Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000637842
Ethics application status
Approved
Date submitted
15/05/2020
Date registered
27/05/2021
Date last updated
27/05/2021
Date data sharing statement initially provided
27/05/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Impact of Colchicine To Improve long-COVID-19 or ARDS Outcomes
Scientific title
A multi-centre trial of colchicine vs control to improve clinical outcomes in adults with long-SARS-CoV-2 (COVID-19) or ARDS
Secondary ID [1] 301288 0
None
Universal Trial Number (UTN)
Trial acronym
IMPACT-ICO
Linked study record

Health condition
Health condition(s) or problem(s) studied:
COVID-19 Respiratory Infection 317469 0
Acute respiratory distress syndrome 320470 0
Condition category
Condition code
Respiratory 315570 315570 0 0
Other respiratory disorders / diseases
Inflammatory and Immune System 315630 315630 0 0
Other inflammatory or immune system disorders
Infection 318355 318355 0 0
Other infectious diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm A: Colchicine 0.5 mg tablet twice daily given orally or crushed via nasogastric/PEG tube for 6 months + standard of care
Arm B: Standard of care
Intervention code [1] 317594 0
Treatment: Drugs
Comparator / control treatment
Standard of care:

There is no specific antiviral treatment recommended for COVID-19. Standard treatment is symptomatic, and may include oxygen therapy and intubation and protective mechanical ventilation, as well as pharmacologic therapies such as corticosteroids, antiviral agents (e.g. remdesivir), immunomodulators (e.g. chloroquine), serotherapy, anticoagulant therapy and inflammatory inhibitors (e.g. tocilizumab).
Treatment will be directed at the underlying cause of ARDS, as well as supportive measures to ensure adequate tissue oxygenation. Such supportive measures would include supplemental oxygen therapy and/or mechanical ventilation (either non-invasive or invasive via endotracheal tube). There is currently no specific pharmacotherapy proven to be effective in ARDS.
Treatment of both conditions will vary based on hospital processes and the specific condition of the participant.
Control group
Active

Outcomes
Primary outcome [1] 323807 0
To compare COVID-19 WHO score greater than or equal to 2 (for participants with COVID-19) or Dyspnoea Management Questionnaire-30 (for participants with ARDS) breathlessness scores at 6 months. This is composite primary outcome.
Timepoint [1] 323807 0
6 months post randomisation
Primary outcome [2] 323808 0
Maximum oxygen requirement (increase or decrease) over 6 months defined as follows:
- An increase in oxygen requirement will be defined by 1. Increasing oxygen flow rate or FiO2 using the same oxygen delivery device, or 2. Escalation to invasive and non-invasive mechanical ventilation/ECMO or vasopressor/ionotropic support.
- A decrease in oxygen requirement will be defined as a decrease in oxygen flow rate or FiO2 using the same oxygen delivery device, or cessation of oxygen support requirement.

The peak oxygen requirement (i.e. increase from that at baseline) will be recorded, irrespective of the time of occurrence up until discharge and 6 months. Likewise, the greatest decrease will also be recorded, irrespective of the time of occurrence up until discharge and 6 months.
Timepoint [2] 323808 0
6 months post randomisation
Primary outcome [3] 327377 0
Death at 6 months and end of study. This will be ascertained by assessment of medical records.
Timepoint [3] 327377 0
6 months post randomisation and end of study.
Secondary outcome [1] 382960 0
PRIMARY OUTCOME:

To determine changes in inflammatory biomarkers (hs-TnT, hs-CRP, differential WCC, IL-1ß, IL-6, IL-10, pro-calcitonin, MCP1, MMP9, using standard hospital and lab methods) at any time from baseline (prior to study treatment) up to day 21 (i.e. nadir result).
Timepoint [1] 382960 0
Day 1, day 7 and day 21 post-randomisation.
Secondary outcome [2] 382961 0
PRIMARY OUTCOME:
To determine whether there is a reduction of 25% or more in at least 3 activated monocyte phenotypes (CD1a, CD2, CD3, CD4, CD5, CD8, CD11a, CD11c, CD14, CD15, CD16, CD19, CD25, CD26, CD27, CD28, CD44, CD45RA, CD45RO, CD49d, CD56, CD62L, CD64, CD66b, CD69, CD95, CD127, CD137, CD160, CD178, CD183, CD184, CD192, CD195, CD197, CD223, CD279, CD314, CD366, HLA DR, CCR10, FoxP3 [as per standard CyTOF Helios analysis]) at any time from baseline to day 21 (i.e. nadir result).
Timepoint [2] 382961 0
Day 1, day 7 and day 21 post-randomisation.
Secondary outcome [3] 383073 0
PRIMARY OUTCOME:
To determine whether there is a reduction of 10% or more in the number of circulating inflammatory monocytes from baseline to day 5-7, and 6 months post randomisation.
Timepoint [3] 383073 0
Baseline to day 5-7, and 6 months post randomisation.
Secondary outcome [4] 391997 0
To compare cause of death of both participants with COVID-19 and non-COVID-19 ARDS. This will be ascertained via assessment of medical records.
Timepoint [4] 391997 0
6 months post randomisation.
Secondary outcome [5] 391998 0
To compare changes in serial ECG at baseline in both COVID-19 and non-COVID-19 ARDS participants at baseline and 6 months post-randomisation. The following will be assessed: rhythm, ST segement, QRS complex.
Timepoint [5] 391998 0
Baseline and 6 months post randomisation.
Secondary outcome [6] 391999 0
To compare changes in spirometry at baseline and 6 months post randomisation in COVID-19 and non-COVID-19 ARDS participants. The following will be assessed: FEV1, FVC, FVC ratio
Timepoint [6] 391999 0
Baseline and 6 months post randomisation.
Secondary outcome [7] 394853 0
To compare days in hospital for COVID-19 and non-COVID-19 ARDS participants, as assessed through medical records at 6 months compared to baseline.
Timepoint [7] 394853 0
Baseline and 6 months post-randomisation.
Secondary outcome [8] 394854 0
To compare time in ICU (hours) for COVID-19 and non-COVID-19 ARDS participants, as assessed through medical records.
Timepoint [8] 394854 0
6 months post randomisation.
Secondary outcome [9] 394855 0
To compare quality of life as measured by EQ-5D-5L questionnaire in patients with COVID-19 and non-COVID-19 ARDS at baseline and 6 month post-randomisation.
Timepoint [9] 394855 0
6 months post randomisation.
Secondary outcome [10] 394856 0
To compare return to work at 6 months post randomisation compared to pre-COVID-19/non-COVID-19 ARDS. This will be assessed by study specific questionnaire.
Timepoint [10] 394856 0
6 months post randomisation.
Secondary outcome [11] 395509 0
To compare changes in echocardiogram data at baseline and 6 months post randomisation in COVID-19 and non-COVID-19 ARDS participants. The following will be assessed: LV thickness LV ejection fraction, LV dimension, RV dimension, LA size, RA size.

Timepoint [11] 395509 0
Baseline and 6 months post randomisation

Eligibility
Key inclusion criteria
Inclusion criteria for COVID-19 participants:
1. Aged 18 years and older.
2. Hospitalised with confirmed COVID-19 respiratory infection by swab-positive PCR with hypoxia (SpO2 less than or equal to 93% on room air) requiring oxygen therapy.
3. Patients that score 4-5 on the WHO COVID Ordinal Scale for Clinical Improvement.
4. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments.
5. Signed, written informed consent from the participant.

Inclusion criteria for non-COVID-19/ARDS participants:
1. Aged 18 years and older.
2. Hospitalised with non-COVID-19 ARDS with hypoxia (SpO2 less than or equal to 93% on room air) requiring oxygen therapy.
3. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments.
4. Signed, written informed consent from the participant.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Treating team deems enrolment in the study is not in the best interests of the participant.
2. Death is deemed to be imminent and inevitable within the next 24 hours.
3. Either the patient or their primary treating clinician is not committed to active treatment.
4. Current treatment with colchicine.
5. Known severe allergic response (e.g. profuse diarrhoea) to colchicine.
6. Potential severe drug interaction with colchicine.
7. Receiving concurrent Anakinra.
8. End-stage renal disease with eGFR less than or equal to 30 ml/min/m2.
9. Acute or chronic hepatitis, with liver enzyme abnormalities > 5 x ULN at baseline.
10. Known HIV infection or other immunocompromised status (with the exception of steroids including dexamethasone and tocilizumab).
11. Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or use a reliable means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration. Men must have been surgically sterilised or use a (double if required) barrier method of contraception.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Prospective randomised open blinded endpoint design
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
COVID-19:
With 300 participants (Australian cohort), the study will offer over 80% power at 2P=0.05, to identify as statistically significant a reduction in mean WHO COVID-19 score at 6 months from 2 (SD 1.5) to 1.5 (SD 1.5). With 50 participants in the monocyte sub-study, differences in monocyte characteristics of less than 25% (SD 10) between groups will be significant at 2P=0.05.
With up to 1,000 participants recruited in total (including international participants), the study would offer >80% power to identify as significant (at 2P=0.05) a reduction of 2 points in WHO COVID-Ordinal Score, 2 days (SD 2) less time in ICU, or death of 20%.

Non-COVID-19 ARDS
With 300 participants, we will have 90% power at 2P=0.05 to identify as statistically significant a reduction from a mean DMQ-30 composite score of 11±4 to 9.5±4 (i.e. <14% improvement).
Similarly, with 1000 participants, the study would offer 90% power at 2P=0.01, to identify as statistically significant, an improvement from 11±4 to 10±4 (i.e an improvement of 9%).

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
2/08/2021
Actual
Date of last participant enrolment
Anticipated
2/08/2022
Actual
Date of last data collection
Anticipated
6/02/2023
Actual
Sample size
Target
1000
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 17810 0
Royal Prince Alfred Hospital - Camperdown
Recruitment postcode(s) [1] 31667 0
2050 - Camperdown
Recruitment outside Australia
Country [1] 23523 0
India
State/province [1] 23523 0

Funding & Sponsors
Funding source category [1] 305733 0
Government body
Name [1] 305733 0
NSW Health COVID-19 Research Grant
Country [1] 305733 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
NHMRC Clinical Trials Centre
Medical Foundation Building (K25)
The University of Sydney
Level 6, 92-94 Parramatta Rd
CAMPERDOWN NSW 2050
Country
Australia
Secondary sponsor category [1] 307508 0
None
Name [1] 307508 0
None
Address [1] 307508 0
None
Country [1] 307508 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306008 0
Sydney Local Health District (RPAH Zone) Human Research Ethics Committee
Ethics committee address [1] 306008 0
Research Ethics and Governance Office (REGO)
Royal Prince Alfred Hospital
Missenden Road
CAMPERDOWN NSW 2050
Ethics committee country [1] 306008 0
Australia
Date submitted for ethics approval [1] 306008 0
24/02/2021
Approval date [1] 306008 0
11/05/2021
Ethics approval number [1] 306008 0

Summary
Brief summary
SARS CoV-2 (COVID-19) is highly infectious, with each case transmitting infection to between 2 to 3 other people. Approximately 15% of COVID-19 infected individuals are hospitalised and 1 in 3 require artificial ventilatory support. Up to a third have a poor prognosis with the main cause of death being overwhelming respiratory failure and/or cardiac failure and cardiac arrest associated with a cytokine storm. Approximately 30% of hospitalised individuals will ultimately require artificial ventilatory support for deteriorating respiratory status while under clinical observation. Conservatively, at least one third of intubated people will succumb to the infection with the most common causes of death being overwhelming respiratory failure associated with acute respiratory distress syndrome (ARDS) and/or cardiac failure and cardiac arrest, both associated with cytokine storm. Over 1.9 million individuals of the 46 million infected individuals globally have died from COVID-19 infection (as of January 2021), with many more deaths projected over the next 6-12 months. Fatal outcomes are thought to be driven by inflammatory responses to the virus resulting in host-mediated tissue damage to the lung, heart, and kidney and a prothrombotic milieu. Approximately 10% of patients with COVID-19 suffer from symptoms beyond 3-4 weeks, labelled as ‘long COVID-19.’ A variety of symptoms are experienced including cough, breathlessness, fever, sore throat, chest pain and cognitive deficits. Oral colchicine has demonstrated striking anti-inflammatory properties in patients with vascular disease and a “single shot” of colchicine markedly suppresses monocyte inflammasome activation, which is pivotal in the cascade leading to the cytokine storm. Troublesome side effects with colchicine appears to be rare. Thus, this treatment may reduce the serious complications associated with COVID-19 and non-COVID-19 ARDS.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 102402 0
Prof Anthony Keech
Address 102402 0
NHMRC Clinical Trials Centre
Level 6, Medical Foundation Building (K25)
92-94 Parramatta Rd
CAMPERDOWN NSW 2050
Country 102402 0
Australia
Phone 102402 0
+61 2 9562 5000
Fax 102402 0
Email 102402 0
[email protected]
Contact person for public queries
Name 102403 0
Ms Annie Yeung
Address 102403 0
NHMRC Clinical Trials Centre
Level 6, Medical Foundation Building (K25)
92-94 Parramatta Rd
CAMPERDOWN NSW 2050
Country 102403 0
Australia
Phone 102403 0
+61 2 9561 5000
Fax 102403 0
Email 102403 0
[email protected]
Contact person for scientific queries
Name 102404 0
Prof Anthony Keech
Address 102404 0
NHMRC Clinical Trials Centre
Level 6, Medical Foundation Building (K25)
92-94 Parramatta Rd
CAMPERDOWN NSW 2050
Country 102404 0
Australia
Phone 102404 0
+61 2 9562 5000
Fax 102404 0
Email 102404 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual participant data will not be shared. A summary of the study data will be published in a peer reviewed journal.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.