Article Text
Abstract
Objective The Tysabri Observational Programme (TOP), which began >10 years ago, is an open-label, multinational, prospective observational study evaluating the long-term safety and effectiveness of natalizumab in relapsing-remitting multiple sclerosis patients.
Methods These data provide a 10-year interim analysis of safety and effectiveness in TOP. Annualised relapse rates (ARRs) and disability progression/improvement were analysed using the Poisson model and the Kaplan-Meier method, respectively. Analyses included patients on natalizumab and those who discontinued natalizumab but remained in TOP.
Results As of November 2017, TOP included 6148 patients. Overall, 829 patients (13.5%) experienced ≥1 serious adverse event (SAE), with infection the most common (4.1%). Fifty-three patients (0.9%) had confirmed progressive multifocal leukoencephalopathy. SAE data were consistent with natalizumab’s known safety profile; no new safety signals were identified. A total of 3210 patients (52.2%) discontinued natalizumab; 2117 (34.4%) withdrew from TOP. Median time on natalizumab was 3.3 (range 0–11.6) years; median follow-up time was 5.2 (range 0–10.8) years. The on-natalizumab ARR was 0.15, a 92.5% reduction from the year before initiation. Ten-year cumulative probabilities of disability worsening and improvement were 27.8% and 33.1%, respectively. On-natalizumab ARRs were similar between patients who discontinued or remained on natalizumab, suggesting limited attrition bias.
Conclusions Since the TOP 5-year interim analysis (December 2012), cohort size (6148 vs 4821), median exposure (3.3 vs 1.8 years) and median follow-up time (62 vs 26 months) have increased. This 10-year interim analysis further supports the robust real-world effectiveness and well-established safety profile of natalizumab.
Trial registration number NCT00493298.
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Footnotes
Collaborators Site investigators who participated in data collection: Roby Abraham, Jana Adamkova, Laura Airas, Orhan Aktas, Holger Albrecht, Roger Alsassa, Amaya Alvarez de Arcaya Esquide, Klemens Angstwurm, Olivier Anne, Kerstin Anvari, Julia Aram, Sari Atula, Regine Augspach-Hofmann, Michael Barnett, Bruno Barroso, Emmanuel Barthomolé, Jordi Batlle Nadal, Antonios Bayas, Arnfin Bergmann, Ralf Berkenfeld, Achim Berthele, Antonio Bertolotto, Christophe Billy, Andreas Bitsch, Kin-Arno Bohr, Johannes Böhringer, Jean Paul Borsotti, M. Bos, Olivier Bouquiaux, Hélène Bourteel, Thomas Brosch, Bernhard Buehler, Michel Bureau, Philippe Busson, Helmut Butzkueven, Jo Caekebeke, Carmen Calles Hernández, Ana Belén Caminero Rodríguez, Alejandro Caride, Tamara Castillo Triviño, Cris Constantinescu, Jorge Correale, José Manuel Costa Guerra, Roeland Crols, Miguel D’Haeseleer, Koen de Gans, Maria de Jesus Jimeez, Ma de la Luz Villalpando, Adinda De Pauw, Danny Decoo, Sophie Delalande, Olivier Delerue, Valérie Delvaux, Olivier Dereeper, Norma H. Deri, Olivier Deryck, Richard Devy, Marie D'Hooghe, Sylke Domke, Benedicte Dubois, Martin Duddy, Michal Dufek, Emeline Duhin, Michel Dupuis, Philippe Eck, Hans-Thomas Eder, Astrid Edland, Sven Ehrlich, Eli Skromne Eisenberg, Wolfgang-Gerhard Elias, Evelyn Erdmann, Michael Ernst, Rocio Márquez Estudillo, Juergen Faiss, Guy Fanjaud, Elisabeth Farbu, Jean Marc Faucheux, Jiri Fiedler, Jesús Alfredo Flores Ciro, Francisco Gerardo Flores Ramirez, Jose de Jesus Flores Rivera, Ciro Florio, Benedikt Frank, Claudio Gasperini, Karine Geens, Klaus Gehring, Sohrab Mostoufizadeh Ghalamfarsa, Pierric Giraud, Etienne Godet, Antonio Gonzalez Guardado, Jens Gössling, François Grand'Maison, Thomas Gratz, Orla Gray, Luigi Grimaldi, Christoph Grothe, Daniel Guillaume, Stefan Günther, Carmen Gurau Vasilescu, Kersten Guthke, Judith Haas, Lutz Harms, Timothy Harrower, Päivi Hartikainen, Patrick Hautecoeur, Eva Havrdova, Kerstin Hellwig, G.J.D. Hengstman, Mieke Hermans, Birgit Herting, Suzanne Hodgkinson, Olaf Hoffmann, Roelfien Ida Hogenesch, Tone Hognestad, Markus Horn, Rolf Horn, R.M.M. Hupperts, Rosy N'gbo N'gbo Ikazabo, Olivier Ille, Teis Barclay Ingvaldsen, Samir Ismail, Francois Jacques, Joachim Jaeger, Draga Jichici, Maria José Sá, Waldemar Kafke, Boris Kallmann, Iveta Kastnerová, Ulrich Kausch, Jean Bertin N. Kendjuo, Allan Kermode, John King, Michael Kirsch, Matthias Kittlitz, Chris Kneebone, Karl Christian Knop, Keijo Koivisto, Reinhard Krug, Borries Kukowski, Arnaud Kwiatkowski, Harald Landefeld, Michael Lang, Thomas Lange, Jean-Marc Larrieu, Christoph Lassek, Guy Laureys, Jeannette Lechner-Scott, Leonardo Llamas López, Christian Lund, Richard Macdonell, Gregg MacLean, Alain Maertens de Noordhout, Marcel Maillet Vioud, Carolina Mainella, Rolf Malessa, Imad Malkoun, Renato Mantegazza, Paul Marchetti, Jan Mares, Gisela Martin Ozaeta, Sergio Martínez-Yélamos, María Eugenia Marzo Sola, Said Masri, Uwe Mauz, R. Medaer, Annick Melin, Eva Meluzinová, Christian Menges, Marc Merienne, Sven Meuth, Rune Midgard, Enrico Millefiorini, Daniel Molitor, J.W.B. Moll, Armando Morganho, Antoine Moulignier, Kjell Morten Myhr, Christian Neudert, Richard Nicholas, Chantal Nifle, Alena Novotna, Francis Odeh, Basile Ondze, Michael Osei-Bonsu, Massimo Pandolfo, Katelijne Peeters, Ines Peglau, Domingo Pérez Ruiz, Ilaria Pesci, Oliver Pfeffer, Maria Pia Amato, Christopher Pilz, Chris Plummer, Udo Polzer, Andre Pouliquen, Sandra Quiñones Aguilar, Lluis Ramio i Torrenta, Cristina Ramo, Sebastian Rauer, Ian Redmond, Elisabeth Rehkopf, Gerd Reifschneider, José Rente, Cecile Retif, Nils Richter, Kerstin Roch, Roland Roth, Mariarosa Rottoli, Oliver Ruhnke, Klemens Ruprecht, Michael Sailer, Noel Saines, Rosilda Santos Montero, Serena Scarel, Elio Scarpini, Jürgen Schierenbeck, Sebastian Schimrigk, Eugen Schlegel, Sylke Schlemilch-Paschen, Stephan Schmidt, Frank Schmitz, Peter Scholz, Michael Schroeter, Ivo Schuetze, Stephan Schüler, Matthias Schwab, Angélique Schyns-Soeterboek, Pierrette Seeldrayers, Nicolas Seiller, François Sellal, Juha Matti Seppä, Melad Shawush, Arno Siever, L.G.F. Sinnige, Ondrej Skoda, Charlotte Smetcoren, Diana Soares, Tiago Souto, Magdalena Stankiewicz, Ivana Stetkarova, Helmut Stienker-Fisse, Klara Stolarikova, Pavel Stourac, Hubert Stratmann, Sergio Sauri Suárez, Manuel Suceveanu, Björn Tackenberg, Jean Philippe Thenint, Oliver Tiedge, Maria Trojano, Hayrettin Tumani, Maritta Ukkonen, Etienne Urbain, Marie-Sylvie Artaud Uriot, Melanie Ursell, Marta Vachova, Martin Valis, Anneke Van Der Walt, Caspar van Munster, Vincent Van Pesch, Wilma Van Steenbergen, Bart Van Wijmeersch, Patrick Vanderdonckt, Erwin Vanroose, W.I.M. Verhagen, François Viallet, Bert Wagner, Marc Wagner, Ronald Wersching, Stephan Wiehler, Brigitte Wildemann, Barbara Willekens, Christina Willems, Martin Wilson, Jörg Windsheimer, Olga Zapletalová, Uwe Ziebold, François Ziegler
Contributors HB contributed to the study design, patient recruitment, data collection, analysis and interpretation of data, and drafting and revising of the manuscript; he takes full responsibility for the finished article and for access to any data and controlled the decision to publish. LK and HW contributed to the study design, analysis and interpretation of data, and drafting and revising of the manuscript. MT contributed to the study design, patient recruitment, data collection, analysis and interpretation of data, and drafting and revising of the manuscript. TS contributed to the analysis and interpretation of data, and drafting and revising of the manuscript. IC, RK and SJ contributed to the statistical analysis, analysis and interpretation of data, and drafting and revising of the manuscript. NC, P-RH and SL contributed to the analysis and interpretation of data, and drafting and revising of the manuscript.
Funding This study was supported by Biogen. Biogen also provided funding for medical writing support in development of this manuscript. Biogen reviewed the manuscript and provided feedback to the authors. The authors provided their final approval of all content.
Competing interests HB has received compensation for steering committee, advisory board and consultancy fees from Biogen, Merck, Roche, Novartis, Oxford Pharmagenesis and Teva and research support from Biogen, Merck, Novartis, MS Research Australia, NHMRC Australia and the UK MS Trust. LK’s institution (University Hospital Basel) has received the following in the last 3 years and used exclusively for research support at the department: steering committee, advisory board and consultancy fees from Actelion, Alkermes, Almirall, Bayer, Biogen, Celgene/Receptos, df-mp, Excemed, GeNeuro SA, Genzyme, Japan Tobacco, Merck, Minoryx, Mitsubishi Pharma, Novartis, Roche, Sanofi, Santhera, Teva and Vianex, as well as royalties for Neurostatus-UHB products; the Research of the MS Centre in Basel has been supported by grants from Bayer, Biogen, Novartis, the European Union, the Roche Research Foundations, the Swiss MS Society and the Swiss National Research Foundation. HW has received honoraria from AbbVie, Actelion, Alexion, Biogen, Cognomed, Evgen, F. Hoffmann-La Roche, MedDay, Merck Serono, Novartis, Roche Pharma AG, Sanofi Genzyme and Teva and research support from Biogen, GlaxoSmithKline GmbH, Roche Pharma AG and Sanofi Genzyme. MT has received compensation for consulting from Biogen, Merck Serono and Novartis; speaker honoraria from Biogen, Merck Serono, Novartis, Sanofi and Teva; and research grants from Biogen, Merck Serono and Novartis. TS has received honoraria for consultancy and funding for travel from Biogen and Novartis. IC, NC, P-RH and SL are employees of and may hold stock and/or stock options in Biogen. RK and SJ were employees of Biogen at the time of these analyses and may hold stock and/or stock options in Biogen.
Patient consent for publication Obtained.
Ethics approval The study was approved by ethics committees for all participating study centres.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement The datasets generated and/or analysed during the current study are not publicly available. The authors and company are fully supportive of allowing independent assessment and verification of these results. Requests for de-identified data should be made via the established company data-sharing policies and processes as detailed on the website http://clinicalresearch.biogen.com/ .