A Phase III Multicenter Randomized Trial Comparing Anakinra and Intravenous Immunoglobulin in Kawasaki Disease Patients Unresponsive to Initial IVIG Therapy

The primary objective of this study is to compare the **efficacy** of Anakinra, an IL-1R1 receptor antagonist, with a second infusion of intravenous immunoglobulin (IVIG) in patients with **Kawasaki disease** who did not respond to the initial standard IVIG treatment. This comparison is clinically relevant as it aims to determine a more effective second-line treatment option for managing fever in these patients, potentially improving outcomes and reducing complications associated with persistent fever in Kawasaki disease.

Secondary objectives include evaluating the efficacy of the treatments on: - Fever at 72 hours - Disease activity - Symptoms of Kawasaki disease - Coronary lesions, such as dilatation and aneurysm - Inflammation Additionally, the study will assess the safety and tolerability of the treatments. These secondary objectives are crucial for understanding the broader impact of the treatments on disease progression and patient safety.

The clinical trial focuses on evaluating the efficacy of Anakinra in patients with **Kawasaki disease** who have not responded to the standard treatment of one infusion of IVIG. The study population comprises both male and female children aged from 3 months to less than 18 years, with a minimum weight of 5 kg. Participants are required to meet the American Heart Association's criteria for complete or incomplete Kawasaki disease, including persistent fever and specific clinical signs. The trial includes a vulnerable population, as it involves children. However, the total number of participants and specific lifestyle considerations such as diet or physical activity are not provided by the sponsor. Key inclusion criteria include the requirement for written informed consent from the patient, parents, or legal guardians, and the necessity for health insurance coverage. Additionally, efficient contraception is required for childbearing-aged females during the study period.

The clinical trial is a **randomized**, **double-blind**, **controlled** study designed to evaluate the efficacy and safety of **anakinra** compared to intravenous **immunoglobulin** (IVIG) retreatment in patients with **Kawasaki disease** who have not responded to initial standard IVIG treatment. The trial is a Phase III multicenter study, with an estimated duration from October 20, 2023, to December 31, 2027. Participants will be randomly assigned to receive either anakinra or a second infusion of IVIG. The primary objective is to assess the reduction in fever, with a primary endpoint of achieving a body temperature below 38°C within two days of treatment initiation.

The study will include several visits, starting with a screening visit to confirm eligibility based on criteria such as age (3 months to <18 years), weight (≥5 kg), and diagnosis of Kawasaki disease according to the American Heart Association's definition. Participants must have failed to respond to standard IVIG therapy, evidenced by persistent or recurrent fever within 24 to 48 hours post-infusion. Written informed consent from the patient, parents, or legal guardians is required, along with health insurance coverage.

Following the screening, participants will undergo baseline assessments before randomization. The treatment phase will last up to 14 days, with follow-up visits scheduled to monitor efficacy and safety outcomes. Secondary endpoints include temperature control within 72 hours, reduction in C-reactive protein (CRP) levels by day 30, and improvement in disease activity assessments by day 14. The end-of-study visit will occur at day 45, where resolution of coronary abnormalities will be evaluated via echocardiogram.

Participant involvement is expected to last approximately 45 days, with conditions for early termination including withdrawal of consent, adverse events, or non-compliance with the study protocol. The trial aims to provide valuable insights into the comparative effectiveness of anakinra and IVIG in managing Kawasaki disease, potentially influencing future treatment guidelines.

The clinical trial involves the use of **Privigen**, a **solution for infusion** containing **human normal immunoglobulin** as the active substance. This medication is administered via **intravenous infusion**. The dosage is set at a maximum of 2 mg/kg per day, with a total maximum dose of 2 mg/kg over the treatment period. The treatment duration is limited to 1 day. Privigen is manufactured by CSL Behring GmbH and is classified under the ATC code J06BA02, which denotes its use as a normal human immunoglobulin for intravascular administration. The immunoglobulin is derived from blood, ensuring a structurally diverse substance origin.

The trial also includes the use of **Kineret**, a **solution for injection** in a pre-filled syringe, containing **anakinra** as the active substance. This medication is administered **subcutaneously**. The maximum daily dose is 300 mg, with a total maximum dose of 4200 mg over the treatment period. The treatment duration is set for a maximum of 14 days. Kineret is produced by Swedish Orphan Biovitrum AB (publ) and is categorized under the ATC code L04AC03. Anakinra is a protein-based substance, classified as a protein of other origin.

In this randomized phase III multicenter trial, the efficacy and safety of Anakinra are compared to a second infusion of intravenous immunoglobulin (IVIG) in patients with Kawasaki disease who did not respond to the initial standard IVIG treatment. The trial aims to evaluate the impact of these treatments on fever reduction in the specified patient population. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment protocol.

The efficacy of the clinical trial will be assessed by evaluating the primary and secondary endpoints. The primary endpoint is the achievement of a body temperature below 38°C within two days after the initiation of treatment, which will be measured using axillary, tympanic, or oral methods. This outcome is binary, categorized as success or failure. Secondary endpoints include achieving a temperature below 38°C within three days, a decrease in C-reactive protein (CRP) values to less than 6 mg/L by day 30, and a reduction in disease activity as assessed by both physicians and patients' parents by at least 50% on a 10-point scale between baseline and day 14. Additionally, the resolution of coronary abnormalities, defined as a worst Z score of less than 2.5 by echocardiogram at day 45, will be evaluated. Adverse events such as pain or redness at the injection site, bacterial infection, hepatitis, macrophage activation syndrome, and severe neutropenia will also be monitored.