An active surveillance, post-authorization safety study (PASS) of serious infection, malignancy, cardiovascular and other safety events of interest among patients treated with tofacitinib for moderately to severely active rheumatoid arthritis within the British Society for Rheumatology Biologics Register-Rheumatoid Arthritis (BSRBR-RA) (Safety of tofacitinib in BSRBR-RA)

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

• Medicinal product name:
  XELJANZ
• Study drug International non-proprietary name (INN) or common name:
  TOFACITINIB CITRATE
• Anatomical Therapeutic Chemical (ATC) code:
  (L04AF01) tofacitinib

  tofacitinib
• Medical condition to be studied:
  Rheumatoid arthritis

Population studied

• Short description of the study population:
  The active surveillance population includes rheumatoid arthritis patients already enrolled in the register who met the criteria for the cohorts as defined in protocol section 9.3.2 as well as patients with rheumatoid arthritis, newly treated with tofacitinib following EMA approval and UK launch of the product (fully available January 2018) and registered with the BSRBR-RA.
• Age groups:
  • Adults (18 to < 46 years)
  • Adults (46 to < 65 years)
  • Adults (65 to < 75 years)
  • Adults (75 to < 85 years)
  • Adults (85 years and over)
• Estimated number of subjects:
  500

Study design details

• Study design:
  This is an active surveillance study using existing data within the existing British Society for Rheumatology Biologics Register for RA (BSRBR-RA), an ongoing prospective observational cohort study started in 2001.
• Main study objective:
  To evaluate the rates of serious infections, malignancy (overall, excluding NMSC), subtypes of lymphoma, lung cancer, CV, MACE, MI, VTE (DVT and PE) and other specified outcomes, including fractures, among patients with RA in an existing UK based register who initiate tofacitinib. ; Rates will also be estimated among existing cohorts of patients treated with TNFi therapies to provide context for rates observed on tofacitinib. No a priori hypotheses will be tested in this descriptive study. Pending feasibility, rates of malignancy (overall, excluding NMSC), lung cancer, subtypes of lymphoma, serious infection, CV events, MACE, and MI, VTE, and other event rates, including fractures, will be compared between tofacitinib treated RA patients and the comparator cohorts using methods that adjust for sex, age, year of treatment start, treatment history, disease severity, comorbidities, and other potential confounders. ; In response to the June 2021 signal evaluation procedure, subtypes of lymphoma, lung cancer, and MACE have been added as study endpoints (MI and lymphoma (overall) were already included as a study endpoint). ; Further, rates of events, including serious infections, MACE, MI, VTE and malignancies excluding NMSC, will be estimated in elderly patients aged 65 years and older.
• Setting:
  The BSRBR-RA was established in 2001 to study the safety of biologic therapies in RA patients living in the UK. For the first 78 years the main focus was on the study of the safety profile of the first three TNFi agents (ie, ADA, ETA and INF) as a class and as individual therapies. ; With the exception of the risk of developing tuberculosis, data within the BSRBRRA has not demonstrated any clear differences in AE profile between these agents. ; At the time the register was established, the most appropriate comparison group for these three TNFi agents was patients with active RA receiving treatment with csDMARDs. ; The register remains a relevant resource for studying the safety profile of new biologic, biosimilar and other targeted therapies as they receive National Institute for Health and Clinical Excellence (NICE) approval and are used in real-world practice where patients have more diverse clinical background and comorbidities than a typical clinical trial population.; ; Unique features of BSRBR-RA include recruitment and collection of data from parallel comparison groups of patients consisting of (i) those with active RA who were treated with csDMARDs, and (ii) those with active RA who are biologic naïve treated with TNFi, a high proportion of recruited patients in the UK (>80%), and linkage with national mortality and malignancy registries. 9 Several studies have been conducted using data from the; BSRBR-RA including work regarding risks of infections,10 and malignancies. 19,25 All patients within the BSRBR-RA provided informed and signed consent for participation (Study Reference 00/8/053).; ; External validity, ie, generalizability to RA patients who are not enrolled in the register, is maximised by encouraging physicians to enroll each and every patient meeting inclusion criteria, regardless of their baseline demographic or clinical characteristics or treatment history.
• Comparators:
  Initiation of biologic (comparator cohort 1), discontinuation of biologic (comparator cohort 2)
• Outcomes:
  1. Aplastic Anaemia, Pancytopaenia, Serious Neutropenia; ; 2. Cerebrovascular Accident; ; 3. Death; ; 4. Demyelination, Optic Neuritis; ; 5. Fractures; ; 6. Hepatitis B Reactivation; ; 7. Malignancy (overall, excluding NMSC); ; 8. Lymphoma (overall and independently by subtype, including non-Hodgkin lymphoma, Hodgkin lymphoma, and chronic lymphatic leukemia); ; 9. Lung Cancer; ; 10. NMSC; ; 11. Myocardial Infarction/Acute Coronary Syndrome; ; 12. Major Adverse Cardiac Events (MACE) ; 13. Pregnancy; ; 14. Progressive Multifocal Leukoencephalopathy (PML); ; 15. Pulmonary Embolism; ; 16. Serious Congestive Heart Failure; ; 17. Serious Infusion/Immunologic Reaction; ; 18. Serious Hypersensitivity Reaction; ; 19. Serious Infection; ; 20. Herpes Zoster; ; 21. Serious Hepatic Dysfunction/Failure; ; 22. Serious Lower Gastrointestinal Ulcer/Bleed/Perforation; ; 23. Serious Lupus/ Lupus-Like Illness; ; 24. Serious Skin Reaction (eg, Stevens Johnson syndrome, erythema multiforme, toxic epidermal necrosis); ; 25. Serious Haemorrhage; ; 26. Tuberculosis; ; 27. Venous thromboembolic events (DVT and PE); ; 28. All-cause mortality.
• Data analysis plan:
  The initial analyses will consist of descriptive comparisons of baseline status and crude event rates between the different cohorts. The final analysis of endpoints will provide the rates of events overall and in subgroups defined by baseline characteristics. ; Pending feasibility, rates of malignancy, serious infection, CV and other event rates will be compared between tofacitinib treated RA patients and the comparator cohorts using methods that adjust for sex, age, year of treatment start, treatment history, disease severity, comorbidities, and other potential confounders.