xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT06037200</url>
    </required_header>
    <id_info>
      <org_study_id>AZ 194/22</org_study_id>
      <nct_id>NCT06037200</nct_id>
    </id_info>
    <brief_title>Urin-based Point-of-Care Testing for Direct Oral Anticoagulants in Stroke Patients</brief_title>
    <acronym>UPTURN</acronym>
    <official_title>Evaluation of a Urin-based Point-of-Care Testing Device for Direct Oral Anticoagulants in Patients With Acute Ischemic or Hemorrhagic Stroke</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>University of Giessen</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>University of Giessen</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        The goal of this study is to test a urine-based point-of-care testing device for direct oral&#xD;
        anticoagulants in patients with stroke. The main questions are:&#xD;
  &#xD;
          -  Can the test identify patients with direct oral anticoagulant intake?&#xD;
  &#xD;
          -  Is there a time benefit of urine-based point-of-care testing compared to standard&#xD;
             blood-based coagulation assessment?&#xD;
  &#xD;
          -  Is the device feasible in the setting of acute stroke care?&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Stroke is the second leading cause of death worldwide and the most common cause of acquired&#xD;
        disability in adulthood. During the acute phase of ischemic brain infarction, the goal of&#xD;
        therapy is the rapid re-opening of the occluded vessel through recanalization procedures.&#xD;
        This aims to restore blood flow to the penumbra, the tissue surrounding the infarct core with&#xD;
        reduced blood supply, and prevent irreversible damage. Established approaches include&#xD;
        systemic thrombolysis (intravenous thrombolysis, IVT) using Actilyse® (rt-PA), which is the&#xD;
        only approved and proven effective therapy available within the first 4.5 hours. Mechanical&#xD;
        thrombectomy (endovascular thrombectomy, EVT) has also been employed in recent years for&#xD;
        highly selected patients with large vessel occlusion. However, this treatment requires&#xD;
        interdisciplinary center structures and specialized imaging-based patient selection.&#xD;
        Nonetheless, these patients also clearly benefit from prior or concomitant IVT, making it the&#xD;
        foundation of stroke care in Germany and worldwide for decades.&#xD;
  &#xD;
        The rate of patients eligible for IVT treatment remains improvable, stabilizing around 20% of&#xD;
        all acute cerebral ischemia patients, depending on the center and region. Various reasons&#xD;
        contribute to this, but among the primary causes for not considering IVT (besides&#xD;
        contraindications such as delayed or unknown symptom onset window) is the growing fraction of&#xD;
        patients (about 8%) who are on oral anticoagulation or cannot receive IVT due to the lack of&#xD;
        exclusion thereof (e.g., in patients with altered consciousness or aphasia). Current&#xD;
        estimates suggest that nearly 2 million people in Germany require oral anticoagulation, with&#xD;
        an increasing trend.&#xD;
  &#xD;
        Current Problem:&#xD;
  &#xD;
        The availability of oral anticoagulation options includes Vitamin K antagonists (e.g.,&#xD;
        Marcumar) and direct oral anticoagulants (DOACs). DOACs are classified into two subgroups&#xD;
        based on their mechanism: Factor IIa inhibitors (e.g., Dabigatran) and Factor Xa inhibitors&#xD;
        (e.g., Apixaban, Rivaroxaban, Edoxaban). For stroke treatment, it's crucial to know the&#xD;
        presence and extent of anticoagulation because it significantly increases the risk of&#xD;
        bleeding under additional IVT, rendering IVT contraindicated or requiring immediate&#xD;
        hemostatic therapy in the event of bleeding. While reliable and rapid anticoagulation&#xD;
        assessment is possible with Vitamin K antagonists using point-of-care (PoC) devices (e.g.,&#xD;
        CoaguCheks®), this is more challenging for DOAC patients.&#xD;
  &#xD;
        The accurate determination or exclusion of anticoagulation is therapeutically relevant since&#xD;
        it affects the administration of substance-specific antidotes like Idarucizumab (for Factor&#xD;
        IIa inhibitors) and Andexanet alfa (for Factor Xa inhibitors). Urgently needed for DOAC&#xD;
        patients with acute stroke symptoms, PoC devices are essential. Many of these patients,&#xD;
        lacking the ability to assess drug levels, cannot receive IVT in a timely manner. This&#xD;
        situation is particularly problematic when reliable information about DOAC usage is absent&#xD;
        due to patient or caregiver inability to provide an accurate history.&#xD;
  &#xD;
        Medical need:&#xD;
  &#xD;
        Management of anticoagulated stroke patients in emergency settings needs improvement to&#xD;
        swiftly provide relevant information about existing oral anticoagulation, even for DOAC use.&#xD;
        DOACs have surpassed Vitamin K antagonists in atrial fibrillation therapy, and around 3% of&#xD;
        the general population is now anticoagulated with DOACs. Routine coagulation lab parameters,&#xD;
        including INR or aPTT, are minimally affected in DOAC-treated patients, making exclusion or&#xD;
        confirmation of anticoagulation challenging. There is currently no globally available routine&#xD;
        lab parameter or straightforward PoC test system. Presently, assessing DOAC presence and&#xD;
        extent requires complex substance-specific and calibrated coagulation parameters. Chromogenic&#xD;
        Anti-Xa assays for Factor Xa inhibitors and modified thrombin time assays for Dabigatran&#xD;
        (Hemoclot® Thrombin-Inhibitor-Test) are available but only in a few high-level central&#xD;
        laboratories, with results taking at least an hour, assuming 24/7 emergency testing&#xD;
        availability.&#xD;
  &#xD;
        IVT for acute stroke patients on DOACs is therefore mainly feasible in centers with drug&#xD;
        level assessment options, and even then, it's considerably delayed. This dilemma leads to a&#xD;
        substantial number of patients being admitted to stroke units across Germany who ultimately&#xD;
        don't receive IVT, despite meeting criteria, due to either the absence of effective&#xD;
        anticoagulation or inaccurate patient history. This scenario is especially common in patients&#xD;
        where reliable information about DOAC use isn't available due to absent patient or caregiver&#xD;
        history. Enabling these patients, initially not treated due to a lack of valid information,&#xD;
        to benefit from an ideal therapy with potentially significant socio-economic impact through&#xD;
        improved outcomes and reduced dependency, poses a significant challenge to increasing IVT&#xD;
        rates consistently across clinics.&#xD;
  &#xD;
        In Germany, it's estimated that timely identification of DOAC patients and the use of&#xD;
        specific antidotes could lead to a 6% increase in the IVT rate. An even greater increase can&#xD;
        be expected for patients with a falsely positive history of DOAC use.&#xD;
  &#xD;
        Urine based Point-of-Care Testing Device:&#xD;
  &#xD;
        A potential solution to this problem is the urine-based point-of-care testing system offered&#xD;
        by DOASENSE - the DOAC Dipstick. This system allows for semi-quantitative determination of&#xD;
        individual DOAC agents in patient urine within 10 minutes, aided by a machine, and is&#xD;
        reliable. Clinically relevant DOAC concentrations were excluded in a preliminary study by&#xD;
        DOASENSE, setting a concentration of &gt;30 ng/ml in plasma using either spontaneous or&#xD;
        catheterized urine samples. The test is based on the fact that all currently approved DOACs&#xD;
        are renal filtrated and secreted within 1-2 hours. Two pharma-funded studies involving &gt;800&#xD;
        and &gt;100 patients respectively demonstrated a sensitivity and specificity for urine samples&#xD;
        above 95% compared to mass spectrometry. However, these studies lacked sufficient numbers of&#xD;
        stroke patients and lacked clinical characteristics, making them inconclusive for stroke&#xD;
        patient treatment.&#xD;
  &#xD;
        A dedicated investigation of the Dipstick method in the acute treatment of stroke patients,&#xD;
        especially as a decision-making aid for thrombolytic therapy, is lacking. This hampers the&#xD;
        widespread application of this potentially valuable system and limits patient care.&#xD;
        Therefore, this proposed study aims to apply the DOAC Dipstick method specifically to&#xD;
        patients where the last DOAC intake is unclear based on self-report or external history, or&#xD;
        where DOAC intake is confirmed but lacks sufficient anticoagulatory effect, thus making IVT a&#xD;
        potential treatment option.&#xD;
  &#xD;
        Goals and Phases of the Proposed Study Program:&#xD;
  &#xD;
        The planned research project pursues two objectives, which are intended to be achieved in two&#xD;
        consecutive study phases:&#xD;
  &#xD;
        In the first phase of the study, the data from two previously published studies will be&#xD;
        specifically examined for patients with ischemic stroke who are being treated in our Stroke&#xD;
        Unit. For this purpose, urine and blood plasma samples will be collected simultaneously from&#xD;
        patients with and without direct oral anticoagulant (DOAC) intake, and these samples will be&#xD;
        analyzed using the DOASENSE urine test and the standard DOAC concentration determination&#xD;
        performed in the coagulation laboratory at the Gießen site. The results will be correlated&#xD;
        with each other. For the clinical establishment of the procedure, a sensitivity and&#xD;
        specificity of &gt;95% are to be demanded within this patient cohort.&#xD;
  &#xD;
        In the second phase, the DOAC Dipstick test will be evaluated in parallel with plasma&#xD;
        concentration determination in acute stroke patients admitted to our central emergency&#xD;
        department, who could potentially benefit from intravenous thrombolysis (IVT) (time window&#xD;
        since symptom onset &lt;4.5 hours) and have unclear or confirmed DOAC intake. Through the&#xD;
        correlation between Dipstick analysis and plasma concentrations, the real-time savings&#xD;
        achieved by using the Dipstick in a central emergency department setting will be documented&#xD;
        (i), and a specific number of patients will be verified who could potentially be treated with&#xD;
        IVT through this approach due to the evidence of a DOAC concentration below 30 ng/ml (ii).&#xD;
  &#xD;
        These two analyses are essential in order to (i) document the significance and specificity&#xD;
        (&quot;safety &amp; feasibility&quot;) of the device in acute stroke patients with common co-medication,&#xD;
        (ii) detect the potential time savings of urine testing compared to the standard laboratory&#xD;
        determination in the acute care setting, and (iii) demonstrate a resulting potential increase&#xD;
        in the IVT rate at the treatment site. In a further step, (iv) specific incidences of these&#xD;
        patient constellations (i.e., how often does this situation actually occur in everyday&#xD;
        practice) will be generated, and specific effect sizes (i.e., therapy versus no therapy in&#xD;
        peripheral hospitals and the effect of earlier therapy in maximal care hospitals) will be&#xD;
        modeled. Based on this, a comprehensive Phase-3 study with clinical endpoints can then be&#xD;
        advanced.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">January 1, 2023</start_date>
    <completion_date type="Anticipated">July 31, 2024</completion_date>
    <primary_completion_date type="Anticipated">June 30, 2024</primary_completion_date>
    <study_type>Observational</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <observational_model>Cohort</observational_model>
      <time_perspective>Prospective</time_perspective>
    </study_design_info>
    <primary_outcome>
      <measure>Time-benefit of urine-based POC-testing versus standard blood-based coagulation assessment</measure>
      <time_frame>24 hours</time_frame>
      <description>i.e. difference between time delay of anti-Xa or Hemoclot testing (duration of blood sampling until result) and time delay of POC-test (duration of urine sampling until result)</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Sensitivity of POC-test</measure>
      <time_frame>24 hours</time_frame>
      <description>Rate of correctly identified patients with either a anti-Xa level (factor-Xa-inhibitor) or hemoclot level (dabigatran) ≥ 30 ng/ml</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Feasibility of POC test during acute stroke care</measure>
      <time_frame>24 hours</time_frame>
      <description>Rate of patients presenting with stroke in the emergency room in whom urine-based point-of-care testing can be performed</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Rate of DOAC-test within 4.5 hours</measure>
      <time_frame>24 hours</time_frame>
      <description>To estimate the potential benefit, the rate of available result on DOAC-testing (either blood- or urine-based) within 4.5 hours of stroke onset (time-window for IVT) will be recorded</description>
    </secondary_outcome>
    <other_outcome>
      <measure>Specificity</measure>
      <time_frame>24 hours</time_frame>
      <description>Rate of patients without DOAC-intake correctly detected by the urine-based POC-test device</description>
    </other_outcome>
    <other_outcome>
      <measure>Cost-benefit of treatment of urine-based POC versus blood-based coagulation assessment</measure>
      <time_frame>7 days</time_frame>
      <description>Cost comparison of urine based POC-test versus blood-based coagulation assessment</description>
    </other_outcome>
    <number_of_groups>2</number_of_groups>
    <enrollment type="Anticipated">200</enrollment>
    <condition>Stroke</condition>
    <arm_group>
      <arm_group_label>Patients with suspected DOAC intake</arm_group_label>
      <description>Stroke patients with safe or suspected intake of direct oral anticoagulants</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Patients without DOAC intake</arm_group_label>
      <description>Stroke patients without intake of direct oral anticoagulants</description>
    </arm_group>
    <intervention>
      <intervention_type>Device</intervention_type>
      <intervention_name>Urin-based test by the DOASENSE Dipstick Device</intervention_name>
      <description>Routinely assessed urine is tested by the DOASENSE Dipstick device for presence of direct oral anticoagulants. Readout is performed after 10 minutes visually and by a automated reader.</description>
      <arm_group_label>Patients with suspected DOAC intake</arm_group_label>
      <arm_group_label>Patients without DOAC intake</arm_group_label>
    </intervention>
    <eligibility>
      <study_pop>
        <textblock>
          For Phase 1, approximately 40 patients are allocated to both the experimental group (i.e.,&#xD;
          stroke patients with confirmed intake of a Direct Oral Anticoagulant) and the control group&#xD;
          (i.e., stroke patients without intake of a Direct Oral Anticoagulant). For Phase 2,&#xD;
          consecutive patients with suspected or confirmed intake of a Direct Oral Anticoagulant,&#xD;
          admitted to our central emergency department with a presumptive diagnosis of acute stroke,&#xD;
          will be enrolled.&#xD;
        </textblock>
      </study_pop>
      <sampling_method>Probability Sample</sampling_method>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Patient age ≥18 years at the time of admission&#xD;
  &#xD;
            -  Clinical diagnosis of ischemic or hemorrhagic stroke.&#xD;
  &#xD;
            -  Treatmet at our certified stroke-unit, University Hospital Giessen.&#xD;
  &#xD;
            -  Phase 1 only: Confirmed intake of a direct oral anticoagulant (DOAC) for at least 48&#xD;
               hours (test group) or no intake of a DOAC (control group for specificity&#xD;
               determination)&#xD;
  &#xD;
            -  Phase II only, anamnestic intake of DOAC or no information about OAC-intake.&#xD;
  &#xD;
            -  Phase II only, presentation with 4.5 hours after onset.&#xD;
  &#xD;
          Exclusion Criteria (only Phase II):&#xD;
  &#xD;
            -  Contraindications for intravenous thrombolysis other than intake of DOAC&#xD;
  &#xD;
            -  large vessel occlusion with indication for immediate endovascular thrombectomy&#xD;
  &#xD;
            -  chronic renal insufficiency with need for hemodialysis&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Stefan Gerner, MD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Department of Neurology, University Hospital Giessen/Germany</affiliation>
    </overall_official>
    <overall_official>
      <last_name>Thorsten Doeppner, MD</last_name>
      <role>Study Chair</role>
      <affiliation>Department of Neurology, University Hospital Giessen/Germany</affiliation>
    </overall_official>
    <overall_official>
      <last_name>Hagen Huttner, MD, PhD</last_name>
      <role>Study Chair</role>
      <affiliation>Department of Neurology, University Hospital Giessen/Germany</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Stefan Gerner, MD</last_name>
      <phone>+49-641/985-45301</phone>
      <email>stefan.gerner@neuro.med.uni-giessen.de</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Thorsten Doeppner, MD</last_name>
      <phone>+49-641/985-45301</phone>
      <email>thorsten.doeppner@neuro.med.uni-giessen.de</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Department of Neurology, University Hospital Giessen</name>
        <address>
          <city>Gießen</city>
          <state>Hesse</state>
          <zip>35392</zip>
          <country>Germany</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Stefan Gerner, MD</last_name>
        <email>stefan.gerner@neuro.med.uni-giessen.de</email>
      </contact>
      <contact_backup>
        <last_name>Thorsten Doeppner, MD</last_name>
        <email>thorsten.doeppner@neuro.med.uni-giessen.de</email>
      </contact_backup>
    </location>
    <location_countries>
      <country>Germany</country>
    </location_countries>
    <link>
      <url>https://www.doasense.de/</url>
      <description>Website of the manufacturer of the DOASENSE Dipstick</description>
    </link>
    <reference>
      <citation>Harenberg J, Beyer-Westendorf J, Crowther M, Douxfils J, Elalamy I, Verhamme P, Bauersachs R, Hetjens S, Weiss C; Working Group Members. Accuracy of a Rapid Diagnostic Test for the Presence of Direct Oral Factor Xa or Thrombin Inhibitors in Urine-A Multicenter Trial. Thromb Haemost. 2020 Jan;120(1):132-140. doi: 10.1055/s-0039-1700545. Epub 2019 Nov 8.</citation>
      <PMID>31705521</PMID>
    </reference>
    <reference>
      <citation>Siedler G, Macha K, Stoll S, Plechschmidt J, Wang R, Gerner ST, Strasser E, Schwab S, Kallmunzer B. Monitoring of direct oral anticoagulants plasma levels for secondary stroke prevention. J Thromb Haemost. 2022 May;20(5):1138-1145. doi: 10.1111/jth.15677. Epub 2022 Mar 12.</citation>
      <PMID>35171533</PMID>
    </reference>
    <reference>
      <citation>Gerner ST, Huttner HB. Patients on NOACs in the Emergency Room. Curr Neurol Neurosci Rep. 2019 May 29;19(7):40. doi: 10.1007/s11910-019-0954-7.</citation>
      <PMID>31144111</PMID>
    </reference>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>August 30, 2023</study_first_submitted>
    <study_first_submitted_qc>September 13, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">September 14, 2023</study_first_posted>
    <last_update_submitted>September 13, 2023</last_update_submitted>
    <last_update_submitted_qc>September 13, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 14, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>University of Giessen</investigator_affiliation>
      <investigator_full_name>Stefan Gerner</investigator_full_name>
      <investigator_title>Principal Investigator, Associate professor</investigator_title>
    </responsible_party>
    <keyword>oral anticoagulation</keyword>
    <keyword>direct oral anticoagulants</keyword>
    <keyword>point-of-care test</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Stroke</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>Undecided</sharing_ipd>
      <ipd_description>Reasonable requests for IPD will be reviewed by the steering committee.</ipd_description>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT06037200
  org study id: AZ 194/22
  nct id: NCT06037200
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  The goal of this study is to test a urine-based point-of-care testing device for direct oral
        anticoagulants in patients with stroke. The main questions are:
  
          -  Can the test identify patients with direct oral anticoagulant intake?
  
          -  Is there a time benefit of urine-based point-of-care testing compared to standard
             blood-based coagulation assessment?
  
          -  Is the device feasible in the setting of acute stroke care?
  Stroke is the second leading cause of death worldwide and the most common cause of acquired
        disability in adulthood. During the acute phase of ischemic brain infarction, the goal of
        therapy is the rapid re-opening of the occluded vessel through recanalization procedures.
        This aims to restore blood flow to the penumbra, the tissue surrounding the infarct core with
        reduced blood supply, and prevent irreversible damage. Established approaches include
        systemic thrombolysis (intravenous thrombolysis, IVT) using Actilyse® (rt-PA), which is the
        only approved and proven effective therapy available within the first 4.5 hours. Mechanical
        thrombectomy (endovascular thrombectomy, EVT) has also been employed in recent years for
        highly selected patients with large vessel occlusion. However, this treatment requires
        interdisciplinary center structures and specialized imaging-based patient selection.
        Nonetheless, these patients also clearly benefit from prior or concomitant IVT, making it the
        foundation of stroke care in Germany and worldwide for decades.
  
        The rate of patients eligible for IVT treatment remains improvable, stabilizing around 20% of
        all acute cerebral ischemia patients, depending on the center and region. Various reasons
        contribute to this, but among the primary causes for not considering IVT (besides
        contraindications such as delayed or unknown symptom onset window) is the growing fraction of
        patients (about 8%) who are on oral anticoagulation or cannot receive IVT due to the lack of
        exclusion thereof (e.g., in patients with altered consciousness or aphasia). Current
        estimates suggest that nearly 2 million people in Germany require oral anticoagulation, with
        an increasing trend.
  
        Current Problem:
  
        The availability of oral anticoagulation options includes Vitamin K antagonists (e.g.,
        Marcumar) and direct oral anticoagulants (DOACs). DOACs are classified into two subgroups
        based on their mechanism: Factor IIa inhibitors (e.g., Dabigatran) and Factor Xa inhibitors
        (e.g., Apixaban, Rivaroxaban, Edoxaban). For stroke treatment, it's crucial to know the
        presence and extent of anticoagulation because it significantly increases the risk of
        bleeding under additional IVT, rendering IVT contraindicated or requiring immediate
        hemostatic therapy in the event of bleeding. While reliable and rapid anticoagulation
        assessment is possible with Vitamin K antagonists using point-of-care (PoC) devices (e.g.,
        CoaguCheks®), this is more challenging for DOAC patients.
  
        The accurate determination or exclusion of anticoagulation is therapeutically relevant since
        it affects the administration of substance-specific antidotes like Idarucizumab (for Factor
        IIa inhibitors) and Andexanet alfa (for Factor Xa inhibitors). Urgently needed for DOAC
        patients with acute stroke symptoms, PoC devices are essential. Many of these patients,
        lacking the ability to assess drug levels, cannot receive IVT in a timely manner. This
        situation is particularly problematic when reliable information about DOAC usage is absent
        due to patient or caregiver inability to provide an accurate history.
  
        Medical need:
  
        Management of anticoagulated stroke patients in emergency settings needs improvement to
        swiftly provide relevant information about existing oral anticoagulation, even for DOAC use.
        DOACs have surpassed Vitamin K antagonists in atrial fibrillation therapy, and around 3% of
        the general population is now anticoagulated with DOACs. Routine coagulation lab parameters,
        including INR or aPTT, are minimally affected in DOAC-treated patients, making exclusion or
        confirmation of anticoagulation challenging. There is currently no globally available routine
        lab parameter or straightforward PoC test system. Presently, assessing DOAC presence and
        extent requires complex substance-specific and calibrated coagulation parameters. Chromogenic
        Anti-Xa assays for Factor Xa inhibitors and modified thrombin time assays for Dabigatran
        (Hemoclot® Thrombin-Inhibitor-Test) are available but only in a few high-level central
        laboratories, with results taking at least an hour, assuming 24/7 emergency testing
        availability.
  
        IVT for acute stroke patients on DOACs is therefore mainly feasible in centers with drug
        level assessment options, and even then, it's considerably delayed. This dilemma leads to a
        substantial number of patients being admitted to stroke units across Germany who ultimately
        don't receive IVT, despite meeting criteria, due to either the absence of effective
        anticoagulation or inaccurate patient history. This scenario is especially common in patients
        where reliable information about DOAC use isn't available due to absent patient or caregiver
        history. Enabling these patients, initially not treated due to a lack of valid information,
        to benefit from an ideal therapy with potentially significant socio-economic impact through
        improved outcomes and reduced dependency, poses a significant challenge to increasing IVT
        rates consistently across clinics.
  
        In Germany, it's estimated that timely identification of DOAC patients and the use of
        specific antidotes could lead to a 6% increase in the IVT rate. An even greater increase can
        be expected for patients with a falsely positive history of DOAC use.
  
        Urine based Point-of-Care Testing Device:
  
        A potential solution to this problem is the urine-based point-of-care testing system offered
        by DOASENSE - the DOAC Dipstick. This system allows for semi-quantitative determination of
        individual DOAC agents in patient urine within 10 minutes, aided by a machine, and is
        reliable. Clinically relevant DOAC concentrations were excluded in a preliminary study by
        DOASENSE, setting a concentration of >30 ng/ml in plasma using either spontaneous or
        catheterized urine samples. The test is based on the fact that all currently approved DOACs
        are renal filtrated and secreted within 1-2 hours. Two pharma-funded studies involving >800
        and >100 patients respectively demonstrated a sensitivity and specificity for urine samples
        above 95% compared to mass spectrometry. However, these studies lacked sufficient numbers of
        stroke patients and lacked clinical characteristics, making them inconclusive for stroke
        patient treatment.
  
        A dedicated investigation of the Dipstick method in the acute treatment of stroke patients,
        especially as a decision-making aid for thrombolytic therapy, is lacking. This hampers the
        widespread application of this potentially valuable system and limits patient care.
        Therefore, this proposed study aims to apply the DOAC Dipstick method specifically to
        patients where the last DOAC intake is unclear based on self-report or external history, or
        where DOAC intake is confirmed but lacks sufficient anticoagulatory effect, thus making IVT a
        potential treatment option.
  
        Goals and Phases of the Proposed Study Program:
  
        The planned research project pursues two objectives, which are intended to be achieved in two
        consecutive study phases:
  
        In the first phase of the study, the data from two previously published studies will be
        specifically examined for patients with ischemic stroke who are being treated in our Stroke
        Unit. For this purpose, urine and blood plasma samples will be collected simultaneously from
        patients with and without direct oral anticoagulant (DOAC) intake, and these samples will be
        analyzed using the DOASENSE urine test and the standard DOAC concentration determination
        performed in the coagulation laboratory at the Gießen site. The results will be correlated
        with each other. For the clinical establishment of the procedure, a sensitivity and
        specificity of >95% are to be demanded within this patient cohort.
  
        In the second phase, the DOAC Dipstick test will be evaluated in parallel with plasma
        concentration determination in acute stroke patients admitted to our central emergency
        department, who could potentially benefit from intravenous thrombolysis (IVT) (time window
        since symptom onset <4.5 hours) and have unclear or confirmed DOAC intake. Through the
        correlation between Dipstick analysis and plasma concentrations, the real-time savings
        achieved by using the Dipstick in a central emergency department setting will be documented
        (i), and a specific number of patients will be verified who could potentially be treated with
        IVT through this approach due to the evidence of a DOAC concentration below 30 ng/ml (ii).
  
        These two analyses are essential in order to (i) document the significance and specificity
        ("safety & feasibility") of the device in acute stroke patients with common co-medication,
        (ii) detect the potential time savings of urine testing compared to the standard laboratory
        determination in the acute care setting, and (iii) demonstrate a resulting potential increase
        in the IVT rate at the treatment site. In a further step, (iv) specific incidences of these
        patient constellations (i.e., how often does this situation actually occur in everyday
        practice) will be generated, and specific effect sizes (i.e., therapy versus no therapy in
        peripheral hospitals and the effect of earlier therapy in maximal care hospitals) will be
        modeled. Based on this, a comprehensive Phase-3 study with clinical endpoints can then be
        advanced.
  observational model: Cohort
  time perspective: Prospective
  measure: Time-benefit of urine-based POC-testing versus standard blood-based coagulation assessment
  time frame: 24 hours
  description: i.e. difference between time delay of anti-Xa or Hemoclot testing (duration of blood sampling until result) and time delay of POC-test (duration of urine sampling until result)
  measure: Sensitivity of POC-test
  time frame: 24 hours
  description: Rate of correctly identified patients with either a anti-Xa level (factor-Xa-inhibitor) or hemoclot level (dabigatran) ≥ 30 ng/ml
  measure: Feasibility of POC test during acute stroke care
  time frame: 24 hours
  description: Rate of patients presenting with stroke in the emergency room in whom urine-based point-of-care testing can be performed
  measure: Rate of DOAC-test within 4.5 hours
  time frame: 24 hours
  description: To estimate the potential benefit, the rate of available result on DOAC-testing (either blood- or urine-based) within 4.5 hours of stroke onset (time-window for IVT) will be recorded
  measure: Specificity
  time frame: 24 hours
  description: Rate of patients without DOAC-intake correctly detected by the urine-based POC-test device
  measure: Cost-benefit of treatment of urine-based POC versus blood-based coagulation assessment
  time frame: 7 days
  description: Cost comparison of urine based POC-test versus blood-based coagulation assessment
  arm group label: Patients with suspected DOAC intake
  description: Stroke patients with safe or suspected intake of direct oral anticoagulants
  arm group label: Patients without DOAC intake
  description: Stroke patients without intake of direct oral anticoagulants
  intervention type: Device
  intervention name: Urin-based test by the DOASENSE Dipstick Device
  description: Routinely assessed urine is tested by the DOASENSE Dipstick device for presence of direct oral anticoagulants. Readout is performed after 10 minutes visually and by a automated reader.
  arm group label: Patients with suspected DOAC intake
  arm group label: Patients without DOAC intake
  study pop: 
  sampling method: Probability Sample
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Stefan Gerner, MD
  role: Principal Investigator
  affiliation: Department of Neurology, University Hospital Giessen/Germany
  last name: Thorsten Doeppner, MD
  role: Study Chair
  affiliation: Department of Neurology, University Hospital Giessen/Germany
  last name: Hagen Huttner, MD, PhD
  role: Study Chair
  affiliation: Department of Neurology, University Hospital Giessen/Germany
  last name: Stefan Gerner, MD
  phone: +49-641/985-45301
  email: stefan.gerner@neuro.med.uni-giessen.de
  last name: Thorsten Doeppner, MD
  phone: +49-641/985-45301
  email: thorsten.doeppner@neuro.med.uni-giessen.de
  facility: 
  status: Recruiting
  contact: 
  contact backup: 
  country: Germany
  url: https://www.doasense.de/
  description: Website of the manufacturer of the DOASENSE Dipstick
  citation: Harenberg J, Beyer-Westendorf J, Crowther M, Douxfils J, Elalamy I, Verhamme P, Bauersachs R, Hetjens S, Weiss C; Working Group Members. Accuracy of a Rapid Diagnostic Test for the Presence of Direct Oral Factor Xa or Thrombin Inhibitors in Urine-A Multicenter Trial. Thromb Haemost. 2020 Jan;120(1):132-140. doi: 10.1055/s-0039-1700545. Epub 2019 Nov 8.
  PMID: 31705521
  citation: Siedler G, Macha K, Stoll S, Plechschmidt J, Wang R, Gerner ST, Strasser E, Schwab S, Kallmunzer B. Monitoring of direct oral anticoagulants plasma levels for secondary stroke prevention. J Thromb Haemost. 2022 May;20(5):1138-1145. doi: 10.1111/jth.15677. Epub 2022 Mar 12.
  PMID: 35171533
  citation: Gerner ST, Huttner HB. Patients on NOACs in the Emergency Room. Curr Neurol Neurosci Rep. 2019 May 29;19(7):40. doi: 10.1007/s11910-019-0954-7.
  PMID: 31144111
  responsible party type: Principal Investigator
  investigator affiliation: University of Giessen
  investigator full name: Stefan Gerner
  investigator title: Principal Investigator, Associate professor
  mesh term: Stroke
  sharing ipd: Undecided
  ipd description: Reasonable requests for IPD will be reviewed by the steering committee.