Additional Pharmacovigilance Study to Evaluate the Risks of Major Hemorrhage With the Administration of IMBRUVICA® (ibrutinib)

Study type

• Study topic:
  Disease /health condition

  Human medicinal product
• Study type:
  Non-interventional study
• Scope of the study:
  Assessment of risk minimisation measure implementation or effectiveness
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Cohort

  Other
• Non-interventional study design, other:
  Case-series, Retrospective analysis of clinical trials data (cohort study) and post-marketing safety data (case series).

Study drug and medical condition

• Study drug International non-proprietary name (INN) or common name:
  IBRUTINIB
• Anatomical Therapeutic Chemical (ATC) code:
  (L01XE27) ibrutinib

  ibrutinib
• Medical condition to be studied:
  Subarachnoid haemorrhage

  Subdural haemorrhage

  Cerebral haemorrhage

Population studied

• Short description of the study population:
  Patients treated with ibrutinib therapy.
• 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:
  2838

Study design details

• Main study objective:
  Primary objective: to characterize the risks of major hemorrhage associated with ibrutinibtherapy in various patient populations from all completed clinical trials and postmarketingsources. Secondary objective: To evaluate the risks of major hemorrhagic events and theirpotential association with the concomitant use of anti-platelet and/or anticoagulant drugs.
• Outcomes:
  major hemorrhage(MH) incidence. Clinical studies:MH defined as G3+ non-serious AEs,SAEs, or any-grade CNS hemorrhage terms that mapped to MedDRA v 21.0 'Haemorrhageterms (excluding laboratory terms)' sub-SMQ. GSD: MH defined as any SAE terms thatmapped to MedDRA v21.0 SMQ of 'Haemorrhages', incl sub-SMQs of 'Haemorrhagelaboratory terms' and 'Haemorrhage terms (excluding laboratory terms)'. The relative risk (RR) of MH associated with concomitant use of antiplatelet (AP) and/oranticoagulant (AC) was evaluated with both the crude incidence and AC and/or APexposure-adjusted incidence rates (EAIRs).
• Data analysis plan:
  Demographics and baseline characteristics were summarized using descriptive statistics.Major hemorrhage incidence was summarized by system organ class, preferred term, and maximum NCI-CTCAE toxicity grade. Exposure-adjusted incidence rate (per subject, per preferred term, per system organ class, and on a global level) was calculated usingpatient-months as denominator. Cox-regression analysis was used to perform univariate and multivariate analysis of risk factors including baseline characteristics and time-dependent variables for developing major hemorrhage. All analyses were performed for Total Ibrutinib Pool and Randomized Controlled Trial Pool separately.