COlchicine in Moderate-severe Hospitalized Patients Before ARDS to Treat COVID-19 (the COMBAT-COVID-19 Pilot Study)
Phase: PHASE2
Conditions: Coronavirus Infection
Sponsor: Maimonides Medical Center

Official Title: Colchicine in moderate severity hospitalized patients before ARDS 
to treat COVID-19 (the COMBAT-COVID-19 Pilot Study) 
 
NCT Number: NCT04363437 
 
Protocol ID: 2020-04-12 
 
Date of Document:  April 24, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

COlchicine in Moderate severity hospitalized patients Before ARDS to Treat COVID-19  
(the COMBAT-COVID-19 Pilot Study) 
                                                                        
 
PROTOCOL 
 
TITLE Colchicine in moderate severity hospitalized patients before ARDS to treat COVID-19 
(the COMBAT-COVID-19 Pilot Study) 
 
INTRODUCTION 
 
The most prevalent complication of COVID-19 infection is respiratory failure from 
severe acute respiratory syndrome (SARS), the leading cause of mortality. There is 
increasing indication that the decompensation in severe COVD-19 infection may be 
due to a cytokine storm syndrome. This hyperinflammatory syndrome results in a 
fulminant and fatal hypercytokinemia and multiorgan failure. There are a number of 
trials currently underway testing Remdesivir, Lopinavir/Ritonavir, Interferon, 
Hydroxychloroquine or Chloroquine, Tociluzimab, and Sarilumab however there is a 
concern that treatment in the late stages of COVID-19 infection may still yield poor 
outcomes. Approximately 15% of patients with COVID-19 infection are hospitalized 
and 20-30% of these hospitalized patients require ICU care and/or mechanical 
ventilation.1 2 Overall mortality in hospitalized patients is approximately 20-25%. 
There is significant interest in therapies that can be given upstream to reduce the 
rate of mechanical ventilation and thus mortality. 
 
BACKGROUND AND SIGNIFICANCE 
 
Cytokine storm and the inflammatory cascade activation is believed to be 
associated with significant rises in IL1B, IL6, IL12, IFNgamma, TNFalpha, IL15, 
IL17 and others. Several research studies are currently evaluating powerful anti-
inflammatory drugs for COVID-19 including, steroids, IL1 inhibitors, and IL6 
inhibitors. Colchicine is a strong anti-inflammatory medication approved for the 
                                                
1 The Incubation Period of Coronavirus Disease 2019 (COVID-19) From Publicly Reported Confirmed 
Cases: Estimation and Application. Lauer SA et al. Ann Intern Med. 2020 Mar 10. 
2 Viral dynaics in mild and severe cases of COVID-19. Yang Liu et al. The Lancet, March 19, 2020. 

treatment of Familial Mediterranean Fever and gout, in doses ranging from 0.3 to 
2.4mg daily. 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.  
 
Regarding COVID-19, there have been reports that myocardial injury is frequently 
present. Cardiac biomarker elevation was found to be an independent predictor of 
the need for mechanical support.3 Additionally, 33% of the patients had myocarditis 
and circulatory failure in one study from Wuhan.4  
 
Experimental models have demonstrated that NLRP3 has a significant role in the 
development of ARDS.5 6 Structural dry-lab models have shown that the new SARS-
CoV-2 proteins such as viroporins E, 3a and 8a play a significant role in viral 
                                                
3 Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 
in Wuhan, China: a retrospective cohort study. Lancet. March 2020. doi:10.1016/s0140-6736(20)30566-3  
4 Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on 
an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. March 2020. 
doi:10.1007/s00134-020-05991-x  
5 Grailer JJ, Canning BA, Kalbitz M, et al. Critical Role for the NLRP3 Inflammasome during Acute Lung 
Injury. J Immunol. 2014;192(12):5974-5983. doi:10.4049/jimmunol.1400368  
6 Jones HD, Crother TR, Gonzalez-Villalobos RA, et al. The NLRP3 inflammasome is required for the 
development of hypoxemia in LPS/mechanical ventilation acute lung injury. Am J Respir Cell Mol Biol. 
2014;50(2):270-280. doi:10.1165/rcmb.2013-0087OC  
 
 

replication and pathogenetic injury7 and that these proteins provoke activation of 
inflammasome NLP3.8 9 10 
Colchicine is a non-selective inhibitor of NLRP3 inflammasome .  
 
Colchicine, after oral administration, is absorbed after 1-2 hours and reaches peak 
anti-inflammatory effect within 24-48 hours. This is the time required for drug to 
accumulate in granulocytes (neutrophils, eosinophils, basophils) and monocytes 
(macrophages). Patients generally present to the hospital after a week after 
inoculation and 3-4 days of symptoms. Progression into florid ARDS frequently 
occurs rapidly a few days after hospitalization. Initiation of anti-inflammatory 
therapy may be best utilized early in the hospital course, to deter a potential 
cytokine storm and clinical deterioration. 
 
Colchicine has been demonstrated to be well tolerated in an acute population 
recently. Low-dose colchicine administered to patients who survived from acute 
coronary syndrome resulted in a statistically significant reduction of cardiovascular 
complications. Markers of inflammation including IL1b, IL18 and IL6 were also 
demonstrated to be reduced by colchicine in ACS.11 12 Our proposed trial seeks to 
                                                
7 Castano-Rodriguez C, Honrubia JM, Gutierrez-Alvarez J, et al. Role of Severe Acute Respiratory 
Syndrome Coronavirus Viroporins E, 3a and 8a in Replication and Pathogenesis. MBio. 2018;9(3). 
doi:10..1128/mBio.02325-17. 
8 Nieto-Torres JL, Verdiá -Bá guena C, Jimenez-Guardeño JM, et al. Severe acute respiratory syndrome 
coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome. Virology. 
2015;485:330-339. doi:10.1016/j.virol.2015.08.010  
9 Shi C-S, Nabar NR, Huang N-N, Kehrl JH. SARS-Coronavirus Open Reading Frame- 8b triggers 
intracellular stress pathways and activates NLRP3 inflammasomes. Cell death Discov. 2019;5(1):101. 
doi:10.1038/s41420-019-0181-7  
 
10 Chen I-Y, Moriyama M, Chang M-F, Ichinohe T. Severe Acute Respiratory Syndrome Coronavirus 
Viroporin 3a Activates the NLRP3 Inflammasome. Front Microbiol. 2019;10(JAN):50. 
doi:10.3389/fmicb.2019.00050  
11 Martínez GJ, Robertson S, Barraclough J, et al. Colchicine Acutely Suppresses Local Cardiac 
Production of Inflammatory Cytokines in Patients With an Acute Coronary Syndrome. J Am Heart Assoc. 
2015;4(8):e002128. doi:10.1161/JAHA.115.002128  
12 Robertson S, Martínez GJ, Payet CA, et al. Colchicine therapy in acute coronary syndrome patients 
acts on caspase-1 to suppress NLRP3 inflammasome monocyte activation. Clin Sci (Lond). 
2016;130(14):1237-1246. doi:10.1042/CS20160090  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 

randomize patients to test the hypothesis that colchicine reduces the incidence and 
progression of cytokine storm to reduce oxygen requirements and mortality in 
patients with COVID-19 infection. 
 
Regarding the safety and tolerability of colchicine, the drug has been safely used in 
the outpatient setting for gout in the doses utilized for this trial. Additionally as 
mentioned, the medication has been given in patients with acute myocardial 
infarctions with favorable outcomes. The side effect of GI upset and diarrhea, while 
not uncommon, can be attenuated with dose reduction and if necessary cessation of 
the medication.  
 
STUDY OBJECTIVES 
To demonstrate that Colchicine in moderate/high-risk COVID patients: 
1) Reduces the need for oxygen supplementation beyond 8L nasal cannula 
2) Reduces the need for mechanical ventilation 
3) Reduces max troponin elevations 
4) Reduces inflammatory markers 
5) Reduces length of hospitalization 
6) Reduces mortality 
  
HYPOTHESIS 
We hypothesize that treatment with colchicine in COVID-19 moderate/high-risk 
patients may decrease the risk of progression into ARDS requiring increased oxygen 
requirements, mechanical ventilation, and mortality.  
  
STUDY DESIGN 
Prospective, completely randomized, open labeled, controlled study. Patients will be 
randomized into two groups (A and B). Patients of group A will be treated under what 
is considered current standard of care at Maimonides Medical Center while group B 
patients will receive colchicine in addition to standard of care.  
 
Treatment arm 
In addition to the local standard of care for COVID 19 patients, the patient will receive 
colchicine PO as such: 
 
                                                
 

● Loading dose of 1.2 mg followed by 0.6mg after 2 hours if without significant 
gastrointestinal symptoms (day 1)  
● The next day 0.6mg bid for 14 days or until discharge 
 
Patients who are on HMG-Co A Reductase Inhibitors (atorvastatin, fluvastatin, 
pravastatin, simvastatin), fibrates, genfibrozil, amiodarone, dronedarone or digoxin 
should have the colchicine dosage reduced to a loading dose of 0.6mg followed by 
0.3mg after two hours (day 1) followed by 0.3mg BID for 14 days or until discharge.  
 
If patients have significant gastrointestinal symptoms after loading, the dosage may 
be reduced to 0.3mg BID for the rest of the 14 day course or until discharge. If 
gastrointestinal symptoms continue, the medication should then be discontinued. 
Patients who experience sensory motor neuropathy, or symptoms and laboratory 
findings consistent with rhabdomyolysis should prompt immediate discontinuation of 
the drug. If renal function deteriorates during the treatment course and CrCl 
<30ml/min, colchicine should also be discontinued.  
 
Control arm 
Usual medical therapy (can include medications such as hydroxychloroquine, 
azithromycin) 
 
Patients should NOT receive Steroids (IV/PO), Remdesivir, IL-6 inhibitors 
(Tociluzimab, Sarilumab), JAK inhibitors, IL-1 inhibitors, or other 
immunomodulators for COVID-19 after randomization while not intubated. Since 
the primary clinical endpoint is progression of disease, if the patient requires 
mechanical ventilation, the primary clinical endpoint is met and the above 
experimental salvage medications will be permitted. To rephrase, the patient will be 
allowed steroids, Remdesivir, IL-6 inhibitors and other immunomodulators only 
after intubation if deemed medically necessary by the treating physician. 
 
Subjects:  
  
Eligibility Criteria: 
Inclusion criteria:  
● Males and females >=18 years of age 
● Willing and able to provide written informed consent prior to performing study 
procedures 
● Currently hospitalized and requiring medical care for COVID-19 
● Patient must have a positive COVID-19 PCR result 
● Peripheral capillary oxygen saturation <94% on room air at screening  
 
Exclusion criteria:  

● Requirement of oxygen supplementation >8L nasal cannula 
● Pregnancy 
● Known hypersensitivity to colchicine 
● Patient currently in shock or with hemodynamic instability requiring pressors 
● History of cirrhosis 
● Alanine Aminotransferase (ALT) or aspartate aminotransferase (AST) > 5X 
upper limit of normal (ULN) 
● Patients with severe renal disease, CrCl <30ml/min 
● Patients requiring invasive mechanical ventilation at screening or Clinical 
estimation that the patient will require mechanical respiratory support within 
24 hours 
● Patient is currently taking colchicine for other indications (gout or Familial 
Mediterranean Fever) 
● Patient received IV or PO steroids during the hospitalization 
● Patient received Remdesivir, Sarilumab, Tociluzimab, Lopinavir/Ritonavir or 
other immunomodulator given for COVID-19 treatment (Note: convaslescent 
plasma infusion is NOT an exclusion) 
● Patient is on (and cannot discontinue) a strong CYP3A4 inhibitor (eg 
clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, 
ritonavir, saquinavir, telithromycin, atazanavir), a moderate CYP3A4 inhbitor 
(eg diltiazem, verapamil, fluconazole, amprenavir, aprepitant, 
fosamprenavir) or a P-gp Inhibitor (eg cyclosporine, ranolazine) 
● Patient is undergoing chemotherapy for cancer 
● Patient is considered by the investigator, for any reason, to be unsuitable 
candidate for the study 
  
Design: The pilot study is a prospective randomized study involving colchicine in the 
experimental arm. The study will be performed in the inpatient wards at Maimonides 
Medical Center.  
  
Data Collection Procedures: Data will be collected from Sunrise Clinical Manager 
Electronic records at Maimonides Medical Center.  
 
Patients with COVID-19 infection are usually assessed with laboratory tests to 
determine their inflammatory state. Markers such as CRP, troponin, LDH and Ferritin, 
and IL6 level are used routinely during the patient’s hospitalization. These markers 
are also frequently repeated during hospitalization to gauge a patient’s clinical status.  
At the time of study randomization, a set of these markers will be obtained if not 
already obtained in the prior 24 hours. We recommend clinical follow up of these 
markers as medically indicated by the treating physician. We recommend 
ascertainment of a peak troponin elevation during the hospitalization and peak CRP 
as would be expected in standard medical care.  

 
Biochemical end points 
● Maximum troponin elevation 
● Maximum CRP; Time (days) from colchicine initiation to achieve CRP <1 
 
Clinical end points 
● PRIMARY:  
○ Percentage of patients who require escalation of supplemental oxygen 
beyond low-flow nasal cannula (>8L/min) 
● SECONDARY:  
○ Percentage of patients who will require mechanical ventilation 
○ Hospital length of stay 
○ Mortality 
 
Safety Monitoring 
We anticipate colchicine to have an excellent safety profile given the medication’s 
widespread use in the outpatient and inpatient setting. However, given the 
medication’s widespread use in the outpatient and inpatient setting. However 
outcome data at each 20 patients will be evaluated to ensure there are no adverse 
events which would would necessitate pausing or discontinuation of the study. A 
signal for adverse events will be discussed internally with the investigators and 
reported to the IRB. Serious adverse events will be reported within 24 hours to the 
IRB.  
 
 
Data Analysis:   
All continuous variables will be summarized with mean and SD, where applicable, and 
median and IQR where necessary. All categorical variables will be summarized using 
frequency and percentage. 
 
Primary endpoint analysis of patients who require an escalation of supplemental 
oxygen beyond low-flow nasal cannula will be performed using Fisher’s exact test. 
Percentage of patients requiring mechanical ventilation and mortality will also be 
examined using Fisher’s exact test. Student’s t-test, Mann-Whitney’s U, and Mood’s 
Medial test will be utilized to examine maximum troponin elevation, maximum CRP 
and time from admission to achieve CRP<1, and hospital length of stay, depending 
on which statistical assumptions are met.  
  
 
All analyses will be performed using SAS version 9.4. 
  
 

 
Sample Size:  
We will collect 70 patients, 35 in each arm, for this pilot study. Results of this pilot 
study will be utilized to power a larger study. 
  
Expected Outcomes: We hope to demonstrate that colchicine reduces the 
percentage of patients who will require increased oxygen requirements, mechanical 
ventilation during hospitalization and reduce mortality. We hope to also demonstrate 
a lower peak serum CRP and troponin in the patients who receive colchicine. 
Decreased peak troponin may translate to improved cardiac outcomes.  
  
Timetable: We estimate enrollment to be completed in 1 month and follow up to be 
completed in approximately 2 weeks following enrollment. We hope to have data 
analyzed and results ready to submit for publication in 2 months from start date.