[TEMPORARILY RENAMED] Immunomodulatory therapy in children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS, MIS-C; RECOVERY): a randomised, controlled, open-label, platform trial

Faust, Saul N; Jones, Christine E; Staplin, Natalie; Whittaker, Elizabeth; Jaki, Thomas; Juszczak, Ed; Spata, Enti; Wan, Mandy; Bamford, Alasdair; Dmitri, Paul; Finn, Adam; Furness, John; Ramanan, Athimalaipet V; Gale, Chris; Cathie, Katrina; Drysdale, Simon B; Bernatoniene, Jolanta; Murray, Clare; Roehr, Charles C; Fleming, Paul F; Riordan, Andrew; Bandi, Srini; Jyothish, Deepthi; Evans, Jennifer; Emonts, Marieke; Kelly, Dominic; Pathan, Nazima; Davies, Patrick; Hague, Rosie; Pollock, Louisa; Sample, Malcolm G; Peto, Leon; Kenneth Baillie, J; Buch, Maya; Jeffery, Katie; Knight, Marian; Shen Lim, Wei; Montgomery, Alan; Mukherjee, Aparna; Mumford, Andrew; Rowan, Kathryn; Thwaites, Guy; Mafham, Marion; Emberson, Jonathan R; Landray, Martin J; Horby, Peter W; Haynes, Richard

Abstract

Background

Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS), also known as multisystem inflammatory syndrome in children (MIS-C) emerged in April, 2020. The paediatric comparisons within the RECOVERY trial aimed to assess the effect of intravenous immunoglobulin or corticosteroids compared with usual care on duration of hospital stay for children with PIMS-TS and to compare tocilizumab (anti-IL-6 receptor monoclonal antibody) or anakinra (anti-IL-1 receptor antagonist) with usual care for those with inflammation refractory to initial treatment.

Methods

We did this randomised, controlled, open-label, platform trial in 51 hospitals in the UK. Eligible patients were younger than 18 years and had been admitted to hospital for PIMS-TS. In the first randomisation, patients were randomly assigned (1:1:1) to usual care (no additional treatments), usual care plus methylprednisolone (10mg/kg per day for 3 consecutive days), or usual care plus intravenous immunoglobulin (a single dose of 2 g/kg). If further anti-inflammatory treatment was considered necessary, children aged at least 1 year could be considered for a second randomisation, in which patients were randomly assigned (1:2:2) to usual care, intravenous tocilizumab (12 mg/kg in patients <30 kg; 8mg/kg in patients ≥30 kg, up to a maximum dose of 800 mg), or subcutaneous anakinra (2 mg/kg once per day in patients ≥10 kg). Randomisation was by use of a web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was duration of hospital stay. Analysis was by intention to treat. For treatments assessed in each randomisation, a single Bayesian framework assuming uninformative priors for treatment was used to jointly assess the efficacy of each intervention compared with usual care. The trial was registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936).

Findings

Between May 18, 2020, and Jan 20, 2022, 237 children with PIMS-TS were enrolled and included in the intention-to-treat analysis. Of the 214 patients who entered the first randomisation, 73 were assigned to receive intravenous immunoglobulin, 61 methylprednisolone, and 80 usual care. Of the 70 children who entered the second randomisation (including 23 who did not enter the first randomisation), 28 were assigned to receive tocilizumab, 14 anakinra, and 28 usual care. Mean age was 9·5 years (SD 3·8) in the randomisation and 9·6 years (3·6) in the second randomisation. 118 (55%) of 214 patients in the first randomisation and 39 (56%) of 70 patients in the second randomisation were male. 130 (55%) of 237 patients were Black, Asian, or minority ethnic, and 105 (44%) were White. Mean duration of hospital stay was 7·4 days (SD 0·4) in children assigned to intravenous immunoglobulin and 7·6 days (0·4) in children assigned to usual care (difference –0·1 days, 95% credible interval [CrI] –1·3 to 1·0; posterior probability 59%). Mean duration of hospital stay was 6·9 days (SD 0·5) in children assigned to methylprednisolone (difference from usual care –0·7 days, 95% CrI –1·9 to 0·6; posterior probability 87%). Mean duration of hospital stay was 6·6 days (SD 0·7) in children assigned to second-line tocilizumab and 9·9 days (0·9) in children assigned to usual care (difference –3·3 days, 95% CrI –5·6 to –1·0; posterior probability >99%). Mean duration of hospital stay was 8·5 days (SD 1·2) in children assigned to anakinra (difference from usual care –1·4 days, 95% CrI –4·3 to 1·8; posterior probability 84%). Two persistent coronary artery aneurysms were reported among patients assigned to usual care in the first randomisation. There were few cardiac arrythmias, bleeding, or thrombotic events in any group. Two children died; neither was considered related to study treatment.

Interpretation

Moderate evidence suggests that, compared with usual care, first-line intravenous methylprednisolone reduces duration of hospital stay for children with PIMS-TS. Good evidence suggests that second-line tocilizumab reduces duration of hospital stay for children with inflammation refractory to initial treatment. Neither intravenous immunoglobulin nor anakinra had any effect on duration of hospital stay compared with usual care.

Funding

Medical Research Council and National Institute of Health Research.

• Journal Article Type: Article
• Acceptance Date: Jan 22, 2024
• Online Publication Date: Jan 22, 2024
• Publication Date: Jan 22, 2024
• Deposit Date: Jan 31, 2024
• Journal: The Lancet Child & Adolescent Health
• Electronic ISSN: 2352-4650
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Public URL: https://nottingham-repository.worktribe.com/output/30641496
• Publisher URL: https://linkinghub.elsevier.com/retrieve/pii/S2352464223003164