Niclosamide 500mg chewable tablets

Aim Niclosamide is an established anthelmintic substance and a promising candidate for treating cancer, viral infections, and other diseases. However, its solubility in aqueous media is low, and the systemic bioavailability of the commercially available chewing tablet is poor, limiting the use of niclosamide for systemic treatment. A liquid oral formulation using polyethylene glycol 400 was developed and investigated in healthy volunteers to assess safety, tolerability, and pharmacokinetics in comparison to the marketed tablet. (ClinicalTrials.gov: NCT04644705). Methods The study consisted of three parts: Part A was a double-blind placebo-controlled single ascending dose trial in three dose groups (200, 600, and 1600 mg) with four participants receiving either the investigational niclosamide formulation or placebo (3:1) under fasted and/or fed conditions. Part B was a crossover study comparing 1600 mg investigational niclosamide solution with the marketed 2000 mg chewing tablet in four healthy volunteers. Part C was a double-blind placebo-controlled multiple-dose trial comparing 1200 mg and 1600 mg (verum: placebo 4:2) in two dose groups with six subjects each, who received daily doses for seven days. Results No serious or severe adverse events occurred. The most frequent adverse events were mild to moderate gastrointestinal reactions. There was also no apparent dependence between drug exposure levels (AUC, Cmax) and the severity and incidence of adverse events detectable. A relevant food effect was observed with a mean AUC last about 2-fold higher in fed condition compared to fasted condition. In Part B, dose-normalized C max and AUC last were similar for niclosamide solution and tablet. Absorption of niclosamide solution was highly variable. Some individuals showed high absorption (C max > 2µg/ml) whereas others did absorb only marginally. Importantly, there was no dose linearity in the range of 200 mg – 1600 mg. No signs of relevant systemic drug accumulation after multiple administrations were observed. Conclusion Overall safety and tolerability observed in healthy subjects were benign. This is also true for individuals with high absorption (C max > 2µg/ml), encouraging further research into niclosamide as a potential therapeutic agent. Galenic optimization, however, will remain challenging as evident from the observed exposure variability and non-linear PK. Non-linearity, if confirmed by additional data, might make niclosamide more suitable for multi-dose rather than high single dose regimens. The observed food effect should also be considered when further investigating systemic niclosamide exposures. Trial registration ClinicalTrials.gov NCT04644705

Abstract licence: CC BY 4.0

Effective and reliable treatments for SARS-CoV-2 infections are a key part of global COVID-19 management. Based on vitro studies, niclosamide has been considered as a potential drug candidate for SARS-CoV-2, but its clinical development has been limited due to poor solubility and bioavailability. Here we report results from a randomized, double-blind, placebo-controlled clinical trial involving 300 patients (Clinical Trial Registration Number: KCT0007307) that assessed the efficacy and safety of the niclosamide nanohybrid CP-COV03 at two different doses. Oral CP-COV03 was well tolerated, with no serious adverse events reported in any treatment group. The primary endpoints demonstrated that CP-COV03 significantly alleviated all 12 FDA-recommended COVID-19 symptoms, with symptom improvement sustained for more than 48 h. Additionally, CP-COV03 reduced SARS-CoV-2 viral load by 56.7% within 16 h of the initial dose compared to baseline. Secondary endpoints, including time to sustained symptom resolution, time to return to usual health, and reduction in hospitalization risk, also showed favorable results in the CP-COV03 group compared to placebo. These findings indicate that CP-COV03 is a safe and effective therapeutic option for the treatment of mild to moderate COVID-19 and represents a promising advancement in the repurposing of niclosamide through nanohybrid engineering.

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PurposeDespite vaccination, many patients remain vulnerable to COVID-19 infection and poorer outcomes, because of underlying health conditions resulting in sub-optimal vaccine responses. This study aims to demonstrate whether intranasal niclosamide confers additional protection against COVID-19 infection above standard preventative measures including vaccination.MethodsPROTECT-V (PROphylaxis for paTiEnts at risk of COVID-19 infecTion) is a platform trial testing multiple pre-exposure COVID-19 prophylactic agents in vulnerable patients. This paper reports results from the randomised, double blind, placebo controlled intranasal niclosamide arm. 1651 adult patients on dialysis, with a kidney transplant or renal autoimmune conditions on immunosuppression were randomised from 48 sites (37 UK; 11 Indian). Intranasal niclosamide or matched placebo was administered twice daily, for up to nine months. Primary outcome was time to symptomatic COVID-19 infection.Results1651 patients were randomised (826 niclosamide;825 placebo) between February 2021 to November 2022. 655(39.7%) were dialysis patients, 622(37.7%) kidney transplant recipients and 374(22.7%) had renal autoimmune disease. 97.5% patients in the UK and 66.4% patients in India with comparable proportions in both treatment groups had received COVID-19 vaccinations. Despite no adverse safety signal, there was a high withdrawal rate (40% niclosamide;23.8% placebo) due to local upper airway irritation leading to a significantly shorter treatment duration in the niclosamide group). Symptomatic COVID-19 infection during study treatment was observed in 103 patients in the niclosamide group and 133 in the placebo group (estimated hazard ratio 1.02(95%CI 0.79-1.32)).ConclusionIntranasal niclosamide did not reduce risk of symptomatic COVID-19 infection in this cohort compared to placebo.Trial registrationThis study is registered with ClinicalTrials.gov: NCT04870333 (submitted 01/03/2021; posted 03/05/2021), EudraCT: 2020-004144-28 and the Clinical Trials Registry of India (CTRI):#CTRI/2022/03/040802.

Abstract licence: CC BY