Clinical trial NCT06224452: Is Ibrutinib-related Atrial Fibrillation Dose Dependent
Official title: Is Ibrutinib-related Atrial Fibrillation Dose Dependent: Insights From the WHO Pharmacovigilance Database
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: Hematological Malignancy
Atrial Fibrillation
Lead sponsor: University Hospital, Caen
Sponsor class: OTHER
First posted: 2024-01-25
Enrollment: 18000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Observational model: OTHER
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: * ibrutinib-related atrial fibrillation reports in Vigibase at the time of data extraction
* involving adult patients
* with an available ibrutinib daily dose

Brief summary: Ibrutinib, an oral inhibitor of Bruton tyrosine kinase (BTK), has recently revolutionized the treatment of various chronic B-cell malignancies and particularly chronic lymphocytic leukemia (CLL). Atrial fibrillation (AF) has early emerged as a cardiovascular adverse effect (CVAE) of ibrutinib but underlying mechanisms of IRAF are not fully understood.

While a dose-reduction or an interruption of ibrutinib is mentioned in the summary of product characteristics of ibrutinib, any beneficial effect on IRAF management of such a management is unclear.

The main aim of this study is to determine if IRAF is a dose-dependent CVAE in chronic B-cell malignancies patients by studying the association between ibrutinib dose and IRAF reporting in Vigibase®, the World Health Organization (WHO) pharmacovigilance database.

Detailed description: Ibrutinib, an oral inhibitor of Bruton tyrosine kinase (BTK), has recently revolutionized the treatment of various chronic B-cell malignancies and particularly chronic lymphocytic leukemia (CLL). Atrial fibrillation (AF) has early emerged as a cardiovascular adverse effect (CVAE) of ibrutinib. In phase 3 randomized clinical trials (RCT), ibrutinib exhibits a ≈4-fold increase-risk of AF compared with controls (pooled relative-risk (RR) 3.9; 95% confidence interval (CI): (2.0-7.5); p\<0.0001). The annualized incidence rate of ibrutinib-related AF (IRAF) reporting in clinical trials is estimated to 4.9 (95% CI: 2.9-8.3) per 100 person-years. IRAF risk persists throughout ibrutinib exposition and seems to be cumulative with the extension of follow-up and cardiac monitoring.

Underlying mechanisms of IRAF are not fully understood. Ibrutinib potently inhibits multiple off-target kinases at therapeutic concentrations.

While a dose-reduction or an interruption of ibrutinib is mentioned in the summary of product characteristics of ibrutinib, any beneficial effect on IRAF management of such a management is unclear.

The main aim of this study is to determine if IRAF is a dose-dependent CVAE in chronic B-cell malignancies patients by studying the association between ibrutinib dose and IRAF reporting in Vigibase®, the World Health Organization (WHO) pharmacovigilance database.

Eligibility criteria: Inclusion Criteria:

* ibrutinib-related atrial fibrillation reports in Vigibase at the time of data extraction
* involving adult patients
* with an available ibrutinib daily dose

Exclusion Criteria:

* minors
* no ibrutinib dose available

Primary outcomes:
measure: to determine the influence of ibrutinib dosing on IRAF reporting. Results were expressed as 2-by2 comparisons against the lowest dosing regimen (140mg/day).
timeFrame: Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023
Secondary outcomes:
measure: Description of ibrutinib-related atrial fibrillation cases
timeFrame: Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023
measure: To determine the influence of ibrutinib dosing on IRAF reporting after exclusion of IRAF cases containing concurrent anticoagulant and/or antiarrhythmic drugs, assuming this approach could exclude reports with history of AF preceding IRAF reporting
timeFrame: Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023
measure: To determine the influence of ibrutinib dosing on IRAF reporting according to the underlying chronic B-cell malignancy indication.
timeFrame: Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023
measure: To determine if the time to IRAF onset is dependent of the ibrutinib dosing regimen
timeFrame: Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023
measure: Sensitivity analysis will also be performed regarding the influence of ibrutinib dosing on 2 dose-dependent ADRs (neutropenia and thrombocytopenia) reporting related to ibrutinib exposure
timeFrame: Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023
Other outcomes:
Locations:
city: Caen
country: France
facility: Caen University Hospital, Department of Pharmacology
state: Normandie
Study officials:
affiliation: University Hospital, Caen
name: Joachim Alexandre, MD
role: PRINCIPAL_INVESTIGATOR
References: