<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/NCT04418531</url>
  </required_header>
  <id_info>
    <org_study_id>DFPP COVID 19 Early</org_study_id>
    <nct_id>NCT04418531</nct_id>
  </id_info>
  <brief_title>Convalescent Antibodies Infusion in COVID 19 Patients</brief_title>
  <official_title>A Pilot Study to Explore the Efficacy and Safety of Rescue Therapy With Antibodies From Convalescent Patients Obtained With Double-filtration Plasmapheresis (DFPP) and Infused in Patients With Coronavirus Disease 2019 (COVID-19) and Need of Oxygen Support Without Mechanical Ventilation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Piero Luigi Ruggenenti</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Aferetica</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>A.O. Ospedale Papa Giovanni XXIII</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 outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which&#xD;
      originated in Wuhan, China, has become a major concern all over the world.&#xD;
&#xD;
      Convalescent plasma or immunoglobulins have been used as a last resort to improve the&#xD;
      survival rate of patients with SARS whose condition continued to deteriorate despite&#xD;
      treatment with pulsed methylprednisolone. Moreover, several studies showed a shorter hospital&#xD;
      stay and lower mortality in patients treated with convalescent plasma than those who were not&#xD;
      treated with convalescent plasma. Evidence shows that convalescent plasma from patients who&#xD;
      have recovered from viral infections can be used effectively as a treatment of patients with&#xD;
      active disease.&#xD;
&#xD;
      The use of solutions enriched of antiviral antibodies has several important advantages over&#xD;
      the convalescent plasma including the high level of neutralizing antibodies supplied.&#xD;
      Moreover, plasma-exchange is expensive and requires large volumes of substitution fluid With&#xD;
      either albumin or fresh frozen plasma, increasing the risk of cardiovascular instability in&#xD;
      the plasma donor and in the recipient, which can be detrimental in a critically ill patient&#xD;
      with COVID 19 pneumonia. The use of plasma as a substitution fluid further increases&#xD;
      treatment costs and is associated with risk of infections, allergic reactions and&#xD;
      citrate-induced hypocalcemia. Albumin is better tolerated and less expensive, but exchanges&#xD;
      using albumin solutions increase the risk of bleeding because of progressive coagulation&#xD;
      factor depletion.&#xD;
&#xD;
      The aforementioned limitations of plasma therapy can be in part overcome by using selective&#xD;
      apheresis methods, such as double-filtration plasmapheresis (DFPP)3. During DFPP, plasma is&#xD;
      separated from cellular components by a plasma filter, and is then allowed to pass through a&#xD;
      fractionator filter. Depending on the membrane cut-off, the fractionator filter retains&#xD;
      larger molecules and returns fluid along with smaller molecules to the circulation. Thus, the&#xD;
      selection of a membrane with an appropriate sieving coefficient for IgG allows to efficiently&#xD;
      clear autoantibodies in patients with antibody-mediated diseases (e.g., macroglobulinemia,&#xD;
      myasthenia gravis and rheumatoid arthritis) with negligible fluid losses and limited removal&#xD;
      of albumin and coagulation factors1.&#xD;
&#xD;
      In patients with severe membranous nephropathy and high titer of autoreactive, nephritogenic&#xD;
      antibodies against the podocyte-expressed M type phospholipase A2 receptor (PLA2R), DFPP&#xD;
      accelerated anti PLA2R depletion4. Measurement of the antibody titer in treated patient and&#xD;
      recovered fluid showed that antibody removal was extremely effective and that large part of&#xD;
      antibodies was removed during the first DFPP procedure. This therapeutic regimen was safe and&#xD;
      well tolerated and easy to apply4. In an ongoing pilot study we found that the same&#xD;
      methodological approach can be used to remove circulating antibodies from patients who&#xD;
      recovered from COVID 19 and to infuse these antibodies in patients with active viral&#xD;
      infection. Treatment was well tolerated and preliminary findings are encouraging. Thus, in&#xD;
      this novel pilot study we aim to explore whether the infusion of antibodies obtained with one&#xD;
      single DFPP procedure from voluntary convalescent donors could offer an effective and safe&#xD;
      therapeutic option for patients with earlier stages of coronavirus (COVID-19) pneumonia&#xD;
      requiring oxygen supply without mechanical ventilation.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Organizative problems&#xD;
  </why_stopped>
  <start_date type="Actual">June 1, 2020</start_date>
  <completion_date type="Actual">September 21, 2022</completion_date>
  <primary_completion_date type="Actual">September 21, 2022</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Time to weaning of oxygen support</measure>
    <time_frame>Through study completion, an average of 3 months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Chest XR or CT scan evaluation</measure>
    <time_frame>Changes during the study up completion, an average of 3 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Survival,</measure>
    <time_frame>Through study completion, an average of 3 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Viral titer</measure>
    <time_frame>Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Anti COVID 19 IgG antibodies</measure>
    <time_frame>Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Anti COVID 19 IgM antibodies</measure>
    <time_frame>Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>C5a concentration</measure>
    <time_frame>Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.</time_frame>
    <description>Marker of complement activation in plasma.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>C3a concentration</measure>
    <time_frame>Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.</time_frame>
    <description>Marker of complement activation in plasma.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum C5b-9 concentration Marker of complement activation</measure>
    <time_frame>Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.</time_frame>
    <description>Marker of complement activation in plasma.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum IL-6 levels</measure>
    <time_frame>Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.</time_frame>
    <description>Marker of complement activation in plasma.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum IL-1b levels</measure>
    <time_frame>Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.</time_frame>
    <description>Marker of complement activation in plasma.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum IFNγ levels</measure>
    <time_frame>Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.</time_frame>
    <description>Marker of complement activation in plasma.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum MCP-1 levels</measure>
    <time_frame>Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.</time_frame>
    <description>Marker of complement activation in plasma.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum TNFα levels</measure>
    <time_frame>Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.</time_frame>
    <description>Marker of complement activation in plasma.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum IL-10 levels</measure>
    <time_frame>Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.</time_frame>
    <description>Marker of complement activation in plasma.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum IL-2 levels</measure>
    <time_frame>Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.</time_frame>
    <description>Marker of complement activation in plasma.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum IL-7 levels</measure>
    <time_frame>Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.</time_frame>
    <description>Marker of complement activation in plasma.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Pneumonia, Viral</condition>
  <condition>Corona Virus Infection</condition>
  <arm_group>
    <arm_group_label>Experimental antibodies (immunoglobulins) infusion</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Anti-coronavirus obtained with double-filtration plasmapheresis (DFPP) from convalescent patients</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Anti-coronavirus antibodies (immunoglobulins) obtained with DFPP form convalescent patients</intervention_name>
    <description>Antibodies obtained from consenting convalescent donors will be administered to ten consecutive patients who fulfill the inclusion criteria .</description>
    <arm_group_label>Experimental antibodies (immunoglobulins) infusion</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Plasma Ig Donors&#xD;
&#xD;
          -  Adult (&gt;18 and &lt;65-yr-old) men and women&#xD;
&#xD;
          -  Convalescent donor who recovered from COVID 19 from at least 14 days according to the&#xD;
             clinical and laboratory criteria defined by the Consiglio Superiore di Sanità on&#xD;
             February 20, 2019 (&quot;The recovered patient is the one who resolves the symptoms of&#xD;
             COVID-19 infection and who is negative in two consecutive tests for the search for&#xD;
             SARS-Cov-2, performed 24 hours apart&quot;) with the exceptions mentioned in the attached&#xD;
             derogation (that is &quot;no upper age limit to donation provided there are no clinical&#xD;
             contraindications to the procedure and independent of documented evidence of two&#xD;
             negative tests for SARS-Cov 2 naso-faringeal contamination&quot;)&#xD;
&#xD;
          -  Male or female donor; if female only if nulliparous; in both cases with a negative&#xD;
             history of blood component transfusions&#xD;
&#xD;
          -  Careful clinical evaluation of the patient-donor with particular reference to the&#xD;
             criteria established by current legislation to protect the health of the donor who&#xD;
             donates by apheresis&#xD;
&#xD;
          -  Presence of adequate levels of neutralizing anti-SARS-COV-2 antibodies;&#xD;
&#xD;
          -  Biological qualification test negative defined by current indications (performed at&#xD;
             SIMT of HPG23)&#xD;
&#xD;
          -  Test negative for: HAV RNA, HEV RNA, PVB19 DNA (performed at HPG23)&#xD;
&#xD;
          -  Informed written consent&#xD;
&#xD;
        Recipients&#xD;
&#xD;
          -  &gt;18 years of age&#xD;
&#xD;
          -  COVID-19 pneumonia diagnosed by standard criteria (viral detection in naso-faringeal&#xD;
             or bronco-alveolar lavage by RT-PCR for SARS-COV-2, typical Chest X Ray or CT Scan,&#xD;
             ventilatory dysfunction not directly explained by heart failure or fluid overload)&#xD;
&#xD;
          -  Respiratory failure (i.e. room air PaO2&lt;60 mmHg) needing oxygen support with Venturi&#xD;
             mask (FiO2 between 28 and 60%), non-rebreathing mask or high flow-nasal cannula&#xD;
             (HFNC);&#xD;
&#xD;
          -  Patient written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Need of Continuous Positive Airway Pressure (CPAP) ventilator support, Non-Invasive&#xD;
             Ventilation (NIV) or intubation for invasive mechanical ventilation&#xD;
&#xD;
          -  Involvement in any clinical trial&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <removed_countries>
    <country>Italy</country>
  </removed_countries>
  <verification_date>September 2022</verification_date>
  <study_first_submitted>June 3, 2020</study_first_submitted>
  <study_first_submitted_qc>June 4, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 5, 2020</study_first_posted>
  <last_update_submitted>September 21, 2022</last_update_submitted>
  <last_update_submitted_qc>September 21, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">September 23, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>A.O. Ospedale Papa Giovanni XXIII</investigator_affiliation>
    <investigator_full_name>Piero Luigi Ruggenenti</investigator_full_name>
    <investigator_title>Director, Unit of Nephrology</investigator_title>
  </responsible_party>
  <keyword>Pneumonia viral</keyword>
  <keyword>COVID 19</keyword>
  <keyword>Double-filtration plasmapheresis</keyword>
  <keyword>Convalescent antibodies</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
    <mesh_term>Pneumonia</mesh_term>
    <mesh_term>Coronavirus Infections</mesh_term>
    <mesh_term>Pneumonia, Viral</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Antibodies</mesh_term>
    <mesh_term>Immunoglobulins</mesh_term>
    <mesh_term>Immunoglobulins, Intravenous</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT04418531
org study id: DFPP COVID 19 Early
nct id: NCT04418531
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which
      originated in Wuhan, China, has become a major concern all over the world.

      Convalescent plasma or immunoglobulins have been used as a last resort to improve the
      survival rate of patients with SARS whose condition continued to deteriorate despite
      treatment with pulsed methylprednisolone. Moreover, several studies showed a shorter hospital
      stay and lower mortality in patients treated with convalescent plasma than those who were not
      treated with convalescent plasma. Evidence shows that convalescent plasma from patients who
      have recovered from viral infections can be used effectively as a treatment of patients with
      active disease.

      The use of solutions enriched of antiviral antibodies has several important advantages over
      the convalescent plasma including the high level of neutralizing antibodies supplied.
      Moreover, plasma-exchange is expensive and requires large volumes of substitution fluid With
      either albumin or fresh frozen plasma, increasing the risk of cardiovascular instability in
      the plasma donor and in the recipient, which can be detrimental in a critically ill patient
      with COVID 19 pneumonia. The use of plasma as a substitution fluid further increases
      treatment costs and is associated with risk of infections, allergic reactions and
      citrate-induced hypocalcemia. Albumin is better tolerated and less expensive, but exchanges
      using albumin solutions increase the risk of bleeding because of progressive coagulation
      factor depletion.

      The aforementioned limitations of plasma therapy can be in part overcome by using selective
      apheresis methods, such as double-filtration plasmapheresis (DFPP)3. During DFPP, plasma is
      separated from cellular components by a plasma filter, and is then allowed to pass through a
      fractionator filter. Depending on the membrane cut-off, the fractionator filter retains
      larger molecules and returns fluid along with smaller molecules to the circulation. Thus, the
      selection of a membrane with an appropriate sieving coefficient for IgG allows to efficiently
      clear autoantibodies in patients with antibody-mediated diseases (e.g., macroglobulinemia,
      myasthenia gravis and rheumatoid arthritis) with negligible fluid losses and limited removal
      of albumin and coagulation factors1.

      In patients with severe membranous nephropathy and high titer of autoreactive, nephritogenic
      antibodies against the podocyte-expressed M type phospholipase A2 receptor (PLA2R), DFPP
      accelerated anti PLA2R depletion4. Measurement of the antibody titer in treated patient and
      recovered fluid showed that antibody removal was extremely effective and that large part of
      antibodies was removed during the first DFPP procedure. This therapeutic regimen was safe and
      well tolerated and easy to apply4. In an ongoing pilot study we found that the same
      methodological approach can be used to remove circulating antibodies from patients who
      recovered from COVID 19 and to infuse these antibodies in patients with active viral
      infection. Treatment was well tolerated and preliminary findings are encouraging. Thus, in
      this novel pilot study we aim to explore whether the infusion of antibodies obtained with one
      single DFPP procedure from voluntary convalescent donors could offer an effective and safe
      therapeutic option for patients with earlier stages of coronavirus (COVID-19) pneumonia
      requiring oxygen supply without mechanical ventilation.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Time to weaning of oxygen support
time frame: Through study completion, an average of 3 months
measure: Chest XR or CT scan evaluation
time frame: Changes during the study up completion, an average of 3 months
measure: Survival,
time frame: Through study completion, an average of 3 months
measure: Viral titer
time frame: Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.
measure: Anti COVID 19 IgG antibodies
time frame: Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.
measure: Anti COVID 19 IgM antibodies
time frame: Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.
measure: C5a concentration
time frame: Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.
description: Marker of complement activation in plasma.
measure: C3a concentration
time frame: Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.
description: Marker of complement activation in plasma.
measure: Serum C5b-9 concentration Marker of complement activation
time frame: Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.
description: Marker of complement activation in plasma.
measure: Serum IL-6 levels
time frame: Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.
description: Marker of complement activation in plasma.
measure: Serum IL-1b levels
time frame: Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.
description: Marker of complement activation in plasma.
measure: Serum IFNγ levels
time frame: Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.
description: Marker of complement activation in plasma.
measure: Serum MCP-1 levels
time frame: Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.
description: Marker of complement activation in plasma.
measure: Serum TNFα levels
time frame: Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.
description: Marker of complement activation in plasma.
measure: Serum IL-10 levels
time frame: Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.
description: Marker of complement activation in plasma.
measure: Serum IL-2 levels
time frame: Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.
description: Marker of complement activation in plasma.
measure: Serum IL-7 levels
time frame: Changes from before Ig administration, one day after Ig administration and every week through study completion, an average of 3 months.
description: Marker of complement activation in plasma.
arm group label: Experimental antibodies (immunoglobulins) infusion
arm group type: Experimental
description: Anti-coronavirus obtained with double-filtration plasmapheresis (DFPP) from convalescent patients
intervention type: Biological
intervention name: Anti-coronavirus antibodies (immunoglobulins) obtained with DFPP form convalescent patients
description: Antibodies obtained from consenting convalescent donors will be administered to ten consecutive patients who fulfill the inclusion criteria .
arm group label: Experimental antibodies (immunoglobulins) infusion
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
country: Italy
responsible party type: Sponsor-Investigator
investigator affiliation: A.O. Ospedale Papa Giovanni XXIII
investigator full name: Piero Luigi Ruggenenti
investigator title: Director, Unit of Nephrology
mesh term: COVID-19
mesh term: Pneumonia
mesh term: Coronavirus Infections
mesh term: Pneumonia, Viral
mesh term: Antibodies
mesh term: Immunoglobulins
mesh term: Immunoglobulins, Intravenous
sharing ipd: Undecided