU/mL
        geometric mean (geometric coefficient of variation)
    0.752 ± 18
    0.903 ± 45
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Time Curve From Time 0 Extrapolated to Infinite Time (AUCinf)

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    End point title
    		 Area Under the Plasma Time Curve From Time 0 Extrapolated to Infinite Time (AUCinf) [7]
    End point description
    AUCinf is the area under the plasma concentration-time profile from time 0 extrapolated to infinite time. It was calculated as International units*hour per milliliter (IU*hr/mL). PK parameter analysis population included all enrolled subjects who received at least 1 dose of ReFacto AF. Here, "number of subjects analysed" signifies subjects who were evaluable for this endpoint. Data was not planned to be collected and analysed for reporting group “ReFacto AF: Less Than 6 Years”, as pre-specified in protocol.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.5, 1, 3, 6, 9, 24, 28, 32, 48 hours post-dose on Day 1
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be assessed for "ReFacto AF: 6 to Less Than 12 Years" reporting group only. 
    End point values
    		 ReFacto AF: 6 to Less Than 12 Years
    Number of subjects analysed
    14
    Units: IU*hr/mL
        geometric mean (geometric coefficient of variation)
    9.89 ± 41
    No statistical analyses for this end point

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

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    End point title
    		 Area Under the Plasma Time Curve From Time Zero to Time of Last Measurable Concentration (AUClast) [8]
    End point description
    AUClast is the area under the plasma versus time curve from time zero to time of last measurable concentration (AUClast). PK parameter analysis population included all enrolled subjects who received at least 1 dose of ReFacto AF. Here, "number of subjects analysed" signifies subjects who were evaluable for this endpoint. Data was not planned to be collected and analysed for reporting group “ReFacto AF: Less Than 6 Years”, as pre-specified in protocol.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.5, 1, 3, 6, 9, 24, 28, 32, 48 hours post-dose on Day 1
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be assessed for "ReFacto AF: 6 to Less Than 12 Years" reporting group only. 
    End point values
    		 ReFacto AF: 6 to Less Than 12 Years
    Number of subjects analysed
    14
    Units: IU*hr/mL
        geometric mean (geometric coefficient of variation)
    9.49 ± 41
    No statistical analyses for this end point

    Secondary: Volume of Distribution at Steady State (Vss)

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    End point title
    		 Volume of Distribution at Steady State (Vss) [9]
    End point description
    Volume of distribution was defined as the theoretical volume in which the total amount of drug was uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) was the apparent volume of distribution at steady-state. PK parameter analysis population included all enrolled subjects who received at least 1 dose of ReFacto AF. Here, "number of subjects analysed" signifies subjects who were evaluable for this endpoint. Data was not planned to be collected and analysed for reporting group “ReFacto AF: Less Than 6 Years”, as pre-specified in protocol.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.5, 1, 3, 6, 9, 24, 28, 32, 48 hours post-dose on Day 1
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be assessed for "ReFacto AF: 6 to Less Than 12 Years" reporting group only. 
    End point values
    		 ReFacto AF: 6 to Less Than 12 Years
    Number of subjects analysed
    14
    Units: mL/kg
        geometric mean (geometric coefficient of variation)
    56.42 ± 15
    No statistical analyses for this end point

    Secondary: Mean Residence Time (MRT) of ReFacto AF

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    End point title
    		 Mean Residence Time (MRT) of ReFacto AF [10]
    End point description
    MRT was calculated as AUMCinf / AUCinf-TI/2, where AUMCinf is the area under the first moment curve from time zero to infinity and TI was the duration of infusion. PK parameter analysis population included all enrolled subjects who received at least 1 dose of ReFacto AF. Here, "number of subjects analysed" signifies subjects who were evaluable for this endpoint. Data was not planned to be collected and analysed for reporting group “ReFacto AF: Less Than 6 Years”, as pre-specified in protocol.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.5, 1, 3, 6, 9, 24, 28, 32, 48 hours post-dose on Day 1
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be assessed for "ReFacto AF: 6 to Less Than 12 Years" reporting group only. 
    End point values
    		 ReFacto AF: 6 to Less Than 12 Years
    Number of subjects analysed
    14
    Units: hour
        median (full range (min-max))
    13.91 (8.51 to 18.3)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs): All Subjects

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs): All Subjects
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject who received study treatment without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death, initial or prolonged inpatient hospitalization, life-threatening experience (immediate risk of dying), persistent or significant disability or incapacity, congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious adverse events.
    End point type
    Secondary
    End point timeframe
    Baseline up to 30 days after last study visit (Month 25)
    End point values
    		 ReFacto AF: All Subjects
    Number of subjects analysed
    37
    Units: subjects
        AEs
    28
        SAEs
    6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 30 days after last study visit (Month 25)
    Adverse event reporting additional description
    Same event may appear both as an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both serious and nonserious event during the study. Adverse events data was planned to be reported for the overall population.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    ReFacto AF: All Subjects
    Reporting group description
    		 All subjects (aged less than or equal to [<=] 12 years of age) were treated with IV injections of ReFacto AF at a dose and frequency prescribed by the investigator (minimum dose of 17 IU/kg up to maximum dose of 51 IU/kg) as per local standard of care in accordance with the SmPC.

    Serious adverse events
    		 ReFacto AF: All Subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 37 (16.22%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Factor VIII inhibition
         subjects affected / exposed
    4 / 37 (10.81%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Scrotal disorder
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Laryngitis
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rhinitis
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 ReFacto AF: All Subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 37 (75.68%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    4 / 37 (10.81%)
         occurrences all number
    6
    Head injury
         subjects affected / exposed
    4 / 37 (10.81%)
         occurrences all number
    5
    Joint injury
         subjects affected / exposed
    3 / 37 (8.11%)
         occurrences all number
    3
    Limb injury
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    6
    Tooth fracture
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    2
    Arthropod sting
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Contusion
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    3
    Craniocerebral injury
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Laceration
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Lip injury
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Mouth injury
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    2
    Haematoma
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Surgical and medical procedures
    Tooth extraction
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    10
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 37 (8.11%)
         occurrences all number
    6
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    2
    Vomiting
         subjects affected / exposed
    3 / 37 (8.11%)
         occurrences all number
    3
    Dental caries
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    2
    Dyspepsia
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Lip haemorrhage
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Mouth haemorrhage
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Oral cavity fistula
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Tooth pulp haemorrhage
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Toothache
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 37 (8.11%)
         occurrences all number
    3
    Epistaxis
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    2
    Obstructive airways disorder
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Skin mass
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Solar urticaria
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 37 (18.92%)
         occurrences all number
    19
    Pain in extremity
         subjects affected / exposed
    4 / 37 (10.81%)
         occurrences all number
    7
    Haemarthrosis
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    2
    Joint swelling
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    2
    Groin pain
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Joint range of motion decreased
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    2
    Muscle haemorrhage
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    12 / 37 (32.43%)
         occurrences all number
    16
    Influenza
         subjects affected / exposed
    3 / 37 (8.11%)
         occurrences all number
    4
    Adenoiditis
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    6
    Bronchitis
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    4
    Otitis media acute
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    2
    Respiratory tract infection viral
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    2
    Rhinitis
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    6
    Cestode infection
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Infectious mononucleosis
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Laryngitis
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Otitis media
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Pharyngitis
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Pyoderma streptococcal
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Sinusitis
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Tonsillitis
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    2
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Varicella
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Underweight
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 May 2009
    The purpose of this amendment was to update safety section to provide further details of the primary and secondary safety outcome measures.
    27 May 2009
    The purpose of this amendment was to modify the definition of “clinically significant FVIII inhibitor” to remove any association of this definition with LETEs
    24 Mar 2011
    The purpose of this amendment was to clarify the the timing of the follow-up call and the SAE reporting time lines

    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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