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Factor VII, Prothrombin Complex Concentrate, and Fresh Frozen Plasma in Warfarin-Related Intracranial Hemorrhage

Primary Purpose

Intracranial Hemorrhage

Status
Terminated
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
Recombinant Activated Factor VII (rFVIIa)
Prothrombin Complex Concentrate
Fresh Frozen Plasma
Sponsored by
University of Utah
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Intracranial Hemorrhage focused on measuring intracranial hemorrhage, warfarin, anticoagulant, Factor VII, Prothrombin

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • Non-traumatic intracranial hemorrhage (subdural or intraparenchymal)
  • Known warfarin ingestion
  • INR ≥2.0
  • GCS <13

Exclusion Criteria:

  • Pregnancy
  • History of venous thrombosis or pulmonary embolus
  • Acute myocardial infarction
  • Acute stroke

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm 3

    Arm Type

    Experimental

    Experimental

    Active Comparator

    Arm Label

    Recombinant Activated Factor VII

    Prothrombin Complex Concentrate (PCC)

    Fresh Frozen Plasma (FFP)

    Arm Description

    The first five patients who meet the selection criteria will be administered an intravenous dose of rFVIIa 1mg upon arrival. INR will be drawn at 20 minutes post-rFVIIa administration. If normalized (≤1.3), then repeat INR with be drawn every 2 hours thereafter for 6 hours total, and again at 24 hours after initial administration. If at any time, the INR is >1.3, then rFVIIa 1mg will be readministered and the INR will again be checked 20 minutes after administration and every 2 hours for 6 hours total and again at 24 hours post-administration. This may be repeated until a total dose of 80mcg/kg has been given. If a maximum total of 80mcg/kg has been administered without successful correction of INR, then FFP infusions will be utilized to complete correction.

    5 patients will receive PCC based on ideal body weight. Each patient will receive 30 i.u./kg ideal body weight as is rounded to the nearest dispensed vial size. Vials are dispensed as 5mL (500 i.u.), 10mL (1000 i.u.), or 10mL (1500i.u.). INR will be drawn at 20 minutes post-administration and, if normalized (≤1.3), 2 hours post-administration and every 2 hours for 6 hours total. The INR will also be checked 24 hours post-administration. If at any time, the INR is >1.3, then PCC will be readministered at the same dose and the INR will again be checked 20 minutes after administration and every 2 hours for 6 hours total and again at 24 hours post-administration. A maximum total of 60 iu/kg can be administered before FFP will be used to complete the correction.

    The last five patients will receive transfusions of FFP to normalize INR. If the initial INR is between 2-4, then 2 units of FFP (Round 1) will be administered emergently. If the initial INR is >4, then 4 units of FFP will be administered (Round 1). The INR will be checked after each round of FFP infusion completed. Once INR ≤1.3, then the INR will be again checked every 2 hours after normalization for 6 hours total and then 24 hours post-initial infusion. If the INR should ever return to >1.3, then repeat infusions of FFP will begin as outlined above and the INR will be checked serially as defined above.

    Outcomes

    Primary Outcome Measures

    Normalization of INR (<1.4)

    Secondary Outcome Measures

    Hematoma progression
    Neurological status
    Timing of intervention completion
    Dosing of intervention required
    Medical complications during hospitalization

    Full Information

    First Posted
    October 9, 2008
    Last Updated
    November 22, 2011
    Sponsor
    University of Utah
    Collaborators
    Sheila B. Terry Memorial Research Fund
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    1. Study Identification

    Unique Protocol Identification Number
    NCT00770718
    Brief Title
    Factor VII, Prothrombin Complex Concentrate, and Fresh Frozen Plasma in Warfarin-Related Intracranial Hemorrhage
    Official Title
    A Comparison of Recombinant Activated Factor VII, Prothrombin Complex Concentrate, and Fresh Frozen Plasma for Anticoagulation Reversal in Warfarin-Associated Acute Intracranial Hemorrhage: A Dose Ranging Pilot Study
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    November 2011
    Overall Recruitment Status
    Terminated
    Why Stopped
    poor enrollment
    Study Start Date
    April 2008 (undefined)
    Primary Completion Date
    April 2010 (Actual)
    Study Completion Date
    April 2010 (Actual)

    3. Sponsor/Collaborators

    Name of the Sponsor
    University of Utah
    Collaborators
    Sheila B. Terry Memorial Research Fund

    4. Oversight

    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    The purpose of this dose-ranging pilot study is to compare Recombinant Activated Factor VII, Prothrombin Complex Concentrate and Fresh Frozen Plasma (each starting at low doses with escalation if necessary) for the reversal of warfarin in the setting of acute intracranial hemorrhage.
    Detailed Description
    Both recombinant activated Factor VIIa (rFVIIa) as well as Prothrombin Complex Concentrate (PCC) are labeled for the treatment of bleeding episodes in patients with hemophilia. Many hospitals are also using each for the following unlabeled indications: bleeding rescue in surgical patients, severe multiple trauma with ongoing bleeding, intracranial bleeding < 4 hours since symptom onset, traumatic head injury with evidence of expanding bleed, retroperitoneal bleed, and life-threatening bleeding due to idiopathic coagulopathy. To our knowledge, these two products have never been clinically compared head to head for the reversal of warfarin in the setting of intracranial hemorrhage. The rFVIIa (Novoseven) guidelines are based off of national data and utilize a dose range of 40-90 mcg/kg of ideal body weight (2.8-6.3 mg for a 70 kg. patient) with an additional dose if needed. The dose cited in the literature for the management of intracerebral bleeds ranges from 10 to 120 mcg/kg (0.7 - 8.4 mg for a 70 kg. patient,) with higher doses associated with increased risk of thromboembolic events. The recommended dosing of PCC is 30-50 i.u. per kilogram of ideal body weight with additional dosing if needed. PCC (Profilnine®SD) is a mixture of the following vitamin K-dependent clotting factors: II (prothrombin), VII (proconvertin), IX (plasma thromboplastin component; PTC; Christmas factor), and X (Stuart-Prower factor). These factors are required for the conversion of prothrombin to thrombin and thus adequate hemostasis, and are synthesized in the liver. Currently at the most hospitals around the country, fresh frozen plasma (FFP) is the mainstay for reversal of warfarin-related coagulopathy in intracranial hemorrhage at the discretion of the treating attending physician. We propose to study all the current reversal practices in the intracranial hemorrhage population here at the University of Utah as part of a quality improvement project for both patient safety and cost. We will perform a safety and feasibility study comparing dosage regimens of rFVIIa, FIXa and fresh frozen plasma (FFP) infusion in the normalization of coagulopathy in the context of warfarin-related intracerebral hemorrhage. Our primary outcome is time to INR normalization defined as INR≤ 1.3 on two consecutive readings separated by 2 hours.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Intracranial Hemorrhage
    Keywords
    intracranial hemorrhage, warfarin, anticoagulant, Factor VII, Prothrombin

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 1
    Interventional Study Model
    Parallel Assignment
    Masking
    None (Open Label)
    Allocation
    Non-Randomized
    Enrollment
    2 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Recombinant Activated Factor VII
    Arm Type
    Experimental
    Arm Description
    The first five patients who meet the selection criteria will be administered an intravenous dose of rFVIIa 1mg upon arrival. INR will be drawn at 20 minutes post-rFVIIa administration. If normalized (≤1.3), then repeat INR with be drawn every 2 hours thereafter for 6 hours total, and again at 24 hours after initial administration. If at any time, the INR is >1.3, then rFVIIa 1mg will be readministered and the INR will again be checked 20 minutes after administration and every 2 hours for 6 hours total and again at 24 hours post-administration. This may be repeated until a total dose of 80mcg/kg has been given. If a maximum total of 80mcg/kg has been administered without successful correction of INR, then FFP infusions will be utilized to complete correction.
    Arm Title
    Prothrombin Complex Concentrate (PCC)
    Arm Type
    Experimental
    Arm Description
    5 patients will receive PCC based on ideal body weight. Each patient will receive 30 i.u./kg ideal body weight as is rounded to the nearest dispensed vial size. Vials are dispensed as 5mL (500 i.u.), 10mL (1000 i.u.), or 10mL (1500i.u.). INR will be drawn at 20 minutes post-administration and, if normalized (≤1.3), 2 hours post-administration and every 2 hours for 6 hours total. The INR will also be checked 24 hours post-administration. If at any time, the INR is >1.3, then PCC will be readministered at the same dose and the INR will again be checked 20 minutes after administration and every 2 hours for 6 hours total and again at 24 hours post-administration. A maximum total of 60 iu/kg can be administered before FFP will be used to complete the correction.
    Arm Title
    Fresh Frozen Plasma (FFP)
    Arm Type
    Active Comparator
    Arm Description
    The last five patients will receive transfusions of FFP to normalize INR. If the initial INR is between 2-4, then 2 units of FFP (Round 1) will be administered emergently. If the initial INR is >4, then 4 units of FFP will be administered (Round 1). The INR will be checked after each round of FFP infusion completed. Once INR ≤1.3, then the INR will be again checked every 2 hours after normalization for 6 hours total and then 24 hours post-initial infusion. If the INR should ever return to >1.3, then repeat infusions of FFP will begin as outlined above and the INR will be checked serially as defined above.
    Intervention Type
    Drug
    Intervention Name(s)
    Recombinant Activated Factor VII (rFVIIa)
    Other Intervention Name(s)
    Novoseven®
    Intervention Description
    Five patients who meet the selection criteria will be administered an intravenous dose of rFVIIa 1mg upon arrival. INR will be drawn at 20 minutes post-rFVIIa administration. If normalized (≤1.3), then repeat INR with be drawn every 2 hours thereafter for 6 hours total, and again at 24 hours after initial administration. If at any time, the INR is >1.3, then rFVIIa 1mg will be readministered and the INR will again be checked 20 minutes after administration and every 2 hours for 6 hours total and again at 24 hours post-administration. This may be repeated until a total dose of 80mcg/kg has been given.
    Intervention Type
    Drug
    Intervention Name(s)
    Prothrombin Complex Concentrate
    Other Intervention Name(s)
    Profilnine®
    Intervention Description
    5 patients will receive PCC based on ideal body weight. Each patient will receive 30 i.u./kg ideal body weight as is rounded to the nearest dispensed vial size. Vials are dispensed as 5mL (500 i.u.), 10mL (1000 i.u.), or 10mL (1500i.u.). INR will be drawn at 20 minutes post-administration and, if normalized (≤1.3), 2 hours post-administration and every 2 hours for 6 hours total. The INR will also be checked 24 hours post-administration. If at any time, the INR is >1.3, then PCC will be readministered at the same dose and the INR will again be checked 20 minutes after administration and every 2 hours for 6 hours total and again at 24 hours post-administration. A maximum total of 60 iu/kg can be administered.
    Intervention Type
    Biological
    Intervention Name(s)
    Fresh Frozen Plasma
    Other Intervention Name(s)
    FFP
    Intervention Description
    Five patients will receive transfusions of FFP to normalize INR. If the initial INR is between 2-4, then 2 units of FFP (Round 1) will be administered emergently. If the initial INR is >4, then 4 units of FFP will be administered (Round 1). The INR will be checked after each round of FFP infusion completed. Once INR ≤1.3, then the INR will be again checked every 2 hours after normalization for 6 hours total and then 24 hours post-initial infusion. If the INR should ever return to >1.3, then repeat infusions of FFP will begin as outlined above and the INR will be checked serially as defined above.
    Primary Outcome Measure Information:
    Title
    Normalization of INR (<1.4)
    Time Frame
    20min, 2hrs, 4hrs, 6hrs, 24hrs
    Secondary Outcome Measure Information:
    Title
    Hematoma progression
    Time Frame
    24hrs
    Title
    Neurological status
    Time Frame
    24hrs & 1month
    Title
    Timing of intervention completion
    Time Frame
    24hrs
    Title
    Dosing of intervention required
    Time Frame
    24hrs
    Title
    Medical complications during hospitalization
    Time Frame
    days

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    Accepts Healthy Volunteers
    Eligibility Criteria
    Inclusion Criteria: Non-traumatic intracranial hemorrhage (subdural or intraparenchymal) Known warfarin ingestion INR ≥2.0 GCS <13 Exclusion Criteria: Pregnancy History of venous thrombosis or pulmonary embolus Acute myocardial infarction Acute stroke

    12. IPD Sharing Statement

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    Factor VII, Prothrombin Complex Concentrate, and Fresh Frozen Plasma in Warfarin-Related Intracranial Hemorrhage

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