Two studies in one: A propensity-score-matched comparison of fingolimod versus interferons and glatiramer acetate using real-world data from the independent German studies, PANGAEA and PEARL

RESEARCH ARTICLE Two studies in one: A propensity-scorematched comparison of fingolimod versus interferons and glatiramer acetate using realworld data from the independent German studies, PANGAEA and PEARL a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 Jonathan Alsop1, Jennie Medin2, Christian Cornelissen3, Stefan Viktor Vormfelde3, Tjalf Ziemssen4* 1 Numerus Ltd, Wokingham, United Kingdom, 2 Novartis Pharma AG, Basel, Switzerland, 3 Novartis Pharma GmbH, Nuremberg, Germany, 4 Center of Clinical Neuroscience, Carl Gustav Carus University Clinic, Dresden University of Technology, Dresden, Germany * OPEN ACCESS Citation: Alsop J, Medin J, Cornelissen C, Vormfelde SV, Ziemssen T (2017) Two studies in one: A propensity-score-matched comparison of fingolimod versus interferons and glatiramer acetate using real-world data from the independent German studies, PANGAEA and PEARL. PLoS ONE 12(5): e0173353. https://doi.org/10.1371/journal. pone.0173353 Editor: Sreeram V. Ramagopalan, University of Oxford, UNITED KINGDOM Received: August 25, 2016 Accepted: February 19, 2017 Published: May 5, 2017 Copyright: © 2017 Alsop et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: Data cannot be made publicly available to protect patient privacy and confidentiality. Interested and qualified researchers may contact Dr. Tjalf Ziemssen, tjalf. for data requests and access. Funding: The funders (Novartis Pharma GmbH and Novartis Pharma AG) had a role in study design, data collection and analysis, decision to publish, Abstract Background This study compared outcomes following fingolimod or BRACE treatments (beta-interferons/glatiramer acetate) in patients with active MS ( 1 relapse in the previous year) following previous BRACE treatment. Methods and findings Patients with active MS who previously received BRACE were identified from German prospective, observational studies, PANGAEA and PEARL. A novel methodology was developed to compare outcomes between propensity-score-matched cohorts (3:1 ratio) from the independent single-arm studies. Patients in PANGAEA (n = 1287) experienced 48% fewer relapses per year than those in PEARL (n = 429; annualized relapse rate ratio: 0.52; p < 0.001). The risk of 3-month or 6-month confirmed disability progression (CDP) was reduced in PANGAEA versus PEARL (3-month: 37% reduction; hazard ratio [HR], 0.63; p < 0.001; 6-month: 47% reduction; HR, 0.53; p < 0.001). A higher proportion of patients in PANGAEA (n = 1234) than PEARL (n = 401) were free from relapses and 3-month (65.7% vs 38.7%; p < 0.001) or 6-month (68.2% vs 39.2%; p < 0.001) CDP. The probability of confirmed disability improvement was higher in PANGAEA (n = 1163) than PEARL (n = 372; 3-month: 175% increase; HR, 2.75; p < 0.001; 6-month: 126% increase; HR, 2.26; p < 0.001). Patients in PANGAEA (n = 149) were less likely than those in PEARL (n = 307) to have taken sick leave (proportion with 0 days off work: 62.4% vs 44.6%; p = 0.0005). For change in disease severity from baseline (assessed by clinicians using the Clinical Global Impressions scale; PANGAEA, n = 1207; PEARL, n = 427), a larger proportion of patients had subjective improvement and a smaller proportion had worsening status in PANGAEA than PEARL (improvement: 28.2% vs 15.2%; worsening: 16.4% vs 30.4%; p < 0.0001). PLOS ONE | https://doi.org/10.1371/journal.pone.0173353 May 5, 2017 1 / 15 Real-world study: Fingolimod versus BRACE in patients with active MS and preparation of the manuscript. The design of the study and the collection, analysis and interpretation of data were funded by Novartis Pharma GmbH, Nuremberg, Germany. The writing of the manuscript was funded by Novartis Pharma AG, Basel, Switzerland. Novartis Pharma GmbH provided support in the form of salaries for two authors [CC, SVV (at the time of manuscript preparation)]. Novartis Pharma AG provided support in the form of salaries for one author [JM]. One author was employed by Numerus [JA] which received funding from Novartis Pharma GmbH and Novartis Pharma AG to conduct the data analysis. The specific roles of these authors are articulated in the ‘author contributions’ section. Competing interests: JA is a paid employee of Numerus Ltd, Wokingham, UK. Numerus Ltd received funding from Novartis Pharma GmbH, Nuremberg, Germany. CC is a paid employee of Novartis Pharma GmbH, Nuremberg, Germany. JM and SV are paid employees of Novartis Pharma AG, Basel, Switzerland. TZ has received speaker honoraria and travel expenses for scientific meetings and has been a steering committee member of clinical trials or participated in advisory boards for clinical trials for Almirall, Bayer Schering Pharma, Biogen Idec, EMD Merck Serono, Genentech, Genzyme, Novartis, Sanofi-Aventis and Teva Pharmaceuticals. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Conclusions Fingolimod appears to be more effective than BRACE in improving clinical and physician-/ patient-reported outcomes in individuals with active MS. Introduction Multiple sclerosis (MS) is a chronic, inflammatory, degenerative disease of the central nervous system [1]. It is a leading cause of disability in young and middle-aged people, and affects approximately 2.3 million individuals worldwide [2]. Most patients (80–85%) present with the relapsing–remitting form of MS (RRMS), which is characterized by clearly defined symptomatic attacks (relapses) followed by periods of remission [3]. Loss of function in RRMS is caused by two types of damage. Widespread diffuse damage starts early in the disease and often goes unnoticed [4–7]. It is associated with progressive reduction in brain volume and accumulated loss of physical and cognitive function [4–7]; brain volume loss appears to be an important predictor of future disability [7]. The other type of damage is focal damage (distinct inflammatory lesions detected by magnetic resonance imaging [MRI]). Focal damage is associated with relapses, which are primary clinical manifestations of RRMS, that are followed by stretches of full or partial recovery [1, 5]. Incomplete recovery from relapses can lead to an accumulation of disability in patients with RRMS [1]. Patients with this form of MS initially experience relapses at a mean frequency of one per year, with wide inter-individual variation [1]. The frequency of relapses typically decreases over time [1]. Treatments for MS traditionally aim to modify the disease by reducing the number of relapses and delaying the progression of disability [8]. Glatiramer acetate (GA) and beta-interferons (IFN beta) collectively comprise the BRACE treatments (Betaseron1, Rebif1, Avonex1, Copaxone1, Extavia1), which are widely approved as disease-modifying therapies (DMTs) for MS. F (...truncated)