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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.
11 publications
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2020 · Alzheimer's & Dementia
Dickson, Samuel · Knowlton, Newman · Hendrix, Suzanne
Background: Alzheimer’s disease (AD) is a multi-symptom disease which has cognitive, behavioral, functional and global outcomes. These outcomes are all important measures of disease severity and are driven by the underlying disease process. These symptoms provide multiple, potentially conflicting, answers to the question, “Did the treatment work?” Method: Outcomes can be combined through standardization of outcomes using ranks or z-scores. Additionally, the standardization can be performed before calculating change from baseline or after. These four combinations are explored by simulations with no effect, corroborative effects across outcomes, and disparate effects across outcomes (a mix of positive and null effects) to demonstrate the type I error (no effect) and power under various secenarios along with other performance metrics. Result: All four methods of calculating a GST adequately control type I error. In the absence of ceiling and floor effects, the GST that calculates change from baseline first then combines evidence using z-scores has the highest power. In the presence of disparate effects, the GST can still be more powerful than any single outcome, though the effect is appropriately attenuated. The GSTs that use ranking outperform z-score methods in the presence of strong floor or ceiling effects. Conclusion: A clinical trial with a GST analyzed first can show success as a proof of concept even if the individual outcomes fail to achieve significance, signalling that a development can proceed to later phases. Change from baseline should be calculated first. If there are no ceiling or floor effects, standardization should be performed using z-scores, otherwise percentiles should be used. GSTs offer a good way to combine outcomes to demonstrate efficacy using fewer subjects.
2020 · Alzheimer's & Dementia
Knowlton, Newman · Hendrix, Suzanne
Background: The Sapphire II platform is a clinical diagnostic device intended for aiding clinical evaluation and measurement of beta-amyloid aggregation in anatomically defined regions of the anterior segment of the eye. It detects a specific fluorescent signature emission of ligand-marked beta amyloid complex in the supranuclear region of the human lens. The current study results are Sapphire II scan to be used to classify patients as normal, MCI and mild Alzheimer’s disease and the utility of Sapphire II screening compared to b-amyloid PET scans in MCI and Mild AD subjects. Method: A naïve Bayes classifier using a base model with the three most theoretically relevant parameters (τ1, τ2, φ). Sensitivity and specificity is assessed comparing the normal group to the collective MCI/Mild AD group. 48 participants; 28 MCI, 16 Mild AD patients and 4 Normal Control subjects were studied. Results: The Sapphire II naïve Bayes classifier with cross validation had sensitivity of 96%, specificity of 75%, and overall accuracy of 92%. Results based on 4 healthy controls only, with one of the control subjects tested positive in Sapphire II; additional testing on 10 healthy controls is in progress. Conclusion: Sapphire II offers a non-invasive, safe, easy to use, community based inexpensive method for accurately classifying individuals as normal, MCI or mild AD dementia on the basis of the beta amyloid in the lens of the eye. Sapphire II may offer a practical alternative to PET amyloid scans for biomarker confirmed AD diagnosis. Evaluation of individual PET scans and cognitive testing suggests that Sapphire II is more sensitive than PET.
2020 · Alzheimer's & Dementia
Background The AMBAR study enrolled 496 mild-to-moderate Alzheimer’s disease (AD) patients from Spain and US centers, 347 of which were randomized [1:1:1:1] to three treatment arms of plasma exchange (PE) with different doses of albumin with or without intravenous immunoglobulin (IVIG) or placebo (sham PE) arm. PE treatment showed slow cognitive and functional decline in AD patients, with variable significance in outcome (primary: ADCS-ADL, ADAS-Cog; secondary: CDR-Sb, ADCS-CGIC), baseline disease severity, and treatment arm (low-albumin; low-albumin+IVIG, high-albumin+IVIG, and all three combined). The percentage of patient dropouts ranged from 20% in the placebo to 34.9% in the low-albumin+IVIG group. In this analysis we investigated the effect of possible biases due to discontinuations and baseline imbalances, and assessed the consistency across outcomes. Method The impact of discontinuations was determined by least squares mean estimates from the Mixed Model for Repeated Measures (MMRM) analysis using the z-score carried forward analysis (zLOCF). The overall impact of the treatment on the disease was determined by a global statistical test which combined with equal weighting three outcomes (ADCS-ADL, ADAS-Cog, CDR-Sb) into a single outcome. An analysis of relevant outcomes was performed adjusting for key baseline characteristics. Result Analysis of discontinuations suggested that the treatment differences and effect sizes estimated using the primary model MMRM are likely to be conservative and that lowering dropouts is likely to increase effect sizes. Effect sizes were consistent across outcomes (between 51% and 76%). The GST score showed slowing of progression at month 14 with statistically significant differences between all active treatments and placebo from month 9 onward. When the model was adjusted for key baseline characteristics, the analysis showed statistically significant differences against placebo of all treatment groups in most of the relevant outcomes. Conclusion Results of this analysis disprove the possible bias of dropout effect in the AMBAR trial. Effect sizes were consistent across outcomes and the Global Statistical Test showed an overall impact of the treatment on the disease. The analysis corrected for baseline factors supports and reinforces the findings that the PE-treated arms were superior to the placebo group.
2020 · 2020 Alzheimer's Association International Conference
Background: Diet and nutrition are important modifiable risk factors for Alzheimer’s disease (AD). For the last two decades, the LipiDiDiet consortium has been investigating the role of nutrients and their synergistic action on key AD pathological features. Based on preclinical results, 11 nutrients were selected which, when applied in this specific combination, gave the best results in rodent AD models: i.e. the omega-3 fatty acids DHA and EPA, phospholipids, vitamins B6, B12, folic acid, C and E, choline, selenium, and UMP. The LipiDiDiet trial1 is a 6-year, double-blind, parallel-group, multi-centre, randomised controlled clinical trial, designed to investigate effects of the specific multinutrient combination Fortasyn Connect on cognition and related measures in prodromal AD. Initial 24 month results showed significant benefit on clinical dementia rating-sum of boxes (CDR-SB) and hippocampal and ventricular volumes in the modified intention-to-treat population. Here we report previously specified primary and secondary outcomes over 36 months of intervention. Method: Prodromal AD participants (n=311) were randomised to receive either active product (125 mL drink containing Fortasyn Connect) or a calorie-matched placebo control once daily. Result: 162 participants completed the 36-month period. With increasing treatment duration, the benefit of the active group over the control group exceeded what had been observed for the first 24 months (Soininen et al., Lancet Neurology 2017). For the 5-item neuropsychological test battery (NTB) on cognition, a significant between-group difference was observed in estimated mean change from baseline over 36 months favouring active intervention (0.212 [95% CI 0.044 to 0.380]; p=0.014; 60% reduction in decline). In addition, significant benefits were found on CDR-SB, NTB memory, and hippocampal, ventricular, and whole brain volumes on MRI. Self-reported compliance to the study product was high and there was no indication of safety concern. Conclusion: We observed significantly slower decline in cognition including memory, CDR-SB measuring cognition and function, and brain structural measures. Importantly, prolonged intervention with this specific combination of nutrients resulted in a broader range of endpoints showing statistically significant differences. Sustainable benefits lasting for 3 or more years have not been reported before in prodromal AD.
2020 · New England Journal of Medicine
2020 · International Journal of Geriatric Psychiatry
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