Periodic Reporting for period 4 - PRECIOUS (PREvention of Complications to Improve OUtcome in elderly patients with acute Stroke)
Reporting period: 2019-12-01 to 2021-05-31
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 mentioned above is addressed in a large, international, randomised, clinical trial. A protocol for this trial has been developed that reflects ethical principles that have their origin in 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 with the EudraCT under number 2015-003179-32, and with the ISRCTN registry as ISRCTN82217627.
In addition, standard operating procedures (SOPs) have been developed for training of local study teams and monitors; to facilitate recruitment into the trial; and to support trial treatment and follow-up. SOPs are available for training of local study teams and training of study monitors; SOPs and working instructions for the electronic case report form (eCRF) are available in an online manual at the secured area of the PRECIOUS website www.precious-trial.eu. Training of the local study teams is performed before the start of PRECIOUS at each site.
UMC has built a web-based treatment allocation service that is available 24/7. Treatment allocation is stratified by country and includes 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 have the opportunity to censor a specific randomisation arm in a specific patient before randomisation, for example in case of an allergy to one of the investigational medicinal products (IMPs).
National Competent Authority (CA) and national Research Ethics Committee (REC) approval has been obtained in each of the nine participating countries: Estonia, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, and the United Kingdom. In each of the countries, the approval by the CA and REC is followed by local hospital management approval at each site. By May 2021, such approval had been obtained for 84 sites across these countries, four more than the original target.
As of 31 May 2021, 1249 patients have been included in the trial, against a target of 2500 to be reached in June 2022. Unfortunately, there have been delays in patient recruitment. These delays were mainly caused by two factors: 1. Delays in obtaining approvals from local hospital management of the individual study sites and in the initiation of these sites; and 2. Lower recruitment rates at active study sites than expected. To increase recruitment, a range of mitigation measures have been applied, including: a shift in the number of trial sites from countries with lower recruitment to the UK and the Netherlands, where recruitment was generally better; an increase in the time window for inclusion from 12 to 24 hours; a 24/7 helpline for local investigators across Europe; and a modest increase in the per-patient reimbursement at subcontracted sites. As of February 2020, recruitment has been hampered seriously by the COVID-19 pandemic. Inclusion in any clinical trial not related to COVID-19 was suspended by local hospital managements and investigators had much less time to include patients in trials because of increased clinical activities. Even in spring 2021, recruitment is still considerably lower than before the pandemic because of a temporary loss of research routines, changed patient pathways, patients isolated and tested for COVID-19 before they can be accessed by research staff, and a shift to more clinical activities for research personnel.
To be able to address our objective and collect information on as many patients as possible, a request for an extension of the project by two years has fortunately been granted by the European Commission. The urgent need for new stroke treatments has remained unchanged over the course of the project and is illustrated by the recently published Stroke Action Plan for Europe 2018 to 2030 of the European Stroke Organisation and the patient organisation Stroke Alliance for Europe. 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 assesses such a strategy.
In the meanwhile, the Safety Desk for PRECIOUS continuously monitored patient safety. Reported serious adverse events have been checked for completeness and expectedness, documented and coded according to MedDRA. A Development Safety Update Report (DSUR) has been developed each year of the project and has been submitted to the responsible Ethics Committees and Competent Authorities.
The independent Data and Safety Monitoring Board of the trial has met on an annual basis and has observed no safety issues. Each year, it therefore recommended to continue the trial as planned.
For outcome adjudication, an HealthCarePoint mRS training and certification web-based resource was launched at http://precious.trainingcampus.net. Investigators at each study site have been trained in outcome assessment, and outcomes have been adjudicated via the Central Adjudication of Rankin Scores (CARS) portal.
Through the yearly participation at ESOC, PRECIOUS has reached the worldwide scientific community and used the opportunity to promote the project and to network.
In addition, standard operating procedures (SOPs) have been developed for training of local study teams and monitors; to facilitate recruitment into the trial; and to support trial treatment and follow-up. SOPs are available for training of local study teams and training of study monitors; SOPs and working instructions for the electronic case report form (eCRF) are available in an online manual at the secured area of the PRECIOUS website www.precious-trial.eu. Training of the local study teams is performed before the start of PRECIOUS at each site.
UMC has built a web-based treatment allocation service that is available 24/7. Treatment allocation is stratified by country and includes 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 have the opportunity to censor a specific randomisation arm in a specific patient before randomisation, for example in case of an allergy to one of the investigational medicinal products (IMPs).
National Competent Authority (CA) and national Research Ethics Committee (REC) approval has been obtained in each of the nine participating countries: Estonia, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, and the United Kingdom. In each of the countries, the approval by the CA and REC is followed by local hospital management approval at each site. By May 2021, such approval had been obtained for 84 sites across these countries, four more than the original target.
As of 31 May 2021, 1249 patients have been included in the trial, against a target of 2500 to be reached in June 2022. Unfortunately, there have been delays in patient recruitment. These delays were mainly caused by two factors: 1. Delays in obtaining approvals from local hospital management of the individual study sites and in the initiation of these sites; and 2. Lower recruitment rates at active study sites than expected. To increase recruitment, a range of mitigation measures have been applied, including: a shift in the number of trial sites from countries with lower recruitment to the UK and the Netherlands, where recruitment was generally better; an increase in the time window for inclusion from 12 to 24 hours; a 24/7 helpline for local investigators across Europe; and a modest increase in the per-patient reimbursement at subcontracted sites. As of February 2020, recruitment has been hampered seriously by the COVID-19 pandemic. Inclusion in any clinical trial not related to COVID-19 was suspended by local hospital managements and investigators had much less time to include patients in trials because of increased clinical activities. Even in spring 2021, recruitment is still considerably lower than before the pandemic because of a temporary loss of research routines, changed patient pathways, patients isolated and tested for COVID-19 before they can be accessed by research staff, and a shift to more clinical activities for research personnel.
To be able to address our objective and collect information on as many patients as possible, a request for an extension of the project by two years has fortunately been granted by the European Commission. The urgent need for new stroke treatments has remained unchanged over the course of the project and is illustrated by the recently published Stroke Action Plan for Europe 2018 to 2030 of the European Stroke Organisation and the patient organisation Stroke Alliance for Europe. 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 assesses such a strategy.
In the meanwhile, the Safety Desk for PRECIOUS continuously monitored patient safety. Reported serious adverse events have been checked for completeness and expectedness, documented and coded according to MedDRA. A Development Safety Update Report (DSUR) has been developed each year of the project and has been submitted to the responsible Ethics Committees and Competent Authorities.
The independent Data and Safety Monitoring Board of the trial has met on an annual basis and has observed no safety issues. Each year, it therefore recommended to continue the trial as planned.
For outcome adjudication, an HealthCarePoint mRS training and certification web-based resource was launched at http://precious.trainingcampus.net. Investigators at each study site have been trained in outcome assessment, and outcomes have been adjudicated via the Central Adjudication of Rankin Scores (CARS) portal.
Through the yearly participation at ESOC, PRECIOUS has reached the worldwide scientific community and used the opportunity to promote the project and to network.
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.