Clinical trial NCT03728478: STep-up and Step-down Therapeutic Strategies in Childhood ARthritiS
Official title: Comparison of STep-up and Step-down Therapeutic Strategies in Childhood ARthritiS
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Oligoarthritis, Juvenile
Polyarthritis, Juvenile, Rheumatoid Factor Negative
Keywords: juvenile idiopathic arthritis
treatment
treat to target
Lead sponsor: Istituto Giannina Gaslini
Sponsor class: OTHER
Collaborators: name: Agenzia Italiana del Farmaco
name: Compagnia di San Paolo
name: Pfizer
First posted: 2018-11-02
Enrollment: 260
Sex: ALL
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a a 12-month open label, randomised, actively controlled, multi-centre, prospective, superiority trial of two different treatment strategies (Step-down versus Step-up).

After signature of informed consent/assent 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.

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, and long-term disease-related morbidity.
Primary purpose: TREATMENT

Brief summary: 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.

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:

1. Active TB or a history of incompletely treated TB
2. 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.
3. Suspected extrapulmonary TB infection
4. 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:

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

Primary outcomes:
measure: Clinical remission on or off medication at 12 months
timeFrame: 12 months
Secondary outcomes:
measure: Inactive disease
timeFrame: 12 months
measure: Time to inactive disease as per JADAS/JIA ACR criteria
timeFrame: 12 months
measure: Time to JADAS/JIA ACR clinical remission
timeFrame: 12 months
measure: Time spent in JADAS/JIA ACR inactive disease
timeFrame: 12 months
measure: Cumulative level of disease activity throughout the study period
timeFrame: 12 months
measure: Time spent on therapy
timeFrame: 12 months
measure: Rate of flares
timeFrame: 12 months
measure: Rate of uveitis onset
timeFrame: 12 months
Other outcomes:
Locations:
city: Genova
country: Italy
facility: IRCCS Istituto Giannina Gaslini
state: GE
Study officials:
References:
citation: 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 Rheum. 2012 Jun;64(6):2012-21. doi: 10.1002/art.34343. Epub 2011 Dec 19.
citation: 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 target: recommendations of an international task force. Ann Rheum Dis. 2018 Jun;77(6):819-828. doi: 10.1136/annrheumdis-2018-213030. Epub 2018 Apr 11.
citation: 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 strategies in childhood ARthritiS" (STARS) trial. Pediatr Rheumatol Online J. 2022 Sep 7;20(1):80. doi: 10.1186/s12969-022-00739-x.