Validation of the interview-based life-space assessment in institutionalized settings (LSA-IS) for older persons with and without cognitive impairment.

BACKGROUND: Self-reported life-space assessment methods so far focus on community-dwelling persons, with a lack of validated assessment methods for institutionalized settings. This study evaluated construct validity, test-retest reliability, sensitivity to change, and feasibility of a new Life-Space Assessment for Institutionalized Settings (LSA-IS) in geriatric patients. METHODS: Psychometric properties of the LSA-IS in 119 hospitalized geriatric patients (83.0 ± 6.2 years) with and without cognitive impairment (CI) [Mini-Mental State Examination: 22.4 ± 4.9 scores] were evaluated within a comprehensive validation design. For the total group and subgroups according to cognitive status, construct validity was assessed by calculating Spearman's rank correlation coefficients (rho) with established construct variables, test-retest reliability by intra-class correlation coefficients (ICCs), sensitivity to change by standardized response means (SRMs) calculated for effects of early ward-based rehabilitation during hospital stay. RESULTS: The LSA-IS (total score) demonstrated good test-retest reliability (ICC = .704), and large sensitivity to change (SRM = .806), while construct validity was small to high indicated by significant correlations of the LSA-IS to construct variables (rho = .208-716), depending on relative construct association. On average results of LSA-IS sub-scores confirmed results of the total score. Subgroups according to cognitive status did not differ for most analyzed variables. A completion rate of 100% and a completion time of 3.2 ± 1.2 min documented excellent feasibility. CONCLUSIONS: The interview-based LSA-IS has proven to be valid, reliable, sensitive, and feasible in hospitalized, multi-morbid, geriatric patients with and without CI documenting good psychometric properties for institutionalized settings. TRIAL REGISTRATION: DRKS00016028.

Adverse events and dropouts in Alzheimer's disease studies: what can we learn?

BACKGROUND: Interpreting Alzheimer's disease (AD) clinical trial (CT) outcomes is complicated by treatment dropouts and adverse events (AEs). In elderly participants, AE rates, dropouts, and deaths are important considerations as they may undermine the validity of clinical trials. Published discontinuation and safety data are limited. METHODS: Safety data from 1054 placebo-treated participants in IDENTITY and IDENTITY-2, 76-week, Phase 3 AD studies conducted in 31 countries, were pooled, annualized, and summarized overall, by country and age group. RESULTS: Median age was 74.2 (interquartile range 67.9-79.5) years; 57.4% were female; and median observation time was 63.2 (interquartile range 41.6-77.4) weeks when study drug dosing was halted. Overall annualized rates for discontinuations, discontinuations due to AEs, serious adverse events (SAEs), and deaths were 21.6% (range 19.6%-24.0%), 8.2% (range 8.1%-8.3%), 12.0%, and 1.7%, respectively. AE and discontinuation rates varied by country and age groups. Fall, pneumonia, and atrial fibrillation AEs were more frequent in the oldest age group. CONCLUSIONS: These annualized placebo safety data provide insight into the course of enrolled patients with mild-to-moderate AD, and are useful in planning longer term trials and in monitoring safety.

Clinical Trial Inclusion and Impact on Early Adoption of Medical Innovation in Diverse Populations.

BACKGROUND: Inadequate inclusion in clinical trial enrollment may contribute to health inequities by evaluating interventions in cohorts that do not fully represent target populations. OBJECTIVES: The aim of this study was to determine if characteristics of patients with heart failure (HF) enrolled in a pivotal trial are associated with who receives an intervention after approval. METHODS: Demographics from 2,017,107 Medicare patients hospitalized for HF were compared with those of the first 10,631 Medicare beneficiaries who received implantable pulmonary artery pressure sensors. Characteristics of the population studied in the pivotal CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients) clinical trial (n = 550) were compared with those of both groups. All demographic data were analyzed nationally and in 4 U.S. regions. RESULTS: The Medicare HF cohort included 80.9% White, 13.3% African American, 1.9% Hispanic, 1.3% Asian, and 51.5% female patients. Medicare patients <65 years of age were more likely to be African American (33%) and male (58%), whereas older patients were mostly White (84%) and female (53%). Forty-one percent of U.S. HF hospitalizations occurred in the South; demographic characteristics varied significantly across all U.S. regions. The CHAMPION trial adequately represented African Americans (23% overall, 35% <65 years of age), Hispanic Americans (2%), and Asian Americans (1%) but underrepresented women (27%). The trial's population characteristics were similar to those of the first patients who received pulmonary artery sensors (82% White, 13% African American, 1% Asian, 1% Hispanic, and 29% female). CONCLUSIONS: Demographics of Centers for Medicare and Medicaid Services beneficiaries hospitalized with HF vary regionally and by age, which should be considered when defining "adequate" representation in clinical studies. Enrollment diversity in clinical trials may affect who receives early application of recently approved innovations.

Exploring the divergence in perspectives on clinical trial operations in South Korea during the COVID-19 pandemic: a comparison of a trial site and sponsors.

Introduction: During the COVID-19 pandemic, novel clinical trial methods known as decentralized clinical trials (DCTs) were rapidly introduced. The attitude toward operating clinical trials and perspectives on DCTs may differ between clinical trial sites and sponsors. The impact of the COVID-19 pandemic on clinical trials was investigated for a society of sponsors and a trial site in South Korea. Methods: The current difficulties and future perspectives on clinical trials were assessed and compared between the site and sponsors. Results: Both the site and sponsors reported on their experiences with the challenges of conducting clinical trials during the pandemic era. While 64% of personnel from the site judged that the difficulties were solved by their own solutions, 67.6% of personnel from sponsors considered cooperation with trial sites as a key solution to overcome the difficulties. While half of the personnel from the site were skeptical of the changes in trial operation methods, the sponsors expected the institutionalization of DCT elements. Conclusion: In conclusion, with varying attitudes, sponsors and sites attempted to overcome the challenges of conducting clinical trials during the pandemic era. To conduct clinical trials effectively, both sponsors and sites must work closely together to find solutions with efficient communication. For the successful implementation of new tools such as DCTs, the government needs to solicit support from sponsors and sites and change regulations.

Feasibility and acceptability of a new web-based cognitive training platform for cognitively healthy older adults: the breakfast task.

BACKGROUND: Developing efficient cognitive training for the older population is a major public health goal due to its potential cognitive benefits. A promising training target is executive control, critical for multitasking in everyday life. The aim of this pilot study was to establish the feasibility and acceptability of the Breakfast Task training in older adults, a new web-based cognitive training platform that simulates real-life multitasking demands. METHODS: A community-based sample of 24 cognitively healthy participants aged between 60 and 75 (M = 69.12, SD = 3.83) underwent 5-session cognitive training protocol, delivered online. Each session lasted 45 min and occurred twice a week at participant's homes. Performance was recorded, and participants completed questionnaires at baseline and after the intervention. RESULTS: Feasibility metrics showed overall high recruitment (82.7%), adherence and retention rates (100%). Acceptability was considered good based on participant's quantitative and qualitative responses. On average, participants rated the game as interesting, enjoyable and did not report difficulties in accessing the game online without supervision or in understanding the instructions. Participants showed a learning curve across sessions, suggesting improvement in the game outcomes and potential benefits from the emphasis change training approach. The study identified relevant areas that need improvements and adjustments, such as technical issues, session's structure, and dose. CONCLUSIONS: The findings provide preliminary support for the feasibility and acceptability of the web-based Breakfast Task training platform in cognitively healthy older adults. Results suggest the value of further research to investigate the Breakfast Task training features and dose-response relationship, as well as its potential efficacy in older adults via larger randomized controlled trials. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04195230 (Registered 11 December 2019).

Identifying Age Based Maturation in the ERP Response to Faces in Children With Autism: Implications for Developing Biomarkers for Use in Clinical Trials.

Recent proposals have suggested the potential for neural biomarkers to improve clinical trial processes in neurodevelopmental conditions; however, few efforts have identified whether chronological age-based adjustments will be necessary (as used in standardized behavioral assessments). Event-related potentials (ERPs) demonstrate early differences in the processing of faces vs. objects in the visual processing system by 4 years of age and age-based improvement (decreases in latency) through adolescence. Additionally, face processing has been proposed to be related to social skills as well as autistic social-communication traits. While previous reports suggest delayed latency in individuals with autism spectrum disorder (ASD), extensive individual and age based heterogeneity exists. In this report, we utilize a sample of 252 children with ASD and 118 children with typical development (TD), to assess the N170 and P100 ERP component latencies (N170L and P100L, respectively), to upright faces, the face specificity effect (difference between face and object processing), and the inversion effect (difference between face upright and inverted processing) in relation to age. First, linear mixed models (LMMs) were fitted with fixed effect of age at testing and random effect of participant, using all available data points to characterize general age-based development in the TD and ASD groups. Second, LMM models using only the TD group were used to calculate age-based residuals in both groups. The purpose of residualization was to assess how much variation in ASD participants could be accounted for by chronological age-related changes. Our data demonstrate that the N170L and P100L responses to upright faces appeared to follow a roughly linear relationship with age. In the ASD group, the distribution of the age-adjusted residual values suggest that ASD participants were more likely to demonstrate slower latencies than would be expected for a TD child of the same age, similar to what has been identified using unadjusted values. Lastly, using age-adjusted values for stratification, we found that children who demonstrated slowed age-adjusted N170L had lower verbal and non-verbal IQ and worse face memory. These data suggest that age must be considered in assessing the N170L and P100L response to upright faces as well, and these adjusted values may be used to stratify children within the autism spectrum.

Psychometric Properties of the Proxy-Reported Life-Space Assessment in Institutionalized Settings (LSA-IS-Proxy) for Older Persons with and without Cognitive Impairment.

(1) Background: Life-space mobility assessments for institutionalized settings are scarce and there is a lack of comprehensive validation and focus on persons with cognitive impairment (CI). This study aims to evaluate the psychometric properties of the Life-Space Assessment for Institutionalized Settings by proxy informants (LSA-IS-proxy) for institutionalized, older persons, with and without CI. (2) Methods: Concurrent validity against the self-reported version of the LSA-IS, construct validity with established construct variables, test-retest reliability, sensitivity to change during early multidisciplinary geriatric rehabilitation treatment, and feasibility (completion rate, floor/ceiling effects) of the LSA-IS-proxy, were assessed in 94 hospitalized geriatric patients (83.3 ± 6.1 years), with and without CI. (3) Results: The LSA-IS-proxy total score showed good-to-excellent agreement with the self-reported LSA-IS (Intraclass Correlations Coefficient, ICC3,1 = 0.77), predominantly expected small-to-high correlations with construct variables (r = 0.21-0.59), good test-retest reliability (ICC3,1 = 0.74), significant sensitivity to change over the treatment period (18.5 ± 7.9 days; p < 0.001, standardized response mean = 0.44), and excellent completion rates (100%) with no floor/ceiling effects. These results were predominantly confirmed for the sub-scores of the LSA-IS-proxy and were comparable between the sub-groups with different cognitive status. (4) Conclusions: The LSA-IS-proxy has proven to be feasible, valid, reliable, and sensitive to change in hospitalized, geriatric patients with and without CI.

Personality Moderates Intervention Effects on Cognitive Function: A 6-Week Conversation-Based Intervention.

BACKGROUND AND OBJECTIVES: Social isolation is associated with a higher risk of dementia. We previously conducted and showed the efficacy of an intervention which uses conversation (the core component of social interactions) as a tool to enhance cognitive function. We now explore whether cognitive improvements through conversation-based intervention depend on an individual's personality. RESEARCH DESIGN AND METHODS: We reexamined data from a 6-week randomized controlled trial (ClinicalTrials.gov Number: NCT01571427) to determine whether conversation-based intervention effects were moderated by personality traits in 83 older adults (mean age = 80.51 years, 49 cognitively intact, 34 individuals with mild cognitive impairment). The intervention group participated in daily 30-min face-to-face semi-structured conversations with trained interviewers through a web-enabled system for 6 weeks. At baseline, psychosocial questionnaires and a neuropsychological battery were completed. RESULTS: Intervention group participants with high agreeableness, conscientiousness, and extraversion exhibited significant improvements in language-based executive function tasks beyond changes in the control group (ps < .05). An opposite pattern for delayed recall memory and working memory tasks emerged among highly extraverted participants (ps < .05). DISCUSSION AND IMPLICATIONS: Our exploratory findings suggest the adaptive role of personality traits in conversation-based cognitive interventions may be limited to tasks incorporating a language component, and offer initial evidence for personalized approaches to cognitive health in late life.

Biomarker Acquisition and Quality Control for Multi-Site Studies: The Autism Biomarkers Consortium for Clinical Trials.

The objective of the Autism Biomarkers Consortium for Clinical Trials (ABC-CT) is to evaluate a set of lab-based behavioral video tracking (VT), electroencephalography (EEG), and eye tracking (ET) measures for use in clinical trials with children with autism spectrum disorder (ASD). Within the larger organizational structure of the ABC-CT, the Data Acquisition and Analytic Core (DAAC) oversees the standardization of VT, EEG, and ET data acquisition, data processing, and data analysis. This includes designing and documenting data acquisition and analytic protocols and manuals; facilitating site training in acquisition; data acquisition quality control (QC); derivation and validation of dependent variables (DVs); and analytic deliverables including preparation of data for submission to the National Database for Autism Research (NDAR). To oversee consistent application of scientific standards and methodological rigor for data acquisition, processing, and analytics, we developed standard operating procedures that reflect the logistical needs of multi-site research, and the need for well-articulated, transparent processes that can be implemented in future clinical trials. This report details the methodology of the ABC-CT related to acquisition and QC in our Feasibility and Main Study phases. Based on our acquisition metrics from a preplanned interim analysis, we report high levels of acquisition success utilizing VT, EEG, and ET experiments in a relatively large sample of children with ASD and typical development (TD), with data acquired across multiple sites and use of a manualized training and acquisition protocol.

Validation of a Modified Life-Space Assessment in Multimorbid Older Persons With Cognitive Impairment.

BACKGROUND AND OBJECTIVES: To investigate the validity, reliability, sensitivity to change, and feasibility of a modified University of Alabama at Birmingham Study of Aging Life-Space Assessment (UAB-LSA) in older persons with cognitive impairment (CI). RESEARCH DESIGN AND METHODS: The UAB-LSA was modified for use in persons with CI Life-Space Assessment for Persons with Cognitive Impairment (LSA-CI). Measurement properties of the LSA-CI were investigated using data of 118 multimorbid older participants with CI [mean age (SD): 82.3 (6.0) years, mean Mini-Mental State Examination score: 23.3 (2.4) points] from a randomized controlled trial (RCT) to improve motor performance and physical activity. Construct validity was asessed by Spearman's rank (rs) and point-biseral correlations (rpb) with age, gender, motor, and cognitive status, psychosocial factors, and sensor-derived (outdoor) physical activity variables. Test-retest reliability was analyzed using intra-class correlation coefficients (ICCs). Sensitivity to change was determined by standardized response means (SRMs) calculated for the RCT intervention group. RESULTS: The LSA-CI demonstrated moderate to high construct validity, with significant correlations of the LSA-CI scores with (outdoor) physical activity (rs = .23-.63), motor status (rs = .27-.56), fear of falling-related psychosocial variables (rs = |.24-.44|), and demographic characteristics (rpb = |.27-.32|). Test-retest reliability was good to excellent (ICC = .65-.91). Sensitivity to change was excellent for the LSA-CI composite score (SRM = .80) and small to moderate for the LSA-CI subscores (SRM = .35-.60). A completion rate of 100% and a mean completion time of 4.1 min) documented good feasibility. DISCUSSION AND IMPLICATIONS: The LSA-CI represents a valid, reliable, sensitive, and feasible interview-based life-space assessment tool in multimorbid older persons with CI.

Efficacy Endpoints in Clinical Trials in Actinic Keratosis.

INTRODUCTION: Actinic keratosis is regarded as a chronic disease of the skin and, although fluctuating, is chronically progressive. Approval of new products for the treatment of actinic keratosis requires the use of a standard methodology in clinical trials which emphasize complete clearance of all actinic keratoses in a treatment field in a defined time span and the evaluation of long-term efficacy in terms of recurrence rate among completely cleared patients. METHODS: Analysis of data from six previously published clinical trials in patients with actinic keratosis. RESULTS: There was poor agreement over a period of 1 month in the complete clearance endpoint. This variation in assessment renders recurrence in cleared patients invalid as the estimate of long-term efficacy. Furthermore, complete clearance was shown to depend heavily on the number of baseline actinic keratoses. CONCLUSION: The main endpoints presently in use for the assessment of short- and long-term efficacy of actinic keratosis field-directed therapy, namely, complete clearance and recurrence rate, are obsolete and should be replaced by the percentage reduction in actinic keratosis count or the absolute actinic keratosis count. FUNDING: LEO Pharma A/S.

Randomized clinical trial assessing whether additional massage treatments for chronic neck pain improve 12- and 26-week outcomes.

BACKGROUND CONTEXT: This is the first study to systematically evaluate the value of a longer treatment period for massage. We provide a framework of how to conceptualize an optimal dose in this challenging setting of nonpharmacologic treatments. PURPOSE: The aim was to determine the optimal dose of massage for neck pain. STUDY DESIGN/SETTING: Two-phase randomized trial for persons with chronic nonspecific neck pain. Primary randomization to one of five groups receiving 4 weeks of massage (30 minutes 2x/or 3x/wk or 60 minutes 1x, 2x, or 3x/wk). Booster randomization of participants to receive an additional six massages, 60 minutes 1x/wk, or no additional massage. PATIENT SAMPLE: A total of 179 participants from Group Health and the general population of Seattle, WA, USA recruited between June 2010 and August 2011 were included. OUTCOME MEASURES: Primary outcomes self-reported neck-related dysfunction (Neck Disability Index) and pain (0-10 scale) were assessed at baseline, 12, and 26 weeks. Clinically meaningful improvement was defined as greater than or equal to 5-point decrease in dysfunction and greater than or equal to 30% decrease in pain from baseline. METHODS: Clinically meaningful improvement for each primary outcome with both follow-up times was analyzed using adjusted modified Poisson generalized estimating equations (GEEs). Secondary analyses for the continuous outcomes used linear GEEs. RESULTS: There were no observed differences by primary treatment group at 12 or 26 weeks. Those receiving booster dose had improvements in both dysfunction and pain at 12 weeks (dysfunction: relative risk [RR]=1.56 [1.08-2.25], p=.018; pain: RR=1.25 [0.98-1.61], p=.077), but those were nonsignificant at 26 weeks (dysfunction: RR=1.22 [0.85-1.74]; pain: RR=1.09 [0.82-1.43]). Subgroup analysis by primary and booster treatments found the booster dose only effective among those initially randomized to one of the 60-minute massage groups. CONCLUSIONS: "Booster" doses for those initially receiving 60 minutes of massage should be incorporated into future trials of massage for chronic neck pain.