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    Clinical Trial Results:
    Prospective, Randomised, Controlled Phase 2 Study Investigating the Haemostatic Efficacy and Safety of Fibrinogen Concentrate (Octafibrin) and Cryoprecipitate as Fibrinogen Supplementation Sources in Patients Undergoing Cytoreductive Surgery for Pseudomyxoma Peritonei.

    Summary
    EudraCT number
    2016-003749-27
    Trial protocol
    GB  
    Global end of trial date
    20 Jul 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Aug 2019
    First version publication date
    02 Aug 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    FORMA-05
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Octapharma AG
    Sponsor organisation address
    Seidenstrasse 2, Lachen, Switzerland, CH-8853
    Public contact
    Sigurd Knaub, Octapharma AG, +41 (0)55 451 21 41, sigurd.knaub@octapharma.com
    Scientific contact
    Sigurd Knaub, Octapharma AG, +41 (0)55 451 21 41, sigurd.knaub@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
    19 Dec 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to compare the overall (i.e. intra- and postoperative) haemostatic efficacy (ability to stop bleeding) of Octafibrin, a human blood-derived protein with that of cryoprecipitate in bleeding patients developing acquired fibrinogen deficiency during removal of tumour growth from the abdomen (cytoreductive surgery) for Pseudomyxoma Peritonei (PMP).
    Protection of trial subjects
    This trial was conducted in accordance to the principles of ICH- GCP, ensuring that the rights, safety and well-being of patients are protected and in consistency with the Declaration of Helsinki. Inclusion and exclusion criteria were carefully defined in order to protect subjects from contraindications, interactions with other medication and risk factors associated with the investigational medicinal product. Throughout the study safety was assessed, such as collecting information (e.g., frequency, severity, causality) on adverse events (AEs), treatment-emergent adverse events (TEAEs), serious AEs (SAEs) and adverse drug reactions (ADRs). In addition, monitoring of vital signs, routine clinical laboratory assessment including of coagulation parameters and viral safety testing were performed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    13 Mar 2017
    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
    United Kingdom: 45
    Worldwide total number of subjects
    45
    EEA total number of subjects
    45
    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)
    31
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Patients undergoing cytoreductive surgery for Pseudomyxoma peritonei with need of Fibrinogen supplementation were screened according to predefined in- and exclusion criteria.

    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
    Octafibirn
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Octafibrin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Octafibrin was administered by IV injection, using an established IV route. The first dose of Octafibrin (4 g) was pre-emptively administered based on clinical judgement for fibrinogen supplementation made at the ‘bleeding risk assessment’ time point, which took place approximately 60–90 minutes after the beginning of surgery, before 2 L of blood had been lost. Further Octafibrin administration intraoperatively was based on the FIBTEM test of the ROTEM® analysis. A FIBTEM A20 of 12 mm or less triggered the administration of 4 g Octafibrin. Any administration of Octafibrin during the first 24 hours postoperatively was based on clinical judgement of need for further haemostatic support and guided by the FIBTEM test of the ROTEM® analysis. A FIBTEM A20 of 12 mm or less triggered the administration of 2 g Octafibrin.

    Arm title
    Cryoprecipitate
    Arm description
    -
    Arm type
    Active comparator

    Investigational medicinal product name
    Cryoprecipitate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cryoprecipitate was used as comparator and administered by IV injection, using an established IV route. A single unit contained a mean of approximately 400–460 mg fibrinogen. First dose of cryoprecipitate (2 pools of 5 units each) was pre-emptively administered based on clinical judgement for fibrinogen supplementation made at the ‘bleeding risk assessment’ time point, which took place approximately 60–90 minutes after the beginning of surgery, before 2 L of blood had been lost. Further cryoprecipitate administration intraoperatively was based on the FIBTEM test of the ROTEM® analysis. A FIBTEM A20 of 12 mm or less triggered the administration of 2 cryoprecipitate pools of 5 units each. Any administration of cryoprecipitate during the first 24 hours postoperatively was based on clinical judgement of need for further haemostatic support and guided by the FIBTEM test of the ROTEM® analysis. A FIBTEM A20 of 12 mm or less triggered the administration of 1 cryoprecipitate pool of 5 units.

    Number of subjects in period 1
    Octafibirn Cryoprecipitate
    Started
    22
    23
    Completed
    22
    22
    Not completed
    0
    1
         Adverse event, non-fatal
    -
    1

    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
    45 45
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    61 (34 to 76) -
    Gender categorical
    Units: Subjects
        Female
    25 25
        Male
    20 20

    End points

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    End points reporting groups
    Reporting group title
    Octafibirn
    Reporting group description
    -

    Reporting group title
    Cryoprecipitate
    Reporting group description
    -

    Subject analysis set title
    Difference in overall haemostatic success
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Test for non-inferiority between treatment groups (Octafibrin - Cryoprecipitate)

    Subject analysis set title
    N (ratings)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Number of ratings Octafibrin

    Subject analysis set title
    % (ratings)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    % ratings Octafibrin

    Subject analysis set title
    N (ratings)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Number of ratings Cryoprecipitate

    Subject analysis set title
    % (ratings)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Percentage of ratings Cryoprecipitate

    Subject analysis set title
    N (total)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Total number of ratings

    Subject analysis set title
    % (total)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Percentage of total ratings

    Primary: Frequency of the Overall Haemostatic Success Adjudicated by the IDMEAC (PP-population)

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    End point title
    Frequency of the Overall Haemostatic Success Adjudicated by the IDMEAC (PP-population) [1]
    End point description
    The primary efficacy endpoint was the overall haemostatic efficacy rating as assessed by the IDMEAC. Haemostatic efficacy was rated as ‘excellent,’ ‘good,’ ‘moderate,’ or ‘none’. Ratings of ‘excellent’ and ‘good’ were considered ‘haemostatic success’, whereas ratings of ‘moderate’ and ‘none’ were considered ‘haemostatic failure’. In the primary analysis population (PP set), 100% (95% CI 83.89–100.0%) of 21 patients in the Octafibrin group and 100% (95% CI 84.56–100.0%) of the 22 patients in the cryoprecipitate group were adjudicated as having achieved ‘treatment success.
    End point type
    Primary
    End point timeframe
    Overall haemostatic efficacy was determined using a predefined composite assessment algorithm based on the intraoperative and postoperative efficacy assessments and was adjudicated in a treatment-blinded manner by the IDMEAC.
    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: Due to the pathological situation (both success probabilities being equal to 1) no statistical inference on difference in proportions can be performed.
    End point values
    Octafibirn Cryoprecipitate
    Number of subjects analysed
    21
    22
    Units: Rating as Success
    number (not applicable)
        Success Rating (N)
    21
    22
        Success Rate (%)
    100
    100
        95%-Pearson Clopper interval lower
    83.89
    84.56
        95%-Pearson Clopper interval upper
    100
    100
    No statistical analyses for this end point

    Primary: Non-inferiority between treatment groups on the overall haemostatic success adjudicated by the IDMEAC (PP-population)

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    End point title
    Non-inferiority between treatment groups on the overall haemostatic success adjudicated by the IDMEAC (PP-population) [2]
    End point description
    End point type
    Primary
    End point timeframe
    Treatment success assesed intraoperatively and postoperatively.
    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: Due to the pathological situation (both success probabilities being equal to 1) the statistical test was performed by adding/subtracting a small epsilon (0.00001) to the subject count per treatment group. Non-inferiority margin = 0.2
    End point values
    Difference in overall haemostatic success
    Number of subjects analysed
    43
    Units: Difference
    number (not applicable)
        Difference in overall haemostatic success
    0.0000
        Lower 95% confidence limit
    -0.1671
        Upper 95% confidence limit
    0.1671
        p-value for the Farrington-Manning test
    0.0095
    No statistical analyses for this end point

    Secondary: Intraoperative haemostatic efficacy assessed by surgeon and anaesthesiologist (Octafibrin)

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    End point title
    Intraoperative haemostatic efficacy assessed by surgeon and anaesthesiologist (Octafibrin)
    End point description
    Intraoperative haemostatic efficacy as assessed at end of surgery using an objective 4-point haemostatic efficacy scale p-value for the Cochran-Mantel-Haenszel test as comparison between both treatment groups on the distribution of intraoperative haemostatic efficacy: 0.3319.
    End point type
    Secondary
    End point timeframe
    Intraoperative
    End point values
    N (ratings) % (ratings)
    Number of subjects analysed
    21
    21
    Units: Rating
    number (not applicable)
        Excellent
    13
    61.90
        Good
    7
    33.33
        Moderate
    1
    4.76
        Total
    21
    100
    No statistical analyses for this end point

    Secondary: Intraoperative haemostatic efficacy assessed by surgeon and anaesthesiologist (Cryoprecipitate)

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    End point title
    Intraoperative haemostatic efficacy assessed by surgeon and anaesthesiologist (Cryoprecipitate)
    End point description
    Intraoperative haemostatic efficacy as assessed at end of surgery using an objective 4-point haemostatic efficacy scale. p-value for the Cochran-Mantel-Haenszel test as comparison between both treatment groups on the distribution of intraoperative haemostatic efficacy: 0.3319.
    End point type
    Secondary
    End point timeframe
    Intraoperative
    End point values
    N (ratings) % (ratings)
    Number of subjects analysed
    22
    22
    Units: Rating
    number (not applicable)
        Excellent
    12
    54.55
        Good
    6
    27.27
        Moderate
    4
    18.18
        Total
    22
    100
    No statistical analyses for this end point

    Secondary: Intraoperative haemostatic efficacy assessed by surgeon and anaesthesiologist (Total)

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    End point title
    Intraoperative haemostatic efficacy assessed by surgeon and anaesthesiologist (Total)
    End point description
    Intraoperative haemostatic efficacy assessed by surgeon and anaesthesiologist. p-value for the Cochran-Mantel-Haenszel test as comparison between both treatment groups on the distribution of intraoperative haemostatic efficacy: 0.3319.
    End point type
    Secondary
    End point timeframe
    Intraoperative
    End point values
    N (total) % (total)
    Number of subjects analysed
    43
    43
    Units: Rating
    number (not applicable)
        Excellent
    25
    58.14
        Good
    13
    30.23
        Moderate
    5
    11.63
        Total
    43
    100
    No statistical analyses for this end point

    Secondary: Postoperative haemostatic efficacy ratings assessed by haematologist (Octafibrin)

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    End point title
    Postoperative haemostatic efficacy ratings assessed by haematologist (Octafibrin)
    End point description
    Due to the pathological situation (both treatment groups with excellent assessments being equal to 1) no statistical inference on distribution of postoperative hemostatic efficacy can be performed.
    End point type
    Secondary
    End point timeframe
    Post operative
    End point values
    N (ratings) % (ratings)
    Number of subjects analysed
    21
    21
    Units: Rating
    number (not applicable)
        Exellent
    21
    100
        Total
    21
    100
    No statistical analyses for this end point

    Secondary: Postoperative haemostatic efficacy ratings assessed by haematologist (Cryoprecipitate)

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    End point title
    Postoperative haemostatic efficacy ratings assessed by haematologist (Cryoprecipitate)
    End point description
    Due to the pathological situation (both treatment groups with excellent assessments being equal to 1) no statistical inference on distribution of postoperative hemostatic efficacy can be performed
    End point type
    Secondary
    End point timeframe
    Post-operative
    End point values
    N (ratings) % (ratings)
    Number of subjects analysed
    22
    22
    Units: Rating
    number (not applicable)
        Excellent
    22
    100
        Total
    22
    100
    No statistical analyses for this end point

    Secondary: Postoperative haemostatic efficacy ratings assessed by haematologist (Total)

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    End point title
    Postoperative haemostatic efficacy ratings assessed by haematologist (Total)
    End point description
    Due to the pathological situation (both treatment groups with excellent assessments being equal to 1) no statistical inference on distribution of postoperative hemostatic efficacy can be performed.
    End point type
    Secondary
    End point timeframe
    Post-operative
    End point values
    N (total) % (total)
    Number of subjects analysed
    43
    43
    Units: Rating
    number (not applicable)
        Excellent
    43
    100
        Total
    43
    100
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the whole study starting from the pre-operative assessment until end of the study assessment 21 days after surgery or end of hospitalization which ever came first.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Octafibrin
    Reporting group description
    -

    Reporting group title
    Cryoprecipitate
    Reporting group description
    -

    Serious adverse events
    Octafibrin Cryoprecipitate
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 22 (22.73%)
    13 / 23 (56.52%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Gastrointestinal stoma complication
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal anastomotic leak
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic leak
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural bile leak
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Haemodynamic instability
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 23 (8.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Parenteral nutrition
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 22 (0.00%)
    5 / 23 (21.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 23 (8.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 23 (4.35%)
         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
    Octafibrin Cryoprecipitate
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 22 (100.00%)
    23 / 23 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 23 (4.35%)
         occurrences all number
    2
    1
    Hypotension
         subjects affected / exposed
    6 / 22 (27.27%)
    4 / 23 (17.39%)
         occurrences all number
    6
    4
    Deep vein thrombosis
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 23 (8.70%)
         occurrences all number
    1
    3
    Oedema
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 23 (0.00%)
         occurrences all number
    2
    0
    Oedema peripheral
         subjects affected / exposed
    6 / 22 (27.27%)
    3 / 23 (13.04%)
         occurrences all number
    8
    4
    Pain
         subjects affected / exposed
    3 / 22 (13.64%)
    5 / 23 (21.74%)
         occurrences all number
    4
    5
    Peripheral swelling
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 23 (0.00%)
         occurrences all number
    2
    0
    Pyrexia
         subjects affected / exposed
    5 / 22 (22.73%)
    8 / 23 (34.78%)
         occurrences all number
    5
    8
    Psychiatric disorders
    Hallucination
         subjects affected / exposed
    17 / 22 (77.27%)
    17 / 23 (73.91%)
         occurrences all number
    17
    17
    Insomnia
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 23 (0.00%)
         occurrences all number
    2
    0
    Panic attack
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 23 (8.70%)
         occurrences all number
    1
    2
    Injury, poisoning and procedural complications
    Gastrointestinal stoma complication
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 23 (4.35%)
         occurrences all number
    3
    1
    Wound complication
         subjects affected / exposed
    1 / 22 (4.55%)
    3 / 23 (13.04%)
         occurrences all number
    1
    4
    Wound dehiscence
         subjects affected / exposed
    3 / 22 (13.64%)
    3 / 23 (13.04%)
         occurrences all number
    3
    3
    Wound secretion
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 23 (8.70%)
         occurrences all number
    1
    2
    Pancreatic leak
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    2
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 23 (8.70%)
         occurrences all number
    2
    2
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 23 (8.70%)
         occurrences all number
    2
    2
    Tachycardia
         subjects affected / exposed
    12 / 22 (54.55%)
    8 / 23 (34.78%)
         occurrences all number
    13
    8
    Blood and lymphatic system disorders
    Thrombocytosis
         subjects affected / exposed
    5 / 22 (22.73%)
    8 / 23 (34.78%)
         occurrences all number
    5
    8
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    7 / 22 (31.82%)
    8 / 23 (34.78%)
         occurrences all number
    7
    8
    Dyspnoea
         subjects affected / exposed
    2 / 22 (9.09%)
    3 / 23 (13.04%)
         occurrences all number
    2
    3
    Lung consolidation
         subjects affected / exposed
    2 / 22 (9.09%)
    3 / 23 (13.04%)
         occurrences all number
    2
    3
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 23 (4.35%)
         occurrences all number
    2
    1
    Oropharyngeal pain
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 23 (0.00%)
         occurrences all number
    2
    0
    Pleural effusion
         subjects affected / exposed
    11 / 22 (50.00%)
    11 / 23 (47.83%)
         occurrences all number
    11
    12
    Pleuritic pain
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 23 (4.35%)
         occurrences all number
    2
    1
    Pneumothorax
         subjects affected / exposed
    4 / 22 (18.18%)
    9 / 23 (39.13%)
         occurrences all number
    5
    9
    Pulmonary embolism
         subjects affected / exposed
    0 / 22 (0.00%)
    5 / 23 (21.74%)
         occurrences all number
    0
    5
    Wheezing
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 22 (13.64%)
    3 / 23 (13.04%)
         occurrences all number
    3
    3
    Hypoaesthesia
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 23 (4.35%)
         occurrences all number
    2
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 23 (4.35%)
         occurrences all number
    2
    1
    Abdominal pain
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 23 (8.70%)
         occurrences all number
    2
    2
    Constipation
         subjects affected / exposed
    7 / 22 (31.82%)
    4 / 23 (17.39%)
         occurrences all number
    7
    4
    Diarrhoea
         subjects affected / exposed
    3 / 22 (13.64%)
    3 / 23 (13.04%)
         occurrences all number
    3
    3
    Ileus
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 23 (8.70%)
         occurrences all number
    1
    2
    Intra-abdominal fluid collection
         subjects affected / exposed
    2 / 22 (9.09%)
    3 / 23 (13.04%)
         occurrences all number
    2
    3
    Nausea
         subjects affected / exposed
    12 / 22 (54.55%)
    7 / 23 (30.43%)
         occurrences all number
    12
    7
    Vomiting
         subjects affected / exposed
    8 / 22 (36.36%)
    10 / 23 (43.48%)
         occurrences all number
    8
    10
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    2
    Retching
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 23 (8.70%)
         occurrences all number
    0
    2
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 22 (13.64%)
    2 / 23 (8.70%)
         occurrences all number
    3
    2
    Skin and subcutaneous tissue disorders
    Subcutaneous emphysema
         subjects affected / exposed
    3 / 22 (13.64%)
    3 / 23 (13.04%)
         occurrences all number
    3
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    6 / 22 (27.27%)
    1 / 23 (4.35%)
         occurrences all number
    6
    1
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 22 (13.64%)
    3 / 23 (13.04%)
         occurrences all number
    3
    3
    Oral candidiasis
         subjects affected / exposed
    2 / 22 (9.09%)
    1 / 23 (4.35%)
         occurrences all number
    2
    1
    Pneumonia
         subjects affected / exposed
    4 / 22 (18.18%)
    3 / 23 (13.04%)
         occurrences all number
    4
    3
    Urinary tract infection
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 23 (8.70%)
         occurrences all number
    2
    2
    Wound infection
         subjects affected / exposed
    1 / 22 (4.55%)
    3 / 23 (13.04%)
         occurrences all number
    1
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Nov 2016
    Amendment 1 : Text changed upon request of MHRA: - text regarding relevant protocol deviations has been expanded. - text has been amended to clearly specify where in the Investigator’s Brochure the Reference Safety Information and list of ADRs can be found - text has been amended to stipulate reporting of all SAEs within 24 hours of their occurrence, as per the clarification of UK Statutory Instrument 2004 No 1031 Part 5 in the EC guidance document 2011/C 172/01 (CT-3), Section 4.3, paragraph 29 - Text has been added to define the Sponsor’s responsibility in reporting all SAEs at least possibly related to the study drug as suspected unexpected serious adverse reactions (SUSARs)
    21 Apr 2017
    Amendment 2: -Text stating tumour stage/grade as one of the planned pre-operative baseline assessments has been deleted as pre-operative assessment of tumor grade/stage will not be performed at baseline. - The text describing planned intraoperative assessments has been updated to include assessment of tumour stage/grade. -The text regarding blood sampling for coagulation parameters has been expanded to provide greater clarity. -The text defining what constitutes the end of surgery, at which point end-of-surgery assessments are to be made, has been revised to make it clearer. - Some sentences and typos have been corrected for clearer understanding.
    21 Nov 2017
    Amendment 3: An administrative interim analysis when approximately 50% of the planned patients have completed the study and adjudicated efficacy endpoint evaluation is available in these patients. has been added. This interim analysis is for administrative purposes only, no stopping rules based on statistical tests will be applied.
    05 Feb 2018
    Amendment 4: - The planned clinical end date has been updated to 2 quarter 2018

    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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