Swissped-RECOVERY: masked independent adjudication for the interpretation of non-randomised treatment in a two-arm open-label randomised controlled trial (methylprednisolone vs immunoglobulins) in Paediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 (PIMS-TS) involving 10 secondary and tertiary paediatric hospitals in Switzerland

Abstract

Objectives: In trials of acute severe infections or inflammations frequent administration of non-randomised treatment (ie, intercurrent event) in response to clinical events is expected. These events may affect the interpretation of trial findings. Swissped-RECOVERY was set up as one of the first randomised controlled trials worldwide, investigating the comparative effectiveness of anti-inflammatory treatment with intravenous methylprednisolone or intravenous immunoglobulins in children and adolescents with Paediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 (PIMS-TS). We present one approach towards improving the interpretation of non-randomised treatment in a randomised controlled trial.; Design: This is a pre-planned ancillary analysis of the Swissped-RECOVERY trial, a randomised multicentre open-label two-arm trial.; Setting: 10 Swiss paediatric hospitals (secondary and tertiary care) participated.; Participants: Paediatric patients hospitalised with PIMS-TS.; Interventions: All patient-first intercurrent events, if applicable, were presented to an independent adjudication committee consisting of four international paediatric COVID-19 experts to provide independent clinical adjudication to a set of standardised questions relating to whether additional non-randomised treatments were clinically indicated and disease classification at the time of the intercurrent event.; Results: Of 41 treatments in 75 participants (24/41 (59%) and 17/41 (41%) in the intravenous methylprednisolone and immunoglobulin arms of the trial, respectively), two-thirds were considered indicated. The most common treatment (oral glucocorticoids, 14/41, 35%) was mostly considered not indicated (11/14, 79%), although in line with local guidelines. Intercurrent events among patients with Shock-like PIMS-TS at baseline were mostly considered indicated. A significant proportion of patients with undifferentiated PIMS-TS at baseline were not attributed to the same group at the time of the intercurrent event (6/12 unchanged, 4/12 Kawasaki disease-like, 2/12 Shock-like).; Conclusion: The masked adjudication of intercurrent events contributes to the interpretation of results in open-label trials and should be incorporated in the future.; Trial Registration Numbers: SNCTP000004720 and NCT04826588.; Competing Interests: Competing interests: JAB received grant support paid to the institution from the European and Developing Countries Clinical Trials Partnership (PediCaP, RIA2017MC-2023), Horizon 2020 (NeoIPC, grant 965328), the Swiss National Science Foundation (KIDS-STEP, grant 173532), National Institute for Health Research (CAP-IT, project 13/88/11), Innosuisse (SPEARHEAD flagship grant), the Swiss Personalised Health Network (Secretariat for Education Research and Innovation) (SwissPedHealth, award NDS-2021-911), in the past 36 months; consulting fees paid to the institution from Shionogi, Sandoz, Basilea, and GSK; payments to the institution for presentations, lectures, speakers bureaus, manuscript writing or educational events in the past 36 months from Pfizer, Sandoz and Bayer; participated at independent data monitoring committee boards of Avenir trial (member, expenses), Lakana trial (member, unfunded), CURLY trial (Chair, unfunded) in the past 36 months; is the vice president of the SwissPedNet (unpaid) and leadership of Severe Bacterial Infection and Antimicrobial Resistance working group of the Penta Foundation (unpaid). TW gave presentations for Novartis (payment to the institution) in the past 36 months. AB had received fixed-term consultancy fees from Gilead. KW is supported by the Crick African Network (CAN). The CAN receives its funding from the UK’s Global Challenges Research Fund (MR/P028071/1), the Francis Crick Institute which receives its core funding from Cancer Research UK (FC1001647), the UK Medical Research Council (FC1001647) and the Wellcome Trust (FC1001647). KW is also supported by the South African Medical Research Council with funds received from the National Treasury. PR received grant sup ort from ViiV and consulting fees from MSD. AT received grant support paid to the institution/UCSD from the National Institute of Health and consulted Janssen Pharmaceuticals and Kiniksa with no payment received. All other authors declared no conflicts of interest. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)