Multicenter Randomized Trial of Methylprednisolone vs. Intravenous Immunoglobulins to Treat the Pediatric Inflammatory Multisystem Syndrome—Temporally Associated With SARS-CoV-2 (PIMS-TS): Protocol of the Swissped RECOVERY Trial

Abstract

IntroductionIn 2020, a new disease entitled Pediatric Inflammatory Multisystem Syndrome temporally associated with COVID-19 (PIMS-TS), or Multisystem Inflammatory Syndrome in Children (MIS-C), emerged, with thousands of children affected globally. There is no available evidence based on randomized controlled trials (RCT) to date on the two most commonly used immunomodulatory treatments, intravenous immunoglobulins (IVIG) and corticosteroids. Therefore, the Swissped RECOVERY trial was conducted to assess whether intravenous (IV) methylprednisolone shortens hospital length of stay compared with IVIG.Methods and AnalysisSwissped RECOVERY is an ongoing investigator-initiated, open-label, multicenter two-arm RCT in children and adolescents <18 years hospitalized with a diagnosis of PIMS-TS. The trial is recruiting at 10 sites across Switzerland. Patients diagnosed with PIMS-TS are randomized 1:1 to methylprednisolone IV (10 mg/kg/day for 3 days) or IVIG (2 g/kg as a single dose). The primary outcome is hospital length of stay censored at day 28, death, or discharge (whichever is first). The target total sample size is ~80 patients 1:1 randomized to each study arm. Ancillary and exploratory studies on inflammation, vaccination acceptance and coverage, long-term outcomes, and healthcare costs are pre-planned.SignificanceCurrently, robust trial evidence for the treatment of PIMS-TS is lacking, with a controversy surrounding the use of corticosteroids vs. IVIG. This trial will provide evidence for the effectiveness and safety of these two treatments.Ethics and DisseminationThe study protocol, which was designed based on the U.K. RECOVERY trial, the patient information and consent forms, and other study-specific study documents were approved by the local ethics committees (Project ID: 2021-00362).Registration DetailsThe study is registered on the Swiss National Clinical Trials Portal (SNCTP000004720) and Clinicaltrials.gov (NCT 04826588).

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

“…While we did not identify a relevant difference in effectiveness between the first treatment with IVMP or IVIG in the main trial analysis taking a standard intention-to-treat approach,6 we noted the high proportion of participants receiving non-randomised anti-inflammatory treatment (41/75, 55%). With 55% of patients receiving non-randomised anti-inflammatory treatment, there is a risk of many patients converging on a single treatment or being exposed to both treatments, reducing the informativeness of the trial.…”

“…Of these, 75 patients were included in the primary analysis (37 were allocated to IVMP and 38 were allocated to IVIG). Detailed information on the cohort, including baseline characteristics, is presented in the original publication 6…”

COVID-19 Vaccine Acceptance Among Parents of Children With Multisystem Inflammatory Syndrome in Children

“…Detailed information on the cohort, including baseline characteristics, is presented in the original publication. 9 The vaccination questionnaire was completed for 56 children presenting with a MIS-C (74%; 56/75), resulting in 56 patients and 112 parents with available data for this analysis. We have included the patient characteristics from the original manuscript in Table, Supplemental Digital Content 3, http://links.lww.com/INF/F339 (“Total patients”) to observe any important difference that could suggest a bias in our analysis.…”

“…9,10 Cohort characteristics and outcomes have been published previously. 9 Included children were followed until 6 months after randomization, and their families received a questionnaire (Questionnaire, Supplemental Digital Content 2, http://links.lww.com/INF/F338) regarding COVID-19 vaccination at 6 months after hospital discharge. For parents, the criterion for not being opposed to vaccination was having received at least 1 dose of the SARS-CoV-2 vaccine.…”

The Soluble Urokinase Plasminogen Activator Receptor as a Severity Biomarker in Children With Acute COVID-19 or Multisystem Inflammatory Syndrome

“…33,34 Randomized trials evaluating pharmacological therapy in children with COVID-19 or MIS-C are limited. 35 Pediatricians mostly provide supportive care for hospitalized children with COVID-19; supplemental oxygen and ventilatory support, electrolyte support, empiric antibiotics and in some cases thromboprophylaxis. Antiviral therapy and systemic glucocorticoids are recommended only for selected children with severe or critical disease.…”