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International Clinical Trials Day: A focus on the ASTONISH trial at the Wellcome-HRB Clinical Research Facility

With financial support from the Health Research Board (HRB) and the Wellcome Trust, the Wellcome-HRB Clinical Trials Facility (CRF) at St James’s Hospital opened in 2013 and has gone from strength to strength. The state-of-the-art CRF conducts a wide range of studies from observational studies to complex overnight Phase 1 clinical trials. The unit supports research across a wide range of disease areas. Currently the CRF employs around 20 highly-trained staff including a Clinical Director, Associate Directors, Program Manager, Assistant Director of Nursing, Research Pharmacist, Quality and Regulatory Affairs Manager, Research Nurses, Research Assistants, Data Manager and Administration staff. Since its inception, more than 10,000 patients have been recruited to studies with over 20,000 visits.

International Clinical Trials Day takes place on the 20th May each year to commemorate the date of one of the first known clinical trial in which James Lind investigated if citrus fruit alleviated symptoms of scurvy, thus establishing the foundation of modern clinical research. To coincide with this date, we are focusing on the ASTONISH Trial, a study involving intensive care unit (ICU) patients with septic shock.

The ASTONISH Trial is a Phase 2B blinded trial investigating the safety and efficacy of the drug nangibotide versus a placebo in the treatment of ICU patients with septic shock. The fact that it is ‘blinded’ means that the patients, researchers, and other staff do not know whether the patient has received the active drug or whether they have received the placebo (a sham version of the drug.) The ASTONISH Trial is an international collaboration, with 30 sites participating Europe-wide. Four patients were enrolled in the Irish arm of the study following a lengthy screening process. Consent is a crucial part of clinical trials. This means that study participants must be fully aware of what they are signing up for, they must be fully aware of their options and be able to decline to participate. In the case of ICU patients, the majority of whom are very unwell and unable to provided initial consent themselves, the patient’s family or next-of-kin assent on the patients’ behalf. Andrea Kelly, Lead CRF Research Nurse explains the process:

When patients improved and regained capacity, they were then approached for retrospective consent to continue. This process of obtaining assent from a next of kin had approval from the Research Ethics Committee. Recruited participants were allocated randomly to receive either the trial drug or a placebo (in this case, saline). This allocation was blinded – neither staff nor patients were aware of which the patient would receive. The drug/placebo was administered via continuous intravenous infusion for up to a maximum of 5 days, dependent on the participants requirement for blood pressure medication. Participants also underwent physical assessments, ECGs and blood sampling.”

The ASTONISH Trial, which completed recruitment in April 2022, required a collaborative approach between the CRF and ICU staff and is truly a team effort. Potential participants were screened by CRF research nurses and eligibility discussed with ICU consultant Principal Investigator, Professor Ignacio Martin-Loeches, a Clinical Professor in the School of Medicine and a Consultant in Intensive Care Medicine at St James’s Hospital. Consent or assent was obtained by Professor Loeches. The trial drug or placebo was prepared by CRF pharmacy and administered by CRF research nurses or ICU nurses, and blood samples were processed by the CRF laboratory. Follow-up visits, trial administration and liaising with the sponsor was coordinated by the CRF research nurse. The CRF also provided weekend and out of hours cover to facilitate this trial. Other key team members at the St James’s Hospital site were Sub-Investigators Dr Rachel Cusack, Dr Adina Nesa and Dr Elisabeth Connolly and ICU Pharmacist Edel O’Dea.

The ASTONISH Trial is funded by its sponsors INOTREM and PPD, and has study sites throughout Spain, Belgium, France, Finland, and Denmark, with the CRF being among the top recruiters. The primary outcome (the measure by which drug efficacy will be measured) is sequential organ failure assessment score, known as the SOFA score. Secondary outcome measures will be survival and all-cause mortality on day 28. The study aims to find a more effective treatment for septic shock, which has a high mortality rate. While this trial has finished, a phase 3 trial will open soon. A successful trial could mean that this drug may be incorporated into standard practice and improve the survival of patients with septic shock.

To date, the CRF at St James’s Hospital has supported almost 70 regulated clinical trials and almost 130 clinical studies (including observational studies and interventional studies).

To learn more about the HRB Welcome Clinical Research Facility, see here: https://www.sjhcrf.ie