Statistical properties of continuous composite scales and implications for drug development

Liu‐Seifert, Hong; Andersen, Scott W.; Case, Michael; Sparks, JonDavid; Holdridge, Karen C.; Wessels, Alette M.; Hendrix, Suzanne; Aisen, Paul S.; Siemers, Eric

doi:10.1080/10543406.2017.1315819

Cited by 20 publications

(33 citation statements)

References 27 publications

(24 reference statements)

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“…Together, findings from this clinical study and CSF biomarker analyses suggest a differential response to nilvadipine treatment in AD related to the severity of the disease at treatment initiation. These findings are also consistent with the results of several other experimental AD treatments where only very early stage AD subjects demonstrated benefit, such as Solanezumab (7,10,30), aducanumab (8), and LipiDiDiet trials (9). Consequently, the Alzheimer's therapeutic field is increasingly targeting the early stages of AD (43).…”

Section: Resultssupporting

confidence: 84%

“…Many clinical trials in combined populations of mild and moderate AD patients have failed to show overall cognitive benefits. Frequently, the same drugs that have failed in combined mild and moderate populations have suggested cognitive benefits for subjects in mild AD (7)(8)(9)(10)30), when the extent of amyloid and tau pathologies are considerably lower than in moderate AD (31)(32)(33). Exploratory analyses of the NILVAD dataset presented here show similar findings where a lower rate of cognitive decline was only seen in the very mild AD group.…”

Section: Discussionsupporting

confidence: 69%

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The Influence of Baseline Alzheimer's Disease Severity on Cognitive Decline and CSF Biomarkers in the NILVAD Trial

et al. 2020

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Section: Resultssupporting

confidence: 84%

Section: Discussionsupporting

confidence: 69%

The Influence of Baseline Alzheimer's Disease Severity on Cognitive Decline and CSF Biomarkers in the NILVAD Trial

et al. 2020

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“…Together, findings from the clinical studies and CSF biomarker analyses suggest a differential response to nilvadipine treatment in AD based on the severity of the disease at treatment initiation. These findings are also consistent with the results of several other experimental AD treatments where only very early stage AD subjects demonstrated benefit, such as Solanezumab (7,10,30), aducanumab (8) and LipiDiDiet trials (9). Consequently, the Alzheimer's therapeutic field is increasingly targeting the early stages of AD (49).…”

Section: Discussionsupporting

confidence: 84%

Exploratory analyses suggest less cognitive decline with nilvadipine treatment in very mild Alzheimer’s disease subjects

Abdullah

Crawford

Langlois

et al. 2018

Preprint

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Background: We explored whether the effects of nilvadipine on cognition were influenced by baseline Alzheimer's disease (AD) severity. Methods: Exploratory analyses were performed on the modified intentionto-treat (mITT) dataset (n = 497) of a phase III randomized placebo-controlled trial to examine the response to nilvadipine in very mild, mild and moderate AD subjects. The outcome measures included total and subscale scores of the Alzheimer's Disease Assessment Scale Cognitive 12 (ADAS-Cog 12), the Clinical Dementia Rating Scale sum of boxes (CDR-sb) and the AD composite score (ADCOMS), an outcome measure recently developed to detect treatment responses in subjects with prodromal AD. Cerebrospinal fluid (CSF) biomarkers Aβ38, Aβ40, Aβ42, total tau and P181 tau were measured in a subset of samples (n = 55). Regression analyses were adjusted for potential confounders and effect modifiers in order to examine the interactive effects of nilvadipine and AD severity on cognitive outcomes over 78-weeks. Results: Compared to their respective placebo-controls, nilvadipine-treated, very mild AD subjects showed less decline, whereas moderate AD subjects showed greater decline on the ADAS-Cog 12. Also in very mild AD, a beneficial effect (as measured by ADCOMS), was detected in the nilvadipine treated group. Therapeutic effects of nilvadipine were also observed for a composite memory trait in very mild AD subjects and a composite language trait in mild AD subjects. CSF Aβ42/Aβ40 ratios were increased in mild AD and decreased in moderate AD patients treated with nilvadipine, compared to their respective controls. Conclusion: These data suggest that very mild AD subjects benefited from nilvadipine and that future clinical trials of nilvadipine in this population are required to confirm these findings.keywords: mild Alzheimer's disease, nilvadipine, exploratory analysis, cognitive decline, cerebrospinal fluid Aβ42/Aβ40 ratios Introduction:Alzheimer's disease (AD) is the most common neurodegenerative disease, affecting nearly 5.3 million US citizens. By 2050, the prevalence of AD is expected to reach 13 million in the US alone and 100 million worldwide. The presence of amyloid plaques and neurofibrillary tangles in the brain are key hallmarks of AD (1-3) and are also accompanied by cerebrovascular disease, α-synuclein and TDP-43 deposits and inflammation (4-6). Recent clinical trials have shown that moderate AD patients, with established brain amyloid and tau pathologies, are unresponsive to anti-amyloid therapeutic approaches, although some trials have shown potential benefits in mild and early stage AD patients (7-11). As such, early and mild AD patient populations may be more appropriate for anti-amyloid and anti-tau approaches.Findings of the Systolic Hypertension in Europe (SYST-EUR) trial of 2400 participants showed that intervention with nitrendipine, a dihydropyridine (DHP) calcium channel blocker (CCB) similar in structure to nilvadipine, resulted in a reduction of AD incidence (12). A small clinical trial of nilvadipi...

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“…Recent investigations showed correlations of about .3 to .6 between cognitive and functional abilities at 80 weeks . Accordingly, we fixed the correlation ρ 12 at .5, which is within the aforementioned range.…”

Section: Methodsmentioning

confidence: 98%

Sequential parallel comparison design with two coprimary endpoints

Homma

Daimon

2019

Pharmaceutical Statistics

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A placebo-controlled randomized clinical trial is required to demonstrate that an experimental treatment is superior to its corresponding placebo on multiple coprimary endpoints. This is particularly true in the field of neurology. In fact, clinical trials for neurological disorders need to show the superiority of an experimental treatment over a placebo in two coprimary endpoints. Unfortunately, these trials often fail to detect a true treatment effect for the experimental treatment versus the placebo owing to an unexpectedly high placebo response rate. Sequential parallel comparison design (SPCD) can be used to address this problem. However, the SPCD has not yet been discussed in relation to clinical trials with coprimary endpoints. In this article, our aim was to develop a hypothesis-testing method and a method for calculating the corresponding sample size for the SPCD with two coprimary endpoints. In a simulation, we show that the proposed hypothesis-testing method achieves the nominal type I error rate and power and that the proposed sample size calculation method has adequate power accuracy. In addition, the usefulness of our methods is confirmed by returning to an SPCD trial with a single primary endpoint of Alzheimer disease-related agitation. KEYWORDSbivariate normally distributed endpoint, enrichment design, intersection-union test, placebo nonresponder, placebo responder Pharmaceutical Statistics. 2019;1-12. wileyonlinelibrary.com/journal/pst

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Statistical properties of continuous composite scales and implications for drug development

Cited by 20 publications

References 27 publications

The Influence of Baseline Alzheimer's Disease Severity on Cognitive Decline and CSF Biomarkers in the NILVAD Trial

The Influence of Baseline Alzheimer's Disease Severity on Cognitive Decline and CSF Biomarkers in the NILVAD Trial

Exploratory analyses suggest less cognitive decline with nilvadipine treatment in very mild Alzheimer’s disease subjects

Sequential parallel comparison design with two coprimary endpoints

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