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    Clinical Trial Results:
    A Prospective, Single-blind, Randomized, Phase II/III Study to Evaluate the Safety and Efficacy of Fibrin Sealant Grifols (FS Grifols) as an Adjunct to Hemostasis During Peripheral Vascular Surgery

    Summary
    EudraCT number
    		 2008-000072-25
    Trial protocol
    		 ES   GB  
    Global end of trial date
    05 May 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    IG402
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00684047
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Instituto Grifols, S.A.
    Sponsor organisation address
    Can Guasch, Parets del Vallés, Spain, 08150
    Public contact
    Paul Pinciaro, Instituto Grifols, S.A., 1 443-375-8825, Paul.Pinciaro@grifols.com
    Scientific contact
    Paul Pinciaro, Instituto Grifols, S.A., 1 443-375-8825, Paul.Pinciaro@grifols.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001598-PIP01-13
    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
    05 May 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 May 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    05 May 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and hemostasis effectiveness of human plasma-derived fibrin sealant Grifols (FS Grifols) in peripheral vascular surgery
    Protection of trial subjects
    For each investigative site, the Primary Part (II) started only after the enrollment of at least 2 subjects in the Preliminary Part (I). In addition, for any trial site, the Primary Part (II) could start only after the enrollment of a set of at least 20 subjects at any site(s) into the Preliminary Part (I), with no safety issues raised by the independent Medical Monitor. As requested by the Main Research Ethics Committee for the study in the UK, trial sites in the UK had the additional requirement that the Data Safety Monitoring Board (DSMB) raised no safety issues that recommended against starting the Primary Part (II) in the UK. Further, at any trial site, the Primary Part (II) could not begin until formally approved for each country by the Sponsor.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Oct 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
    Spain: 78
    Country: Number of subjects enrolled
    United Kingdom: 117
    Country: Number of subjects enrolled
    Canada: 44
    Worldwide total number of subjects
    239
    EEA total number of subjects
    195
    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)
    79
    From 65 to 84 years
    153
    85 years and over
    7

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study Initiation Date: 20 October 2008; Study Completion Date: 05 May 2014 Nineteen sites were initiated in Canada, Spain, and the United Kingdom (UK). From these, 18 sites enrolled patients.

    Pre-assignment
    Screening details
    		 A total of 371 subjects were enrolled in the study (signed informed consent). Of these, 240 (64.7%) subjects complied with eligibility criteria and underwent vascular surgery.

    Pre-assignment period milestones
    Number of subjects started
    		 371 [1]
    Number of subjects completed
    		 239

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Protocol deviation: 2
    Reason: Number of subjects
    		 Adverse event, serious fatal: 9
    Reason: Number of subjects
    		 Lost to follow-up: 7
    Reason: Number of subjects
    		 Consent withdrawn by subject: 15
    Reason: Number of subjects
    		 Screening failures: 98
    Reason: Number of subjects
    		 Dropout after randomize & prior to treatment: 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The worldwide number of subjects enrolled in the trial is the same as the total number of subjects at the end of the pre-assignment period. The patients that did not complete the pre-assignment period are those that were screening failures and were not enrolled in the trial, due to different reasons.
    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject
    Blinding implementation details
    In the Preliminary Part (I) of the study, all subjects were treated with FS Grifols. In the Primary Part (II) of the study, subjects were blinded to their study treatment, but the Investigator was not blinded as this was not feasible due to the very different nature of the 2 hemostatic treatments to be applied. Treatment group assignments were made using sealed blinded randomization envelopes that were only opened upon identification of an eligible TBS during the procedure.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Preliminary Part (I) - FS Grifols
    Arm description
    		 All subjects enrolled in the Preliminary Part (I) were treated with FS Grifols. This part of the trial had 2 main objectives: 1) To ensure that local study teams familiarized themselves with the technique of FS Grifols application and with the intra-operative procedures required by the protocol. To meet this objective, the first 2 subjects at each site were enrolled and treated with FS Grifols. 2) To assess the clinical safety of FS Grifols. Treatment of 20 subjects with FS Grifols was considered sufficient for an initial assessment of clinical safety.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fibrin Sealant Grifols
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for sealant
    Routes of administration
    Topical use
    Dosage and administration details
    Up to two 3-mL kits applied topically via drip applicator tip at the target bleeding site (TBS)

    Arm title
    		 Primary Part (II) - FS Grifols
    Arm description
    		 In the Primary Part (II), subjects were randomly assigned 2:1 to treatment with Fibrin Sealant Grifols or Manual Compression, respectively.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fibrin Sealant Grifols
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for sealant
    Routes of administration
    Topical use
    Dosage and administration details
    Up to two 3-ml kits applied topically via drip applicator tip at the target bleeding site (TBS).

    Arm title
    		 Primary Part (II) - Manual compression
    Arm description
    		 In the Primary Part (II), subjects were randomly assigned 2:1 to treatment with Fibrin Sealant Grifols or Manual Compression, respectively. Subjects randomized to Manual Compression received application of manual compression with surgical gauzes at the target bleeding site (TBS).
    Arm type
    		 hemostatic action considered standard &effective

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Preliminary Part (I) - FS Grifols Primary Part (II) - FS Grifols Primary Part (II) - Manual compression
    Started
    72
    110
    57
    Completed
    59
    94
    52
    Not completed
    13
    16
    5
         Adverse event, serious fatal
    6
    2
    1
         Consent withdrawn by subject
    4
    9
    2
         loss of contact
    1
    -
    -
         Lost to follow-up
    1
    5
    1
         Protocol deviation
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Preliminary Part (I) - FS Grifols
    Reporting group description
    		 All subjects enrolled in the Preliminary Part (I) were treated with FS Grifols. This part of the trial had 2 main objectives: 1) To ensure that local study teams familiarized themselves with the technique of FS Grifols application and with the intra-operative procedures required by the protocol. To meet this objective, the first 2 subjects at each site were enrolled and treated with FS Grifols. 2) To assess the clinical safety of FS Grifols. Treatment of 20 subjects with FS Grifols was considered sufficient for an initial assessment of clinical safety.

    Reporting group title
    Primary Part (II) - FS Grifols
    Reporting group description
    		 In the Primary Part (II), subjects were randomly assigned 2:1 to treatment with Fibrin Sealant Grifols or Manual Compression, respectively.

    Reporting group title
    Primary Part (II) - Manual compression
    Reporting group description
    		 In the Primary Part (II), subjects were randomly assigned 2:1 to treatment with Fibrin Sealant Grifols or Manual Compression, respectively. Subjects randomized to Manual Compression received application of manual compression with surgical gauzes at the target bleeding site (TBS).

    Reporting group values
    		 Preliminary Part (I) - FS Grifols Primary Part (II) - FS Grifols Primary Part (II) - Manual compression Total
    Number of subjects
    		 72 110 57 239
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 20 34 25 79
        From 65-84 years
    		 52 72 29 153
        85 years and over
    		 0 4 3 7
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 70 (63 to 75) 69 (63 to 74) 67 (59 to 75) -
    Gender categorical
    Units: Subjects
        Female
    		 17 15 18 50
        Male
    		 55 95 39 189

    End points

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    End points reporting groups
    Reporting group title
    Preliminary Part (I) - FS Grifols
    Reporting group description
    		 All subjects enrolled in the Preliminary Part (I) were treated with FS Grifols. This part of the trial had 2 main objectives: 1) To ensure that local study teams familiarized themselves with the technique of FS Grifols application and with the intra-operative procedures required by the protocol. To meet this objective, the first 2 subjects at each site were enrolled and treated with FS Grifols. 2) To assess the clinical safety of FS Grifols. Treatment of 20 subjects with FS Grifols was considered sufficient for an initial assessment of clinical safety.

    Reporting group title
    Primary Part (II) - FS Grifols
    Reporting group description
    		 In the Primary Part (II), subjects were randomly assigned 2:1 to treatment with Fibrin Sealant Grifols or Manual Compression, respectively.

    Reporting group title
    Primary Part (II) - Manual compression
    Reporting group description
    		 In the Primary Part (II), subjects were randomly assigned 2:1 to treatment with Fibrin Sealant Grifols or Manual Compression, respectively. Subjects randomized to Manual Compression received application of manual compression with surgical gauzes at the target bleeding site (TBS).

    Subject analysis set title
    Preliminary Part (I) - FS Grifols (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    In the Preliminary Part (I), the intent-to-treat (ITT) analysis set was defined asall subjects who underwent surgery and met the intra-operative inclusion criterion.

    Subject analysis set title
    Primary Part (II) - FS Grifols (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    In the Primary Part (II), intent-to-treat (ITT) analysis set was defined as all subjects who underwent surgery, met the intra-operative inclusion criterion, had a randomization envelope opened, and still met the intra-operative inclusion criterion after randomization.

    Subject analysis set title
    Primary Part (II) - Manual Compression (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    In the Primary Part (II), intent-to-treat (ITT) analysis set was defined as all subjects who underwent surgery, met the intra-operative inclusion criterion, had a randomization envelope opened, and still met the intra-operative inclusion criterion after randomization.

    Subject analysis set title
    Preliminary Part (I) - FS Grifols (PP)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol (PP) population was defined as the ITT population excluding any subjects who did not actually receive either study treatment or who had a major protocol violation. Major protocol violations and the final PP population were determined before database lock.

    Subject analysis set title
    Primary Part (II) - FS Grifols (PP)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol (PP) population was defined as the ITT population excluding any subjects who did not actually receive either study treatment or who had a major protocol violation. Major protocol violations and the final PP population were determined before database lock.

    Subject analysis set title
    Primary Part (II) - Manual Compression (PP)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per protocol (PP) population was defined as the ITT population excluding any subjects who did not actually receive either study treatment or who had a major protocol violation. Major protocol violations and the final PP population were determined before database lock.

    Primary: Time to Hemostasis (TTH)

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    End point title
    		 Time to Hemostasis (TTH)
    End point description
    The precise TTH was not observable in this study. However, if hemostasis had not been achieved at a given assessment time point, but had been achieved at the next assessment time point, then it was inferred that the true TTH was between the 2 assessment time points. Therefore, TTH, although not observed directly, was ascertained as falling into 1 of 5 hemostatic time categories (HTCs) or the non-HTC as follows: 1. HTC≤3: ≤3 minutes from TStart to hemostasis. 2. HTC>3 to ≤4: >3 minutes to ≤4 minutes from TStart to hemostasis. 3. HTC>4 to ≤5: >4 minutes to ≤5 minutes from TStart to hemostasis. 4. HTC>5 to ≤7: >5 minutes to ≤7 minutes from TStart to hemostasis. 5. HTC>7 to ≤10: >7 minutes to ≤10 minutes from TStart to hemostasis. Treatment failure includes: brisk bleeding from the TBS during the 10 minutes observational period, TTH > 10 minutes and re-bleeding from the TBS before surgical closure of the field containing the TBS
    End point type
    Primary
    End point timeframe
    TTH is measured in minutes from the start of treatment application (TStart) at the Target Bleeding Site (TBS) to the achievement of hemostasis at that site or to the end of the 10-minute observational period if hemostasis has not yet been achieved.
    End point values
    		 Preliminary Part (I) - FS Grifols (ITT) Primary Part (II) - FS Grifols (ITT) Primary Part (II) - Manual Compression (ITT) Preliminary Part (I) - FS Grifols (PP) Primary Part (II) - FS Grifols (PP) Primary Part (II) - Manual Compression (PP)
    Number of subjects analysed
    72
    110
    57
    57
    86
    48
    Units: subjects
        TTH ≤ 3 minutes
    41
    51
    15
    32
    40
    13
        TTH > 3 but ≤ 4 minutes
    11
    18
    3
    8
    13
    3
        TTH > 4 but ≤ 5 minutes
    5
    13
    10
    4
    12
    6
        TTH > 5 but ≤ 7 minutes
    3
    5
    4
    3
    3
    3
        TTH > 7 but ≤ 10 minutes
    5
    10
    9
    4
    7
    7
        Treatment failures
    7
    13
    16
    6
    11
    16
    Statistical analysis title
    		 Primary efficacy endpoint analysis (ITT)
    Comparison groups
    Primary Part (II) - FS Grifols (ITT) v Primary Part (II) - Manual Compression (ITT)
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    		 Primary efficacy endpoint analysis (PP)
    Comparison groups
    Primary Part (II) - FS Grifols (PP) v Primary Part (II) - Manual Compression (PP)
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Cumulative proportion of subjects achieving hemostasis at TBS at each of the 5 HTCs

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    End point title
    		 Cumulative proportion of subjects achieving hemostasis at TBS at each of the 5 HTCs
    End point description
    End point type
    Secondary
    End point timeframe
    From the start of treatment application (TStart) at the Target Bleeding Site to the achievement of hemostasis at that site or to the end of the 10-minute observational period if hemostasis has not yet been achieved.
    End point values
    		 Preliminary Part (I) - FS Grifols (ITT) Primary Part (II) - FS Grifols (ITT) Primary Part (II) - Manual Compression (ITT)
    Number of subjects analysed
    72
    110
    57
    Units: percent
    number (not applicable)
        TTH ≤ 3 minutes
    56.9
    46.4
    26.3
        TTH ≤ 4 minutes
    72.2
    62.7
    31.6
        TTH ≤ 5 minutes
    79.2
    74.5
    49.1
        TTH ≤ 7 minutes
    83.3
    79.1
    56.1
        TTH ≤ 10 minutes
    90.3
    88.2
    71.9
    Statistical analysis title
    		 Proportions of subjects achieving hemostasis
    Comparison groups
    Primary Part (II) - FS Grifols (ITT) v Primary Part (II) - Manual Compression (ITT)
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.013 [1]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [1] - TTH ≤3 minutes: p = 0.013. TTH ≤4 minutes (cumulative): p < 0.001. TTH ≤5 minutes (cumulative): p = 0.002. TTH ≤7 minutes (cumulative): p = 0.004. TTH ≤10 minutes (cumulative): p = 0.016.

    Secondary: Prevalence of treatment failures

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    End point title
    		 Prevalence of treatment failures
    End point description
    Reasons for treatment failure: Brisk bleeding from the target bleeding site Time to hemostasis > 10 minutes Re-bleeding after 10 minutes observational period and before closure
    End point type
    Secondary
    End point timeframe
    From the Tstart until the completion (when the last skin closure stitch is placed) of the surgical closure by layers of the exposed surgical field containing the TBS (TClosure).
    End point values
    		 Preliminary Part (I) - FS Grifols (ITT) Primary Part (II) - FS Grifols (ITT) Primary Part (II) - Manual Compression (ITT)
    Number of subjects analysed
    72
    110
    57
    Units: percent
    number (not applicable)
        Brisk bleeding from the target bleeding site
    4.2
    5.5
    8.8
        Time to hemostasis > 10 min
    1.4
    4.5
    17.5
        Re-bleeding after 10 min and before closure
    4.2
    1.8
    1.8
        Total
    9.7
    11.8
    28.1
    Statistical analysis title
    		 Prevalence of treatment failures
    Comparison groups
    Primary Part (II) - FS Grifols (ITT) v Primary Part (II) - Manual Compression (ITT)
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.016
    Method
    		 Fisher exact
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Subjects were monitored from the time of the signature of the informed consent to Post-Operative Week 6 ± 4 Days for assessment of Adverse Events.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    FS Grifols [pooled Preliminary Part (I) + Primary Part (II)]
    Reporting group description
    		 Subjects from the Preliminary Part (I) and from the Primary Part (II) of the study treated with Fibrin Sealant Grifols have been pooled for summarizing safety data of the study. This reporting group includes subjects randomized to Manual Compression but received Fibrin Sealant Grifols by mistake.

    Reporting group title
    Manual Compression Primary Part (II)
    Reporting group description
    		 Subjects randomized to Manual Compression treatment in the Primary Part (II) of the study.

    Serious adverse events
    		 FS Grifols [pooled Preliminary Part (I) + Primary Part (II)] Manual Compression Primary Part (II)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    47 / 187 (25.13%)
    9 / 52 (17.31%)
         number of deaths (all causes)
    7
    1
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Graft haemorrhage
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Operative haemorrhage
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Post procedural haemorrhage
         subjects affected / exposed
    2 / 187 (1.07%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular graft occlusion
         subjects affected / exposed
    2 / 187 (1.07%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    2 / 187 (1.07%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    1 / 187 (0.53%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal haemorrhage
         subjects affected / exposed
    2 / 187 (1.07%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 187 (1.07%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 187 (1.07%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    2 / 187 (1.07%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    2 / 187 (1.07%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 187 (1.07%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Transient ischemic attack
         subjects affected / exposed
    2 / 187 (1.07%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiorgan failure
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Abdominal adhesions
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernial eventration
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    2 / 187 (1.07%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin lesion
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 187 (1.07%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure chronic
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal sepsis
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot infection
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 187 (1.07%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post operative wound infection
         subjects affected / exposed
    4 / 187 (2.14%)
    1 / 52 (1.92%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 187 (1.07%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 52 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    3 / 187 (1.60%)
    2 / 52 (3.85%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 52 (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
    		 FS Grifols [pooled Preliminary Part (I) + Primary Part (II)] Manual Compression Primary Part (II)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    151 / 187 (80.75%)
    45 / 52 (86.54%)
    Investigations
    Blood potassium decreased
         subjects affected / exposed
    12 / 187 (6.42%)
    5 / 52 (9.62%)
         occurrences all number
    13
    5
    Blood magnesium decreased
         subjects affected / exposed
    5 / 187 (2.67%)
    3 / 52 (5.77%)
         occurrences all number
    5
    3
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    112 / 187 (59.89%)
    36 / 52 (69.23%)
         occurrences all number
    113
    36
    Vascular disorders
    Hypotension
         subjects affected / exposed
    32 / 187 (17.11%)
    8 / 52 (15.38%)
         occurrences all number
    34
    8
    Haematoma
         subjects affected / exposed
    7 / 187 (3.74%)
    3 / 52 (5.77%)
         occurrences all number
    8
    4
    Hypertension
         subjects affected / exposed
    7 / 187 (3.74%)
    3 / 52 (5.77%)
         occurrences all number
    8
    3
    Nervous system disorders
    Hypoaesthesia
         subjects affected / exposed
    3 / 187 (1.60%)
    3 / 52 (5.77%)
         occurrences all number
    3
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    16 / 187 (8.56%)
    1 / 52 (1.92%)
         occurrences all number
    17
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    14 / 187 (7.49%)
    3 / 52 (5.77%)
         occurrences all number
    15
    3
    Oedema peripheral
         subjects affected / exposed
    9 / 187 (4.81%)
    5 / 52 (9.62%)
         occurrences all number
    9
    5
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    44 / 187 (23.53%)
    10 / 52 (19.23%)
         occurrences all number
    51
    11
    Constipation
         subjects affected / exposed
    39 / 187 (20.86%)
    8 / 52 (15.38%)
         occurrences all number
    39
    8
    Vomiting
         subjects affected / exposed
    14 / 187 (7.49%)
    6 / 52 (11.54%)
         occurrences all number
    25
    6
    Abdominal pain
         subjects affected / exposed
    8 / 187 (4.28%)
    3 / 52 (5.77%)
         occurrences all number
    8
    4
    Diarrhoea
         subjects affected / exposed
    10 / 187 (5.35%)
    2 / 52 (3.85%)
         occurrences all number
    12
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 187 (3.74%)
    3 / 52 (5.77%)
         occurrences all number
    7
    3
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    14 / 187 (7.49%)
    3 / 52 (5.77%)
         occurrences all number
    14
    3
    Postoperative wound infection
         subjects affected / exposed
    11 / 187 (5.88%)
    2 / 52 (3.85%)
         occurrences all number
    11
    2
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    11 / 187 (5.88%)
    3 / 52 (5.77%)
         occurrences all number
    12
    3

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Nov 2010
    Balanced the ratio of grafts enrolled in the Primary Part (II) of the study: in order to achieve a similar representation of both types of graft (PTFE or Dacron), after the enrollment of approximately 90 subjects with one of both types of graft (PTFE or Dacron), the Sponsor of the clinical trial permitted enrollment of only subjects with the other type of graft into the Primary Part (II) of the study. Added femoral endarterectomy with patch angioplasty and ilio-femoral bypass grafting as acceptable surgical procedures.

    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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