The Experts below are selected from a list of 291 Experts worldwide ranked by ideXlab platform
Eric Siemers - One of the best experts on this subject based on the ideXlab platform.
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delayed start analyses in the phase 3 Solanezumab expedition3 study in mild alzheimer s disease
The Journal Of Prevention of Alzheimer's Disease, 2018Co-Authors: Hong Liuseifert, Paul S Aisen, Michael Case, Karen C Holdridge, Scott W Andersen, Sara Kollackwalker, Eric SiemersAbstract:A delayed-start design has been proposed to assess a potential disease-modifying effect in investigational drugs for Alzheimer’s disease that target the underlying disease process. We extended this methodology to recently obtained data from the EXPEDITION3. EXPEDITION3 was a Phase 3, double-blind study with participants randomized to Solanezumab (400 mg) or placebo every 4 weeks for 80 weeks, with an optional extension of active treatment. The delayed-start analysis was designed to determine if a statistically significant treatment difference established during the placebo-controlled period is maintained (at predefined level) during the delayed-start period, which would suggest the active drug has a disease-modifying effect. The delayed-start analysis was assessed across multiple efficacy measures, and includes data from baseline in the placebo-controlled period and up to 9 months in the delayed-start period. No significant difference was observed between the placebo and Solanezumab treatment groups at the end of the placebo-controlled period for the Alzheimer’s Disease Assessment Scale-Cognitive 14-item subscale. A significant treatment difference was observed at the end of the placebo-controlled period for the Alzheimer’s Disease Cooperative Study-Activities of Daily Living instrumental items, an effect also seen at 6 months in the delayed-start period, and the noninferiority criterion was met. No other efficacy measures met these criteria. Delayed-start statistical methodology was used to understand the longitudinal outcomes in EXPEDITION3 and its extension. The small treatment differences observed at the end of the placebo-controlled phase prevented adequate assessment of any putative disease modifying effect.
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central pharmacodynamic activity of Solanezumab in mild alzheimer s disease dementia
Alzheimer's & Dementia: Translational Research & Clinical Interventions, 2018Co-Authors: Brian A Willis, Eric Siemers, Karen Sundell, Joel Raskin, Michael Case, Lisa Fergusonsells, Richard D Lachno, Karen C Holdridge, Ronald B Demattos, Robert A DeanAbstract:Abstract Introduction Solanezumab treatment was previously shown to significantly increase total (bound + unbound) cerebrospinal fluid (CSF) levels of amyloid β (Aβ)1–40 and Aβ1–42 in patients with mild to moderate Alzheimer's disease dementia yet did not produce meaningful cognitive effects. This analysis assessed Solanezumab's central nervous system target engagement by evaluating changes in CSF total and free Aβ isoforms and their relationship with Solanezumab exposure. Methods CSF Aβ isoform concentrations were measured in patients with mild Alzheimer's disease dementia from a pooled EXPEDITION + EXPEDITION2 population and from EXPEDITION3. CSF Solanezumab concentrations were determined from EXPEDITION3. Results Solanezumab produced statistically significant increases in CSF total Aβ isoforms versus placebo, which correlated with CSF Solanezumab concentration. Inconsistent effects on free Aβ isoforms were observed. Solanezumab penetration into the central nervous system was low. Discussion Solanezumab administration engaged the central molecular target, and molar ratio analyses demonstrated that higher exposures may further increase CSF total Aβ concentrations.
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use of white matter reference regions for detection of change in florbetapir positron emission tomography from completed phase 3 Solanezumab trials
Alzheimers & Dementia, 2017Co-Authors: Adam S Fleisher, Karen Sundell, Yunfei Chen, Abhinay D Joshi, Sara Kollackwalker, Sherry Chen, Michael D Devous, John Seibyl, Kenneth Marek, Eric SiemersAbstract:Abstract Introduction We compared subject-specific white matter (SSWM) and whole cerebellum (CBL) reference regions for power to detect longitudinal change in amyloid positron emission tomography signal. Methods Positive florbetapir positron emission tomography scans were analyzed from participants (66 placebo treated and 63 Solanezumab treated) with mild dementia caused by Alzheimer's disease from the EXPEDITION and EXPEDITION2 studies. For comparison to CBL, a second normalization was performed on longitudinal data using an SSWM correction factor (SSWM normalization ratio [SSWMnr]). Analysis of covariance assessed baseline to 18-month change between treatment with Solanezumab and placebo. Sample and effect size estimations provided magnitude of observed treatment changes. Results Longitudinal percent change between placebo and Solanezumab using CBL was not significant ( P = .536) but was significant for SSWMnr ( P = .042). Compared with CBL, SSWMnr technique increased the power to detect a treatment difference, more than tripling the effect size and reducing the sample size requirements by 85% to 90%. Discussion Adjusting longitudinal standardized uptake value ratios with an SSWM reference region in these antiamyloid treatment trials increased mean change detection and decreased variance resulting in the substantial improvement in statistical power to detect change.
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Statistical properties of continuous composite scales and implications for drug development
2017Co-Authors: Hong Liu-seifert, Michael Case, Karen C Holdridge, Scott Andersen, Jondavid Sparks, Alette M. Wessels, Suzanne Hendrix, Paul Aisen, Eric SiemersAbstract:Little research has been conducted on the statistical properties of composite measures comprising linear combinations of continuous component scales. We assessed the quantitative relationship between the composites and their individual components regarding their abilities to detect treatment effects. In particular, we developed the mathematical derivation of the treatment effect size of a continuous composite in relation to the treatment effect sizes of its components and proved multiple properties of the composite. We demonstrated that the treatment effect size of a composite is greater than the minimum treatment effect size of its components and that above certain thresholds of correlations of components and ratios of component effect sizes, the composite may outperform its components. Examples from Alzheimer’s disease (AD) clinical studies of Solanezumab and donepezil using the composite Integrated AD Rating Scale (iADRS) and its components, the AD Assessment Scale-Cognitive subscale (ADAS-Cog) and AD Cooperative Study-Activities of Daily Living inventory, instrumental items (ADCS-iADL) were consistent with the theoretical statistical properties. The understanding of the quantitative relationships between continuous composites and their components will be useful in clinical trial design and the development of new scales and composites across therapeutic areas.
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RESEARCH ARTICLE A Novel Approach to Delayed-Start Analyses for Demonstrating Disease-Modifying Effects in Alzheimer’s Disease
2016Co-Authors: Hong Liu-seifert, Karen C Holdridge, Scott W Andersen, Ilya Lipkovich, Eric SiemersAbstract:One method for demonstrating disease modification is a delayed-start design, consisting of a placebo-controlled period followed by a delayed-start period wherein all patients receive active treatment. To address methodological issues in previous delayed-start approaches, we propose a new method that is robust across conditions of drug effect, discontinuation rates, and missing data mechanisms. We propose a modeling approach and test procedure to test the hypothesis of noninferiority, comparing the treatment difference at the end of the delayed-start period with that at the end of the placebo-controlled period. We conducted simulations to identify the optimal noninferiority testing procedure to ensure the method was robust across scenarios and assumptions, and to evaluate the appropriate modeling ap-proach for analyzing the delayed-start period. We then applied this methodology to Phase 3 Solanezumab clinical trial data for mild Alzheimer’s disease patients. Simulation results showed a testing procedure using a proportional noninferiority margin was robust for detect-ing disease-modifying effects; conditions of high and moderate discontinuations; and with various missing data mechanisms. Using all data from all randomized patients in a singl
Robert A Dean - One of the best experts on this subject based on the ideXlab platform.
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central pharmacodynamic activity of Solanezumab in mild alzheimer s disease dementia
Alzheimer's & Dementia: Translational Research & Clinical Interventions, 2018Co-Authors: Brian A Willis, Eric Siemers, Karen Sundell, Joel Raskin, Michael Case, Lisa Fergusonsells, Richard D Lachno, Karen C Holdridge, Ronald B Demattos, Robert A DeanAbstract:Abstract Introduction Solanezumab treatment was previously shown to significantly increase total (bound + unbound) cerebrospinal fluid (CSF) levels of amyloid β (Aβ)1–40 and Aβ1–42 in patients with mild to moderate Alzheimer's disease dementia yet did not produce meaningful cognitive effects. This analysis assessed Solanezumab's central nervous system target engagement by evaluating changes in CSF total and free Aβ isoforms and their relationship with Solanezumab exposure. Methods CSF Aβ isoform concentrations were measured in patients with mild Alzheimer's disease dementia from a pooled EXPEDITION + EXPEDITION2 population and from EXPEDITION3. CSF Solanezumab concentrations were determined from EXPEDITION3. Results Solanezumab produced statistically significant increases in CSF total Aβ isoforms versus placebo, which correlated with CSF Solanezumab concentration. Inconsistent effects on free Aβ isoforms were observed. Solanezumab penetration into the central nervous system was low. Discussion Solanezumab administration engaged the central molecular target, and molar ratio analyses demonstrated that higher exposures may further increase CSF total Aβ concentrations.
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quantile regression to characterize Solanezumab effects in alzheimer s disease trials
Alzheimer's & Dementia: Translational Research & Clinical Interventions, 2016Co-Authors: Yunfei Chen, Karen Sundell, Joel Raskin, Karla Alaka, Kory Schuh, Robert A DeanAbstract:Abstract Introduction In two Solanezumab trials for mild-to-moderate Alzheimer's disease (AD) dementia, 27% of patients had biomarker confirmation of amyloid status. Of these, approximately 25% of mild patients and approximately 10% of moderate patients were amyloid negative and, as a group, did not exhibit clinical progression typical of AD. This post-hoc analysis describes a statistical surrogate for amyloid status. Methods Quantile regression was used to examine Solanezumab treatment effects at fixed percentiles of varying degrees of clinical progression, with lowest percentiles (minimal progression atypical of AD) and higher percentiles acting as surrogates for amyloid negativity or positivity, respectively. Results In mild patients, Solanezumab treatment effect was greater in higher percentiles of progression and less in lowest percentiles (AD-atypical). In moderate patients, Solanezumab did not show effects across most percentiles. Discussion Results are compatible with design of the ongoing Solanezumab EXPEDITION 3 trial that limits patients to those with mild AD dementia and evidence of amyloid pathology.
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phase 3 Solanezumab trials secondary outcomes in mild alzheimer s disease patients
Alzheimers & Dementia, 2016Co-Authors: Eric Siemers, Hong Liuseifert, Karen Sundell, Christopher Carlson, Michael Case, Robert A Dean, Gopalan Sethuraman, Sherie A Dowsett, Michael J Pontecorvo, Ronald B DemattosAbstract:Abstract Introduction EXPEDITION and EXPEDITION2 were identically designed placebo-controlled phase 3 studies assessing effects of Solanezumab, an antiamyloid monoclonal antibody binding soluble amyloid-β peptide, on cognitive and functional decline over 80 weeks in patients with mild-to-moderate Alzheimer's disease (AD). Primary findings for both studies have been published. Methods Secondary analyses of efficacy, biomarker, and safety endpoints in the pooled (EXPEDTION + EXPEDITION2) mild AD population were performed. Results In the mild AD population, less cognitive and functional decline was observed with Solanezumab (n = 659) versus placebo (n = 663), measured by Alzheimer's Disease Assessment Scale Cognitive subscale, Mini-Mental State Examination, and Alzheimer's Disease Cooperative Study–Activities of Daily Living functional scale Instrumental ADLs. Baseline-to-endpoint changes did not differ between treatment groups for Alzheimer's Disease Cooperative Study–Activities of Daily Living functional scale, basic items of the ADCS-ADL, and Clinical Dementia Rating Sum of Boxes. Plasma/cerebrospinal fluid biomarker findings indicated target engagement by Solanezumab. Solanezumab demonstrated acceptable safety. Efficacy findings for the moderate AD population are also provided. Discussion These findings describe Solanezumab effects on efficacy/safety measures in a mild AD population. Another phase 3 study, EXPEDITION3, will investigate Solanezumab's effects in a mild AD population.
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featured article phase 3 Solanezumab trials secondary outcomes in mild alzheimer s disease patients
2016Co-Authors: Eric Siemers, Hong Liuseifert, Karen Sundell, Christopher Carlson, Michael Case, Robert A Dean, Gopalan Sethuraman, Sherie A Dowsett, Michael J Pontecorvo, Ronald B DemattosAbstract:Introduction: EXPEDITION and EXPEDITION2 were identically designed placebo-controlled phase 3 studies assessing effects of Solanezumab, an antiamyloid monoclonal antibody binding soluble amyloid-b peptide, on cognitive and functional decline over 80 weeks in patients with mild-tomoderate Alzheimer’s disease (AD). Primary findings for both studies have been published. Methods: Secondary analyses of efficacy, biomarker, and safety endpoints in the pooled (EXPEDTION 1 EXPEDITION2) mild AD population were performed. Results: In the mild AD population, less cognitive and functional decline was observed with Solanezumab (n 5 659) versus placebo (n 5 663), measured by Alzheimer’s Disease Assessment Scale Cognitivesubscale,Mini-MentalStateExamination,andAlzheimer’sDiseaseCooperativeStudy–Activities of Daily Living functional scale Instrumental ADLs. Baseline-to-endpoint changes did not differbetweentreatmentgroupsforAlzheimer’sDiseaseCooperativeStudy–ActivitiesofDailyLiving functionalscale,basicitemsoftheADCS-ADL,andClinicalDementiaRatingSumofBoxes.Plasma/ cerebrospinal fluid biomarker findings indicated target engagement by Solanezumab. Solanezumab demonstrated acceptable safety. Efficacy findings for the moderate AD population are also provided. Discussion: These findings describe Solanezumab effects on efficacy/safety measures in a mild AD population. Another phase 3 study, EXPEDITION3, will investigate Solanezumab’s effects in a mild AD population. 2016 Eli Lilly and Company, Indianapolis, IN. Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
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featured article quantile regression to characterize Solanezumab effects in alzheimer s disease trials
2016Co-Authors: Yunfei Chen, Karen Sundell, Joel Raskin, Karla Alaka, Kory Schuh, Robert A DeanAbstract:Introduction: IntwoSolanezumabtrialsformild-to-moderateAlzheimer’sdisease(AD)dementia,27% of patients had biomarker confirmation of amyloid status. Of these, approximately 25% of mild patients and approximately 10% of moderate patients were amyloid negative and, as a group, did not exhibit clinical progression typical of AD. This post-hoc analysis describes a statistical surrogate for amyloid status. Methods: Quantile regression was used to examine Solanezumab treatment effects at fixed percentiles of varying degrees of clinical progression, with lowest percentiles (minimal progression atypical of AD) and higher percentiles acting as surrogates for amyloid negativity or positivity, respectively. Results: In mild patients, Solanezumab treatment effect was greater in higher percentiles of progression and less in lowest percentiles (AD-atypical). In moderate patients, Solanezumab did not show effects across most percentiles. Discussion: Results are compatible with design of the ongoing Solanezumab EXPEDITION 3 trial that limits patients to those with mild AD dementia and evidence of amyloid pathology. 2016 Eli Lilly and Company. Published by Elsevier Inc. on behalf of the Alzheimer’s Association. Thisisan open access articleunder theCCBY-NC-ND license(http://creativecommons.org/licenses/ by-nc-nd/4.0/).
Karen Sundell - One of the best experts on this subject based on the ideXlab platform.
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magnetic resonance imaging measures of brain atrophy from the expedition3 trial in mild alzheimer s disease
Alzheimer's & Dementia: Translational Research & Clinical Interventions, 2019Co-Authors: Adam J Schwarz, Karen Sundell, Michael Case, Joyce Suhy, Arnaud Charil, Ralf K Jaeger, David Scott, Luc Bracoud, Joonmi Oh, Michael J PontecorvoAbstract:Abstract Introduction Solanezumab is a humanized monoclonal antibody that preferentially binds to soluble amyloid β and promotes its clearance from the brain in preclinical studies. The objective of this study was to assess the effect of Solanezumab in slowing global and anatomically localized brain atrophy as measured by volumetric magnetic resonance imaging (MRI). Methods In the EXPEDITION3 phase 3 trial, participants with mild Alzheimer's disease were randomized to receive intravenous infusions of either 400 mg of Solanezumab or placebo every 4 weeks for 76 weeks. Volumetric MRI scans were acquired at baseline and at 80 weeks from 275 MRI facilities using a standardized imaging protocol. A subset of 1462 patients who completed both MRI and 14-item Alzheimer's Disease Assessment Scale–Cognitive Subscale assessments at both time points were selected for analysis. Longitudinal MRI volume changes were analyzed centrally by tensor-based morphometry with a standard FreeSurfer brain parcellation. Prespecified volumetric measures, including whole brain and ventricles, along with anatomically localized regions in the temporal, parietal, and frontal lobes were evaluated in those participants. Results Group-mean differences in brain atrophy rates were directionally consistent across a number of brain regions but small in magnitude (1.3–6.9% slowing) and not statistically significant when corrected for multiple comparisons. The annualized rates of change of the volumetric measures and the correlation of these changes with cognitive changes in placebo-treated subjects were similar to those reported previously. Discussion In the EXPEDITION3 trial, Solanezumab did not significantly slow down rates of global or anatomically localized brain atrophy. Brain volume changes and their relationship to cognition were consistent with previous reports.
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central pharmacodynamic activity of Solanezumab in mild alzheimer s disease dementia
Alzheimer's & Dementia: Translational Research & Clinical Interventions, 2018Co-Authors: Brian A Willis, Eric Siemers, Karen Sundell, Joel Raskin, Michael Case, Lisa Fergusonsells, Richard D Lachno, Karen C Holdridge, Ronald B Demattos, Robert A DeanAbstract:Abstract Introduction Solanezumab treatment was previously shown to significantly increase total (bound + unbound) cerebrospinal fluid (CSF) levels of amyloid β (Aβ)1–40 and Aβ1–42 in patients with mild to moderate Alzheimer's disease dementia yet did not produce meaningful cognitive effects. This analysis assessed Solanezumab's central nervous system target engagement by evaluating changes in CSF total and free Aβ isoforms and their relationship with Solanezumab exposure. Methods CSF Aβ isoform concentrations were measured in patients with mild Alzheimer's disease dementia from a pooled EXPEDITION + EXPEDITION2 population and from EXPEDITION3. CSF Solanezumab concentrations were determined from EXPEDITION3. Results Solanezumab produced statistically significant increases in CSF total Aβ isoforms versus placebo, which correlated with CSF Solanezumab concentration. Inconsistent effects on free Aβ isoforms were observed. Solanezumab penetration into the central nervous system was low. Discussion Solanezumab administration engaged the central molecular target, and molar ratio analyses demonstrated that higher exposures may further increase CSF total Aβ concentrations.
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use of white matter reference regions for detection of change in florbetapir positron emission tomography from completed phase 3 Solanezumab trials
Alzheimers & Dementia, 2017Co-Authors: Adam S Fleisher, Karen Sundell, Yunfei Chen, Abhinay D Joshi, Sara Kollackwalker, Sherry Chen, Michael D Devous, John Seibyl, Kenneth Marek, Eric SiemersAbstract:Abstract Introduction We compared subject-specific white matter (SSWM) and whole cerebellum (CBL) reference regions for power to detect longitudinal change in amyloid positron emission tomography signal. Methods Positive florbetapir positron emission tomography scans were analyzed from participants (66 placebo treated and 63 Solanezumab treated) with mild dementia caused by Alzheimer's disease from the EXPEDITION and EXPEDITION2 studies. For comparison to CBL, a second normalization was performed on longitudinal data using an SSWM correction factor (SSWM normalization ratio [SSWMnr]). Analysis of covariance assessed baseline to 18-month change between treatment with Solanezumab and placebo. Sample and effect size estimations provided magnitude of observed treatment changes. Results Longitudinal percent change between placebo and Solanezumab using CBL was not significant ( P = .536) but was significant for SSWMnr ( P = .042). Compared with CBL, SSWMnr technique increased the power to detect a treatment difference, more than tripling the effect size and reducing the sample size requirements by 85% to 90%. Discussion Adjusting longitudinal standardized uptake value ratios with an SSWM reference region in these antiamyloid treatment trials increased mean change detection and decreased variance resulting in the substantial improvement in statistical power to detect change.
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quantile regression to characterize Solanezumab effects in alzheimer s disease trials
Alzheimer's & Dementia: Translational Research & Clinical Interventions, 2016Co-Authors: Yunfei Chen, Karen Sundell, Joel Raskin, Karla Alaka, Kory Schuh, Robert A DeanAbstract:Abstract Introduction In two Solanezumab trials for mild-to-moderate Alzheimer's disease (AD) dementia, 27% of patients had biomarker confirmation of amyloid status. Of these, approximately 25% of mild patients and approximately 10% of moderate patients were amyloid negative and, as a group, did not exhibit clinical progression typical of AD. This post-hoc analysis describes a statistical surrogate for amyloid status. Methods Quantile regression was used to examine Solanezumab treatment effects at fixed percentiles of varying degrees of clinical progression, with lowest percentiles (minimal progression atypical of AD) and higher percentiles acting as surrogates for amyloid negativity or positivity, respectively. Results In mild patients, Solanezumab treatment effect was greater in higher percentiles of progression and less in lowest percentiles (AD-atypical). In moderate patients, Solanezumab did not show effects across most percentiles. Discussion Results are compatible with design of the ongoing Solanezumab EXPEDITION 3 trial that limits patients to those with mild AD dementia and evidence of amyloid pathology.
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phase 3 Solanezumab trials secondary outcomes in mild alzheimer s disease patients
Alzheimers & Dementia, 2016Co-Authors: Eric Siemers, Hong Liuseifert, Karen Sundell, Christopher Carlson, Michael Case, Robert A Dean, Gopalan Sethuraman, Sherie A Dowsett, Michael J Pontecorvo, Ronald B DemattosAbstract:Abstract Introduction EXPEDITION and EXPEDITION2 were identically designed placebo-controlled phase 3 studies assessing effects of Solanezumab, an antiamyloid monoclonal antibody binding soluble amyloid-β peptide, on cognitive and functional decline over 80 weeks in patients with mild-to-moderate Alzheimer's disease (AD). Primary findings for both studies have been published. Methods Secondary analyses of efficacy, biomarker, and safety endpoints in the pooled (EXPEDTION + EXPEDITION2) mild AD population were performed. Results In the mild AD population, less cognitive and functional decline was observed with Solanezumab (n = 659) versus placebo (n = 663), measured by Alzheimer's Disease Assessment Scale Cognitive subscale, Mini-Mental State Examination, and Alzheimer's Disease Cooperative Study–Activities of Daily Living functional scale Instrumental ADLs. Baseline-to-endpoint changes did not differ between treatment groups for Alzheimer's Disease Cooperative Study–Activities of Daily Living functional scale, basic items of the ADCS-ADL, and Clinical Dementia Rating Sum of Boxes. Plasma/cerebrospinal fluid biomarker findings indicated target engagement by Solanezumab. Solanezumab demonstrated acceptable safety. Efficacy findings for the moderate AD population are also provided. Discussion These findings describe Solanezumab effects on efficacy/safety measures in a mild AD population. Another phase 3 study, EXPEDITION3, will investigate Solanezumab's effects in a mild AD population.
Christopher Carlson - One of the best experts on this subject based on the ideXlab platform.
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phase 3 Solanezumab trials secondary outcomes in mild alzheimer s disease patients
Alzheimers & Dementia, 2016Co-Authors: Eric Siemers, Hong Liuseifert, Karen Sundell, Christopher Carlson, Michael Case, Robert A Dean, Gopalan Sethuraman, Sherie A Dowsett, Michael J Pontecorvo, Ronald B DemattosAbstract:Abstract Introduction EXPEDITION and EXPEDITION2 were identically designed placebo-controlled phase 3 studies assessing effects of Solanezumab, an antiamyloid monoclonal antibody binding soluble amyloid-β peptide, on cognitive and functional decline over 80 weeks in patients with mild-to-moderate Alzheimer's disease (AD). Primary findings for both studies have been published. Methods Secondary analyses of efficacy, biomarker, and safety endpoints in the pooled (EXPEDTION + EXPEDITION2) mild AD population were performed. Results In the mild AD population, less cognitive and functional decline was observed with Solanezumab (n = 659) versus placebo (n = 663), measured by Alzheimer's Disease Assessment Scale Cognitive subscale, Mini-Mental State Examination, and Alzheimer's Disease Cooperative Study–Activities of Daily Living functional scale Instrumental ADLs. Baseline-to-endpoint changes did not differ between treatment groups for Alzheimer's Disease Cooperative Study–Activities of Daily Living functional scale, basic items of the ADCS-ADL, and Clinical Dementia Rating Sum of Boxes. Plasma/cerebrospinal fluid biomarker findings indicated target engagement by Solanezumab. Solanezumab demonstrated acceptable safety. Efficacy findings for the moderate AD population are also provided. Discussion These findings describe Solanezumab effects on efficacy/safety measures in a mild AD population. Another phase 3 study, EXPEDITION3, will investigate Solanezumab's effects in a mild AD population.
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amyloid related imaging abnormalities from trials of Solanezumab for alzheimer s disease
Alzheimer's & Dementia: Diagnosis Assessment & Disease Monitoring, 2016Co-Authors: Christopher Carlson, Eric Siemers, Ann Marie Hake, Michael Case, Roza Hayduk, Joyce Suhy, Jerome BarakosAbstract:Abstract Introduction Solanezumab, a humanized monoclonal antibody that binds soluble amyloid beta peptide, is being developed for treatment of Alzheimer's disease (AD). Methods Patients (n = 2042) with mild and moderate AD were randomized 1:1 to 400-mg Solanezumab or placebo infusion every 4 weeks for 80 weeks and 1457 patients entered an open-label extension. Magnetic resonance imaging scans monitored for amyloid-related imaging abnormalities-edema/effusion (ARIA-E) and amyloid-related imaging abnormalities-hemorrhage/hemosiderin deposition. Results Sixteen patients (Solanezumab, n = 11; placebo, n = 5) developed ARIA-E during the double-blind phase, and 7 patients developed ARIA-E during the open-label extension as of July 31, 2014. Unique cases are discussed including Solanezumab patients who were given Solanezumab, while ARIA-E was present and a patient who developed ARIA-E during placebo treatment and again during Solanezumab treatment. Discussion Asymptomatic ARIA-E was detected in Solanezumab-treated and placebo-treated AD patients. ARIA-E occurs infrequently during Solanezumab and placebo treatments but may occur repeatedly in some patients.
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featured article phase 3 Solanezumab trials secondary outcomes in mild alzheimer s disease patients
2016Co-Authors: Eric Siemers, Hong Liuseifert, Karen Sundell, Christopher Carlson, Michael Case, Robert A Dean, Gopalan Sethuraman, Sherie A Dowsett, Michael J Pontecorvo, Ronald B DemattosAbstract:Introduction: EXPEDITION and EXPEDITION2 were identically designed placebo-controlled phase 3 studies assessing effects of Solanezumab, an antiamyloid monoclonal antibody binding soluble amyloid-b peptide, on cognitive and functional decline over 80 weeks in patients with mild-tomoderate Alzheimer’s disease (AD). Primary findings for both studies have been published. Methods: Secondary analyses of efficacy, biomarker, and safety endpoints in the pooled (EXPEDTION 1 EXPEDITION2) mild AD population were performed. Results: In the mild AD population, less cognitive and functional decline was observed with Solanezumab (n 5 659) versus placebo (n 5 663), measured by Alzheimer’s Disease Assessment Scale Cognitivesubscale,Mini-MentalStateExamination,andAlzheimer’sDiseaseCooperativeStudy–Activities of Daily Living functional scale Instrumental ADLs. Baseline-to-endpoint changes did not differbetweentreatmentgroupsforAlzheimer’sDiseaseCooperativeStudy–ActivitiesofDailyLiving functionalscale,basicitemsoftheADCS-ADL,andClinicalDementiaRatingSumofBoxes.Plasma/ cerebrospinal fluid biomarker findings indicated target engagement by Solanezumab. Solanezumab demonstrated acceptable safety. Efficacy findings for the moderate AD population are also provided. Discussion: These findings describe Solanezumab effects on efficacy/safety measures in a mild AD population. Another phase 3 study, EXPEDITION3, will investigate Solanezumab’s effects in a mild AD population. 2016 Eli Lilly and Company, Indianapolis, IN. Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
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delayed start analysis mild alzheimer s disease patients in Solanezumab trials 3 5 years
Alzheimer's & Dementia: Translational Research & Clinical Interventions, 2015Co-Authors: Hong Liuseifert, Eric Siemers, Christopher Carlson, Roza Hayduk, Karen C Holdridge, Scott W Andersen, Ilya Lipkovich, Gopalan Sethuraman, Sharon L Hoog, Rachelle S DoodyAbstract:Abstract Introduction Solanezumab is an anti-amyloid monoclonal antibody in clinical testing for treatment of Alzheimer's disease (AD). Its mechanism suggests the possibility of slowing the progression of AD. Methods A possible disease-modifying effect of Solanezumab was assessed using a new statistical method including noninferiority testing. Performance differences were compared during the placebo-controlled period with performance differences after the placebo patients crossed over to Solanezumab in the delayed-start period. Results Noninferiority of the 14-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog 14 ) and Alzheimer's Disease Cooperative Study Activities of Daily Living inventory instrumental items (ADCS-iADL) differences was met through 132 weeks, indicating that treatment differences observed in the placebo-controlled period remained, within a predefined margin, after the placebo group initiated Solanezumab. Solanezumab was well tolerated, and no new safety concerns were identified. Discussion The results of this secondary analysis show that the mild subgroup of Solanezumab-treated patients who initiated treatment early, at the start of the placebo-controlled period, retained an advantage at most time points in the delayed-start period.
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efficacy and safety of intravenous Solanezumab in patients with mild to moderate alzheimer s disease results of two phase 3 studies
American Journal of Geriatric Psychiatry, 2013Co-Authors: Ann Marie Hake, Eric Siemers, Karen Sundell, Christopher Carlson, Robert A Dean, Wahiba Estergard, David Henley, Jennifer Eads, Cora Sexton, Brian A WillisAbstract:Poster Number: NR 14 Efficacy and Safety of Intravenous Solanezumab in Patients with Mild to Moderate Alzheimer’s Disease: Results of Two Phase 3 Studies Ann M. Hake, MD; Eric Siemers, MD; Christopher Carlson, PhD; Wahiba Estergard, PharmD; Karen Sundell, BS; David Henley, MD; Jennifer Eads, PharmD; Cora Sexton, BSN; Robert A. Dean, PhD, MD; Brian Willis, PhD; Ronald DeMattos, PhD; Richard Mohs, PhD
Hong Liuseifert - One of the best experts on this subject based on the ideXlab platform.
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delayed start analyses in the phase 3 Solanezumab expedition3 study in mild alzheimer s disease
The Journal Of Prevention of Alzheimer's Disease, 2018Co-Authors: Hong Liuseifert, Paul S Aisen, Michael Case, Karen C Holdridge, Scott W Andersen, Sara Kollackwalker, Eric SiemersAbstract:A delayed-start design has been proposed to assess a potential disease-modifying effect in investigational drugs for Alzheimer’s disease that target the underlying disease process. We extended this methodology to recently obtained data from the EXPEDITION3. EXPEDITION3 was a Phase 3, double-blind study with participants randomized to Solanezumab (400 mg) or placebo every 4 weeks for 80 weeks, with an optional extension of active treatment. The delayed-start analysis was designed to determine if a statistically significant treatment difference established during the placebo-controlled period is maintained (at predefined level) during the delayed-start period, which would suggest the active drug has a disease-modifying effect. The delayed-start analysis was assessed across multiple efficacy measures, and includes data from baseline in the placebo-controlled period and up to 9 months in the delayed-start period. No significant difference was observed between the placebo and Solanezumab treatment groups at the end of the placebo-controlled period for the Alzheimer’s Disease Assessment Scale-Cognitive 14-item subscale. A significant treatment difference was observed at the end of the placebo-controlled period for the Alzheimer’s Disease Cooperative Study-Activities of Daily Living instrumental items, an effect also seen at 6 months in the delayed-start period, and the noninferiority criterion was met. No other efficacy measures met these criteria. Delayed-start statistical methodology was used to understand the longitudinal outcomes in EXPEDITION3 and its extension. The small treatment differences observed at the end of the placebo-controlled phase prevented adequate assessment of any putative disease modifying effect.
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phase 3 Solanezumab trials secondary outcomes in mild alzheimer s disease patients
Alzheimers & Dementia, 2016Co-Authors: Eric Siemers, Hong Liuseifert, Karen Sundell, Christopher Carlson, Michael Case, Robert A Dean, Gopalan Sethuraman, Sherie A Dowsett, Michael J Pontecorvo, Ronald B DemattosAbstract:Abstract Introduction EXPEDITION and EXPEDITION2 were identically designed placebo-controlled phase 3 studies assessing effects of Solanezumab, an antiamyloid monoclonal antibody binding soluble amyloid-β peptide, on cognitive and functional decline over 80 weeks in patients with mild-to-moderate Alzheimer's disease (AD). Primary findings for both studies have been published. Methods Secondary analyses of efficacy, biomarker, and safety endpoints in the pooled (EXPEDTION + EXPEDITION2) mild AD population were performed. Results In the mild AD population, less cognitive and functional decline was observed with Solanezumab (n = 659) versus placebo (n = 663), measured by Alzheimer's Disease Assessment Scale Cognitive subscale, Mini-Mental State Examination, and Alzheimer's Disease Cooperative Study–Activities of Daily Living functional scale Instrumental ADLs. Baseline-to-endpoint changes did not differ between treatment groups for Alzheimer's Disease Cooperative Study–Activities of Daily Living functional scale, basic items of the ADCS-ADL, and Clinical Dementia Rating Sum of Boxes. Plasma/cerebrospinal fluid biomarker findings indicated target engagement by Solanezumab. Solanezumab demonstrated acceptable safety. Efficacy findings for the moderate AD population are also provided. Discussion These findings describe Solanezumab effects on efficacy/safety measures in a mild AD population. Another phase 3 study, EXPEDITION3, will investigate Solanezumab's effects in a mild AD population.
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featured article phase 3 Solanezumab trials secondary outcomes in mild alzheimer s disease patients
2016Co-Authors: Eric Siemers, Hong Liuseifert, Karen Sundell, Christopher Carlson, Michael Case, Robert A Dean, Gopalan Sethuraman, Sherie A Dowsett, Michael J Pontecorvo, Ronald B DemattosAbstract:Introduction: EXPEDITION and EXPEDITION2 were identically designed placebo-controlled phase 3 studies assessing effects of Solanezumab, an antiamyloid monoclonal antibody binding soluble amyloid-b peptide, on cognitive and functional decline over 80 weeks in patients with mild-tomoderate Alzheimer’s disease (AD). Primary findings for both studies have been published. Methods: Secondary analyses of efficacy, biomarker, and safety endpoints in the pooled (EXPEDTION 1 EXPEDITION2) mild AD population were performed. Results: In the mild AD population, less cognitive and functional decline was observed with Solanezumab (n 5 659) versus placebo (n 5 663), measured by Alzheimer’s Disease Assessment Scale Cognitivesubscale,Mini-MentalStateExamination,andAlzheimer’sDiseaseCooperativeStudy–Activities of Daily Living functional scale Instrumental ADLs. Baseline-to-endpoint changes did not differbetweentreatmentgroupsforAlzheimer’sDiseaseCooperativeStudy–ActivitiesofDailyLiving functionalscale,basicitemsoftheADCS-ADL,andClinicalDementiaRatingSumofBoxes.Plasma/ cerebrospinal fluid biomarker findings indicated target engagement by Solanezumab. Solanezumab demonstrated acceptable safety. Efficacy findings for the moderate AD population are also provided. Discussion: These findings describe Solanezumab effects on efficacy/safety measures in a mild AD population. Another phase 3 study, EXPEDITION3, will investigate Solanezumab’s effects in a mild AD population. 2016 Eli Lilly and Company, Indianapolis, IN. Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
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delayed start analysis mild alzheimer s disease patients in Solanezumab trials 3 5 years
Alzheimer's & Dementia: Translational Research & Clinical Interventions, 2015Co-Authors: Hong Liuseifert, Eric Siemers, Christopher Carlson, Roza Hayduk, Karen C Holdridge, Scott W Andersen, Ilya Lipkovich, Gopalan Sethuraman, Sharon L Hoog, Rachelle S DoodyAbstract:Abstract Introduction Solanezumab is an anti-amyloid monoclonal antibody in clinical testing for treatment of Alzheimer's disease (AD). Its mechanism suggests the possibility of slowing the progression of AD. Methods A possible disease-modifying effect of Solanezumab was assessed using a new statistical method including noninferiority testing. Performance differences were compared during the placebo-controlled period with performance differences after the placebo patients crossed over to Solanezumab in the delayed-start period. Results Noninferiority of the 14-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog 14 ) and Alzheimer's Disease Cooperative Study Activities of Daily Living inventory instrumental items (ADCS-iADL) differences was met through 132 weeks, indicating that treatment differences observed in the placebo-controlled period remained, within a predefined margin, after the placebo group initiated Solanezumab. Solanezumab was well tolerated, and no new safety concerns were identified. Discussion The results of this secondary analysis show that the mild subgroup of Solanezumab-treated patients who initiated treatment early, at the start of the placebo-controlled period, retained an advantage at most time points in the delayed-start period.
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delayed start analyses of Solanezumab phase 3 studies in mild alzheimer s disease p7 108
Neurology, 2015Co-Authors: Hong Liuseifert, Karen C Holdridge, Scott W Andersen, Eric SiemersAbstract:OBJECTIVE: Compare delayed- and early-start treatment to test hypothesis of disease-modifying effect of Solanezumab. BACKGROUND: Currently, no Alzheimer9s disease (AD) treatments are thought to slow underlying disease progression. One method to evaluate effect on disease progression is a delayed-start design: a placebo-controlled period followed by a delayed-start period when all patients receive active treatment. DESIGN/METHODS: EXPEDITION and EXPEDITION2 were Phase 3, 18-month, placebo-controlled studies investigating Solanezumab. EXPEDITION-ext is an open-label extension study in patients who completed EXPEDITION or EXPEDITION2. In EXPEDITION-ext, all patients receive Solanezumab. Patients and site personnel remain blinded to original treatment assignment. We used a new statistical methodology to test hypothesis of disease-modifying effect using a noninferiority test of treatment differences at the delayed-start end compared with the placebo-controlled period end using data from mild AD patients through 28 weeks of treatment in EXPEDITION-ext. RESULTS: Treatment differences between Solanezumab and placebo at 28 weeks in EXPEDITION-ext (Δ 2 ) were 2.20 (p=.011) for ADAS-Cog 14 and 1.04 (p=.188) for ADCS-iADL, similar to differences at the beginning of the delayed-start period (Δ 1 ) (ADAS-Cog 14 : 2.01, p=.002; ADCS-iADL: 1.17, p=.027). For ADAS-Cog 14 , the lower limit of the 90[percnt] CI for Δ 2 − 50[percnt] × Δ 1 was 0.3697; thus, noninferiority was met, indicating treatment difference in cognition at end of the placebo-controlled studies was preserved at end of delayed-start period within a pre-defined margin. Noninferiority was not met for instrumental function. CONCLUSIONS: Results from 28 weeks’ treatment in EXPEDITION-ext suggest patients who received Solanezumab during the double-blind studies had a cognitive benefit not recovered by patients who began Solanezumab later in EXPEDITION-ext. This is thought consistent with a treatment effect that changes the underlying pathology of AD. Another interim analysis with more patients at 6 months and including 2 years of treatment in EXPEDITION-ext is planned. Study Supported by: Eli Lilly Disclosure: Dr. Liu-Seifert has received personal compensation for activities with Eli Lilly & Company as an employee. Dr. Andersen has received personal compensation for activities with Eli Lilly and Company as an employee. Dr. Andersen hold stock and/or stock options in Eli Lilly and Company. Dr. Holdridge has received personal compensation for activities with Eli Lilly & Company as an employee. Dr. Siemers has received personal compensation for activities with Eli Lilly & Company as an employee.
