Treatment for COVID-19 in High-Risk Adult Outpatients

NCT04354428 | Terminated Phase 2 Results DMC FDA Drug

• 2 other identifiers: STUDY00009878INV-017062
• Study Type: interventional
• Target: 289
• Locations: 1 country
• Sites: 6

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.

Conditions

COVID-19; SARS-CoV-2

Keywords

Outpatient; Treatment; COVID-19

Outcome Measures

Primary Outcomes (4)

• 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

  28 days from enrolment

• Number of Participants With Hospitalization or Mortality

  Number of participants with hospitalization or mortality

  Day 28 after enrolment

• Time to Clearance of Nasal SARS-CoV-2

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

  Day 1 through Day 14 after enrolment

• 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.

  Day 1 through Day 14 after enrolment

Secondary Outcomes (2)

• Number of Participants With Serious Adverse Events and Adverse Events Resulting in Treatment Discontinuation

  28 days from enrolment

• COVID-19-related Hospitalization Days

  28 days from enrolment

Study Arms (5)

Ascorbic acid and Folic acid

PLACEBO COMPARATOR

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

Hydroxychloroquine and Folic Acid

EXPERIMENTAL

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

Hydroxychloroquine and Azithromycin

EXPERIMENTAL

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

Lopinavir-ritonavir

EXPERIMENTAL

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]

Ascorbic acid

PLACEBO COMPARATOR

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

Drug: Ascorbic Acid

Interventions

Ascorbic Acid DRUG

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

Ascorbic acid; Ascorbic acid and Folic acid

Hydroxychloroquine Sulfate DRUG

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

Also known as: Intervention A

Hydroxychloroquine and Azithromycin; Hydroxychloroquine and Folic Acid

Azithromycin DRUG

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

Also known as: Intervention B

Hydroxychloroquine and Azithromycin

Folic Acid DRUG

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

Also known as: Placebo

Ascorbic acid and Folic acid; Hydroxychloroquine and Folic Acid

Lopinavir 200 MG / Ritonavir 50 MG [Kaletra] DRUG

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

Also known as: Intervention C

Lopinavir-ritonavir

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)
• 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)

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Washington: lead
• Bill and Melinda Gates Foundation: collaborator

Study Sites (6)

Ruth M. Rothstein CORE Center - Cook County Health

Chicago, Illinois, 60612, United States

Location

Tulane University

New Orleans, Louisiana, 70118, United States

Location

Boston University

Boston, Massachusetts, 02215, United States

Location

SUNY Upstate Medical University

Syracuse, New York, 13210, United States

Location

University of Washington Coordinating Center

Seattle, Washington, 98104, United States

Location

UW Virology Research Clinic

Seattle, Washington, 98104, United States

Location

Related Publications (3)

• 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.

  PMID: 35604806 DERIVED

• 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.

  PMID: 34473343 DERIVED

• 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.

  PMID: 33681731 DERIVED

MeSH Terms

Conditions

COVID-19

Interventions

Ascorbic Acid; Hydroxychloroquine; Azithromycin; Folic Acid; Lopinavir; Ritonavir; lopinavir-ritonavir drug combination

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Sugar Acids; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Hydroxy Acids; Carbohydrates; Chloroquine; Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Erythromycin; Macrolides; Polyketides; Lactones; Pterins; Pteridines; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Thiazoles; Sulfur Compounds; Azoles

Limitations and Caveats

Early termination of HCQ and HCQ/AZ arms as well as lopinavir-ritonavir arms leading to small numbers of participants analyzed.

Results Point of Contact

• Title: Christine Johnston
• Organization: University of Washington

cjohnsto@uw.edu

206-520-4340

Study Officials

• Christine Johnston, MD, MPH

  University of Washington

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: April 16, 2020
• First Posted: April 21, 2020
• Study Start: April 16, 2020
• Primary Completion: November 3, 2020
• Study Completion: November 30, 2020
• Last Updated: August 8, 2022
• Results First Posted: August 8, 2022

Record last verified: 2022-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, 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.

Locations

US (6)