11 research outputs found
Analytic Challenges in Clinical Trials of Early Alzheimer’s Disease
No full textBackground: The heavily right-skewed data seen in recently reported Alzheimer’s disease (AD) clinical trials influenced treatment contrasts when data were analyzed via the typical mixed-effects model for repeated measures (MMRM). Methods: An MMRM analysis similar to what is commonly used in AD clinical trials was compared versus robust regression (RR) and the non-parametric Hodges–Lehman estimator (HL). Results: Results in simulated data patterned after AD trials showed that imbalance across treatment arms in the number of patients in the extreme right tail (those with rapid disease progression) frequently occurred. Each analysis method controlled Type I error at or below the nominal level. The RR analysis yielded smaller standard errors and more power than MMRM and HL. In data sets with appreciable imbalance in the number of rapid progressing patients, MMRM results favored the treatment arm with fewer rapid progressors. Results from HL showed the same trend but to a lesser degree. Robust regression yielded similar results regardless of the ratio of rapid progressors. Conclusions: Although more research is needed over a wider range of scenarios, it should not be assumed that MMRM is the optimal approach for trials in early Alzheimer’s disease
A randomized, double-blind, placebo-controlled study of escitalopram in patients with social anxiety disorder in Japan
No full textObjective: This randomised, double-blind placebo-controlled study compared the efficacy and tolerability of escitalopram (10 and 20mg/day) in Japanese patients with social anxiety disorder (SAD). Research design and methods: Patients aged 18-64 years with a primary diagnosis of DSM-IV-TR defined SAD, a Liebowitz Social Anxiety Scale Japanese version (LSAS-J) total score ≥60 and a Clinical Global Impression-Severity (CGI-S) score ≥4 at baseline were randomly assigned (1:1:1) to placebo, escitalopram 10mg or 20mg. The primary endpoint was change from baseline to Week 12 in the LSAS-J total score for both escitalopram 10mg and 20mg versus placebo (ANCOVA, FAS, LOCF), using a hierarchical testing procedure. Pre-specified secondary endpoints included LSAS-J sensitivity analyses. Clinical trial registration: This study has the www.japic.or.jp identifier: JapicCTI-121842. Results: For the primary efficacy endpoint, the difference from placebo in the LSAS-J was -3.9 (p=0.089) for escitalopram 10mg. Since the superiority of escitalopram 10mg over placebo was not confirmed, an analysis without multiplicity adjustment was made, which showed a difference for escitalopram 20mg versus placebo of -9.8 (p<0.001). In pre-specified sensitivity analyses, the difference versus placebo was -4.9 (p=0.035) (ANCOVA, FAS, OC) and -5.0 (p=0.028) (MMRM, FAS) (escitalopram 10mg) and -10.1 (p<0.001) (ANCOVA, FAS, OC) and -10.6 (p<0.001) (MMRM, FAS) (escitalopram 20mg). Common adverse events (incidence ≥5% and significantly different from placebo) were somnolence, nausea and ejaculation disorder. Conclusion: Escitalopram was efficacious, safe and well tolerated by patients with SAD in Japan. Study limitations are discussed including patient characteristics
Avoiding future controversies in the Alzheimer’s disease space through understanding the aducanumab data and FDA review
No full textAbstract Key points of disagreement between the aducanumab FDA statistical review, which had primarily negative conclusions, and the clinical review, which had primarily positive conclusions, were investigated. Results from secondary endpoints in positive Study 302 were significant and these endpoints provided meaningful additional information. Findings indicate the statistical review of the aducanumab data was incorrect in a number of key areas. Greater placebo decline was not responsible for the significant results in Study 302. Correlations did exist between reduction in β-amyloid and clinical outcomes. Missing data and functional unblinding did not likely bias results. In contrast, the clinical review went too far in saying the negative results in Study 301 did not detract from the positive results in Study 302, as all clinical data should be considered in the evaluation, and the clinical review accepted the company’s explanation for divergence of the results between the studies although much of the divergence remained unexplained. Interestingly, both the statistical review and the clinical review considered the available efficacy evidence despite both studies being terminated early. Implications of these findings include that the divergence in results seen in the two phase 3 aducanumab studies can be expected in other studies with similar design and analysis. Therefore, further research is needed to determine if analysis methods other than MMRM and/or optimized outcomes will provide more consistent results across studies
Decay model for handling missing data due to intercurrent events in clinical trials
No full textUS Food and Drug Association (FDA) presented a draft guidance of E9(R1) Statistical Principles for Clinical Trials Addendum: Estimands and Sensitivity Analysis in Clinical Trials in June 2017. This draft guidance has been widely referenced during recent research discussions. The aim of the draft guidance was to clarify the concept of estimand and to connect estimand with the concept of trial objective. An emphasized discussion about the impact and handling methods of missing data was also addressed. The draft guidance introduced the concept of ‘intercurrent event’ to describe all events that would cause either potential missing data or discontinuation from initial randomized treatment assignment. Five intercurrent event handling strategies were proposed with each strategy targeting a specific estimand which eventually represents a trial objective. Some of these strategies would result in missing data problem that required additional assumptions regarding the missing mechanism. In this dissertation, I will propose an alternative procedure in terms of connecting the intercurrent event handling strategy with estimand specification. The proposed procedure can be considered as an event-type driven strategy that selects the desirable estimand based on not only primary trial objective but also potential intercurrent event types. In this dissertation, I will also discuss the importance of sensitivity analysis and the relationship between sensitivity analysis missing mechanism assumptions and primary analysis missing mechanism assumptions. Literature review will be focused on recent developments on the topic of sensitivity analysis methods, especially the reference based imputation (RBI) method and the δ-adjustment tipping point analysis method. The benefits and drawbacks of both methods will be discussed in detail. This dissertation will contain a proposal of a modified Mixed Model Repeated Measure (MMRM) model that targets the ‘De Facto’ estimand when rescue medication is offered in a randomized clinical trial. Primary estimator can be represented as a linear combination of this modified MMRM model parameters. Delta approximation method will be used to directly derive the inference of the estimator. The result and performance will be compared with the result using multiple imputation method. Secondly, I will propose an alternative sensitivity analysis method called ‘decay model tipping point analysis method’. The highlights of this method are as follows, 1) It is capable of covering all possible sensitivity scenarios, including but not limited to the ones studied using RBI method. 2) The adjusted missing data effect is associated with dropout time. Patients who dropped out early will be adjusted with a greater value comparing to those who dropped out later. The adjustment decreases for time points that are further away from the patient dropout time point. This is a more reasonable approach comparing to δ-adjustment tipping point method which adjusts the effect at each time point with a same constant. 3) The range of the adjustment can be set within the a clinical meaningful boundary. This will avoid the over-adjustment problem in δ-adjustment tipping point method. 4) The decay rate parameter serves as a unified sensitivity parameter. It can be compared between different studies as a measurement of robustness of primary analysis result in terms of the missing mechanism assumption. 5) The tipping point can be solved directly without iterative searching the total domain sensitivity parameter, therefore saving computing resource and power. Simulation studies will be conducted to verify the modified MMRM model. Inference derived based on delta approximation method will be verified using empirical inference result from simulation. A simulated study will be presented to verify the direct calculation for the tipping point and demonstrate the features of decay model tipping point method. In addition, a case study of using the decay model sensitivity analysis in a real world rare blood disease trial study will be presented. The possibility of extending the decay model beyond continuous endpoint will be briefly discussed and some technical issues occurred in the current research will be included in future research plan.Ph.D.Includes bibliographical referencesby Tao Shen
Treatment with fenfluramine in patients with Dravet syndrome has no long-term effects on weight and growth
No full textAbstract: Objective: Appetite disturbance and growth abnormalities are commonly reported in children with Dravet syndrome (DS). Fenfluramine (Fintepla) has demonstrated profound reduction in convulsive seizure frequency in DS and was recently approved for use in DS in the US and EU. Prior to its use in epilepsy, fenfluramine was approved to suppress appetite in obese adults. Here, we evaluated the impact of fenfluramine on weight and growth in patients with DS treated for >12 months or >24 months and compared the results with growth curves in normative reference populations and published historical controls among patients with DS. Methods: Historical control data from a recent study of 68 patients with DS show decreases in height and weight Z-scores of -0.1 standard deviation (SD) for every 12-month increase in age (Eschbach K. Seizure. 2017;52:117-22). Anthropometric data for fenfluramine were extracted from an open-label extension (OLE) study of eligible patients with DS (2-18 y/o; fenfluramine dose: 0.2-0.7 mg/kg/day). Z-score analyses were based on the Boston Children's Hospital algorithm and assessed potential impact of fenfluramine on growth at OLE baseline, at Month 12, and at Month 24. A mixed-effect model for repeated measures (MMRM) estimated changes in height and weight over time. Height and weight Z-scores were also analyzed by dose group (0.2-12 months; 128 were treated for >24 months. Relative to the reference population with DS, fenfluramine treatment for >12 months or for >24 months had minimal impact on height or weight over time as assessed by Zscore analyses. No substantial dose-dependent changes from baseline were observed at Month 12 nor at Month 24. MMRM showed that patients treated with fenfluramine for >12 months (N = 262) had an estimated change in Z-score per year of -0.056 for height and -0.166 for weight. For patients with data from all three time points (baseline, 12 months, and 24 months; N = 110), estimated changes in Z-scores per year were -0.025 for height and -0.188 for weight. MMRM projections based on normative reference growth curves were comparable to growth data from historical control populations with DS. Significance/Conclusion: Long-term treatment with fenfluramine had minimal impact on the growth of patients with DS as demonstrated by differences in Z-scores for height and weight at 12 months and at 24 months. Changes in Z-scores for height and weight were consistent with published reports on patients with DS. (c) 2021 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
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Cumulative, additive benefits of memantine-donepezil combination over component monotherapies in moderate to severe Alzheimer’s dementia: a pooled area under the curve analysis
No full textIntroduction: Treatment in moderate or severe Alzheimer’s disease (AD) often involves adding memantine to a cholinesterase-inhibitor (ChEI: donepezil, galantamine, rivastigmine). Evidence from six-month randomized trials and long-term observational studies supports superiority of memantine-ChEI combination to ChEI monotherapy. We utilized area-under-the-curve (AUC) analysis to assess six-month cumulative treatment efficacy of memantine-donepezil combination versus component monotherapies on individual clinical domains and on a composite index. Methods: Data were pooled from 1,408 individuals with moderate to severe AD from four six-month randomized trials of memantine monotherapy (n = 570) or add-on therapy (donepezil-only subset: n = 847). AUC changes from baseline on measures of cognition (SIB), function (ADCS-ADL19), behavior (NPI), global status (CIBIC-Plus), and a composite index (4D-CI: equally weighted composite of four domain measures) were calculated using the trapezoidal rule and evaluated via analysis of covariance (ANCOVA) (2-sided-α = 0.05). AUC results were contrasted with visit-by-visit changes from baseline (“snapshot analysis”), performed using a mixed-effects model with repeated measures (MMRM). Results: Over the entire six-month period, placebo-only treatment was associated with significant cumulative worsening on all outcomes. Memantine-donepezil combination showed significantly greater AUC improvements (point x week) on the SIB, NPI, and CIBIC-Plus than placebo-donepezil (SIB: 68.4 versus 32.0, P = 0.019; NPI: −74.3 versus −28.2, P = 0.003; CIBIC-Plus: −2.5 versus 1.4, P = 0.006) and memantine-only monotherapies (SIB: 68.4 versus 12.0, P <0.001; NPI: −74.3 versus −7.4, P <0.001; CIBIC-Plus: −2.5 versus 2.7, P <0.001), whereas these comparisons were not significant for the ADCS-ADL19 (memantine-donepezil (1.4) versus placebo-donepezil (−0.9), P = 0.407; versus memantine-only (−12.2), P = 0.310). Composite index analysis demonstrated significant cumulative advantages of memantine-donepezil combination (630.0) over placebo-donepezil (344.7, P <0.001) and memantine-only (152.1, P <0.001) treatments. Combining memantine and donepezil had an additive effect. Compared with AUC analysis, baseline-to-endpoint change-score analysis underestimated effects of combination therapy, monotherapies, or both. Conclusions: This large pooled area-under-the-curve analysis of randomized-trial data in moderate to severe AD provides ecologically valid support that adding memantine to stable donepezil results in overall clinical benefits that are additive compared with individual monotherapies, continue to accumulate through six-month treatment, and are at least 50% greater than those of monotherapies.Version of Recor
Nanoscale fibrillar crystals of PET from dilute quiescent solution
No full textThe crystallization behavior of poly(ethylene terephthalate) (PET, IV 2 dL/g) from solution in biphenyl¿diphenyl ether mixed solvent is examined. Reversible gelation of the polymer solution is observed during cooling of the solutions. Light scattering and DSC analysis are used to follow the heating and cooling processes, thus determining the crystallization temperature and the melting point, which are found to be nearly independent of the polymer concentration (0.25¿5%). High degree of crystallization (>50%) is observed in the PET crystallized from the solution at 170 ¿C. Morphological characteristics of the crystals obtained after solvent removal are determined by WAXD, FTIR, SEM and TEM examination. The crystallization of PET into unique high aspect ratio fibrillar morphology during cooling of the solutions explains their gelation even at low PET concentration. Thin films made from the thus obtained PET could be drawn five times at 250 ¿C, resulting in only moderate values of modulus and strength
Mild Behavioral Impairment as a Marker of Cognitive Decline in Cognitively Normal Older Adults
No full textThis is the author accepted manuscript. the final version is available from Elsevier via the DOI in this recordObjective: Mild Behavioral Impairment (MBI) is a neurobehavioural syndrome characterized by later life emergent neuropsychiatric symptoms (NPS) which represent an at-risk state for incident cognitive decline and dementia in people with Mild Cognitive Impairment. We undertook a study to determine whether MBI was associated with progressive changes in neuropsychological performance in people without significant cognitive impairment.
Methods: 9,931 older adults enrolled in the PROTECT study who did not have MCI or dementia undertook a comprehensive neuropsychological battery measuring attention, reasoning, executive function and working memory at baseline and one year. MBI was ascertained using self-administration of the MBI-C at one year, and participants grouped according to MBI status: no symptoms, intermediate neuropsychiatric symptoms and MBI. All assessments were completed online and data analyzed using MMRM ANOVA.
Results: 949 (10%) people had MBI. These individuals had significantly worse cognitive performance at baseline and significantly greater decline over one year in the four composites cognitive scores measuring attentional intensity (F(2,8578)=3.97,p=0.019), sustained attention (F(2,8578)=18.63, p<.0001), attentional fluctuation (F(2,8578)=10.13, p=<.0001) and working memory F(2,9895)=13.1, p<.0001.
Conclusions: Our novel findings show that MBI is associated with faster decline in attention and working memory in this cognitively normal sample. MBI may be an earlier
marker of neurodegenerative disease than MCI, captured at the stage of SCD or before, raising the possibility that MBI represents a novel target for dementia clinical trials or prevention strategies.National Institute for Health Research (NIHR
Risk and protective factors for recovery at 3-year follow-up after first-episode psychosis onset: a multivariate outcome approach
No full text[Purpose] Recovery in people with first-episode psychosis (FEP) remains a major issue. When risk factors are studied in relation to the disorder, potential protective factors should also be considered since they can modulate this relationship. This study is aimed at exploring which premorbid and baseline characteristics are associated with a good and poor global recovery in patients with FEP at 3-year follow-up.[Methods] We categorized patients’ outcome by using a Latent Class Analysis (LCA) considering a multimodal set of symptomatic and functional outcomes. A Mixed effects Models Repeated Measures analysis of variance (MMRM) was used to highlight group differences over time on symptomatic and functional outcomes assessed during the 3-year follow-up.[Results] A total of 325 patients with FEP aged between 18 and 35 years were included. Two groups were identified. A total of 187 patients (57.5%) did not achieve recovery, and 138 patients (42.5%) achieved recovery. Recovered patients had generally a better premorbid and baseline profile in comparison with non-recovered patients (as among which shorter duration of untreated psychosis (DUP), higher degree of insight, better functional level and lower illness severity at baseline). The trajectories for the psychopathological and functional outcomes over 36 months differed between the non-recovered and the recovered group of patients.[Conclusions] Our results pointed to some variables associated with recovery, acting as potential protective factors. These should be considered for early intervention programs to promote psychological resilience specifically in those with a worse prognosis in order to mitigate the effects of the variables that make them more vulnerable to poorer outcome.This work was supported by the Agència de Gestió d'Ajuts Universitaris i de Recerca (AGAUR) co-financed by the European Social Fund (ESF) [predoctoral grant number 2022 FI_B2 00047, given to CSA]. Also, by the Facultat de Medicina i Ciències de la Salut of the Universitat de Barcelona (UB) through the program “Ajuts per a estades de recerca a l'estranger per a fomentar la menció de Doctor Internacional durant els curs 2022–2023” for predoctoral students of the Programa de Doctorat de Medicina i Recerca Translacional [given to the first author].Peer reviewe
The origin of high activity of amorphous MoS2 in the hydrogen evolution reaction
No full text\u3cp\u3eMolybdenum disulfide (MoS
\u3csub\u3e2\u3c/sub\u3e) and related transition metal chalcogenides can replace expensive precious metal catalysts such as Pt for the hydrogen evolution reaction (HER). The relations between the nanoscale properties and HER activity of well-controlled 2H and Li-promoted 1T phases of MoS
\u3csub\u3e2\u3c/sub\u3e, as well as an amorphous MoS
\u3csub\u3e2\u3c/sub\u3e phase, have been investigated and a detailed comparison is made on Mo−S and Mo−Mo bond analysis under operando HER conditions, which reveals a similar bond structure in 1T and amorphous MoS
\u3csub\u3e2\u3c/sub\u3e phases as a key feature in explaining their increased HER activity. Whereas the distinct bond structure in 1T phase MoS
\u3csub\u3e2\u3c/sub\u3e is caused by Li
\u3csup\u3e+\u3c/sup\u3e intercalation and disappears under harsh HER conditions, amorphous MoS
\u3csub\u3e2\u3c/sub\u3e maintains its intrinsic short Mo−Mo bond feature and, with that, its high HER activity. Quantum-chemical calculations indicate similar electronic structures of small MoS
\u3csub\u3e2\u3c/sub\u3e clusters serving as models for amorphous MoS
\u3csub\u3e2\u3c/sub\u3e and the 1T phase MoS
\u3csub\u3e2\u3c/sub\u3e, showing similar Gibbs free energies for hydrogen adsorption (ΔG
\u3csub\u3eH*\u3c/sub\u3e) and metallic character.
\u3c/p\u3
