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.

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

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

Exclusion Criteria

1. Patients with KD and already established coronary artery aneurysms (CAA), as per AHA definition, at screening.
2. Clinical picture consistent with Kawasaki Shock Syndrome (KDSS) or Macrophage Activation Syndrome (MAS) OR Multisystem Inflammatory Syndrome in Children (MIS-C)
3. History or evidence of any previous heart disease
4. Known hypersensitivity to anakinra, IVIG and ASA or any medical condition that contraindicates the use of these treatments
5. Patients with KD receiving IVIG, corticosteroids, immunosuppressants, biologic treatments at the time of screening