Non Inferiority KawasakI Trial With Anakinra

Official title

A Randomized, Controlled, Open-label, Non Inferiority KawasakI Trial With Anakinra

Overview

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

• Drug Anakinra
  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
• Drug Intravenous Immunoglobulins, Human
  see previous section

Primary outcome measures

• Number of patients with treatment response in both treatment arms [Time frame: 12 months]
• Number of patients with CAA (as per Z-scores) at the end of the study period in both treatment arms [Time frame: 12 months]

Secondary outcome measures (8)

• Number of days with fever in both treatment arms [Time frame: 90 days]
• Time to reach CRP values<50% from the highest value and to normalize it in both treatment arms (days) [Time frame: 90 days]
• Time to normalize coronary artery abnormalities (days) [Time frame: 90 days]
• Severity of coronary artery abnormalities (as per Z-score) at the end of follow-up [Time frame: 24 months]
• Length of hospitalization in both treatment arms (days) [Time frame: 90 days]
• Time to stop anakinra (days) [Time frame: 90 days]
• Adverse event and severe adverse event developed during the study and follow/up period [Time frame: 24 months]
• Cumulative drug exposure (mg/kg/day) [Time frame: 12 months]

Eligibility criteria

Inclusion criteria

• 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)
• less than 5 days of fever but all 5 clinical criteria above
• 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).

• To be enrolled children need to show persistent fever ≤7 days
• Written informed consent from an appropriate legal representative(s), and assent from patients older than 7 years

Exclusion criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Yang J, Jain S, Capparelli EV, Best BM, Son MB, Baker A, Newburger JW, Franco A, Printz BF, He F, Shimizu C, Hoshino S, Bainto E, Moreno E, Pancheri J, Burns JC, Tremoulet AH. Anakinra Treatment in Patients with Acute Kawasaki Disease with Coronary Artery Aneurysms: A Phase I/IIa Trial. J Pediatr. 2022 Apr;243:173-180.e8. doi: 10.1016/j.jpeds.2021.12.035. Epub 2021 Dec 23. PMID 34953816
• Kone-Paut I, Tellier S, Belot A, Brochard K, Guitton C, Marie I, Meinzer U, Cherqaoui B, Galeotti C, Boukhedouni N, Agostini H, Arditi M, Lambert V, Piedvache C. Phase II Open Label Study of Anakinra in Intravenous Immunoglobulin-Resistant Kawasaki Disease. Arthritis Rheumatol. 2021 Jan;73(1):151-161. doi: 10.1002/art.41481. Epub 2020 Nov 17. PMID 32779863
• Kessel C, Kone-Paut I, Tellier S, Belot A, Masjosthusmann K, Wittkowski H, Fuehner S, Rossi-Semerano L, Dusser P, Marie I, Boukhedouni N, Agostini H, Piedvache C, Foell D. An Immunological Axis Involving Interleukin 1beta and Leucine-Rich-alpha2-Glycoprotein Reflects Therapeutic Response of Children with Kawasaki Disease: Implications from the KAWAKINRA Trial. J Clin Immunol. 2022 Aug;42(6):1330-1 PMID 35699824
• 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. PMID 32073531
• 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. PMID 35626849
• 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. PMID 33149772
• 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. PMID 32457855
• 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. PMID 33854568

Identifiers

NCT: NCT06697431 · NIKITA

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗