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Atovaquone for Treatment of COVID-19

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04456153
Recruitment Status : Completed
First Posted : July 2, 2020
Results First Posted : December 14, 2021
Last Update Posted : December 14, 2021
Sponsor:
Information provided by (Responsible Party):
Mamta K. Jain, MD,MPH, University of Texas Southwestern Medical Center

Tracking Information
First Submitted Date  ICMJE June 30, 2020
First Posted Date  ICMJE July 2, 2020
Results First Submitted Date  ICMJE November 10, 2021
Results First Posted Date  ICMJE December 14, 2021
Last Update Posted Date December 14, 2021
Actual Study Start Date  ICMJE July 22, 2020
Actual Primary Completion Date January 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 10, 2021)
Primary Analysis [ Time Frame: Day 1 to Day 10 ]
Between group differences in viral load (Log copy number/ml) using generalized linear mixed-effect models of repeated measures (GLMM), using data from all available samples
Original Primary Outcome Measures  ICMJE
 (submitted: June 30, 2020)
Viral Load [ Time Frame: Up to 16 days ]
Log copy number/ml by RT-PCR) from saliva collection at Day 8 from trial entry, or at hospital discharge
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 12, 2021)
  • Secondary Between Group Differences in Viral Load [ Time Frame: baseline to day7 ]
    Change in viral load at Day 3, 5, and 7 days. This shows the group differences between intervention and placebo and log 10 viral load at specific days 3, 5, and 7 for atovaquone arm and placebo arm.
  • Change in Viral Load at Day 10 Stratified by Sex [ Time Frame: baseline to day 10 ]
    Between group differences in viral load (Log copy number/ml) using GLMM stratified by
  • Percentage With 2 Log Viral Load Drop at Day 3 [ Time Frame: baseline to day 3 ]
    Between group comparison of time to drop in viral load (Log copy number/ml) of 2 log units using Kaplan-Meier estimation. Examined the percentage of participants who achieved this viral load drop in 3 days.
  • Number of Participants With Change in Ordinal Scale ≥2 Points by Day 15. [ Time Frame: Day 15 ]
    Ordinal scale 1 indicated death, and higher scores were various degrees of hospitalizations and incapacity to being out of hospital. Ordinal Scale 1-7 with higher score indicating improvement in clinical status. Change of ≥2 points on the ordinal scale by Day 15 using chi-square analysis
  • Area Under the Curve Copies/ml*Day at Day 7 [ Time Frame: day 7 ]
    This is a alternative method of measurement of area which examines the viral load ( copies/ml )(y-axis) by day (x-axis) using the trapezoidal method. The area under the curve was calculated via the trapezoidal rule. As such, this is a numeric value that is different than the traditional use of the term "mean" or "median." However, in order to calculate a measure of error associated with this quantity, bootstrapping with 500 replications would need to be performed to assess statistical significance or lack thereof. The mean of the bootstrap samples could be reported as the "mean area under the curve."
  • Stratifed by Remdesivir [ Time Frame: day 10 ]
    change in log RNA 10 day 1 to 10 stratified by remdesivir by GLMM
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Atovaquone for Treatment of COVID-19
Official Title  ICMJE Atovaquone for Treatment of COVID-19
Brief Summary

The purpose of the current study is to accelerate the use of a clinically available therapeutic already FDA-approved for other indications in the setting of pandemic COVID-19 addressing a serious and emergent unmet medical need.

This is a randomized, double-blind study of atovaquone therapy in adult participants hospitalized with COVID-19. Approximately 60 participants who meet all eligibility criteria may be randomized in a 2:1 atovaquone/placebo ratio into one of the following treatment groups:

Treatment Group 1: continued standard of care therapy together with an oral dose of 1500 mg atovaquone twice daily (administered with a meal or snack) for up to 10 days

Treatment Group 2: continued standard of care therapy together with matching placebo

Detailed Description

Design of the ATaQ COVID-19 Trial:

The purpose of the current study is to accelerate the use of a clinically available therapeutic already FDA-approved for other indications in the setting of pandemic COVID-19 addressing a serious and emergent unmet medical need. In consideration of the information included in this protocol, the overall risks to participants are outweighed by the potential benefits of atovaquone experimental therapy for the treatment of COVID-19. The benefit-risk balance for this study is considered positive.

Inclusion Criteria:

  1. Diagnosis of COVID-19 by positive RT-PCR requiring hospitalization within 72 hours
  2. Age ≥18 years old
  3. Able to provide informed consent, or (as allowed by IRB), immediate availability of designated legally authorized representative to provide consent by proxy
  4. Anticipated hospitalization for >48 hours

Exclusion Criteria

Patients who meet any of the following exclusion criteria are not to be enrolled in this study:

  1. Participation in any other clinical trial with antiviral activity against COVID-19
  2. Breastfeeding women
  3. Known hypersensitivity to atovaquone or formulation excipient
  4. Active treatment with rifampin
  5. HIV patients with AIDS requiring treatment for Pneumocystis jirovecii or Toxoplasma gondii
  6. Not expected to survive for 72 hours.
  7. >14 days from symptom onset

    Randomization:

    Patients who meet eligibility criteria and volunteer to participate will be randomized in a 2:1 ratio to atovaquone or placebo on Day 1 using computerized randomization. An unblinded investigational pharmacist not otherwise involved in the trial will know treatment assignment and dispense investigational product. As GI absorption of atovaquone increased when taken with food, so we will administer with a meal or snack.

    Blinding:

    Double blinding of treatment assignments will be performed in this study, with the study team and patients blinded to treatment assignment.

    The list of concomitant medications will be assessed only from Day 1 prior to enrollment to Day 15 or discharge, whichever is earlier.

    Patient Enrollment and Treatment Assignment:

    Entry into screening does not guarantee enrollment into the study. In order to manage the total study enrollment, the study researchers may suspend screening and/or enrollment at any at any time.

    Pretreatment Assessments:

    Screening Visit

    Patients will be screened within 2 days before randomization and dosing to determine eligibility for participation in the study. Screening will occur under approved HIPAA waiver for research to identify and screen all hospitalized COVID-19 positive patients on a daily basis.

    Obtain informed consent.

    After informed consent has been negotiated and the form signed, the following assessments will be performed to determine eligibility requirements as specified in the inclusion and exclusion criteria:

    • Review of focused medical history including the following information (e.g., date of first symptoms, overall symptoms, exposure source, demographics, baseline characteristics), allergies and past medical history.
    • Review and record medications and therapies for the current illness
    • Recording of vital signs (heart rate, temperature, blood pressure), body weight, and height
    • Documentation of respiratory support: Respiratory Rate, Oxygen supplementation: room air, nasal canula, face mask, non-rebreather, high-flow device, mechanical ventilation; and FiO2
    • SpO2 at rest or PaO2
    • Radiographic findings

    Study patients who qualify and volunteer to participate should be immediately consented and randomized. Randomization and initiation of dosing should occur on the same day if possible.

    Baseline/Day 1 Assessments

    The following evaluations are to be completed at the Day 1 visit. The investigator must have confirmed eligibility and signing of consent before proceeding with randomization on the Day 1 visit, followed immediately by first dose of investigational product. The assessments can be completed by the patient care team and do not need to be repeated by research personnel. The following assessments must be documented before administering investigational product, using the most recent data available at the time of randomization:

    Recording of vital signs (heart rate, temperature, blood pressure, body weight, height)

    Documentation of respiratory status:

    Respiratory rate

    Oxygen supplementation and FiO2: room air, nasal canula, face mask, non-rebreather, noninvasive ventilation or high flow oxygen devices, mechanical ventilation, or ECMO

    Oxygenation: (SpO2 or PaO2)

    Radiographic findings (if available)

    Review AEs and document concomitant medications

    Document Ordinal Scale at baseline

    Obtain saliva sample and nasopharyngeal swab sample for viral load quantification at day 1 prior to initial dose

    Obtain blood for research sample

    Daily Study Assessments (Days 2-15):

    The following evaluations are to be documented daily from Days 2 - 15 or until discharge whichever comes earlier, using the data recorded at or closest to 12:00 noon each day:

    • Vital signs (heart rate, temperature, blood pressure), body weight (if available).
    • Documentation of respiratory status: Respiratory rate, Oxygen supplementation and FiO2: room air, nasal canula, face mask, non-rebreather, noninvasive ventilation or high flow oxygen devices, mechanical ventilation, or ECMO
    • Oxygenation: (SpO2 or PaO2)
    • Radiographic findings (if available)
    • Review of AEs and document concomitant medications
    • Saliva sample for COVID-19 RT-PCR every 12 hours (Days 2-8)
    • Saliva sample for COVID-19 RT-PCR once daily (Days 9-15)
    • Additional blood draws for biobanking (Day 3, and 5 only)

    Clinical Laboratory Assessments:

    Clinical laboratory assessments will be conducted as clinically indicated and all laboratory testing will be completed by local laboratories. Clinical laboratory data to be captured in the trial database will include serum chemistries, liver function tests, complete blood counts including absolute neutrophil count, hs-CRP, D-dimer, ferritin, IL-6, troponin, NTpBNP.

    SARS-CoV-2 testing will include RT-qPCR to detect or quantify SARS-CoV-2 or virus sequencing results from saliva (baseline and daily until discharge or death, and 8 days and last day of hospitalization or Day 15 if still hospitalized.

    Pretreatment and posttreatment samples with detectable SARS-CoV-2 may be sequenced for resistance monitoring of the viral polymerase gene. For all clinical laboratory tests, except those at Day 1, when more than 1 result is available in a calendar day, the value closest to 12:00 noon should be captured in the eCRF. For Day 1 tests, the most recent result before dosing should be used.

    Physical Examination:

    No physical examination is mandated by the study protocol beyond the capture of vital signs (heart rate, respiratory rate, temperature, blood pressure, SpO2 at rest or PaO2) as documented clinically.

    Post-treatment Assessments:

    Treatment will continue to complete a 10 Day course or until viral clearance is documented, whichever occurs first.

    Telephone call on Day 15 and 29 for those discharged. The phone call will include a brief survey on symptoms and information on any re-hospitalizations.

    Final review of AEs and concomitant medication.

    Vital signs will be captured if still inpatient and the ordinal scale will be assessed.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE COVID-19
Intervention  ICMJE
  • Drug: Experimental Group
    Continued standard of care therapy together with an oral dose of 1500 mg atovaquone twice daily (administered with a meal or snack) for up to 10 days
    Other Name: Atovaquone
  • Drug: Placebo Group
    Continued standard of care therapy together with matching placebo
Study Arms  ICMJE
  • Experimental: standard of care therapy with atovaquone
    The first treatment group will receive continued standard of care therapy together with an oral dose of 1500 mg atovaquone twice daily (administered with a meal or snack) for up to 10 days.
    Intervention: Drug: Experimental Group
  • Placebo Comparator: standard of care therapy with matching placebo
    The second treatment group will receive continued standard of care therapy together with matching placebo.
    Intervention: Drug: Placebo Group
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 Completed
Actual Enrollment  ICMJE
 (submitted: June 30, 2020)
60
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE January 31, 2021
Actual Primary Completion Date January 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Diagnosis of COVID-19 by positive RT-PCR requiring hospitalization within 72 hours
  2. Age ≥18 years old
  3. Able to provide informed consent, or (as allowed by IRB), immediate availability of designated legally authorized representative to provide consent by proxy
  4. Anticipated hospitalization for >48 hours

Exclusion Criteria:

  1. Participation in any other clinical trial with antiviral activity against COVID-19
  2. Breastfeeding women
  3. Known hypersensitivity to atovaquone or formulation excipient
  4. Active treatment with rifampin
  5. HIV patients with AIDS requiring treatment for Pneumocystis jirovecii or Toxoplasma gondii
  6. Not expected to survive for 72 hours. 7) >14 days from symptom onset
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 States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04456153
Other Study ID Numbers  ICMJE STU-2020-0707
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: There is no specified plan made.
Current Responsible Party Mamta K. Jain, MD,MPH, University of Texas Southwestern Medical Center
Original Responsible Party University of Texas Southwestern Medical Center
Current Study Sponsor  ICMJE University of Texas Southwestern Medical Center
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Mamta Jain, M.D. University of Texas Southwestern Medical Center
Principal Investigator: Hesham Sadek, M.D. University of Texas Southwestern Medical Center
Principal Investigator: Ezimamaka Ajufo, M.D. University of Texas Southwestern Medical Center
Principal Investigator: Reuben Arasaratnam, M.D. University of Texas Southwestern Medical Center
Principal Investigator: James De Lemos, M.D. University of Texas Southwestern Medical Center
Principal Investigator: Helen King, M.D. University of Texas Southwestern Medical Center
Principal Investigator: Amneris Luque, M.D. University of Texas Southwestern Medical Center
Principal Investigator: Jessica Meisner, M.D. University of Texas Southwestern Medical Center
Principal Investigator: Satish Mocherla, M.D. University of Texas Southwestern Medical Center
Principal Investigator: John Schoggins, Ph.D. University of Texas Southwestern Medical Center
PRS Account University of Texas Southwestern Medical Center
Verification Date December 2021

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