Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disease of presumed autoimmune etiology that affects ~1 of 1,000 children worldwide (1). It is the most common chronic rheumatic disease in the pediatric age and an important cause of short-term and long-term disability. A number of therapeutic options are available for the management of JIA, ranging from NSAIDs to systemic or intra-articular corticosteroids, to the traditional disease modifying anti-rheumatic drugs (DMARDs), to the novel biologic agents. However, although treatment recommendations and standards of care for JIA have recently been published, the therapeutic approach to JIA is not standardized and no treatment guidelines have been prospectively evaluated, internationally accepted, and widely and systematically implemented

In the past two decades, there have been major advances also in the management of JIA, which include the widespread use of intra-articular corticosteroids, the tendency toward earlier introduction of methotrexate, and, more recently, the availability of biologic medications.  This progress has increased considerably the potential to achieve disease remission or, at least, minimal levels of disease activity, and has consequently moved the therapeutic aims increasingly toward the attainment of an inactive disease status.

The comparison of STep-up and step-down therapeutic strategies in childhood ARthritiS trial (STARS) is a new interventional trial financed by AIFA (Agenzia Italiana del Farmaco) and by the Italian Foundation Compagnia di San Paolo that will be conducted by PRINTO only in the Italian centres. This clinical trial has the aim to investigate whether an early aggressive therapeutic intervention in children with JIA, based on the initial start of synthetic and biologic DMARDs (Step-down strategy), is superior to an approach based on treatment escalation conducted following the treat-to-target principle (Step-up strategy). The effectiveness of the two strategies will be assessed by comparing their ability to induce sustained clinical disease remission on/off treatment.

After screening of inclusion and exclusion criteria and recording of informed consent, patients will be randomized into two therapeutic arms: “Step up” or “Step down”. Patients in the Step-up arm will be treated according to a conventional strategy based on treatment escalation and driven by the treat-to-target strategy. Patients in the Step-Down arm will be treated with an early, combined, aggressive therapy for 6 months.



Rationale

The primary goal of the trial is to reach a sustained and complete disease quiescence. The achievement of such state implies the disappearance of joint pain, morning stiffness and functional limitation. This objective may lead to restoration of the ability of the child to make the activities of daily living and to improve the quality of life of the child and the family. Continued suppression of the inflammatory disease process may also help prevent long-term joint damage and, consequently, reduce the expenses of the health care system in terms of physiotherapy, need of devices (e.g. crutches, wheelchairs), orthopedic surgery, etc. The resulting reduced need of advanced therapies, particularly with biologic medications, that may be deserved in case of inadequate response to the conventional medications, may minimize the exposure of children to the potential side effects of long-term drug therapies and diminish the expenditures related to the administration of the costly biologic agents. Another potential advantage of the therapeutic regimens assessed in the trial is to avoid disease exacerbations, which may require the prescription of systemic corticosteroids. Minimizing the use of these medications may lessen the frequency of serious adverse events secondary to their prolonged administration, particularly growth failure, weight gain, and cushingoid features. Sustained disease control may also reduce the need of repeated corticosteroid joint injections, which cause distress to the child and the family and may increase the organizational and financial burden to the health care system in case of the need of general anesthesia in the operatory theatre. Broader objectives are the avoidance of absences of children from school and of parents from work, which may be caused by disease exacerbations or the request of frequent clinical visits or laboratory tests due to persistently active disease or continued treatment with potentially toxic medications. Particularly innovative aspects of the trial include the use of standardized quantitative measures to assess the disease state and the disease course over time and the involvement of patients and parents in clinical decision making, through their assessment of disease activity by child- or patient-centered outcome measures.



Objectives

The study is aimed to compare the effectiveness of a conventional therapeutic regimen, based on treatment escalation (Step-up strategy) and driven by the treat-to-target approach, with that of an early aggressive intervention based on a combination of conventional and biological DMARDs (Step-down strategy).

The hypothesis tested in this trial is whether an early aggressive therapy with a 6-month course of an anti-TNF agent in combination with methotrexate or with methotrexate alone in the milder forms of oligoarthritis (Step-down arm) is more effective in inducing clinical remission on medication (i.e. at least 6-month of continuous inactive disease while receiving anti-rheumatic medications) than a conventional therapeutic approach based on treatment escalation (Step-up arm), which efficacy is maximized through the implementation of a treat-to-target approach



Endpoints

Primary endpoint

Clinical remission on or off medication at 12 months.

The effectiveness of the two therapeutic strategies will be compared by assessing the frequency of clinical remission (CR) at 12 months. CR is defined as the persistence of the JADAS state of ID for at least 6 months.

Secondary endpoints

• Inactive disease

The rate of patients who achieve the JADAS/JIA ACR state of ID at any single point in time throughout the study period will be compared between the 2 arms.

• Time to inactive disease as per JADAS/JIA ACR criteria

Time to achieve the JADAS/JIA ACR state of ID will be calculated as the time difference (in days) between the date of randomization and the date of the visit at which the patient will be observed to be in ID.

• Time to JADAS/JIA ACR clinical remission

Time to achieve the JADAS/JIA ACR state of clinical remission will be calculated as the time difference (in days) between the date of randomization and the date of the visit at which the patient will be observed to be in clinical remission (i.e. persistent inactive disease for at least 6 months).

• Time spent in JADAS/JIA ACR inactive disease

The cumulative time spent in the JADAS/JIA ACR state of ID will be calculated as the time difference (in days) between the date of the first visit at which the patient will be observed to be in ID and the date at which he/she will be observed to be no longer in ID that is when the disease will flare (see later for definitions), or database closure for analysis purposes. We will assume that if a patient is found to be in ID at 2 consecutive visits, the patient had ID on all days between these visits. If a patient will be found to have  ID at a particular visit, but lost the ID status at the subsequent visit, the patient will be considered to have been in ID until the recurrence of active disease. Patients found to be in ID only at the time of database closure will contribute a single day of ID. The time in inactive disease per patient will be recorded and compared between the 2 arms.

• Cumulative level of disease activity throughout the study period

The area under the curve (AUC) of the JADAS10 score assessed at every study visit and the AUC of the parent version of the JADAS (parJADAS) assessed monthly will be recorded and compared between the 2 arms.

• Time spent on therapy

The cumulative time on therapy will be calculated as the time difference (in days) between the date of the visit at which the patient will start a systemic medication (synthetic or biologic DMARDs or steroids) until the date at which he/she will be observed to no longer be in treatment with a systemic medication, or completed the study. We assume that if a patient does not receive medications at 2 consecutive visits, the patient had not received medications all days between these visits. Patients initiating a systemic treatment at the final visit of the study will contribute a single day of time in therapy. The mean percentage of time spent on therapy per patient will be recorded and compared between the 2 arms.

• Rate of flares

The rate of patients who develop flare, defined as the recurrence of active disease after attaining inactive disease at last visit according JADAS or JIA ACR definition, and the number of flares and the time to flare per patient will be recorded and compared. Notably, all patients prescribed intra-articular injections, synthetic or biologic DMARDs or systemic steroids will be considered as flare independently from JADAS or ACR criteria.

• Rate of uveitis onset

The rate of patients who develop uveitis according to the Standardized Uveitis Nomenclature (SUN) will be recorded and compared between the 2 arms. The rate of patients requiring systemic medications for treatment of uveitis will be also recorded and compared between the 2 arms. However, these patients will be excluded from the study and followed for safety only.



After the conclusion of the 12-month observation period of the trial, patients will be followed for up to 5 years for the evaluation of disease course, medication requirements, adverse events of medications, and long-term disease-related morbidity.

The trial will enroll newly-diagnosed and DMARD-naïve children with a diagnosis of oligoarthritis or rheumatoid factor negative polyarthritis according to the ILAR criteria.

The desired sample size for the study is 260 patients. Enrollment will start as soon as Ethics Committee approvals are obtained. The PRINTO coordinating centre will offer assistance during the process of the Ethics Committees submission.



At the moment...

In collaboration with the Consorzio per Valutazioni Biologiche e Farmacologiche (CVBF, https://www.cvbf.net/it/) PRINTO has recently begun the phase of submission of the study documents to the Ethics Committees of the participating sites in Italy, and the very first patients have been already enrolled at the coordinating centre in Genoa.



For any further information, please contact PRINTO at printo@gaslini.org