PMID- 33842908 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230921 IS - 2666-7762 (Electronic) IS - 2666-7762 (Linking) VI - 4 DP - 2021 May TI - A randomized, double-blind, placebo-controlled phase 1 trial of inhaled and intranasal niclosamide: A broad spectrum antiviral candidate for treatment of COVID-19. PG - 100084 LID - 10.1016/j.lanepe.2021.100084 [doi] LID - 100084 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 beta2-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. CI - (c) 2021 The Authors. FAU - Backer, Vibeke AU - Backer V AD - Department of Otorhinolaryngology, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark. AD - Center for Physical Activity Research, Rigshospitalet, Ole Maaloes vej 24, 2200 Copenhagen, Denmark. FAU - Sjobring, Ulf AU - Sjobring U AD - UNION therapeutics, Tuborg Havnevej 18, 2900 Hellerup, Denmark. FAU - Sonne, Jesper AU - Sonne J AD - Department of Clinical Pharmacology, Bispebjerg and Frederiksberg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen, NV, Denmark. FAU - Weiss, Anne AU - Weiss A AD - Novo Nordisk Center for Biosustainability, Technical University Denmark, Kemitorvet 220, Kongens Lyngby, Denmark. AD - UNION therapeutics Research Services, Tuborg Havnevej 18, 2900 Hellerup, Denmark. FAU - Hostrup, Morten AU - Hostrup M AD - Department of Nutrition, Exercise and Sports, Section of Integrative Physiology, University of Copenhagen, Universitetsparken 13, 2100 Copenhagen, Denmark. FAU - Johansen, Helle Krogh AU - Johansen HK AD - Novo Nordisk Center for Biosustainability, Technical University Denmark, Kemitorvet 220, Kongens Lyngby, Denmark. AD - Department of Clinical Microbiology, Rigshospitalet, Henrik Harpestrengs Vej 4A, 2100 Copenhagen, Denmark. AD - Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark. FAU - Becker, Victoria AU - Becker V AD - Center for Physical Activity Research, Rigshospitalet, Ole Maaloes vej 24, 2200 Copenhagen, Denmark. FAU - Sonne, David P AU - Sonne DP AD - Department of Clinical Pharmacology, Bispebjerg and Frederiksberg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen, NV, Denmark. FAU - Balchen, Torben AU - Balchen T AD - DanTrials, Bispebjerg and Frederiksberg Hospital, Nielsine Nielsens Vej 6B, 2400 Copenhagen NV, Denmark. FAU - Jellingso, Mads AU - Jellingso M AD - UNION therapeutics, Tuborg Havnevej 18, 2900 Hellerup, Denmark. FAU - Sommer, Morten Otto Alexander AU - Sommer MOA AD - UNION therapeutics, Tuborg Havnevej 18, 2900 Hellerup, Denmark. AD - Novo Nordisk Center for Biosustainability, Technical University Denmark, Kemitorvet 220, Kongens Lyngby, Denmark. LA - eng PT - Journal Article DEP - 20210406 PL - England TA - Lancet Reg Health Eur JT - The Lancet regional health. Europe JID - 101777707 PMC - PMC8021896 COIS- Dr. Sommer, Ms. Weiss and Mr Jellingso are shareholders or benefit from an employee incentive scheme in UNION therapeutics. All other authors have nothing to disclose. EDAT- 2021/04/13 06:00 MHDA- 2021/04/13 06:01 PMCR- 2021/04/06 CRDT- 2021/04/12 06:29 PHST- 2021/04/13 06:00 [pubmed] PHST- 2021/04/13 06:01 [medline] PHST- 2021/04/12 06:29 [entrez] PHST- 2021/04/06 00:00 [pmc-release] AID - S2666-7762(21)00061-2 [pii] AID - 100084 [pii] AID - 10.1016/j.lanepe.2021.100084 [doi] PST - ppublish SO - Lancet Reg Health Eur. 2021 May;4:100084. doi: 10.1016/j.lanepe.2021.100084. Epub 2021 Apr 6.