MIS-C Comparative Effectiveness Study (MISTIC)

Multisystem Inflammatory Syndrome Therapies in Children (MISTIC) Comparative Effectiveness Study

In March 2020, children exposed to the virus that causes the COVID-19 illness, SARS-CoV-2, presented with fever and significant inflammation about a month after exposure to the virus. Some children were sick enough to require care in the intensive care unit for what came to be known as Multisystem Inflammatory Syndrome-Children (MIS-C).The clinical presentation shared many features with Kawasaki disease (KD), a self-limited inflammation that can cause ballooning of the arteries of the heart. Thus, physicians reached for many of the therapies used to treat children with KD. Despite the surge of COVID-19 cases and children continuing to present with MIS-C, there are no data that guide the choice of therapy. Thus, the investigators have designed a study to determine which combination of therapies is most effective in helping children with MIS-C recover quickly.

Study Overview

• Status: Completed
• Conditions: Multisystem Inflammatory Syndrome-Children
• Intervention / Treatment: Drug: Infliximab; Drug: Methylprednisolone; Drug: Anakinra

Detailed Description

This study is a multi-site, randomized, pragmatic, comparative effectiveness study of children with MIS-C. The current standard of care is that all MIS-C patients are initially treated with IVIG and receive additional therapy if they are severely ill or do not improve clinically. This study design will randomize subjects who have received IVIG but clinically warrant further anti-inflammatory therapy to one of three treatment arms (infliximab, steroids or anakinra) and allow for re-randomization to one of the two remaining arms if clinically warranted.

• Study Type: Interventional
• Enrollment (Actual): 73
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • San Diego, California, United States, 92123
      • Rady Children's Hospital
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Children's Hospital Michigan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 20 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. An individual aged <21 years presenting with

   1. Fever (>38.0°C for ≥24 hours; may be by subjective report) AND

   2. Two or more of the following (from two different systems; e.g. one from cardiac and one from mucocutaneous):

      Cardiac

      • Hypotension
      • Shock
      • Arrhythmia
      • Tachycardia
      • Left ventricular ejection fraction <55%
      • Valvulitis
      • Coronary artery enlargement (LAD or RCA Z-score ≥ 2.5)
      • Pericardial effusion Gastrointestinal
      • Diarrhea
      • Nausea/vomiting
      • Significant abdominal pain Immunologic
      • Lymphadenopathy (unilateral cervical or diffuse) Mucocutaneous
      • Bilateral conjunctival injection
      • Extremity swelling or erythema
      • Rash
      • Lip erythema/Strawberry tongue Neurologic
      • Altered mental status
      • Focal neurological deficits
      • Headache
      • Meningismus
   3. Laboratory evidence of inflammation, including but not limited to, an elevated C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fibrinogen, procalcitonin, D-dimer, ferritin, lactic acid dehydrogenase (LDH), neutrophilia, lymphopenia or hypoalbuminemia AND
   4. No alternative plausible diagnoses based on clinical judgement AND
   5. Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or suspected COVID-19 exposure AND
   6. Parent or legal guardian (or self if at least 18 years old) able and willing to provide informed consent and subject willing and able to provide assent when appropriate.

Exclusion Criteria:

1. Known immunodeficiency
2. Pre-existing medical condition that precludes receiving one or more of the study medications (e.g. TB, drug allergy to study medication).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Infliximab; Infliximab will be administered as a single IV dose of 10 mg/kg over 2 hours.	Drug: Infliximab; Infliximab will be administered as a single IV dose of 10 mg/kg over 2 hours.; Other Names: Remicade; Remsima; Inflectra
Active Comparator: Methylprednisilone (steroids); Methylprednisilone (steroids) will be administered as 2 mg/kg IV or orally divided every 12 hours. At the time of hospital discharge the patient will be given a steroid taper that will take at least 3 weeks to complete.	Drug: Methylprednisolone; Methylprednisilone (steroids) will be administered as 2 mg/kg IV or orally divided every 12 hours. At the time of hospital discharge the patient will be given a steroid taper that will take at least 3 weeks to complete.; Other Names: Steriods
Active Comparator: Anakinra; Anakinra will be administered at a dose of 8 mg/kg/day IV or SQ with 100 mg every 6 hours as the max dose. This is discontinued with a taper during the hospitalization over 2-4 days once a patient is stable with significantly improved clinical course and laboratory profile.	Drug: Anakinra; Anakinra will be administered at a dose of 8 mg/kg/day IV or SQ with 100 mg every 6 hours as the max dose. This is discontinued with a taper during the hospitalization over 2-4 days once a patient is stable with significantly improved clinical course and laboratory profile.; Other Names: Kineret

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Needing Additional Anti-inflammatory Therapy Within the First Week of First Randomization	The three arms of the study will be compared to see which initial randomization arm (infliximab, anakinra or steroids) has the lowest rate of additional anti-inflammatory therapy within the first week of first randomization.	1 week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events	Of the three initial randomization arms (infliximab, steroids or anakinra), the rate of adverse events will be compared. The goal is to determine which arm has the lowest rate of adverse events. The AEs reported in the AE section include: All Cause, SAE and Others.	6 weeks

Collaborators and Investigators

• Sponsor: University of California, San Diego
• Collaborators: Children's Hospital of Michigan
• Investigators: Principal Investigator: Adriana Tremoulet, MD, MAS, University of California, San Diego

Publications and helpful links

General Publications

• Jain S, He F, Brown K, Burns JC, Tremoulet AH. Multisystem Inflammatory Syndrome therapies in children (MISTIC): A randomized trial. Contemp Clin Trials Commun. 2023 Apr;32:101060. doi: 10.1016/j.conctc.2023.101060. Epub 2023 Jan 20.

Study record dates

Study Major Dates

• Study Start (Actual): December 22, 2020
• Primary Completion (Actual): December 22, 2023
• Study Completion (Actual): April 25, 2024

Study Registration Dates

• First Submitted: May 13, 2021
• First Submitted That Met QC Criteria: May 20, 2021
• First Posted (Actual): May 24, 2021

Study Record Updates

• Last Update Posted (Estimated): November 4, 2025
• Last Update Submitted That Met QC Criteria: October 14, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Disease; Syndrome; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Polycyclic Compounds; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Intercellular Signaling Peptides and Proteins; Pregnadienetriols; Cytokines; Prednisolone; Infliximab; Methylprednisolone; Interleukin 1 Receptor Antagonist Protein; CT-P13
• Other Study ID Numbers: 202109

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes