<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/NCT04490161</url>
  </required_header>
  <id_info>
    <org_study_id>1193/2018</org_study_id>
    <nct_id>NCT04490161</nct_id>
  </id_info>
  <brief_title>Prevention of Vasospasm in SAH Through CSF Treatment</brief_title>
  <acronym>PREVAIL</acronym>
  <official_title>Prevention of Cerebral Vasospasm Following Aneurysmal Subarachnoid Hemorrhage Through Treatment With Intravenous Autologous Cerebrospinal Fluid - a Pilot Trial.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Medical University Innsbruck</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Medical University Innsbruck</source>
  <oversight_info>
    <has_dmc>Yes</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 pathophysiological mechanisms of aneurysmal subarachnoid haemorrhage (aSAH) involve early&#xD;
      brain injury (EBI) and delayed cerebral ischemia (DCI).&#xD;
&#xD;
      Several mechanisms contribute to EBI pathogenesis, including cell death, inflammatory&#xD;
      response, oxidative stress, excitotoxicity, microcirculatory dysfunction, microthrombosis and&#xD;
      cortical spreading depolarization. All are suggested to be linked due to common pathogenic&#xD;
      pathways and direct interaction.&#xD;
&#xD;
      Despite advances in research of diagnostics and treatment strategies, brain injury remains&#xD;
      the major cause of death and disability in SAH patients. There is no sufficient treatment of&#xD;
      SAH and its devastating consequences known so far. Developing and improving diagnostic&#xD;
      methods to monitor SAH patients and to evaluate efficacy of treatment strategies are&#xD;
      essential in SAH research. These include neuroimaging, biomarkers, and other parameters such&#xD;
      as invasive multimodal neuromonitoring and intraoperative electrophysiological monitoring.&#xD;
&#xD;
      Cerebral vasospasm (CV) - mostly responsible for DCI - can be depicted on angiograms.&#xD;
      Altogether, tremendous efforts have been taken to conquer the occurrence and sustainability&#xD;
      of CV. The mortality of patients suffering aSAH rises up to 50% if the patients' condition is&#xD;
      critical (Hunt&amp;Hess (HH) Grade 5, WFNS Grade 5, modified Fisher Grade 4).&#xD;
&#xD;
      Reports of beneficial outcome in patients with pre-existing CSF shunting have been published.&#xD;
      The hypothesis of early CSF reapplication to the bloodstream, in order to prevent CV seems to&#xD;
      be positively approved by the mentioned reports. Nevertheless, no data could be found on the&#xD;
      mechanisms of action in this phenomenon.&#xD;
&#xD;
      To confirm the presence of interaction of the mechanisms of EBI and evaluate the application&#xD;
      of cerebrospinal fluid (CSF), a pilot clinical trial was planned. Due to the lack of&#xD;
      validated animal models for aSAH it is necessary to perform the trial first-in-human. A pilot&#xD;
      (proof of concept) trial - is done through inclusion of 10 patients with severe aSAH (≥HH4).&#xD;
      According to clinical guidelines, these patients receive external ventricular drainages in&#xD;
      order to drain CSF and lower intracranial pressure. An interim analysis of data will be&#xD;
      performed after inclusion and treatment of 5 patients. Blood-/CSF-sampling for further&#xD;
      analysis will be collected before, during and after treatment according to the study&#xD;
      protocol.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Aneurysmal subarachnoid haemorrhage (aSAH) is associated with high morbidity and mortality&#xD;
      with an incidence of 5-9 per 100,000 population. The incidence of aSAH peaks amongst those of&#xD;
      40-60 years1; aSAH carries a high overall mortality rate of up to 67%2 with only around half&#xD;
      of the survivors able to live independently. Given the age-related incidence 3 and high&#xD;
      morbidity and mortality, SAH has a high burden on society . Conventionally following SAH,&#xD;
      treatment is directed to securing the aneurysm to prevent further re-bleed. In addition to&#xD;
      the primary brain injury due to the rupture of the aneurysm the occurrence of cerebral&#xD;
      vasospasm (VS) with narrowing of the brain supplying arteries potentially lading to brain&#xD;
      ischemia is as well - known and serious complication following aSAH. The development of VS is&#xD;
      thought to be caused by various factors. Interestingly, this is not an instant phenomenon&#xD;
      occurring right after the hemorrhagic event. VS develops rather in a time dependent fashion&#xD;
      with a peak incidence around 7-10 days following from acute event.&#xD;
&#xD;
      From angiographic studies, it is known that up to 70% of all patients with a aSAH will&#xD;
      develop VS and in about 40% of these it will result in clinical deterioration and in 10-15%&#xD;
      in permanent delayed ischemic neurologic deficits (DIND) leading to an increased morbidity 4,&#xD;
      5 and mortality&#xD;
&#xD;
      . Based on the fact that VS develops with a time delay, this is thought to provide a&#xD;
      &quot;therapeutic window&quot; allowing to initiate measures for its prevention. However, in spite of&#xD;
      intensive experimental and clinical research the investigators still do not have any&#xD;
      effective treatment for the prevention of VS in patients with aSAH. Many concepts have been&#xD;
      elaborated in the past, mostly based o sound pharmacologic considerations such as calcium&#xD;
      antagonists (Nimodipin), antioxidants (Tirilazad) and endothelin antagonists (Clazosentan).&#xD;
      In clinical trials, however, none of these drugs have shown a therapeutic effect on VS and&#xD;
      most of them have been abandoned since then. The only exception is the use of oral Nimodipin,&#xD;
      which is still used showing a marginal effect 6-8.&#xD;
&#xD;
      In contrast to all previous studies, which were based on the use of specific drugs, the&#xD;
      present hypothesis is different. It is based on the assumption that the brain is a&#xD;
      &quot;privileged&quot; organ, where the in- and outflow is regulated by discrete barrier mechanisms&#xD;
      (e.g. blood-brain- barrier). In the event of aSAH - factors that are thought to play an&#xD;
      important role in the development of VS are released into the CSF. However, it is not clear&#xD;
      whether these factors will enter the systemic circulation. This is further supported by the&#xD;
      clinical observation that in many patients with aSAH, acute disturbances of CSF circulation&#xD;
      can be seen, often resulting in hydrocephalus. This in return can be treated by CSF flow&#xD;
      diversion with the use of external ventricular drainage, which is a routine procedure in the&#xD;
      management of aSAH patients.&#xD;
&#xD;
      Based on the assumption that those factors responsible for the development of VS are&#xD;
      contained in the CSF, but do not enter the systemic circulation, it then might make sense to&#xD;
      use the externally drained CSF for intravenous re-administration and thereby activating a&#xD;
      systemic response mechanism with in turn could prevent the development of VS.&#xD;
&#xD;
      The potential therapeutic benefits outweigh any potential risks for patients with aSAH.&#xD;
&#xD;
      The proposed clinical study involves autologous CSF without any changes made to the liquid.&#xD;
      The CSF will be taken from the external ventricular drain (EVD) under sterile environment and&#xD;
      reinfused intravenously.&#xD;
&#xD;
      An interval of approximately 21 days will permit a timely review and evaluation of interim&#xD;
      safety (after 5 patients) and tolerability data collected The potential benefit to patients&#xD;
      is significant with reduced delayed cerebral infarction (DCI), improved cognition and&#xD;
      cerebral function. As such, studies in patients with aSAH are warranted, with a view to&#xD;
      establishing the optimal dose, safety and exploratory efficacy profiles.&#xD;
&#xD;
      This is a pilot trial involving higher grade (see inclusion criteria) aSAH patients.&#xD;
&#xD;
      The human brain is protected and enjoying privileged immune status. The blood-brain- barrier&#xD;
      (BBB) leads to consequent isolation of brain tissue from humoral immunity. The brain is&#xD;
      experiencing several major changes during rupture of a cerebral aneurysm. First, the&#xD;
      intracranial pressure increases immediately, caused by the actual bleeding. Second, the&#xD;
      extravasation of blood disrupts the BBB and several immunogenic molecules travel through the&#xD;
      spontaneous rupture into the CSF. Additionally, microscopic particles of the vessel wall are&#xD;
      present in the CSF as a consequence of the wall rupture. Usually, these potentially&#xD;
      spasmogenic fractions are never encountered by the brain and the external surface of its&#xD;
      vessels. Interestingly, the perioperative collection of blood in subarachnoid spaces does not&#xD;
      induce vasospasm.&#xD;
&#xD;
      The investigators hypothesized that the reported steps were crucial for the formation of&#xD;
      cerebral vasospasm.&#xD;
&#xD;
      This study will be conducted in compliance with the protocol and according to Good Clinical&#xD;
      Practice and applicable regulatory standards. No deviation from the protocol will be&#xD;
      implemented without the prior review and approval by the relevant ethics and regulatory&#xD;
      authorities, except where it may be necessary to eliminate an immediate hazard to a research&#xD;
      subject. In such case, the deviation will be reported to the relevant ethics and regulatory&#xD;
      authorities as soon as possible.&#xD;
&#xD;
      Ten patients with an angiographically confirmed aSAH, who in addition are in need of early&#xD;
      external ventricular drainage (routine procedure), irrespective of the clinical grade on&#xD;
      admission and in whom definite treatment (clip ligation or interventional treatment) is&#xD;
      achievable within 72 hours following aSAH.&#xD;
&#xD;
      Following aneurysm clip ligation, the predetermined amount of CSF (10ml) will be obtained&#xD;
      under sterile conditions directly from the external ventricular drain and administered in a&#xD;
      peripheral vein. To reduce the possibility of contamination, the application of CSF will be&#xD;
      done immediately. In case of extensive intraventricular hemorrhage, causing the aspiration of&#xD;
      clotted blood while obtaining CSF, the patient needs to be excluded from the trial.&#xD;
&#xD;
      A number of patients will have an EVD placed for clinical reasons. These patients would&#xD;
      regularly have CSF sampling ranging from daily to twice weekly.&#xD;
&#xD;
      In this study, approximately 2 ml CSF will be taken and stored for translational study&#xD;
      purposes (starting on day of EVD fitting) until day 21 or until the EVD is removed as per&#xD;
      standard of care.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 1, 2020</start_date>
  <completion_date type="Anticipated">June 1, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 1, 2023</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of severe radiographic vasospasm</measure>
    <time_frame>8 (+/- 1) day post SAH</time_frame>
    <description>measured upon digital subtraction angiography</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Infectious complications</measure>
    <time_frame>7 days</time_frame>
    <description>presence of infections complications according to the study intervention (intravenous administration)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of vasospasm-related morbidity / mortality</measure>
    <time_frame>within 21 days post-aneurysm securing</time_frame>
    <description>Defined by on of the following: DIND (confirmed by mGCS); cerebral infarction upon CT scan (day 14), need for anti-vasospasm therapy within 14 day post securing</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Subarachnoid Hemorrhage</condition>
  <condition>Subarachnoid Hemorrhage, Aneurysmal</condition>
  <condition>Vasospasm, Cerebral</condition>
  <condition>Aneurysmal Subarachnoid Hemorrhage</condition>
  <arm_group>
    <arm_group_label>Interventional</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will receive reinstallation of CSF intravenously.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Observational</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Subjects will not receive study intervention; CSF will be sampled and analyzed in comparison to the Interventional arm,</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>intravenous reinstallation of cerebrospinal fluid</intervention_name>
    <description>10ml of CSF will be taken under sterile conditions from the external ventricular drain and immediately administered intravenously.</description>
    <arm_group_label>Interventional</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Age: &gt;18, &lt;90&#xD;
&#xD;
          -  SAH HH 3 - 5&#xD;
&#xD;
          -  Cerebral saccular Aneurysm&#xD;
&#xD;
          -  Digital subtraction angiography prior to aneurysm repair&#xD;
&#xD;
          -  Aneurysm repair within 72h&#xD;
&#xD;
          -  Modified Fisher Grade 3+4&#xD;
&#xD;
          -  Presence of aneurysm needing treatment (clipping or coiling)&#xD;
&#xD;
          -  Treatment within 24 hours of symptom onset&#xD;
&#xD;
          -  External ventricular drain (clinical need)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Non-aneurysmal SAH&#xD;
&#xD;
               -  SAH HH&lt;3&#xD;
&#xD;
               -  Extensive intraventricular haemorrhage (unable to obtain CSF without massive&#xD;
                  aspiration of clotted blood)&#xD;
&#xD;
               -  Contraindication for digital subtraction angiography&#xD;
&#xD;
               -  Aneurysm repair &gt;72h after rupture&#xD;
&#xD;
               -  Signs of radiographic vasospasm upon diagnosis&#xD;
&#xD;
               -  Presence of systemic or CSF infection&#xD;
&#xD;
               -  Contraindication for oral Nimodipin&#xD;
&#xD;
               -  Pregnancy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Christian F Freyschlag, MD</last_name>
    <phone>+4350504</phone>
    <phone_ext>27452</phone_ext>
    <email>christian.freyschlag@i-med.ac.at</email>
  </overall_contact>
  <location>
    <facility>
      <name>Medical University of Innsbruck</name>
      <address>
        <city>Innsbruck</city>
        <state>Tirol</state>
        <zip>6020</zip>
        <country>Austria</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Christian F. Freyschlag, MD</last_name>
      <phone>+4350504</phone>
      <phone_ext>27452</phone_ext>
      <email>christian.freyschlag@i-med.ac.at</email>
    </contact>
    <contact_backup>
      <last_name>Johannes Kerschbaumer, MD</last_name>
      <phone>+4350504</phone>
      <phone_ext>27452</phone_ext>
      <email>johannes.kerschbaumer@tirol-kliniken.at</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Austria</country>
  </location_countries>
  <reference>
    <citation>de Rooij NK, Linn FH, van der Plas JA, Algra A, Rinkel GJ. Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends. J Neurol Neurosurg Psychiatry. 2007 Dec;78(12):1365-72. doi: 10.1136/jnnp.2007.117655. Epub 2007 Apr 30.</citation>
    <PMID>17470467</PMID>
  </reference>
  <reference>
    <citation>Nieuwkamp DJ, Setz LE, Algra A, Linn FH, de Rooij NK, Rinkel GJ. Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis. Lancet Neurol. 2009 Jul;8(7):635-42. doi: 10.1016/S1474-4422(09)70126-7. Epub 2009 Jun 6.</citation>
    <PMID>19501022</PMID>
  </reference>
  <reference>
    <citation>Kreiter KT, Copeland D, Bernardini GL, Bates JE, Peery S, Claassen J, Du YE, Stern Y, Connolly ES, Mayer SA. Predictors of cognitive dysfunction after subarachnoid hemorrhage. Stroke. 2002 Jan;33(1):200-8. doi: 10.1161/hs0102.101080.</citation>
    <PMID>11779911</PMID>
  </reference>
  <reference>
    <citation>Connolly ES Jr, Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Higashida RT, Hoh BL, Kirkness CJ, Naidech AM, Ogilvy CS, Patel AB, Thompson BG, Vespa P; American Heart Association Stroke Council; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; Council on Cardiovascular Surgery and Anesthesia; Council on Clinical Cardiology. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/american Stroke Association. Stroke. 2012 Jun;43(6):1711-37. doi: 10.1161/STR.0b013e3182587839. Epub 2012 May 3.</citation>
    <PMID>22556195</PMID>
  </reference>
  <reference>
    <citation>Langham J, Reeves BC, Lindsay KW, van der Meulen JH, Kirkpatrick PJ, Gholkar AR, Molyneux AJ, Shaw DM, Copley L, Browne JP; Steering Group for National Study of Subarachnoid Haemorrhage. Variation in outcome after subarachnoid hemorrhage: a study of neurosurgical units in UK and Ireland. Stroke. 2009 Jan;40(1):111-8. doi: 10.1161/STROKEAHA.108.517805. Epub 2008 Nov 13.</citation>
    <PMID>19008474</PMID>
  </reference>
  <reference>
    <citation>Pickard JD, Murray GD, Illingworth R, Shaw MD, Teasdale GM, Foy PM, Humphrey PR, Lang DA, Nelson R, Richards P, et al. Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ. 1989 Mar 11;298(6674):636-42. doi: 10.1136/bmj.298.6674.636.</citation>
    <PMID>2496789</PMID>
  </reference>
  <reference>
    <citation>Dorhout Mees SM, Rinkel GJ, Feigin VL, Algra A, van den Bergh WM, Vermeulen M, van Gijn J. Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev. 2007 Jul 18;2007(3):CD000277. doi: 10.1002/14651858.CD000277.pub3.</citation>
    <PMID>17636626</PMID>
  </reference>
  <reference>
    <citation>Vergouwen MD; Participants in the International Multi-Disciplinary Consensus Conference on the Critical Care Management of Subarachnoid Hemorrhage. Vasospasm versus delayed cerebral ischemia as an outcome event in clinical trials and observational studies. Neurocrit Care. 2011 Sep;15(2):308-11. doi: 10.1007/s12028-011-9586-8.</citation>
    <PMID>21748502</PMID>
  </reference>
  <reference>
    <citation>Vergouwen MD, Vermeulen M, van Gijn J, Rinkel GJ, Wijdicks EF, Muizelaar JP, Mendelow AD, Juvela S, Yonas H, Terbrugge KG, Macdonald RL, Diringer MN, Broderick JP, Dreier JP, Roos YB. Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group. Stroke. 2010 Oct;41(10):2391-5. doi: 10.1161/STROKEAHA.110.589275. Epub 2010 Aug 26.</citation>
    <PMID>20798370</PMID>
  </reference>
  <verification_date>December 2022</verification_date>
  <study_first_submitted>April 30, 2020</study_first_submitted>
  <study_first_submitted_qc>July 24, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 28, 2020</study_first_posted>
  <last_update_submitted>December 12, 2022</last_update_submitted>
  <last_update_submitted_qc>December 12, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">December 14, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>EVD</keyword>
  <keyword>Aneurysm</keyword>
  <keyword>SAH</keyword>
  <keyword>Subarachnoid hemorrhage</keyword>
  <keyword>cerebral vasospasm</keyword>
  <keyword>cerebrospinal fluid</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Subarachnoid Hemorrhage</mesh_term>
    <mesh_term>Vasospasm, Intracranial</mesh_term>
    <mesh_term>Hemorrhage</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/NCT04490161
org study id: 1193/2018
nct id: NCT04490161
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The pathophysiological mechanisms of aneurysmal subarachnoid haemorrhage (aSAH) involve early
      brain injury (EBI) and delayed cerebral ischemia (DCI).

      Several mechanisms contribute to EBI pathogenesis, including cell death, inflammatory
      response, oxidative stress, excitotoxicity, microcirculatory dysfunction, microthrombosis and
      cortical spreading depolarization. All are suggested to be linked due to common pathogenic
      pathways and direct interaction.

      Despite advances in research of diagnostics and treatment strategies, brain injury remains
      the major cause of death and disability in SAH patients. There is no sufficient treatment of
      SAH and its devastating consequences known so far. Developing and improving diagnostic
      methods to monitor SAH patients and to evaluate efficacy of treatment strategies are
      essential in SAH research. These include neuroimaging, biomarkers, and other parameters such
      as invasive multimodal neuromonitoring and intraoperative electrophysiological monitoring.

      Cerebral vasospasm (CV) - mostly responsible for DCI - can be depicted on angiograms.
      Altogether, tremendous efforts have been taken to conquer the occurrence and sustainability
      of CV. The mortality of patients suffering aSAH rises up to 50% if the patients' condition is
      critical (Hunt&Hess (HH) Grade 5, WFNS Grade 5, modified Fisher Grade 4).

      Reports of beneficial outcome in patients with pre-existing CSF shunting have been published.
      The hypothesis of early CSF reapplication to the bloodstream, in order to prevent CV seems to
      be positively approved by the mentioned reports. Nevertheless, no data could be found on the
      mechanisms of action in this phenomenon.

      To confirm the presence of interaction of the mechanisms of EBI and evaluate the application
      of cerebrospinal fluid (CSF), a pilot clinical trial was planned. Due to the lack of
      validated animal models for aSAH it is necessary to perform the trial first-in-human. A pilot
      (proof of concept) trial - is done through inclusion of 10 patients with severe aSAH (≥HH4).
      According to clinical guidelines, these patients receive external ventricular drainages in
      order to drain CSF and lower intracranial pressure. An interim analysis of data will be
      performed after inclusion and treatment of 5 patients. Blood-/CSF-sampling for further
      analysis will be collected before, during and after treatment according to the study
      protocol.
Aneurysmal subarachnoid haemorrhage (aSAH) is associated with high morbidity and mortality
      with an incidence of 5-9 per 100,000 population. The incidence of aSAH peaks amongst those of
      40-60 years1; aSAH carries a high overall mortality rate of up to 67%2 with only around half
      of the survivors able to live independently. Given the age-related incidence 3 and high
      morbidity and mortality, SAH has a high burden on society . Conventionally following SAH,
      treatment is directed to securing the aneurysm to prevent further re-bleed. In addition to
      the primary brain injury due to the rupture of the aneurysm the occurrence of cerebral
      vasospasm (VS) with narrowing of the brain supplying arteries potentially lading to brain
      ischemia is as well - known and serious complication following aSAH. The development of VS is
      thought to be caused by various factors. Interestingly, this is not an instant phenomenon
      occurring right after the hemorrhagic event. VS develops rather in a time dependent fashion
      with a peak incidence around 7-10 days following from acute event.

      From angiographic studies, it is known that up to 70% of all patients with a aSAH will
      develop VS and in about 40% of these it will result in clinical deterioration and in 10-15%
      in permanent delayed ischemic neurologic deficits (DIND) leading to an increased morbidity 4,
      5 and mortality

      . Based on the fact that VS develops with a time delay, this is thought to provide a
      "therapeutic window" allowing to initiate measures for its prevention. However, in spite of
      intensive experimental and clinical research the investigators still do not have any
      effective treatment for the prevention of VS in patients with aSAH. Many concepts have been
      elaborated in the past, mostly based o sound pharmacologic considerations such as calcium
      antagonists (Nimodipin), antioxidants (Tirilazad) and endothelin antagonists (Clazosentan).
      In clinical trials, however, none of these drugs have shown a therapeutic effect on VS and
      most of them have been abandoned since then. The only exception is the use of oral Nimodipin,
      which is still used showing a marginal effect 6-8.

      In contrast to all previous studies, which were based on the use of specific drugs, the
      present hypothesis is different. It is based on the assumption that the brain is a
      "privileged" organ, where the in- and outflow is regulated by discrete barrier mechanisms
      (e.g. blood-brain- barrier). In the event of aSAH - factors that are thought to play an
      important role in the development of VS are released into the CSF. However, it is not clear
      whether these factors will enter the systemic circulation. This is further supported by the
      clinical observation that in many patients with aSAH, acute disturbances of CSF circulation
      can be seen, often resulting in hydrocephalus. This in return can be treated by CSF flow
      diversion with the use of external ventricular drainage, which is a routine procedure in the
      management of aSAH patients.

      Based on the assumption that those factors responsible for the development of VS are
      contained in the CSF, but do not enter the systemic circulation, it then might make sense to
      use the externally drained CSF for intravenous re-administration and thereby activating a
      systemic response mechanism with in turn could prevent the development of VS.

      The potential therapeutic benefits outweigh any potential risks for patients with aSAH.

      The proposed clinical study involves autologous CSF without any changes made to the liquid.
      The CSF will be taken from the external ventricular drain (EVD) under sterile environment and
      reinfused intravenously.

      An interval of approximately 21 days will permit a timely review and evaluation of interim
      safety (after 5 patients) and tolerability data collected The potential benefit to patients
      is significant with reduced delayed cerebral infarction (DCI), improved cognition and
      cerebral function. As such, studies in patients with aSAH are warranted, with a view to
      establishing the optimal dose, safety and exploratory efficacy profiles.

      This is a pilot trial involving higher grade (see inclusion criteria) aSAH patients.

      The human brain is protected and enjoying privileged immune status. The blood-brain- barrier
      (BBB) leads to consequent isolation of brain tissue from humoral immunity. The brain is
      experiencing several major changes during rupture of a cerebral aneurysm. First, the
      intracranial pressure increases immediately, caused by the actual bleeding. Second, the
      extravasation of blood disrupts the BBB and several immunogenic molecules travel through the
      spontaneous rupture into the CSF. Additionally, microscopic particles of the vessel wall are
      present in the CSF as a consequence of the wall rupture. Usually, these potentially
      spasmogenic fractions are never encountered by the brain and the external surface of its
      vessels. Interestingly, the perioperative collection of blood in subarachnoid spaces does not
      induce vasospasm.

      The investigators hypothesized that the reported steps were crucial for the formation of
      cerebral vasospasm.

      This study will be conducted in compliance with the protocol and according to Good Clinical
      Practice and applicable regulatory standards. No deviation from the protocol will be
      implemented without the prior review and approval by the relevant ethics and regulatory
      authorities, except where it may be necessary to eliminate an immediate hazard to a research
      subject. In such case, the deviation will be reported to the relevant ethics and regulatory
      authorities as soon as possible.

      Ten patients with an angiographically confirmed aSAH, who in addition are in need of early
      external ventricular drainage (routine procedure), irrespective of the clinical grade on
      admission and in whom definite treatment (clip ligation or interventional treatment) is
      achievable within 72 hours following aSAH.

      Following aneurysm clip ligation, the predetermined amount of CSF (10ml) will be obtained
      under sterile conditions directly from the external ventricular drain and administered in a
      peripheral vein. To reduce the possibility of contamination, the application of CSF will be
      done immediately. In case of extensive intraventricular hemorrhage, causing the aspiration of
      clotted blood while obtaining CSF, the patient needs to be excluded from the trial.

      A number of patients will have an EVD placed for clinical reasons. These patients would
      regularly have CSF sampling ranging from daily to twice weekly.

      In this study, approximately 2 ml CSF will be taken and stored for translational study
      purposes (starting on day of EVD fitting) until day 21 or until the EVD is removed as per
      standard of care.
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Prevention
masking: None (Open Label)
measure: Incidence of severe radiographic vasospasm
time frame: 8 (+/- 1) day post SAH
description: measured upon digital subtraction angiography
measure: Infectious complications
time frame: 7 days
description: presence of infections complications according to the study intervention (intravenous administration)
measure: Incidence of vasospasm-related morbidity / mortality
time frame: within 21 days post-aneurysm securing
description: Defined by on of the following: DIND (confirmed by mGCS); cerebral infarction upon CT scan (day 14), need for anti-vasospasm therapy within 14 day post securing
arm group label: Interventional
arm group type: Experimental
description: Subjects will receive reinstallation of CSF intravenously.
arm group label: Observational
arm group type: No Intervention
description: Subjects will not receive study intervention; CSF will be sampled and analyzed in comparison to the Interventional arm,
intervention type: Other
intervention name: intravenous reinstallation of cerebrospinal fluid
description: 10ml of CSF will be taken under sterile conditions from the external ventricular drain and immediately administered intravenously.
arm group label: Interventional
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: Christian F Freyschlag, MD
phone: +4350504
phone ext: 27452
email: christian.freyschlag@i-med.ac.at
facility: 
status: Recruiting
contact: 
contact backup: 
country: Austria
citation: de Rooij NK, Linn FH, van der Plas JA, Algra A, Rinkel GJ. Incidence of subarachnoid haemorrhage: a systematic review with emphasis on region, age, gender and time trends. J Neurol Neurosurg Psychiatry. 2007 Dec;78(12):1365-72. doi: 10.1136/jnnp.2007.117655. Epub 2007 Apr 30.
PMID: 17470467
citation: Nieuwkamp DJ, Setz LE, Algra A, Linn FH, de Rooij NK, Rinkel GJ. Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis. Lancet Neurol. 2009 Jul;8(7):635-42. doi: 10.1016/S1474-4422(09)70126-7. Epub 2009 Jun 6.
PMID: 19501022
citation: Kreiter KT, Copeland D, Bernardini GL, Bates JE, Peery S, Claassen J, Du YE, Stern Y, Connolly ES, Mayer SA. Predictors of cognitive dysfunction after subarachnoid hemorrhage. Stroke. 2002 Jan;33(1):200-8. doi: 10.1161/hs0102.101080.
PMID: 11779911
citation: Connolly ES Jr, Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Higashida RT, Hoh BL, Kirkness CJ, Naidech AM, Ogilvy CS, Patel AB, Thompson BG, Vespa P; American Heart Association Stroke Council; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; Council on Cardiovascular Surgery and Anesthesia; Council on Clinical Cardiology. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/american Stroke Association. Stroke. 2012 Jun;43(6):1711-37. doi: 10.1161/STR.0b013e3182587839. Epub 2012 May 3.
PMID: 22556195
citation: Langham J, Reeves BC, Lindsay KW, van der Meulen JH, Kirkpatrick PJ, Gholkar AR, Molyneux AJ, Shaw DM, Copley L, Browne JP; Steering Group for National Study of Subarachnoid Haemorrhage. Variation in outcome after subarachnoid hemorrhage: a study of neurosurgical units in UK and Ireland. Stroke. 2009 Jan;40(1):111-8. doi: 10.1161/STROKEAHA.108.517805. Epub 2008 Nov 13.
PMID: 19008474
citation: Pickard JD, Murray GD, Illingworth R, Shaw MD, Teasdale GM, Foy PM, Humphrey PR, Lang DA, Nelson R, Richards P, et al. Effect of oral nimodipine on cerebral infarction and outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ. 1989 Mar 11;298(6674):636-42. doi: 10.1136/bmj.298.6674.636.
PMID: 2496789
citation: Dorhout Mees SM, Rinkel GJ, Feigin VL, Algra A, van den Bergh WM, Vermeulen M, van Gijn J. Calcium antagonists for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev. 2007 Jul 18;2007(3):CD000277. doi: 10.1002/14651858.CD000277.pub3.
PMID: 17636626
citation: Vergouwen MD; Participants in the International Multi-Disciplinary Consensus Conference on the Critical Care Management of Subarachnoid Hemorrhage. Vasospasm versus delayed cerebral ischemia as an outcome event in clinical trials and observational studies. Neurocrit Care. 2011 Sep;15(2):308-11. doi: 10.1007/s12028-011-9586-8.
PMID: 21748502
citation: Vergouwen MD, Vermeulen M, van Gijn J, Rinkel GJ, Wijdicks EF, Muizelaar JP, Mendelow AD, Juvela S, Yonas H, Terbrugge KG, Macdonald RL, Diringer MN, Broderick JP, Dreier JP, Roos YB. Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group. Stroke. 2010 Oct;41(10):2391-5. doi: 10.1161/STROKEAHA.110.589275. Epub 2010 Aug 26.
PMID: 20798370
responsible party type: Sponsor
mesh term: Subarachnoid Hemorrhage
mesh term: Vasospasm, Intracranial
mesh term: Hemorrhage
sharing ipd: No