Multisystem Inflammatory Syndrome-Children
Conditions
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.
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.
Interventions
DRUGInfliximab
Infliximab will be administered as a single IV dose of 10 mg/kg over 2 hours.
DRUGAnakinra
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.
DRUGMethylprednisolone
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.
Sponsors
Children's Hospital of Michigan
University of California, San Diego
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is a randomized trial of 3 treatment arms
Eligibility
Sex/Gender
ALL
Age
No minimum to 20 Years
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Needing Additional Anti-inflammatory Therapy Within the First Week of First Randomization | 1 week | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | 6 weeks | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Infliximab Infliximab will be administered as a single IV dose of 10 mg/kg over 2 hours.
Infliximab: Infliximab will be administered as a single IV dose of 10 mg/kg over 2 hours. | 25 |
| 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.
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. | 24 |
| 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.
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. | 24 |
| Total | 73 |
Baseline characteristics
| Characteristic | Methylprednisilone (steroids) | Anakinra | Total | Infliximab |
|---|---|---|---|---|
| Age, Categorical <=18 years | 24 Participants | 24 Participants | 73 Participants | 25 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 7.95 years | 6.78 years | 7.64 years | 7.1 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 4 Participants | 10 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 1 Participants | 6 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 20 Participants | 19 Participants | 54 Participants | 15 Participants |
| Region of Enrollment United States | 24 participants | 24 participants | 73 participants | 25 participants |
| Sex: Female, Male Female | 11 Participants | 9 Participants | 28 Participants | 8 Participants |
| Sex: Female, Male Male | 13 Participants | 15 Participants | 45 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 24 | 0 / 22 |
| other Total, other adverse events | 0 / 25 | 16 / 24 | 1 / 22 |
| serious Total, serious adverse events | 0 / 25 | 0 / 24 | 0 / 22 |
Outcome results
Primary
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.
Time frame: 1 week
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Infliximab | Number of Participants Needing Additional Anti-inflammatory Therapy Within the First Week of First Randomization | 10 Participants |
| Methylprednisilone (steroids) | Number of Participants Needing Additional Anti-inflammatory Therapy Within the First Week of First Randomization | 10 Participants |
| Anakinra | Number of Participants Needing Additional Anti-inflammatory Therapy Within the First Week of First Randomization | 14 Participants |
Secondary
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.
Time frame: 6 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Infliximab | Number of Participants With Adverse Events | 0 Participants |
| Methylprednisilone (steroids) | Number of Participants With Adverse Events | 16 Participants |
| Anakinra | Number of Participants With Adverse Events | 1 Participants |