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.

Alfred Hospital Melbourne Victoria Australia

American University of Beirut Beirut Lebanon

American University of Beirut Medical Center Beirut Lebanon

Amiri Hospital Kuwait City Kuwait

CHUM MS Center and Department of Neuroscience Université de Montréal Montreal Québec Canada

Clinical Outcomes Research Unit The University of Melbourne Department of Medicine Royal Melbourne Hospital Parkville Victoria Australia

Department of Health Sciences Section of Biostatistics University of Genova Genoa Italy

Department of Medicine University of Melbourne Melbourne Victoria Australia

Department of Neurology and Center of Clinical Neuroscience Charles University Prague 1st Faculty of Medicine and General University Hospital Prague Prague Czech Republic

Department of Neurology Hacettepe University Faculty of Medicine Ankara Turkey

Department of Neurology Royal Melbourne Hospital Melbourne Victoria Australia

Department of Neurology University Hospital Basel Basel Switzerland

Department of Neuroscience University of Catania Department of Surgical and Medical Sciences and Advanced Technologies 'G F Ingrassia' Catania Italy

Dokuz Eylul University İzmir Turkey

Hospital Universitario Virgen Macarena Seville Spain

Hotel Dieu de Levis Levis Quebec Canada

Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Policlinico San Martino Genoa Italy

Monash University Central Clinical School Melbourne Victoria Australia

Nehme and Therese Tohme Multiple Sclerosis Center American University of Beirut Medical Center Beirut Lebanon

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