Clinical trial NCT06697431: Non Inferiority KawasakI Trial With Anakinra
Official title: A Randomized, Controlled, Open-label, Non Inferiority KawasakI Trial With Anakinra
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE4
Conditions: Kawasaki Disease
Anakinra
Lead sponsor: Meyer Children's Hospital IRCCS
Sponsor class: OTHER
Collaborators: name: Asst Degli Spedali Civili Di Brescia
name: IRCCS Burlo Garofolo
First posted: 2024-11-20
Enrollment: 38
Sex: ALL
Minimum age (years): 1
Maximum age (years): 16
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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
Primary purpose: TREATMENT

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

Eligibility criteria: 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

Primary outcomes:
measure: Number of patients with treatment response in both treatment arms
timeFrame: 12 months
measure: Number of patients with CAA (as per Z-scores) at the end of the study period in both treatment arms
timeFrame: 12 months
Secondary outcomes:
measure: Number of days with fever in both treatment arms
timeFrame: 90 days
measure: Time to reach CRP values<50% from the highest value and to normalize it in both treatment arms (days)
timeFrame: 90 days
measure: Time to normalize coronary artery abnormalities (days)
timeFrame: 90 days
measure: Severity of coronary artery abnormalities (as per Z-score) at the end of follow-up
timeFrame: 24 months
measure: Length of hospitalization in both treatment arms (days)
timeFrame: 90 days
measure: Time to stop anakinra (days)
timeFrame: 90 days
measure: Adverse event and severe adverse event developed during the study and follow/up period
timeFrame: 24 months
measure: Cumulative drug exposure (mg/kg/day)
timeFrame: 12 months
Other outcomes:
Locations:
Study officials:
affiliation: Meyer Children's Hospital IRCCS
name: Gabriele Simonini, Prof
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Blonz G, Lacroix S, Benbrik N, Warin-Fresse K, Masseau A, Trewick D, Hamidou M, Stephan JL, Neel A. Severe Late-Onset Kawasaki Disease Successfully Treated With Anakinra. J Clin Rheumatol. 2020 Mar;26(2):e42-e43. doi: 10.1097/RHU.0000000000000814. No abstract available.
citation: Bossi G, Codazzi AC, Vinci F, Clerici E, Regalbuto C, Crapanzano C, Veraldi D, Moiraghi A, Marseglia GL. Efficacy of Anakinra on Multiple Coronary Arteries Aneurysms in an Infant with Recurrent Kawasaki Disease, Complicated by Macrophage Activation Syndrome. Children (Basel). 2022 May 5;9(5):672. doi: 10.3390/children9050672.
citation: Maniscalco V, Abu-Rumeileh S, Mastrolia MV, Marrani E, Maccora I, Pagnini I, Simonini G. The off-label use of anakinra in pediatric systemic autoinflammatory diseases. Ther Adv Musculoskelet Dis. 2020 Oct 16;12:1759720X20959575. doi: 10.1177/1759720X20959575. eCollection 2020.
citation: Gambacorta A, Buonsenso D, De Rosa G, Lazzareschi I, Gatto A, Brancato F, Pata D, Valentini P. Resolution of Giant Coronary Aneurisms in a Child With Refractory Kawasaki Disease Treated With Anakinra. Front Pediatr. 2020 May 7;8:195. doi: 10.3389/fped.2020.00195. eCollection 2020.
citation: Mastrolia MV, Abbati G, Signorino C, Maccora I, Marrani E, Pagnini I, Simonini G. Early anti IL-1 treatment replaces steroids in refractory Kawasaki disease: clinical experience from two case reports. Ther Adv Musculoskelet Dis. 2021 Mar 29;13:1759720X211002593. doi: 10.1177/1759720X211002593. eCollection 2021.