The PANGAEA study design – a prospective, multicenter, non-interventional, long-term study on fingolimod for the treatment of multiple sclerosis in daily practice

Ziemssen et al. BMC Neurology (2015) 15:93 DOI 10.1186/s12883-015-0342-0 STUDY PROTOCOL Open Access The PANGAEA study design – a prospective, multicenter, non-interventional, long-term study on fingolimod for the treatment of multiple sclerosis in daily practice Tjalf Ziemssen1*, Raimar Kern1 and Christian Cornelissen2 Abstract Background: Fingolimod (Gilenya®) is an oral medication for patients with highly active relapsing-remitting Multiple Sclerosis (RRMS). Clinical trials and post-marketing experience on more than 114,000 patients have established a detailed safety profile. Total patient exposure now exceeds 195,000 patient-years as stated in the last financial report (Dec 2014) of the Novartis Pharma AG, Basel, Switzerland. However, less is known about the safety of long-term fingolimod use in daily practice. Here, we describe the study design of PANGAEA (Post-Authorization Non-interventional German sAfety of GilEnyA in RRMS patients), a prospective, multicenter, non-interventional, long-term study to collect safety, efficacy, and pharmacoeconomic data on RRMS patients treated with fingolimod (0.5 mg/daily) under real-world conditions in Germany. Methods: PANGAEA is striving to assess a real-world safety and efficacy profile of fingolimod, based on data from 4,000 RRMS patients, obtained during a 60-month observational phase. A pharmacoeconomic sub-study of 800 RRMS patients further collects patient-reported outcome measures of disability, quality of life, compliance, treatment satisfaction, and usage of resources during a 24-month observational phase. Descriptive statistical analyses of the safety set as well as of stratified subgroups such as patients with concomitant diabetes mellitus and pretreated patients (e.g., natalizumab) will be conducted. Discussion: PANGAEA seeks to confirm the current safety profile of fingolimod obtained in phase I-III clinical trials. The study design presented here will additionally provide guidance on the therapeutic use of fingolimod in clinical practice and possibly assists physicians in making evidence-based decisions. Keywords: Multiple sclerosis, Relapsing remitting, RRMS, Fingolimod, Gilenya, Efficacy, Safety, Pharmacoeconomics, PANGAEA Background In Europe, fingolimod (Gilenya®) has been approved as an oral disease-modifying therapy (DMT) both for patients who have a highly active relapsing-remitting MS (RRMS) despite previous treatment with at least one DMT, and for patients who have a rapidly evolving severe RRMS [1]. * 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 Fingolimod is the prodrug of a sphingosine 1-phosphate (S1P) receptor agonist [2] that undergoes phosphorylation by sphingosine kinase in vivo [3]. Phosphorylated fingolimod interacts with S1P receptors expressed on the surface of immune cells, neurons, and cells of the cardiovascular system, leading to subsequent receptor internalization from the cell membrane. Fingolimod then induces polyubiquitination and degradation of internalized S1P receptors, thereby preventing immune cells expressing S1P receptors from sensing the S1P gradient between lymphnodes and periphery and, hence, from exiting the lymphoid tissue [4]. This prevention consequently results in a © 2015 Ziemssen et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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 (2015) 15:93 long-term functional antagonism that differentially affects subsets of lymph-node immune cells and per se attenuates autoimmune pathology [5, 6]. In MS, the mechanism of action of fingolimod prevents infiltration of autoreactive lymphocytes into the central nervous system. Preclinical data further suggest that fingolimod has also direct effects in the central nervous system, reducing demyelination and promoting remyelination [7]. In 2010, two phase-III studies, FREEDOMS [8] and TRANSFORMS [9], demonstrated the efficacy of fingolimod in patients with RRMS. FREEDOMS, a placebocontrolled trial, showed a relative reduction of the relapse rate by 54 % to 60 % with corresponding effects on disability progression and magnetic resonance imaging (MRI)-related measures [8]. These beneficial effects on relapse rate were reproduced by FREEDOMS II [10]. TRANSFORMS then demonstrated superiority of fingolimod over treatment with intramuscular interferon beta1a, with significantly lower relapse rates and better MRI outcomes [9]. Adverse events reported for patients treated with fingolimod might be caused by its interaction with S1P receptors both inside and outside the immune system. The first dose of fingolimod needs to be applied under medical supervision because heart rate and atrioventricular conduction time might decrease within the first hours after the first application of fingolimod [11, 12]. The risk of certain infections might be increased by a dose-dependent but reversible reduction of blood-lymphocyte counts by fingolimod [13], but the overall rate of infections under fingolimod is similar to placebo [8]. However, since two fatal cases of varicella-zoster virus infection were reported in fingolimod-treated patients, [9], varicella-zoster virus immune status has to be assessed before fingolimod treatment initiation. In certain subsets of patients, such as patients with diabetes mellitus or a history of ophthalmological abnormalities, fingolimod has been further associated with macular edema that occurred in 0.4 % of fingolimod-treated patients and usually resolves after discontinuation of medication [8, 9, 14]. The experience both in clinical trials and in the postmarketing setting now exceeds 114,000 fingolimod-treated patients or 195,000 patient-years on fingolimod [15]. This experience has established a well-characterized safety and efficacy profile of fingolimod. However, validity for the real-world treatment setting might be considered being different to the situation in clinical trials due to the number of patients enrolled and selection criteria applied [11, 16]. We therefore sought to obtain a more generalizable safety and efficacy profile on the basis of long-term experience with fingolimod in daily routine practice. To address the above mentioned and other safety cenocerns, a detailed data acquisition and monitoring algorithm taking the Risk Management Plan (RMP) of the European Medicines Page 2 of 8 Agency (EMA) into consideration (...truncated)