Effect of spirulina on risk of hospitalization among patients with COVID-19: the TOGETHER randomized trial
Gilmar Reis, Eduardo Augusto Dos Santos Moreira Silva, Daniela Carla Medeiros Silva, Lehana Thabane, Thiago Santiago Ferreira, Castilho Vitor Quirino Dos Santos, Ana Paula Figueiredo Guimaraes Almeida, Leonardo Cançado Monteiro Savassi, Adhemar Dias De Figueiredo Neto, Luiza Lanna França Reis, Vitoria Helena De Souza Campos, Carina Bitarães, Eduardo Diniz Callegari, Maria Izabel Campos Simplicio, Luciene Barra Ribeiro, Rosemary Oliveira, Ofir Harari, Jamie I Forrest, Prince Kumar Lat, Louis Dron, Kristian Thorlund, Edward J Mills
The American Journal of Clinical Nutrition, doi:10.1016/j.ajcnut.2024.06.016
Background: Algae-derived nutraceuticals, such as spirulina, have been reported to have biological activities that may minimize clinical consequences to COVID-19 infections. Objectives: This study aimed to determine whether spirulina is an effective treatment for high-risk patients with early COVID-19 in an outpatient setting. Methods: The TOGETHER trial is a placebo-controlled, randomized, platform trial conducted in Brazil. Eligible participants were symptomatic adults with a positive rapid test for SARS-CoV-2 older than 50 y or with a known risk factor for disease severity. Patients were randomly assigned to receive placebo or spirulina (1 g twice daily for 14 d). The primary end point was hospitalization defined as either retention in a COVID-19 emergency setting for >6 h or transfer to tertiary hospital owing to COVID-19 at 28 d. Secondary outcomes included time-to-hospitalization, mortality, and adverse drug reactions. We used a Bayesian framework to compare spirulina with placebo. Results: We recruited 1126 participants, 569 randomly assigned to spirulina and 557 to placebo. The median age was 49.0 y, and 65.3% were female. The primary outcome occurred in 11.2% in the spirulina group and 8.1% in the placebo group (odds ratio [OR]: 1.24; 95% credible interval: 0.84, 1.86). There were no differences in emergency department visit (OR: 1.21; 95% credible interval: 0.81, 1.83), nor time to symptom relief (hazard ratio: 0.90; 95% credible interval: 0.79, 1.03). Spirulina also not demonstrate important treatment effects in the prespecified subgroups defined by age, sex, BMI, days since symptom onset, or vaccination status. Conclusions: Spirulina has no any clinical benefits as an outpatient therapy for COVID-19 compared with placebo with respect to reducing the retention in an emergency setting or COVID-19-related hospitalization. There are no differences between spirulina and placebo for other secondary outcomes. This trial was registered at clinicaltrials.gov as NCT04727424.
Author Contributions The authors' responsibilities were as follows -GR, EAdSMS, DCMS, OH, JIF, KT, EJM: conceived and designed the study; GR, LCMS, TSF, LLFR, MICS, LBR, DCMS, EAdSMS, APFGA, ADdFN, VHdSC, CB, EDC, RO, PL, OH, JIF, LD, EJM: performed acquisition, analysis, or interpretation of data; GR, DCMS, PL, OH, JIF, LD, EJM: drafted the manuscript; GR, LT, LCMS, TSF, LLFR, MICS, LBR, DCMS, EAdSMS, APFGA, ADdFN, VHdSC, CB, EDC, RO, PL, OH, LD, EJM: critically reviewed the manuscript for important intellectual content; GR, PL, OH, EJM: performed statistical analysis; GR, LCMS, TSF, LLFR, MICS, LBR, JIF, LD, EJM: were responsible for administrative and technical of material support; GR, TSF, LLFR, MICS, LBR, DCMS, KT, EJM: supervised the study; and all authors: read and approved the final manuscript.
Conflict of interest The authors report no conflicts of interest.
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.ajcnut.2024.06.016 .
References
Aiello, Li, Boschin, Bollati, Arnoldi et al., Chemical and biological characterization of spirulina protein hydrolysates: focus on ACE and DPP-IV activities modulation, J. Funct. Foods,
doi:10.1016/j.jff.2019.103592Blette, Granholm, Li, Shankar-Hari, Lange et al., Causal Bayesian machine learning to assess treatment effect heterogeneity by dexamethasone dose for patients with COVID-19 and severe hypoxemia, Sci. Rep,
doi:10.1038/s41598-023-33425-3Brown, Obasi, Barrett, Rasch analysis of the WURSS-21 dimensional validation and assessment of invariance, J. Lung Pulm. Respir. Res,
doi:10.15406/jlprr.2015.03.00076Ceban, Ling, Lui, Lee, Gill et al., Fatigue and cognitive impairment in post-COVID-19 syndrome: a systematic review and meta-analysis, Brain Behav Immun,
doi:10.1016/j.bbi.2021.12.020Chei, Oh, Song, Seo, Lee et al., Spirulina maxima extract prevents activation of the NLRP3 inflammasome by inhibiting ERK signaling, Sci. Rep,
doi:10.1038/s41598-020-58896-6Garcia-Ruiz, Villalobos-S Anchez, Alam-Escamilla, Elizondo-Quiroga, In vitro inhibition of SARS-CoV-2 infection by dry algae powders, Sci. Rep,
doi:10.1038/s41598-022-22148-6Goligher, Lawler, Jensen, Talisa, Berry et al., Heterogeneous treatment effects of therapeutic-dose heparin in patients hospitalized for COVID-19, JAMA,
doi:10.1001/jama.2023.3651Herdman, Gudex, Lloyd, Janssen, Kind et al., Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L), Qual. Life Res,
doi:10.1007/s11136-011-9903-xHirahashi, Matsumoto, Hazeki, Saeki, Ui et al., Activation of the human innate immune system by spirulina: augmentation of interferon production and NK cytotoxicity by oral administration of hot water extract of Spirulina platensis, Int. Immunopharmacol,
doi:10.1016/S1567-5769(01)00166-7Javid, Santos, Norouzi, Taghavi, Hatami et al., The effects of Spirulina platensis supplementation on COVID-19 severity in critically ill patients: a randomized clinical trial, ResearchSquare,
doi:10.21203/rs.3.rs-2382997/v1Niraula, Baral, Lamsal, Bataju, Thapa, Potential role of biochemical markers in the prognosis of COVID-19 patients, SAGE Open Med,
doi:10.1177/20503121221108613Ratha, Renuka, Rawat, Bux, Prospective options of algae-derived nutraceuticals as supplements to combat COVID-19 and human coronavirus diseases, Nutrition,
doi:10.1016/j.nut.2020.111089Reis, Moreira-Silva, Silva, Thabane, Milagres et al., Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial, Lancet Glob. Health,
doi:10.1016/S2214-109X(21)00448-4Reis, Santos Moreira Silva, Medeiros Silva, Thabane, Cruz Milagres et al., Effect of early treatment with metformin on risk of emergency care and hospitalization among patients with COVID-19: the TOGETHER randomized platform clinical trial, Lancet Reg. Health Am,
doi:10.1016/j.lana.2021.100142Reis, Santos Moreira Silva, Silva, Thorlund, Thabane et al., A multi-center, adaptive, randomized, platform trial to evaluate the effect of repurposed medicines in outpatients with early coronavirus disease 2019 (COVID-19) and high-risk for complications: the TOGETHER master trial protocol, Gates Open Res,
doi:10.12688/gatesopenres.13304.1Reis, Silva, Medeiros Silva, Thabane, Singh et al., Effect of early treatment with hydroxychloroquine or lopinavir and ritonavir on risk of hospitalization among patients with COVID-19: the TOGETHER randomized clinical trial, JAMA Netw. Open,
doi:10.1001/jamanetworkopen.2021.6468Reis, Silva, Silva, Thabane, Milagres et al., Effect of early treatment with ivermectin among patients with COVID-19, N. Engl. J. Med,
doi:10.1056/NEJMoa2115869Schandelmaier, Briel, Varadhan, Schmid, Devasenapathy et al., Development of the Instrument to assess the Credibility of Effect Modification Analyses (ICEMAN) in randomized controlled trials and meta-analyses, CMAJ,
doi:10.1503/cmaj.200077Selmi, Leung, Fischer, German, Yang et al., The effects of spirulina on anemia and immune function in senior citizens, Cell. Mol. Immunol,
doi:10.1038/cmi.2010.76Shenoy, Mohanty, Suganthy, Manavalan, Alexander, Utility of biochemical markers in predicting severe COVID-19: experience from a tertiary hospital in South India, EJIFCC
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