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High Dose Ivermectin for the Early Treatment of COVID-19 (COVER Study): A Randomised, Double-Blind, Multicentre, Phase II, Dose-Finding, Proof of Concept Clinical Trial

26 Pages Posted: 6 Sep 2021

See all articles by Dora Buonfrate

Dora Buonfrate

Negrar di Valpolicella - Dept of Infectious Tropical diseases and Microbiology

Fabio Chesini

Azienda Ospedaliera Universitaria Integrata di Verona - Dipartimento ad attività integrata medico-generale

Davide Martini

Negrar di Valpolicella - Dept of Infectious Tropical diseases and Microbiology

Maria Carla Roncaglioni

Istituto di Ricerche Farmacologiche Mario Negri IRCCS - Department of Cardiovascular Medicine

Maria Luisa Ojeda Fernandez

Istituto di Ricerche Farmacologiche Mario Negri IRCCS - Department of Cardiovascular Medicine

Maria Francesca Alvisi

Istituto di Ricerche Farmacologiche Mario Negri IRCCS - Department of Oncology

Irene De Simone

Istituto di Ricerche Farmacologiche Mario Negri IRCCS - Department of Oncology

Eliana Rulli

Istituto di Ricerche Farmacologiche Mario Negri IRCCS - Department of Oncology

Alessandro Nobili

Istituto di Ricerche Farmacologiche Mario Negri IRCCS - Department of Neuroscience

Giacomo Casalini

Università degli Studi di Milano - Dipartimento di Scienze Biomediche e Cliniche “Luigi Sacco”

Spinello Antinori

Università degli Studi di Milano - Dipartimento di Scienze Biomediche e Cliniche “Luigi Sacco”

Marco Gobbi

Università degli Studi di Milano - Dipartimento di Scienze Biomediche e Cliniche “Luigi Sacco”

Caterina Campoli

IRCCS Azienda Ospedaliero-Universitaria di Bologna - Infectious Disease Unit

Michela Deiana

Negrar di Valpolicella - Dept of Infectious Tropical diseases and Microbiology

Elena Pomari

Negrar di Valpolicella - Dept of Infectious Tropical diseases and Microbiology

Gianluigi Lunardi

IRCCS-Sacro Cuore Don Calabria Hospital

Roberto Tessari

Negrar di Valpolicella - Hospital Pharmacy

Zeno Bisoffi

Negrar di Valpolicella - Dept of Infectious Tropical diseases and Microbiology

More...

Abstract

Background: High concentrations of ivermectin demonstrated antiviral activity against SARS-CoV-2 in vitro.  Aim of this study was to assess safety and efficacy of high-dose ivermectin in reducing viral load in individuals with initial SARS-CoV-2 infection.

Methods: Randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial performed in outpatients in Italy. Participants: adults recently diagnosed with asymptomatic/oligosymptomatic SARS-CoV-2 infection, providing informed consent. Exclusion criteria: pregnant or lactating women; CNS diseases; participants under dialysis; severe medical condition with  prognosis < 6 months; warfarin treatment; antiviral/chloroquine phosphate/hydroxychloroquine treatment. Participants were assigned according to a randomized permuted block procedure to one of the following arms with allocation ratio 1:1:1: placebo (arm A); single dose ivermectin 600 μg/kg plus placebo for 5 days (arm B); single dose ivermectin 1200 μg/kg for 5 days (arm C). The pharmacist prepared the treatment according to the randomization list and on the basis of the participant’s weight. Primary outcomes: serious adverse drug reactions (SADR) and change of viral load at Day 7. The protocol was registered with ClinicalTrials.gov , NCT04438850.

Findings. From 31th July, 2020 to 26th May, 2021, 32 participants were randomized to arm A, 29 to arm B and 32 to arm C. The recruitment was stopped on 10th June, because of a dramatic drop of cases. Eighty-nine participants were included in the safety analysis set, the change in viral load was calculated on 87 participants. No SADR were registered. The mean log10 viral load reduction was 2.9 in arm C (SD 1.6), 2.5 (2.2) in arm B and 2.0 (2.1) in arm A, with no significant differences (p=0.099 and 0.122 for C versus A and B versus A, respectively).

Interpretation: High- dose ivermectin demonstrated safe, but did not prove efficacy to reduce viral load.

Trial Registration: The protocol was registered with ClinicalTrials.gov , NCT04438850.

Funding: The trial was partly funded by the Italian Ministry of Health.

Declaration of Interest: None to declare.

Ethical Approval: This study was approved by the national Ethics Committee of INMI – Spallanzani in Rome that is competent for all COVID-19 trials in Italy (resolution 139/2020 of 28th May, 2020), and by the Italian drug agency AIFA (resolution 136BIS/2020 of 18th May, 2020).

Keywords: Ivermectin, COVID-19, SARS-CoV-2, clinical trial, treatment

Suggested Citation

Buonfrate, Dora and Chesini, Fabio and Martini, Davide and Roncaglioni, Maria Carla and Ojeda Fernandez, Maria Luisa and Alvisi, Maria Francesca and De Simone, Irene and Rulli, Eliana and Nobili, Alessandro and Casalini, Giacomo and Antinori, Spinello and Gobbi, Marco and Campoli, Caterina and Deiana, Michela and Pomari, Elena and Lunardi, Gianluigi and Tessari, Roberto and Bisoffi, Zeno, High Dose Ivermectin for the Early Treatment of COVID-19 (COVER Study): A Randomised, Double-Blind, Multicentre, Phase II, Dose-Finding, Proof of Concept Clinical Trial. Available at SSRN: https://ssrn.com/abstract=3918289 or http://dx.doi.org/10.2139/ssrn.3918289

Dora Buonfrate (Contact Author)

Negrar di Valpolicella - Dept of Infectious Tropical diseases and Microbiology ( email )

Verona
Italy

Fabio Chesini

Azienda Ospedaliera Universitaria Integrata di Verona - Dipartimento ad attività integrata medico-generale ( email )

Verona
Italy

Davide Martini

Negrar di Valpolicella - Dept of Infectious Tropical diseases and Microbiology ( email )

Verona
Italy

Maria Carla Roncaglioni

Istituto di Ricerche Farmacologiche Mario Negri IRCCS - Department of Cardiovascular Medicine ( email )

Milan
Italy

Maria Luisa Ojeda Fernandez

Istituto di Ricerche Farmacologiche Mario Negri IRCCS - Department of Cardiovascular Medicine ( email )

Milan
Italy

Maria Francesca Alvisi

Istituto di Ricerche Farmacologiche Mario Negri IRCCS - Department of Oncology ( email )

Milan
Italy

Irene De Simone

Istituto di Ricerche Farmacologiche Mario Negri IRCCS - Department of Oncology ( email )

Milan
Italy

Eliana Rulli

Istituto di Ricerche Farmacologiche Mario Negri IRCCS - Department of Oncology ( email )

Milan
Italy

Alessandro Nobili

Istituto di Ricerche Farmacologiche Mario Negri IRCCS - Department of Neuroscience ( email )

Milan
Italy

Giacomo Casalini

Università degli Studi di Milano - Dipartimento di Scienze Biomediche e Cliniche “Luigi Sacco” ( email )

Milan
Italy

Spinello Antinori

Università degli Studi di Milano - Dipartimento di Scienze Biomediche e Cliniche “Luigi Sacco” ( email )

Milan
Italy

Marco Gobbi

Università degli Studi di Milano - Dipartimento di Scienze Biomediche e Cliniche “Luigi Sacco” ( email )

Milan
Italy

Caterina Campoli

IRCCS Azienda Ospedaliero-Universitaria di Bologna - Infectious Disease Unit ( email )

Bologna
Italy

Michela Deiana

Negrar di Valpolicella - Dept of Infectious Tropical diseases and Microbiology ( email )

Verona
Italy

Elena Pomari

Negrar di Valpolicella - Dept of Infectious Tropical diseases and Microbiology ( email )

Verona
Italy

Gianluigi Lunardi

IRCCS-Sacro Cuore Don Calabria Hospital ( email )

Via Sempreboni, 5
Negrar di Valpolicella, Verona 37024
Italy

Roberto Tessari

Negrar di Valpolicella - Hospital Pharmacy ( email )

Verona
Italy

Zeno Bisoffi

Negrar di Valpolicella - Dept of Infectious Tropical diseases and Microbiology ( email )

Verona
Italy

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