Trial of Sequential Medications AfteR TNFi Failure in Juvenile Idiopathic Arthritis

NCT ID: NCT06654882

Last Updated: 2025-10-15

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 400 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-11-30
• Study Completion Date: 2026-12-31

Brief Summary

This study is an open-label, randomized, multicenter trial that incorporates a multi-arm design comparing each of 3 non-TNFi (Tumor Necrosis Factor inhibitor) medications to a second TNFi (active control) within a sequential multiple assignment randomized trial design with 2 randomization stages corresponding with clinical decision points. The first randomization addresses whether each of the 3 non-TNFi medications is superior to treatment with a second TNFi. The second randomization allows identification of optimal sequential use of biologics (treatment strategies).

Detailed Description

The goal of the study is to provide an evidence base for selecting sequential medication(s) if a JIA patient fails initial bDMARD. SMART-JIA is a pragmatic, international, open-label, randomized trial comparing treatment with a second TNFi (active control) to each of 3 different medications (IL-6i, JAKi, or ABA) in children aged 2 to 17 years with pcJIA and inadequate response to initial TNFi. Leveraging sequential multiple assignment randomized trial (SMART) design methodology, we will implement a second randomization to assess the effectiveness of changing medication if there is inadequate response to the first study medication. This approach allows identification of optimal strategies for medication sequencing based on individual characteristics and provides critical insights to inform future studies.

SMART-JIA will study the efficacy of a second TNFi (active control) compared to each of 3 other already US Food and Drug Administration (FDA)-approved and European Union (EU)-approved non-TNFi medications currently used to treat pcJIA (IL-6i, JAKi, and ABA). TNFi, IL-6i, and ABA are administered by subcutaneous (SQ) injection weekly, or every other week, or every three weeks, and JAKi (e.g., tofacitinib) is taken orally twice daily. All study treatments have similar safety profiles and are standard of care (SOC) worldwide. This in addition to the pragmatic and full-scale nature of the trial will ensure its completion. Successful completion of this trial will substantially impact the clinical care and outcomes of children with pcJIA, shifting the current trial-and-error treatment paradigm to a smart, precise approach.

Conditions

Polyarticular Course Juvenile Idiopathic Arthritis (JIA)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Second TNFi (Tumor Necrosis Factor inhibitor) medication

Adalimumab originator or biosimilar; etanercept originator or biosimilar depending on which TNFi the participant had failed.

Group Type: ACTIVE_COMPARATOR

TNFi (Tumor Necrosis Factor inhibitor) medication

Intervention Type: DRUG

Adalimumab 10 kg (22 lbs) to <15 kg (33 lbs) 10 mg every other week* 15 kg (33 lbs) to <30 kg (66 lbs) 20 mg every other week ≥30 kg (66 lbs) 40 mg every other week

Etanercept

≥63 kg (138 lb) 50 mg weekly <63 kg (138 lb) 0.8 mg/kg weekly

Abatacept

The 50 mg, 87.5 mg and 125 mg SQ doses will be available for weight-based dosing. All participants randomized to abatacept in the first or second stage randomization will receive abatacept SQ weekly at a dosage based on the participant's body weight

Group Type: ACTIVE_COMPARATOR

Abatacept

Intervention Type: DRUG

10 kg to <25 kg 50 mg once weekly 25 kg to <50 kg 87.5 mg once weekly

≥50 kg 125 mg once weekly

Tocilizumab originator or biosimilar

Tocilizumab will be provided in prefilled syringes (162 mg tocilizumab/0.9 mL solution). All participants randomized to tocilizumab in the first or second stage randomization will be receiving 1 prefilled syringe (162 mg) with a dosing interval based on the body weight criteria.

Group Type: ACTIVE_COMPARATOR

Tocilizumab

Intervention Type: DRUG

<30 kg 162 mg once every 3 weeks

≥30 kg 162 mg once every 2 weeks

Tofacitinib

Tofacitinib will be provided as oral tablets (tofacitinib citrate 5 mg) and as an oral solution (1 mg/mL). All participants randomized to tofacitinib in the first or second stage randomization will receive tofacitinib oral tablets or oral solution twice daily, approximately 12 hours apart, in the morning and evening, at a dosage based on the participant's body weight .

Group Type: ACTIVE_COMPARATOR

Tofacitinib

Intervention Type: DRUG

10 to <20 kg 3.2 mg (3.2 mL oral solution) BID 20 to <40 kg 4 mg (4 mL oral solution) BID

≥40 kg 5 mg (one 5 mg tablet or 5 mL oral solution) BID

Interventions

TNFi (Tumor Necrosis Factor inhibitor) medication

Adalimumab 10 kg (22 lbs) to <15 kg (33 lbs) 10 mg every other week* 15 kg (33 lbs) to <30 kg (66 lbs) 20 mg every other week ≥30 kg (66 lbs) 40 mg every other week

Etanercept

≥63 kg (138 lb) 50 mg weekly <63 kg (138 lb) 0.8 mg/kg weekly

Intervention Type: DRUG

Abatacept

10 kg to <25 kg 50 mg once weekly 25 kg to <50 kg 87.5 mg once weekly

≥50 kg 125 mg once weekly

Intervention Type: DRUG

Tocilizumab

<30 kg 162 mg once every 3 weeks

≥30 kg 162 mg once every 2 weeks

Intervention Type: DRUG

Tofacitinib

10 to <20 kg 3.2 mg (3.2 mL oral solution) BID 20 to <40 kg 4 mg (4 mL oral solution) BID

≥40 kg 5 mg (one 5 mg tablet or 5 mL oral solution) BID

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Polyarticular course JIA
• Moderate or high-disease activity (cJADAS10 >5) despite treatment with an initial TNFi for ≥3 months
• Age ≥2 years and <18 years and weight ≥ 10kg
• No systemic glucocorticoids or systemic glucocorticoids at a stable dose of ≤0.2 mg/kg/day (maximum 10 mg/day) for ≥2 weeks prior to baseline visit
• Documented informed consent/assent obtained from the parent/caregiver/patient

Exclusion Criteria

• Systemic JIA
• Enthesitis-related arthritis/juvenile spondyloarthritis (2001 International League of Associations for Rheumatology [ILAR] criteria)30
• History of or currently active inflammatory bowel disease
• History of or currently active psoriasis
• Active uveitis within 3 months of the baseline visit
• History of or currently active sacroiliitis
• History of or current malignancy
• Active tuberculosis (TB) or a history of incompletely treated TB; Purified Protein derivative (PPD) or QuantiFERON-TB positive patients (without active TB) unless it is documented that the patient has been adequately treated for TB and can start treatment with a biologic agent, based on the medical judgment of the site investigator and/or an infectious disease specialist; suspected extrapulmonary TB infection; or at high risk of contracting TB, such as close contact with individual with active or latent TB
• Prior treatment with more than one TNFi molecule; exposure to more than one biosimilar of the same TNFi molecule is allowed
• Prior treatment with non-TNFi bDMARDs and/or any JAKi
• Aspartate aminotransferase (AST) or alanine transaminase (ALT) ≥3 × upper limit of normal (ULN) for age and sex
• Serum creatinine >1.5 × ULN for age and sex
• Platelet count <150 × 103/μL (<150,000/mm3)
• Hemoglobin <7.0 g/dL (<4.3 mmol/L)
• White blood cell (WBC) count <3,000/mm3 (<3.0 × 109/L)
• Neutrophil count <1,500/mm3 (<1.5 × 109/L)
• Any active acute, subacute, chronic, or recurrent bacterial, viral, or systemic fungal infection or any major episode of infection requiring hospitalization or treatment during screening or treatment with IV antibiotics completed within 4 weeks of the screening visit or oral antibiotics completed within 2 weeks of the screening visit
• Any medical history that may be considered a contraindication/safety concern with the use of adalimumab, etanercept, tofacitinib, ABA, or an IL-6 inhibitor or their biosimilars, in the opinion of the site investigator

• Minimum Eligible Age: 2 Years
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Patient-Centered Outcomes Research Institute

OTHER

Sponsor Role: collaborator

Duke University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Central Contacts

Laura E Schanberg (Contact PI)

Role: CONTACT

laura.schanberg@duke.edu

919-373-3863

Huiman Barnhart (Dual PI)

Role: CONTACT

huiman.barnhart@duke.edu

919-668-8828

Other Identifiers

PLACER-2022C3-30331

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

EPM #8533

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

Pro00115808

Identifier Type: -

Identifier Source: org_study_id