Mixed Model For Repeated Measures Research Articles

Efficacy of Amphetamine Extended-Release Oral Suspension in Children with Attention-Deficit/Hyperactivity Disorder: Effect Size Across the Day.

Objective: To evaluate the treatment effect size throughout the day of amphetamine extended-release oral suspension (AMPH EROS; Tris Pharma, Inc., Monmouth Junction, NJ, USA) in a laboratory classroom study conducted in children aged 6-12 years with attention-deficit/hyperactivity disorder (ADHD). Methods: A post hoc analysis was performed to assess the overall effect size as well as the effect size at each time point from early morning through evening (1, 2, 4, 6, 8, 10, 12, and 13 hours postdose) for each efficacy measure evaluated in a 5-week, randomized, dose-optimized, double-blind, placebo-controlled, laboratory classroom assessment, efficacy, and safety study of AMPH EROS (N = 99). Change from baseline of the primary (Swanson, Kotkin, Agler, M-Flynn, Pelham [SKAMP]-C) and key secondary (secondary efficacy assessments included the SKAMP attention [SKAMP-A], SKAMP-deportment subscale [SKAMP-D], Permanent Product Measure of Performance-number of problems attempted [PERMP-A], PERMP-number of problems correct [PERMP-C]) efficacy measures were analyzed using a linear mixed model repeated-measures analysis model. Comparisons among treatments were adjusted for multiple comparisons using the Bonferroni method. The effect size was estimated using Cohen's d, to determine "small," (0.2), "medium," (0.5), or "large" (0.8) magnitudes of treatment effects. Results: Large overall effect sizes were observed for all primary and key secondary efficacy assessments. Moreover, the SKAMP-C, PERMP-number of problems attempted, and PERMP-C scores showed large effect sizes at each time point evaluated across the day, from 1 to 13 hours postdose. The SKAMP-A and SKAMP-D scores showed a medium to large effect size at each time point. Conclusions: AMPH EROS demonstrated a large and consistent effect size across the day, including early in the morning, in the treatment of symptoms of ADHD in children aged 6-12 years. Trial Registration: clinicaltrials.gov identifier: NCT02083783.

P736 Factors associated with partial Mayo Clinic Score over time in patients with Ulcerative Colitis treated with filgotinib in the phase 2b/3 SELECTION trial

Abstract Background Responses to ulcerative colitis (UC) treatments vary considerably between individuals, and factors associated with a stable response are not well defined. Filgotinib (FIL) is an oral, Janus kinase 1 preferential inhibitor approved in the EU and the UK as a UC therapy. We aimed to identify factors associated with partial Mayo Clinic Score (pMCS) over time in FIL-treated patients with UC in the phase 2b/3 SELECTION trial (NCT02914522). Methods In SELECTION, adults with moderately to severely active UC received FIL 200 mg (FIL200), FIL 100 mg (FIL100) or placebo once daily for 11 weeks in Induction (IND) Study A (biologic-naive) or B (biologic-experienced).1 Patients in clinical remission or with a Mayo Clinic Score (MCS) response at week 10 could enter the 47-week Maintenance (MNT) Study. To evaluate factors associated with pMCS during MNT this post hoc analysis used a mixed model for repeated measures (MMRM), which included fixed effects of time, IND dose (FIL200 or FIL100), the factor of interest and pMCS at IND baseline, and correlated patient residual errors. For categorical factors, the least-squares mean difference with 95% confidence interval (CI) and the overall type III p value were calculated. For continuous factors, the difference in pMCS for a one-unit change in the factor of interest was estimated with 95% CI. Multiplicity adjustment of p values was not performed. Results Data from 371 patients treated with FIL200 (n=199) or FIL100 (n=172) were included. Previous use of at least one biologic therapy or a tumour necrosis factor antagonist/vedolizumab, and week 10 MCS subscores of ≤1 were associated with higher pMCS over time than their respective reference categories (p<0.0001; Table 1). Over time, pMCS was 0.45 units higher in patients assigned to IND Study A versus IND Study B (p=0.0002). Week 10 endoscopic score ≤1, Geboes histologic remission and Inflammatory Bowel Disease Questionnaire total score >170 were associated with lower pMCS over time than their respective reference categories (p≤0.0001). Change from baseline in pMCS at week 10 and faecal calprotectin levels at week 10 were positively associated with pMCS over time (p<0.0001; Table 2). Patient-reported outcome (PRO) measures at week 10 were negatively associated with pMCS over time (p≤0.0001). Conclusion History of previous biologic therapy, and week 10 assessments (endoscopic, clinical, biomarker and PRO) were among the factors influencing pMCS over the course of 1 year of FIL treatment, consistent with previous findings from trajectory modeling.2 Further MMRM analyses may help to identify patients who benefit most from FIL treatment. 1. Feagan BG et al. Lancet 2021;397:2372–84. 2. Schreiber S et al. MP443 [abstract]. UEGJ 2022;10:459.

Natural cubic splines for the analysis of Alzheimer's clinical trials.

Mixed model repeated measures (MMRM) is the most common analysis approach used in clinical trials for Alzheimer's disease and other progressive diseases measured with continuous outcomes over time. The model treats time as a categorical variable, which allows an unconstrained estimate of the mean for each study visit in each randomized group. Categorizing time in this way can be problematic when assessments occur off-schedule, as including off-schedule visits can induce bias, and excluding them ignores valuable information and violates the intention to treat principle. This problem has been exacerbated by clinical trial visits which have been delayed due to the COVID19 pandemic. As an alternative to MMRM, we propose a constrained longitudinal data analysis with natural cubic splines that treats time as continuous and uses test version effects to model the mean over time. Compared to categorical-time models like MMRM and models that assume a proportional treatment effect, the spline model is shown to be more parsimonious and precise in real clinical trial datasets, and has better power and Type I error in a variety of simulation scenarios.

Examining racial differences in smoking outcomes among smokers enrolled in an intravenous nicotine infusion study

IntroductionLarge racial disparities exist in the prevention and treatment of smoking-related diseases, and minoritized populations carry a heavier burden of smoking-related morbidity and mortality. To date, most studies investigating smoking-related illnesses have been conducted in samples in which the majority, or totality, self-identified as White or Caucasian. While Black individuals who smoke tend to have a lower rate of nicotine clearance, in part due to the use of mentholated cigarettes, less is known about how slower clearance affects their acute subjective and physiologic responses in response to either overnight abstinence or subsequent nicotine administration. This study aimed to investigate differences between the experiences of Black and White individuals who smoke across these outcomes after a period of short-term abstinence and after IV nicotine infusion. MethodsThe study included 206 smokers (N = 103 Black, N = 103 White, by self-report). The study investigated self-report, physiological, and biochemical smoking-related outcomes following confirmed overnight abstinence followed by IV nicotine infusion. The outcome measures were separately analyzed with repeated-measures mixed-models. ResultsBlack individuals had lower rates of nicotine clearance and were more likely to smoke mentholated cigarettes than White individuals. Despite these differences, no differences in withdrawal, cravings, or physiological outcomes were observed between the two groups. There were some trends toward differences in subjective experiences, in that an interaction with trend level significance between race and dose was observed for negative subjective drug effects, with White smokers trending towards endorsing higher levels of negative affect after abstinence and nicotine infusion. We also observed that Black individuals trended towards experiencing more negative drug effects in response to initial nicotine delivery than to saline, whereas White individuals had no differences in negative drug effects across saline or nicotine doses. ConclusionsDespite slower nicotine clearance, Black participants exhibited withdrawal and urges to smoke as severe as White participants, and did not have blunted physiological responses to overnight abstinence or administration of nicotine, which were contrary to our hypotheses. Our findings suggest minimal differences across races in the acute pharmacologic effects of nicotine. We observed trend-level differences in subjective and affective responses to nicotine. Greater insight into these differences may lead to improved prevention and treatment strategies for smoking-related illnesses for Black individuals who smoke.

Assessing chronic stress in wild mammals using claw-derived cortisol: a validation using European badgers (Meles meles).

Measuring stress experienced by wild mammals is increasingly important in the context of human-induced rapid environmental change and initiatives to mitigate human-wildlife conflicts. Glucocorticoids (GC), such as cortisol, mediate responses by promoting physiological adjustments during environmental perturbations. Measuring cortisol is a popular technique; however, this often reveals only recent short-term stress such as that incurred by restraining the animal to sample blood, corrupting the veracity of this approach. Here we present a protocol using claw cortisol, compared with hair cortisol, as a long-term stress bio-indicator, which circumvents this constraint, where claw tissue archives the individual's GC concentration over preceding weeks. We then correlate our findings against detailed knowledge of European badger life history stressors. Based on a solid-phase extraction method, we assessed how claw cortisol concentrations related to season and badger sex, age and body-condition using a combination of generalized linear mixed models (GLMM) (n= 668 samples from 273 unique individuals) followed by finer scale mixed models for repeated measures (MMRM) (n= 152 re-captured individuals). Claw and hair cortisol assays achieved high accuracy, precision and repeatability, with similar sensitivity. The top GLMM model for claw cortisol included age, sex, season and the sex*season interaction. Overall, claw cortisol levels were significantly higher among males than females, but strongly influenced by season, where females had higher levels than males in autumn. The top fine scale MMRM model included sex, age and body condition, with claw cortisol significantly higher in males, older and thinner individuals. Hair cortisol was more variable than claw; nevertheless, there was a positive correlation after removing 34 outliers. We discuss strong support for these stress-related claw cortisol patterns from previous studies of badger biology. Given the potential of this technique, we conclude that it has broad application in conservation biology.

Patient-reported outcomes for the Intergroup Sentinel Mamma study (INSEMA): A randomised trial with persistent impact of axillary surgery on arm and breast symptoms in patients with early breast cancer.

In clinically node-negative breast cancer patients, the INSEMA trial (NCT02466737) assessed the non-inferiority of avoiding sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND). Here we present patient-reported outcomes (PROs) as a secondary endpoint. PROs were assessed for patients with no axillary surgery, SLNB alone, and ALND. Quality of life (QoL) questionnaire EORTC QLQ-C30 and its breast cancer module (BR23) were used at baseline (pre-surgery) and 1, 3, 6, 12, and 18 months after surgery. The QoL scores were compared using repeated measures mixed models based on the safety set. Between 2015 and 2019, 5502 patients were recruited for the first randomization, and 5154 were included inthe intent-to-treat set (4124 SLNB versus 1030 no SLNB). In the case of one to three macrometastases after SLNB, 485 patients underwent second randomization (242 SLNB alone versus 243 ALND). Questionnaire completion response remained high throughout the trial: over 70% at all time points for the first randomization. There were significant differences for the BRBS (breast symptoms) and BRAS (arm symptoms) scores favoring the no SLNB group in all post-baseline assessments. Patients in the SLNB group showed significantly and clinically relevant higher scores for BRAS (differences in mean values ≥5.0 points at all times), including pain, arm swelling, and impaired mobility in all postoperative visits, with the highest difference at one month after surgery. Scoring of theQLQ-C30 questionnaire revealed no relevant differences between the treatment groups, although some comparisons were statistically significant. This is one of the first randomized trials investigating the omission of SLNB in clinically node-negative patients and the first to report comprehensive QoL data. Patients with no SLNB benefitted regarding arm symptoms/functioning, while no relevant differences in other scales were seen. Supported by German Cancer Aid (Deutsche Krebshilfe, Bonn, Germany), Grant No. 110580 and Grant No. 70110580 to University Medicine Rostock.

Effects of Combined Exercises and Short Foot Exercise With and Without Isometric Hip Abduction In Women With Flatfoot

Purpose: This study aims to examine the effect of 6 weeks of combined exercises (CE), short foot exercise (SFE), and SFE with isometric hip abduction (IHA) on dynamic balance (DB), joint position sense (JPS), and strength in women with flexible flatfoot (FF). Methods: A total of 40 women with flexible flatfoot (FF) participated in this semi-experimental study and were randomly assigned to three groups as follows: CE (n=14), SFE (n=13), and IHA (n=13). Six weeks of exercise were split into 3 sessions under supervision and 3 sessions at home were completed by the participants. The Y balance test, goniometer, and dynamometer were used to assess DB, JPS, and strength before and after the exercises, respectively. The mixed-model repeated-measures multivariate analysis of variance statistical test was used to analyze the data with a significance level of 0.05. Results: The results revealed that after performing the exercises, there was a significant difference in the DB in the SFE group in two posteromedial and posterolateral directions; meanwhile, in the IHA group this difference was in three directions, while in the CE group, it was in the posterolateral direction (P<0.05). After the exercises, no significant difference was observed in either group’s JPS or plantar flexors and dorsal flexors strength (P>0.05). Between the groups, there was no difference in any of the other variables (P>0.05). Conclusion: Considering that the DB changes in the IHA group were more than in the other two groups, these exercises are suggested to improve the DB in women with FF.

Feasibility and Effectiveness of a Worksite-Weight-Loss Program for Cancer Prevention among School-District Employees with Overweight and Obesity

The effects of Vibrant Lives, a 6-month worksite-weight-loss program, were examined in a cohort of school-district employees with overweight or obesity. The VL Basic (VLB) participants received materials and tailored text messages, the VL Plus (VLP) participants additionally received WIFI-enabled activity monitors and scales and participated in health challenges throughout the school year, and the VL Plus with Support (VLP + S) participants additionally received coaching support. The levels of program satisfaction and retention and changes in weight, physical activity (PA), and diet were compared across groups using Pearson chi-square tests, repeated-measure mixed models, and logistic regression. After the program, the VLB (n = 131), VLP (n = 87), and VLP + S (n = 88) groups had average weight losses of 2.5, 2.5, and 3.4 kg, respectively, and average increases in weekly PA of 40.4, 35.8, and 65.7 min, respectively. The VLP + S participants were more likely than the other participants to have clinically significant weight loss (≥3%; p = 0.026). Compared with the VLB participants, the VLP participants were less likely to meet the recommendations for consuming fast food (p = 0.022) and sugar-sweetened beverages (p = 0.010). The VLP and VLP + S participants reported higher program satisfaction than the VLB participants. The VL program facilitates weight loss among school-district employees with overweight and obesity by increasing their PA and healthy diet.

Persisting neuropsychiatric symptoms, Alzheimer’s disease, and cerebrospinal fluid cortisol and dehydroepiandrosterone sulfate

IntroductionNeuropsychiatric symptoms are important treatment targets in the management of dementia and can be present at very early clinical stages of neurodegenerative diseases. Increased cortisol has been reported in Alzheimer’s disease (AD) and has been associated with faster cognitive decline. Elevated cortisol output has been observed in relation to perceived stress, depression, and anxiety. Dehydroepiandrosterone sulfate (DHEAS) has known anti-glucocorticoid effects and may counter the effects of cortisol.ObjectivesWe aimed to examine whether CSF cortisol and DHEAS levels were associated with (1) neuropsychiatric symptoms at baseline, (2) changes in neuropsychiatric symptoms over 3 years, and (3) whether these associations were related to or independent of AD pathology.MethodsOne hundred and eighteen participants on a prospective study in a memory clinic setting, including patients with cognitive impairment (n = 78), i.e., mild cognitive impairment or mild dementia, and volunteers with normal cognition (n = 40), were included. Neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q). CSF cortisol and DHEAS, as well as CSF AD biomarkers, were obtained at baseline. Neuropsychiatric symptoms were re-assessed at follow-up visits 18 and 36 months from baseline. We constructed linear regression models to examine the links between baseline neuropsychiatric symptoms, the presence of AD pathology as indicated by CSF biomarkers, and CSF cortisol and DHEAS. We used repeated-measures mixed ANCOVA models to examine the associations between the neuropsychiatric symptoms’ changes over time, baseline CSF cortisol and DHEAS, and AD pathology.ResultsHigher CSF cortisol was associated with higher NPI-Q severity scores at baseline after controlling for covariates including AD pathology status (B = 0.085 [0.027; 0.144], p = 0.027; r = 0.277). In particular, higher CSF cortisol was associated with higher baseline scores of depression/dysphoria, anxiety, and apathy/indifference. Elevated CSF cortisol was also associated with more marked increase in NPI-Q scores over time regardless of AD status (p = 0.036, η2 = 0.207), but this association was no longer significant after controlling for BMI and the use of psychotropic medications. CSF DHEAS was associated neither with NPI-Q scores at baseline nor with their change over time. Cortisol did not mediate the association between baseline NPI-Q and changes in clinical dementia rating sum of boxes over 36 months.ConclusionHigher CSF cortisol may reflect or contribute to more severe neuropsychiatric symptoms at baseline, as well as more pronounced worsening over 3 years, independently of the presence of AD pathology. Our findings also suggest that interventions targeting the HPA axis may be helpful to treat neuropsychiatric symptoms in patients with dementia.

Effect of Diet and Exercise on Knee Pain in Patients With Osteoarthritis and Overweight or Obesity

Some weight loss and exercise programs that have been successful in academic center-based trials have not been evaluated in community settings. To determine whether adaptation of a diet and exercise intervention to community settings resulted in a statistically significant reduction in pain, compared with an attention control group, at 18-month follow-up. Assessor-blinded randomized clinical trial conducted in community settings in urban and rural counties in North Carolina. Patients were men and women aged 50 years or older with knee osteoarthritis and overweight or obesity (body mass index ≥27). Enrollment (N = 823) occurred between May 2016 and August 2019, with follow-up ending in April 2021. Patients were randomly assigned to either a diet and exercise intervention (n = 414) or an attention control (n = 409) group for 18 months. The primary outcome was the between-group difference in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) knee pain score (range, 0 [none] to 20 [severe]; minimum clinically important difference, 1.6) over 18 months, tested using a repeated-measures mixed linear model with adjustments for covariates. There were 7 secondary outcomes including body weight. Among the 823 randomized patients (mean age, 64.6 years; 637 [77%] women), 658 (80%) completed the trial. At 18-month follow-up, the adjusted mean WOMAC pain score was 5.0 in the diet and exercise group (n = 329) compared with 5.5 in the attention control group (n = 316) (adjusted difference, -0.6; 95% CI, -1.0 to -0.1; P = .02). Of 7 secondary outcomes, 5 were significantly better in the intervention group compared with control. The mean change in unadjusted 18-month body weight for patients with available data was -7.7 kg (8%) in the diet and exercise group (n = 289) and -1.7 kg (2%) in the attention control group (n = 273) (mean difference, -6.0 kg; 95% CI, -7.3 kg to -4.7 kg). There were 169 serious adverse events; none were definitely related to the study. There were 729 adverse events; 32 (4%) were definitely related to the study, including 10 body injuries (9 in diet and exercise; 1 in attention control), 7 muscle strains (6 in diet and exercise; 1 in attention control), and 6 trip/fall events (all 6 in diet and exercise). Among patients with knee osteoarthritis and overweight or obesity, diet and exercise compared with an attention control led to a statistically significant but small difference in knee pain over 18 months. The magnitude of the difference in pain between groups is of uncertain clinical importance. ClinicalTrials.gov Identifier: NCT02577549.

Consistency of efficacy results across various clinical measures and statistical methods in the lecanemab phase 2 trial of early Alzheimer’s disease

Lecanemab (BAN2401) is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (protofibrils) with activity at insoluble fibrils and slowed clinical decline in an 18-month phase 2 proof-of-concept study (Study 201; ClinicalTrials.gov NCT01767311) in 856 subjects with early Alzheimer's disease (AD). In this trial, subjects were randomized to five lecanemab dose regimens or placebo. The primary efficacy endpoint was change from baseline in the Alzheimer's Disease Composite Score (ADCOMS) at 12 months with Bayesian analyses. The key secondary endpoints were ADCOMS at 18 months and Clinical Dementia Rating-Sum-of-Boxes (CDR-SB) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) at 18 months. The results have been published previously. Herein, we describe the results of sensitivity analyses evaluating the consistency of the lecanemab efficacy results in Study 201 at the identified dose, the ED90, across multiple statistical methods and multiple endpoints over the duration of the study. The protocol-specified analysis model was a mixed model for repeated measures (MMRM). Sensitivity analyses address the consistency of the conclusions using multiple statistical methods. These include a disease progression model (DPM), a natural cubic spline (NCS) model, a quadratic mixed model (QMM), and 2 MMRMs with additional covariates. The sensitivity analyses showed positive lecanemab treatment effects for all endpoints and all statistical models considered. The protocol-specified ADCOMS analysis showed a 29.7% slower decline than placebo for ADCOMS at 18 months. The various other analyses of 3 key endpoints showed declines ranging from 26.5 to 55.9%. The results at 12 months are also consistent with those at 18 months. The conclusion of the primary analysis of the lecanemab Study 201 is strengthened by the consistently positive conclusions across multiple statistical models, across efficacy endpoints, and over time, despite missing data. The 18-month data from this trial was utilized in the design of the confirmatory phase 3 trial (Clarity AD) and allowed for proper powering for multiple, robust outcomes.

Evaluation of the performance of alternative models in analyzing longitudinal data for Alzheimer clinical trials compared to MMRM

AbstractBackgroundSecondary prevention clinical trials (stage 2) for Alzheimer disease (AD) typically employs a cognitive composite score, consisting of multiple cognitive test scores, as the primary endpoint because of its sensitivity to subtle cognitive change. The underlying assumptions of using a composite score are that: (i) the treatment if effective will lead to similar treatment effects in each of its component (e.g., ∼25% reduction in the placebo progression); and (ii) the estimated treatment is an average of the treatment effects across the components regardless the satisfaction of assumption (i). The composite is typically analyzed using mixed models for repeated measurements (MMRM). Under the same assumptions, we proposed to analyze the composite using the multivariate MMRM (mMMRM) and the proportional mMMRM (PmMMRM). On the other hand, CDR SB is often used as the primary endpoint in early‐stage AD trials (stage 3), however, 20% to 30% of the placebo patients demonstrated no progression during an 18‐month follow‐up. These non‐progression participants would dilute the treatment effect comparison under the MMRM analysis. Because CDR SB is an ordinal rank measure, we propose to analyze it using the Cox proportional hazards model for recurrent events, where a recurrent event is defined as any ordinal increment over the previous visit. The goal of this study is to evaluate the performance (i.e., power) of these alternative models relative to MMRM.MethodWe evaluate the performance using both simulated data and the real trial data from the EXPEDITION 1 and EXPEDITION‐2 placebo arms.ResultBased on simulated data, for the cognitive composite, mMMRM yielded similar power to MMRM and PmMMRM led to 5‐8% power improvement over MMRM for a two‐component composite. PmMMRM’s power advantage is expected to increase with the number of components in the composite. For CDR SB, Cox model for recurrent events yielded up to 20% greater power than MMRM. Comprehensive evaluation will be reported based on real trial data.ConclusionAlternative models such as PmMMRM or Cox model with the same underlying assumption as or analyzing the data with a different angle from MMRM should be explored to obtain greater power.

A new approach for estimating and quantifying disease‐modification in Alzheimer’s disease clinical trials

AbstractBackgroundThe standard methodology for estimating treatment effects in Alzheimer’s disease clinical trials has remained unchanged for decades. With an increasing focus on disease‐modifying treatments, there are opportunities for developing more powerful methods for detecting such types of treatment effects and quantifying them in more interpretable ways.MethodsThe Progression Model for Repeated Measures (PMRM) was developed as an alternative to the Mixed Model for Repeated Measures (MMRM). The assumptions and flexibility of the PMRM are like the MMRM except treatment effects are handled differently (Figure 1). The PMRM estimates treatment effects as time‐delays/slowing of progression relative to the control group while the MMRM estimates treatment effects as point differences/reduction in decline on the outcome scale at a given visit. Because the unit of the treatment effect is shared with the time variable, PMRMs can simultaneously handle multiple outcomes in a natural and efficient manner. The power and interpretability of the PMRM was compared to the MMRM and other methods in a range of scenarios based on simulated and historical clinical trial data.ResultsThe PMRM was found to produce accurate and interpretable estimates of treatment effects across a range of simulated scenarios. Using CDR‐SB as an outcome, the PMRM produced the overall highest power to detect treatment effects across all simulated scenarios compared to all studied approaches. When treatment effects were simulated as time delays or slowing of progression, the PMRM offered substantial power gains compared to the MMRM. Using CDR‐SB, ADAS‐cog and ADCS‐ADL as multivariate outcomes, the PMRM was found to outperform models that combined the information in the outcome using the global test statistic and iADRS.ConclusionThe PMRM offers advantages in terms of interpretation and meaningful quantification of treatment effects, also in situations where the average decline observed in the control group is small. PMRMs can seamlessly include multiple outcome measures to estimate a single treatment effect and it was found that PMRMs offered substantially increased power to detect slowing of disease progression compared to conventional methods using both single and multiple outcome measures.

Examining I‐CONECT Intervention Effect on Psychosocial Wellbeing

AbstractBackgroundThe Internet‐based Conversational Engagement Clinical Trial (I‐CONECT, ClinicalTrials.gov:NCT02871921) intervention provided interpersonal interactions with video calls to socially isolated older adults. It is hypothesized that such intervention could improve individuals' psychosocial wellbeing by increasing social contacts. This abstract examines I‐CONECT intervention effects on psychological wellbeing outcomes.MethodThe intervention group received 30‐minute video chats 4 times/week for 6 months followed by 2 times/week for additional 6 months. The control group received weekly check‐in calls for 12 months. We used data from the baseline, six‐month and twelve‐month follow‐ups. Psychosocial outcomes were measured with NIH Toolbox Emotional Battery (NIHTB‐EB). Three domain scores, negative affect, social satisfaction, and psychological wellbeing, were calculated with 17 subscale scores weighted by factor loading. Mixed Models for Repeated Measures (MMRM) were run for the three psychosocial outcomes, controlling for age, sex, education, and experience of COVID‐19 pandemic. Participants were considered affected by COVID‐19 if any of the data points were collected after March 2020. Subsample analyses were conducted by participants' cognitive status (with normal cognition vs. MCI).ResultThe analysis included 134 participants, 70 with normal cognition and 64 with MCI. The sample’s mean age was 82.3, 44.9% were in the intervention group, 67.0% were female, the average year of education was 15.1, and 51.6% were affected by the pandemic. For the subsamples of individuals of normal cognition and MCI, we did not find any significant change in psychosocial outcomes due to the intervention. However, both intervention and control groups increased social satisfaction scores at both 6‐month and 12‐month (Table 1, Figure 1), suggesting that weekly phone check‐ins and frequent video‐chats interactions can provide the same magnitude of improvement in psychosocial wellbeing. We observed the COVID‐19 pandemic affected social satisfaction of both intervention and control groups negatively for those with MCI but did not affect the individuals with normal cognition.ConclusionBoth intervention and control groups improved in a measure of social satisfaction. Once per week 10‐minutes phone check‐ins provided for the control group seemed to be sufficient for improving social wellbeing. Implementing weekly phone check‐ins in the community might help improve psychological wellbeing among socially isolated older adults.

Sensory stimulation improves daily functions in Alzheimer’s disease

AbstractBackgroundAbnormal neuronal function in Alzheimer’s disease (AD) is characterized by unbalanced neuronal excitatory‐inhibitory tone, distorted neuronal synchrony, and network oscillations, presumably contributing to the pathogenesis of the disease and accelerating disease progression. The probability that abnormal neuronal activity directly contributes to the pathogenesis of the disease has been recently proposed. It has been demonstrated that induction of synchronized gamma oscillation of neuronal networks by sensory stimulation reverses AD‐related pathological markers in transgenic mice carrying AD‐related human pathological genes. The current study evaluated whether non‐invasive sensory stimulation inducing cortical 40 Hz gamma oscillation is clinically beneficial for patients in AD spectrum.MethodThe data studied here is from Overture clinical trial (NCT03556280). The study included a treatment group, where participants received daily, 1‐hour, 40Hz gamma visual and auditory stimulation for 6‐months at home, and a placebo group. To assess the treatment efficacy on daily functional abilities, the Alzheimer’s Disease Cooperative Study ‐ Activities of Daily Living (ADCS‐ADL) scale was used. Assessments were made at baseline and every four weeks throughout the study. ADCS‐ADL consists of 23‐items where each item aims to assess different functional abilities. The change in ADCS‐ADL as well as change in each individual item’s score between the treatment group (n = 33) and the placebo group (n‐ = 19) were compared using a mixed model for repeated measures (MMRM).ResultWe observed that treatment group participants were able to maintain their functional abilities while placebo group participants showed a decline as assessed by ADCS‐ADL, p<0.001. Within the instrumental ADCS‐ADL individual items, the most significant differences between the two groups, all favoring treatment group, were observed in: (1) Attentive participation in conversations, p<0.001, and (2) Finding personal belongings, p<0.043.ConclusionOur results suggest that daily, 1‐hour 40Hz gamma sensory stimulation may help prevent functional decline in patients with AD spectrum disorder. Preventing functional loss would help both patients and caregivers. Furthermore, it may reduce the need for institutionalization and reduce healthcare costs. Larger studies are planned to confirm these initial findings on the benefits of gamma sensory stimulation on function.

Prevalence and longitudinal clinical outcomes of negative, moderate, and advanced [18F]flortaucipir PET visual patterns across the Alzheimer's disease spectrum

AbstractBackgroundThe advent of positron emission tomography (PET) imaging with tracers such as [18F]flortaucipir (FTP) has allowed in‐vivo visualization of aggregated tau in Alzheimer’s disease (AD). Recently, a clinically applicable visual interpretation method for FTP PET yielding negative, moderate, and advanced AD visual patterns was developed, leading to its subsequent approval by the US Food and Drug Administration (FDA). Yet, the prevalence and longitudinal clinical outcomes of the different AD‐associated visual patterns, in particular the moderate AD pattern, have not been investigated systematically across the clinical spectrum of AD.MethodWe included cognitively normal individuals and patients with mild cognitive impairment and AD dementia from five observational cohort studies — Alzheimer’s Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain study (HABS), A4 study, AVID’s A05 study and Geneva Memory Clinic cohort — all of which had available FTP PET scans. Furthermore, Aβ status, established with Aβ PET, was available in 1924 participants (98%), and longitudinal clinical and cognitive data was obtained for 968 participants over an average follow‐up time of 2.2 years. Three readers, blinded to clinical and imaging information, will independently evaluate each FTP PET scan, and an individual’s FTP uptake pattern will be interpreted as negative, moderate, or advanced AD tau pattern, based on the majority read of the three readers. Multinomial generalized additive models (GAM) will be fitted to provide prevalence estimates of each FTP AD pattern. Mixed models for repeated measures (MMRM) will be used to estimate cognitive decline trajectories.ResultA total of 1963 participants had available FTP PET scans. We will investigate the prevalence of the different FTP AD patterns as a function of age per diagnostic group, stratifying participants by β‐amyloid status and APOE genotype. Further, in the subset of participants with available longitudinal clinical data, we will explore how the different FTP patterns associate with clinical decline across the aforementioned diagnostic groups.ConclusionOur large‐scale study will contribute significantly to elucidating the clinical relevance of FTP visual reads across the AD spectrum, potentially widening its applicability and promoting its use in patient assessment and in clinical prevention trials.

Prevalence and longitudinal clinical outcomes of negative, moderate, and advanced 18F‐flortaucipir PET visual patterns in aging and Alzheimer’s disease

AbstractBackgroundThe advent of positron emission tomography (PET) imaging with tracers such as [18F]flortaucipir (FTP) has allowed in‐vivo visualization of aggregated tau in Alzheimer’s disease (AD). Recently, a clinically applicable visual interpretation method for FTP PET yielding negative, moderate, and advanced AD visual patterns was developed, leading to its subsequent approval by the US Food and Drug Administration (FDA). Yet, the prevalence and longitudinal clinical outcomes of the different AD‐associated visual patterns, in particular the moderate AD pattern, have not been investigated systematically across the clinical spectrum of AD.MethodWe included cognitively normal individuals and patients with mild cognitive impairment and AD dementia from five observational cohort studies — Alzheimer’s Disease Neuroimaging Initiative (ADNI), Harvard Aging Brain study (HABS), A4 study, AVID’s A05 study and Geneva Memory Clinic cohort — all of which had available FTP PET scans. Furthermore, Aβ status, established with Aβ PET, was available in 1924 participants (98%), and longitudinal clinical and cognitive data was obtained for 968 participants over an average follow‐up time of 2.2 years. Three readers, blinded to clinical and imaging information, will independently evaluate each FTP PET scan, and an individual’s FTP uptake pattern will be interpreted as negative, moderate, or advanced AD tau pattern, based on the majority read of the three readers. Multinomial generalized additive models (GAM) will be fitted to provide prevalence estimates of each FTP AD pattern. Mixed models for repeated measures (MMRM) will be used to estimate cognitive decline trajectories.ResultA total of 1963 participants had available FTP PET scans. We will investigate the prevalence of the different FTP AD patterns as a function of age per diagnostic group, stratifying participants by β‐amyloid status and APOE genotype. Further, in the subset of participants with available longitudinal clinical data, we will explore how the different FTP patterns associate with clinical decline across the aforementioned diagnostic groups.ConclusionOur large‐scale study will contribute significantly to elucidating the clinical relevance of FTP visual reads across the AD spectrum, potentially widening its applicability and promoting its use in patient assessment and in clinical prevention trials.

Progressive aortic enlargement in medically managed acute type B aortic dissections with visceral aortic involvement.

Aortic remodeling of the thoracic aorta has been studied in patients treated with medical or endovascular therapy for the treatment of acute aortic dissections; however, particular attention has not yet focused on identifying specific growth patterns and rates across all aortic zones. Additionally, previous studies have not delineated between dissections with and without visceral aortic involvement, and we hypothesize that these two cohorts may exhibit distinct differences. The aim of this study is to investigate aortic behavior over time in medically managed acute Society for Vascular Surgery/Society of Thoracic Surgeons (SVS/STS) type B dissections with visceral aortic involvement and identify potential associations of subsequent aortic behavior with clinical outcomes. A single-center retrospective review was performed of all patients between 2010 and 2020 with acute SVS/STS type B aortic dissections with visceral aortic involvement that were not surgically managed. Short-axis centerline measurements of the true/false lumen and total aortic diameter (TAD) were taken at standardized locations relative to aortic anatomy within each aortic zone, including nondissected zones. Measurements were taken at the time of diagnosis and at six subsequent yearly intervals. Diameter changes over time were evaluated using repeated measures mixed models linear growth analysis. Aortic enlargement was classified by growth in TAD ≥5mm in either the thoracic (thoracic segment enlargement [TSE], zone 0-4) or visceral segments (visceral segment enlargement [VSE], zone 5-9). A total of 78 patients were identified with a median length of follow-up of 3.3years (interquartile range [IQR], 1.3-6.6years). Follow-up past 5years was seen in 31% of the cohort. For the entire cohort, mean thoracic growth in TAD was 2.0± 2.0mm/year, and visceral growth in TAD was 2.5± 2.4mm/year. TSE was observed in 65% of patients, with a median time until onset of 0.8years (IQR, 0.4-2.3years). VSE was observed in 57% of the cohort, with a median time until onset of 1.6years (IQR, 0.9-3.3years). Repeat measures mixed models linear growth analysis identified significant predictable linear growth in all aortic zones except for the nondissected zones 0-2. Odds for TSE are significantly increased in patients with known genetically triggered aortic conditions (odds ratio [OR], 2; 95% confidence interval [CI], 1.8-4.5; P= .044) and in cases where the dissection entry tear was in either zone 1 or 2 (OR, 4.8; 95% CI, 1.2-8.4; P= .044). In adjusted regression analysis, odds for intervention in the thoracic aorta were significantly increased in patients with rapid TSE in zone 3 (OR, 3.6; 95% CI, 1.1-8.4; P= .045). Similarly, odds for intervention targeting the visceral aortic segment were significantly increased in patients with zone 9 VSE (OR, 9.3; 95% CI, 1.1-13.3; P= .014). Odds for 5-year all-cause mortality were significantly increased in cases with large thoracic aneurysms (OR, 6.1; 95% CI, 1.1-14.9; P= .042). Aortic enlargement was present in the majority of patients with medically managed acute SVS/STS Type B aortic dissections with visceral aortic involvement, with analysis demonstrating predictable linear growth in all dissected zones. Patients with aortic enlargement demonstrated higher gross changes in diameter in addition to higher yearly rates of change compared with all comers. Odds for enlargement were impacted by both patient demographic and anatomic dissection characteristics. Growth in zone 3 and zone 9 significantly increased odds for aortic intervention. Odds for 5-year mortality were significantly increased in the presence of large thoracic aneurysms. Results highlight risk of progressive degeneration beyond acute phase in SVS/STS Type B aortic dissections with visceral aortic involvement, with life-long surveillance remaining crucial in management of dissections.

Food Insecurity, Federal Nutrition Support, and Parent Feeding Practices During COVID-19: A 1-Year Follow-up Study.

COVID-19 caused stark increases in food insecurity. To maintain food provision, policy changes to the National School Lunch Program (NSLP) and Supplemental Nutrition Assistance Program (SNAP) were instated. This longitudinal study examined (1) food security patterns across the timeline of COVID-19; (2) the relationship among food security patterns, NSLP/SNAP use, and parent feeding practices; and (3) parent perceptions of NSLP/SNAP policy changes. A total of 333 US parents completed online surveys during the COVID-19 pandemic: May 2020 (T1), September 2020 (T2), and May 2021 (T3). Food security and parent feeding practices were reported at each time point; pre-COVID-19 behaviors were retrospectively reported at T1. Use and perceptions of NSLP/SNAP policy changes were reported at T3. We examined associations between food security and parent feeding practices using repeated-measures mixed models. The percentage of parents with very low food security increased from pre-COVID-19 (9.6%) to T1 (29.1%) and remained elevated at T3 (16.8%). One-third (31.2%) of families fluctuated between food security and food insecurity, with 27.0% remaining food insecure at T3. Thirty percent of consistently food-insecure families reported not receiving school-provided meals, and 45% did not receive SNAP benefits. Most parents reported that pickup school meal sites (71.4%), Pandemic Electronic Benefit Transfer cards (51.4%), and increased SNAP benefits (79.6%) were beneficial. Initial changes in parent feeding practices reported at T1 returned to pre-COVID-19 levels by T3, yet concern for child overweight remained significantly elevated. Continued policy efforts to support food-insecure families via expanded food access in NSLP/SNAP are critical.

The Impact of Momelotinib on Patient Reported Quality of Life for Symptomatic and Anemic Patients with Myelofibrosis: Results from the Phase 3 Momentum Study

Introduction Disease-related inflammation, anemia and splenomegaly contribute to a host of burdensome symptoms in patients with myelofibrosis (MF), including fatigue, bone pain, night sweats, and others, which can negatively impact health-related quality of life (HRQoL). There are no approved treatments for patients with intermediate- and high-risk MF that specifically target anemia, and approved MF therapies for splenomegaly and symptoms often exacerbate anemia. Momelotinib (MMB) is a Janus kinase (JAK) 1, JAK2, and activin A receptor type 1 (ACVR1) inhibitor with demonstrated symptom, spleen, and anemia benefits in patients with MF. MOMENTUM, a phase 3 study in symptomatic, anemic patients with MF who were previously treated with a JAKi, showed that MMB significantly improved disease-related symptoms compared to danazol (DAN) (24.6% vs 9.2%) as measured by achieving at least a 50% reduction in total symptom score (TSS50) at week 24 compared to baseline. Herein we report the results of patient-reported health status and HRQoL analyses, including impact on fatigue and physical function, for patients treated with MMB compared to DAN in the MOMENTUM study. Methods Patient-reported outcome (PRO) analyses were performed for the following assessments in the intent-to-treat (ITT) population: Myelofibrosis Symptom Assessment Form (MFSAF) v4.0 TSS and individual items, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30)-derived scales and items, and Patient-Reported Outcomes Measurement Information System (PROMIS) short form physical function total score 10b and additional PROMIS bank items. Analyses of PRO response were summarized by corresponding meaningful change threshold (MCT) for each PRO. Longitudinal change from baseline scores were analyzed using mixed model for repeated measures (MMRM). Longitudinal responder analyses were performed by generalized estimating equation (GEE) after multiple imputation for missing scores. Odds ratio (OR) for response, 95% confidence interval (CI), and p-value were presented as the treatment effect (MMB vs DAN). Time to first response was analyzed using the Kaplan-Meier method. A stratified log-rank test was performed to compare treatment arms, and hazard ratios (HR) were estimated from a stratified Cox regression model. Results Proportionally greater improvements in MF-related symptoms, physical function, and global quality of life were observed with MMB versus DAN as measured at week 24 by the MFSAF, PROMIS, and EORTC QLQ-C30 questionnaires, respectively. Improvements in all MFSAF individual item scores from baseline at week 24 were greater in the MMB group than in the DAN group based on median scores (Figure 1) and MMRM analysis (Table 1), with the greatest treatment differences noted for night sweats, abdominal discomfort, bone pain, and rib pain, favoring MMB. Longitudinal MFSAF TSS response analysis indicated a higher likelihood of response for patients in the MMB group: an overall OR of 2.50 throughout the 24-week randomized treatment period. HRs for response were greater than 1 (ranging from 1.47 - 3.82) in the time to first response analysis for MFSAF TSS and individual items, excluding itching (0.77), indicating a faster symptom response for more patients in the MMB group for TSS and 6 of 7 individual items. Responder analyses showed that the proportion improved for fatigue was greater in the MMB group based on MFSAF fatigue (18.5% MMB, 9.2% DAN) and EORTC QLQ-C30 fatigue (41.5% MMB, 21.5% DAN), where missing data was considered nonresponse. Consistent with these results, responder analysis using the PROMIS assessments related to physical function also favored MMB (17.7% MMB, 4.6% DAN). This trend was supported by shorter times to first response for physical function in more patients in the MMB group versus the DAN group (HR = 1.93, 95% CI 0.95, 3.91). Improvement in global quality of life as measured by EORTC QLQ-C30 was also greater in the MMB group with a proportion difference of 14.6% between MMB and DAN (95% CI: 1.5-27.7%; p = 0.04). Conclusions Consistent with the positive primary endpoint (TSS50) result of the MOMENTUM study, these responder, longitudinal, and time-to-event analyses demonstrate that MMB provides comprehensive improvements in disease-related symptoms with associated improvement in physical function and overall HRQoL compared with DAN in patients with MF. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal