An Open-Label Randomized Trial Comparing Anakinra and Prednisone in Pediatric Colchicine-Resistant Recurrent Pericarditis

The primary objective of this study is to evaluate the efficacy of **anakinra** compared to steroids in controlling disease activity and preventing further flares in pediatric patients with colchicine-resistant recurrent pericarditis. This condition, which is not responsive to first-line treatment with NSAIDs and colchicine, poses significant clinical challenges, particularly in children aged 8 months to less than 18 years. Demonstrating the superiority of anakinra could provide a more effective therapeutic option for managing this condition, potentially improving patient outcomes and reducing the frequency of disease relapses.

Secondary objectives include the collection of RNA samples at various time points (baseline, day 14, day 28, and at relapse or last visit for responders) to perform transcriptomic analysis. This analysis aims to correlate clinical and laboratory parameters with treatment response, identifying transcripts associated with a higher probability of response and long-term remission off-therapy. Such findings could enhance understanding of the disease mechanism and inform future therapeutic strategies.

The clinical trial involves a **pediatric** population aged from 8 months to less than 18 years, comprising both male and female participants. The study focuses on individuals diagnosed with **recurrent pericarditis**, either idiopathic or secondary to invasive cardiac procedures, who have not responded to colchicine and NSAIDs after the first relapse. The trial population was selected based on inadequate response or intolerance to non-steroidal anti-inflammatory drugs or colchicine. Participants are required to have a previous diagnosis of acute pericarditis and must provide written informed consent from a parent or legal guardian, with child assent if appropriate. The sponsor has not provided information regarding the total number of participants. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, emphasizing the need for careful ethical considerations in the study design and execution.

The clinical trial is designed to evaluate the efficacy of **anakinra** compared to **steroids** in managing **recurrent pericarditis** in pediatric patients who have not responded to first-line treatments such as NSAIDs and colchicine. This study is structured as an open-label, randomized trial, with a focus on demonstrating the superiority of anakinra in controlling the disease and preventing further flares. The trial is expected to run from July 2023 to June 2026, with participant involvement lasting up to 24 months. The trial will include male and female patients aged from 8 months to less than 18 years, with a confirmed diagnosis of pericarditis relapse and inadequate response or intolerance to previous treatments.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on the inclusion criteria. This will be followed by randomization into treatment groups receiving either anakinra or prednisone. The primary endpoints include achieving a complete response to disease flare by day 7 and preventing relapse by month 3. Secondary endpoints will assess the time to achieve complete control of the flare, time to flare after treatment tapering, number of flares during follow-up, behavior of acute phase reactants over six months, quality of life, safety, number of hospitalization days, and a transcriptomic study.

Study visits will be scheduled at regular intervals to monitor the participants' response to treatment and any adverse effects. The end-of-study visit will conclude the trial, assessing the long-term outcomes and safety of the interventions. Participants may be withdrawn from the study early if they experience significant adverse effects, fail to adhere to the study protocol, or if the investigator deems it necessary for their safety. The trial is categorized as a low-intervention study, justified by the reimbursement of Kineret for treating corticosteroid-dependent and colchicine-resistant recurrent idiopathic pericarditis under Decree Law 648/1996.

The clinical trial involves the administration of **PREDNISONE**, a corticosteroid, as a comparator treatment. **PREDNISONE** is provided in the form of tablets for **oral use**. The maximum daily dose is 50 mg, with a total maximum dose of 1400 mg over a treatment period of 24 weeks. The administration schedule is determined based on the clinical judgment of the investigator, and participant compliance is monitored through regular follow-up visits and pill counts. **PREDNISONE** is not a paediatric formulation and is used in this study to compare its efficacy against the experimental treatment.

The experimental treatment in this trial is **Kineret**, which contains the active substance **ANAKINRA**. **Kineret** is provided as a solution for injection in a pre-filled syringe, intended for **subcutaneous use**. The maximum daily dose is 100 mg, with a total maximum dose of 12600 mg over a 24-week treatment period. The administration of **Kineret** is performed by healthcare professionals or trained caregivers, ensuring proper technique and adherence to the dosing schedule. Compliance is monitored through regular assessments and documentation of injection logs. **Kineret** is not a paediatric formulation and is being evaluated for its effectiveness in controlling disease activity and preventing flares in patients with colchicine-resistant recurrent pericarditis.

Efficacy in this clinical trial will be assessed using both primary and secondary endpoints. The primary endpoints include the **complete response** of disease flare at day 7 and the lack of relapse at month 3. These endpoints are designed to evaluate the immediate and sustained control of recurrent pericarditis in pediatric patients who are resistant to colchicine and non-steroidal anti-inflammatory drugs (NSAIDs).

Secondary endpoints will provide additional insights into the treatment's efficacy and include the time to achieve complete control of the flare, time to flare after treatment tapering, number of flares during follow-up, behavior of acute phase reactants over a 6-month observation period, quality of life assessments, safety through the registration of side effects throughout the study, number of days of hospitalization, and a transcriptomic study. These parameters will be measured and collected at specified intervals to ensure comprehensive data analysis.