Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized With Coronavirus Disease 2019 The GRECCO-19 Randomized Clinical Trial

Design

Prospective, multicenter, open-label, randomized clinical trial

N=105

Objective

To evaluate the effect of treatment with colchicine on cardiac and inflammatory biomarkers and clinical outcomes in patients hospitalized with coronavirus disease 2019 (COVID-19)

Study Groups

Colchicine (n=55)

Control (n=50)

Inclusion Criteria

>18 years old with laboratory-confirmed SARS-COV-2 (by reverse transcription-polymerase chain reaction [RT-PCR]), presented with clinical symptoms including body temperature >37.5 °C; At least two of the following criteria: persistent cough, persistent throat pain, anosmia or ageusia, asthenia, arterial blood partial pressure of oxygen (PaO2)​ <95 mm Hg

Exclusion Criteria

Hypersensitivity to colchicine; severe hepatic impairment; Estimated glomerular filtration rate (eGFR) ​<20 mL/min; QTc >450 sec; severe gastrointestinal failure; under treatment or had received within 14 days drugs belonging to the classes of P-glycoprotein inhibitors or CYP3A4 inhibitiors

Methods

Participants were randomized to receive colchicine or standard of care. In the treatment arm, colchicine 1.5 mg was given as a loading dose followed by 0.5 mg of colchicine 60 minutes later if no adverse gastrointestinal effects were observed. If azithromycin was coadministred, then a single 1 mg loading dose of colchicine was given. The maintenance dose was colchicine 0.5 mg twice daily for 21 days. 

The control group was given other treatments as individual hospital protocols.

Duration

April 3 to 27, 2020

3 weeks

Outcome Measures

Primary: clinical deterioration by 2 points on the World Health Organization 7-point clinical status scale (ranging from able to resume normal activities to death)

Co-primary: maximum high-sensitivity cardiac troponin level; time for C-reactive protein to reach more than 3 times the upper limit of normal (ULN)

Baseline Characteristics

Control (n=50)

Colchicine (n=55)

Age, years (IQR)

Male

Body mass index, kg/m² (IQR)

High-sensitivity cardiac troponin level, ng/mL (IQR)

C-reactive protein, U/L (IQR)

Clinical Status Score

3: hospitalized not requiring oxygen

4: hospitalized requiring oxygen

5: requiring high flow oxygen or ventilation

17 (34%)

30 (60%)

3 (6%)

19 (34.5%)

36 (65.5)

0

0 (-18 to 18)

-6 (-25 to 13)

6 (-1 to 13)

Concomitant COVID-19 treatment

Chloroquine/hydroxychloroquine

Azithromycin

Lopinavir/ritonavir

Tocilizumab

Anticoagulaition

19 (38.0%)

46 (92.0%)

19 (38.0%)

2 (4.0%)

26 (52.0%)

14 (25.5%)

51 (92.7%)

14 (25.5%)

2 (3.6%)

31 (56.3%)

–13 (–5 tο 31)

–1 (–11 to 9)

–13 (–5 tο 31)

0 (–8 to 8)

–4 (–23 to 15)

Results

Control (n=50)

Colchicine (n=55)

P-value

Clinical deterioration by 2 points

Event-free survival time, days

High-sensitivity cardiac troponin level, ng/mL (IQR)

C-reactive protein, U/L (IQR)

Adverse Events

Common Adverse Events: vomiting (2% vs 1.8%); diarrhea (18% vs. 45.5%);nausea (2% vs 3.6%); abdominal pain (0% vs 9.1%); muscle spasm (0% vs 1.8%); headache (6% vs 10.9%)

Study Author Conclusions

In this randomized clinical trial, participants who received colchicine had statistically significantly improved time to clinical deterioration. There were no significant differences in high-sensitivity cardiac troponin or C-reactive protein levels. These findings should be interpreted with caution.

InpharmD Researcher Critique

The study was underpowered due to a smaller than needed sample size and a small number of clinical events. This study was conducted in April 2020, as reflected by the inappropriate concomitant therapies (e.g., hydroxychloroquine, lopinavir/ritonavir). The use of steroids was not reported in this study, as the results of the RECOVERY trial were not presented until after the study period was completed. The inappropriate control group suggests these results may not be accurate in a current real-world setting.

Beneficial Effects of Colchicine for Moderate to Severe COVID-19: An Interim Analysis of a Randomized, Double-blinded, Placebo Controlled Clinical Trial

Design

Single-center, randomized, double-blinded, placebo-controlled trial

N=35

Objective

To evaluate the use of colchicine for the treatment of hospitalized patients with moderate to severe COVID-19

Study Groups

Placebo (n=18)

Colchicine (n=17)

Inclusion Criteria

Patients with moderate to severe COVID-19 diagnosed by RT-PCR in nasopharyngeal swab specimens and lung CT scan involvement compatible with COVID-19 pneumonia; older than 18 years old; body weight >50 kg; normal levels of serum Ca²⁺ and K⁺; negative serum or urinary β-HCG in females under 50 years

Exclusion Criteria

Mild COVID-19 or in need of ICU admission; diarrhea resulting in dehydration; known allergy to colchicine; diagnosis of porphyria, myasthenia gravis or uncontrolled arrhythmia at enrollment; immunosuppressive chemotherapy; regular use of digoxin, verapamil, amiodarone, or protease inhibitor; chronic liver disease with hepatic failure

Methods

Participants were randomized 1:1 to receive either colchicine or place in addition to standard of care for moderate-to-severe COVID-19.

Patients in the colchicine arm received 0.5 mg TID for 5 days, then 0.5 mg BID for 5 days; if bodyweight ≥80 kg, the first dose was 1.0 mg. If a patient had chronic kidney disease with glomerular filtration rate <30 mL/min/1.73 m², the dose was reduced to 0.25 mg TID for 5 days, then 0.25 BID for 5 days regardless of body weight.

Patients were also given azithromycin 500 mg once daily for 7 days; hydroxychloroquine 400 mg BID for 2 days, then 400 mg once daily for 8 days; and unfractionated heparin 5000 IU TID until the end of hospitalization. Methylprednisolone 0.5 mg/kg/day for 5 days could be added if oxygen supplementation was 6 L/min or more.

Study medication was discontinued when a patient was admitted to the intensive care unit. Patients were evaluated daily and blood collected on days zero, 2, 4, and 7 if discharge did not occur before.

Duration

April 11 to July 6, 2020

Treatment: 10 days

Outcome Measures

Primary: time of need for supplemental oxygen; time of hospitalization; need for admission and length of stay in ICU; death rate and causes of mortality

Secondary: measures of serum CRP, serum LDH and relation neutrophil to lymphocyte of peripheral blood samples from day zero to day 7; the number, type, and severity of adverse events; frequency of interruption of the study protocol due to adverse events; and frequency of QT interval above 450 ms.

Baseline Characteristics

Placebo (n=18)

Colchicine (n=17)

Age, years (IQR)

Male

Fatigue*

*other common symptoms (e.g., fever, cough, myalgia, diarrhea) did not differ significantly at baseline.

IQR=interquartile range

Results

Colchicine (n=17)

p-Value

Time of supplemental O₂, days (IQR)

Time of hospitalization, days (IQR)

8.5 (5.5-11.0)

C-reactive protein (IQR)

Baseline

Day 7

8.2 (5.5-14.3)

2.2 (0.9-2.4)

7.8 (5.6-10.3)

0.4 (0.3-0.4)

Neutrophil to lymphocyte (IQR)

Baseline

Day 7

3.4  (2.2-6.2)

3.5 (1.6-8.2)

2.8 (2.4-4.4)

1.5 (1.3-5.6)

Lactate dehydrogenase (IQR)

Baseline

Day 7

317 (262-433)

213 (195-313)

339 (274-474)

259 (228-311)

One patient from each group was admitted to the ICU; the length of stay in the ICU was 12 and 11 days, respectively. No patients died.

Adverse Events

There were more patients in the colchicine group compared to the placebo group that had new or worsened diarrhea at 6% vs 24%, respectively.

No patient had a QT interval above 450 ms.

Nosocomial pneumonia was 11% in the placebo group vs 12% in the colchicine group.

Study Author Conclusions

Patients who received colchicine in this randomized, double-blinded, placebo-controlled clinical trial presented better evolution in terms of the need for supplemental oxygen and the length of hospitalization. Serum CRP was a laboratory marker of clinical improvement. Colchicine was safe and well-tolerated.

InpharmD Researcher Critique

The study was conducted at one Brazilian center and the sample size was very small. The majority of the patient population were obese women, making it difficult to apply the results to the general population. The exclusion criteria restricted cardiovascular drugs, however, this was due to the drugs impairing colchicine metabolism or excretion and the effects they might have in combination with hydroxychloroquine and azithromycin.

While this pilot study shows promising, hypothesis-generating results, a larger trial is needed to see if these results are valid and apply to a more generalized population.

Association Between Treatment With Colchicine and Improved Survival in a Single-Centre Cohort of Adult Hospitalised Patients With COVID-19 Pneumonia And Acute Respiratory Distress Syndrome

Design

Retrospective, single-center, cohort study

N=262

Objective

To assess the benefit of colchicine in improving survival in patients with COVID-19 pneumonia and acute respiratory distress syndrome

Study Groups

Colchicine plus standard of care (n=122)

Standard of care (n=140)

Inclusion Criteria

Patients admitted to the hospital with COVID-19 during the time frame

Exclusion Criteria

CrCl <30 mL/min; colchicine used as a rescue therapy

Methods

Standard of care at this Italian hospital during March 2020 included antivirals drugs, and/or hydroxychloroquine (HCQ), and/or corticosteroids. The combination of drugs given was dependent upon the physician's indication and drug availability. Some patients were also given off-label colchicine 1 mg daily (reduced to 0.5 mg if they had severe diarrhea).

Hydroxychloroquine was given orally 200 mg two times per day. Intravenous dexamethasone was administered at 20 mg/day for 5 days, followed by 10mg/day for 5 days. Patients received antibiotics and supportive care when required.

Duration

March 5 to April 5, 2020

Outcome Measures

Primary: Survival after 21 days

Baseline Characteristics

Colchicine (n=122)

Control (n=140)

Age, years

Male

Observation time. days

Treated with

Hydroxychloroquine

Lopinavir/ritonavir

Dexamethasone

46/102 (45%)

10/106 (9%)

62/107 (58%)

78/138 (57%)

53/139 (38%)

44/139 (32%)

0.08

<0.0001 

<0.0001 

Results

Colchicine (n=122)

Control (n= 140)

P-value

Survival at 21 days

Adverse Events

Doses were reduced due to diarrhea reported in 9 patients in colchicine (7.4%). Otherwise, no adverse events were reported.

Study Author Conclusions

This proof-of-concept study may support the rationale for the use of colchicine for the treatment of COVID-19. Efficacy and safety must be determined in controlled clinical trials.

InpharmD Researcher Critique

The patients who received colchicine significantly received more dexamethasone, which was later found out to have a mortality benefit. The possibility that these results may be confounded by dexamethasone usage cannot be excluded. This study did not present the severity of disease experienced by included patients. They also excluded 2 patients who received colchicine for rescue therapy, which suggests there is selection bias. Certain treatments offered in the standard of care varied based on physician discretion and availability of drugs which showed that some patients seem to suffer from a less severe disease.

A Case Control Study to Evaluate the Impact of Colchicine on Patients Admitted to the Hospital with Moderate to Severe COVID-19 Infection

Design

Prospective, comparative cohort study

N=112

Objective

To assess the efficacy of colchicine in treating patients with COVID-19

Study Groups

Colchicine (n=34)

Control (n=78)

Inclusion Criteria

18 years or older; admitted to a pulmonary floor of a hospital in New York; clinically suspected COVID-19 or a positive SARS-CoV-2 nasal swab PCR; at least two separate timepoint measurements for at least 2 out of 4 inflammatory markers (D-dimer, CRP, LDH, or ferritin)

Exclusion Criteria

Pregnancy; end-stage renal disease (ESRD); concurrent use of protease inhibitor, ketoconazole, cyclosporine, clarithromycin, lamivudine, dolutegravir, tocilizumab, or convalescent plasma

Methods

This was a study comparing two pulmonary-oriented floors of a hospital in New York. The decision of whether or not to use colchicine was not reported.

If given, colchicine was dosed 0.6 mg BID for 3 days, then 0.6 mg once daily for a total of 12 days. Colchicine would not be continued if patients were discharged before completing 15 doses. Dose adjustments were made for reduced glomerular filtration rate (GFR) due to chronic kidney disease (CKD) and were stopped if patients developed new renal failure or if there was a progression of preexisting CKD.

Duration

March 21 to May 2, 2020

Treatment: 12 days

Outcome Measures

Primary: rate of intubation, mortality, and discharge rate

Baseline Characteristics

Colchicine (n=34)

Control (n=78)

Age, years

Male

Comorbid Illnesses

Hypertension

Diabetes Mellitus

Renal Failure

18 (52.9%)

11 (32.4%)

12 (35.2%)

56 (71.8%)

40 (51.3%)

47 (60.3%)

0.053

0.064

0.015

Concomitant treatments

Hydroxychloroquine

Steroids

Oseltamivir

Anticoagulation

32 (94.1%)

19 (55.9%)

30 (88.2%)

32 (94.1%)

68 (87.2%)

47 (60.3%)

68 (87.2%)

74 (94.9%)

0.651

0.665

1.00

0.871

Baseline inflammatory markers (e.g., D-dimer, C-reactive protein, lactate dehydrogenase) were not significantly different between the groups.

Results

Colchicine (n=34)

Control (n=78)

p-Value

Intubated

Mortality in intubated patients

16 (47.1%)

15/16 (93.8%)

68 (87.2%)

60/68 (88.2%)

<0.0001

0.455

Length of hospitalization, days

Change in D-dimer and C-reactive protein from baseline showed significantly lower levels in the colchicine group.

Adverse Events

Not reported

Study Author Conclusions

In conclusion, these results show that colchicine given to patients admitted to the hospital with COVID-19-related symptoms may improve outcome and is associated with lower levels of inflammatory markers and faster normalization of these markers.

InpharmD Researcher Critique

The study was not randomized or blinded. The sample size was small, causing the lack of statistically significant difference between the groups for the raw delta values. This study had strict exclusion criteria that did not allow for other common COVID-19 treatments at the time. There may have been some selection bias in the colchicine group (that allowed for its use), as the control group had more hypertension and diabetes, which represents a higher risk of severe COVID-19. The baseline severity of COVID-19 was also not reported.

Clinical Outcome of Patients with COVID-19 Pneumonia Treated with Corticosteroids and Colchicine in Colombia

Design

Prospective, cross-sectional, observational, cohort study 

N=301

Objective

To describe the clinical manifestations and outcomes of patients with severe COVID-19 pneumonia treated with corticosteroids and colchicine

Study Groups

Corticosteroids and colchicine (n=301)

Inclusion Criteria

>18 years hospitalized for COVID-19 pneumonia confirmed positive by Real-Time Reverse Transcription Polymerase Chain Reaction (RT-PCR) nasal swab; radiological confirmation of pneumonia

Exclusion Criteria

None listed

Methods

Participants at three centers in Colombia were given corticosteroid treatment with dexamethasone, prednisolone or methylprednisolone, and/or colchicine 0.5 mg q12h for 7 to 14 days.

Duration

March 20 to August 7, 2020

14 days

Outcome Measures

Primary Outcome: Survival 

Baseline Characteristics

Corticosteroids and colchicine (n=301)

Age, years

Male

Common comorbidities

COPD/Asthma

Hypertension

30 (10%)

137 (45.5%)

Received steroids

Received colchicine

240 (79.7%)

145 (48.2%)

Results

Dead (n=37; 12.3%)

Alive (n=264; 87.7%)

P-value

Received steroids

32 (86.5%)

208 (78.8%)

0.275

Received colchicine

14 (37.8%)

131 (49.6%)

0.179

Adverse Events

Study Author Conclusions

Treatment with corticosteroids and colchicine for managing patients with severe Covid-19 pneumonia was associated with low mortality at the hospital level. Randomized, placebo-controlled studies are required to evaluate the effect of corticosteroids and colchicine on complications or death from Covid-19.

InpharmD Researcher Critique

This study is a pre-print and not yet peer-reviewed. Due to the observational nature of this study, the reported findings should be interpreted with caution. The number of patients who received both steroids and colchicine was not reported, as were the individual characteristics of the patients who received colchicine. Randomized, placebo-controlled clinical studies are required to evaluate the effect of administered drug therapy. Additionally, this is a pre-print that has not yet been peer-reviewed.

Colchicine to Weather the Cytokine Storm in Hospitalized Patients with COVID-19

Design

Retrospective, single-center, propensity-matched cohort study

N=66

Objective

To determine the clinical outcomes of a small cohort of patients who received colchicine versus a propensity score-matched control group

Study Groups

Colchicine (n=33)

Standard (n=33)

Inclusion Criteria

Severe COVID-19 patients with confirmed SARS-CoV-2 infection (positive PCR)

Exclusion Criteria

NA

Methods

Patients were stratified according to the receipt of colchicine. The type of colchicine administered as well as the timing of administration was based on the clinician’s judgment. However, the overall approach was to administer colchicine before the progression of respiratory failure. Patients were given a loading dose of 1.2 mg, and a maintenance dose was 0.6 mg BID.

All patients were prescribed hydroxychloroquine and azithromycin during the study unless the clinician felt there was a risk of toxicity (i.e., QT prolongation, cardiac risk). Patients were given remdesivir only in the context of a clinical trial or under the expanded-use access program. Patients were given tocilizumab on a case-by-case basis after a patient assessment and evidence of cytokine storm based on the ferritin concentration >300 ng/mL. Corticosteroids were not routinely given to patients because at the time of the study there was inadequate data to support corticosteroid use in COVID-19 patients.

Key clinical events such as laboratory data, hospital discharge, and reported adverse events, (including those leading to discontinuation of treatment, serious adverse events, and death) were quantified. Additionally, the Ordinal Scale for Clinical Improvement (OSCI) was used at baseline and on days 7, 14, and 28.

Duration

March 1 to May 30, 2020

Follow-up: 28 days

Outcome Measures

Primary endpoint: in-hospital death within 28-days follow-up

Secondary endpoints: favorable change in the Ordinal Scale for Clinical Improvement on days 14 and 28 versus baseline, proportion of patients not requiring supplemental oxygen on days 14 and 28, proportion of patients discharged by day 28

Baseline Characteristics

Colchicine (n=33)

Standard (n=33)

Age, years

Female

White

C-reactive protein, mg/dL

Concomitant medications

Hydroxychloroquine

Azithromycin

Remdesivir

Tocilizumab

54.5%

33.3%

12.1%

36.4%

90.9%

78.8%

12.1%

33.3% 

0.001

>0.001

1.00

0.796

Results

Colchicine (n=33)

Standard (n=33)

P-value

All-cause mortality by day 28

Favorable change in WHO clinical status

By day 14

By day 28

19 (57.6%)

26 (78.8%)

17 (51.5%)

17 (51.5%)

0.621

0.023

No need for supplemental oxygen

By day 14

By day 28

18 (54.5%)

26 (78.8%)

18 (54.5%)

18 (54.5%)

1.00

0.04

Discharged by day 28

Adverse Events

Study Author Conclusions

In this cohort study, treatment with colchicine was associated with a higher rate of discharge and was associated with a decrease in mortality in patients with severe COVID-19 by day 28.

InpharmD Researcher Critique

This study is limited by the small sample size and single-center design. While the authors stated corticosteroids were not routinely given, they did not report if (and how many) patients received any.

Other limitations: 73% of patients received the 1.2 mg colchicine loading dose, no adverse events were reported for the patients who received colchicine, there was a difference in the proportion of patients receiving hydroxychloroquine and azithromycin in the colchicine group versus the control group, hydroxychloroquine and azithromycin were removed from the COVID-19 treatment protocol during the study period because available evidence suggested their lack of effect and possible toxicity.

Successful Treatment of Covid-19 Associated Cytokine Release Syndrome with Colchicine. A Case Report and Review of Literature

Design

Case report

Case Presentation 

A 42-year-old patient with no prior medical history presented with fever, dry cough, myalgia, weakness, and sore throat beginning 3 days earlier. He had normal vital signs, except for fever of 38.5°C, O₂ saturation 94% on ambient air, and a nasopharyngeal swab PCR that was negative for all respiratory viruses except COVID-19. A chest computed tomography (CT) revealed bilateral basilar ground-glass opacities. He was given oseltamivir 75 mg BID and hydroxychloroquine 200 mg BID for 5 days.

Five days after the patient's presentation his respiratory symptoms improved; however, his fever, fatigue, and loss of appetite remained. Then on day 10, the patient felt a stabbing pain in his right first metatarsal joint. This toe pain was associated with warmth and severe tenderness but there was no erythema or edema. The patient had no past medical history of gout until this presentation. The patient was started on oral colchicine at a dose of 1 mg BID with intravenous and oral hydration at home because he no longer had respiratory symptoms, his imaging showed improvements in lung infiltrates and he refused to be admitted into the hospital.

After 48 hours of colchicine treatment the patient experienced clinical improvement, he became afebrile, urine output returned to normal, he regained his appetite, and he had no more toe pain. He was kept on colchicine 1 mg once a day for a total of 14 days. After completing his colchicine treatment his nasopharyngeal swab was negative two separate times; his WBC, platelet count, LDH, ferritin, fibrinogen, D-dimer, IL-6, and uric acid levels all returned to normal range.

Study Author Conclusion

It is likely that the patient experienced a late-onset mild cytokine release syndrome (CRS) presenting with a monoarticular gout flare. Colchicine inhibits microtubule formation and interferes with the inflammasome complex in immune cells. Colchicine treatment in this patient not only alleviated the gout flare but also reduced the patient’s clinical symptoms and inflammatory markers.

This case report suggests that colchicine might be an appropriate candidate to prevent CRS in COVID-19 patients with early lung involvement in addition to routine antiviral agents.

COVID-19 in kidney transplant recipients

Case series

Case 1

A 75-year-old male kidney transplant recipient was diagnosed with COVID-19 at 120 months post-transplant. He was taking tacrolimus, mycophenolate mofetil, and steroids. Upon admission, tacrolimus and mycophenolate mofetil were discontinued and hydroxychloroquine 200 mg BID was started in addition to lopinavir + ritonavir.

Abrupt worsening of respiratory conditions developed over 24-38 hours and he died after 5 days before intubation.

Case 2

A 52-year-old female kidney transplant recipient was diagnosed with COVID-19 at 8 months post-transplant. She was taking tacrolimus, mycophenolate mofetil, and steroids. Upon admission, tacrolimus and mycophenolate mofetil were discontinued and hydroxychloroquine 200 mg BID was started in addition to darunavir + cobicistat.

Six days after admission, she showed signs of systemic inflammation (plasma IL‐6: 108.2 pg/mL [normal range 0‐10 pg/mL]). After progressive worsening of respiratory conditions requiring non‐invasive ventilation, she received colchicine (1 mg on day 8, and 0.5 mg/day thereafter) due to the unavailability of tocilizumab. 

One day after colchicine administration, her plasma IL-6 concentration decreased to 36 pg/mL and respiratory conditions stabilized. Fourteen days after admission, the patient is alert and stable on non-invasive ventilation. 

Study Authors' Conclusions

Colchicine prevents NLRP3 inflammasome assembly, thereby reducing the release of IL‐1b and other interleukins, including IL‐6. In case 2, colchicine was associated with a fast decrease of IL-6 levels.

In the presented kidney transplant recipients, the course of COVID‐19 did not significantly differ from that of non‐transplant individuals. Immunosuppression interruption combined with the anti‐inflammatory effects of colchicine may have synergized with antiviral therapy and hydroxychloroquine to lower viral replication and minimize the cytokine storm triggered by SARS‐CoV‐2.