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A Trial to Evaluate Safety and Efficacy of Rivaroxaban (COVID-19)

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ClinicalTrials.gov Identifier: NCT04504032
Recruitment Status : Terminated (Based on Data Monitoring Committee''s recommendation on 3 February 2021, the study was stopped on 4 February 2021 due to futility.)
First Posted : August 7, 2020
Results First Posted : October 22, 2021
Last Update Posted : October 22, 2021
Sponsor:
Information provided by (Responsible Party):
Bill & Melinda Gates Medical Research Institute

Tracking Information
First Submitted Date  ICMJE August 5, 2020
First Posted Date  ICMJE August 7, 2020
Results First Submitted Date  ICMJE September 29, 2021
Results First Posted Date  ICMJE October 22, 2021
Last Update Posted Date October 22, 2021
Actual Study Start Date  ICMJE September 2, 2020
Actual Primary Completion Date March 10, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 29, 2021)
  • Number of Participants With Grade 3 and Grade 4 Adverse Events (AEs) Through Day 35 [ Time Frame: Up to Day 35 ]
    An AE is any untoward medical occurrence that occurs in a participant. An AE can be any unfavorable and unintended sign (including abnormal laboratory findings), symptom, or disease temporally associated with treatment, whether considered related to the product. AEs may include the onset of a new illness or undesirable medical condition or the exacerbation of pre-existing medical conditions. AE severity was graded as Grade 3 (Severe) and Grade 4 (Potentially Life-threatening) per the specific toxicity grading by the Division of Acquired Immunodeficiency Syndrome (DAIDS) AE Grading Table.
  • Number of Participants With AEs Resulting in Study Intervention Discontinuation Through Day 35 [ Time Frame: Up to Day 35 ]
    An AE is any untoward medical occurrence that occurs in a participant. An AE can be any unfavorable and unintended sign (including abnormal laboratory findings), symptom, or disease temporally associated with treatment, whether considered related to the product. AEs may include the onset of new illness or undesirable medical condition or the exacerbation of pre-existing medical conditions.
  • Number of Participants With Serious Adverse Events Through Day 35 [ Time Frame: Up to Day 35 ]
    A serious AE is any untoward medical occurrence or effect, that, at any dose: results in death; is life-threatening; requires hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; is an important medical event that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the participant or may require intervention to prevent one of the other outcomes.
  • Number of Participants Who Progressed to Moderate or Severe Disease or Higher Based on the Gates MRI Ordinal Scale Through Day 28 [ Time Frame: Up to Day 28 ]
    Participants who progressed to a moderate or severe disease category or higher (Bill & Melinda Gates Medical Research Institute [Gates MRI] ordinal scale ≥3) are reported. Gates MRI scale scores are assessed on a 7-point scale: 1=Asymptomatic/symptoms similar to pre-COVID-19 status; 2=Mild; 3=Moderate or severe; 4=Critically ill; 5=Critically ill with invasive mechanical ventilation or extrapulmonary complication; 6=Critically ill with Extra-Corporeal Membrane Oxygenation (ECMO); 7=Death.
Original Primary Outcome Measures  ICMJE
 (submitted: August 5, 2020)
  • Number of Participants With Grade 3 or Grade 4 Adverse Events (AEs) [ Time Frame: Up to approximately 35 days ]
  • Number of Participants With AEs Leading to Study Discontinuation [ Time Frame: Up to approximately 35 days ]
  • Number of Participants With Serious Adverse Events (SAEs) [ Time Frame: Up to approximately 35 days ]
  • Proportion of Participants With Disease Progression [ Time Frame: Up to Day 28 ]
    Disease progression is defined as the proportion of participants who progress to moderate or severe disease category or higher (Gates Medical Research Institute ordinal scale ≥3). The assessments will be performed using Gates Medical Research Institute ordinal scale.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 29, 2021)
  • Median Time to Disease Resolution Based on Symptoms Resolution Through Day 28 [ Time Frame: Up to Day 28 ]
    Time to disease resolution is defined as the time from the first dose to the date of symptoms resolution (new-onset Coronavirus Disease 2019 [COVID-19] symptoms resolved, and pre-existing symptoms returned to Baseline) through Day 28. Baseline refers to health status prior to contracting new-onset COVID-19 symptoms. The 95% confidence interval (CI) for median and quartiles of time to disease resolution were calculated using the Kaplan Meier estimates.
  • Median Time to Disease Resolution Based on Viral Clearance and Symptoms Resolution Through Day 28 [ Time Frame: Up to Day 28 ]
    Time to disease resolution is defined as the time from the first dose to the date of both viral clearance (two consecutive negative diagnostic tests) and symptoms resolution (new-onset COVID-19 symptoms resolved, and pre-existing symptoms returned to Baseline) through Day 28. Baseline refers to health status prior to contracting new-onset COVID-19 symptoms. The 95% CI for median and quartiles of time to disease resolution were calculated using the Kaplan Meier estimates.
  • Number of Participants Who Progressed to Moderate or Severe Disease or Higher Based on the Gates MRI Ordinal Scale at Day 8, 14, and 21 [ Time Frame: Days 8, 14, and 21 ]
    Participants who progressed to a moderate or severe disease category or higher (Gates MRI ordinal scale ≥3) are reported. Gates MRI ordinal scale scores are assessed on a 7-point scale: 1=Asymptomatic/symptoms similar to pre-COVID-19 status; 2=Mild; 3=Moderate or severe; 4=Critically ill; 5=Critically ill with invasive mechanical ventilation or extrapulmonary complication; 6=Critically ill with ECMO; 7=Death.
  • Number of Participants Who Achieved Disease Resolution Based on Symptoms Resolution at Days 8, 14, 21, and 28 [ Time Frame: Days 8, 14, 21, and 28 ]
    Symptoms resolution is defined as new-onset COVID-19 symptoms resolved, and pre-existing symptoms returned to Baseline. Baseline refers to health status prior to contracting new-onset COVID-19 symptoms.
  • Number of Participants Who Achieved Disease Resolution Based on Viral Clearance and Symptoms Resolution at Days 8, 14, 21, and 28 [ Time Frame: Days 8, 14, 21, and 28 ]
    Viral clearance is defined as two consecutive negative diagnostic tests. Symptoms resolution is defined as new-onset COVID-19 symptoms resolved, and pre-existing symptoms returned to Baseline. Baseline refers to health status prior to contracting new-onset COVID-19 symptoms.
  • Number of Participants With the Indicated Gates Medical Research Institute (MRI) Scale Clinical Status at Days 8, 14, 21, and 28 [ Time Frame: Days 8, 14, 21, and 28 ]
    Participants who progressed to a moderate or severe disease category or higher (Gates MRI ordinal scale ≥3) are reported. Gates MRI ordinal scale scores are assessed on a 7-point scale: 1=Asymptomatic/symptoms similar to pre-COVID-19 status; 2=Mild; 3=Moderate or severe; 4=Critically ill; 5=Critically ill with invasive mechanical ventilation or extrapulmonary complication; 6=Critically ill with ECMO; 7=Death.
  • Number of Participants With the Indicated World Health Organization (WHO) Ordinal Scale Clinical Status at Days 8, 14, 21, and 28 [ Time Frame: Days 8, 14, 21, and 28 ]
    The WHO ordinal scale score is used to analyze the overall burden of disease and disease severity using an 11-point scale ranging from 0 to 10: 0=Uninfected; No viral ribonucleic acid (RNA) detected; 1=Asymptomatic; viral RNA detected; 2=Symptomatic; independent; 3=Symptomatic; assistance needed; 4=Hospitalized; no oxygen therapy (for isolation only); 5=Hospitalized; oxygen by mask or nasal prongs; 6=Hospitalized; oxygen by non-invasive ventilation (NIV) or high flow; 7=Intubation and mechanical ventilation, partial pressure of oxygen (pO2)/fraction of inspired oxygen (FiO2) ≥150 or oxygen saturation (SpO2)/FiO2 ≥200; 8=Mechanical ventilation pO2/FiO2 <150 (SpO2/FiO2 <200) or Vasopressors; 9=Mechanical ventilation pO2/FiO2 <150 and vasopressors, dialysis, or ECMO; 10=Dead.
  • Number of Participants With Hospitalization Through Days 8, 14, 21, and 28 [ Time Frame: Days 8, 14, 21, and 28 ]
    Participants who had clinical worsening and who had at least one hospitalization during the study were analyzed.
  • Median Number of Days of Hospitalization Through Day 35 [ Time Frame: Up to Day 35 ]
    Participants who had clinical worsening and who had at least one hospitalization during the study were analyzed. Hospitalized participants without an end date of hospitalization were not included.
  • Shift in Gates Medical Research Institute Ordinal Scale Score at Days 8, 14, 21, and 28 [ Time Frame: Days 8, 14, 21, and 28 ]
    Gates MRI ordinal scale scores are assessed on a 7-point scale: 1=Asymptomatic/symptoms similar to pre-COVID-19 status; 2=Mild; 3=Moderate or severe; 4=Critically ill; 5=Critically ill with invasive mechanical ventilation or extrapulmonary complication; 6=Critically ill with ECMO; 7=Death. BS= Baseline; PBS= Post-Baseline; NA= Data not available.
  • Shift in World Health Organization Ordinal Scale Score at Days 8, 14, 21, and 28 [ Time Frame: Baseline; Days 8, 14, 21, and 28 ]
    The WHO ordinal scale score is used to analyze the overall burden of disease and disease severity using an 11-point scale ranging from 0 to 10: 0=Uninfected; No viral ribonucleic acid (RNA) detected; 1=Asymptomatic; viral RNA detected; 2=Symptomatic; independent; 3=Symptomatic; assistance needed; 4=Hospitalized; no oxygen therapy (for isolation only); 5=Hospitalized; oxygen by mask or nasal prongs; 6=Hospitalized; oxygen by non-invasive ventilation (NIV) or high flow; 7=Intubation and mechanical ventilation, partial pressure of oxygen (pO2)/fraction of inspired oxygen (FiO2) ≥150 or oxygen saturation (SpO2)/FiO2 ≥200; 8=Mechanical ventilation pO2/FiO2 <150 (SpO2/FiO2 <200) or Vasopressors; 9=Mechanical ventilation pO2/FiO2 <150 and vasopressors, dialysis, or ECMO; 10=Dead. BS= Baseline; PBS= Post-Baseline; NA= Data not available.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 5, 2020)
  • Median Time to Disease Resolution [ Time Frame: Up to Day 28 ]
    Time to disease resolution is defined as symptoms resolution (new onset Coronavirus Disease 2019 [COVID-19] symptoms resolved, and pre-existing symptoms returned to baseline) with viral clearance (two consecutive negative diagnostic tests) through Day 28. Baseline refers to health status prior to contracting new onset COVID-19 symptoms.
  • Median Time to Disease Resolution [ Time Frame: Up to Day 28 ]
    Time to disease resolution is defined as symptoms resolution only (new onset COVID-19 symptoms resolved, and preexisting symptoms returned to baseline) through Day 28. Baseline refers to health status prior to contracting new onset COVID-19 symptoms.
  • Proportion of Participants With Disease Progression [ Time Frame: Days 8, 14, and 21 ]
  • Proportion of Participants Who Achieve Disease Resolution [ Time Frame: Days 8, 14, 21, and 28 ]
  • Mean Gates Medical Research Institute Ordinal Scale Score [ Time Frame: Days 8, 14, 21, and 28 ]
  • Change From Baseline in Gates Medical Research Institute Ordinal Scale Score [ Time Frame: Days 8, 14, 21, and 28 ]
  • Mean World Health Organization Ordinal Scale Score [ Time Frame: Days 8, 14, 21, and 28 ]
  • Change From Baseline in World Health Organization Ordinal Scale Score [ Time Frame: Days 8, 14, 21, and 28 ]
  • Incidence of Hospitalization [ Time Frame: Days 8, 14, 21, and 28 ]
  • Number of Days of Hospitalization [ Time Frame: Days 8, 14, 21, and 28 ]
Current Other Pre-specified Outcome Measures
 (submitted: September 29, 2021)
  • Change From Baseline in Gates Medical Research Institute Ordinal Scale Score at Days 8, 14, 21, and 28 [ Time Frame: Baseline; Days 8, 14, 21, and 28 ]
    Gates MRI ordinal scale scores are assessed on a 7-point scale: 1=Asymptomatic/symptoms similar to pre- COVID-19 status; 2=Mild; 3=Moderate or severe; 4=Critically ill; 5=Critically ill with invasive mechanical ventilation or extrapulmonary complication; 6=Critically ill with ECMO; 7=Death. Instead of change from baseline, shift in scores from baseline was measured and have been presented in outcome measure 14.
  • Change From Baseline in World Health Organization Ordinal Scale Score at Days 8, 14, 21, and 28 [ Time Frame: Baseline; Days 8, 14, 21, and 28 ]
    The WHO ordinal scale score is used to analyze the overall burden of disease and disease severity using an 11-point scale ranging from 0 to 10: 0=Uninfected; No viral ribonucleic acid (RNA) detected; 1=Asymptomatic; viral RNA detected; 2=Symptomatic; independent; 3=Symptomatic; assistance needed; 4=Hospitalized; no oxygen therapy (for isolation only); 5=Hospitalized; oxygen by mask or nasal prongs; 6=Hospitalized; oxygen by non-invasive ventilation (NIV) or high flow; 7=Intubation and mechanical ventilation, partial pressure of oxygen (pO2)/fraction of inspired oxygen (FiO2) ≥150 or oxygen saturation (SpO2)/FiO2 ≥200; 8=Mechanical ventilation pO2/FiO2 <150 (SpO2/FiO2 <200) or Vasopressors; 9=Mechanical ventilation pO2/FiO2 <150 and vasopressors, dialysis, or ECMO; 10=Dead. Instead of change from baseline, shift in scores from baseline was measured and have been presented in outcome measure 16.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Trial to Evaluate Safety and Efficacy of Rivaroxaban (COVID-19)
Official Title  ICMJE A Randomized, Controlled, Phase 2b Study to Evaluate Safety and Efficacy of Rivaroxaban (Xarelto®) for High Risk People With Mild COVID-19
Brief Summary The purpose of this study is to assess safety and clinical efficacy of rivaroxaban in people with mild Coronavirus Disease 2019 who are at increased risk of disease progression.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE COVID-19
Intervention  ICMJE
  • Drug: Rivaroxaban
    Participants self-administered rivaroxaban, 10 milligrams (mg) (1 tablet) orally once daily for 21 days.
  • Drug: Placebo
    Participants self-administered rivaroxaban matching placebo orally once daily for 21 days.
Study Arms  ICMJE
  • Experimental: Rivaroxaban
    Intervention: Drug: Rivaroxaban
  • Placebo Comparator: Placebo
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: April 14, 2021)
497
Original Estimated Enrollment  ICMJE
 (submitted: August 5, 2020)
600
Actual Study Completion Date  ICMJE March 29, 2021
Actual Primary Completion Date March 10, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Participants must be at high-risk for Coronavirus disease 2019 (COVID-19) disease progression by fulfilling at least one of the following criteria at screening:

    • Presence of chronic pulmonary disease, chronic obstructive pulmonary disease (COPD), pulmonary hypertension
    • Diabetes mellitus (type 1 or type 2), requiring oral medication or insulin for treatment
    • Hypertension, requiring at least one oral medication for treatment
    • Immunocompromised status due to disease (e.g., those living with human immunodeficiency virus with a cluster of differentiation 4 [CD4] T-cell count of <200 per cubic millimeter [mm^3])
    • Immunocompromised status due to medication (e.g., taking 20 milligram [mg] or more of prednisone equivalents a day, anti-inflammatory monoclonal antibody therapies, cancer therapies)
    • Any chronic disease that is associated with high risk for severe COVID in the opinion of the site investigator
    • Body mass index ≥35 Kilogram per square meter (kg/m^2) (based on self-reported weight and height).
  • Documented Severe Acute Respiratory Syndrome Coronavirus 2 positive diagnostic test of ≤7 days at the time of screening
  • Symptomatic for COVID-19 for ≤72 hours at the time of screening (defined as having at least 2 of the following symptoms of COVID-19 that is of new onset or has worsened from baseline, and include fever, chills, myalgia, arthralgia, headache, fatigue, cough, sore throat, nasal congestion, anosmia, ageusia, nausea, vomiting, or diarrhea. If only two symptoms are present, they cannot both be anosmia and ageusia)
  • Capable of giving informed consent, which includes compliance with the requirements and restrictions listed in the inform consent form and in this protocol
  • Agree to participate in all remote, in-person or home visits as required in the protocol and provide updated contact information as necessary.
  • Female of childbearing potential must agree to practice adequate contraception during the study

Exclusion Criteria:

Participants are excluded from the study if any of the following criteria apply:

  • Currently hospitalized or under immediate consideration for hospitalization at screening and Day 1
  • Have new onset shortness of breath or increased shortness of breath from pre-COVID-19 (for people with known COPD) at screening and Day 1
  • Hypoxemia (oxygen saturation <94% in ambient air or oxygen saturation below pre-COVID-19 level for people with known COPD) at Day 1
  • Require supplemental oxygen (new requirement or increase in requirement from pre-COVID-19 condition) at screening and Day 1
  • Have a history of (in the past 3 months) or current active pathological bleeding
  • Have a history of hemorrhagic stroke or intracranial hemorrhage
  • Have a recent severe head trauma within 30 days which includes concussion, skull fracture or hospitalization for head injury
  • Have known intracranial neoplasm, cerebral metastases, arteriovenous malformation or aneurysm
  • Have history of pregnancy-related hemorrhage
  • Have active gastroduodenal ulcer or other gastrointestinal bleeding diagnosed in the past 3 months
  • Currently are in a hemodynamically unstable state
  • Currently require thrombolysis or pulmonary embolectomy
  • Have history of severe hypersensitivity reaction to Xarelto®
  • Currently have a prosthetic heart valve
  • Have known diagnosis of triple positive antiphospholipid syndrome
  • Have known diagnosis of chronic kidney disease (stage IV or receiving dialysis)
  • Have a history of thrombocytopenia or known platelet count <100,000 cells/mm^3
  • Have history of bronchiectasis and pulmonary cavitation
  • Have active cancer (e.g, receiving chemotherapy or treatment for complication of the active cancer)
  • Had epidural or neuraxial anesthesia or spinal puncture in the past 2 weeks and plan to undergo these procedures during the study
  • Had surgery in the past 4 weeks or plan to undergo surgery during the study
  • Currently is pregnant or plans to become pregnant
  • Currently is breastfeeding
  • Share household with an enrolled participant in this study
  • Co-enrollment in any clinical trial that includes prohibited procedures (spinal puncture or surgery) or that includes treatments within the same drug class as rivaroxaban or treatments for which co-administration with rivaroxaban are prohibited. Note that any co-enrollment other than this requires approval by the Sponsor. For any co-enrolled study, the total volume of blood samples collected across the studies should not exceed 275 milliliters (mL) in 4 weeks.
  • Currently using and plan to use the following medications during the study

    • Rivaroxaban or drugs in the same class
    • Dual anti-platelets therapy
    • Other anticoagulants
    • Combined Permeability glycoprotein (P-gp) and cytochrome P450 3A (CYP3A) inhibitors and inducers
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04504032
Other Study ID Numbers  ICMJE Gates MRI - COD-01-T01-01
2020-005395-35 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Responsible Party Bill & Melinda Gates Medical Research Institute
Study Sponsor  ICMJE Bill & Melinda Gates Medical Research Institute
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: GatesMRI Bill & Melinda Gates Medical Research Institute
PRS Account Bill & Melinda Gates Medical Research Institute
Verification Date October 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP