Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Mar 7;6(1):15.
doi: 10.1186/s42466-024-00310-x.

Prospective study validating a multidimensional treatment decision score predicting the 24-month outcome in untreated patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis, the ProVal-MS study

Antonios Bayas #  1 , Ulrich Mansmann #  2 , Begum Irmak Ön  2 , Verena S Hoffmann  2 , Achim Berthele  3 , Mark Mühlau  3 , Markus C Kowarik  4 , Markus Krumbholz  4 , Makbule Senel  5 , Verena Steuerwald  6 , Markus Naumann  6 , Julia Hartberger  3 , Martin Kerschensteiner  7 , Eva Oswald  7 , Christoph Ruschil  4 , Ulf Ziemann  4 , Hayrettin Tumani  5 , Ioannis Vardakas  5 , Fady Albashiti  8 , Frank Kramer  9 , Iñaki Soto-Rey  10 , Helmut Spengler  11 , Gerhard Mayer  12 , Hans Armin Kestler  13 , Oliver Kohlbacher  14   15   16 , Marlien Hagedorn  8 , Martin Boeker  17 , Klaus Kuhn  17 , Stefan Buchka  2 , Florian Kohlmayer  18 , Jan S Kirschke  19 , Lars Behrens  20 , Hanna Zimmermann  21 , Benjamin Bender  22 , Nico Sollmann  23 , Joachim Havla #  7 , Bernhard Hemmer #  3   24 ; ProVal-MS study group
Collaborators, Affiliations

Prospective study validating a multidimensional treatment decision score predicting the 24-month outcome in untreated patients with clinically isolated syndrome and early relapsing-remitting multiple sclerosis, the ProVal-MS study

Antonios Bayas et al. Neurol Res Pract. .

Abstract

Introduction: In Multiple Sclerosis (MS), patients´ characteristics and (bio)markers that reliably predict the individual disease prognosis at disease onset are lacking. Cohort studies allow a close follow-up of MS histories and a thorough phenotyping of patients. Therefore, a multicenter cohort study was initiated to implement a wide spectrum of data and (bio)markers in newly diagnosed patients.

Methods: ProVal-MS (Prospective study to validate a multidimensional decision score that predicts treatment outcome at 24 months in untreated patients with clinically isolated syndrome or early Relapsing-Remitting-MS) is a prospective cohort study in patients with clinically isolated syndrome (CIS) or Relapsing-Remitting (RR)-MS (McDonald 2017 criteria), diagnosed within the last two years, conducted at five academic centers in Southern Germany. The collection of clinical, laboratory, imaging, and paraclinical data as well as biosamples is harmonized across centers. The primary goal is to validate (discrimination and calibration) the previously published DIFUTURE MS-Treatment Decision score (MS-TDS). The score supports clinical decision-making regarding the options of early (within 6 months after study baseline) platform medication (Interferon beta, glatiramer acetate, dimethyl/diroximel fumarate, teriflunomide), or no immediate treatment (> 6 months after baseline) of patients with early RR-MS and CIS by predicting the probability of new or enlarging lesions in cerebral magnetic resonance images (MRIs) between 6 and 24 months. Further objectives are refining the MS-TDS score and providing data to identify new markers reflecting disease course and severity. The project also provides a technical evaluation of the ProVal-MS cohort within the IT-infrastructure of the DIFUTURE consortium (Data Integration for Future Medicine) and assesses the efficacy of the data sharing techniques developed.

Perspective: Clinical cohorts provide the infrastructure to discover and to validate relevant disease-specific findings. A successful validation of the MS-TDS will add a new clinical decision tool to the armamentarium of practicing MS neurologists from which newly diagnosed MS patients may take advantage. Trial registration ProVal-MS has been registered in the German Clinical Trials Register, `Deutsches Register Klinischer Studien` (DRKS)-ID: DRKS00014034, date of registration: 21 December 2018; https://drks.de/search/en/trial/DRKS00014034.

Keywords: Clinical trial; Clinically isolated syndrome; Data integration; Multiple sclerosis; Prospective cohort; Routine data; Treatment decision; Validation.

PubMed Disclaimer

Conflict of interest statement

A. Bayas: personal compensation from Merck Serono, Biogen, Novartis, TEVA, Roche, Sanofi/Genzyme, Celgene/Bristol Myers Squibb, Janssen, Sandoz/HEXAL, Horizon, Alexion, Argenx; grants for congress travel and participation from Biogen, TEVA, Novartis, Sanofi/Genzyme, Merck Serono, Celgene, Janssen. None related to this report. U. Mansmann: no competing interests to declare that are relevant to the content of this article. B.I. Ön: no competing interests to declare that are relevant to the content of this article. V.S. Hoffmann: partially funded by the German Federal Ministry of Education and Research ((DIFUTURE), Grant Numbers 01ZZ1603[A-D] and 01ZZ1804[A-H]). A. Berthele: received consulting and/or speaker fees from Alexion, Bayer Healthcare, Biogen, Celgene, Novartis, Roche and Sandoz/Hexal, and his institution has received compensation for clinical trials from Alexion, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme; all outside the submitted work. M. Mühlau: funding from German Research Foundation (PP2177, 428223038), the National Institutes of Health (1R01NS112161); Bavarian State Ministry for Science and Art (Program Bavaria—Québec: F.4-V0134.K5.1/86/34); German Federal Ministry of Education and Research (BMBF), DIFUTURE 01ZZ1603[A-D] and 01ZZ1804[A-I]. M.C. Kowarik: advisory boards and received speaker fees/travel grants from Merck, Sanofi-Genzyme, Novartis, Biogen, Jansen, Alexion, Celgene/Bristol-Myers Squibb and Roche. He also received research grants from Merck, Sanofi-Genzyme and Celgene/Bristol-Myers Squibb, Roche, Janssen. None related to this work. M. Krumbholz: research grants from Merck and Novartis; travel support and personal fees from BMS, Merck, Novartis and Roche; all unrelated to this manuscript. M. Senel: consulting and/or speaker honoraria from Alexion, Bayer, Biogen, Bristol-Myers-Squibb, Horizon, Merck, Roche, and Sanofi Genzyme. She has received travel support from Celgene, and TEVA. She has received research funding from the Hertha-Nathorff-Program. None of this related to the current study. V. Steuerwald: partially funded by the German Federal Ministry of Education and Research (DIFUTURE). M. Naumann: no competing interests to declare that are relevant to the content of this article. J. Hartberger: no competing interests to declare that are relevant to the content of this article. M. Kerschensteiner: no competing interests to declare that are relevant to the content of this article. E. Oswald: no competing interests to declare that are relevant to the content of this article. C. Ruschil: supported by fortüne/PATE (no. 2536-0-0/1) from the medical faculty Eberhard-Karls University of Tübingen; not related to this project. U. Ziemann: no competing interests to declare that are relevant to the content of this article. H. Tumani: funding for research projects, lectures, and travel from Alexion, Bayer, Biogen, Celgene/Bristol-Myers-Squibb, GlaxoSmithKline, Janssen, Merck Serono, Novartis, Roche, Sanofi/Genzyme, Siemens and Teva, and received research support from Chemische Fabrik Karl Bucher GmbH, German Multiple Sclerosis Society (DMSG), and the German Ministry for Education and Research (BMBF). I. Vardakas: no competing interests to declare that are relevant to the content of this article. F. Albashiti is partially funded by the German Federal Ministry of Education and Research {(DIFUTURE), Grant Numbers 01ZZ1603[A-D] and 01ZZ1804[A-H]}. F. Kramer: no competing interests to declare that are relevant to the content of this article. I. Soto-Rey: no competing interests to declare that are relevant to the content of this article. Helmut Spengler: funded by the German Federal Ministry of Education and Research ((DIFUTURE), Grant Numbers 01ZZ1603[A-D] and 01ZZ1804[A-I]). G. Mayer: funded by the Digital Europe program of the European Commission (EDITH project no. 101083771). H.A. Kestler: partially funded by the German Federal Ministry of Education and Research ((DIFUTURE), Grant Numbers 01ZZ1804I). O. Kohlbacher: no competing interests to declare that are relevant to the content of this article. M. Hagedorn: no competing interests to declare that are relevant to the content of this article. M. Boeker: no competing interests to declare that are relevant to the content of this article. K. Kuhn: no competing interests to declare that are relevant to the content of this article. S. Buchka: no competing interests to declare that are relevant to the content of this article. F. Kohlmayer: funding for providing and maintaining of the study software, DIS from Bitcare GmbH. J. Kirschke: Co-Founder of Bonescreen GmbH. Speaker fees from Novartis. L. Behrens: no competing interests to declare that are relevant to the content of this article. H. Zimmermann: no competing interests to declare that are relevant to the content of this article. B. Bender: Co-Founder and CTO of AIRAmed GmbH, Tübingen. N. Sollmann: no competing interests to declare that are relevant to the content of this article. J. Havla: reports grants from the Friedrich-Baur-Stiftung, Merck and Horizon, personal fees and non-financial support from Alexion, Horizon, Roche, Merck, Novartis, Biogen, BMS and Janssen, and non-financial support from the Guthy-Jackson Charitable Foundation and The Sumaira Foundation. JH was partially funded by the German Federal Ministry of Education and Research ((DIFUTURE), Grant Numbers 01ZZ1603[A-D] and 01ZZ1804[A-H]). B. Hemmer: funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology [EXC 2145 SyNergy – ID 390857198] and the European commission (MultipleMS). He has served on scientific advisory boards for Novartis and Sandoz; he has served as DMSC member for AllergyCare, Sandoz, Polpharma, Biocon and TG therapeutics; his institution received research grants from Roche for multiple sclerosis research. He has received honoraria for counseling (Gerson Lehrmann Group). He holds part of two patents; one for the detection of antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis and one for genetic determinants of neutralizing antibodies to interferon. All conflicts are not relevant to the topic of the study.

Figures

Fig. 1
Fig. 1
The multi-centric study infrastructure of ProVal-MS established at each study center. The routine clinical data is imported, and the study specific data is entered into the Data Integration System (DIS). The study data is made available in the DataSHIELD Opal server and accessible by the ProVal-MS study analyst to perform privacy preserving analysis using the R Client or Webclient (R, free software environment for statistical computing and graphics)
See this image and copyright information in PMC

References

    1. Aytulun A, Cruz-Herranz A, Aktas O, Balcer LJ, Balk L, Barboni P, Blanco AA, Calabresi PA, Costello F, Sanchez-Dalmau B, DeBuc DC, Feltgen N, Finger RP, Frederiksen JL, Frohman E, Frohman T, Garway-Heath D, Gabilondo I, Graves JS, Albrecht P. APOSTEL 2.0 recommendations for reporting quantitative optical coherence tomography studies. Neurology. 2021;97(2):68–79. doi: 10.1212/WNL.0000000000012125. - DOI - PMC - PubMed
    1. Eichinger P, Schon S, Pongratz V, Wiestler H, Zhang H, Bussas M, Hoshi MM, Kirschke J, Berthele A, Zimmer C, Hemmer B, Muhlau M, Wiestler B. Accuracy of unenhanced MRI in the detection of new brain lesions in multiple sclerosis. Radiology. 2019;291(2):429–435. doi: 10.1148/radiol.2019181568. - DOI - PubMed
    1. Hapfelmeier A, Hornung R, Haller B. Efficient permutation testing of variable importance measures by the example of random forests. Computational Statistics & Data Analysis. 2023;181:107689. doi: 10.1016/j.csda.2022.107689. - DOI
    1. Hapfelmeier A, On BI, Muhlau M, Kirschke JS, Berthele A, Gasperi C, Mansmann U, Wuschek A, Bussas M, Boeker M, Bayas A, Senel M, Havla J, Kowarik MC, Kuhn K, Gatz I, Spengler H, Wiestler B, Grundl L, Hemmer B. Retrospective cohort study to devise a treatment decision score predicting adverse 24-month radiological activity in early multiple sclerosis. Therapeutic Advances in Neurological Disorders. 2023;16:17562864231161892. doi: 10.1177/17562864231161892. - DOI - PMC - PubMed
    1. Hemingway H, Croft P, Perel P, Hayden JA, Abrams K, Timmis A, Briggs A, Udumyan R, Moons KG, Steyerberg EW, Roberts I, Schroter S, Altman DG, Riley RD, Group P. Prognosis research strategy (PROGRESS) 1: a framework for researching clinical outcomes. BMJ. 2013;346:e5595. doi: 10.1136/bmj.e5595. - DOI - PMC - PubMed

Associated data