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    Clinical Trial Results:
    Efficacy and Safety of Long-Term (6 Months) Innohep® Treatment Versus Anticoagulation with a Vitamin K Antagonist (Warfarin) for the Treatment of Acute Venous Thromboembolism in Cancer Patients / IN 0901 INT

    Summary
    EudraCT number
    2009-018141-20
    Trial protocol
    ES   DE   SK   CZ   AT   PT   IT   DK   GR   LV   BG  
    Global end of trial date
    31 May 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    19 Feb 2016
    First version publication date
    22 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    IN0901INT
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01130025
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    LEO Pharma A/S
    Sponsor organisation address
    Industriparken 55, Ballerup, Denmark,
    Public contact
    Clinical Trial Disclosure Manager, LEO Pharma A/S, +45 44945888, ctr.disclosure@leo-pharma.com
    Scientific contact
    Clinical Trial Disclosure Manager, LEO Pharma A/S, +45 44945888, ctr.disclosure@leo-pharma.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
    31 May 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 May 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    31 May 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to assess the efficacy of Innohep® in preventing the recurrence of Venous Thromboembolism (VTE) in patients with active cancer who have had an acute Venous Thromboembolism (VTE) episode.
    Protection of trial subjects
    Frequent visits and telephone contacts.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    30 Aug 2010
    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
    Slovakia: 31
    Country: Number of subjects enrolled
    South Africa: 30
    Country: Number of subjects enrolled
    Spain: 34
    Country: Number of subjects enrolled
    Taiwan: 16
    Country: Number of subjects enrolled
    Thailand: 68
    Country: Number of subjects enrolled
    Ukraine: 24
    Country: Number of subjects enrolled
    Jordan: 2
    Country: Number of subjects enrolled
    Argentina: 12
    Country: Number of subjects enrolled
    Austria: 10
    Country: Number of subjects enrolled
    Brazil: 75
    Country: Number of subjects enrolled
    Bulgaria: 20
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Chile: 5
    Country: Number of subjects enrolled
    Czech Republic: 16
    Country: Number of subjects enrolled
    Egypt: 43
    Country: Number of subjects enrolled
    Germany: 20
    Country: Number of subjects enrolled
    Greece: 12
    Country: Number of subjects enrolled
    Guatemala: 7
    Country: Number of subjects enrolled
    India: 148
    Country: Number of subjects enrolled
    Israel: 18
    Country: Number of subjects enrolled
    Italy: 13
    Country: Number of subjects enrolled
    Korea, Republic of: 73
    Country: Number of subjects enrolled
    Latvia: 14
    Country: Number of subjects enrolled
    Lebanon: 29
    Country: Number of subjects enrolled
    Mexico: 24
    Country: Number of subjects enrolled
    Peru: 46
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Portugal: 7
    Country: Number of subjects enrolled
    Romania: 28
    Country: Number of subjects enrolled
    Russian Federation: 32
    Country: Number of subjects enrolled
    Saudi Arabia: 12
    Country: Number of subjects enrolled
    Serbia: 20
    Worldwide total number of subjects
    900
    EEA total number of subjects
    210
    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)
    579
    From 65 to 84 years
    312
    85 years and over
    9

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    There was a screening visit period of up to 72 hours prior to randomisation (-72 hrs to 0 hr). The screening visit included evaluation of eligibility criteria, objective diagnosis of venous thromboembolism (VTE), signed informed consent, and laboratory assessments.

    Period 1
    Period 1 title
    6-month treatment period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    This was an open-label trial. All efficacy endpoints (lower limb DVTs and PEs) and major safety endpoints (bleeding events, HIT events, and causes of death) were adjudicated blindly by the independent adjudication committee (IAC)

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Innohep®
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Innohep® (tinzaparin sodium)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Innohep® (tinzaparin sodium) 20,000 anti-Xa IU/mL was dispensed in syringes of 0.5 mL, 0.7 mL, and 0.9 mL. The dose was 175 anti-Xa IU/kg body weight once daily by s.c. injection. The duration of the treatment was 6 months (180 calendar days).

    Arm title
    Warfarin
    Arm description
    -
    Arm type
    Active comparator

    Investigational medicinal product name
    Warfarin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Wafarin was dispensed as oral tablets of 1 mg, 3 mg, and 5 mg in combination with initial (5-10 days) overlapping s.c. treatment with innohep®. The dose was adjusted to maintain international normalised ratio (INR) target level 2-3.

    Number of subjects in period 1
    Innohep® Warfarin
    Started
    449
    451
    Completed
    309
    279
    Not completed
    140
    172
         Target INR not achieved
    -
    18
         Patient/physician preference
    24
    23
         Protocol violation
    12
    16
         Progressive cancer
    39
    35
         Adverse event, non-fatal
    24
    22
         Contraindication for anticoagulation
    17
    30
         Consent withdrawn by subject
    17
    17
         Unable to obtain blood sample for INR
    -
    3
         Reason not specified
    4
    3
         Lost to follow-up
    3
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Innohep®
    Reporting group description
    -

    Reporting group title
    Warfarin
    Reporting group description
    -

    Reporting group values
    Innohep® Warfarin Total
    Number of subjects
    449 451 900
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    280 299 579
        From 65-84 years
    165 147 312
        85 years and over
    4 5 9
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    59.7 (19 to 89) 58.8 (18 to 86) -
    Gender categorical
    Units: Subjects
        Female
    262 273 535
        Male
    187 178 365

    End points

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    End points reporting groups
    Reporting group title
    Innohep®
    Reporting group description
    -

    Reporting group title
    Warfarin
    Reporting group description
    -

    Primary: Efficacy Endpoint

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    End point title
    Efficacy Endpoint
    End point description
    The primary efficacy endpoint is a composite endpoint represented by the time in days from randomisation to the first occurrence of any of the following 5 objectively documented components: Symptomatic non-fatal deep vein thrombosis (DVT), symptomatic non-fatal pulmonary embolism (PE), fatal pulmonary embolism (PE), incidental proximal deep vein thrombosis (DVT) (popliteal vein or higher), incidental proximal pulmonary embolism (PE) (segmental arteries or larger). All recurrent VTE outcomes were adjudicated blindly by a independent adjudication committee. The estimated subdistribution hazard ratio (SHR) is presented as a measure of relative risk between the two treatment groups (innohep® versus warfarin) together with the 95% confidence interval (CI).
    End point type
    Primary
    End point timeframe
    All recurrent VTE outcomes occurring from the time of randomisation up until day 180 regardless of whether the patient was on or off IMP-treatment (including 24 hours after the last dose of IMP) were eligible for the primary efficacy analysis.
    End point values
    Innohep® Warfarin
    Number of subjects analysed
    449
    451
    Units: Subdistribution HR - point estimate
        number (confidence interval 95%)
    0.65 (0.41 to 1.03)
    0.65 (0.41 to 1.03)
    Statistical analysis title
    Primary efficacy analysis: Recurrent VTE
    Statistical analysis description
    Competing Risk Regression of Recurrent VTE (Full analysis set 900 subjects): The competing risk regression analysis adjusting for region, tumour stratum, and history of VTE
    Comparison groups
    Innohep® v Warfarin
    Number of subjects included in analysis
    900
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.068 [2]
    Method
    Wald's test
    Confidence interval
    Notes
    [1] - Competing Risk Regression of Recurrent VTE - The test for no treatment effect
    [2] - A reduction in recurrent VTE was seen in the innohep® treated patients versus the warfarin treated patients, but the primary endpoint did not meet the 5% significant level.
    Statistical analysis title
    Per protocol analysis: Recurrent VTE
    Statistical analysis description
    Per protocol analysis set (658 subjects): The competing risk regression analysis adjusting for region, tumour stratum, and history of VTE
    Comparison groups
    Innohep® v Warfarin
    Number of subjects included in analysis
    900
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.048 [3]
    Method
    Competing risk regression analysis
    Parameter type
    Subdistribution hazard ratio
    Point estimate
    0.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.38
         upper limit
    1
    Notes
    [3] - The competing risk regression analysis, based on the PP analysis set and adjusting for region, tumour stratum, and history of VTE, resulted in an SHR of 0.62 (95% CI: 0.38-1.00) in favour of innohep®; very similar to the full analysis set analysis.
    Statistical analysis title
    Sensitivity Analysis: Recurrent VTE
    Statistical analysis description
    Sensitivity analysis: The stratified competing risk analyses of recurrent VTE including a combination of all stratification factors or 1 covariate at a time.
    Comparison groups
    Innohep® v Warfarin
    Number of subjects included in analysis
    900
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.069 [4]
    Method
    Gray's test
    Confidence interval
    Notes
    [4] - The analyses resulted in p-values (range: 0.069-0.085) very similar to the p-value (p=0.068) for the primary analysis.
    Statistical analysis title
    Stratified Competing Risk Analysis: Recurrent VTE
    Statistical analysis description
    Stratified competing risk analysis: A proportional hazards regression analysis (treating deaths other than fatal PEs as censored) was performed with treatment group, region, tumour stratum, and history of VTE as main effects
    Comparison groups
    Innohep® v Warfarin
    Number of subjects included in analysis
    900
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.079 [5]
    Method
    Proportional hazards regression analysis
    Parameter type
    Hazards ratio (innohep/warfarin)
    Point estimate
    0.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.42
         upper limit
    1.05
    Notes
    [5] - The outcome of this sensitivity analysis showed very similar results to that of the primary efficacy analysis, supporting the robustness of these results.

    Secondary: Symptomatic non-fatal PE

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    End point title
    Symptomatic non-fatal PE
    End point description
    6 subjects (innohep®: 3; warfarin: 3) experienced a symptomatic PE whereof 5 were bilateral; 1 of the symptomatic PEs in the warfarin group was not a first event and was thus not counted in the efficacy analyses. 5 subjects with symptomatic PE (innohep®: 3; warfarin: 2) are counted in the efficacy analyses. The 6-month incidence of recurrent symptomatic non-fatal PE was low, not allowing for a meaningful competing risk regression analysis.
    End point type
    Secondary
    End point timeframe
    The secondary endpoints are given as the time in days from randomisation to the first occurrence of the respective secondary endpoint.
    End point values
    Innohep® Warfarin
    Number of subjects analysed
    449
    451
    Units: The 6-month incidence (percent)
        number (not applicable)
    0.7
    0.4
    No statistical analyses for this end point

    Secondary: Fatal PE

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    End point title
    Fatal PE
    End point description
    Adjudication of cause of death classified a death due to PE as: PE confirmed by autopsy; PE confirmed by objective testing/imaging; sudden and unexplained death, which could not be attributed to a documented cause and for which PE was the most probably cause.
    End point type
    Secondary
    End point timeframe
    The secondary endpoints are given as the time in days from randomisation to the first occurrence of the respective secondary endpoint.
    End point values
    Innohep® Warfarin
    Number of subjects analysed
    449
    451
    Units: The 6-month incidence (percent)
        number (not applicable)
    3.8
    3.8
    Statistical analysis title
    Competing risk regression of fatal PE
    Statistical analysis description
    full analysis set
    Comparison groups
    Innohep® v Warfarin
    Number of subjects included in analysis
    900
    Analysis specification
    Pre-specified
    Analysis type
    other [6]
    P-value
    = 0.9 [7]
    Method
    Competing risk regression analysis
    Parameter type
    Subdistribution hazard ratio
    Point estimate
    0.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.49
         upper limit
    1.88
    Notes
    [6] - 36 subjects (innohep®: 17; warfarin: 19) had a fatal PE whereof 2 in the warfarin group were not first events and thus not counted in the efficacy analyses. 34 fatal PEs (innohep®: 17; warfarin: 17) are counted in the efficacy analyses.
    [7] - The 6-month incidence of fatal PE was identical in the treatment groups. None of the fatal PEs counted in the efficacy analyses were objectively confirmed.

    Secondary: Incidental proximal DVT (popliteal vein or higher)

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    End point title
    Incidental proximal DVT (popliteal vein or higher)
    End point description
    1 subject in the warfarin group experienced an incidental DVT, which is counted in the efficacy analyses. The 6-month incidence or recurrent incidental DVT was low with only 1 case occurring in the warfaring group, not allowing for a meaningful competing risk regression analysis.
    End point type
    Secondary
    End point timeframe
    The secondary endpoints are given as the time in days from randomisation to the first occurrence of the respective secondary endpoint.
    End point values
    Innohep® Warfarin
    Number of subjects analysed
    449
    451
    Units: The 6-month incidence
        number (not applicable)
    0
    1
    No statistical analyses for this end point

    Secondary: Incidental proximal PE (segmental arteries or larger)

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    End point title
    Incidental proximal PE (segmental arteries or larger)
    End point description
    2 subjects (innohep®: 1; warfarin: 1) had an incidental proximal PE whereof 1 in the innohep® group was not a first event and thus not counted in the efficacy analyses. 1 incidental non-fatal PEs in the warfarin group is counted in the efficacy analyses. The 6-month incidence of recurrent incidental PE was low with only 1 case occurring in the warfarin group, not allowing for a meaningful competing risk regression analysis.
    End point type
    Secondary
    End point timeframe
    The secondary endpoints are given as the time in days from randomisation to the first occurrence of the respective secondary endpoint.
    End point values
    Innohep® Warfarin
    Number of subjects analysed
    449
    451
    Units: The 6-month incidence
        number (not applicable)
    0
    1
    No statistical analyses for this end point

    Secondary: Any symptomatic DVT and/or PE, including fatal PE

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    End point title
    Any symptomatic DVT and/or PE, including fatal PE
    End point description
    The composite endpoint of the 3 symptomatic components of the primary endpoint
    End point type
    Secondary
    End point timeframe
    The secondary endpoints are given as the time in days from randomisation to the first occurrence of the respective secondary endpoint.
    End point values
    Innohep® Warfarin
    Number of subjects analysed
    449
    451
    Units: The 6-month incidence (percent)
        number (not applicable)
    6.9
    9.5
    Statistical analysis title
    Competing risk regression analysis
    Statistical analysis description
    Competing risk regression analysis of the secondary efficacy analysis of symptomatic events (i.e. symptomatic DVTs plus symptomatic non-fatal PEs plus fatal PEs) adjusting for region, tumour stratum, and history of VTE.
    Comparison groups
    Innohep® v Warfarin
    Number of subjects included in analysis
    900
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.11 [8]
    Method
    Competing risk regression analysis
    Parameter type
    Subdistribution hazard ratio
    Point estimate
    0.69
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.43
         upper limit
    1.09
    Notes
    [8] - The result of the analysis was in favour of innohep®, but not at the 5% significance level.

    Secondary: Recurrent Symptomatic non-fatal DVT

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    End point title
    Recurrent Symptomatic non-fatal DVT
    End point description
    36 subjects (innohep®: 12; warfarin: 24) who experienced 41 symptomatic DVTs are counted in the efficacy analyses. 5 of the confirmed DVTs were bilateral events (innohep®: 2; warfarin: 3) and only count once in the efficacy analyses.
    End point type
    Secondary
    End point timeframe
    The secondary endpoints are given as the time in days from randomisation to the first occurrence of the respective secondary endpoint.
    End point values
    Innohep® Warfarin
    Number of subjects analysed
    449
    451
    Units: The 6-month incidence (percent)
        number (not applicable)
    2.7
    5.3
    Statistical analysis title
    Competing risk regression analysis
    Statistical analysis description
    Competing risk regression analysis of symptomatic non-fatal DVT adjusting for region, tumor stratum, and history of VTE
    Comparison groups
    Innohep® v Warfarin
    Number of subjects included in analysis
    900
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.038 [9]
    Method
    Risk regression analysis
    Parameter type
    Subdistribution hazard ratio
    Point estimate
    0.48
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.24
         upper limit
    0.96
    Notes
    [9] - The result of the analysis was statistically in favour of innohep®

    Secondary: Overall bleeding events

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    End point title
    Overall bleeding events
    End point description
    Bleeding events were sent to the central adjudication committee for blinded adjudication. Bleeding was defined in accordance with the International Society of Thrombosis and Haemostasis (ISTH). Major bleeding criteria were defined as any event meeting any one or more of the following: bleeding with a fall in haemoglobin of >2 g/dL; bleeding requiring a transfusion of >2 units of red cells or whole blood; bleeding in a critical location, i.e. intracranial, intraspinal, intraocular, retroperitoneal, intraarticular, or pericardial; bleeding causing death. All non-major bleeding events (i.e. bleeding events that did not meet the criteria for major bleeding above) that required any medical or surgical intervention, including unscheduled contact (visit or telephone call) with a physician, or (temporary) cessation of IMP were classified as "clinically relevant non-major bleeding".
    End point type
    Secondary
    End point timeframe
    From the first dose of IMP and included in the analysis up to 24 hours following the last administration of IMP (i.e. more than 5 x the half-life of innohep®)
    End point values
    Innohep® Warfarin
    Number of subjects analysed
    449
    451
    Units: Overall bleeding incidence (percent)
        number (not applicable)
    25.4
    24.4
    Statistical analysis title
    Trivial bleeding
    Comparison groups
    Innohep® v Warfarin
    Number of subjects included in analysis
    900
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.063 [10]
    Method
    Chi-squared
    Confidence interval
    Notes
    [10] - Test for no treatment effect
    Statistical analysis title
    Clinically relevant non-major bleeding
    Comparison groups
    Innohep® v Warfarin
    Number of subjects included in analysis
    900
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.051 [11]
    Method
    Chi-squared
    Confidence interval
    Notes
    [11] - Test for no treatment effect
    Statistical analysis title
    Any non-trivial bleeding events
    Comparison groups
    Innohep® v Warfarin
    Number of subjects included in analysis
    900
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.101 [12]
    Method
    Chi-squared
    Confidence interval
    Notes
    [12] - Test for no treatment effect

    Secondary: Major bleeding events

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    End point title
    Major bleeding events
    End point description
    Bleeding events were sent to the central adjudication committee for blinded adjudication. Bleeding was defined in accordance with the International Society of Thrombosis and Haemostasis (ISTH). Major bleeding criteria were defined as any event meeting any one or more of the following: bleeding with a fall in haemoglobin of >2 g/dL; bleeding requiring a transfusion of >2 units of red cells or whole blood; bleeding in a critical location, i.e. intracranial, intraspinal, intraocular, retroperitoneal,intraarticular, or pericardial; bleeding causing death.
    End point type
    Secondary
    End point timeframe
    Bleeding events were recorded througout the trial, starting from the first dose of IMP and included in the analysis up to 24 hours (i.e. more thatn 5 x the half-life of innohep®) following the last administration of IMP.
    End point values
    Innohep® Warfarin
    Number of subjects analysed
    449
    451
    Units: Major bleeding event incidence (percent)
        number (not applicable)
    2.7
    2.4
    Statistical analysis title
    Major bleeding
    Comparison groups
    Innohep® v Warfarin
    Number of subjects included in analysis
    900
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.824 [13]
    Method
    Chi-squared
    Confidence interval
    Notes
    [13] - Test for no treatment effect

    Secondary: Heparin-induced Thrombocytopenia (HIT)

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    End point title
    Heparin-induced Thrombocytopenia (HIT)
    End point description
    The diagnosis of heparin-induced thrombocytopenia (HIT) reported as AEs required both clinical and laboratory diagnostic confirmation that was consistent with standard practice including the use of the Warkentin 4T score. The IMP treatment was permanently discontinued if HIT was confirmed. Laboratory analyses performed for confirmation of HIT were performed locally and had to be confirmed at the central laboratory. The subject was treated according to the site practice and followed up. All cases of HIT occurring up to 1 month after the last dose of IMP were sent to the blinded independent adjudication committee (IAC) for adjudication. No statistical analyses for this end point (as there were no confirmed events).
    End point type
    Secondary
    End point timeframe
    The period from the first dose of IMP up to 1 month after the last dose of IMP.
    End point values
    Innohep® Warfarin
    Number of subjects analysed
    449
    451
    Units: Incidence of occurrences (percent)
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: Overall mortality

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    End point title
    Overall mortality
    End point description
    The time to death (overall mortality) up to and including Day 180 was assessed in a proportional hazards model including treatment group and the 3 stratification factors as main effects. The hazard ratio and associated 95% CI is presented. The test for no treatment effect was conducted as a Wald’s test within this model. All deaths were adjudicated and cause of death was classified in the following way: 1) due to PE, 2) due to cancer progression, 3) due to bleeding or due to 4) other specific cause (as specified by the IAC)
    End point type
    Secondary
    End point timeframe
    The overall mortality status on Day 180
    End point values
    Innohep® Warfarin
    Number of subjects analysed
    449
    451
    Units: number of subjects
        number (not applicable)
    150
    138
    Statistical analysis title
    Proportional hazards regression overall mortality
    Comparison groups
    Innohep® v Warfarin
    Number of subjects included in analysis
    900
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.536 [14]
    Method
    Wald's test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.85
         upper limit
    1.36
    Notes
    [14] - The numbers indicate that there was no difference in mortality rate across the 6 months trial period

    Secondary: Thromboses other than objectively confirmed VTE

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    End point title
    Thromboses other than objectively confirmed VTE
    End point description
    Other objectively confirmed thromboses, i.e. other than objectively confirmed VTE, were collected throughout the trial and included e.g. upper limb DVT, incidental subsegmental PE, portal or renal vein thrombosis, as well as arterial thrombosis, e.g. myocardial infarction (MI), stroke, or systemic embolic events.
    End point type
    Secondary
    End point timeframe
    The period from the first dose of IMP until day 180 regardless of whether the patient was on or off IMP treatment (including 24 hours after the last dose of IMP).
    End point values
    Innohep® Warfarin
    Number of subjects analysed
    449
    451
    Units: number of events
        number (not applicable)
    9
    13
    Statistical analysis title
    Chi-square test for no treatment effect
    Comparison groups
    Innohep® v Warfarin
    Number of subjects included in analysis
    900
    Analysis specification
    Pre-specified
    Analysis type
    superiority [15]
    P-value
    = 0.801 [16]
    Method
    Chi-squared
    Confidence interval
    Notes
    [15] - Test for no treatment effect
    [16] - Test for no treatment effect

    Secondary: Significant abnormal vital signs

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    End point title
    Significant abnormal vital signs
    End point description
    Vital signs include: systolic and diastolic blood pressure and heart rate. If an investigator found a vital sign to be of clinical significance, this was to be reported as an AE. In a population of subjects with cancer, and in addition different cancer diagnoses and stages, the vital signs are likely to fluctuate due to the underlying disease. Hence, analyses were made for change from Baseline to End of Treatment, only. The results from these analyses did not give reason to perform any further analyses. Two AEs associated with vital signs were reported in the innohep® group; blood pressure increased and blood pressure fluctuation – both were mild and not related to treatment.
    End point type
    Secondary
    End point timeframe
    Vital signs were assessed at all visits, except at Visit 3 (Week 2) and Visit 10 (Month 7)
    End point values
    Innohep® Warfarin
    Number of subjects analysed
    449
    451
    Units: Number of occurrences
        number (not applicable)
    2
    0
    No statistical analyses for this end point

    Secondary: Elevated liver enzymes

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    End point title
    Elevated liver enzymes
    End point description
    In a population of subjects with cancer, and in addition with different cancer diagnoses and stages, the values of liver enzymes are likely to fluctuate due to the underlying disease and treatment regimens. Hence, analyses were made of change from Baseline to End of Treatment, only. The results from these analyses did not give reason to perform any further analyses. If an investigator found a laboratory result to be of clinical significance, this was to be reported as an AE. No subject discontinued treatment due to liver enzyme elevation.
    End point type
    Secondary
    End point timeframe
    Clinical laboratory safety parameters were assessed every month
    End point values
    Innohep® Warfarin
    Number of subjects analysed
    449
    451
    Units: No. of subjects with events (in percent)
        number (not applicable)
    2.4
    1.1
    No statistical analyses for this end point

    Secondary: Post-thrombotic Syndrome (PTS)

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    End point title
    Post-thrombotic Syndrome (PTS)
    End point description
    The development and severity of post-thrombotic syndrome (PTS) were analysed using the Villalta scale. PTS was assessed after diagnosis of the initial VTE at Baseline; therefore, the Baseline Villalta score reflects signs and symptoms of both the initial VTA as well as any previous VTE(s). Consequently, the Baseline Villalta score does not reflect the presence of absence of PTS. The villalta scores are given for the completers. The total mean Villalta score declined (improved) in both groups during the trial. At End of Treatment, 398 subjects in the innohep® group and 409 in the warfarin group had no or mild PTS, whereas 15 and 18 subjects had moderate PTS, and 17 versus 9 had severe PTS, respectively.
    End point type
    Secondary
    End point timeframe
    From the first dose of IMP until completion of the 30-day follow-up visit for subjects who completed treatment
    End point values
    Innohep® Warfarin
    Number of subjects analysed
    449
    451
    Units: Villalta score
        number (not applicable)
    1.3
    1.2
    No statistical analyses for this end point

    Secondary: Health-related Quality of Life (QoL) by Change inEQ-5D Utility index

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    End point title
    Health-related Quality of Life (QoL) by Change inEQ-5D Utility index
    End point description
    The EQ-5D is a brief questionnaire designed to measure health status. The 5-item descriptive portion addresses 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) with respondents indicating 1 of 3 possible responses for each dimension. The second portion, EQ VAS, is a single item (0 to 100) visual analogue scale (VAS), on which 0 corresponds to ‘the worst health you can imagine’ and 100 corresponds to ‘the best health you can imagine’. The VAS is used to report overall health status and offers a simple method for obtaining a self-rating of current health status. Overall, the health status levels were similar between the treatment groups both at Visit 1 and End of Treatment.
    End point type
    Secondary
    End point timeframe
    The health related QoL was assessed at Baseline, at all monthly visits, at the End of Treatment Visit and at the Post-Treatment Follow-Up Visit.
    End point values
    Innohep® Warfarin
    Number of subjects analysed
    449
    451
    Units: Change inEQ-5D Utility Index
        arithmetic mean (standard deviation)
    0.07 ± 0.34
    0.06 ± 0.35
    No statistical analyses for this end point

    Secondary: Number of Blood Transfusions

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    End point title
    Number of Blood Transfusions
    End point description
    Percentage of subjects with blood transfusion
    End point type
    Secondary
    End point timeframe
    From the first dose of IMP and up to 30 days following the last administration of IMP
    End point values
    Innohep® Warfarin
    Number of subjects analysed
    449
    451
    Units: Percentage
        number (not applicable)
    25.8
    31.5
    No statistical analyses for this end point

    Secondary: All adverse events including serious adverse events

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    End point title
    All adverse events including serious adverse events
    End point description
    Percentage of subjects with adverse events including serious adverse events
    End point type
    Secondary
    End point timeframe
    The period from the first dose of IMP up to 24 hours after the last dose of IMP. Serious adverse events were collected up to 30 days following the last dose of IMP.
    End point values
    Innohep® Warfarin
    Number of subjects analysed
    449
    451
    Units: Percentage
        number (not applicable)
    87.5
    85.4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The period from the first dose of IMP up to 24 hours after the last dose of IMP. Serious-adverse events were collected up to 30 days following the last dose of IMP.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Innohep®
    Reporting group description
    -

    Reporting group title
    Warfarin
    Reporting group description
    -

    Serious adverse events
    Innohep® Warfarin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    221 / 449 (49.22%)
    195 / 451 (43.24%)
         number of deaths (all causes)
    159
    147
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    7 / 449 (1.56%)
    16 / 451 (3.55%)
         occurrences causally related to treatment / all
    0 / 7
    2 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    International normalized ratio increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 449 (0.00%)
    18 / 451 (3.99%)
         occurrences causally related to treatment / all
    0 / 0
    10 / 20
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
    alternative assessment type: Non-systematic
         subjects affected / exposed
    77 / 449 (17.15%)
    39 / 451 (8.65%)
         occurrences causally related to treatment / all
    0 / 77
    0 / 41
         deaths causally related to treatment / all
    0 / 64
    0 / 33
    Respiratory, thoracic and mediastinal disorders
    Pneumonia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    12 / 449 (2.67%)
    10 / 451 (2.22%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 10
         deaths causally related to treatment / all
    0 / 4
    0 / 2
    Pulmonary embolism
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 449 (0.67%)
    7 / 451 (1.55%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    1 / 5
    Blood and lymphatic system disorders
    Anaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    10 / 449 (2.23%)
    8 / 451 (1.77%)
         occurrences causally related to treatment / all
    1 / 11
    1 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    8 / 449 (1.78%)
    7 / 451 (1.55%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Neutropenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    10 / 449 (2.23%)
    3 / 451 (0.67%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 449 (0.67%)
    7 / 451 (1.55%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 449 (1.11%)
    4 / 451 (0.89%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Rectal haemorrhage
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 449 (1.34%)
    6 / 451 (1.33%)
         occurrences causally related to treatment / all
    0 / 7
    1 / 6
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Vomiting
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 449 (1.11%)
    6 / 451 (1.33%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 449 (1.11%)
    7 / 451 (1.55%)
         occurrences causally related to treatment / all
    1 / 5
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    7 / 449 (1.56%)
    4 / 451 (0.89%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    8 / 449 (1.78%)
    2 / 451 (0.44%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 4
         deaths causally related to treatment / all
    0 / 5
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Innohep® Warfarin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    358 / 449 (79.73%)
    364 / 451 (80.71%)
    Investigations
    International normalised ratio increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 449 (0.00%)
    146 / 451 (32.37%)
         occurrences all number
    0
    263
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative assessment type: Non-systematic
         subjects affected / exposed
    27 / 449 (6.01%)
    30 / 451 (6.65%)
         occurrences all number
    30
    34
    Dyspnoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    24 / 449 (5.35%)
    26 / 451 (5.76%)
         occurrences all number
    27
    33
    Blood and lymphatic system disorders
    Anaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    49 / 449 (10.91%)
    59 / 451 (13.08%)
         occurrences all number
    65
    73
    Neutropenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    24 / 449 (5.35%)
    30 / 451 (6.65%)
         occurrences all number
    35
    40
    General disorders and administration site conditions
    pyrexia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    27 / 449 (6.01%)
    42 / 451 (9.31%)
         occurrences all number
    34
    60
    Asthenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    26 / 449 (5.79%)
    24 / 451 (5.32%)
         occurrences all number
    28
    25
    Oedema peripheral
    alternative assessment type: Non-systematic
         subjects affected / exposed
    19 / 449 (4.23%)
    24 / 451 (5.32%)
         occurrences all number
    24
    25
    Gastrointestinal disorders
    Nausea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    52 / 449 (11.58%)
    51 / 451 (11.31%)
         occurrences all number
    62
    72
    Vomiting
    alternative assessment type: Non-systematic
         subjects affected / exposed
    40 / 449 (8.91%)
    42 / 451 (9.31%)
         occurrences all number
    62
    48
    Constipation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    36 / 449 (8.02%)
    45 / 451 (9.98%)
         occurrences all number
    47
    53
    Diarrhoea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    41 / 449 (9.13%)
    33 / 451 (7.32%)
         occurrences all number
    53
    47
    Abdominal pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    29 / 449 (6.46%)
    21 / 451 (4.66%)
         occurrences all number
    35
    23
    Musculoskeletal and connective tissue disorders
    Pain in extremity
    alternative assessment type: Non-systematic
         subjects affected / exposed
    21 / 449 (4.68%)
    26 / 451 (5.76%)
         occurrences all number
    29
    31
    Back pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    26 / 449 (5.79%)
    22 / 451 (4.88%)
         occurrences all number
    28
    27
    Metabolism and nutrition disorders
    Decreased appetite
    alternative assessment type: Non-systematic
         subjects affected / exposed
    39 / 449 (8.69%)
    34 / 451 (7.54%)
         occurrences all number
    46
    37
    Hypokalaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    19 / 449 (4.23%)
    23 / 451 (5.10%)
         occurrences all number
    21
    24
    Infections and infestations
    Urinary tract infection
    alternative assessment type: Non-systematic
         subjects affected / exposed
    25 / 449 (5.57%)
    20 / 451 (4.43%)
         occurrences all number
    34
    23

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Jun 2010
    Before the inclusion of the first subject, the number of subject to be randomized was reduced from 1000 to 900 subjects, 450 in each treatment group. This was based on a time-to-event approach replacing the more conservative approach based on Fisher’s exact test. The overall power of the trial of 90%, the assumptions of a 6-month event rate of 12.6% in the control group, and a 50% reduction in the innohep® group remained unchanged.
    24 Feb 2011
    Time points of assessments (outcome events) were clarified in several sections to give better guidance to investigators and site staff. The amendment clarified that post treatment-emergent AEs/SAEs covered only new SAEs and SAEs with worsening of intensity within 30 days after the last dose of IMP, while AEs with onset more than 24 hours after the last dose of IMP were not to be collected.
    07 Jul 2011
    Taro Pharmaceuticals UK Ltd and Crescent Pharma UK Ltd, were added as alternative suppliers of warfarin to be used only if the supplier Goldshield Marevan was unable to provide new stocks of their warfarin product. It was added to the protocol that INR was to be closely monitored if a subject in the warfarin group switched warfarin product during the treatment period.
    06 Oct 2011
    Change of CRO responsible for the conduct of the trial from PRA International Ltd (PRA) to INC Research (INC), and change in planned number of sites and participating countries from 180 sites in 25 countries to approximately 230 sites in approximately 30 countries.
    30 Jan 2012
    Updates were made with regard to regions due to inclusion of additional countries: the region “Canada” was changed to “North America”, “Asia Pacific” was changed to “Asia”, and “South Africa” was changed to “Africa”. Israel and India were omitted as separate regions.

    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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