COVidIVERmectin: Ivermectin for Treatment of Covid-19 (COVER)

Randomized, Double-blind, Multi Centre Phase II, Proof of Concept, Dose Finding Clinical Trial on Ivermectin for the Early Treatment of COVID-19

Prospective, multi-centre, randomized, double-blind trial to assess efficacy and safety of ivermectin for the treatment of initial infection with SARS-CoV2 infection.

Study arms: A) placebo B) ivermectin 600 μg/kg daily for 5 consecutive days (I_600) + placebo. C) ivermectin 1200 μg/kg daily at empty stomach with water for 5 consecutive days (I_1200). Patients will be randomized at emergency room of hospitals as well as at outpatient ambulatory care as well as at home, according to routine procedures of recruiting centres.

In arm A and B, the number of placebo tablets to be administered will be calculated by the study dedicated pharmacist considering the number of tablets that should be taken in case a patient with the same weight is assigned to arm C.

Study Overview

• Status: Terminated
• Conditions: Covid19
• Intervention / Treatment: Drug: Ivermectin; Other: Placebo

Detailed Description

Primary objectives

The study is aimed:

1. at defining if ivermectin, administered at dosage of 600 μg/kg or 1200 μg/kg QD for five consecutive days is safe in patients with initial, asymptomatic or oligosymptomatic SARS_CoV-2 infection,
2. at defining if ivermectin, administered at the dosage(s) found to be safe decreases the viral load of SARS-CoV-2 at Day 7.

Secondary objectives To assess

1. the temporal profile of viral load at baseline, day 7, 14 and 30
2. the time to clinical cure (for symptomatic patients)
3. the proportion of patients with virological clearance at day 14 and 30.
4. the hospitalization rate.
5. the COVID-19 Severity Score at day 14 and 30

STUDY DESIGN

This is a multicentre, prospective, randomized, double-blind, adaptive phase II dose finding study.

Patients meeting the inclusion criteria will be asked to participate to the study and randomized in a 1:1:1 ratio to either:

• Placebo arm (arm A): placebo will be identical in appearance to ivermectin in order to preserve blinding and will be administered p.o. at empty stomach with water once daily, for 5 days
• Intervention arms: a) Ivermectin, single dose 600 μg/kg, for 5 days (I_600) and placebo (arm B) ; b) Ivermectin, single dose 1200 μg/kg, for 5 days (I_1200) (arm C) ); these drugs will be administered p.o. once daily, for 5 days.

In arm A and B, the number of placebo tablets to be administered will be calculated by the study dedicated pharmacist considering the number of tablets that should be taken in case a patient with the same weight is assigned to arm C.

Patients will be randomized by a centralized computer system. At randomization a treatment ID is assigned to the patient. Once a treatment ID is assigned this must not be re-assigned even in cases of errors.

Enrolled subjects will be identified by a unique subject number (patient code) that will remain consistent for the duration of the study.

Patients will be recruited at the emergency room of hospitals, and/or among asymptomatic hospital workers found positive for SARS-CoV-2 at routine screening and/or in outpatient ambulatory settings, and/or at home, if not meeting the clinical criteria for hospitalization, according to the routine procedure of each participating site. The expected duration of subject inclusion in the study is of 1 month, or until the planned number of subjects to be enrolled will be reached.

• Study Type: Interventional
• Enrollment (Actual): 93
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Bologna, Italy
    • Policlinico S. Orsola
  • Milan, Italy
    • Ospedale Luigi Sacco
  • Rovereto, Italy
    • Ospedale di Rovereto
  • Turin, Italy
    • Ospedale Amedeo di Savoia
  • Verona
    • Negrar, Verona, Italy, 37024
      • IRCCS Sacro Cuore Don Calabria hospital

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:

• Age >=18 years
• Positivity at RT-PCR per SARS_CoV2 (nasopharyngeal swabs)
• Consent to participation to the study and to the processing of personal data
• COVID-19 Severity Score < 3
• Patient able to take oral drugs

Exclusion Criteria:

• Pregnant or lactating women (pregnancy test not required, if doubt patient is excluded)
• Subjects suffering from known CNS diseases
• Lack of (or inability to provide) informed consent
• Patient under dialysis
• Any severe medical condition with a prognosis of < 6 months
• Patients under warfarin treatment
• Patients under antiviral treatment
• Patients under chloroquine phosphate or hydroxychloroquine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; placebo	Other: Placebo; Patients should take placebo orally on an empty stomach with water; Other Names: Placebo supplied by chemo group
Experimental: I_600; ivermectin 600 μg/kg daily for 5 consecutive days (I_600) + placebo	Drug: Ivermectin; Patients will be administered a single oral daily dose of approximately 600 μg/Kg (486-679 μg/Kg as rounded to a whole number of tablets), or 1200 μg/Kg (1098-1286 μg/Kg).; Other Names: Ivermectin 9 mg cp by Chemo group
Experimental: I_1200; ivermectin 1200 μg/kg daily at empty stomach with water for 5 consecutive days	Drug: Ivermectin; Patients will be administered a single oral daily dose of approximately 600 μg/Kg (486-679 μg/Kg as rounded to a whole number of tablets), or 1200 μg/Kg (1098-1286 μg/Kg).; Other Names: Ivermectin 9 mg cp by Chemo group

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SADR	Number of serious adverse drug reaction	14 days
Viral load	Quantitative viral load as measured by quantitative, digital droplet PCR.	Assessed at day 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Trend viral load	1. Trend over time of quantitative viral load at Day 7 and 14 as measured by quantitative, digital droplet PCR.	Days 7 and 14 from baseline
Clinical resolution	Time to clinical resolution (for symptomatic patients).	Assessed on Day 30
Viral clearance	Time from diagnosis to documented viral clearance	assessed on days 14 and 30
Virological clearance	Proportion of patients with virological clearance	Assessed at day 14 and 30
hospitalization rate	rate of hospitalization	Day 30
Severity score	COVID-19 Severity Score (Coronavirus Diseases 19 Severity Score) - min value 1 ("no limitation of activities), max value 8 ("death"). Higher scores mean worse outcome	Assessed at Day 14 and Day 30

Collaborators and Investigators

• Sponsor: IRCCS Sacro Cuore Don Calabria di Negrar
• Collaborators: Istituto Di Ricerche Farmacologiche Mario Negri
• Investigators: Principal Investigator: Zeno Bisoffi, IRCCS Sacro Cuore Don Calabria hospital

Study record dates

Study Major Dates

• Study Start (Actual): July 31, 2020
• Primary Completion (Actual): June 8, 2021
• Study Completion (Actual): June 8, 2021

Study Registration Dates

• First Submitted: April 10, 2020
• First Submitted That Met QC Criteria: June 18, 2020
• First Posted (Actual): June 19, 2020

Study Record Updates

• Last Update Posted (Actual): June 23, 2021
• Last Update Submitted That Met QC Criteria: June 17, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: ivermectin
• 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; Anti-Infective Agents; Antiparasitic Agents; Ivermectin
• Other Study ID Numbers: cover_1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: The anonymized database will be uploaded into a public repository
• IPD Sharing Time Frame: The database will be available upon publication of the results
• IPD Sharing Access Criteria: The data will be available in a public repository
• IPD Sharing Supporting Information Type: Study Protocol

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No