Study design of PANGAEA 2.0, a non-interventional study on RRMS patients to be switched to fingolimod

Ziemssen et al. BMC Neurology (2016) 16:129 DOI 10.1186/s12883-016-0648-6 STUDY PROTOCOL Open Access Study design of PANGAEA 2.0, a noninterventional study on RRMS patients to be switched to fingolimod Tjalf Ziemssen1* , Raimar Kern1 and Christian Cornelissen2 Abstract Background: The therapeutic options for patients with Multiple Sclerosis (MS) have steadily increased due to the approval of new substances that now supplement traditional first-line agents, demanding a paradigm shift in the assessment of disease activity and treatment response in clinical routine. Here, we report the study design of PANGAEA 2.0 (Post-Authorization Non-interventional GermAn treatment benefit study of GilEnyA in MS patients), a non-interventional study in patients with relapsing-remitting MS (RRMS) identify patients with disease activity and monitor their disease course after treatment switch to fingolimod (Gilenya®), an oral medication approved for patients with highly active RRMS. Method/Design: In the first phase of the PANGAEA 2.0 study the disease activity status of patients receiving a disease-modifying therapy (DMT) is evaluated in order to identify patients at risk of disease progression. This evaluation is based on outcome parameters for both clinical disease activity and magnetic resonance imaging (MRI) , and subclinical measures, describing disease activity from the physician’s and the patient’s perspective. In the second phase of the study, 1500 RRMS patients identified as being non-responders and switched to fingolimod (oral, 0.5 mg/daily) are followed-up for 3 years. Data on relapse activity, disability progression, MRI lesions, and brain volume loss will be assessed in accordance to ‘no evidence of disease activity-4’ (NEDA-4). The modified Rio score, currently validated for the evaluation of treatment response to interferons, will be used to evaluate the treatment response to fingolimod. The MS management software MSDS3D will guide physicians through the complex processes of diagnosis and treatment. A sub-study further analyzes the benefits of a standardized quantitative evaluation of routine MRI scans by a central reading facility. PANGAEA 2.0 is being conducted between June 2015 and December 2019 in 350 neurological practices and centers in Germany, including 100 centers participating in the sub-study. Discussion: PANGAEA 2.0 will not only evaluate the long-term benefit of a treatment change to fingolimod but also the applicability of new concepts of data acquisition, assessment of MS disease activity and evaluation of treatment response for the in clinical routine. Trial registration: BfArM6532; Trial Registration Date: 20/05/2015. Keywords: Multiple sclerosis, Relapsing remitting, Fingolimod, Efficacy, Safety, Modified Rio score, NEDA, No evident disease activity, Clinical routine * Correspondence: 1 Zentrum für klinische Neurowissenschaften, Klinik und Poliklinik für Neurologie, Universitätsklinikum Carl Gustav Carus Dresden, Technische Universität Dresden, Fetscherstr. 43, D-01307 Dresden, Germany Full list of author information is available at the end of the article © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ziemssen et al. BMC Neurology (2016) 16:129 Background In recent years, the therapeutic options for patients with Multiple Sclerosis (MS) have steadily increased. Substances such as Fingolimod (Gilenya®) supplement the traditional first-line agents interferon (IFN) and glatiramer acetate, offering physicians the opportunity to optimize individual MS-treatment [1, 2]. The safety and tolerability profile of fingolimod and natalizumab is well understood. However, experience with new treatment options such as alemtuzumab, dimethylfumarate, and teriflunomide is limited in comparison to former approved substances, and especially data on the safety and tolerability of sequentially changed disease-modifying therapies (DMTs) are mostly not available. Since defined treatment algorithms for individual patients have not yet been developed, many MS patients may continue to receive suboptimal treatment for long periods of time. To optimize treatment, a switch to a more effective medication generally needs to be considered if patients do not respond to or fail with their current therapy [2]. It is well accepted that the earlier in MS pathogenesis the therapy is adjusted (in the lower Expanded Disability Status Scale [EDSS [3]] range up to 3), the higher would be the benefit on long-term outcomes because MS progression might be more difficult to slow down at later stages [4, 5]. Since magnetic resonance imaging (MRI) parameters frequently assessed during therapy are sensitive markers to identify patients who are insufficiently responding to therapy [6], quantitative scoring systems incorporating relapses and MRI activity have been suggested as valuable diagnostic tools in clinical routine. Among them, Lublin et al. [7] defined disease activity at a particular time point on the basis of clinical relapses and MRI activity in the previous 12 months. Sormani et al. [8] modified the Rio score [9] to define treatment response based on relapse activity and MRI activity over a period of 1 year of treatment. However, the data underlying the modified Rio score was obtained from clinical studies on IFN-β [10], and the modified Rio score has not been evaluated for other therapies or under real-life conditions. Other scoring systems have been developed that assess parameters besides relapse and MRI activity, but there is currently no consensus among MS experts on the most sensitive measures applicable in clinical practice for identifying patients on suboptimal treatment [11, 12]. With the possibility to optimize treatment by sequentially applying novel and highly effective MS therapeutics, the MS community is increasingly accepting ‘no evidence of disease activity’ (NEDA) as an early objective for individual treatment. This new treatment paradigm is based on the view that the mere reduction of relapse rate and the attenuation of disease progression can no longer be accepted as sufficient in clinical routine. Page 2 of 11 Therefore, NEDA was defined as no relapse activity, no EDSS progression, and no new MRI lesions (T1 Gd + and/or active T2 lesion; [13, 14]). Since these measures may not be able to address all aspects of the disease [7, 15, 16], brain volume loss (BVL) has been suggested as fourth NEDA measure (NEDA-4) to p (...truncated)