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    Clinical Trial Results:
    Efficacy and safety of two dose regimens of Octaplex in patients with intracranial haemorrhage related to oral anticoagulant therapy: a multicentre, prospective, randomised, open-label study.

    Summary
    EudraCT number
    2007-000602-73
    Trial protocol
    FR  
    Global end of trial date
    16 Apr 2011

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Jan 2017
    First version publication date
    04 Jan 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LEX-206
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Octapharma France SAS
    Sponsor organisation address
    62bis Avenue André Morizet, Boulogne-Billancourt, France, 92100
    Public contact
    Mag. Friedrich W. Kursten , Octapharma Pharmazeutika Produktionsges.m.b.H. , +43 161 032 1245, friedrich.kursten@octapharma.com
    Scientific contact
    Mag. Friedrich W. Kursten , Octapharma Pharmazeutika Produktionsges.m.b.H. , +43 161 032 1245, friedrich.kursten@octapharma.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
    26 Jan 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Apr 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary study objective was to compare the efficacy of two dose regimens of Octaplex on the INR at 10 ± 5 minutes after the end of injection in patients with intracranial haemorrhage related to oral anticoagulant therapy.
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles of the Declaration of Helsinki, and ICH-GCP, and national regulatory requirements. In- 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 adverse events, lab values, vital signs and physical examinations.
    Background therapy
    Octaplex was administered as a single dose, by intravenous infusion. All patients were also given 5 mg vitamin K.
    Evidence for comparator
    N.A.
    Actual start date of recruitment
    07 Nov 2008
    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
    France: 59
    Worldwide total number of subjects
    59
    EEA total number of subjects
    59
    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)
    7
    From 65 to 84 years
    38
    85 years and over
    14

    Subject disposition

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    Recruitment
    Recruitment details
    Studied Period: FPI 07-NOV-2008 and LPO 16-APR-2011. In total 59 patients suffering from intracranial haemorrhage related to oral anticoagulant therapy were enrolled from 15 active study sites in France.

    Pre-assignment
    Screening details
    Patients of 18 years of age or older, Intracranial haemorrhage (intracerebral and acute subdural) confirmed by medical imaging (CT-scan only), use of oral anticoagulant, vitamin K antagonists only, written informed consent from the patient or a legally acceptable representative.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Octaplex 25 IU/kg
    Arm description
    Octaplex was administered as a single dose by intravenous infusion (at the standard dose) in accordance with the randomisation. All patients were also given 5 mg vitamin K. Throughout the stay in the hospital, efficacy and safety assessments were performed at precise time points calculated from the end of Octaplex infusion: The medical part of the study ended on Day 30 (or the last day of hospitalisation if the patient was discharged earlier) after the Octaplex infusion. Three months after the Octaplex infusion, patients had to complete a quality of life (SF-36) and a pharmaco-economic self-questionnaire.
    Arm type
    Experimental

    Investigational medicinal product name
    Octaplex
    Investigational medicinal product code
    ATC B02BD01
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Standard dose (25 IU/kg). There were only two infusion speed groups: the low (≥3 mL/min and <8 mL/min) and the high (≥8 mL/min) infusion speed group, which included 20 and 39 patients, respectively, in the FAS and 18 and 35 patients, respectively, in the PP Set.

    Arm title
    Octaplex 40 IU/kg
    Arm description
    Octaplex was administered as a single dose by intravenous infusion (at the high dose) in accordance with the randomisation. All patients were also given 5 mg vitamin K. Throughout the stay in the hospital, efficacy and safety assessments were performed at precise time points calculated from the end of Octaplex infusion: The medical part of the study ended on Day 30 (or the last day of hospitalisation if the patient was discharged earlier) after the Octaplex infusion. Three months after the Octaplex infusion, patients had to complete a quality of life (SF-36) and a pharmaco-economic self-questionnaire. less
    Arm type
    Experimental

    Investigational medicinal product name
    Octaplex
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    High dose (40 IU/kg). There were only two infusion speed groups: the low (≥3 mL/min and <8 mL/min) and the high (≥8 mL/min) infusion speed group, which included 20 and 39 patients, respectively, in the FAS and 18 and 35 patients, respectively, in the PP Set.

    Number of subjects in period 1
    Octaplex 25 IU/kg Octaplex 40 IU/kg
    Started
    29
    30
    Completed
    23
    22
    Not completed
    6
    8
         Patient transfer
             1
             2
         Adverse event, serious fatal
             4
             4
         No benefit to stay at hospital
             -
             1
         Lost to follow-up
             1
             1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Octaplex 25 IU/kg
    Reporting group description
    Octaplex was administered as a single dose by intravenous infusion (at the standard dose) in accordance with the randomisation. All patients were also given 5 mg vitamin K. Throughout the stay in the hospital, efficacy and safety assessments were performed at precise time points calculated from the end of Octaplex infusion: The medical part of the study ended on Day 30 (or the last day of hospitalisation if the patient was discharged earlier) after the Octaplex infusion. Three months after the Octaplex infusion, patients had to complete a quality of life (SF-36) and a pharmaco-economic self-questionnaire.

    Reporting group title
    Octaplex 40 IU/kg
    Reporting group description
    Octaplex was administered as a single dose by intravenous infusion (at the high dose) in accordance with the randomisation. All patients were also given 5 mg vitamin K. Throughout the stay in the hospital, efficacy and safety assessments were performed at precise time points calculated from the end of Octaplex infusion: The medical part of the study ended on Day 30 (or the last day of hospitalisation if the patient was discharged earlier) after the Octaplex infusion. Three months after the Octaplex infusion, patients had to complete a quality of life (SF-36) and a pharmaco-economic self-questionnaire. less

    Reporting group values
    Octaplex 25 IU/kg Octaplex 40 IU/kg Total
    Number of subjects
    29 30 59
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    8 4 12
        From 65-84 years
    18 20 38
        85 years and over
    3 6 9
    Gender categorical
    Units: Subjects
        Female
    10 7 17
        Male
    19 23 42
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set (FAS) - Octaplex 25 IU/kg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All randomised patients who received at least one infusion of study medication.

    Subject analysis set title
    Full Analysis Set (FAS) - Octaplex 40 IU/kg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All randomised patients who received at least one infusion of study medication.

    Subject analysis sets values
    Full Analysis Set (FAS) - Octaplex 25 IU/kg Full Analysis Set (FAS) - Octaplex 40 IU/kg
    Number of subjects
    29
    30
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    8
    4
        From 65-84 years
    18
    20
        85 years and over
    3
    6
    Age continuous
    Units:
        
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    10
    7
        Male
    19
    23

    End points

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    End points reporting groups
    Reporting group title
    Octaplex 25 IU/kg
    Reporting group description
    Octaplex was administered as a single dose by intravenous infusion (at the standard dose) in accordance with the randomisation. All patients were also given 5 mg vitamin K. Throughout the stay in the hospital, efficacy and safety assessments were performed at precise time points calculated from the end of Octaplex infusion: The medical part of the study ended on Day 30 (or the last day of hospitalisation if the patient was discharged earlier) after the Octaplex infusion. Three months after the Octaplex infusion, patients had to complete a quality of life (SF-36) and a pharmaco-economic self-questionnaire.

    Reporting group title
    Octaplex 40 IU/kg
    Reporting group description
    Octaplex was administered as a single dose by intravenous infusion (at the high dose) in accordance with the randomisation. All patients were also given 5 mg vitamin K. Throughout the stay in the hospital, efficacy and safety assessments were performed at precise time points calculated from the end of Octaplex infusion: The medical part of the study ended on Day 30 (or the last day of hospitalisation if the patient was discharged earlier) after the Octaplex infusion. Three months after the Octaplex infusion, patients had to complete a quality of life (SF-36) and a pharmaco-economic self-questionnaire. less

    Subject analysis set title
    Full Analysis Set (FAS) - Octaplex 25 IU/kg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All randomised patients who received at least one infusion of study medication.

    Subject analysis set title
    Full Analysis Set (FAS) - Octaplex 40 IU/kg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All randomised patients who received at least one infusion of study medication.

    Primary: INR at 10 +/- 5 minutes

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    End point title
    INR at 10 +/- 5 minutes [1]
    End point description
    The primary study objective was to compare the efficacy of two dose regimens of Octaplex on the INR (International normalised ratio) at 10 ± 5 minutes after the end of injection in patients with intracranial haemorrhage related to oral anticoagulant therapy.
    End point type
    Primary
    End point timeframe
    after the end of injection
    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 inferential statistical analysis was pre-planned for this study, but the endpoint was to be presented descriptively only.
    End point values
    Full Analysis Set (FAS) - Octaplex 25 IU/kg Full Analysis Set (FAS) - Octaplex 40 IU/kg
    Number of subjects analysed
    27 [2]
    29 [3]
    Units: INR at 10 +/- 5 min
        arithmetic mean (standard deviation)
    1.26 ± 0.13
    1.16 ± 0.1
    Notes
    [2] - there were missing values for primary endpoint data in 3 patients, which were not replaced.
    [3] - there were missing values for primary endpoint data in 3 patient, which were not replaced.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were assessed throughout the whole study.
    Adverse event reporting additional description
    All SAEs, whether suspected to be related to study treatment or not, are reported by telephone, fax or e-mail immediately to the responsible Clinical Project Manager, study monitor, or to the responsible local CRO.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    11.0
    Reporting groups
    Reporting group title
    Octaplex 25 IU/kg
    Reporting group description
    Octaplex was administered as a single dose by intravenous infusion (at the standard dose) in accordance with the randomisation. All patients were also given 5 mg vitamin K. Throughout the stay in the hospital, efficacy and safety assessments were performed at precise time points calculated from the end of Octaplex infusion: The medical part of the study ended on Day 30 (or the last day of hospitalisation if the patient was discharged earlier) after the Octaplex infusion. Three months after the Octaplex infusion, patients had to complete a quality of life (SF-36) and a pharmaco-economic self-questionnaire.

    Reporting group title
    Octaplex 40 IU/kg
    Reporting group description
    Octaplex was administered as a single dose by intravenous infusion (at the high dose) in accordance with the randomisation. All patients were also given 5 mg vitamin K. Throughout the stay in the hospital, efficacy and safety assessments were performed at precise time points calculated from the end of Octaplex infusion: The medical part of the study ended on Day 30 (or the last day of hospitalisation if the patient was discharged earlier) after the Octaplex infusion. Three months after the Octaplex infusion, patients had to complete a quality of life (SF-36) and a pharmaco-economic self-questionnaire. less

    Serious adverse events
    Octaplex 25 IU/kg Octaplex 40 IU/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 29 (37.93%)
    12 / 30 (40.00%)
         number of deaths (all causes)
    4
    6
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Hypercoagulation
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain stem ischaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebral Haematoma
         subjects affected / exposed
    3 / 29 (10.34%)
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cerebral haemorrhage
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hydorcephalus
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial haematoma
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Intracranial pressure increased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological symptom
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         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
    Brain death
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infections and infestations
    Endocarditis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
         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
    Octaplex 25 IU/kg Octaplex 40 IU/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 29 (82.76%)
    25 / 30 (83.33%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 30 (3.33%)
         occurrences all number
    3
    1
    General disorders and administration site conditions
    Hyperthermia
         subjects affected / exposed
    3 / 29 (10.34%)
    2 / 30 (6.67%)
         occurrences all number
    3
    2
    Pain
         subjects affected / exposed
    4 / 29 (13.79%)
    3 / 30 (10.00%)
         occurrences all number
    4
    3
    Pyrexia
         subjects affected / exposed
    2 / 29 (6.90%)
    4 / 30 (13.33%)
         occurrences all number
    2
    4
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 30 (3.33%)
         occurrences all number
    4
    1
    Anxiety
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Confusional state
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    3
    Depression
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Insomnia
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 30 (10.00%)
         occurrences all number
    1
    3
    Investigations
    International normalised ratio increased
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 30 (6.67%)
         occurrences all number
    3
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    Leukocytosis
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 30 (6.67%)
         occurrences all number
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Lung disorder
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    Pneumonia aspiration
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 30 (10.00%)
         occurrences all number
    1
    3
    Pulmonary congestion
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    Cerebral haematoma
         subjects affected / exposed
    3 / 29 (10.34%)
    2 / 30 (6.67%)
         occurrences all number
    3
    2
    Cerebral haemorrhage
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    Ischaemic stroke
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorder
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 30 (6.67%)
         occurrences all number
    1
    2
    Somnolence
         subjects affected / exposed
    2 / 29 (6.90%)
    3 / 30 (10.00%)
         occurrences all number
    2
    3
    Gastrointestinal disorders
    ABdominal pain
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 30 (6.67%)
         occurrences all number
    1
    2
    Constipation
         subjects affected / exposed
    11 / 29 (37.93%)
    4 / 30 (13.33%)
         occurrences all number
    11
    4
    Diarrhoea
         subjects affected / exposed
    3 / 29 (10.34%)
    4 / 30 (13.33%)
         occurrences all number
    3
    5
    Vomiting
         subjects affected / exposed
    3 / 29 (10.34%)
    6 / 30 (20.00%)
         occurrences all number
    3
    7
    Renal and urinary disorders
    Oliguria
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Renal failure acute
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 30 (6.67%)
         occurrences all number
    1
    2
    Urinary retention
         subjects affected / exposed
    3 / 29 (10.34%)
    2 / 30 (6.67%)
         occurrences all number
    3
    2
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Erythema
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Back pain
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    6 / 29 (20.69%)
    3 / 30 (10.00%)
         occurrences all number
    6
    3
    Hypokalaemia
         subjects affected / exposed
    2 / 29 (6.90%)
    4 / 30 (13.33%)
         occurrences all number
    2
    4
    Infections and infestations
    Fungal skin infection
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Pneumonia
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 30 (10.00%)
         occurrences all number
    1
    3
    Urinary tract infection
         subjects affected / exposed
    5 / 29 (17.24%)
    3 / 30 (10.00%)
         occurrences all number
    5
    3

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jun 2008
    Amendment No. 1 • The CT scan imaging technique only was allowed at inclusion to confirm diagnosis and at 48 hours to evaluate the haematoma volume. The same technique had to be used at inclusion and 48 hours. If CT scan and MRI are commonly used to confirm diagnosis, CT scan is preferred at 48 hours for control imaging. • Modification of the exclusion criteria: Some exclusion criteria needed an explanation for a better understanding. General seizure has been deleted as they are frequently associated with intracranial haemorrhage. • Modification of Octaplex administration: According to Scientific Committee members request (Pr P. Coriat, principal investigator and Pr B. Riou, investigator, Dr B. Vigué and Pr. C Négrier), an additional Octaplex dose could be administered at 10 ± 5 minutes and at 6 hours after the first Octaplex infusion, following precise recommendation and not at the discretion of the investigator. The recommendation was 1.5 as target INR for the first rescue dose. The table has been simplified to facilitate the additional dose calculation by the investigators. • Modification of Octaplex infusion rate: The context of very high emergency implies to shorten all the delays in patient care including treatment administration. • Update of information on Octaplex storage (new Octaplex variation approved by reference member state via Mutual Recognition Procedure in 30-Nov-2007). • New laboratory parameters: Digital glucose was performed instead of being analysed in the laboratory. Additional laboratory tests were done (liver function, haematology) in order to follow the overall safety data.
    30 Jun 2008
    Amendment No. 2 • Modification of the informed consent procedure: The previous procedure was not adapted to the emergency situation. According to the law, in emergency situations, if prior informed consent of the patient is not possible and the patient’s legally acceptable representative is not available, the patient can be enrolled without prior informed consent. The informed consent procedure was modified in consequence: if the patient’s legally acceptable representative was not available, the patient could be included by the investigator in presence of a witness independent from the investigator and the Sponsor. • Because of the change of the informed consent procedure, the patient concomitant disability could not be assessed by the physician if the patient’s legally acceptable representative was absent. This exclusion criterion was thus suppressed. • Population of the study better defined: The type of intracranial haemorrhage has been precisely defined for a better understanding.
    22 Aug 2008
    Amendment No. 3 • Modification of biological analyses: Some of the centralised analyses (fibrin degradation products and thrombin-prothrombin complexes) have been cancelled with the agreement of the central laboratory, in order to lighten plasma tubes preparation for local laboratories. Moreover, central laboratory analyses were only to be performed in the centres that possessed laboratory facilities (adequate devices and personnel during night and day) to prepare plasma tubes. The laboratory parameters analysis was performed locally or centrally upon local laboratory facilities. • ECG surveillance: ECG is monitored continuously during the whole stay in the investigator’s ward, thus the surveillance at 48 hours was added. • Modification of the determination of sample size based on the results obtained from previous studies with Octaplex. • Precision of the anticoagulant therapy: The type of anticoagulant therapy has been added. Only patients under vitamin K antagonist therapy were admitted. • Precision of the type of subdural haematoma: Only patients with acute subdural haematoma were admitted. This criterion was assessed by CT scan.
    17 Dec 2008
    Amendment No. 5 • Change of Sponsor: Octapharma France SAS (Boulogne-Billancourt, France) replaced Octapharma AG (Lachen, Switzerland). • Modification of the sample labels for investigational medicinal products: Addition of FIX content in Octaplex and change of Sponsor. • Modification of the study duration: Due to the late clinical study start, the study duration was prolonged accordingly.
    03 Aug 2009
    Amendment No. 6 • In the entire text, thrombin generation assay (TGA) analysis was suppressed. The results of TGA analysis in the first patients included in the study were not interpretable due to a bad plasma preparation. As this test was still experimental, it was decided to stop this analysis in agreement with Pr Negrier (Head of Central Laboratory). • In the entire text, a time window of 15 minutes before and 15 minutes after the fixed time points 1 hour, 3 hours, 6 hours and 24 hours was added. As this study was carried out in a context of emergency, it appeared that greater flexibility in the times of blood sample collection was appropriate to avoid protocol deviations and give more comfort to the investigator during the care of patient. • In the entire text, the National Institute of Health (NIH) stroke scale was suppressed. As the NIH stroke scale was not usually used by most study investigators and requires a specific training, it was decided to not perform this scale anymore. Alternatively, the neurological worsening was assessed by a routine neurological examination. • An English translation, certified by a sworn translator, of the Informed consent and the Patient information approved by the IEC on 01-Jul-2008 was added to Appendix 2 of the protocol. This translation was supplied, for information, to two patients speaking English.
    18 Nov 2009
    Amendment No. 7 • Modification of the study duration: Due to a recruitment rate below what was expected, the duration of the study had to be extended accordingly.
    15 Sep 2010
    Amendment No. 8 • Modification of the study duration: Due to a recruitment rate below what was expected, the duration of the study had to be extended accordingly.

    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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