Kawasaki Disease, Mucocutaneous Lymph Node Syndrome
Conditions
Keywords
Etanercept
Brief summary
The purpose of this study is to determine whether Etanercept (Enbrel) when used in conjunction with IVIG and aspirin, improves treatment response to IVIG in patients with Kawasaki Disease. Funding Source- FDA/OOPD
Detailed description
Kawasaki Disease (KD) is a potentially life threatening acute vasculitis in children with a predilection for involvement of the coronary arteries. Aspirin and Intravenous gamma globulin (IVIG) are principally used for the treatment of the symptoms of Kawasaki Disease. Aspirin reduces inflammation and platelet formation, but has no effect in attenuating the development of coronary abnormalities. Although IVIG reduces inflammation and the prevalence of coronary artery abnormalities, it has a relatively high failure rate of 23-30%, warranting new treatment methods for Kawasaki Disease. We propose a placebo controlled double blinded randomized study to determine if etanercept 0.8 mg/kg subcutaneously (max 25 mg) given three times at weekly intervals starting at initial diagnosis is safe in this patient population and if it is a successful adjunct therapy with IVIG in reducing the incidence of persistent or recurrent fever.
Interventions
DRUGEtanercept
etanercept 0.8 mg/kg subcutaneously (max 50 mg) given three times, once a week for three weeks starting at initial diagnosis.
DRUGPlacebo
Placebo 0.8 mg/kg subcutaneously (max 50 mg) given three times, once a week for three weeks starting at initial diagnosis.
Sponsors
Amgen
Michael Portman
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Approximately 200 subjects will be randomized in a 1:1 ratio to receive Etanercept or Placebo. Subjects are randomized after hospital admission and diagnosis of Kawasaki Disease at eight participating sites. The primary analysis time-point is visit 5 (day 44). Sample size calculation is based on initial IVIG refractory rate at Seattle Children's. Assuming a 17.4% refractory rate in the control group and a 4.3% refractory rate in the Etanercept group, 200 subjects will provide 80% power at a 5% 2-sided type I error rate. Analyses will be based on a modified intention to treat population, including all subjects who were randomized and received at least 1 dose of study drug. Efficacy analyses will be based on randomization assignment, and safety analyses will be based on the treatment actually received. The statistical analysis plan will be finalized prior to database lock and study unblinding.
Eligibility
Sex/Gender
ALL
Age
2 Months to 20 Years
Healthy volunteers
No
Inclusion criteria
* Male Age 2 months to 20 years of age Female Age 2 months to 11 years of age * Provision of Parental Consent * Kawasaki Disease Presentation
Exclusion criteria
* Laboratory Criteria: Any laboratory toxicity, at the time of the screening visit or at any time during the study that in the opinion of the Investigator would preclude participation in the study or: 1. Platelet count \< 100,000/mm3 2. WBC count \< 3,000 cells/mm3 3. Hemoglobin, hematocrit, or red blood cell count outside 30% of the upper or lower limits of normal for the Lab * Subject is currently enrolled in another investigational device or drug trial(s), or subject has received other investigational agent(s) within 28 days of baseline visit. * Female subjects diagnosed with KD 12 years of age and older. * Subjects who have known hypersensitivity to Enbrel or any of its components or who is known to have antibodies to etanercept * Prior or concurrent cyclophosphamide therapy * Prior treatment with any TNF alpha antagonist or steroid within 48 hours prior to initiation of IVIG * Concurrent sulfasalazine therapy * Active severe infections within 4 weeks before screening visit, or between the screening and baseline visits. * SLE, history of multiple sclerosis, transverse myelitis, optic neuritis, or chronic seizure disorder * Known HIV-positive status or known history of any other immuno-suppressing disease. * Any mycobacterial disease or high risk factors for tuberculosis, such as family member with TB or taking INH * Untreated Lyme disease * Severe comorbidities (diabetes mellitus requiring insulin, CHF of any severity, MI, CVA or TIA within 3 months of screening visit, unstable angina pectoris, uncontrolled hypertension (sitting systolic BP \> 160 or diastolic BP \> 100 mm Hg), oxygen-dependent severe pulmonary disease, history of cancer within 5 years \[other than resected cutaneous basal or squamous cell carcinoma or in situ cervical cancer\]) * Exposure to hepatitis B or hepatitis C or high risk factors such as intravenous drug abuse in patient's mother, or history of jaundice (other than neonatal jaundice). SLE, history of multiple sclerosis, transverse myelitis, optic neuritis or chronic seizure disorder. * Use of a live vaccine (Measles Mumps Rubella or Varicella) 30 days prior to or during this study. * Any condition judged by the patient's physician to cause this clinical trial to be detrimental to the patient * History of non-compliance with other therapies * Must not have received immunosuppressive agents for at least three months prior to enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| IVIG Refractory | 42 days after initial dose | The primary outcome is the proportion of subjects who become refractory to IVIG. Subjects requiring 1 dose of IVIG are classified as responders and subjects requiring more than 1 dose are classified as IVIG refractory. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Determine if Etanercept Treatment Alters the Rate of Coronary Artery Dilation and Disease (CAD) at 2 and 6 Weeks After Treatment in Patients With Dilated Coro | 42 days after initial dose | The primary echocardiographic outcome will be the proportion of subjects with improvement defined as (20% change in coronary artery) from the worst findings during the acute study period (scheduled visits from admission to visit 4, including any unscheduled visits) to the primary study outcome time-point at visit 5 (visit 5). This calculation will be based on changes in absolute values and not z-scores as initially planned. Groups will be compared using a logistic model including a binary term for age \< versus \> 1 year. Two aspects of the echo findings will be considered: * Maximum aneurysm size and * Maximum measurements for left main coronary artery (LMCA), left anterior descending artery (LAD) and right coronary artery (RCA). * Change in diameter of each coronary artery will be determined at standard measurement location or aneurysm with the latter taking precedent. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Coronary Artery Dimension by z Score Compared With General Estimating Equation | 6 weeks | Overall change in coronary z score over time determined using General Estimating Equation in patients from baseline within patients. No change or improved defined by 20% change in z score. A Z score normalized for body surface area represents how much larger (or smaller) a measured coronary artery internal diameter by echocardiography is compared to the average coronary artery diameter for a child of the same size (body surface area includes both height and weight). There is no minimum or maximum value. Z score above 2.0 is at least 2 standard deviations above mean for population and is considered abnormal. A decrease in z score is favorable. |
| Overall Change in z Score Over Time in Patients With Dilated Coronary Artery at Baseline Within Patients. | 6 weeks | Overall change in z score over time determined using General Estimating Equation in patients with dilated coronary artery at baseline within patients. Overall change in coronary z score over time determined using General Estimating Equation in patients from baseline within patients. A Z score normalized for body surface area represents how much larger (or smaller) a measured coronary artery internal diameter by echocardiography is compared to the average coronary artery diameter for a child of the same size (body surface area includes both height and weight). There is no minimum or maximum value. Z score above 2.0 is at least 2 standard deviations above mean for population and is considered abnormal. A decrease in z score is favorable. |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm 1 -Etanercept Drug - Treatment with Etanercept as adjunct to standard treatment with IVIG and aspirin
Etanercept: etanercept 0.8 mg/kg subcutaneously (max 50 mg) given three times, once a week for three weeks starting at initial diagnosis. | 100 |
| Arm-2 Placebo Placebo
Placebo: Placebo 0.8 mg/kg subcutaneously (max 50 mg) given three times, once a week for three weeks starting at initial diagnosis. | 101 |
| Total | 201 |
Baseline characteristics
| Characteristic | Arm 1 -Etanercept | Total | Arm-2 Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 100 Participants | 201 Participants | 101 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 3.77 years STANDARD_DEVIATION 2.67 | 3.70 years STANDARD_DEVIATION 2.71 | 3.66 years STANDARD_DEVIATION 2.75 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 19 Participants | 36 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 81 Participants | 165 Participants | 84 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| KD Patients treated with IVIG | 100 Participants | 201 Participants | 101 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 15 Participants | 29 Participants | 14 Participants |
| Race (NIH/OMB) Black or African American | 12 Participants | 21 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 18 Participants | 36 Participants | 18 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 54 Participants | 114 Participants | 60 Participants |
| Region of Enrollment Canada | 16 participants | 32 participants | 16 participants |
| Region of Enrollment United States | 84 participants | 169 participants | 85 participants |
| Sex: Female, Male Female | 34 Participants | 74 Participants | 40 Participants |
| Sex: Female, Male Male | 66 Participants | 127 Participants | 61 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 99 | 0 / 102 |
| other Total, other adverse events | 10 / 99 | 12 / 102 |
| serious Total, serious adverse events | 9 / 99 | 10 / 102 |
Outcome results
Primary
IVIG Refractory
The primary outcome is the proportion of subjects who become refractory to IVIG. Subjects requiring 1 dose of IVIG are classified as responders and subjects requiring more than 1 dose are classified as IVIG refractory.
Time frame: 42 days after initial dose
Population: All patients receiving study drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 -Etanercept | IVIG Refractory | 13 Participants |
| ARM 2 Placebo | IVIG Refractory | 22 Participants |
p-value: 0.1Chi-squared
Secondary
Determine if Etanercept Treatment Alters the Rate of Coronary Artery Dilation and Disease (CAD) at 2 and 6 Weeks After Treatment in Patients With Dilated Coro
The primary echocardiographic outcome will be the proportion of subjects with improvement defined as (20% change in coronary artery) from the worst findings during the acute study period (scheduled visits from admission to visit 4, including any unscheduled visits) to the primary study outcome time-point at visit 5 (visit 5). This calculation will be based on changes in absolute values and not z-scores as initially planned. Groups will be compared using a logistic model including a binary term for age \< versus \> 1 year. Two aspects of the echo findings will be considered: * Maximum aneurysm size and * Maximum measurements for left main coronary artery (LMCA), left anterior descending artery (LAD) and right coronary artery (RCA). * Change in diameter of each coronary artery will be determined at standard measurement location or aneurysm with the latter taking precedent.
Time frame: 42 days after initial dose
Population: All patients receiving study drug with coronary measures improved
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm 1 -Etanercept | Determine if Etanercept Treatment Alters the Rate of Coronary Artery Dilation and Disease (CAD) at 2 and 6 Weeks After Treatment in Patients With Dilated Coro | 56 Participants |
| ARM 2 Placebo | Determine if Etanercept Treatment Alters the Rate of Coronary Artery Dilation and Disease (CAD) at 2 and 6 Weeks After Treatment in Patients With Dilated Coro | 53 Participants |
Comparison: We applied a Generalized Estimating Equation (GEE) model to determine z score change values (see Protocol page 36 in Supplement).p-value: 0.86Regression, Cox
Other Pre-specified
Change in Coronary Artery Dimension by z Score Compared With General Estimating Equation
Overall change in coronary z score over time determined using General Estimating Equation in patients from baseline within patients. No change or improved defined by 20% change in z score. A Z score normalized for body surface area represents how much larger (or smaller) a measured coronary artery internal diameter by echocardiography is compared to the average coronary artery diameter for a child of the same size (body surface area includes both height and weight). There is no minimum or maximum value. Z score above 2.0 is at least 2 standard deviations above mean for population and is considered abnormal. A decrease in z score is favorable.
Time frame: 6 weeks
Population: Includes patients categorized by baseline coronary artery dilation (echocardiography) with stable or improved coronary artery z score
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 -Etanercept | Change in Coronary Artery Dimension by z Score Compared With General Estimating Equation | -0.4 units on a scale | Standard Error 0.122 |
| ARM 2 Placebo | Change in Coronary Artery Dimension by z Score Compared With General Estimating Equation | -0.10 units on a scale | Standard Error 0.159 |
Comparison: General Estimating Equationp-value: 0.83GEE
Comparison: We analyzed change from baseline for both etanercept and placebo. LS mean change J(standard error) reportedp-value: 0.1279GEE
Other Pre-specified
Overall Change in z Score Over Time in Patients With Dilated Coronary Artery at Baseline Within Patients.
Overall change in z score over time determined using General Estimating Equation in patients with dilated coronary artery at baseline within patients. Overall change in coronary z score over time determined using General Estimating Equation in patients from baseline within patients. A Z score normalized for body surface area represents how much larger (or smaller) a measured coronary artery internal diameter by echocardiography is compared to the average coronary artery diameter for a child of the same size (body surface area includes both height and weight). There is no minimum or maximum value. Z score above 2.0 is at least 2 standard deviations above mean for population and is considered abnormal. A decrease in z score is favorable.
Time frame: 6 weeks
Population: KD patients with dilated coronary arteries at baseline (improved or stable)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm 1 -Etanercept | Overall Change in z Score Over Time in Patients With Dilated Coronary Artery at Baseline Within Patients. | -081 score on a scale | Standard Error 0.39 |
| ARM 2 Placebo | Overall Change in z Score Over Time in Patients With Dilated Coronary Artery at Baseline Within Patients. | 0.4 score on a scale | Standard Error 0.81 |
Comparison: General Estimating Equationp-value: 0.03GEE
Comparison: GEE performed to compare with change in coronary z score from baselinep-value: 0.619GEE