- Email: [email protected]
The impact of electronic administration of the adas-cog on clinical trial data quality
Developing Topics Hospital, Second Military Medical University, Shanghai, China; 4 Department of Neurology, The 10th People’s Hospital, Tongji University, Shanghai, China; 5Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China; 6Department of Geriatric Neurology, Chinese PLA General Hospital, Beijing, China; 7Department of Neurology, The First Hospital of Jilin University, Shanghai, China; 8Mental Health Center of Hebei Province, Baoding, China; 9Department of Neurology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; 10Beijing Hui-Long-Guan Hospital, Peking University, Beijing, China; 11Department of Geratology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; 12First Affiliated Hospital of Kunming Medicine University, Kunming, China; 13Guangzhou Psychiatric Hospital, Guangzhou, China; 14Department of Neurology, Beijing Shijitan Hospital, Capital Medical University, Beijing, China; 15 Affiliated Hospital of Guilin Medical School, Guilin, China; 16Department of Neurology, The First Affiliated Hospital of Xiamen University, Xiamen, China; 17Neurological Department, The Third Xiangya Hospital of Central South University, Hunan, China; 18Department of Health Statistics, Second Military Medical University, Shanghai, China. Contact e-mail: wtshhwy@ 163.com Background: The octohydroaminoacridine, a new humanized acetylcholinesterase inhibitor, is a potential treatment for Alzheimer’s disease. Methods: We conducted a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase 2 clinical trial to investigate the effects of octohydroaminoacridine in patients with mild-to-moderate Alzheimer’s disease. 284 patients were randomized to receive placebo thrice-daily (TID), octohydroaminoacridine 1 mg TID (low dose group), or to titrate up to 2 mg TID (middle dose group) in two weeks, or to titrated up to 4 mg TID (high dose group) in four weeks. Changes from baseline to week 16 were assessed with the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog), Clinician’s InterviewBased Impression of Change Plus (CIBIC+), Activities of Daily Living (ADL) and the Neuropsychiatric Inventory (NPI). A 2way analysis of covariance and least squares mean (LSM) t-test were used. (ClinicalTrials.gov Identifier: NCT01569516). Results: In this study, 71, 70, 71 and 72 patients were randomized to low dose group, middle dose group, high dose group, and placebo group, respectively. At week 16, the between-group differences of the change from baseline in the primary outcome of ADAScog (octohydroaminoacridine groups minus placebo group) were 3.16, 3.27 and 5.01 for low, middle, and high dose groups, respectively (p<0.0001 for all these tests). For secondary outcomes, the patients in three drug groups had better performance in CIBICplus score and ADL score, but there were no significant betweengroup differences in NPI score. There was not any evidence for more adverse events occurred in different drug groups than placebo group. Conclusions: Octohydroaminoacridine significantly improved cognitive function and behavior among these patients with mild-to-moderate Alzheimer’s disease.
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COMPOSITE MEASURES IN ALZHEIMER’S DISEASE CLINICAL TRIALS: HOW AN IN-STUDY DATA QUALITY PROGRAM ENSURES IMMEDIATE AND ONGOING QUALITY OF THE SUM OF THEIR PARTS
David Miller1, Chad Swanson2, Veronika Logovinsky2, Antonio Hernandez1, Samantha Bellitz1, 1Bracket, Wayne, PA, USA; 2Eisai, Woodcliff Lake, NJ, USA. Contact e-mail: [email protected] Background: Research in Alzheimer’s disease (AD) clinical trials
has shown that customized, In-Study data quality programs effectively identify rater errors, and after remediation, significantly reduce their subsequent occurrence. This is particularly valuable in earlier disease stage trials using composite measures. We expand earlier research evaluating such a program’s impact in a multi-national clinical trial using the ADCOMS – a composite of the Clinical Dementia Rating scale (CDR) and elements of the Mini-Mental State Exam (MMSE) and Alzheimer’s Disease Assessment Scale – Cognitive subscale (ADAS-Cog). Methods: The customized data quality program’s impact was assessed in the ongoing, blinded BAN2401-G000201 study in early AD (analysis reflects a pooled cohort: 5 doses and placebo arms). All raters received extensive training on proper scale administration and scoring for all component scales. Additionally, raters had to demonstrate competency to rate the CDR and ADAS-Cog prior to evaluating subjects instudy. Rater performance on all 3 scales was assessed by worksheet review at clinical visits conducted every 3 months. When errors in scale administration and/or scoring occurred, raters were remediated and their errors corrected. Results: 1,527 subjects have been screened to date; 835 advanced to Baseline and 178 progressed to the 4th post-randomization clinical visit (week 53). Overall, the following reductions in proportion of worksheets requiring remediation in administration and/or scoring technique were seen from initial assessment to week 53: 29% for the MMSE (7% to 5%); 79% for the CDR (14% to 3%) and 30% for the ADAS-Cog (10% to 7%). Further, for the ADCOMS component items alone, there was a 57% reduction in errors (23% to 10%). Compared to earlier research, ongoing remediations reduced errors made on subsequent initial assessments by 44-50% (depending on the scale). Conclusions: Ensuring the highest quality data is crucial to the success of any clinical trial. This research further highlights the value of an In-Study data quality program, and its impact not only for reducing errors for subsequent assessments on the same subject, but also for assessments on new subjects. This beneficial effect was seen across all scales, and therefore may improve a composite measure’s sensitivity to change in cognition and function.
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THE IMPACT OF ELECTRONIC ADMINISTRATION OF THE ADAS-COG ON CLINICAL TRIAL DATA QUALITY
H. Todd Feaster1, David Miller1, Alan Kott2, 1Bracket, Wayne, PA, USA; Bracket, Prague, Czech Republic. Contact e-mail: todd.feaster@ bracketglobal.com 2
Figure 1. Randomization, Study Completion and Reason for Withdrawal in the Trial
Background: The Alzheimer’s Disease Assessment Scale –
Cognitive subscale (ADAS-Cog) is the most commonly used
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Developing Topics
primary efficacy measure in Alzheimer’s disease (AD) clinical trials. Earlier research has demonstrated considerable variability in how raters have been trained to administer and score the ADAS-Cog in clinical trials. Moreover, prior research has also demonstrated that ADAS-Cog error rates among clinical trial raters tend to be upwards of 32% on initial administration when using the paper-pencil version of the scale. Technological advancements are being incorporated into the conduct of AD clinical trials. One example is the use of electronic versions of assessment scales. An enhanced electronic version of the ADAS-Cog was used in a multi-national clinical trial of subjects with mild AD. We evaluated its impact on overall data quality. Methods: After being trained and certified to rate the ADAS-Cog, all raters’ performance regarding accuracy in scale administration and scoring was assessed by a calibrated clinician at the initial Screening visit. The electronic ADAS-Cog (eADAS-Cog) used in this trial was designed to be equivalent to the paper version of the scale. Additionally, the eADASCog was augmented with standardized instructions and scoring conventions taken directly from the ADAS-Cog manual and study specific training curriculum. These enhancements were intended to increase the likelihood the scale would be consistently administered and scored according to standard conventions. Results: 1009 eADAS-Cogs at Screening were reviewed by a calibrated clinician to assess accuracy of rater scoring. 101 of these eADAS-Cog reviews, or 10%, required a Contact with the rater due to an error noted in scoring. This represents a significant reduction (p < 0.001) in error rates compared to the previously reported 32% found with the paper-pencil version of the scale. Conclusions: The use of an eADAS-Cog designed with enhancements beyond the paper-pencil version, coupled with an instudy ratings surveillance program to identify errors in scoring, can significantly improve data quality by reducing rater error, enhancing standardized administration/scoring and minimizing rater drift.
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WITHDRAWN
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MARKED NEUROPROTECTION USING DUAL KINASE INHIBITION IN Ab NEUROTOXICITY: A NEW BITHERAPY
Sarah Gourmaud1, Franc¸ois Mouton-Liger2, Claire Abadie3, Eliane Meurs4, Claire Paquet1,5, Jacques Hugon1,5, 1INSERM U942, Paris, France; 2ICM Brain and Spine Institute, Paris, France; 3Solid Drug Development, Geneva, Switzerland; 4Pasteur Institute, Paris, France; 5CMRR, Paris, France. Contact e-mail: [email protected] Background: In Alzheimer’s disease (AD) the amyloid cascade hypothesis proposes that Ab neurotoxicity leads to neuroinflammation, synaptic loss, and neuronal degeneration. In AD patients, anti-amyloid immunotherapies did not succeed because they could act late in AD progression. Finding new targets associated with Ab toxicity, such as PKR (double-stranded RNA dependant kinase), and JNK (c-Jun N-terminal kinase) is a major goal. These two pro-apoptotic kinases are involved in Ab production and neurotoxicity, tau phosphorylation, and neuroinflammation. Methods: We used siRNA directed against PKR in HEK cells cultures and PKR knockout (PKR-/-) mice neuronal cultures. Apoptosis was measured by the level of cleaved PARP (Poly ADP-ribose polymerase) and cleaved caspase 3
by immunoblot and by the level of caspase 3 activity by enzyme assay. Results: Our results showed in vitro that PKR induces JNK activation. A significant decrease of Ab-induced neuronal death was observed in PKR-/- neurons: -49% of cleaved PARP, -70% of cleaved caspase 3, and -68% of caspase 3 activity. In cultured neurons, two selective JNK inhibitory peptides also produced a striking reduction of Ab toxicity (-55% and -77% of cleaved PARP). Finally, the dual inhibition of PKR and JNK nearly abolished Ab toxicity in primary neurons (-92% of cleaved PARP). Conclusions: These results reveal that dual kinase inhibition of PKR and JNK is a new therapeutic way to afford neuroprotection in AD patients.
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EPITOPE-SPECIFIC AMYLOID-b OLIGOMER VACCINATION AMELIORATES AMYGDALADEPENDENT MEMORY DEFICITS AND INHIBITS REGION-TO-REGION SPREAD OF PLAQUE PATHOLOGY IN APP/PS1 MICE
Judith M. Silverman1, Kristina Martens1, Ebrima Gibbs1, Jing Wang1, Xiaobing Han2, Masoud Yousefi1, Cory L. Nykiforuk2, Laura Saward2, Cheryl Wellington1, Neil R. Cashman1, 1University of British Columbia, Vancouver, BC, Canada; 2Emergent BioSolutions, Winnipeg, MB, Canada. Contact e-mail: [email protected] Background: We have previously identified an amyloid-b oligomer-selective epitope, namely cyclized-Serine-AsparagineLysine (cSNK), which is not present on Ab fibrils or monomers. Antibodies against cSNK recognize authentic Ab oligomers (AbOs) present in brain and CSF of human Alzheimer’s disease (AD) patients and brain tissues of transgenic mouse models of AD, but not monomers or fibrils. Here, we conducted testing of cSNK as a vaccine in APP/PS1 mice. Methods: Sex matched cohorts of 38 APP/PS1 mice on a C3H/BL6 background were vaccinated subcutaneously with 100 mg of cSNK-KLH, with Emulsigen-D as adjuvant or Emulsigen-D alone, beginning at 3 months of age (MOA). Animals were treated monthly. Plasma was collected at baseline and throughout immunization. At 11 MOA, animals were tested for memory function with cued and contextual fear conditioning (CFC) tasks and the novel object recognition (NOR) task. Following sacrifice at 12 MOA, plaque load was determined with ThioflavinS. Plasma anticSNK titers were quantified using MagPlex immunoassay. The Shapiro-Wilk test determined data normality. Differences between groups and genders were tested using a regression model with categorical covariates (ANOVA) and t-test or Mann-Whitney test when appropriate, using XLSTAT V2014.6.04. Results: Baseline and control (adjuvant-alone) anti-cSNK titers were below detection limits throughout the study. In comparison, anti-cSNK titers were elevated following immunization and remained at or above this benchmark throughout the study in cSNK-KLH treated animals. Vaccination with cSNK significantly improved performance in the Cued FC task, which tests amygdala-dependent memory. In contrast, performance was not significantly improved in the Contextual FC or NOR tasks, both indicative of hippocampus-dependent memory. Correspondingly, analysis of these regions show cSNK immunization had no effect on hippocampal plaque burden, but significant reductions in plaque burden were observed in the amygdala and parahippocampal cortex, both of which receive projections from the hippocampus. Conclusions: This study establishes that vaccination of APP/PS1 mice with cSNK generates a polyclonal
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COMPOSITE MEASURES IN ALZHEIMER’S DISEASE CLINICAL TRIALS: HOW AN IN-STUDY DATA QUALITY PROGRAM ENSURES IMMEDIATE AND ONGOING QUALITY OF THE SUM OF THEIR PARTS
David Miller1, Chad Swanson2, Veronika Logovinsky2, Antonio Hernandez1, Samantha Bellitz1, 1Bracket, Wayne, PA, USA; 2Eisai, Woodcliff Lake, NJ, USA. Contact e-mail: [email protected] Background: Research in Alzheimer’s disease (AD) clinical trials
has shown that customized, In-Study data quality programs effectively identify rater errors, and after remediation, significantly reduce their subsequent occurrence. This is particularly valuable in earlier disease stage trials using composite measures. We expand earlier research evaluating such a program’s impact in a multi-national clinical trial using the ADCOMS – a composite of the Clinical Dementia Rating scale (CDR) and elements of the Mini-Mental State Exam (MMSE) and Alzheimer’s Disease Assessment Scale – Cognitive subscale (ADAS-Cog). Methods: The customized data quality program’s impact was assessed in the ongoing, blinded BAN2401-G000201 study in early AD (analysis reflects a pooled cohort: 5 doses and placebo arms). All raters received extensive training on proper scale administration and scoring for all component scales. Additionally, raters had to demonstrate competency to rate the CDR and ADAS-Cog prior to evaluating subjects instudy. Rater performance on all 3 scales was assessed by worksheet review at clinical visits conducted every 3 months. When errors in scale administration and/or scoring occurred, raters were remediated and their errors corrected. Results: 1,527 subjects have been screened to date; 835 advanced to Baseline and 178 progressed to the 4th post-randomization clinical visit (week 53). Overall, the following reductions in proportion of worksheets requiring remediation in administration and/or scoring technique were seen from initial assessment to week 53: 29% for the MMSE (7% to 5%); 79% for the CDR (14% to 3%) and 30% for the ADAS-Cog (10% to 7%). Further, for the ADCOMS component items alone, there was a 57% reduction in errors (23% to 10%). Compared to earlier research, ongoing remediations reduced errors made on subsequent initial assessments by 44-50% (depending on the scale). Conclusions: Ensuring the highest quality data is crucial to the success of any clinical trial. This research further highlights the value of an In-Study data quality program, and its impact not only for reducing errors for subsequent assessments on the same subject, but also for assessments on new subjects. This beneficial effect was seen across all scales, and therefore may improve a composite measure’s sensitivity to change in cognition and function.
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THE IMPACT OF ELECTRONIC ADMINISTRATION OF THE ADAS-COG ON CLINICAL TRIAL DATA QUALITY
H. Todd Feaster1, David Miller1, Alan Kott2, 1Bracket, Wayne, PA, USA; Bracket, Prague, Czech Republic. Contact e-mail: todd.feaster@ bracketglobal.com 2
Figure 1. Randomization, Study Completion and Reason for Withdrawal in the Trial
Background: The Alzheimer’s Disease Assessment Scale –
Cognitive subscale (ADAS-Cog) is the most commonly used
P904
Developing Topics
primary efficacy measure in Alzheimer’s disease (AD) clinical trials. Earlier research has demonstrated considerable variability in how raters have been trained to administer and score the ADAS-Cog in clinical trials. Moreover, prior research has also demonstrated that ADAS-Cog error rates among clinical trial raters tend to be upwards of 32% on initial administration when using the paper-pencil version of the scale. Technological advancements are being incorporated into the conduct of AD clinical trials. One example is the use of electronic versions of assessment scales. An enhanced electronic version of the ADAS-Cog was used in a multi-national clinical trial of subjects with mild AD. We evaluated its impact on overall data quality. Methods: After being trained and certified to rate the ADAS-Cog, all raters’ performance regarding accuracy in scale administration and scoring was assessed by a calibrated clinician at the initial Screening visit. The electronic ADAS-Cog (eADAS-Cog) used in this trial was designed to be equivalent to the paper version of the scale. Additionally, the eADASCog was augmented with standardized instructions and scoring conventions taken directly from the ADAS-Cog manual and study specific training curriculum. These enhancements were intended to increase the likelihood the scale would be consistently administered and scored according to standard conventions. Results: 1009 eADAS-Cogs at Screening were reviewed by a calibrated clinician to assess accuracy of rater scoring. 101 of these eADAS-Cog reviews, or 10%, required a Contact with the rater due to an error noted in scoring. This represents a significant reduction (p < 0.001) in error rates compared to the previously reported 32% found with the paper-pencil version of the scale. Conclusions: The use of an eADAS-Cog designed with enhancements beyond the paper-pencil version, coupled with an instudy ratings surveillance program to identify errors in scoring, can significantly improve data quality by reducing rater error, enhancing standardized administration/scoring and minimizing rater drift.
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MARKED NEUROPROTECTION USING DUAL KINASE INHIBITION IN Ab NEUROTOXICITY: A NEW BITHERAPY
Sarah Gourmaud1, Franc¸ois Mouton-Liger2, Claire Abadie3, Eliane Meurs4, Claire Paquet1,5, Jacques Hugon1,5, 1INSERM U942, Paris, France; 2ICM Brain and Spine Institute, Paris, France; 3Solid Drug Development, Geneva, Switzerland; 4Pasteur Institute, Paris, France; 5CMRR, Paris, France. Contact e-mail: [email protected] Background: In Alzheimer’s disease (AD) the amyloid cascade hypothesis proposes that Ab neurotoxicity leads to neuroinflammation, synaptic loss, and neuronal degeneration. In AD patients, anti-amyloid immunotherapies did not succeed because they could act late in AD progression. Finding new targets associated with Ab toxicity, such as PKR (double-stranded RNA dependant kinase), and JNK (c-Jun N-terminal kinase) is a major goal. These two pro-apoptotic kinases are involved in Ab production and neurotoxicity, tau phosphorylation, and neuroinflammation. Methods: We used siRNA directed against PKR in HEK cells cultures and PKR knockout (PKR-/-) mice neuronal cultures. Apoptosis was measured by the level of cleaved PARP (Poly ADP-ribose polymerase) and cleaved caspase 3
by immunoblot and by the level of caspase 3 activity by enzyme assay. Results: Our results showed in vitro that PKR induces JNK activation. A significant decrease of Ab-induced neuronal death was observed in PKR-/- neurons: -49% of cleaved PARP, -70% of cleaved caspase 3, and -68% of caspase 3 activity. In cultured neurons, two selective JNK inhibitory peptides also produced a striking reduction of Ab toxicity (-55% and -77% of cleaved PARP). Finally, the dual inhibition of PKR and JNK nearly abolished Ab toxicity in primary neurons (-92% of cleaved PARP). Conclusions: These results reveal that dual kinase inhibition of PKR and JNK is a new therapeutic way to afford neuroprotection in AD patients.
P4-314
EPITOPE-SPECIFIC AMYLOID-b OLIGOMER VACCINATION AMELIORATES AMYGDALADEPENDENT MEMORY DEFICITS AND INHIBITS REGION-TO-REGION SPREAD OF PLAQUE PATHOLOGY IN APP/PS1 MICE
Judith M. Silverman1, Kristina Martens1, Ebrima Gibbs1, Jing Wang1, Xiaobing Han2, Masoud Yousefi1, Cory L. Nykiforuk2, Laura Saward2, Cheryl Wellington1, Neil R. Cashman1, 1University of British Columbia, Vancouver, BC, Canada; 2Emergent BioSolutions, Winnipeg, MB, Canada. Contact e-mail: [email protected] Background: We have previously identified an amyloid-b oligomer-selective epitope, namely cyclized-Serine-AsparagineLysine (cSNK), which is not present on Ab fibrils or monomers. Antibodies against cSNK recognize authentic Ab oligomers (AbOs) present in brain and CSF of human Alzheimer’s disease (AD) patients and brain tissues of transgenic mouse models of AD, but not monomers or fibrils. Here, we conducted testing of cSNK as a vaccine in APP/PS1 mice. Methods: Sex matched cohorts of 38 APP/PS1 mice on a C3H/BL6 background were vaccinated subcutaneously with 100 mg of cSNK-KLH, with Emulsigen-D as adjuvant or Emulsigen-D alone, beginning at 3 months of age (MOA). Animals were treated monthly. Plasma was collected at baseline and throughout immunization. At 11 MOA, animals were tested for memory function with cued and contextual fear conditioning (CFC) tasks and the novel object recognition (NOR) task. Following sacrifice at 12 MOA, plaque load was determined with ThioflavinS. Plasma anticSNK titers were quantified using MagPlex immunoassay. The Shapiro-Wilk test determined data normality. Differences between groups and genders were tested using a regression model with categorical covariates (ANOVA) and t-test or Mann-Whitney test when appropriate, using XLSTAT V2014.6.04. Results: Baseline and control (adjuvant-alone) anti-cSNK titers were below detection limits throughout the study. In comparison, anti-cSNK titers were elevated following immunization and remained at or above this benchmark throughout the study in cSNK-KLH treated animals. Vaccination with cSNK significantly improved performance in the Cued FC task, which tests amygdala-dependent memory. In contrast, performance was not significantly improved in the Contextual FC or NOR tasks, both indicative of hippocampus-dependent memory. Correspondingly, analysis of these regions show cSNK immunization had no effect on hippocampal plaque burden, but significant reductions in plaque burden were observed in the amygdala and parahippocampal cortex, both of which receive projections from the hippocampus. Conclusions: This study establishes that vaccination of APP/PS1 mice with cSNK generates a polyclonal