Post-Authorisation Active Safety Surveillance Program Among Patients Treated With Tofacitinib for Polyarticular Juvenile Idiopathic Arthritis (pJIA) and Juvenile Psoriatic Arthritis (PsA) Within the German Biologics in Pediatric Rheumatology Registry (BiKeR) and Juvenile Arthritis Methotrexate/Biologics Long-term Observation (JuMBO) Registries (BiKeRJuMBO)

Study type

• Study topic:
  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Safety study (incl. comparative)
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Name of medicine:
  XELJANZ
• Study drug International non-proprietary name (INN) or common name:
  TOFACITINIB CITRATE
• Anatomical Therapeutic Chemical (ATC) code:
  (L04AA29) tofacitinib

  tofacitinib
• Medical condition to be studied:
  Juvenile psoriatic arthritis

  Juvenile idiopathic arthritis

Population studied

• Short description of the study population:
  The study population will comprise all patients with pJIA or juvenile PsA enrolled within the BiKeR and JuMBO registries who receive tofacitinib following product availability in Germany on 01 March 2022 through 01 July 2031. One comparator cohort comprised of patients with pJIA or juvenile PsA treated with approved bDMARDs will be assembled to provide context for rates observed among patients treated with tofacitinib.
• Age groups:
  Children (2 to < 12 years)

  Adolescents (12 to < 18 years)

Study design details

• Study design:
  This is an active surveillance cohort study utilizing data from patients with pJIA or juvenile PsA from the two German registries separately, namely the BiKeR and JuMBO registries.
• Main study objective:
  To estimate the incidence rate of the following outcomes of interest among patients with pJIA or juvenile PsA who initiate tofacitinib and patients with pJIA or juvenile PsA treated with approved bDMARDs: venous thromboembolism, serious infections and other important infections, all malignancies combined (excluding NMSC), lymphoma (examined separately), and lung cancer (examined separately).
• Setting:
  The study period will be defined from 01 March 2022 (corresponding to Tofacitinib availability in Germany) to 01 July 2032. The German BiKeR registry is a longitudinal multicenter observational registry that is an initiative of the Centre for Pediatric Rheumatology Sankt Augustin supported by the German Society for Childhood Rheumatology [Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)]. The registry was set up in 2001 by pediatric rheumatologists in Germany to prospectively monitor the long term safety and effectiveness of biologics in treatment of JIA. During the first six years of BiKeR, one-third of patients were lost to follow-up for age-related reasons. It is recognized that follow-up of patients beyond adolescence is necessary to yield scientifically rigorous long-term safety information about bDMARDs in JIA patients. Therefore, JuMBO was launched as the BiKeR follow-up register for adult JIA patients in 2007. In general, BiKeR and JuMBO registries have been used in previously published studies to assess the safety and effectiveness of DMARDs in JIA patients and these registries aim to provide results that help to guide therapeutic decisions by providers for affected children, families; to; improve post-marketing drug surveillance; and to reduce cost.
• Comparators:
  BiKeR comparator cohort: Patients with pJIA or juvenile PsA treated with approved bDMARDs; 1. Diagnosis of pJIA defined as extended oligoarthritis, Polyarthritis (RF+), or Polyarthritis (RF-) or juvenile PsA by a rheumatologist; 2. Patients younger than 16 years at diagnosis of pJIA or juvenile PsA; 3. Patients aged 2-17 years at initiation of any bDMARD approved for pJIA or juvenile PsA treatment in Germany (e.g., etanercept, adalimumab, abatacept, tocilizumab, golimumab). This is first use of unique bDMARD, not restricted to first bDMARD use (i.e., not restricted to bDMARD naïve patients). For example, a patient starting etanercept for the first time during the period of 01 March 2022 to 01 July 2031 will be eligible regardless of this patient’s prior use of another bDMARD, for example tocilizumab.; 4. Patients initiating a bDMARD as a monotherapy or in combination with MTX identified from the BiKeR registry between 01 March 2022 through 01 July 2031; ; JuMBO Comparator Cohort: Patients with pJIA or juvenile PsA treated with approved bDMARDs ; 1. Must be previously enrolled in BiKeR registry; 2. Diagnosis of pJIA defined as extended oligoarthritis, Polyarthritis (RF+), or Polyarthritis (RF-) or juvenile PsA by a pediatric or adult rheumatologist; 3. Patients younger than 16 years at diagnosis of pJIA or juvenile PsA; 4. Patients aged 2-17 years at initiation of any bDMARD approved for pJIA or juvenile PsA treatment in Germany (e.g., etanercept, adalimumab, abatacept, tocilizumab, golimumab). This is first use of unique bDMARD, not restricted to first bDMARD use (i.e., not restricted to bDMARD naïve patients). For example, a patient starting etanercept for the first time during the period of 01 March 2022 to 01 July 2031 will be eligible regardless of this patient’s prior use of another bDMARD, for example tocilizumab.; 5. Patients initiating a bDMARD as a monotherapy or in combination with MTX identified from the JuMBO registry between 01 March 2022 through 01 July 2031;
• Outcomes:
  All outcomes, with the exception of growth or development disturbances, will be identified using the Medical Dictionary for Regulatory Activities (MedDRA) codes in both registries. Please see protocol Annex 1 for relevant MedDRA codes.; • Venous thromboembolism; • Serious infections and other important infections (including opportunistic infection, tuberculosis and ; vaccine preventable infections); • All malignancies combined (excluding NMSC); • Lymphoma (examined as a separate outcome); • Lung cancer (examined as a separate outcome); • Gastrointestinal perforations; • Major adverse cardiac events (including MI)
• Data analysis plan:
  Crude incidence rates (IRs) of events overall and stratified by baseline characteristics such as disease activity, subtype of JIA, treatment type defined as monotherapy or combination therapy with MTX on the index date, and prior JIA therapy in both tofacitinib cohort and comparator cohort will be calculated. A comparative analysis will examine the risk of the outcomes of interest among patients from the tofacitinib cohort compared to the patients from the comparator cohort adjusting for confounding by baseline characteristics. Propensity scores will be estimated using baseline characteristics described in the study protocol. Propensity score adjusted IR (per 100 PY) and associated 95% CI will be calculated for the outcomes of interest, for which there are adequate data using an exact Poisson method. Where there are adequate data to compare the risk between cohorts, multivariable Cox proportional hazards models will be fit to compare risk of the outcome of interest.