key: cord-1044870-3e11ssoq authors: Figueroa, J. M.; Lombardo, M.; Dogliotti, A.; Flynn, L.; Giugliano, R. P.; Simonelli, G.; Valentini, R.; Ramos, A.; Romano, P.; Marcote, M.; Michelini, A.; Salvado, A.; Sykora, E.; Kniz, C.; Kobelinsky, M.; Salzberg, D.; Jerusalinsky, D.; Uchitel, O.; Group, CARR-COV2 Trial title: Efficacy of a nasal spray containing Iota-Carrageenan in the prophylaxis of COVID-19 in hospital personnel dedicated to patients care with COVID-19 disease. A pragmatic multicenter, randomized, double-blind, placebo-controlled trial (CARR-COV-02) date: 2021-04-15 journal: nan DOI: 10.1101/2021.04.13.21255409 sha: 86b9f0b9ad3f622d194de73feb26262ae09eb588 doc_id: 1044870 cord_uid: 3e11ssoq Background Iota-Carrageenan (I-C) is a sulfate polysaccharide synthesized by red algae, with demonstrated antiviral activity and clinical efficacy as nasal spray in the treatment of common cold. In vitro, I-C inhibits SARS-CoV-2 infection in cell culture. Methods This is a pragmatic multicenter, randomized, double-blind, placebo-controlled trial assessing the use of a nasal spray containing I-C in the prophylaxis of COVID-19 in hospital personnel dedicated to care of COVID-19 patients. Clinically healthy physicians, nurses, kinesiologists and others medical providers were assigned in a 1:1 ratio to receive four daily doses of I-C spray or placebo for 21 days. The primary end point was clinical COVID-19, as confirmed by reverse-transcriptase-polymerase-chain-reaction testing, over a period of 21 days. The trial is registered at ClinicalTrials.gov (NCT04521322). Findings A total of 394 individuals were randomly assigned to receive I-C or placebo. Both treatment groups had similar baseline characteristics. The incidence of COVID-19 was significantly lower in the I-C group compared to placebo (1.0% vs 5.0%) (Odds Ratio 0.19 (95% confidence interval 0.05 to 0.77; p= 0.03). Workday loss in placebo group compared to I-C were 1.6% days / person (95% CI, 1.0 to 2.2); p <0.0001 There were no differences in the incidence of adverse events across the two groups (17.3% in the I-C group and 15.2% in the placebo group, p= 0.5). Interpretation I-C showed significant efficacy in preventing SARS-CoV-2 infection in hospital personnel dedicated to care patients with COVID-19 disease. Background Iota-Carrageenan (I-C) is a sulfate polysaccharide synthesized by red algae, with demonstrated antiviral activity and clinical efficacy as nasal spray in the treatment of common cold. In vitro, I-C inhibits SARS-CoV-2 infection in cell culture. This is a pragmatic multicenter, randomized, double-blind, placebo-controlled trial assessing the use of a nasal spray containing I-C in the prophylaxis of in hospital personnel dedicated to care of COVID-19 patients. Clinically healthy physicians, nurses, kinesiologists and others medical providers were assigned in a 1:1 ratio to receive four daily doses of I-C spray or placebo for 21 days. The primary end point was clinical COVID-19, as confirmed by reversetranscriptase-polymerase-chain-reaction testing, over a period of 21 days. The trial is registered at ClinicalTrials.gov (NCT04521322). A total of 394 individuals were randomly assigned to receive I-C or placebo. Both treatment groups had similar baseline characteristics. The incidence of COVID19 was significantly lower in the I-C group compared to placebo (1·0% vs 5·0%) (Odds Ratio 0·19 (95% confidence interval 0·05 to 0·77; p= 0·03). Workday loss in placebo group compared to I-Cc were 1.6% days / person (95% ci, 1.0 to 2.2); p <0.0001 There were no differences in the incidence of adverse events across the two groups (17·3% in the I-C group and 15·2% in the placebo group, p= 0·5). Interpretation I-C showed significant efficacy in preventing SARS-Cov-2 infection in hospital personnel dedicated to care patients with COVID-19 disease. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 15, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 Introduction A novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first identified in December 2019 as the cause of a respiratory illness designated Coronavirus disease 2019, or COVID-19. Current available evidence shows that COVID-19 virus is transmitted between people through close contact and droplets. Being in close contact with infected individuals is therefore a risk factor to contract COVID19. Unvaccinated health care providers, who are in close contact with COVID-19 patient are therefore at an increased risk for COVID19. This inevitably places unvaccinated health and other hospital workers at a high risk of infection. Recent COVID19 vaccine developments have shown a high efficacy at preventing COVID19 (1, 2) , and vaccination rate among healthcare workers in high income countries has grown steadily over the first quarter of 2020 (3-6) . Because the primary site of infection and replication of most cold-causing viruses is the nasal mucosa, it has been hypothesized that early and targeted treatment of . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 15, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 the nasal mucosa with Iota-Carrageenan may block viral entry on that level and interfere locally with the propagation of viral replication. In three randomized clinical trials (two in adults and one in children) that compared Iota-Carrageenan nasal spray with saline solution (placebo) there were strong indications of efficacy, including significantly reduced cold symptoms;(11) positive effects on symptoms in patients in whom less co-medication or no co-medication was used;(12) significantly reduced viral loads;(11-13) and faster reduction of common cold symptoms. (12) (13) Treatments were safe and well tolerated. (11) (12) (13) In cell culture Iota-Carrageenan has demonstrated antiviral activity against SARS-CoV-2 virus (14, 15) and SARSCoV-2 Spike Pseudotyped Lentivirus (SSPL). (16) Taking into account that the concentrations found to be active in vitro against SARS-CoV-2 may be easily achieved by the application of nasal sprays already marketed in several countries, (14) and that during the first days of disease the virus is localized mainly in the nasal cavity and the nasopharynx,(17) we hypothesized that a nasal spray with Iota-Carrageenan could potentially be used as preexposure and during exposure prophylaxis, to prevent symptomatic infection in health workers at high risk of COVID19 infection. We conducted a pragmatic randomized, placebo-controlled clinical trial to determine if a nasal spray with Iota-Carrageenan can prevent COVID-19 infection in healthcare workers caring for COVID-19 patients. This study was carried out when vaccination plans had not yet begun in Argentina. We randomly assigned participants in a 1:1 ratio to receive either Iota-Carrageenan or placebo. Trial enrollment began on July 24, 2020. Health and other hospital workers attending patients with a positive polymerase-chain-reaction (PCR) assay for SARS-CoV-2 admitted in hospitals were eligible. This trial was approved by the institutional review board and by the ethics committees of each participating center, and participants provided written consent prior to participation. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 15, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 The primary outcome was prespecified as symptomatic illness confirmed by a positive molecular assay (PCR) at a local testing facility (using a protocol-defined acceptable test). COVID-19 -related symptoms were the self-reported (any of them) presence of cough, shortness of breath, or difficulty breathing, fever, chills, rigors, myalgia, headache, sore throat, new olfactory and taste disorders, diarrhea and/or vomiting. In any case, the participants received a daily message on their phone, with a structured questionnaire with the symptoms that should be reported. These symptoms were reported to the center's main investigating doctor, who confirmed the clinical suspicion and requested the test to determine the presence of COVID-19 disease. We estimated that 200 participants would need to be enrolled in each group to give the trial approximately 80% power, at two-sided type I error rate of 5%, to show that COVID-19 would be 50% lower in active treatment group than in the placebo. The strength of association was expressed as a relative risk reduction and its 95% confidence intervals (95% CI). Proportions were compared with the chi-square test or Fisher´s exact test, and the continuous quantitative variables with the Student's t test. We conducted all analyses with SAS software, version 9·4 (SAS Institute), according to the intention-to-treat principle, with two-sided type I error with an alpha of 0·05. From July 24, 2020, to December 20, 2020, a total of 400 hospital workers were enrolled and underwent randomization at 10 hospitals in Argentina. Six participants were excluded from the final analysis because they had symptoms suggestive of COVID-19 at the time of randomization. Of the remaining 394 participants, 196 had been assigned to receive Iota-Carrageenan and 198 to receive placebo. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 15, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 Thirteen individuals in Iota-Carrageenan group and 14 in placebo group withdrew consent before day 21 and did not provide information about their health status. The mean age of participants was 38.5±9 years old, and 75.1% were female gender ( Table 1) . Forty three participants underwent a PCR test for presenting symptoms compatible with COVID-19 (Table 2) , 31 were negative (7·6% in the Iota-Carrageenan group and 8.6% in the placebo group; p= 0·8). Overall, new COVID-19 (symptomatic with PCR-confirmed) developed in 12 of 394 participants (3.04%) during the 21 days of follow-up ( Business day losses censored at day 21 were lower in I-C group (0.5% and 2.0%; p< 0.0001). In sensitivity analysis in which we removed from our analyses individuals who presented symptoms before 7 days after randomization, the risk reduction was 95% (95% CI, 6.0% to 99.7%), p= 0.04. OR: 0.05 (95% CI, 0.003 to 0.9), p=0.04. Days off work in placebo group compared to I-C were 1.6% days / person (95% CI, 1.0 to 2.2); p <0.0001 In the Iota-Carrageenan group and placebo group, 17.3% and 15.2%, respectively, reported at least one adverse effect (p = 0.5) The results of this study show that the Iota-Carrageenan nasal spray is safe and effective to prevent COVID-19 disease in hospital workers providing care for COVID-19 patients. In our study we identified a risk reduction greater than 80%. This finding is particularly relevant as until now the only prophylactic interventions with demonstrated efficacy are vaccines who are not yet accessible worldwide. In facts, vaccination rates among healthcare workers remain particularly low, specially in the global south. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 15, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 There has been growing interest in the potential efficacy of drugs with demonstrated in vitro efficacy. During the early days of the COVID-19 pandemic, there was an increased attention to the use of hydroxychloroquine, an agent that was active in vitro but did not prevent COVID-19 when used as pre or postexposure prophylaxis (18) (19) (20) . With at least two registered clinical trials as of Our study have some limitations. First, we included apparently healthy individuals without confirmation by PCR test. Second, those who remained asymptomatic were also not tested. Third, we do not know the exposure dose of each participant, although, the number of active principle and placebos administered in each participating center were identical. The devastating urgency of the COVID-19 pandemic requires a simple and pragmatic design trial with the ability to give, in this context, a quick and efficient answer. This is particularly important considering that health providers are overworked and extremely busy, and a higher burden associated with completing numerous data would have resulted in low study compliance. Our study has also a number of strengths. First, we chose healthcare and other hospital workers to participate in this research as a simple and easy-to-follow model. Second, enrollment took place during a high rate of community . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 15, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 transmission in Argentina, therefore, our participants were also exposed outside the hospital. Third, and following the pragmatic nature of this randomized controlled clinical trial and according to the regulations established by the Nation Ministry of Health, we performed only one PCR test between 48 and 72 hours after the onset of symptoms, assuming that a negative first test may not have been enough, nor we have carried out antibody dosages to confirm the disease. Finally, a small number of individuals were lost to follow up (6.8%). In sensitivity analysis where it was hypothesized that the 13 lost individuals from the Iota-Carrageenan group were infected, and that the 14 lost individuals from the placebo group were not infected, no differences were found in infection rates of both groups (p= 0.3). The nasal spray with I-C showed significant efficacy in preventing SARS-Cov-2 infection in personnel dedicated to care patients with Covid-19 disease. This finding should be replicated in future clinical trials. . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 15, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 Table 1 : Baseline characteristics of the intention-to-treat population . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted April 15, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted April 15, 2021. ; https://doi.org/10.1101 https://doi.org/10. /2021 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 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Efficacy and Safety of Hydroxychloroquine vs Placebo for Pre-exposure SARS-CoV-2 Prophylaxis Among Health Care Workers: A Randomized Clinical Trial Acknowledgements: We thank the participating hospitals, their staff and persons included in this study.