Clinical trial NCT04328480: The ECLA PHRI COLCOVID Trial. Effects of Colchicine on Moderate/High-risk Hospitalized COVID-19 Patients.
Official title: The ECLA PHRI COLCOVID Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: COVID-19
Lead sponsor: Estudios Clínicos Latino América
Sponsor class: OTHER
Collaborators: name: Population Health Research Institute
First posted: 2020-03-31
Enrollment: 1279
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Simple pragmatic randomized open controlled trial
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Composite outcome: New requirement for mechanical ventilation or death
timeFrame: 28 days post randomization
measure: Mortality
timeFrame: 28 days post randomization
Secondary outcomes:
measure: New requirement for mechanical ventilation or death from respiratory failure
timeFrame: 28 days post randomization
measure: New requirement for mechanical ventilation or death from non-respiratory failure
timeFrame: 28 days post randomization
measure: Mortality due to respiratory failure
timeFrame: 28 days post randomization
measure: Mortality due to non-respiratory failure
timeFrame: 28 days post randomization
measure: In hospital - Composite outcome
timeFrame: During hospitalization or until death, whichever comes first, assessed up to 28 days
measure: In hospital - Mortality
timeFrame: During hospitalization or until death, whichever comes first, assessed up to 28 days
measure: Composite outcome (New requirement for mechanical ventilation or death) evaluated in Non-intubated population
timeFrame: 28 days post randomization
measure: Mortality evaluated in Non-intubated population
timeFrame: 28 days post randomization
measure: Mean WHO descriptive score of COVID-19 during hospitalization
timeFrame: During hospitalization or until death, whichever comes first, assessed up to 28 days
measure: Highest WHO descriptive score of COVID-19 during hospitalization
timeFrame: During hospitalization or until death, whichever comes first, assessed up to 28 days
Other outcomes:
Locations:
city: Rosario
country: Argentina
facility: Sanatorio Parque
state: Santa Fe
Study officials:
affiliation: ECLA- ICR
name: Rafael Diaz, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.