A Trial Comparing the Efficacy and Safety of Anakinra Versus Intravenous Immunoglobulin (IVIG) Retreatment, in Patients With Kawasaki Disease Who Failed to Respond to Initial Standard IVIG Treatment

NCT04656184 | Recruiting Phase 3

• 1 other identifier: P200009
• Study Type: interventional
• Target: 84
• Locations: 1 country
• Sites: 1

Brief Summary

Kawasaki disease (KD) is the most frequent vasculitis in younger children \<5years, and the first cause of acquired ischemic myocardiopathy in childhood. Exceptionally, KD may cause early death during the acute phase by myocardial infarction, but may compromise the long-term cardiovascular outcome by accelerating atherosclerotic disease. The incidence of KD is high in far-Eastern countries and Hawaii but KD is relatively rare in other regions (10/100000 children \<5years in northern Europe) which makes it difficult to develop research on these rare population. Early recognition and treatment by intravenous immunoglobulins (IVIG) influences the prognosis positively. IVIG are the standard of care and decrease significantly the risk of coronary aneurysms. However, despite a first infusion of IVIG, 20% of KD patients remain febrile and have high risk of coronary vasculitis. Recent Japanese research group assessed additional cyclosporine treatment in first line KD treatment but failed preventing relapse. To date there is no agreement for a more effective second line treatment. Based on the auto-inflammatory pattern of KD, the investigators hypothesize that anti IL-1 blocking agents could bring a rapid and sustained effect on systemic and coronary inflammation in patients with KD. Our hypotheses are:

1. 1.Anakinra treatment may reduce the early and long-term mortality of patients with Kawasaki Disease (KD), by a rapid and sustained effect on vascular inflammation.
2. 2.The safety of anakinra is good, as the drug has a very short half-life, which allows its rapid withdrawal in case of serious adverse event.

Conditions

Kawasaki Disease

Outcome Measures

Primary Outcomes (1)

• Fever

  The main criterion-evaluating efficacy in both groups is: the patient must reach a body (axillary (+0.5°C), tympanic, oral) temperature \<38˚C within 2 days after initiation of treatment (i.e. a binary outcome: success/failure).

  48 hours

Secondary Outcomes (6)

• Fever

  day 3, day 4, day 6, day 7, day 14, day 30, day 45, day 60

• CRP

  day 3 (or day 4) day 7, day 14, day 30 and day 45.

• Disease activity (physician assessment)

  day 2, day 3, day 4, day 6, day 7, day 14, day 30, day 45, day 60

• Disease activity (patient's parent's assessment)

  day 2, day 3, day 4, day 6, day 7, day 14, day 30, day 45, day 60

• Coronary abnormalities

  Day 45

Study Arms (2)

KINERET

EXPERIMENTAL

The patients will receive anakinra, an analogue of the IL-1 receptor antagonist, at a starting dose of 4 mg/kg. If patients are still febrile with 12 hours (H12) of treatment, they will receive a supplementary dose of 2 mg/Kg; otherwise, they will remain at a starting dose of 4 mg/kg. If they are still febrile at H24, they will receive a dose of 8mg/kg; otherwise, they will maintain their dose of 6 mg/kg. Patients with temperature \<38°C at any point between initiation and day 14, but who develop secondary fever due to KD could have further escalation dose of anakinra until a maximum dose of 8mg/Kg. Patients will receive anakinra during 14 days independently of the period of escalation dose if any. After the last escalation dose, if any necessary, the primary criteria will be measured. Patients not responding to anakinra will follow usual standard care and will complete information related to all the study visits

Drug: ANAKINRA

Intravenous Immunoglobulin

ACTIVE COMPARATOR

The patients will receive a standard therapy, IVIG infusion of 2g/kg, and their treatment will follow usual standard care. Patients in the IVIG treatment will complete information related to the study visits.

Drug: Intravenous immunoglobulin

Interventions

ANAKINRA DRUG

The patients will receive anakinra, an analogue of the IL-1 receptor antagonist, at a starting dose of 4 mg/kg. If patients are still febrile with 12 hours (H12) of treatment, they will receive a supplementary dose of 2 mg/Kg; otherwise, they will remain at a starting dose of 4 mg/kg. If they are still febrile at H24, they will receive a dose of 8mg/kg; otherwise, they will maintain their dose of 6 mg/kg. Patients with temperature \<38°C at any point between initiation and day 14, but who develop secondary fever due to KD could have further escalation dose of anakinra until a maximum dose of 8mg/Kg. Patients will receive anakinra during 14 days independently of the period of escalation dose if any. After the last escalation dose, if any necessary, the primary criteria will be measured. Patients not responding to anakinra will follow usual standard care and will complete information related to all the study visits

Also known as: Kineret

KINERET

Intravenous immunoglobulin DRUG

The patients will receive a standard therapy, IVIG infusion of 2g/kg, and their treatment will follow usual standard care. Patients in the IVIG treatment will complete information related to the study visits.

Intravenous Immunoglobulin

Eligibility Criteria

• Age: 3 Months - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Children, male and female, from 3 months to \<18 years old
• Patient ≥ 5 kg
• Patient with KD according to the American Heart Association definition for complete or incomplete KD. (Fever ≥ 5 days (or at least 3 days if KD with American Heart Association criteria since the third days of fever) and ≥ 4 of 5 main clinical signs: modification of the extremities, polymorphic exanthema, and bilateral bulbar not exudative conjunctivitis, erythema of the lips or oral cavity, and cervical lymph nodes usually unilateral \> 1.5 cm in diameter.
• Patients who failed to respond to the standard therapy of KD, e.g. Persistence or recrudescence of fever ≥ 38°C, 48 hours after the infusion of 2g/kg of IV Ig. Patients may be screened 24h after the end of the first infusion if they remain febrile 24h after the end of the first infusion.
• Patient, parents or legal guardian's written informed consent is required
• Patient with health insurance (SS or CMU).
• Efficient contraception for the duration of participation in the research for childbearing aged women

You may not qualify if:

• Preterm and neonates, pregnancy, pregnancy and breast feeding
• Suspicion of another diagnosis
• Patient with overt concomitant bacterial, viral or fungal infection
• Patient previously treated with steroids and/or another biotherapy
• Patient with increased risk of tuberculosis infection
• Recent tuberculosis infection or with active tuberculosis
• Patient with any type of immunodeficiency or cancer
• Patients with severe renal impairment (CLcr \< 30 ml/minute)
• Patients with hepatic insufficiency
• Patients with neutropenia (ANC\<1.5 x109/l)
• Patients included in another interventional protocol
• Patient under the following treatments:
• Preventive Antipyretics (paracetamol, NSAIDs other than aspirin 30-50mg/kg given for purpose of KD inflammation), as long as the patient receives the study medication
• Immunosuppressive medications given in a period less than twice of their half-life prior the patient receives the study medication (systemic steroids, cyclosporine, tacrolimus, azathioprine, cyclophosphamide, interferon, mycophenolate, other anti-IL-1, anti IL-6, anti CD20 and anti TNF (Tumor Necrosis Factor)), plasmapheresis)
• Hypersensitivity to anakinra or excipients (citric acid, sodium chloride, disodium EDTA (Ethylene Diamine Tetra Acetic), polysorbate 80, sodium hydroxide, in water for injection)

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• Swedish Orphan Biovitrum: collaborator

Study Sites (1)

CHU de Bicêtre

Le Kremlin-Bicêtre, Val De Marne, 94270, France

RECRUITING

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

Central Study Contacts

Isabelle Koné-Paut, Pr

CONTACT

00 33 1 45 21 32 46; isabelle.kone-paut@aphp.fr

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Parallel Assignment

Study Record Dates

• First Submitted: November 30, 2020
• First Posted: December 7, 2020
• Study Start: October 20, 2023
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2027
• Last Updated: February 28, 2024

Record last verified: 2024-02

Locations

FR (1)