<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/NCT02997371</url>
  </required_header>
  <id_info>
    <org_study_id>CCTU0185</org_study_id>
    <nct_id>NCT02997371</nct_id>
  </id_info>
  <brief_title>IL-1ra Dose-range Study for Moderate-to-severe TBI Patients</brief_title>
  <acronym>IL1ra</acronym>
  <official_title>A Randomised Double Blind Placebo Controlled Dose-range Study Using Placebo, 1.5g and 3.0g of Intravenous Recombinant Interleukin-1 Receptor Antagonist (Anakinra) for Patients With Moderate-to-severe TBI</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Adel Helmy</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Cambridge University Hospitals NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Cambridge</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Traumatic brain injury (TBI) is a common condition with high degree of morbidity and&#xD;
      mortality (Hyder et al., 2007). Current treatment paradigms for TBI focus on mitigating&#xD;
      secondary injury and maintaining cerebral physiology (Carney et al., 2016), however, there&#xD;
      are currently no approved drugs that target the underlying conditions for patients suffering&#xD;
      from TBI (Bullock et al., 1999). It is increasingly recognised that the innate inflammatory&#xD;
      response to TBI may inflict injury (Lucas et al., 2006), and one of the most prominent&#xD;
      mediators of inflammation in the injured brain is the Interleukin-1 (IL-1) receptor pathway&#xD;
      (Allan et al., 2005). An endogenous antagonist to IL-1, is available in recombinant form&#xD;
      (IL-1ra, Kineret), and is known to be safe in TBI (Helmy et al., 2014).&#xD;
&#xD;
      In order to fully understand, and potentially optimize, the effect of Kineret, the&#xD;
      investigators wish to conduct a dose-response study by giving three cohorts (n=20 per group)&#xD;
      either placebo (isotonic saline), 1.5g or 3.0g of active substance administered intravenously&#xD;
      in a double-blind, randomized setting. The concentrations have in previous studies not been&#xD;
      shown to present any side-effects (Singh et al., 2014). The drug will be provided within 12&#xD;
      hours after trauma. The goal will be to provide a dose-response effect on the cerebral&#xD;
      inflammatory response. As secondary goals, the investigators will assess the brain damage by&#xD;
      measuring proteins in blood and cerebrospinal fluid, functional outcome and inflammation in&#xD;
      the brain using positron emission tomography.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Aim&#xD;
&#xD;
      The hypothesis is that an increasing dose of the anti-inflammatory drug recombinant human&#xD;
      Interleukin-1 receptor antagonist (IL-1ra, Kineret) will modulate the inflammatory state of&#xD;
      the traumatically injured brain, which will attenuate the injurious processes that occur&#xD;
      following TBI.&#xD;
&#xD;
      Study Design&#xD;
&#xD;
      While different doses of Anakinra have been used in trials, there is no knowledge of what&#xD;
      constitutes an optimized concentration of the drug. To address this limitation, the current&#xD;
      study will be a dose-response study in a double blind randomised clinical fashion, using&#xD;
      placebo (n=20), 1.5 g (&quot;intermediate dose&quot;) or (n=20) and 3.0 g (&quot;high dose&quot;)(n=20) of&#xD;
      Anakinra provided the first 48 hours (drug/placebo administered initially as 500 mg infusion&#xD;
      bolus and later as an 1g or 2.5g infusion for 48 hours). Thus, a total of n=60 patients will&#xD;
      be included. Sample-size analyses have indicated that the number of patients is sufficient to&#xD;
      detect differences in the inflammatory response as gauged with cytokine measurements using&#xD;
      cerebral microdialysis.&#xD;
&#xD;
      As surrogate markers of outcome for these patients, several protein biomarkers of brain&#xD;
      injury and proteins of the innate immune responses will be quantified using techniques called&#xD;
      ELISA and multiplex assay technology. The investigators also wish to use radiological&#xD;
      techniques, such as magnetic resonance imaging to study damages in white matter tracts in the&#xD;
      brain and positron emission tomography to assess the degree of microglial activation. All&#xD;
      these methods will be used to assess the potential benefit of the treatment vs placebo.&#xD;
&#xD;
      By this type of study design, it will minimize bias and confounders that may influence the&#xD;
      study.&#xD;
&#xD;
      Patient Recruitment&#xD;
&#xD;
      Patients with a clinical diagnosis of severe and moderate TBI will be identified by the&#xD;
      research team at the daily departmental neuro-critical care unit meeting. Patients meeting&#xD;
      the inclusion criteria will be approached for consent/assent if conscious or if next of kin&#xD;
      is present. If not, consent will be assumed as we know Anakinra to be safe and there is&#xD;
      likely to be a narrow therapeutic window. With the current patient load at Addenbrooke's&#xD;
      Hospital, Cambridge, the investigators deem it possible to recruit one patient per week, thus&#xD;
      estimating that the recruiting phase will take approximately two years to complete.&#xD;
&#xD;
      Sampling&#xD;
&#xD;
      All the sampling will be conducted during the acute phase when the patient is unconscious in&#xD;
      the neuro-critical care unit. Microdialysis probes are sampled hourly. To assess inflammatory&#xD;
      activity in the brain, positron emission tomography will be performed within the first week&#xD;
      and after 2-3 weeks. Magnetic resonance imaging will be performed the first 2-3 weeks and&#xD;
      then after 6 months. To measure the patient's adaptive immune response to brain specific&#xD;
      proteins, specialised auto-immunisation assays will be performed on patient blood at day 1-3&#xD;
      following injury as well as after 2-3 weeks.&#xD;
&#xD;
      During the intensive care phase, blood and cerebrospinal fluid will be sampled twice per day&#xD;
      (approximately 3mL per sampling time per compartment, volumes that we do not deem harmful to&#xD;
      the patient) and will be collected together with hourly microdialysate fluid samples the&#xD;
      first 7 days from admission. Blood will also be sampled at an outpatient clinic follow up at&#xD;
      6 and 12 months following injury. Patient samples will be anonymised and stored at -80degC in&#xD;
      the Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge&#xD;
      before analysis.&#xD;
&#xD;
      It will not to be possible to measure cytokines, the drug and biomarkers from all&#xD;
      microdialysis samples due to volume constraints. Moreover, we believe that a temporal&#xD;
      resolution of 6 hours is probably adequate for the brain concentration of the drug while 12&#xD;
      hours is sufficient in serum. APP and tau will also be measured every 6 hours. The only&#xD;
      parameter that will be hourly analysed in microdialysis is cytokine and chemokines through a&#xD;
      luminex panel.&#xD;
&#xD;
      Clinical Follow-up&#xD;
&#xD;
      Patients will be followed up at a clinic visit at 6 and 12 months after trauma by&#xD;
      questionnaire survey using standardised outcome measures in neurosurgical patients including&#xD;
      the golden standard extended Glasgow Outcome Score and Short Form 36.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">October 2017</start_date>
  <completion_date type="Anticipated">October 2021</completion_date>
  <primary_completion_date type="Anticipated">October 2021</primary_completion_date>
  <phase>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>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Decrease of pro-inflammatory cytokines in brain extracellular fluid (ECF)</measure>
    <time_frame>First 48 hours</time_frame>
    <description>Decrease of Tumor necrosis factor alpha and interferon gamma cytokines in brain ECF</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Patient outcome GOSe</measure>
    <time_frame>6 months and 12 months</time_frame>
    <description>Extended Glasgow Outcome Score (GOSe) assessments at 6 months and 1 year.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient outcome SF36</measure>
    <time_frame>6 months and 12 months</time_frame>
    <description>Short Form - 36 (SF-36) assessments at 6 months and 1 year.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Imaging outcome - PET-MRI</measure>
    <time_frame>During the first 14 days</time_frame>
    <description>To determine degree of microglial activation globally and in the locality of the microdialysis catheter, using magnetic resonance imaging (MRI) in combination with positron emission tomography (PET) PK-11195 (an an isoquinoline carboxamide) ligand.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Imaging outcome - DTI-MRI</measure>
    <time_frame>During the first 14 days</time_frame>
    <description>To determine degree of axonal injury globally and in the locality of the microdialysis catheter, using magnetic resonance imaging (MRI) in combination with diffuse tensor imaging (DTI).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biochemical outcome - S100B</measure>
    <time_frame>During the first 7 days + at 6 months and 12 months</time_frame>
    <description>Concentrations of protein biomarkers of tissue fate, S100B in serum (µg/L) twice per day as well as after 6 months and 12 months.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biochemical outcome - NF-L</measure>
    <time_frame>During the first 7 days</time_frame>
    <description>Concentrations of protein biomarkers of tissue fate, Concentrations of protein biomarkers of tissue fate, Neurofilament Light (NF-L) in serum (µg/L) twice per day as well as after 6 months and 12 months.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biochemical outcome - Tau</measure>
    <time_frame>During the first 7 days</time_frame>
    <description>Concentrations of protein biomarkers of tissue fate, microtubuli associated protein tau (tau) measured in microdialysis every 6 hours.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biochemical outcome - APP</measure>
    <time_frame>During the first 7 days</time_frame>
    <description>Concentrations of protein biomarkers of tissue fate, Amyloid Precursor Protein Beta (APP) associated protein tau measured in microdialysis every 6 hours.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biochemical outcome - Autoreactivity versus MBP</measure>
    <time_frame>During the first 7 days + at 6 months and 12 months</time_frame>
    <description>Concentration of circulating T-cells with autoreactivity towards myelin basic protein (MBP) in serum.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Monitoring outcome - ICP</measure>
    <time_frame>First 7 days</time_frame>
    <description>Intracranial pressure (ICP, mmHg) during the neuro-critical care unit (NCCU) stay.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Monitoring outcome - CPP</measure>
    <time_frame>First 7 days</time_frame>
    <description>Cerebral perfusion pressure (CPP, mmHg) during the NCCU stay.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Monitoring outcome - Cerebral Metabolism LPR</measure>
    <time_frame>First 7 days</time_frame>
    <description>Cerebral metabolism, by measuring lactate:pyruvate ratio (LPR) in microdialysis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Monitoring outcome - Brain tissue oxygenation</measure>
    <time_frame>First 7 days</time_frame>
    <description>Brain tissue oxygen (mmHg).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Monitoring outcome - PRx</measure>
    <time_frame>First 7 days</time_frame>
    <description>Derived variables of cerebral elastance (Pressure reactivity index, PRx).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacological outcome - Concentration of IL1ra in brain tissue</measure>
    <time_frame>First week</time_frame>
    <description>IL-1ra brain concentration (pg/ml), measured every 6 hours by cerebral microdialysis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacological outcome - Concentration of IL1ra in serum</measure>
    <time_frame>First week</time_frame>
    <description>IL-1ra serum concentration (pg/ml), measured every 12 hours.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Side effects of the IL1ra</measure>
    <time_frame>First week + up to 12 months follow-up</time_frame>
    <description>To study any potential side-effect of the drug, both known and unknown.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Traumatic Brain INjury</condition>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Isotonic saline administered as an injection and infusion</description>
  </arm_group>
  <arm_group>
    <arm_group_label>1.5 g Kineret</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Kineret provided as a 500 mg injection followed by a 1g infusion.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>3.0 g Kineret</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Kineret provided as a 500 mg injection followed by a 2.5g infusion.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Anakinra Prefilled Syringe</intervention_name>
    <description>Administration as initially intravenous injection followed by a intravenous infusion</description>
    <arm_group_label>1.5 g Kineret</arm_group_label>
    <arm_group_label>3.0 g Kineret</arm_group_label>
    <other_name>Kineret</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Isotonic saline</intervention_name>
    <description>Placebo, administration as initially intravenous injection followed by a intravenous infusion</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Placebo</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Suffer from a TBI, present with a Glasgow Coma Scale (GCS) of 3-13 and be deemed to be&#xD;
             in need of neuro-critical care and intracranial monitoring for at least 72 hours.&#xD;
&#xD;
          2. Be aged 18-65&#xD;
&#xD;
          3. The first dose of Kineret (or placebo) must be provided within 12 hours after trauma.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Head injury unlikely to survive 5 days (radiological evidence of above as judged by&#xD;
             clinical team, bilateral fixed and dilated pupils).&#xD;
&#xD;
          2. Follow up not possible&#xD;
&#xD;
          3. Not suitable for insertion of cranial access device to monitor the brain (such as&#xD;
             bleeding complications)&#xD;
&#xD;
          4. Active immunosuppression therapy (evidence of neutropenia, immunosuppression secondary&#xD;
             to immunomodulatory medications, chemotherapy or radiation therapy in the 3 months&#xD;
             preceding study entry)&#xD;
&#xD;
          5. Severe Renal Insufficiency or End Stage Renal Disease (defined as a creatinine&#xD;
             clearance &lt;30 ml/min)&#xD;
&#xD;
          6. Pregnancy/Nursing mothers&#xD;
&#xD;
          7. Known hypersensitivity to E. coli derived products&#xD;
&#xD;
          8. Administration of live vaccine&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Adel Helmy, MA, MB BChir, FRCS, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Cambridge</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Adel Helmy, MA, MB BChir, FRCS, PhD</last_name>
    <phone>00441223 216147</phone>
    <email>adelhelmy@cantab.net</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Eric P Thelin, MD, PhD</last_name>
    <phone>0046739365450</phone>
    <email>thelin.eric@gmail.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Cambridge University Hospital NHS Trust</name>
      <address>
        <city>Cambridge</city>
        <state>Cambridgeshire</state>
        <zip>CB2 0QQ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <reference>
    <citation>Allan SM, Tyrrell PJ, Rothwell NJ. Interleukin-1 and neuronal injury. Nat Rev Immunol. 2005 Aug;5(8):629-40. doi: 10.1038/nri1664.</citation>
    <PMID>16034365</PMID>
  </reference>
  <reference>
    <citation>Bullock MR, Lyeth BG, Muizelaar JP. Current status of neuroprotection trials for traumatic brain injury: lessons from animal models and clinical studies. Neurosurgery. 1999 Aug;45(2):207-17; discussion 217-20. doi: 10.1097/00006123-199908000-00001.</citation>
    <PMID>10449064</PMID>
  </reference>
  <reference>
    <citation>Carney N, Totten AM, O'Reilly C, Ullman JS, Hawryluk GW, Bell MJ, Bratton SL, Chesnut R, Harris OA, Kissoon N, Rubiano AM, Shutter L, Tasker RC, Vavilala MS, Wilberger J, Wright DW, Ghajar J. Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery. 2017 Jan 1;80(1):6-15. doi: 10.1227/NEU.0000000000001432.</citation>
    <PMID>27654000</PMID>
  </reference>
  <reference>
    <citation>Helmy A, Guilfoyle MR, Carpenter KL, Pickard JD, Menon DK, Hutchinson PJ. Recombinant human interleukin-1 receptor antagonist in severe traumatic brain injury: a phase II randomized control trial. J Cereb Blood Flow Metab. 2014 May;34(5):845-51. doi: 10.1038/jcbfm.2014.23. Epub 2014 Feb 26.</citation>
    <PMID>24569690</PMID>
  </reference>
  <reference>
    <citation>Hyder AA, Wunderlich CA, Puvanachandra P, Gururaj G, Kobusingye OC. The impact of traumatic brain injuries: a global perspective. NeuroRehabilitation. 2007;22(5):341-53.</citation>
    <PMID>18162698</PMID>
  </reference>
  <reference>
    <citation>Lucas SM, Rothwell NJ, Gibson RM. The role of inflammation in CNS injury and disease. Br J Pharmacol. 2006 Jan;147 Suppl 1(Suppl 1):S232-40. doi: 10.1038/sj.bjp.0706400.</citation>
    <PMID>16402109</PMID>
  </reference>
  <reference>
    <citation>Singh N, Hopkins SJ, Hulme S, Galea JP, Hoadley M, Vail A, Hutchinson PJ, Grainger S, Rothwell NJ, King AT, Tyrrell PJ. The effect of intravenous interleukin-1 receptor antagonist on inflammatory mediators in cerebrospinal fluid after subarachnoid haemorrhage: a phase II randomised controlled trial. J Neuroinflammation. 2014 Jan 3;11:1. doi: 10.1186/1742-2094-11-1.</citation>
    <PMID>24383930</PMID>
  </reference>
  <verification_date>May 2017</verification_date>
  <study_first_submitted>December 7, 2016</study_first_submitted>
  <study_first_submitted_qc>December 15, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 20, 2016</study_first_posted>
  <last_update_submitted>May 3, 2017</last_update_submitted>
  <last_update_submitted_qc>May 3, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">May 8, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Cambridge</investigator_affiliation>
    <investigator_full_name>Adel Helmy</investigator_full_name>
    <investigator_title>MA, MB BChir, PhD, FRCS (SN)</investigator_title>
  </responsible_party>
  <keyword>Traumatic brain injury</keyword>
  <keyword>Microdialysis</keyword>
  <keyword>Interleukin-1 receptor antagonist</keyword>
  <keyword>Magnetic Resonance Imaging</keyword>
  <keyword>Positron Emission Tomography</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brain Injuries</mesh_term>
    <mesh_term>Brain Injuries, Traumatic</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Interleukin 1 Receptor Antagonist Protein</mesh_term>
  </intervention_browse>
  <!-- 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/NCT02997371
org study id: CCTU0185
nct id: NCT02997371
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Traumatic brain injury (TBI) is a common condition with high degree of morbidity and
      mortality (Hyder et al., 2007). Current treatment paradigms for TBI focus on mitigating
      secondary injury and maintaining cerebral physiology (Carney et al., 2016), however, there
      are currently no approved drugs that target the underlying conditions for patients suffering
      from TBI (Bullock et al., 1999). It is increasingly recognised that the innate inflammatory
      response to TBI may inflict injury (Lucas et al., 2006), and one of the most prominent
      mediators of inflammation in the injured brain is the Interleukin-1 (IL-1) receptor pathway
      (Allan et al., 2005). An endogenous antagonist to IL-1, is available in recombinant form
      (IL-1ra, Kineret), and is known to be safe in TBI (Helmy et al., 2014).

      In order to fully understand, and potentially optimize, the effect of Kineret, the
      investigators wish to conduct a dose-response study by giving three cohorts (n=20 per group)
      either placebo (isotonic saline), 1.5g or 3.0g of active substance administered intravenously
      in a double-blind, randomized setting. The concentrations have in previous studies not been
      shown to present any side-effects (Singh et al., 2014). The drug will be provided within 12
      hours after trauma. The goal will be to provide a dose-response effect on the cerebral
      inflammatory response. As secondary goals, the investigators will assess the brain damage by
      measuring proteins in blood and cerebrospinal fluid, functional outcome and inflammation in
      the brain using positron emission tomography.
Aim

      The hypothesis is that an increasing dose of the anti-inflammatory drug recombinant human
      Interleukin-1 receptor antagonist (IL-1ra, Kineret) will modulate the inflammatory state of
      the traumatically injured brain, which will attenuate the injurious processes that occur
      following TBI.

      Study Design

      While different doses of Anakinra have been used in trials, there is no knowledge of what
      constitutes an optimized concentration of the drug. To address this limitation, the current
      study will be a dose-response study in a double blind randomised clinical fashion, using
      placebo (n=20), 1.5 g ("intermediate dose") or (n=20) and 3.0 g ("high dose")(n=20) of
      Anakinra provided the first 48 hours (drug/placebo administered initially as 500 mg infusion
      bolus and later as an 1g or 2.5g infusion for 48 hours). Thus, a total of n=60 patients will
      be included. Sample-size analyses have indicated that the number of patients is sufficient to
      detect differences in the inflammatory response as gauged with cytokine measurements using
      cerebral microdialysis.

      As surrogate markers of outcome for these patients, several protein biomarkers of brain
      injury and proteins of the innate immune responses will be quantified using techniques called
      ELISA and multiplex assay technology. The investigators also wish to use radiological
      techniques, such as magnetic resonance imaging to study damages in white matter tracts in the
      brain and positron emission tomography to assess the degree of microglial activation. All
      these methods will be used to assess the potential benefit of the treatment vs placebo.

      By this type of study design, it will minimize bias and confounders that may influence the
      study.

      Patient Recruitment

      Patients with a clinical diagnosis of severe and moderate TBI will be identified by the
      research team at the daily departmental neuro-critical care unit meeting. Patients meeting
      the inclusion criteria will be approached for consent/assent if conscious or if next of kin
      is present. If not, consent will be assumed as we know Anakinra to be safe and there is
      likely to be a narrow therapeutic window. With the current patient load at Addenbrooke's
      Hospital, Cambridge, the investigators deem it possible to recruit one patient per week, thus
      estimating that the recruiting phase will take approximately two years to complete.

      Sampling

      All the sampling will be conducted during the acute phase when the patient is unconscious in
      the neuro-critical care unit. Microdialysis probes are sampled hourly. To assess inflammatory
      activity in the brain, positron emission tomography will be performed within the first week
      and after 2-3 weeks. Magnetic resonance imaging will be performed the first 2-3 weeks and
      then after 6 months. To measure the patient's adaptive immune response to brain specific
      proteins, specialised auto-immunisation assays will be performed on patient blood at day 1-3
      following injury as well as after 2-3 weeks.

      During the intensive care phase, blood and cerebrospinal fluid will be sampled twice per day
      (approximately 3mL per sampling time per compartment, volumes that we do not deem harmful to
      the patient) and will be collected together with hourly microdialysate fluid samples the
      first 7 days from admission. Blood will also be sampled at an outpatient clinic follow up at
      6 and 12 months following injury. Patient samples will be anonymised and stored at -80degC in
      the Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge
      before analysis.

      It will not to be possible to measure cytokines, the drug and biomarkers from all
      microdialysis samples due to volume constraints. Moreover, we believe that a temporal
      resolution of 6 hours is probably adequate for the brain concentration of the drug while 12
      hours is sufficient in serum. APP and tau will also be measured every 6 hours. The only
      parameter that will be hourly analysed in microdialysis is cytokine and chemokines through a
      luminex panel.

      Clinical Follow-up

      Patients will be followed up at a clinic visit at 6 and 12 months after trauma by
      questionnaire survey using standardised outcome measures in neurosurgical patients including
      the golden standard extended Glasgow Outcome Score and Short Form 36.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Decrease of pro-inflammatory cytokines in brain extracellular fluid (ECF)
time frame: First 48 hours
description: Decrease of Tumor necrosis factor alpha and interferon gamma cytokines in brain ECF
measure: Patient outcome GOSe
time frame: 6 months and 12 months
description: Extended Glasgow Outcome Score (GOSe) assessments at 6 months and 1 year.
measure: Patient outcome SF36
time frame: 6 months and 12 months
description: Short Form - 36 (SF-36) assessments at 6 months and 1 year.
measure: Imaging outcome - PET-MRI
time frame: During the first 14 days
description: To determine degree of microglial activation globally and in the locality of the microdialysis catheter, using magnetic resonance imaging (MRI) in combination with positron emission tomography (PET) PK-11195 (an an isoquinoline carboxamide) ligand.
measure: Imaging outcome - DTI-MRI
time frame: During the first 14 days
description: To determine degree of axonal injury globally and in the locality of the microdialysis catheter, using magnetic resonance imaging (MRI) in combination with diffuse tensor imaging (DTI).
measure: Biochemical outcome - S100B
time frame: During the first 7 days + at 6 months and 12 months
description: Concentrations of protein biomarkers of tissue fate, S100B in serum (µg/L) twice per day as well as after 6 months and 12 months.
measure: Biochemical outcome - NF-L
time frame: During the first 7 days
description: Concentrations of protein biomarkers of tissue fate, Concentrations of protein biomarkers of tissue fate, Neurofilament Light (NF-L) in serum (µg/L) twice per day as well as after 6 months and 12 months.
measure: Biochemical outcome - Tau
time frame: During the first 7 days
description: Concentrations of protein biomarkers of tissue fate, microtubuli associated protein tau (tau) measured in microdialysis every 6 hours.
measure: Biochemical outcome - APP
time frame: During the first 7 days
description: Concentrations of protein biomarkers of tissue fate, Amyloid Precursor Protein Beta (APP) associated protein tau measured in microdialysis every 6 hours.
measure: Biochemical outcome - Autoreactivity versus MBP
time frame: During the first 7 days + at 6 months and 12 months
description: Concentration of circulating T-cells with autoreactivity towards myelin basic protein (MBP) in serum.
measure: Monitoring outcome - ICP
time frame: First 7 days
description: Intracranial pressure (ICP, mmHg) during the neuro-critical care unit (NCCU) stay.
measure: Monitoring outcome - CPP
time frame: First 7 days
description: Cerebral perfusion pressure (CPP, mmHg) during the NCCU stay.
measure: Monitoring outcome - Cerebral Metabolism LPR
time frame: First 7 days
description: Cerebral metabolism, by measuring lactate:pyruvate ratio (LPR) in microdialysis.
measure: Monitoring outcome - Brain tissue oxygenation
time frame: First 7 days
description: Brain tissue oxygen (mmHg).
measure: Monitoring outcome - PRx
time frame: First 7 days
description: Derived variables of cerebral elastance (Pressure reactivity index, PRx).
measure: Pharmacological outcome - Concentration of IL1ra in brain tissue
time frame: First week
description: IL-1ra brain concentration (pg/ml), measured every 6 hours by cerebral microdialysis.
measure: Pharmacological outcome - Concentration of IL1ra in serum
time frame: First week
description: IL-1ra serum concentration (pg/ml), measured every 12 hours.
measure: Side effects of the IL1ra
time frame: First week + up to 12 months follow-up
description: To study any potential side-effect of the drug, both known and unknown.
arm group label: Placebo
arm group type: Placebo Comparator
description: Isotonic saline administered as an injection and infusion
arm group label: 1.5 g Kineret
arm group type: Experimental
description: Kineret provided as a 500 mg injection followed by a 1g infusion.
arm group label: 3.0 g Kineret
arm group type: Experimental
description: Kineret provided as a 500 mg injection followed by a 2.5g infusion.
intervention type: Drug
intervention name: Anakinra Prefilled Syringe
description: Administration as initially intravenous injection followed by a intravenous infusion
arm group label: 1.5 g Kineret
arm group label: 3.0 g Kineret
other name: Kineret
intervention type: Drug
intervention name: Isotonic saline
description: Placebo, administration as initially intravenous injection followed by a intravenous infusion
arm group label: Placebo
other name: Placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Adel Helmy, MA, MB BChir, FRCS, PhD
role: Principal Investigator
affiliation: University of Cambridge
last name: Adel Helmy, MA, MB BChir, FRCS, PhD
phone: 00441223 216147
email: adelhelmy@cantab.net
last name: Eric P Thelin, MD, PhD
phone: 0046739365450
email: thelin.eric@gmail.com
facility: 
country: United Kingdom
citation: Allan SM, Tyrrell PJ, Rothwell NJ. Interleukin-1 and neuronal injury. Nat Rev Immunol. 2005 Aug;5(8):629-40. doi: 10.1038/nri1664.
PMID: 16034365
citation: Bullock MR, Lyeth BG, Muizelaar JP. Current status of neuroprotection trials for traumatic brain injury: lessons from animal models and clinical studies. Neurosurgery. 1999 Aug;45(2):207-17; discussion 217-20. doi: 10.1097/00006123-199908000-00001.
PMID: 10449064
citation: Carney N, Totten AM, O'Reilly C, Ullman JS, Hawryluk GW, Bell MJ, Bratton SL, Chesnut R, Harris OA, Kissoon N, Rubiano AM, Shutter L, Tasker RC, Vavilala MS, Wilberger J, Wright DW, Ghajar J. Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery. 2017 Jan 1;80(1):6-15. doi: 10.1227/NEU.0000000000001432.
PMID: 27654000
citation: Helmy A, Guilfoyle MR, Carpenter KL, Pickard JD, Menon DK, Hutchinson PJ. Recombinant human interleukin-1 receptor antagonist in severe traumatic brain injury: a phase II randomized control trial. J Cereb Blood Flow Metab. 2014 May;34(5):845-51. doi: 10.1038/jcbfm.2014.23. Epub 2014 Feb 26.
PMID: 24569690
citation: Hyder AA, Wunderlich CA, Puvanachandra P, Gururaj G, Kobusingye OC. The impact of traumatic brain injuries: a global perspective. NeuroRehabilitation. 2007;22(5):341-53.
PMID: 18162698
citation: Lucas SM, Rothwell NJ, Gibson RM. The role of inflammation in CNS injury and disease. Br J Pharmacol. 2006 Jan;147 Suppl 1(Suppl 1):S232-40. doi: 10.1038/sj.bjp.0706400.
PMID: 16402109
citation: Singh N, Hopkins SJ, Hulme S, Galea JP, Hoadley M, Vail A, Hutchinson PJ, Grainger S, Rothwell NJ, King AT, Tyrrell PJ. The effect of intravenous interleukin-1 receptor antagonist on inflammatory mediators in cerebrospinal fluid after subarachnoid haemorrhage: a phase II randomised controlled trial. J Neuroinflammation. 2014 Jan 3;11:1. doi: 10.1186/1742-2094-11-1.
PMID: 24383930
responsible party type: Sponsor-Investigator
investigator affiliation: University of Cambridge
investigator full name: Adel Helmy
investigator title: MA, MB BChir, PhD, FRCS (SN)
mesh term: Brain Injuries
mesh term: Brain Injuries, Traumatic
mesh term: Interleukin 1 Receptor Antagonist Protein