key: cord-0867887-olv2kuwx
authors: Diaz, Rafael; Orlandini, Andrés; Castellana, Noelia; Caccavo, Alberto; Corral, Pablo; Corral, Gonzalo; Chacón, Carolina; Lamelas, Pablo; Botto, Fernando; Díaz, María Luz; Domínguez, Juan Manuel; Pascual, Andrea; Rovito, Carla; Galatte, Agustina; Scarafia, Franco; Sued, Omar; Gutierrez, Omar; Jolly, Sanjit S.; Miró, José M.; Eikelboom, John; Loeb, Mark; Maggioni, Aldo Pietro; Bhatt, Deepak L.; Yusuf, Salim
title: Effect of Colchicine vs Usual Care Alone on Intubation and 28-Day Mortality in Patients Hospitalized With COVID-19: A Randomized Clinical Trial
date: 2021-12-29
journal: JAMA Netw Open
DOI: 10.1001/jamanetworkopen.2021.41328
sha: 40e4fcde2c5c4e8c970bded125286199b5b9fbf0
doc_id: 867887
cord_uid: olv2kuwx

IMPORTANCE: Hospitalized patients with COVID-19 pneumonia have high rates of morbidity and mortality. OBJECTIVE: To assess the efficacy of colchicine in hospitalized patients with COVID-19 pneumonia. DESIGN, SETTING, AND PARTICIPANTS: The Estudios Clínicos Latino América (ECLA) Population Health Research Institute (PHRI) COLCOVID trial was a multicenter, open-label, randomized clinical trial performed from April 17, 2020, to March 28, 2021, in adults with confirmed or suspected SARS-CoV-2 infection followed for up to 28 days. Participants received colchicine vs usual care if they were hospitalized with COVID-19 symptoms and had severe acute respiratory syndrome or oxygen desaturation. The main exclusion criteria were clear indications or contraindications for colchicine, chronic kidney disease, and negative results on a reverse transcription–polymerase chain reaction test for SARS-CoV-2 before randomization. Data were analyzed from June 20 to July 25, 2021. INTERVENTIONS: Patients were assigned in a 1:1 ratio to usual care or usual care plus colchicine. Colchicine was administered orally in a loading dose of 1.5 mg immediately after randomization, followed by 0.5 mg orally within 2 hours of the initial dose and 0.5 mg orally twice a day for 14 days or discharge, whichever occurred first. MAIN OUTCOMES AND MEASURES: The first coprimary outcome was the composite of a new requirement for mechanical ventilation or death evaluated at 28 days. The second coprimary outcome was death at 28 days. RESULTS: A total of 1279 hospitalized patients (mean [SD] age, 61.8 [14.6] years; 449 [35.1%] women and 830 [64.9%] men) were randomized, including 639 patients in the usual care group and 640 patients in the colchicine group. Corticosteroids were used in 1171 patients (91.5%). The coprimary outcome of mechanical ventilation or 28-day death occurred in 160 patients (25.0%) in the colchicine group and 184 patients (28.8%) in the usual care group (hazard ratio [HR], 0.83; 95% CI, 0.67-1.02; P = .08). The second coprimary outcome, 28-day death, occurred in 131 patients (20.5%) in the colchicine group and 142 patients (22.2%) in the usual care group (HR, 0.88; 95% CI, 0.70-1.12). Diarrhea was the most frequent adverse effect of colchicine, reported in 68 patients (11.3%). CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that compared with usual care, colchicine did not significantly reduce mechanical ventilation or 28-day mortality in patients hospitalized with COVID-19 pneumonia. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04328480

This supplemental material has been provided by the authors to give readers additional information about their work.

The trial was conducted at 42 Argentinian hospitals. The trial was coordinated by ECLA (Estudios Clinicos Latino America), the trial sponsor and with the collaboration of PHRI (Population Health Research Institute). Treatment supply to local sites was supported by Spedrong Caillion Pharma and registry data was supported by Red Cap.

COLCOVID is a randomized trial among patients hospitalized for COVID-19. All eligible patients receive usual standard of care in the participating hospital and are randomly allocated between no additional treatment and one active treatment arm. The original and final protocols are included in the supplementary material to this publication, together with summaries of the changes made. The following modifications were made to the protocol during the trial: 

Three methods of obtaining informed consent were accepted by our local health authorities (ANMAT): a) Written consent b) Oral consent in the presence of two witnesses belonging to the health team, who formally documented this act c) If the patient could not give consent due to cognitive disfunction, and a legal representative was not available, the patient could be included based on the decision of at least two members of the health team, one of whom must be a doctor.

Confirmed positive PCR is defined as Laboratory-confirmed SARS-CoV-2throug PCR at randomization or pending result at randomization and positive result confirmed later

All randomized patients who have received study treatments (active or control) are included in this population. Patients are analyzed within the intervention group to which they were randomized after exclusion of non-compliant patients. Non-compliant patients for colchicine group were defined as patients who did not received colchicine or patients who received colchicine but discontinued. Non-compliant patients for standard care group were defined as patients who received colchicine.

The colchicine dosage schedule will vary according to the following scenarios: 1. In patients not receiving Lopinavir/Ritonavir o Loading dose of 1.5 mg followed by 0.5 mg after two hours (day 1) o The next day 0.5 mg bid for 14 days or until discharge.

o Loading dose of 0.5 mg (day 1) o After 72 hours from the loading dose, 0.5 mg every 72 hours for 14 days or until discharge.

Lopinavir/Ritonavir o Dose of 0.5 mg 72 hours after starting Lopinavir/Ritonavir. o Continue with 0.5 mg every 72 hours for 14 days or until discharge. Only the oral route will be used except in the case of patients associated with mechanical ventilation or with contraindications to the oral route, in whom it will be administered by nasogastric tube. Renal failure dose adjustment Creatinine clearance > 50 ml/min: -Loading dose 1.5 mg follow by 0.5 mg 2 hours after the loading dose.

(day 1) -Day 2, 0.5 mg bid for 14 days or until discharge. Creatinine clearance < 50ml/min: -Loading dose 0.5 mg (day 1) -New dose at 72 hours from the loading dose and then 0.5 mg every 72 hours until day 14 or until discharge.

-Loading dose 1.5 mg follow by 0.5 mg 2 hours after the loading dose.

(day 1) -Day 2, 0.5 mg bid for 14 days or until discharge.

-Loading dose 0.5 mg (day 1) -New dose at 72 hours from the loading dose and then 0.5 mg every 72 hours until day 14 or until discharge. 

Patients are analyzed within the intervention group to which they were randomized after exclusion of patients who were non-compliant. Patients defined as non-compliant for the colchicine group did not receive colchicine or received colchicine but discontinued (N=125). Patients defined as non-compliant for the usual care group received colchicine (N=5)