Category: Work Packages

PRISM 2 addresses the treatment needs of the three most prevalent brain disorders in Europe, i.e. schizophrenia (SZ), Alzheimer’s (AD), and major depressive disorders (MDD). The economic burden of these three disorders is huge, collectively estimated to cost over € 300 billion per year. Most of these costs are indirect (lack of productivity). Social withdrawal is an important source of indirect cost and has been identified as one of the main reasons for health-related disability benefit claims in the UK (UK Department of Work and Pensions Annual Report, 2012). PRISM 2 has a massive potential to significantly alter future clinical decision-making as it will transcend the traditional domains of neurology and psychiatry and significantly impact on pharma R&D by providing a reliable route from preclinical results to patient outcomes.

The project will bridge the important translation gap between discovery and the validation of biomarkers and their associated technologies. The PRISM 2 consortium will establish that quantitative biological parameters can be used to effectively stratify patients using biomarkers for social dysfunction. Thereby, it will help establish in the consciousness of patients and the general public that psychiatric disorders are “real” in the sense of having a biomedical substrate similar to other physical illnesses reducing the stigma associated with mental disorders.

The objective of WP6 is the development of a communication strategy and dissemination plan based on Open Science principles and tailored to the different target groups of PRISM 2, namely scientists, clinicians (medical community), pharmaceutical industry, CROs, patients and their families, and regulatory agencies (e.g. EMA).

There is a need to involve end users, ethics experts and regulators in decisions that relate to clinical protocols, assessments, and ecological outcomes. Effective use of all data and biobank materials already acquired and yet to be acquired following strict ethical parameters is an important issue in collaborative research in different countries. Clinical trial use of digital biomarkers for population stratification is an innovative development methodology that will require further interaction with regulators including scientific advice from the European Medicines Agency (EMA) and agreement on the necessary steps for future qualification. WP5 will therefore take care of three main aspects of PRISM 2 structure and outreach:

• Ethical requirements for the work undertaken by PRISM 2
• Implementation of a strategy to continue and strengthen the collaboration with patients, learned societies, and health care providers to ensure that project results have an impact on future clinical trials and health care practices
• Expansion of initiated dialogue with the EMA to determine how to best support the progression and validation of a promising digital biomarker from our trans-diagnostic approach and to advice on the design and conduct of the studies planned in WP3

WP4 comprises partners with expertise focus on behavioural and EEG studies (PGI, BI, RUG). This includes the capacity and expertise for chemogenetic activation of OFC neurons innervated by DMN tracts to locally activate or inhibit the specific neural structures that have been identified in the human study, and to test specifically their involvement in the expression of social behaviour. For that purpose, the automated system to monitor individual social behavioural components in group housed animals that was developed and validated in the PRISM project will be used to study the effects of specific neural circuit manipulation on social behaviour. In addition, using EEG, DMN activity will be assessed in relation to social dysfunction in rodents.

This work package will be led by P1vital and BI. P1vital will ensure that WP3 is conducted to the highest standards of Good Clinical Practice (GCP), on time and within budget. P1vital will be responsible for the overall study management including all preparation for all documentation related to the set up and execution of the clinical trial. They will also be responsible for study setup, site training, recruitment management and completion of the clinical investigation and the development, deployment, and standardization of relevant behavioural and fMRI paradigms. Where possible deployment of self-report questionnaires and behavioural tasks within the clinical trial will be via the online P1vital ePRO clinical system, as was the case in the original PRISM clinical study, ensuring high and standardized data quality and allowing easier data management across the assessment battery. P1vital will also be responsible for the providing data from the clinical study to the Brains Commons platform (WP2).

BIOTRIAL will be responsible for the development, deployment and standardization of EEG paradigms for the study. Together these two SMEs will provide a strong basis for the setup, execution and completion of the planned clinical investigation. Clinical sites will be responsible for the development, deployment and standardization of rs-fMRI and Diffusion Tensor Imaging (DTI) fMRI for the study. The total number of subjects will be comparable to those recruited in PRISM (N=160) and they will be recruited and assessed over two days. On Day 1 the participants will be screened and complete clinical interviews, questionnaires, provide blood samples, and install the BEHAPP smartphone app; on Day 2 the EEG and fMRI procedures will be performed. CIBER (Study sponsor), VUMC, and LUMC will be responsible for recruitment and deep-phenotyping of all participants (Note that CIBER includes 2 clinical sites (already included in PRISM): Hospital General Universitario Gregorio Marañón and Hospital La Princesa). BI will assist with protocol development and review and provide pre-final protocol approval on behalf of the EFPIA stakeholders. Final protocol approval will be provided by the PRISM 2 Steering Committee.

Building on the strong basis that PRISM has provided, PRISM 2 will focus on statistical analyses solidifying the PRISM approach into establishing reproducible and generalisable biomarkers that allow confident stratification of patients and advanced data management towards generating a sustainable resource for future utility beyond the funding period of the project. These biomarkers are the endpoint measures from the methods selected on the basis of the PRISM study to assess social functioning (total SFS score and BEHAPP digital measure of social functioning) measure DMN integrity (EEG, fMRI and DTI endpoints) and are presented in the Excellence section of the project plan. These biomarkers will be derived from both the unimodal and multimodal analyses, as described in this work package. Specific objectives:

• To develop and implement a data management and sustainability plan and provide a mechanism for effective external use of data and biobank materials. We will augment the PRISM data management plan to incorporate procedures detailing continued data governance beyond the end of the PRISM & PRISM 2 projects (Task 1). According to our sustainability roadmap, through BRAIN Commons we will provide a mechanism for data accessibility to both consortium members and other qualified researchers extending beyond the duration of PRISM 2. This will be described in a data sustainability plan. Data anonymization and access limitations will be implemented in accordance with the EU General Data Protection Regulation (GDPR).
• To test the level of reproducibility of the transdiagnostic and pathophysiological relationship between Default Mode Network (DMN) integrity and social dysfunction in schizophrenia (SZ) and Alzheimer disease (AD) and its potential to generalise to Major Depressive Disorders (MDD). Analyses on data obtained from newly assessed SZ and AD patients in WP3 will inform about reproducibility, while inclusion of MDD patients in WP3 will establish the generalisability of the selected biomarkers.
• To test the causality of DMN integrity on sociability in large-scale, publicly available population-based samples using Mendelian randomization.

The responsibility for project management in PRISM 2 lies primarily with the Coordinator. RUG has longstanding experience and provides adequate staffing resources for the management of large-scale research projects. BI acts as the project leader, and is responsible for overall scientific and action related governance. VUMC is further joining the COOR-team and concentris, a German SME, that is specialized in the management of H2020 and IMI2 (and previously FP7 and IMI1) research projects in the “HEALTH” area. The coordinator, the project leader and concentris together form the project management office (PMO) (see 3.2). The project management office at concentris is the first point of reference for beneficiaries involved in PRISM 2. The Coordinator (RUG) will be responsible for the tasks defined in the IMI Grant agreement and PRISM 2 Consortium Agreement and represents the Consortium vis-à-vis for the IMI JU. It is their responsibility to: monitor that the project is implemented properly, act as the intermediary for all communications between the beneficiaries and the JU); request and review any documents or information required by the JU and verify their completeness and correctness before passing them on to IMI, submit the deliverables and reports to IMI in accordance with the timing and conditions set out in the GA; receive payments from IMI and to ensure that all payments are made to the other beneficiaries without unjustified delay; inform IMI of the amounts paid to each beneficiary, when required under the Agreement or requested by the JU, provide any information relevant to checks, reviews and audits or the evaluation of impact, submit any required ethical documents to IMI.