Periodic Reporting for period 5 - PRECIOUS (PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke)
Periodo di rendicontazione: 2021-06-01 al 2022-11-30
Every year, 1.3 million Europeans have a first stroke. About one in every five patients dies in the first month after stroke, and one third of patients remain dependent on the help of others. The annual costs for stroke care in Europe have been estimated at €45 billion. Stroke incidence increases almost exponentially with age, and the personal, societal, and economic burden of stroke is therefore largely driven by its frequent occurrence in the elderly. Elderly patients are at the highest risk of complications after stroke, such as infections and fever. These complications are strongly associated with a higher risk of death or long-term dependency. The central objective of the PRECIOUS study is to assess whether prevention of complications in the first days after stroke onset – using simple, inexpensive, existing, and generally available interventions – reduces the risk of death or dependency and improves quality of life in elderly patients with acute stroke.
The objective was addressed in an international, randomised, open-label clinical trial with blinded outcome assessment in patients aged > 66 years with acute ischaemic stroke or intracerebral haemorrhage and moderately severe to severe symptoms. A protocol has been developed that reflects ethical principles of the Declaration of Helsinki, and that is consistent with guidelines for Good Clinical Practice of the International Conference on Harmonisation and all applicable regulatory requirements. The study has been registered: 2015-003179-32 (EudraCT), ISRCTN: ISRCTN82217627.
Standard operating procedures (SOPs) have been developed for training of local study teams and monitors; to facilitate recruitment and to support treatment and follow-up. SOPs and working instructions for the electronic case report form (eCRF) were available in an online manual at the PRECIOUS website. Training of local study teams was performed before start of PRECIOUS at each site. UMC built a web-based treatment allocation service that was available 24/7. Patients were randomly allocated to any combination of oral, rectal, or intravenous metoclopramide (10 mg thrice daily); intravenous ceftriaxone (2000 mg once daily); oral, rectal, or intravenous paracetamol (1000 mg four times daily); or standard care, within 24 h after symptom onset and continued for four days. Allocation was stratified by country and included the following minimisation factors for balance in baseline characteristics: age (66 – 75 years vs. > 75 years); sex (male vs. female); stroke type (ischaemic stroke vs. intracerebral haemorrhage); stroke severity (NIHSS 6 – 12 vs. > 12); and diabetes mellitus (yes vs. no). Investigators had the opportunity to censor a specific arm in a specific patient before randomisation.The primary outcome was the score on the modified Rankin Scale (mRS) after 90 days (+/-14 days), analysed with multivariable ordinal logistic regression. National Competent Authority and national Research Ethics Committee approval was obtained in each of the nine participating countries for 85 sites across these countries, five more than the original target: Estonia, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, and the United Kingdom.
From April 2016 until June 2022, a total of 1493 patients from 68 European sites were randomised to metoclopramide (n=704) or no metoclopramide (n=709), ceftriaxone (n=594) or no ceftriaxone (n=482), and paracetamol (n=706) or no paracetamol (n=739). One patient was excluded because the informed consent form was lost, five patients withdrew consent immediately after randomisation, ten withdrew consent during follow-up, and six patients were lost to follow-up, resulting in 1471 patients in the intention-to-treat analysis. The main results will be presented at the ESOC in May 2023.
The recruitment target was 2500 patients but there were delays in recruitment throughout the project, resulting in a smaller number. These delays were mainly caused by two factors: 1. Delays in obtaining approvals from local hospital management of individual study sites and in the initiation of these sites; 2. Lower recruitment rates at study sites than expected. To increase recruitment, a range of mitigation measures were applied, including: a shift in the number of trial sites from countries with lower recruitment to the UK and the Netherlands, where recruitment was better; an increase in the time window for inclusion from 12 to 24 hours; a 24/7 helpline for local investigators across Europe; and an increase in the per-patient reimbursement at subcontracted sites. As of February 2020, recruitment was hampered by the COVID-19 pandemic. Inclusion in clinical trials not related to COVID-19 was suspended by local hospital managements and investigators had less time to include patients. After main COVID-19 measures had been released, recruitment never caught up to pre-COVID numbers because of a loss of research routines, changed patient pathways, and a shift to more clinical activities for research personnel.
The urgent need for new stroke treatments has remained unchanged over the course of the project and is illustrated by the Stroke Action Plan for Europe 2018 to 2030 of ESO and the patient organisation SAFE. One key research priority mentioned in the Action Plan is to assess “which strategies will improve outcomes in ischaemic stroke patients who are not eligible for reperfusion therapies, or who do not recover after recanalisation.” PRECIOUS assessed such a strategy.
The PRECIOUS Safety Desk continuously monitored patient safety. Reported serious adverse events were checked for completeness and expectedness, documented and coded according to MedDRA. A Development Safety Update Report was developed each year of the project and was submitted to the responsible Ethics Committees and Competent Authorities. The independent Data and Safety Monitoring Board of the trial has met yearly and observed no safety issues and recommended each year to continue the trial.
For outcome adjudication, an mRS training and certification web-based resource was launched. Investigators at each study site were trained in outcome assessment, and outcomes have been adjudicated via the Central Adjudication of Rankin Scores portal.
Through yearly participation at ESOC, PRECIOUS reached the worldwide scientific community.
Standard operating procedures (SOPs) have been developed for training of local study teams and monitors; to facilitate recruitment and to support treatment and follow-up. SOPs and working instructions for the electronic case report form (eCRF) were available in an online manual at the PRECIOUS website. Training of local study teams was performed before start of PRECIOUS at each site. UMC built a web-based treatment allocation service that was available 24/7. Patients were randomly allocated to any combination of oral, rectal, or intravenous metoclopramide (10 mg thrice daily); intravenous ceftriaxone (2000 mg once daily); oral, rectal, or intravenous paracetamol (1000 mg four times daily); or standard care, within 24 h after symptom onset and continued for four days. Allocation was stratified by country and included the following minimisation factors for balance in baseline characteristics: age (66 – 75 years vs. > 75 years); sex (male vs. female); stroke type (ischaemic stroke vs. intracerebral haemorrhage); stroke severity (NIHSS 6 – 12 vs. > 12); and diabetes mellitus (yes vs. no). Investigators had the opportunity to censor a specific arm in a specific patient before randomisation.The primary outcome was the score on the modified Rankin Scale (mRS) after 90 days (+/-14 days), analysed with multivariable ordinal logistic regression. National Competent Authority and national Research Ethics Committee approval was obtained in each of the nine participating countries for 85 sites across these countries, five more than the original target: Estonia, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, and the United Kingdom.
From April 2016 until June 2022, a total of 1493 patients from 68 European sites were randomised to metoclopramide (n=704) or no metoclopramide (n=709), ceftriaxone (n=594) or no ceftriaxone (n=482), and paracetamol (n=706) or no paracetamol (n=739). One patient was excluded because the informed consent form was lost, five patients withdrew consent immediately after randomisation, ten withdrew consent during follow-up, and six patients were lost to follow-up, resulting in 1471 patients in the intention-to-treat analysis. The main results will be presented at the ESOC in May 2023.
The recruitment target was 2500 patients but there were delays in recruitment throughout the project, resulting in a smaller number. These delays were mainly caused by two factors: 1. Delays in obtaining approvals from local hospital management of individual study sites and in the initiation of these sites; 2. Lower recruitment rates at study sites than expected. To increase recruitment, a range of mitigation measures were applied, including: a shift in the number of trial sites from countries with lower recruitment to the UK and the Netherlands, where recruitment was better; an increase in the time window for inclusion from 12 to 24 hours; a 24/7 helpline for local investigators across Europe; and an increase in the per-patient reimbursement at subcontracted sites. As of February 2020, recruitment was hampered by the COVID-19 pandemic. Inclusion in clinical trials not related to COVID-19 was suspended by local hospital managements and investigators had less time to include patients. After main COVID-19 measures had been released, recruitment never caught up to pre-COVID numbers because of a loss of research routines, changed patient pathways, and a shift to more clinical activities for research personnel.
The urgent need for new stroke treatments has remained unchanged over the course of the project and is illustrated by the Stroke Action Plan for Europe 2018 to 2030 of ESO and the patient organisation SAFE. One key research priority mentioned in the Action Plan is to assess “which strategies will improve outcomes in ischaemic stroke patients who are not eligible for reperfusion therapies, or who do not recover after recanalisation.” PRECIOUS assessed such a strategy.
The PRECIOUS Safety Desk continuously monitored patient safety. Reported serious adverse events were checked for completeness and expectedness, documented and coded according to MedDRA. A Development Safety Update Report was developed each year of the project and was submitted to the responsible Ethics Committees and Competent Authorities. The independent Data and Safety Monitoring Board of the trial has met yearly and observed no safety issues and recommended each year to continue the trial.
For outcome adjudication, an mRS training and certification web-based resource was launched. Investigators at each study site were trained in outcome assessment, and outcomes have been adjudicated via the Central Adjudication of Rankin Scores portal.
Through yearly participation at ESOC, PRECIOUS reached the worldwide scientific community.
One potential socio-economic impact of PRECIOUS is a large reduction in the costs for stroke care throughout Europe. Much of the costs of acute stroke care is related to the occurrence of complications. These not only prolong hospital stays, but it is also more expensive, for instance, to treat an established pneumonia in a single patient than to administer preventive antibiotics for four days in several patients. However, if at least one of the treatment strategies tested is successful, the largest reduction in costs will be related to improved functional outcomes, requiring fewer and shorter admissions to rehabilitation centres and chronic nursing facilities. Assuming average annual costs for care in a chronic nursing facility of €30.000 26.000 fewer patients admitted to such a facility on a yearly basis, and on average two years of admission to such a facility, this would lead to an annual reduction in costs for admission to a chronic nursing facility of €1.56 billion.