Clinical trial NCT04354428: Treatment for COVID-19 in High-Risk Adult Outpatients
Official title: Efficacy of Novel Agents for Treatment of SARS-CoV-2 Infection Among High-Risk Outpatient Adults: An Adaptive Randomized Platform Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: COVID-19
SARS-CoV-2
Keywords: Outpatient
Treatment
COVID-19
Lead sponsor: University of Washington
Sponsor class: OTHER
Collaborators: name: Bill and Melinda Gates Foundation
First posted: 2020-04-21
Enrollment: 289
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: 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
timeFrame: 28 days from enrolment
measure: Number of Participants With Hospitalization or Mortality
timeFrame: Day 28 after enrolment
measure: Time to Clearance of Nasal SARS-CoV-2
timeFrame: Day 1 through Day 14 after enrolment
measure: Time to Resolution of COVID-19 Symptom Resolution in Days
timeFrame: Day 1 through Day 14 after enrolment
Secondary outcomes:
measure: Number of Participants With Serious Adverse Events and Adverse Events Resulting in Treatment Discontinuation
timeFrame: 28 days from enrolment
measure: COVID-19-related Hospitalization Days
timeFrame: 28 days from enrolment
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Ruth M. Rothstein CORE Center - Cook County Health
state: Illinois
city: New Orleans
country: United States
facility: Tulane University
state: Louisiana
city: Boston
country: United States
facility: Boston University
state: Massachusetts
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Seattle
country: United States
facility: University of Washington Coordinating Center
state: Washington
city: Seattle
country: United States
facility: UW Virology Research Clinic
state: Washington
Study officials:
affiliation: University of Washington
name: Christine Johnston, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.