The Clinical Value of Structural and Functional Brain Connectivity MR Biomarkers in Alzheimer's Disease
In: HELIYON-D-21-04938
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In: HELIYON-D-21-04938
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Introduction Based on the advances in the treatment of multiple sclerosis (MS), currently available disease-modifying treatments (DMT) have positively influenced the disease course of MS. However, the efficacy of DMT is highly variable and increasing treatment efficacy comes with a more severe risk profile. Hence, the unmet need for safer and more selective treatments remains. Specifically restoring immune tolerance towards myelin antigens may provide an attractive alternative. In this respect, antigen-specific tolerisation with autologous tolerogenic dendritic cells (tolDC) is a promising approach. Methods and analysis Here, we will evaluate the clinical use of tolDC in a well-defined population of MS patients in two phase I clinical trials. In doing so, we aim to compare two ways of tolDC administration, namely intradermal and intranodal. The cells will be injected at consecutive intervals in three cohorts receiving incremental doses of tolDC, according to a best-of-five design. The primary objective is to assess the safety and feasibility of tolDC administration. For safety, the number of adverse events including MRI and clinical outcomes will be assessed. For feasibility, successful production of tolDC will be determined. Secondary endpoints include clinical and MRI outcome measures. The patients' immune profile will be assessed to find presumptive evidence for a tolerogenic effect in vivo. Ethics and dissemination Ethics approval was obtained for the two phase I clinical trials. The results of the trials will be disseminated in a peer-reviewed journal, at scientific conferences and to patient associations. ; A FACTT network (Cost Action) [BM1305]; EU Framework Program Horizon 2020; European Union's Horizon 2020 research and innovation program [779316]; applied biomedical research project of the Institute for the Promotion of Innovation by Science and Technology in Flanders [IWT-TBM 140191]; Platform for Clinical Research and Clinical Trial Units, Spanish Clinical Research Network, SCReN [PI11/02416, PI14/01175, PI16/01737, PT13/0002/0038]; Health Institute Carlos III -Subdireccion General de Evaluacion y Fomento de la Investigacion of the Spanish Ministry of Economy and Competitiveness; Fondo Europeo de Desarrollo Regional (FEDER)European Union (EU); Fundacio La Marato de TV3 [07/2410]; Sanofi Genzyme, Belgium; Research Foundation Flanders (FWO)FWO; Hospital Germans Trias i Pujol ('Germans Trias Talents 2016-2018'); University of Antwerp; Research Foundation FlandersFWO [FWO 1701919N]; Spanish Patient association 'Treball de Vida' (Associacio d'Afectats d'Esclerosi Multiple del Barcelones Nord i Maresme)
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Abstract: Background: The European Union (EU) aims to optimize patient protection and efficiency of health-care research by harmonizing procedures across Member States. Nonetheless, further improvements are required to increase multicenter research efficiency. We investigated IRB procedures in a large prospective European multicenter study on traumatic brain injury (TBI), aiming to inform and stimulate initiatives to improve efficiency. Methods: We reviewed relevant documents regarding IRB submission and IRB approval from European neurotrauma centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI). Documents included detailed information on IRB procedures and the duration from IRB submission until approval(s). They were translated and analyzed to determine the level of harmonization of IRB procedures within Europe. Results: From 18 countries, 66 centers provided the requested documents. The primary IRB review was conducted centrally (N = 11, 61%) or locally (N = 7, 39%) and primary IRB approval was obtained after one (N = 8, 44%), two (N = 6, 33%) or three (N = 4, 23%) review rounds with a median duration of respectively 50 and 98 days until primary IRB approval. Additional IRB approval was required in 55% of countries and could increase duration to 535 days. Total duration from submission until required IRB approval was obtained was 114 days (IQR 75–224) and appeared to be shorter after submission to local IRBs compared to central IRBs (50 vs. 138 days, p = 0.0074). Conclusion: We found variation in IRB procedures between and within European countries. There were differences in submission and approval requirements, number of review rounds and total duration. Research collaborations could benefit from the implementation of more uniform legislation and regulation while acknowledging local cultural habits and moral values between countries.
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