CClinicalTrials.gg
Sign In
TerminatedNCT04354428Updated Aug 8, 2022Results posted

Treatment for COVID-19 in High-Risk Adult Outpatients

A Phase 2/3 interventional study of Ascorbic Acid and Hydroxychloroquine Sulfate in COVID-19 and SARS-CoV-2, sponsored by University of Washington. Terminated at 6 sites in United States. Open to participants aged 18 Years to 80 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2022-08-08.

Sponsored by University of Washington · Phase 2/3, Interventional, and Treatment

Why this study was terminated
Low number of events contributing to primary outcome
Phase
Phase 2/3
Study type
Interventional
Enrollment
289
Allocation
Randomized
Ages
18 Years to 80 Years
Sex
All
01

Study 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.

Read the 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.

02

Conditions studied

  • COVID-19
  • SARS-CoV-2

Browse trials for

Keywords

  • Outpatient
  • Treatment
  • COVID-19
03

In context

COVID-19

7,640 studies on the registry are indexed under COVID-19; 488 are open to participants now.

This study's enrollment of 289 is above the median of 100 across 4,099 interventional studies indexed under COVID-19.

Browse COVID-19 studies →

Lead sponsor

University of Washington is the lead sponsor of 1,397 studies on the registry; 225 are open to participants now.

Of its 154 completed or terminated interventional studies of FDA-regulated products, 132 (86%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years to 80 Years
Sexes eligible
All
Accepts healthy volunteers
Yes

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

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
05

Study design

Phase
Phase 2 / Phase 3
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Double (Participant, Investigator)
Enrollment
289 participants (actual)

Study arms

  • 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 · Drug: Folic Acid

  • 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: Hydroxychloroquine Sulfate · Drug: Folic Acid

  • 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 · Drug: Azithromycin

  • 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]

  • 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

Interventions

  • DrugAscorbic Acid

    Eligible participants in a household randomized to this study arm will receive ascorbic acid only or ascorbic acid and additional drug therapy

    Also known as: Placebo

  • DrugHydroxychloroquine Sulfate

    Eligible participants in a household randomized to this study arm will receive hydrochloroquine and folic acid therapy

    Also known as: Intervention A

  • DrugAzithromycin

    Eligible participants in a household randomized to this study arm will receive hydrochloroquine and azithromycin therapy

    Also known as: Intervention B

  • DrugFolic Acid

    Eligible participants in a household will receive folic acid and an additional intervention drug

    Also known as: Placebo

  • DrugLopinavir 200 MG / Ritonavir 50 MG [Kaletra]

    Eligible participants in a household randomized to this study arm will receive lopinavir-ritonavir therapy

    Also known as: Intervention C

06

What researchers measure

Primary outcomes

  1. 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

    Time frame: 28 days from enrolment

  2. Number of Participants With Hospitalization or Mortality

    Number of participants with hospitalization or mortality

    Time frame: Day 28 after enrolment

  3. Time to Clearance of Nasal SARS-CoV-2

    Time to clearance of nasal SARS-CoV-2, defined as 2 consecutive negative swabs

    Time frame: Day 1 through Day 14 after enrolment

  4. 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.

    Time frame: Day 1 through Day 14 after enrolment

Secondary outcomes

  1. 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

    Time frame: 28 days from enrolment

  2. COVID-19-related Hospitalization Days

    Duration of hospitalization among persons who become hospitalized with COVID-19 disease

    Time frame: 28 days from enrolment

07

Results

Posted Aug 8, 2022
Limitations and caveats
Early termination of HCQ and HCQ/AZ arms as well as lopinavir-ritonavir arms leading to small numbers of participants analyzed.

Participant flow

Participant flow — Overall Study
MilestoneAscorbic Acid and Folic AcidHydroxychloroquine and Folic AcidHydroxychloroquine and AzithromycinLopinavir-ritonavirAscorbic Acid
Started8371772929
Completed enrollment8065742728
Completed7562711925
Not completed896104

Outcome measures

PrimaryNumber 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

Time frame:
28 days from enrolment
Reported as:
Count of participants · Participants
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
ParticipantsAscorbic Acid and Folic AcidHydroxychloroquine and Folic AcidHydroxychloroquine and AzithromycinLopinavir-ritonavirAscorbic Acid
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 Cough20421
PrimaryNumber of Participants With Hospitalization or Mortality

Number of participants with hospitalization or mortality

Time frame:
Day 28 after enrolment
Reported as:
Count of participants · Participants
Number of Participants With Hospitalization or Mortality
ParticipantsAscorbic Acid and Folic AcidHydroxychloroquine and Folic AcidHydroxychloroquine and AzithromycinLopinavir-ritonavirAscorbic Acid
Number of Participants With Hospitalization or Mortality42301
PrimaryTime to Clearance of Nasal SARS-CoV-2

Time to clearance of nasal SARS-CoV-2, defined as 2 consecutive negative swabs

Time frame:
Day 1 through Day 14 after enrolment
Reported as:
Median · Days
Time to Clearance of Nasal SARS-CoV-2
DaysAscorbic Acid and Folic AcidHydroxychloroquine and Folic AcidHydroxychloroquine and AzithromycinLopinavir-ritonavirAscorbic Acid
Time to Clearance of Nasal SARS-CoV-27 (6 to 10)5 (4 to 6)6 (4 to 8)4 (3 to NA)5 (3 to 9)
PrimaryTime 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.

Time frame:
Day 1 through Day 14 after enrolment
Reported as:
Median · Days
Time to Resolution of COVID-19 Symptom Resolution in Days
DaysAscorbic Acid and Folic AcidHydroxychloroquine and Folic AcidHydroxychloroquine and AzithromycinLopinavir-ritonavirAscorbic Acid
Time to Resolution of COVID-19 Symptom Resolution in Days11.5 (8.5 to NA)10.5 (6.5 to NA)NA (9.5 to NA)NA (NA to NA)NA (10.5 to NA)
SecondaryNumber 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

Time frame:
28 days from enrolment
Reported as:
Count of participants · Participants
Number of Participants With Serious Adverse Events and Adverse Events Resulting in Treatment Discontinuation
ParticipantsAscorbic Acid and Folic AcidHydroxychloroquine and Folic AcidHydroxychloroquine and AzithromycinLopinavir-ritonavirAscorbic Acid
Number of Participants With Serious Adverse Events and Adverse Events Resulting in Treatment Discontinuation66891
SecondaryCOVID-19-related Hospitalization Days

Duration of hospitalization among persons who become hospitalized with COVID-19 disease

Time frame:
28 days from enrolment
Reported as:
Number · Days
COVID-19-related Hospitalization Days
DaysAscorbic Acid and Folic AcidHydroxychloroquine and Folic AcidHydroxychloroquine and AzithromycinLopinavir-ritonavirAscorbic Acid
COVID-19-related Hospitalization DaysNANANANANA

Adverse events

Collected over 28 days. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Ascorbic Acid and Folic Acid0/83 (0%)4/83 (4.8%)2/83 (2.4%)
Hydroxychloroquine and Folic Acid0/71 (0%)2/71 (2.8%)4/71 (5.6%)
Hydroxychloroquine and Azithromycin0/77 (0%)3/77 (3.9%)5/77 (6.5%)
Lopinavir-ritonavir0/29 (0%)0/29 (0%)9/29 (31%)
Ascorbic Acid0/29 (0%)1/29 (3.4%)0/29 (0%)
Most frequent serious events
Most frequent serious events
EventAscorbic Acid and Folic AcidHydroxychloroquine and Folic AcidHydroxychloroquine and AzithromycinLopinavir-ritonavirAscorbic Acid
PneumoniaRespiratory, thoracic and mediastinal disorders3/830/712/770/290/29
Pulmonary embolismBlood and lymphatic system disorders0/830/710/770/291/29
Chest PainCardiac disorders1/831/710/770/290/29
pericarditisCardiac disorders0/831/710/770/290/29
hemorrhagic colitisGastrointestinal disorders0/830/711/770/290/29
Most frequent other events
Most frequent other events
EventAscorbic Acid and Folic AcidHydroxychloroquine and Folic AcidHydroxychloroquine and AzithromycinLopinavir-ritonavirAscorbic Acid
Event leading to treatment discontinuationGastrointestinal disorders2/831/713/779/290/29
QT ProlongationCardiac disorders0/832/710/770/290/29
Drug ReactionImmune system disorders0/830/712/770/290/29
HeadacheNervous system disorders0/831/710/770/290/29

Baseline characteristics

Age, Customized
Age, Customized(Participants)Ascorbic Acid and Folic AcidHydroxychloroquine and Folic AcidHydroxychloroquine and AzithromycinLopinavir-ritonavirAscorbic AcidTotal
18-29 years2119247879
30-39 years2628219993
40-49 years1613147656
50-59 years12596335
60-69 years7580222
70-80 years111014
Sex/Gender, Customized
Sex/Gender, Customized(Participants)Ascorbic Acid and Folic AcidHydroxychloroquine and Folic AcidHydroxychloroquine and AzithromycinLopinavir-ritonavirAscorbic AcidTotal
Female4539471720168
Male383230129121
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Ascorbic Acid and Folic AcidHydroxychloroquine and Folic AcidHydroxychloroquine and AzithromycinLopinavir-ritonavirAscorbic AcidTotal
Hispanic or Latino3023187482
Not Hispanic or Latino5248592225206
Unknown or Not Reported100001
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Ascorbic Acid and Folic AcidHydroxychloroquine and Folic AcidHydroxychloroquine and AzithromycinLopinavir-ritonavirAscorbic AcidTotal
American Indian or Alaska Native1211160039
Asian4340011
Native Hawaiian or Other Pacific Islander201003
Black or African American71095435
White4137391824159
More than one race151076038
Unknown or Not Reported201014
High Risk
High Risk(Participants)Ascorbic Acid and Folic AcidHydroxychloroquine and Folic AcidHydroxychloroquine and AzithromycinLopinavir-ritonavirAscorbic AcidTotal
Count of participants483744810147
08

Study locations

6 sites
  • Ruth M. Rothstein CORE Center - Cook County Health
    Chicago, Illinois 60612, United States
  • Tulane University
    New Orleans, Louisiana 70118, United States
  • Boston University
    Boston, Massachusetts 02215, United States
  • SUNY Upstate Medical University
    Syracuse, New York 13210, United States
  • University of Washington Coordinating Center
    Seattle, Washington 98104, United States
  • UW Virology Research Clinic
    Seattle, Washington 98104, United States
09

References and documents

Publications

  • 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. PubMed 35604806 ↗
  • 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. PubMed 34473343 ↗
  • 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. PubMed 33681731 ↗

Study documents

  • Study protocol · Apr 11, 2020
  • Study protocol · Aug 17, 2020
  • Statistical analysis plan · Jan 24, 2022
  • Informed consent form · Apr 15, 2020
  • Informed consent form · Aug 17, 2020

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — De-identified data from the study will be made available in accordance with the funder's open access policy.

Supporting information: Study protocol, Icf

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Aug 8, 2022, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT04354428
Lead sponsor
University of Washington
Collaborators
Bill and Melinda Gates Foundation
Responsible party
Christine Johnston (Associate Professor, University of Washington) — Principal investigator
First posted
Apr 21, 2020
Start date
Apr 16, 2020
Primary completion
Nov 3, 2020
Completion
Nov 30, 2020
Results posted
Aug 8, 2022
Last update
Aug 8, 2022

Study contacts

Christine Johnston, MD, MPH
principal investigator · University of Washington

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is terminated, as verified in Jul 2022. You cannot join it, but the record below documents what was studied.

Follow this study

Get an email when the registry record changes — status, dates, results — or when someone posts here.

Sign in to follow

Discussion

Questions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.

Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.

Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.

Other studies in this condition

COVID-19→

Other studies from this sponsor

University of Washington

Start the discussion