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    Clinical Trial Results:
    A Multicenter, Open‑Label Study to Evaluate the Long‑Term Safety, Tolerability and Efficacy of Subcutaneous PF‑06741086 in Subjects With Severe Hemophilia

    Summary
    EudraCT number
    		 2017-001255-31
    Trial protocol
    		 PL   ES   BG   HR  
    Global end of trial date
    05 Aug 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Jun 2021
    First version publication date
    02 Jun 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    B7841003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03363321
    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 Centre, Pfizer Inc, +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc, +1 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
    19 Jan 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Aug 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study was designed to evaluate the safety, tolerability and efficacy of long-term treatment with PF-06741086 in severe hemophilia A or B subjects with or without inhibitors to FVIII or FIX who participated in the 3-month Phase 1b/2 Study B7841002. Additionally, de novo subjects were recruited into this study.
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial subjects.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 May 2018
    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
    Brazil: 1
    Country: Number of subjects enrolled
    Chile: 7
    Country: Number of subjects enrolled
    Croatia: 1
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    South Africa: 7
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    United States: 1
    Worldwide total number of subjects
    20
    EEA total number of subjects
    3
    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)
    0
    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
    		 -

    Pre-assignment
    Screening details
    		 Twenty-four individuals were screened and 4 failed at screening. All the 20 subjects who met the eligibility criteria were assigned to the study treatment and were treated with marstacimab. Among 20 subjects, 18 completed the study, and 2 discontinued from study due to withdrawal by subject, which were not related to safety.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: 300mg - 300mg Non-Inhibitor
    Arm description
    		 Subjects without inhibitors to Factor VIII (FVIII) or Factor IX (FIX) from Cohort 1 of Study 1002 (B7841002) continued to receive PF-06741086 300 mg subcutaneously (SC) once weekly (QW) from Day 1 to Day 365.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Marstacimab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Marstacimab 300 mg was administered SC every week.

    Arm title
    		 Cohort 2: 300mg Loading (L)+150mg-300mg L+150mg Non-Inhibitor
    Arm description
    		 Subjects without inhibitors to FVIII or FIX from Cohort 2 of Study 1002 continued to receive PF-06741086 300 mg loading dose on Day 1 and 150 mg SC QW from Day 29 to Day 365.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Marstacimab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Marstacimab 300 mg loading dose, followed by 150 mg was administered SC every week.

    Arm title
    		 Cohort 3: 450mg - 300mg L + 150mg Non-Inhibitor
    Arm description
    		 Subjects without inhibitors to FVIII or FIX from Cohort 3 (450 mg SC) of Study 1002 started to receive PF-06741086 300 mg loading dose on Day 1 and 150 mg SC QW from Day 29 to Day 365.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Marstacimab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Marstacimab 300 mg loading dose, followed by 150 mg was administered SC every week.

    Arm title
    		 Cohort 4: 300mg - 300mg Inhibitor
    Arm description
    		 Subjects with inhibitors to FVIII or FIX from Cohort 4 (300 mg SC) of Study 1002 continued to receive PF-06741086 300 mg SC QW from Day 1 to Day 365.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Marstacimab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Marstacimab 300 mg was administered SC every week.

    Arm title
    		 Cohort 5: De Novo 300mg L + 150mg Inhibitors
    Arm description
    		 De Novo subjects with inhibitors to FVIII or FIX received a 300 mg SC loading dose on Day 1, and then followed by 150 mg SC QW to Day 365.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Marstacimab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Marstacimab 300 mg loading dose, followed by 150 mg was administered SC every week.

    Number of subjects in period 1
    		Cohort 1: 300mg - 300mg Non-Inhibitor Cohort 2: 300mg Loading (L)+150mg-300mg L+150mg Non-Inhibitor Cohort 3: 450mg - 300mg L + 150mg Non-Inhibitor Cohort 4: 300mg - 300mg Inhibitor Cohort 5: De Novo 300mg L + 150mg Inhibitors
    Started
    5
    4
    4
    5
    2
    Completed
    5
    3
    4
    4
    2
    Not completed
    0
    1
    0
    1
    0
         Consent withdrawn by subject
    -
    1
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: 300mg - 300mg Non-Inhibitor
    Reporting group description
    		 Subjects without inhibitors to Factor VIII (FVIII) or Factor IX (FIX) from Cohort 1 of Study 1002 (B7841002) continued to receive PF-06741086 300 mg subcutaneously (SC) once weekly (QW) from Day 1 to Day 365.

    Reporting group title
    Cohort 2: 300mg Loading (L)+150mg-300mg L+150mg Non-Inhibitor
    Reporting group description
    		 Subjects without inhibitors to FVIII or FIX from Cohort 2 of Study 1002 continued to receive PF-06741086 300 mg loading dose on Day 1 and 150 mg SC QW from Day 29 to Day 365.

    Reporting group title
    Cohort 3: 450mg - 300mg L + 150mg Non-Inhibitor
    Reporting group description
    		 Subjects without inhibitors to FVIII or FIX from Cohort 3 (450 mg SC) of Study 1002 started to receive PF-06741086 300 mg loading dose on Day 1 and 150 mg SC QW from Day 29 to Day 365.

    Reporting group title
    Cohort 4: 300mg - 300mg Inhibitor
    Reporting group description
    		 Subjects with inhibitors to FVIII or FIX from Cohort 4 (300 mg SC) of Study 1002 continued to receive PF-06741086 300 mg SC QW from Day 1 to Day 365.

    Reporting group title
    Cohort 5: De Novo 300mg L + 150mg Inhibitors
    Reporting group description
    		 De Novo subjects with inhibitors to FVIII or FIX received a 300 mg SC loading dose on Day 1, and then followed by 150 mg SC QW to Day 365.

    Reporting group values
    		 Cohort 1: 300mg - 300mg Non-Inhibitor Cohort 2: 300mg Loading (L)+150mg-300mg L+150mg Non-Inhibitor Cohort 3: 450mg - 300mg L + 150mg Non-Inhibitor Cohort 4: 300mg - 300mg Inhibitor Cohort 5: De Novo 300mg L + 150mg Inhibitors Total
    Number of subjects
    		 5 4 4 5 2 20
    Age Categorical
    Units: Subjects
        <18 Years
    		 0 0 0 0 0 0
        18-44 Years
    		 4 4 2 3 2 15
        45-64 Years
    		 1 0 2 2 0 5
        >=65 Years
    		 0 0 0 0 0 0
        Unspecified Years
    		 0 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 33.0 ( 9.70 ) 31.3 ( 10.63 ) 41.8 ( 16.24 ) 42.0 ( 5.24 ) 20.0 ( 1.41 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 0 0 0 0 0 0
        Male
    		 5 4 4 5 2 20
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 3 2 4 3 2 14
        Black or African American
    		 2 2 0 2 0 6
        Asian
    		 0 0 0 0 0 0
        American Indian or Alaska Native
    		 0 0 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0
        Other
    		 0 0 0 0 0 0
        Unknown
    		 0 0 0 0 0 0
        Multiracial
    		 0 0 0 0 0 0
        Not reported
    		 0 0 0 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 3 2 1 1 0 7
        Not Hispanic or Latino
    		 2 2 3 4 2 13
        Unknown or Not Reported
    		 0 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: 300mg - 300mg Non-Inhibitor
    Reporting group description
    		 Subjects without inhibitors to Factor VIII (FVIII) or Factor IX (FIX) from Cohort 1 of Study 1002 (B7841002) continued to receive PF-06741086 300 mg subcutaneously (SC) once weekly (QW) from Day 1 to Day 365.

    Reporting group title
    Cohort 2: 300mg Loading (L)+150mg-300mg L+150mg Non-Inhibitor
    Reporting group description
    		 Subjects without inhibitors to FVIII or FIX from Cohort 2 of Study 1002 continued to receive PF-06741086 300 mg loading dose on Day 1 and 150 mg SC QW from Day 29 to Day 365.

    Reporting group title
    Cohort 3: 450mg - 300mg L + 150mg Non-Inhibitor
    Reporting group description
    		 Subjects without inhibitors to FVIII or FIX from Cohort 3 (450 mg SC) of Study 1002 started to receive PF-06741086 300 mg loading dose on Day 1 and 150 mg SC QW from Day 29 to Day 365.

    Reporting group title
    Cohort 4: 300mg - 300mg Inhibitor
    Reporting group description
    		 Subjects with inhibitors to FVIII or FIX from Cohort 4 (300 mg SC) of Study 1002 continued to receive PF-06741086 300 mg SC QW from Day 1 to Day 365.

    Reporting group title
    Cohort 5: De Novo 300mg L + 150mg Inhibitors
    Reporting group description
    		 De Novo subjects with inhibitors to FVIII or FIX received a 300 mg SC loading dose on Day 1, and then followed by 150 mg SC QW to Day 365.

    Primary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), TEAEs by Severity, and Serious Adverse Events (SAEs) (All Causality and Treatment-related)

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (TEAEs), TEAEs by Severity, and Serious Adverse Events (SAEs) (All Causality and Treatment-related) [1]
    End point description
    An adverse event (AE) was any untoward medical occurrence in a clinical investigation subject administered a product; the event did not need to have a causal relationship with the treatment. An SAE was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. AEs included both SAEs and non-serious AEs. TEAEs were AEs occurred following the start of treatment or AEs increasing in severity during treatment. Treatment-related TEAEs were determined by the investigator. The analysis population included all subjects who received at least 1 dose of investigational product. Here "Number of Subjects Analyzed" signifies number of subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Day 1 up to Day 393
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    		 Cohort 1: 300mg - 300mg Non-Inhibitor Cohort 2: 300mg Loading (L)+150mg-300mg L+150mg Non-Inhibitor Cohort 3: 450mg - 300mg L + 150mg Non-Inhibitor Cohort 4: 300mg - 300mg Inhibitor Cohort 5: De Novo 300mg L + 150mg Inhibitors
    Number of subjects analysed
    5
    4
    4
    5
    2
    Units: Subjects
        All-causalities TEAE
    5
    2
    4
    2
    1
        Treatment-related TEAE
    2
    0
    0
    0
    1
        All-causalities serious TEAE
    1
    0
    0
    0
    0
        Treatment-related serious TEAE
    0
    0
    0
    0
    0
        All-causalities Grade 3 or 4 TEAE
    1
    0
    0
    0
    1
        Treatment-related Grade 3 or 4 TEAE
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Abnormal Laboratory Findings Without Regard to Baseline Abnormality (Including Hematology, Serum Chemistry, and Urinalysis)

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    End point title
    		 Number of Subjects With Abnormal Laboratory Findings Without Regard to Baseline Abnormality (Including Hematology, Serum Chemistry, and Urinalysis) [2]
    End point description
    Following parameters were analyzed for laboratory examination: hematology, clinical chemistry, and urinalysis. The hematology parameters and pre-defined criteria included: neutrophils (10^3/millimeter[mm]^3) <0.8*lower limit of normal (LLN), and basophils (10^3/mm^3) >1.2*upper limit of normal (ULN). The clinical chemistry parameter and pre-defined criteria included: biliirubin (milligrams [mg]/decilitre [dL]) >1.5 ULN, aspartate aminotransferase (units [U]/liter [L]) >3.0 ULN, glucose (mg/dL) >1.5*ULN. The urinalysis parameter and pre-defined criteria included: urine glucose ≥1, ketones (scalar) ≥1, urine protein ≥1, urine hemoglobin (scalar) ≥1, and hyaline casts per low power field (/LPF). The analysis population included all subjects who received at least 1 dose of investigational product. Here "Number of Subjects Analyzed" signifies number of subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Hematology and serum chemistry: Baseline, Days 1, 29, 57, 85, 169, 253, and 365 visits. Urinalysis: Baseline, Days 1, 85, 169, 253, and 365 visits.
    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: No statistical analysis was planned for this endpoint
    End point values
    		 Cohort 1: 300mg - 300mg Non-Inhibitor Cohort 2: 300mg Loading (L)+150mg-300mg L+150mg Non-Inhibitor Cohort 3: 450mg - 300mg L + 150mg Non-Inhibitor Cohort 4: 300mg - 300mg Inhibitor Cohort 5: De Novo 300mg L + 150mg Inhibitors
    Number of subjects analysed
    5 [3]
    3 [4]
    4 [5]
    5 [6]
    2 [7]
    Units: Subjects
        Neutrophils (10^3/mm^3) <0.8*LLN
    1
    1
    0
    0
    0
        Basophils (10^3/mm^3) >1.2*ULN
    0
    0
    0
    1
    1
        Bilirubin (mg/dL) >1.5*ULN
    0
    0
    0
    0
    1
        Aspartate Aminotransferase (U/L) >3.0*ULN
    0
    0
    0
    0
    1
        Glucose (mg/dL) >1.5*ULN
    0
    0
    1
    1
    0
        Urine Glucose ≥1
    0
    0
    1
    0
    0
        Ketones (Scalar) ≥1
    1
    0
    0
    0
    0
        Urine Protein ≥1
    0
    1
    0
    0
    0
        Urine Hemoglobin (Scalar) ≥1
    0
    0
    1
    0
    0
        Hyaline Casts (/LPF) >1
    0
    1
    0
    1
    0
    Notes
    [3] - Number of Subjects Evaluable for Hyaline Casts was 0.
    [4] - Number of Subjects Evaluable for Hyaline Casts was 1.
    [5] - Number of Subjects Evaluable for Hyaline Casts was 0.
    [6] - Number of Subjects Evaluable for Hyaline Casts was 1.
    [7] - Number of Subjects Evaluable for Hyaline Casts was 1.
    No statistical analyses for this end point

    Primary: Number of Subjects With Changes From Baseline in Vital Signs Measurements Meeting the Pre-defined Categorical Summarization Criteria

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    End point title
    		 Number of Subjects With Changes From Baseline in Vital Signs Measurements Meeting the Pre-defined Categorical Summarization Criteria [8]
    End point description
    Following parameters were analyzed for vital sign examination: blood pressure (BP), pulse rate (PR), temperature, respiration rate. Categorical vital signs: Temperature >38.5 degree(s) Celsius (℃), Supine PR: <40 or >120 beats per minute (BPM), Systolic BP: <90 millimeter of mercury (mm Hg), >=30 mm Hg change from baseline, Diastolic BP: <50 mm Hg, >=20 mm Hg change from baseline. The analysis population included all subjects who received at least 1 dose of investigational product.
    End point type
    Primary
    End point timeframe
    Baseline, Days 1, 29, 57, 85, 113, 141, 169, 197, 225, 253, 281, 309, 337, 365 and 393 visits.
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    		 Cohort 1: 300mg - 300mg Non-Inhibitor Cohort 2: 300mg Loading (L)+150mg-300mg L+150mg Non-Inhibitor Cohort 3: 450mg - 300mg L + 150mg Non-Inhibitor Cohort 4: 300mg - 300mg Inhibitor Cohort 5: De Novo 300mg L + 150mg Inhibitors
    Number of subjects analysed
    5
    4
    4
    5
    2
    Units: Subjects
        Systolic BP (mmHg) < 90
    0
    0
    0
    0
    0
        Systolic BP Change ≥30 mm Hg increase
    0
    0
    1
    0
    0
        Systolic BP Change ≥30 mm Hg decrease
    0
    1
    0
    1
    0
        Diastolic BP (mmHg) < 50
    0
    0
    0
    0
    0
        Diastolic BP Change ≥20 mm Hg increase
    1
    0
    1
    1
    0
        Diastolic BP Change ≥20 mm Hg decrease
    0
    1
    1
    1
    0
        Supine PR (BPM) <40
    0
    0
    0
    0
    0
        Supine PR (BPM) >120
    0
    0
    0
    0
    0
        Temperature >38.5 ℃
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Change From Baseline in Electrocardiogram (ECG) Parameters Meeting the Pre-defined Categorical Summarization Criteria

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    End point title
    		 Number of Subjects With Change From Baseline in Electrocardiogram (ECG) Parameters Meeting the Pre-defined Categorical Summarization Criteria [9] [10]
    End point description
    ECG was only evaluated in de novo subjects. Baseline was defined as the average of triplicate ECG measurements collected prior to dosing on Day 1 in B7841003. Criteria for potentially clinically important changes in ECG were defined as: PR interval value >=300 millisecond (msec); PR interval baseline >200 msec and change >=25%; PR interval baseline <=200 msec and change >=50%; QRS complex value >=140 msec and change >=50%; QTcF value >=450 msec and change >=30 msec. Only the number of participants meeting pre-defined criteria was reported below.
    End point type
    Primary
    End point timeframe
    Baseline, Days 1 and 29 visits.
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    [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: Analysis was only planned for the arm identified
    End point values
    		 Cohort 5: De Novo 300mg L + 150mg Inhibitors
    Number of subjects analysed
    2
    Units: Subjects
        PR interval value >=300 msec
    0
        PR interval baseline >200 msec and Change >=25%
    0
        PR interval baseline <=200 msec and change >=50%
    0
        QRS complex value >=140 msec
    0
        QRS complex change >=50%
    0
        450 msec<= QTcF Value <480 msec
    0
        480 msec<= QTcF Value <500 msec
    0
        QTcF Value >=500 msec
    0
        30 msec<= QTcF Change <60 msec
    0
        QTcF Change >=60 msec
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Abnormalities in Physical Examination Findings

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    End point title
    		 Number of Subjects With Abnormalities in Physical Examination Findings [11]
    End point description
    Physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. The analysis population included all subjects who received at least 1 dose of investigational product.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 393
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    		 Cohort 1: 300mg - 300mg Non-Inhibitor Cohort 2: 300mg Loading (L)+150mg-300mg L+150mg Non-Inhibitor Cohort 3: 450mg - 300mg L + 150mg Non-Inhibitor Cohort 4: 300mg - 300mg Inhibitor Cohort 5: De Novo 300mg L + 150mg Inhibitors
    Number of subjects analysed
    5
    4
    4
    5
    2
    Units: Subjects
    5
    2
    3
    4
    2
    No statistical analyses for this end point

    Primary: Number of Subjects With Injection Site Reactions

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    End point title
    		 Number of Subjects With Injection Site Reactions [12]
    End point description
    Injection site reactions included but were not limited to: erythema, induration, ecchymosis, pain and pruritus. Grade of severity was defined as follows: Mild: Transient or mild discomfort (< 48 hours); no medical intervention/therapy required. Moderate: Mild to moderate limitation in activity - some assistance may be needed; no or minimal medical intervention/therapy required. Severe: Marked limitation in activity, some assistance usually required; medical intervention/therapy required, hospitalizations possible. The analysis population included all subjects who received at least 1 dose of investigational product.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 365, and Day 393 visit.
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    		 Cohort 1: 300mg - 300mg Non-Inhibitor Cohort 2: 300mg Loading (L)+150mg-300mg L+150mg Non-Inhibitor Cohort 3: 450mg - 300mg L + 150mg Non-Inhibitor Cohort 4: 300mg - 300mg Inhibitor Cohort 5: De Novo 300mg L + 150mg Inhibitors
    Number of subjects analysed
    5
    4
    4
    5
    2
    Units: Subjects
        Erythema (redness) Mild
    0
    0
    0
    0
    0
        Erythema (redness) Moderate
    0
    0
    0
    0
    0
        Erythema (redness) Severe
    0
    0
    0
    0
    1
        Induration (swelling) Mild
    1
    0
    0
    0
    0
        Induration (swelling) Moderate
    0
    0
    0
    0
    0
        Induration (swelling) Severe
    0
    0
    0
    0
    1
        Ecchymosis (bruising) Mild
    1
    0
    0
    0
    0
        Ecchymosis (bruising) Moderate
    0
    0
    0
    0
    0
        Ecchymosis (bruising) Severe
    0
    0
    0
    0
    0
        Pain (after injection) Mild
    1
    0
    0
    0
    0
        Pain (after injection) Moderate
    0
    0
    0
    0
    0
        Pain (after injection) Severe
    0
    0
    0
    0
    0
        Pruritus (itching) Mild
    1
    0
    0
    0
    0
        Pruritus (itching) Moderate
    0
    0
    0
    0
    0
        Pruritus (itching) Severe
    0
    0
    0
    0
    0
        Other Mild
    1
    0
    0
    0
    0
        Other Moderate
    0
    0
    0
    0
    0
        Other Severe
    0
    0
    0
    0
    1
        Any injection site reaction Mild
    2
    0
    0
    0
    0
        Any injection site reaction Moderate
    0
    0
    0
    0
    0
        Any injection site reaction Severe
    0
    0
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Annualized Bleeding Rate (ABR)

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    End point title
    		 Annualized Bleeding Rate (ABR)
    End point description
    The ABR was calculated as ([number of bleeding events × 365.25] / observed treatment period in days)
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 365, and Day 393 visit. Pre-Treatment summarized the data up to 6 months prior to participation in B7841003 for de novo subjects and up to 6 months prior to participation in B7841002 for roll over subjects.
    End point values
    		 Cohort 1: 300mg - 300mg Non-Inhibitor Cohort 2: 300mg Loading (L)+150mg-300mg L+150mg Non-Inhibitor Cohort 3: 450mg - 300mg L + 150mg Non-Inhibitor Cohort 4: 300mg - 300mg Inhibitor Cohort 5: De Novo 300mg L + 150mg Inhibitors
    Number of subjects analysed
    5
    4
    4
    5
    2
    Units: Bleeding episodes per subject per year
    arithmetic mean (standard deviation)
        Pre-Treatment
    22.000 ( 7.8740 )
    14.000 ( 1.6330 )
    22.000 ( 13.5647 )
    18.400 ( 1.6733 )
    15.000 ( 4.2426 )
        On-Study
    2.971 ( 2.7895 )
    3.586 ( 7.1726 )
    1.916 ( 1.4492 )
    0.000 ( 0.0000 )
    2.488 ( 3.5187 )
    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 Day 393
    Adverse event reporting additional description
    The same event may appear as both AE and SAE; however, what is presented are distinct events. An event may be categorized as serious in 1 subject and as non-serious in another subject, or 1 subject may have experienced both a serious and non-serious event during the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Cohort 1: 300mg - 300mg Non-Inhibitor
    Reporting group description
    		 Subjects without inhibitors to FVIII or FIX from Cohort 1 of Study 1002 continued to receive PF-06741086 300 mg SC QW from Day 1 to Day 365.

    Reporting group title
    Cohort 2: 300mg L+150mg-300mg L+150mg Non-Inhibitor
    Reporting group description
    		 Subjects without inhibitors to FVIII or FIX from Cohort 2 of Study 1002 continued to receive PF-06741086 300 mg loading dose on Day 1 and 150 mg SC QW from Day 29 to Day 365.

    Reporting group title
    Cohort 3: 450mg - 300mg L + 150mg Non-Inhibitor
    Reporting group description
    		 Subjects without inhibitors to FVIII or FIX from Cohort 3 (450 mg SC) of Study 1002 started to receive PF-06741086 300 mg loading dose on Day 1 and 150 mg SC QW from Day 29 to Day 365.

    Reporting group title
    Cohort 4: 300mg - 300mg Inhibitor
    Reporting group description
    		 Subjects with inhibitors to FVIII or FIX from Cohort 4 (300 mg SC) of Study 1002 continued to receive PF-06741086 300 mg SC QW from Day 1 to Day 365.

    Reporting group title
    Cohort 5: De Novo 300mg Loading + 150mg Inhibitors
    Reporting group description
    		 De Novo subjects with inhibitors to FVIII or FIX received a 300 mg SC loading dose on Day 1, and then followed by 150 mg SC QW to Day 365.

    Serious adverse events
    		 Cohort 1: 300mg - 300mg Non-Inhibitor Cohort 2: 300mg L+150mg-300mg L+150mg Non-Inhibitor Cohort 3: 450mg - 300mg L + 150mg Non-Inhibitor Cohort 4: 300mg - 300mg Inhibitor Cohort 5: De Novo 300mg Loading + 150mg Inhibitors
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1: 300mg - 300mg Non-Inhibitor Cohort 2: 300mg L+150mg-300mg L+150mg Non-Inhibitor Cohort 3: 450mg - 300mg L + 150mg Non-Inhibitor Cohort 4: 300mg - 300mg Inhibitor Cohort 5: De Novo 300mg Loading + 150mg Inhibitors
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 5 (100.00%)
    2 / 4 (50.00%)
    4 / 4 (100.00%)
    2 / 5 (40.00%)
    1 / 2 (50.00%)
    Investigations
    Weight increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Burns second degree
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Contusion
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Limb injury
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    2
    Skull fracture
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Soft tissue injury
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    Hypertension
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 5 (20.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Headache
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    1
    General disorders and administration site conditions
    Injection site haematoma
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Injection site reaction
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    2
    0
    0
    0
    1
    Inflammation
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Gastrointestinal disorders
    Food poisoning, unspecified
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Vomiting
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Skin harmorrhage
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Psychiatric disorders
    Disorientation
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    1
    0
    0
    0
    3
    Arthropathy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Haemarthrosis
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    4
    2
    0
    0
    0
    Joint range of motion decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Joint swelling
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Joint warmth
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Pain in extremit
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Synovitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 2 (50.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Tonsillitis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    0 / 2 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Nov 2018
    1. Protocol Summary: Revised treatment duration from 6 months to up to 365 days; Revised visit day numbers to correspond to up to 365 days treatment duration. 3. Added clinic visits on Days 225, 253, 281, 309, 337, and 365; Revised Table 1 title and footnotes to correspond to additional clinic visits and extended treatment duration. 4. Revised treatment duration from 6 months to up to 365 days. 5. Study Duration: Revised maximum study duration to 15 months. 6. Revised Inclusion Criterion #2 for de novo subjects to add the requirement for episodic (on-demand) treatment prior to screening, as mandated by the FDA; Added Inclusion Criterion #3 for de novo subjects to add the requirement for 6 or more breakthrough bleeding episodes in the 6 month period prior to screening, as mandated by the FDA. 7. Preparation and Dispensing: Revised visit day numbers to correspond to up to 365 days treatment duration. 8. Added text to clarify that Day 57 hematology and serum chemistry samples are for de novo subjects only; Removed Day 29 PK sample collection as it is intended for de novo subjects only (referenced in Section 6.2.2). 9. Section 6.2.4 Day 393 – End of Study Visit: Revised section to add clinic visit on Day 393. 10. Blood Volume: Revised Table 4 to include additional samples.

    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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