IMPACT CASE STUDY
The Irish Critical Care-Clinical Trials Network at UCD has carried out significant clinical research in preparation for, and in response to, the COVID-19 pandemic.
Through collaborative networks of hospitals across 63 countries, this research has had a profound impact on patients with COVID-19, their families, and wider society. The Network’s outputs have saved thousands of lives and ICU bed days by identifying treatments that improve patient survival and recovery (as well as identifying treatments that are ineffective or even harmful), and by informing HSE and WHO treatment guidelines for the clinical management of severe COVID-19 infection.
The Irish Critical Care-Clinical Trials Network (ICC-CTN) boasts a substantial portfolio of clinical research in preparation for and in response to pandemics. This began more than 10 years ago with research into the 2009 swine flu pandemic. However, by the time research studies were established in 2009, that pandemic had passed, and so had the opportunity to determine effective treatments safely and definitively through controlled clinical trials. This missed opportunity became the foundation of the Network’s research on pandemic preparedness, informing several new initiatives:
PREPARE included studies into various aspects of pandemic research: a clinical trial to test treatments, research on ethical and regulatory barriers to conducting clinical trials during a pandemic, and studies of public and clinician perceptions of such research.
As part of PREPARE, the group established a clinical trial called REMAP-CAP, studying community-acquired pneumonia (i.e., pneumonia acquired outside of the hospital). However, because the trial is what’s known as “adaptive”, it could also quickly be applied in the event of a future pandemic, and it was able to do just that during the COVID-19 pandemic. What’s more, the novel design of REMAP-CAP means it can also test multiple treatments simultaneously. It has yielded many important findings, in a time-sensitive manner, including identifying treatments that are beneficial to hospitalised COVID-19 patients, along with other treatments that are potentially ineffective or harmful (see References for further detail).
11 further treatments are currently being tested as part of REMAP-CAP. The ICC-CTN investigators lead and co-lead five aspects of the project (each looking at different potential treatments for COVID-19) and coordinated national trial activity in Ireland.
Within PREPARE, the team also conducted public surveys and focus groups looking at how the public and clinicians view pandemic research. This work has provided key insights into public acceptability of emergency consent in a clinical trial during a pandemic (where a patient may not be able to consent for themselves due to their illness and their relative or physician may initially decide on their behalf) and is now shaping how clinical trials are conducted.
This study was also established pre-COVID to make sure the research environment is ready to tackle a pandemic. This includes ensuring data is collected in the same way across different countries and settings. Because of this, in response to COVID-19, 1,651 hospitals across 63 countries have collected data in a harmonised, coordinated fashion on patients with severe acute respiratory infection.
These data have been crucial for understanding the disease (including new variants) as the pandemic has evolved. ICC-CTN Investigators helped establish this project and coordinate activities in 18 Irish hospitals. To date, 15 reports have been publicly published.
This global research effort lead from Edinburgh University seeks to understand the genetic factors that influence outcomes in critically ill patients. It has since been applied to COVID-19, with more than 14,000 genetic samples taken so far.
This research identified, for the first time, several genetic factors which make an individual susceptible to critical illness with COVID-19 and identified new therapeutic targets which are now helping to inform the design of new clinical trials. The ICC-CTN co-ordinates this study in Ireland.
The Irish Critical Care-Clinical Trials Network is a team of clinician-researchers, project managers, research coordinators and researchers. They coordinate the ICC-CTN’s pandemic response and COVID-19 research throughout Ireland and are essential contributors to pandemic research studies globally. The UCD core team leaders are:
The ICC-CTN’s research has had a significant impact on patients, their families, wider society, the economy, clinicians and researchers throughout Ireland and internationally, with over 530,000 patients collectively involved in this global research portfolio.
To date, the ICC-CTN have fully tested ten COVID-19 treatments. They found several treatments that improve ICU patient survival and recovery (see here and here), two that are ineffective, and one that may actually harm patients. They also discovered that another treatment might be beneficial to COVID-19 patients who are not critically ill.
These results have been incorporated into treatment guidelines by the HSE and WHO (see References below), which inform clinicians’ management of their patients with COVID-19. These evidence-based changes in treatment are benefitting patients worldwide, saving lives, resources and money. Eleven further treatments are currently being tested. These results will also inform and update treatment guidelines and the best practice standard of care, with the goal to further improve patient outcomes.
Researchers at the ICC-CTN have identified, for the first time, genetic factors which affect the likelihood of becoming critically ill with COVID-19. These can inform the search for potential future treatments for the disease.
The COVID-19 pandemic has affected the lives of everyone, with around 350 million cases worldwide, more than 5 million deaths, and a significant number of critically ill patients. In Ireland, there have been over 1 million cases and 6,000 deaths. The pandemic has affected all aspects of society and has had significant economic effects.
As well as increasing knowledge and informing treatment guidelines, the ICC-CTN’s research has raised awareness of the specialised nature of intensive care medicine, its role in treating severe infectious disease, and how life-saving critical care treatments are informed by research. The ICC-CTN have heightened this awareness through public outreach work, media appearances and podcasts.
Furthermore, the treatments identified by the ICC-CTN are relatively low-cost, and since being adopted into practice have resulted in savings for healthcare systems in Ireland and internationally.
Researchers at the ICC-CTN have contributed to our understanding of COVID-19. The wider public have benefited from media appearances and press releases, which includes direct patient and public involvement in communicating and disseminating the research findings. Clinicians and researchers have learned more about the disease and its treatment though publications, conference presentations, webinar series, training and trials methodology. There has been substantial involvement of clinicians and researchers (of all career stages) in this work, which includes 1651 hospitals across 63 countries, including 18 hospitals in Ireland.
This work has significantly contributed to knowledge of COVID-19, with more than 50 reports and 17 manuscripts prepared so far.
The REMAP-CAP study uses a new type of “adaptive” trial design, which is paving the way for more cost-effective trials that can be embedded in the healthcare system. This trial has analysed a significant amount of data from over 10,000 patients, and has answered 10 life-saving questions within 18 months – only possible due to this new, more efficient trial design. Furthermore, the team are developing new protocols for sampling biological material, which will benefit other researchers working in this area.
As mentioned, the ICC-CTN has facilitated the involvement of 18 Irish hospitals in pandemic research, including 6 in a clinical trial (REMAP-CAP) of COVID-19 treatments. This has allowed an all-Ireland approach to COVID-19 research, with UCD at the forefront.
The group’s research will continue and expand into the future, to help researchers respond to and prepare for any future pandemics. We responded better this time than in 2009, but further work will undoubtedly better inform future efforts.
Results are first reported publicly (as preprints) and to the relevant bodies (like the WHO) as soon as possible and prior to peer-reviewed journal publication due to their importance in combatting and treating COVID-19.
The Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia (REMAP-CAP) Study: Rationale and Design. Angus DC, et al. Ann Am Thorac Soc. 2020 Apr 8. PMID: 32267771
Talking to the people that really matter about their participation in pandemic clinical research: A qualitative study in four European countries. Gobat NH, et al. Health Expect. 2017 Sep 27. PMID:28960624
Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial. Writing Committee for the REMAP-CAP Investigators, Angus DC, et al. JAMA. 2020 Oct 6;324(13):1317-1329. PMID: 32876697
A living WHO guideline on drugs for covid-19. Rochwerg B et al. BMJ 2020; 370 :m3379
Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. REMAP-CAP Investigators, Gordon AC, et al. N Engl J Med. 2021 Feb 25. PMID: 33631065
Lopinavir-ritonavir and hydroxychloroquine for critically ill patients with COVID-19: REMAP-CAP randomized controlled trial. Arabi YMet al. REMAP-CAP Investigators. Intensive Care Med. 2021 Jul 12:1-20. PMID: 34251506
Therapeutic Anticoagulation in Non-Critically Ill Patients with Covid-19. The ATTACC, ACTIV-4a, and REMAP-CAP Investigators, et al. August 26, 2021 N Engl J Med 2021; 385:790-802
Therapeutic Anticoagulation in Critically Ill Patients with Covid-19 – Preliminary Report. The REMAP-CAP, ACTIV-4a, ATTACC Investigators, Ryan Zarychanski. August 26, 2021 N Engl J Med 2021; 385:777-789
Genetic mechanisms of critical illness in Covid-19. Pairo-Castineira E, et al. Nature. 2020 Dec 11. PMID: 33307546