- Email: [email protected]
day on language function in patients with moderate-to-severe Alzheimer's disease (AD): Subgroup analysis of United States (U.S.)-based patients
Poster Presentations: P3 were selected from an original list of 212. Of 45 MRI and 54 PET imaging sites based on proximity, 28 and 24, respectively, were selected. One fullservice CRO and 12 specialty vendors have been enlisted. While it was difficult to select sites with appropriate infrastructure, through a rigorous site identification and site activation process, the performance of the study has exceeded expectations. The study has met enrollment in 30% less time than projected, and subject attrition through 9 months has been w30% lower than expected. The number of subjects consenting to lumbar puncture has been higher than in previous studies. Conclusions: Clinical trials in AD have increased both in number and size, and the use of biomarkers has increased their operational difficulties. A more holistic view of site infrastructure is required; considerations include the accessibility of research quality imaging sites, the requirement for multiple specialty assessments that has expanded the list of vendors, and the need for seamless flow of data for subject selection and monitoring of safety. This case study will explore how rigorous site selection and ongoing training have been implemented successfully in this challenging multicenter study.
P3-386
RESPONSE ACROSS MULTIPLE OUTCOME MEASURES IN A RANDOMIZED TRIAL OF EXTENDED-RELEASE MEMANTINE (28 MG, ONCE DAILY) IN PATIENTS WITH MODERATETO-SEVERE ALZHEIMER’S DISEASE
Stephen Graham1, Suzanne Hendrix2, Michael Miller3, Vojislav Pejovic3, Michael Tocco4, 1Forest Reseach Institute, Jersey City, New Jersey, United States; 2Pentara Corporation, Salt Lake City, Utah, United States; 3Prescott Medical Communications Group, Chicago, Illinois, United States; 4Forest Research Institute, Jersey City, New Jersey, United States. Background: The efficacy of a new, extended-release (ER) formulation of memantine (28 mg, once daily) has been demonstrated previously in a 24week, multinational, randomized, double-blind, placebo-controlled, parallel-group trial (MEM-MD-50, NCT00322153; placebo, n¼335; memantine, n¼342) in patients with moderate to severe Alzheimer’s disease (AD) concurrently taking a cholinesterase inhibitor. The current study is a post hoc analysis, designed to explore the effects of memantine ER on combinations of outcome measures utilized in that trial. Methods: Efficacy outcomes included measures of cognition (SIB), function (ADCS-ADL 19), behavior (NPI), and global status (CIBIC-Plus). For each measure, two levels of response were defined: improvement or stabilization ("no decline"; baseline-to-endpoint improvement of 0 points for the SIB, ADCS-ADL 19, and NPI; endpoint score 4 for the CIBIC-Plus) and clinically notable response (baseline-to-endpoint improvement of 3 points for the SIB, ADCS-ADL 19, and NPI; endpoint score 3 for the CIBIC-Plus). The treatment groups were compared by calculating the proportions of patients who achieved no decline or a clinically notable response on any combination of 2, 3, or all 4 efficacy measures. Data were analyzed using observed cases and Wald’s test (6¼0.05); numbers needed to treat (NNTs) were also calculated. Due to the exploratory nature of this analysis, no corrections for multiple comparisons were performed. Results: For both response levels and all outcome combinations, proportions of responders in the memantine ER group (n¼266-269) exceeded those in the placebo group (n¼ 271-272). The difference between proportions of memantine ER- and placebo-treated patients who experienced no decline approached statistical significance for the SIB/CIBIC-Plus combination (54.6% vs 46.1%; P ¼0.054, NNT¼12). For clinically notable responses, memantine ER was significantly superior to placebo for the 2-measure combination of ADCS-ADL 19/NPI (21.3% vs 15.8%; P ¼0.042, NNT¼18), and the 3-measure combinations of ADCS-ADL 19/NPI/SIB (15.4% vs 9.6%; P ¼0.027, NNT¼17), and ADCS-ADL 19/SIB/CIBIC-Plus (12.4% vs 7.4%; P ¼0.030, NNT¼20). Conclusions: This exploratory post hoc analysis suggests that, in patients with moderate to severe AD, memantine ER may provide simultaneous benefits on multiple clinical domains, especially when improvements in cognition and function are observed, and when a response to therapy is relatively strong.
P3-387
P591 ASSESSING LANGUAGE FUNCTION USING THE SEVERE IMPAIRMENT BATTERY (SIB) AND MINIMENTAL STATE EXAMINATION (MMSE): CORRELATION ANALYSIS IN PATIENTS WITH MODERATE-TO-SEVERE ALZHEIMER’S DISEASE
Steven Ferris1, Joan Mackell2, Zane Bai3, Yijun Sun3, 1Alzheimer’s Disease Center, Center of Excellence on Brain Aging, NYU Langone Medical Center, New York, New York, United States; 2Pfizer Inc., New York, New York, United States; 3Eisai Inc., Woodcliff Lake, New Jersey, United States. Background: Previous analysis of data from a study of donepezil 23 mg/ day vs. donepezil 10 mg/day in patients with moderate-to-severe AD showed strong correlations at baseline and week 24 between scores on the 21-item SIB-Language Scale (SIB-L) and on the full MMSE (r z0.70), while changes from baseline in SIB-L scores and changes from baseline in full MMSE scores had low-moderate correlation (r z0.35) [Ferris et al. Alz Res Ther 2011]. We extended these prior analyses by further evaluating specific correlations between the SIB-L and the 8 language items of the MMSE. Methods: A post hoc correlation analysis was conducted using data from 1370 patients with moderate-to-severe AD (MMSE 0-20) who participated in a 24-week, double-blind study comparing donepezil 23 mg/day with 10 mg/day. Relationships between the SIB-L and the 8 language items of the MMSE (MMSE-L; naming objects [2 items], repeating phrase “no ifs, ands, or buts” [1 item], following verbal directions [3 items], following read instructions [1 item], and writing a sentence [1 item]) were examined. Pearson correlation coefficients were calculated for baseline, week 24 (LOCF) and change from baseline scores (LOCF). Because higher scores on the SIB-L and the MMSE indicate less impairment, a positive correlation coefficient would indicate a positive association between these measures. Results: Correlation coefficients for the relationship between SIB-L and MMSE-L scores at baseline and week 24 were strong (r ¼0.7147 and r ¼0.7767, respectively; P<0.0001), while the coefficient for the relationship between the change from baseline scores on the SIBL and the MMSE-L was weak (r ¼0.2909; P<0.0001). Conclusions: Statistically significant positive correlations were observed between the SIB-L and the MMSE-L. Strong correlations (r>0.70) were observed for baseline and week 24 scores and a weak correlation (r<0.30) was observed for changes from baseline scores. This suggests that the severity of language impairment measured by both instruments is relatively consistent, but that the sensitivity of each instrument for detecting changes in language function may be different. These findings may have implications for the use of these respective scales to assess language improvement or decline in patients with moderate-to-severe AD. P3-388
EFFECT OF DONEPEZIL 23 MG/DAY ON LANGUAGE FUNCTION IN PATIENTS WITH MODERATE-TO-SEVERE ALZHEIMER’S DISEASE (AD): SUBGROUP ANALYSIS OF UNITED STATES (U.S.)-BASED PATIENTS
Steven Ferris1, Joan Mackell2, Zane Bai3, Yijun Sun3, 1Alzheimer’s Disease Center, Center of Excellence on Brain Aging, NYU Langone Medical Center, New York, New York, United States; 2Pfizer Inc., New York, New York, United States; 3Eisai Inc., Woodcliff Lake, New Jersey, United States. Background: Language plays a critical role in the emotional and physical well-being of patients with AD because it helps maintain personal relationships as the disease progresses. In a previous multinational clinical trial of patients with moderate-to-severe AD, donepezil 23 mg/day provided statistically significant incremental language benefits vs. donepezil 10 mg/day. Since donepezil 23 mg/day is currently only available in the US, we evaluated language effects in the U.S. subgroup from this global study by analyzing change from baseline to Week 24 in scores on the 21-item Severe Impairment Battery-Language Scale (SIB-L). Methods: A post hoc analysis was conducted in a subgroup of patients with moderate-to-severe AD (MMSE 0-20) who enrolled at U.S. sites participating in a 24-week,
P592
Poster Presentations: P3
double-blind study comparing donepezil 23 mg/day with 10 mg/day. Treatment effects on language were evaluated using the SIB-L (score range 0-41; higher scores reflect greater language function) in the overall US subgroup, in the cohort of US-based patients with more advanced AD at baseline (MMSE 0-16), and in US-based patients stratified by concomitant memantine use. Results: In the overall US subgroup ITT population (N¼433), the change in SIB-L score from baseline to Week 24 favored donepezil 23 mg/ day over 10 mg/day (LS mean [SE]: +0.4 [0.25] vs. -1.1 [0.37], LOCF; treatment difference: 1.4 [95% CI: 0.57, 2.32], p¼0.0013). Similar benefits favoring donepezil 23 mg/day were observed in the cohort of patients with more advanced AD at baseline (n¼330; treatment difference: 1.7 [95% CI: 0.62, 2.77], p¼0.0021) and in patients taking concomitant memantine (n¼326; treatment difference: 1.5 [95% CI: 0.54, 2.56], p¼0.0028). Numerical benefits in favor of donepezil 23 mg/day were also observed in the US-based patients not taking concomitant memantine (n¼107; treatment difference: 1.1 [95% CI: -0.63, 2.93]). Conclusions: In this post hoc subgroup analysis of US-based patients with moderate-to-severe AD, donepezil 23 mg/day provided statistically significant incremental language benefits over donepezil 10 mg/day, as measured using the SIB-L. These results mirror those reported for the overall global study population and further support donepezil 23 mg/day as a meaningful treatment option for patients with moderate-to-severe AD, for whom language preservation is especially important.
P3-389
ROLE OF AN ADJUDICATION COMMITTEE IN AN ALZHEIMER’S DISEASE TRIAL (THE ARGO TRIAL)
Teresa Leon1, Teodoro del Ser2, 1Noscira, Tres Cantos, Spain; 2Noscira, Madrid, Spain. Background: Adjudication committees (AC) are traditionally involved in the standard assessment of endpoints and milestones, but their role may be also relevant for patient selection at the time of study inclusion. A systematic process to review clinical information at screening in order to centrally confirm patient’s eligibility may prove to be quite useful. Methods: Two board certified neurologists reviewed clinical data of all patients included in a phase II AD trial (ARGO) before randomization (for more information about the study, visit www.clinicaltrials.gov). A neuro-radiologist reviewed all MRIs performed at sites participating in the neuroimaging substudy. When information was missing or conflicting with inclusion or exclusion criteria, queries were raised and issues clarified. The electronic CRF, e-mail and occasional phone calls were the communication tools between AC and investigators. Results: Of the 437 patients screened, 129 were considered screen failures. There was only one protocol violation in the study (a patient with a prolonged out-of-range QTc at baseline whose value at screening visit had been normal). The main reasons for not recommending patient eligibility coming from the AC were: abnormal lab values, prohibited medications, out-of-range neuropsychological assessments and MRI findings. The area of most conflicts was the MRI interpretation of vascular load. Conclusions: The advantages of an AC during the screening period include: early data entry into eCRF and prompt verification that reduce errors and potential data loss; real-time access to adjudicated data; almost elimination of protocol violations.
P3-390
DISEASE PROGRESSION IN PATIENTS WITH MILD-TO-MODERATE ALZHEIMER’S DISEASE TREATED WITH GALANTAMINE: RESULTS OF A TWO-YEAR OPEN-LABEL STUDY
Maren Gaudig1, Ute Richarz2, Klaus Rettig3, Miriam Djelani4, Barbara Schauble5, 1Janssen, Neuss, Germany; 2Janssen Global Services, LLC, Zug, Switzerland; 3GEM, Meerbusch, Germany; 4Janssen Cilag, Neuss, Germany; 5Janssen Cilag EMEA Medical Affairs, Neuss, Germany. Background: Frequently, pharmacologcal therapy in patients with Alzheimer’s disease is discontinued after 6-9 months of treatment. The current
study explores long-term effectiveness of galantamine in patients with mild to moderate Alzheimer’s disease for up to 24 months to support longer-term use. Methods: Prospective open-label trial including patients with mild to moderate AD (NINCDS-ADRDA criteria) treated with galantamine for at least one year and followed for up to 24 months in total. Outcome parameters included ADAS-cog/11, Bayer-ADL scale (self and proxy ratings), 10-item NPI and CGI-severity, safety and tolerability measures. Data are presented based on ITT analyses (LOCF). Results: 159 patients (60% women; mean ADAS-cog 22.8; mean age 71 years) were treated with Gal. 53.5% (n¼85) received a total daily dose of 24mg Gal. at final visit. After 3 and 6 months of treatment, mean changes in ADAS-cog improved by 2.3 points (p<0.001). After 12 months of treatment ADAS-cog returned to baseline value approximately and thereafter patients slightly deteriorated, on average by 2.9 points after 24 months (p¼0.0003). Compared to baseline, behavioral symptoms measured by NPI improved between 3-12 months (p<0.05); at 18 months of therapy, NPI returned to baseline level and thereafter a slight deterioration was noted (p>0.05). Activities of daily-living scores (B-ADL) worsened slightly from 3.5 to 3.7 at 12 months of treatment (p>0.05). At 18 and 24 months of treatment, self-rated B-ADL changed from 3.5 to 3.8 and 4.1, respectively (p<0.05). Findings were reflected in the proxy ratings. 121 patients (76.1%) reported a total of 451 AEs with 50 AEs being rated as serious (36 patients). Two SAEs were rated as possibly related to galantamine therapy (intestinal bleeding and gastritis). Seriousness was due to hospitalization. Both SAEs resolved without sequelae. The most frequently (>10% of patients) reported AEs include nausea (16%), nervous system symptoms not specified (13%), depression (11%) and musculoskeletal system (10%). Conclusions: Galantamine was generally safe and well tolerated during the 2-year observation period. Behavior and cognition were improved during the first 12 months. Compared to baseline, there was only a slight deterioration after 24 months of treatment with galantamine. P3-391
EFFECTIVENESS OF GALANTAMINE IN PATIENTS WITH MILD-TO-MODERATE DEMENTIA: 12 MONTHS’ OUTCOME DATA
Maren Gaudig1, Ute Richarz2, Klaus Rettig3, Miriam Djelani1, Barbara Schauble4, 1Janssen Cilag, Neuss, Germany; 2Janssen Global Services, LLC, Baar, Switzerland; 3GEM, Meerbusch, Germany; 4Janssen Cilag EMEA Medical Affairs, Neuss, Germany. Background: There is limited data available on the efficacy and safety outcomes in patients with mild to moderate Alzheimer’s disease treated with galantamine beyond 6 months. The current study reports 12 months outcomes data in patients seen in daily practice. Methods: Prospective openlabel 12-month trial including patients > 50 years with mild to moderate AD (NINCDS-ADRDA criteria) treated with galantamine for up to 12 months in total. Outcome parameters included NOSGER (Nurses’ Observation Scale for Geriatric patients), MMSE, caregiver time, safety and tolerability measures. Data are presented based on ITT (LOCF) analyses. Results: A total of 82 patients (60% women; mean MMSE 19.60 €ı,6 4.91; mean age 76.7 years; 34% mild dementia) were treated with Gal and 65 had evaluable post-baseline efficacy data . 97% of patients had a caregiver (55% partner). 25% (n¼16) received a total daily dose of 24mg Gal at last visit. MMSE improved slightly to 20.31 €ı,6 6.71 at endpoint (P¼0.0976, LOCF analysis). Changes in NOSGER were non-significant (P>0.05, ITT- LOCF). Total care giver time decreased from 88.4 mins / day to 84.3 mins at endpoint (ITT- LOCF, P¼0.86). Overall observation/supervision time decreased from 135.9 mins / day to 114.8 mins / day (ITT, P¼0.43). 29% of patients reported a total of 39 AEs with 11 AEs being rated as serious (6 patients). One SAE was rated as very likely related to galantamine therapy ("delirium"). Most frequently (>5% of patients) reported AEs were nausea or vomiting (17%), and falls (5%). Conclusions: galantamine was generally safe and well tolerated during the 1-year observation period. Despite the moderately advanced stage of the disease, there were still slight improvements in memory function as well as improvements in observation/supervision time. Instrumental activities of daily living, behavior, mood and deportment remained stable.
P3-386
RESPONSE ACROSS MULTIPLE OUTCOME MEASURES IN A RANDOMIZED TRIAL OF EXTENDED-RELEASE MEMANTINE (28 MG, ONCE DAILY) IN PATIENTS WITH MODERATETO-SEVERE ALZHEIMER’S DISEASE
Stephen Graham1, Suzanne Hendrix2, Michael Miller3, Vojislav Pejovic3, Michael Tocco4, 1Forest Reseach Institute, Jersey City, New Jersey, United States; 2Pentara Corporation, Salt Lake City, Utah, United States; 3Prescott Medical Communications Group, Chicago, Illinois, United States; 4Forest Research Institute, Jersey City, New Jersey, United States. Background: The efficacy of a new, extended-release (ER) formulation of memantine (28 mg, once daily) has been demonstrated previously in a 24week, multinational, randomized, double-blind, placebo-controlled, parallel-group trial (MEM-MD-50, NCT00322153; placebo, n¼335; memantine, n¼342) in patients with moderate to severe Alzheimer’s disease (AD) concurrently taking a cholinesterase inhibitor. The current study is a post hoc analysis, designed to explore the effects of memantine ER on combinations of outcome measures utilized in that trial. Methods: Efficacy outcomes included measures of cognition (SIB), function (ADCS-ADL 19), behavior (NPI), and global status (CIBIC-Plus). For each measure, two levels of response were defined: improvement or stabilization ("no decline"; baseline-to-endpoint improvement of 0 points for the SIB, ADCS-ADL 19, and NPI; endpoint score 4 for the CIBIC-Plus) and clinically notable response (baseline-to-endpoint improvement of 3 points for the SIB, ADCS-ADL 19, and NPI; endpoint score 3 for the CIBIC-Plus). The treatment groups were compared by calculating the proportions of patients who achieved no decline or a clinically notable response on any combination of 2, 3, or all 4 efficacy measures. Data were analyzed using observed cases and Wald’s test (6¼0.05); numbers needed to treat (NNTs) were also calculated. Due to the exploratory nature of this analysis, no corrections for multiple comparisons were performed. Results: For both response levels and all outcome combinations, proportions of responders in the memantine ER group (n¼266-269) exceeded those in the placebo group (n¼ 271-272). The difference between proportions of memantine ER- and placebo-treated patients who experienced no decline approached statistical significance for the SIB/CIBIC-Plus combination (54.6% vs 46.1%; P ¼0.054, NNT¼12). For clinically notable responses, memantine ER was significantly superior to placebo for the 2-measure combination of ADCS-ADL 19/NPI (21.3% vs 15.8%; P ¼0.042, NNT¼18), and the 3-measure combinations of ADCS-ADL 19/NPI/SIB (15.4% vs 9.6%; P ¼0.027, NNT¼17), and ADCS-ADL 19/SIB/CIBIC-Plus (12.4% vs 7.4%; P ¼0.030, NNT¼20). Conclusions: This exploratory post hoc analysis suggests that, in patients with moderate to severe AD, memantine ER may provide simultaneous benefits on multiple clinical domains, especially when improvements in cognition and function are observed, and when a response to therapy is relatively strong.
P3-387
P591 ASSESSING LANGUAGE FUNCTION USING THE SEVERE IMPAIRMENT BATTERY (SIB) AND MINIMENTAL STATE EXAMINATION (MMSE): CORRELATION ANALYSIS IN PATIENTS WITH MODERATE-TO-SEVERE ALZHEIMER’S DISEASE
Steven Ferris1, Joan Mackell2, Zane Bai3, Yijun Sun3, 1Alzheimer’s Disease Center, Center of Excellence on Brain Aging, NYU Langone Medical Center, New York, New York, United States; 2Pfizer Inc., New York, New York, United States; 3Eisai Inc., Woodcliff Lake, New Jersey, United States. Background: Previous analysis of data from a study of donepezil 23 mg/ day vs. donepezil 10 mg/day in patients with moderate-to-severe AD showed strong correlations at baseline and week 24 between scores on the 21-item SIB-Language Scale (SIB-L) and on the full MMSE (r z0.70), while changes from baseline in SIB-L scores and changes from baseline in full MMSE scores had low-moderate correlation (r z0.35) [Ferris et al. Alz Res Ther 2011]. We extended these prior analyses by further evaluating specific correlations between the SIB-L and the 8 language items of the MMSE. Methods: A post hoc correlation analysis was conducted using data from 1370 patients with moderate-to-severe AD (MMSE 0-20) who participated in a 24-week, double-blind study comparing donepezil 23 mg/day with 10 mg/day. Relationships between the SIB-L and the 8 language items of the MMSE (MMSE-L; naming objects [2 items], repeating phrase “no ifs, ands, or buts” [1 item], following verbal directions [3 items], following read instructions [1 item], and writing a sentence [1 item]) were examined. Pearson correlation coefficients were calculated for baseline, week 24 (LOCF) and change from baseline scores (LOCF). Because higher scores on the SIB-L and the MMSE indicate less impairment, a positive correlation coefficient would indicate a positive association between these measures. Results: Correlation coefficients for the relationship between SIB-L and MMSE-L scores at baseline and week 24 were strong (r ¼0.7147 and r ¼0.7767, respectively; P<0.0001), while the coefficient for the relationship between the change from baseline scores on the SIBL and the MMSE-L was weak (r ¼0.2909; P<0.0001). Conclusions: Statistically significant positive correlations were observed between the SIB-L and the MMSE-L. Strong correlations (r>0.70) were observed for baseline and week 24 scores and a weak correlation (r<0.30) was observed for changes from baseline scores. This suggests that the severity of language impairment measured by both instruments is relatively consistent, but that the sensitivity of each instrument for detecting changes in language function may be different. These findings may have implications for the use of these respective scales to assess language improvement or decline in patients with moderate-to-severe AD. P3-388
EFFECT OF DONEPEZIL 23 MG/DAY ON LANGUAGE FUNCTION IN PATIENTS WITH MODERATE-TO-SEVERE ALZHEIMER’S DISEASE (AD): SUBGROUP ANALYSIS OF UNITED STATES (U.S.)-BASED PATIENTS
Steven Ferris1, Joan Mackell2, Zane Bai3, Yijun Sun3, 1Alzheimer’s Disease Center, Center of Excellence on Brain Aging, NYU Langone Medical Center, New York, New York, United States; 2Pfizer Inc., New York, New York, United States; 3Eisai Inc., Woodcliff Lake, New Jersey, United States. Background: Language plays a critical role in the emotional and physical well-being of patients with AD because it helps maintain personal relationships as the disease progresses. In a previous multinational clinical trial of patients with moderate-to-severe AD, donepezil 23 mg/day provided statistically significant incremental language benefits vs. donepezil 10 mg/day. Since donepezil 23 mg/day is currently only available in the US, we evaluated language effects in the U.S. subgroup from this global study by analyzing change from baseline to Week 24 in scores on the 21-item Severe Impairment Battery-Language Scale (SIB-L). Methods: A post hoc analysis was conducted in a subgroup of patients with moderate-to-severe AD (MMSE 0-20) who enrolled at U.S. sites participating in a 24-week,
P592
Poster Presentations: P3
double-blind study comparing donepezil 23 mg/day with 10 mg/day. Treatment effects on language were evaluated using the SIB-L (score range 0-41; higher scores reflect greater language function) in the overall US subgroup, in the cohort of US-based patients with more advanced AD at baseline (MMSE 0-16), and in US-based patients stratified by concomitant memantine use. Results: In the overall US subgroup ITT population (N¼433), the change in SIB-L score from baseline to Week 24 favored donepezil 23 mg/ day over 10 mg/day (LS mean [SE]: +0.4 [0.25] vs. -1.1 [0.37], LOCF; treatment difference: 1.4 [95% CI: 0.57, 2.32], p¼0.0013). Similar benefits favoring donepezil 23 mg/day were observed in the cohort of patients with more advanced AD at baseline (n¼330; treatment difference: 1.7 [95% CI: 0.62, 2.77], p¼0.0021) and in patients taking concomitant memantine (n¼326; treatment difference: 1.5 [95% CI: 0.54, 2.56], p¼0.0028). Numerical benefits in favor of donepezil 23 mg/day were also observed in the US-based patients not taking concomitant memantine (n¼107; treatment difference: 1.1 [95% CI: -0.63, 2.93]). Conclusions: In this post hoc subgroup analysis of US-based patients with moderate-to-severe AD, donepezil 23 mg/day provided statistically significant incremental language benefits over donepezil 10 mg/day, as measured using the SIB-L. These results mirror those reported for the overall global study population and further support donepezil 23 mg/day as a meaningful treatment option for patients with moderate-to-severe AD, for whom language preservation is especially important.
P3-389
ROLE OF AN ADJUDICATION COMMITTEE IN AN ALZHEIMER’S DISEASE TRIAL (THE ARGO TRIAL)
Teresa Leon1, Teodoro del Ser2, 1Noscira, Tres Cantos, Spain; 2Noscira, Madrid, Spain. Background: Adjudication committees (AC) are traditionally involved in the standard assessment of endpoints and milestones, but their role may be also relevant for patient selection at the time of study inclusion. A systematic process to review clinical information at screening in order to centrally confirm patient’s eligibility may prove to be quite useful. Methods: Two board certified neurologists reviewed clinical data of all patients included in a phase II AD trial (ARGO) before randomization (for more information about the study, visit www.clinicaltrials.gov). A neuro-radiologist reviewed all MRIs performed at sites participating in the neuroimaging substudy. When information was missing or conflicting with inclusion or exclusion criteria, queries were raised and issues clarified. The electronic CRF, e-mail and occasional phone calls were the communication tools between AC and investigators. Results: Of the 437 patients screened, 129 were considered screen failures. There was only one protocol violation in the study (a patient with a prolonged out-of-range QTc at baseline whose value at screening visit had been normal). The main reasons for not recommending patient eligibility coming from the AC were: abnormal lab values, prohibited medications, out-of-range neuropsychological assessments and MRI findings. The area of most conflicts was the MRI interpretation of vascular load. Conclusions: The advantages of an AC during the screening period include: early data entry into eCRF and prompt verification that reduce errors and potential data loss; real-time access to adjudicated data; almost elimination of protocol violations.
P3-390
DISEASE PROGRESSION IN PATIENTS WITH MILD-TO-MODERATE ALZHEIMER’S DISEASE TREATED WITH GALANTAMINE: RESULTS OF A TWO-YEAR OPEN-LABEL STUDY
Maren Gaudig1, Ute Richarz2, Klaus Rettig3, Miriam Djelani4, Barbara Schauble5, 1Janssen, Neuss, Germany; 2Janssen Global Services, LLC, Zug, Switzerland; 3GEM, Meerbusch, Germany; 4Janssen Cilag, Neuss, Germany; 5Janssen Cilag EMEA Medical Affairs, Neuss, Germany. Background: Frequently, pharmacologcal therapy in patients with Alzheimer’s disease is discontinued after 6-9 months of treatment. The current
study explores long-term effectiveness of galantamine in patients with mild to moderate Alzheimer’s disease for up to 24 months to support longer-term use. Methods: Prospective open-label trial including patients with mild to moderate AD (NINCDS-ADRDA criteria) treated with galantamine for at least one year and followed for up to 24 months in total. Outcome parameters included ADAS-cog/11, Bayer-ADL scale (self and proxy ratings), 10-item NPI and CGI-severity, safety and tolerability measures. Data are presented based on ITT analyses (LOCF). Results: 159 patients (60% women; mean ADAS-cog 22.8; mean age 71 years) were treated with Gal. 53.5% (n¼85) received a total daily dose of 24mg Gal. at final visit. After 3 and 6 months of treatment, mean changes in ADAS-cog improved by 2.3 points (p<0.001). After 12 months of treatment ADAS-cog returned to baseline value approximately and thereafter patients slightly deteriorated, on average by 2.9 points after 24 months (p¼0.0003). Compared to baseline, behavioral symptoms measured by NPI improved between 3-12 months (p<0.05); at 18 months of therapy, NPI returned to baseline level and thereafter a slight deterioration was noted (p>0.05). Activities of daily-living scores (B-ADL) worsened slightly from 3.5 to 3.7 at 12 months of treatment (p>0.05). At 18 and 24 months of treatment, self-rated B-ADL changed from 3.5 to 3.8 and 4.1, respectively (p<0.05). Findings were reflected in the proxy ratings. 121 patients (76.1%) reported a total of 451 AEs with 50 AEs being rated as serious (36 patients). Two SAEs were rated as possibly related to galantamine therapy (intestinal bleeding and gastritis). Seriousness was due to hospitalization. Both SAEs resolved without sequelae. The most frequently (>10% of patients) reported AEs include nausea (16%), nervous system symptoms not specified (13%), depression (11%) and musculoskeletal system (10%). Conclusions: Galantamine was generally safe and well tolerated during the 2-year observation period. Behavior and cognition were improved during the first 12 months. Compared to baseline, there was only a slight deterioration after 24 months of treatment with galantamine. P3-391
EFFECTIVENESS OF GALANTAMINE IN PATIENTS WITH MILD-TO-MODERATE DEMENTIA: 12 MONTHS’ OUTCOME DATA
Maren Gaudig1, Ute Richarz2, Klaus Rettig3, Miriam Djelani1, Barbara Schauble4, 1Janssen Cilag, Neuss, Germany; 2Janssen Global Services, LLC, Baar, Switzerland; 3GEM, Meerbusch, Germany; 4Janssen Cilag EMEA Medical Affairs, Neuss, Germany. Background: There is limited data available on the efficacy and safety outcomes in patients with mild to moderate Alzheimer’s disease treated with galantamine beyond 6 months. The current study reports 12 months outcomes data in patients seen in daily practice. Methods: Prospective openlabel 12-month trial including patients > 50 years with mild to moderate AD (NINCDS-ADRDA criteria) treated with galantamine for up to 12 months in total. Outcome parameters included NOSGER (Nurses’ Observation Scale for Geriatric patients), MMSE, caregiver time, safety and tolerability measures. Data are presented based on ITT (LOCF) analyses. Results: A total of 82 patients (60% women; mean MMSE 19.60 €ı,6 4.91; mean age 76.7 years; 34% mild dementia) were treated with Gal and 65 had evaluable post-baseline efficacy data . 97% of patients had a caregiver (55% partner). 25% (n¼16) received a total daily dose of 24mg Gal at last visit. MMSE improved slightly to 20.31 €ı,6 6.71 at endpoint (P¼0.0976, LOCF analysis). Changes in NOSGER were non-significant (P>0.05, ITT- LOCF). Total care giver time decreased from 88.4 mins / day to 84.3 mins at endpoint (ITT- LOCF, P¼0.86). Overall observation/supervision time decreased from 135.9 mins / day to 114.8 mins / day (ITT, P¼0.43). 29% of patients reported a total of 39 AEs with 11 AEs being rated as serious (6 patients). One SAE was rated as very likely related to galantamine therapy ("delirium"). Most frequently (>5% of patients) reported AEs were nausea or vomiting (17%), and falls (5%). Conclusions: galantamine was generally safe and well tolerated during the 1-year observation period. Despite the moderately advanced stage of the disease, there were still slight improvements in memory function as well as improvements in observation/supervision time. Instrumental activities of daily living, behavior, mood and deportment remained stable.