The ECLA PHRI COLCOVID Trial. Effects of Colchicine on Moderate/High-risk Hospitalized COVID-19 Patients.

Study Overview
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Brief Summary
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The ECLA PHRI COLCOVID Trial is a simple, pragmatic randomized open controlled trial to test the effects of colchicine on moderate/high-risk hospitalized COVID-19 patients with the aim of reducing mortality and/or new requirement for mechanical ventilation.

Detailed Description
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Various anti-viral treatments are being tested in clinical trials worldwide. The World Health Organization (WHO) launched a simple,pragmatic worldwide open-label trial to test Remdesivir, Lopinavir/Ritonavir, Interferon and Hydroxychloroquine or Chloroquine.The most important complication of COVID-19 severe cases is respiratory failure from severe acute respiratory syndrome (SARS), the leading cause of mortality. Accumulating evidence suggests that patients with severe COVID-19 might have a cytokine storm syndrome, a hyperinflammatory syndrome characterized by a fulminant and fatal hypercytokinemia and multiorgan failure. The proposed pathophysiological mechanism of cytokine storm and inflammatory cascade activation is based on evidence collected primarily during the SARS-CoV and MERS-CoV epidemics (with a significant increase in IL1B, IL6, IL12, IFNγ, IP10, TNFα, IL15, and IL17 among others). The data collected during the pandemic with COVID-19 also shows a significant increase in inflammatory cytokines (GCSF, IP10, MCP1, MIP1A, and TNFα, among others) in sicker patients admitted to intensive care. In the absence of effective treatments for the management of patients with COVID-19 and respiratory failure, the immunomodulatory and anti-inflammatory effect of colchicine on cytokines involved in the hyper-inflammatory state is postulated. Several lines of research worldwide are testing powerful anti-inflammatory drugs for the pandemic, with different options including steroids, cytokine blockers, and other potent anti-inflammatory agents. Steroids are partially contraindicated in viral infections. Colchicine is a powerful anti-inflammatory drug approved for the treatment or prevention of gout and Familial Mediterranean Fever at doses ranging between 0.3 mg and 2.4 mg/day. Its mechanism of action is through the inhibition of tubulin polymerization, as well as through potential effects on cellular adhesion molecules and inflammatory chemokines. It might also have direct anti-inflammatory effects by inhibiting key inflammatory signalling networks known as inflammasome and pro-inflammatory cytokines. Additionally, evidence suggests that colchicine exerts a direct anti-inflammatory effect by inhibiting the synthesis of tumor necrosis factor alpha and IL-6, monocyte migration, and the secretion of matrix metalloproteinase-9. Through the disruption of the cytoskeleton, colchicine is believed to suppress secretion of cytokines and chemokines as well as in vitro platelet aggregation. All these are potentially beneficial effects that might diminish or ameliorate the COVID-19 inflammatory storm associated with severe forms of the disease. Importantly, in one contemporary trial low-dose colchicine administered to patients who survived from acute coronary syndrome shows a statistically significantly reduction of cardiovascular complications. We have therefore designed in a simple, pragmatic randomized controlled trial to test the effects of colchicine on severe hospitalized COVID-19 cases with the aim of reducing mortality. Sample size calculation: A minimum sample size of 1200 patients will provide 80% power to detect a relative risk reduction of approximately 30% in the treated group if the assumed composite rate (new requirement of intubation and / or death) in the control group is about 24%. The ECLA PHRI COLCOVID Trial allows randomization to another trial, specifically patients included in the trial might be (or not) randomized to an antithrombotic strategy.

Official Title
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The ECLA PHRI COLCOVID Trial

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Colchicine
* Other: Local standard of care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (case definition) Consented adults (age ≥18 years) and COVID-19 suspicious and Admitted to hospital or already in hospital and COVID-19 suggestive symptoms (fever or febrile equivalent, loss of smell and taste, fatigue, etc.) that may be present or absent at randomization time and SARS (severe acute respiratory syndrome) shortness of breath (dyspnea) or image of typical or atypical pneumonia or oxygen desaturation (SpO2 ≤ 93) Exclusion criteria Clear indication or contraindication for the use of colchicine Pregnant or breastfeeding female. Chronic renal disease with creatinine clearance <15 ml/min/m2 Negative PCR test for SARS-COV2

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Simple pragmatic randomized open controlled trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Local standard of care plus colchicine<br>Local standard of care plus colchicine (specific dosage schedule) | Drug: Colchicine<br>* The colchicine dosage schedule will vary according to the following scenarios: In patients not receiving Lopinavir/Ritonavir Loading dose of 1.5 mg followed by 0.5 mg after two hours (day 1) The next day 0.5 mg bid for 14 days or until discharge. In patients receiving Lopinavir/Ritonavir Loading dose of 0.5 mg (day 1) After 72 hours from the loading dose, 0.5 mg every 72 hours for 14 days or until discharge. Patients under treatment with Colchicine that are starting with Lopinavir/Ritonavir Dose of 0.5 mg 72 hours after starting Lopinavir/Ritonavir. 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.<br>* Other names: Colchicina;Other: Local standard of care<br>* Local standard of care for COVID-19 SARS moderate /high-risk patients<br>|
| Other: Local standard of care<br>Local standard of care for COVID-19 SARS moderate / high-risk patients | Other: Local standard of care<br>* Local standard of care for COVID-19 SARS moderate /high-risk patients<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite outcome: New requirement for mechanical ventilation or death | Number of participants who require new intubation for mechanical ventilation or die | 28 days post randomization | 
| Mortality | Number of participants who die | 28 days post randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| New requirement for mechanical ventilation or death from respiratory failure | Number of participants who require new intubation for mechanical ventilation or die from respiratory failure | 28 days post randomization | 
| New requirement for mechanical ventilation or death from non-respiratory failure | Number of participants who require new intubation for mechanical ventilation or die from non-respiratory failure | 28 days post randomization | 
| Mortality due to respiratory failure | Number of participants who die from respiratory failure | 28 days post randomization | 
| Mortality due to non-respiratory failure | Number of participants who die from non-respiratory failure | 28 days post randomization | 
| In hospital - Composite outcome | Number of participants who require intubation for mechanical ventilation or die | During hospitalization or until death, whichever comes first, assessed up to 28 days | 
| In hospital - Mortality | Number of participants who die | During hospitalization or until death, whichever comes first, assessed up to 28 days | 
| Composite outcome (New requirement for mechanical ventilation or death) evaluated in Non-intubated population | Number of participants who were not intubated at randomization and require new intubation for mechanical ventilation or die | 28 days post randomization | 
| Mortality evaluated in Non-intubated population | Number of participants who were not intubated at randomization and die | 28 days post randomization | 
| Mean WHO descriptive score of COVID-19 during hospitalization | Mean WHO descriptive score of COVID-19 in the active treatment group compared to the placebo group | During hospitalization or until death, whichever comes first, assessed up to 28 days | 
| Highest WHO descriptive score of COVID-19 during hospitalization | Mean highest WHO descriptive score of COVID-19 in the active treatment group compared to the placebo group | During hospitalization or until death, whichever comes first, assessed up to 28 days |