<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/NCT04492891</url>
  </required_header>
  <id_info>
    <org_study_id>H-48163</org_study_id>
    <nct_id>NCT04492891</nct_id>
  </id_info>
  <brief_title>Cyclosporine For The Treatment Of COVID-19(+)</brief_title>
  <official_title>Randomized Phase IIa Clinical Trial Of Cyclosporine For The Treatment Of COVID-19(+) Non-ICU Hospital Inpatients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Bryan Burt, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Brigham and Women's Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Baylor College of Medicine</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Phase IIa clinical trial in which 75 non-ICU hospital inpatients will be randomized 2:1 to 7&#xD;
      days of an oral formulation of cyclosporine, Neoral (2.5mg/kg PO BID) + standard of care&#xD;
      (SOC) or no Neoral + SOC. The primary endpoint is disease severity based on the World Health&#xD;
      Organization (WHO) COVID Ordinal Outcomes Scale, on day 14. Secondary endpoints include&#xD;
      safety and changes in serum inflammatory markers.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      1. OBJECTIVES&#xD;
&#xD;
           1.1 Primary Objectives&#xD;
&#xD;
           1.1.1 To assess the effect of a 7-day course of oral cyclosporine Neoral on clinical&#xD;
           outcome using the World Health Organization (WHO) COVID Ordinal Clinical Outcomes Scale,&#xD;
           on day 14.&#xD;
&#xD;
           1.2 Secondary Objectives&#xD;
&#xD;
           1.2.1 To establish the safety of Neoral in this patient population (adverse events).&#xD;
&#xD;
           1.2.2 To determine the effect of Neoral on serum inflammatory markers (CRP, d-dimer,&#xD;
           ferritin, ANC (Absolute Neutrophil Count), absolute lymphocyte count, WBC, PLT (daily&#xD;
           while inpatient and including day 14 and 28 for those discharged).&#xD;
&#xD;
           1.2.3 To determine the effect Neoral on viral SARS-CoV2 PCR positivity from baseline&#xD;
           (day 0 to -2) before receiving Neoral to day 14, and from baseline to day 28.&#xD;
&#xD;
           1.2.4 To determine the effect of Neoral on survival (days 14 and 28).&#xD;
&#xD;
           1.2.5 To determine the effect of Neoral on disease improvement (alive and free of&#xD;
           invasive or non-invasive mechanical ventilation; days 14 and 28).&#xD;
&#xD;
           1.2.6 To determine the effect of Neoral on proportion of those requiring invasive&#xD;
           mechanical ventilation.&#xD;
&#xD;
           1.2.7 To determine the effect of Neoral on incidence of deep vein thrombosis.&#xD;
&#xD;
           1.2.8 To determine the effect of Neoral on proportion of patients discharged on day 28.&#xD;
&#xD;
           1.2.9 To determine the effect of Neoral on time to hospital discharge.&#xD;
&#xD;
           1.2.10 To determine the effect of Neoral on disease resolution (alive and discharged&#xD;
           home without oxygen; days 14 and 28).&#xD;
&#xD;
        2. BACKGROUND&#xD;
&#xD;
      2.1 Study Disease(s)&#xD;
&#xD;
      Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel coronavirus that&#xD;
      causes coronavirus disease 2019 (COVID-19). Since initial detection of the virus, more than&#xD;
      10 million cases of COVID-19 have been confirmed worldwide, and COVID-19 is responsible for&#xD;
      more than 505,500 deaths. The United States has seen over 2.5 million cases of COVID-19 and&#xD;
      126,000 deaths from this disease (as of June, 30, 2020). SARS-CoV-2 is efficiently&#xD;
      transmitted from person-to-person and the World Health Organization (WHO) has declared&#xD;
      coronavirus disease 2019 (COVID-19) to be a pandemic.&#xD;
&#xD;
      COVID-19 primarily spreads through the respiratory tract, by droplets, respiratory&#xD;
      secretions, and direct contact. Current data suggest an incubation period of 1-14 days, in&#xD;
      most cases 3-7 days. The virus is highly transmissible in humans and causes severe problems&#xD;
      especially in the elderly and people with underlying chronic diseases. COVID-19 patients&#xD;
      typically present with specific, similar symptoms, such as fever, malaise, and cough. Most&#xD;
      adults or children infected with SARS-CoV-2 have presented with mild flu-like symptoms, but a&#xD;
      few patients are in critical condition and rapidly develop acute respiratory distress&#xD;
      syndrome (ARDS), respiratory failure, multiple organ failure, and death. The case fatality&#xD;
      rate increases with the severity of illness and can reach up to 49% in critically ill&#xD;
      patients.&#xD;
&#xD;
      Unfortunately, specific and effective therapies for COVID-19 are highly limited. Recent&#xD;
      evidence suggest that administration of the anti-viral agent, Remdesivir, to hospital&#xD;
      inpatients with COVID-19 decreases time to recovery from 15 to 11 days and decreases&#xD;
      mortality at 14 days from 11.9% to 7.1%. A preliminary, unpublished analysis from a large,&#xD;
      multicenter, randomized, open-label trial for hospitalized patients in the United Kingdom&#xD;
      showed that patients who were randomized to receive dexamethasone had a reduced rate of&#xD;
      mortality compared to those who received standard of care. This benefit was observed in&#xD;
      patients with severe COVID-19 and was greatest in those who required mechanical ventilation&#xD;
      at enrollment (RECOVERY Trial). These 2 agents are considered in the standard of care (SOC)&#xD;
      for treating patients with COVID-19. However, additional therapies with larger effect sizes&#xD;
      and that are administered at earlier stages to prevent progression to severe COVID-19 are&#xD;
      critically needed.&#xD;
&#xD;
      2.1.1 IND (Investigational New Drug) Agent(s)&#xD;
&#xD;
      The PI has filed an IND with cross-reference letter from Novartis and has received a Safe to&#xD;
      Proceed determination (IND #152065).The rationale for the proposed starting dose is based on&#xD;
      the standard renal transplantation dose, which has a time-honored profile of safety in this&#xD;
      population.&#xD;
&#xD;
      2.2 Rationale&#xD;
&#xD;
      Severe COVID-19. Initial reports from cases identified between February 12 to March 16 in the&#xD;
      United States (U.S.) show rates of hospitalization for COVID-19 to be 21-31%, intensive care&#xD;
      unit (ICU) admissions to be 5- 12%, and fatality to be 2%-3%. High-risk groups for severe&#xD;
      COVID-19 have been identified as the elderly population and those with underlying&#xD;
      comorbidities such as cardiovascular disease, liver disease, pulmonary disease, renal&#xD;
      disease, and diabetes mellitus.&#xD;
&#xD;
      Severe COVID-19 results from a dysregulated hyperimmune state. Severe symptoms of COVID-19&#xD;
      are associated with a hyperimmune response referred to as a cytokine storm. In one study, all&#xD;
      41 patients with COVID-19 admitted to the hospital demonstrated elevated plasma levels of&#xD;
      cytokines and chemokines compared with healthy volunteers that included IL (Interleukin) -1,&#xD;
      -1R, -7, -8, -9, -10, and basic FGF2, GCSF, GMCSF, IFN-γ, IP10, MCP1, M1P1A, MIP1B, PDGF,&#xD;
      TNF-α, and VEGF. Patients admitted to the ICU had higher levels of IL-2, IL-7, IL-10, GCSF,&#xD;
      IP10, MCP1, MIP1A, and TNF-α than patients who did not require ICU admission. Emerging data&#xD;
      has shown that early rapid SARS-CoV-2 replication causes massive epithelial and endothelial&#xD;
      cell death that initiates a cytokine storm and vascular leakage, causes pyroptosis in&#xD;
      macrophages and lymphocytes, and results in exhaustion of T cells and NK (Natural Killer)&#xD;
      cells.&#xD;
&#xD;
      COVID-19 similarities to hemophagocytic lymphohistiocytosis (HLH). HLH is an&#xD;
      under-recognized, hyperinflammatory syndrome characterized by a fulminant and fatal cytokine&#xD;
      storm and multi-organ failure. In adults, HLH is most commonly triggered by viral infections&#xD;
      and occurs in 3.7% to 4.3% cases of sepsis. Cardinal features include unremitting fever,&#xD;
      cytopenias, and hyperferritinemia. Pulmonary involvement (including ARDS) occurs in ~50% of&#xD;
      patients. Each of these clinical features and a highly overlapping cytokine profile is seen&#xD;
      in severe COVID-19. This demonstrates that the clinical presentation and pathologic&#xD;
      mechanisms of severe COVID-19 is similar to, or is HLH.&#xD;
&#xD;
      Cyclosporine (CSA) suppresses hyperimmune states. Calcineurin inhibitors such as CSA suppress&#xD;
      the phosphatase activity of calcineurin, which results in decreased IL-2 production and IL-2&#xD;
      receptor expression. This interrupts a central pathway of T-cell activation and dampens T&#xD;
      cell responses and their associated cytokine storms. CSA is approved by the FDA for three&#xD;
      indications including 1) prophylaxis of organ rejection in kidney, liver, and heart&#xD;
      transplants, 2) treatment of severe active rheumatoid arthritis, and 3) treatment of adult&#xD;
      severe recalcitrant plaque psoriasis. It is critical to consider whether dampening of T-cell&#xD;
      responses using CSA would curtail the vigor of T-cell hyperactivity in COVID-19 disease and&#xD;
      provide an opportunity for these patients to recover.&#xD;
&#xD;
      CSA for COVID-19. Proposed is the use of the calcineurin inhibitor, CSA, for the treatment of&#xD;
      patients with COVID-19. This is based on: 1) observations that COVID-19 disease is associated&#xD;
      with a hyperimmune response very similar to HLH, for which treatment with CSA is effective&#xD;
      and recommended, 2) COVID-19 is associated with dysregulated macrophage activation similar to&#xD;
      macrophage activation syndrome (MAS) which is also therapeutically suppressed by CSA, and 3)&#xD;
      in vitro studies demonstrating that CSA specifically inhibits the replication of&#xD;
      coronaviruses including SARS-CoV-2 with a high degree of specificity.&#xD;
&#xD;
      CSA specifically inhibits coronavirus replication. Coronaviruses are RNA viruses with large&#xD;
      genomes that enter host cells through binding of its transmembrane spike protein with&#xD;
      angiotensin-converting enzyme 2 (ACE2) receptors expressed by host target cells, which is the&#xD;
      same mechanism utilized by SARS-CoV (i.e., SARS). Cyclophilins appear to play a critical role&#xD;
      in the replication of many viruses including coronaviruses, HIV, and hepatitis C virus.&#xD;
      Although the exact mechanisms are not yet well understood, in vitro studies suggest that the&#xD;
      coronavirus' nonstructural protein (Nsp) and nucleocapsid protein bind to cyclophilins, and&#xD;
      knockdown of cyclophilin expression results in near complete inhibition of coronavirus&#xD;
      replication. These data show that viral protein binding to cyclophilins is an important step&#xD;
      for successful coronavirus replication, and inhibition of this interaction by CSA prevents&#xD;
      viral replication. An important study demonstrated that CSA dominantly inhibited replication&#xD;
      of human coronavirus 229E (HCoV-229E), mouse hepatitis virus (MHV), and SARS, and that&#xD;
      treatment with increasing doses of CSA caused a dose-dependent decrease in SARS-CoV&#xD;
      replication in human cells in vitro without affecting cell viability. The same group&#xD;
      demonstrated that CSA inhibited replication of MERS-CoV without affecting cell viability of&#xD;
      mock-infected cells. An independent group demonstrated that increasing concentrations of CSA&#xD;
      treatment of SARS-CoV-infected human cells resulted in a dose-dependent decrease in viral&#xD;
      replication, and inhibited the replication of other coronaviruses, including human CoV-NL63,&#xD;
      CoV-229E, feline CoV serotypes I and II, porcine transmissible gastroenteritis virus (TGEV),&#xD;
      avian infection bronchitis virus (IBV), and two isolates of SARS-CoV. Taken together it is&#xD;
      proposed a dual mechanism in which (1) calcineurin inhibition by CSA inhibits the&#xD;
      phosphorylation of NFAT-P, thus preventing the production of IL-2 and other proinflammatory&#xD;
      cytokines, and (2) CSA inhibits viral replication of coronaviruses, likely through blockade&#xD;
      of calcineurin, causing the inhibition of cyclophilins required for viral replication. Most&#xD;
      recently, it was demonstrated that CSA is highly specific and effective at inhibiting&#xD;
      SARS-CoV-2 replication in various human cells, via inhibition of Cyclophilin.&#xD;
&#xD;
      Safety of CSA in COVID-19. Since April 2020 mounting evidence from various patient&#xD;
      populations has strongly suggested that CSA can be used safely in patients with COVID-19. It&#xD;
      was recently demonstrated that patients with &quot;Immune Mediated Inflammatory Diseases&quot; (IMID)&#xD;
      on various immunosuppressive drugs related to CSA have a &quot;significantly reduced incidence of&#xD;
      SARS-CoV-2 infection&quot;. It was reported no significant increase in the incidence or severity&#xD;
      of COVID-19 disease in patients undergoing CSA therapy for Psoriasis, but rather suggested a&#xD;
      potentially milder disease in these patients. Another study of over 4000 patients in Madrid,&#xD;
      Spain demonstrated &quot;a universal relationship between the use of Cyclosporine A and better&#xD;
      outcomes&quot; in patients with COVID-19 disease. In line with the findings from Spain, Cavagna in&#xD;
      Italy observed that transplant patients with ongoing Calcineurin Inhibitor therapy developed&#xD;
      only mild symptoms of COVID-19 disease and concluded that &quot;Calcineurin inhibitor-based&#xD;
      immunosuppressive regimens appear safe&quot; in COVID-19 disease and should not be discontinued.&#xD;
      These recent clinical outcomes data suggest that the use of CSA in patients with COVID-19 is&#xD;
      safe and potentially effective.&#xD;
&#xD;
      2.3 Correlative Studies Background&#xD;
&#xD;
      Correlative studies in this protocol are included as secondary endpoints and are based on: 1)&#xD;
      serum inflammatory markers used clinically as biomarkers to monitor the severity of COVID-19&#xD;
      (CRP, d-dimer, ferritin, ANC, absolute lymphocyte count, WBC (White Blood Cells), PLT), and&#xD;
      2) SARS-CoV-2 viral load by a clinical PCR (Polymerase Chain Reaction) test.&#xD;
&#xD;
      6. TREATMENT AND/OR IMAGING PLAN&#xD;
&#xD;
      6.1 Agent Administration&#xD;
&#xD;
      Treatment will be administered on an inpatient basis.&#xD;
&#xD;
      Arm A Regimen Description Agent Neoral, Investigational, Generic Acceptable, N=50 Patients&#xD;
      2.5 mg/kg PO BID 7 days&#xD;
&#xD;
      Arm B Regimen Description Agent None*, N= 25 Patients 7 days&#xD;
&#xD;
      *Note: The PI has undertaken thorough discussions with the sponsor and generation of placebo&#xD;
      capsules is not feasible for the timing of this study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 23, 2020</start_date>
  <completion_date type="Actual">December 10, 2021</completion_date>
  <primary_completion_date type="Actual">December 10, 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>
    <intervention_model_description>Phase IIa clinical trial in which 75 non-ICU hospital inpatients will be randomized 2:1 to 7 days of Neoral (2.5mg/kg PO BID) + standard of care (SOC) or no CSA + SOC.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>WHO(World Health Organization) COVID-19 Clinical Severity Scale</measure>
    <time_frame>on day 14</time_frame>
    <description>WHO(World Health Organization) COVID-19 clinical severity scale. Score 0-9. 0=Uninfected, 8=Death.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">47</enrollment>
  <condition>SARS (Disease)</condition>
  <arm_group>
    <arm_group_label>Arm A Cyclosporine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Neoral, N=50 Patients 2.5 mg/kg PO BID 7 days</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm B Standard of Care</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Standard of Care Treatment, N= 25 Patients 7 days</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclosporine</intervention_name>
    <description>2.5 mg/kg PO BID 7 days</description>
    <arm_group_label>Arm A Cyclosporine</arm_group_label>
    <other_name>Neoral</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Standard of Care Treatment</intervention_name>
    <description>Standard of Care Treatment, N= 25 Patients, 7 days</description>
    <arm_group_label>Arm B Standard of Care</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        3.1.1 Laboratory-confirmed SARS-CoV-2 infection within the past 10 days.&#xD;
&#xD;
        3.1.2 Patients admitted to non-ICU hospital floors or in an emergency department awaiting&#xD;
        admission to a non-ICU hospital bed.&#xD;
&#xD;
        3.1.3 WHO COVID Scale Score 4 (Oxygen by mask or nasal prongs or WHO COVID Scale Score 5&#xD;
        (non-invasive ventilation or high-flow oxygen).&#xD;
&#xD;
        3.1.4 Age 18 to 90 years old.&#xD;
&#xD;
        3.1.5 ECOG (Eastern Cooperative Oncology Group) performance status ≤2 (see Appendix A).&#xD;
&#xD;
        3.1.6 Patients receiving or who have received standard of care therapy for COVID-19 can be&#xD;
        included. This includes Remdesivir, Dexamethasone (or other steroids), and convalescent&#xD;
        plasma.&#xD;
&#xD;
        3.1.7 Ability to understand and the willingness to sign a written informed consent&#xD;
        document.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        3.2.1 Allergy and/or hypersensitivity to CSA.&#xD;
&#xD;
        3.2.2 GFR&lt;30 mL/min.&#xD;
&#xD;
        3.2.3 ALT (Alanine transaminase) or AST (Aspartate transaminase) &gt;3X upper limits of&#xD;
        normal.&#xD;
&#xD;
        3.2.4 Resistant hypertension (BP&gt;140/90 mm Hg despite adherence to maximal doses of three&#xD;
        antihypertensive agents).&#xD;
&#xD;
        3.2.5 Active bacterial or mycobacterial infection.&#xD;
&#xD;
        3.2.6 Pregnant and/or nursing patients. 3.2.7 Participation in a COVID-19 therapeutic drug&#xD;
        trial.&#xD;
&#xD;
        3.2.8 Patients who have received or who are receiving anti-viral medications including&#xD;
        hydroxychloroquine will not be excluded.&#xD;
&#xD;
        3.2.9 Patients with psychiatric illness/social situations that would limit compliance with&#xD;
        study requirements.&#xD;
&#xD;
        3.2.10 Total cholesterol is &lt; 100 (increased risk of seizure)&#xD;
&#xD;
        3.2.11 Concomitant dosing with Tacrolimus is a relative contraindication (increases overall&#xD;
        immunosuppression and decrease seizure threshold&#xD;
&#xD;
        3.2.12 Concomitant malignancy is a relative contraindication (Neoral can increase&#xD;
        susceptibility to development of neoplasia)&#xD;
&#xD;
        3.2.13 Inability to swallow oral medication&#xD;
&#xD;
        3.2.14 Treatment with immunomodulators or immunosuppressant drugs, including but not&#xD;
        limited to IL-6 inhibitors, TNF inhibitors, anti-IL-1 agents, and JAK inhibitors.&#xD;
&#xD;
        3.2.15 Investigational Antiviral agents&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Bryan Burt, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Baylor College of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Baylor College of Medicine</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>July 20, 2020</study_first_submitted>
  <study_first_submitted_qc>July 28, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 30, 2020</study_first_posted>
  <results_first_submitted>March 29, 2023</results_first_submitted>
  <results_first_submitted_qc>June 28, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">July 20, 2023</results_first_posted>
  <last_update_submitted>June 28, 2023</last_update_submitted>
  <last_update_submitted_qc>June 28, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 20, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Baylor College of Medicine</investigator_affiliation>
    <investigator_full_name>Bryan Burt, MD</investigator_full_name>
    <investigator_title>Associate Professor, Surgery General Thoracic</investigator_title>
  </responsible_party>
  <keyword>COVID-19</keyword>
  <keyword>SARS-COV-2</keyword>
  <keyword>Corona Virus</keyword>
  <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>Cyclosporine</mesh_term>
    <mesh_term>Cyclosporins</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>September 18, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/91/NCT04492891/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Participants were recruited at one institution between November 2020 and October 2021. The first participant enrolled on November 23, 2020, and the last participant enrolled on October 12, 2021.</recruitment_details>
      <pre_assignment_details>Due to the decline of COVID-19 cases which led to slow accrual, the study was closed to enrollment on April 6, 2022. For this reason, the total number of participants reported in the Brief Summary and the enrollment number of participants have a discrepancy.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Arm A Cyclosporine</title>
          <description>Participants received Neoral 2.5mg/kg PO BID, based on the renal transplant dose for 7 days.&#xD;
Neoral is an oral formulation of cyclosporine.</description>
        </group>
        <group group_id="P2">
          <title>Arm B Standard of Care</title>
          <description>Participants received standard of Care Treatment(no taking Neoral) for 7 days</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="30"/>
                <participants group_id="P2" count="17"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="30"/>
                <participants group_id="P2" count="17"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Arm A Cyclosporine</title>
          <description>Participants received Neoral 2.5mg/kg PO BID, based on the renal transplant dose for 7 days.&#xD;
Neoral is an oral formulation of cyclosporine.</description>
        </group>
        <group group_id="B2">
          <title>Arm B Standard of Care</title>
          <description>Participants received standard of Care Treatment(no taking Neoral) for 7 days</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="30"/>
            <count group_id="B2" value="17"/>
            <count group_id="B3" value="47"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="59.8" spread="14.8"/>
                    <measurement group_id="B2" value="59.8" spread="14.9"/>
                    <measurement group_id="B3" value="59.8" spread="14.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Age category</title>
              <category_list>
                <category>
                  <title>&lt; 60 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="14"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="22"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;= 60 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="16"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="19"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="28"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="14"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="32"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="14"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="32"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>WHO score - score 4</title>
          <description>WHO COVID-19 clinical severity scale range is from 0 (uninfected) to 8 (death). WHO score 4 is in Hospitalized Mild disease status which a patient needs Oxygen by mask or nasal prongs.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="30"/>
                    <measurement group_id="B2" value="17"/>
                    <measurement group_id="B3" value="47"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Comorbidity</title>
          <description>if participants had at least one of the following- hypertension, coronary artery disease, congestive heart failure, or diabetes, then comorbidity is &quot;Presence&quot; otherwise &quot;absence&quot;</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Absence</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Presence</title>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>WHO(World Health Organization) COVID-19 Clinical Severity Scale</title>
        <description>WHO(World Health Organization) COVID-19 clinical severity scale. Score 0-9. 0=Uninfected, 8=Death.</description>
        <time_frame>on day 14</time_frame>
        <population>WHO scores were obtained during ± 3 days on each planned day 14. If no WHO score is available on the planned day because of early discharge, the last WHO score was used for analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Arm A Cyclosporine</title>
            <description>Participants received Neoral 2.5mg/kg PO BID, based on the renal transplant dose for 7 days.&#xD;
Neoral is an oral formulation of cyclosporine.</description>
          </group>
          <group group_id="O2">
            <title>Arm B Standard of Care</title>
            <description>Participants received standard of Care Treatment(no taking Neoral) for 7 days</description>
          </group>
        </group_list>
        <measure>
          <title>WHO(World Health Organization) COVID-19 Clinical Severity Scale</title>
          <description>WHO(World Health Organization) COVID-19 clinical severity scale. Score 0-9. 0=Uninfected, 8=Death.</description>
          <population>WHO scores were obtained during ± 3 days on each planned day 14. If no WHO score is available on the planned day because of early discharge, the last WHO score was used for analysis.</population>
          <units>units on a scale</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
                <count group_id="O2" value="17"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2" lower_limit="0" upper_limit="3"/>
                    <measurement group_id="O2" value="2" lower_limit="1" upper_limit="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>60 days</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Arm A Cyclosporine</title>
          <description>Participants received Neoral 2.5mg/kg PO BID, based on the renal transplant dose for 7 days.&#xD;
Neoral is an oral formulation of cyclosporine.</description>
        </group>
        <group group_id="E2">
          <title>Arm B Standard of Care</title>
          <description>Participants received standard of Care Treatment(no taking Neoral) for 7 days</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE v5.0</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Chest pain - cardiac</sub_title>
                <description>Chest pain - cardiac</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Death NOS</sub_title>
                <description>Death NOS</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <description>Alanine aminotransferase increased</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <description>Aspartate aminotransferase increased</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>CTCAE v5.0</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="13" subjects_at_risk="30"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Chest pain - cardiac</sub_title>
                <description>Chest pain - cardiac</description>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="30"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Ear pain</sub_title>
                <description>Ear pain</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Constipation</sub_title>
                <description>Constipation</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <description>Nausea</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <description>Vomiting</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Sepsis</sub_title>
                <description>Sepsis</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <description>Alanine aminotransferase increased</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <description>Aspartate aminotransferase increased</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Investigations - Other, specify</sub_title>
                <description>Investigations - Other, specify</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <description>Back pain</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <description>Headache</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Confusion</sub_title>
                <description>Confusion</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <description>Acute kidney injury</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Adult respiratory distress syndrome</sub_title>
                <description>Adult respiratory distress syndrome</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Hypoxia</sub_title>
                <description>Hypoxia</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="17"/>
              </event>
              <event>
                <sub_title>Respiratory, thoracic and mediastinal disorders - Other, specify</sub_title>
                <description>Respiratory, thoracic and mediastinal disorders - Other, specify</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="30"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <description>Hypertension</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="30"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="17"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Michelle Almarez: Clinical Research Manager</name_or_title>
      <organization>Baylor College of Medicine</organization>
      <phone>713-798-3680</phone>
      <email>malmarez@bcm.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT04492891
org study id: H-48163
nct id: NCT04492891
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Phase IIa clinical trial in which 75 non-ICU hospital inpatients will be randomized 2:1 to 7
      days of an oral formulation of cyclosporine, Neoral (2.5mg/kg PO BID) + standard of care
      (SOC) or no Neoral + SOC. The primary endpoint is disease severity based on the World Health
      Organization (WHO) COVID Ordinal Outcomes Scale, on day 14. Secondary endpoints include
      safety and changes in serum inflammatory markers.
1. OBJECTIVES

           1.1 Primary Objectives

           1.1.1 To assess the effect of a 7-day course of oral cyclosporine Neoral on clinical
           outcome using the World Health Organization (WHO) COVID Ordinal Clinical Outcomes Scale,
           on day 14.

           1.2 Secondary Objectives

           1.2.1 To establish the safety of Neoral in this patient population (adverse events).

           1.2.2 To determine the effect of Neoral on serum inflammatory markers (CRP, d-dimer,
           ferritin, ANC (Absolute Neutrophil Count), absolute lymphocyte count, WBC, PLT (daily
           while inpatient and including day 14 and 28 for those discharged).

           1.2.3 To determine the effect Neoral on viral SARS-CoV2 PCR positivity from baseline
           (day 0 to -2) before receiving Neoral to day 14, and from baseline to day 28.

           1.2.4 To determine the effect of Neoral on survival (days 14 and 28).

           1.2.5 To determine the effect of Neoral on disease improvement (alive and free of
           invasive or non-invasive mechanical ventilation; days 14 and 28).

           1.2.6 To determine the effect of Neoral on proportion of those requiring invasive
           mechanical ventilation.

           1.2.7 To determine the effect of Neoral on incidence of deep vein thrombosis.

           1.2.8 To determine the effect of Neoral on proportion of patients discharged on day 28.

           1.2.9 To determine the effect of Neoral on time to hospital discharge.

           1.2.10 To determine the effect of Neoral on disease resolution (alive and discharged
           home without oxygen; days 14 and 28).

        2. BACKGROUND

      2.1 Study Disease(s)

      Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a novel coronavirus that
      causes coronavirus disease 2019 (COVID-19). Since initial detection of the virus, more than
      10 million cases of COVID-19 have been confirmed worldwide, and COVID-19 is responsible for
      more than 505,500 deaths. The United States has seen over 2.5 million cases of COVID-19 and
      126,000 deaths from this disease (as of June, 30, 2020). SARS-CoV-2 is efficiently
      transmitted from person-to-person and the World Health Organization (WHO) has declared
      coronavirus disease 2019 (COVID-19) to be a pandemic.

      COVID-19 primarily spreads through the respiratory tract, by droplets, respiratory
      secretions, and direct contact. Current data suggest an incubation period of 1-14 days, in
      most cases 3-7 days. The virus is highly transmissible in humans and causes severe problems
      especially in the elderly and people with underlying chronic diseases. COVID-19 patients
      typically present with specific, similar symptoms, such as fever, malaise, and cough. Most
      adults or children infected with SARS-CoV-2 have presented with mild flu-like symptoms, but a
      few patients are in critical condition and rapidly develop acute respiratory distress
      syndrome (ARDS), respiratory failure, multiple organ failure, and death. The case fatality
      rate increases with the severity of illness and can reach up to 49% in critically ill
      patients.

      Unfortunately, specific and effective therapies for COVID-19 are highly limited. Recent
      evidence suggest that administration of the anti-viral agent, Remdesivir, to hospital
      inpatients with COVID-19 decreases time to recovery from 15 to 11 days and decreases
      mortality at 14 days from 11.9% to 7.1%. A preliminary, unpublished analysis from a large,
      multicenter, randomized, open-label trial for hospitalized patients in the United Kingdom
      showed that patients who were randomized to receive dexamethasone had a reduced rate of
      mortality compared to those who received standard of care. This benefit was observed in
      patients with severe COVID-19 and was greatest in those who required mechanical ventilation
      at enrollment (RECOVERY Trial). These 2 agents are considered in the standard of care (SOC)
      for treating patients with COVID-19. However, additional therapies with larger effect sizes
      and that are administered at earlier stages to prevent progression to severe COVID-19 are
      critically needed.

      2.1.1 IND (Investigational New Drug) Agent(s)

      The PI has filed an IND with cross-reference letter from Novartis and has received a Safe to
      Proceed determination (IND #152065).The rationale for the proposed starting dose is based on
      the standard renal transplantation dose, which has a time-honored profile of safety in this
      population.

      2.2 Rationale

      Severe COVID-19. Initial reports from cases identified between February 12 to March 16 in the
      United States (U.S.) show rates of hospitalization for COVID-19 to be 21-31%, intensive care
      unit (ICU) admissions to be 5- 12%, and fatality to be 2%-3%. High-risk groups for severe
      COVID-19 have been identified as the elderly population and those with underlying
      comorbidities such as cardiovascular disease, liver disease, pulmonary disease, renal
      disease, and diabetes mellitus.

      Severe COVID-19 results from a dysregulated hyperimmune state. Severe symptoms of COVID-19
      are associated with a hyperimmune response referred to as a cytokine storm. In one study, all
      41 patients with COVID-19 admitted to the hospital demonstrated elevated plasma levels of
      cytokines and chemokines compared with healthy volunteers that included IL (Interleukin) -1,
      -1R, -7, -8, -9, -10, and basic FGF2, GCSF, GMCSF, IFN-γ, IP10, MCP1, M1P1A, MIP1B, PDGF,
      TNF-α, and VEGF. Patients admitted to the ICU had higher levels of IL-2, IL-7, IL-10, GCSF,
      IP10, MCP1, MIP1A, and TNF-α than patients who did not require ICU admission. Emerging data
      has shown that early rapid SARS-CoV-2 replication causes massive epithelial and endothelial
      cell death that initiates a cytokine storm and vascular leakage, causes pyroptosis in
      macrophages and lymphocytes, and results in exhaustion of T cells and NK (Natural Killer)
      cells.

      COVID-19 similarities to hemophagocytic lymphohistiocytosis (HLH). HLH is an
      under-recognized, hyperinflammatory syndrome characterized by a fulminant and fatal cytokine
      storm and multi-organ failure. In adults, HLH is most commonly triggered by viral infections
      and occurs in 3.7% to 4.3% cases of sepsis. Cardinal features include unremitting fever,
      cytopenias, and hyperferritinemia. Pulmonary involvement (including ARDS) occurs in ~50% of
      patients. Each of these clinical features and a highly overlapping cytokine profile is seen
      in severe COVID-19. This demonstrates that the clinical presentation and pathologic
      mechanisms of severe COVID-19 is similar to, or is HLH.

      Cyclosporine (CSA) suppresses hyperimmune states. Calcineurin inhibitors such as CSA suppress
      the phosphatase activity of calcineurin, which results in decreased IL-2 production and IL-2
      receptor expression. This interrupts a central pathway of T-cell activation and dampens T
      cell responses and their associated cytokine storms. CSA is approved by the FDA for three
      indications including 1) prophylaxis of organ rejection in kidney, liver, and heart
      transplants, 2) treatment of severe active rheumatoid arthritis, and 3) treatment of adult
      severe recalcitrant plaque psoriasis. It is critical to consider whether dampening of T-cell
      responses using CSA would curtail the vigor of T-cell hyperactivity in COVID-19 disease and
      provide an opportunity for these patients to recover.

      CSA for COVID-19. Proposed is the use of the calcineurin inhibitor, CSA, for the treatment of
      patients with COVID-19. This is based on: 1) observations that COVID-19 disease is associated
      with a hyperimmune response very similar to HLH, for which treatment with CSA is effective
      and recommended, 2) COVID-19 is associated with dysregulated macrophage activation similar to
      macrophage activation syndrome (MAS) which is also therapeutically suppressed by CSA, and 3)
      in vitro studies demonstrating that CSA specifically inhibits the replication of
      coronaviruses including SARS-CoV-2 with a high degree of specificity.

      CSA specifically inhibits coronavirus replication. Coronaviruses are RNA viruses with large
      genomes that enter host cells through binding of its transmembrane spike protein with
      angiotensin-converting enzyme 2 (ACE2) receptors expressed by host target cells, which is the
      same mechanism utilized by SARS-CoV (i.e., SARS). Cyclophilins appear to play a critical role
      in the replication of many viruses including coronaviruses, HIV, and hepatitis C virus.
      Although the exact mechanisms are not yet well understood, in vitro studies suggest that the
      coronavirus' nonstructural protein (Nsp) and nucleocapsid protein bind to cyclophilins, and
      knockdown of cyclophilin expression results in near complete inhibition of coronavirus
      replication. These data show that viral protein binding to cyclophilins is an important step
      for successful coronavirus replication, and inhibition of this interaction by CSA prevents
      viral replication. An important study demonstrated that CSA dominantly inhibited replication
      of human coronavirus 229E (HCoV-229E), mouse hepatitis virus (MHV), and SARS, and that
      treatment with increasing doses of CSA caused a dose-dependent decrease in SARS-CoV
      replication in human cells in vitro without affecting cell viability. The same group
      demonstrated that CSA inhibited replication of MERS-CoV without affecting cell viability of
      mock-infected cells. An independent group demonstrated that increasing concentrations of CSA
      treatment of SARS-CoV-infected human cells resulted in a dose-dependent decrease in viral
      replication, and inhibited the replication of other coronaviruses, including human CoV-NL63,
      CoV-229E, feline CoV serotypes I and II, porcine transmissible gastroenteritis virus (TGEV),
      avian infection bronchitis virus (IBV), and two isolates of SARS-CoV. Taken together it is
      proposed a dual mechanism in which (1) calcineurin inhibition by CSA inhibits the
      phosphorylation of NFAT-P, thus preventing the production of IL-2 and other proinflammatory
      cytokines, and (2) CSA inhibits viral replication of coronaviruses, likely through blockade
      of calcineurin, causing the inhibition of cyclophilins required for viral replication. Most
      recently, it was demonstrated that CSA is highly specific and effective at inhibiting
      SARS-CoV-2 replication in various human cells, via inhibition of Cyclophilin.

      Safety of CSA in COVID-19. Since April 2020 mounting evidence from various patient
      populations has strongly suggested that CSA can be used safely in patients with COVID-19. It
      was recently demonstrated that patients with "Immune Mediated Inflammatory Diseases" (IMID)
      on various immunosuppressive drugs related to CSA have a "significantly reduced incidence of
      SARS-CoV-2 infection". It was reported no significant increase in the incidence or severity
      of COVID-19 disease in patients undergoing CSA therapy for Psoriasis, but rather suggested a
      potentially milder disease in these patients. Another study of over 4000 patients in Madrid,
      Spain demonstrated "a universal relationship between the use of Cyclosporine A and better
      outcomes" in patients with COVID-19 disease. In line with the findings from Spain, Cavagna in
      Italy observed that transplant patients with ongoing Calcineurin Inhibitor therapy developed
      only mild symptoms of COVID-19 disease and concluded that "Calcineurin inhibitor-based
      immunosuppressive regimens appear safe" in COVID-19 disease and should not be discontinued.
      These recent clinical outcomes data suggest that the use of CSA in patients with COVID-19 is
      safe and potentially effective.

      2.3 Correlative Studies Background

      Correlative studies in this protocol are included as secondary endpoints and are based on: 1)
      serum inflammatory markers used clinically as biomarkers to monitor the severity of COVID-19
      (CRP, d-dimer, ferritin, ANC, absolute lymphocyte count, WBC (White Blood Cells), PLT), and
      2) SARS-CoV-2 viral load by a clinical PCR (Polymerase Chain Reaction) test.

      6. TREATMENT AND/OR IMAGING PLAN

      6.1 Agent Administration

      Treatment will be administered on an inpatient basis.

      Arm A Regimen Description Agent Neoral, Investigational, Generic Acceptable, N=50 Patients
      2.5 mg/kg PO BID 7 days

      Arm B Regimen Description Agent None*, N= 25 Patients 7 days

      *Note: The PI has undertaken thorough discussions with the sponsor and generation of placebo
      capsules is not feasible for the timing of this study.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Phase IIa clinical trial in which 75 non-ICU hospital inpatients will be randomized 2:1 to 7 days of Neoral (2.5mg/kg PO BID) + standard of care (SOC) or no CSA + SOC.
primary purpose: Treatment
masking: None (Open Label)
measure: WHO(World Health Organization) COVID-19 Clinical Severity Scale
time frame: on day 14
description: WHO(World Health Organization) COVID-19 clinical severity scale. Score 0-9. 0=Uninfected, 8=Death.
arm group label: Arm A Cyclosporine
arm group type: Experimental
description: Neoral, N=50 Patients 2.5 mg/kg PO BID 7 days
arm group label: Arm B Standard of Care
arm group type: Other
description: Standard of Care Treatment, N= 25 Patients 7 days
intervention type: Drug
intervention name: Cyclosporine
description: 2.5 mg/kg PO BID 7 days
arm group label: Arm A Cyclosporine
other name: Neoral
intervention type: Other
intervention name: Standard of Care Treatment
description: Standard of Care Treatment, N= 25 Patients, 7 days
arm group label: Arm B Standard of Care
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Bryan Burt, MD
role: Principal Investigator
affiliation: Baylor College of Medicine
facility: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: Baylor College of Medicine
investigator full name: Bryan Burt, MD
investigator title: Associate Professor, Surgery General Thoracic
mesh term: COVID-19
mesh term: Cyclosporine
mesh term: Cyclosporins
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 