Trial design

STARS is a 12-month multicentre randomised single-blinded superiority clinical trial of two different treatment strategies (Step-down versus Step-up) in a treat-to-target setting. After the conclusion of the observation period of the trial, patients will be followed for up to 5 years for the evaluation of the disease course, medication requirements, adverse events and long-term disease-related morbidity. Recruitment started on 21st May, 2019.

Selection of centres

In a first phase, all Italian centres belonging to the Paediatric Rheumatology International Trials Organization (PRINTO) were invited to participate in the study. In January 2022, after a feasibility survey, PRINTO centers outside Italy were also invited to participate, based on the possibility to prescribe MTX in oligoarthritis and etanercept in polyarthritis as a first-line treatment according to local rules.

Study population

Recent-onset JIA patients with oligoarthritis or rheumatoid factor negative polyarthritis aged between 2 and 17 will be included in the study. Participants must be DMARD-naïve (only treatment with one NSAID is allowed for no more than 6 weeks from diagnosis) and must not have received corticosteroid joint injections in the 3 months before enrolment.

After obtaining written consents (and assent where appropriate) from the participant, parent or legal guardian, patients’ disease severity will be assessed based on the clinical phenotype (irrespective of the ILAR classification) and the severity of the disease. Disease severity will be defined according to the extension of arthritis and based on the presence/absence of features of poor prognosis according to the 2011 American College of Rheumatology (ACR) recommendations for the treatment of JIA [2] (Table 1). Children with oligoarthritis without features of poor prognosis will be considered as “less severe patients”, children with RF-negative arthritis and children with oligoarthritis and features of poor prognosis will be considered as “more severe patients”. As stated in the 2011 recommendations, risk stratification is crucial for guiding optimal treatment; features of poor prognosis for oligoarthritis were defined by the recommendations panel based both on literature revision and on the panellists’ clinical experience [2]. In particular, the possible role of erythrocyte sedimentation rate as a predictor of a less favourable outcome for oligoarthritis patients was more recently confirmed by the results of a clinical trial on this subgroup of patients [17].

Table 1 Subjects in both arms are grouped according to the severity of the disease, based on the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis (ref. [2])Interventions

After the screening visit and recording of informed consent, patients will be randomised into two treatment arms: “Step-up” and “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.

In the Step-up arm, less severe patients will receive IACI in all affected joints without systemic therapies. If the juvenile arthritis disease activity score-10 (JADAS10) state of minimal disease activity (MiDA) after 3 months or the JADAS10 inactive disease (ID) state at 6 months are not reached, treatment with MTX will be started preferably subcutaneously in a single weekly dose of 15 mg/m2 (max 20 mg) and IACI can be repeated. Then, if the states of JADAS MiDA after 3 months or JADAS ID at 6 months are not reached, treatment with an anti-TNF agent in a single weekly dose of 0.8 mg/kg (max 50 mg) subcutaneously will be started. More severe patients in Step-up arm will receive IACI(s) and MTX as a first step and then escalate therapy with the same pathway, adding an anti-TNF treatment as a second step and switching to a different biologic medication as a third step (Fig. 1).

Fig. 1

Step-up arm design. T2T Group 1: Subjects with oligoarthritis without features of poor prognosis. T2T Group 2: Subjects with oligoarthritis with features of poor prognosis and subjects with polyarthritis. JADAS: Juvenile Arthritis Disease Activity Score-10. JADAS< 50%: improvement of JADAS10 of at least 50%, JADAS<ID: JADAS10 score below inactive disease cutoff. JADAS<HDA: JADAS10 score under HDA cutoffs. JADAS>HDA: JADAS10 score above HDA cutoffs. If at the visit 3 months after step 1, 2, and 3 the patient is improved by less than 50% in the JADAS score, but he/she reaches the JADAS state of minimal disease activity, treatment is not escalated ID = inactive disease, HDA = high disease activity. CR on med.: clinical remission on medication. IACI: intra-articular corticosteroids injection. +MTX: start methotrexate (repeating IACI or adding a short course of prednisone can be considered). +TNF: add therapy with an anti-TNF agent (repeating IACI or adding a short course of prednisone can be considered). +TNF2: replace anti-TNF agent with another an anti-TNF agent or with an anti IL-6 agent (repeating IACI or adding a short course of prednisone can be considered)

Patients allocated to the Step-down arm (Fig. 2) will receive an early combined treatment (MTX plus IACI for less severe oligoarthritis, MTX plus etanercept for severe oligoarthritis and polyarthritis). After 6 months, if JADAS10 ID is achieved, less severe patients will have MTX discontinued, whereas more severe patients will stop etanercept and continue MTX. Children in Step-down arm experiencing a worsening from the baseline of the JADAS10 at 3 months, not achieving JADAS10 ID at month 6, or losing the state of ID after month 6 will be considered as treatment failures and will change treatment according to the attending physician decision.

Fig. 2

Step-down arm design. Step A is start methotrexate plus intra-articular joint injections for oligoarthritis without features of poor prognosis, methotrexate plus etanercept and optional intra-articular joint injections for other patients. Step B is withdraw methotrexate for oligoarthritis without features of poor prognosis, withdraw etanercept and continue methotrexate for other patients. JADAS: Juvenile Arthritis Disease Activity Score-10. JADAS<ID: JADAS10 score below inactive disease cutoff. CR on med.: clinical remission on medication

For the IACIs, triamcinolone hexacetonide will be administered at a dose of 1 mg/kg (max 40 mg) in the hips, knees and shoulders, at the dose of 0.75 mg/kg (max 30 mg) in the ankles and elbows, at the dose of 0.5 mg/kg (max 20 mg) in the wrists; methylprednisolone acetate will be administered at the dose of 1 mg/kg (max 40 mg) in the subtalar and inter-tarsal joints and at the dose of 5–10 mg, depending on the size of the child, in the small joints of hands and feet. A course of oral prednisone instead of or in addition to joint injection can be prescribed in case hip, temporomandibular joints or cervical spine are involved, or in case more than four joints are affected or joint injections cannot be performed.

Patients’ assessment and disease activity monitoring

Complete physical examination with joints assessment, main patient/parent reported outcomes collection (including pain level, morning stiffness duration, disease activity self-assessment, physical function, and health-related quality of life), uveitis screening, medication history, treatment adverse events evaluation, and laboratory tests (haematological and biochemical analysis and urinalysis) will be performed at each trial visit.

The level and state of disease activity will be measured in all patients at each step of the study by means of the JADAS10. The JADAS10 [18] is a composite disease activity score validate for use in children with JIA and includes the following 4 measures: physician’s global assessment of disease activity, measured on a 0–10 21-circle Visual Analogue Scale (VAS) where 0 = no activity and 10 = maximum activity; parent/patient global assessment of well-being, measured on a 0–10 21-circle VAS where 0 = very well and 10 = very poor; the count of joints with active disease cut at 10 joints (i.e. 1 point for each active joint up to a maximum of 10 points); and the erythrocyte sedimentation rate (ESR), normalised to a 0 to 10 scale according to the following formula: (ESR (mm/hour) – 20)/10. Before making the calculation, ESR values < 20 mm/hour are converted to 20 and ESR values > 120 m/hour are converted to 120. The definition of the disease states of ID, MiDA, and high disease activity (HDA) based on the JADAS10 refers to the newest version of JADAS10 cut-off values [19, 20]. New cutoffs for oligoarthritis and polyarthritis are shown in Table 2. Data will be collected electronically in the PRINTO web-based platform designed for the PharmaChild registry.

Table 2 New JADAS10 and cJADAS10 cutoffs for disease activity states (Refs [16, 17])Endpoints

The effectiveness of the two therapeutic strategies will be compared by assessing the frequency of clinical remission (CR) at 12 months [21]. CR is defined as the persistence of the JADAS10 state of ID for at least 6 months. Patients will be considered to be in ID from the day of the first visit with JADAS10 ID until the day before the first subsequent visit in which the patient is found to have lost the state of JADAS10 ID. Then, a number of secondary endpoints will be assessed in order to better understand the efficacy of the two treatment strategies (Table 3). The rate of patients achieving the JADAS-defined and the ACR-defined state of ID, the time to achieve ID and clinical remission, the time spent in inactive disease, the cumulative level of disease activity and the rate of uveitis will be compared between the two arms.

Table 3 STARS trial endpointsTreatment adherence

Compliance will be monitored by study personnel at each study visit using diary cards and verbal information from the parent and/or subject. Reasons for missed doses must be recorded in the subject’s source documents and CRF.

Subjects provided with pre-filled syringes of investigational product will be instructed to return the empty packages and unused prefilled syringes in order to review drug accountability and subject compliance.

If more than four consecutive doses are missed due to adverse events (AEs), infections or surgeries, or if more than 2 consecutive doses are missed due to reasons other than AEs, infections or surgery, the Study Coordinating Centre must be consulted in order to determine whether the subject should continue taking investigational product.

Sample size

Sample size calculations were extrapolated from a recent study of early aggressive therapy on JIA patients [11]. Using the sample size calculation for superiority trials with a delta of at least 20% (being the expected proportion of favourable outcome in the first arm p1 = 0.45 and in the second arm p2 = 0.25) and considering a drop out rate of 10%, a sample size of 109 patients in each group for a total of 218 patients will be required. Since an interim analysis is planned at enrolment of half of the sample, the total sample size was increased to 260 subjects. The trial will have 0.8 power for comparisons of the treatment arms, 0.05 type I error.

Analysis plan

For proportional data the chi-square test or, where appropriate, the Fisher’s exact test will be applied. For continuous variables the t-test procedure or the ANOVA will be applied as appropriate. Non-parametric ANOVA will be applied in case of ordinal data or not-normally distributed variables; the Bonferroni correction will be applied for all a-posterior tests, in order to avoid multiple comparisons’ error. Treatment effect size will be calculated by dividing the difference between the baseline and the final visit value by the standard deviation of the first visit value. Survival analysis with censored data will be used in order to evaluate time to remission and time to flare. Survival curves will be drawn with the Kaplan-Meyer method and compared with the Log-Rank test. Emphasis will be placed on the intention-to-treat approach rather than on the analysis of the completers of the trial only. All analysis will be done in a blinded manner. Safety events are recoded by a medical monitor; all visit data are checked by the PRINTO coordinating centre and by a medical monitor. All moderate/severe AEs (including those leading to MTX or biologic treatment discontinuation) will be summarised per patient year of follow-up, describing the relationship to the treatment. The AE incidence rate by drug will be estimated after partitioning the follow-up periods of each patient into subintervals corresponding to the administration of the drug, with any event being attributed to the drug itself. This implicitly assumes the independence of the outcome in different subintervals pertaining to the same patient. Trial data will be entered online by the participating centres on a secure web system managed by the coordinating calculated to compare the primary AE rates with the remaining comparator groups. As possible covariate for the analysis JIA category, gender, age and drug use history will be considered.

Trial registration

The Trial is registered on the ClinicalTrials.gov registry (NCT03728478) on October 31st, 2018 and EU Clinical Trials Register on May 14th, 2018, Eudract Number 2018–001931-27.

Study organisation and funding

The STARS trial is coordinated from the Paediatric Rheumatology InterNational Trials Organisation (PRINTO at www.printo.it) coordinating centre in Genoa, Italy. It is an independent trial funded by the Italian Drug Agency (Agenzia Italiana del Farmaco) and the Compagnia di San Paolo. The trial has an Independent Data and Safety Monitoring Board. In Italian centres, Etanercept as a first-line treatment in subjects in the Step-down arm is provided by Pfizer through an Investigator Initiated Research grant.