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Treatment for COVID-19 in High-Risk Adult Outpatients

Primary Purpose

COVID-19, SARS-CoV-2

Status
Terminated
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Ascorbic Acid
Hydroxychloroquine Sulfate
Azithromycin
Folic Acid
Lopinavir 200 MG / Ritonavir 50 MG [Kaletra]
Sponsored by
University of Washington
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for COVID-19 focused on measuring Outpatient, Treatment, COVID-19

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

  • Ruth M. Rothstein CORE Center - Cook County Health
  • Tulane University
  • Boston University
  • SUNY Upstate Medical University
  • University of Washington Coordinating Center
  • UW Virology Research Clinic

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Placebo Comparator

Experimental

Experimental

Experimental

Placebo Comparator

Arm Label

Ascorbic acid and Folic acid

Hydroxychloroquine and Folic Acid

Hydroxychloroquine and Azithromycin

Lopinavir-ritonavir

Ascorbic acid

Arm Description

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)

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])

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).

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)

Ascorbic acid 1 gm orally twice on Day 1, followed by 500 mg orally twice daily for 9 days

Outcomes

Primary Outcome Measures

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
Resting blood oxygen saturation (SpO2<93%) level sustained for 2 readings 2 hours apart and presence of subjective dyspnea or cough
Number of Participants With Hospitalization or Mortality
Number of participants with hospitalization or mortality
Time to Clearance of Nasal SARS-CoV-2
Time to clearance of nasal SARS-CoV-2, defined as 2 consecutive negative swabs
Time to Resolution of COVID-19 Symptom Resolution in Days
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.

Secondary Outcome Measures

Number of Participants With Serious Adverse Events and Adverse Events Resulting in Treatment Discontinuation
Serious adverse events (including death and hospitalization) and adverse events resulting in treatment discontinuation
COVID-19-related Hospitalization Days
Duration of hospitalization among persons who become hospitalized with COVID-19 disease

Full Information

First Posted
April 16, 2020
Last Updated
July 12, 2022
Sponsor
University of Washington
Collaborators
Bill and Melinda Gates Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT04354428
Brief Title
Treatment for COVID-19 in High-Risk Adult Outpatients
Official Title
Efficacy of Novel Agents for Treatment of SARS-CoV-2 Infection Among High-Risk Outpatient Adults: An Adaptive Randomized Platform Trial
Study Type
Interventional

2. Study Status

Record Verification Date
July 2022
Overall Recruitment Status
Terminated
Why Stopped
Low number of events contributing to primary outcome
Study Start Date
April 16, 2020 (Actual)
Primary Completion Date
November 3, 2020 (Actual)
Study Completion Date
November 30, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Washington
Collaborators
Bill and Melinda Gates Foundation

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
COVID-19, SARS-CoV-2
Keywords
Outpatient, Treatment, COVID-19

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
289 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Ascorbic acid and Folic acid
Arm Type
Placebo Comparator
Arm Description
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)
Arm Title
Hydroxychloroquine and Folic Acid
Arm Type
Experimental
Arm Description
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])
Arm Title
Hydroxychloroquine and Azithromycin
Arm Type
Experimental
Arm Description
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).
Arm Title
Lopinavir-ritonavir
Arm Type
Experimental
Arm Description
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)
Arm Title
Ascorbic acid
Arm Type
Placebo Comparator
Arm Description
Ascorbic acid 1 gm orally twice on Day 1, followed by 500 mg orally twice daily for 9 days
Intervention Type
Drug
Intervention Name(s)
Ascorbic Acid
Other Intervention Name(s)
Placebo
Intervention Description
Eligible participants in a household randomized to this study arm will receive ascorbic acid only or ascorbic acid and additional drug therapy
Intervention Type
Drug
Intervention Name(s)
Hydroxychloroquine Sulfate
Other Intervention Name(s)
Intervention A
Intervention Description
Eligible participants in a household randomized to this study arm will receive hydrochloroquine and folic acid therapy
Intervention Type
Drug
Intervention Name(s)
Azithromycin
Other Intervention Name(s)
Intervention B
Intervention Description
Eligible participants in a household randomized to this study arm will receive hydrochloroquine and azithromycin therapy
Intervention Type
Drug
Intervention Name(s)
Folic Acid
Other Intervention Name(s)
Placebo
Intervention Description
Eligible participants in a household will receive folic acid and an additional intervention drug
Intervention Type
Drug
Intervention Name(s)
Lopinavir 200 MG / Ritonavir 50 MG [Kaletra]
Other Intervention Name(s)
Intervention C
Intervention Description
Eligible participants in a household randomized to this study arm will receive lopinavir-ritonavir therapy
Primary Outcome Measure Information:
Title
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
Description
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
Title
Number of Participants With Hospitalization or Mortality
Description
Number of participants with hospitalization or mortality
Time Frame
Day 28 after enrolment
Title
Time to Clearance of Nasal SARS-CoV-2
Description
Time to clearance of nasal SARS-CoV-2, defined as 2 consecutive negative swabs
Time Frame
Day 1 through Day 14 after enrolment
Title
Time to Resolution of COVID-19 Symptom Resolution in Days
Description
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.
Time Frame
Day 1 through Day 14 after enrolment
Secondary Outcome Measure Information:
Title
Number of Participants With Serious Adverse Events and Adverse Events Resulting in Treatment Discontinuation
Description
Serious adverse events (including death and hospitalization) and adverse events resulting in treatment discontinuation
Time Frame
28 days from enrolment
Title
COVID-19-related Hospitalization Days
Description
Duration of hospitalization among persons who become hospitalized with COVID-19 disease
Time Frame
28 days from enrolment

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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) Age ≥60 years Presence of pulmonary disease, specifically moderate or severe persistent asthma, chronic obstructive pulmonary disease, pulmonary hypertension, emphysema Diabetes mellitus (type 1 or type 2), requiring oral medication or insulin for treatment Hypertension, requiring at least 1 oral medication for treatment Immunocompromised status due to disease (e.g., those living with human immunodeficiency virus with a CD4 T-cell count of <200/mm3) 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) 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Christine Johnston, MD, MPH
Organizational Affiliation
University of Washington
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ruth M. Rothstein CORE Center - Cook County Health
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
Tulane University
City
New Orleans
State/Province
Louisiana
ZIP/Postal Code
70118
Country
United States
Facility Name
Boston University
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
Facility Name
SUNY Upstate Medical University
City
Syracuse
State/Province
New York
ZIP/Postal Code
13210
Country
United States
Facility Name
University of Washington Coordinating Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98104
Country
United States
Facility Name
UW Virology Research Clinic
City
Seattle
State/Province
Washington
ZIP/Postal Code
98104
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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 URL
https://www.gatesfoundation.org/how-we-work/general-information/open-access-policy
Citations:
PubMed Identifier
35604806
Citation
Mayfield JJ, Chatterjee NA, Noseworthy PA, Poole JE, Ackerman MJ, Stewart J, Kissinger PJ, Dwyer J, Hosek S, Oyedele T, Paasche-Orlow MK, Paolino K, Friedman PA, Waters C, Moreno J, Leingang H, Heller KB, Morrison SA, Krows ML, Barnabas RV, Baeten J, Johnston C; COVID-19 Early Treatment Team; Sridhar AR. Implementation of a fully remote randomized clinical trial with cardiac monitoring. Commun Med (Lond). 2021 Dec 20;1:62. doi: 10.1038/s43856-021-00052-w. eCollection 2021.
Results Reference
derived
PubMed Identifier
34473343
Citation
Kreuzberger N, Hirsch C, Chai KL, Tomlinson E, Khosravi Z, Popp M, Neidhardt M, Piechotta V, Salomon S, Valk SJ, Monsef I, Schmaderer C, Wood EM, So-Osman C, Roberts DJ, McQuilten Z, Estcourt LJ, Skoetz N. SARS-CoV-2-neutralising monoclonal antibodies for treatment of COVID-19. Cochrane Database Syst Rev. 2021 Sep 2;9(9):CD013825. doi: 10.1002/14651858.CD013825.pub2.
Results Reference
derived
PubMed Identifier
33681731
Citation
Johnston C, Brown ER, Stewart J, Karita HCS, Kissinger PJ, Dwyer J, Hosek S, Oyedele T, Paasche-Orlow MK, Paolino K, Heller KB, Leingang H, Haugen HS, Dong TQ, Bershteyn A, Sridhar AR, Poole J, Noseworthy PA, Ackerman MJ, Morrison S, Greninger AL, Huang ML, Jerome KR, Wener MH, Wald A, Schiffer JT, Celum C, Chu HY, Barnabas RV, Baeten JM; COVID-19 Early Treatment Study Team. Hydroxychloroquine with or without azithromycin for treatment of early SARS-CoV-2 infection among high-risk outpatient adults: A randomized clinical trial. EClinicalMedicine. 2021 Mar;33:100773. doi: 10.1016/j.eclinm.2021.100773. Epub 2021 Feb 27.
Results Reference
derived

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Treatment for COVID-19 in High-Risk Adult Outpatients

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