Over 200 publications, including the composite endpoints regulators now recognize. We publish our methodology in the open so reviewers meet it before your submission does.
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.
31 publications
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2025 · CNS Drugs
Hendrix, Suzanne · Dickson, Samuel · Durrant, Abe
Amyloid-plaque reduction is currently the only recognized surrogate outcome for Alzheimer’s disease (AD) trials, allowing accelerated approval of plaque-clearing amyloid antibodies. However, plaque reduction does not facilitate the development of new non-plaque-clearing treatments. The hippocampus is among the first brain regions affected by AD pathology, exhibiting synaptic dysfunction and neurodegeneration that manifests as hippocampal atrophy and memory decline. We evaluated hippocampal volume (HV) as a potential surrogate outcome that can predict clinical benefit in disease-modification trials. Using published data from observational and interventional studies that examined both cognition and HV on volumetric magnetic resonance imaging (vMRI), we evaluated the cross-sectional correlations of HV to cognitive performance, the longitudinal correlations of HV atrophy to cognitive decline, HV sensitivity to drug effects, and the correlations between drug effects on HV atrophy and cognitive decline. We also examined the magnitude of HV protection that corresponds to meaningful clinical benefit. Analyses from 30 observational studies encompassing 13,187 individuals (2633 cognitively normal; 10,554 early AD) showed significant cross-sectional correlations between baseline HV and cognition, and longitudinal correlations between HV atrophy and cognitive decline over ≥ 1 year. The relationship of HV–cognitive drug effects was examined at the group level in nine placebo-controlled trials of five antiamyloid agents that evaluated HV in early AD trials of at least 18 months’ duration. These trials included four amyloid antibodies (aducanumab, lecanemab, donanemab, and gantenerumab) and one oral anti-oligomer agent (valiltramiprosate). Individual-level HV–cognition relationships were examined in two valiltramiprosate studies, one of which included diffusion tensor imaging (DTI) providing microstructural correlates of HV drug effects and helping distinguish neuroprotection from brain edema. Across these anti-amyloid drug trials (total N ~10,000), there was a linear relationship between drug effects on slowing of cognitive decline and slowing of HV atrophy. Two anti-oligomer trials (valiltramiprosate) reported significant subject-level correlations between drug effects on HV and cognition over 18–24 months (r = −0.40 to −0.44, p < 0.005, N = 50/69), with significant correlations of drug effects on brain microstructure (decreased mean diffusivity) with both HV and cognitive benefits, supporting reduced neurodegeneration. The minimal HV preservation at the mild cognitive impairment (MCI) stage that is associated with clinical benefit is estimated to be ≥ 40 mm3 or ≥ 10% of atrophy in the placebo arm over 18 months. Our findings demonstrate that hippocampal atrophy is an early indicator of cognitive decline in AD, linked to amyloid and tau-related neurodegeneration. HV on standardized vMRI is sensitive to anti-amyloid treatments, demonstrating strong correlations between slowed hippocampal atrophy and slowed cognitive decline. Data from over 23,000 subjects over three decades support HV as a surrogate marker for predicting clinical benefit in early symptomatic AD.
2025 · Journal of Alzheimer’s Disease
Haaland, Benjamin · Dickson, Samuel · Christensen, Joshua · Mallinckrodt, Craig · Hendrix, Suzanne
Background The AFF006 trial (NCT01117818) provided unexpected evidence of benefits of the vaccine adjuvant AD04 (aluminum oxyhydroxide) in patients with early Alzheimer's disease (AD), compared with AD02, a vaccine consisting of a peptide that mimics the N-terminal region of human amyloid-β (Aβ) conjugated with keyhole limpet hemocyanin. Objective The objective of this post hoc analysis was to assess whether this unexpected benefit of AD04 was an artifact of multiple testing (i.e., type I error inflation) or a robust result. Methods In this post hoc assessment, we used permutation testing to estimate type I error inflation due to the evaluation of multiple outcomes in AFF006. Efficacy was assessed using a patient-level global statistical test combining composite endpoints of cognition, function, and global AD. In addition, we examined the observed treatment benefits of AD04 in the context of effects observed in trials of aducanumab, donanemab, and lecanemab, monoclonal anti-Aβ antibodies that received regulatory approval for AD. Results The global statistical test suggested a treatment benefit of AD04 versus ineffective AD02 arms, even after accounting for multiplicity (primary methodology p-value, 0.03; permutation test p-value, 0.02). The observed effect estimates for AD04 compared favorably with approved monoclonal antibodies. Conclusions Post-hoc analyses are hypothesis generating rather than confirmatory. Adjusting for multiplicity using permutation testing can determine whether post-hoc effects are worth pursuing, or unlikely to be confirmed. These analyses have motivated a follow-up prospective randomized controlled trial, ADVANCE (EudraCT 2022-003532-73), in which optimized AD04 dosing will be compared to placebo in early AD.
2024 · J Clin Pharmacol
Dayley, Caleb · Salt, Andrew · Pick, Christina · Durrant, Abe · Johnson, Sam · Nicodemus-Johnson, Jessie · Dickson, Samuel · Hendrix, Suzanne
To evaluate the pharmacodynamic effects and clinical outcomes of orally administered once-daily govorestat (AT-007), a central nervous system penetrant aldose reductase inhibitor, the double-blind placebo-controlled ACTION-Galactosemia Kids study (NCT04902781) randomly assigned 47 participants (2-17 years old) with Classic Galactosemia to 18 months of govorestat or placebo (2:1) treatment. Mean change in galactitol was compared between the treatment groups at each post-baseline timepoint using a t-test, with a mixed model for repeated measures (MMRM) analysis as a sensitivity analysis. Changes from baseline in clinical outcomes were compared between treatment groups also using a t-test with two different MMRM models as sensitivity models, one including baseline clinical outcome score. The pharmacodynamic effect of govorestat was assessed by correlating galactitol level at 3 months with change from baseline in clinical measures at 18 months using a Pearson correlation. Govorestat treatment resulted in a rapid and sustained reduction in plasma galactitol. Govorestat treatment stabilized or improved clinical measures of behavior, daily living skills, adaptive skills, cognition, tremor, and fine motor skills, which declined over time in the placebo group. Govorestat treatment did not demonstrate a benefit compared with placebo on speech outcomes or gross motor skills, which improved in both treatment groups over 18 months. Govorestat was safe and well tolerated, with adverse events well balanced between the active and placebo groups. Aldose reductase inhibition with govorestat represents a potential opportunity to lower galactitol and improve clinical outcomes in children with Classic Galactosemia.
2024 · Alzheimers Dement (N Y)
Hendrix, Suzanne · Nicodemus-Johnson, Jessie · Knowlton, Newman
Introduction: Sodium phenylbutyrate and taurursodiol (PB and TURSO) is hypothesized to mitigate endoplasmic reticulum stress and mitochondrial dysfunction, two of many mechanisms implicated in Alzheimer's disease (AD) pathophysiology. Methods: The first-in-indication phase 2a PEGASUS trial was designed to gain insight into PB and TURSO effects on mechanistic targets of engagement and disease biology in AD. The primary clinical efficacy outcome was a global statistical test combining three endpoints relevant to disease trajectory (cognition [Mild/Moderate Alzheimer's Disease Composite Score], function [Functional Activities Questionnaire], and total hippocampal volume on magnetic resonance imaging). Secondary clinical outcomes included various cognitive, functional, and neuropsychiatric assessments. Cerebrospinal fluid (CSF) biomarkers spanning multiple pathophysiological pathways in AD were evaluated in participants with both baseline and Week 24 samples (exploratory outcome). Results: PEGASUS enrolled 95 participants (intent-to-treat [ITT] cohort); cognitive assessments indicated significantly greater baseline cognitive impairment in the PB and TURSO (n = 51) versus placebo (n = 44) group. Clinical efficacy outcomes did not significantly differ between treatment groups in the ITT cohort. CSF interleukin-15 increased from baseline to Week 24 within the placebo group (n = 34). In the PB and TURSO group (n = 33), reductions were observed in core AD biomarkers phosphorylated tau-181 (p-tau181) and total tau; synaptic and neuronal degeneration biomarkers neurogranin and fatty acid binding protein-3 (FABP3); and gliosis biomarker chitinase 3-like protein 1 (YKL-40), while the oxidative stress marker 8-hydroxy-2-deoxyguanosine (8-OHdG) increased. Between-group differences were observed for the Aβ42/40 ratio, p-tau181, total tau, neurogranin, FABP3, YKL-40, interleukin-15, and 8-OHdG. Additional neurodegeneration, inflammation, and metabolic biomarkers showed no differences between groups. Discussion: While between-group differences in clinical outcomes were not observed, most likely due to the small sample size and relatively short treatment duration, exploratory biomarker analyses suggested that PB and TURSO engages multiple pathophysiologic pathways in AD.
2024 · J Prev Alzheimers Dis
Dickson, Samuel · Brownlee, Allison · Haaland, Benjamin · Mallinckrodt, Craig · Hendrix, Suzanne
Assessment of meaningfulness in randomized clinical trials (RCTs) in Alzheimer's disease (AD) is challenging, particularly in early disease. Converting clinical outcomes to disease progression time allows assessment of treatment effects using a metric that is understandable and meaningful: time. We demonstrate time savings assessments using meta time component tests (TCTs) in the LipiDiDiet multinutrient RCT. Dietary patterns are important for dementia prevention, likely due to individual cumulative nutrient effects. LipiDiDiet used a multinutrient (Fortasyn Connect) formulation in patients with prodromal AD, benefitting cognition (5-item composite NTB, effect 0.089), cognition and function (CDR-SB, -0.605), and slowing hippocampal atrophy (0.122 cm3). Meaningfulness of point differences is unclear. However, a combination TCT showed 9-month disease time savings at 24 months (38% slowing of disease time): 9.0, 10.5, and 7.2 months for NTB, CDR-SB, and hippocampal volume, underscoring the value of TCTs in AD RCTs and the need for continued validation of this approach.
2020 · 2020 Alzheimer's Association International Conference
Background: Diet and nutrition are important modifiable risk factors for Alzheimer’s disease (AD). For the last two decades, the LipiDiDiet consortium has been investigating the role of nutrients and their synergistic action on key AD pathological features. Based on preclinical results, 11 nutrients were selected which, when applied in this specific combination, gave the best results in rodent AD models: i.e. the omega-3 fatty acids DHA and EPA, phospholipids, vitamins B6, B12, folic acid, C and E, choline, selenium, and UMP. The LipiDiDiet trial1 is a 6-year, double-blind, parallel-group, multi-centre, randomised controlled clinical trial, designed to investigate effects of the specific multinutrient combination Fortasyn Connect on cognition and related measures in prodromal AD. Initial 24 month results showed significant benefit on clinical dementia rating-sum of boxes (CDR-SB) and hippocampal and ventricular volumes in the modified intention-to-treat population. Here we report previously specified primary and secondary outcomes over 36 months of intervention. Method: Prodromal AD participants (n=311) were randomised to receive either active product (125 mL drink containing Fortasyn Connect) or a calorie-matched placebo control once daily. Result: 162 participants completed the 36-month period. With increasing treatment duration, the benefit of the active group over the control group exceeded what had been observed for the first 24 months (Soininen et al., Lancet Neurology 2017). For the 5-item neuropsychological test battery (NTB) on cognition, a significant between-group difference was observed in estimated mean change from baseline over 36 months favouring active intervention (0.212 [95% CI 0.044 to 0.380]; p=0.014; 60% reduction in decline). In addition, significant benefits were found on CDR-SB, NTB memory, and hippocampal, ventricular, and whole brain volumes on MRI. Self-reported compliance to the study product was high and there was no indication of safety concern. Conclusion: We observed significantly slower decline in cognition including memory, CDR-SB measuring cognition and function, and brain structural measures. Importantly, prolonged intervention with this specific combination of nutrients resulted in a broader range of endpoints showing statistically significant differences. Sustainable benefits lasting for 3 or more years have not been reported before in prodromal AD.
2019 · Journal of the American Medical Directors Association
Objective Benzodiazepines and related drugs (BDZRs) have been associated with an increased risk of Alzheimer's disease (AD) in later life. Despite this, it remains unclear whether ongoing BDZR use may further accelerate cognitive decline in those diagnosed with mild to moderate AD. Design This study was embedded within NILVAD, a randomized controlled trial of nilvadipine in mild to moderate AD. Cognition was measured at baseline and 18 months using the Alzheimer Disease Assessment Scale, Cognitive Subsection (ADAS-Cog). We assessed predictors of long-term BDZR use and analyzed the effect of ongoing BDZR use on ADAS-Cog scores at 18 months. Additionally, the impact of BDZR use on adverse events, incident delirium, and falls over 18-month follow-up was assessed adjusting for relevant covariates. Setting and Participants 448 participants with mild to moderate AD recruited from 23 academic centers in 9 European countries. Results Overall, 14% (62/448) were prescribed an ongoing BDZR for the study duration. Increasing total number of (non-BDZR) medications was associated with a greater likelihood of BDZR prescription (odds ratio 1.16, 95% confidence interval 1.05-1.29). At 18 months, BDZR use was not associated with greater cognitive decline on the ADAS-Cog controlling for baseline ADAS-Cog scores, age, gender, study arm, and other clinical covariates (β = 1.62, −1.34 to 4.56). However, ongoing BDZR use was associated with a greater likelihood of adverse events [incidence rate ratio (IRR) 1.19, 1.05-1.34], incident delirium (IRR 2.31, 1.45-3.68), and falls (IRR 1.66, 1.02-2.65) over 18 months that persisted after robust adjustment for covariates. Conclusions and Implications This study found no effect of ongoing BDZR use on ADAS-Cog scores in those with mild to moderate AD over 18 months. However, ongoing use of these medications was associated with an increased risk of adverse events, delirium, and falls. Thus, BDZR use should be avoided where possible and deprescribing interventions should be encouraged in older adults with AD.
2019 · The Journal of Prevention of Alzheimer's Disease
As research evolves in prodromal AD, the need to validate sufficiently sensitive outcome measures, e.g. the Alzheimer's Disease Composite Score (ADCOMS) is clear. In the LipiDiDiet randomized trial in prodromal AD, cognitive decline in the study population was much less than expected in the timeframe studied. While the primary composite endpoint was insufficiently sensitive to detect a difference in the modified intention to treat population, the per-protocol population showed less decline in the active than the control group, indicating better treatment effects with regular product intake. These results were further strengthened by significant benefits on secondary endpoints of cognition and function, and brain atrophy. The present post-hoc analysis investigated whether ADCOMS could detect a difference between groups in the LipiDiDiet population (138 active, 140 control). The estimated mean change in ADCOMS from baseline (standard error) was 0.085 (0.018) in the active and 0.133 (0.018) in the control group; estimated mean treatment difference −0.048 (95% confidence intervals −0.090, −0.007; p=0.023), or 36% less decline in the active group. This suggests ADCOMS identified the cognitive and functional benefits observed previously, confirming the sensitivity of this composite measure.
2019 · Handbook of Behavioral Neuroscience
A challenge to the endeavor of assessing cognition in patients with Alzheimer's disease (AD) is the lack of reliability, validity, and responsiveness of the tests that have been traditionally employed. A further consideration is the lack of continuity between tests preferred for use in memory clinics and other specialist centers as compared with those selected for use in clinical drug trials of putative new therapies for AD. In contrast to the lack of continuity in AD, in other indications, such as major depressive disorder (MDD), similar paradigms, though different tests, have been employed to detect cognitive deficits, to measure cognitive change and, more recently, to identify cognitive markers that might indicate risk factors for disease onset. In this chapter, we contrast the assessment of cognition in AD and MDD, especially in the context of identifying cognitive deficits and the measurement of efficacy.
2019 · Neurology
Objective: To evaluate the effect of the combination of memantine (MEM) with a cholinesterase inhibitor (ChEI) vs placebo (PBO) with ChEI on total Severe Impairment Battery (SIB) and three higher-order cognitive domains (memory, language, and praxis). Background: The SIB is used to assess cognitive changes in patients with Alzheimer’s disease (AD), allowing for reliable, valid, and sensitive detection of treatment effects when floor effects may be present on other cognitive tests. MEM results in significant improvements on the SIB compared with PBO in moderate to severe AD patients treated concurrently with a ChEI. Design/Methods: Data were pooled from two phase 3, randomized, double-blind, PBO-controlled 24-week trials (Tariot et al. JAMA, 2004; Grossberg et al. CNS Drugs, 2013) in patients with moderate to severe AD (baseline MMSE score<20). The SIB was administered at baseline and weeks 4, 8, 12, 18, and 24. Based on Schmitt et al. Alzheimer Dis Assoc Disord, 2006, SIB domains were aggregated to create higher-order subscales of memory (memory, attention, orientation, orienting to name), language (language, social interaction), and praxis (praxis, visuospatial ability, construction). Results: Compared with PBO/ChEI, MEM/ChEI significantly improved total SIB scores at weeks 8, 12, 18, and 24 (all, P<0.05). An analysis of higher-order domains demonstrated that MEM/ChEI treatment conferred significant effects on memory and language vs PBO/ChEI at weeks 12, 18, and 24 (all, P<0.05). On the higher-order domain of praxis, MEM/ChEI showed significant effects vs PBO/ChEI at all timepoints (weeks 4, 8, 12, 18, and 24, all P<0.05). Conclusions: The combination of MEM with a ChEI produced early and consistent improvements in cognition for patients with moderate to severe AD. Analysis of higher-order domains on the SIB further supported the efficacy of MEM in maintaining key cognitive functions (memory, language, and praxis), even when these patients are receiving the standard of ongoing ChEI treatment.
2019 · Neurology
Objective: This clinical trial investigated the effects of a precision medicine intervention on cognition in asymptomatic and mildly symptomatic patients. Background: Multidomain approaches to treating modifiable risk factors in Alzheimer’s disease (AD) have shown cognitive benefits for patients at-risk for dementia. Design/Methods: Patients aged 25–86 were recruited from an Alzheimer’s prevention clinic and categorized into two groups. The prevention group (group 1) included normal cognition, subjective cognitive decline, and preclinical AD patients. The early treatment group (group 2) included predominantly MCI due to AD as well as mild AD dementia patients. Primary outcome was change in performance on a cognitive composite (m-APCC) measuring AD pathology in higher- versus lower-compliance participants at 18 months in groups 1 and 2. We also compared groups versus matched historical controls from NACC/Rush University. Secondary outcome was change in performance on a non-pathological cognitive aging composite (CAC). Trial registered at ClinicalTrials.gov (NCT03687710). Results: Of 202 participants screened, 178 met inclusion criteria; 154 (87%) had at least one post-baseline assessment and were included in analyses. Group 1 improved on the m-APCC by 0.426 at 18-months (p<0.0001). Similar effects were seen for higher and lower compliance groups (p=0.1467). Group 1 higher-compliance participants improved more than NACC (p=0.0039) and Rush controls (p=0.0133). Group 1 lower compliance participants also improved more than NACC (p=0.0105) and Rush (p=0.0259) controls. In group 2, higher compliance participants improved relative to lower compliance participants (p<0.0001) and NACC (p=0.0069), but not compared to Rush (p=0.3953). For group 1, the CAC improved by 2.67 years for higher-compliance participants and 3.52 years for lower-compliance participants (p=0.4039). Group 2 improved by 2.95 years in the CAC for higher-compliance participants and worsened by 5.06 years for lower-compliance participants (p=0.0004). Conclusions: Findings suggest a precision medicine multidomain intervention can improve cognitive function. Intervening earlier in the pre-AD dementia diagnostic spectrum led to greater improvements.
2018 · Alzheimer's & Dementia
Abstract: Like virtually all age-related chronic diseases, late-onset Alzheimer's disease (AD) develops over an extended preclinical period and is associated with modifiable lifestyle and environmental factors. We hypothesize that multimodal interventions that address many risk factors simultaneously and are individually tailored to patients may help reduce AD risk. We describe a novel clinical methodology used to evaluate and treat patients at two Alzheimer's Prevention Clinics. The framework applies evidence-based principles of clinical precision medicine to tailor individualized recommendations, follow patients longitudinally to continually refine the interventions, and evaluate N-of-1 effectiveness (trial registered at ClinicalTrials.gov NCT03687710). Prior preliminary results suggest that the clinical practice of AD risk reduction is feasible, with measurable improvements in cognition and biomarkers of AD risk. We propose using these early findings as a foundation to evaluate the comparative effectiveness of personalized risk management within an international network of clinician researchers in a cohort study possibly leading to a randomized controlled trial.
2018 · Neurology
Objective: To examine Severe Impairment Battery (SIB) score changes (improvement or worsening) of ≥5, ≥10, and ≥15 points for patients with moderate to severe Alzheimer’s disease (AD) receiving memantine ER (MemER)/cholinesterase inhibitors (ChEI) vs placebo (PBO)/ChEI. Background: Rigorous phase 3 studies demonstrated memantine efficacy, in combination with ChEI, on cognition, function, and global outcomes in patients with moderate-to-severe AD. In a randomized, double-blind, PBO-controlled study (NCT00322153, MemER/ChEI treatment significantly improved SIB scores vs PBO/ChEI, with a PBO-adjusted mean difference of 2.6 points at week 24. Design/Methods: Post hoc analyses examined SIB baseline-to-endpoint (week 24) score changes in patients receiving an ChEI randomized to MemER (28 mg/day) or PBO. SIB score changes were examined in 5-point increments (eg, absolute changes of 1–5, 6–10, 11–15). “Improvement/decline” was noted at 5-point changes; “notable improvement/decline” at 10-point changes; and “remarkable improvement/decline” at 15-point changes. Results: Of 676 patients (safety population), 541 had SIB scores at baseline and week 24 (n=270 MemER/ChEI; n=271 PBO/ChEI). At week 24, 40% of MemER/ChEI patients experienced a ≥5-point SIB improvement vs 31% of PBO/ChEI patients. More MemER/ChEI patients had notable improvements of ≥10 points vs PBO/ChEI patients (23% vs 13%); twice as many had remarkable improvements (≥15 points) with MemER/ChEI vs PBO/ChEI (14% vs 7%). Fewer MemER/ChEI patients declined by ≥5 points vs PBO/ChEI (19% vs 24%), with similar results at declines of ≥10 (10% vs 13%) and ≥15 (6% vs 7%). Conclusions: Compared with PBO/ChEI, more MemER/ChEI-treated patients experienced improvements of ≥5, ≥10 and ≥15 points on the SIB, all greater than the PBO-adjusted mean of 2.6 points; fewer MemER/ChEI-patients experienced a decline in cognition. As no disease-modifying AD treatments are available, these data reaffirm the efficacy of combination therapy with MemER/ChEI on cognition and support its use in patients with moderate to severe AD.
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 · 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 · 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 · 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 · 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 · 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.
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 · The Journal of Prevention of Alzheimer's Disease
Background: Optimized scales and composite outcomes have been proposed as a way to more accurately measure Alzheimer's disease related decline. AFFITOPE® AD02, is an amyloid-beta (Aβ)-targeting vaccine to elicit anti-Aβ antibodies. IMM-AD04, commonly known as Alum, originally designated as a control agent, appeared to have disease-modifying activity in a multicenter, parallel group phase II study in early AD patients. Objectives: To develop adapted outcomes for cognition, function and a composite scale with improved sensitivity to decline and treatment effects in early AD (mild plus prodromal AD) based on historical data and to assess these adapted outcomes in this phase II study. Design: Data from public datasets was analyzed using a partial least squares model in order to identify an optimally weighted cognitive outcome, Adapted ADAS-cog, and an optimally weighted ADL outcome, Adapted ADCS-ADL which were prospectively defined as co-primary endpoints for the study and were also combined into a composite scale. Data from 162 patients in the placebo groups of ADCS studies and 156 mild patients in the ADNI I study were pooled for this analysis. The Adapted ADAS-cog scale considered 13 ADAS-cog items as well as several Neuropsychological test items and CogState items, the Adapted ADCS-ADL considered all ADCS-ADL items. After the pre-specified analyses were complete, additional adapted and composite scales were investigated in a post-hoc manner. Evaluation of the adapted and composite scales was performed on Phase II trial data for AFFITOPE® AD02 (AFF006, Clinical Trial Identifier: NCT01117818) and historic data in early AD. Least square means, standard deviations, and least squares mean to standard deviation ratios were compared among adapted and composite scales and traditional scales for the 5 treatment groups in the phase II study and overall for the historic data. Treatment effect sizes and p-values were also compared for the phase II study. Results: Cognitive items that were selected for the adapted cognitive scale (aADAS-cog) and had the highest weights were Word Recall, Word Recognition, and Orientation. Delayed Word Recall and Digit Cancellation were among the items excluded due to lack of improved sensitivity to decline. Highly weighted ADL items included in the adapted functional scale (aADCS-ADL) were using the telephone, traveling, preparing a meal/snack, selecting clothing, shopping and using appliances. Excluded items were primarily basic ADLs such as eating, walking, toileting and bathing. Comparisons between traditional scales and primary outcome adapted scales show improved sensitivity to group differences with the adapted scales in the phase II trial. Most of the improvement in the sensitivity of the aADAS-cog and the aADCS-ADL is due to a larger treatment difference observed rather than the improved sensitivity to decline in the comparison groups. Conclusion: To our knowledge, this is the first study to prospectively use optimized scales as primary endpoints and to demonstrate the superior power of optimized scales and composites in early disease. Although it is possible that the treatment difference between randomized groups is due to a factor other than the treatment itself, for instance baseline imbalance, the improved power to detect these differences still argues in favor of the adapted scales. The issue of oversensitivity to detect treatment effects is controlled by selection of the alpha level for significance, and in our case will happen less than 5% of the time. Clinical relevance of the treatment difference should be assessed separately from statistical significance, and in this phase II study, is supported by significant or similar sizes of effect on function, behaviour and quality of life outcomes, which are important to patients and caregivers.
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.
2014 · PLoS One
Identifying safe and effective adjuvants is critical for the advanced development of protein-based vaccines. Pattern recognition receptor (PRR) agonists are increasingly being explored as potential adjuvants, but there is concern that the efficacy of these molecules may be dependent on potentially dangerous levels of non-specific immune activation. The filovirus virus-like particle (VLP) vaccine protects mice, guinea pigs, and nonhuman primates from viral challenge. In this study, we explored the impact of a stabilized dsRNA mimic, polyICLC, on VLP vaccination of C57BL/6 mice and Hartley guinea pigs. We show that at dose levels as low as 100 ng, the adjuvant increased the efficacy of the vaccine in mice. Antigen-specific, polyfunctional CD4 and CD8 T cell responses and antibody responses increased significantly upon inclusion of adjuvant. To determine whether the efficacy of polyICLC correlated with systemic immune activation, we examined serum cytokine levels and cellular activation in the draining lymph node. PolyICLC administration was associated with increases in TNFα, IL6, MCP1, MIP1α, KC, and MIP1β levels in the periphery and with the activation of dendritic cells (DCs), NK cells, and B cells. However, this activation resolved within 24 to 72 hours at efficacious adjuvant dose levels. These studies are the first to examine the polyICLC-induced enhancement of antigen-specific immune responses in the context of non-specific immune activation, and they provide a framework from which to consider adjuvant dose levels.
2014 · Neurology
Objective: To explore treatment effects of once-daily 28-mg extended-release memantine (MemER) over the entire course of a randomized placebo-controlled trial (RCT) in moderate-to-severe Alzheimer’s disease (AD) using an area under the curve (AUC) analysis. Background: Efficacy and safety of MemER were demonstrated in a 24-week RCT (N=677) in patients with moderate-to-severe AD concurrently receiving cholinesterase inhibitor (ChEI) therapy. Protocol-specified analyses revealed significant MemER benefits on baseline-to-endpoint changes in cognition (SIB), global clinical status (CIBIC-Plus), behavior (NPI), and semantic processing (VFT), but not on a measure of daily function (ADCS-ADL19). Methods: ANCOVA analysis was performed for each efficacy parameter and a composite Z-score of patient-level AUCs for changes from baseline across all study visits (n=540). Results: Over the entire 24-week study, MemER-ChEI AUCs for SIB, CIBIC-Plus, and NPI showed mean improvements of 88% (P=0.014), 133% (P=0.019), and 109% (P<0.001), relative to placebo-ChEI. Mean VFT AUC cumulative worsening in the placebo-ChEI group was 139% greater than the AUC improvement in the Mem-ChEI group (P=0.014). Mean ADCS-ADL19 AUC improvement in the MemER-ChEI group was 117% greater than the AUC worsening in the placebo-ChEI group (P=0.528). Other time intervals yielded similar results. In composite Z-score analysis a significant cumulative improvement of 56% across all clinical domains for MemER-ChEI vs placebo-ChEI was observed in Weeks 0-12 (P=0.053), which increased to 198% over the entire 24-week study period (P<0.001). Conclusions: In this post-hoc AUC analysis of an AD RCT, mean cumulative treatment benefits of 198% were observed across five clinical domains for memantine ER added to background ChEI therapy. This approach provides a more complete, ecologically valid, robust and dynamic representation of longitudinal efficacy than the usual baseline-to-endpoint change-score trial analyses. These results support that memantine ER add-on therapy yielded consistent, cumulative and meaningful therapeutic benefits across 24 weeks in patients with moderate-to-severe AD.
2013 · Alzheimer's & Dementia
An international task force of investigators from academia, industry, nonprofit foundations, and regulatory agencies met in Monte Carlo, Monaco, on October 31, 2012, to review lessons learned from the recent bapineuzumab and solanezumab trials, and to incorporate insights gained from these trials into future clinical studies. Although there is broad consensus that Alzheimer's disease (AD) should be treated during its earliest stages, the concept of secondary prevention has evolved to be described more accurately as treatment of preclinical, presymptomatic, or early AD. There continues to be a strong emphasis on biomarkers and a need for new biomarkers; however, there has also been a realization, based on completed trials, that the most reliable indicator of clinical efficacy across the entire spectrum of disease from asymptomatic to AD dementia is likely a measure of cognition. The task force made many recommendations that should improve the likelihood of success in future trials, including larger phase 2 or combined phase 2/phase 3 studies, clear evidence of target engagement in the central nervous system, evidence of downstream effects on biomarkers before initiating phase 3 studies, consideration of adaptive and targeted trial designs, and use of sensitive measures of cognition as the most robust indicator of treatment benefit.
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.
2012 · Alzheimer's & Dementia
Background The efficacy of a new, extended-release (ER) formulation of memantine (28 mg, once daily) has been demonstrated previously in a 24-week, multinational, randomized, double-blind, placebo-controlled, parallel-group trial (MEM-MD-50, NCT00322153; placebo, n=335; memantine, n=342) 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 (±=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 For both response levels and all outcome combinations, proportions of responders in the memantine ER group (n=266-269) exceeded those in the placebo group (n= 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 =0.054, NNT=12). 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 =0.042, NNT=18), and the 3-measure combinations of ADCS-ADL 19/NPI/SIB (15.4% vs 9.6%; P =0.027, NNT=17), and ADCS-ADL 19/SIB/CIBIC-Plus (12.4% vs 7.4%; P =0.030, NNT=20). 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.
2012 · Alzheimer's & Dementia
Background: No well-established, validated endpoints exist that are sensitive to change in MCI populations in clinical trials. Our goal was to develop a tool based on standard clinical items that would demonstrate maximum responsiveness to progression and to treatment in an MCI population and would also perform well in a mild AD population (collectively referred to as Early AD). This analysis uses a novel approach by utilizing data from multiple studies to investigate responsiveness to progression and treatment effects rather than sensitivity to baseline deficits. Methods: This tool was built empirically with no a priori assumptions. A partial least squares (PLS) regression model used placebo data from 4 MCI studies over 12 months to select the combination of cognitive and functional items which is most sensitive to change over time, using items from a variety of well-established and validated scales. The PLS regression coefficients from the model were used to form a weighted composite score. The resulting composite score is comprised of ADAS-Cog, MMSE and CDR items. Performance of the composite score was assessed against the original scales in an MCI population, in enriched (CSF Aβ positive) MCI subgroups, with split sample validation, in the presence of a treatment effect and in a mild AD patient population combining data from 3 studies. Results: A composite clinical score was devised from 12 items from the ADAS-Cog, MMSE, and CDR-SB that assess both cognition and global function. This score demonstrates improved sensitivity to decline, as well as reduced heterogeneity, as compared with original scales, and is responsive to treatment effect in MCI, enriched MCI and mild AD populations. The composite score allows for substantial sample sizes reductions in non-enriched and enriched MCI populations for a 12-month study (see Figure). Conclusions: A new composite clinical score that utilizes relevant items from validated and well-established clinical tools provides a tool that can be used as a single clinical outcome in studies that target MCI, enriched MCI and mild AD populations. This tool will enable the use of substantially smaller sample sizes due to improved sensitivity to disease progression and treatment effects.
2007 · Patent
Abstract: In general, the invention relates to a pharmaceutical dose having R-flurbiprofen as the active ingredient that upon oral administration of a single dose to a fasting subject provides a Cmax of about 30-95 µg per mL. When the dose is administered to an individual having mild-to-moderate Alzheimer's disease (or desiring protection against Alzheimer's disease) twice daily for at least 4 months according to the described guidelines, an improvement or lessening in decline of cognitive function as characterized by cognition tests is observed in the patient. The composition of the invention is formulated with one or more pharmaceutically acceptable excipients, salts or carriers.
2007 · European Journal of Neurology
Background: Tarenflurbil is a Selective Ab42-Lowering Agent (SALA) that lowers brain levels of Ab42 in a mouse model of AD and chronic dosing in this model prevents defects in learning and memory. These data and the Phase-2 study indicating sustained benefit in activities of daily living, global function and cognition in mild AD patients, suggest the potential for tarenflurbil to have disease-modifying properties. Methods: This was a placebo-controlled, 1-year study evaluating tarenflurbil in 207 patients with mild-to-moderate AD. At randomization, 94% of subjects were on stable acetylcholinesterase inhibitor therapy. An exploratory post-hoc analysis was performed which compared time to adverse psychiatric events between treatment groups. Results: In subjects with mild AD (MMSE 20–26) was a significant delay in time to clinically significant adverse psychiatric events, 800 mg BID compared to placebo (p=0.011). Among 35% of the placebo group who had an event, the median time was approximately 106 days. In the 800 mg BID group, the median time to event was greater than 333 days with only 14% of this group having an event. The most common psychiatric events reported in the placebo group were agitation, aggression, confusional state and depression.
2006 · Alzheimer's & Dementia
Background: MPC–7869 (R–flurbiprofen) is a Selective Aβ42–Lowering Agent (SALA). In a mouse model of AD (Tg2576), MPC–7869 lowers brain levels of Aβ42 and chronic dosing in this model reduces brain amyloid pathology and prevents defects in learning and memory. These data suggest a potential for MPC–7869 to have disease–modifying properties. Objective(s): This study evaluated the efficacy and safety of treatment with MPC–7869 for 12 months in subjects with mild–to–moderate AD, and includes data from a 1–year follow–on study. Methods: This was a placebo–controlled, double–blind, 1–year trial evaluating 400 mg BID and 800 mg BID of MPC–7869 in 207 patients with mild–to–moderate AD (MMSE 15–26, with an average MMSE score of 21). The mean age of the subjects at baseline was 75 years and 94% of subjects were on stable acetylcholinesterase inhibitor therapy. Primary outcomes included measures of cognition (ADAS–cog), activities of daily living (ADCS–ADL), and global function (CDR–sb). A population pharmacokinetic analysis was also performed. At the end of this study, over 80% of eligible patients were enrolled into a 1–year follow–on treatment study in which placebo patients were randomized into one of the two treatment groups and treated patients continued their stable dose. Treatment groups remained blinded to patient/investigator. Results: A prespecified interaction analysis revealed that mild and moderate AD patients responded differently to MPC–7869 (P= 0.03). In mild AD patients (MMSE 20–26) taking the 800–mg BID dose, statistically significant benefit was observed at 12 months in activities of daily living with a treatment effect size of d=0.44 (P= 0.033) and global function with a treatment effect size of d=0.42 (P= 0.042) with a positive trend observed in cognition. In addition, there was a significant plasma drug concentration to response relationship (ADCS–ADL, P= 0.037 and CDR–sb, P= 0.019). No benefit was observed in moderate AD patients. MPC–7869 was well tolerated and patients taking the 800–mg BID dose continued to show benefit in the 1–year follow–on study. Conclusions: MPC–7869 has an attractive therapeutic and safety profile in patients with mild AD. This study justifies larger–scale confirmatory trials of MPC–7869 as an amyloid–based intervention strategy for AD treatment.
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