xml: <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/NCT05965726</url>
    </required_header>
    <id_info>
      <org_study_id>Pro00111697_A</org_study_id>
      <secondary_id>OTA-21-015G</secondary_id>
      <nct_id>NCT05965726</nct_id>
    </id_info>
    <brief_title>RECOVER-VITAL: Platform Protocol, Appendix to Measure the Effects of Paxlovid on Long COVID Symptoms</brief_title>
    <acronym>RECOVER-VITAL</acronym>
    <official_title>RECOVER-VITAL: A Platform Protocol for Evaluation of Interventions for Viral Persistence, Viral Reactivation, and Immune Dysregulation in Post-Acute Sequelae of SARS-CoV-2 Infection (PASC)</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Kanecia Obie Zimmerman</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Duke University</source>
    <oversight_info>
      <has_dmc>Yes</has_dmc>
      <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        This is an appendix of master protocol (NCT05595369) designed to be flexible so that it is&#xD;
        suitable for a wide range of settings within health care systems and in community settings&#xD;
        where it can be integrated into COVID-19 programs and subsequent treatment plans. This&#xD;
        sub-study is a prospective, multi-center, double-blind, randomized, controlled trial&#xD;
        evaluating nirmatrelvir/ritonavir (Paxlovid) in two dosing durations for the treatment of&#xD;
        Post-Acute Sequelae of SARS-CoV-2 Infection (PASC). The study is evaluating potential&#xD;
        mechanisms of action, efficacy, and safety of antivirals and other therapeutics in&#xD;
        individuals with PASC, according to the platform protocol objectives. The hypothesis is that&#xD;
        persistent viral infection and/or overactive/chronic immune response and inflammation are&#xD;
        underlying contributors to PASC and that antiviral and other applicable therapies may result&#xD;
        in viral clearance or decreased inflammation and improvement in PASC symptoms.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        For this appendix of the master protocol (NCT05595369), participants will be randomized to&#xD;
        Paxlovid (nirmatrelvir/ritonavir) vs. ritonavir control plus nirmatrelvir-matching placebo.&#xD;
  &#xD;
        When there are multiple study interventions (sub-studies) available under the master protocol&#xD;
        (NCT05595369), randomization will occur based on the specific inclusion/exclusion criteria of&#xD;
        each appendix.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Enrolling by invitation</overall_status>
    <start_date type="Actual">July 26, 2023</start_date>
    <completion_date type="Anticipated">July 2024</completion_date>
    <primary_completion_date type="Anticipated">April 2024</primary_completion_date>
    <phase>Phase 2</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <intervention_model_description>As part of screening, potential participants will answer symptom questions. Eligible participants will then complete relevant Symptom Cluster assessments at the Baseline visit. Participants will subsequently be assigned to one or more of the three Symptom Clusters based on the baseline assessments. Participants must meet certain criteria within a specific symptom cluster in order to be included in the cluster. After study enrollment and initial cluster assignment, further assessments will be performed. Participants will undergo assessments for all of the symptom clusters for which the the participants qualify.</intervention_model_description>
      <primary_purpose>Treatment</primary_purpose>
      <masking>Triple (Participant, Care Provider, Investigator)</masking>
      <masking_description>Double-blind</masking_description>
    </study_design_info>
    <primary_outcome>
      <measure>Change in cognitive dysfunction symptom cluster, as measured by Patient-Reported Outcomes Measurement Information System (PROMIS) cognitive function T-score</measure>
      <time_frame>Baseline to Day 90</time_frame>
      <description>The PROMIS cognitive function-8a (PRO assessment) T-score is a quantitative measure of current cognitive function.&#xD;
  The primary endpoint for cognitive dysfunction is improvement of at least 5 T-score points on the PROMIS-cognitive function as measured at 90 days compared to baseline.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Change in autonomic dysfunction symptom cluster, as measured by the orthostatic hypotension questionnaire (OHQ)</measure>
      <time_frame>Baseline to Day 90</time_frame>
      <description>The OHQ [Orthostatic Hypotension Questionnaire [PRO assessment)] is a measure of orthostatic intolerance, which has been the primary presentation of patients with PASC-related autonomic dysfunction. This measure includes the Orthostatic Intolerance Daily Activity Scale (OIDAS) and the Orthostatic Intolerance Symptom Assessment (OISA).&#xD;
  The primary endpoint for autonomic dysfunction is improvement in autonomic function as defined by a ≥ 1-point decrease in the OHQ question 1 at 90 days compared to baseline.</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Change in exercise intolerance symptom cluster, as measured by the Modified Depaul Symptom Questionnaire-Post Exertional Malaise (DSQ-PEM)</measure>
      <time_frame>Baseline to Day 90</time_frame>
      <description>DSQ-PEM assesses symptom frequency and severity over a 6-month look back period, however, for the purposes of this study, it will be modified to assess over a 1-week look back period. Frequency is rated on a 5-point Likert scale: 0 = none of the time, 1 = a little of the time, 2 = about half the time, 3 = most of the time, and 4 = all of the time. Severity is also rated on a 5-point Likert scale: 0 = symptom not present, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe.&#xD;
  For exercise intolerance, the primary endpoint is improvement in PEM, defined as having no symptoms of moderate or greater severity with 50% or more frequency as determined by the DSQ-PEM short form at day 90.</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Change in cognitive dysfunction symptom cluster, as measured by a neurocognitive battery</measure>
      <time_frame>Baseline to Day 90</time_frame>
      <description>The neurocognitive battery outcome is a binary indicator of whether the participant has evidence of deficits (at least one standard deviation below the mean on at least one test within the battery).</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in autonomic dysfunction symptom cluster, as measured by the active stand test</measure>
      <time_frame>Baseline to Day 90</time_frame>
      <description>The active stand test outcome is a binary indicator of whether the follow-up active stand test result was abnormal or normal.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Change in exercise intolerance symptom cluster, as measured by the endurance shuttle walk test (ESWT)</measure>
      <time_frame>Baseline to Day 90</time_frame>
      <description>The ESWT [endurance shuttle walk test (performance measure)] consists of timed walking on a 10m course.The ESWT will primarily be analyzed as a binary endpoint defined as an increase of at least 3 minutes of walking time at follow-up compared to baseline.</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Occurrence of individual SAEs</measure>
      <time_frame>Baseline to Day 90</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Occurrence of one or more SAEs</measure>
      <time_frame>Baseline to Day 90</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Occurrence of AEs and SAEs leading to discontinuation</measure>
      <time_frame>Baseline to Day 90</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Occurrence of Events of Special Interest (ESIs)</measure>
      <time_frame>Baseline to Day 90</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Duration of ESIs</measure>
      <time_frame>Baseline to Day 90</time_frame>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Adherence in intervention versus control groups as measured by number of missed doses</measure>
      <time_frame>Baseline to Day 90</time_frame>
    </secondary_outcome>
    <number_of_arms>3</number_of_arms>
    <enrollment type="Anticipated">900</enrollment>
    <condition>Long COVID-19</condition>
    <condition>Long COVID</condition>
    <arm_group>
      <arm_group_label>Paxlovid 25 day dosing</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Paxlovid (nirmatrelvir 300mg, ritonavir 100mg) bid x 25 days</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Paxlovid 15 day dosing</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Paxlovid (nirmatrelvir 300mg, ritonavir 100mg) bid x 15 days then ritonavir 100mg plus nirmatrelvir-matching placebo x 10 days</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Control</arm_group_label>
      <arm_group_type>Placebo Comparator</arm_group_type>
      <description>ritonavir 100mg plus nirmatrelvir-matching placebo bid x 25 days</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Paxlovid 25 day dosing</intervention_name>
      <description>nirmatrelvir 300mg and ritonavir 100mg taken bid for 30 days</description>
      <arm_group_label>Paxlovid 25 day dosing</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Paxlovid 15 day dosing</intervention_name>
      <description>nirmatrelvir 300mg and ritonavir 100mg taken bid for 15 days then ritonavir 100mg taken bid plus nirmatrelvir matching placebo bid for 15 days</description>
      <arm_group_label>Paxlovid 15 day dosing</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Control</intervention_name>
      <description>ritonavir 100mg taken bid plus nirmatrelvir matching placebo bid for 30 days</description>
      <arm_group_label>Control</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          See NCT NCT05595369 for RECOVER-VITAL: Platform Protocol level exclusion criteria which&#xD;
          applies to this appendix&#xD;
  &#xD;
          Additional Appendix Level Exclusion Criteria:&#xD;
  &#xD;
            1. Known pregnancy*&#xD;
  &#xD;
            2. Active or expected breastfeeding during the study&#xD;
  &#xD;
            3. Known eGFR &lt; 30 mL/min&#xD;
  &#xD;
            4. Known severe hepatic impairment (Child-Pugh Class C)&#xD;
  &#xD;
            5. Current use of drugs highly dependent on CYP3A for clearance** and for which elevated&#xD;
               concentrations are associated with serious and/or life-threatening reactions and which&#xD;
               cannot be interrupted during the time of study administration and within seven days&#xD;
               before and after study drug administration&#xD;
  &#xD;
            6. Current use of potent CYP3A inducers** where significantly reduced nirmatrelvir or&#xD;
               ritonavir plasma concentrations may be associated with the potential for loss of&#xD;
               virologic response and possible resistance&#xD;
  &#xD;
                 -  A pregnancy test must be performed at the Baseline Visit for participants who are&#xD;
                    capable of becoming pregnant.&#xD;
  &#xD;
                      -  A guide of drugs that may be contraindicated are listed in Section 4&#xD;
                         CONTRAINDICATIONS of the Full Prescribing Information of the EUA for&#xD;
                         PAXLOVID. https://labeling.pfizer.com/ShowLabeling.aspx?id=16474&amp;format=pdf&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>N/A</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <location>
      <facility>
        <name>Jadestone Clinical Research, LLC</name>
        <address>
          <city>Silver Spring</city>
          <state>Maryland</state>
          <zip>20904</zip>
          <country>United States</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>Brigham and Womens Hospital</name>
        <address>
          <city>Boston</city>
          <state>Massachusetts</state>
          <zip>02115</zip>
          <country>United States</country>
        </address>
      </facility>
    </location>
    <location>
      <facility>
        <name>West Virginia Clinical and Translational Science Institute</name>
        <address>
          <city>Morgantown</city>
          <state>West Virginia</state>
          <zip>26506</zip>
          <country>United States</country>
        </address>
      </facility>
    </location>
    <location_countries>
      <country>United States</country>
    </location_countries>
    <verification_date>September 2023</verification_date>
    <study_first_submitted>July 25, 2023</study_first_submitted>
    <study_first_submitted_qc>July 25, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">July 28, 2023</study_first_posted>
    <last_update_submitted>September 6, 2023</last_update_submitted>
    <last_update_submitted_qc>September 6, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">September 7, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Sponsor-Investigator</responsible_party_type>
      <investigator_affiliation>Duke University</investigator_affiliation>
      <investigator_full_name>Kanecia Obie Zimmerman</investigator_full_name>
      <investigator_title>Associate Professor of Pediatrics</investigator_title>
    </responsible_party>
    <keyword>PASC</keyword>
    <keyword>Paxlovid</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Post-Acute COVID-19 Syndrome</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Nirmatrelvir and ritonavir drug combination</mesh_term>
    </intervention_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
      <ipd_description>The investigators will share the summary of results on the study website: https:// recovercovid.org/</ipd_description>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT05965726
  org study id: Pro00111697_A
  secondary id: OTA-21-015G
  nct id: NCT05965726
  lead sponsor: 
  has dmc: Yes
  is fda regulated drug: Yes
  is fda regulated device: No
  This is an appendix of master protocol (NCT05595369) designed to be flexible so that it is
        suitable for a wide range of settings within health care systems and in community settings
        where it can be integrated into COVID-19 programs and subsequent treatment plans. This
        sub-study is a prospective, multi-center, double-blind, randomized, controlled trial
        evaluating nirmatrelvir/ritonavir (Paxlovid) in two dosing durations for the treatment of
        Post-Acute Sequelae of SARS-CoV-2 Infection (PASC). The study is evaluating potential
        mechanisms of action, efficacy, and safety of antivirals and other therapeutics in
        individuals with PASC, according to the platform protocol objectives. The hypothesis is that
        persistent viral infection and/or overactive/chronic immune response and inflammation are
        underlying contributors to PASC and that antiviral and other applicable therapies may result
        in viral clearance or decreased inflammation and improvement in PASC symptoms.
  For this appendix of the master protocol (NCT05595369), participants will be randomized to
        Paxlovid (nirmatrelvir/ritonavir) vs. ritonavir control plus nirmatrelvir-matching placebo.
  
        When there are multiple study interventions (sub-studies) available under the master protocol
        (NCT05595369), randomization will occur based on the specific inclusion/exclusion criteria of
        each appendix.
  allocation: Randomized
  intervention model: Parallel Assignment
  intervention model description: As part of screening, potential participants will answer symptom questions. Eligible participants will then complete relevant Symptom Cluster assessments at the Baseline visit. Participants will subsequently be assigned to one or more of the three Symptom Clusters based on the baseline assessments. Participants must meet certain criteria within a specific symptom cluster in order to be included in the cluster. After study enrollment and initial cluster assignment, further assessments will be performed. Participants will undergo assessments for all of the symptom clusters for which the the participants qualify.
  primary purpose: Treatment
  masking: Triple (Participant, Care Provider, Investigator)
  masking description: Double-blind
  measure: Change in cognitive dysfunction symptom cluster, as measured by Patient-Reported Outcomes Measurement Information System (PROMIS) cognitive function T-score
  time frame: Baseline to Day 90
  description: The PROMIS cognitive function-8a (PRO assessment) T-score is a quantitative measure of current cognitive function.
  The primary endpoint for cognitive dysfunction is improvement of at least 5 T-score points on the PROMIS-cognitive function as measured at 90 days compared to baseline.
  measure: Change in autonomic dysfunction symptom cluster, as measured by the orthostatic hypotension questionnaire (OHQ)
  time frame: Baseline to Day 90
  description: The OHQ [Orthostatic Hypotension Questionnaire [PRO assessment)] is a measure of orthostatic intolerance, which has been the primary presentation of patients with PASC-related autonomic dysfunction. This measure includes the Orthostatic Intolerance Daily Activity Scale (OIDAS) and the Orthostatic Intolerance Symptom Assessment (OISA).
  The primary endpoint for autonomic dysfunction is improvement in autonomic function as defined by a ≥ 1-point decrease in the OHQ question 1 at 90 days compared to baseline.
  measure: Change in exercise intolerance symptom cluster, as measured by the Modified Depaul Symptom Questionnaire-Post Exertional Malaise (DSQ-PEM)
  time frame: Baseline to Day 90
  description: DSQ-PEM assesses symptom frequency and severity over a 6-month look back period, however, for the purposes of this study, it will be modified to assess over a 1-week look back period. Frequency is rated on a 5-point Likert scale: 0 = none of the time, 1 = a little of the time, 2 = about half the time, 3 = most of the time, and 4 = all of the time. Severity is also rated on a 5-point Likert scale: 0 = symptom not present, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe.
  For exercise intolerance, the primary endpoint is improvement in PEM, defined as having no symptoms of moderate or greater severity with 50% or more frequency as determined by the DSQ-PEM short form at day 90.
  measure: Change in cognitive dysfunction symptom cluster, as measured by a neurocognitive battery
  time frame: Baseline to Day 90
  description: The neurocognitive battery outcome is a binary indicator of whether the participant has evidence of deficits (at least one standard deviation below the mean on at least one test within the battery).
  measure: Change in autonomic dysfunction symptom cluster, as measured by the active stand test
  time frame: Baseline to Day 90
  description: The active stand test outcome is a binary indicator of whether the follow-up active stand test result was abnormal or normal.
  measure: Change in exercise intolerance symptom cluster, as measured by the endurance shuttle walk test (ESWT)
  time frame: Baseline to Day 90
  description: The ESWT [endurance shuttle walk test (performance measure)] consists of timed walking on a 10m course.The ESWT will primarily be analyzed as a binary endpoint defined as an increase of at least 3 minutes of walking time at follow-up compared to baseline.
  measure: Occurrence of individual SAEs
  time frame: Baseline to Day 90
  measure: Occurrence of one or more SAEs
  time frame: Baseline to Day 90
  measure: Occurrence of AEs and SAEs leading to discontinuation
  time frame: Baseline to Day 90
  measure: Occurrence of Events of Special Interest (ESIs)
  time frame: Baseline to Day 90
  measure: Duration of ESIs
  time frame: Baseline to Day 90
  measure: Adherence in intervention versus control groups as measured by number of missed doses
  time frame: Baseline to Day 90
  arm group label: Paxlovid 25 day dosing
  arm group type: Experimental
  description: Paxlovid (nirmatrelvir 300mg, ritonavir 100mg) bid x 25 days
  arm group label: Paxlovid 15 day dosing
  arm group type: Experimental
  description: Paxlovid (nirmatrelvir 300mg, ritonavir 100mg) bid x 15 days then ritonavir 100mg plus nirmatrelvir-matching placebo x 10 days
  arm group label: Control
  arm group type: Placebo Comparator
  description: ritonavir 100mg plus nirmatrelvir-matching placebo bid x 25 days
  intervention type: Drug
  intervention name: Paxlovid 25 day dosing
  description: nirmatrelvir 300mg and ritonavir 100mg taken bid for 30 days
  arm group label: Paxlovid 25 day dosing
  intervention type: Drug
  intervention name: Paxlovid 15 day dosing
  description: nirmatrelvir 300mg and ritonavir 100mg taken bid for 15 days then ritonavir 100mg taken bid plus nirmatrelvir matching placebo bid for 15 days
  arm group label: Paxlovid 15 day dosing
  intervention type: Drug
  intervention name: Control
  description: ritonavir 100mg taken bid plus nirmatrelvir matching placebo bid for 30 days
  arm group label: Control
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  facility: 
  facility: 
  facility: 
  country: United States
  responsible party type: Sponsor-Investigator
  investigator affiliation: Duke University
  investigator full name: Kanecia Obie Zimmerman
  investigator title: Associate Professor of Pediatrics
  mesh term: Post-Acute COVID-19 Syndrome
  mesh term: Nirmatrelvir and ritonavir drug combination
  sharing ipd: No
  ipd description: The investigators will share the summary of results on the study website: https:// recovercovid.org/