Treatment for COVID-19 in High-Risk Adult Outpatients

• ClinicalTrials.gov Identifier: NCT04354428
• Recruitment Status: Active, not recruiting
• First Posted: April 21, 2020
• Last Update Posted: November 12, 2020
• Sponsor: University of Washington
• Collaborator: Bill and Melinda Gates Foundation
• Information provided by (Responsible Party): Christine Johnston, University of Washington

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.

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.

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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

Eligibility Criteria

• 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

Contacts and Locations

Locations

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

• Principal Investigator: Christine Johnston, MD, MPH; University of Washington

  Study Documents (Full-Text)

Documents provided by Christine Johnston, University of Washington:

Study Protocol: Hydroxychloroquine and Azithromycin arms  [PDF] April 11, 2020

Study Protocol: Lopinavir-Ritonavir arm  [PDF] August 17, 2020

Informed Consent Form: Hydroxychloroquine and Azithromycin arms  [PDF] April 15, 2020

Informed Consent Form: Lopinavir-Ritonavir arm  [PDF] August 17, 2020

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• 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
• 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

Keywords provided by Christine Johnston, University of Washington:

Outpatient; Treatment; COVID-19

Additional relevant MeSH terms:

Folic Acid; Ascorbic Acid; Ritonavir; Lopinavir; Azithromycin; Hydroxychloroquine; 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