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  string(1900) "Background: Having APOE-?4 allele[s] is strongly associated with the development of Alzheimer?s disease (AD), and is also associated with some cerebrovascular risk factors such as hyperlipidemia or atherosclerosis. In this point, during clinical trials for AD, participants with APOE-?4 allele[s] may experience additional adverse events (AEs) due to APOE-e4 which resembles cerebrovascular events, in addition to the baseline risk of adverse events as expected for their age and comorbidities. Since some cerebrovascular event symptoms are difficult to distinguish from symptomatic Amyloid Related Imaging Abnormalities (ARIA), this may require investigators to consider more carefully about the prior probability of being ARIA in the safety monitoring.
Objectives: In this study, we aim to investigate the degree of contribution of APOE-?4 allele[s] to the reporting of AEs during clinical trials for AD participants, using randomized controlled trials (RCT) data of placebo arm.
Study Design: Retrospective analysis on the reported adverse events during clinical trials.
Participants: We will include data of thousands of AD participants of placebo arm of RCT of AD treatment, obtained from YODA project and Critical Path for Alzheimer?s disease (CPAD) databases. The treatment drug includes disease-modifying therapy for AD.
Primary outcome measure: The reporting odds ratio as a measure to evaluate to what extent each AE is more likely to be reported in association with APOE-e4 allele[s] than other kinds of AEs.
Statistical analysis: As in the case of conventional pharmacovigilance analysis, we evaluated whether each AE is more likely to be reported in participants with APOE-?4 allele[s] than in those without. This was quantified with reporting odds ratio (ROR) using a mixed effect model in which each clinical trial was appointed as random intercept." ["project_brief_bg"]=> string(2994) "Having APOE-?4 allele[s] is a strong genetic risk factor of Alzheimer?s disease (AD) and is critical in observational studies for AD or dementia [ref1]. It is also known to be associated with the increased risk of developing Amyloid Related Imaging Abnormalities (ARIA)-E in clinical trials of disease-modifying therapies (DMT) for the treatment / prevention of AD (e.g., bapineuzumab, aduacnumab, or lecanemab), which means APOE genotype is also important for clinicians and investigators in the safety monitoring of the administered drugs during clinical trials for AD.
Furthermore, having APOE-?4 allele[s] is also associated with the increased risk [ref1,2] of hyperlipidemia (HL), increased carotid artery intima media thickness (IMT), coronary heart disease (CHD), intracranial atherosclerosis [ref], or increased white matter lesions (WMLs). These features overlap the risk factors of cerebrovascular disease, and ischemic stroke is also reported to be associated with having APOE-?4, although not always consistent in earlier studies. In this point, in addition to the baseline risk of events as expected for the age of individuals, clinical trial participants with APOE-?4 allele[s] may experience additional adverse events (AEs) related to cerebrovascular diseases via the increased vascular risks due to positive APOE-?4 allele[s], irrespective of the enrolled arm in the trials.
The cerebrovascular risk due to APOE-?4 is usually not recognized as critical by itself probably due to its modest effect size; however, since the cerebrovascular event symptoms sometimes cannot always be easily distinguishable from symptoms of ARIA-E or ARIA-H without brain imaging, this may potentially cause confusion for clinicians and investigators in the safety monitoring during clinical trials. For example, when a participant with APOE-?4 allele[s] experienced a new AE that cannot be determined by its symptomatic appearance whether the symptom is caused by ARIA (e.g., dizziness), and in the hypothetical situation where the ?dizziness? AE were actually turned out to be highly reported in the clinical trials in positive association with having APOE-?4 allele[s] itself, the probability of the dizziness actually being due to ARIA will be lowered than previously (e.g., when the cerbrovascular risk by having APOE-?4 allele[s] is not considered or is ignored).
Thus, understanding the degree of contribution of having APOE-?4 allele[s] to the observed reporting of AEs including cerebrovascular symptoms during trials might be informative for clinicians and investigators of clinicl trials for AD, in a viewpoint to distinguish some potentially confusing AEs from the true ARIA symptoms. This is especially true in some trials that are designed in a way to concentrate participants with APOE-?4 allele[s]. In this study, we aim to evaluate above points using a large database collecting data of placebo arm in randomized controlled trials (RCT) for the treatment of AD." ["project_specific_aims"]=> string(822) "The purpose of this study is as follows:
1) to measure the degree of contribution of having APOE-?4 allele[s] to the reporting of AEs including cerebrovascular or any similar symptoms during clinical trials, while adjusting with age and sex. This is achieved by calculating reporting odds ratio (ROR), which derived from one of the metrics frequently used in the post-marketing drug safety pharmacovigilance activity by the authorities.
2) to evaluate how the above consideration of inherent risk by having APOE-?4 allele[s] can influence on the safety monitoring activity mainly focusing early detection and management of ARIA. This is done by formulating the relationship between the ROR and positive predictive value (PPV); the PPV is the probability of being ARIA in participants presenting a certain AE." ["project_study_design"]=> array(2) { ["value"]=> string(8) "meth_res" ["label"]=> string(23) "Methodological research" } ["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(559) "We use placebo arm data from clinical trials for AD, derived from YODA Project database as well as other database named 'Critical Path for Alzheimer?s disease (CPAD)' database.
Among the clinical trial participants included in the obtained database, early to moderate AD (regardless biomarker-based diagnosis or not) participants who are 50-85 years old men and women at baseline are to be included. AD biomarker information (e.g., CSF amyloid beta or phosphorylated tau, or amyloid PET) is not mandatory.
Those without APOE status are excluded." ["project_main_outcome_measure"]=> string(607) "The ROR is based on a 2-by-2 contingency table where all the participants who reported any AEs from placebo arm are classified by the reporting of a certain AE (with or without the AE) and by the status of APOE (with or without e4 allele[s]). ROR is calculated as of conventional odds ratio (OR), although their epidemiological significance differ. ROR is calculated for each AE, and when the lower 95% of ROR is higher than 1, the AE is determined as significantly highly reported in association with the APOE-e4 allele[s]. We enumerate significant AEs and their RORs, which is the primary outcome measure." ["project_main_predictor_indep"]=> string(430) "Chief independent variables we use as follows: age at baseline, sex, ethnicity, education years, family history of dementia/AD, APOE genotype, Clinical Dementia Rating (CDR) (global and sum of boxes), MMSE score, ADAS-cog score (if applicable), ADL score, and the use of cholinesterase inhibitors or memantine during trial. In addition, observed AE terms, date of start and end of AE, severity of AE, and prognosis were also used." ["project_other_variables_interest"]=> string(0) "" ["project_stat_analysis_plan"]=> string(1052) "Unadjusted ROR is calculated as of OR, by conventional 2-by-2 contingency table.
We next obtain adjusted ROR. Since the used data includes dozens of different clinical trials data altogether, we conduct mixed-effect model generalized linear regression: occurrence of a certain AE (in binary) is set as a target binary variable, and age, sex, use of anti-dementia drugs (w/wo), APOE genotype (w/wo e4 allele[s]) were included as fixed variables. Clinical trial ID is included as random variables. Then the coefficient of APOE genotype and its 95%CI are calculated for each AE, and AEs of which coefficient showed significant elevation (lower 95% >1), the AE is determined as significantly highly reported in association with the APOE-e4 allele[s]. The obtained coefficient just corresponds to the adjusted ROR.
We evaluate the ROR value, and the degree of influence the change in ROR may have on the PPV of the AE being symptomatic ARIA.
Robustness of the results will be confirmed by sensitivity analysis changing hyperparameters." ["project_timeline"]=> string(205) "Anticipated project start date: Jan/2023
Date of data analysis completion: Apr/2023
Date of manuscript first submitted: Jul/2023
Date of results reported back to YODA project: Dec/2023" ["project_dissemination_plan"]=> string(151) "We are planning to submit the manuscript to journals of which scope is clinical trials for AD (such as "Journal of Prevention of Alzheimer's Disease")." ["project_bibliography"]=> string(382) "

1) Lumsden, A. L., Mulugeta, A., Zhou, A., & Hyppnen, E. (2020). Apolipoprotein E (APOE) genotype-associated disease risks: a phenome-wide, registry-based, case-control study utilising the UK Biobank. EBioMedicine, 59, 102954.
2) Bennet, A. M., et al. (2007). Association of apolipoprotein E genotypes with lipid levels and coronary risk. JAMA, 298(11), 1300?1311.

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2022-5053

General Information

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

Conflict of Interest

Request Clinical Trials

Associated Trial(s):
  1. NCT00253201 - Efficacy, Tolerability and Safety of Galantamine in the Treatment of Alzheimer's Disease
  2. NCT00304629 - Long Term Safety and Efficacy of Galantamine in Alzheimer's Disease (Extension INT-8)
  3. NCT00253188 - Efficacy, Tolerability and Safety of Galantamine in the Treatment of Alzheimer's Disease
  4. NCT00253214 - Placebo-Controlled Evaluation of Galantamine in the Treatment of Alzheimer's Disease: Safety and Efficacy of a Controlled-Release Formulation
  5. NCT00236574 - A Randomized Double Blind Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Galantamine in Patients With Mild Cognitive Impairment (MCI) Clinically at Risk for Development of Clinically Probable Alzheimer's Disease
  6. NCT00236431 - A Randomized Double-Blind Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Galantamine in Patients With Mild Cognitive Impairment (MCI) Clinically at Risk for Development of Clinically Probable Alzheimer's Disease
  7. NCT00679627 - A Randomized, Double-Blind, Placebo-controlled Trial of Long-term (2-year) Treatment of Galantamine in Mild to Moderately-Severe Alzheimer's Disease
  8. Placebo-controlled evaluation of galantamine in the treatment of Alzheimer’s disease: Evaluation of safety and efficacy under a slow titration regimen
  9. NCT00575055 - A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy and Safety Trial of Bapineuzumab (AAB-001, ELN115727) In Patients With Mild to Moderate Alzheimer's Disease Who Are Apolipoprotein E4 Carriers
  10. NCT00574132 - A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy and Safety Trial of Bapineuzumab (AAB-001, ELN115727) In Patients With Mild to Moderate Alzheimer's Disease Who Are Apolipoprotein E4 Non- Carriers
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: Withdrawn/Closed

Research Proposal

Project Title: Adverse events reported in association with APOE genotype during clinical trials

Scientific Abstract: Background: Having APOE-?4 allele[s] is strongly associated with the development of Alzheimer?s disease (AD), and is also associated with some cerebrovascular risk factors such as hyperlipidemia or atherosclerosis. In this point, during clinical trials for AD, participants with APOE-?4 allele[s] may experience additional adverse events (AEs) due to APOE-e4 which resembles cerebrovascular events, in addition to the baseline risk of adverse events as expected for their age and comorbidities. Since some cerebrovascular event symptoms are difficult to distinguish from symptomatic Amyloid Related Imaging Abnormalities (ARIA), this may require investigators to consider more carefully about the prior probability of being ARIA in the safety monitoring.
Objectives: In this study, we aim to investigate the degree of contribution of APOE-?4 allele[s] to the reporting of AEs during clinical trials for AD participants, using randomized controlled trials (RCT) data of placebo arm.
Study Design: Retrospective analysis on the reported adverse events during clinical trials.
Participants: We will include data of thousands of AD participants of placebo arm of RCT of AD treatment, obtained from YODA project and Critical Path for Alzheimer?s disease (CPAD) databases. The treatment drug includes disease-modifying therapy for AD.
Primary outcome measure: The reporting odds ratio as a measure to evaluate to what extent each AE is more likely to be reported in association with APOE-e4 allele[s] than other kinds of AEs.
Statistical analysis: As in the case of conventional pharmacovigilance analysis, we evaluated whether each AE is more likely to be reported in participants with APOE-?4 allele[s] than in those without. This was quantified with reporting odds ratio (ROR) using a mixed effect model in which each clinical trial was appointed as random intercept.

Brief Project Background and Statement of Project Significance: Having APOE-?4 allele[s] is a strong genetic risk factor of Alzheimer?s disease (AD) and is critical in observational studies for AD or dementia [ref1]. It is also known to be associated with the increased risk of developing Amyloid Related Imaging Abnormalities (ARIA)-E in clinical trials of disease-modifying therapies (DMT) for the treatment / prevention of AD (e.g., bapineuzumab, aduacnumab, or lecanemab), which means APOE genotype is also important for clinicians and investigators in the safety monitoring of the administered drugs during clinical trials for AD.
Furthermore, having APOE-?4 allele[s] is also associated with the increased risk [ref1,2] of hyperlipidemia (HL), increased carotid artery intima media thickness (IMT), coronary heart disease (CHD), intracranial atherosclerosis [ref], or increased white matter lesions (WMLs). These features overlap the risk factors of cerebrovascular disease, and ischemic stroke is also reported to be associated with having APOE-?4, although not always consistent in earlier studies. In this point, in addition to the baseline risk of events as expected for the age of individuals, clinical trial participants with APOE-?4 allele[s] may experience additional adverse events (AEs) related to cerebrovascular diseases via the increased vascular risks due to positive APOE-?4 allele[s], irrespective of the enrolled arm in the trials.
The cerebrovascular risk due to APOE-?4 is usually not recognized as critical by itself probably due to its modest effect size; however, since the cerebrovascular event symptoms sometimes cannot always be easily distinguishable from symptoms of ARIA-E or ARIA-H without brain imaging, this may potentially cause confusion for clinicians and investigators in the safety monitoring during clinical trials. For example, when a participant with APOE-?4 allele[s] experienced a new AE that cannot be determined by its symptomatic appearance whether the symptom is caused by ARIA (e.g., dizziness), and in the hypothetical situation where the ?dizziness? AE were actually turned out to be highly reported in the clinical trials in positive association with having APOE-?4 allele[s] itself, the probability of the dizziness actually being due to ARIA will be lowered than previously (e.g., when the cerbrovascular risk by having APOE-?4 allele[s] is not considered or is ignored).
Thus, understanding the degree of contribution of having APOE-?4 allele[s] to the observed reporting of AEs including cerebrovascular symptoms during trials might be informative for clinicians and investigators of clinicl trials for AD, in a viewpoint to distinguish some potentially confusing AEs from the true ARIA symptoms. This is especially true in some trials that are designed in a way to concentrate participants with APOE-?4 allele[s]. In this study, we aim to evaluate above points using a large database collecting data of placebo arm in randomized controlled trials (RCT) for the treatment of AD.

Specific Aims of the Project: The purpose of this study is as follows:
1) to measure the degree of contribution of having APOE-?4 allele[s] to the reporting of AEs including cerebrovascular or any similar symptoms during clinical trials, while adjusting with age and sex. This is achieved by calculating reporting odds ratio (ROR), which derived from one of the metrics frequently used in the post-marketing drug safety pharmacovigilance activity by the authorities.
2) to evaluate how the above consideration of inherent risk by having APOE-?4 allele[s] can influence on the safety monitoring activity mainly focusing early detection and management of ARIA. This is done by formulating the relationship between the ROR and positive predictive value (PPV); the PPV is the probability of being ARIA in participants presenting a certain AE.

Study Design: Methodological research

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: We use placebo arm data from clinical trials for AD, derived from YODA Project database as well as other database named 'Critical Path for Alzheimer?s disease (CPAD)' database.
Among the clinical trial participants included in the obtained database, early to moderate AD (regardless biomarker-based diagnosis or not) participants who are 50-85 years old men and women at baseline are to be included. AD biomarker information (e.g., CSF amyloid beta or phosphorylated tau, or amyloid PET) is not mandatory.
Those without APOE status are excluded.

Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study: The ROR is based on a 2-by-2 contingency table where all the participants who reported any AEs from placebo arm are classified by the reporting of a certain AE (with or without the AE) and by the status of APOE (with or without e4 allele[s]). ROR is calculated as of conventional odds ratio (OR), although their epidemiological significance differ. ROR is calculated for each AE, and when the lower 95% of ROR is higher than 1, the AE is determined as significantly highly reported in association with the APOE-e4 allele[s]. We enumerate significant AEs and their RORs, which is the primary outcome measure.

Main Predictor/Independent Variable and how it will be categorized/defined for your study: Chief independent variables we use as follows: age at baseline, sex, ethnicity, education years, family history of dementia/AD, APOE genotype, Clinical Dementia Rating (CDR) (global and sum of boxes), MMSE score, ADAS-cog score (if applicable), ADL score, and the use of cholinesterase inhibitors or memantine during trial. In addition, observed AE terms, date of start and end of AE, severity of AE, and prognosis were also used.

Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study:

Statistical Analysis Plan: Unadjusted ROR is calculated as of OR, by conventional 2-by-2 contingency table.
We next obtain adjusted ROR. Since the used data includes dozens of different clinical trials data altogether, we conduct mixed-effect model generalized linear regression: occurrence of a certain AE (in binary) is set as a target binary variable, and age, sex, use of anti-dementia drugs (w/wo), APOE genotype (w/wo e4 allele[s]) were included as fixed variables. Clinical trial ID is included as random variables. Then the coefficient of APOE genotype and its 95%CI are calculated for each AE, and AEs of which coefficient showed significant elevation (lower 95% >1), the AE is determined as significantly highly reported in association with the APOE-e4 allele[s]. The obtained coefficient just corresponds to the adjusted ROR.
We evaluate the ROR value, and the degree of influence the change in ROR may have on the PPV of the AE being symptomatic ARIA.
Robustness of the results will be confirmed by sensitivity analysis changing hyperparameters.

Narrative Summary: Having APOE-?4 allele[s] is a strong risk factor of Alzheimer?s disease (AD), and is also associated with some cerebrovascular risk factors such as hyperlipidemia or atherosclerosis to a smaller extent. In this point, during clinical trials for AD, participants with APOE-?4 allele[s] may experience additional adverse events (AEs) due to APOE-e4 which resembles cerebrovascular events, in addition to the baseline risk of adverse events as expected for their age and comorbidities. We aim to evaluate the degree of APOE-related risk, which might be informative for clinicians and investigators of clinicl trials for AD.

Project Timeline: Anticipated project start date: Jan/2023
Date of data analysis completion: Apr/2023
Date of manuscript first submitted: Jul/2023
Date of results reported back to YODA project: Dec/2023

Dissemination Plan: We are planning to submit the manuscript to journals of which scope is clinical trials for AD (such as "Journal of Prevention of Alzheimer's Disease").

Bibliography:

1) Lumsden, A. L., Mulugeta, A., Zhou, A., & Hyppnen, E. (2020). Apolipoprotein E (APOE) genotype-associated disease risks: a phenome-wide, registry-based, case-control study utilising the UK Biobank. EBioMedicine, 59, 102954.
2) Bennet, A. M., et al. (2007). Association of apolipoprotein E genotypes with lipid levels and coronary risk. JAMA, 298(11), 1300?1311.