array(44) {
  ["project_title"]=>
  string(103) "CYP3A4 Interactions and Adverse Drug Reactions in Ibrutinib Therapy: Revisting multiple clinical trials"
  ["project_narrative_summary"]=>
  string(669) "The proposed study aims to investigate the prevalence and clinical consequences of drug-drug interactions involving the CYP3A4 enzyme in patients treated with ibrutinib. Ibrutinib is an oral chemotherapy medication that is used to treat chronic lymphocytic leukemia and mantle cell lymphoma. It is metabolized by the CYP3A4 enzyme, and interactions with other medications that affect the activity of this enzyme can alter ibrutinib plasma concentrations and potentially affect its efficacy and safety.
Understanding the impact of CYP3A4 interactions on ibrutinib plasma concentrations and ADRs is important for optimizing ibrutinib treatment and minimizing ADRs." ["project_learn_source"]=> string(10) "web_search" ["project_learn_source_exp"]=> string(0) "" ["project_key_personnel"]=> array(1) { [0]=> array(6) { ["p_pers_f_name"]=> string(8) "Cathrine" ["p_pers_l_name"]=> string(8) "Korsholm" ["p_pers_degree"]=> string(2) "MD" ["p_pers_pr_affil"]=> string(31) "Copenhagen University Hospital " ["p_pers_scop_id"]=> string(0) "" ["requires_data_access"]=> string(3) "yes" } } ["project_ext_grants"]=> array(2) { ["value"]=> string(2) "no" ["label"]=> string(68) "No external grants or funds are being used to support this research." } ["project_funding_source"]=> string(0) "" ["project_assoc_trials"]=> array(6) { [0]=> object(WP_Post)#4638 (24) { ["ID"]=> int(1763) ["post_author"]=> string(4) "1363" ["post_date"]=> string(19) "2019-02-19 10:31:00" ["post_date_gmt"]=> string(19) "2019-02-19 10:31:00" ["post_content"]=> string(0) "" ["post_title"]=> string(246) "NCT01722487 - Randomized, Multicenter, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase Inhibitor Ibrutinib Versus Chlorambucil in Patients 65 Years or Older With Treatment-naive Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma" ["post_excerpt"]=> string(0) "" ["post_status"]=> string(7) "publish" ["comment_status"]=> string(4) "open" ["ping_status"]=> string(4) "open" ["post_password"]=> string(0) "" ["post_name"]=> string(194) "nct01722487-randomized-multicenter-open-label-phase-3-study-of-the-brutons-tyrosine-kinase-inhibitor-ibrutinib-versus-chlorambucil-in-patients-65-years-or-older-with-treatment-naive-chronic-lymp" ["to_ping"]=> string(0) "" ["pinged"]=> string(0) "" ["post_modified"]=> string(19) "2023-12-06 10:31:15" ["post_modified_gmt"]=> string(19) "2023-12-06 15:31:15" ["post_content_filtered"]=> string(0) "" ["post_parent"]=> int(0) ["guid"]=> string(243) "https://dev-yoda.pantheonsite.io/clinical-trial/nct01722487-randomized-multicenter-open-label-phase-3-study-of-the-brutons-tyrosine-kinase-inhibitor-ibrutinib-versus-chlorambucil-in-patients-65-years-or-older-with-treatment-naive-chronic-lymp/" ["menu_order"]=> int(0) ["post_type"]=> string(14) "clinical_trial" ["post_mime_type"]=> string(0) "" ["comment_count"]=> string(1) "0" ["filter"]=> string(3) "raw" } [1]=> object(WP_Post)#4637 (24) { ["ID"]=> int(1764) ["post_author"]=> string(4) "1363" ["post_date"]=> string(19) "2019-02-19 10:40:00" ["post_date_gmt"]=> string(19) "2019-02-19 10:40:00" ["post_content"]=> string(0) "" ["post_title"]=> string(142) "NCT01236391 - Multicenter Phase 2 Study of Bruton's Tyrosine Kinase (Btk) Inhibitor, PCI-32765, in Relapsed or Refractory Mantle Cell Lymphoma" ["post_excerpt"]=> string(0) "" ["post_status"]=> string(7) "publish" ["comment_status"]=> string(4) "open" ["ping_status"]=> string(4) "open" ["post_password"]=> string(0) "" ["post_name"]=> string(135) "nct01236391-multicenter-phase-2-study-of-brutons-tyrosine-kinase-btk-inhibitor-pci-32765-in-relapsed-or-refractory-mantle-cell-lymphoma" ["to_ping"]=> string(0) "" ["pinged"]=> string(0) "" ["post_modified"]=> string(19) "2023-12-06 10:27:07" ["post_modified_gmt"]=> string(19) "2023-12-06 15:27:07" ["post_content_filtered"]=> string(0) "" ["post_parent"]=> int(0) ["guid"]=> string(184) "https://dev-yoda.pantheonsite.io/clinical-trial/nct01236391-multicenter-phase-2-study-of-brutons-tyrosine-kinase-btk-inhibitor-pci-32765-in-relapsed-or-refractory-mantle-cell-lymphoma/" ["menu_order"]=> int(0) ["post_type"]=> string(14) "clinical_trial" ["post_mime_type"]=> string(0) "" ["comment_count"]=> string(1) "0" ["filter"]=> string(3) "raw" } [2]=> object(WP_Post)#4636 (24) { ["ID"]=> int(1765) ["post_author"]=> string(4) "1363" ["post_date"]=> string(19) "2019-02-19 10:43:00" ["post_date_gmt"]=> string(19) "2019-02-19 10:43:00" ["post_content"]=> string(0) "" ["post_title"]=> string(131) "NCT01105247 - A Phase 1b/2 Fixed-dose Study of Bruton's Tyrosine Kinase (Btk) Inhibitor, PCI-32765, in Chronic Lymphocytic Leukemia" ["post_excerpt"]=> string(0) "" ["post_status"]=> string(7) "publish" ["comment_status"]=> string(4) "open" ["ping_status"]=> string(4) "open" ["post_password"]=> string(0) "" ["post_name"]=> string(124) "nct01105247-a-phase-1b-2-fixed-dose-study-of-brutons-tyrosine-kinase-btk-inhibitor-pci-32765-in-chronic-lymphocytic-leukemia" ["to_ping"]=> string(0) "" ["pinged"]=> string(0) "" ["post_modified"]=> string(19) "2023-12-06 10:25:10" ["post_modified_gmt"]=> string(19) "2023-12-06 15:25:10" ["post_content_filtered"]=> string(0) "" ["post_parent"]=> int(0) ["guid"]=> string(173) "https://dev-yoda.pantheonsite.io/clinical-trial/nct01105247-a-phase-1b-2-fixed-dose-study-of-brutons-tyrosine-kinase-btk-inhibitor-pci-32765-in-chronic-lymphocytic-leukemia/" ["menu_order"]=> int(0) ["post_type"]=> string(14) "clinical_trial" ["post_mime_type"]=> string(0) "" ["comment_count"]=> string(1) "0" ["filter"]=> string(3) "raw" } [3]=> object(WP_Post)#4633 (24) { ["ID"]=> int(1922) ["post_author"]=> string(4) "1363" ["post_date"]=> string(19) "2023-08-05 04:45:19" ["post_date_gmt"]=> string(19) "2023-08-05 04:45:19" ["post_content"]=> string(0) "" ["post_title"]=> string(250) "NCT01578707 - A Randomized, Multicenter, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor Ibrutinib (PCI-32765) Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma" ["post_excerpt"]=> string(0) "" ["post_status"]=> string(7) "publish" ["comment_status"]=> string(4) "open" ["ping_status"]=> string(4) "open" ["post_password"]=> string(0) "" ["post_name"]=> string(190) "nct01578707-a-randomized-multicenter-open-label-phase-3-study-of-the-brutons-tyrosine-kinase-btk-inhibitor-ibrutinib-pci-32765-versus-ofatumumab-in-patients-with-relapsed-or-refractory-chron" ["to_ping"]=> string(0) "" ["pinged"]=> string(0) "" ["post_modified"]=> string(19) "2023-12-06 10:28:48" ["post_modified_gmt"]=> string(19) "2023-12-06 15:28:48" ["post_content_filtered"]=> string(0) "" ["post_parent"]=> int(0) ["guid"]=> string(239) "https://dev-yoda.pantheonsite.io/clinical-trial/nct01578707-a-randomized-multicenter-open-label-phase-3-study-of-the-brutons-tyrosine-kinase-btk-inhibitor-ibrutinib-pci-32765-versus-ofatumumab-in-patients-with-relapsed-or-refractory-chron/" ["menu_order"]=> int(0) ["post_type"]=> string(14) "clinical_trial" ["post_mime_type"]=> string(0) "" ["comment_count"]=> string(1) "0" ["filter"]=> string(3) "raw" } [4]=> object(WP_Post)#4635 (24) { ["ID"]=> int(1923) ["post_author"]=> string(4) "1363" ["post_date"]=> string(19) "2022-02-04 09:52:00" ["post_date_gmt"]=> string(19) "2022-02-04 09:52:00" ["post_content"]=> string(0) "" ["post_title"]=> string(278) "NCT01611090 - Randomized, Double-blind, Placebo-controlled Phase 3 Study of Ibrutinib, a Bruton's Tyrosine Kinase (BTK) Inhibitor, in Combination With Bendamustine and Rituximab (BR) in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma" ["post_excerpt"]=> string(0) "" ["post_status"]=> string(7) "publish" ["comment_status"]=> string(4) "open" ["ping_status"]=> string(4) "open" ["post_password"]=> string(0) "" ["post_name"]=> string(188) "nct01611090-randomized-double-blind-placebo-controlled-phase-3-study-of-ibrutinib-a-brutons-tyrosine-kinase-btk-inhibitor-in-combination-with-bendamustine-and-rituximab-br-in-subjects-with" ["to_ping"]=> string(0) "" ["pinged"]=> string(0) "" ["post_modified"]=> string(19) "2023-12-06 10:22:30" ["post_modified_gmt"]=> string(19) "2023-12-06 15:22:30" ["post_content_filtered"]=> string(0) "" ["post_parent"]=> int(0) ["guid"]=> string(237) "https://dev-yoda.pantheonsite.io/clinical-trial/nct01611090-randomized-double-blind-placebo-controlled-phase-3-study-of-ibrutinib-a-brutons-tyrosine-kinase-btk-inhibitor-in-combination-with-bendamustine-and-rituximab-br-in-subjects-with/" ["menu_order"]=> int(0) ["post_type"]=> string(14) "clinical_trial" ["post_mime_type"]=> string(0) "" ["comment_count"]=> string(1) "0" ["filter"]=> string(3) "raw" } [5]=> object(WP_Post)#4634 (24) { ["ID"]=> int(1945) ["post_author"]=> string(4) "1363" ["post_date"]=> string(19) "2023-08-05 04:44:39" ["post_date_gmt"]=> string(19) "2023-08-05 04:44:39" ["post_content"]=> string(0) "" ["post_title"]=> string(137) "NCT02195869 - A Multicenter Open-Label Phase 1b/2 Study of Ibrutinib in Steroid Dependent or Refractory Chronic Graft Versus Host Disease" ["post_excerpt"]=> string(0) "" ["post_status"]=> string(7) "publish" ["comment_status"]=> string(4) "open" ["ping_status"]=> string(4) "open" ["post_password"]=> string(0) "" ["post_name"]=> string(135) "nct02195869-a-multicenter-open-label-phase-1b-2-study-of-ibrutinib-in-steroid-dependent-or-refractory-chronic-graft-versus-host-disease" ["to_ping"]=> string(0) "" ["pinged"]=> string(0) "" ["post_modified"]=> string(19) "2023-08-05 04:45:02" ["post_modified_gmt"]=> string(19) "2023-08-05 04:45:02" ["post_content_filtered"]=> string(0) "" ["post_parent"]=> int(0) ["guid"]=> string(184) "https://dev-yoda.pantheonsite.io/clinical-trial/nct02195869-a-multicenter-open-label-phase-1b-2-study-of-ibrutinib-in-steroid-dependent-or-refractory-chronic-graft-versus-host-disease/" ["menu_order"]=> int(0) ["post_type"]=> string(14) "clinical_trial" ["post_mime_type"]=> string(0) "" ["comment_count"]=> string(1) "0" ["filter"]=> string(3) "raw" } } ["project_date_type"]=> string(18) "full_crs_supp_docs" ["property_scientific_abstract"]=> string(1604) "Background: Ibrutinib is an oral, first-in-class, Bruton's tyrosine kinase inhibitor approved for the treatment of chronic lymphocytic leukemia and mantle cell lymphoma. It is metabolized by the CYP3A4 enzyme, and drug-drug interactions with CYP3A4 inhibitors or inducers can alter ibrutinib plasma concentrations and potentially affect its efficacy and safety.
Objective: The purpose of this study is to investigate the prevalence and clinical consequences of CYP3A4 interactions in patients treated with ibrutinib.
Study Design: This is a retrospective, observational study using patient level data from previous controlled clinical ibrutinib trials.
Participants: The study population includes adult patients who were included in the clinical studies of ibrutinib.
Primary Outcome Measure: The primary outcome is the incidence of adverse drug reactions (ADRs) in patients with and without CYP3A4 interactions.
Secondary Outcome Measures: The secondary outcomes include the effect of CYP3A4 interactions on ibrutinib plasma concentrations and the relationship between ibrutinib plasma concentrations and ADRs.
Statistical Analysis: Descriptive statistics will be used to characterize the study population and the prevalence of CYP3A4 interactions. The incidence of ADRs will be compared between patients with and without CYP3A4 interactions using chi-square or Fisher's exact test. The relationship between ibrutinib plasma concentrations and ADRs will be analyzed using Pearson's correlation coefficient. All statistical tests will be two-tailed and a p-value" ["project_brief_bg"]=> string(1308) "Ibrutinib is a widely-used oral chemotherapy medication that is metabolized by the CYP3A4 enzyme. Drug-drug interactions with CYP3A4 inhibitors or inducers can alter ibrutinib plasma concentrations and potentially affect its efficacy and safety. The proposed study aims to investigate the prevalence and clinical consequences of CYP3A4 interactions in patients treated with ibrutinib.
Understanding the impact of CYP3A4 interactions on ibrutinib plasma concentrations and adverse drug reactions (ADRs) is important for optimizing ibrutinib treatment and minimizing ADRs. The results of this study will provide valuable information for healthcare providers and researchers, allowing them to better understand the potential consequences of CYP3A4 interactions and make informed decisions about ibrutinib treatment.
This research is significant because it will contribute to the existing body of knowledge on ibrutinib and its interactions with other medications, and it will inform the development of guidelines and recommendations for the safe and effective use of ibrutinib. This information will be beneficial for patients, healthcare providers, and researchers, and it has the potential to materially enhance generalizable scientific and medical knowledge to inform science and public health." ["project_specific_aims"]=> string(1198) "The specific aims of the project are as follows:
To determine the prevalence of CYP3A4 interactions in patients treated with ibrutinib.
To evaluate the effect of CYP3A4 interactions on ibrutinib plasma concentrations.
To assess the incidence of ADRs in patients with and without CYP3A4 interactions.
To examine the relationship between ibrutinib plasma concentrations and ADRs.
The study objectives are:
To characterize the prevalence of CYP3A4 interactions in patients treated with ibrutinib.
To assess the impact of CYP3A4 interactions on ibrutinib plasma concentrations.
To compare the incidence of ADRs between patients with and without CYP3A4 interactions.
To examine the relationship between ibrutinib plasma concentrations and ADRs.
The specific hypotheses to be evaluated are:
CYP3A4 interactions are prevalent in patients treated with ibrutinib.
CYP3A4 interactions alter ibrutinib plasma concentrations.
Patients with CYP3A4 interactions have a higher incidence of ADRs compared to those without CYP3A4 interactions.
There is a relationship between ibrutinib plasma concentrations and ADRs." ["project_study_design"]=> array(2) { ["value"]=> string(7) "meta_an" ["label"]=> string(52) "Meta-analysis (analysis of multiple trials together)" } ["project_study_design_exp"]=> string(0) "" ["project_purposes"]=> array(0) { } ["project_purposes_exp"]=> string(0) "" ["project_software_used"]=> string(0) "" ["project_software_used_exp"]=> string(0) "" ["project_research_methods"]=> string(160) "Inclusion criteria:
Adult patients (age ? 18 years)
Prescribed ibrutinib for the treatment of chronic lymphocytic leukemia or mantle cell lymphoma" ["project_main_outcome_measure"]=> string(955) "Primary Outcome Measure: The primary outcome is the incidence of adverse drug reactions (ADRs) in patients with and without CYP3A4 interactions.
Secondary Outcome Measures: Overall survival, progression-free survival and the effect of CYP3A4 interactions on ibrutinib plasma concentrations and the relationship between ibrutinib plasma concentrations and ADRs.
ADRs will be identified from the adverse event reports in the clinical trial by systematically reviewing and analyzing all reported adverse events. We will start with the known important ADRs such as artrial fibriliation and neutropenia. We will then compare the incidence of these adverse reactions in persons with CYP3A4 inhibitors with persons without to determine if there is a significant difference between the two groups. Any adverse reactions that occur at a higher rate in the treatment group than in the control group will be considered to be related to the study drug." ["project_main_predictor_indep"]=> string(1135) "The reviewer has raised a valid concern about the availability of information on CYP3A4 inhibitors for the proposed trials. It is important to note that the exclusion criteria for one of the trials, specifically the requirement for treatment with a strong CYP3A4/5 and/or CYP2D6 inhibitor, may limit the ability to conduct the proposed analyses on the effects of CYP3A4 interactions on ibrutinib plasma concentrations.
The primary focus of this study is the impact of CYP3A4 interactions on ibrutinib plasma concentrations. To investigate this, the study will be looking at the presence or absence of CYP3A4 interactions during ibrutinib treatment. CYP3A4 interactions will be defined as the concurrent use of ibrutinib with a CYP3A4 inhibitor or inducer. The list of CYP3A4 inhibitors and inducers will be based on the most current recommendations from the US Food and Drug Administration and other reputable sources. Additionally, because of the exclusion criteria mentioned, the team will categorize the CYP3A4 inhibitors into mild, moderate, and severe categories in order to estimate the effect of each category separately." ["project_other_variables_interest"]=> string(1243) "Demographic variables: age, gender, race/ethnicity
Clinical variables: diagnosis (chronic lymphocytic leukemia or mantle cell lymphoma), stage of disease, prior treatment, comorbidities
Ibrutinib treatment variables: dose, duration of treatment, concomitant medications
CYP3A4 interaction variables: type (inhibitor or inducer), duration of use, dose
Adverse drug reaction variables: type, severity, outcome (resolved or ongoing)
These variables will be collected from electronic medical records and will be defined as follows:
Demographic variables:
Age: patient's age at the time of ibrutinib treatment
Gender: male or female
Race/ethnicity: self-reported race/ethnicity of the patient
Clinical variables:
Diagnosis: chronic lymphocytic leukemia or mantle cell lymphoma
Stage of disease: based on the most current staging system for the respective diagnosis
Prior treatment: type and duration of any previous treatment for the diagnosis
Comorbidities: other medical conditions present at the time of ibrutinib treatment
Ibrutinib treatment variables:
Dose: daily dose of ibrutinib
Duration of treatment: total length of ti" ["project_stat_analysis_plan"]=> string(2097) "The statistical analysis plan for this study will include both descriptive and inferential statistics.
Descriptive statistics will be used to characterize the study population, including the prevalence of CYP3A4 interactions, the distribution of demographic and clinical variables, and the incidence of ADRs. Measures of central tendency (e.g. mean, median) and dispersion (e.g. standard deviation, range) will be calculated for continuous variables, and frequencies and percentages will be calculated for categorical variables.
Bivariate analyses will be conducted to examine the association between the main independent variable (CYP3A4 interactions) and the primary and secondary outcome measures. Chi-square or Fisher's exact test will be used to compare the incidence of ADRs between patients with and without CYP3A4 interactions. Pearson's correlation coefficient will be used to assess the relationship between ibrutinib plasma concentrations and ADRs.
Multivariable analyses will be conducted to adjust for potential confounders and to assess the independent effect of CYP3A4 interactions on the outcome measures. Logistic regression will be used to examine the association between CYP3A4 interactions and the incidence of ADRs, adjusting for demographic and clinical variables. Linear regression will be used to examine the association between CYP3A4 interactions and ibrutinib plasma concentrations, adjusting for demographic and clinical variables.
In addition to the above analyses, further advanced analyses may be conducted depending on the specific research question and study design. For example, propensity score methods may be used to control for confounding in the analysis of the relationship between CYP3A4 interactions and ADRs. Kaplan-Meier or Cox modeling approaches may be used to evaluate the effect of CYP3A4 interactions on time-to-event outcomes, such as disease progression or survival. Non-parametric testing may be used for variables that do not follow a normal distribution.
All statistical tests will be two-tailed and a p-value" ["project_timeline"]=> string(427) "The timeline for the proposed study is as follows:
Anticipated project start date: 2 months after approval of the data request
Data cleaning and preparation: 1 month
Statistical analysis: 2 months
Manuscript drafting: 3 months
Manuscript review and revision: 2 months
Manuscript submission: 1 month
Results reported back to the YODA Project: 2 months after manuscript acceptance" ["project_dissemination_plan"]=> string(1261) "The primary product of the completed research project will be a manuscript reporting the findings of the study. The manuscript will be written in accordance with the standards of a peer-reviewed scientific journal and will include a clear and concise description of the study objectives, methods, results, and conclusions.
The target audience for the manuscript will be healthcare providers and researchers who are interested in ibrutinib treatment and drug-drug interactions involving CYP3A4. The manuscript will be suitable for submission to a general or specialty medical journal with a focus on oncology, hematology, or pharmacology. Some examples of suitable journals for submission include the Journal of Clinical Oncology, Blood, and Clinical Pharmacology and Therapeutics.
In addition to the manuscript, other products of the study may include presentations at scientific conferences, posters, and webinars. The target audience for these products will be similar to that of the manuscript and will include healthcare providers and researchers who are interested in ibrutinib treatment and drug-drug interactions involving CYP3A4.
The results of the study will also be reported back to the YODA Project as per the Data Use Agreement." ["project_bibliography"]=> string(8967) "

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2022-5123

General Information

How did you learn about the YODA Project?: Internet Search

Conflict of Interest

Request Clinical Trials

Associated Trial(s):
  1. NCT01722487 - Randomized, Multicenter, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase Inhibitor Ibrutinib Versus Chlorambucil in Patients 65 Years or Older With Treatment-naive Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma
  2. NCT01236391 - Multicenter Phase 2 Study of Bruton's Tyrosine Kinase (Btk) Inhibitor, PCI-32765, in Relapsed or Refractory Mantle Cell Lymphoma
  3. NCT01105247 - A Phase 1b/2 Fixed-dose Study of Bruton's Tyrosine Kinase (Btk) Inhibitor, PCI-32765, in Chronic Lymphocytic Leukemia
  4. NCT01578707 - A Randomized, Multicenter, Open-label, Phase 3 Study of the Bruton's Tyrosine Kinase (BTK) Inhibitor Ibrutinib (PCI-32765) Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
  5. NCT01611090 - Randomized, Double-blind, Placebo-controlled Phase 3 Study of Ibrutinib, a Bruton's Tyrosine Kinase (BTK) Inhibitor, in Combination With Bendamustine and Rituximab (BR) in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
  6. NCT02195869 - A Multicenter Open-Label Phase 1b/2 Study of Ibrutinib in Steroid Dependent or Refractory Chronic Graft Versus Host Disease
What type of data are you looking for?: Individual Participant-Level Data, which includes Full CSR and all supporting documentation

Request Clinical Trials

Data Request Status

Status: Ongoing

Research Proposal

Project Title: CYP3A4 Interactions and Adverse Drug Reactions in Ibrutinib Therapy: Revisting multiple clinical trials

Scientific Abstract: Background: Ibrutinib is an oral, first-in-class, Bruton's tyrosine kinase inhibitor approved for the treatment of chronic lymphocytic leukemia and mantle cell lymphoma. It is metabolized by the CYP3A4 enzyme, and drug-drug interactions with CYP3A4 inhibitors or inducers can alter ibrutinib plasma concentrations and potentially affect its efficacy and safety.
Objective: The purpose of this study is to investigate the prevalence and clinical consequences of CYP3A4 interactions in patients treated with ibrutinib.
Study Design: This is a retrospective, observational study using patient level data from previous controlled clinical ibrutinib trials.
Participants: The study population includes adult patients who were included in the clinical studies of ibrutinib.
Primary Outcome Measure: The primary outcome is the incidence of adverse drug reactions (ADRs) in patients with and without CYP3A4 interactions.
Secondary Outcome Measures: The secondary outcomes include the effect of CYP3A4 interactions on ibrutinib plasma concentrations and the relationship between ibrutinib plasma concentrations and ADRs.
Statistical Analysis: Descriptive statistics will be used to characterize the study population and the prevalence of CYP3A4 interactions. The incidence of ADRs will be compared between patients with and without CYP3A4 interactions using chi-square or Fisher's exact test. The relationship between ibrutinib plasma concentrations and ADRs will be analyzed using Pearson's correlation coefficient. All statistical tests will be two-tailed and a p-value

Brief Project Background and Statement of Project Significance: Ibrutinib is a widely-used oral chemotherapy medication that is metabolized by the CYP3A4 enzyme. Drug-drug interactions with CYP3A4 inhibitors or inducers can alter ibrutinib plasma concentrations and potentially affect its efficacy and safety. The proposed study aims to investigate the prevalence and clinical consequences of CYP3A4 interactions in patients treated with ibrutinib.
Understanding the impact of CYP3A4 interactions on ibrutinib plasma concentrations and adverse drug reactions (ADRs) is important for optimizing ibrutinib treatment and minimizing ADRs. The results of this study will provide valuable information for healthcare providers and researchers, allowing them to better understand the potential consequences of CYP3A4 interactions and make informed decisions about ibrutinib treatment.
This research is significant because it will contribute to the existing body of knowledge on ibrutinib and its interactions with other medications, and it will inform the development of guidelines and recommendations for the safe and effective use of ibrutinib. This information will be beneficial for patients, healthcare providers, and researchers, and it has the potential to materially enhance generalizable scientific and medical knowledge to inform science and public health.

Specific Aims of the Project: The specific aims of the project are as follows:
To determine the prevalence of CYP3A4 interactions in patients treated with ibrutinib.
To evaluate the effect of CYP3A4 interactions on ibrutinib plasma concentrations.
To assess the incidence of ADRs in patients with and without CYP3A4 interactions.
To examine the relationship between ibrutinib plasma concentrations and ADRs.
The study objectives are:
To characterize the prevalence of CYP3A4 interactions in patients treated with ibrutinib.
To assess the impact of CYP3A4 interactions on ibrutinib plasma concentrations.
To compare the incidence of ADRs between patients with and without CYP3A4 interactions.
To examine the relationship between ibrutinib plasma concentrations and ADRs.
The specific hypotheses to be evaluated are:
CYP3A4 interactions are prevalent in patients treated with ibrutinib.
CYP3A4 interactions alter ibrutinib plasma concentrations.
Patients with CYP3A4 interactions have a higher incidence of ADRs compared to those without CYP3A4 interactions.
There is a relationship between ibrutinib plasma concentrations and ADRs.

Study Design: Meta-analysis (analysis of multiple trials together)

What is the purpose of the analysis being proposed? Please select all that apply.:

Software Used:

Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: Inclusion criteria:
Adult patients (age ? 18 years)
Prescribed ibrutinib for the treatment of chronic lymphocytic leukemia or mantle cell lymphoma

Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study: Primary Outcome Measure: The primary outcome is the incidence of adverse drug reactions (ADRs) in patients with and without CYP3A4 interactions.
Secondary Outcome Measures: Overall survival, progression-free survival and the effect of CYP3A4 interactions on ibrutinib plasma concentrations and the relationship between ibrutinib plasma concentrations and ADRs.
ADRs will be identified from the adverse event reports in the clinical trial by systematically reviewing and analyzing all reported adverse events. We will start with the known important ADRs such as artrial fibriliation and neutropenia. We will then compare the incidence of these adverse reactions in persons with CYP3A4 inhibitors with persons without to determine if there is a significant difference between the two groups. Any adverse reactions that occur at a higher rate in the treatment group than in the control group will be considered to be related to the study drug.

Main Predictor/Independent Variable and how it will be categorized/defined for your study: The reviewer has raised a valid concern about the availability of information on CYP3A4 inhibitors for the proposed trials. It is important to note that the exclusion criteria for one of the trials, specifically the requirement for treatment with a strong CYP3A4/5 and/or CYP2D6 inhibitor, may limit the ability to conduct the proposed analyses on the effects of CYP3A4 interactions on ibrutinib plasma concentrations.
The primary focus of this study is the impact of CYP3A4 interactions on ibrutinib plasma concentrations. To investigate this, the study will be looking at the presence or absence of CYP3A4 interactions during ibrutinib treatment. CYP3A4 interactions will be defined as the concurrent use of ibrutinib with a CYP3A4 inhibitor or inducer. The list of CYP3A4 inhibitors and inducers will be based on the most current recommendations from the US Food and Drug Administration and other reputable sources. Additionally, because of the exclusion criteria mentioned, the team will categorize the CYP3A4 inhibitors into mild, moderate, and severe categories in order to estimate the effect of each category separately.

Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: Demographic variables: age, gender, race/ethnicity
Clinical variables: diagnosis (chronic lymphocytic leukemia or mantle cell lymphoma), stage of disease, prior treatment, comorbidities
Ibrutinib treatment variables: dose, duration of treatment, concomitant medications
CYP3A4 interaction variables: type (inhibitor or inducer), duration of use, dose
Adverse drug reaction variables: type, severity, outcome (resolved or ongoing)
These variables will be collected from electronic medical records and will be defined as follows:
Demographic variables:
Age: patient's age at the time of ibrutinib treatment
Gender: male or female
Race/ethnicity: self-reported race/ethnicity of the patient
Clinical variables:
Diagnosis: chronic lymphocytic leukemia or mantle cell lymphoma
Stage of disease: based on the most current staging system for the respective diagnosis
Prior treatment: type and duration of any previous treatment for the diagnosis
Comorbidities: other medical conditions present at the time of ibrutinib treatment
Ibrutinib treatment variables:
Dose: daily dose of ibrutinib
Duration of treatment: total length of ti

Statistical Analysis Plan: The statistical analysis plan for this study will include both descriptive and inferential statistics.
Descriptive statistics will be used to characterize the study population, including the prevalence of CYP3A4 interactions, the distribution of demographic and clinical variables, and the incidence of ADRs. Measures of central tendency (e.g. mean, median) and dispersion (e.g. standard deviation, range) will be calculated for continuous variables, and frequencies and percentages will be calculated for categorical variables.
Bivariate analyses will be conducted to examine the association between the main independent variable (CYP3A4 interactions) and the primary and secondary outcome measures. Chi-square or Fisher's exact test will be used to compare the incidence of ADRs between patients with and without CYP3A4 interactions. Pearson's correlation coefficient will be used to assess the relationship between ibrutinib plasma concentrations and ADRs.
Multivariable analyses will be conducted to adjust for potential confounders and to assess the independent effect of CYP3A4 interactions on the outcome measures. Logistic regression will be used to examine the association between CYP3A4 interactions and the incidence of ADRs, adjusting for demographic and clinical variables. Linear regression will be used to examine the association between CYP3A4 interactions and ibrutinib plasma concentrations, adjusting for demographic and clinical variables.
In addition to the above analyses, further advanced analyses may be conducted depending on the specific research question and study design. For example, propensity score methods may be used to control for confounding in the analysis of the relationship between CYP3A4 interactions and ADRs. Kaplan-Meier or Cox modeling approaches may be used to evaluate the effect of CYP3A4 interactions on time-to-event outcomes, such as disease progression or survival. Non-parametric testing may be used for variables that do not follow a normal distribution.
All statistical tests will be two-tailed and a p-value

Narrative Summary: The proposed study aims to investigate the prevalence and clinical consequences of drug-drug interactions involving the CYP3A4 enzyme in patients treated with ibrutinib. Ibrutinib is an oral chemotherapy medication that is used to treat chronic lymphocytic leukemia and mantle cell lymphoma. It is metabolized by the CYP3A4 enzyme, and interactions with other medications that affect the activity of this enzyme can alter ibrutinib plasma concentrations and potentially affect its efficacy and safety.
Understanding the impact of CYP3A4 interactions on ibrutinib plasma concentrations and ADRs is important for optimizing ibrutinib treatment and minimizing ADRs.

Project Timeline: The timeline for the proposed study is as follows:
Anticipated project start date: 2 months after approval of the data request
Data cleaning and preparation: 1 month
Statistical analysis: 2 months
Manuscript drafting: 3 months
Manuscript review and revision: 2 months
Manuscript submission: 1 month
Results reported back to the YODA Project: 2 months after manuscript acceptance

Dissemination Plan: The primary product of the completed research project will be a manuscript reporting the findings of the study. The manuscript will be written in accordance with the standards of a peer-reviewed scientific journal and will include a clear and concise description of the study objectives, methods, results, and conclusions.
The target audience for the manuscript will be healthcare providers and researchers who are interested in ibrutinib treatment and drug-drug interactions involving CYP3A4. The manuscript will be suitable for submission to a general or specialty medical journal with a focus on oncology, hematology, or pharmacology. Some examples of suitable journals for submission include the Journal of Clinical Oncology, Blood, and Clinical Pharmacology and Therapeutics.
In addition to the manuscript, other products of the study may include presentations at scientific conferences, posters, and webinars. The target audience for these products will be similar to that of the manuscript and will include healthcare providers and researchers who are interested in ibrutinib treatment and drug-drug interactions involving CYP3A4.
The results of the study will also be reported back to the YODA Project as per the Data Use Agreement.

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