Is Ibrutinib-related Atrial Fibrillation Dose Dependent

Atrial Fibrillation Clinical Trial

Official title:

Is Ibrutinib-related Atrial Fibrillation Dose Dependent: Insights From the WHO Pharmacovigilance Database

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06224452
• Other study ID #: Pharmaco011624
• Status: Not yet recruiting
• Start date: March 1, 2024
• Est. completion date: July 1, 2024

Study information

• Verified date: January 2024
• Source: University Hospital, Caen
• Contact: Joachim Alexandre, MD
• Phone: +33231064670
• Email: alexandre-j[@]chu-caen.fr
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 18000
• Est. completion date: July 1, 2024
• Est. primary completion date: May 1, 2024
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Atrial Fibrillation
• Hematologic Neoplasms
• Hematological Malignancy

Intervention

Drug:
• ibrutinib exposure
We will extract all atrial fibrillation cases involving adult patients associated with ibrutinib exposure with an available ibrutinib daily dose

Locations

Country	Name	City	State
France	Caen University Hospital, Department of Pharmacology	Caen	Normandie

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Caen

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	to determine the influence of ibrutinib dosing on IRAF reporting. Results were expressed as 2-by2 comparisons against the lowest dosing regimen (140mg/day).	Disproportionality estimates will be perform using both univariate and multivariate analyses and a global p-value will measure the difference between dosing regimen	Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023
Secondary	Description of ibrutinib-related atrial fibrillation cases	Clinical caracteristics of ibrutinib-related atrial fibrillation cases (sex, age, time to onset, hematological malignacy, coreported drugs, coreported adverse events)	Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023
Secondary	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	Disproportionality estimates will be perform both univariate and multivariate analysesand a global p-value will measure the difference between dosing regimen	Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023
Secondary	To determine the influence of ibrutinib dosing on IRAF reporting according to the underlying chronic B-cell malignancy indication.	Disproportionality estimates will be perform using both univariate and multivariate analyses and a global p-value will measure the difference between dosing regimen	Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023
Secondary	To determine if the time to IRAF onset is dependent of the ibrutinib dosing regimen	We will use a linear regression to test if the association between ibrutinib-related atrial fibrillation reporting and time to onset is dependent of the dose regimen (the 140 mg/day ibrutinib dosing regimen will set as the reference)	Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023
Secondary	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	Disproportionality estimates will be perform using univariate analysis and a global p-value will measure the difference between dosing regimen	Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023