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    Clinical Trial Results:
    A prospective, controlled, randomised, cross-over study investigating the pharmacokinetic properties, surrogate efficacy and safety of Octafibrin compared to Haemocomplettan® P/ RiaSTAPTM in subjects with congenital fibrinogen deficiency

    Summary
    EudraCT number
    2011-002403-15
    Trial protocol
    GB   DE   IT  
    Global end of trial date
    19 Jan 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    31 Jul 2016
    First version publication date
    31 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Forma-01
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01575756
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Octapharma AG
    Sponsor organisation address
    Seidenstrasse 2, Lachen, Switzerland, CH-8853
    Public contact
    Clinical Research and Development, Octapharma Pharmazeutika Produktionsgesellschaft m.b.H, 0043 1610320, clinical.department@octapharma.com
    Scientific contact
    Clinical Research and Development, Octapharma Pharmazeutika Produktionsgesellschaft m.b.H, 0043 1610320, clinical.department@octapharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001208-PIP01-11
    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
    14 Aug 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • To determine the single dose pharmacokinetics of Octafibrin and Haemocomplettan® P/RiaSTAPTM in subjects with congenital fibrinogen deficiency • To determine maximum clot strength (maximum clot firmness [MCF]) as a surrogate marker for haemostatic efficacy before and after administration of Octafibrin and Haemocomplettan® P/ RiaSTAPTM in subjects with congenital fibrinogen deficiency.
    Protection of trial subjects
    This trial was conducted in accordance to the principles of GCP, ensuring that the rights, safety and well-being of patients are protected and in consistency with the the Declaration of Helsinki. Inclusion and exclusion criteria were carefully defined in order to protect subjects from contraindications, interactions with other medication and safety factors associated with the investigational medicinal product. Throughout the study safety was assessed, such as occurrence of AEs, labvalues, vital signs and physical examinations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    04 Jun 2013
    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
    United Kingdom: 3
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    India: 8
    Country: Number of subjects enrolled
    Iran, Islamic Republic of: 7
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    United States: 2
    Worldwide total number of subjects
    22
    EEA total number of subjects
    4
    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)
    6
    Adults (18-64 years)
    16
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    -

    Pre-assignment period milestones
    Number of subjects started
    22
    Number of subjects completed
    22

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Octafibrin Followed by Haemocomplettan® P or RiaSTAPTM
    Arm description
    Participants received a single dose of Octafibrin 70 mg/kg intravenously once followed by Haemocomplettan® P or RiaSTAPTM 70 mg/kg intravenously 45 days later or Haemocomplettan® P or RiaSTAPTM 70 mg/kg intravenously followed by Octafibrin 70 mg/kg intravenously 45 days later in a randomized crossover design
    Arm type
    Experimental

    Investigational medicinal product name
    Octafibrin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Octafibrin is a human plasma-derived fibrinogen concentrate for intravenous use.The product was packed and labelled according to local regulations in vials containing 1 g of lyophilised fibrinogen concentrate powder for reconstitution with 50 mL of water for injection (WFI). Octafibrin was administered at a dose of 70 mg/kg body weight (BW) It was administered as an intravenous bolus injection at a maximum speed of 5 mL/min.(based on the labelled potency).

    Investigational medicinal product name
    Haemocomplettan® P/RiaSTAPTM
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The reference therapy in this study was Haemocomplettan® P/RiaSTAPTM, which is a marketed fibrinogen concentrate. It was administered intravenously at a dose of 70 mg/kg BW (based on the labelled potency).

    Arm title
    Haemocomplettan® P or RiaSTAPTM Followed by Octafibrin
    Arm description
    Participants received a single dose of Haemocomplettan® P or RiaSTAPTM 70 mg/kg intravenously in a randomized crossover design followed by Octafibrin 70 mg/kg intravenously 45 days later.
    Arm type
    Experimental

    Investigational medicinal product name
    Haemocomplettan® P/RiaSTAPTM
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The reference therapy in this study was Haemocomplettan® P/RiaSTAPTM, which is a marketed fibrinogen concentrate. It was administered intravenously at a dose of 70 mg/kg BW (based on the labelled potency).

    Investigational medicinal product name
    Octafibrin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Octafibrin is a human plasma-derived fibrinogen concentrate for intravenous use.The product was packed and labelled according to local regulations in vials containing 1 g of lyophilised fibrinogen concentrate powder for reconstitution with 50 mL of water for injection (WFI). Octafibrin was administered at a dose of 70 mg/kg body weight (BW) It was administered as an intravenous bolus injection at a maximum speed of 5 mL/min.(based on the labelled potency).

    Number of subjects in period 1
    Octafibrin Followed by Haemocomplettan® P or RiaSTAPTM Haemocomplettan® P or RiaSTAPTM Followed by Octafibrin
    Started
    11
    11
    Completed
    11
    11
    Period 2
    Period 2 title
    Octafibrin
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Octafibrin
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Octafibrin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Octafibrin is a human plasma-derived fibrinogen concentrate for intravenous use.The product was packed and labelled according to local regulations in vials containing 1 g of lyophilised fibrinogen concentrate powder for reconstitution with 50 mL of water for injection (WFI). Octafibrin was administered at a dose of 70 mg/kg body weight (BW) It was administered as an intravenous bolus injection at a maximum speed of 5 mL/min.(based on the labelled potency).

    Number of subjects in period 2
    Octafibrin
    Started
    22
    Completed
    22
    Period 3
    Period 3 title
    Haemocomplettan® P or RiaSTAPTM
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Haemocomplettan® P or RiaSTAPTM
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Haemocomplettan® P/RiaSTAPTM
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    The reference therapy in this study was Haemocomplettan® P/RiaSTAPTM, which is a marketed fibrinogen concentrate. It was administered intravenously at a dose of 70 mg/kg BW (based on the labelled potency).

    Number of subjects in period 3
    Haemocomplettan® P or RiaSTAPTM
    Started
    22
    Completed
    22

    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
    22 22
    Age categorical
    Units: Subjects
        < 18 years
    6 6
        >= 18-65 years
    16 16
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    26 (12 to 53) -
    Gender categorical
    Units: Subjects
        Female
    15 15
        Male
    7 7
    Subject analysis sets

    Subject analysis set title
    PK Analysis Set (PK-PP)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The PK analysis set will include all patients who completed the PK assessment per protocol (PP)

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The full analysis set, defined according to the intention-to-treat (ITT) principle, will include all randomized patients who received at least one infusion of study medication (Octafibrin and/or any part of an infusion of Haemocomplettan® P/ RiaSTAPTM) and for whom any post-treatment data is available.

    Subject analysis sets values
    PK Analysis Set (PK-PP) Full Analysis Set (FAS)
    Number of subjects
    21
    22
    Age categorical
    Units: Subjects
        < 18 years
    5
    6
        >= 18-65 years
    16
    16
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    26.6 (12 to 53)
    26 (12 to 53)
    Gender categorical
    Units: Subjects
        Female
    14
    15
        Male
    7
    7

    End points

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    End points reporting groups
    Reporting group title
    Octafibrin Followed by Haemocomplettan® P or RiaSTAPTM
    Reporting group description
    Participants received a single dose of Octafibrin 70 mg/kg intravenously once followed by Haemocomplettan® P or RiaSTAPTM 70 mg/kg intravenously 45 days later or Haemocomplettan® P or RiaSTAPTM 70 mg/kg intravenously followed by Octafibrin 70 mg/kg intravenously 45 days later in a randomized crossover design

    Reporting group title
    Haemocomplettan® P or RiaSTAPTM Followed by Octafibrin
    Reporting group description
    Participants received a single dose of Haemocomplettan® P or RiaSTAPTM 70 mg/kg intravenously in a randomized crossover design followed by Octafibrin 70 mg/kg intravenously 45 days later.
    Reporting group title
    Octafibrin
    Reporting group description
    -
    Reporting group title
    Haemocomplettan® P or RiaSTAPTM
    Reporting group description
    -

    Subject analysis set title
    PK Analysis Set (PK-PP)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The PK analysis set will include all patients who completed the PK assessment per protocol (PP)

    Subject analysis set title
    Full Analysis Set (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The full analysis set, defined according to the intention-to-treat (ITT) principle, will include all randomized patients who received at least one infusion of study medication (Octafibrin and/or any part of an infusion of Haemocomplettan® P/ RiaSTAPTM) and for whom any post-treatment data is available.

    Primary: Fibrinogen Activity Normalized Area Under the Curve Standardized

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    End point title
    Fibrinogen Activity Normalized Area Under the Curve Standardized [1]
    End point description
    Fibrinogen activity was determined via a validated Clauss assay (fibrinogen activity) and fibrinogen-specific enzyme-linked immunosorbent assay (ie, fibrinogen antigen) using paired antibodies for fibrinogen antigen. All determinations were performed on frozen plasma samples in a central laboratory. The Clauss assay was modified and validated to achieve a limit of quantification of 0.2 g/L. The pharmacokinetic analysis was assessed individually using a non-compartmental model. Plasma levels were measured at Baseline, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment. The normalized area under the curve was standardized to a dose of 70 mg/kg.
    End point type
    Primary
    End point timeframe
    Blood samples for the PK assessments were taken over a period of 14 days at baseline, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216 and 312 hours post-infusion
    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: The pharmacokinetic analysis was assessed individually using a non-compartmental model. Plasma levels were measured at Baseline, 0.5, 1, 2, 4, 8, 24, 48, 96, 144, 216, and 312 hours post-treatment. The normalized area under the curve was standardized to a dose of 70 mg/kg. Because of the cross over design the statistical analyses of this endpoint is already reported as Fibrinogen Activity Normalized AUC.
    End point values
    Octafibrin Haemocomplettan® P or RiaSTAPTM
    Number of subjects analysed
    21
    21
    Units: g•h/L
        arithmetic mean (confidence interval 95%)
    113.7 (101.96 to 124.55)
    96.39 (84.006 to 108.76)
    No statistical analyses for this end point

    Primary: Change in Maximum Clot Firmness 1 Hour Post-treatment From Baseline

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    End point title
    Change in Maximum Clot Firmness 1 Hour Post-treatment From Baseline [2]
    End point description
    Thromboelastometry (ROTEM®) was used to measure maximum clot firmness. Thromboelastometry is a method for the continuous measurement of clot formation. Maximum clot firmness is a functional parameter that depends on the activation of coagulation, the platelet and fibrinogen content of the blood sample, and the polymerisation and cross-linking of the fibrin network. In order to obtain comparable results from all study centres, maximum clot firmness data were assessed from frozen citrated plasma samples in a central laboratory. As these samples did not contain platelets that would be found in the whole blood assay, only the fibrinogen content defined the maximum clot firmness.
    End point type
    Primary
    End point timeframe
    baseline and 1 hour post-infusion
    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: For each time point and treatment group, the mean, SD, median and range has been provided for the absolute MCF values and the changes from baseline (i.e. from pre-infusion). Mean changes in MCF between baseline and the 1 hour value have been described with two-sided 95% CIs based on the paired t-test. Further, the intra-individual differences between the changes from BL for each treatment will be described; corresponding 95% CI intervals based on the paired t-test was generated.
    End point values
    Octafibrin Haemocomplettan® P or RiaSTAPTM
    Number of subjects analysed
    22
    22
    Units: mm
        arithmetic mean (confidence interval 95%)
    9.68 (8.37 to 10.99)
    10 (8.07 to 11.93)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs occurring from Day 1 up to Day 14 post administration in each study period and SAEs occurring from Day 1 to Day 45 in each study period
    Adverse event reporting additional description
    Treatment-emergent adverse events (TEAEs) were defined as AEs occurring from Day 1 up to Day 14 post administration in each study period. Additionally, SAEs were considered TEAEs from Day 1 in first study period until study completion on day 45
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Octafibrin
    Reporting group description
    AEs occurring from Day 1 up to Day 14 post administration in each study period and SAEs occurring from Day 1 to Day 45 in each study period.

    Reporting group title
    Haemocomplettan® P/RiaSTAPTM
    Reporting group description
    AEs occurring from Day 1 up to Day 14 post administration in each study period and SAEs occurring from Day 1 to Day 45 in each study period.

    Serious adverse events
    Octafibrin Haemocomplettan® P/RiaSTAPTM
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vaginal Haemmorage
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Octafibrin Haemocomplettan® P/RiaSTAPTM
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 22 (9.09%)
    5 / 22 (22.73%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 22 (9.09%)
    3 / 22 (13.64%)
         occurrences all number
    2
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Pain in extremity
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 22 (9.09%)
         occurrences all number
    1
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 22 (9.09%)
         occurrences all number
    1
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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