<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/NCT04473053</url>
  </required_header>
  <id_info>
    <org_study_id>AC20063</org_study_id>
    <nct_id>NCT04473053</nct_id>
  </id_info>
  <brief_title>DEFINE - Evaluating Therapies for COVID-19</brief_title>
  <acronym>DEFINE</acronym>
  <official_title>DEFINE - Evaluating Therapies for COVID-19</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Edinburgh</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Oxford</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Latus Therapeutics</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Edinburgh</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>
      COVID-19 is a community acquired pneumonia caused by infection with a novel coronavirus, SARS&#xD;
      CoV2 and is a serious condition with high mortality in hospitalised patients, for which there&#xD;
      is no currently approved treatment other than supportive care. Urgent investigation of&#xD;
      potential treatments for this condition is required.&#xD;
&#xD;
      This protocol describes an overarching and adaptive trial designed to provide safety,&#xD;
      pharmacokinetic (PK)/ pharmacodynamic (PD) information and exploratory biological surrogates&#xD;
      of efficacy which may support further development and deployment of candidate therapies in&#xD;
      larger scale trials of COVID-19 positive patients receiving normal standard of care.&#xD;
&#xD;
      Given the spectrum of clinical disease, community based infected patients or hospitalised&#xD;
      patients can be included. Products requiring parenteral administration will only be&#xD;
      investigated in hospitalised patients. Patients will be divided into cohorts, a) community b)&#xD;
      hospitalised patients with new changes on a chest x-ray (CXR) or a computed tomography (CT)&#xD;
      scan or requiring supplemental oxygen and c) hospitalised requiring assisted ventilation.&#xD;
      Participants may be recruited from all three of these cohorts, depending on the experimental&#xD;
      therapy, its route of administration and mechanism of action. The relevant cohort(s) for any&#xD;
      given therapy will be detailed in the therapy-specific appendix.&#xD;
&#xD;
      Candidate therapies can be added to the protocol and previous candidates removed from further&#xD;
      investigation as evidence emerges. The trial will be monitored by an independent Data&#xD;
      Monitoring Committee (DMC) to ensure patient safety.&#xD;
&#xD;
      Each candidate cohort will include a small cohort of patients randomised to candidate therapy&#xD;
      or existing standard of care management dependent on disease stage at entry. Cohort numbers&#xD;
      will be defined in the protocol appendices.&#xD;
&#xD;
      This is a Phase IIa experimental medicine trial and as such formal sample size calculations&#xD;
      are not appropriate.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This trial platform aims to support the repurposing of promising therapeutic assets with&#xD;
      prior use in humans but without prior information on use in COVID-19, to determine the PK-PD&#xD;
      profile of the agent, compared to standard of care supportive therapy, in small cohorts of&#xD;
      COVID-19 patients. The results of these studies are intended to provide initial safety,&#xD;
      pharmacokinetic and pharmacodynamic data and experimental medicine data to support further&#xD;
      evaluation in existing national and international trial networks for candidates demonstrating&#xD;
      appropriate impact on the dynamic marker of interest. The key interception is to mitigate the&#xD;
      lung damage in patients with COVID-19 that leads to respiratory failure. As such, the assets&#xD;
      in this programme will focus on abrogating putative mechanisms implicated in COVID-19&#xD;
      respiratory disease.&#xD;
&#xD;
      Existing approaches in clinical trials involve novel or repurposed antivirals or&#xD;
      immunomodulatory approaches involving agents such as corticosteroids, interferon-β or&#xD;
      hydroxychloroquine. A major limitation in the design of many early clinical trials is the&#xD;
      limited amount of mechanistic data from patients with COVID-19. Mechanisms have been inferred&#xD;
      from animal models, related infections or clinical syndromes. These approaches have&#xD;
      infrequently translated to human disease. For example, remdesivir efficacy in animal models&#xD;
      of Ebola Virus Disease (EVD) did not translate to human disease and hydroxychloroquine&#xD;
      antiviral affects in vitro have not translated to humans against other viruses. Some drugs,&#xD;
      such as repurposing of the anti-retroviral protease Kaletra, are still being pursued despite&#xD;
      uncertain mechanism and despite evidence that this aspartyl protease cannot bind to the&#xD;
      cysteine chymotrypsin-like protease that is Kaletra's putative target in COVID-19.&#xD;
&#xD;
      There is a clear and urgent need to pursue experimental medicine studies in humans to&#xD;
      establish a solid mechanistic basis for rapid evaluation, including in existing clinical&#xD;
      trial platforms against COVID-19 (e.g DoH RECOVERY and NIHR-CLRN industry adopted studies).&#xD;
&#xD;
      The trial will be as flexible as possible to ensure a broad range of patients can be&#xD;
      recruited and candidate therapies can be added or removed as evidence emerges. The interim&#xD;
      trial results will be monitored by an independent DMC to evaluate any patient safety signals.&#xD;
&#xD;
      As COVID-19 follows a variable clinical path in individual patients, the protocol is designed&#xD;
      to enable inclusion of patients across the disease stages. The trial is intended to provide&#xD;
      mechanistic data from patients receiving standard of care therapy and from patients treated&#xD;
      with the therapy candidates. The study will enable delivery of pharmacokinetic information&#xD;
      and effects of standard of care and candidate agents on surrogate biomarkers of the disease&#xD;
      process and the specific drug target.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">July 3, 2020</start_date>
  <completion_date type="Anticipated">December 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2023</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Randomised clinical trial - currently two treatment arms and one standard of care arm. More assets will be added to the protocol as evidence emerges.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
    <masking_description>The biomarker analysis team will be masked to the trial treatment.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>The safety of the candidate therapies in COVID-19 patients by measuring physiological changes in the circulatory and respiratory system.</measure>
    <time_frame>Up to 16 days post treatment</time_frame>
    <description>Measure vital signs (blood pressure/heart rate/temperature and respiratory rate)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>The safety of the candidate therapies in COVID-19 patients by recording the number of treatment related adverse events.</measure>
    <time_frame>Up to 90 days post treatment</time_frame>
    <description>Record number of participants With treatment-related adverse events</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Measuring the PK of the proposed trial treatments in COVID-19 patients.</measure>
    <time_frame>6 months</time_frame>
    <description>Measure maximum plasma concentration [Cmax] in blood samples.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measure a change in the expression of key coagulation biomarkers in the blood of COVID-19 patients during and after treatment period.</measure>
    <time_frame>6 months</time_frame>
    <description>Change in expression or activity of coagulation markers in serial blood samples taken before, during and after treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measure a change in the expression of key cytokines in the blood of COVID-19 patients during and after treatment period.</measure>
    <time_frame>6 months</time_frame>
    <description>Change in expression or activity of inflammatory cytokines in serial blood samples taken before, during and after treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate the improvement or deteroriation of patients in each treatment arm.</measure>
    <time_frame>16 days</time_frame>
    <description>Record changes in National Early Warning Score (NEWS) 2 score. Scale is from 0-20, with a higher number indicating a higher risk of morbidity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate the number of oxygen-free days.</measure>
    <time_frame>16 days</time_frame>
    <description>Duration (days) of oxygen use</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate incidence of any form of new ventilation use.</measure>
    <time_frame>16 days</time_frame>
    <description>Duration (days) of ventilation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate ventilator-free days</measure>
    <time_frame>16 days</time_frame>
    <description>Duration of ventilation-free days.&#xD;
• Incidence of any form of new ventilation use and duration (days) of new ventilation use.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in the ratio of the oxygen saturation to fraction of inspired oxygen concentration (SpO2/FiO2)</measure>
    <time_frame>16 days</time_frame>
    <description>SpO2/FiO2, measured daily from randomisation to Day 15, hospital discharge, or death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate SARS-CoV-2 viral load.</measure>
    <time_frame>15 days</time_frame>
    <description>Qualitative and quantitative polymerase chain reaction (PCR) determination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in oropharyngeal/nasal/saliva swab while hospitalised on Days 1, 3, 5, 8, 11, 15.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate time to discharge</measure>
    <time_frame>16 days</time_frame>
    <description>Duration of total hospital stay&#xD;
• Duration to discharge following treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate the use of renal dialysis or haemofiltration for each treatment arm.</measure>
    <time_frame>16 days</time_frame>
    <description>Record requirement for renal dialysis or haemofiltration</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">200</enrollment>
  <condition>COVID-19</condition>
  <arm_group>
    <arm_group_label>Nafamostat</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>It is intended that the licensed dose (0.2mg/kg/hr) in Japan will be used. Patients randomised to Nafamostat will receive a continuous intravenous infusion at 0.2 mg/kg/hr for 7 days. If a participant is discharged from hospital or can no longer receive this treatment, the treatment will be stopped.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>TD139</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will inhale 5mg x 2 (10 mg) twice daily for the first 48 hrs and then subsequently 5mg x 2 (10 mg) once daily for the remaining 12 days. Unless a participant is discharged from hospital or can no longer use an inhaler - in which case treatment will be stopped at such time.&#xD;
CE marked inhalers will be provided by the Manufacturer. All patients will receive guidance on how to use the inhaler by an appropriately trained member of the research team. Two individual inhalers will be used by each patient over the course of the 14 day study period (each inhaler will be used by one patient for 7 days) and will be thoroughly cleaned with an antiseptic wipe before and after each use.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard of Care</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>All treatment arms will be compared to the Standard of Care arm.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nafamostat Mesilate</intervention_name>
    <description>Nafamostat has been shown to have potential antiviral effects against MERS CoV and is thought to possibly inhibit SARS CoV2 infection via inhibition of viral entry due to inhibition of TMPRSS2. In addition, nafamostat has potent anticoagulant properties which may provide benefit in patients with DIC, a common finding in serious cases of COVID-19. Nafamostat has been broadly well tolerated in clinical trials in patients with DIC and acute pancreatitis.</description>
    <arm_group_label>Nafamostat</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>TD139</intervention_name>
    <description>TD139 is a specific inhibitor of galectin-3 which has been investigated in healthy volunteers and patients with IPF. No serious drug related serious adverse events have been reported to date. TD139 had no impact on cardiac, haematological or biochemical measures of safety during trials in humans to date. Beneficial effects on biomarker measures of lung inflammation were observed in patients with IPF. It is the purpose of this investigation to examine the potential for delivery of this inhibitor in pre-ventilator patients hospitalised with COVID-19 to examine whether this may lead to detectable changes in blood biomarkers, reduce viral load and also reduce disease severity such as time to ventilation.</description>
    <arm_group_label>TD139</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Standard care</intervention_name>
    <description>Patients will receive standard care.</description>
    <arm_group_label>Standard of Care</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Provision of informed consent from the patient or representative&#xD;
&#xD;
          -  Aged at least 16 years&#xD;
&#xD;
          -  If the patient is of child bearing potential, the patient, and their partner(s), agree&#xD;
             to use medically-accepted double-barrier methods of contraception (eg, barrier&#xD;
             methods, including male condom, female condom or diaphragm with spermicidal gel)&#xD;
             during the study (if randomised to a treatment arm) and for at least 90 days after&#xD;
             termination of study therapy. A vasectomised partner would be considered an&#xD;
             appropriate birth control method provided that the partner is the sole male sexual&#xD;
             partner and the absence of sperm has been confirmed.&#xD;
&#xD;
          -  COVID-19 positive&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Current or recent history, as determined by the Investigator, of severe, progressive,&#xD;
             and/or uncontrolled cardiac disease (NYHA class IV), uncontrolled renal disease (eGFR&#xD;
             &lt;30 mL/min/1.73 m2), severe liver dysfunction (ALT/AST &gt;5x ULN) or bone marrow failure&#xD;
             (Hb &lt;80 g/L AND ANC&lt;0.5 mm3 AND platelet count &lt;50,000 uL)&#xD;
&#xD;
          -  Women who are pregnant or breastfeeding.&#xD;
&#xD;
          -  Participation in another clinical trial of an investigational medicinal product&#xD;
             (CTIMP)&#xD;
&#xD;
          -  Known hypersensitivity to the IMP or excipients (e.g. lactose)&#xD;
&#xD;
          -  Pre-existing or Cconcomittant use of off-label treatments for COVID-19 that are not&#xD;
             recognised as locally approved standard care.&#xD;
&#xD;
          -  Significant electrolyte disturbance (hyperkalaemia potassium &gt;5.0 mmol/L or&#xD;
             hyponatraemia sodium &lt; 120mmol/L)&#xD;
&#xD;
          -  Patient currently receiving potassium sparing diuretics that cannot be reasonably&#xD;
             withheld&#xD;
&#xD;
          -  Patient currently receiving prophylactic or therapeutic anticoagulantsanticoagulation&#xD;
             or antiplatelet agents that cannot be reasonably withheld if randomised to Nafamostat&#xD;
&#xD;
          -  Patients (or their partners) planning on donating sperm/eggs during the trial period&#xD;
&#xD;
          -  Ongoing dialysis&#xD;
&#xD;
          -  History of serious liver disease (Child Pugh score &gt; 10)&#xD;
&#xD;
          -  Hemoglobin &lt; 80 g/L&#xD;
&#xD;
          -  Any known allergy to the IMP/excipients&#xD;
&#xD;
          -  Severe uncontrolled diabetes mellitus&#xD;
&#xD;
          -  In the Investigator's opinion, patient is unwilling or unable to comply with drug&#xD;
             administration plan, laboratory tests or other study procedures.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>16 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kev Dhaliwal</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Edinburgh</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Annya Bruce, PhD</last_name>
    <phone>01312429180</phone>
    <email>Annya.Bruce@ed.ac.uk</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Kevin Dhaliwal</last_name>
    <phone>01312429180</phone>
    <email>kev.dhaliwal@ed.ac.uk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>NHS Lothian</name>
      <address>
        <city>Edinburgh</city>
        <zip>EH16 4TJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kev Dhaliwal</last_name>
      <phone>01312426579</phone>
      <email>Kev.Dhaliwal@ed.ac.uk</email>
    </contact>
    <contact_backup>
      <last_name>Annya Bruce</last_name>
      <phone>01312429180</phone>
      <email>Annya.Bruce@ed.ac.uk</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>July 9, 2020</study_first_submitted>
  <study_first_submitted_qc>July 15, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 16, 2020</study_first_posted>
  <last_update_submitted>November 1, 2022</last_update_submitted>
  <last_update_submitted_qc>November 1, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 2, 2022</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>Nafamostat</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>The research team actively encourage data sharing to expedite the development of COVID-19 treatments. The study team will provide data to other researchers on request and following the agreement of a data sharing plan. No confidential information regarding participants will be shared.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>90 days after data analysis has been completed for each arm. This data will be available on request and a time frame can be discussed further when required.</ipd_time_frame>
  </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/NCT04473053
org study id: AC20063
nct id: NCT04473053
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
COVID-19 is a community acquired pneumonia caused by infection with a novel coronavirus, SARS
      CoV2 and is a serious condition with high mortality in hospitalised patients, for which there
      is no currently approved treatment other than supportive care. Urgent investigation of
      potential treatments for this condition is required.

      This protocol describes an overarching and adaptive trial designed to provide safety,
      pharmacokinetic (PK)/ pharmacodynamic (PD) information and exploratory biological surrogates
      of efficacy which may support further development and deployment of candidate therapies in
      larger scale trials of COVID-19 positive patients receiving normal standard of care.

      Given the spectrum of clinical disease, community based infected patients or hospitalised
      patients can be included. Products requiring parenteral administration will only be
      investigated in hospitalised patients. Patients will be divided into cohorts, a) community b)
      hospitalised patients with new changes on a chest x-ray (CXR) or a computed tomography (CT)
      scan or requiring supplemental oxygen and c) hospitalised requiring assisted ventilation.
      Participants may be recruited from all three of these cohorts, depending on the experimental
      therapy, its route of administration and mechanism of action. The relevant cohort(s) for any
      given therapy will be detailed in the therapy-specific appendix.

      Candidate therapies can be added to the protocol and previous candidates removed from further
      investigation as evidence emerges. The trial will be monitored by an independent Data
      Monitoring Committee (DMC) to ensure patient safety.

      Each candidate cohort will include a small cohort of patients randomised to candidate therapy
      or existing standard of care management dependent on disease stage at entry. Cohort numbers
      will be defined in the protocol appendices.

      This is a Phase IIa experimental medicine trial and as such formal sample size calculations
      are not appropriate.
This trial platform aims to support the repurposing of promising therapeutic assets with
      prior use in humans but without prior information on use in COVID-19, to determine the PK-PD
      profile of the agent, compared to standard of care supportive therapy, in small cohorts of
      COVID-19 patients. The results of these studies are intended to provide initial safety,
      pharmacokinetic and pharmacodynamic data and experimental medicine data to support further
      evaluation in existing national and international trial networks for candidates demonstrating
      appropriate impact on the dynamic marker of interest. The key interception is to mitigate the
      lung damage in patients with COVID-19 that leads to respiratory failure. As such, the assets
      in this programme will focus on abrogating putative mechanisms implicated in COVID-19
      respiratory disease.

      Existing approaches in clinical trials involve novel or repurposed antivirals or
      immunomodulatory approaches involving agents such as corticosteroids, interferon-β or
      hydroxychloroquine. A major limitation in the design of many early clinical trials is the
      limited amount of mechanistic data from patients with COVID-19. Mechanisms have been inferred
      from animal models, related infections or clinical syndromes. These approaches have
      infrequently translated to human disease. For example, remdesivir efficacy in animal models
      of Ebola Virus Disease (EVD) did not translate to human disease and hydroxychloroquine
      antiviral affects in vitro have not translated to humans against other viruses. Some drugs,
      such as repurposing of the anti-retroviral protease Kaletra, are still being pursued despite
      uncertain mechanism and despite evidence that this aspartyl protease cannot bind to the
      cysteine chymotrypsin-like protease that is Kaletra's putative target in COVID-19.

      There is a clear and urgent need to pursue experimental medicine studies in humans to
      establish a solid mechanistic basis for rapid evaluation, including in existing clinical
      trial platforms against COVID-19 (e.g DoH RECOVERY and NIHR-CLRN industry adopted studies).

      The trial will be as flexible as possible to ensure a broad range of patients can be
      recruited and candidate therapies can be added or removed as evidence emerges. The interim
      trial results will be monitored by an independent DMC to evaluate any patient safety signals.

      As COVID-19 follows a variable clinical path in individual patients, the protocol is designed
      to enable inclusion of patients across the disease stages. The trial is intended to provide
      mechanistic data from patients receiving standard of care therapy and from patients treated
      with the therapy candidates. The study will enable delivery of pharmacokinetic information
      and effects of standard of care and candidate agents on surrogate biomarkers of the disease
      process and the specific drug target.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Randomised clinical trial - currently two treatment arms and one standard of care arm. More assets will be added to the protocol as evidence emerges.
primary purpose: Treatment
masking: Single (Outcomes Assessor)
masking description: The biomarker analysis team will be masked to the trial treatment.
measure: The safety of the candidate therapies in COVID-19 patients by measuring physiological changes in the circulatory and respiratory system.
time frame: Up to 16 days post treatment
description: Measure vital signs (blood pressure/heart rate/temperature and respiratory rate)
measure: The safety of the candidate therapies in COVID-19 patients by recording the number of treatment related adverse events.
time frame: Up to 90 days post treatment
description: Record number of participants With treatment-related adverse events
measure: Measuring the PK of the proposed trial treatments in COVID-19 patients.
time frame: 6 months
description: Measure maximum plasma concentration [Cmax] in blood samples.
measure: Measure a change in the expression of key coagulation biomarkers in the blood of COVID-19 patients during and after treatment period.
time frame: 6 months
description: Change in expression or activity of coagulation markers in serial blood samples taken before, during and after treatment.
measure: Measure a change in the expression of key cytokines in the blood of COVID-19 patients during and after treatment period.
time frame: 6 months
description: Change in expression or activity of inflammatory cytokines in serial blood samples taken before, during and after treatment.
measure: To evaluate the improvement or deteroriation of patients in each treatment arm.
time frame: 16 days
description: Record changes in National Early Warning Score (NEWS) 2 score. Scale is from 0-20, with a higher number indicating a higher risk of morbidity.
measure: To evaluate the number of oxygen-free days.
time frame: 16 days
description: Duration (days) of oxygen use
measure: To evaluate incidence of any form of new ventilation use.
time frame: 16 days
description: Duration (days) of ventilation
measure: To evaluate ventilator-free days
time frame: 16 days
description: Duration of ventilation-free days.
• Incidence of any form of new ventilation use and duration (days) of new ventilation use.
measure: Change in the ratio of the oxygen saturation to fraction of inspired oxygen concentration (SpO2/FiO2)
time frame: 16 days
description: SpO2/FiO2, measured daily from randomisation to Day 15, hospital discharge, or death
measure: To evaluate SARS-CoV-2 viral load.
time frame: 15 days
description: Qualitative and quantitative polymerase chain reaction (PCR) determination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in oropharyngeal/nasal/saliva swab while hospitalised on Days 1, 3, 5, 8, 11, 15.
measure: To evaluate time to discharge
time frame: 16 days
description: Duration of total hospital stay
• Duration to discharge following treatment
measure: To evaluate the use of renal dialysis or haemofiltration for each treatment arm.
time frame: 16 days
description: Record requirement for renal dialysis or haemofiltration
arm group label: Nafamostat
arm group type: Experimental
description: It is intended that the licensed dose (0.2mg/kg/hr) in Japan will be used. Patients randomised to Nafamostat will receive a continuous intravenous infusion at 0.2 mg/kg/hr for 7 days. If a participant is discharged from hospital or can no longer receive this treatment, the treatment will be stopped.
arm group label: TD139
arm group type: Experimental
description: Patients will inhale 5mg x 2 (10 mg) twice daily for the first 48 hrs and then subsequently 5mg x 2 (10 mg) once daily for the remaining 12 days. Unless a participant is discharged from hospital or can no longer use an inhaler - in which case treatment will be stopped at such time.
CE marked inhalers will be provided by the Manufacturer. All patients will receive guidance on how to use the inhaler by an appropriately trained member of the research team. Two individual inhalers will be used by each patient over the course of the 14 day study period (each inhaler will be used by one patient for 7 days) and will be thoroughly cleaned with an antiseptic wipe before and after each use.
arm group label: Standard of Care
arm group type: Active Comparator
description: All treatment arms will be compared to the Standard of Care arm.
intervention type: Drug
intervention name: Nafamostat Mesilate
description: Nafamostat has been shown to have potential antiviral effects against MERS CoV and is thought to possibly inhibit SARS CoV2 infection via inhibition of viral entry due to inhibition of TMPRSS2. In addition, nafamostat has potent anticoagulant properties which may provide benefit in patients with DIC, a common finding in serious cases of COVID-19. Nafamostat has been broadly well tolerated in clinical trials in patients with DIC and acute pancreatitis.
arm group label: Nafamostat
intervention type: Drug
intervention name: TD139
description: TD139 is a specific inhibitor of galectin-3 which has been investigated in healthy volunteers and patients with IPF. No serious drug related serious adverse events have been reported to date. TD139 had no impact on cardiac, haematological or biochemical measures of safety during trials in humans to date. Beneficial effects on biomarker measures of lung inflammation were observed in patients with IPF. It is the purpose of this investigation to examine the potential for delivery of this inhibitor in pre-ventilator patients hospitalised with COVID-19 to examine whether this may lead to detectable changes in blood biomarkers, reduce viral load and also reduce disease severity such as time to ventilation.
arm group label: TD139
intervention type: Other
intervention name: Standard care
description: Patients will receive standard care.
arm group label: Standard of Care
criteria: 
gender: All
minimum age: 16 Years
maximum age: N/A
healthy volunteers: No
last name: Kev Dhaliwal
role: Principal Investigator
affiliation: University of Edinburgh
last name: Annya Bruce, PhD
phone: 01312429180
email: Annya.Bruce@ed.ac.uk
last name: Kevin Dhaliwal
phone: 01312429180
email: kev.dhaliwal@ed.ac.uk
facility: 
status: Recruiting
contact: 
contact backup: 
country: United Kingdom
responsible party type: Sponsor
mesh term: COVID-19
mesh term: Nafamostat
sharing ipd: Yes
ipd description: The research team actively encourage data sharing to expedite the development of COVID-19 treatments. The study team will provide data to other researchers on request and following the agreement of a data sharing plan. No confidential information regarding participants will be shared.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd time frame: 90 days after data analysis has been completed for each arm. This data will be available on request and a time frame can be discussed further when required.