A study protocol for a double-blind randomised placebo-controlled trial evaluating the efficacy of carrageenan nasal and throat spray for COVID-19 prophylaxis-ICE-COVID

Z M Jessop, J Gibson, J Y Lim, T H Jovic, E Combellack, T D Dobbs, K Carter, S Hiles, S Islam, B Healy, I Humphreys, R Eccles, H A Hutchings, I S Whitaker, Z M Jessop, J Gibson, J Y Lim, T H Jovic, E Combellack, T D Dobbs, K Carter, S Hiles, S Islam, B Healy, I Humphreys, R Eccles, H A Hutchings, I S Whitaker

Abstract

Introduction: At present, vaccines form the only mode of prophylaxis against COVID-19. The time needed to achieve mass global vaccination and the emergence of new variants warrants continued research into other COVID-19 prevention strategies. The severity of COVID-19 infection is thought to be associated with the initial viral load, and for infection to occur, viruses including SARS-CoV-2 must first penetrate the respiratory mucus and attach to the host cell surface receptors. Carrageenan, a sulphated polysaccharide extracted from red edible seaweed, has shown efficacy against a wide range of viruses in clinical trials through the prevention of viral entry into respiratory host cells. Carrageenan has also demonstrated in vitro activity against SARS-CoV-2.

Methods and analysis: A single-centre, randomised, double-blinded, placebo-controlled phase III trial was designed. Participants randomised in a 1:1 allocation to either the treatment arm, verum Coldamaris plus (1.2 mg iota-carrageenan (Carragelose®), 0.4 mg kappa-carrageenan, 0.5% sodium chloride and purified water), or placebo arm, Coldamaris sine (0.5% sodium chloride) spray applied daily to their nose and throat for 8 weeks, while completing a daily symptom tracker questionnaire for a total of 10 weeks.

Primary outcome: Acquisition of COVID-19 infection as confirmed by a positive PCR swab taken at symptom onset or seroconversion during the study. Secondary outcomes include symptom type, severity and duration, subsequent familial/household COVID-19 infection and infection with non-COVID-19 upper respiratory tract infections. A within-trial economic evaluation will be undertaken, with effects expressed as quality-adjusted life years.

Discussion: This is a single-centre, phase III, double-blind, randomised placebo-controlled clinical trial to assess whether carrageenan nasal and throat spray reduces the risk of development and severity of COVID-19. If proven effective, the self-administered prophylactic spray would have wider utility for key workers and the general population.

Trial registration: NCT04590365; ClinicalTrials.gov NCT04590365. Registered on 19 October 2020.

Keywords: COVID-19.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
ICE-COVID research question (PICO format)
Fig. 2
Fig. 2
ICE-COVID trial design. The flow chart summarises the design of the ICE-COVID trial
Fig. 3
Fig. 3
ICE-COVID inclusion and exclusion criteria

References

    1. Dong E, Du H, Gardner L. An interactive web-based dashboard to track COVID-19 in real time. Lancet Infect Dis. 2020;20:533–534. doi: 10.1016/S1473-3099(20)30120-1.
    1. Transmission of SARS-CoV-2: implications for infection prevention precautions. Available from: . Accessed 8 May 2021.
    1. Klompas M, Baker MA, Rhee C. Airborne Transmission of SARS-CoV-2: Theoretical Considerations and Available Evidence. JAMA. 2020;324:441. doi: 10.1001/jama.2020.12458.
    1. Nguyen LH, Drew DA, Graham MS, Joshi AD, Guo C-G, Ma W, et al. Risk of COVID-19 among front-line health-care workers and the general community: a prospective cohort study. Lancet Public Health. 2020;5:e475–e483. doi: 10.1016/S2468-2667(20)30164-X.
    1. Mutambudzi M, Niedzwiedz C, Macdonald EB, Leyland A, Mair F, Anderson J, et al. Occupation and risk of severe COVID-19: prospective cohort study of 120 075 UK Biobank participants. Occup Environ Med. 2021;78:307–314. doi: 10.1136/oemed-2020-106731.
    1. WHO: Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19). Available from: . Accessed 11 Mar 2020.
    1. Karlsson U, Fraenkel C-J. Covid-19: risks to healthcare workers and their families. BMJ. 2020;371:m3944. doi: 10.1136/bmj.m3944.
    1. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395:1054–1062. doi: 10.1016/S0140-6736(20)30566-3.
    1. Shah ASV, Wood R, Gribben C, Caldwell D, Bishop J, Weir A, et al. Risk of hospital admission with coronavirus disease 2019 in healthcare workers and their households: nationwide linkage cohort study. BMJ. 2020;371:m3582. doi: 10.1136/bmj.m3582.
    1. Smit M, Marinosci A, Agoritsas T, Calmy A. Prophylaxis for COVID-19: a systematic review. Clin Microbiol Infect. 2021;27:532–537. doi: 10.1016/j.cmi.2021.01.013.
    1. The Economist. More than 85 poor countries will not have widespread access to coronavirus vaccines before 2023. Available from: . Accessed 8 May 2021.
    1. Centers for Disease Control and Prevention. SARS-CoV-2 Variant Classifications and Definitions. Available from: . Accessed 8 May 2021.
    1. Volz E, Mishra S, Chand M, et al. Transmission of SARS-CoV-2 Lineage B.1.1.7 in England: Insights from linking epidemiological and genetic data. MedRxiv 2020.12.30.20249034 [Preprint]. January 11, 2021 [cited 2021 May 8] Available from: 10.1101/2020.12.30.20249034
    1. Tegally H, Wilkinson E, Giovanetti M, et al.. Emergence and rapid spread of a new severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa. MedRxviv 2020.12.21.20248640 [Preprint]. December 22, 2020 [cited 2021 May 8] Available from: 10.1101/2020.12.21.20248640
    1. Liu Y, Liu J, Plante KS, et al. The N501Y spike substitution enhances SARS-CoV-2 transmission. bioRxiv 2021.03.08.434499 [Preprint]. 9 March, 2021 [cited 2021, May 8] Available from: 10.1101/2021.03.08.434499
    1. Xie X, Liu Y, Liu J, Zhang X, Zou J, Fontes-Garfias CR, et al. Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K and N501Y variants by BNT162b2 vaccine-elicited sera. Nat Med. 2021;27:620–621. doi: 10.1038/s41591-021-01270-4.
    1. Wu K, Werner AP, Koch M, Choi A, Narayanan E, Stewart-Jones GBE, et al. Serum Neutralizing Activity Elicited by mRNA-1273 Vaccine. N Engl J Med. 2021;384:1468–1470. doi: 10.1056/NEJMc2102179.
    1. Emary KRW, Golubchik T, Aley PK, Ariani CV, Angus B, Bibi S, et al. Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory analysis of a randomised controlled trial. Lancet. 2021;397:1351–1362. doi: 10.1016/S0140-6736(21)00628-0.
    1. Horby P, Huntley C, Davies N, Edmunds J, Ferguson N, Medley G, et al. NERVTAG. 2021. Available from: . Accessed 8 May 2021.
    1. Campo VL, Kawano DF, Silva DB da, Carvalho I. Carrageenans: biological properties, chemical modifications and structural analysis – A review. Carbohydr Polym. 2009;77:167–80.
    1. Gerber P, Dutcher JD, Adams EV, Sherman JH. Protective Effect of Seaweed Extracts for Chicken Embryos Infected with Influenza B or Mumps Virus. Proc Soc Exp Biol Med. 1958;99:590–593. doi: 10.3181/00379727-99-24429.
    1. Grassauer A, Weinmuellner R, Meier C, Pretsch A, Prieschl-Grassauer E, Unger H. Iota-Carrageenan is a potent inhibitor of rhinovirus infection. Virol J. 2008;5:107. doi: 10.1186/1743-422X-5-107.
    1. Girond S, Crance JM, Van Cuyck-Gandre H, Renaudet J, Deloince R. Antiviral activity of carrageenan on hepatitis A virus replication in cell culture. Res Virol. 1991;142:261–270. doi: 10.1016/0923-2516(91)90011-Q.
    1. Buck CB, Thompson CD, Roberts JN, Müller M, Lowy DR, Schiller JT. Carrageenan is a potent inhibitor of papillomavirus infection. PLoS Pathog. 2006;2:e69. doi: 10.1371/journal.ppat.0020069.
    1. Talarico LB, Pujol CA, Zibetti RGM, Faría PCS, Noseda MD, Duarte MER, et al. The antiviral activity of sulfated polysaccharides against dengue virus is dependent on virus serotype and host cell. Antiviral Res. 2005;66:103–110. doi: 10.1016/j.antiviral.2005.02.001.
    1. González ME, Alarcón B, Carrasco L. Polysaccharides as antiviral agents: antiviral activity of carrageenan. Antimicrob Agents Chemother. 1987;31:1388–1393. doi: 10.1128/AAC.31.9.1388.
    1. Baba M, Snoeck R, Pauwels R, de Clercq E. Sulfated polysaccharides are potent and selective inhibitors of various enveloped viruses, including herpes simplex virus, cytomegalovirus, vesicular stomatitis virus, and human immunodeficiency virus. Antimicrob Agents Chemother. 1988;32:1742–1745. doi: 10.1128/AAC.32.11.1742.
    1. Carlucci MJ, Scolaro LA, Noseda MD, Cerezo AS, Damonte EB. Protective effect of a natural carrageenan on genital herpes simplex virus infection in mice. Antiviral Res. 2004;64:137–141. doi: 10.1016/j.antiviral.2004.07.001.
    1. Pujol CA, Scolaro LA, Ciancia M, Matulewicz MC, Cerezo AS, Damonte EB. Antiviral activity of a carrageenan from Gigartina skottsbergii against intraperitoneal murine herpes simplex virus infection. Planta Med. 2006;72:121–125. doi: 10.1055/s-2005-373168.
    1. Guo C, Zhu Z, Yu P, Zhang X, Dong W, Wang X, et al. Inhibitory effect of iota-carrageenan on porcine reproductive and respiratory syndrome virus in vitro. Antivir Ther. 2019;24:261–270. doi: 10.3851/IMP3295.
    1. Wang W, Zhang P, Hao C, Zhang X-E, Cui Z-Q, Guan H-S. In vitro inhibitory effect of carrageenan oligosaccharide on influenza A H1N1 virus. Antiviral Res. 2011;92:237–246. doi: 10.1016/j.antiviral.2011.08.010.
    1. Leibbrandt A, Meier C, König-Schuster M, Weinmüllner R, Kalthoff D, Pflugfelder B, et al. Iota-carrageenan is a potent inhibitor of influenza A virus infection. PloS One. 2010;5:e14320. doi: 10.1371/journal.pone.0014320.
    1. Morokutti-Kurz M, Graf P, Grassauer A, et al.. SARS-CoV-2 in-vitro neutralization assay reveals inhibition of virus entry by iota-carrageenan. bioRxiv 2020;:2020.07.28.224733 [Preprint]. July 28, 2020 [cited 2021, May 8] Available from: 10.1101/2020.07.28.224733
    1. Koenighofer M, Lion T, Bodenteich A, Prieschl-Grassauer E, Grassauer A, Unger H, et al. Carrageenan nasal spray in virus confirmed common cold: individual patient data analysis of two randomized controlled trials. Multidiscip Respir Med. 2014;9:57. doi: 10.1186/2049-6958-9-57.
    1. Eccles R. Iota-Carrageenan as an Antiviral Treatment for the Common Cold. Open Virol J. 2020;2020(14):9–15.
    1. Eccles R, Meier C, Jawad M, Weinmüllner R, Grassauer A, Prieschl-Grassauer E. Efficacy and safety of an antiviral Iota-Carrageenan nasal spray: a randomized, double-blind, placebo-controlled exploratory study in volunteers with early symptoms of the common cold. Respir Res. 2010;11:108. doi: 10.1186/1465-9921-11-108.
    1. Eccles R, Winther B, Johnston SL, Robinson P, Trampisch M, Koelsch S. Efficacy and safety of iota-carrageenan nasal spray versus placebo in early treatment of the common cold in adults: the ICICC trial. Respir Res. 2015;16:121. 10.1186/s12931-015-0281-8.
    1. Ludwig M, Enzenhofer E, Schneider S, Rauch M, Bodenteich A, Neumann K, et al. Efficacy of a carrageenan nasal spray in patients with common cold: a randomized controlled trial. Respir Res. 2013;14:124. doi: 10.1186/1465-9921-14-124.
    1. Bansil R, Turner BS. The biology of mucus: Composition, synthesis and organization. Adv Drug Deliv Rev. 2018;124:3–15. doi: 10.1016/j.addr.2017.09.023.
    1. Grove J, Marsh M. The cell biology of receptor-mediated virus entry. J Cell Biol. 2011;195:1071–1082. doi: 10.1083/jcb.201108131.
    1. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost JTH. 2020;18:844–847. doi: 10.1111/jth.14768.
    1. Zhang L, Yan X, Fan Q, Liu H, Liu X, Liu Z, et al. D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19. J Thromb Haemost JTH. 2020;18:1324–1329. doi: 10.1111/jth.14859.
    1. Ferrari D, Motta A, Strollo M, Banfi G, Locatelli M. Routine blood tests as a potential diagnostic tool for COVID-19. Clin Chem Lab Med. 2020;58:1095–1099. doi: 10.1515/cclm-2020-0398.
    1. Wang X, Fang J, Zhu Y, Chen L, Ding F, Zhou R, et al. Clinical characteristics of non-critically ill patients with novel coronavirus infection (COVID-19) in a Fangcang Hospital. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis. 2020;26:1063–1068.
    1. Cai Q, Huang D, Yu H, Zhu Z, Xia Z, Su Y, et al. COVID-19: Abnormal liver function tests. J Hepatol. 2020;73:566–574. doi: 10.1016/j.jhep.2020.04.006.
    1. Liu Y, Liao W, Wan L, Xiang T, Zhang W. Correlation Between Relative Nasopharyngeal Virus RNA Load and Lymphocyte Count Disease Severity in Patients with COVID-19. Viral Immunol. 2020;34(5):330–335. doi: 10.1089/vim.2020.0062.
    1. Ilie PC, Stefanescu S, Smith L. The role of vitamin D in the prevention of coronavirus disease 2019 infection and mortality. Aging Clin Exp Res. 2020;32:1195–1198. doi: 10.1007/s40520-020-01570-8.
    1. Wan S, Yi Q, Fan S, Lv J, Zhang X, Guo L, et al. Relationships among lymphocyte subsets, cytokines, and the pulmonary inflammation index in coronavirus (COVID-19) infected patients. Br J Haematol. 2020;189:428–437. doi: 10.1111/bjh.16659.
    1. Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of Immune Response in Patients With Coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis Off Publ Infect Dis Soc Am. 2020;71:762–768. doi: 10.1093/cid/ciaa248.
    1. EuroQol Group EuroQol--a new facility for the measurement of health-related quality of life. Health Policy Amst Neth. 1990;16:199–208. doi: 10.1016/0168-8510(90)90421-9.
    1. NICE. Position statement on use of the EQ-5D-5L value set for England. 2019. Available from: . Accessed 8 May 2021.
    1. Lancet T. The plight of essential workers during the COVID-19 pandemic. Lancet. 2020;395:1587. doi: 10.1016/S0140-6736(20)31200-9.
    1. Shields A, Faustini SE, Perez-Toledo M, Jossi S, Aldera E, Allen JD, et al. SARS-CoV-2 seroprevalence and asymptomatic viral carriage in healthcare workers: a cross-sectional study. Thorax. 2020;75:1089–1094. doi: 10.1136/thoraxjnl-2020-215414.
    1. NICE. Guide to the methods of technology appraisal 2013. 2013. Available from: . Accessed 8 May 2021.
    1. OVl B, Kim HK, Park J. Usability and user experience of medical devices: An overview of the current state, analysis methodologies, and future challenges. Int J Ind Ergon. 2020;76:102932. doi: 10.1016/j.ergon.2020.102932.
    1. Pleil AM, Coyne KS, Reese PR, Jumadilova Z, Rovner ES, Kelleher CJ. The Validation of Patient-Rated Global Assessments of Treatment Benefit, Satisfaction, and Willingness to Continue—The BSW. Value Health. 2005;8:S25–S34. doi: 10.1111/j.1524-4733.2005.00069.x.

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