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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.
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2017 · Therapeutic Innovation & Regulatory Science
Background: Numerous statistically derived composite measures have recently been proposed as clinical outcome assessments (COAs) for clinical trials in the early stages of Alzheimer disease. Critical Path Institute’s Coalition Against Major Diseases (CAMD) advanced a proposed statistically derived composite measure to regulatory agencies with the goal of qualifying it as a COA for pre-dementia trials. In response to FDA’s requirement to demonstrate that proposed COAs are meaningful to patients, this project aimed to identify the most important cognition-related concerns patients and informants report early in the disease and determine how this information maps to what is assessed by several statistically derived composite measures. Methods: Leveraging qualitative research completed by Critical Path Institute’s Patient-Reported Outcome Consortium, CAMD utilized a summary report that included frequency grids of reported concerns of amnestic mild cognitive impairment patients and their informants, as well as the narrative transcripts from focus groups. Transcripts were reviewed and analyzed to identify which cognitive domains the patient- and informant-reported concerns mapped onto. The results were then compared to see how well these cognitive domains were represented in various statistically derived composite measures. Results: The patient- and informant-reported concerns primarily mapped to the cognitive domains of episodic memory and, secondarily, orientation and language. Depending on the specified composite, there were varying levels of alignment between their subcomponents and these cognitive domains. Conclusion: Through secondary analyses of existing qualitative data, this study examined several statistically derived composite measures and found that they generally capture cognitive domains that reflect aspects of day-to-day functioning that patients and informants consider meaningful.
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 · Alzheimer's & Dementia
Background: Alzheimer's disease clinical trials have had an excessively high failure rate over the past 15 years, with 99.6% of drugs failing in 2002–2012 (Cummings 2014). Although many of these drugs were likely inactive, a 2-sided 0.05 alpha should result in a 2.5% success rate on the primary endpoint by chance alone. Other addressable factors such as patient heterogeneity, variable outcomes and variable measurement processes contribute to this particularly high failure rate. Methods: Public results from several failed clinical trials were evaluated to assess potential contributors to failure. The loss of power associated with each reason for failure and the potential impact of a solution for recovering that power were estimated. The risk and benefit of these solutions were also evaluated to determine whether they can be practically implemented. Results: Many failed studies showed no evidence of a treatment benefit; however, several studies illustrated known problems in AD research that could be addressed. Some failed studies blame population heterogeneity for failure, and target a more homogeneous population in future studies (e.g.: tramiprosate). Phase 2 studies often use pivotal-study standards for success, including co-primary endpoints, endpoints for mild/moderate disease in mild-only populations, models that don't account for patient heterogeneity and fitting separate visit means rather than a linear time model. Many studies are underpowered, resulting in equivocal results when effects are smaller than expected. Elementary issues, such as equivalence of forms for psychometric tests are often assumed, and not checked. For example, a glance at the Expedition 1, 2, and 3 ADAS-cog figures reveals an abnormally high score at Month 9 for all 3 studies, likely due to an easier wordlist at that visit. Conclusions: Successful Alzheimer's clinical trials require an active compound and successful study design demonstrated by narrow confidence intervals. Phase 2 studies should use different standards for success than phase 3 studies, and statistical and psychometric issues should be fully considered. Accurately identifying compounds with small effect sizes is the first step toward developing better treatments with larger effect sizes. Narrow confidence intervals indicate more precision in treatment effect size estimates leading to failing ineffective treatments and success for effective treatments.
2017 · Neurology
Objective: To detect treatment effects in severe patients with Alzheimer’s disease (AD) using a composite score of Severe Impairment Battery (SIB) items. Background: While the SIB detects treatment effects in patients with moderate-to-severe AD who perform at floor level on other cognitive scales, traditional total SIB scoring may lack sensitivity in severe AD. Design/Methods: A quantitative-SIB composite score (qSIB-total) and a severe SIB composite score (qSIB-severe) were developed using partial least squares (PLS) regressions and tested in separate datasets (Training-dataset and Test-dataset, respectively) utilizing an MMRM approach. The Training-dataset (N=966) was pooled from three 24-week phase 3 memantine trials in moderate-to-severe AD patients. A composite of weighted SIB items (qSIB-composite) with variable importance projection (VIP) ≥0.80 was derived using PLS regression. The qSIB-composite and qSIB-severe were tested in the Test-dataset (N=661) from an independent study of memantine in moderate-to-severe AD patients using MMRM regression. Results: For all patients, the SIB total score identified significant treatment effects in memantine-vs placebo-treated patients at weeks 18 and 24 (P<0.05). The qSIB-total scores did not improve sensitivity. The qSIB-severe composite included 5 items (language, memory, praxis, attention, and orientation) with weights of 0.009, 0.003, 0.021, 0.020, and 0.044, respectively, and a minimum VIP=0.8101. Compared with SIB total score, the qSIB-severe score improved sensitivity (lower P-values) in severe AD patients (baseline MMSE<9) at weeks 8 (qSIB-composite, P=0.6304; total SIB, P=0.7057), 12 (P=0.6305; P=0.8403), 18 (P=0.0204; P=0.0491), and 24 (P=0.002; P=0.0241). Conclusions: In severe AD patients, qSIB-severe provided additional measurement sensitivity and differentiation between memantine- and placebo-treated versus total SIB score. The qSIB-total did not improve sensitivity, indicating that SIB total score is optimized for combined moderate-to-severe patients. Development and utilization of quantitatively optimized composite scales from established clinical trial measures may improve scale sensitivity in patient subgroups, particularly when floor effects are present.
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 Alzheimer's Disease
The probable-amnestic (Pr-a) mild cognitive impairment (MCI)-storage subtype is a phenotype with 8.5 times more risk of conversion to dementia, mainly Alzheimer's disease (AD), than the possible non-amnestic (Pss-na) MCI. The aim of this study was to find the optimized cognitive composites (CCs) domain scores most related to neuroimaging biomarkers within Pr-aMCI-storage subtype patients. The Fundació ACE (ACE) study with 20 Pr-aMCI-storage subtype subjects (MCI) were analyzed. All subjects underwent a neuropsychological assessment, a structural MRI, FDG-PET, and PIB-PET. The adjusted hippocampal volume (aHV) on MRI, the standard uptake value ratio (SUVR) on FDG-PET and PIB-PET SUVR measures were analyzed. The construction of the CCs domain scores, and the aHV on MRI and FDG-PET SUVR measures, were replicated in the parental AB255 study database (n = 133 MCI). Partial correlations adjusted by age, gender, and education were calculated with the associated p-value among every CC domain score and the neuroimaging biomarkers. The results were replicated in the "MCI due to AD" with memory storage impairments from ADNI. Delayed Recall CC domain score was significantly correlated with PIB-PET SUVR (β= -0.61, p = 0.003) in the ACE study and also with aHV on MRI (β= 0.27, p = 0.01) and FDG-PET SUVR (β= 0.27, p = 0.01) in the AB255 study. After a median survival time of 20.6 months, 85% from the ACE MCI converted to AD. The replication of our results in the ADNI dataset also confirmed our findings. Delayed Recall is the CC domain score best correlated with neuroimaging biomarkers associated with prodromal AD diagnosis.
2017 · The Journal of Prevention of Alzheimer's Disease
At a meeting of the EU/US/Clinical Trials in Alzheimer's Disease (CTAD) Task Force in December 2016, an international group of investigators from industry, academia, and regulatory agencies reviewed lessons learned from ongoing and planned prevention trials, which will help guide future clinical trials of AD treatments, particularly in the pre-clinical space. The Task Force discussed challenges that need to be addressed across all aspects of clinical trials, calling for innovation in recruitment and retention, infrastructure development, and the selection of outcome measures. While cognitive change provides a marker of disease progression across the disease continuum, there remains a need to identify the optimal assessment tools that provide clinically meaningful endpoints. Patient- and informant-reported assessments of cognition and function may be useful but present additional challenges. Imaging and other biomarkers are also essential to maximize the efficiency of and the information learned from clinical trials.
2017 · Alzheimer's & Dementia
Hendrix, Suzanne · Brown, Bruce
2017 · The Lancet Neurology
Background Nutrition is an important modifiable risk factor in Alzheimer's disease. Previous trials of the multinutrient Fortasyn Connect showed benefits in mild Alzheimer's disease dementia. LipiDiDiet investigated the effects of Fortasyn Connect on cognition and related measures in prodromal Alzheimer's disease. Here, we report the 24-month results of the trial. Methods LipiDiDiet was a 24-month randomised, controlled, double-blind, parallel-group, multicentre trial (11 sites in Finland, Germany, the Netherlands, and Sweden), with optional 12-month double-blind extensions. The trial enrolled individuals with prodromal Alzheimer's disease, defined according to the International Working Group (IWG)-1 criteria. Participants were randomly assigned (1:1) to active product (125 mL once-a-day drink containing Fortasyn Connect) or control product. Randomisation was computer-generated centrally in blocks of four, stratified by site. All study personnel and participants were masked to treatment assignment. The primary endpoint was change in a neuropsychological test battery (NTB) score. Analysis was by modified intention to treat. Safety analyses included all participants who consumed at least one study product dose. This trial is registered with the Dutch Trial Register, number NTR1705. Findings Between April 20, 2009, and July 3, 2013, 311 of 382 participants screened were randomly assigned to the active group (n=153) or control group (n=158). Mean change in NTB primary endpoint was −0·028 (SD 0·453) in the active group and −0·108 (0·528) in the control group; estimated mean treatment difference was 0·098 (95% CI −0·041 to 0·237; p=0·166). The decline in the control group was less than the prestudy estimate of −0·4 during 24 months. 66 (21%) participants dropped out of the study. Serious adverse events occurred in 34 (22%) participants in the active group and 30 (19%) in control group (p=0·487), none of which were regarded as related to the study intervention. Interpretation The intervention had no significant effect on the NTB primary endpoint over 2 years in prodromal Alzheimer's disease. However, cognitive decline in this population was much lower than expected, rendering the primary endpoint inadequately powered. Group differences on secondary endpoints of disease progression measuring cognition and function and hippocampal atrophy were observed. Further study of nutritional approaches with larger sample sizes, longer duration, or a primary endpoint more sensitive in this pre-dementia population, is needed.
2017 · American Journal of Geriatric Psychiatry
Objective: To evaluate the effect of memantine added to cholinesterase inhibitors (ChEIs) on agitation, other neuropsychiatric symptoms, and related caregiver burden in patients with Alzheimer’s disease (AD) experiencing agitation. Background: Agitation, a common, problematic neuropsychiatric symptom associated with AD, can increase caregiver burden and costs. Memantine and its extended-release formulation are approved for moderate-to-severe AD; ChEIs are additionally approved in mild AD. Previous studies suggest that ChEIs, memantine, and memantine added to ChEIs provide benefits for neuropsychiatric symptoms in AD. Design/Methods: Data were pooled from three phase 3, randomized, double-blind, placebo-controlled 24-week trials evaluating memantine for patients with moderate-to-severe or mild-to-moderate AD receiving concurrent ChEIs. Inclusion for these analyses required Neuropsychiatric Inventory-agitation (NPI-agitation) scores >0 at baseline or end-of-treatment. A mixed-effect repeated-measure model evaluated least squares mean differences (LSMD) between groups on NPI-agitation and NPI Caregiver Distress-agitation (NPI-D-agitation), as well as total and subdomain scores, from baseline to weeks 12 and 24, with alpha 0.05. Effect sizes were estimated with Cohen’s d. Results: Of 1140 patients, 532 had symptomatic agitation and were analyzed (mean age±SEM 76.10±0.349 years; mean baseline MMSE±SEM 10.83±0.137): 269 placebo/ChEIs, 263 memantine/ChEIs. Memantine/ChEIs significantly improved NPI-agitation at weeks 12 (P=0.0003; d,−0.3193) and 24 (P=0.0001; d, −0.3554) compared with placebo/ChEIs. Similar between-group effects were observed for NPI-D-agitation at week 12 (P=0.0067; d, −0.3346) and week 24 (P=0.0147; d,−0.3126). Congruent benefits of memantine were observed for NPI total score (week 12: P=0.0003; d,−0.3174; week 24: P=0.0004; d,−0.3213), NPI-delusion (week 12: P=0.0217; d,−0.2016; week 24: P=0.0365; d,−0.1913), NPI-D-delusion (week 12: P=0.0191; d,−0.2894), NPI-irritability/lability (week 12: P=0.0001; d,−0.3400; week 24: P=0.0013; d,−0.2933), NPI-D-irritability/lability (week 12: P=0.0109; d,−0.3152), and NPI-anxiety and NPI-apathy/indifference (week 24: P=0.0400; d,−0.1875; P=0.0127; d,−0.2287). Conclusions: Memantine added to ChEIs may substantially reduce agitation and other behavioral disturbances in AD patients who experience agitation, and also may reduce caregiver burden related to these symptoms.
2017 · Innovations in clinical neuroscience
An evolving paradigm shift in the diagnostic conceptualization of Alzheimer’s disease is reflected in its recently updated diagnostic criteria from the National Institute on Aging-Alzheimer’s Association and the International Working Group. Additionally, it is reflected in the increased focus in this field on conducting prevention trials in addition to improving cognition and function in people with dementia. These developments are making key contributions towards defining new regulatory thinking around Alzheimer’s disease treatment earlier in the disease continuum. As a result, the field as a whole is now concentrated on exploring the next-generation of cognitive and functional outcome measures that will support clinical trials focused on treating the slow slide into cognitive and functional impairment. With this backdrop, the International Society for CNS Clinical Trials and Methodology convened semi-annual working group meetings which began in spring of 2012 to address methodological issues in this area. This report presents the most critical issues around primary outcome assessments in Alzheimer’s disease clinical trials, and summarizes the presentations, discussions, and recommendations of those meetings, within the context of the evolving landscape of Alzheimer’s disease clinical trials.
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.
2017 · Neurology
Objective: To examine the effects of memantine extended-release (ER) on Activities of Daily Living (ADLs) in patients with moderate-to-severe Alzheimer’s disease (AD). Background: In a 24-week, randomized, double-blind, placebo-controlled, parallel-group trial (NCT00322153), the efficacy of memantine ER (28 mg, once daily) on co-primary measures of cognition and global change was demonstrated in patients with moderate-to-severe AD (MMSE 3–14) concurrently taking a cholinesterase inhibitor (ChEI); treatment with adjunctive memantine ER did not achieve significance on the secondary measure of function, the 19-item Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL19). The lack of observed benefit of memantine on ADLs is in contrast to results from two pivotal memantine trials conducted in a similar patient population (MMSE 3–14 and MMSE 5–14). In those trials, monotherapy treatment with the immediate-release memantine conferred significant therapeutic benefits vs placebo on the ADCS-ADL. Design/Methods: In this post hoc analysis, the percentage of responders with ADCS-ADL19 change scores of ≤0, −2, −4, −6 and −8 were compared between treatment groups (memantine- and placebo-treated patients concurrently receiving a ChEI) using Fisher’s exact test. Results: While functional abilities declined in all patients, a greater percentage of patients treated with placebo (ChEI only) declined compared with those treated with memantine and ChEIs, with significant between-group differences observed among those with a change score of ≤-4 (20.0% placebo vs 12.1% memantine; P=0.0137), ≤-6 (13.3% vs 8.0%; P=0.0499), and ≤-8 (9.6% vs 4.9%; P=0.0453) by study end (weeks 18–24). Conclusions: This post hoc analysis suggests that the inevitable decline in function in moderate-to-severe AD patients may be ameliorated with memantine treatment compared with treatment with ChEIs alone.
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