Non Inferiority KawasakI Trial With Anakinra

NCT06697431 | Not Yet Recruiting Phase 4 DMC

• 1 other identifier: NIKITA
• Study Type: interventional
• Target: 38
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Kawasaki Disease; Anakinra

Outcome Measures

Primary Outcomes (2)

• Number of patients with treatment response in both treatment arms

  Response rate

  12 months

• Number of patients with CAA (as per Z-scores) at the end of the study period in both treatment arms

  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

  12 months

Secondary Outcomes (8)

• Number of days with fever in both treatment arms

  90 days

• Time to reach CRP values<50% from the highest value and to normalize it in both treatment arms (days)

  90 days

• Time to normalize coronary artery abnormalities (days)

  90 days

• Severity of coronary artery abnormalities (as per Z-score) at the end of follow-up

  24 months

• Length of hospitalization in both treatment arms (days)

  90 days

Study Arms (2)

Anakinra

EXPERIMENTAL

Anakinra 2mg/kg intravenously, max 100 mg/dose 4 times/day

Drug: Anakinra

Intravenous immunoglobulins

ACTIVE COMPARATOR

IVIG 2g/kg administered in 10-12 hours as per local standard of care

Drug: Intravenous Immunoglobulins, Human

Interventions

Anakinra DRUG

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.

Also known as: Kineret

Anakinra

Intravenous Immunoglobulins, Human DRUG

see previous section

Also known as: IVIG

Intravenous immunoglobulins

Eligibility Criteria

• Age: 1 Month - 16 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Meyer Children's Hospital IRCCS: lead
• Asst Degli Spedali Civili Di Brescia: collaborator
• IRCCS Burlo Garofolo: collaborator

Related Publications (8)

• 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 BACKGROUND

• 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 BACKGROUND

• 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):1330-1341. doi: 10.1007/s10875-022-01301-w. Epub 2022 Jun 14.

  PMID: 35699824 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

• 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 BACKGROUND

MeSH Terms

Conditions

Mucocutaneous Lymph Node Syndrome

Interventions

Interleukin 1 Receptor Antagonist Protein; Immunoglobulins, Intravenous

Condition Hierarchy (Ancestors)

Vasculitis; Vascular Diseases; Cardiovascular Diseases; Lymphatic Diseases; Hemic and Lymphatic Diseases; Skin Diseases, Vascular; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Immunoglobulin G; Immunoglobulin Isotypes; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins

Study Officials

• Gabriele Simonini, Prof

  Meyer Children's Hospital IRCCS

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Gabriele Simonini, Prof

CONTACT

0555662913; gabriele.simonini@unifi.it

Maria Vincenza Mastrolia, MD

CONTACT

0555662913; maria.mastrolia@meyer.it

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: 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

Study Record Dates

• First Submitted: November 1, 2024
• First Posted: November 20, 2024
• Study Start: April 1, 2025
• Primary Completion: April 1, 2026
• Study Completion (Estimated): April 1, 2027
• Last Updated: November 21, 2024

Record last verified: 2024-11

Data Sharing

• IPD Sharing: Will not share