Anakinra and Kawasaki Disease

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Brief Title

Anakinra and Kawasaki Disease

Official Title

A Phase IIa Multicenter Trial to Assess the Efficacy, and Safety of Anakinra in Patients With Intravenous Immunoglobulin-resistant Kawasaki Disease

Brief Summary

      The study is designed to assess the efficacy and safety of anakinra, an interleukin 1
      receptor antagonist, in patients with Kawasaki disease who failed to respond to standard
      treatment:e.g. one infusion of 2g/kg of intravenous immunoglobulins.
    

Detailed Description

      Kawasaki disease (KD), is the most frequent vasculitis in children before 5 years, and the
      main cause of acquired cardiomyopathy in adulthood. The prognosis of KD is influenced by
      early recognition and treatment by intravenous immunoglobulins (IVIG), which represent the
      standard of care and decrease significantly the risk of coronary aneurysms. Despite a first
      infusion of IVIG, 20% of KD patients remain febrile and are at high risk of coronary
      vasculitis. To date there is no agreement for a more effective second line treatment. On the
      basis of the autoinflammatory pattern of KD, we hypothesize that anti IL-1 blocking agents
      could bring a rapid and sustained effect on systemic and coronary inflammation in patients
      with KD.

      Aim of the study

        -  To assess the efficacy of anakinra (IL-1R1receptor antagonist) in patients with KD who
           fail to respond to one infusion of IVIg (standard treatment).

        -  To assess the efficacy of anakinra on disease activity

        -  To assess the efficacy of anakinra on coronary lesions (eg: dilatation and aneurysm

        -  To assess the safety and tolerability of anakinra Patients and methods A Proof of
           concept (quasi experimental, non randomized cohort) study. This is a 3-year open-label,
           prospective multicenter trial of Anakinra in patients with acute KD who failed to
           respond to a first infusion of IVIG within 48h. Patients will be eligible to enter the
           study if they have persistence (or recrudescence of fever) within 48 hours after the
           infusion of IVIg, and if they have given their informed consent to enter the study.
           After appropriate screening, the study treatment will be initiated between J7 and J14
           days of illness to expect full clinical effect. The only primary endpoint will be the
           absence of fever after 48 h of treatment (assessed at J3 of study treatment, visit 3,
           before the third injection of anakinra). If the patient remains febrile (fever >38°C),
           he will receive a double dose of anakinra (4mg/kg) at day 3 instead of 2mg/kg. Treatment
           will be continued until they have achieved complete response as defined in the outcome
           measurement section, and during a maximum of 15 days.

      Expected results and expected public health benefit Anakinra treatment is expected to reduce
      the early and long term mortality of patients with KD, by a rapid and sustained effect on
      vascular inflammation. The safety of anakinra is expected to be good, as the drug has a very
      short half-life, which allows its rapid withdrawal in case of serious adverse event. The use
      of anakinra, is not associated with the risk of contamination by infectious agents, which
      remains even minimal, a possibility with the use of IVIG
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Absence of fever

Secondary Outcome

 Reduction in physician assessment of disease activity, on a 10 points scale, of at least to 50%

Condition

Kawasaki Disease

Intervention

Anakinra

Study Arms / Comparison Groups

 Anakinra
Description:  

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

16

Start Date

February 5, 2016

Completion Date

February 18, 2019

Primary Completion Date

January 21, 2019

Eligibility Criteria

        Inclusion Criteria:

          -  Patients, male and female, at any age ≥ 3 months (5 kg) of life, with KD according to
             the American Heart Association definition for complete or incomplete KD. fever ≥ 5
             days and ≥ 4 of 5 main clinical signs: modification of the extremities, polymorphic
             exanthema, bilateral bulbar not exudative conjunctivitis, erythema of the lips or oral
             cavity, and cervical lymph nodes usually unilateral > 1.5 cm in diameter. In the
             presence of less than 4 clinical criteria and 5 days of fever, the diagnosis of
             disease KD is proposed in case of coronary abnormalities (at least one dilated
             coronary artery with internal diameter ≥ 2,5 SD from the mean normalized for body
             surface area (Z score) as determined by echocardiography. For indicative purpose, in
             case of incomplete KD, other biological supportive criteria for incomplete KD can help
             to ensure the diagnosis: leucocytosis, elevated CRP, elevated ESR, anaemia,
             hyponatremia, elevated ASAT, ALAT and gGT, hyperlipidaemia.

          -  Patients who failed to respond to standard therapy of KD:, e.g. Persistence or
             recrudescence of fever ≥ 38°C, 48 hours after the infusion of 2g/kg of IV Ig,

          -  Weight ≥5Kg

          -  Patient, parent or legal guardian's written informed consent is required

          -  Patient with health insurance

          -  Patient agrees to have effective contraception for the duration of participation in
             the research

        Exclusion Criteria:

          -  Preterm and neonates, pregnancy

          -  Patients suspected with another diagnosis

          -  Patients with overt concomitant bacterial infection

          -  Patients previously treated with another biotherapy

          -  Patients with any type of immunodeficiency or cancer

          -  Patients with increased risk of TB infection

          -  Recent tuberculosis infection or with active TB

               -  Close contact with a patient with TB

               -  Patients recently arrived less than 3 months from a country with high prevalence
                  of TB

               -  A chest radiograph suggestive of TB

          -  Patients with end stage renal disease: NKF stages ≥4; eGFR≤29mL/min/1.73 m2 or
             diabetes mellitus or neutropenia <1500/mm3 or liver failure

          -  Hypersensitivity to the active substance or to any of the excipients (citric acid and
             anhydrous; sodium chloride disodium edetate dehydrate polysorbate 80; sodium
             hydroxide; water for injections)

          -  Patient already included in a biomedical research other than observational (e.g.;
             cohort, registry)
      

Gender

All

Ages

3 Months - 18 Years

Accepts Healthy Volunteers

No

Contacts

Isabelle Koné-Paut, MD, PhD, , 

Location Countries

France

Location Countries

France

Administrative Informations


NCT ID

NCT02390596

Organization ID

AOM13520

Secondary IDs

2014-002715-41

Responsible Party

Sponsor

Study Sponsor

Assistance Publique - Hôpitaux de Paris

Collaborators

 Swedish Orphan Biovitrum

Study Sponsor

Isabelle Koné-Paut, MD, PhD, Principal Investigator, AP-HP, Bicêtre Hospital


Verification Date

September 2018