Treatment for Moderate/Severe COVID-19 in a Fragile and Vulnerable Population, Admitted to a Geriatric Hospital Unit or in a Transicional Care Center

Study Overview
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Brief Summary
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Study to compare the efficacy and safety of colchicine and glucocorticoids compared with the standard of treatment for moderate/severe COVID-19 in a fragile and vulnerable population, admitted to a geriatric hospital unit or in a transicional care center

Official Title
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Phase 2/3, Randomized, Open Study to Compare the Efficacy and Safety of Colchicine and Glucocorticoids Compared With the Standard of Treatment for Moderate/Severe COVID-19 in a Fragile and Vulnerable Population, Admitted to a Geriatric Hospital Unit or in a Transicional Care Center

Conditions
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Covid19

Intervention / Treatment
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* Drug: Colchicine
* Drug: Prednisone tablet
* Drug: standard of care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be at least 65 years old and be admitted to the Geriatrics Unit of the Internal Medicine Service (Hospital Clínic de Barcelona) or to a transicional care center Clinical diagnosis compatible with COVID-19 (in a favourable epidemiological context), with a disease considered moderate (grade 3-4) or severe (grade 5) according to the WHO 8-point ordinal scale for assessing clinical severity (https://www.who.int/publications/i/item/covid-19-therapeutic-trial-synopsis). This same scale will also be used to evaluate the evolution after the application of the corresponding treatment. Baseline clinical parameters will include the presentation of fever and any respiratory symptoms, both of upper respiratory tract and dyspnea, affecting the general state or gastrointestinal manifestations, since it is known that in elderly people the COVID-19 can present with atypical symptoms for a time that is difficult to determine, but it also tends to evolve to respiratory failure quickly and is associated with high mortality. For this reason, regardless of the time that has elapsed since the estimated onset of symptoms, patients with moderate - WHO grade 3, in whom the presence of fever, mild dyspnea or any gastrointestinal manifestation attributable to COVID-19 make an admission (in the case of hospital) and directed treatment (in all cases) advisable, will be candidates for inclusion in the study. Patients with moderate disease and oxygen requirements (WHO grade 4) and patients with severe pneumonia, but who can be managed initially with high flow oxygen therapy (WHO grade 5) may also be included in the study. The clinical diagnosis may be supported by radiological changes (via chest radiography, if available) suggestive of bilateral (established or incipient) pneumonia. At the time of diagnosis, biomarkers will also be collected, in an analysis that will include increased levels of C-reactive protein [PCR] and/or ferritin and microbiological confirmation of SARS-CoV-2. Patients in whom the current clinical situation and the basal functional situation condition a prognosis that makes them consider a limited therapeutic ceiling, which includes the contraindication of applying more aggressive (e.g. non-invasive ventilation) or invasive measures (e.g. cardiopulmonary resuscitation or orotracheal intubation and mechanical ventilation), both in patients admitted to the Geriatric Unit (Hospital Clínic de Barcelona) and in those admitted to a transicional care center. The latter patients are also not considered for transfer to a third level hospital (according to the criteria of fragility, available on page 14 of the CatSalut action protocols (https://canalsalut.gencat.cat/web/.content/_A-Z/C/coronavirus-2019-ncov/material-divulgatiu/recull-protocol-pneumonia.pdf). Patient with a general condition that allows him/her to take the medication orally, without risk of bronchial aspiration. Acceptance by the patient or responsible family member to participate in the study (written consent). Exclusion Criteria: The clinical situation of an advanced or terminal illness, according to the clinical judgment of the doctor in charge and as defined by the Spanish Society for Palliative Care (SECPAL), which describes it as an advanced illness in an evolutionary and irreversible phase with multiple symptoms, emotional impact, loss of autonomy, with very little or no capacity to respond to specific treatment and with a life expectancy limited to weeks or months, in a context of progressive fragility (http://envejecimiento.csic.es/documentos/documentos/navarro-cuidadospaliativos-01.pdf). Clinical status which is advanced and severe or in which the level of consciousness has deteriorated and the oral route of taking the medication is not safely tolerated (in the opinion of the doctor in charge) Taking any of the drugs in the trial (colchicine or prednisone) chronically or intermittently in the 7 days prior to study inclusion. Absolute contraindication to the use of the study medication, including hypersensitivity to the active substance or to any of its excipients, severe renal failure (glomerular filtration [GF] creatinine clearance or Clcr <30 ml/min) and patients undergoing haemodialysis, severe liver failure, severe gastrointestinal disorders, gastric ulcer or blood dyscrasias. Concomitant treatment with macrolides (clarithromycin, erythromycin, telithromycin), antifungals (itraconazole, ketoconazole), cyclosporine and antivirals (lopinavir/ritonavir, indinavir, nelfinavir, saquinavir), all potent inhibitors of CYP3A4 (key cytochrome in the colchicine metabolism pathway).

Ages Eligible for Study
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Minimum Age: 65 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: colchicine + prednisone<br>Prednisone should be administered for 3 consecutive days (60 mg/d) together with colchicine (at doses of 0.5 to 1.5 mg/d, adjusted for weight and renal function) for 3 days and maintained for 14 days in total (0.5 mg/d). | Drug: Colchicine<br>* Colchicine: ideal dose of 0.3 mg/kg/day (or the dose that approximates that adjusted for age, weight and kidney function, and 0.5 mg and 1 mg tablets)<br>Drug: Prednisone tablet<br>* Prednisone 60 mg/day, in a single dose, during 3 days<br>|
| Active Comparator: Standard treatment<br>The standard treatment used in each site will be administered to the patients assigned to the control group. | Drug: standard of care<br>* The standard treatment used in each site will be administered to the patients assigned to the control group.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients that a short cycle of steroids administered together with colchicine reduces mortality from COVID-19 | Number of patients that a short cycle of steroids (with prednisone 60 mg/d, in a single dose, for 3 consecutive days) administered together with colchicine (at doses of 0.5 to 1.5 mg/d, adjusted for weight and renal function, for 3 days and maintenance of 0.5 mg/d for 14 days in total) reduces mortality from COVID-19 in this population by at least 20%, compared to the approved standard treatment at participating centers. | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and grade of adverse events at group of colchicine and glucocorticoids throughout the treatment and in the two weeks following treatment | Number and grade of adverse events at group of colchicine and glucocorticoids throughout the treatment and in the two weeks following treatment according to the incidence of: mild adverse event serious adverse events hypersensitivity (allergic) reactions of grade >=2 | 28 days | 
| Percentage of patients who stop medication due to adverse events. | Percentage of patients who stop medication due to adverse events. | 28 days | 
| Severity of symptoms by COVID-19 in the two treatment arms | Severity of symptoms by COVID-19 in the two treatment arms (response to treatment to be assessed by overall survival at 28 days from the start of treatment). | 28 days |