<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/NCT04462757</url>
  </required_header>
  <id_info>
    <org_study_id>282110</org_study_id>
    <secondary_id>2020-001636-95</secondary_id>
    <nct_id>NCT04462757</nct_id>
  </id_info>
  <brief_title>SCIL-1Ra in COVID-19 Feasibility &amp; PK/PD</brief_title>
  <acronym>SCIL_COV19</acronym>
  <official_title>Subcutaneous and Intravenous IL-1Ra (Anakinra) in COVID-19 Infection - Feasibility &amp; Pharmacokinetics/Pharmacodynamics Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Manchester</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Manchester</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The current COVID-19 pandemic is a worldwide healthcare crisis. Of concern is the large&#xD;
      number of patients that are/will require mechanical ventilation, and the associated strain&#xD;
      that this will place on healthcare resources. At present, there are no specific therapeutic&#xD;
      interventions directed at COVID-19 infection. However, observational data suggest that there&#xD;
      is a subgroup of patients that demonstrate a hyperinflammatory response in response to&#xD;
      COVID-19 and have a higher requirement for Critical Care and higher mortality.&#xD;
&#xD;
      There is a strong case for the use of the naturally occurring anti-inflammatory cytokine&#xD;
      interleukin-1 receptor antagonist (IL-1Ra) in these patients. Anakinra is a recombinant form&#xD;
      of IL-1Ra that is licensed for clinical use. Success of use of anakinra in COVID-19 trials&#xD;
      will be greatly enhanced by robust scientific evidence and established pharmacokinetics which&#xD;
      inform the most effective dosing regimens. The latter is especially important when, as in the&#xD;
      case of anakinra, drug supplies are limited, the drug has short half-life and clinical ease&#xD;
      of application is critical.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The investigators plan a small trial of an existing drug in patients with COVID-19 at Salford&#xD;
      Royal NHS Foundation Trust (SRFT) and Manchester Foundation Trust (MFT). The investigators&#xD;
      will recruit patients with suspected or confirmed COVID-19 infection within 24 hours of being&#xD;
      transfer in a Critical Care department. The investigators have been testing interleukin-1&#xD;
      receptor antagonist: IL-1Ra (known as Anakinra) for many years. Marketed as a treatment for&#xD;
      rheumatoid arthritis and for some rare autoimmune diseases, we have shown Anakinra also&#xD;
      reduces or blocks inflammation in a number of other conditions e.g. stroke and brain&#xD;
      haemorrhage. The investigators have found it to be safe, easily administered and well&#xD;
      tolerated. As part of the global response to the SARS-COV-2 pandemic, researchers have&#xD;
      identified drugs that repurposing existing drugs. Anakinra has been proposed as a candidate&#xD;
      therapy for COVID-19 and will be used in REMAP-CAP clinical trial as an intravenous (IV)&#xD;
      therapy four times daily (qds). Whilst there is uncertainty about the therapeutic benefits,&#xD;
      the investigators wish to explore the theory that they can achieve comparable concentrations&#xD;
      in the blood using a subcutaneous (SC) injection twice daily (bd), as observed with IV&#xD;
      therapy qds. We will randomise up to 40 patients to receive either SC Anakinra twice daily or&#xD;
      IV Anakinra four-times daily for 14 days (or until discharge from CCU). They will measure&#xD;
      changes in biomarkers in both groups and use the data to inform a mathematical model to&#xD;
      simulate the effect the drug may have on the body. The aim is to the provide evidence that a&#xD;
      lower dose SC Anakinra is as effective as higher dose IV.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Lack of patients in the trial population from which to recruit and lack of funding&#xD;
  </why_stopped>
  <start_date type="Actual">May 28, 2020</start_date>
  <completion_date type="Actual">December 23, 2020</completion_date>
  <primary_completion_date type="Actual">August 31, 2020</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>
    <intervention_model_description>Patients will be randomly assigned to one of two arms:-&#xD;
Subcutaneous arm: 100mg anakinra SC will be administered subcutaneously at consistent times that are convenient and practical for the patients and research/nursing staff providing there is a minimum 8 hours and maximum 16 hours between administrations.&#xD;
Intravenous arm: 100mg anakinra in 100mL 0.9% NaCl will be administered intravenously four times a day every 6 hours.</intervention_model_description>
    <primary_purpose>Health Services Research</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Plasma IL-1Ra levels</measure>
    <time_frame>1 week</time_frame>
    <description>Plasma IL-1Ra levels from Day 1 to Day 7 following administration of SC anakinra in patients with SARS-CoV-2</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Plasma IL-6 levels</measure>
    <time_frame>1 week</time_frame>
    <description>Plasma IL-6 levels from Day 1 to Day 7 following administration of SC anakinra in patients with SARS-CoV-2</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Plasma markers</measure>
    <time_frame>2 weeks</time_frame>
    <description>Plasma markers including IL-6 from Day 1 to Day 14 in all participants</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma markers</measure>
    <time_frame>2 weeks</time_frame>
    <description>Plasma markers including CRP from Day 1 to Day 14 in all participants</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma markers</measure>
    <time_frame>2 weeks</time_frame>
    <description>Plasma markers including CXCL9 from Day 1 to Day 14 in all participants</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma markers</measure>
    <time_frame>2 weeks</time_frame>
    <description>Plasma markers including IL-1 from Day 1 to Day 14 in all participants</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma markers</measure>
    <time_frame>2 weeks</time_frame>
    <description>Plasma markers including IL-2 from Day 1 to Day 14 in all participants</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma markers</measure>
    <time_frame>2 weeks</time_frame>
    <description>Plasma markers including HMBG-1 from Day 1 to Day 14 in all participants</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma markers</measure>
    <time_frame>2 weeks</time_frame>
    <description>Plasma markers including IL-33 from Day 1 to Day 14 in all participants</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety Endpoints related to the Serious adverse reactions of the IMP</measure>
    <time_frame>2 weeks</time_frame>
    <description>Safety endpoints include:&#xD;
a. Severe fatal or life-threatening serious adverse reactions (duration of IMP plus 30h from last dose).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety Endpoints related to the anaphylactic reactions of the IMP</measure>
    <time_frame>2 weeks</time_frame>
    <description>Safety endpoints include:&#xD;
b. Anaphylactic/anaphylactoid reactions (duration of IMP plus 30h from last dose).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety Endpoints related to neutropenia caused by the IMP</measure>
    <time_frame>2 weeks</time_frame>
    <description>Safety endpoints include:&#xD;
c. Severe neutropenia (&lt; 1.5 x 109 /L) (duration of IMP)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety Endpoints related to any severe laboratory abnormalities</measure>
    <time_frame>2 weeks</time_frame>
    <description>Safety endpoints include:&#xD;
d. IMP related severe laboratory abnormalities (duration of IMP)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Feasibility endpoints related to IMP and deviations</measure>
    <time_frame>2 weeks</time_frame>
    <description>Feasibility endpoints include protocol deviations in terms of timing and delivery of scheduled medication.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Exploratory Data on Clinical efficacy by time to recovery</measure>
    <time_frame>4 weeks</time_frame>
    <description>Exploratory data on clinical efficacy as defined by:&#xD;
a. Time to recovery defined by hospital discharge or improvement of two points on the ordinal scale: not hospitalised; hospitalised without need for supplemental oxygen; requiring supplemental oxygen; requiring HFNC or non-invasive mechanical ventilation; requiring ECMO or mechanical intervention; dead. Improvement mechanical ventilation (from recruitment to time of ventilation)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Exploratory Data on Clinical efficacy</measure>
    <time_frame>4 weeks</time_frame>
    <description>Exploratory data on clinical efficacy as defined by:&#xD;
b. Ventilation free days (at 28 days)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Exploratory Data on Clinical efficacy of the ordinal scale</measure>
    <time_frame>4 weeks</time_frame>
    <description>Exploratory data on clinical efficacy as defined by:&#xD;
c. Status on the above ordinal scale (at 14 and 28 days)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">5</enrollment>
  <condition>COVID-19</condition>
  <arm_group>
    <arm_group_label>Subcutaneous Arm</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>100mg anakinra SC will be administered subcutaneously at consistent times that are convenient and practical for the patients and research/nursing staff providing there is a minimum 8 hours and maximum 16 hours between administrations.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Intravenous Arm</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>100mg anakinra in 100mL 0.9% NaCl will be administered intravenously four times a day every 6 hours.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Anakinra 100Mg/0.67Ml Inj Syringe</intervention_name>
    <description>100 mg interleukin-1 receptor antagonist (r-meth-Hu-IL-1Ra), anakinra; marketed as Kineret® in 0.67 mL prefilled syringe for single use</description>
    <arm_group_label>Intravenous Arm</arm_group_label>
    <arm_group_label>Subcutaneous Arm</arm_group_label>
    <other_name>Kineret</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patient age 18 or above.&#xD;
&#xD;
          -  Clinically suspected/proven COVID-19.&#xD;
&#xD;
          -  Requiring organ support with one or more of:&#xD;
&#xD;
          -  Non-invasive or invasive ventilatory support&#xD;
&#xD;
          -  Receiving infusion of vasopressor or inotropes or both.&#xD;
&#xD;
          -  No concomitant health problems that, in the opinion of the PI or designee in agreement&#xD;
             with the treating clinician, would interfere with participation, administration of&#xD;
             study drug or assessment of outcomes including safety.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  More than 24h has elapsed since CCU admission.&#xD;
&#xD;
          -  Death is deemed to be imminent and inevitable during the next 24h.&#xD;
&#xD;
          -  One or more of: the patient, substitute decision-maker or the attending physician are&#xD;
             not committed to full active treatment.&#xD;
&#xD;
          -  Known condition resulting in ongoing immunosuppression including neutropenia (count &lt;&#xD;
             1.5 x 10^9/L) prior to hospitalisation, malignancy, latent tuberculosis or chronic&#xD;
             liver disease (if known).&#xD;
&#xD;
          -  Previous or current treatment with anakinra or medication suspected of interacting&#xD;
             with anakinra, listed in the drug SmPC, known at the time of trial entry or previous&#xD;
             participation in this trial.&#xD;
&#xD;
          -  Known to have received active treatment in a clinical trial of an investigational&#xD;
             immunomodulatory agent (not including corticosteroids) within 30 days prior to study&#xD;
             entry.&#xD;
&#xD;
          -  Known to be pregnant or breast feeding or inability to reliably confirm that the&#xD;
             patient is not pregnant.&#xD;
&#xD;
          -  Known allergy to anakinra or any of the excipients listed in the drug SmPC&#xD;
&#xD;
          -  Known allergy to other products that are produced by DNA technology using the&#xD;
             micro-organism E. coli (e.g. Escherichia coli derived protein).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Timothy Felton, Dr</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Manchester</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Manchester Univesity NHS Foundation Trust</name>
      <address>
        <city>Manchester</city>
        <zip>M13 9WL</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Salford Royal NHS Foundation Tust</name>
      <address>
        <city>Salford</city>
        <zip>M6 8HD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>April 2021</verification_date>
  <study_first_submitted>June 12, 2020</study_first_submitted>
  <study_first_submitted_qc>July 7, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 8, 2020</study_first_posted>
  <last_update_submitted>April 27, 2021</last_update_submitted>
  <last_update_submitted_qc>April 27, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 30, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</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>
  <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/NCT04462757
org study id: 282110
secondary id: 2020-001636-95
nct id: NCT04462757
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The current COVID-19 pandemic is a worldwide healthcare crisis. Of concern is the large
      number of patients that are/will require mechanical ventilation, and the associated strain
      that this will place on healthcare resources. At present, there are no specific therapeutic
      interventions directed at COVID-19 infection. However, observational data suggest that there
      is a subgroup of patients that demonstrate a hyperinflammatory response in response to
      COVID-19 and have a higher requirement for Critical Care and higher mortality.

      There is a strong case for the use of the naturally occurring anti-inflammatory cytokine
      interleukin-1 receptor antagonist (IL-1Ra) in these patients. Anakinra is a recombinant form
      of IL-1Ra that is licensed for clinical use. Success of use of anakinra in COVID-19 trials
      will be greatly enhanced by robust scientific evidence and established pharmacokinetics which
      inform the most effective dosing regimens. The latter is especially important when, as in the
      case of anakinra, drug supplies are limited, the drug has short half-life and clinical ease
      of application is critical.
The investigators plan a small trial of an existing drug in patients with COVID-19 at Salford
      Royal NHS Foundation Trust (SRFT) and Manchester Foundation Trust (MFT). The investigators
      will recruit patients with suspected or confirmed COVID-19 infection within 24 hours of being
      transfer in a Critical Care department. The investigators have been testing interleukin-1
      receptor antagonist: IL-1Ra (known as Anakinra) for many years. Marketed as a treatment for
      rheumatoid arthritis and for some rare autoimmune diseases, we have shown Anakinra also
      reduces or blocks inflammation in a number of other conditions e.g. stroke and brain
      haemorrhage. The investigators have found it to be safe, easily administered and well
      tolerated. As part of the global response to the SARS-COV-2 pandemic, researchers have
      identified drugs that repurposing existing drugs. Anakinra has been proposed as a candidate
      therapy for COVID-19 and will be used in REMAP-CAP clinical trial as an intravenous (IV)
      therapy four times daily (qds). Whilst there is uncertainty about the therapeutic benefits,
      the investigators wish to explore the theory that they can achieve comparable concentrations
      in the blood using a subcutaneous (SC) injection twice daily (bd), as observed with IV
      therapy qds. We will randomise up to 40 patients to receive either SC Anakinra twice daily or
      IV Anakinra four-times daily for 14 days (or until discharge from CCU). They will measure
      changes in biomarkers in both groups and use the data to inform a mathematical model to
      simulate the effect the drug may have on the body. The aim is to the provide evidence that a
      lower dose SC Anakinra is as effective as higher dose IV.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Patients will be randomly assigned to one of two arms:-
Subcutaneous arm: 100mg anakinra SC will be administered subcutaneously at consistent times that are convenient and practical for the patients and research/nursing staff providing there is a minimum 8 hours and maximum 16 hours between administrations.
Intravenous arm: 100mg anakinra in 100mL 0.9% NaCl will be administered intravenously four times a day every 6 hours.
primary purpose: Health Services Research
masking: None (Open Label)
measure: Plasma IL-1Ra levels
time frame: 1 week
description: Plasma IL-1Ra levels from Day 1 to Day 7 following administration of SC anakinra in patients with SARS-CoV-2
measure: Plasma IL-6 levels
time frame: 1 week
description: Plasma IL-6 levels from Day 1 to Day 7 following administration of SC anakinra in patients with SARS-CoV-2
measure: Plasma markers
time frame: 2 weeks
description: Plasma markers including IL-6 from Day 1 to Day 14 in all participants
measure: Plasma markers
time frame: 2 weeks
description: Plasma markers including CRP from Day 1 to Day 14 in all participants
measure: Plasma markers
time frame: 2 weeks
description: Plasma markers including CXCL9 from Day 1 to Day 14 in all participants
measure: Plasma markers
time frame: 2 weeks
description: Plasma markers including IL-1 from Day 1 to Day 14 in all participants
measure: Plasma markers
time frame: 2 weeks
description: Plasma markers including IL-2 from Day 1 to Day 14 in all participants
measure: Plasma markers
time frame: 2 weeks
description: Plasma markers including HMBG-1 from Day 1 to Day 14 in all participants
measure: Plasma markers
time frame: 2 weeks
description: Plasma markers including IL-33 from Day 1 to Day 14 in all participants
measure: Safety Endpoints related to the Serious adverse reactions of the IMP
time frame: 2 weeks
description: Safety endpoints include:
a. Severe fatal or life-threatening serious adverse reactions (duration of IMP plus 30h from last dose).
measure: Safety Endpoints related to the anaphylactic reactions of the IMP
time frame: 2 weeks
description: Safety endpoints include:
b. Anaphylactic/anaphylactoid reactions (duration of IMP plus 30h from last dose).
measure: Safety Endpoints related to neutropenia caused by the IMP
time frame: 2 weeks
description: Safety endpoints include:
c. Severe neutropenia (< 1.5 x 109 /L) (duration of IMP)
measure: Safety Endpoints related to any severe laboratory abnormalities
time frame: 2 weeks
description: Safety endpoints include:
d. IMP related severe laboratory abnormalities (duration of IMP)
measure: Feasibility endpoints related to IMP and deviations
time frame: 2 weeks
description: Feasibility endpoints include protocol deviations in terms of timing and delivery of scheduled medication.
measure: Exploratory Data on Clinical efficacy by time to recovery
time frame: 4 weeks
description: Exploratory data on clinical efficacy as defined by:
a. Time to recovery defined by hospital discharge or improvement of two points on the ordinal scale: not hospitalised; hospitalised without need for supplemental oxygen; requiring supplemental oxygen; requiring HFNC or non-invasive mechanical ventilation; requiring ECMO or mechanical intervention; dead. Improvement mechanical ventilation (from recruitment to time of ventilation)
measure: Exploratory Data on Clinical efficacy
time frame: 4 weeks
description: Exploratory data on clinical efficacy as defined by:
b. Ventilation free days (at 28 days)
measure: Exploratory Data on Clinical efficacy of the ordinal scale
time frame: 4 weeks
description: Exploratory data on clinical efficacy as defined by:
c. Status on the above ordinal scale (at 14 and 28 days)
arm group label: Subcutaneous Arm
arm group type: Active Comparator
description: 100mg anakinra SC will be administered subcutaneously at consistent times that are convenient and practical for the patients and research/nursing staff providing there is a minimum 8 hours and maximum 16 hours between administrations.
arm group label: Intravenous Arm
arm group type: Active Comparator
description: 100mg anakinra in 100mL 0.9% NaCl will be administered intravenously four times a day every 6 hours.
intervention type: Drug
intervention name: Anakinra 100Mg/0.67Ml Inj Syringe
description: 100 mg interleukin-1 receptor antagonist (r-meth-Hu-IL-1Ra), anakinra; marketed as Kineret® in 0.67 mL prefilled syringe for single use
arm group label: Intravenous Arm
arm group label: Subcutaneous Arm
other name: Kineret
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Timothy Felton, Dr
role: Principal Investigator
affiliation: University of Manchester
facility: 
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: COVID-19
mesh term: Interleukin 1 Receptor Antagonist Protein
sharing ipd: No