Hematological MalignancyNCT06224452
Is Ibrutinib-related Atrial Fibrillation Dose Dependent
An observational study of Hematological Malignancy and Atrial Fibrillation, run by University Hospital, Caen at 1 site in France.
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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hematological Malignancy, Atrial Fibrillation
- What is being tested?
- ibrutinib exposure
- How many people
- 18,000 participants
- Where
- 1 siteFrance
- Study dates
- 1 Mar 2024to 1 Jul 2024
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- Adult, Older adult
Study population: * ibrutinib-related atrial fibrillation reports in Vigibase at the time of data extraction * involving adult patients * with an available ibrutinib daily dose
Who may be able to join
- ibrutinib-related atrial fibrillation reports in Vigibase at the time of data extraction
- involving adult patients
- with an available ibrutinib daily dose
Who cannot join
- minors
- no ibrutinib dose available
Trial locations and contacts
1 site in 1 country.
France1 site
Caen University Hospital, Department of Pharmacology
Caen, Normandy
About this study
Official title: Is Ibrutinib-related Atrial Fibrillation Dose Dependent: Insights From the WHO Pharmacovigilance Database
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.
Read the 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.
- Conditions
- Hematological Malignancy, Atrial Fibrillation
- Being tested
- ibrutinib exposure
- Medical subject headings
- Hematologic Neoplasms, Atrial Fibrillation
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ibrutinib exposureDrug
We will extract all atrial fibrillation cases involving adult patients associated with ibrutinib exposure with an available ibrutinib daily dose
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023
Secondary outcomes (5)
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)
Measured: Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023
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
Measured: Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023
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
Measured: Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023
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)
Measured: Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023
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
Measured: Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Jan 2024
- Study start1 Mar 2024 (estimated)
- Primary completion1 May 2024 (estimated)
- Study completion1 Jul 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Hematological MalignancyStudies of the same condition, open and under way.
- More trials run by University Hospital, CaenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Other
- Time perspective
- Retrospective
- Enrolment
- 18,000 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Hospital, Caen
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Joachim Alexandre, MD, Principal investigator, University Hospital, Caen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06224452
- Sponsor's protocol ID
- Pharmaco011624
- Status last verified
- Jan 2024
- First submitted
- 16 Jan 2024
- Last updated
- 5 Mar 2024
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No: data are extracted from vigibase; data sharement is conditionned to the opinion of the Uppsala Monitoring Centre
Publications
Alexandre J, Font J, Angelique DS, Delapierre B, Damaj G, Plane AF, Legallois D, Milliez P, Dolladille C, Chretien B. Is ibrutinib-related atrial fibrillation dose dependent? Insights from an individual case level analysis of the World Health Organization pharmacovigilance database. Leukemia. 2024 Dec;38(12):2628-2635. doi: 10.1038/s41375-024-02413-5. Epub 2024 Sep 19.
PubMed 39300222
Study at a glance
From the registry record, last updated by the sponsor on 5 Mar 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Is Ibrutinib-related Atrial Fibrillation Dose Dependent: Insights From the WHO Pharmacovigilance Database
- ClinicalTrials.gov ID
- NCT06224452
- Acronym / sponsor ID
- Pharmaco011624
- Conditions
- Hematological Malignancy, Atrial Fibrillation
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 18,000 participants (estimated)
- Lead sponsor
- University Hospital, CaenUniversity, hospital or other
- Study start
- 1 Mar 2024 (estimated)
- Primary completion
- 1 May 2024 (estimated)
- Study completion
- 1 Jul 2024 (estimated)
- First posted
- 25 Jan 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Observational model
- Other
- Time perspective
- Retrospective
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Age groups
- Adult, Older adult
- Study population
- * ibrutinib-related atrial fibrillation reports in Vigibase at the time of data extraction * involving adult patients * with an available ibrutinib daily dose
Key inclusion criteria (3 listed)
- ibrutinib-related atrial fibrillation reports in Vigibase at the time of data extraction
- involving adult patients
- with an available ibrutinib daily dose
Key exclusion criteria (2 listed)
- minors
- no ibrutinib dose available
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ibrutinib exposureWe will extract all atrial fibrillation cases involving adult patients associated with ibrutinib exposure with an available ibrutinib daily dose | Drug | – |
Primary outcome
to determine the influence of ibrutinib dosing on IRAF reporting. Results were expressed as 2-by2 comparisons against the lowest dosing regimen (140mg/day).
Time frame: Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023
Disproportionality estimates will be perform using both univariate and multivariate analyses and a global p-value will measure the difference between dosing regimen
5 secondary outcomes
Description of ibrutinib-related atrial fibrillation cases
Time frame: Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023
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
Time frame: Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023
To determine the influence of ibrutinib dosing on IRAF reporting according to the underlying chronic B-cell malignancy indication.
Time frame: Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023
To determine if the time to IRAF onset is dependent of the ibrutinib dosing regimen
Time frame: Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023
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
Time frame: Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Mar 2024.
- Derived from this study: PubMed 39300222Alexandre J, Font J, Angelique DS, Delapierre B, Damaj G, Plane AF, Legallois D, Milliez P, Dolladille C, Chretien B. Is ibrutinib-related atrial fibrillation dose dependent? Insights from an individual case level analysis of the World Health Organization pharmacovigilance database. Leukemia. 2024 Dec;38(12):2628-2635. doi: 10.1038/s41375-024-02413-5. Epub 2024 Sep 19.
- Individual participant dataSharing planned: No. data are extracted from vigibase; data sharement is conditionned to the opinion of the Uppsala Monitoring Centre
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Joachim Alexandre, MD principal investigator
University Hospital, Caen
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Hematological Malignancy and Atrial Fibrillation, run by University Hospital, Caen at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 5 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Joachim Alexandre, MD (+33231064670, alexandre-j@chu-caen.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome 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). (time frame: Cases reported in the World Health Organization (WHO) of individual safety case reports to 26th July 2023). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06224452, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 Mar 2024.