Treatment for COVID-19 in High-Risk Adult Outpatients

July 12, 2022 updated by: Christine Johnston, University of Washington

Efficacy of Novel Agents for Treatment of SARS-CoV-2 Infection Among High-Risk Outpatient Adults: An Adaptive Randomized Platform Trial

This is a randomized trial for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in high-risk adults not requiring hospital admission.The overarching goal of this study is to assess the effectiveness of interventions on the incidence of lower respiratory tract infection (LRTI) progression among high-risk adult outpatients with SARS-CoV-2 infection to inform public health control strategies.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

This is a randomized, multi-center, placebo-equivalent (ascorbic acid + folic acid)-controlled, blinded platform trial. Eligible participants will be enrolled and randomized to Hydrocychloroquine (HCQ) + placebo (folic acid), HCQ + azithromycin, lopinavir-ritonavir (LPV/r) or placebo (ascorbic acid + folic acid). Initially, this study will enroll up to 495 eligible adults ( with high risk for Lower respiratory tract infection (LRTI) progression at baseline who are PCR-confirmed SARS-CoV-2 infection (165 per arm). An additional cohort of 135 eligible adults without risk factors for LRTI progression at baseline who are PCR-confirmed SARS-CoV-2 infection will be enrolled for the co-primary virologic outcome. During the 28 study days, participants will take the medication, complete surveys, collect mid nasal swab for viral quantification, and assess symptoms for progression to LRTI. Additional arms will be added should new potential agents be discovered or combination treatments be proposed. In addition, arms may be dropped prior to completion if deemed futile or if there is a safety signal.

Study Type

Interventional

Enrollment (Actual)

289

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Illinois
      • Chicago, Illinois, United States, 60612
        • Ruth M. Rothstein CORE Center - Cook County Health
    • Louisiana
      • New Orleans, Louisiana, United States, 70118
        • Tulane University
    • Massachusetts
      • Boston, Massachusetts, United States, 02215
        • Boston University
    • New York
      • Syracuse, New York, United States, 13210
        • SUNY Upstate Medical University
    • Washington
      • Seattle, Washington, United States, 98104
        • UW Virology Research Clinic
      • Seattle, Washington, United States, 98104
        • University of Washington Coordinating Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Men or women 18 to 80 years of age, inclusive, at the time of signing the informed consent
  • Willing and able to provide informed consent
  • Laboratory confirmed SARS-CoV-2 infection, with test results within past 72 hours
  • COVID-19 symptoms, based on the following criteria: At least TWO of the following symptoms: Fever (≥ 38ºC), chills, rigors, myalgia, headache, sore throat, new olfactory and taste disorder(s), OR o At least ONE of the following symptoms: cough, shortness of breath or difficulty breathing (Lopinavir-Ritonavir Platform)
  • Access to device and internet for Telehealth visits

  • At increased risk of developing severe COVID-19 disease (at least one of the following)

    1. Age ≥60 years
    2. Presence of pulmonary disease, specifically moderate or severe persistent asthma, chronic obstructive pulmonary disease, pulmonary hypertension, emphysema
    3. Diabetes mellitus (type 1 or type 2), requiring oral medication or insulin for treatment
    4. Hypertension, requiring at least 1 oral medication for treatment
    5. Immunocompromised status due to disease (e.g., those living with human immunodeficiency virus with a CD4 T-cell count of <200/mm3)
    6. Immunocompromised status due to medication (e.g., persons taking 20 mg or more of prednisone equivalents a day, anti-inflammatory monoclonal antibody therapies, or cancer therapies)
    7. Body mass index ≥30 (self-reported)

Exclusion Criteria:

  • Known hypersensitivity to HCQ or other 4-aminoquinoline compounds
  • Known hypersensitivity to azithromycin or other azalide or macrolide antibiotics
  • Currently hospitalized
  • Signs of respiratory distress prior to randomization, including respiratory rate >24
  • Current medications include HCQ
  • Concomitant use of other anti-malarial treatment or chemoprophylaxis
  • History of retinopathy of any etiology
  • Psoriasis
  • Porphyria
  • Chronic kidney disease (Stage IV or receiving dialysis)
  • Known bone marrow disorders with significant neutropenia (polymorphonuclear leukocytes <1500) or thrombocytopenia (<100 K)
  • Concomitant use of digoxin, cyclosporin, cimetidine, amiodarone, or tamoxifen
  • Known cirrhosis
  • Known personal or family history of long QT syndrome
  • History of coronary artery disease with a history of graft or stent
  • History of heart failure, Class 2 or greater using the New York Heart Association functional class
  • Taking medications associated with prolonged QT and known risk of torsades de points. These medications may include some antipsychotic and antidepressant medications. (Lopinavir-Ritonavir Platform)
  • Taking medications associated with prolonged QT such as antipsychotic medications or antidepressants (e.g., citalopram, venlafaxine, and bupropion) and unable to stop during the trial
  • Taking warfarin (Coumadin or Jantoven)
  • Known history of glucose-6-phosphate-dehydrogenase deficiency
  • History of myasthenia gravis

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Ascorbic acid and Folic acid
Ascorbic acid 500 mg orally twice on Day 1, followed by 250 mg orally twice daily for 9 days + folic acid 800 µg orally once on Day 1, followed by 400 µg orally once daily for an additional 4 days (Days 2 to 5)
Drug: Ascorbic Acid
Eligible participants in a household randomized to this study arm will receive ascorbic acid only or ascorbic acid and additional drug therapy
Other Names:
  • Placebo
Drug: Folic Acid
Eligible participants in a household will receive folic acid and an additional intervention drug
Other Names:
  • Placebo
Experimental: Hydroxychloroquine and Folic Acid
HCQ 400 mg orally twice on Day 1, followed by 200 mg orally twice daily for an additional 9 days (Days 2 to 10) + placebo (folic acid 800 µg orally once on Day 1, followed by 400 µg orally once daily for an additional 4 days [Days 2 to 5])
Drug: Folic Acid
Eligible participants in a household will receive folic acid and an additional intervention drug
Other Names:
  • Placebo
Drug: Hydroxychloroquine Sulfate
Eligible participants in a household randomized to this study arm will receive hydrochloroquine and folic acid therapy
Other Names:
  • Intervention A
Experimental: Hydroxychloroquine and Azithromycin
HCQ 400 mg orally twice on Day 1, followed by 200 mg orally twice daily for an additional 9 days (Days 2 to 10) + azithromycin 500 mg orally once on Day 1, followed by 250 mg orally once daily for an additional 4 days (Days 2 to 5).
Drug: Hydroxychloroquine Sulfate
Eligible participants in a household randomized to this study arm will receive hydrochloroquine and folic acid therapy
Other Names:
  • Intervention A
Drug: Azithromycin
Eligible participants in a household randomized to this study arm will receive hydrochloroquine and azithromycin therapy
Other Names:
  • Intervention B
Experimental: Lopinavir-ritonavir
LPV/r 800 mg-200 mg orally twice on Day 1, followed by 400 mg 100 mg orally twice daily for an additional 9 days (Days 2 to 10)
Drug: Lopinavir 200 MG / Ritonavir 50 MG [Kaletra]
Eligible participants in a household randomized to this study arm will receive lopinavir-ritonavir therapy
Other Names:
  • Intervention C
Placebo Comparator: Ascorbic acid
Ascorbic acid 1 gm orally twice on Day 1, followed by 500 mg orally twice daily for 9 days
Drug: Ascorbic Acid
Eligible participants in a household randomized to this study arm will receive ascorbic acid only or ascorbic acid and additional drug therapy
Other Names:
  • Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Persons With Lower Respiratory Tract Infection (LRTI), Defined as Resting Blood Oxygen Saturation (SpO2<93%) Level Sustained for 2 Readings 2 Hours Apart and Presence of Subjective Dyspnea or Cough
Time Frame: 28 days from enrolment
Resting blood oxygen saturation (SpO2<93%) level sustained for 2 readings 2 hours apart and presence of subjective dyspnea or cough
28 days from enrolment
Number of Participants With Hospitalization or Mortality
Time Frame: Day 28 after enrolment
Number of participants with hospitalization or mortality
Day 28 after enrolment
Time to Clearance of Nasal SARS-CoV-2
Time Frame: Day 1 through Day 14 after enrolment
Time to clearance of nasal SARS-CoV-2, defined as 2 consecutive negative swabs
Day 1 through Day 14 after enrolment
Time to Resolution of COVID-19 Symptom Resolution in Days
Time Frame: Day 1 through Day 14 after enrolment

COVID-19 symptoms are based on the following criteria:

  • At least TWO of the following symptoms: Fever (≥ 38ºC), chills, rigors, myalgia, headache, sore throat, new olfactory and taste disorder(s), OR
  • At least ONE of the following symptoms: cough, shortness of breath or difficulty breathing, OR

  • Severe respiratory illness with at least 1 of the following:

    • Clinical or radiological evidence of pneumonia, OR
    • Acute respiratory distress syndrome (ARDS), OR
    • LRTI, defined by resting SpO2<93% sustained for 2 readings 2 hours apart AND presence of subjective dyspnea or cough Death or COVID-19-related hospitalizations will count as a failure to resolve symptoms.
Day 1 through Day 14 after enrolment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants With Serious Adverse Events and Adverse Events Resulting in Treatment Discontinuation
Time Frame: 28 days from enrolment
Serious adverse events (including death and hospitalization) and adverse events resulting in treatment discontinuation
28 days from enrolment
COVID-19-related Hospitalization Days
Time Frame: 28 days from enrolment
Duration of hospitalization among persons who become hospitalized with COVID-19 disease
28 days from enrolment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Washington

Collaborators

Bill and Melinda Gates Foundation

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 16, 2020

Primary Completion (Actual)

November 3, 2020

Study Completion (Actual)

November 30, 2020

Study Registration Dates

First Submitted

April 16, 2020

First Submitted That Met QC Criteria

April 16, 2020

First Posted (Actual)

April 21, 2020

Study Record Updates

Last Update Posted (Actual)

August 8, 2022

Last Update Submitted That Met QC Criteria

July 12, 2022

Last Verified

July 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • STUDY00009878
  • INV-017062 (Other Grant/Funding Number: Bill and Melinda Gates Foundation)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

De-identified data from the study will be made available in accordance with the funder's open access policy.

IPD Sharing Time Frame

Within 3 months of publication of primary results.

IPD Sharing Access Criteria

De-identified data from the study will be made available in accordance with the funder's open access policy.

IPD Sharing Supporting Information Type

  • Study Protocol
  • Informed Consent Form (ICF)

Drug and device information, study documents

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.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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