MISTIC: MIS-C Comparative Effectiveness Study

Sponsor

University of California, San Diego (Other)

Overall Status

Recruiting

CT.gov ID

NCT04898231

Collaborator

Children's Hospital of Michigan (Other)

180

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

2.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Multisystem Inflammatory Syndrome-Children	Drug: Infliximab Drug: Anakinra Drug: Methylprednisolone	Phase 2/Phase 3

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 Design

Study Type:

Interventional

Anticipated Enrollment :

180 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

This is a randomized trial of 3 treatment armsThis is a randomized trial of 3 treatment arms

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Dec 22, 2020

Anticipated Primary Completion Date :

Dec 22, 2023

Anticipated Study Completion Date :

Dec 22, 2023

Arms and Interventions

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 Inflectra Remsima
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

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

Inflectra

Remsima

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

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

Other Names:

Kineret

Outcome Measures

Primary Outcome Measures

Anti-inflammatory treatment regimen lowest rate of second randomization [1 week]
To determine the anti-inflammatory treatment from first randomization that has the lowest rate of second randomization.

Secondary Outcome Measures

Anti-inflammatory treatment regimen decrease CRP from baseline [6 weeks]
To determine the anti-inflammatory treatment regimen that results in the most rapid reduction by 50 percent in the CRP level compared to baseline (pre-IVIG).
Anti-inflammatory treatment regimen quickest return of left ventricular ejection fraction [6 weeks]
To determine the anti-inflammatory treatment regimen that results in the most rapid return to a sustained left ventricular ejection fraction of at least 55 percent from the start of the IVIG infusion.
Anti-inflammatory treatment regimen fewest adverse events [6 weeks]
To determine the anti-inflammatory treatment regimen that results in the fewest serious adverse events attributed to study drug.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 20 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

An individual aged <21 years presenting with
Fever (>38.0°C for ≥24 hours; may be by subjective report) AND
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

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
No alternative plausible diagnoses based on clinical judgement AND
Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or suspected COVID-19 exposure AND
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:

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