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A randomized, double-blind, placebo-controlled phase 1 trial of inhaled and intranasal niclosamide: A broad spectrum antiviral candidate for treatment of COVID-19

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@article{aed8af5ea524469b847859ec6111299d,
title = "A randomized, double-blind, placebo-controlled phase 1 trial of inhaled and intranasal niclosamide: A broad spectrum antiviral candidate for treatment of COVID-19",
abstract = "Background: Coronavirus disease 19 (COVID-19) is spreading globally and treatment options remain limited. A formulation of niclosamide, a potent anti-SARS-CoV-2 agent and a broad-spectrum antiviral treatment candidate, optimized for inhalation and intranasal administration (UNI91104) was developed.Methods: We conducted a randomized, placebo-controlled, double-blind, single-centre, dose-ascending Phase 1 trial to assess the safety of UNI91104 in Denmark (NCT04576312). Healthy volunteers were randomly assigned to a ascending single dose in cohort 1-4 and five doses over 2.5 days in cohort 5. Inclusion criteria included a minimum 80% of predicted lung function. Exclusion criteria included severe, clinically significant allergies and current acute or chronic condition especially airway diseases. Safety was evaluated through adverse events (AEs) and pulmonary function tests including forced expiratory volume in one second (FEV1) and fractional exhaled nitric oxide (FeNO) tests. The primary endpoints were defined as the frequency of reported AEs and the change of safety variables relative to pre-dose. Data from all enroled healthy volunteers receiving any amount of IMP was included in the primary analyses. The pharmacokinetics of UNI91104 was determined.Findings: The trial was conducted between 29 June 2020 and 08 August 2020. Thirty-four healthy volunteers received UNI91104 and ten placebo. No serious AEs or discontinuation were reported. Mild irritation in the upper respiratory tract following inhalation of UNI91104 was reported as most frequent AE (45 events in 26 healthy volunteers, 59% of all healthy volunteers). Nasal application was well-tolerated. There was no evidence of difference in the change of mean levels of pulmonary function tests between active and placebo group across all cohorts. Five healthy volunteers (11.4%) (1 on placebo) had signs of increased transient FeNO and 4 on active (9.1%) experienced asymptomatic drops in FEV1, which resolved spontaneously or were reversible with a β2-agonist. Niclosamide exhibited dose-proportional pharmacokinetics following inhalation and intranasal administration.Interpretation: UNI91104, a promising candidate for inhalation and intranasal therapy against COVID-19 and other viral respiratory tract infections is well-tolerated in healthy volunteers and warrants further testing in patient trials.Funding: The study was funded by Innovationsfonden Denmark and UNION therapeutics.",
author = "Vibeke Backer and Ulf Sj{\"o}bring and Jesper Sonne and Anne Weiss and Morten Hostrup and Johansen, {Helle Krogh} and Victoria Becker and Sonne, {David P} and Torben Balchen and Mads Jellings{\o} and Sommer, {Morten Otto Alexander}",
note = "{\textcopyright} 2021 The Authors.",
year = "2021",
month = may,
doi = "10.1016/j.lanepe.2021.100084",
language = "English",
volume = "4",
pages = "100084",
journal = "The Lancet regional health. Europe",
issn = "2666-7762",

}

RIS

TY - JOUR

T1 - A randomized, double-blind, placebo-controlled phase 1 trial of inhaled and intranasal niclosamide

T2 - A broad spectrum antiviral candidate for treatment of COVID-19

AU - Backer, Vibeke

AU - Sjöbring, Ulf

AU - Sonne, Jesper

AU - Weiss, Anne

AU - Hostrup, Morten

AU - Johansen, Helle Krogh

AU - Becker, Victoria

AU - Sonne, David P

AU - Balchen, Torben

AU - Jellingsø, Mads

AU - Sommer, Morten Otto Alexander

N1 - © 2021 The Authors.

PY - 2021/5

Y1 - 2021/5

N2 - Background: Coronavirus disease 19 (COVID-19) is spreading globally and treatment options remain limited. A formulation of niclosamide, a potent anti-SARS-CoV-2 agent and a broad-spectrum antiviral treatment candidate, optimized for inhalation and intranasal administration (UNI91104) was developed.Methods: We conducted a randomized, placebo-controlled, double-blind, single-centre, dose-ascending Phase 1 trial to assess the safety of UNI91104 in Denmark (NCT04576312). Healthy volunteers were randomly assigned to a ascending single dose in cohort 1-4 and five doses over 2.5 days in cohort 5. Inclusion criteria included a minimum 80% of predicted lung function. Exclusion criteria included severe, clinically significant allergies and current acute or chronic condition especially airway diseases. Safety was evaluated through adverse events (AEs) and pulmonary function tests including forced expiratory volume in one second (FEV1) and fractional exhaled nitric oxide (FeNO) tests. The primary endpoints were defined as the frequency of reported AEs and the change of safety variables relative to pre-dose. Data from all enroled healthy volunteers receiving any amount of IMP was included in the primary analyses. The pharmacokinetics of UNI91104 was determined.Findings: The trial was conducted between 29 June 2020 and 08 August 2020. Thirty-four healthy volunteers received UNI91104 and ten placebo. No serious AEs or discontinuation were reported. Mild irritation in the upper respiratory tract following inhalation of UNI91104 was reported as most frequent AE (45 events in 26 healthy volunteers, 59% of all healthy volunteers). Nasal application was well-tolerated. There was no evidence of difference in the change of mean levels of pulmonary function tests between active and placebo group across all cohorts. Five healthy volunteers (11.4%) (1 on placebo) had signs of increased transient FeNO and 4 on active (9.1%) experienced asymptomatic drops in FEV1, which resolved spontaneously or were reversible with a β2-agonist. Niclosamide exhibited dose-proportional pharmacokinetics following inhalation and intranasal administration.Interpretation: UNI91104, a promising candidate for inhalation and intranasal therapy against COVID-19 and other viral respiratory tract infections is well-tolerated in healthy volunteers and warrants further testing in patient trials.Funding: The study was funded by Innovationsfonden Denmark and UNION therapeutics.

AB - Background: Coronavirus disease 19 (COVID-19) is spreading globally and treatment options remain limited. A formulation of niclosamide, a potent anti-SARS-CoV-2 agent and a broad-spectrum antiviral treatment candidate, optimized for inhalation and intranasal administration (UNI91104) was developed.Methods: We conducted a randomized, placebo-controlled, double-blind, single-centre, dose-ascending Phase 1 trial to assess the safety of UNI91104 in Denmark (NCT04576312). Healthy volunteers were randomly assigned to a ascending single dose in cohort 1-4 and five doses over 2.5 days in cohort 5. Inclusion criteria included a minimum 80% of predicted lung function. Exclusion criteria included severe, clinically significant allergies and current acute or chronic condition especially airway diseases. Safety was evaluated through adverse events (AEs) and pulmonary function tests including forced expiratory volume in one second (FEV1) and fractional exhaled nitric oxide (FeNO) tests. The primary endpoints were defined as the frequency of reported AEs and the change of safety variables relative to pre-dose. Data from all enroled healthy volunteers receiving any amount of IMP was included in the primary analyses. The pharmacokinetics of UNI91104 was determined.Findings: The trial was conducted between 29 June 2020 and 08 August 2020. Thirty-four healthy volunteers received UNI91104 and ten placebo. No serious AEs or discontinuation were reported. Mild irritation in the upper respiratory tract following inhalation of UNI91104 was reported as most frequent AE (45 events in 26 healthy volunteers, 59% of all healthy volunteers). Nasal application was well-tolerated. There was no evidence of difference in the change of mean levels of pulmonary function tests between active and placebo group across all cohorts. Five healthy volunteers (11.4%) (1 on placebo) had signs of increased transient FeNO and 4 on active (9.1%) experienced asymptomatic drops in FEV1, which resolved spontaneously or were reversible with a β2-agonist. Niclosamide exhibited dose-proportional pharmacokinetics following inhalation and intranasal administration.Interpretation: UNI91104, a promising candidate for inhalation and intranasal therapy against COVID-19 and other viral respiratory tract infections is well-tolerated in healthy volunteers and warrants further testing in patient trials.Funding: The study was funded by Innovationsfonden Denmark and UNION therapeutics.

UR - http://www.scopus.com/inward/record.url?scp=85109285406&partnerID=8YFLogxK

U2 - 10.1016/j.lanepe.2021.100084

DO - 10.1016/j.lanepe.2021.100084

M3 - Journal article

C2 - 33842908

VL - 4

SP - 100084

JO - The Lancet regional health. Europe

JF - The Lancet regional health. Europe

SN - 2666-7762

M1 - 100084

ER -

ID: 65747440