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

• ClinicalTrials.gov Identifier: NCT04328480
• Recruitment Status: Completed
• First Posted: March 31, 2020
• Last Update Posted: April 27, 2021
• Sponsor: Estudios Clínicos Latino América
• Collaborator: Population Health Research Institute
• Information provided by (Responsible Party): Estudios Clínicos Latino América

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
COVID-19	Drug: Colchicine; Other: Local standard of care	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1279 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Simple pragmatic randomized open controlled trial
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: The ECLA PHRI COLCOVID Trial
• Actual Study Start Date: April 17, 2020
• Actual Primary Completion Date: April 25, 2021
• Actual Study Completion Date: April 26, 2021

Arms and Interventions

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/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.; Other Name: Colchicina; Other: Local standard of care; Local standard of care for COVID-19 SARS moderate /high-risk patients
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

Outcome Measures

Primary Outcome Measures :

1. Composite outcome: New requirement for mechanical ventilation or death [ Time Frame: 28 days post randomization ]
   Number of participants who require new intubation for mechanical ventilation or die
2. Mortality [ Time Frame: 28 days post randomization ]
   Number of participants who die

Secondary Outcome Measures :

1. New requirement for mechanical ventilation or death from respiratory failure [ Time Frame: 28 days post randomization ]
   Number of participants who require new intubation for mechanical ventilation or die from respiratory failure
2. New requirement for mechanical ventilation or death from non-respiratory failure [ Time Frame: 28 days post randomization ]
   Number of participants who require new intubation for mechanical ventilation or die from non-respiratory failure
3. Mortality due to respiratory failure [ Time Frame: 28 days post randomization ]
   Number of participants who die from respiratory failure
4. Mortality due to non-respiratory failure [ Time Frame: 28 days post randomization ]
   Number of participants who die from non-respiratory failure
5. In hospital - Composite outcome [ Time Frame: During hospitalization or until death, whichever comes first, assessed up to 28 days ]
   Number of participants who require intubation for mechanical ventilation or die
6. In hospital - Mortality [ Time Frame: During hospitalization or until death, whichever comes first, assessed up to 28 days ]
   Number of participants who die
7. Composite outcome (New requirement for mechanical ventilation or death) evaluated in Non-intubated population [ Time Frame: 28 days post randomization ]
   Number of participants who were not intubated at randomization and require new intubation for mechanical ventilation or die
8. Mortality evaluated in Non-intubated population [ Time Frame: 28 days post randomization ]
   Number of participants who were not intubated at randomization and die
9. Mean WHO descriptive score of COVID-19 during hospitalization [ Time Frame: During hospitalization or until death, whichever comes first, assessed up to 28 days ]
   Mean WHO descriptive score of COVID-19 in the active treatment group compared to the placebo group
10. Highest WHO descriptive score of COVID-19 during hospitalization [ Time Frame: During hospitalization or until death, whichever comes first, assessed up to 28 days ]
    Mean highest WHO descriptive score of COVID-19 in the active treatment group compared to the placebo group

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

Argentina

Sanatorio Parque

Rosario, Santa Fe, Argentina, 2000

Sponsors and Collaborators

Estudios Clínicos Latino América

Population Health Research Institute

Investigators

• Principal Investigator: Rafael Diaz, MD; ECLA- ICR

More Information

Additional Information:

WHO opening remarks 

Publications of Results:

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.

Other Publications:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Estudios Clínicos Latino América
• ClinicalTrials.gov Identifier: NCT04328480
• Other Study ID Numbers: COLCOVID version 2.0
• First Posted: March 31, 2020
• Last Update Posted: April 27, 2021
• Last Verified: April 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Additional relevant MeSH terms:

COVID-19; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Colchicine; Gout Suppressants; Antirheumatic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents