Periodic Reporting for period 2 - SimCardioTest (Simulation of Cardiac Devices & Drugs for in-silico Testing and Certification)
Période du rapport: 2022-07-01 au 2023-12-31
Cardiovascular disease (CVD) is the leading cause of death worldwide. Almost 50 million people in Europe live with CVD, among which 15 million patients suffer from heart failure, whose prevalence continue to rise. Beyond its associated risk of sudden death, heart failure, has not only a significant and lasting impact on the health and well-being of patients, but has also become a societal and economic burden. In particular, despite the current huge investments in healthcare, the number of newly approved and more effective drugs has not increased. The search for new drugs and devices is particularly challenging due to the significant R&D costs and the complexity of regulatory procedures; thus, hampering the commercialisation of new solutions and putting many patients at risk of not receiving timely and adequate therapy. Additionally, the dramatically increasing attrition rate across all phases of drug and device development pipeline highlights the lack of reliability of both existing preclinical animal models and the current design strategies for clinical trials, urging the need for new predictive tools.
An innovative and non-invasive solution to these critical problems is offered by computer modelling and personalised simulations, which have the capacity to create scientific evidence based on controlled investigations, including satisfying demands for safety, efficacy & improved access. Cardiac simulations have previously demonstrated great potential in generating clinically relevant predictions of heart function in certain pathologic conditions, providing the clinicians with powerful insights for more accurate diagnosis, an improved personalized therapy planning, and a better outcome (i.e. higher success in response to therapy).
SimCardioTest takes the mature field of cardiac simulations and brings it further through a web-based platform to perform standardised in-silico trials for testing the efficacy and safety of drugs and devices in 3 concrete use cases. The main objective of SimCardioTest is to create a unique, digitised, personalised testing environment for cardiac devices and drugs.
An innovative and non-invasive solution to these critical problems is offered by computer modelling and personalised simulations, which have the capacity to create scientific evidence based on controlled investigations, including satisfying demands for safety, efficacy & improved access. Cardiac simulations have previously demonstrated great potential in generating clinically relevant predictions of heart function in certain pathologic conditions, providing the clinicians with powerful insights for more accurate diagnosis, an improved personalized therapy planning, and a better outcome (i.e. higher success in response to therapy).
SimCardioTest takes the mature field of cardiac simulations and brings it further through a web-based platform to perform standardised in-silico trials for testing the efficacy and safety of drugs and devices in 3 concrete use cases. The main objective of SimCardioTest is to create a unique, digitised, personalised testing environment for cardiac devices and drugs.
Three use-cases:
USE CASE 1 aims to quantify mechanical and electrical properties of cardiac stimulation devices using computer modelling and simulations. In particular, the UC1 focuses on bradycardia leads and aims at designing a numerical workflow that can be later extended to other implantable devices. To date, two distinct computational pipelines have been built by our teams: one aims to address several critical questions on the electrical pacing and sensing performances of the lead, while the other investigates the navigation possibilities of the lead, as well as long-term mechanical fatigue.
USE CASE 2 aims to generate in-silico personalised hemodynamic indices of left atrial geometries, complementing their morphological analysis. Furthermore, this case aims: to identify the risk of thrombus formation in atrial fibrillation patients; to improve patient selection for the implantation of left atrial appendage occluders (LAAO); and, to optimise their settings. To date, a computational modelling pipeline has already been designed and is able at-present to generate patient-specific meshes and patient-specific boundary conditions in a large number of cases. In addition, extensive sensitivity analyses and model calibrations are also being currently tested in order to determine the optimal methodological choices for simulations pertaining computational fluid dynamics prior to, during and after LAAO implantation. Detailed verification and validation (V&V) investigations enabled us to assess the credibility of these developed models, current research is on distinct aspects relevant to the clinical translation in silico LAAO studies to realistically predict the risk of stroke in relation to the device implantation.
USE CASE 3 aims to assess efficacy and safety of drugs in populations of electrophysiological and electromechanical models. A specific pipeline has been defined for this purpose, with the ultimate goal of integrating it in a cloud-based platform to implement in silico trials of efficacy and safety. To date, several stages in the pipeline are considered, starting with the construction of pharmacokinetic models for selected drugs. These models can provide the user with the precise drugs concentration that is needed to be considered in the pipeline. An important and realistic aspect of our population of models is that gender, age and pathology is properly considered. Moreover, the credibility of the models used through the pipeline was assessed by following a detailed verification and validation process, including sensitivity analyses and uncertainty quantification. Importantly, a crucial step in the assessment of efficacy and safety of drugs is the definition of biomarkers derived from our simulations, which will help in building accurate classifications tools and next generation models.
Several key results were achieved so far. In particular, we would like to highlight:
- the complete Verification and Validation process that has been performed for all the three use-cases, establishing the credibility of the in silico approach in answering the different questions of interest
- the implementation of three different in silico trials on the cloud-based platform in order to evaluate the performance on the different models
USE CASE 1 aims to quantify mechanical and electrical properties of cardiac stimulation devices using computer modelling and simulations. In particular, the UC1 focuses on bradycardia leads and aims at designing a numerical workflow that can be later extended to other implantable devices. To date, two distinct computational pipelines have been built by our teams: one aims to address several critical questions on the electrical pacing and sensing performances of the lead, while the other investigates the navigation possibilities of the lead, as well as long-term mechanical fatigue.
USE CASE 2 aims to generate in-silico personalised hemodynamic indices of left atrial geometries, complementing their morphological analysis. Furthermore, this case aims: to identify the risk of thrombus formation in atrial fibrillation patients; to improve patient selection for the implantation of left atrial appendage occluders (LAAO); and, to optimise their settings. To date, a computational modelling pipeline has already been designed and is able at-present to generate patient-specific meshes and patient-specific boundary conditions in a large number of cases. In addition, extensive sensitivity analyses and model calibrations are also being currently tested in order to determine the optimal methodological choices for simulations pertaining computational fluid dynamics prior to, during and after LAAO implantation. Detailed verification and validation (V&V) investigations enabled us to assess the credibility of these developed models, current research is on distinct aspects relevant to the clinical translation in silico LAAO studies to realistically predict the risk of stroke in relation to the device implantation.
USE CASE 3 aims to assess efficacy and safety of drugs in populations of electrophysiological and electromechanical models. A specific pipeline has been defined for this purpose, with the ultimate goal of integrating it in a cloud-based platform to implement in silico trials of efficacy and safety. To date, several stages in the pipeline are considered, starting with the construction of pharmacokinetic models for selected drugs. These models can provide the user with the precise drugs concentration that is needed to be considered in the pipeline. An important and realistic aspect of our population of models is that gender, age and pathology is properly considered. Moreover, the credibility of the models used through the pipeline was assessed by following a detailed verification and validation process, including sensitivity analyses and uncertainty quantification. Importantly, a crucial step in the assessment of efficacy and safety of drugs is the definition of biomarkers derived from our simulations, which will help in building accurate classifications tools and next generation models.
Several key results were achieved so far. In particular, we would like to highlight:
- the complete Verification and Validation process that has been performed for all the three use-cases, establishing the credibility of the in silico approach in answering the different questions of interest
- the implementation of three different in silico trials on the cloud-based platform in order to evaluate the performance on the different models
SimCardioTest is challenging the huge burden of cardiovascular diseases worldwide, through advanced in-silico testing approaches which are non-invasive and can provide superior technological solutions. Overall, this project has the exceptional potential to transform the existing system of clinical trials, while reducing their costs and accelerating the availability of medical drugs/devices. SimCardioTest can help develop better devices and more effective drugs, as well as reduce the cost and time to market, while gaining the trust of scientists, companies, regulatory bodies, physicians and patients. Another important objective is to impact the whole design of clinical trials by replacing several invasive aspects of the current trials, and possibly provide novel biomarkers for more accurate diagnostic methods or more effective personalized therapies.
We already achieved several scientific publications and presentations, that enabled to disseminate the research results and progress beyond the state of the art
We organised a major event InnovaHeart, a joint European workshop on the digital heart, jointly with other European projects to bring together the large community of industry, academia, startups interested in the future development of research activities on the digital heart. We also showed case at Science Festivals and at the World AI Cannes Festival to communicate on SimCardioTest activity and maximise the impact of the project on the general public.
We actively worked on the exploitation aspects and benefited from the services of the Horizon Results Booster (a service supported by the EC to provide expert free of charge, support services to boost the exploitation potential of research results and go to market.
Until the end of the project, we expect to obtain results on the in silico trials that can support the regulatory process, to interact with regulatory bodies in order to optimise the use of in silico approaches, and to expand the exploitation opportunities of the project.
We already achieved several scientific publications and presentations, that enabled to disseminate the research results and progress beyond the state of the art
We organised a major event InnovaHeart, a joint European workshop on the digital heart, jointly with other European projects to bring together the large community of industry, academia, startups interested in the future development of research activities on the digital heart. We also showed case at Science Festivals and at the World AI Cannes Festival to communicate on SimCardioTest activity and maximise the impact of the project on the general public.
We actively worked on the exploitation aspects and benefited from the services of the Horizon Results Booster (a service supported by the EC to provide expert free of charge, support services to boost the exploitation potential of research results and go to market.
Until the end of the project, we expect to obtain results on the in silico trials that can support the regulatory process, to interact with regulatory bodies in order to optimise the use of in silico approaches, and to expand the exploitation opportunities of the project.