An Active Safety Surveillance Study to Estimate Incidence Rates of Safety Events of Interest among Patients Treated with Tofacitinib for Polyarticular Course Juvenile Idiopathic Arthritis (pcJIA) within the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry in the United States

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:
  (L04AF01) tofacitinib

  tofacitinib
• Additional medical condition(s):
  polyarticular course juvenile idiopathic arthritis

Population studied

• Short description of the study population:
  The study population will include pcJIA patients ≥2 years who receive tofacitinib within the CARRA registry, following US approval, through one year prior to the end of the study period. ; The study population will also include a contemporaneous cohort of pcJIA patients ≥2 years who initiate approved bDMARDs on or after the tofacitinib approval date, through one year prior to the end of the study period.
• Age groups:
  Children (2 to < 12 years)

  Adolescents (12 to < 18 years)

Study design details

• Study design:
  This is an active surveillance, cohort study using prospectively collected data from the existing CARRA Registry.
• Main study objective:
  1) The primary objective is to estimate the incidence rate of thrombosis, infections (including opportunistic infections and serious infections), all malignancies combined (excluding NMSC), NMSC, lymphoma, lung cancer, growth effects, and fractures among pcJIA patients who initiate tofacitinib post-approval as well as pcJIA patients who initiate approved bDMARDs.; 2) The secondary objective is to estimate the incidence rate of major adverse cardiovascular events (MACE) and vaccine preventable infections among pcJIA patients who initiate tofacitinib post-approval as well as pcJIA patients who initiate approved bDMARDs.
• Setting:
  CARRA is a research network of 107 pediatric rheumatology clinical practice sites in the US and internationally, founded in 2002 by pediatric rheumatologists. ; The CARRA Registry is an observational registry that collects longitudinal information on children and adolescents who have pediatric rheumatic diseases at approximately 70 academic pediatric rheumatology centers in the US, Canada, and Israel. ; The objectives of the CARRA Registry are to collect and analyze safety data in the context of the natural history of rheumatic disease in children with a focus on robust collection of medication data, serious adverse events (SAEs), and long-term follow-up.; The CARRA Registry began prospectively collecting data in the US and Canada in July 2015 with the primary aim of studying the safety of new therapies for JIA during routine clinical use and has since expanded to include sites outside of North America as well as patients with childhood-onset systemic lupus erythematosus, juvenile dermatomyositis, localized scleroderma. The CARRA Registry is used extensively to conduct safety surveillance and satisfy post-marketing commitments and requirements to regulatory authorities, such as the FDA. ; The Registry has currently enrolled over 10,000 participants with JIA from approximately 70 geographically diverse pediatric rheumatology centers in the United States, Canada, and Israel.; Data are collected every 6 months from standard-of-care clinical encounters and include clinical assessments, detailed medication use, and safety events. ; Patients who stop receiving care at a CARRA registry site continue to contribute data to the registry every six months via a long-term follow-up program. Long-term follow-up data collection is managed by the Registry’s coordinating center and may occur over the phone or via online survey. ; The Registry follows all patients for a minimum of 10 years each with no cap to the upper age of; follow-up.
• Outcomes:
  Primary; 1) Overall thrombosis (venous thromboembolism [VTE] and arterial thromboembolism [ATE]); a) VTE (which includes deep vein thrombosis [DVT] and pulmonary embolism [PE); b) ATE; 2) Infections; a) Opportunistic infections; b) Tuberculosis; c) Herpes zoster; d) Serious infections: defined as any serious infection event that meets any of the following criteria: death, life- ; threatening, require inpatient hospitalization or prolongation of existing hospitalization, persistent or ; significant disability/incapacity, congenital anomaly or birth defect, important medical event or requiring ; treatment with IV antimicrobials.; 3) All malignancies combined (excluding NMSC); 4) NMSC; 5) Lymphoma; 6) Lung cancer; 7) Growth effects; a) Height velocity z-score: Annual height velocity will be determined for each patient; every 12 months after the index date by subtracting the height measured 12 months previously from the current height. The mean and standard deviation of the height velocity in centimeters per year will be determined for both exposure cohorts for each year of the study. Because height velocity is dependent upon age and sex, and these characteristics may differ between the tofacitinib and bDMARD exposure cohorts, the age- and sex-adjusted standard score (z-score) will be determined for each patient’s annual height velocity using a standard reference. The mean and standard deviation of the age- and sex-adjusted z-score will be determined for both exposure cohorts for each year of the study.; Secondary; 9) Vaccine preventable infections (e.g., treated with IV antimicrobial or opportunistic infection); 10) Major adverse CV events (which includes stroke, MI, and CV death)
• Data analysis plan:
  The interim analysis will consist of descriptive comparisons of baseline characteristics, drug utilization data describing all tofacitinib treatment patterns, including switching patterns from tofacitinib to any other biologic agent including TNFi or nonbiologic agent used in the treatment of pcJIA and vice versa and duration of use before switch, and crude event rates by treatment cohorts.; The final analysis of outcomes will provide treatment group-specific rates of events overall and in subgroups defined by baseline characteristics. ; Data analysis will include malignancy outcomes defined as all malignancies combined (excluding NMSC), NMSC, lymphoma and lung cancer and non-malignancy outcomes defined as all outcomes of interest other than the malignancy outcomes. ; Non-malignancy outcomes are thought to potentially occur at a higher rate while on drug, but that increased risk subsides after the drug is discontinued (ie, serious infections).