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    Clinical Trial Results:
    A MULTICENTER, OPEN LABEL STUDY TO COMPARE ON DEMAND TREATMENT TO A PROPHYLAXIS REGIMEN OF NONACOG ALFA (BENEFIX) IN SUBJECTS WITH MODERATELY SEVERE TO SEVERE HEMOPHILIA B (FIX:C ≤2%)

    Summary
    EudraCT number
    2011-000520-15
    Trial protocol
    PL   BG   GR   Outside EU/EEA  
    Global end of trial date
    23 Apr 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    11 May 2016
    First version publication date
    08 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    B1821010
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01335061
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd St,, New York,, United States,
    Public contact
    Clinical Trials.gov Call Center, Pfizer Inc., 011 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Clinical Trials.gov Call Center, Pfizer Inc., 011 8007181021, 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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Oct 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Apr 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Apr 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to demonstrate that a prophylaxis regimen of BeneFIX reduces the ABR compared to on-demand treatment in subjects with moderately-severe to severe hemophilia B. The secondary objective is to describe the safety and efficacy of BeneFIX when administered for prophylaxis at a dose of 100 IU/kg once weekly.
    Protection of trial subjects
    The External Data Monitoring Committee met approximately every 6 months to review safety data. Per the DMC charter, safety data included line listings and summaries of all AEs, SAEs, discontinuations, demographic and other baseline characteristics, treatment information, and medically important events. Efficacy data could be reviewed if necessary for an accurate risk-benefit assessment.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    19 Sep 2011
    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: 4
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Croatia: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 3
    Country: Number of subjects enrolled
    Malaysia: 4
    Country: Number of subjects enrolled
    Singapore: 2
    Country: Number of subjects enrolled
    Turkey: 5
    Country: Number of subjects enrolled
    Mexico: 2
    Worldwide total number of subjects
    25
    EEA total number of subjects
    8
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    5
    Adults (18-64 years)
    20
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participation included 25 enrolled participants from 15 study centers and 9 countries.

    Pre-assignment
    Screening details
    The duration of participation was approximately 86 weeks, consisting of a Screening period (1 day to 4 weeks), Period 1 (on-demand treatment for 26 weeks), Period 2 (prophylaxis therapy for 52 weeks), and a follow-up safety period (4 weeks).

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

    Arms
    Arm title
    All participants
    Arm description
    Data for all the participants were analyzed.
    Arm type
    Experimental

    Investigational medicinal product name
    BeneFIX
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The first treatment period was 6 months (26 weeks) of on-demand treatment when BeneFIX was to be administered by participants according to the locally approved BeneFIX label or the BeneFIX Core Data Sheet to treat bleeding events at the discretion of the study physician. The participant began the second treatment period when the BeneFIX prophylaxis regimen of approximately 100 IU/kg was used once weekly for 12 months (52 weeks).

    Number of subjects in period 1
    All participants
    Started
    25
    Completed
    25

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    -

    Reporting group values
    Overall Trial Total
    Number of subjects
    25 25
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    5 5
        Adults (18-64 years)
    20 20
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    31.3 ± 12.6 -
    Gender categorical
    Units: Subjects
        Female
    0 0
        Male
    25 25

    End points

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    End points reporting groups
    Reporting group title
    All participants
    Reporting group description
    Data for all the participants were analyzed.

    Subject analysis set title
    On-Demand Therapy
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants were treated for the bleeding events at the discretion of the study physician according to BeneFIX label.

    Subject analysis set title
    Prophylaxis therapy
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The prophylaxis regimen of approximately 100 IU/kg once weekly was initiated at Visit 4.

    Subject analysis set title
    On-Demand therapy-First infusion
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants were treated for the bleeding events at the discretion of the study physician according to BeneFIX label.

    Subject analysis set title
    On-Demand therapy-Follow-up infusions
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants were treated for the bleeding events at the discretion of the study physician according to BeneFIX label.

    Primary: Annualized number of bleeding episodes

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    End point title
    Annualized number of bleeding episodes
    End point description
    The annualized bleed rate (ABR) or the annualized number of bleeding episodes per year, will be derived for each participant for each treatment period by using the following formula: ABR = number of bleeds / (Days on treatment period / 365.25) The number of bleeds for the ABR calculation includes all bleeds requiring treatment with factor IX product during the time on treatment. The efficacy analysis set (EAS) was used for the primary efficacy analyses with respect to ABR.
    End point type
    Primary
    End point timeframe
    2 years
    End point values
    On-Demand Therapy Prophylaxis therapy
    Number of subjects analysed
    25
    25
    Units: Number of bleeds per year
        arithmetic mean (standard deviation)
    32.9 ± 17.4
    3.6 ± 4.6
    Statistical analysis title
    Annualized number of bleeding episodes
    Statistical analysis description
    This analysis compares within-subject difference in ABRs between 2 treatment periods (crossover design): On-Demand and Prophylaxis therapy. Both the groups (On-Demand and prophylaxis therapy) are not mutually exclusive, overall 25 participants data were analysed.
    Comparison groups
    On-Demand Therapy v Prophylaxis therapy
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001
    Method
    Paired t-test
    Confidence interval

    Secondary: Response to On-Demand Treatment for all Bleeding Episodes

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    End point title
    Response to On-Demand Treatment for all Bleeding Episodes
    End point description
    Assessment scores on a 4-point Response Scale for an on-demand bleeding episode, as assessed by participant/caregiver or investigator/qualified staff. The 4-point scale assessments are Excellent, Good, Moderate or No response. Responses to number of observations were noted. The safety analysis set (SAS) was used. The SAS was any participant who received at least one dose of BeneFIX, including the dose given during the enrollment visit (Visit 2) for the factor IX (FIX) recovery study. 507 bleeds were analysed in the On-Demand therapy-First infusion group and 152 bleeds were analysed in the On-Demand therapy-Follow-up infusion group.
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    On-Demand therapy-First infusion On-Demand therapy-Follow-up infusions
    Number of subjects analysed
    25
    18 [1]
    Units: Number of observations with response
    number (not applicable)
        Excellent
    271
    39
        Good
    177
    80
        Moderate
    55
    33
        No response
    3
    0
        Data not recorded
    1
    0
    Notes
    [1] - Follow-up infusion was only required for 18 participants.
    No statistical analyses for this end point

    Secondary: Number of Nonacog Alfa, Recombinant Factor IX (BeneFIX) Infusions Used to Treat Each Bleeding Episode

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    End point title
    Number of Nonacog Alfa, Recombinant Factor IX (BeneFIX) Infusions Used to Treat Each Bleeding Episode
    End point description
    The number of study drug infusions administered to treat a bleed will be calculated by adding the initial (on-demand) infusion to any subsequent (on-demand) infusions for the same bleed (same bleed start date/time). The number of infusions needed to treat a bleed will be classified into the following categories: 1, 2, 3, 4 and >4 infusions. If there were more than one bleed location (e.g., ankle and joint) with identical bleed start date and time, it was treated as one bleed occurrence. The SAS was any participant who received at least one dose of BeneFIX, including the dose given during the enrollment visit (Visit 2) for the factor IX (FIX) recovery study. 507 bleeds were analysed.
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    All participants
    Number of subjects analysed
    25
    Units: Number of bleeds requiring infusion
    number (not applicable)
        Number of Infusion: 1
    416
        Number of Infusions: 2
    69
        Number of Infusions: 3
    9
        Number of Infusions: 4
    3
        Number of Infusions: >4
    10
    No statistical analyses for this end point

    Secondary: Number of Breakthrough (Spontaneous/Non-Traumatic) Bleeds within 48 Hours of a Prophylaxis Dose of BeneFIX.

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    End point title
    Number of Breakthrough (Spontaneous/Non-Traumatic) Bleeds within 48 Hours of a Prophylaxis Dose of BeneFIX.
    End point description
    The number of spontaneous, non-traumatic breakthrough bleeds within 48 hours following a prophylaxis dose of BeneFIX were summarized. If there was more than one bleed location (eg, ankle and joint) with identical bleed start date and time, it was treated as one bleed occurrence. The SAS was any participant who received at least one dose of BeneFIX, including the dose given during the enrollment visit (Visit 2) for the factor IX (FIX) recovery study. Three participants experienced 1 spontaneous bleeding episode each within 48 hours of a previous prophylaxis infusion.
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    All participants
    Number of subjects analysed
    25
    Units: Number of breakthrough bleeds
        arithmetic mean (standard deviation)
    1 ± 0
    No statistical analyses for this end point

    Secondary: Average Infusion Dose.

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    End point title
    Average Infusion Dose.
    End point description
    The mean dose by per infusion by weight (IU/kg) was reported for both prophylaxis and on demand infusions. The SAS was any participant who received at least one dose of BeneFIX, including the dose given during the enrollment visit (Visit 2) for the factor IX (FIX) recovery study.
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    On-Demand Therapy Prophylaxis therapy
    Number of subjects analysed
    25
    25
    Units: IU/Kg
        arithmetic mean (standard deviation)
    52 ± 16
    99 ± 2
    No statistical analyses for this end point

    Secondary: Total Factor Consumption.

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    End point title
    Total Factor Consumption.
    End point description
    The total amount (IU) infused for each infusion recorded were summed to calculate the total factor consumption for each participant. For each infusion, IU/kg was calculated, using the most recently recorded weight measurement and the total factor consumption, divided by number of infusions, and was summarized similarly to average infusion dose (IU). Annualized TFC by weight was reported. Annualized TFC by weight = (Total IU/kg / treatment interval duration)*365.25. The SAS was any participant who received at least one dose of BeneFIX, including the dose given during the enrollment visit (Visit 2) for the factor IX (FIX) recovery study.
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    On-Demand Therapy Prophylaxis therapy
    Number of subjects analysed
    25
    25
    Units: IU/Kg
        arithmetic mean (standard deviation)
    707 ± 519
    4985 ± 233
    No statistical analyses for this end point

    Secondary: Incidence of Less than Expected Therapeutic Effect (LETE)

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    End point title
    Incidence of Less than Expected Therapeutic Effect (LETE)
    End point description
    The following criteria are the definitions for LETE in this study: 1. LETE in the On-Demand Setting: LETE occurs in the on-demand setting if 2 successive “No Response” ratings are recorded after 2 successive BeneFIX drug infusions in the absence of confounding factors. 2. LETE in the Prophylaxis Setting: LETE occurs in the prophylaxis setting if there is a spontaneous bleed within 48 hours (≤ 48 hours) after a regularly scheduled prophylactic dose of BeneFIX in the absence of confounding factors. 3. LETE (Low Recovery): LETE can also be lower than expected recovery of FIX in the opinion of the investigator following infusion of BeneFIX in the absence of confounding factors. Each reported occurrence of low recovery LETE was listed. The SAS was any participant who received at least one dose of BeneFIX, including the dose given during the enrollment visit (Visit 2) for the factor IX (FIX) recovery study.
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    All participants
    Number of subjects analysed
    25
    Units: Percentage of occurence
    number (not applicable)
        LETE in On-Demand setting
    0
        LETE in prophylaxis setting
    0
        LETE (Low recovery)
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Until follow-up 82 weeks +/- 4 days.
    Adverse event reporting additional description
    Five participants experienced six SAEs since one participant experienced the same event twice (nephrolithiasis).
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    On-Demand Therapy
    Reporting group description
    Participants were treated for the bleeding events at the discretion of the study physician according to BeneFIX label.

    Reporting group title
    Prophylaxis therapy
    Reporting group description
    The prophylaxis regimen of approximately 100IU/kg once weekly was initiated at Visit 4.

    Serious adverse events
    On-Demand Therapy Prophylaxis therapy
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 25 (4.00%)
    4 / 25 (16.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Blood pressure decreased
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lipoma
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Varicella
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    On-Demand Therapy Prophylaxis therapy
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 25 (64.00%)
    20 / 25 (80.00%)
    Injury, poisoning and procedural complications
    Inappropriate schedule of drug administration
         subjects affected / exposed
    0 / 25 (0.00%)
    6 / 25 (24.00%)
         occurrences all number
    0
    17
    Drug dose omission
         subjects affected / exposed
    0 / 25 (0.00%)
    4 / 25 (16.00%)
         occurrences all number
    0
    6
    Medication error
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    4
    Underdose
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    3
    Wrong dose administered
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 25 (12.00%)
         occurrences all number
    0
    3
    Head injury
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 25 (32.00%)
    4 / 25 (16.00%)
         occurrences all number
    20
    33
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 25 (16.00%)
    4 / 25 (16.00%)
         occurrences all number
    8
    7
    Local swelling
         subjects affected / exposed
    1 / 25 (4.00%)
    3 / 25 (12.00%)
         occurrences all number
    1
    4
    Gastrointestinal disorders
    Toothache
         subjects affected / exposed
    3 / 25 (12.00%)
    5 / 25 (20.00%)
         occurrences all number
    4
    9
    Gastritis
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 25 (8.00%)
         occurrences all number
    1
    2
    Abdominal pain upper
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 25 (8.00%)
         occurrences all number
    2
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 25 (20.00%)
    5 / 25 (20.00%)
         occurrences all number
    13
    13
    Joint swelling
         subjects affected / exposed
    3 / 25 (12.00%)
    2 / 25 (8.00%)
         occurrences all number
    4
    3
    Back pain
         subjects affected / exposed
    1 / 25 (4.00%)
    3 / 25 (12.00%)
         occurrences all number
    2
    16
    Neck pain
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    0
    3
    Pain in extremity
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 25 (4.00%)
         occurrences all number
    4
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 25 (16.00%)
    5 / 25 (20.00%)
         occurrences all number
    6
    8
    Pharyngitis
         subjects affected / exposed
    2 / 25 (8.00%)
    3 / 25 (12.00%)
         occurrences all number
    2
    3
    Nasopharyngitis
         subjects affected / exposed
    3 / 25 (12.00%)
    1 / 25 (4.00%)
         occurrences all number
    6
    3
    Influenza
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 25 (4.00%)
         occurrences all number
    3
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Sep 2011
    Amendment 1 was due to addition of study procedures, as requested by the Food and Drug Administration (FDA) and changes to statistical methods section of protocol.

    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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