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    Clinical Trial Results:
    Recombinant Factor VIIa: Local treatment of severe postpartum hemorrhage

    Summary
    EudraCT number
    		 2013-005036-20
    Trial protocol
    		 DK  
    Global end of trial date
    15 Apr 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Dec 2021
    First version publication date
    05 Dec 2021
    Other versions
    Summary report(s)
    		 Results

    Trial information

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    Trial identification
    Sponsor protocol code
    VEK40624
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Stellaris Pharmaceuticals ApS
    Sponsor organisation address
    Vaernedamsvej 10,4 tv, Copenhagen, Denmark, 1619
    Public contact
    Birgit Schjoldager, Stellaris Pharmaceuticals ApS, 45 29852973, birgit.schjoldager@gmail.com
    Scientific contact
    Birgit Schjoldager, Stellaris Pharmaceuticals ApS, 45 29852973, birgit.schjoldager@gmail.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
    15 Apr 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Apr 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Through a pilot study involving 1-5 patients undergoing cesaren section for Placenta Previa to demonstrate hemostatic effect of recombinant FVIIa placed directly upon the placenta site. To ensure that rFVIIa was not entering the systemic circulation blood samples were taken from an arm vene for analysis just before the Cesarean Section and 15 minutes after the removal of the placenta. To investigate possible coagulation changes in the systemic circulation due to the Cesarean Section itself blood samples were likewise drawn from a control group of 5 patients undergoing Cesarean Section for other reasons.
    Protection of trial subjects
    The protocol was approved by the Danish Medicines Agency (DMA) and the local ethis committe. The trial was conducted in accordance with good clinical practice. The Clinical Good Practice Unit, Aarhus, Denmark, were monitoring the trial including safety precautions. Oral and written informed consent were obtained prior to any trial events.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Sep 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 12
    Worldwide total number of subjects
    12
    EEA total number of subjects
    12
    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)
    12
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients with Placenta Previa verified by ultrasound in week 34-35, defined as cases where the placenta covered the internal os of the cervix, were enrolled after both oral and written consent to receive local treatment with recombinant, activated FVII during cesarean section. No known coagulative disease.

    Pre-assignment
    Screening details
    		 All pregnant women were screeened for placenta previa in second trimester and in week 32 and finally in week 34-35 if suspicion. An elective Cesarean Section was planned.

    Period 1
    Period 1 title
    overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placenta Previa patients
    Arm description
    		 Patients presenting with a Placenta Previa in Week 34-35 undergoing a planned Cesarean Section were enrolled to receive local treatment with recombinant activated FVII at the placenta site.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NovoSeven
    Investigational medicinal product code
    PR1
    Other name
    rFVIIa, recombinant activated Factor VII
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intrauterine use
    Dosage and administration details
    1mg rFVIIa (NovoSeven, Novo Nordisk A/S,Bagsværd, Denmark) was dissolved in an enclosed 6-mL histidine solution and brought up to 246 mL with a sterile saline solution just a few minutes before use. As the carrier, a nonwowen abdominal swab (Barrier; Mölnlycke Health Care Aps, Allerød, Denmark) was soaked in this solution.

    Arm title
    		 Controls
    Arm description
    		 Patients undergoing a planned Cesarean Section for other reasons than Placenta Previa
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Placenta Previa patients Controls
    Started
    7
    5
    Completed
    5
    5
    Not completed
    2
    0
         Protocol deviation
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placenta Previa patients
    Reporting group description
    		 Patients presenting with a Placenta Previa in Week 34-35 undergoing a planned Cesarean Section were enrolled to receive local treatment with recombinant activated FVII at the placenta site.

    Reporting group title
    Controls
    Reporting group description
    		 Patients undergoing a planned Cesarean Section for other reasons than Placenta Previa

    Reporting group values
    		 Placenta Previa patients Controls Total
    Number of subjects
    		 7 5 12
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 7 5 12
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 7 5 12
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Placenta Previa patients
    Reporting group description
    		 Patients presenting with a Placenta Previa in Week 34-35 undergoing a planned Cesarean Section were enrolled to receive local treatment with recombinant activated FVII at the placenta site.

    Reporting group title
    Controls
    Reporting group description
    		 Patients undergoing a planned Cesarean Section for other reasons than Placenta Previa

    Subject analysis set title
    Placenta previa patients before
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Blood samples collected before cesarean section in placenta previa group.

    Subject analysis set title
    Placenta previa patients after
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Blood samples collected 15 minutes after removal of the placenta in placenta previa group.

    Subject analysis set title
    Controls before
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Blood samples collected before cesarean section in control group.

    Subject analysis set title
    Controls after
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    blood samples collected 15 minutes after reæoval of the placenta in control group.

    Primary: Bleeding amount

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    End point title
    		 Bleeding amount [1]
    End point description
    As soon as the placenta was removed, bleeding from the placenta site was assessed. A swab soaked in NovoSeven solution was placed at the bleeding placenta site for 2 min. Upon gently removal the placenta site was visualized and bleeding from the site reassessed. Total blood loss was estimated.
    End point type
    Primary
    End point timeframe
    End of cesarean section
    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: We have used Mann-Whitneys test for unpaired data, see all informations in attached article from AJOG.
    End point values
    		 Placenta Previa patients Controls
    Number of subjects analysed
    5
    5
    Units: millilitre(s)
        median (full range (min-max))
    490 (300 to 800)
    400 (250 to 700)
    No statistical analyses for this end point

    Secondary: FVII:clot

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    End point title
    		 FVII:clot
    End point description
    FVII:clot will augment in case of augmentation of coagulation in the blood circulation
    End point type
    Secondary
    End point timeframe
    Blood samples from the systemic circulation were taken just before the Cesarean Section and 15 minutes after removal of the placenta.
    End point values
    		 Placenta previa patients before Placenta previa patients after Controls before Controls after
    Number of subjects analysed
    5
    5
    5
    5
    Units: 1000 IU/L
        median (full range (min-max))
    1.87 (1.72 to 2.04)
    1.65 (1.58 to 1.87)
    1.40 (1.09 to 1.95)
    1.40 (1.13 to 1.91)
    No statistical analyses for this end point

    Secondary: Fibrinogen

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    End point title
    		 Fibrinogen
    End point description
    End point type
    Secondary
    End point timeframe
    Blood samples from the systemic circulation were taken just before the Cesarean Section and 15 minutes after removal of the placenta.
    End point values
    		 Placenta previa patients before Placenta previa patients after Controls before Controls after
    Number of subjects analysed
    5
    5
    5
    5
    Units: micromole(s)/litre
        median (full range (min-max))
    12.8 (6.5 to 18.1)
    12.9 (11.6 to 16.6)
    13.6 (12.9 to 14.8)
    12.1 (11.1 to 14.2)
    No statistical analyses for this end point

    Secondary: APTT

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    End point title
    		 APTT
    End point description
    End point type
    Secondary
    End point timeframe
    Blood samples from the systemic circulation were taken just before the Cesarean Section and 15 minutes after removal of the placenta.
    End point values
    		 Placenta previa patients before Placenta previa patients after Controls before Controls after
    Number of subjects analysed
    5
    5
    5
    5
    Units: second
        median (full range (min-max))
    28 (25 to 30)
    30 (25 to 31)
    31 (28 to 35)
    31 (29 to 35)
    No statistical analyses for this end point

    Secondary: INR

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    End point title
    		 INR
    End point description
    End point type
    Secondary
    End point timeframe
    Blood samples from the systemic circulation were taken just before the Cesarean Section and 15 minutes after removal of the placenta.
    End point values
    		 Placenta previa patients before Placenta previa patients after Controls before Controls after
    Number of subjects analysed
    5
    5
    5
    5
    Units: None
        median (full range (min-max))
    1 (1 to 1)
    1 (1 to 1)
    1 (1 to 1)
    1 (1.0 to 1.1)
    No statistical analyses for this end point

    Secondary: Platelet count

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    End point title
    		 Platelet count
    End point description
    End point type
    Secondary
    End point timeframe
    Blood samples from the systemic circulation were taken just before the Cesarean Section and 15 minutes after removal of the placenta.
    End point values
    		 Placenta previa patients before Placenta previa patients after Controls before Controls after
    Number of subjects analysed
    5
    5
    5
    5
    Units: Giga L
        median (full range (min-max))
    235 (177 to 275)
    216 (184 to 246)
    206 (173 to 239)
    176 (158 to 198)
    No statistical analyses for this end point

    Secondary: Hemoglobin

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    End point title
    		 Hemoglobin
    End point description
    End point type
    Secondary
    End point timeframe
    Blood samples from the systemic circulation were taken just before the Cesarean Section and 15 minutes after removal of the placenta.
    End point values
    		 Placenta previa patients before Placenta previa patients after Controls before Controls after
    Number of subjects analysed
    5
    5
    5
    5
    Units: millimole(s)/litre
        median (full range (min-max))
    7.9 (6.4 to 8.2)
    7.2 (6.5 to 7.9)
    7.6 (7.0 to 8.1)
    7.2 (6.4 to 7.7)
    No statistical analyses for this end point

    Secondary: Thrombin generation, Lagtime

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    End point title
    		 Thrombin generation, Lagtime
    End point description
    Thrombin generation, Lagtime is reduced when thrombin generation augments.
    End point type
    Secondary
    End point timeframe
    Blood samples from the systemic circulation were taken just before the Cesarean Section and 15 minutes after removal of the placenta.
    End point values
    		 Placenta previa patients before Placenta previa patients after Controls before Controls after
    Number of subjects analysed
    5
    5
    5
    5
    Units: minute
        median (full range (min-max))
    2.67 (2.67 to 3.00)
    2.44 (2.33 to 3.00)
    3.00 (2.33 to 3.33)
    2.33 (2.33 to 3.00)
    No statistical analyses for this end point

    Secondary: Thrombin generation, Peak

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    End point title
    		 Thrombin generation, Peak
    End point description
    Thrombin generation, Peak augments when Thrombin generation augments.
    End point type
    Secondary
    End point timeframe
    Blood samples from the systemic circulation were taken just before the Cesarean Section and 15 minutes after removal of the placenta.
    End point values
    		 Placenta previa patients before Placenta previa patients after Controls before Controls after
    Number of subjects analysed
    5
    5
    5
    5
    Units: nM
        median (full range (min-max))
    163.53 (132.66 to 240.75)
    206.98 (176.35 to 315.85)
    188.43 (148.84 to 291.89)
    279.66 (196.11 to 310.80)
    No statistical analyses for this end point

    Secondary: Thrombin generation, ttpeak

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    End point title
    		 Thrombin generation, ttpeak
    End point description
    Thrombin generation, ttpeak diminishes with augmentation in thrombin generation.
    End point type
    Secondary
    End point timeframe
    Blood samples from the systemic circulation were taken just before the Cesarean Section and 15 minutes after removal of the placenta.
    End point values
    		 Placenta previa patients before Placenta previa patients after Controls before Controls after
    Number of subjects analysed
    5
    5
    5
    5
    Units: minute
        median (full range (min-max))
    8.56 (5.67 to 10.11)
    6.44 (5.33 to 7.56)
    7.11 (5.33 to 8.67)
    5.11 (4.33 to 6.33)
    No statistical analyses for this end point

    Secondary: Thrombin generation, ETP

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    End point title
    		 Thrombin generation, ETP
    End point description
    Thrombin generation, endogenous thrombin potential (ETP) augments with augmentation in thrombin generation.
    End point type
    Secondary
    End point timeframe
    Blood samples from the systemic circulation were taken just before the Cesarean Section and 15 minutes after removal of the placenta.
    End point values
    		 Placenta previa patients before Placenta previa patients after Controls before Controls after
    Number of subjects analysed
    5
    5
    5
    5
    Units: NM x Minute
        median (full range (min-max))
    1493 (1203 to 1908)
    1574 (1417 to 2359)
    1464 (1432 to 1584)
    1470 (1323 to 1568)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    24 hours after end Cesarean Section
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 GCP, SOP I02-13
    Dictionary version
    F3
    Reporting groups
    Reporting group title
    Placenta Previa patients
    Reporting group description
    		 Patients with Placenta Previa undergoing planned Cesarean Section and receiving local treatment with recombinant, activated FVII solution at the placenta site.

    Serious adverse events
    		 Placenta Previa patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 5 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Placenta Previa patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 5 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: There were no reports of any sign of adverse effects after local application of recombinant, activated FVII at the placenta site. In addition all blood samples drawn 15 minutes after end of cesarean section showed no signs of overspill of rFVIIa through the placenta site to the systemic circulation.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28219621
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