Trial of Sequential Medications AfteR TNFi Failure in Juvenile Idiopathic Arthritis (SMART-JIA)

Duke University

Status and phase: Begins enrollment in 1 month; Phase 3

Conditions: Polyarticular Course Juvenile Idiopathic Arthritis (JIA)

Treatments: Drug: Tocilizumab; Drug: Abatacept; Drug: Tofacitinib; Drug: TNFi (Tumor Necrosis Factor inhibitor) medication

Study type: Interventional

Funder types: Other

Identifiers

NCT06654882

EPM #8533 (Other Grant/Funding Number)

PLACER-2022C3-30331 (Other Grant/Funding Number)

Pro00115808

Details and patient eligibility

About

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).

Full 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.

Enrollment: 400 estimated patients

Sex: All

Ages: 2 to 17 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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400 participants in 4 patient groups

Second TNFi (Tumor Necrosis Factor inhibitor) medication

Active Comparator group

Description:

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

Treatment:

Drug: TNFi (Tumor Necrosis Factor inhibitor) medication

Abatacept

Active Comparator group

Description:

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

Treatment:

Drug: Abatacept

Tocilizumab originator or biosimilar

Active Comparator group

Description:

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.

Treatment:

Drug: Tocilizumab

Tofacitinib

Active Comparator group

Description:

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 .

Treatment:

Drug: Tofacitinib