Trial to Study the Benefit of Colchicine in Patients With COVID-19 (COL-COVID)

Administration of Colchicine Plus Standard Treatment vs. Standard Therapy, in Hospitalized Patients With COVID-19, Within the First 48 Hours, and no Severity Criteria.

COVID-19 is associated with a cytokine storm that leads to respiratory distress, multiorgan failure and elevated mortality. Oral colchicine exhibits high anti-inflammatory capacity attributed to the inhibition of microtubules polymerization, inflammasome and production of IL-1β and IL-6, which could prevent the inflammatory storm in COVID-19 patients at risk. We present a randomized clinical trial, controlled, open-label and pragmatic, including COVID-19 patients requiring hospitalization but no intensive care yet. Colchicine will be started within the first 48 hours and then administered for four weeks using a descending dose. The benefit will be study in terms of clinical evolution (WHO 7-point scale) and IL-6 levels, as well as other clinical and biochemical secondary end-points. In the case of positive results, the clinical impact would be relevant given that this oral medication is widely accessible which would help to prevent the inflammatory complications associated with COVID-19.

Study Overview

• Status: Completed
• Conditions: COVID19
• Intervention / Treatment: Drug: Colchicine Tablets; Drug: Standard therapy for COVID-19 according to the stablished hospital protocols.

Detailed Description

This is a Phase III, prospective, pragmatic, randomized, controlled and open-label trial, comparing standard of care vs. standard of care plus COLCHICINE for four weeks, in patients hospitalized due to COVID-19 and confirmed infection by SARSCov2, within the first 48 hours after the hospital admission. Patients meeting severity criteria will be excluded, defined as established limitation of therapeutic effort or need for invasive mechanical ventilation at the time of inclusion. The colchicine treatment includes an initial dose of 1.5 mg (1 mg and 0.5 mg two hours after), followed by 0.5 mg every 12 hours during the next 7 days and 0.5 mg every 24 hours until the completion of 28 days of total treatment. In patients receiving ritonavir or lopinavir or with reduced renal clearance (<50 ml/min/1.37m2), weight <70 kg or age >75 years old, the dose will be adjusted to the half.

Patients meeting all the inclusion criteria and none of the exclusion ones (see below), after signing the informed consent, will be centrally randomized to "colchicine" or "control" group. Patients in both groups will receive the standard therapy for COVID-19 according to the stablished hospital protocols. Randomization will be controlled by: age, sex, time from initiation of symptoms, cardiovascular disease, the 7 point WHO and levels of C-reactive protein, ferritin, D-dimer, IL-6 and lymphocyte levels.

• Study Type: Interventional
• Enrollment (Actual): 102
• Phase: Phase 3

Contacts and Locations

Study Locations

• Spain
  • Murcia, Spain, 30120
    • Virgen de la Arrixaca University Clinical Hospital

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:

1. SARS-CoV-2 infection confirmed by PCR.
2. Admitted in the hospital in the previous 48 hours, with clinical status 3, 4 or 5 of WHO classification.
3. Age above 18 years old.
4. Informed written consent.

Exclusion Criteria:

1. Invasive mechanical ventilation needed.
2. Established limitation of the therapeutic effort
3. Inflammatory bowel disease (IBD: Chron Syndrome or Ulcerative colitis), chronic diarrhea or malabsorption.
4. Previous neuromuscular disease.
5. Other disease with an estimated vital prognosis under 1 year.
6. Severe renal insufficiency (glomerular filtration rate <30 mL/min/1.73m2)
7. Medical records of cirrhosis, active chronic hepatitis or severe hepatic disease defined by GOT or GPT levels three times above the normal upper limit.
8. Patients with previous colchicine treatment for other diseases (mainly chronic prescriptions for familial Mediterranean fever or gout). Clearance period will not be required for patients treated with colchicine who stopped the treatment before the randomization.
9. Patients with history of allergic reaction or significant sensitivity to colchicine.
10. Treatment with immunosuppressive agents, corticoids or interleukine-1 antagonists for 6 months before inclusion.
11. Pregnant or breastfeeding female, confirmed by a positive result in the human chorionic gonadotropin (hCG) test.
12. Fertile woman, or post-menopausal during less than one year and non-surgically sterilized. Women of fertile age may be included if using at least one contraceptive method and preferably two complementary contraceptive methods.
13. Use of other investigational drugs in the moment of inclusion, or during 30 days previous to inclusion.

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
Experimental: COLCHICINE; The colchicine treatment includes an initial dose of 1.5 mg (1 mg and 0.5 mg two hours after), followed by 0.5 mg every 12 hours during the next 7 days and 0.5 mg every 24 hours until the completion of 28 days of total treatment. In patients receiving ritonavir or lopinavir or with reduced renal clearance (<50 ml/min/1.37m2), weight <70 kg or age >75 years old, the dose will be adjusted to the half. + standard therapy for COVID-19 according to the stablished hospital protocols.	Drug: Colchicine Tablets; standard therapy for COVID-19 according to the stablished hospital protocols.; Drug: Standard therapy for COVID-19 according to the stablished hospital protocols.; standard therapy for COVID-19 according to the stablished hospital protocols.
Placebo Comparator: control group; Standard therapy for COVID-19 according to the stablished hospital protocols.	Drug: Standard therapy for COVID-19 according to the stablished hospital protocols.; standard therapy for COVID-19 according to the stablished hospital protocols.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in the patients' clinical status through the 7 points ordinal scale WHO R&D Blueprint expert group	improve in the clinical evolution of patients hospitalized	7,14,28 Days
Changes in IL-6 concentrations	improve in the clinical evolution of patients hospitalized	up to day 28.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in the clinical status	time needed to reduce at least 2 points in the 7-point Ordinal Scale for Clinical Improvement by WHO R&D Blueprint expert group (0-7)	up to day 28.
Changes in the score for the Sequential Organ Failure Assessment (SOFA score)	Sequential Organ Failure Assessment (SOFA score) (0-14)	up to day 28.
Changes in the punctuation in the National Early Warning Score	National Early Warning Score (NEWS scale	up to day 28.
Number of days with invasive mechanical ventilation		up to day 28.
Number of days with high flow oxygen therapy		up to day 28.
Changes in other inflammatory markers	C-reactive protein,	up to day 28
Changes in other inflammatory markers	TNF-alfa,	up to day 28
Changes in other inflammatory markers	GDF-15,	up to day 28
Changes in other inflammatory markers	IL-1β	up to day 28
Changes in severity markers	D-dimer	up to day 28
Changes in severity markers	leucocytes	up to day 28
Changes in severity markers	lymphocytes	up to day 28
Changes in severity markers	platelets	up to day 28
Changes in severity markers	LDH	up to day 28
Changes in severity markers	ferritin	up to day 28
Changes in myocardial damage	myocardial stress markers hsTnT	up to day 28
Changes in myocardial damage	myocardial stress markers NT-proBNP	up to day 28
Time until reaching a virus negative status	RT-PCR assay	up to day 28
Length of hospital stay	Length of hospital stay	up to day 28
Number of days in the intensive care unit.	Number of days in the intensive care unit.	up to day 28
Mortality	Mortality	up to day 28

Collaborators and Investigators

• Sponsor: Fundacion para la Formacion e Investigacion Sanitarias de la Region de Murcia
• Investigators: Principal Investigator: Domingo A Pascual Figal, MD, HCUVA

Publications and helpful links

General Publications

• Mikolajewska A, Fischer AL, Piechotta V, Mueller A, Metzendorf MI, Becker M, Dorando E, Pacheco RL, Martimbianco ALC, Riera R, Skoetz N, Stegemann M. Colchicine for the treatment of COVID-19. Cochrane Database Syst Rev. 2021 Oct 18;10(10):CD015045. doi: 10.1002/14651858.CD015045.
• Pascual-Figal DA, Roura-Piloto AE, Moral-Escudero E, Bernal E, Albendín-Iglesias H, Pérez-Martínez MT, Noguera-Velasco JA, Cebreiros-López I, Hernández-Vicente Á, Vázquez-Andrés D, Sánchez-Pérez C, Khan A, Sánchez-Cabo F, García-Vázquez E; COL-COVID Investigators. Colchicine in Recently Hospitalized Patients with COVID-19: A Randomized Controlled Trial (COL-COVID). Int J Gen Med. 2021 Sep 11;14:5517-5526. doi: 10.2147/IJGM.S329810. eCollection 2021.

Study record dates

Study Major Dates

• Study Start (Actual): April 30, 2020
• Primary Completion (Actual): October 20, 2020
• Study Completion (Actual): December 30, 2020

Study Registration Dates

• First Submitted: April 14, 2020
• First Submitted That Met QC Criteria: April 16, 2020
• First Posted (Actual): April 17, 2020

Study Record Updates

• Last Update Posted (Actual): January 12, 2021
• Last Update Submitted That Met QC Criteria: January 11, 2021
• Last Verified: January 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: IMIB-COLVID-2020-03

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