Article Text

Download PDFPDF
Original research
Emulating randomised clinical trials in relapsing-remitting multiple sclerosis with non-randomised real-world evidence: an application using data from the MSBase Registry
  1. Alessio Signori1,
  2. Marta Ponzano1,
  3. Tomas Kalincik2,3,
  4. Serkan Ozakbas4,
  5. Dana Horakova5,
  6. Eva Kubala Havrdova5,
  7. Raed Alroughani6,
  8. Francesco Patti7,
  9. Jens Kuhle8,
  10. Guillermo Izquierdo9,
  11. Sara Eichau9,
  12. Bassem Yamout10,
  13. Samia Joseph Khoury11,12,
  14. Rana Karabudak13,
  15. Pierre Grammond14,
  16. Pierre Duquette15,
  17. Izanne Roos16,
  18. Helmut Butzkueven17,18,
  19. Anneke van der Walt17,18,
  20. Maria Pia Sormani1,19
  1. 1 Department of Health Sciences, Section of Biostatistics, University of Genova, Genoa, Italy
  2. 2 Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
  3. 3 Department of Neurology, Royal Melbourne Hospital, Melbourne, Victoria, Australia
  4. 4 Dokuz Eylul University, İzmir, Turkey
  5. 5 Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic
  6. 6 Amiri Hospital, Kuwait City, Kuwait
  7. 7 Department of Neuroscience, University of Catania Department of Surgical and Medical Sciences and Advanced Technologies 'G.F. Ingrassia', Catania, Italy
  8. 8 Department of Neurology, University Hospital Basel, Basel, Switzerland
  9. 9 Hospital Universitario Virgen Macarena, Seville, Spain
  10. 10 American University of Beirut Medical Center, Beirut, Lebanon
  11. 11 Nehme and Therese Tohme Multiple Sclerosis Center, American University of Beirut Medical Center, Beirut, Lebanon
  12. 12 American University of Beirut, Beirut, Lebanon
  13. 13 Department of Neurology, Hacettepe University Faculty of Medicine, Ankara, Turkey
  14. 14 Hotel-Dieu de Levis, Levis, Quebec, Canada
  15. 15 CHUM MS Center and Department of Neuroscience, Université de Montréal, Montreal, Québec, Canada
  16. 16 Clinical Outcomes Research Unit, The University of Melbourne Department of Medicine Royal Melbourne Hospital, Parkville, Victoria, Australia
  17. 17 Monash University Central Clinical School, Melbourne, Victoria, Australia
  18. 18 Alfred Hospital, Melbourne, Victoria, Australia
  19. 19 Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Policlinico San Martino, Genoa, Italy
  1. Correspondence to Dr Alessio Signori, Department of Health Sciences, University of Genoa, Genova, Liguria, Italy; alessio.signori{at}


Background To mimic as closely as possible a randomised controlled trial (RCT) and calibrate the real-world evidence (RWE) studies against a known treatment effect would be helpful to understand if RWE can support causal conclusions in selected circumstances. The aim was to emulate the TRANSFORMS trial comparing Fingolimod (FTY) versus intramuscular interferon β-1a (IFN) using observational data.

Methods We extracted from the MSBase registry all the patients with relapsing-remitting multiple sclerosis (RRMS) collected in the period 2011–2021 who received IFN or FTY (0.5 mg) and with the same inclusion and exclusion criteria of the TRANSFORMS RCT. The primary endpoint was the annualised relapse rate (ARR) over 12 months. Patients were 1:1 propensity-score (PS) matched. Relapse-rate ratio (RR) was calculated by mean of a negative binomial regression.

Results A total of 4376 patients with RRMS (1140 in IFN and 3236 in FTY) were selected. After PS, 856 patients in each group were matched. The ARR was 0.45 in IFN and 0.25 in FTY with a significant difference between the two groups (RR: 0.55, 95% CI: 0.45 to 0.68; p<0.001). The result of the emulation was very similar and fell within the 95% CI of that observed in the RCT (RR: 0.49, 95% CI: 0.37 to 0.64; p<0.001) with a standardised difference of 0.66 (p=0.51).

Conclusions By applying the same inclusion and exclusion criteria used in the RCT and employing appropriate methodology, we successfully replicated the RCT results with only minor discrepancies. Also, even if the confounding bias cannot be fully eliminated, conducting a rigorous target trial emulation could still yield valuable insights for comparative effectiveness research.

  • multiple sclerosis
  • statistics
  • randomised trials
  • epidemiology
  • neuroepidemiology

Data availability statement

Data are available upon reasonable request. MSBase is a data processor, and warehouses data from individual principal investigators who agree to share their datasets on a project-by-project basis. Data access to external parties can be granted at the sole discretion of each MSBase Principal Investigator (the data controllers), who will need to be approached individually for permission.

Statistics from

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Data availability statement

Data are available upon reasonable request. MSBase is a data processor, and warehouses data from individual principal investigators who agree to share their datasets on a project-by-project basis. Data access to external parties can be granted at the sole discretion of each MSBase Principal Investigator (the data controllers), who will need to be approached individually for permission.

View Full Text


  • AS and MP are joint first authors.

  • AS and MP contributed equally.

  • Contributors Guarantor of the study: AS. AS and MP conceptualised and designed the study, carried out statistical analysis, interpreted the results, have drafted and edited the manuscript. MPS conceptualised and designed the study, interpreted the results and edited the manuscript. TK, SO, DH, EKH, RA, FP, JK, GI, SE, BY, SJK, RK, PG, PD, IR, HB and AvdW have recruited patients, contributed data and have edited the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests MP, SO, BY, RK, AYS have nothing to disclose; AS received speaker’s honoraria from Chiesi and grant from MSBase outside from this work. TK served on scientific advisory boards for BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Sanofi-Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck. DH received speaker honoraria and consulting fees from Biogen, Merck, Teva, Roche, Sanofi Genzyme, and Novartis, as well as support for research activities from Biogen and Czech Minsitry of Education [project Progres Q27/LF1]. EKH received honoraria/research support from Biogen, Merck Serono, Novars, Roche, and Teva; has been member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novars, and Sanofi Genzyme; has been supported by the Czech Ministry of Educaon research project PROGRES Q27/LF1. RA received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche and Sanofi-Genzyme. JK received speaker fees, research support, travel support, and/or advisory boards Swiss Multiple Sclerosis Society, SNSF, University of Basel, Progressive Multiple Sclerosis Alliance, Bayer, Biogen, Celgene, Merck, Novartis, Octave Bioscience, Roche, Sanofi. FP served an advisory board Alexion, Almirall, Bayer, Biogen, Bristol Meyers&Squibb, Merck, Novartis and Roche; he also received personal fee for speaking activities; he also received research grants by Biogen, Merck, Roche, FISM, Reload Onlus and MIUR Ministero Italiano della Ricerca e della Università. GI received speaking honoraria from Biogen, Novartis, Sanofi, Merck, Roche, Almirall and Teva. SJK received compensation for scientific advisory board activity from Merck and Roche and for serving on IDMC for Biogen. SE received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche and Teva. PG has served in advisory boards for Novartis, EMD Serono, Roche, Biogen idec, Sanofi Genzyme, Pendopharm and has received grant support from Genzyme and Roche, has received research grants for his institution from Biogen idec, Sanofi Genzyme, EMD Serono. PD served on editorial boards and has been supported to attend meetings by EMD, Biogen, Novartis, Genzyme, and TEVA Neuroscience. He holds grants from the CIHR and the MS Society of Canada and has received funding for investigator-initiated trials from Biogen, Novartis, and Genzyme. HB has received institutional (Monash University) funding from Biogen, F. Hoffmann-La Roche Ltd, Merck, Alexion, CSL, and Novartis; has carried out contracted research for Novartis, Merck, F. Hoffmann-La Roche Ltd and Biogen; has taken part in speakers’ bureaus for Biogen, Genzyme, UCB, Novartis, F. Hoffmann-La Roche Ltd and Merck; has received personal compensation from Oxford Health Policy Forum for the Brain Health Steering Committee. AV served on advisory boards for Novartis, Biogen, Merck and Roche and NervGen. She received unrestricted research grants from Novartis, Biogen, Merck and Roche. She is currently a co-Principal investigator on a co-sponsored observational study with Roche, evaluating a Roche-developed smartphone app, Floodlight-MS. She has received speaker’s honoraria and travel support from Novartis, Roche, Biogen and Merck. She serves as the Chief operating Officer of the MSBase Foundation (not for profit). Her primary research support is from the National Health and Medical Research Council of Australia and MS Research Australia. MPS received consulting fees from Roche, Biogen, Merck, Novartis, Sanofi, Celgene, Immunic, Geneuro, GSK, Medday; received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Roche, Biogen Merck, Novartis, Sanofi, Celgene; participated on a Data Safety Monitoring Board or Advisory Board for Roche, Sanofi, Novartis, Merck.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.