STep-up and Step-down Therapeutic Strategies in Childhood ARthritiS

Official title

Comparison of STep-up and Step-down Therapeutic Strategies in Childhood ARthritiS

Overview

This study aims 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 the initial start of a combination of conventional and biological DMARDs (step-down strategy).

Detailed description

Although their approach is different, both interventions are aimed to obtain a quick and robust disease control and to maintain it over time. Compelling evidence exists that in children with chronic arthritis early intensive therapy may take advantage of the so-called "window of opportunity", in which the biology of the disease can be altered to improve long-term disease outcomes, including prevention of cumulative joint damage. Recent experiences in children with systemic JIA have shown that early anti-IL-1 therapy may lead to rapid achievement of inactive disease and allow early treatment discontinuation without disease relapses in many patients. The benefits of early treatment with biologic agents in other JIA categories are less clear, but convincing evidence has been recently reported for polyarthritis.

Interventions

• Drug Etanercept
  Patients will receive etanercept subcutaneously at a dose of 0.8 mg/kg weekly (up to a maximum dose of 50 mg weekly).
• Drug Methotrexate
  Methotrexate will be administered subcutaneously, in a single weekly dose of 15 mg/m2 (max 20 mg).
• Drug Intra-articular corticosteroid injections
  Triamcinolone hexacetonide and methylprednisolone acetate doses depend on the affected joint.

Primary outcome measures

• Clinical remission on or off medication at 12 months [Time frame: 12 months]

Secondary outcome measures (8)

• Inactive disease [Time frame: 12 months]
• Time to inactive disease as per JADAS/JIA ACR criteria [Time frame: 12 months]
• Time to JADAS/JIA ACR clinical remission [Time frame: 12 months]
• Time spent in JADAS/JIA ACR inactive disease [Time frame: 12 months]
• Cumulative level of disease activity throughout the study period [Time frame: 12 months]
• Time spent on therapy [Time frame: 12 months]
• Rate of flares [Time frame: 12 months]
• Rate of uveitis onset [Time frame: 12 months]

Eligibility criteria

Inclusion criteria

Each patient must meet all the following criteria in order to be enrolled in the trial:

I. Newly-diagnosed and synthetic or biologic DMARD-naïve children (only treatment with 1 NSAID is allowed and no corticosteroid joint injections prior to randomization ) with a JIA classified according to the following ILAR categories:

i. Oligoarthritis ii. Rheumatoid factor negative polyarthritis

II. Active arthritis

III. Onset of JIA symptoms no more than 6 months before randomization

IV. Age 2 to 17 years at enrolment.

V. Female of child-bearing potential must have a negative pregnancy test at the beginning of the trial. If sexually active, they must agree to use highly effective contraceptive measures, throughout study participation, and must have no intention of conceiving during the course of the study. Post-pubertal males must have no plans to father a child during the study and agree to use highly effective contraceptive measures if sexually active.

VI. Ability to comply with the entire study procedures, ability to communicate meaningfully with the investigational staff, competence to give written informed consent; to be applied to the parents and/or patients, as appropriate

VII. Duly executed, written, informed consent/assent obtained from the parents/patient.

Exclusion criteria

I. Classification in one of the following JIA categories: systemic arthritis, RF-positive polyarthritis, psoriatic arthritis, enthesitis-related arthritis, undifferentiated arthritis

II. Patients who need systemic treatment for uveitis

III. Tuberculosis related issues: patients are excluded from the study if they have:

• Active TB or a history of incompletely treated TB
• PPD or QuantiFERON-TB positive patients (with no active disease) unless it is documented by a specialist that the patient has been adequately treated for TB and can start treatment with a biologic agent, based on the medical judgment of the study investigator and / or an infectious disease specialist.
• Suspected extrapulmonary TB infection
• Patients at high risk of contracting TB, such as close contact with individual with active or latent TB

IV. Previous treatment with any synthetic or biologic DMARD

V. Any live attenuated vaccine within 4 weeks prior to the baseline visit, such as varicella-zoster, oral polio, measles, mumps or rubella vaccines and throughout the study. Killed or inactive vaccine may be permitted based on the investigator's judgment

VI. Prior or current history of malignancy or any other significant concomitant illness(es) as per the treating physician evaluation

VII. Any of the following laboratory abnormalities based on the most recent laboratory results:

• White blood cell (WBC) count <3.50 x 103/mm3 (SI units: <3.50 x 109/L) and neutrophils < 1x109/L;
• Hemoglobin < 8.5 g/dL (SI units: <85 g/L);
• Platelet Count < 125,0000/mm3 or ≥1,000,000/mm3 (SI units: <125 x 109/L or ≥1,000 x 109/L
• Aspartate aminotransaminase (AST) or alanine aminotransaminase (ALT) ≥ 2.0 x upper limit of normal (ULN).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Italy · 1 center

• IRCCS Istituto Giannina Gaslini — Genova

Publications

• Wallace CA, Giannini EH, Spalding SJ, Hashkes PJ, O'Neil KM, Zeft AS, Szer IS, Ringold S, Brunner HI, Schanberg LE, Sundel RP, Milojevic D, Punaro MG, Chira P, Gottlieb BS, Higgins GC, Ilowite NT, Kimura Y, Hamilton S, Johnson A, Huang B, Lovell DJ; Childhood Arthritis and Rheumatology Research Alliance. Trial of early aggressive therapy in polyarticular juvenile idiopathic arthritis. Arthritis Rh PMID 22183975
• Ravelli A, Consolaro A, Horneff G, Laxer RM, Lovell DJ, Wulffraat NM, Akikusa JD, Al-Mayouf SM, Anton J, Avcin T, Berard RA, Beresford MW, Burgos-Vargas R, Cimaz R, De Benedetti F, Demirkaya E, Foell D, Itoh Y, Lahdenne P, Morgan EM, Quartier P, Ruperto N, Russo R, Saad-Magalhaes C, Sawhney S, Scott C, Shenoi S, Swart JF, Uziel Y, Vastert SJ, Smolen JS. Treating juvenile idiopathic arthritis to ta PMID 29643108
• Tan J, Renton WD, Whittle SL, Takken T, Johnston RV, Tiller G, Munro J, Buchbinder R. Methotrexate for juvenile idiopathic arthritis. Cochrane Database Syst Rev. 2024 Feb 9;2(2):CD003129. doi: 10.1002/14651858.CD003129.pub2. PMID 38334147
• Burrone M, Mazzoni M, Naddei R, Pistorio A, Spelta M, Scala S, Patrone E, Garrone M, Lombardi M, Villa L, Pascale G, Cavanna R, Ruperto N, Ravelli A, Consolaro A; Paediatric Rheumatology International Trials Organisation (PRINTO). Looking for the best strategy to treat children with new onset juvenile idiopathic arthritis: presentation of the "comparison of STep-up and step-down therapeutic strate PMID 36071444

Identifiers

NCT: NCT03728478 · 2018-001931-27

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗