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

The ECLA PHRI COLCOVID Trial

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.

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Drug: Colchicine; Other: Local standard of care

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 1279
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Santa Fe
    • Rosario, Santa Fe, Argentina, 2000
      • Sanatorio Parque

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Local standard of care plus colchicine; Local standard of care plus colchicine (specific dosage schedule)	Drug: Colchicine; The colchicine dosage schedule will vary according to the following scenarios: In patients not receiving Lopinavir/RitonavirLoading 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/RitonavirLoading 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/RitonavirDose 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.; Other Names: Colchicina; Other: Local standard of care; Local standard of care for COVID-19 SARS moderate /high-risk patients
Other: Local standard of care; Local standard of care for COVID-19 SARS moderate / high-risk patients	Other: Local standard of care; Local standard of care for COVID-19 SARS moderate /high-risk patients

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Estudios Clínicos Latino América
• Collaborators: Population Health Research Institute
• Investigators: Principal Investigator: Rafael Diaz, MD, ECLA- ICR

Publications and helpful links

General Publications

• Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 28;395(10229):1033-1034. doi: 10.1016/S0140-6736(20)30628-0. Epub 2020 Mar 16. No abstract available.
• Slobodnick A, Shah B, Krasnokutsky S, Pillinger MH. Update on colchicine, 2017. Rheumatology (Oxford). 2018 Jan 1;57(suppl_1):i4-i11. doi: 10.1093/rheumatology/kex453.
• Tardif JC, Kouz S, Waters DD, Bertrand OF, Diaz R, Maggioni AP, Pinto FJ, Ibrahim R, Gamra H, Kiwan GS, Berry C, Lopez-Sendon J, Ostadal P, Koenig W, Angoulvant D, Gregoire JC, Lavoie MA, Dube MP, Rhainds D, Provencher M, Blondeau L, Orfanos A, L'Allier PL, Guertin MC, Roubille F. Efficacy and Safety of Low-Dose Colchicine after Myocardial Infarction. N Engl J Med. 2019 Dec 26;381(26):2497-2505. doi: 10.1056/NEJMoa1912388. Epub 2019 Nov 16.
• Yusuf S, Collins R, Peto R. Why do we need some large, simple randomized trials? Stat Med. 1984 Oct-Dec;3(4):409-22. doi: 10.1002/sim.4780030421. No abstract available.
• McDermott MM, Newman AB. Preserving Clinical Trial Integrity During the Coronavirus Pandemic. JAMA. 2020 Jun 2;323(21):2135-2136. doi: 10.1001/jama.2020.4689. No abstract available.
• Diaz R, Orlandini A, Castellana N, Caccavo A, Corral P, Corral G, Chacon C, Lamelas P, Botto F, Diaz ML, Dominguez JM, Pascual A, Rovito C, Galatte A, Scarafia F, Sued O, Gutierrez O, Jolly SS, Miro JM, Eikelboom J, Loeb M, Maggioni AP, Bhatt DL, Yusuf S; ECLA PHRI COLCOVID Trial Investigators. Effect of Colchicine vs Usual Care Alone on Intubation and 28-Day Mortality in Patients Hospitalized With COVID-19: A Randomized Clinical Trial. JAMA Netw Open. 2021 Dec 1;4(12):e2141328. doi: 10.1001/jamanetworkopen.2021.41328. Erratum In: JAMA Netw Open. 2022 Feb 1;5(2):e223150.

Helpful Links

• WHO opening remarks

Study record dates

Study Major Dates

• Study Start (Actual): April 17, 2020
• Primary Completion (Actual): April 25, 2021
• Study Completion (Actual): April 26, 2021

Study Registration Dates

• First Submitted: March 30, 2020
• First Submitted That Met QC Criteria: March 30, 2020
• First Posted (Actual): March 31, 2020

Study Record Updates

• Last Update Posted (Actual): April 27, 2021
• Last Update Submitted That Met QC Criteria: April 26, 2021
• Last Verified: April 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Gout Suppressants; Colchicine
• Other Study ID Numbers: COLCOVID version 2.0

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No