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.
20 publications
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2019 · Journal of the American Medical Directors Association
Objective Benzodiazepines and related drugs (BDZRs) have been associated with an increased risk of Alzheimer's disease (AD) in later life. Despite this, it remains unclear whether ongoing BDZR use may further accelerate cognitive decline in those diagnosed with mild to moderate AD. Design This study was embedded within NILVAD, a randomized controlled trial of nilvadipine in mild to moderate AD. Cognition was measured at baseline and 18 months using the Alzheimer Disease Assessment Scale, Cognitive Subsection (ADAS-Cog). We assessed predictors of long-term BDZR use and analyzed the effect of ongoing BDZR use on ADAS-Cog scores at 18 months. Additionally, the impact of BDZR use on adverse events, incident delirium, and falls over 18-month follow-up was assessed adjusting for relevant covariates. Setting and Participants 448 participants with mild to moderate AD recruited from 23 academic centers in 9 European countries. Results Overall, 14% (62/448) were prescribed an ongoing BDZR for the study duration. Increasing total number of (non-BDZR) medications was associated with a greater likelihood of BDZR prescription (odds ratio 1.16, 95% confidence interval 1.05-1.29). At 18 months, BDZR use was not associated with greater cognitive decline on the ADAS-Cog controlling for baseline ADAS-Cog scores, age, gender, study arm, and other clinical covariates (β = 1.62, −1.34 to 4.56). However, ongoing BDZR use was associated with a greater likelihood of adverse events [incidence rate ratio (IRR) 1.19, 1.05-1.34], incident delirium (IRR 2.31, 1.45-3.68), and falls (IRR 1.66, 1.02-2.65) over 18 months that persisted after robust adjustment for covariates. Conclusions and Implications This study found no effect of ongoing BDZR use on ADAS-Cog scores in those with mild to moderate AD over 18 months. However, ongoing use of these medications was associated with an increased risk of adverse events, delirium, and falls. Thus, BDZR use should be avoided where possible and deprescribing interventions should be encouraged in older adults with AD.
2019 · The Journal of Prevention of Alzheimer's Disease
As research evolves in prodromal AD, the need to validate sufficiently sensitive outcome measures, e.g. the Alzheimer's Disease Composite Score (ADCOMS) is clear. In the LipiDiDiet randomized trial in prodromal AD, cognitive decline in the study population was much less than expected in the timeframe studied. While the primary composite endpoint was insufficiently sensitive to detect a difference in the modified intention to treat population, the per-protocol population showed less decline in the active than the control group, indicating better treatment effects with regular product intake. These results were further strengthened by significant benefits on secondary endpoints of cognition and function, and brain atrophy. The present post-hoc analysis investigated whether ADCOMS could detect a difference between groups in the LipiDiDiet population (138 active, 140 control). The estimated mean change in ADCOMS from baseline (standard error) was 0.085 (0.018) in the active and 0.133 (0.018) in the control group; estimated mean treatment difference −0.048 (95% confidence intervals −0.090, −0.007; p=0.023), or 36% less decline in the active group. This suggests ADCOMS identified the cognitive and functional benefits observed previously, confirming the sensitivity of this composite measure.
2019 · Alzheimer's & Dementia
Background: Amylyx has developed a novel therapeutic, AMX0035, for the treatment of neurodegenerative disease. AMX0035 is a proprietary combination of two small molecule compounds, Sodium Phenylbutyrate (PB) and Tauroursodeoxycholic Acid (TUDCA), de-signed to promote neuronal viability through simultaneous inhibition of ER stress and mitochondrial stress. PB and TUDCA have been evaluated separately in in vitro and in vivo models of Alzheimer’s disease (AD), and clinical trials in amyotrophic lateral sclerosis, Parkinson’s disease and Huntington’s disease. Amylyx discovered a synergy between these two compounds when administered together in a particular range of ratios across multiple preclinical models. Recruitment for the clinical trial began in late 2018. Methods: The study will evaluate safety, tolerability, and biomarkers of molecular target engagement, AD pathology, neurodegeneration and neurophysiology that indicate AMX0035 target engagement and neurobiological effects over 24 weeks. This will be a 6-month, parallel-group, randomized, double-blind, placebo-controlled study of people with late mild cognitive impairment (MCI) or early to moderate dementia due to AD. Participants in the active treatment arm will receive 3g of PB and 1g TUDCA administered orally twice daily. Results: Participants will be evaluated at Poster Presentations: Wednesday, July 17, 2019P1282baseline and at week 24 with multi-sequence structural and functional MRI to assess changes in regional brain volumes (T1), cerebral perfusion (ASL), functional connectivity (BOLD) and cerebrovascular pathology (FLAIR, SWI). Lumbar punctures will be performed at baseline and 24 weeks for selected CSF biomarkers including: amyloid-b1-42, tau, neurofilament light chain (NfL), and markers of mitochondrial redox, HDAC activity, neuronal injury, and neuroinflammation. Patients will be evaluated at weeks 1, 6,12, 18, and 24 for safety, tolerability, and changes in symptoms, as measured with the ADAS-Cog 13, ADCS-ADL, and NPI. Conclusions: This early phase trial is designed to evince target engagement, neurobiological effects, safety and tolerability of AMX0035with multiple objective endpoints including, standard clinical assessments and both established and novel biomarkers associated with neurocognitive impairment. Data will help determine whether to advance AMX0035 to a larger study to establish efficacy and safety and inform choices in study design, patient characteristics and outcome measures.
2019 · Neurology
Objective: To assess the effect of memantine (MEM) and a cholinesterase inhibitor (ChEI) vs ChEI alone on four syndrome domains of the Neuropsychiatric Inventory (NPI). Background: Neuropsychiatric symptoms negatively impact daily function and quality of life, hasten time to institutionalization, and increase overall healthcare costs. MEM significantly improved multiple domain scores of the NPI in patients with Alzheimer’s disease (AD) compared with placebo (PBO). Design/Methods: Data were pooled for participants with moderate to severe AD (baseline MMSE<20) from three, phase 3, randomized, double-blind, PBO-controlled 24-week trials (Tariot et al. JAMA, 2004; Porsteinsson et al. Alzheimer Research, 2008; Grossberg et al. CNS Drugs, 2013). The NPI has 12 items that were grouped into four syndrome domains: psychosis (agitation/aggression, hallucinations, delusions, irritability/lability), neurovegetative (aberrant motor behavior, nighttime behavior, appetite/eating change), frontal (disinhibition, euphoria/elation), and mood (anxiety, depression/dysphoria, apathy), based on previous analyses (Frisoni et al. Dement Geriatr Cogn Disord, 10:130–138, 1999). MEM/ChEI- and PBO/ChEI-treated participants were compared using an ANCOVA model estimating change from baseline at each time point. Results: Of 1262 patients, 637 were treated with MEM/ChEIs and 625 with PBO/ChEIs (age [mean±SD]: 75.7±8.3 years; baseline MMSE: 11.5±3.5; baseline NPI total score: 14.9±14.6). For all syndrome domains, mean treatment differences favored MEM/ChEIs over PBO/ChEIs. For psychosis symptoms, MEM/ChEI-treated patients improved significantly compared with PBO/ChEI-treated patients at 12 (LSMD −1.167, P<0.0001) and 24 (LSMD −1.238, P<0.0001) weeks. Similarly, neurovegetative scores were significantly improved for MEM/ChEI vs PBO/ChEI-treated patients at 12 (LSMD −0.621, P=0.0103) and 24 (LSMD −0.583, P=0.0441) weeks. For frontal and mood symptoms, no significant LSMDs were observed at 12 or 24 weeks. No analyses showed PBO/ChEI to be superior to MEM/ChEI. Conclusions: In patients with moderate to severe AD taking ChEIs, treatment with the combination of memantine and a ChEI was associated with significant benefit for psychosis and neurovegetative behavioral syndromes compared with ChEI alone.
2019 · Neurology
Objective: To assess maintenance of response on the Severe Impairment Battery (SIB) in participants treated with memantine (MEM) in combination with a cholinesterase inhibitor (ChEI) vs placebo (PBO) with ChEI. Background: Rigorous phase 3 studies have demonstrated the efficacy of memantine (MEM) on cognitive and behavioral symptoms of Alzheimer’s disease (AD) when added to ongoing ChEI treatment. Design/Methods: Data were pooled from two phase 3, randomized, double-blind, PBO-controlled 24-week trials (Tariot et al. JAMA, 2004; Grossberg et al. CNS Drugs, 2013) evaluating MEM for patients with moderate to severe AD (baseline MMSE score<20) receiving stable ongoing ChEI treatment. SIB scores were categorized by level of improvement (≥0-, ≥5-, ≥10-point improvement from baseline) at each timepoint (weeks 4, 8, 12, 18) and were considered maintained if the patient remained in the same improvement category at all following tests through endpoint (week 24). The percentages of patients who maintained response were compared between MEM/ChEI and PBO/ChEI. Results: A significantly greater proportion of MEM/ChEI-treated patients maintained ≥5-point improvements vs PBO/ChEI from weeks 4 to 24 (P=0.0182). From weeks 8 to 24 and 12 to 24, a significantly greater proportion of MEM/ChEItreated patients maintained ≥5- and ≥10-point improvements compared with PBO/ChEI-treated patients (Pvalues< 0.01). From week 18 to 24, a significantly higher proportion of patients treated with MEM/ChEI vs PBO/ChEI maintained score improvements of ≥0 (P=0.0478), ≥5 (P=0.0137), and ≥10 (P=0.0003) points. Conclusions: The combination of MEM with a ChEI resulted in greater percentages of patients who achieved and maintained cognitive improvements over 24 weeks vs PBO/ChEI. This treatment response was particularly pronounced among patients who experienced a 5-point or greater improvement on the SIB. Treatment effects continued to emerge at week 18 and were maintained through week 24, further demonstrating SIB sensitivity and the benefit of MEM when added to ongoing ChEI treatment.
2019 · Alzheimer's & Dementia
2019 · Handbook of Behavioral Neuroscience
A challenge to the endeavor of assessing cognition in patients with Alzheimer's disease (AD) is the lack of reliability, validity, and responsiveness of the tests that have been traditionally employed. A further consideration is the lack of continuity between tests preferred for use in memory clinics and other specialist centers as compared with those selected for use in clinical drug trials of putative new therapies for AD. In contrast to the lack of continuity in AD, in other indications, such as major depressive disorder (MDD), similar paradigms, though different tests, have been employed to detect cognitive deficits, to measure cognitive change and, more recently, to identify cognitive markers that might indicate risk factors for disease onset. In this chapter, we contrast the assessment of cognition in AD and MDD, especially in the context of identifying cognitive deficits and the measurement of efficacy.
2019 · Alzheimer's & Dementia: Translational Research & Clinical Interventions
2019 · Journal of the American Heart Association
2019 · The Journal of Prevention of Alzheimer's Disease
There is an urgent need to develop reliable and sensitive blood-based biomarkers of Alzheimer's disease (AD) that can be used for screening and to increase the efficiency of clinical trials. The European Union-North American Clinical Trials in Alzheimer's Disease Task Force (EU/US CTAD Task Force) discussed the current status of blood-based AD biomarker development at its 2018 annual meeting in Barcelona, Spain. Recent improvements in technologies to assess plasma levels of amyloid beta indicate that a single sample of blood could provide an accurate estimate of brain amyloid positivity. Plasma neurofilament light protein appears to provide a good marker of neurodegeneration, although not specific for AD. Plasma tau shows some promising results but weak or no correlation with CSF tau levels, which may reflect rapid clearance of tau in the bloodstream. Blood samples analyzed using -omics and other approaches are also in development and may provide important insight into disease mechanisms as well as biomarker profiles for disease prediction. To advance these technologies, international multidisciplinary, multi-stakeholder collaboration is essential.
2019 · Neurology
Objective: To evaluate the effect of the combination of memantine (MEM) with a cholinesterase inhibitor (ChEI) vs placebo (PBO) with ChEI on total Severe Impairment Battery (SIB) and three higher-order cognitive domains (memory, language, and praxis). Background: The SIB is used to assess cognitive changes in patients with Alzheimer’s disease (AD), allowing for reliable, valid, and sensitive detection of treatment effects when floor effects may be present on other cognitive tests. MEM results in significant improvements on the SIB compared with PBO in moderate to severe AD patients treated concurrently with a ChEI. Design/Methods: Data were pooled from two phase 3, randomized, double-blind, PBO-controlled 24-week trials (Tariot et al. JAMA, 2004; Grossberg et al. CNS Drugs, 2013) in patients with moderate to severe AD (baseline MMSE score<20). The SIB was administered at baseline and weeks 4, 8, 12, 18, and 24. Based on Schmitt et al. Alzheimer Dis Assoc Disord, 2006, SIB domains were aggregated to create higher-order subscales of memory (memory, attention, orientation, orienting to name), language (language, social interaction), and praxis (praxis, visuospatial ability, construction). Results: Compared with PBO/ChEI, MEM/ChEI significantly improved total SIB scores at weeks 8, 12, 18, and 24 (all, P<0.05). An analysis of higher-order domains demonstrated that MEM/ChEI treatment conferred significant effects on memory and language vs PBO/ChEI at weeks 12, 18, and 24 (all, P<0.05). On the higher-order domain of praxis, MEM/ChEI showed significant effects vs PBO/ChEI at all timepoints (weeks 4, 8, 12, 18, and 24, all P<0.05). Conclusions: The combination of MEM with a ChEI produced early and consistent improvements in cognition for patients with moderate to severe AD. Analysis of higher-order domains on the SIB further supported the efficacy of MEM in maintaining key cognitive functions (memory, language, and praxis), even when these patients are receiving the standard of ongoing ChEI treatment.
2019 · Neurology
Objective: This clinical trial investigated the effects of a precision medicine intervention on cognition in asymptomatic and mildly symptomatic patients. Background: Multidomain approaches to treating modifiable risk factors in Alzheimer’s disease (AD) have shown cognitive benefits for patients at-risk for dementia. Design/Methods: Patients aged 25–86 were recruited from an Alzheimer’s prevention clinic and categorized into two groups. The prevention group (group 1) included normal cognition, subjective cognitive decline, and preclinical AD patients. The early treatment group (group 2) included predominantly MCI due to AD as well as mild AD dementia patients. Primary outcome was change in performance on a cognitive composite (m-APCC) measuring AD pathology in higher- versus lower-compliance participants at 18 months in groups 1 and 2. We also compared groups versus matched historical controls from NACC/Rush University. Secondary outcome was change in performance on a non-pathological cognitive aging composite (CAC). Trial registered at ClinicalTrials.gov (NCT03687710). Results: Of 202 participants screened, 178 met inclusion criteria; 154 (87%) had at least one post-baseline assessment and were included in analyses. Group 1 improved on the m-APCC by 0.426 at 18-months (p<0.0001). Similar effects were seen for higher and lower compliance groups (p=0.1467). Group 1 higher-compliance participants improved more than NACC (p=0.0039) and Rush controls (p=0.0133). Group 1 lower compliance participants also improved more than NACC (p=0.0105) and Rush (p=0.0259) controls. In group 2, higher compliance participants improved relative to lower compliance participants (p<0.0001) and NACC (p=0.0069), but not compared to Rush (p=0.3953). For group 1, the CAC improved by 2.67 years for higher-compliance participants and 3.52 years for lower-compliance participants (p=0.4039). Group 2 improved by 2.95 years in the CAC for higher-compliance participants and worsened by 5.06 years for lower-compliance participants (p=0.0004). Conclusions: Findings suggest a precision medicine multidomain intervention can improve cognitive function. Intervening earlier in the pre-AD dementia diagnostic spectrum led to greater improvements.
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.
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