<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/NCT04465513</url>
  </required_header>
  <id_info>
    <org_study_id>20CCHH</org_study_id>
    <nct_id>NCT04465513</nct_id>
  </id_info>
  <brief_title>Investigation of the Efficacy of CARDIO Softgels PLUS Best-standard-of-care in the Recovery of Patients With COVID-19</brief_title>
  <official_title>A Randomized, Open-label, Parallel Study to Investigate the Efficacy of CARDIO Softgels PLUS Best-standard-of-care in the Recovery of Patients With COVID-19 Who Are Hospitalized as Well as Patients Following the Guidance From Public Health</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hofseth Biocare ASA</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>KGK Science Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Hofseth Biocare ASA</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>
      Corona virus disease 2019 (COVID-19) is caused by SARS-CoV-2, a plus-sense single-stranded&#xD;
      RNA virus. After an incubation period, which typically lasts for 5-6 days, COVID-19 patients&#xD;
      present with a mild illness that lasts for a few days. Common symptoms are reminiscent of the&#xD;
      flu, and include fever, dry cough and dyspnea. A large percentage of patients resolve the&#xD;
      infection whereas others progress onto adult respiratory distress syndrome (ARDS) which&#xD;
      impedes gas exchange between the alveolar space and the bloodstream and creates the need for&#xD;
      assisted respiration. The objective of this study is to investigate the safety and efficacy&#xD;
      of CARDIO supplementation in the recovery of those with COVID-19 infection following the&#xD;
      guidance from public health by reducing the need for mechanical respiratory support,&#xD;
      alleviating respiratory symptoms and reducing mortality.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      SARS-CoV-2, a plus-sense single-stranded RNA virus, is the etiologic agent of COVID-19. After&#xD;
      an incubation period, which typically lasts for 5-6 days. COVID-19 patients present with a&#xD;
      mild illness that lasts for a few days. Common symptoms are reminiscent of the flu, and&#xD;
      include fever, dry cough and dyspnea. A large percentage of patients resolve the infection&#xD;
      whereas others progress onto adult respiratory distress syndrome (ARDS) which impedes gas&#xD;
      exchange between the alveolar space and the bloodstream and creates the need for assisted&#xD;
      respiration.&#xD;
&#xD;
      It is estimated that between 5-10% of asthma patients do not respond to steroid-based&#xD;
      therapies and require higher doses of medication to achieve control of their disease, or have&#xD;
      asthma exacerbations, persistent symptoms and airway obstruction despite greater medication&#xD;
      use. These steroid-resistant asthmatics typically have greater morbidity and&#xD;
      disproportionately require 50-80% of asthma-related health care costs. The compromised state&#xD;
      of the lung in steroid-resistant asthma patients is similar to former smoker patients, for&#xD;
      which eosinophil presence in the lung is believed to be a major pro-inflammatory effector&#xD;
      cell in the pathogenesis of asthma. Further, in the United States, chronic lung disease&#xD;
      (primarily asthma) was the second most prevalent underlying condition in those admitted to&#xD;
      hospital for COVID-19 infection in adults ages 18-49.&#xD;
&#xD;
      CARDIO is a safe, natural, salmon oil based, eosinophil effector function (EEF) reducing,&#xD;
      softgel formulation. Fish oil, inclusive of salmon oil, or marine-derived omega-3 supplements&#xD;
      have been established as cardioprotective. CARDIO has been studied in human clinical studies&#xD;
      for the treatment of cardiovascular disease, and as an antioxidant, with an excellent safety&#xD;
      record. CARDIO has demonstrated therapeutic potential for the treatment of allergic and&#xD;
      inflammatory conditions, particularly those involving eosinophil effector functions.&#xD;
      Specifically, CARDIO at 100 ug/ml inhibited eosinophil response to chemoattractant CCL11 in a&#xD;
      Shape Change assay; inhibited eosinophil response to chemoattractant CCL11 in an integrin&#xD;
      (CD11b) surface upregulation assay; and significantly enhanced apoptosis, in eosinophils&#xD;
      sourced from immuno-modulated individuals. Previous studies have shown that fish oil reduces&#xD;
      recruitment and infiltration of eosinophils into airways. Among the bioactive components in&#xD;
      fish oil, it has been demonstrated that the docosahexaenoic acid (DHA) has an inhibitory&#xD;
      effect on proliferation and migration of eosinophils. In vitro and animal dosing studies have&#xD;
      been completed for therapeutic dose determination for an accelerated Phase 2 trial&#xD;
      application.&#xD;
&#xD;
      Rationale:&#xD;
&#xD;
      Although the exact mechanism of action is unknown, based on in vitro and in vivo studies, it&#xD;
      is hypothesized that CARDIO may reduce morbidity and mortality from COVID-19 by protecting&#xD;
      respiratory epithelium and alveolar pneumocytes from eosinophil-mediated damage. In light of&#xD;
      the mechanism of action outlined above, it is possible that CARDIO could be used as a&#xD;
      therapeutic for COVID-19 with the goal of preventing progression into severe disease and in&#xD;
      particular in preventing the need of a mechanical ventilation.&#xD;
&#xD;
      Study population:&#xD;
&#xD;
      The population being investigated are hospitalized patients, all with mild to moderate&#xD;
      respiratory distress due to COVID-19. Though the age has a reasonably wide range to&#xD;
      facilitate recruitment, the exclusions in place provide the required guidance measures to&#xD;
      ensure patient safety and address associated comorbidities. Individuals most prone to&#xD;
      SARS-CoV-2 and hospitalization as a result of SARS-CoV-2 infection are those with&#xD;
      co-morbidities such as older age, cancer, cardiovascular disease and hypertension, type I or&#xD;
      II diabetes, chronic obstructive pulmonary disease, obesity and on immunosuppressive&#xD;
      treatments. Therefore, participants with the above co-morbidities will comprise the&#xD;
      population of interest. However, in this context, each participant will be assessed on a&#xD;
      case-by-case basis by the Qualified Investigator to ensure all inclusions and none of the&#xD;
      exclusions are met, and that the safety of their participation in the study is critically&#xD;
      evaluated. The requirement of mild to moderate COVID-19 will be assessed using the most up-&#xD;
      to-date National Institutes of Health (NIH) Treatment Guidelines for the Clinical&#xD;
      Presentation of People with SARS-CoV-2 Infection. Using the NIH guidelines for clinical&#xD;
      presentation of COVID-19 and identification of mild and moderate disease severity will ensure&#xD;
      potential patients are evaluated based on the most up-to-date information in the ever&#xD;
      changing COVID-19 research landscape. The safety of patients will be assessed at each&#xD;
      assessment day, a Data and Safety Monitoring Board will be established, and an interim&#xD;
      analysis is planned to guide safe continuation of the study.&#xD;
&#xD;
      The objectives of this randomized, open-label study is to investigate the safety and efficacy&#xD;
      of CARDIO plus best standard-of-care in reducing the need for mechanical respiratory support,&#xD;
      alleviating respiratory symptoms and reducing mortality in patients with COVID-19 infection&#xD;
      in patients who are hospitalized. The SPIRIT statement for protocols items for trials are&#xD;
      followed and the reporting will be done in accordance with the Consolidated Standards of&#xD;
      Reporting Trials (CONSORT) Statement.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 31, 2020</start_date>
  <completion_date type="Actual">October 4, 2021</completion_date>
  <primary_completion_date type="Actual">October 4, 2021</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Proportion of patients requiring mechanical ventilator until end of study (Day 28)</measure>
    <time_frame>Day 28</time_frame>
    <description>Proportion of patients requiring mechanical ventilator until end-of-study, when comparing Best Standard of Care treatment (BSC) plus CARDIO unrefined salmon oil vs. BSC alone</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Clinical improvement</measure>
    <time_frame>Day 10, Day 14, Day 28, or Day of discharge</time_frame>
    <description>Clinical improvement assessed by the National Early Warning Score (NEWS) at Day 10, Day 14, Day 28 or day of discharge. Assessed by the National Early Warning Score (NEWS) which is a standardized tool that assesses disease severity and monitoring of patients in hospital. An aggregate score of respiration rate, oxygen saturation, systolic blood pressure, pulse rate, level of consciousness and temperature and the score is increased if supplemental oxygen is required. Each parameter is based on a scale of 0 - 3. 0=good, 3=poor</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical status</measure>
    <time_frame>Day 10, Day 14, Day 28, or Day of discharge</time_frame>
    <description>Clinical status assessed by the WHO Ordinal Scale for Clinical Improvement at Day 10, Day 14, Day 28 or day of discharge. Assessed by the WHO Ordinal Scale for Clinical Improvement which examines changes in clinical status and/or survival specific to COVID-19. This 8-point scale measures illness severity over time. 0 = no infection and 8 = dead</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to clinical recovery</measure>
    <time_frame>Day 28 or Day of discharge</time_frame>
    <description>Time to clinical recovery, defined as normalization of fever, respiratory rate, oxygen saturation, and alleviation of cough, sustained for at least 72 hours, at Day 28 or day of discharge</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to improvement in oxygenation for at least 48 hours</measure>
    <time_frame>Day 28 or Day of discharge</time_frame>
    <description>Time to improvement in oxygenation for at least 48 hours, defined by an increase in SpO2/FiO2 of 50 mmHg or greater compared to the nadir SpO2/FiO2, at Day 28 or day of discharge</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life (QoL)</measure>
    <time_frame>Day 0, Day 10, Day 14, and Day 28</time_frame>
    <description>Quality of life assessed by the COVID-19 QoL questionnaire at Day 0, Day 10, Day 14, and Day 28. Assessed by the COVID-19 QoL questionnaire which asks questions about incident of different parameters related to deteriorating. It is on a scale of 1-5. 1=completely disagree, 5 = completely agree.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>All-cause mortality</measure>
    <time_frame>Day 28</time_frame>
    <description>Death due to COVID-19 and other reasons</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of mechanical ventilator use until end-of-study (Day 28)</measure>
    <time_frame>Day 28</time_frame>
    <description>The difference between BSC plus CARDIO vs. BSC alone on duration of mechanical ventilator use until end-of-study</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Oxygenation requirements assessed by oxygen saturation rates based on number of oxygenation free days during hospital stay</measure>
    <time_frame>During hospital stay, on day of discharge if prior to Day 28, and on Day 28</time_frame>
    <description>Oxygenation requirements during hospital stay, on day of discharge if prior to Day 28 and on Day 28, assessed by oxygen saturation rates based on number of oxygenation free days during hospital stay</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Oxygenation requirements assessed by oxygen saturation rates based on incidence of new oxygen use, non-invasive ventilation or high flow oxygen devices</measure>
    <time_frame>During hospital stay, on day of discharge if prior to Day 28, and on Day 28</time_frame>
    <description>Oxygenation requirements during hospital stay, on day of discharge if prior to Day 28 and on Day 28, assessed by oxygen saturation rates based on incidence of new oxygen use, non-invasive ventilation or high flow oxygen devices</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Oxygenation requirements assessed by oxygen saturation rates based on duration of new oxygen use, non-invasive ventilation or high flow oxygen devices</measure>
    <time_frame>During hospital stay, on day of discharge if prior to Day 28, and on Day 28</time_frame>
    <description>Oxygenation requirements during hospital stay, on day of discharge if prior to Day 28 and on Day 28, assessed by oxygen saturation rates based on duration of new oxygen use, non-invasive ventilation or high flow oxygen devices</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serial chest CT or X-ray findings</measure>
    <time_frame>Day 10 and Day 28 or Day of discharge</time_frame>
    <description>Serial chest CT or X-ray findings at Day 10, Day 28 or day of discharge</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The number of days from hospital admission to hospital discharge</measure>
    <time_frame>Up to Day 28</time_frame>
    <description>The difference between BSC plus CARDIO vs. BSC alone on the number of days from hospital admission to hospital discharge</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The total number of days on ventilator at Day 28 or day of discharge</measure>
    <time_frame>Day 28 or Day of discharge</time_frame>
    <description>The difference between BSC plus CARDIO vs. BSC alone on the total number of days on ventilator at Day 28 or day of discharge</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The number of days in intensive care unit (ICU) at Day 28 or day of discharge</measure>
    <time_frame>Day 28 or Day of discharge</time_frame>
    <description>The difference between BSC plus CARDIO vs. BSC alone on the number of days in intensive care unit (ICU) at Day 28 or day of discharge</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Temperature measurements after discharge and to end of study (Day 28)</measure>
    <time_frame>Day 28 and after discharge</time_frame>
    <description>The difference between BSC plus CARDIO vs. BSC alone on body temperature measurements after discharge and to end of study (Day 28)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Oxygen saturation measurements after discharge and to end of study (Day 28)</measure>
    <time_frame>Day 28 and after discharge</time_frame>
    <description>The difference between BSC plus CARDIO vs. BSC alone on oxygen saturation measurements after discharge and to end of study (Day 28). Oxygen saturation saturation measurements recorded using a pulse oximeter.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>COVID-19 QoL measurements after discharge and to end of study (Day 28)</measure>
    <time_frame>Day 28 and after discharge</time_frame>
    <description>The difference between BSC plus CARDIO vs. BSC alone on COVID-19 QoL measurements after discharge and to end of study (Day 28). Quality of life assessed by the COVID-19 QoL questionnaire which asks questions about incident of different parameters related to deteriorating. It is on a scale of 1-5. 1=completely disagree, 5 = completely agree.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Adverse Events</measure>
    <time_frame>Day 0 and up to day 28</time_frame>
    <description>Incidence of pre-emergent and post-emergent adverse events (AEs) and serious adverse events (SAEs) during the 28 days of supplementation or until day of discharge and during home follow up</description>
  </other_outcome>
  <other_outcome>
    <measure>Blood pressure</measure>
    <time_frame>Day 0 and up to day 28</time_frame>
    <description>Systolic and diastolic blood pressure values for the CARDIO softgel + BSC group will be compared with those of the BSC group during the 28-day supplementation period or until day of discharge and during home follow up</description>
  </other_outcome>
  <other_outcome>
    <measure>Heart rate</measure>
    <time_frame>Day 0 and up to day 28</time_frame>
    <description>Heart rate values for the CARDIO softgel + BSC group will be compared with those of the BSC group during the 28-day supplementation period or until day of discharge and during home follow up</description>
  </other_outcome>
  <other_outcome>
    <measure>Abnormality in laboratory tests</measure>
    <time_frame>Day 28 or Day of discharge</time_frame>
    <description>Frequency of clinically significant laboratory abnormalities at Day 28 or day of discharge</description>
  </other_outcome>
  <other_outcome>
    <measure>Body mass Index (BMI)</measure>
    <time_frame>Day 0, Day 10, Day 14, and Day 28 from baseline</time_frame>
    <description>BMI values for the CARDIO softgel + BSC group will be compared with those of the BSC group using statistical analysis to determine significant difference between the two groups. Samples are taken in the days stated below.</description>
  </other_outcome>
  <other_outcome>
    <measure>Complete blood count (CBC)</measure>
    <time_frame>Day 0, Day 10, Day 14, and Day 28 from baseline</time_frame>
    <description>CBC values for the CARDIO softgel + BSC group will be compared with those of the BSC group using statistical analysis to determine significant difference between the two groups. Samples are taken in the days stated below.</description>
  </other_outcome>
  <other_outcome>
    <measure>Aspartate transaminase (AST)</measure>
    <time_frame>Day 0, Day 10, Day 14, and Day 28 from baseline</time_frame>
    <description>AST values for the CARDIO softgel + BSC group will be compared with those of the BSC group using statistical analysis to determine significant difference between the two groups. Samples are taken in the days stated below.</description>
  </other_outcome>
  <other_outcome>
    <measure>Alanine transaminase (ALT)</measure>
    <time_frame>Day 0, Day 10, Day 14, and Day 28 from baseline</time_frame>
    <description>ALT values for the CARDIO softgel + BSC group will be compared with those of the BSC group using statistical analysis to determine significant difference between the two groups. Samples are taken in the days stated below.</description>
  </other_outcome>
  <other_outcome>
    <measure>Alkaline phosphatase (ALP)</measure>
    <time_frame>Day 0, Day 10, Day 14, and Day 28 from baseline</time_frame>
    <description>ALP values for the CARDIO softgel + BSC group will be compared with those of the BSC group using statistical analysis to determine significant difference between the two groups. Samples are taken in the days stated below.</description>
  </other_outcome>
  <other_outcome>
    <measure>Bilirubin</measure>
    <time_frame>Day 0, Day 10, Day 14, and Day 28 from baseline</time_frame>
    <description>Bilirubin values for the CARDIO softgel + BSC group will be compared with those of the BSC group using statistical analysis to determine significant difference between the two groups. Samples are taken in the days stated below.</description>
  </other_outcome>
  <other_outcome>
    <measure>Sodium ion</measure>
    <time_frame>Day 0, Day 10, Day 14, and Day 28 from baseline</time_frame>
    <description>Sodium ion values for the CARDIO softgel + BSC group will be compared with those of the BSC group using statistical analysis to determine significant difference between the two groups. Samples are taken in the days stated below.</description>
  </other_outcome>
  <other_outcome>
    <measure>Potassium ion</measure>
    <time_frame>Day 0, Day 10, Day 14, and Day 28 from baseline</time_frame>
    <description>Potassium ion values for the CARDIO softgel + BSC group will be compared with those of the BSC group using statistical analysis to determine significant difference between the two groups. Samples are taken in the days stated below.</description>
  </other_outcome>
  <other_outcome>
    <measure>Chloride ion</measure>
    <time_frame>Day 0, Day 10, Day 14, and Day 28 from baseline</time_frame>
    <description>Chloride ion values for the CARDIO softgel + BSC group will be compared with those of the BSC group using statistical analysis to determine significant difference between the two groups. Samples are taken in the days stated below.</description>
  </other_outcome>
  <other_outcome>
    <measure>Creatinine</measure>
    <time_frame>Day 0, Day 10, Day 14, and Day 28 from baseline</time_frame>
    <description>Creatinine values for the CARDIO softgel + BSC group will be compared with those of the BSC group using statistical analysis to determine significant difference between the two groups. Samples are taken in the days stated below.</description>
  </other_outcome>
  <other_outcome>
    <measure>eGFR</measure>
    <time_frame>Day 0, Day 10, Day 14, and Day 28 from baseline</time_frame>
    <description>eGFR values for the CARDIO softgel + BSC group will be compared with those of the BSC group using statistical analysis to determine significant difference between the two groups. Samples are taken in the days stated below.</description>
  </other_outcome>
  <other_outcome>
    <measure>HbA1c</measure>
    <time_frame>Day 0, Day 10, Day 14, and Day 28 from baseline</time_frame>
    <description>HbA1c values for the CARDIO softgel + BSC group will be compared with those of the BSC group using statistical analysis to determine significant difference between the two groups. Samples are taken in the days stated below.</description>
  </other_outcome>
  <other_outcome>
    <measure>Glucose</measure>
    <time_frame>Day 0, Day 10, Day 14, and Day 28 from baseline</time_frame>
    <description>eGFR values for the CARDIO softgel + BSC group will be compared with those of the BSC group using statistical analysis to determine significant difference between the two groups. Samples are taken in the days stated below.</description>
  </other_outcome>
  <other_outcome>
    <measure>C-Reactive protein (CRP)</measure>
    <time_frame>Day 0, Day 10, Day 14, and Day 28 from baseline</time_frame>
    <description>Changes in CRP from screening</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">14</enrollment>
  <condition>COVID</condition>
  <condition>Covid-19</condition>
  <arm_group>
    <arm_group_label>Best Standard of Care + CARDIO</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Combination of CARDIO and Best Standard of Care</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Best Standard of Care</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo and Best Standard of Care</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Best Standard of Care + CARDIO</intervention_name>
    <description>Combination of dietary supplement with clinical care</description>
    <arm_group_label>Best Standard of Care + CARDIO</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Best Standard of Care</intervention_name>
    <description>Combination of placebo with clinical care</description>
    <arm_group_label>Best Standard of Care</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients with signs and symptoms corresponding to COVID-19 viral infection and:&#xD;
&#xD;
          2. Admitted to hospital and who have been initiated with BSC treatment with mild to&#xD;
             moderate disease as defined by the National Institutes of Health (NIH) Treatment&#xD;
             Guidelines&#xD;
&#xD;
          3. Confirmation of COVID-19 infection This will be assessed by secondary laboratory&#xD;
             confirmation of SARS-CoV-2 infection by reverse-transcription polymerase chain&#xD;
             reaction (RT-PCR) or comparable methodology used by the hospital from any diagnostic&#xD;
             sampling - source for analysis and recovery&#xD;
&#xD;
          4. Males and females between 18 and 75 years of age, inclusive&#xD;
&#xD;
          5. Female patient is not of child-bearing potential, defined as females who have&#xD;
             undergone a sterilization procedure (e.g. hysterectomy, bilateral oophorectomy,&#xD;
             bilateral tubal ligation, complete endometrial ablation) or have been post-menopausal&#xD;
             for at least 1 year prior to screening&#xD;
&#xD;
             Or,&#xD;
&#xD;
             Females of child-bearing potential must have a negative urine pregnancy test and agree&#xD;
             to use a medically approved method of birth control for the duration of the study. All&#xD;
             hormonal birth control must have been in use for a minimum of three months. Acceptable&#xD;
             methods of birth control include:&#xD;
&#xD;
               -  Hormonal contraceptives including oral contraceptives, hormone birth control&#xD;
                  patch (Ortho Evra), vaginal contraceptive ring (NuvaRing), injectable&#xD;
                  contraceptives (Depo-Provera, Lunelle), or hormone implant (Norplant System)&#xD;
&#xD;
               -  Double-barrier method&#xD;
&#xD;
               -  Intrauterine devices&#xD;
&#xD;
               -  Non-heterosexual lifestyle or agrees to use contraception if planning on changing&#xD;
                  to heterosexual partner(s)&#xD;
&#xD;
               -  Vasectomy of partner at least 6 months prior to screening&#xD;
&#xD;
          6. Willingness to complete assessments, questionnaires and records associated with the&#xD;
             study&#xD;
&#xD;
          7. Provided voluntary, written, informed consent to participate in the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Women who are pregnant, breast feeding, or planning to become pregnant during the&#xD;
             study&#xD;
&#xD;
          2. Inability to take medications orally&#xD;
&#xD;
          3. Individuals with a known fish allergy or hypersensitivity reaction&#xD;
&#xD;
          4. Individuals with uncontrolled hypotension (systolic blood pressure &lt; 90 mmHg) or need&#xD;
             for vasopressor/inotropic medication&#xD;
&#xD;
          5. Individuals with renal impairment This will be assessed by increase of creatinine by&#xD;
             50% from baseline, glomerular filtration rate reduction by &gt;25% from baseline or urine&#xD;
             output of &lt;0.5 ml/kg for 6 hours)&#xD;
&#xD;
          6. Individuals with gastrointestinal symptoms that require hospitalization (e.g. severe&#xD;
             nausea, vomiting, diarrhea or/and abdominal pain) Any other condition, that, in the&#xD;
             opinion of the QI, may adversely affect the patient's ability to complete the study or&#xD;
             its measures or pose significant risk to the patient.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>David Crowley, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>KGK Science Inc.</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital Universitario Cassiano Antonio de Morais</name>
      <address>
        <city>Vitória</city>
        <state>Espírito Santo</state>
        <zip>29041-295</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>- Instituto de Pesquisa Clínica de Campinas</name>
      <address>
        <city>Campinas</city>
        <zip>13060-080</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Instituto Santa Marta de Ensino e Pesquisa</name>
      <address>
        <city>Taguatinga</city>
        <zip>72025-072</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>KGK Science Inc.</name>
      <address>
        <city>London</city>
        <state>Ontario</state>
        <zip>N6A 5R8</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Markhot Ferenc Oktatókórház és Rendelőintézet, Eger</name>
      <address>
        <city>Eger</city>
        <zip>3300</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Albert Schweitzer Kórház-Rendelőintézet, Hatvan</name>
      <address>
        <city>Hatvan</city>
        <zip>3000</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The American British Cowdray Medical Center I.A.P.</name>
      <address>
        <city>Ciudad de México</city>
        <zip>01120</zip>
        <country>Mexico</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>General Hospital Paracin</name>
      <address>
        <city>Paracin</city>
        <zip>35250</zip>
        <country>Serbia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Brazil</country>
    <country>Canada</country>
    <country>Hungary</country>
    <country>Mexico</country>
    <country>Serbia</country>
  </location_countries>
  <verification_date>June 2021</verification_date>
  <study_first_submitted>July 8, 2020</study_first_submitted>
  <study_first_submitted_qc>July 9, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 10, 2020</study_first_posted>
  <last_update_submitted>October 4, 2021</last_update_submitted>
  <last_update_submitted_qc>October 4, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">October 5, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>COVID-19</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04465513
org study id: 20CCHH
nct id: NCT04465513
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Corona virus disease 2019 (COVID-19) is caused by SARS-CoV-2, a plus-sense single-stranded
      RNA virus. After an incubation period, which typically lasts for 5-6 days, COVID-19 patients
      present with a mild illness that lasts for a few days. Common symptoms are reminiscent of the
      flu, and include fever, dry cough and dyspnea. A large percentage of patients resolve the
      infection whereas others progress onto adult respiratory distress syndrome (ARDS) which
      impedes gas exchange between the alveolar space and the bloodstream and creates the need for
      assisted respiration. The objective of this study is to investigate the safety and efficacy
      of CARDIO supplementation in the recovery of those with COVID-19 infection following the
      guidance from public health by reducing the need for mechanical respiratory support,
      alleviating respiratory symptoms and reducing mortality.
SARS-CoV-2, a plus-sense single-stranded RNA virus, is the etiologic agent of COVID-19. After
      an incubation period, which typically lasts for 5-6 days. COVID-19 patients present with a
      mild illness that lasts for a few days. Common symptoms are reminiscent of the flu, and
      include fever, dry cough and dyspnea. A large percentage of patients resolve the infection
      whereas others progress onto adult respiratory distress syndrome (ARDS) which impedes gas
      exchange between the alveolar space and the bloodstream and creates the need for assisted
      respiration.

      It is estimated that between 5-10% of asthma patients do not respond to steroid-based
      therapies and require higher doses of medication to achieve control of their disease, or have
      asthma exacerbations, persistent symptoms and airway obstruction despite greater medication
      use. These steroid-resistant asthmatics typically have greater morbidity and
      disproportionately require 50-80% of asthma-related health care costs. The compromised state
      of the lung in steroid-resistant asthma patients is similar to former smoker patients, for
      which eosinophil presence in the lung is believed to be a major pro-inflammatory effector
      cell in the pathogenesis of asthma. Further, in the United States, chronic lung disease
      (primarily asthma) was the second most prevalent underlying condition in those admitted to
      hospital for COVID-19 infection in adults ages 18-49.

      CARDIO is a safe, natural, salmon oil based, eosinophil effector function (EEF) reducing,
      softgel formulation. Fish oil, inclusive of salmon oil, or marine-derived omega-3 supplements
      have been established as cardioprotective. CARDIO has been studied in human clinical studies
      for the treatment of cardiovascular disease, and as an antioxidant, with an excellent safety
      record. CARDIO has demonstrated therapeutic potential for the treatment of allergic and
      inflammatory conditions, particularly those involving eosinophil effector functions.
      Specifically, CARDIO at 100 ug/ml inhibited eosinophil response to chemoattractant CCL11 in a
      Shape Change assay; inhibited eosinophil response to chemoattractant CCL11 in an integrin
      (CD11b) surface upregulation assay; and significantly enhanced apoptosis, in eosinophils
      sourced from immuno-modulated individuals. Previous studies have shown that fish oil reduces
      recruitment and infiltration of eosinophils into airways. Among the bioactive components in
      fish oil, it has been demonstrated that the docosahexaenoic acid (DHA) has an inhibitory
      effect on proliferation and migration of eosinophils. In vitro and animal dosing studies have
      been completed for therapeutic dose determination for an accelerated Phase 2 trial
      application.

      Rationale:

      Although the exact mechanism of action is unknown, based on in vitro and in vivo studies, it
      is hypothesized that CARDIO may reduce morbidity and mortality from COVID-19 by protecting
      respiratory epithelium and alveolar pneumocytes from eosinophil-mediated damage. In light of
      the mechanism of action outlined above, it is possible that CARDIO could be used as a
      therapeutic for COVID-19 with the goal of preventing progression into severe disease and in
      particular in preventing the need of a mechanical ventilation.

      Study population:

      The population being investigated are hospitalized patients, all with mild to moderate
      respiratory distress due to COVID-19. Though the age has a reasonably wide range to
      facilitate recruitment, the exclusions in place provide the required guidance measures to
      ensure patient safety and address associated comorbidities. Individuals most prone to
      SARS-CoV-2 and hospitalization as a result of SARS-CoV-2 infection are those with
      co-morbidities such as older age, cancer, cardiovascular disease and hypertension, type I or
      II diabetes, chronic obstructive pulmonary disease, obesity and on immunosuppressive
      treatments. Therefore, participants with the above co-morbidities will comprise the
      population of interest. However, in this context, each participant will be assessed on a
      case-by-case basis by the Qualified Investigator to ensure all inclusions and none of the
      exclusions are met, and that the safety of their participation in the study is critically
      evaluated. The requirement of mild to moderate COVID-19 will be assessed using the most up-
      to-date National Institutes of Health (NIH) Treatment Guidelines for the Clinical
      Presentation of People with SARS-CoV-2 Infection. Using the NIH guidelines for clinical
      presentation of COVID-19 and identification of mild and moderate disease severity will ensure
      potential patients are evaluated based on the most up-to-date information in the ever
      changing COVID-19 research landscape. The safety of patients will be assessed at each
      assessment day, a Data and Safety Monitoring Board will be established, and an interim
      analysis is planned to guide safe continuation of the study.

      The objectives of this randomized, open-label study is to investigate the safety and efficacy
      of CARDIO plus best standard-of-care in reducing the need for mechanical respiratory support,
      alleviating respiratory symptoms and reducing mortality in patients with COVID-19 infection
      in patients who are hospitalized. The SPIRIT statement for protocols items for trials are
      followed and the reporting will be done in accordance with the Consolidated Standards of
      Reporting Trials (CONSORT) Statement.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Proportion of patients requiring mechanical ventilator until end of study (Day 28)
time frame: Day 28
description: Proportion of patients requiring mechanical ventilator until end-of-study, when comparing Best Standard of Care treatment (BSC) plus CARDIO unrefined salmon oil vs. BSC alone
measure: Clinical improvement
time frame: Day 10, Day 14, Day 28, or Day of discharge
description: Clinical improvement assessed by the National Early Warning Score (NEWS) at Day 10, Day 14, Day 28 or day of discharge. Assessed by the National Early Warning Score (NEWS) which is a standardized tool that assesses disease severity and monitoring of patients in hospital. An aggregate score of respiration rate, oxygen saturation, systolic blood pressure, pulse rate, level of consciousness and temperature and the score is increased if supplemental oxygen is required. Each parameter is based on a scale of 0 - 3. 0=good, 3=poor
measure: Clinical status
time frame: Day 10, Day 14, Day 28, or Day of discharge
description: Clinical status assessed by the WHO Ordinal Scale for Clinical Improvement at Day 10, Day 14, Day 28 or day of discharge. Assessed by the WHO Ordinal Scale for Clinical Improvement which examines changes in clinical status and/or survival specific to COVID-19. This 8-point scale measures illness severity over time. 0 = no infection and 8 = dead
measure: Time to clinical recovery
time frame: Day 28 or Day of discharge
description: Time to clinical recovery, defined as normalization of fever, respiratory rate, oxygen saturation, and alleviation of cough, sustained for at least 72 hours, at Day 28 or day of discharge
measure: Time to improvement in oxygenation for at least 48 hours
time frame: Day 28 or Day of discharge
description: Time to improvement in oxygenation for at least 48 hours, defined by an increase in SpO2/FiO2 of 50 mmHg or greater compared to the nadir SpO2/FiO2, at Day 28 or day of discharge
measure: Quality of life (QoL)
time frame: Day 0, Day 10, Day 14, and Day 28
description: Quality of life assessed by the COVID-19 QoL questionnaire at Day 0, Day 10, Day 14, and Day 28. Assessed by the COVID-19 QoL questionnaire which asks questions about incident of different parameters related to deteriorating. It is on a scale of 1-5. 1=completely disagree, 5 = completely agree.
measure: All-cause mortality
time frame: Day 28
description: Death due to COVID-19 and other reasons
measure: Duration of mechanical ventilator use until end-of-study (Day 28)
time frame: Day 28
description: The difference between BSC plus CARDIO vs. BSC alone on duration of mechanical ventilator use until end-of-study
measure: Oxygenation requirements assessed by oxygen saturation rates based on number of oxygenation free days during hospital stay
time frame: During hospital stay, on day of discharge if prior to Day 28, and on Day 28
description: Oxygenation requirements during hospital stay, on day of discharge if prior to Day 28 and on Day 28, assessed by oxygen saturation rates based on number of oxygenation free days during hospital stay
measure: Oxygenation requirements assessed by oxygen saturation rates based on incidence of new oxygen use, non-invasive ventilation or high flow oxygen devices
time frame: During hospital stay, on day of discharge if prior to Day 28, and on Day 28
description: Oxygenation requirements during hospital stay, on day of discharge if prior to Day 28 and on Day 28, assessed by oxygen saturation rates based on incidence of new oxygen use, non-invasive ventilation or high flow oxygen devices
measure: Oxygenation requirements assessed by oxygen saturation rates based on duration of new oxygen use, non-invasive ventilation or high flow oxygen devices
time frame: During hospital stay, on day of discharge if prior to Day 28, and on Day 28
description: Oxygenation requirements during hospital stay, on day of discharge if prior to Day 28 and on Day 28, assessed by oxygen saturation rates based on duration of new oxygen use, non-invasive ventilation or high flow oxygen devices
measure: Serial chest CT or X-ray findings
time frame: Day 10 and Day 28 or Day of discharge
description: Serial chest CT or X-ray findings at Day 10, Day 28 or day of discharge
measure: The number of days from hospital admission to hospital discharge
time frame: Up to Day 28
description: The difference between BSC plus CARDIO vs. BSC alone on the number of days from hospital admission to hospital discharge
measure: The total number of days on ventilator at Day 28 or day of discharge
time frame: Day 28 or Day of discharge
description: The difference between BSC plus CARDIO vs. BSC alone on the total number of days on ventilator at Day 28 or day of discharge
measure: The number of days in intensive care unit (ICU) at Day 28 or day of discharge
time frame: Day 28 or Day of discharge
description: The difference between BSC plus CARDIO vs. BSC alone on the number of days in intensive care unit (ICU) at Day 28 or day of discharge
measure: Temperature measurements after discharge and to end of study (Day 28)
time frame: Day 28 and after discharge
description: The difference between BSC plus CARDIO vs. BSC alone on body temperature measurements after discharge and to end of study (Day 28)
measure: Oxygen saturation measurements after discharge and to end of study (Day 28)
time frame: Day 28 and after discharge
description: The difference between BSC plus CARDIO vs. BSC alone on oxygen saturation measurements after discharge and to end of study (Day 28). Oxygen saturation saturation measurements recorded using a pulse oximeter.
measure: COVID-19 QoL measurements after discharge and to end of study (Day 28)
time frame: Day 28 and after discharge
description: The difference between BSC plus CARDIO vs. BSC alone on COVID-19 QoL measurements after discharge and to end of study (Day 28). Quality of life assessed by the COVID-19 QoL questionnaire which asks questions about incident of different parameters related to deteriorating. It is on a scale of 1-5. 1=completely disagree, 5 = completely agree.
measure: Adverse Events
time frame: Day 0 and up to day 28
description: Incidence of pre-emergent and post-emergent adverse events (AEs) and serious adverse events (SAEs) during the 28 days of supplementation or until day of discharge and during home follow up
measure: Blood pressure
time frame: Day 0 and up to day 28
description: Systolic and diastolic blood pressure values for the CARDIO softgel + BSC group will be compared with those of the BSC group during the 28-day supplementation period or until day of discharge and during home follow up
measure: Heart rate
time frame: Day 0 and up to day 28
description: Heart rate values for the CARDIO softgel + BSC group will be compared with those of the BSC group during the 28-day supplementation period or until day of discharge and during home follow up
measure: Abnormality in laboratory tests
time frame: Day 28 or Day of discharge
description: Frequency of clinically significant laboratory abnormalities at Day 28 or day of discharge
measure: Body mass Index (BMI)
time frame: Day 0, Day 10, Day 14, and Day 28 from baseline
description: BMI values for the CARDIO softgel + BSC group will be compared with those of the BSC group using statistical analysis to determine significant difference between the two groups. Samples are taken in the days stated below.
measure: Complete blood count (CBC)
time frame: Day 0, Day 10, Day 14, and Day 28 from baseline
description: CBC values for the CARDIO softgel + BSC group will be compared with those of the BSC group using statistical analysis to determine significant difference between the two groups. Samples are taken in the days stated below.
measure: Aspartate transaminase (AST)
time frame: Day 0, Day 10, Day 14, and Day 28 from baseline
description: AST values for the CARDIO softgel + BSC group will be compared with those of the BSC group using statistical analysis to determine significant difference between the two groups. Samples are taken in the days stated below.
measure: Alanine transaminase (ALT)
time frame: Day 0, Day 10, Day 14, and Day 28 from baseline
description: ALT values for the CARDIO softgel + BSC group will be compared with those of the BSC group using statistical analysis to determine significant difference between the two groups. Samples are taken in the days stated below.
measure: Alkaline phosphatase (ALP)
time frame: Day 0, Day 10, Day 14, and Day 28 from baseline
description: ALP values for the CARDIO softgel + BSC group will be compared with those of the BSC group using statistical analysis to determine significant difference between the two groups. Samples are taken in the days stated below.
measure: Bilirubin
time frame: Day 0, Day 10, Day 14, and Day 28 from baseline
description: Bilirubin values for the CARDIO softgel + BSC group will be compared with those of the BSC group using statistical analysis to determine significant difference between the two groups. Samples are taken in the days stated below.
measure: Sodium ion
time frame: Day 0, Day 10, Day 14, and Day 28 from baseline
description: Sodium ion values for the CARDIO softgel + BSC group will be compared with those of the BSC group using statistical analysis to determine significant difference between the two groups. Samples are taken in the days stated below.
measure: Potassium ion
time frame: Day 0, Day 10, Day 14, and Day 28 from baseline
description: Potassium ion values for the CARDIO softgel + BSC group will be compared with those of the BSC group using statistical analysis to determine significant difference between the two groups. Samples are taken in the days stated below.
measure: Chloride ion
time frame: Day 0, Day 10, Day 14, and Day 28 from baseline
description: Chloride ion values for the CARDIO softgel + BSC group will be compared with those of the BSC group using statistical analysis to determine significant difference between the two groups. Samples are taken in the days stated below.
measure: Creatinine
time frame: Day 0, Day 10, Day 14, and Day 28 from baseline
description: Creatinine values for the CARDIO softgel + BSC group will be compared with those of the BSC group using statistical analysis to determine significant difference between the two groups. Samples are taken in the days stated below.
measure: eGFR
time frame: Day 0, Day 10, Day 14, and Day 28 from baseline
description: eGFR values for the CARDIO softgel + BSC group will be compared with those of the BSC group using statistical analysis to determine significant difference between the two groups. Samples are taken in the days stated below.
measure: HbA1c
time frame: Day 0, Day 10, Day 14, and Day 28 from baseline
description: HbA1c values for the CARDIO softgel + BSC group will be compared with those of the BSC group using statistical analysis to determine significant difference between the two groups. Samples are taken in the days stated below.
measure: Glucose
time frame: Day 0, Day 10, Day 14, and Day 28 from baseline
description: eGFR values for the CARDIO softgel + BSC group will be compared with those of the BSC group using statistical analysis to determine significant difference between the two groups. Samples are taken in the days stated below.
measure: C-Reactive protein (CRP)
time frame: Day 0, Day 10, Day 14, and Day 28 from baseline
description: Changes in CRP from screening
arm group label: Best Standard of Care + CARDIO
arm group type: Active Comparator
description: Combination of CARDIO and Best Standard of Care
arm group label: Best Standard of Care
arm group type: Placebo Comparator
description: Placebo and Best Standard of Care
intervention type: Dietary Supplement
intervention name: Best Standard of Care + CARDIO
description: Combination of dietary supplement with clinical care
arm group label: Best Standard of Care + CARDIO
intervention type: Dietary Supplement
intervention name: Best Standard of Care
description: Combination of placebo with clinical care
arm group label: Best Standard of Care
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: David Crowley, MD
role: Principal Investigator
affiliation: KGK Science Inc.
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Brazil
country: Canada
country: Hungary
country: Mexico
country: Serbia
responsible party type: Sponsor
mesh term: COVID-19
sharing ipd: No