Trial of Sequential Medications AfteR TNFi Failure in Juvenile Idiopathic Arthritis

Обзор

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).

Подробное описание

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.

Вмешательства

• Препарат 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
• Препарат 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
• Препарат Tocilizumab
  \<30 kg 162 mg once every 3 weeks ≥30 kg 162 mg once every 2 weeks
• Препарат 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

Первичные конечные точки

• Number of participants with MiDA [Срок оценки: Month 6]

Вторичные конечные точки (6)

• PROMIS® Pain Interference at Month 6 [Срок оценки: Month 6]
• PROMIS® Fatigue at Month 6 [Срок оценки: Month 6]
• PROMIS® Physical Function at Month 6 [Срок оценки: Month 6]
• Change in arthritis disease activity (cJADAS10) [Срок оценки: Month 6]
• Change in arthritis disease activity (JIA American College of Rheumatology Pediatric 70 [ACR 70]) at Month 6 [Срок оценки: Month 6]
• Number of participants with MiDA (Change in arthritis disease activity [cJADAS10] at Month 12) [Срок оценки: Month 12]

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 4 центра

• University of California San Francisco Pediatric Rheumatology — San Francisco
• University of Florida — Gainesville
• Hackensack Meridian Health - Joseph M. Sanzari Children's Hospital — Hackensack
• Nationwide Children's Hospital — Columbus

Германия · 1 центр

• Asklepios Children's Hospital — Sankt Augustin

Италия · 1 центр

• IRCCS Giannina Gaslini Institute — Genoa

Идентификаторы

NCT: NCT06654882 · Pro00115808 · PLACER-2022C3-30331 · EPM #8533

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗