Anakinra, Kawasaki Disease
Conditions
Brief summary
This is a multicenter, open-label, randomized, controlled, interventional trial followed by a long-term observational extension period in patients with Kawasaki Disease (KD) to be treated eitherwith endovenous Immunoglobulins (IVIG-standard treatment) versus anakinra Aim of the study: to demonstrate that anakinra is non-inferior to IVIG in KD, in terms of fever control in the acute phase and development of coronary artery dilation/aneurisms (CAA) within one year from the onset.
Detailed description
This is a multicenter national, open label, randomized, controlled, interventional trial followed by a long-term observational extension period. This is a non-inferiority study Patients who fulfill the eligibility criteria and whose parent/carer (legal representative) has provided informed consent will be randomized 1:1 to receive either 1. IVIG 2g/kg administered in 10-12 hours as per local standard of care (standard treatment) OR 2. Anakinra 2mg/kg intravenously, max 100 mg/dose 4 times/day (investigational treatment) PLUS Aspirin (ASA) 50mg/kg QID until 36 hours from fever disappearance, then switched to low-dose (3-5 mg/Kg once a day) as per standard of care
Interventions
DRUGAnakinra
Patients who fulfill the eligibility criteria a will be randomized 1:1 to receive either 1. IVIG 2g/kg administered in 10-12 hours as per local standard of care (standard treatment) OR 2. Anakinra 2mg/kg intravenously, max 100 mg/dose 4 times/day (investigational treatment) Patients showing fever, between 36 hours and 72 hours from the end of first line treatment will be considered failures. Failures from the investigational treatment arm will receive a dose of IVIG and they will drop from the study. Children who remained afebrile between the 36th and 72nd hour will be considered as responders, and they will proceed into the study. Patients in the standard treatment arm will continue ancillary treatment and follow-up . Patients in the investigational treatment arm will enter the tapering phase.
see previous section
Sponsors
Asst Degli Spedali Civili Di Brescia
IRCCS Burlo Garofolo
Meyer Children's Hospital IRCCS
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Patients who fulfill the eligibility criteria and whose parent/carer (legal representative) have provided informed consent will be randomized 1:1 to receive standard of care IVIG and aspirin or anakinra and ASA. As epidemiological data suggest worse outcomes in terms of CAA for very young patients (age \<1 years), in this setting, proper randomisation 1:1 procedure will be matched for age \< or\> than 1 year
Eligibility
Sex/Gender
ALL
Age
1 Months to 16 Years
Healthy volunteers
No
Inclusion criteria
1. KD defined in at least one of the three following ways as per American Heart Association (AHA) criteria: Fever for at least 5 days in addition to 4 of the following 5 clinical criteria: * bilateral non-purulent conjunctivitis * cervical lymphadenopathy * polymorphous skin rash * changes in lips or mucosa (strawberry tongue, red cracked lips, diffuse erythematous oropharynx) * extremity changes (erythema, oedema of palms and soles in initial phase, and at convalescent stage skin peeling) 2. less than 5 days of fever but all 5 clinical criteria above 3. incomplete KD cases defined as: * children/adolescents (\>1 year old) with fever greater than or equal to 5 days AND at least 2 other compatible clinical criteria as listed above; * OR infants ≤ 1 year old with fever greater than or equal to 7 days without other explanation; AND for both age groups, CRP ≥30 mg/L or erythrocyte sedimentation rate (ESR) ≥40 mm/hr (or both) AND for both age groups EITHER the presence of any 3 or more of: anaemia for age (haemoglobin \< lower limit of normal reference range for local laboratory); platelet count ≥450,000/L or \<140,000/L; albumin \<30 g/L; elevated ALT (\> upper limit of normal reference range for local laboratory); white cell count ≥15,000/L; urine ≥10 white blood cells per high power field iv. OR abnormal echocardiogram compatible with KD but without established CAA, with ≥ 3 of the following suggestive features: decreased left ventricular function, mitral regurgitation, pericardial effusion, or dilated but non-aneurysmal coronary arteries (internal diameter 2≤Z\<2.5; and not meeting the
Exclusion criteria
for aneurysmal change as defined below). 4. To be enrolled children need to show persistent fever ≤7 days 5. Written informed consent from an appropriate legal representative(s), and assent from patients older than 7 years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of patients with treatment response in both treatment arms | 12 months | Response rate |
| Number of patients with CAA (as per Z-scores) at the end of the study period in both treatment arms | 12 months | CAA rate in both arms. CAAs will be classified in accordance with the scheme based on Z scores proposed by AHA. No coronary involvement with Z score \<2, dilation only with Z score \> 2 to \<2.5 or if initially \<2 with a decrease during follow-up ≥1 3, small aneurysm with Z score ≥2.5 to \<5, medium aneurysm with Z score ≥5 to \<10 and absolute dimension \<8 mm and large or giant aneurysm with Z score ≥10, or absolute dimension ≥8 mm |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to normalize coronary artery abnormalities (days) | 90 days | CAAs will be classified in accordance with the scheme based on Z scores proposed by AHA. No coronary involvement with Z score \<2, dilation only with Z score \> 2 to \<2.5 or if initially \<2 with a decrease during follow-up ≥1 3, small aneurysm with Z score ≥2.5 to \<5, medium aneurysm with Z score ≥5 to \<10 and absolute dimension \<8 mm and large or giant aneurysm with Z score ≥10, or absolute dimension ≥8 mm |
| Severity of coronary artery abnormalities (as per Z-score) at the end of follow-up | 24 months | CAAs will be classified in accordance with the scheme based on Z scores proposed by AHA. No coronary involvement with Z score \<2, dilation only with Z score \> 2 to \<2.5 or if initially \<2 with a decrease during follow-up ≥1 3, small aneurysm with Z score ≥2.5 to \<5, medium aneurysm with Z score ≥5 to \<10 and absolute dimension \<8 mm and large or giant aneurysm with Z score ≥10, or absolute dimension ≥8 mm |
| Length of hospitalization in both treatment arms (days) | 90 days | Defined by days of hospitalization from disease onset to discharge |
| Number of days with fever in both treatment arms | 90 days | Fever as defined as T\>38°C |
| Adverse event and severe adverse event developed during the study and follow/up period | 24 months | Medical Dictionary for Regulatory Activities (MeDRA) will be used for the description of adverse events (AEs), according to the regulatory requirements |
| Cumulative drug exposure (mg/kg/day) | 12 months | Calculated for both iv e sc administration |
| Time to stop anakinra (days) | 90 days | From the first administration iv to the last sc |
| Time to reach CRP values<50% from the highest value and to normalize it in both treatment arms (days) | 90 days | CRP values expressed in mg/dL |
Contacts
Primary ContactGabriele Simonini, Prof
Backup ContactMaria Vincenza Mastrolia, MD
Outcome results
None listed