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.
15 publications
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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.
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