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.
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.
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
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
Sanatorio Parque
Rosario, Santa Fe, Argentina
Rafael Diaz, MD, Principal Investigator
ECLA- ICR