<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/NCT01713491</url>
  </required_header>
  <id_info>
    <org_study_id>2010_04</org_study_id>
    <secondary_id>912079</secondary_id>
    <nct_id>NCT01713491</nct_id>
  </id_info>
  <brief_title>Pre-stroke Cognitive Status and Thrombolytic Therapy</brief_title>
  <acronym>OPHELIE-COG</acronym>
  <official_title>Influence of the Pre-existing Cognitive Status on the Outcome in Patients Treated by Thrombolytic Therapy for Acute Cerebral Ischaemia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital, Lille</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Hospital, Lille</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      At the acute stage of cerebral ischaemia, the only effective drug that increases the&#xD;
      proportion of patients who survive without dependency is thrombolytic therapy by intravenous&#xD;
      (i.v.) tissue-plasminogen activator (t-PA). This treatment is entered into routine practice&#xD;
      with similar results than in trials, in various places of the world including Europe and&#xD;
      Japan.&#xD;
&#xD;
      Stroke and dementia are closely related. About one patient in ten has dementia before a&#xD;
      first-ever stroke, and more than one in three has dementia after a recurrent stroke.&#xD;
      Pre-existing dementia is associated with a worse outcome of stroke, and pre-existing&#xD;
      cognitive impairment without dementia is associated with a higher rate of&#xD;
      institutionalisation within 3 years. In many patients cognitive impairment is due to the&#xD;
      summation of the effects of vascular and Alzheimer lesions of the brain.&#xD;
&#xD;
      More and more patients nowadays who are eligible for rt-PA are already known as demented at&#xD;
      admission. A retrospective study conducted in a cohort of patients with dementia who had an&#xD;
      ischaemic stroke and were treated by rtPA suggested that there is no increased risk of&#xD;
      cerebral bleeding and death as compared with non demented patients. However, pre-existing&#xD;
      cognitive impairment is possibly associated with (i) an increased risk of bleeding in&#xD;
      patients with cognitive impairment, and (ii) a higher sensitivity to the neurotoxic effect of&#xD;
      rt-PA on the brain tissue.&#xD;
&#xD;
      Japanese patients differ from European patients by a higher risk of spontaneous intracranial&#xD;
      haemorrhage, and a higher proportion of patients with small-vessel diseases.&#xD;
&#xD;
      The primary objective of the OPHELIE-COG study is to determine whether ischaemic stroke&#xD;
      patients who are treated with i.v. rt-PA are more likely to have a poor outcome (defined as a&#xD;
      modified Rankin scale 2 to 6 at month 3) in the presence of pre-existing cognitive impairment&#xD;
      or dementia. The secondary objectives are to determine whether (i) they have an increased&#xD;
      risk of symptomatic intracerebral haemorrhages, (ii) the proportion of patients who have a&#xD;
      poor outcome is lower than expected from the placebo group of randomised trials for patients&#xD;
      with a similar range of baseline severity, and (iii) the influence of the cognitive state on&#xD;
      outcome differs between Japanese and European patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The French part of OPHELIE-COG is run as an ancillary study of OPHELIE, a multicenter French&#xD;
      study conducted in the clinical centres of the Strokavenir research network (co-PI Didier&#xD;
      Leys, Lille and Denis Vivien, Caen). OPHELIE has been approved by the ethical committee and&#xD;
      is an investigator-driven study supported by the INSERM, the University Lille Nord de France&#xD;
      and the Lille University hospital. OPHELIE includes prospectively all patients who are&#xD;
      treated by i.v. rt-PA for an acute cerebral ischaemia in the participating centres and tests&#xD;
      the hypothesis that the single/two chain-tPA ratio in the infusion influences the 3-month&#xD;
      outcome, evaluated by a score 0 or 1 at the modified Rankin scale(mRS). OPHELIE-COG is&#xD;
      conducted in the same cohort of patients as an ancillary analysis of OPHELIE.&#xD;
&#xD;
      The Japanese part of OPHELIE-COG will be conducted In patients who receive i.v. rt-PA for&#xD;
      acute cerebral ischaemia in participating Japanese centres. Japanese centres will not be part&#xD;
      of the OPHELIE study.&#xD;
&#xD;
      No specific investigation is necessary for the purpose of the study. There is no variable&#xD;
      recorded that is not part of the usual management of stroke patients treated by i.v. rt-PA.&#xD;
      Following-up patients at 3 months and having mRS is recommended to monitor the results of&#xD;
      thrombolysis in all centres able to deliver the treatment. The informant Questionnaire on&#xD;
      Cognitive Decline in the Elderly (IQCODE)is not part of the care in all centres but is&#xD;
      however highly recommended because of the influence of the pre-existing cognitive state on&#xD;
      stroke outcome in general.&#xD;
&#xD;
      The systematic assessment of pre-existing dementia is conducted within 48 hours of stroke&#xD;
      onset by French or Japanese translations of the short version of the IQCODE. Patients who are&#xD;
      already followed-up by a neurologist and diagnosed as demented before stroke are classified&#xD;
      as previously demented irrespective of the IQCODE score. Patients who cannot have an IQCODE&#xD;
      but have a MMSE score of 30 before discharge are classified as cognitively normal. Patients&#xD;
      who cannot have an IQCODE and have a MMSE score of 29 or less are not eligible.&#xD;
&#xD;
      The sample size calculation for the French patients has been performed for the primary&#xD;
      objective of OPHELIE assuming an expected difference of 5% for the primary end-point with&#xD;
      alpha and beta risks of 5% and 20% respectively and a expected proportion of patients with a&#xD;
      mRS score 0-1 of 40% at month-3, according to trials, observational registries and data&#xD;
      published in the Lille centre for a baseline NIH score of 11: 900 patients will be necessary.&#xD;
      To detect an absolute difference of 10 % for the primary end-point with an alpha risk of 5%&#xD;
      and a power of 80%, a sample size of 1040 eligible patients is necessary, assuming that 12 to&#xD;
      16% of patients will have criteria for pre-existing dementia. This 10% absolute difference in&#xD;
      the proportion of patients with mRS 0-1 at month 3 between those with and without&#xD;
      pre-existing dementia corresponds to the difference below which the beneficial effect of&#xD;
      rt-PA may be lost, taking into account that approximately 30% of patients under placebo, and&#xD;
      40% under rt-PA have a mRS 0-1 at month 3 for a median baseline NIH score of 11. Assuming&#xD;
      that 20% of patients included in OPHELIE will not be eligible for OPHELIE-COG according to&#xD;
      the proportion of exclusions found in previous studies with the IQCODE, we can expect a&#xD;
      recruitment of 720 patients in the French arm of the study. The 320 other patients will be&#xD;
      recruited in Japan, meaning that 400 patients have to be recruited to compensate the usual&#xD;
      20% rate of patients who cannot have an IQCODE in due time.&#xD;
&#xD;
      An intermediate analysis will be performed after inclusion of 500 patients arrived at 3&#xD;
      months of follow-up to re-evaluate the sample size.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>November 2011</start_date>
  <completion_date type="Actual">March 2015</completion_date>
  <primary_completion_date type="Actual">December 2014</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>Modified Rankin Scale score 0 or 1</measure>
    <time_frame>Month-3</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Symptomatic intracerebral haemorrhage defined according to the ECASS2 definition</measure>
    <time_frame>7 days</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Death</measure>
    <time_frame>Day 7</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Modified Rankin Scale 0-2</measure>
    <time_frame>Month-3</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Death</measure>
    <time_frame>Month-3</time_frame>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Actual">205</enrollment>
  <condition>Brain Ischemia</condition>
  <condition>Adverse Effect of Thrombolytic Drugs</condition>
  <condition>Impaired Cognition</condition>
  <condition>Dementia</condition>
  <arm_group>
    <arm_group_label>Cognitively normal</arm_group_label>
    <description>Patients with IQCODE score of 52 or less</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cognitively impaired - no dementia</arm_group_label>
    <description>IQCODE score 53 - 63</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Demented</arm_group_label>
    <description>IQCODE score 64 or more</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        Patients treated by iv tPA for acute cerebral ischaemia in routine practice&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  All patients treated by iv tPA for cerebral ischaemia in routine practice in&#xD;
             participating centres&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  index ischaemic stroke sparing MCA territory;&#xD;
&#xD;
          -  thrombolytic therapy administered intra-arterially or combined with thrombectomy&#xD;
&#xD;
          -  pre-stroke mRS of 2 or more&#xD;
&#xD;
          -  impossibility to perform an IQCODE for any reason (no reliable informant available&#xD;
             within 48 hours, not fluent in French or in Japanese or in a language spoken by the&#xD;
             investigator), except when the patient had been diagnosed as demented by a specialist&#xD;
             used to diagnose dementia (e.g. neurologist, psychiatrist, geriatrician) before&#xD;
             stroke, or has a MMSE score of 30 at discharge.&#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>Kei Murao, MD</last_name>
    <role>Study Director</role>
    <affiliation>Lille University Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Lille University Hospital</name>
      <address>
        <city>Lille</city>
        <zip>59000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fukuoka Redcross Hospital</name>
      <address>
        <city>Fukuoka</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fukuoka-Higashi Medical center</name>
      <address>
        <city>Fukuoka</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kyushu Medical Center</name>
      <address>
        <city>Fukuoka</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kyushu University</name>
      <address>
        <city>Fukuoka</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kyushu Rosai Hospital</name>
      <address>
        <city>Kitakyushu</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Steel Memorial Yawata Hospital</name>
      <address>
        <city>Kitakyushu</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kawasaki Medical University</name>
      <address>
        <city>Kurashiki</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Mary's Hospital</name>
      <address>
        <city>Kurume</city>
        <country>Japan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
    <country>Japan</country>
  </location_countries>
  <verification_date>October 2016</verification_date>
  <study_first_submitted>October 22, 2012</study_first_submitted>
  <study_first_submitted_qc>October 22, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 24, 2012</study_first_posted>
  <last_update_submitted>October 26, 2016</last_update_submitted>
  <last_update_submitted_qc>October 26, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 27, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>brain ischemia</keyword>
  <keyword>thrombolytic therapy</keyword>
  <keyword>Impaired cognition</keyword>
  <keyword>dementia</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dementia</mesh_term>
    <mesh_term>Brain Ischemia</mesh_term>
    <mesh_term>Ischemia</mesh_term>
    <mesh_term>Cognitive Dysfunction</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


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/NCT01713491
org study id: 2010_04
secondary id: 912079
nct id: NCT01713491
lead sponsor: 
has dmc: Yes
At the acute stage of cerebral ischaemia, the only effective drug that increases the
      proportion of patients who survive without dependency is thrombolytic therapy by intravenous
      (i.v.) tissue-plasminogen activator (t-PA). This treatment is entered into routine practice
      with similar results than in trials, in various places of the world including Europe and
      Japan.

      Stroke and dementia are closely related. About one patient in ten has dementia before a
      first-ever stroke, and more than one in three has dementia after a recurrent stroke.
      Pre-existing dementia is associated with a worse outcome of stroke, and pre-existing
      cognitive impairment without dementia is associated with a higher rate of
      institutionalisation within 3 years. In many patients cognitive impairment is due to the
      summation of the effects of vascular and Alzheimer lesions of the brain.

      More and more patients nowadays who are eligible for rt-PA are already known as demented at
      admission. A retrospective study conducted in a cohort of patients with dementia who had an
      ischaemic stroke and were treated by rtPA suggested that there is no increased risk of
      cerebral bleeding and death as compared with non demented patients. However, pre-existing
      cognitive impairment is possibly associated with (i) an increased risk of bleeding in
      patients with cognitive impairment, and (ii) a higher sensitivity to the neurotoxic effect of
      rt-PA on the brain tissue.

      Japanese patients differ from European patients by a higher risk of spontaneous intracranial
      haemorrhage, and a higher proportion of patients with small-vessel diseases.

      The primary objective of the OPHELIE-COG study is to determine whether ischaemic stroke
      patients who are treated with i.v. rt-PA are more likely to have a poor outcome (defined as a
      modified Rankin scale 2 to 6 at month 3) in the presence of pre-existing cognitive impairment
      or dementia. The secondary objectives are to determine whether (i) they have an increased
      risk of symptomatic intracerebral haemorrhages, (ii) the proportion of patients who have a
      poor outcome is lower than expected from the placebo group of randomised trials for patients
      with a similar range of baseline severity, and (iii) the influence of the cognitive state on
      outcome differs between Japanese and European patients.
The French part of OPHELIE-COG is run as an ancillary study of OPHELIE, a multicenter French
      study conducted in the clinical centres of the Strokavenir research network (co-PI Didier
      Leys, Lille and Denis Vivien, Caen). OPHELIE has been approved by the ethical committee and
      is an investigator-driven study supported by the INSERM, the University Lille Nord de France
      and the Lille University hospital. OPHELIE includes prospectively all patients who are
      treated by i.v. rt-PA for an acute cerebral ischaemia in the participating centres and tests
      the hypothesis that the single/two chain-tPA ratio in the infusion influences the 3-month
      outcome, evaluated by a score 0 or 1 at the modified Rankin scale(mRS). OPHELIE-COG is
      conducted in the same cohort of patients as an ancillary analysis of OPHELIE.

      The Japanese part of OPHELIE-COG will be conducted In patients who receive i.v. rt-PA for
      acute cerebral ischaemia in participating Japanese centres. Japanese centres will not be part
      of the OPHELIE study.

      No specific investigation is necessary for the purpose of the study. There is no variable
      recorded that is not part of the usual management of stroke patients treated by i.v. rt-PA.
      Following-up patients at 3 months and having mRS is recommended to monitor the results of
      thrombolysis in all centres able to deliver the treatment. The informant Questionnaire on
      Cognitive Decline in the Elderly (IQCODE)is not part of the care in all centres but is
      however highly recommended because of the influence of the pre-existing cognitive state on
      stroke outcome in general.

      The systematic assessment of pre-existing dementia is conducted within 48 hours of stroke
      onset by French or Japanese translations of the short version of the IQCODE. Patients who are
      already followed-up by a neurologist and diagnosed as demented before stroke are classified
      as previously demented irrespective of the IQCODE score. Patients who cannot have an IQCODE
      but have a MMSE score of 30 before discharge are classified as cognitively normal. Patients
      who cannot have an IQCODE and have a MMSE score of 29 or less are not eligible.

      The sample size calculation for the French patients has been performed for the primary
      objective of OPHELIE assuming an expected difference of 5% for the primary end-point with
      alpha and beta risks of 5% and 20% respectively and a expected proportion of patients with a
      mRS score 0-1 of 40% at month-3, according to trials, observational registries and data
      published in the Lille centre for a baseline NIH score of 11: 900 patients will be necessary.
      To detect an absolute difference of 10 % for the primary end-point with an alpha risk of 5%
      and a power of 80%, a sample size of 1040 eligible patients is necessary, assuming that 12 to
      16% of patients will have criteria for pre-existing dementia. This 10% absolute difference in
      the proportion of patients with mRS 0-1 at month 3 between those with and without
      pre-existing dementia corresponds to the difference below which the beneficial effect of
      rt-PA may be lost, taking into account that approximately 30% of patients under placebo, and
      40% under rt-PA have a mRS 0-1 at month 3 for a median baseline NIH score of 11. Assuming
      that 20% of patients included in OPHELIE will not be eligible for OPHELIE-COG according to
      the proportion of exclusions found in previous studies with the IQCODE, we can expect a
      recruitment of 720 patients in the French arm of the study. The 320 other patients will be
      recruited in Japan, meaning that 400 patients have to be recruited to compensate the usual
      20% rate of patients who cannot have an IQCODE in due time.

      An intermediate analysis will be performed after inclusion of 500 patients arrived at 3
      months of follow-up to re-evaluate the sample size.
observational model: Cohort
time perspective: Prospective
measure: Modified Rankin Scale score 0 or 1
time frame: Month-3
measure: Symptomatic intracerebral haemorrhage defined according to the ECASS2 definition
time frame: 7 days
measure: Death
time frame: Day 7
measure: Modified Rankin Scale 0-2
time frame: Month-3
measure: Death
time frame: Month-3
arm group label: Cognitively normal
description: Patients with IQCODE score of 52 or less
arm group label: Cognitively impaired - no dementia
description: IQCODE score 53 - 63
arm group label: Demented
description: IQCODE score 64 or more
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Kei Murao, MD
role: Study Director
affiliation: Lille University Hospital
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: France
country: Japan
responsible party type: Sponsor
mesh term: Dementia
mesh term: Brain Ischemia
mesh term: Ischemia
mesh term: Cognitive Dysfunction
sharing ipd: No