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Treatment for COVID-19 in High-Risk Adult Outpatients

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
Sponsor:
Collaborator:
Bill and Melinda Gates Foundation
Information provided by (Responsible Party):
Christine Johnston, University of Washington

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.

Condition or disease Intervention/treatment Phase
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

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.

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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
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 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])
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).
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)
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
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




Primary Outcome Measures :
  1. 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

  2. Incidence of hospitalization or mortality [ Time Frame: Day 28 after enrolment ]
    Cumulative incidence of hospitalization or mortality

  3. 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

  4. 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
    • 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 :
  1. 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

  2. COVID-19-related hospitalization days [ Time Frame: 28 days from enrolment ]
    Duration of hospitalization among persons who become hospitalized with COVID-19 disease

  3. 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

  4. 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

  5. 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



Information from the National Library of Medicine

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.


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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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)

    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

Information from the National Library of Medicine

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


Locations
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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
Sponsors and Collaborators
University of Washington
Bill and Melinda Gates Foundation
Investigators
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Principal Investigator: Christine Johnston, MD, MPH University of Washington
  Study Documents (Full-Text)

Documents provided by Christine Johnston, University of Washington:
Study Protocol: Lopinavir-Ritonavir arm  [PDF] August 17, 2020

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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

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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
Keywords provided by Christine Johnston, University of Washington:
Outpatient
Treatment
COVID-19
Additional relevant MeSH terms:
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Hydroxychloroquine
Folic Acid
Ascorbic Acid
Ritonavir
Lopinavir
Azithromycin
HIV 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
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Antirheumatic Agents
Hematinics
Vitamin B Complex
Vitamins
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Antioxidants
Protective Agents