<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/NCT04468087</url>
  </required_header>
  <id_info>
    <org_study_id>REVOLUTIOn</org_study_id>
    <nct_id>NCT04468087</nct_id>
  </id_info>
  <brief_title>Antiviral Agents Against COVID-19 Infection</brief_title>
  <acronym>REVOLUTIOn</acronym>
  <official_title>Antiviral for Adult Patients Hospitalized for SARS-CoV-2 Infection: a Randomized, Phase 2/3, Multicenter, Placebo Controlled, Adaptive, Multi-arm, Multi-stage Clinical Trial - Coalition Brazil COVID-19 IX: REVOLUTIOn</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hospital do Coracao</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hospital do Coracao</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      A key strategy in the treatment of COVID-19 would be to find an effective antiviral agent&#xD;
      that would decrease the peak viral load and, consequently, the associated degree of&#xD;
      immunopathological damage that follows this phase. The clinically approved substances&#xD;
      considered for this study are used for treatment of other virus diseases, like HIV&#xD;
      (atazanavir) and HCV (sofosbuvir and daclatasvir). Severe progression of COVID-19 among&#xD;
      patients under treatment for these aforementioned viruses is empirical less common. Besides,&#xD;
      the clinical rationale, there are pre-clinical evidence pointing out that patients with&#xD;
      COVID-19 could benefit from treatments with atazanavir, sofosbuvir and daclatasvir.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      We have planned an randomized, adaptive, placebo-controlled, double-blind study to be carried&#xD;
      out in 3 seamless stages. The first two stages are phase 2 studies with a third stage phase 3&#xD;
      to be conducted conditional to success of the first phase 2 and second phase 2 stages&#xD;
      including efficacy and safety.&#xD;
&#xD;
      In particular, there is great interest in the possibility of combining the phase II and phase&#xD;
      III stages of the development process and this is the focus here. Phase II trials can be&#xD;
      thought of as part of the learning stage where dose selection and appropriate treatment&#xD;
      groups are assessed together with initial indications of their effects. Phase III trials are&#xD;
      usually more confirmatory in nature where the treatment effects of the selected treatments&#xD;
      are assessed in a full-scale trial. Seamless phase II/III trials are concerned with combining&#xD;
      these two aspects into a single trial. There are a clearly advantages of speed in that the&#xD;
      dose selection and treatment effects are assessed within a single trial rather than&#xD;
      establishing separate trials. In addition, all data available for the selected dose are used&#xD;
      in the analysis rather than just those from the second stage with a consequent gain in power.&#xD;
      The savings in the number of patients is achieved by applying a form of screening of&#xD;
      competing treatments in the initial phase and abandoning those that are ineffective before&#xD;
      the end of the study following pre-established premises of futility. Effect estimates,&#xD;
      confidence intervals and p values need some statistical adjustments to allow for this,&#xD;
      otherwise they will be biased towards a benefit of the treatment. This study design, starting&#xD;
      with a phase II, could give us a treatment regimen composed of one or more repurposed&#xD;
      antivirals drugs that could improve the clinical outcomes of those hospitalized with COVID-19&#xD;
      reducing time to recovery and the need for respiratory support. It will be conducted in about&#xD;
      60 Brazilian hospitals.&#xD;
&#xD;
      Selection of drugs rationale&#xD;
&#xD;
        -  Atazanavir: Atazanavir is a potent inhibitor of HIV-1 protease and is not associated&#xD;
           with significant dyslipidemia, as observed with other protease inhibitors.15 It was&#xD;
           approved by the FDA on January 29, 201516,17 as a combination of atazanavir and&#xD;
           cobicistat. Atazanavir can also be combined with ritonavir18 In a protease-free cell&#xD;
           assay, atazanavir blocked the major protease activity of SARS-Cov-2 at a concentration&#xD;
           of 10 μM. In in vitro models of viral infection/replication performed on Vero cells, a&#xD;
           human pulmonary epithelial cell line and primary human monocytes, atazanavir inhibited&#xD;
           SARS-CoV-2 replication; in addition, the concentrations of interleukin 6 (IL-6) and&#xD;
           tumor necrosis factor type alpha (TNF-α) induced by the virus were reduced.10 Currently,&#xD;
           no clinical study is registered on the ClinicalTrials.com website to assess the effects&#xD;
           of atazanavir in the context of COVID-19.&#xD;
&#xD;
        -  Daclastavir: Daclatasvir is a direct-acting antiviral that inhibits HCV replication by&#xD;
           binding to the N- terminal of the NS5A protein, affecting viral RNA replication. NS5A is&#xD;
           a multifunctional protein in the HCV replicative cycle, involved in the enrollment of&#xD;
           cell lipid bodies, RNA binding and replication, protein phosphorylation, cell signaling&#xD;
           and antagonism of interferon pathways.19 In an in vitro study, daclatasvir consistently&#xD;
           inhibited the production of SARS-CoV-2 infectious particles in Vero cells, in the HuH-7&#xD;
           cell line and in Calu-3 cells, with potencies of 0.8, 0.6 and 1.1 μM, respectively.&#xD;
           Daclatasvir reached early events during the replication cycle of SARS-CoV-2 and&#xD;
           prevented the induction of IL-6 and TNF-α, inflammatory mediators associated with the&#xD;
           cytokine storm typical of SARS-CoV-2 infection.20&#xD;
&#xD;
        -  Sofosbuvir/daclastavir:&#xD;
&#xD;
      Sofosbuvir (SOVALDI®) is a nucleotide analog directed against HCV NS5B polymerase, clinically&#xD;
      approved with potent antiviral effects on the hepatitis C virus with several genotypes21. It&#xD;
      is proposed that the drug could be a potential option in the treatment of COVID-19 especially&#xD;
      at the beginning of the disease and before the invasion of the virus in the cells of the lung&#xD;
      parenchyma, based on the similarity between the replication mechanisms of HCV and&#xD;
      coronavirus22. In vitro, sofosbuvir showed EC50 values of 6.2 and 9.5 µM in HuH-7 (hepatoma)&#xD;
      and Calu-3 (type II pneumocytes) cells respectively, although inactive in Vero cells (these&#xD;
      cells are unable to make this conversion sofosbuvir in the pro-drug to active form)11.&#xD;
&#xD;
      First stage - will have 6 arms with total treatment for 10 days:&#xD;
&#xD;
      First stage Phase II - 6 arms&#xD;
&#xD;
        1. Atazanavir (ATV)&#xD;
&#xD;
        2. Daclatasvir (DCV)&#xD;
&#xD;
        3. Sofusbuvir+Daclatasvir (SFV/DCV)&#xD;
&#xD;
      6. Placebo (PbO) ATV 7. (PbO) DCV 8. (PbO) SFV/DCV&#xD;
&#xD;
      Second stage Phase II - 4 arms:&#xD;
&#xD;
        1. Best from first stage&#xD;
&#xD;
        2. Best from first stage + Second best&#xD;
&#xD;
        3. PbO Best from first stage;&#xD;
&#xD;
        4. PbO Best from first stage + Pbo Second best&#xD;
&#xD;
      Phase III - 2 arms:&#xD;
&#xD;
        1. Best from phase II second stage&#xD;
&#xD;
        2. (PbO) Best from phase 2 second stage&#xD;
&#xD;
      Main questions: The aim of the Coalition IX REVOLUTIOn evaluation is to answer the following&#xD;
      questions:&#xD;
&#xD;
        -  Are antiviral candidates (atazavir, daclatasvir/sofosbuvir) able to reduce the viral&#xD;
           load of SARS-CoV-2 compared to placebo in patients hospitalized with COVID-19 with ≤ 9&#xD;
           days of symptoms?&#xD;
&#xD;
        -  Which antiviral alone has the best effect in reducing the viral load of SARS-CoV-2 in&#xD;
           patients hospitalized with COVID-19 with ≤ 9 days of symptoms? And which is the second&#xD;
           most effective?&#xD;
&#xD;
        -  Are combined antiviral candidates able to reduce the viral load of SARS-CoV-2 compared&#xD;
           to antiviral alone and placebo in patients hospitalized with COVID-19 with ≤ 9 days of&#xD;
           symptoms?&#xD;
&#xD;
        -  Are isolated or combined antiviral candidates safe compared to placebo?&#xD;
&#xD;
        -  Does the antiviral candidate alone or in combination improve clinical outcomes (days&#xD;
           free of respiratory support in 15 days) compared with placebo in patients hospitalized&#xD;
           with COVID-19 with ≤ 9 days of symptoms?&#xD;
&#xD;
      Primary/secondary objectives Primary objectives Phase II/ 1st and 2nd stages: Assess the&#xD;
      effect of treatment with antivirals alone or combined with each other compared to placebo in&#xD;
      reducing the of viral load of SARS-CoV-2 in nasopharyngeal swab samples obtained at baseline&#xD;
      (d0) and days 3, 6 and 10; Phase III: Evaluate the effectiveness of best antivirals from&#xD;
      Phase II alone or combined compared to placebo in increasing days free of respiratory support&#xD;
      defined as the number of days without oxygen, non-invasive ventilation / high-flow nasal&#xD;
      cannula or mechanical ventilation in 15 days.&#xD;
&#xD;
      Secondary Objectives&#xD;
&#xD;
        1. Ordinal 7-stage scale for clinical outcomes on the 15th day (1. not hospitalized with&#xD;
           resumption of normal activities; 2. not hospitalized, but unable to resume normal&#xD;
           activities; 3. hospitalized, without the need for supplemental oxygen; 4. hospitalized ,&#xD;
           requiring supplemental oxygen; 5. hospitalized, requiring high-flow nasal oxygen&#xD;
           therapy, non-invasive mechanical ventilation or both; 6. hospitalized, requiring blood&#xD;
           oxygenation through the membrane system, invasive mechanical ventilation or both; 7.&#xD;
           Death);&#xD;
&#xD;
        2. Ordinal 6-stage scale for clinical outcomes on day 7 1. not hospitalized; 2.&#xD;
           hospitalized, without the need for supplemental oxygen; 3. hospitalized, requiring&#xD;
           supplemental oxygen; 4. hospitalized, requiring high-flow nasal oxygen therapy,&#xD;
           non-invasive mechanical ventilation, or both; 5. hospitalized, requiring blood&#xD;
           oxygenation through a membrane system, invasive mechanical ventilation or both; 6.&#xD;
           Death;&#xD;
&#xD;
        3. Mortality in 28 days&#xD;
&#xD;
        4. Days free from mechanical ventilation within 28 days;&#xD;
&#xD;
        5. Days out of hospital within 28 days;&#xD;
&#xD;
        6. Time to discharge, defined as the number of days from randomization to discharge, within&#xD;
           28 days&#xD;
&#xD;
        7. Evaluate free days of respiratory support in 15 days for Phase II/1 and II/2&#xD;
&#xD;
        8. Grade 2, 3 or 4 adverse events that was not present at patient's admission, defined by&#xD;
           the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric&#xD;
           Adverse Events (corrected version 2.1, July, 2017); 53&#xD;
&#xD;
        9. Evaluate Serious adverse events (SAE);&#xD;
&#xD;
       10. Evaluate discontinuation of study drug-related treatment.&#xD;
&#xD;
      Recruitment and enrollment: The randomization list will be generated electronically using&#xD;
      appropriate software. Randomization will be performed in blocks and stratified by center. The&#xD;
      allocation concealment will be maintained through a centralized, automated, internet-based&#xD;
      randomization system, available 24 hours a day. Hospitalized patients with the inclusion&#xD;
      criteria will be allocated in an allocation ratio 3: 3: 3: 1: 1: 1 (3 for each treatment&#xD;
      group and 1 for placebo) in Phase II / 1. The parameter of interest for the efficacy decision&#xD;
      will be the comparison of the decay rates (slope) of the viral load logarithm from RT-PCR to&#xD;
      COVID-19 in 10 days between the treatment groups in comparison with the control (placebo). In&#xD;
      the 2nd stage, we will allocate patients in the ratio 2: 2: 1: 1 (2 for each active arm and 1&#xD;
      for each placebo) and the same statistic, now comparing combined treatment against the&#xD;
      treatment selected in phase II / 1 and placebo, since it is already known that the treatment&#xD;
      of phase II / 1 is effective for reducing viral load according to the pre specified criteria.&#xD;
      As long as we have success on primary outcome of Phase II/2, Phase III will proceed in a 2: 1&#xD;
      allocation ratio (2 active treatments for each placebo).&#xD;
&#xD;
      Blinding:This is a double-blind study for participants of the same active drug and&#xD;
      researchers. Both participant and investigator can know, after randomization, which&#xD;
      medication they were allocated to. However, none will know whether the capsule to be&#xD;
      administered is active or placebo, ensuring blinding within that specific group to which the&#xD;
      participant was allocated.&#xD;
&#xD;
      Sample size and analysis: 252 patients in total in phase II first stage (189 in active groups&#xD;
      and 63 in placebo) and 189 patients in total in phase II second stage (126 in active groups&#xD;
      and 63 in placebo). In case of success in Phase II, 564 additional participants will be&#xD;
      recruited in phase 3 (376 in the active group and 188 in the placebo). Thus, at the end of&#xD;
      phase III, we will have 314 patients evaluated in the Placebo group and between 439 and 502&#xD;
      patients in the treatment group.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">February 15, 2021</start_date>
  <completion_date type="Anticipated">December 31, 2022</completion_date>
  <primary_completion_date type="Actual">August 4, 2021</primary_completion_date>
  <phase>Phase 2/Phase 3</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>Randomized, multicenter, multi-arm, multi-stage, study. Adults, COVID-19 confirmed by reverse-transcriptase-polymerase-chain-reaction (RT-PCR) or SARS-Cov2 Antigen hospitalized patients with ≤ 9 days duration of symptoms and SpO2&lt;=94% will be randomly assigned to receive antivirals with potential effectiveness for SARS-CoV-2.&#xD;
The study is planned to be an adaptive phase II / III study. The phase II will be divided into 2 stages: first and second stages. First stage will allocate patients into a 3:3:3:1:1:1 allocation ratio (5 for each treatment group and 1 for placebo) and second stage will allocate into 2:2:1:1 (2 for each treatment group and 1 for placebo). The phase 3 study will then proceed in a 2:1 allocation (2 treatments for each placebo).</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>This is a double-blind study for participants of the same active drug and researchers. Both participant and investigator can know, after randomization, which medication they were allocated to. However, none will know whether the capsule to be administered is active or placebo, ensuring blinding within that specific group to which the participant was allocated.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Phase II first step: Change in the slope of SARS-COV 2 viral load</measure>
    <time_frame>days 3, 6 and 10 after randomization</time_frame>
    <description>Change in the slope of the SARS-COV 2 log viral load evaluated by nasopharyngeal swab samples assessed at baseline and days 3, 6 and 10 after randomization (isolated antiviral).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase II second step: Change in the slope of SARS-COV 2 viral load</measure>
    <time_frame>days 3, 6 and 10 after randomization</time_frame>
    <description>Change in the slope of the SARS-COV 2 log viral load curve evaluated by nasopharyngeal swab samples assessed at baseline and days 3, 6 and 10 after randomization (combined antiviral).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Phase III: Number of free days from respiratory support</measure>
    <time_frame>15 days</time_frame>
    <description>Number of days without oxygen, non-invasive ventilation/high flow nasal cannula or need for mechanical ventilation in 15 days.</description>
  </primary_outcome>
  <number_of_arms>6</number_of_arms>
  <enrollment type="Actual">256</enrollment>
  <condition>COVID-19</condition>
  <arm_group>
    <arm_group_label>Atazanavir</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>600 mg (2 capsules) twice daily on the first day and 300 mg (1 capsule) twice daily for the subsequent 9 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Daclatasvir 60 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>initial dose of 120mg (2 capsules), followed by 60mg (1 capsule) once daily for 9 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Sofusbuvir + Daclatasvir 60 mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>400 mg twice daily (2 capsules) on the first day and 400 mg (1 capsules) once daily for the subsequent 9 days (sofosbuvir) + initial dose of 120mg (2 capsules), followed by 60mg (1 capsule) once a day for 9 days (daclastavir)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo Atazanavir</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>2 capsules twice daily on the first day and 1 capsule twice daily for the subsequent 9 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo Daclatasvir</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>2 capsules twice daily on the first day and 1 capsule twice daily for the subsequent 9 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo Sofusbuvir + Daclatasvir</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>2 capsules twice daily on the first day and 1 capsule twice daily for the subsequent 9 days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Atazanavir</intervention_name>
    <description>600 mg (2 capsules) twice daily on the first day and 300 mg (1 capsule) twice daily for the subsequent 9 days.</description>
    <arm_group_label>Atazanavir</arm_group_label>
    <other_name>Active Group</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Daclatasvir 60 mg</intervention_name>
    <description>initial dose of 120mg (2 capsules), followed by 60mg (1 capsule) once daily for 9 days.</description>
    <arm_group_label>Daclatasvir 60 mg</arm_group_label>
    <other_name>Active Group</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sofusbuvir + Daclastavir 60 mg</intervention_name>
    <description>400 mg twice daily (2 capsules) on the first day and 400 mg (1 capsules) once daily for the subsequent 9 days (sofusbuvir) + initial dose of 120mg (2 capsules), followed by 60mg (1 capsule) once a day for 9 days (daclastavir)</description>
    <arm_group_label>Sofusbuvir + Daclatasvir 60 mg</arm_group_label>
    <other_name>Active Group</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Atazanavir</intervention_name>
    <description>2 capsules twice daily on the first day and 1 capsule twice daily for the subsequent 9 days.</description>
    <arm_group_label>Placebo Atazanavir</arm_group_label>
    <other_name>Placebo group</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Daclatasvir 60 mg</intervention_name>
    <description>2 capsules twice daily on the first day and 1 capsule twice daily for the subsequent 9 days.</description>
    <arm_group_label>Placebo Daclatasvir</arm_group_label>
    <other_name>Placebo group</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Sofusbuvir + Daclatasvir 60 mg</intervention_name>
    <description>2 capsules twice daily on the first day and 1 capsule twice daily for the subsequent 9 days.</description>
    <arm_group_label>Placebo Sofusbuvir + Daclatasvir</arm_group_label>
    <arm_group_label>Sofusbuvir + Daclatasvir 60 mg</arm_group_label>
    <other_name>Placebo group</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Adults (≥ 18 years) hospitalized with COVID-19:&#xD;
&#xD;
               -  SARS-CoV-2 positive RT-PCR or Antigen test&#xD;
&#xD;
               -  Typical clinical history and chest CT with typical findings, pending RT-PCR for&#xD;
                  SARS-CoV-2&#xD;
&#xD;
          2. Symptom duration &lt;= 9 days&#xD;
&#xD;
          3. SpO2 &lt;= 94% in room air or need for supplemental oxygen to maintain SpO2&gt; 94%&#xD;
&#xD;
          4. The patient consents to participate in the study and is willing to comply with all&#xD;
             study procedures, including the collection of virology samples&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients in need of respiratory support with invasive mechanical ventilation;&#xD;
&#xD;
          2. Alanine Transaminase (ALT) or Aspartate Transaminase (AST) &gt; 5 times the upper limit&#xD;
             of normal;&#xD;
&#xD;
          3. Total bilirubin &gt; 2 mg/dL;&#xD;
&#xD;
          4. Platelets &lt;50,000 cel/L;&#xD;
&#xD;
          5. Total neutrophil count &lt;750 cell/L;&#xD;
&#xD;
          6. Renal dysfunction (estimated glomerular filtration rate [eGFR] &lt;30 mL / min / 1.73 m2,&#xD;
             using the MDRD or CKD-EPI method); and pre-defined renal failure stage 3 according to&#xD;
             AKINx classification with serum creatinine&gt; 4 mg / dl or patient already on renal&#xD;
             replacement therapy;&#xD;
&#xD;
          7. Previously known liver disease (liver cirrhosis), defined as a report by the&#xD;
             participant or written in the respective cirrhosis chart, esophageal varices, or the&#xD;
             presence of clinical ascites on examination;&#xD;
&#xD;
          8. Decompensated congestive heart failure defined as the presence of dyspnea, edema of&#xD;
             the lower limbs or rales on pulmonary auscultation, jugular turgency or chest X-ray&#xD;
             with signs of pulmonary congestion;&#xD;
&#xD;
          9. Pregnant or breast feeding patients;&#xD;
&#xD;
         10. Known allergy or hypersensitivity to any study drug;&#xD;
&#xD;
         11. Hepatitis C carrier (HCV RNA positive), active Hepatitis B (positive surface antigen&#xD;
             in the past), or HIV (ELISA and confirmatory Western Blot in the past). New screening&#xD;
             tests are NOT required;&#xD;
&#xD;
         12. Patients currently using nucleoside or nucleotide analog drugs for any indication;&#xD;
&#xD;
         13. Corrected Q interval T&gt; 480 on the electrocardiogram;&#xD;
&#xD;
         14. Heart rate &lt;55 bpm;&#xD;
&#xD;
         15. Patients in use or who recently used (&lt;90 days) amiodarone;&#xD;
&#xD;
         16. Women of childbearing potential and men with a partner of childbearing potential who&#xD;
             do NOT agree to use two contraceptive methods (including barrier method) for 100 days.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Israel S Maia, MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>HCor Research Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital do Coracao</name>
      <address>
        <city>Sao Paulo</city>
        <state>SP</state>
        <zip>04005-000</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Brazil</country>
  </location_countries>
  <verification_date>February 2022</verification_date>
  <study_first_submitted>July 3, 2020</study_first_submitted>
  <study_first_submitted_qc>July 10, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 13, 2020</study_first_posted>
  <last_update_submitted>February 25, 2022</last_update_submitted>
  <last_update_submitted_qc>February 25, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">February 28, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>covid-19</keyword>
  <keyword>antivirals</keyword>
  <keyword>atazanavir</keyword>
  <keyword>daclatasvir</keyword>
  <keyword>sofosbuvir</keyword>
  <keyword>multiarm multistage study</keyword>
  <keyword>adaptive</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>Atazanavir Sulfate</mesh_term>
  </intervention_browse>
  <!-- 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/NCT04468087
org study id: REVOLUTIOn
nct id: NCT04468087
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
A key strategy in the treatment of COVID-19 would be to find an effective antiviral agent
      that would decrease the peak viral load and, consequently, the associated degree of
      immunopathological damage that follows this phase. The clinically approved substances
      considered for this study are used for treatment of other virus diseases, like HIV
      (atazanavir) and HCV (sofosbuvir and daclatasvir). Severe progression of COVID-19 among
      patients under treatment for these aforementioned viruses is empirical less common. Besides,
      the clinical rationale, there are pre-clinical evidence pointing out that patients with
      COVID-19 could benefit from treatments with atazanavir, sofosbuvir and daclatasvir.
We have planned an randomized, adaptive, placebo-controlled, double-blind study to be carried
      out in 3 seamless stages. The first two stages are phase 2 studies with a third stage phase 3
      to be conducted conditional to success of the first phase 2 and second phase 2 stages
      including efficacy and safety.

      In particular, there is great interest in the possibility of combining the phase II and phase
      III stages of the development process and this is the focus here. Phase II trials can be
      thought of as part of the learning stage where dose selection and appropriate treatment
      groups are assessed together with initial indications of their effects. Phase III trials are
      usually more confirmatory in nature where the treatment effects of the selected treatments
      are assessed in a full-scale trial. Seamless phase II/III trials are concerned with combining
      these two aspects into a single trial. There are a clearly advantages of speed in that the
      dose selection and treatment effects are assessed within a single trial rather than
      establishing separate trials. In addition, all data available for the selected dose are used
      in the analysis rather than just those from the second stage with a consequent gain in power.
      The savings in the number of patients is achieved by applying a form of screening of
      competing treatments in the initial phase and abandoning those that are ineffective before
      the end of the study following pre-established premises of futility. Effect estimates,
      confidence intervals and p values need some statistical adjustments to allow for this,
      otherwise they will be biased towards a benefit of the treatment. This study design, starting
      with a phase II, could give us a treatment regimen composed of one or more repurposed
      antivirals drugs that could improve the clinical outcomes of those hospitalized with COVID-19
      reducing time to recovery and the need for respiratory support. It will be conducted in about
      60 Brazilian hospitals.

      Selection of drugs rationale

        -  Atazanavir: Atazanavir is a potent inhibitor of HIV-1 protease and is not associated
           with significant dyslipidemia, as observed with other protease inhibitors.15 It was
           approved by the FDA on January 29, 201516,17 as a combination of atazanavir and
           cobicistat. Atazanavir can also be combined with ritonavir18 In a protease-free cell
           assay, atazanavir blocked the major protease activity of SARS-Cov-2 at a concentration
           of 10 μM. In in vitro models of viral infection/replication performed on Vero cells, a
           human pulmonary epithelial cell line and primary human monocytes, atazanavir inhibited
           SARS-CoV-2 replication; in addition, the concentrations of interleukin 6 (IL-6) and
           tumor necrosis factor type alpha (TNF-α) induced by the virus were reduced.10 Currently,
           no clinical study is registered on the ClinicalTrials.com website to assess the effects
           of atazanavir in the context of COVID-19.

        -  Daclastavir: Daclatasvir is a direct-acting antiviral that inhibits HCV replication by
           binding to the N- terminal of the NS5A protein, affecting viral RNA replication. NS5A is
           a multifunctional protein in the HCV replicative cycle, involved in the enrollment of
           cell lipid bodies, RNA binding and replication, protein phosphorylation, cell signaling
           and antagonism of interferon pathways.19 In an in vitro study, daclatasvir consistently
           inhibited the production of SARS-CoV-2 infectious particles in Vero cells, in the HuH-7
           cell line and in Calu-3 cells, with potencies of 0.8, 0.6 and 1.1 μM, respectively.
           Daclatasvir reached early events during the replication cycle of SARS-CoV-2 and
           prevented the induction of IL-6 and TNF-α, inflammatory mediators associated with the
           cytokine storm typical of SARS-CoV-2 infection.20

        -  Sofosbuvir/daclastavir:

      Sofosbuvir (SOVALDI®) is a nucleotide analog directed against HCV NS5B polymerase, clinically
      approved with potent antiviral effects on the hepatitis C virus with several genotypes21. It
      is proposed that the drug could be a potential option in the treatment of COVID-19 especially
      at the beginning of the disease and before the invasion of the virus in the cells of the lung
      parenchyma, based on the similarity between the replication mechanisms of HCV and
      coronavirus22. In vitro, sofosbuvir showed EC50 values of 6.2 and 9.5 µM in HuH-7 (hepatoma)
      and Calu-3 (type II pneumocytes) cells respectively, although inactive in Vero cells (these
      cells are unable to make this conversion sofosbuvir in the pro-drug to active form)11.

      First stage - will have 6 arms with total treatment for 10 days:

      First stage Phase II - 6 arms

        1. Atazanavir (ATV)

        2. Daclatasvir (DCV)

        3. Sofusbuvir+Daclatasvir (SFV/DCV)

      6. Placebo (PbO) ATV 7. (PbO) DCV 8. (PbO) SFV/DCV

      Second stage Phase II - 4 arms:

        1. Best from first stage

        2. Best from first stage + Second best

        3. PbO Best from first stage;

        4. PbO Best from first stage + Pbo Second best

      Phase III - 2 arms:

        1. Best from phase II second stage

        2. (PbO) Best from phase 2 second stage

      Main questions: The aim of the Coalition IX REVOLUTIOn evaluation is to answer the following
      questions:

        -  Are antiviral candidates (atazavir, daclatasvir/sofosbuvir) able to reduce the viral
           load of SARS-CoV-2 compared to placebo in patients hospitalized with COVID-19 with ≤ 9
           days of symptoms?

        -  Which antiviral alone has the best effect in reducing the viral load of SARS-CoV-2 in
           patients hospitalized with COVID-19 with ≤ 9 days of symptoms? And which is the second
           most effective?

        -  Are combined antiviral candidates able to reduce the viral load of SARS-CoV-2 compared
           to antiviral alone and placebo in patients hospitalized with COVID-19 with ≤ 9 days of
           symptoms?

        -  Are isolated or combined antiviral candidates safe compared to placebo?

        -  Does the antiviral candidate alone or in combination improve clinical outcomes (days
           free of respiratory support in 15 days) compared with placebo in patients hospitalized
           with COVID-19 with ≤ 9 days of symptoms?

      Primary/secondary objectives Primary objectives Phase II/ 1st and 2nd stages: Assess the
      effect of treatment with antivirals alone or combined with each other compared to placebo in
      reducing the of viral load of SARS-CoV-2 in nasopharyngeal swab samples obtained at baseline
      (d0) and days 3, 6 and 10; Phase III: Evaluate the effectiveness of best antivirals from
      Phase II alone or combined compared to placebo in increasing days free of respiratory support
      defined as the number of days without oxygen, non-invasive ventilation / high-flow nasal
      cannula or mechanical ventilation in 15 days.

      Secondary Objectives

        1. Ordinal 7-stage scale for clinical outcomes on the 15th day (1. not hospitalized with
           resumption of normal activities; 2. not hospitalized, but unable to resume normal
           activities; 3. hospitalized, without the need for supplemental oxygen; 4. hospitalized ,
           requiring supplemental oxygen; 5. hospitalized, requiring high-flow nasal oxygen
           therapy, non-invasive mechanical ventilation or both; 6. hospitalized, requiring blood
           oxygenation through the membrane system, invasive mechanical ventilation or both; 7.
           Death);

        2. Ordinal 6-stage scale for clinical outcomes on day 7 1. not hospitalized; 2.
           hospitalized, without the need for supplemental oxygen; 3. hospitalized, requiring
           supplemental oxygen; 4. hospitalized, requiring high-flow nasal oxygen therapy,
           non-invasive mechanical ventilation, or both; 5. hospitalized, requiring blood
           oxygenation through a membrane system, invasive mechanical ventilation or both; 6.
           Death;

        3. Mortality in 28 days

        4. Days free from mechanical ventilation within 28 days;

        5. Days out of hospital within 28 days;

        6. Time to discharge, defined as the number of days from randomization to discharge, within
           28 days

        7. Evaluate free days of respiratory support in 15 days for Phase II/1 and II/2

        8. Grade 2, 3 or 4 adverse events that was not present at patient's admission, defined by
           the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric
           Adverse Events (corrected version 2.1, July, 2017); 53

        9. Evaluate Serious adverse events (SAE);

       10. Evaluate discontinuation of study drug-related treatment.

      Recruitment and enrollment: The randomization list will be generated electronically using
      appropriate software. Randomization will be performed in blocks and stratified by center. The
      allocation concealment will be maintained through a centralized, automated, internet-based
      randomization system, available 24 hours a day. Hospitalized patients with the inclusion
      criteria will be allocated in an allocation ratio 3: 3: 3: 1: 1: 1 (3 for each treatment
      group and 1 for placebo) in Phase II / 1. The parameter of interest for the efficacy decision
      will be the comparison of the decay rates (slope) of the viral load logarithm from RT-PCR to
      COVID-19 in 10 days between the treatment groups in comparison with the control (placebo). In
      the 2nd stage, we will allocate patients in the ratio 2: 2: 1: 1 (2 for each active arm and 1
      for each placebo) and the same statistic, now comparing combined treatment against the
      treatment selected in phase II / 1 and placebo, since it is already known that the treatment
      of phase II / 1 is effective for reducing viral load according to the pre specified criteria.
      As long as we have success on primary outcome of Phase II/2, Phase III will proceed in a 2: 1
      allocation ratio (2 active treatments for each placebo).

      Blinding:This is a double-blind study for participants of the same active drug and
      researchers. Both participant and investigator can know, after randomization, which
      medication they were allocated to. However, none will know whether the capsule to be
      administered is active or placebo, ensuring blinding within that specific group to which the
      participant was allocated.

      Sample size and analysis: 252 patients in total in phase II first stage (189 in active groups
      and 63 in placebo) and 189 patients in total in phase II second stage (126 in active groups
      and 63 in placebo). In case of success in Phase II, 564 additional participants will be
      recruited in phase 3 (376 in the active group and 188 in the placebo). Thus, at the end of
      phase III, we will have 314 patients evaluated in the Placebo group and between 439 and 502
      patients in the treatment group.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Randomized, multicenter, multi-arm, multi-stage, study. Adults, COVID-19 confirmed by reverse-transcriptase-polymerase-chain-reaction (RT-PCR) or SARS-Cov2 Antigen hospitalized patients with ≤ 9 days duration of symptoms and SpO2<=94% will be randomly assigned to receive antivirals with potential effectiveness for SARS-CoV-2.
The study is planned to be an adaptive phase II / III study. The phase II will be divided into 2 stages: first and second stages. First stage will allocate patients into a 3:3:3:1:1:1 allocation ratio (5 for each treatment group and 1 for placebo) and second stage will allocate into 2:2:1:1 (2 for each treatment group and 1 for placebo). The phase 3 study will then proceed in a 2:1 allocation (2 treatments for each placebo).
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: This is a double-blind study for participants of the same active drug and researchers. Both participant and investigator can know, after randomization, which medication they were allocated to. However, none will know whether the capsule to be administered is active or placebo, ensuring blinding within that specific group to which the participant was allocated.
measure: Phase II first step: Change in the slope of SARS-COV 2 viral load
time frame: days 3, 6 and 10 after randomization
description: Change in the slope of the SARS-COV 2 log viral load evaluated by nasopharyngeal swab samples assessed at baseline and days 3, 6 and 10 after randomization (isolated antiviral).
measure: Phase II second step: Change in the slope of SARS-COV 2 viral load
time frame: days 3, 6 and 10 after randomization
description: Change in the slope of the SARS-COV 2 log viral load curve evaluated by nasopharyngeal swab samples assessed at baseline and days 3, 6 and 10 after randomization (combined antiviral).
measure: Phase III: Number of free days from respiratory support
time frame: 15 days
description: Number of days without oxygen, non-invasive ventilation/high flow nasal cannula or need for mechanical ventilation in 15 days.
arm group label: Atazanavir
arm group type: Experimental
description: 600 mg (2 capsules) twice daily on the first day and 300 mg (1 capsule) twice daily for the subsequent 9 days.
arm group label: Daclatasvir 60 mg
arm group type: Experimental
description: initial dose of 120mg (2 capsules), followed by 60mg (1 capsule) once daily for 9 days.
arm group label: Sofusbuvir + Daclatasvir 60 mg
arm group type: Experimental
description: 400 mg twice daily (2 capsules) on the first day and 400 mg (1 capsules) once daily for the subsequent 9 days (sofosbuvir) + initial dose of 120mg (2 capsules), followed by 60mg (1 capsule) once a day for 9 days (daclastavir)
arm group label: Placebo Atazanavir
arm group type: Placebo Comparator
description: 2 capsules twice daily on the first day and 1 capsule twice daily for the subsequent 9 days.
arm group label: Placebo Daclatasvir
arm group type: Placebo Comparator
description: 2 capsules twice daily on the first day and 1 capsule twice daily for the subsequent 9 days.
arm group label: Placebo Sofusbuvir + Daclatasvir
arm group type: Placebo Comparator
description: 2 capsules twice daily on the first day and 1 capsule twice daily for the subsequent 9 days.
intervention type: Drug
intervention name: Atazanavir
description: 600 mg (2 capsules) twice daily on the first day and 300 mg (1 capsule) twice daily for the subsequent 9 days.
arm group label: Atazanavir
other name: Active Group
intervention type: Drug
intervention name: Daclatasvir 60 mg
description: initial dose of 120mg (2 capsules), followed by 60mg (1 capsule) once daily for 9 days.
arm group label: Daclatasvir 60 mg
other name: Active Group
intervention type: Drug
intervention name: Sofusbuvir + Daclastavir 60 mg
description: 400 mg twice daily (2 capsules) on the first day and 400 mg (1 capsules) once daily for the subsequent 9 days (sofusbuvir) + initial dose of 120mg (2 capsules), followed by 60mg (1 capsule) once a day for 9 days (daclastavir)
arm group label: Sofusbuvir + Daclatasvir 60 mg
other name: Active Group
intervention type: Drug
intervention name: Placebo Atazanavir
description: 2 capsules twice daily on the first day and 1 capsule twice daily for the subsequent 9 days.
arm group label: Placebo Atazanavir
other name: Placebo group
intervention type: Drug
intervention name: Placebo Daclatasvir 60 mg
description: 2 capsules twice daily on the first day and 1 capsule twice daily for the subsequent 9 days.
arm group label: Placebo Daclatasvir
other name: Placebo group
intervention type: Drug
intervention name: Placebo Sofusbuvir + Daclatasvir 60 mg
description: 2 capsules twice daily on the first day and 1 capsule twice daily for the subsequent 9 days.
arm group label: Placebo Sofusbuvir + Daclatasvir
arm group label: Sofusbuvir + Daclatasvir 60 mg
other name: Placebo group
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: Israel S Maia, MSc
role: Principal Investigator
affiliation: HCor Research Institute
facility: 
country: Brazil
responsible party type: Sponsor
mesh term: COVID-19
mesh term: Atazanavir Sulfate