Sistema de Salut de Catalunya
Institut Català de la Salut
[Montobbio N, Bovis F, Signori A, Schiavetti I, Ponzano M] Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy. [Carmisciano L] Department of Clinical and Experimental Medicine, University of Pisa, Italy. [Tur C] Centre d’Esclerosi Múltiple de Catalunya (CEMCAT), Barcelona, Spain. Universitat Autònoma de Barcelona, Barcelona, Spain
Vall d'Hebron Barcelona Hospital Campus
2025-09-03T06:45:41Z
2025-09-03T06:45:41Z
2025-07
Multiple sclerosis; Treatment effect bias; Progression independent of relapse activity (PIRA)
Esclerosi múltiple; Biaix de l'efecte del tractament; Progressió independent de l'activitat de recaiguda
Esclerosis múltiple; Sesgo del efecto del tratamiento; Progresión independiente de la actividad de recaída
Background: Interest in progression independent of relapse activity (PIRA) as an endpoint in multiple sclerosis (MS) clinical trials is surging. However, established definitions of PIRA may produce biased treatment effect estimates in the presence of a treatment-induced relapse reduction. Methods: We applied different definitions of PIRA to pooled data from the OPERA I/II clinical trials (clinicaltrials.gov identifiers: NCT01247324, NCT01412333). Treatment effects on PIRA according to different methods were quantified by hazard ratios (HRs) and risk ratios (RRs). Next, we evaluated the bias in each definition using synthetic Expanded Disability Status Scale (EDSS) data simulating a control and an experimental arm with varying treatment effects on relapses and on PIRA. We quantified the bias by comparing the estimated effect on PIRA with the known true effect. Findings: The pooled OPERA I/II population included 1656 participants. Estimated treatment effects on PIRA varied from a non-significant HR of 0.83 (CI = 0.66-1.04) to an HR of 0.73 (CI = 0.59-0.90) depending on the definition used. Follow-up analyses on simulated data (n = 800 per arm) revealed an underestimation of the true treatment effect on PIRA when using established definitions, with increasing bias as treatment effect on relapses increased. Defining PIRA as complementary to relapse-associated worsening (RAW) provided a less biased and operationally simple alternative. Interpretation: For clinical trials with PIRA as an endpoint, we suggest a "complementary" definition of PIRA, relying on accurate exclusion of RAW promoted by appropriate visit timing.
Italian Ministry of University and Research.
Article
Published version
English
Esclerosi múltiple - Tractament; Esclerosi múltiple - Prognosi; Esclerosi múltiple - Recaiguda; DISEASES::Nervous System Diseases::Autoimmune Diseases of the Nervous System::Demyelinating Autoimmune Diseases, CNS::Multiple Sclerosis; Other subheadings::Other subheadings::Other subheadings::/drug therapy; DISEASES::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Recurrence; DISEASES::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Disease Attributes::Disease Progression; HEALTH CARE::Health Care Quality, Access, and Evaluation::Quality of Health Care::Epidemiologic Factors::Bias; ENFERMEDADES::enfermedades del sistema nervioso::enfermedades autoinmunitarias del sistema nervioso::enfermedades autoinmunes desmielinizantes del SNC::esclerosis múltiple; Otros calificadores::Otros calificadores::Otros calificadores::/farmacoterapia; ENFERMEDADES::afecciones patológicas, signos y síntomas::procesos patológicos::atributos de la enfermedad::recurrencia; ENFERMEDADES::afecciones patológicas, signos y síntomas::procesos patológicos::atributos de la enfermedad::progresión de la enfermedad; ATENCIÓN DE SALUD::calidad, acceso y evaluación de la atención sanitaria::calidad de la atención sanitaria::factores epidemiológicos::sesgo
Elsevier
eBioMedicine;117
https://doi.org/10.1016/j.ebiom.2025.105802
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
