Periodic Reporting for period 4 - PAPA-ARTIS (Paraplegia Prevention in Aortic Aneurysm Repair by Thoracoabdominal Staging with ‘Minimally-Invasive Segmental Artery Coil-Embolization’: A Randomized Controlled Multicentre Trial)
Periodo di rendicontazione: 2021-07-01 al 2023-03-31
Chronic aortic aneurysms are permanent and localized dilations of the aorta that remain asymptomatic for long periods of time but continue to increase in diameter before they eventually rupture. Left untreated, the patients’ prognosis is dismal: internal bleeding of the rupture may bring about sudden death. Aortic aneurysms are one of the most common and dangerous aortic diseases. While successful aortic repair techniques cure the disease, there is a high risk of paraplegia due to impaired blood supply to the spinal cord during the procedure, particularly for thoracoabdominal aortic aneurysms (TAAA) extending from the thoracic to the abdominal aorta. Although various strategies have achieved a remarkable decrease in the incidence of paraplegia, it is still estimated to be 10 to 20%.
It has recently been found that the deliberate staged occlusion of the segmental arteries to the paraspinous collateral network finally supplying the spinal cord can trigger arterial collateralization, thus stabilizing blood supply from alternate inflow sources and preventing ischaemia. This has been translated into a clinically available therapeutic option, 'minimally invasive staged segmental artery coil embolization' (MIS²ACE), which proceeds in a 'staged' manner to occlude groups of arteries under highly controlled conditions, subsequently inducing arteriogenesis and building of a robust collateral blood supply.
PAPAartis is a multi-national, prospective, open-label, two-arm, randomized controlled trial to demonstrate, that the MIS²ACE approach can reduce paraplegia and mortality in patients undergoing TAAA repair and to assess the clinical safety of the novel therapeutic concept.
Patients with planned aneurysm repair will be included in the study and randomized 1:1 in the control group or the MIS²ACE-group. The control group receives treatment as per standard institutional protocol - open or endovascular repair without MIS²ACE. In the MIS²ACE-group, segmental arteries will be occluded in one to three sessions some weeks before the definite repair. Segmental arteries are occluded with coils or plugs. This induces arteriogenesis and the building of a robust collateral network ultimately supplying the spinal cord. During aneurysm repair, these new arteries provide an alternate blood supply to the spinal cord and thereby help prevent paraplegia.
The primary objective of the PAPAartis trial is to reduce greatly the incidence of ischaemic spinal cord injury and mortality resulting from aneurysm repair.
It has recently been found that the deliberate staged occlusion of the segmental arteries to the paraspinous collateral network finally supplying the spinal cord can trigger arterial collateralization, thus stabilizing blood supply from alternate inflow sources and preventing ischaemia. This has been translated into a clinically available therapeutic option, 'minimally invasive staged segmental artery coil embolization' (MIS²ACE), which proceeds in a 'staged' manner to occlude groups of arteries under highly controlled conditions, subsequently inducing arteriogenesis and building of a robust collateral blood supply.
PAPAartis is a multi-national, prospective, open-label, two-arm, randomized controlled trial to demonstrate, that the MIS²ACE approach can reduce paraplegia and mortality in patients undergoing TAAA repair and to assess the clinical safety of the novel therapeutic concept.
Patients with planned aneurysm repair will be included in the study and randomized 1:1 in the control group or the MIS²ACE-group. The control group receives treatment as per standard institutional protocol - open or endovascular repair without MIS²ACE. In the MIS²ACE-group, segmental arteries will be occluded in one to three sessions some weeks before the definite repair. Segmental arteries are occluded with coils or plugs. This induces arteriogenesis and the building of a robust collateral network ultimately supplying the spinal cord. During aneurysm repair, these new arteries provide an alternate blood supply to the spinal cord and thereby help prevent paraplegia.
The primary objective of the PAPAartis trial is to reduce greatly the incidence of ischaemic spinal cord injury and mortality resulting from aneurysm repair.
The trial protocol is the “manual” for a clinical trial and was developed by the coordinator in consultation with all recruiting centres. It documents the rationale and medical problem pursued by the trial, it's objectives, trial design, sample size calculation, inclusion and exclusion criteria, methods as well as statistical analyses. Accompanied by a risk analysis that will be, if necessary, updated during the trial, the protocol was designed to ensure that all parties involved in the clinical trial implement the trial consistently and systematically. Case report forms (CRFs) and working instructions (WIs) were developed in close cooperation with the coordinating investigator and relevant scientists from all partners involved. In addition, management activities focussed on obtaining all necessary approvals and patient insurance for all recruiting sites in different European countries. Legal activities included the development, negotiation and conclusion of various contracts between trial partners and the coordinator to allow for a better coordination of the trial.
Due to additional funding from the German Research Foundation (DFG), the trial grew from 300 to 500 patients, from 16 to 29 recruiting sites, and now includes Crawford type 1, 2 and 3 patients. Thus, the project underwent a major amendment in its early stage and changes were incorporated so as to benefit all aspects of the project. The first site was officially initiated in June, 2018 in Leipzig. Before recruitment can start, centres were provided with necessary forms, given access to the IT infrastructure set up by the co-ordinating investigator for the trial and enabled to use documentation tools smoothly.
Initial trial management covered the creation of a trial master file as well as a master copy for the investigation site files. A manual for on-site monitoring was prepared as part of the risk-based approach for quality management. Detailed groundwork was carried out for statistical monitoring.
To train staff members correspondingly, teaching material was conceptualised and developed. Upon request, practical sessions on the MIS²ACE procedure were discussed and training sessions have been organized. Trial management was also concerned with gathering feedback on trial implementation and progress from relevant consortium bodies such as the Trial Steering Committee (TSC) and the Expert Advisory Board (EAB). Their reviews were incorporated into the 1st trial protocol amendment. A similarly relevant and consultative role in the initial trial protocol development is played by the Data Safety and Monitoring Board (DSMB) which was set up under the coordination of the European Society of Cardiology (ESC).
In another strand of the project, work has started on health economics aspects as well as on aspects of patient involvement. A literature review was undertaken to select methods and develop an appropriate model structure for economic evaluation in aneurysm repair. It particularly served to determine the analytic scope and structure for cost-effectiveness comparisons of TEVAR and TAAA interventions. Apart from utilizing available trial data for this task, economic interpretations are supported by qualitative patient questionnaires. First drafts were made in close alignment with the development of the trial protocol. They were designed so as to obtain information around resource use and, under particular consideration of age and gender, reflect upon the impact of treatment on the quality of life in patients and their families.
Due to additional funding from the German Research Foundation (DFG), the trial grew from 300 to 500 patients, from 16 to 29 recruiting sites, and now includes Crawford type 1, 2 and 3 patients. Thus, the project underwent a major amendment in its early stage and changes were incorporated so as to benefit all aspects of the project. The first site was officially initiated in June, 2018 in Leipzig. Before recruitment can start, centres were provided with necessary forms, given access to the IT infrastructure set up by the co-ordinating investigator for the trial and enabled to use documentation tools smoothly.
Initial trial management covered the creation of a trial master file as well as a master copy for the investigation site files. A manual for on-site monitoring was prepared as part of the risk-based approach for quality management. Detailed groundwork was carried out for statistical monitoring.
To train staff members correspondingly, teaching material was conceptualised and developed. Upon request, practical sessions on the MIS²ACE procedure were discussed and training sessions have been organized. Trial management was also concerned with gathering feedback on trial implementation and progress from relevant consortium bodies such as the Trial Steering Committee (TSC) and the Expert Advisory Board (EAB). Their reviews were incorporated into the 1st trial protocol amendment. A similarly relevant and consultative role in the initial trial protocol development is played by the Data Safety and Monitoring Board (DSMB) which was set up under the coordination of the European Society of Cardiology (ESC).
In another strand of the project, work has started on health economics aspects as well as on aspects of patient involvement. A literature review was undertaken to select methods and develop an appropriate model structure for economic evaluation in aneurysm repair. It particularly served to determine the analytic scope and structure for cost-effectiveness comparisons of TEVAR and TAAA interventions. Apart from utilizing available trial data for this task, economic interpretations are supported by qualitative patient questionnaires. First drafts were made in close alignment with the development of the trial protocol. They were designed so as to obtain information around resource use and, under particular consideration of age and gender, reflect upon the impact of treatment on the quality of life in patients and their families.
PAPAartis will systematically calculate the individual, healthcare, economic and societal impacts associated with chronic aortic aneurysms. It can be expected not only to have a dramatic impact on the individual patient's (and next of kin’s) quality of life if saved from the fate of being bound to a wheelchair, but also an impact upon financial systems through savings in
● lower costs in the EU health care systems from lower care costs
● lower pay-outs in disability insurance
● loss of output in economic output from unemployment.
An essential element of this project is to understand the impact on the daily lives of patients of disease diagnosis and treatment. The diagnosis of an aneurysm is a traumatic event in the life of any person. It is important to know not only the impact of different interventions on clinical variables, but also to assess the impact on the quality of life of patients and their family, on work and on their social environment.
Please note:
„Initially, an amount of 66,000 EUR was estimated for material expenses. However, we recognized that this estimate was higher than our final needs. Realistically, we changed the way money was allocated. We used 6,000 EUR for material expenses and 60,000 EUR for personal expenses: this way it seemed more reasonable and effective. We obviously needed more study personel as expected at the time point of study set-up“.
● lower costs in the EU health care systems from lower care costs
● lower pay-outs in disability insurance
● loss of output in economic output from unemployment.
An essential element of this project is to understand the impact on the daily lives of patients of disease diagnosis and treatment. The diagnosis of an aneurysm is a traumatic event in the life of any person. It is important to know not only the impact of different interventions on clinical variables, but also to assess the impact on the quality of life of patients and their family, on work and on their social environment.
Please note:
„Initially, an amount of 66,000 EUR was estimated for material expenses. However, we recognized that this estimate was higher than our final needs. Realistically, we changed the way money was allocated. We used 6,000 EUR for material expenses and 60,000 EUR for personal expenses: this way it seemed more reasonable and effective. We obviously needed more study personel as expected at the time point of study set-up“.