Three-Day Icatibant on Top of Standard Care in Patients With Coronavirus Disease 2019 Pneumonia: A Randomized, Open-Label, Phase 2, Proof-of-Concept Trial.

BACKGROUND: We aimed to evaluate icatibant, a competitive antagonist of the bradykinin B2 receptors, for the treatment of inpatients with coronavirus disease 2019 (COVID-19) pneumonia admitted in the early hypoxemic stage. METHODS: The randomized, open-label clinical trial of icatibant for COVID-19 pneumonia (ICAT·COVID, registered as NCT04978051 at ClinicalTrials.gov) was conducted in Barcelona. Inpatients requiring supplemental but not high-flow oxygen or mechanical ventilation were allocated (1:1) to treatment with either three 30-mg icatibant doses/d for 3 consecutive days plus standard care or standard care alone, and followed for up to 28 days after initial discharge. The primary and key secondary outcomes were clinical response on study day 10/discharge and clinical efficacy at 28 days from initial discharge, respectively. RESULTS: Clinical response occurred in 27 of 37 patients (73.0%) in the icatibant group and 20 of 36 patients (55.6%) in the control group (rate difference, 17.42; 95% confidence interval [CI], -4.22 to 39.06; P = .115). Clinical efficacy ensued in 37 patients (100.0%) in the icatibant group and 30 patients (83.3%) in the control group (rate difference, 16.67; 95% CI, 4.49-28.84; P = .011). No patient died in the icatibant group, compared with 6 patients (16.7%) in the control group (P = .011). All patients but 1 had adverse events, which were evenly distributed between study arms. No patient withdrew because of adverse events. CONCLUSIONS: Adding icatibant to standard care was safe and improved both COVID-19 pneumonia and mortality in this proof-of-concept study. A larger, phase 3 trial is warranted to establish the clinical value of this treatment. CLINICAL TRIALS REGISTRATION: NCT04978051.

Prospective individual patient data meta-analysis of two randomized trials on convalescent plasma for COVID-19 outpatients.

Data on convalescent plasma (CP) treatment in COVID-19 outpatients are scarce. We aimed to assess whether CP administered during the first week of symptoms reduced the disease progression or risk of hospitalization of outpatients. Two multicenter, double-blind randomized trials (NCT04621123, NCT04589949) were merged with data pooling starting when <20% of recruitment target was achieved. A Bayesian-adaptive individual patient data meta-analysis was implemented. Outpatients aged ≥50 years and symptomatic for ≤7days were included. The intervention consisted of 200-300mL of CP with a predefined minimum level of antibodies. Primary endpoints were a 5-point disease severity scale and a composite of hospitalization or death by 28 days. Amongst the 797 patients included, 390 received CP and 392 placebo; they had a median age of 58 years, 1 comorbidity, 5 days symptoms and 93% had negative IgG antibody-test. Seventy-four patients were hospitalized, 6 required mechanical ventilation and 3 died. The odds ratio (OR) of CP for improved disease severity scale was 0.936 (credible interval (CI) 0.667-1.311); OR for hospitalization or death was 0.919 (CI 0.592-1.416). CP effect on hospital admission or death was largest in patients with ≤5 days of symptoms (OR 0.658, 95%CI 0.394-1.085). CP did not decrease the time to full symptom resolution. TRIAL REGISTRATION: Clinicaltrials.gov NCT04621123 and NCT04589949. REGISTRATION: NCT04621123 and NCT04589949 on https://www. CLINICALTRIALS: gov.

[Revisit after discharge from the emergency department in a cohort of patients with COVID-19 pneumonia and analysis based on the healthcare resource used for follow-up. RESALSEVID study]. / Análisis de la evolucion tras el alta de urgencias en pacientes con neumonía por COVID-19 en función del recurso sanitario utilizado para el seguimiento: estudio RESALSEVID.

INTRODUCTION: COVID-19 pneumonia is a manifestation of SARS-CoV-2 infection and in most cases involves hospital admission. There are recommendations according to which these patients can be discharged without hospital admission, but there is no evidence regarding the revisit and the most appropriate type of follow-up. The objective of the RESALSEVID study was to investigate the variables associated with the 30-day revisit (Rev30d) in a group of patients discharged directly from 4 emergency departments (ED) with COVID-19 pneumonia, and analyze whether there were differences based on 4 different tracking devices. METHOD: Analysis of a prospective cohort of patients discharged directly from the ED with COVID-19 pneumonia in 4 hospital with different models of follow-up at discharge (primary care, hospitalization at home [HaH] phone and in person, HaH phone, hospital phone). RESULTS: Five hundred twenty patients were included, with a mean age of 50.1 years and 51% men. Rev30d was 18.3% and was related only to immunosuppression, odds ratio 4.49 (95% confidence interval 1.10-18.24); p=0.022. There was no difference in Rev30d based on the follow-up model used at discharge from the ED. CONCLUSIONS: There are some recommendations that allow the safe discharge of patients with COVID-19 pneumonia, with no differences in Rev30d depending on the type of follow-up.

Análisis de la evolucion tras el alta de urgencias en pacientes con neumonía por COVID19 en función del recurso sanitario utilizado para el seguimiento: Estudio RESALSEVID Revisit after discharge from the emergency department in a cohort of patients with COVID19 pneumonia and analysis based on the healthcare resource used for follow-up. RESALSEVID study

Introducción: la neumonía COVID19 es una manifestación de la infección por SARS-CoV-2 y en la mayoría de casos supone ingreso hospitalario. Existen recomendaciones según las cuales se puede dar de alta a estos pacientes sin precisar ingreso hospitalario, pero no hay evidencia en relación a la revisita y el tipo de seguimiento más adecuado. El objetivo del estudio RESALSEVID fue investigar las variables asociadas a la revisita a los 30 días (Rev30d) en un grupo de pacientes dados de alta directamente en 4 servicios de urgencias hospitalarios (SUH) con neumonía COVID19, y analizar si existieron diferencias en función de 4 dispositivos de seguimiento diferentes. Método: análisis de una cohorte prospectiva de pacientes dados de alta directamente desde urgencias con neumonía COVID19 en 4 SUH con diferentes modelos de seguimiento al alta (atención primaria, hospitalización a domicilio [HaD] telefónico y presencial, HaD telefónico, telefónico hospitalario). Resultados: se incluyeron 520 pacientes, con una media de edad de 50,1 años y 51% varones. La Rev30d fue del 18,3% y se relacionó únicamente con la inmunosupresión, odds ratio 4,49 (intervalo de confianza del 95% 1,10 – 18,24);p=0,022. No hubo ninguna diferencia en la Rev30d en función del modelo de seguimiento utilizado al alta de urgencias. Conclusiones: existen una serie de recomendaciones que permiten dar de alta de manera segura a pacientes con neumonía COVID19, no existiendo diferencias en la Rev30d en función del tipo de seguimiento.

A multicenter, open-label, randomized, proof-of-concept phase II clinical trial to assess the efficacy and safety of icatibant in patients infected with SARS-CoV-2 (COVID-19) and admitted to hospital units without invasive mechanical ventilation: study protocol (ICAT-COVID).

BACKGROUND: COVID-19 has quickly become a global pandemic with a substantial number of deaths and is a considerable burden for healthcare systems worldwide. Although most cases are paucisymptomatic and limited to the viral infection-related symptoms, some patients evolve to a second phase, with an impaired inflammatory response (cytokine storm) that may lead to acute respiratory distress syndrome and death. This is thought to be caused by increased bradykinin synthesis. METHODS: ICAT-COVID is a multicenter, randomized, open-label, proof-of-concept phase II clinical trial assessing the clinical efficacy and safety of adding icatibant to the standard of care in patients hospitalized with COVID-19 without invasive mechanical ventilation. Patients hospitalized with a confirmed COVID-19 pneumonia diagnosis (RT-PCR or antigen test ≤ 10 days prior to randomization, and radiographic evidence of pulmonary infiltrates), rated "4" or "5" on the WHO's clinical status scale, are eligible. Patients will be randomized on a 1:1 ratio to either standard of care-plus-icatibant (experimental group) or to standard of care alone (control group). The experimental group will receive 30 mg of icatibant subcutaneously 3 times a day for 3 days (for a total of 9 doses). The expected sample size is 120 patients (60 per group) from 2 sites in Spain. Primary outcomes are the efficacy and safety of Icatibant. The main efficacy outcome is the number of patients reaching grades "2" or "1" on the WHO scale within 10 days of starting treatment. Secondary outcomes include "long-term efficacy": number of patients discharged who do not present COVID-19-related relapse or comorbidity up until 28 days after discharge, and mortality. DISCUSSION: Icatibant, a bradykinin type 2 receptor antagonist with proven effectiveness and safety against hereditary angioedema attacks, may be beneficial for COVID-19 patients by inhibiting bradykinin's action on endothelial cells and by inhibiting the SARS-CoV-2 M protease. Our working hypothesis is that treatment with standard of care-plus-icatibant is effective and safe to treat patients infected with SARS-CoV-2 admitted to hospital for pneumonia without invasive mechanical ventilation. TRIAL REGISTRATION: EudraCT 2020-002166-13. CLINICALTRIALS: gov NCT04978051.

High-titre methylene blue-treated convalescent plasma as an early treatment for outpatients with COVID-19: a randomised, placebo-controlled trial.

BACKGROUND: Convalescent plasma has been proposed as an early treatment to interrupt the progression of early COVID-19 to severe disease, but there is little definitive evidence. We aimed to assess whether early treatment with convalescent plasma reduces the risk of hospitalisation and reduces SARS-CoV-2 viral load among outpatients with COVID-19. METHODS: We did a multicentre, double-blind, randomised, placebo-controlled trial in four health-care centres in Catalonia, Spain. Adult outpatients aged 50 years or older with the onset of mild COVID-19 symptoms 7 days or less before randomisation were eligible for enrolment. Participants were randomly assigned (1:1) to receive one intravenous infusion of either 250-300 mL of ABO-compatible high anti-SARS-CoV-2 IgG titres (EUROIMMUN ratio ≥6) methylene blue-treated convalescent plasma (experimental group) or 250 mL of sterile 0·9% saline solution (control). Randomisation was done with the use of a central web-based system with concealment of the trial group assignment and no stratification. To preserve masking, we used opaque tubular bags that covered the investigational product and the infusion catheter. The coprimary endpoints were the incidence of hospitalisation within 28 days from baseline and the mean change in viral load (in log10 copies per mL) in nasopharyngeal swabs from baseline to day 7. The trial was stopped early following a data safety monitoring board recommendation because more than 85% of the target population had received a COVID-19 vaccine. Primary efficacy analyses were done in the intention-to-treat population, safety was assessed in all patients who received the investigational product. This study is registered with ClinicalTrials.gov, NCT04621123. FINDINGS: Between Nov 10, 2020, and July 28, 2021, we assessed 909 patients with confirmed COVID-19 for inclusion in the trial, 376 of whom were eligible and were randomly assigned to treatment (convalescent plasma n=188 [serum antibody-negative n=160]; placebo n=188 [serum antibody-negative n=166]). Median age was 56 years (IQR 52-62) and the mean symptom duration was 4·4 days (SD 1·4) before random assignment. In the intention-to-treat population, hospitalisation within 28 days from baseline occurred in 22 (12%) participants who received convalescent plasma versus 21 (11%) who received placebo (relative risk 1·05 [95% CI 0·78 to 1·41]). The mean change in viral load from baseline to day 7 was -2·41 log10 copies per mL (SD 1·32) with convalescent plasma and -2·32 log10 copies per mL (1·43) with placebo (crude difference -0·10 log10 copies per mL [95% CI -0·35 to 0·15]). One participant with mild COVID-19 developed a thromboembolic event 7 days after convalescent plasma infusion, which was reported as a serious adverse event possibly related to COVID-19 or to the experimental intervention. INTERPRETATION: Methylene blue-treated convalescent plasma did not prevent progression from mild to severe illness and did not reduce viral load in outpatients with COVID-19. Therefore, formal recommendations to support the use of convalescent plasma in outpatients with COVID-19 cannot be concluded. FUNDING: Grifols, Crowdfunding campaign YoMeCorono.

Predictores de revisita en pacientes con infección aguda COVID-19 con seguimiento al año: estudio de cohorte HUBCOVID365

Objective. To analyze the frequencies of 3 types of hospital revisits by patients after treatment for COVID-19 in the emergency department. Methods. Retrospective observational study of consecutive patients who came to the emergency department in March and April 2020 and were discharged alive with a diagnosis of COVID-19. Baseline and acute episode data were collected and the patients were followed for 1 year. We analyzed variables associated with revisits for any reason, revisits related to COVID-19, and early COVID-19-related revisits (within 30 days). Results. A total of 1352 patients with a mean age of 62.1 years (52.9% male) were studied. A total of 553 revisits were made by 342 patients (25.3%) for any reason;132 (9.8%) revisited in relation to COVID-19 at least once. Of those, 103 (7.6%) revisited within 30 days (early) and 29 (2.2%) came later. COVID-19-related revisits were associated with thrombotic events (odds ratio [OR], 7.58;95% CI, 1.75-32.81) and pulmonary fibrosis (OR, 4.95;95% CI, 1.27-19.24);early revisits were inversely associated with follow-up management by a contracted health care support service (OR, 0.18;95% CI, 0.03-0.92). Hospital admission during the initial visit was significantly associated with fewer revisits for any reason or related to COVID-19 at any time. Conclusions. Fewer than half the total number of emergency department revisits after initial care for COVID-19 were related to the novel coronavirus infection. Revisits occurred more often in the first 30 days after discharge. Later COVID-19-related revisits were uncommon, but given the large number of patients with this infection, such visits can be expected. Objetivo. Analizar diferentes categorías de revisita (RV) al año en pacientes con infección COVID-19 que consultan en un servicio de urgencias hospitalario (SUH). Método. Estudio observacional, retrospectivo, que incluyó pacientes consecutivos que consultaron al SUH en los meses de marzo y abril de 2020 con diagnóstico de COVID-19 y fueron dados de alta vivos del hospital. Se recogieron variables basales y del episodio agudo y se realizó un seguimiento al año. Se hicieron tres comparaciones identificando variables asociadas a la RV total, RV relacionada con COVID-19 (RCovid) y RCovid precoz (# 30 días). Resultados. Se analizaron 1.352 pacientes con edad media de 62,1 años y 52,9% varones. En el seguimiento al año hubo 553 RV en 342 (25,3%) pacientes, 132 (9,8%) con al menos una RCovid, 103 (7,6%) precoz y 29 (2,2%) tardía. La RCovid se relacionó con la presencia de fenómenos trombóticos [OR 7,58 (IC 95%: 1,75-32,81)] y la fibrosis pulmonar [OR 4,95 (IC 95%: 1,27-19,24)];y la RCovid precoz se relacionó inversamente con alta a dispositivo de soporte sanitario [OR 0,18 (IC 95%: 0,03-0,92)]. El ingreso hospitalario en el evento índice disminuyó la RV total y RCovid y las hospitalizaciones derivadas de esta RV de manera significativa a largo plazo. Conclusión. Menos de la mitad de la RV total tras una infección COVID-19 está relacionada con la infección, y es más frecuente en los primeros 30 días. La RCovid tardía no es frecuente, pero dado el elevado número de pacientes que han sido infectados por COVID-19 se debe tener en cuenta.