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Alzheimer's Association International Conference (AAIC) · 2024:Poster Tue-17 · Hendrix, Dickson et al.
Companies recently identified clinical study sites engaging in fraudulent practices, reducing success in Alzheimer's disease (AD) clinical trials. Successful trials are reliable…
When the sample size a conventional design demands is larger than the trial you can run, a Global Statistical Test lets the clinical-endpoint hypotheses be tested anyway. The paper sets out when GST applies, how it is pre-specified, and how it has been received in review.
13 publications
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2018 · Neurology
Objective: To assess cognitive performance via the Severe Impairment Battery (SIB) and maintenance of improvement for memantine-ER/donepezil versus placebo/donepezil during 24-week treatment in moderate-to-severe Alzheimer’s disease (AD). Background: Memantine ER produced a significantly better outcome than placebo on co-primary endpoints of Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) and baseline-to-endpoint change on SIB in a 24-week, randomized, double-blind, placebo-controlled trial (RCT) in patients with moderate-to-severe AD concurrently taking a cholinesterase inhibitor. Design/Methods: This was a post-hoc analysis of NCT00322153 RCT observed data. Baseline-to-endpoint changes were used to classify patients based on equal scoring intervals (score changes of ≥0, ≥5, ≥10, ≥15, and ≥20). Proportions of memantine/donepezil- and placebo/donepezil-treated patients who were responders and who attained score changes at weeks 8, 12, and 18 and maintained those score changes through week 24 were compared using Fisher’s exact test. Results: 370 patients were included (187 memantine/donepezil, 183 placebo/donepezil), with baseline mean age 76.18 (SD=7.54), mean MMSE 10.92 (SD=2.73), and mean SIB total score 75.64 (SD=18.23). Compared with the placebo/donepezil group, a significantly higher percentage of patients in the memantine/donepezil-treated group achieved a score change of ≥10 (15.3% vs 27.3%, P=0.0053) or ≥15 (7.7% vs 16.6%, P=0.0105) on the SIB. The proportion of memantine/donepezil-treated patients numerically exceeded that of placebo/donepezil-treated patients at each cut-off for maintenance of response, with a significantly greater proportion maintaining a change of ≥5 (P=0.0391) and ≥10 (P=0.0283) from weeks 8–24, and a change of ≥10 and ≥15 from weeks 12–24 (P=0.0107 and 0.0349, respectively) and weeks 18–24 (P=0.0051 and 0.0100, respectively). Conclusions: Concomitant treatment with memantine ER/donepezil was associated with significant, maintained improvements over 24 weeks on the SIB than treatment with placebo/donepezil in this observed cases (OC) analysis; this favorable treatment response was particularly pronounced among patients who experienced the highest level of cognitive improvements.
2017 · Alzheimer's & Dementia
Background: Edonerpic (T-817; 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}azetidin-3-ol maleate, Toyama Chemical, Ltd) protects against Aβ42-induced neurotoxicity and memory deficits, promotes cortical and hippocampal neuron outgrowth, and preserves hippocampal synapses and spatial memory in tau transgenic mice, possibly via sigma receptor activation. The primary objective was to assess the efficacy and safety of T-817 in Alzheimer's disease (NCT 02079909). Methods: Outpatients, ages 55 to 85, meeting criteria for probable AD, MMSE 12–22, taking stable doses of donepezil or rivastigmine, taking or not memantine, were randomly assigned (1:1:1) to placebo, 224mg, or 448mg of T-817 once/day for 52 weeks. The primary outcomes were the ADAScog and ADCS-CGIC (CIBIC+) at week 52. Secondary outcomes were the MMSE, ADCS-ADL, FAQ, and NPI at week 52; and the outcomes at weeks 12, 24, 36, and 44. Biomarkers were MRI whole brain, lateral ventricular, and hippocampal volumes; and CSF Aβ40, 42, t-tau, and p-tau; and population pharmacokinetics. Results: 140 of 158 (88.6%) participants assigned to placebo, 117 of 166 (70.5%) to 224mg, and 120 of 158 (75.9%) to 448mg completed the trial, conducted from June 2014 to December 2016 at 52 US sites. LS mean ADAScog change was 7.9, 7.5, and 7.1 for the placebo, 224mg, and 448mg groups, respectively; difference, placebo vs. 448mg, -0.8 (95% CI: -2.8, 1.1; P=0.3919). Mean ADCS-CGIC scores were 5.2, 5.2, and 5.3; difference, 0.04 (95% CI: -0.19, 0.26; P=0.7588). There were no significant differences for the secondary outcomes. P-tau was nominally significantly lower in the 448mg group vs. placebo (n=24 and N=18, P=0.0338). Hippocampal volumes decreased less in the 224mg group than placebo (n=79 and N=89; -0.27 vs. -0.39 mL, P=0.0106) but not in the 448mg group (n=76; -0.31 vs. -0.39 mL, P=0.0996). 4.4%, 13.9% and 14.6% discontinued because of AEs, placebo, 224mg, and 448mg groups, respectively. Most frequent AEs ≥ 5%: diarrhea (12.7%, 20.5%, 31.0%), nausea (3.8%, 7.8%, 5.7%); infections, injuries, falls, agitation and anxiety were more common with placebo. Conclusions: T-817 appeared safe, tolerable, with expected GI symptoms occurring early, but without evidence for clinical effect in the protocol-specified primary and secondary outcomes. Decreased CSF p-tau and hippocampal volumes require confirmation.
2017 · Neurology
Objective: To explore the effects of extended-release (ER) memantine (28 mg, once daily) on outcome measure combinations in the subset of Alzheimer’s disease (AD) patients receiving donepezil during the MEM-MD-50 trial (NCT00322153). Background: The efficacy of memantine ER was demonstrated in the 24-week, randomized, double-blind, placebo-controlled, parallel-group trial, MEM-MD-50 (placebo, n=335; memantine, n=342) in patients with moderate to severe AD concurrently taking a cholinesterase inhibitor. Design/Methods: Efficacy outcomes included measures of cognition (SIB), function (ADCS-ADL19), behavior (NPI), and global status (CIBIC-Plus). In this post hoc analysis, two levels of response were defined for each measure: improvement or stabilization (“no decline”; baseline-to-endpoint improvement of ≥0 points for the SIB, ADCS-ADL19, and NPI; endpoint score ≤4 for CIBIC-Plus) and clinically notable response (baseline-to-endpoint improvement of ≥3 points for the SIB, ADCS-ADL19, and NPI; endpoint score ≤3 for CIBIC-Plus). 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 (α=0.05); numbers needed to treat (NNTs) were also calculated. Due to the exploratory nature of this analysis, no corrections for multiple comparisons were performed. Results: In patients receiving donepezil, the proportions of responders in the memantine ER group (n=187) exceeded those in the placebo group (n=184) for both response levels and all outcome combinations, except for the ADCS-ADL19 (≥3 points) in which responder proportions were almost identical. The difference between proportions of memantine ER- and placebo-treated patients who experienced no decline was significant for the SIB/CIBIC-Plus combination (62.0% vs 50.8%; P=0.0240, NNT=9). Conclusions: This exploratory post-hoc analysis suggests that, in patients with moderate to severe AD receiving donepezil, memantine ER provides simultaneous benefits on multiple clinical domains, especially stabilization of cognition and global status.
2017 · Journal of biopharmaceutical statistics
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.
2015 · Alzheimer's & Dementia
Background: In patients with Alzheimer's disease (AD) either with or without stable cholinesterase inhibitor (ChEI) treatment, clinical trials have shown significant and beneficial Baseline-to-Endpoint effects following memantine (MEM) treatment in comparison with placebo. Time to meaningful levels of change on outcome measures can also provide clinically relevant information for physicians. This new post hoc analysis used a time-to-event Kaplan-Meier methodology to evaluate clinically meaningful changes in four 6-7 month studies of memantine alone or in combination with a ChEI. Methods: The populations of 4 trials were pooled (N=1,628): 3 randomized, double-blind, placebo-controlled trials of MEM IR (10 mg BID; 2 monotherapy; 1 of patients on stable donepezil) and 1 trial of MEM ER (28 mg QD; patients on stable ChEI regimen) in moderate to severe AD. Efficacy outcomes included cognition (SIB), function (ADCS-ADL19), behavior (NPI), and global status (CIBIC-Plus), and clinically meaningful events were defined as the median decline at Endpoint for placebo-only treated patients; the K-M method was used to compare median time to reach this point in the treatment groups and an unadjusted log-rank test was performed on the intent-to-treat population. Results: Meaningful events were defined as declines of ≥4 points on SIB, ≥3 points on ADCS-ADL19, NPI total score increase ≥0, and final score ≥5 for CIBIC-Plus. The median times-to-events (days) were: SIB (PBO-only: 85; PBO+ChEI: 176 [P<0.0001 vs PBO-only]; MEM-only: 188 [P=0.0001 vs PBO-only]; MEM+ChEI: >196 [P<0.0001 vs PBO-only]; all-PBO groups: 168; all-MEM groups: 193 [P=0.0037 vs all-PBO]), ADCS-ADL19 (PBO-only: 125; PBO+ChEI: 127 [P=0.9854 vs PBO-only]; MEM-only: 172 [P=0.0445 vs PBO-only]; MEM+ChEI: 168 [P=0.2390 vs PBO-only]; all-PBO: 127; all-MEM: 168 [P=0.0127 vs all-PBO]), NPI (PBO-only: 85; PBO+ChEI: 84 [P<0.0001 vs PBO-only]; MEM-only: 101 [P=0.3518 vs PBO-only]; MEM+ChEI: 87 [P=0.0333 vs PBO-only]; all-PBO: 85; all-MEM: 88 [P=0.0027 vs all-PBO]), and CIBIC-Plus (PBO-only: 126; PBO+ChEI: 126 [P=0.4567 vs PBO-only]; MEM-only: 168 [P=0.1429 vs PBO-only]; MEM+ChEI: 168 [P=0.4011 vs PBO-only]; all-PBO: 126; all-MEM: 168 [P=0.0205 vs all-PBO]). Conclusions: Time-to-event analyses support the conclusion that memantine alone or in combination with a ChEI is efficacious in delaying cognitive, functional, and behavioral declines in patients with moderate to severe AD.
2015 · Neurology
OBJECTIVE: This subset analysis assessed the efficacy and tolerability of extended-release memantine (MemER; 28 mg/day) in patients with moderate to severe Alzheimer’s disease (AD) receiving donepezil, the most commonly used cholinesterase inhibitor (ChEI). BACKGROUND: In a 24-week randomized trial (N=677) of patients with moderate to severe AD receiving stable ChEI therapy (donepezil, galantamine, or rivastigmine), MemER-treated group significantly outperformed the placebo-treated group on measures of cognition (SIB), global clinical status (CIBIC-Plus), behavior (NPI), and semantic processing ability (VFT), but not on the measure of daily functioning (ADCS-ADL19). DESIGN/METHODS: Prospectively defined assessments in the donepezil subset (MemER/Don, 232; Placebo/Don, 224) utilized the last observation carried forward (LOCF) approach and an ANCOVA model (SIB, NPI, VFT, ADCS-ADL19: baseline-to-endpoint changes) or Cochran-Mantel-Haenszel test (CIBIC-Plus; endpoint scores). Post hoc sensitivity analyses, based on the observed cases (OC), assessed (a) changes from baseline across all visits (mixed-effects model with repeated measures [MMRM]), and (b) areas under the curve (AUC, Week0-Week24; ANCOVA). Tolerability was assessed by examining treatment-emergent adverse events (TEAEs) in the safety population (MemER/Don, 236; Placebo/Don, 227). RESULTS: The prospectively defined analyses revealed a significant endpoint advantage of MemER/Don over Placebo/Don on SIB (P=0.001), NPI (P=0.009), and VFT (P<0.001), but not on CIBIC Plus (P=0.165) or ADCS-ADL19 (P=0.894). The MMRM analysis demonstrated a significant advantage of MemER/Don over Placebo/Don across all visits for SIB (P<0.001), CIBIC-Plus (P=0.008), NPI (P=0.013), and VFT (P<0.001), but not for ADCS-ADL19 (P=0.606), which was corroborated by the AUC analysis (SIB, P=0.028; CIBIC-Plus, P=0.019; NPI, P=0.012; VFT, P=0.008; ADCS-ADL19, P=0.758). Overall TEAE rates were 61.9[percnt] (MemER/Don) and 59.9[percnt] (Placebo/Don). CONCLUSIONS: These analyses suggest that addition of memantine extended release to donepezil in patients with moderate to severe AD is associated with benefits across several clinical domains, with good tolerability. Study Supported by: Forest Laboratories, LLC, a subsidiary of Actavis, Inc.
2013 · Alzheimer's & Dementia
Background: Memantine is an NMDA receptor antagonist approved for the treatment of moderate to severe Alzheimer’s disease (AD); donepezil is a cholinesterase inhibitor (ChEI), approved for mild to severe AD in the US. Treatment of AD typically involves initiation of donepezil therapy in early stages, with memantine added as the disease progresses to moderate and severe stages. Two large 24-week randomized trials and several observational studies suggest that this combined treatment is superior to monotherapy with either drug; while results of one small 52-week randomized trial generated debate. To further investigate the effects of combination therapy vs monotherapy, we pooled four similarly designed randomized, placebo-controlled trials of memantine inpatients with moderate to severe AD and compared Baseline-to-Endpoint changes in measures of cognition (SIB), function (ADCS-ADL 19), behavior (NPI), and global clinical status (CIBIC-Plus), stratified by treatment/concur-rent therapy regimen (placebo, memantine, placebo/donepezil, or memantine/donepezil). Methods: All patients from two memantine monotherapy trials (MRZ-9001-9605 and MEM-MD-01; N¼567) and donepezil-treated patients from two memantine add-on trials (MEM-MD-02 and MEM-MD-50; N¼841) were pooled and Endpoint changes from Baseline for the SIB, ADCS-ADL 19, NPI, and CIBIC-Plus were assessed using a mixed-effects model with repeated measures (observed cases). Due to the exploratory nature of this analysis, no corrections for multiple comparisons were performed. Results: At study Endpoint, the memantine/donepezil treatment group was significantly superior to placebo (P<0.001) and both memantine and placebo/donepezil monotherapy groups (P<0.05) on all four efficacy measures. There were no statistically significant differences between memantine and placebo/donepezil monotherapy groups on the CIBIC-plus, ADCS-ADL 19, and NPI; however, the placebo/donepezil group performed significantly better than the memantine group on the SIB (P<0.001). Both memantine and placebo/donepezil treatment groups were significantly better than placebo on the SIB, ADCS-ADL 19, and CIBIC-plus (P<0.01), but no significant treatment differences were observed among these three treatment groups on the NPI. Conclusions: This pooled analysis is in agreement with evidence suggesting that adding memantine to stable donepezil treatment in patients with moderate to severe AD is associated with improvements across several clinical domains, compared with monotherapy using either drug. Appropriately powered, long-term, prospective studies of add-on therapy in AD are warranted.
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