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.
8 publications
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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.
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