<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/NCT03754725</url>
  </required_header>
  <id_info>
    <org_study_id>PRO00110138</org_study_id>
    <nct_id>NCT03754725</nct_id>
  </id_info>
  <brief_title>Ferritin and Iron Burden in SAH sIRB</brief_title>
  <official_title>A Phase 1/2a Exploratory Clinical Trial to Evaluate the Safety of Oral Deferiprone (14 Days) Including Its Effect on Decreasing the Content of Iron in Subjects With Aneurysmal Subarachnoid Hemorrhage (aSAH) sIRB</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Duke University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Duke University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Ruptured cerebral aneurysms lead to subarachnoid hemorrhage (SAH),that has a high morbidity&#xD;
      and mortality rate, the severity of which is predicted by the &quot;Hunt-Hess grade&quot; (HHG).&#xD;
&#xD;
      SAH leads to iron (Fe) and hemoglobin (Hb) accumulation in the brain, which is toxic for&#xD;
      neurons. Ferritin (iron reported in the brian) and iron overload leads to brain atrophy,&#xD;
      specifically in the mesial temporal lobe (hippocampus, impairing patients' cognition. It is&#xD;
      estimated that 50% of survivors have cognitive deficits.&#xD;
&#xD;
      Most of the survivors of SAH could not return to work. Iron chelation therapy has been&#xD;
      recently gaining ground as a therapeutic intervention in intraparenchymal hemorrhage and in&#xD;
      SAH. However, there has not been any study that assess the iron deposition in the brain and&#xD;
      the level of ferritin in the cerebrospinal fluid of SAH patients. The investigators propose&#xD;
      to conduct a randomized trial using Deferiprone (oral chelating agent, &quot;De&quot;) + standard of&#xD;
      care versus standard of care in patient with SAH to:&#xD;
&#xD;
        1. assess the level of ferritin (Ft) in CSF (CSF withdrawn from ventriculostomy tube),&#xD;
&#xD;
        2. assess functional outcomes measured by the Montreal Cognitive Assessment (MoCA) score, a&#xD;
           score used to assess the level of dementia, mainly in Alzheimer disease patients.&#xD;
&#xD;
        3. quantify the the total iron deposition in the brain based on MRI&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      I) SIGNIFICANCE&#xD;
&#xD;
      1) Significance and Incidence and Burden of the disease Intracranial aneurysm is a prevalent&#xD;
      disease estimated around 2-5% of the population. Aneurysm rupture leads to aneurysmal&#xD;
      subarachnoid hemorrhage , which have a tremendous impact on the patient's health, and a high&#xD;
      mortality rate (~60%), with a large proportion of the survivors becoming functionally&#xD;
      dependent. It accounts for 27% of all stroke-related years of life lost before age 65, and it&#xD;
      has a predilection for a relatively younger age. Survivors have long term cognitive deficits&#xD;
      and memory impairment in their productive years with major responsibilities with respect to&#xD;
      work and family. Despite that, only one-third have neurological deficits. Most of the&#xD;
      survivors could not return to work. Poor functional outcomes are related to iron and heme&#xD;
      toxicity with resultant delayed cerebral ischemia , early brain injury , hydrocephalus and&#xD;
      cerebral edema. As of today, there has not been any intervention that improves neurocognitive&#xD;
      outcomes in these patients. The investigators postulate that iron chelation therapy can&#xD;
      decrease the amount of Iron (Fe) deposition in the brain, reduce ferritin (Ft) in patients'&#xD;
      cerebrospinal fluid (CSF) and potentially improve functional outcome.&#xD;
&#xD;
      Our group was the first in the world to detect and quantify Fe concentration at the interface&#xD;
      of brain aneurysms' wall and brain tissue using QSM-MRI sequence. This technique allowed us&#xD;
      to detect microbleeds associated with sentinel headache in subjects with IAs and negative&#xD;
      non-contrast head CT and negative lumbar puncture. In this proposal, the investigators will&#xD;
      also use high-resolution MRI sequence to assess difference in volumes of amygdala and&#xD;
      hippocampus and correlate that with CSF-ferritin.&#xD;
&#xD;
      This will make our proposal the first go/no-go randomized double-blind placebo vs.&#xD;
      deferiprone trial that attempts to establish Ft (a reporter of total Fe in the brain and CSF)&#xD;
      as a biomarker of neurocognitive decline specifically in subarachnoid hemorrhage subjects and&#xD;
      test the effect of deferiprone in decreasing the levels of Ft and therefore ameliorate the&#xD;
      neurocognitive decline associated with this disease. If our hypothesis is validated, then&#xD;
      this would set the stage for a phase 3 clinical trial and test our hypothesis in larger&#xD;
      cohort of subjects.&#xD;
&#xD;
      III) PRELIMINARY DATA (obtained with collaboration with our colleagues in Europe):&#xD;
&#xD;
      To provide proof-of-concept of the effect of deferiprone on the levels of Ft in the CSF of&#xD;
      subjects with aneurysmal subarachnoid hemorrhage (aSAH), Tthe investigators conducted a pilot&#xD;
      study to analyze the concentration Ft in the CSF of subjects with aSAH and Hunt and Hess&#xD;
      grade 1-3. Fourteen subjects were included (7 with only cisternal SAH but no intraventricular&#xD;
      hemorrhage (IVH), and 7 subjects with cisternal aSAH and IVH). Their CSF (2-3 cc) were drawn&#xD;
      daily (from day 0 to day14) and analyzed with Fe-ELISA kit. Then 4 subjects (2 with aSAH&#xD;
      without IVH and 2 with SAH and IVH) were treated with 1000 mg of deferiprone twice orally for&#xD;
      14 days. The mean Ft level in subjects with aSAH without IVH was 900ng/ml vs. 420 ng/ml for&#xD;
      those receiving deferiprone. The mean Ft level of patients with SAH and IVH was 1500ng/ml&#xD;
      compared to 690 ng/ml in the deferiprone group. This small pilot study provided&#xD;
      proof-of-concept that 1) aSAH increases the CSF-Ft in human, and this effect can be reduced&#xD;
      significantly with deferiprone, and 2) aSAH associated with IVH increases furthermore CSF-Ft,&#xD;
      which is also reduced significantly by deferiprone.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">October 1, 2020</start_date>
  <completion_date type="Anticipated">July 1, 2025</completion_date>
  <primary_completion_date type="Anticipated">May 6, 2025</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Ferritin levels in cerebrospinal fluid</measure>
    <time_frame>Day 10 from enrollment</time_frame>
    <description>Concentration of ferritin in the cerebrospinal fluid</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Assess functional outcomes</measure>
    <time_frame>6 and 12 months from enrollment</time_frame>
    <description>Measured by the Montreal Cognitive Assessment (MoCA) score</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in hippocampus size</measure>
    <time_frame>On admission and at 6 and 12 months</time_frame>
    <description>The size of hippocampus will be matched to historic control subjects matched with age, gender and level of education and measured using high resolution MRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in amygdala measured size</measure>
    <time_frame>On admission and at 6 and 12 months</time_frame>
    <description>The size of amygdala will be matched to historic control subjects matched with age, gender and level of education and measured using high resolution MRI</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in the amount of iron deposition in the brain</measure>
    <time_frame>On admission and at 6 and 12 months</time_frame>
    <description>Calculated using Quantitative susceptibility mapping (QSM) Magnetic Resonance Imaging (MRI)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Indications of clinical vasospasm</measure>
    <time_frame>During hospitalization, up to 4 weeks</time_frame>
    <description>Assessed during hospitalization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Indications for delayed cerebral ischemia</measure>
    <time_frame>During hospitalization, up to 4 weeks</time_frame>
    <description>Assessed during hospitalization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of hydrocephalus requiring shut placement</measure>
    <time_frame>During hospitalization, up to 4 weeks</time_frame>
    <description>Assessed during hospitalization</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Modified Rankin Scale (mRS) score</measure>
    <time_frame>At 6 weeks, and 6 and 12 months</time_frame>
    <description>Documented at 6 weeks, and 6 and 12 months</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">66</enrollment>
  <condition>SAH</condition>
  <condition>Dementia</condition>
  <arm_group>
    <arm_group_label>Deferiprone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This is the drug arm (deferiprone). Patients will receive oral deferiprone</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>this group will only receive the placebo (sugar pill)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Deferiprone pill</intervention_name>
    <description>1000 mg of deferiprone (oral) BID (15 mg/Kg)</description>
    <arm_group_label>Deferiprone</arm_group_label>
    <other_name>Ferritin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>placebo</intervention_name>
    <description>patients will receive placebo orally</description>
    <arm_group_label>Control</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Montreal Cognitive Assessment</intervention_name>
    <description>Neurocognitive assessment, lower score indicates lower cognitive level</description>
    <arm_group_label>Control</arm_group_label>
    <arm_group_label>Deferiprone</arm_group_label>
    <other_name>MoCA</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
          1. Age greater than or equal to 18 and less than or equal to 75 years.&#xD;
&#xD;
          2. Historical modified Rankin Scale Score (mRS) 0-1 (pre-subarachnoid hemorrhage onset).&#xD;
&#xD;
          3. World Federation of Neurosurgical Societies SAH Scale (WFNS) grade less than or equal&#xD;
             to 4, due to a spontaneous SAH attributed to a ruptured cerebral aneurysm. Initial&#xD;
             WFNS grade may be determined at admission or enrollment, preferably after the&#xD;
             patient's mental status has been optimized by resuscitation and interval treatment of&#xD;
             hydrocephalus (i.e., placement of intraventricular catheter or lumbar puncture [LP])&#xD;
             or reversal/wearing-off of sedating medications used commonly during patient transfers&#xD;
             and transport or procedure related anesthesia.&#xD;
&#xD;
          4. Admission head CT showing modified Fisher grade 1-4 due to aneurysmal subarachnoid&#xD;
             hemorrhage (aSAH) primarily in the supratentorial space. The Modified Fisher CT rating&#xD;
             scale is: Grade 1 (minimal or diffuse thing SAH without intraventricular hemorrhage);&#xD;
             Grade 2 (minimal or thin SAH with intraventricular hemorrhage), Grade 3 (thick&#xD;
             cisternal clot without intraventricular hemorrhage), Grade 4 (thick cisternal clot&#xD;
             with intraventricular hemorrhage).&#xD;
&#xD;
          5. Location and pattern of the SAH must have the majority of the SAH in the&#xD;
             supratentorial space caused by either an intradural anterior circulation aneurysm or a&#xD;
             basilar apex/posterior circulation aneurysm with primarily supratentorial hemorrhage&#xD;
             extension. Angiographic location of the aneurysm will be confirmed by catheter digital&#xD;
             subtraction angiography usually obtained during the coil embolization procedure.&#xD;
&#xD;
          6. Onset of symptoms of aSAH (ictus) occurred &lt; 24 hours prior to presentation at the&#xD;
             treating facility.&#xD;
&#xD;
          7. Initiation of aneurysm securement procedure occurred &lt; 48 hours from the ictus and&#xD;
             less than 12 hours from admission to the treating facility.&#xD;
&#xD;
          8. All aneurysm(s) suspected to be responsible for the hemorrhage or potentially&#xD;
             responsible for the hemorrhage must be secured in the following manner prior to&#xD;
             enrollment: endovascular Coil Embolization with a post-embolization Raymond-Roy Score&#xD;
             of 1 (Complete) or 2 (Residual Neck).&#xD;
&#xD;
          9. Ability to screen the patient and obtain head CT and CT perfusion on admission and&#xD;
             follow after recovering from anesthesia following the aneurysm coiling procedure, the&#xD;
             patient must remain a WFNS SAH grade less than or equal to 4 without evidence of a&#xD;
             significant new focal neurological deficit including monoparesis / monoplegia,&#xD;
             hemiparesis / hemiplegia, or receptive, expressive or global aphasia. New minor&#xD;
             cranial nerve defect without any other new findings is permissible. If a national&#xD;
             institute of health stroke scale (NIHSS) score was obtained prior to the aneurysm&#xD;
             coiling procedure, a post-coiling (pre-enrollment) NIHSS score must not have increased&#xD;
             by 4 points or more and Glasgow coma score must not be decreased by 2 points or less.&#xD;
             The clinician should use their best clinical judgment as to whether a significant&#xD;
             neurological decline has occurred due to the coiling procedure.&#xD;
&#xD;
         10. Ability to obtain MRI for ischemic changes evaluation.&#xD;
&#xD;
         11. Subject's Legally Authorized Representative (LAR) has provided written informed&#xD;
             consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Angio-negative SAH.&#xD;
&#xD;
          2. A likely hemorrhage event within several days prior to admission related hemorrhage&#xD;
             ictus due to the increased risk of early vasospasm.&#xD;
&#xD;
          3. Prior sentinel headache with negative CT or prior sentinel headache where the patient&#xD;
             did not seek medical attention does not exclude the patient.&#xD;
&#xD;
          4. Surgical clipping of the ruptured aneurysm or any non-ruptured aneurysm on the same&#xD;
             admission prior to enrollment.&#xD;
&#xD;
          5. SAH not caused by aneurysm rupture or aneurysm is identified to be traumatic, mycotic,&#xD;
             blister or fusiform type by catheter Digital Subtraction Angiography (DSA).&#xD;
&#xD;
          6. Any intracranial stent placement or non-coil intra-aneurysmal device (i.e., stent-&#xD;
             assisted coiling with Neuroform, Enterprise, LVIS, LVIS Jr, Barrel Stent, Pulse Rider,&#xD;
             LUNA, Medina or a similar device) where the stent device is implanted to treat the&#xD;
             ruptured aneurysm and / or antiplatelet therapy is needed.&#xD;
&#xD;
          7. Subject has remaining aneurysm(s) that are untreated and could reasonably be&#xD;
             considered a possible alternate cause of the aSAH based on the observed bleeding&#xD;
             pattern. Adequate treatment of these aneurysms by coiling embolization would result in&#xD;
             the aneurysms no longer causing an exclusion. MRI may be used in some situations to&#xD;
             determine that the associated aneurysms did not rupture based on lack of blood seen&#xD;
             adjacent to the additional aneurysms.&#xD;
&#xD;
          8. Diagnosis of sepsis (systemic inflammatory response syndrome [SIRS] criteria plus the&#xD;
             presence of known or suspected infection) or current documented active bacterial or&#xD;
             viral infection prior to enrollment (Example: significant upper respiratory infection&#xD;
             (URI), community-acquired pneumonia). A minor non-complicated community-acquired&#xD;
             urinary tract infection (UTI) would not be an exclusion but should be treated&#xD;
             promptly.&#xD;
&#xD;
          9. New parenchymal hemorrhage or new infarction larger the 15 milliliters in volume, or&#xD;
             significant increased mass effect as seen on the post coiling pre-enrollment head CT&#xD;
             when compared to baseline admission head CT. New hyperdensity on CT scan related to&#xD;
             contrast staining is not an exclusion.&#xD;
&#xD;
         10. Subject developed SAH-induced cardiac stunning prior to enrollment, with an ejection&#xD;
             fraction&lt; 30%, or requiring intravenous medications for blood pressure maintenance.&#xD;
&#xD;
         11. Concurrent significant intracranial pathology identified prior to enrollment,&#xD;
             including but not limited to, Moyamoya disease, high suspicion or documented CNS&#xD;
             vasculitis, severe fibromuscular dysplasia, arteriovenous malformation, arteriovenous&#xD;
             fistula, significant cervical or intracranial atherosclerotic stenotic disease&#xD;
             (greater or equal to 70%), or malignant brain tumor.&#xD;
&#xD;
         12. Known seizure or epilepsy disorder (diagnosed prior to this aSAH diagnosis) where&#xD;
             anti-epileptic medication was previously taken by the patient or have been recommended&#xD;
             to be taken by the patient. Childhood seizures that have resolved and no longer&#xD;
             require treatment are not part of this exclusion criteria.&#xD;
&#xD;
         13. Serious co-morbidities that could confound study results including but not limited to:&#xD;
             Multiple Sclerosis, dementia, severe major depression, cancer likely to cause death in&#xD;
             2 years, multi-system organ failure, or any other conditions that could cause any&#xD;
             degree of cognitive impairment.&#xD;
&#xD;
         14. Immunosuppression therapy including chronic corticosteroid usage.&#xD;
&#xD;
         15. Remote history of previous ruptured cerebral aneurysm.&#xD;
&#xD;
         16. History of gastrointestinal hemorrhage or major systemic hemorrhage within 30 days,&#xD;
             hemoglobin less than 8 g/dL, international normalized ratio greater than or equal&#xD;
             to1.5, severe liver impairment, creatinine greater than 2.0 mg/dL, or estimated&#xD;
             glomerular filtration rate less than 60 ml/min.&#xD;
&#xD;
         17. Major surgery (including open femoral, aortic, or carotid surgery) within previous 30&#xD;
             days.&#xD;
&#xD;
         18. Currently pregnant.&#xD;
&#xD;
         19. Contraindication for MRI.&#xD;
&#xD;
         20. No hydrocephalus requiring EVD or LP.&#xD;
&#xD;
         21. Known hypersensitivity to Deferiprone or to any of the excipients in the formulation.&#xD;
&#xD;
         22. If endovascular treatment of their aneurysm requires adjunctive antiplatelet&#xD;
             treatment.&#xD;
&#xD;
         23. Uncontrollable hypertension (&gt;180 systolic and/or &gt;110 diastolic) that is not&#xD;
             correctable prior to enrollment.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>David Hasan, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Duke University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>David Hasan, MD</last_name>
    <phone>919-681-2512</phone>
    <email>david.hasan@duke.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Beth Perry, RN</last_name>
    <phone>919-681-2695</phone>
    <email>beth.perry@duke.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Univesity of Iowa Hospital and Clinics</name>
      <address>
        <city>Iowa City</city>
        <state>Iowa</state>
        <zip>52242</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Active, not recruiting</status>
  </location>
  <location>
    <facility>
      <name>Duke University Health System</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>David Hasan, MD</last_name>
      <phone>919-681-2512</phone>
      <email>david.hasan@duke.edu</email>
    </contact>
    <contact_backup>
      <last_name>Beth Perry, RN</last_name>
      <phone>919-681-2695</phone>
      <email>beth.perry@duke.edu</email>
    </contact_backup>
    <investigator>
      <last_name>David Hasan, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>November 24, 2018</study_first_submitted>
  <study_first_submitted_qc>November 26, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 27, 2018</study_first_posted>
  <last_update_submitted>August 18, 2023</last_update_submitted>
  <last_update_submitted_qc>August 18, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 21, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Deferiprone</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dementia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Deferiprone</mesh_term>
  </intervention_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/NCT03754725
org study id: PRO00110138
nct id: NCT03754725
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Ruptured cerebral aneurysms lead to subarachnoid hemorrhage (SAH),that has a high morbidity
      and mortality rate, the severity of which is predicted by the "Hunt-Hess grade" (HHG).

      SAH leads to iron (Fe) and hemoglobin (Hb) accumulation in the brain, which is toxic for
      neurons. Ferritin (iron reported in the brian) and iron overload leads to brain atrophy,
      specifically in the mesial temporal lobe (hippocampus, impairing patients' cognition. It is
      estimated that 50% of survivors have cognitive deficits.

      Most of the survivors of SAH could not return to work. Iron chelation therapy has been
      recently gaining ground as a therapeutic intervention in intraparenchymal hemorrhage and in
      SAH. However, there has not been any study that assess the iron deposition in the brain and
      the level of ferritin in the cerebrospinal fluid of SAH patients. The investigators propose
      to conduct a randomized trial using Deferiprone (oral chelating agent, "De") + standard of
      care versus standard of care in patient with SAH to:

        1. assess the level of ferritin (Ft) in CSF (CSF withdrawn from ventriculostomy tube),

        2. assess functional outcomes measured by the Montreal Cognitive Assessment (MoCA) score, a
           score used to assess the level of dementia, mainly in Alzheimer disease patients.

        3. quantify the the total iron deposition in the brain based on MRI
I) SIGNIFICANCE

      1) Significance and Incidence and Burden of the disease Intracranial aneurysm is a prevalent
      disease estimated around 2-5% of the population. Aneurysm rupture leads to aneurysmal
      subarachnoid hemorrhage , which have a tremendous impact on the patient's health, and a high
      mortality rate (~60%), with a large proportion of the survivors becoming functionally
      dependent. It accounts for 27% of all stroke-related years of life lost before age 65, and it
      has a predilection for a relatively younger age. Survivors have long term cognitive deficits
      and memory impairment in their productive years with major responsibilities with respect to
      work and family. Despite that, only one-third have neurological deficits. Most of the
      survivors could not return to work. Poor functional outcomes are related to iron and heme
      toxicity with resultant delayed cerebral ischemia , early brain injury , hydrocephalus and
      cerebral edema. As of today, there has not been any intervention that improves neurocognitive
      outcomes in these patients. The investigators postulate that iron chelation therapy can
      decrease the amount of Iron (Fe) deposition in the brain, reduce ferritin (Ft) in patients'
      cerebrospinal fluid (CSF) and potentially improve functional outcome.

      Our group was the first in the world to detect and quantify Fe concentration at the interface
      of brain aneurysms' wall and brain tissue using QSM-MRI sequence. This technique allowed us
      to detect microbleeds associated with sentinel headache in subjects with IAs and negative
      non-contrast head CT and negative lumbar puncture. In this proposal, the investigators will
      also use high-resolution MRI sequence to assess difference in volumes of amygdala and
      hippocampus and correlate that with CSF-ferritin.

      This will make our proposal the first go/no-go randomized double-blind placebo vs.
      deferiprone trial that attempts to establish Ft (a reporter of total Fe in the brain and CSF)
      as a biomarker of neurocognitive decline specifically in subarachnoid hemorrhage subjects and
      test the effect of deferiprone in decreasing the levels of Ft and therefore ameliorate the
      neurocognitive decline associated with this disease. If our hypothesis is validated, then
      this would set the stage for a phase 3 clinical trial and test our hypothesis in larger
      cohort of subjects.

      III) PRELIMINARY DATA (obtained with collaboration with our colleagues in Europe):

      To provide proof-of-concept of the effect of deferiprone on the levels of Ft in the CSF of
      subjects with aneurysmal subarachnoid hemorrhage (aSAH), Tthe investigators conducted a pilot
      study to analyze the concentration Ft in the CSF of subjects with aSAH and Hunt and Hess
      grade 1-3. Fourteen subjects were included (7 with only cisternal SAH but no intraventricular
      hemorrhage (IVH), and 7 subjects with cisternal aSAH and IVH). Their CSF (2-3 cc) were drawn
      daily (from day 0 to day14) and analyzed with Fe-ELISA kit. Then 4 subjects (2 with aSAH
      without IVH and 2 with SAH and IVH) were treated with 1000 mg of deferiprone twice orally for
      14 days. The mean Ft level in subjects with aSAH without IVH was 900ng/ml vs. 420 ng/ml for
      those receiving deferiprone. The mean Ft level of patients with SAH and IVH was 1500ng/ml
      compared to 690 ng/ml in the deferiprone group. This small pilot study provided
      proof-of-concept that 1) aSAH increases the CSF-Ft in human, and this effect can be reduced
      significantly with deferiprone, and 2) aSAH associated with IVH increases furthermore CSF-Ft,
      which is also reduced significantly by deferiprone.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Ferritin levels in cerebrospinal fluid
time frame: Day 10 from enrollment
description: Concentration of ferritin in the cerebrospinal fluid
measure: Assess functional outcomes
time frame: 6 and 12 months from enrollment
description: Measured by the Montreal Cognitive Assessment (MoCA) score
measure: Change in hippocampus size
time frame: On admission and at 6 and 12 months
description: The size of hippocampus will be matched to historic control subjects matched with age, gender and level of education and measured using high resolution MRI
measure: Change in amygdala measured size
time frame: On admission and at 6 and 12 months
description: The size of amygdala will be matched to historic control subjects matched with age, gender and level of education and measured using high resolution MRI
measure: Change in the amount of iron deposition in the brain
time frame: On admission and at 6 and 12 months
description: Calculated using Quantitative susceptibility mapping (QSM) Magnetic Resonance Imaging (MRI)
measure: Indications of clinical vasospasm
time frame: During hospitalization, up to 4 weeks
description: Assessed during hospitalization
measure: Indications for delayed cerebral ischemia
time frame: During hospitalization, up to 4 weeks
description: Assessed during hospitalization
measure: Incidence of hydrocephalus requiring shut placement
time frame: During hospitalization, up to 4 weeks
description: Assessed during hospitalization
measure: Change in Modified Rankin Scale (mRS) score
time frame: At 6 weeks, and 6 and 12 months
description: Documented at 6 weeks, and 6 and 12 months
arm group label: Deferiprone
arm group type: Experimental
description: This is the drug arm (deferiprone). Patients will receive oral deferiprone
arm group label: Control
arm group type: Placebo Comparator
description: this group will only receive the placebo (sugar pill)
intervention type: Drug
intervention name: Deferiprone pill
description: 1000 mg of deferiprone (oral) BID (15 mg/Kg)
arm group label: Deferiprone
other name: Ferritin
intervention type: Drug
intervention name: placebo
description: patients will receive placebo orally
arm group label: Control
intervention type: Behavioral
intervention name: Montreal Cognitive Assessment
description: Neurocognitive assessment, lower score indicates lower cognitive level
arm group label: Control
arm group label: Deferiprone
other name: MoCA
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: David Hasan, MD
role: Principal Investigator
affiliation: Duke University
last name: David Hasan, MD
phone: 919-681-2512
email: david.hasan@duke.edu
last name: Beth Perry, RN
phone: 919-681-2695
email: beth.perry@duke.edu
facility: 
status: Active, not recruiting
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
country: United States
responsible party type: Sponsor
mesh term: Dementia
mesh term: Deferiprone
sharing ipd: No