Treatment for COVID-19 in High-Risk Adult Outpatients

NCT ID: NCT04354428

Last Updated: 2022-08-08

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 289 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-04-16
• Study Completion Date: 2020-11-30

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.

Conditions

COVID-19; SARS-CoV-2

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

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)

Group Type: PLACEBO_COMPARATOR

Ascorbic Acid

Intervention Type: DRUG

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

Folic Acid

Intervention Type: DRUG

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

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 \[Days 2 to 5\])

Group Type: EXPERIMENTAL

Hydroxychloroquine Sulfate

Intervention Type: DRUG

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

Folic Acid

Intervention Type: DRUG

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

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).

Group Type: EXPERIMENTAL

Hydroxychloroquine Sulfate

Intervention Type: DRUG

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

Azithromycin

Intervention Type: DRUG

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

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)

Group Type: EXPERIMENTAL

Lopinavir 200 MG / Ritonavir 50 MG [Kaletra]

Intervention Type: DRUG

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

Ascorbic acid

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

Group Type: PLACEBO_COMPARATOR

Ascorbic Acid

Intervention Type: DRUG

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

Interventions

Ascorbic Acid

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

Hydroxychloroquine Sulfate

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

Intervention Type: DRUG

Azithromycin

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

Intervention Type: DRUG

Folic Acid

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

Intervention Type: DRUG

Lopinavir 200 MG / Ritonavir 50 MG [Kaletra]

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

Intervention Type: DRUG

Other Intervention Names

Placebo; Intervention A; Intervention B; Placebo; Intervention C

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)

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Bill and Melinda Gates Foundation

OTHER

Sponsor Role: collaborator

University of Washington

OTHER

Sponsor Role: lead

Responsible Party

Christine Johnston

Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Christine Johnston, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

University of Washington

Locations

Ruth M. Rothstein CORE Center - Cook County Health

Chicago, Illinois, United States

Tulane University

New Orleans, Louisiana, United States

Boston University

Boston, Massachusetts, United States

SUNY Upstate Medical University

Syracuse, New York, United States

University of Washington Coordinating Center

Seattle, Washington, United States

UW Virology Research Clinic

Seattle, Washington, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 35604806 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34473343 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33681731 (View on PubMed)

Provided Documents

Document Type: Study Protocol: Hydroxychloroquine and Azithromycin arms

View Document

Document Type: Study Protocol: Lopinavir-Ritonavir arm

View Document

Document Type: Statistical Analysis Plan

View Document

Document Type: Informed Consent Form: Hydroxychloroquine and Azithromycin arms

View Document

Document Type: Informed Consent Form: Lopinavir-Ritonavir arm

View Document

Other Identifiers

INV-017062

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

STUDY00009878

Identifier Type: -

Identifier Source: org_study_id