Mucocutaneous Lymph Node Syndrome
Conditions
Keywords
Kawasaki disease
Brief summary
Kawasaki disease (KD) is a self-limited illness that affects the heart blood vessels (coronary arteries) of infants and children and is now the most common cause of acquired heart disease in children. A mixture of proteins from human blood (Intravenous immunoglobulin, IVIG) is a treatment that reduces the rate of the major complication of the disease: a bulging of the wall of the coronary arteries called an aneurysm. However, 10-20% of children are resistant to this treatment and the fever returns. These children have the highest rates of aneurysm formation and thus should be treated aggressively. Unfortunately, there are no guidelines for the best secondary treatment for these resistant patients because the problem has never been adequately studied. Most physicians choose either a second infusion of IVIG or an engineered antibody called infliximab that inactivates a molecule that promotes inflammation. This trial will randomize (assign by chance like the flip of a coin) IVIG-resistant patients to receive either a second IVIG infusion or infliximab and the response to treatment will be compared to learn which treatment stops the fever the fastest. In addition, parents and caregivers will provide observations about their child's response to the different treatments.
Detailed description
This is a 3-year (2.75-years of enrollment), Phase III, two-arm, randomized, multi-center, superiority treatment study to compare infliximab to a second intravenous immunoglobulin (IVIG) infusion for treatment of persistent or recrudescent fever in children with KD who fail to become afebrile after the first IVIG infusion. 1. Specific aim 1 will test the hypothesis that infliximab will be superior to a second intravenous immunoglobulin (IVIG) infusion for treatment of persistent or recrudescent fever in children with KD who fail to become afebrile after the first IVIG infusion (resistant KD). Cessation of fever (\<38°C rectally or orally) within 24h of initiation of study treatment infusion will be the primary outcome measure. 2. Specific aim 2 will test the hypothesis that infliximab treatment will result in more rapid resolution of inflammation compared to second IVIG as measured by the change in white blood cell count (WBC), absolute neutrophil count (ANC), and high-sensitivity C-reactive protein (hsCRP) concentration between baseline and 24 hours and 2 weeks following study treatment. 3. Specific aim 3 will test the hypothesis that infliximab treatment will result in a reduction from baseline in coronary artery Zworst score of ≥ 0.05 standard deviation units as compared to second IVIG at 2 weeks following study treatment measured by echocardiography.
Interventions
DRUGIVIG
Subjects randomized to this arm will receive IVIG 2g/kg over 10-12 hours
DRUGInfliximab
Subjects randomized to this arm will receive infliximab 10 mg/kg over 2 hours
Sponsors
Patient-Centered Outcomes Research Institute
University of California, San Diego
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 17 Years
Healthy volunteers
No
Inclusion criteria
* Eligible subjects will be as follows: 1. 4 weeks to 17 years of age, 2. fulfill the American Heart Association case definition for complete or incomplete KD, 3. have had fever (T ≥38°C) for 3 to 10 days prior to initial IVIG treatment, 4. have fever (T ≥38°C orally or rectally) between 36 hours and 7 days after end of the first IVIG infusion without other likely cause
Exclusion criteria
1. Patient treated with infliximab or steroids for present illness (pts who received oral steroids as outpatients prior to KD diagnosis but who otherwise qualify for the study will not be excluded) 2. Known prior infection with tuberculosis, coccidiomycosis, or histoplasmosis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Cessation of Fever Within 24h of Initiation of Study Treatment With no Fever Recurrence Within Next 7 Days. | 7 days | A fever will be considered ≥38°C rectally or orally and ≥ 37.5°C axillary. Cessation of fever within 24h of initiation of study treatment with no fever recurrence within next 7 days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Zworst Score Between Baseline and 2-week (± 4 Days) Echocardiograms | 2 weeks | Zworst score is defined as the largest internal diameter of either the right coronary or left anterior descending arteries normalized for body surface area and expressed as standard deviation units from the mean. A Z-score \>= 2.5 is considered a aneurysm according to the American Heart Association criteria. |
| Total Number of Fever Days (24 Hour Period With a T≥38.0°C) From Enrollment | 7 days | Determine the number of days a participant had a fever once the participant has been enrolled into the study. |
| Duration of Hospitalization | 2 weeks | How long a participant was hospitalized for. |
| Change in White Blood Cell Count (WBC) Between Baseline and 24 Hours and 2 Weeks Following Study Treatment. | 24h | Change in white blood cell count (WBC), between baseline and 24 hours and 2 weeks following study treatment. |
| Change in Absolute Neutrophil Count (ANC) Between Baseline and 24 Hours and 2 Weeks Following Study Treatment. | 24h | Change in absolute neutrophil count (ANC) between baseline and 24 hours and 2 weeks following study treatment. |
| Change in C-reactive Protein (CRP, mg/dL) Concentration Between Baseline and 24 Hours and 2 Weeks Following Study Treatment. | 24h | Change in C-reactive protein (CRP, mg/dL) concentration between baseline and 24 hours and 2 weeks following study treatment. |
| Number of Participants With IVIG and Infliximab Infusion Reactions and Complications | 7 days | Determine any complications and/or reactions to each treatment. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| IVIG Patient will be randomly assigned to receive a second IVIG infusion: 2 g/kg IV over 8-10 hours single infusion
IVIG: Subjects randomized to this arm will receive IVIG 2g/kg over 10-12 hours | 49 |
| Infliximab Patient will be randomly assigned to receive Infliximab 10 mg/kg IV over 2 hours
Infliximab: Subjects randomized to this arm will receive infliximab 10 mg/kg over 2 hours | 54 |
| Total | 103 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Diagnosed with a different disease | 1 | 1 |
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | IVIG | Total | Infliximab |
|---|---|---|---|
| Age, Continuous | 2.1 years | 2.9 years | 3.6 years |
| ANC (absolute neutrophil count | 9384.0 cells | 9062.0 cells | 8449.0 cells |
| CRP (C-reactive protein) | 9.0 mg/dL | 12.0 mg/dL | 14.1 mg/dL |
| ESR (erythrocyte sedimentation rate), | 68.5 mm/h | 63.0 mm/h | 56.5 mm/h |
| Ethnicity (NIH/OMB) Hispanic or Latino | 12 Participants | 29 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 36 Participants | 71 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 2 Participants |
| Illness Day at first IVIG | 6.0 days | 6.0 days | 6.0 days |
| Incomplete KD | 15 Participants | 26 Participants | 11 Participants |
| PLT (platelet count) | 359.5 cells*10^9/L | 349.0 cells*10^9/L | 342.0 cells*10^9/L |
| Race/Ethnicity, Customized Asian | 5 Participants | 11 Participants | 6 Participants |
| Race/Ethnicity, Customized Black or African American | 9 Participants | 19 Participants | 10 Participants |
| Race/Ethnicity, Customized Multi-race | 3 Participants | 9 Participants | 6 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 31 Participants | 60 Participants | 29 Participants |
| Sex: Female, Male Female | 19 Participants | 44 Participants | 25 Participants |
| Sex: Female, Male Male | 30 Participants | 59 Participants | 29 Participants |
| WBC(white blood cells count) | 13.6 cells*10^9/L | 13.0 cells*10^9/L | 12.8 cells*10^9/L |
| zHgb | -2.3 g/dL | -2.3 g/dL | -2.3 g/dL |
| Z-Worst | 1.3 Standard Deviation units | 1.3 Standard Deviation units | 1.1 Standard Deviation units |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 49 | 0 / 54 |
| other Total, other adverse events | 6 / 49 | 14 / 54 |
| serious Total, serious adverse events | 27 / 49 | 10 / 54 |
Outcome results
Primary
Number of Participants With Cessation of Fever Within 24h of Initiation of Study Treatment With no Fever Recurrence Within Next 7 Days.
A fever will be considered ≥38°C rectally or orally and ≥ 37.5°C axillary. Cessation of fever within 24h of initiation of study treatment with no fever recurrence within next 7 days.
Time frame: 7 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IVIG | Number of Participants With Cessation of Fever Within 24h of Initiation of Study Treatment With no Fever Recurrence Within Next 7 Days. | 25 Participants |
| Infliximab | Number of Participants With Cessation of Fever Within 24h of Initiation of Study Treatment With no Fever Recurrence Within Next 7 Days. | 40 Participants |
Secondary
Change in Absolute Neutrophil Count (ANC) Between Baseline and 24 Hours and 2 Weeks Following Study Treatment.
Change in absolute neutrophil count (ANC) between baseline and 24 hours and 2 weeks following study treatment.
Time frame: 24h
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| IVIG | Change in Absolute Neutrophil Count (ANC) Between Baseline and 24 Hours and 2 Weeks Following Study Treatment. | Change ANC (Baseline & 24 hr after study treatment completion | -3398.4 cells |
| IVIG | Change in Absolute Neutrophil Count (ANC) Between Baseline and 24 Hours and 2 Weeks Following Study Treatment. | Change ANC(Baseline & Follow-up visit) | -5853.5 cells |
| Infliximab | Change in Absolute Neutrophil Count (ANC) Between Baseline and 24 Hours and 2 Weeks Following Study Treatment. | Change ANC (Baseline & 24 hr after study treatment completion | -1742 cells |
| Infliximab | Change in Absolute Neutrophil Count (ANC) Between Baseline and 24 Hours and 2 Weeks Following Study Treatment. | Change ANC(Baseline & Follow-up visit) | -4661.0 cells |
Secondary
Change in C-reactive Protein (CRP, mg/dL) Concentration Between Baseline and 24 Hours and 2 Weeks Following Study Treatment.
Change in C-reactive protein (CRP, mg/dL) concentration between baseline and 24 hours and 2 weeks following study treatment.
Time frame: 24h
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| IVIG | Change in C-reactive Protein (CRP, mg/dL) Concentration Between Baseline and 24 Hours and 2 Weeks Following Study Treatment. | Change CRP (Baseline & 24 hr after study treatment completion ) | -4.6 mg/dL |
| IVIG | Change in C-reactive Protein (CRP, mg/dL) Concentration Between Baseline and 24 Hours and 2 Weeks Following Study Treatment. | Change CRP(Baseline & Follow-up visit) | -8.6 mg/dL |
| Infliximab | Change in C-reactive Protein (CRP, mg/dL) Concentration Between Baseline and 24 Hours and 2 Weeks Following Study Treatment. | Change CRP (Baseline & 24 hr after study treatment completion ) | -4.7 mg/dL |
| Infliximab | Change in C-reactive Protein (CRP, mg/dL) Concentration Between Baseline and 24 Hours and 2 Weeks Following Study Treatment. | Change CRP(Baseline & Follow-up visit) | -13.4 mg/dL |
Secondary
Change in White Blood Cell Count (WBC) Between Baseline and 24 Hours and 2 Weeks Following Study Treatment.
Change in white blood cell count (WBC), between baseline and 24 hours and 2 weeks following study treatment.
Time frame: 24h
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| IVIG | Change in White Blood Cell Count (WBC) Between Baseline and 24 Hours and 2 Weeks Following Study Treatment. | Change WBC (Baseline & 24 hr after study treatment completion) | -2.05 cells* 10^9/L |
| IVIG | Change in White Blood Cell Count (WBC) Between Baseline and 24 Hours and 2 Weeks Following Study Treatment. | Change WBC (Baseline & Follow-up Visit ) | -4.9 cells* 10^9/L |
| Infliximab | Change in White Blood Cell Count (WBC) Between Baseline and 24 Hours and 2 Weeks Following Study Treatment. | Change WBC (Baseline & 24 hr after study treatment completion) | 0.15 cells* 10^9/L |
| Infliximab | Change in White Blood Cell Count (WBC) Between Baseline and 24 Hours and 2 Weeks Following Study Treatment. | Change WBC (Baseline & Follow-up Visit ) | -3.5 cells* 10^9/L |
Secondary
Change in Zworst Score Between Baseline and 2-week (± 4 Days) Echocardiograms
Zworst score is defined as the largest internal diameter of either the right coronary or left anterior descending arteries normalized for body surface area and expressed as standard deviation units from the mean. A Z-score \>= 2.5 is considered a aneurysm according to the American Heart Association criteria.
Time frame: 2 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IVIG | Change in Zworst Score Between Baseline and 2-week (± 4 Days) Echocardiograms | -0.31 Standard Deviation units |
| Infliximab | Change in Zworst Score Between Baseline and 2-week (± 4 Days) Echocardiograms | -0.01 Standard Deviation units |
Secondary
Duration of Hospitalization
How long a participant was hospitalized for.
Time frame: 2 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IVIG | Duration of Hospitalization | 4 days |
| Infliximab | Duration of Hospitalization | 2.5 days |
Secondary
Number of Participants With IVIG and Infliximab Infusion Reactions and Complications
Determine any complications and/or reactions to each treatment.
Time frame: 7 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| IVIG | Number of Participants With IVIG and Infliximab Infusion Reactions and Complications | 1 Participants |
| Infliximab | Number of Participants With IVIG and Infliximab Infusion Reactions and Complications | 2 Participants |
Secondary
Total Number of Fever Days (24 Hour Period With a T≥38.0°C) From Enrollment
Determine the number of days a participant had a fever once the participant has been enrolled into the study.
Time frame: 7 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| IVIG | Total Number of Fever Days (24 Hour Period With a T≥38.0°C) From Enrollment | 2 days |
| Infliximab | Total Number of Fever Days (24 Hour Period With a T≥38.0°C) From Enrollment | 1 days |