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.
Showing publications 101–150
Sorted newest first
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.
2019 · Alzheimer's & Dementia: Translational Research & Clinical Interventions
Despite billions of dollars invested in clinical trials to develop novel therapeutics for Alzheimer's disease, no approved treatments have been developed in the past 15 years. In that span, new classes of drugs have been developed and tested, including monoclonal antibodies, γ-secretase modulators, γ-secretase inhibitors, BACE inhibitors, RAGE inhibitors, nicotinic agonists, 5HT6 antagonists, and others. The one constant for all of these clinical trials programs is the use of the ADAS-cog as the primary scale to determine efficacy. The question that needs to be considered is whether it is the target engagement of the drug or the clinical trial measure testing the efficacy. The FDA put out a new position statement in 2018 informing the field on possible considerations for demonstrating efficacy to open the path for approval. Here, we propose and comment on a variety of approaches that are alternatives to the ADAS for FDA-specified stage 3 and 4 Alzheimer's disease. These novel outcomes are being validated in current clinical trials and could be used as efficacy measures moving forward.
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 · Alzheimer Disease & Associated Disorders
Abstract: Memantine extended release (ER) significantly outperformed placebo on co-primary endpoints of Clinician's Interview-based Impression of Change Plus Caregiver Input (CIBIC-Plus) and baseline to endpoint changes on the Severe Impairment Battery (SIB) in a 24-week, randomized trial (NCT00322153) in patients with moderate to severe Alzheimer's disease taking a cholinesterase inhibitor (ChEI). A post hoc analysis compared patients receiving memantine ER/ChEI to placebo/ChEI for time to onset of response and if the response was maintained (achieving improvement at weeks 8, 12, or 18 and maintaining through endpoint/week 24) on the SIB, the Neuropsychiatric Inventory (NPI), CIBIC-Plus, and Activities of Daily Living (ADL) using Fisher exact test. A second post hoc analysis compared percentages of patients for all possible combinations of 2 to 4 assessments with either no decline or clinically notable response using Wald χ. Significantly greater percentages of memantine ER/ChEI patients achieved an early response that was maintained on SIB, NPI, and CIBIC-Plus (P<0.05) versus placebo/ChEI. Significantly greater percentages of memantine ER/ChEI-treated patients achieved and maintained a clinically notable response on ADL/NPI, SIB/ADL/NPI, and SIB/ADL/CIBIC-Plus, compared with placebo/ChEI (P<0.05). Memantine ER results in early, maintained improvement in patients with moderate to severe Alzheimer's disease concurrently taking ChEIs, compared with cholinesterase treatment alone.
2018 · Neurology
Objective: To evaluate Neuropsychiatric Index (NPI) maintenance of response from weeks 12–24 between patients receiving memantine/ChEI vs placebo/ChEI. Background: Neuropsychiatric symptoms, as measured by the NPI, impact daily function and quality of life, hasten time to institutionalization, and increase healthcare costs in patients with AD. Memantine significantly improves NPI scores vs placebo in moderate-to-severe AD. Maintenance of response represents a meaningful treatment benefit and symptom stabilization. Design/Methods: Post hoc analyses used pooled data from moderate to severe (baseline MMSE ≤19)patients (N=1121) in 3 randomized, double-blind, placebo-controlled studies (MEM-MD-02 [Tariot et al, JAMA 2004], MEM-MD-50 [Grossberg et al, CNS Drugs 2013], and MEM-MD-12 [Porsteinsson et al, Curr Alzheimer Res 2008]). To characterize NPI responder rates, evenly spaced change from baseline score groups (≤0, ≤−3, ≤−6, ≤−9, ≤−12) were identified. Maintenance of response was defined as total NPI score change at week 12 (earliest pooled timepoint) that was maintained through week 24 (endpoint). The percentages of patients who maintained response were compared between patients receiving memantine/ChEI or placebo/ChEI using Fisher’s exact test with observed case. Results: Pooled data showed that greater proportions of moderate-to-severe patients treated with memantine/ChEI maintained improvements on total NPI from weeks 12–24 compared with placebo/ChEI patients. For memantine/ChEI-treated vs PBO/ChEI-treated patients, 23.4% vs 18.2% maintained improvements of 6 points or more (P=0.0332); 17.0% vs 11.5% maintained improvements of 9 points or more (P=0.0103); 13.3% vs 7.7% maintained improvements of 12 points or more (P=0.0024). Conclusions: The combination of memantine added to ChEI resulted in improvements on total NPI that were sustained over weeks 12–24 of treatment in this OC analysis, which may represent clinically meaningful improvements for patients with moderate-to-severe AD with neuropsychiatric symptoms. For clinicians, the ability to characterize treatment effects of combination therapy over time may be useful in identifying treatment options and setting patient and caregiver expectations.
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.
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.
2018 · Alzheimer's & Dementia: Translational Research & Clinical Interventions
Introduction: Autosomal-dominant Alzheimer's disease (ADAD) represents a crucial population for identifying prevention strategies that might modify disease course for cognitively unimpaired individuals at high imminent risk for developing symptoms due to Alzheimer's disease (AD), that is, who have “preclinical” AD. Crenezumab is an antiamyloid monoclonal antibody that binds monomeric and aggregated forms of amyloid β, with highest affinity for oligomers; it is in development for early stages of sporadic AD and for ADAD. Methods: This is a prospective, randomized, double-blind, placebo-controlled phase 2 study of the efficacy of crenezumab versus placebo in asymptomatic PSEN1 E280A mutation carriers from family kindreds with ADAD in Colombia. Participants were randomized to receive either crenezumab or placebo for 260 weeks. The study was designed to enroll a planned total of 300 participants, including 200 preclinical mutation carriers (approximately 100 treatment, 100 placebo) and an additional control group of mutation noncarriers from the same family kindreds included to mask mutation carrier status (100 placebo only). The primary outcome is change in the Alzheimer's Prevention Initiative ADAD Composite Cognitive Test Score from baseline to week 260. Secondary outcomes include time to progression to mild cognitive impairment due to AD or dementia due to AD; changes in dementia severity, memory, and overall neurocognitive functioning; and changes in amyloid–positron emission tomography, fluorodeoxyglucose–positron emission tomography, magnetic resonance imaging volumes, and cerebrospinal fluid levels of β amyloid, tau, and p-tau. Safety and tolerability are assessed. Results: Two hundred fifty-two participants were enrolled between December 2013 and February 2017. Discussion: We describe the first large-scale, potentially label-enabling clinical trial of a preclinical treatment for ADAD. Results from this trial will inform on the efficacy of crenezumab for delaying onset of, slowing decline in, or preventing cognitive impairment in individuals with preclinical ADAD and will foster an improved understanding of AD biomarkers and their relationship to clinical outcomes.
2018 · Patent
Brown, Bruce · Hendrix, Suzanne
A method is described for extracting aperiodic components from a time-series wave data set for diagnosis purposes. The method may include collecting time-series wave data within a controlled environment were a plurality of contrasting conditions can be used in collecting the time-series wave data set. Aperiodic components can be extracted from the time-series wave data set and the aperiodic components can then be fitted to the plurality of contrasting conditions of the controlled environment to product regressed aperiodic components from which diagnostic determination can be made.
2018 · Therapeutic Innovation & Regulatory Science
2018 · The Journal of Prevention of Alzheimer's Disease
For the second time in the past 3 years, the EU-US CTAD Task Force addressed challenges related to designing clinical trials for agitation in dementia, which is one of the most disruptive aspects of the condition for both patients and caregivers. Six recommendations emerged from the Task Force meeting: 1 – Operationalizing agitation criteria established by the IPA; 2 – Combining clinician- and caregiver-derived outcomes as primary outcome measures; 3 – Using global ratings to define clinically meaningful effects and power studies; 4 – Improving the accuracy of caregiver reports by better training and education of caregivers; 5 – Employing emerging technologies to collect near real-time behavioral data; and 6 – Utilizing innovative trial designs and increasing the use of biomarkers to maximize the productivity of clinical trials for neuropsychiatric symptoms.
2018 · International Parkinson and Movement Disorder Society
Objective: To evaluate the safety and effectiveness of Spectramax™ specialized bandwidth light therapy (LT) as adjunctive treatment in Parkinson’s disease (PD). Background: Previous studies have suggested that LT improves circadian rhythm and may be effective for both motor and non-motor features of PD. Additionally, pre-clinical studies have suggested that LT may be beneficial in animal models of PD. Methods: We performed a multi-center, randomized, double-blind, controlled clinical trial of LT in PD patients on stable dopaminergic therapy. Patients with severe dyskinesia, cognitive impairment, high doses of dopaminergic therapy, and prior exposure to LT were excluded. Participants were randomized 1:1 to Spectramax™ LT (950 lux blue/green LED light, λ = 460 – 570 nm) or control LT with a bandwidth that was not thought to be biologically active (100 lux white LED light, λ = 415 – 780 nm), for 60 minutes each evening for 6 months. The primary endpoint was the change from Baseline to the final treatment visit in the MDS-UPDRS Parts 1-3 score. Secondary endpoints included change from Baseline in CGI-I, PDQ-39, PDSS-2, ESS and individual MDS-UPDRS components. Results: 92 subjects (45 active, 47 sham) were enrolled at 3 centers in the US and Europe. Baseline demographics were comparable in the 2 groups with the exception that the mean age was higher in the active group (70.2 vs. 65.9, p=0.009). The change (SD) from Baseline to 6 months in the MDS-UPDRS 1-3 score was 17.7(2.8) for the active group vs 9.7(3.4) for the control group (LSM difference = 8.0 (4.4); p=0.074). Nominally significant improvements with Spectramax™ light therapy were observed in PDQ-39 (p=0.038) and MDS-UPDRS part I (p=0.006) with a trend for ESS (p=0.054) scores. One subject in each group discontinued due to an adverse event (dizziness in one sham-treated patient and complaints of vision deterioration and light-headedness in one in the active group). The most common adverse events were ocular (dry eye, teary eye, and eye strain) and were more frequent in the active LT group. Conclusions: Once-daily Spectramax™ LT is associated with a trend in improving PD symptom severity, and improvements of non-motor symptoms and quality of life. LT was well-tolerated. Larger double-blind studies are warranted to further study the effectiveness of LT in PD.
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.
2016 · Alzheimer's & Dementia
Background: Agitation is a common neuropsychiatric comorbidity associated with Alzheimer’s disease (AD) that can increase caregiver burden. The MEM-MD-50 trial demonstrated the behavioral benefits of treatment with extended-release memantine (MemER) in moderate to severe AD patients receiving a cholinesterase inhibitor (ChEI). This post hoc analysis aimed to examine the effects of treatment with MemER+ChEI vs placebo+ChEI on agitation among trial participants with agitation at either baseline or end of treatment. Methods: Patients with moderate to severe AD were randomized to MemER+ChEI or placebo+ChEI treatment in the double-blind MEM-MD-50 study (NCT00322153) for 24 weeks. Least squares mean differences (LSMD) between groups in change from baseline to Weeks 12 and 24 for the Neuropsychiatric Inventory (NPI) total score, Caregiver Distress (NPI-D) total score, and individual item scores were analyzed among participants with a score at either baseline or endpoint >0 for each respective variable, using an analysis of covariance (ANCOVA; α=0.05). Results: A total of 593 participants were included in the analysis, 291 treated with MemER+ChEI and 302 treated with placebo+ChEI. A total of 280 (96.2%) and 291 (96.4%) of those subjects had NPI total scores >0 at baseline or endpoint; 151 (51.9%) and 148 (49.0%) participants, respectively, had NPI-agitation item scores >0 at baseline or endpoint. At Week 12, the LSMD were significant in favor of MemER+ChEI for the NPI total score (-1.89, P<0.05), NPI-Agitation (-0.72, P<0.05), NPI-D total (-0.92, P=0.07), and for NPI-D-Agitation (-0.50, P<0.05). At Week 24, the LSMD for NPI total score was -3.21 (P<0.01), -1.29 for NPI-Agitation (P<0.01), -1.12 for NPI-D total score (P=0.07), and -0.63 for NPI-D-Agitation (P<0.05). Other items with significant between-group differences in LSMD at Week 12 included NPI-Aberrant Motor Behavior, NPI-Delusion, and NPI-D-Delusion; at Week 24, significant between-group differences were also observed for NPI-Delusion, and NPI-Nighttime Behavior (all in favor of MemER+ChEI treatment). Conclusions: This post hoc analysis suggests that the addition of MemER to ChEI treatment may reduce agitation in moderate to severe AD patients, and may also reduce the caregiver burden associated with agitation.
2016 · Immunotherapy and Biomarkers in Neurodegenerative Disorders
Abstract: Parkinson’s disease (PD) is the second most common neurodegenerative disorder. It elicits a broad range of debilitating motor and as well as non-motor symptoms, both of which can lead to serious disability. There is currently no available agent with disease modifying properties. Immunotherapy is increasingly being investigated as a disease modifying treatment for PD based on our improved understanding of the pathophysiology of the disease. Current evidence points to a causal role of misfolded alpha-synuclein (α-syn) in the development and progression of PD and it has therefore become a primary focus for immunotherapy. Today, two principal approaches are being pursued: active and passive immunization. This chapter first addresses progress in active and passive immunotherapeutic approaches targeting α-syn for Parkinson’s disease in animal models. We then discuss clinical progress of α-syn immunotherapy including ongoing clinical trials. Finally, we address challenges and future perspectives for PD immunotherapy.
2016 · Malaria Journal
Background: Due to the ability of the 8-aminoquinolines (8AQs) to kill different stages of the malaria parasite, primaquine (PQ) and tafenoquine (TQ) are vital for causal prophylaxis and the eradication of erythrocytic Plasmodium sp. parasites. Recognizing the potential role of cytochrome (CYP) 450 2D6 in the metabolism and subsequent hepatic efficacy of 8-aminoquinolines, studies were designed to explore whether CYP2D-mediated metabolism was related to the ability of single-dose PQ and TQ to eliminate the asexual and sexual erythrocytic stages of Plasmodium berghei. Methods: An IV P. berghei sporozoite murine challenge model was utilized to directly compare causal prophylactic and erythrocytic activity (asexual and sexual parasite stages) dose-response relationships in C57BL/6 wild-type (WT) mice and subsequently compare the erythrocytic activity of PQ and TQ in WT and CYP2D knock-out (KO) mice. Results: Single-dose administration of either 25 mg/kg TQ or 40 mg/kg PQ eradicated the erythrocytic stages (asexual and sexual) of P. berghei in C57BL WT and CYP2D KO mice. In WT animals, the apparent elimination of hepatic infections occurs at lower doses of PQ than are required to eliminate erythrocytic infections. In contrast, the minimally effective dose of TQ needed to achieve causal prophylaxis and to eradicate erythrocytic parasites was analogous. Conclusion: The genetic deletion of the CYP2D cluster does not affect the ability of PQ or TQ to eradicate the blood stages (asexual and sexual) of P. berghei after single-dose administration.
2016 · J Prev Alzheimers Dis
Brown, Bruce · Hendrix, Suzanne
Background: Tramiprosate is an oral amyloid anti-aggregation agent that reduces amyloid oligomer toxicity in preclinical studies and was evaluated in two 78-week trials in North America and Western Europe that enrolled 2,025 patients with Mild to Moderate Alzheimer's Disease. The completed North American study did not achieve its efficacy objectives, but a pre-specified subgroup analysis suggested potential efficacy in apolipoprotein E4 (APOE4) carriers. To further explore this observation, we analyzed tramiprosate Phase 3 clinical data based on the number of APOE4 alleles. Objectives: To analyze tramiprosate efficacy, safety, and occurrence of vasogenic edema in the three APOE4 subgroups: homozygous, heterozygous and non-carriers. Design: Randomized, double-blind, placebo-controlled parallel-arm multi-center studies. Setting: Academic Alzheimer's disease and dementia centers, community-based dementia and memory clinics, and neuropsychiatric clinical research sites. Participants: Subjects included 2,025 patients, 50 years of age or older, with approximately 60% having APOE4 carrier status (10-15% homozygotes and 45-50% heterozygotes), and mild to moderate disease. All subjects were on stable symptomatic drugs. Intervention: Randomized subjects received placebo, 100 mg BID, or 150 mg BID of tramiprosate. Measurements: Co-primary outcomes in both studies were change from baseline in the ADAS-cog11 and CDR-SB assessment scales. Results: Highest efficacy was observed in APOE4/4 homozygotes receiving 150 mg BID of tramiprosate, showing statistically significant effects on ADAS-cog and positive trends on CDR-SB (respectively, 40-66% and 25-45% benefit compared to placebo). APOE4 heterozygotes showed intermediate efficacy, and non-carriers showed no benefit. In 426 patients with MRI scans, no cases of treatment-emergent vasogenic edema were observed. In the three subgroups, the most common adverse events were nausea, vomiting, and decreased weight. Conclusions: The "APOE4 Gene-Dose effect" is likely explained by the high prevalence of amyloid pathology in symptomatic APOE4 carriers. In APOE4/4 Alzheimer's disease patients, the high dose of tramiprosate showed favorable safety and clinically meaningful efficacy in addition to standard of care.
2016 · Neurology
Objective: A pooled post hoc analysis of ADCS-ADL19 scores from two, 24-week, placebo-controlled trials was performed to evaluate the impact of combining memantine with ChEI treatment on daily functioning and assess potential clusters of functional tasks that improved together. Background: Moderate to severe Alzheimers disease is frequently treated with a cholinesterase inhibitor (ChEI) in combination with memantine. Methods: Data were pooled from trials MEM-MD-02 and MEM-MD-50 (placebo+ChEI, n=525; memantine+ChEI, n=531). Factors were derived using a principal components analysis based on change-from-baseline item values (placebo and memantine groups combined), varimax rotation, maximum loading for each item, and eigenvalues of ≥1 for each factor with a designated maximum of 4 factors. Between-group comparisons of item and factor score changes used a mixed-effects model with repeated measures (MMRM; OC and LOCF) analysis. Results:At Week 24, there were significant advantages of memantine+ChEI treatment over placebo+ChEI for grooming (P<0.001), conversing (P=0.010), and finding belongings (P=0.002). The 4 subscales identified were: basic ADLs (eating, walking, toileting, bathing, grooming, dressing; loading value range [LVR]: 0.41-0.71), higher-level ADLs requiring communication/comprehension skills (using telephone, watching television, conversing, finding belongings, traveling, left alone; LVR: 0.37-0.58), simple praxis (faucet on, faucet off, light on; LVR: 0.53-0.80), and praxis items requiring visuo-spatial and memory skills (clearing table, obtaining beverage, disposing of litter, light off; LVR: 0.35-0.63). At Week 24, the memantine+ChEI group declined less than placebo+ChEI on each subscale: basic ADLs (least squares difference [LSDiff]=0.376; P=0.017), higher level ADLs (LSDiff=0.265; P=0.156), simple praxis (LSDiff=0.077; P=0.043), and praxis items requiring visuo-spatial and memory skills (LSDiff=0.300; P=0.017). Conclusions:The addition of memantine to stable ChEI treatment was associated with significant improvements in grooming, conversing, and finding belongings. The factor analysis identified 4 subscales, and significant advantages of memantine+ChEI treatment over placebo+ChEI for basic ADLs, simple praxis, and praxis items requiring visuo-spatial and memory skills.
2016 · Journal of Neurology, Neurosurgery & Psychiatry
2016 · The Journal of Prevention of Alzheimer's Disease
Abstract: The EU/US/CTAD Task Force, an international collaboration of AD investigators from industry and academia, met in Barcelona, Spain, on November 4th, 2015, to explore existing and planned patient registries and other clinical trial infrastructure meant to expedite recruitment of large numbers of participants into clinical trials and improve their productivity. The Task Force identified a number of approaches currently being tested around the world, including the use of predictive algorithms to identify individuals likely to have prodromal or preclinical AD, the establishment of clinical trial networks to streamline trials, and reforming the informed consent process to make it less burdensome to both investigators and trial participants. Multi-national systems such as the European Prevention of Alzheimer's Dementia (EPAD) and the Global Alzheimer's Platform (GAP) offer value for sponsors, trial sites, and patients by optimizing efforts to find effective disease-modifying and symptomatic treatments.
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 · Alzheimer's & Dementia: The Journal of the Alzheimer's Association
Background: The exponential growth in patient needs, the tremendous personal and societal burden, the high cost of basic and clinical research, and the enormous investments of pharmaceutical companies to develop new therapies for Alzheimer's disease (AD) remain a big challenge. Despite the considerable evidence that links a reduction in hippocampal volume (HV) in the brains of affected subjects to the pathophysiology of the disease, the role and integration of HV as a biomarker in clinical trials will only be realized on a large scale when this marker is endorsed by regulatory agencies worldwide. In 2011, the European Medicines Agency (EMA) qualified HV measured by MRI as a biomarker. The Coalition Against Major Diseases (CAMD), a consortium within the non-profit organization the Critical Path Institute, aims to qualify with FDA the use of low baseline HV biomarker for enrichment in clinical trials of patients with early AD. The team is at the Consultation and Advice Stage of biomarker qualification. We will present lessons learned. Methods: Through collaborative partnerships between industry, academia, regulatory agencies, and patient advocacy groups, CAMD focuses on the development and regulatory qualification of clinical trials tools, such as HV imaging biomarkers, to increase the efficiency and diminish the risks and costs of drug development. Results: The HV measures proposed for qualification will be applicable independent of the specific drug's mechanism of action or target, the MRI scanner that collected the imaging data, and the algorithm used to measure the HV. Our team has evaluated multiple algorithms in independent clinical cohorts that have longitudinal clinical follow-up, including ADNI. We will discuss our approach to repeatability and reproducibility issues. There is an urgent need to obtain biomarker data from relevant clinical trials to achieve regulatory success. Conclusions: The development of a robust evidentiary package to support the qualification of the HV imaging biomarker for use in clinical trials of patients with AD requires significant resources and commitment from a wide range of stakeholders. Successful qualification of this biomarker is expected to accelerate the advent of new therapies for patients at early stages of the disease.
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 · The Journal of Prevention of Alzheimer's Disease
2015 · BMC microbiology
Background: Burkholderia pseudomallei (Bp) and Burkholderia mallei (Bm) are Gram-negative facultative intracellular pathogens, which are the causative agents of melioidosis and glanders, respectively. Depending on the route of exposure, aerosol or transcutaneous, infection by Bp or Bm can result in an extensive range of disease - from acute to chronic, relapsing illness to fatal septicemia. Both diseases are associated with difficult diagnosis and high fatality rates. About ninety five percent of patients succumb to untreated septicemic infections and the fatality rate is 50 % even when standard antibiotic treatments are administered. Results: The goal of this study is to profile murine macrophage-mediated phenotypic and molecular responses that are characteristic to a collection of Bp, Bm, Burkholderia thailandensis (Bt) and Burkholderia oklahomensis (Bo) strains obtained from humans, animals, environment and geographically diverse locations. Burkholderia spp. (N = 21) were able to invade and replicate in macrophages, albeit to varying degrees. All Bp (N = 9) and four Bm strains were able to induce actin polymerization on the bacterial surface following infection. Several Bp and Bm strains showed reduced ability to induce multinucleated giant cell (MNGC) formation, while Bo and Bp 776 were unable to induce this phenotype. Measurement of host cytokine responses revealed a statistically significant Bm mediated IL-6 and IL-10 production compared to Bp strains. Hierarchical clustering of transcriptional data from 84 mouse cytokines, chemokines and their corresponding receptors identified 29 host genes as indicators of differential responses between the Burkholderia spp. Further validation confirmed Bm mediated Il-1b, Il-10, Tnfrsf1b and Il-36a mRNA expressions were significantly higher when compared to Bp and Bt. Conclusions: These results characterize the phenotypic and immunological differences in the host innate response to pathogenic and avirulent Burkholderia strains and provide insight into the phenotypic alterations and molecular targets underlying host-Burkholderia interactions.
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