Treatment for COVID-19 in High-Risk Adult Outpatients
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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: NCT04354428 |
Recruitment Status :
Active, not recruiting
First Posted : April 21, 2020
Last Update Posted : November 12, 2020
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Condition or disease | Intervention/treatment | Phase |
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COVID-19 SARS-CoV-2 | Drug: Ascorbic Acid Drug: Hydroxychloroquine Sulfate Drug: Azithromycin Drug: Folic Acid Drug: Lopinavir 200 MG / Ritonavir 50 MG [Kaletra] | Phase 2 Phase 3 |
Study Type : | Interventional (Clinical Trial) |
Estimated Enrollment : | 300 participants |
Allocation: | Randomized |
Intervention Model: | Parallel Assignment |
Masking: | Double (Participant, Investigator) |
Primary Purpose: | Treatment |
Official Title: | Efficacy of Novel Agents for Treatment of SARS-CoV-2 Infection Among High-Risk Outpatient Adults: An Adaptive Randomized Platform Trial |
Actual Study Start Date : | April 16, 2020 |
Estimated Primary Completion Date : | December 2020 |
Estimated Study Completion Date : | January 2021 |

Arm | Intervention/treatment |
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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)
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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 Name: Placebo Drug: Folic Acid Eligible participants in a household will receive folic acid and an additional intervention drug
Other Name: 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])
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Drug: Hydroxychloroquine Sulfate
Eligible participants in a household randomized to this study arm will receive hydrochloroquine and folic acid therapy
Other Name: Intervention A Drug: Folic Acid Eligible participants in a household will receive folic acid and an additional intervention drug
Other Name: Placebo |
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).
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Drug: Hydroxychloroquine Sulfate
Eligible participants in a household randomized to this study arm will receive hydrochloroquine and folic acid therapy
Other Name: Intervention A Drug: Azithromycin Eligible participants in a household randomized to this study arm will receive hydrochloroquine and azithromycin therapy
Other Name: 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)
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Drug: Lopinavir 200 MG / Ritonavir 50 MG [Kaletra]
Eligible participants in a household randomized to this study arm will receive lopinavir-ritonavir therapy
Other Name: 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
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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 Name: Placebo |
- Lower respiratory tract infection (LRTI) rates [ 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
- Incidence of hospitalization or mortality [ Time Frame: Day 28 after enrolment ]Cumulative incidence of hospitalization or mortality
- Change in upper respiratory viral shedding [ Time Frame: Day 1 through Day 14 after enrolment ]Time to clearance of nasal SARS-CoV-2, defined as 2 consecutive negative swabs
- COVID-19 symptom resolution rates [Lopinavir-ritonavir arm only] [ 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
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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.
- Rate of participant-reported adverse events [ Time Frame: 28 days from enrolment ]Serious adverse events (including death and hospitalization) and adverse events resulting in treatment discontinuation
- COVID-19-related hospitalization days [ Time Frame: 28 days from enrolment ]Duration of hospitalization among persons who become hospitalized with COVID-19 disease
- Rate of disease severity [ Time Frame: Day 1 through Day 14 after enrolment ]
- Peak score on WHO Ordinal Scale for Clinical Improvement
- Peak score on modified inFLUenza patient-reported outcome (Flu-PRO) instrument
- Viral shedding rates [ Time Frame: Day 1 through Day 14 after enrolment ]
- Proportion of days with SARS-CoV-2 detected from mid-nasal swabs by PCR
- Median quantity of SARS-CoV-2 detected from mid-nasal swabs by PCR
- Individual lopinavir-ritonavir concentration profiles and exposure estimates [Lopinavir-ritonavir arm only] [ Time Frame: 28 days from enrolment ]PK-evaluable participants will have post-hoc individual concentration profiles and exposure estimates determined for exploratory exposure-response analyses against primary and secondary efficacy and safety endpoints

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
Ages Eligible for Study: | 18 Years to 80 Years (Adult, Older Adult) |
Sexes Eligible for Study: | 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
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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

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04354428
United States, Illinois | |
Ruth M. Rothstein CORE Center - Cook County Health | |
Chicago, Illinois, United States, 60612 | |
United States, Louisiana | |
Tulane University | |
New Orleans, Louisiana, United States, 70118 | |
United States, Massachusetts | |
Boston University | |
Boston, Massachusetts, United States, 02215 | |
United States, New York | |
SUNY Upstate Medical University | |
Syracuse, New York, United States, 13210 | |
United States, Washington | |
University of Washington Coordinating Center | |
Seattle, Washington, United States, 98104 | |
UW Virology Research Clinic | |
Seattle, Washington, United States, 98104 |
Principal Investigator: | Christine Johnston, MD, MPH | University of Washington |
Documents provided by Christine Johnston, University of Washington:
Responsible Party: | Christine Johnston, Associate Professor, University of Washington |
ClinicalTrials.gov Identifier: | NCT04354428 |
Other Study ID Numbers: |
STUDY00009878 INV-017062 ( Other Grant/Funding Number: Bill and Melinda Gates Foundation ) |
First Posted: | April 21, 2020 Key Record Dates |
Last Update Posted: | November 12, 2020 |
Last Verified: | November 2020 |
Individual Participant Data (IPD) Sharing Statement: | |
Plan to Share IPD: | Yes |
Plan Description: | De-identified data from the study will be made available in accordance with the funder's open access policy. |
Supporting Materials: |
Study Protocol Informed Consent Form (ICF) |
Time Frame: | Within 3 months of publication of primary results. |
Access Criteria: | De-identified data from the study will be made available in accordance with the funder's open access policy. |
URL: | https://www.gatesfoundation.org/how-we-work/general-information/open-access-policy |
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 |
Outpatient Treatment COVID-19 |
COVID-19 Respiratory Tract Infections Infections Pneumonia, Viral Pneumonia Virus Diseases Coronavirus Infections Coronaviridae Infections Nidovirales Infections RNA Virus Infections Lung Diseases Respiratory Tract Diseases Folic Acid Ascorbic Acid Ritonavir |
Lopinavir Azithromycin Hydroxychloroquine HIV Protease Inhibitors Viral Protease Inhibitors Protease Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Anti-HIV Agents Anti-Retroviral Agents Antiviral Agents Anti-Infective Agents Cytochrome P-450 CYP3A Inhibitors Cytochrome P-450 Enzyme Inhibitors Anti-Bacterial Agents |