Anti-inflammatory Drug Algorithm for COVID-19 Home Treatment (COVER3)

A Home-treatment Algorithm Based on Anti-inflammatory Drugs to Prevent Hospitalization of Patients With Early COVID-19: a Three-months, Pragmatic, Cluster Randomized, Open-label,Blinded Endpoint (PROBE) Trial

The newly recognised disease COVID-19 is caused by the Severe-AcuteRespiratory-Syndrome Coronavirus 2 (SARS-CoV-2), which rapidly spread globally in late 2019, reaching pandemic proportions. The clinical spectrum of SARS-CoV-2 infection is broad, encompassing asymptomatic infection, mild upper respiratory tract illness and mild extrapulmonary symptoms, and severe viral pneumonia with respiratory failure and even death.

For COVID-19, most primary care physicians have initially treated their patients according to their judgment, with various treatment regimens they believe are most appropriate based on their experience/expertise. We recently published a note on how we were treating patients at home based on the pathophysiology underlining the mild/moderate symptoms at the onset of the illness and the proposal of simple drugs that theoretically better fir these mechanisms.

Because the common early mild symptoms of COVID-19 highlight a systemic inflammatory process, there is the recommendation of using anti-inflammatory agents to limit excessive host inflammatory responses to the viral infection, including non-steroidal anti-inflammatory drugs and corticosteroids. Moreover, COVID-19 patients are exposed to the risk of thromboembolic events and anticoagulant prophylaxis is recommended even at home, in particular settings, unless contraindicated.

In an academic matched-cohort study, we found that early treatment of COVID-19 patients at home by their family doctors according to the proposed recommendation regimen almost completely prevented the need for hospital admission (the most clinically relevant outcome of the study along with death) due to progression toward more severe illness (2 out of 90 patients), compared to patients in the 'control' cohort who were treated at home according to their family physician's assessments (13 out of 90 patients). However, the rate of hospitalization was a secondary outcome of the study and the possibility of a casual finding cannot be definitely excluded. Moreover, these findings were achieved in a retrospective observational study with two matched cohorts of COVID-19 patients, a possible additional limitation of the robustness of the conclusions that would deserve further validation. Thus, we have considered the observed reduction in patient hospitalization a hypothesis generating finding to be confirmed.

In this pragmatic, prospective, three-months, cluster randomized, open-label, blinded endpoint (PROBE) clinical trial, we will compare two groups of family doctors according to a randomized approach, who will treat their COVID19-patients with the proposed recommendation algorithm or other treatment regimens they normally feel appropriate according to their usual clinical practice, and monitor them longitudinally up to 3 months.

Our working hypothesis is that following the proposed recommendation algorithm the early COVID-19-related inflammatory process is limited, preventing the need of hospital admission at larger extent than with other therapeutic approaches also targeting early symptoms of the illness at home.

Should the findings be confirmed, the tested standardized treatment protocol would achieve major benefits for patients with early COVID-19 in particular in relation to a remarkably reduced risk of hospitalization that is expected to translate into reduced morbility and, possibly, mortality. Notably, these expected clinical benefits would be associated with remarkably reduced treatment costs related to reduced hospitalization.

Study Overview

• Status: Not yet recruiting
• Conditions: COVID-19
• Intervention / Treatment: Drug: Usual care; Drug: Recommended treatment schedule

• Study Type: Interventional
• Enrollment (Anticipated): 1800
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Giuseppe Remuzzi, MD; Phone Number: 003903545351; Email: cover3@marionegri.it
• Study Contact Backup: Name: Norberto Perico, MD; Phone Number: 003903545351; Email: cover3@marionegri.it

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects with early mild/moderate symptoms of COVID-19*, who start the treatment without waiting results of a nasopharyngeal swab, if any**

  * Influenza-like syndrome, (i.e. flu, cough, myalgias/arthralgias or other painful symptoms, fever, gastrointestinal symptoms), no dyspnea, SpO2 >94%, or asthenia,ageusia/dysgeusia, anosmia, or MEWS 0 to 3.

  ** Nasopharyngeal swab should be performed soon after the onset of symptoms possibly related to SARS-CoV-2

• Subjects with or without comorbidities that bring the patients at high risk of COVID-19 progression (heart disease, hypertension, asthma or lung disease, diabetes, chronic kidney disease, stroke or neurological problems, weakened immune system - e.g. receiving chemotherapy -, and self-reported obesity or body-mass index of at least 30 kg/m2)
• Informed consent

Exclusion Criteria:

• Subjects who require immediate hospital admission because of severe COVID-19 symptoms at onset according to family doctor's assessment (MEWS score 5, and/or septic shock, multiorgan failure)
• Known hypersensitivity or allergy to any medication under investigation
• Specific contraindications to the use of each recommended drugs according to their summary of product characteristics and the clinical judgment of family doctor
• Legal incapacity, limited legal incapacity, intellectual disability, uncooperative attitude or any other evidence that the patient will not be able to understand the study aims and procedures
• Pregnancy* *Patient with childbearing potential will be included according to the pragmatic design of the study.

In the context of a pragmatic design, novel therapeutic options including monoclonal antibodies or antiviral medications that are expected to become part of every day clinical practice will be allowed, without restriction, in both treatment arms. Thus they are expected to be similarly distributed among patients allocated to the recommended treatment approach or to standard of care group. This should avoid any risk of bias related to an unbalanced distribution of these medications between treatment arms. Moreover, sensitivity analyses including or not including patients receiving these medications will allow to assess whether and to what extent they will have an impact (if any) on study findings.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 'Recommended algorithm' cohort; COVID-19 patients treated at home by their family doctors according to the proposed recommendations	Drug: Recommended treatment schedule; Non-steroidal anti-inflammatory drugs (NSAiDs), Corticosteroids (Dexamethasone), Anticoagulants (LMW heparin), Gentle oxygen therapy
Active Comparator: Usual care; COVID-19 patients treated at home by their family doctors according to their usual clinical practice expected to be in accordance with AIFA recommendations	Drug: Usual care; Treatment regimens different from the recommended one according to family physician personal practice

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Proportion of patients who reach score ≥ 5 of Modified Early Warning Score (MEWS), an index of the need of hospitalization in the two treatment groups.	From beginning the proposed recommended treatments or other therapeutic regimens, assessed up to 90 days.

Collaborators and Investigators

• Sponsor: Mario Negri Institute for Pharmacological Research
• Collaborators: Prime Care Physicians

Study record dates

Study Major Dates

• Study Start (Anticipated): April 1, 2022
• Primary Completion (Anticipated): April 1, 2023
• Study Completion (Anticipated): April 1, 2023

Study Registration Dates

• First Submitted: February 21, 2022
• First Submitted That Met QC Criteria: February 21, 2022
• First Posted (Actual): February 22, 2022

Study Record Updates

• Last Update Posted (Actual): March 9, 2022
• Last Update Submitted That Met QC Criteria: February 22, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: Hospitalization; COVID-19 treatment at home; Early symptoms; Anti-inflammatory drugs
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: COVER3; 2022-000195-19 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No