Clinical trial NCT05805930: Therapeutic Approach in Colchicine-resistant Recurrent pEricarditis in Children
Official title: Therapeutic Approach in Colchicine-resistant Recurrent pEricarditis in Children: an Open-label Randomized Trial Comparing Anakinra vs sTEroids
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Pericarditis
Lead sponsor: Istituto Giannina Gaslini
Sponsor class: OTHER
First posted: 2023-04-10
Enrollment: 48
Sex: ALL
Minimum age (years): 8
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to demonstrate that anakinra provides more rapid disease control than steroids in the first month of treatment in the event of recurrent pericarditis and is more effective in preventing further exacerbations in patients aged between eight months and eighteen years of age with idiopathic or post-procedural pericarditis, unresponsive to first-line treatment with NSAIDs and colchicine at the appropriate dosage, or in case of colchicine intolerance. The efficacy of the two treatments will be evaluated by the capacity and timing of the two therapies to determine a complete control (clinical, laboratory and instrumental) of the disease and the absence of recurrences.

Detailed description: Although steroids represent the second-line treatment for recurrent pericarditis (RP), to be used in case of inadequate response to NSAIDs and colchicine, their use is controversial due to their side effects.

Indeed, in adult patients with RP it has been demonstrated that the use of steroids is associated with an increased risk of recurrence: in a study carried out in adult patients, 64% of patients taking high-dose steroids (\> 1 mg/kg/ of prednisone or equivalent), and 32% of patients taking this low-dose drug (\< 1 mg/kg/day of prednisone or equivalent) relapsed. Furthermore, the therapy is associated with serious side effects and an increased risk of hospitalization, especially in patients treated with high doses. Finally, a high percentage of RP patients (both adult and pediatric) treated with steroids tend to become steroid-dependent, experiencing a disease exacerbation during tapering of treatment or soon after its discontinuation. The side effects associated with the chronic use of steroids are well known, especially in childhood, as their use is associated not only with reduced bone density, but also with growth retardation. Therefore, their long-term use is contraindicated, especially in children.

In a recent retrospective study of 58 pediatric patients with recurrent pericarditis treated with IL-1 inhibitors, a high steroid dependence rate was observed (45 of 48 treated patients). In this study, the presence of predictive factors associated with the possibility of achieving long-term remission was evaluated. Unfortunately, it could not be shown that avoiding steroid use was associated with an increased chance of withdrawing anakinra without relapse. This is likely due to the large variability of the cohort included in the retrospective study.

Therapy with anakinra in recurrent pericarditis is aimed at obtaining rapid and complete control of the disease and maintaining it over time, allowing the suspension of steroid therapy and thus reducing the risk of complications, chronicity and recurrence.

In the field of pediatric rheumatology, there is convincing evidence that in children with chronic arthritis a more aggressive therapy at an early stage can take advantage of the so-called "window of opportunity": according to this theory, early biological treatment can modify the pathogenetic mechanism of the disease by improving its long-term outcomes.

In particular, it has been shown that anakinra therapy in children with systemic JIA can lead to rapid attainment of inactive disease and allow for early discontinuation of treatment in the absence of recurrence in the majority of patients. Among all the rheumatological pathologies of the pediatric age, systemic JIA is the one that has the greatest similarities with autoinflammatory diseases due to the presence of fever, sometimes recurrent, rash and serositis, typical characteristics of AID, especially of inflammasomopathies. Recurrent pericarditis itself has many similarities to these conditions, as demonstrated by the efficacy of interleukin-1 inhibition. In fact, both of these conditions are considered by many to be real autoinflammatory diseases, with a multifactorial etiology. It is therefore reasonable to think that the concept of the "window of opportunity" can also be translated to recurrent pericarditis: the early blockade of cytokines could in fact abrogate the pathogenetic mechanism of the disease and therefore its chronic course and/or its relapses.

Eligibility criteria: Inclusion Criteria:

1. Male and female patients.
2. Parent or legal guardian written informed consent and child assent, if appropriate, are required before any assessment is performed.
3. Diagnosis of relapse of pericarditis in a patient with previous diagnosis of acute pericarditis (idiopathic or secondary to invasive cardiac procedures).
4. Inadequate response or intolerance to non-steroidal anti-inflammatory drugs or colchicine

Exclusion Criteria:

1. Pericarditis secondary to a known infection (viral, bacterial, mycobacterial).
2. Pericarditis in a patient with a previous diagnosis of any neoplasm and without complete recovery from at least one year.
3. Pericarditis in the context of a systemic disease.

   1. Patients fulfilling diagnostic criteria for an autoimmune systemic disease
   2. Patients with a previous diagnosis of a genetically confirmed autoinflammatory disease
4. Any conditions or significant medical problems, which in the opinion of the investigator places the patient at unacceptable risk for immunomodulatory therapy.
5. Main alteration in the blood count
6. Presence of Human Immunodeficiency Virus (HIV) infection, Hepatitis B or Hepatitis C infections.
7. Evidence of active or latent tuberculosis (TB) determined by positive QuantiFERON (QFT-TB G In-Tube) test or positive Purified Protein Derivative (PPD) test (≥5 mm induration) within 2 months prior to randomization.
8. Administration of any investigational drug or implantation of investigational device, or participation in another trial, within 30 days before screening.
9. Use of steroids at the dosage of 1 mg/kg/day of prednisone or equivalent for at least 5 days in the 30 days before randomization.
10. Live vaccinations within 1 months prior to the start of the trial and during the trial.
11. Pregnancy, confirmed by a positive hCG laboratory test.
12. Female adolescents (≤18 years of age) of childbearing potential who do not agree to abstinence or, if sexually active, do not agree to the use of contraception.

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Primary outcomes:
measure: Number of participants with complete response to treatment
timeFrame: Day 7
measure: Number of participants with disease Flare
timeFrame: 3 months
Secondary outcomes:
measure: Time to response
timeFrame: Up to 24 weeks
measure: Number of participants with improved Quality of life
timeFrame: Up to 24 weeks
Other outcomes:
Locations:
Study officials:
References: