Clinical Meaningfulness Research Articles

Who Benefited Most from the Internet-Based Conversational Engagement RCT (I-CONECT)? Application of the Personalized Medicine Approach to a Behavioral Intervention Study

BackgroundMany Alzheimer’s Disease (AD) clinical trials have failed to demonstrate treatment efficacy on cognition. It is conceivable that a complex disease like AD may not have the same treatment effect due to many heterogeneities of disease processes and individual traits.ObjectivesWe employed an individual-level treatment response (ITR) approach to determine the characteristics of treatment responders and estimated time saved in cognitive decline using the Internet-based Conversational Engagement Clinical Trial (I-CONECT) behavioral intervention study as a model.Design and SettingI-CONECT is a multi-site, single-blind, randomized controlled trial aimed to improve cognitive functions through frequent conversational interactions via internet/webcam. The experimental group engaged in video chats with study staff 4 times/week for 6 months; the control group received weekly 10-minute check-in phone calls.ParticipantsOut of 186 randomized participants, current study used 139 participants with complete information on both baseline and 6-month follow-up (73 with mild cognitive impairment (MCI), 66 with normal cognition; 64 in the experimental group, and 75 in the control group).MeasurementsITR scores were generated for the Montreal Cognitive Assessment (MoCA) (global cognition, primary outcome) and Category Fluency Animals (CFA) (semantic fluency, secondary outcome) that showed significant efficacy in the trial. ITR scores were generated through 300 iterations of 3-fold cross-validated random forest models. The average treatment difference (ATD) curve and the area between the curves (ABC) were estimated to measure the heterogeneity of treatment responses. Responder traits were identified using SHapley Additive exPlanations (SHAP) and decision tree models. The time saved in cognitive decline was explored to gauge clinical meaningfulness.ResultsABC statistics showed substantial heterogeneity in treatment response with MoCA but modest heterogeneity in treatment response with CFA. Age, cognitive status, time spent with family and friends, education, and personality were important characteristics that influenced treatment responses. Intervention group participants in the upper 30% of ITR scores demonstrated potential delays of 3 months in semantic fluency (CFA) and 6 months in global cognition (MoCA), assuming a 5-fold faster natural cognitive decline compared to the control group during the post-treatment period.ConclusionsITR-based analyses are valuable in profiling treatment responders for features that can inform future trial design and clinical practice. Reliably measuring time saved in cognitive decline is an area of ongoing research to gain insight into the clinical meaningfulness of treatment.

Minimal clinically important difference in the World Health Organization Quality of Life Brief (WHOQOL-BREF) for adults with neurofibromatosis.

This study aimed to estimate minimal clinically important difference (MCID) values for the World Health Organization Quality of Life Brief version (WHOQOL-BREF) among adults with neurofibromatosis (NF). An MCID is needed to demonstrate clinical meaningfulness of interventions for NF. We estimated MCID for the WHOQOL-BREF: the quality of life (QoL) measure recommended by the Response Evaluation in Neurofibromatosis and Schwannomatosis International Collaboration. We used data from 228 clinical trial participants with NF type 1, NF type 2-related schwannomatosis, or schwannomatosis (SCHWN) who completed 10weeks of a virtual group mind-body program targeting resiliency or a time- and attention-matched control. Following established guidelines, we estimated MCIDs using both anchor-based and distribution-based methods for physical, psychological, social relationships, and environmental domains of the WHOQOL-BREF. MCID results varied across method and QoL domain. Three anchor-based methods, average change (AC), change difference (CD), and regression (REG), yielded the most consistent and comparable MCID across QoL domains. Based on these methods, we recommend ranges for each QoL domain: Physical QoL (3.9-7.3), Psychological QoL (4.7-8.1), Social QoL (2.6-5.9), and Environmental QoL (4.1-6.6). Establishing a rigorous MCID for QoL in NF is a critical step toward evaluating meaningful change in response to psychosocial interventions.

Clinician's Approach to Advanced Statistical Methods: Win Ratios, Restricted Mean Survival Time, Responder Analyses, and Standardized Mean Differences.

Novel statistical methods have emerged in recent medical literature, which clinicians must understand to properly appraise and integrate evidence into their practice. Some of these key concepts include win ratios, restricted mean survival time, responder analyses, and standardized mean difference. This article offers guidance to busy clinicians on the comprehension and practical applicability of the results to patients. Win ratios provide an alternative method to analyze composite outcomes by prioritizing individual components of the composite; prioritization of the outcomes should be evidence-based, pre-specified, and patient-centered. Restricted mean survival time presents a method to analyze Kaplan-Meier curves when assumptions required for Cox proportional hazards analysis are not met. As it only considers outcomes that occur within a specific timeframe, the duration of follow-up must be appropriately defined and based on prior epidemiologic and mechanistic evidence. Researchers can analyze continuous outcomes with responder analyses, in which participants are dichotomized into "responders" or "non-responders." While clinicians and patients may more easily grasp outcomes analyzed in this way, they should be aware of the loss of information and resulting imprecision, as well as potential to manipulate data presentation. When meta-analyzing continuous outcomes, point estimates can be converted to standardized mean differences to facilitate the combination of data utilizing various outcome measures. However, clinicians may find it challenging to grasp the clinical meaningfulness of a standardized mean difference, and may benefit from converting it to well-known outcomes. By providing the background knowledge of these statistical methods, along with practical applicability, benefits, and inevitable limitations, this article aims to provide clinicians with an approach to appraise the literature and apply the results in clinical practice.

Clinical Meaningfulness in Alzheimer's Disease Clinical Trials. A Report from the EU-US CTAD Task Force.

Recent positive results of three phase III anti-amyloid monoclonal antibody trials are transforming the landscape of disease-modifying therapeutics for Alzheimer's disease, following several decades of failures. Indeed, all three trials have met their primary endpoints. However, the absolute size of the benefit measured in these trials has generated a debate on whether the change scores observed on clinical outcome assessments represent a clinically meaningful benefit to patients. An evidence-based conclusion is urgently required to inform decision-making related to the approval, reimbursement, and ultimately, the management of emerging therapies in clinical practice. The EU-US CTAD Task Force met in Boston to address this important question. The current state-of-the-art knowledge for interpreting clinical meaningfulness of AD clinical trial results, including the point of view of patients and study partners on what is clinically meaningful, was discussed and is summarized here. A combination of methodologies to address the challenges emerged. There remain gaps in the understanding of clinical meaningfulness that only long-term longitudinal studies will be able to address.

Experimental Validation of an Upper Limb Benchmarking Framework in Healthy and Post-Stroke Individuals: A Pilot Study.

In the context of neurorehabilitation, there have been rapid and continuous improvements in sensors-based clinical tools to quantify limb performance. As a result of the increasing integration of technologies in the assessment procedure, the need to integrate evidence-based medicine with benchmarking has emerged in the scientific community. In this work, we present the experimental validation of our previously proposed benchmarking scheme for upper limb capabilities in terms of repeatability, reproducibility, and clinical meaningfulness. We performed a prospective multicenter study on neurologically intact young and elderly subjects and post-stroke patients while recording kinematics and electromyography. 60 subjects (30 young healthy, 15 elderly healthy, and 15 post-stroke) completed the benchmarking protocol. The framework was repeatable among different assessors and instrumentation. Age did not significantly impact the performance indicators of the scheme for healthy subjects. In post-stroke subjects, the movements presented decreased smoothness and speed, the movement amplitude was reduced, and the muscular activation showed lower power and lower intra-limb coordination. We revised the original framework reducing it to three motor skills, and we extracted 14 significant performance indicators with a good correlation with the ARAT clinical scale. The applicability of the scheme is wide, and it may be considered a valuable tool for upper limb functional evaluation in the clinical routine.

The effect of a spinal thrust manipulation's audible pop on brain wave activity: a quasi-experimental repeated measure design.

High velocity thrust manipulation is commonly used when managing joint dysfunctions. Often, these thrust maneuvers will elicit an audible pop. It has been unclear what conclusively causes this audible sound and its clinical meaningfulness. This study sought to identify the effect of the audible pop on brainwave activity directly following a prone T7 thrust manipulation in asymptomatic/healthy subjects. This was a quasi-experimental repeated measure study design in which 57 subjects completed the study protocol. Brain wave activity was measured with the Emotiv EPOC+, which collects data with a frequency of 128 HZ and has 14 electrodes. Testing was performed in a controlled environment with minimal electrical interference (as measured with a Gauss meter), temperature variance, lighting variance, sound pollution, and other variable changes that could have influenced or interfered with pure EEG data acquisition. After accommodation each subject underwent a prone T7 posterior-anterior thrust manipulation. Immediately after the thrust manipulation the brainwave activity was measured for 10 seconds. The non-audible group (N=20) consisted of 55% males, and the audible group (N=37) consisted of 43% males. The non-audible group EEG data revealed a significant change in brain wave activity under some of the electrodes in the frontal, parietal, and the occipital lobes. In the audible group, there was a significant change in brain wave activity under all electrodes in the frontal lobes, the parietal lobe, and the occipital lobes but not the temporal lobes. The audible sounds caused by a thoracic high velocity thrust manipulation did not affect the activity in the audible centers in the temporal brain region. The results support the hypothesis that thrust manipulation with or without audible sound results in a generalized relaxation immediately following the manipulation. The absence of a significant difference in brainwave activity in the frontal lobe in this study might indicate that the audible pop does not produce a "placebo" mechanism.

EXPLORING “LIVING WELL” FROM THE PERSPECTIVE OF PEOPLE LIVING WITH ALZHEIMER’S DISEASE AND RELATED DEMENTIAS

Abstract Alzheimer’s disease is a progressive, degenerative disease; however, at the same time individuals living with dementia experience symptoms, they also want to live well with the disease. Although living well with dementia holds different meaning to different people, it generally includes some commonalities, such as maintaining autonomy and independence. To explore the concept of living well with Alzheimer’s disease and related dementia (ADRD), the Alzheimer’s Association gathered data from nearly 100 individuals living with dementia through focus groups and online surveys. Themes from the focus groups were revealed on living well, including being viewed as an individual (person-centered care), staying involved, and receiving multiple types of support to assist their well-being. Open-ended questions from the surveys illustrated additional themes related to living well, as well as on personal meaningfulness of disease modifying therapies including more time with loved ones and opportunities to be part of significant family events. Within these findings, an underlying theme emphasizing the importance of person-centered care and well-being arose. Further discussion will explore these interconnected concepts of living well, person-centered care, and well-being, specifically including the perspectives of individuals living with ADRD. In addition, these concepts can be utilized to tailor resources and support to better support individuals living with ADRD to live well. Lastly, the concept of living well in relation to the emergence of disease modifying therapies and how personal meaningfulness is just as important as clinical meaningfulness will also be explored.

Translating AD Clinical Trial Results to Meaningful Benefits: Expectations, Definitions, Challenges and Opportunities.

AbstractBackgroundClinical trials in Alzheimer’s disease (AD) are designed and powered to detect treatment impact on validated research outcome measures necessary for regulatory approval. However, what constitutes a clinically meaningful benefit, how to define, measure and translate it from the results of clinical trial results to multiple stakeholders, including clinicians and patients requires better clarification.MethodsReview and synthesis of recent publications (Assuncao, Sperling, et al. Alz Res Therapy 2022; Petersen, Aisen Andrews, Atri, et al. Alzheimers Dementia. 2023 in press) and AD therapeutics developments to provide overview and frameworks for translating AD clinical trial results to meaningful benefits with respect to expectations, definitions, challenges and opportunities that may resonate with multiple stakeholders, including patients, patient care partners and clinicians.ResultsRational for realistic expectations of putative AD disease‐modifying treatments (DMTs) are reviewed including expectations of not improving symptoms but of slowing disease progression and modestly moderating between‐group (treatment versus placebo) clinical decline. Definitions postulated to represent clinically meaningful benefits are reviewed. Confusion, misunderstanding or misinterpretations in regards to representation of thresholds for meaningful within‐patient progression are discussed, including recent misinterpretation of necessary thresholds for determining meaningful group‐level differences having created misguided expectations for clinical meaningfulness in DMT clinical trial results. Discuss confounding minimal detectable change (MCD) and utilizing between‐group differences (to assess outcome efficacy) with and to define minimal clinically important differences (MCID) (an individual, within‐patient change in outcome assessment). Within‐patient change thresholds are not intended to assess meaningfulness of differences between group‐level changes over time, but may represent meaningful within‐patient trajectories via complementary (e.g. responder/progressor) analyses. Multiple frameworks show the challenges and opportunities to multidimensionally better represent and translate results to face‐valid and patient‐centered representations to resonate with AD stakeholders. These include expanded outcomes (e.g. neuropsychiatric symptoms, socioeconomic burden); patient‐ and caregiver‐reported outcomes; complementary analyses (standardized effect‐sizes, RR/OR, NNT, Time‐to‐Event, Time‐Equivalent‐Gained); and concepts such as predictive benefit (via a disease biomarker/core domain) and cumulative benefits (accrual and potentially increasing over time).ConclusionExpanded data, analyses and frameworks for defining and translating clinically meaningful patient‐centered benefit to multiple stakeholders, particularly patients, care‐partners and clinicians, are proposed.

Time saved in disease progression for treatments in AD (including 3 monoclonal antibodies and 2 other promising treatments)

AbstractBackgroundAlzheimer’s disease progression causes worsening on multiple symptoms of disease which can be measured by cognitive, functional and global scales. These scales can be thought of as surrogate outcomes for the true disease progression. The degenerative and therefore progressive nature of the disease indicates that time is a measurable gold standard against which we can assess all other outcomes. Composite endpoints and global statistical tests have been used to approximate this progression outcome since it is not directly measurable. Using time as the gold standard, one can calculate the alignment of any measure against the gold standard using a signal to noise ratio. A combination of the ADAS‐cog, ADCS‐ADL and CDR‐sb aligns more than 90% with the unmeasurable progression outcome.MethodConverting each of the clinical scales to a time scale allows us to measure progression in “disease progression” time: i.e. months of progression per month of treatment, which should be linear in nature despite any non‐linearity in the clinical scale. A recent meta‐analysis was performed and data from relevant studies have been estimated using an overall progression time metric.ResultResults for five studies of interest (three monoclonal antibodies and two other treatments) Aducanumab, Donanemab, Lecanemab, AD04, and Souvenaid show time savings range from 2 months per year to 7 months per year. Results for these five studies are presented in Table 1.ConclusionMeasuring time savings in a degenerative disease reflects the true goal of disease modifying treatments which is to slow down a progressive disease which will result in slowing of progression on all aspects or symptoms of disease. Progressive diseases would cease to be diseases at all if there was no progression of symptoms. Focusing on the clinical meaningfulness of each separate point on each outcome distracts us from this overall goal. Progression time savings is meaningful to patients, caregivers and all stakeholders and can be calculated from meaningful, clinically acceptable outcomes.

Development and validation of a caregiver‐reported outcome measure for Alzheimer’s disease: the Alzheimer’s Disease Caregiver Reported‐Health Index (ADCR‐HI), a fully validated tool to bolster clinical trial and research infrastructure

AbstractBackgroundAs therapeutic advancements are made in the field of Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI), it is important to have a fully validated, sensitive, and reliable, disease‐specific outcome measures that can accurately measure changes in AD and MCI symptomatic disease burden. The U.S. Food and Drug Administration has encouraged the use of caregiver reported outcome measures (CRO) to measure therapeutic benefit of new treatments on patient populations when a patient is unable to report on themselves. This research describes the creation, testing, and validation of a novel, multifactorial CRO: The Alzheimer’s Disease Caregiver Reported‐Health Index (ADCR‐HI).MethodsWe conducted interviews and a large cross‐sectional study involving individuals with AD and MCI and their caregivers to determine what symptoms and issues are most important to patients (Figure 1). Questions were selected for the ADCR‐HI based on their importance to patients with MCI and AD, potential to respond to therapeutic intervention, and generalizability. We beta tested the ADCR‐HI with caregivers of individuals with MCI and AD to determine its clarity, ease of use, and relevance to those with MCI and AD. We performed test‐retest reliability, known groups validity, internal consistency, and area under the curve analyses of the ADCR‐HI to assess the statistical characteristics, performance, and clinical meaningfulness of the outcome measure.ResultsThe content of the ADCR‐HI was validated using a cross‐sectional study of 329 caregivers. The ADCR‐HI contains 8 subscales that measure disease burden in the following areas: 1. Memory, 2. Cognitive health, 3. Social Health, 4. Physical Health, 5. Communication, 6. Fatigue, 7. Sleep, and 8. Emotional Health. The ADCR‐HI was identified as easy to use, relevant to the patient population, responsive, and clear during beta testing. The ADCR‐HI was shown to be reliable during test‐retest reliability testing with 34 caregivers and able to distinguish between patient cohorts with different disease severities.ConclusionThe ADCR‐HI is a valid, sensitive, and reliable marker of disease burden in AD. This disease‐specific outcome measure is available for use by researchers, clinicians, patient organizations, and companies to measure changes in disease burden during therapeutic trials.

Changing the trajectory of Alzheimer’s disease: What is a meaningful delay in disease progression?

AbstractBackgroundRecent trials of anti‐amyloid therapies have shown it is possible to change the course of early symptomatic Alzheimer’s disease (AD). However, the limited durations of these trials with the associated limited decline in the patient populations have left questions about the clinical meaningfulness of the observed treatment differences. Through progression analysis, one can quantify trial results in terms of time delay of progression. Compared to treatment differences on clinical scales, time delays are arguably more interpretable to patients and their families. However, it is yet to be established what constitutes a meaningful time delay in AD progression.MethodAssess how different hypothetical delays in disease progression in early symptomatic AD translate into treatment differences on the Clinical Dementia Rating Sum of Boxes (CDR‐SB) based on published results placebo‐arm trajectories in recent anti‐amyloid trials. Estimates are compared to published estimates of minimal clinically important differences (MCIDs) in AD and meaningful delays in progression in other diseases.ResultBased on placebo arms from six recent trials of anti‐amyloid antibodies, a 6‐month delay over 18 months (33% slowing) corresponded to treatment differences on CDR‐SB between ‐0.5 and ‐0.8, a 12‐month delay (67% slowing) corresponded to treatment differences between ‐1.0 and ‐1.7, and completely stopping progression (18‐month delay) corresponded to treatment differences between ‐1.6 and ‐2.3 (Figure 1, Table 1). Observed treatment effects in the EMERGE, CLARITY‐AD and TRAILBLAZER‐ALZ trials are consistent with approximately 4‐6 months delay of progression (22‐30% slowing, Figure 1). Established MCIDs in CDR‐SB in early AD range between 1.0 and 1.6, suggesting that a 12‐month delay or 67% slowing of disease progression in an 18‐month trial would be considered borderline in terms of clinical meaningfulness.ConclusionQuantifying treatment effects in progressive diseases such as AD in terms of time delays or slowing of progression may offer a more meaningful interpretation of the treatment effects. Based on the trajectories of placebo group in recent trials, we found that treatment effects matching conventionally used MCIDs in AD would correspond to a very substantial slowing of disease (>67%), suggesting that current MCIDs for CDR‐SB are likely inflated.

Development of a patient‐reported outcome measure for Alzheimer’s disease: the Alzheimer’s Disease‐Health Index (AD‐HI), a fully validated tool to bolster clinical trial and research infrastructure

AbstractBackgroundAs therapeutic advancements are made in Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI), it is important to have a fully validated, sensitive, and reliable disease‐specific patient‐reported outcome measure (PRO) to accurately measure changes in AD and MCI symptomatic disease burden. The U.S. Food and Drug Administration has encouraged the use of PROs to measure therapeutic benefit of potential new treatments. This research describes the development, testing, and validation of a novel, multifactorial PRO: The Alzheimer’s Disease‐Health Index (AD‐HI).MethodsWe conducted interviews and a large cross‐sectional study involving individuals with AD and MCI and their caregivers to determine what symptoms and issues are most important to patients (Figure 1). Questions were selected for the AD‐HI based on their importance to patients with MCI and AD, potential to respond to therapeutic intervention, and generalizability to the broader MCI and AD patient population as determined through qualitative interviews and a cross‐sectional study. We beta tested the initial version of the AD‐HI with individuals with MCI and AD to determine its clarity, ease of use, and relevance to those with MCI and AD. We performed test‐retest reliability, known groups validity, internal consistency, and area under the curve analyses of the AD‐HI to assess the statistical characteristics, performance, and clinical meaningfulness of the outcome measure.ResultsThe content of the AD‐HI was validated using a cross‐sectional study of 104 patients. The final version of the AD‐HI contains 9 subscales that measure disease burden in the following areas: 1) Memory, 2) Cognitive health, 3) Fatigue, 4) Sleep, 5) Social health, 6) Communication, 7) Emotional health, 8) Physical health, and 9) Pain. The AD‐HI was identified as easy to use, relevant to the patient population, responsive, and clear during beta testing. The ADCR‐HI was shown to be reliable during test‐retest reliability testing with 22 individuals and able to distinguish between patient cohorts with different disease severities.ConclusionThe AD‐HI is a is a valid, sensitive, and reliable marker of disease burden in AD This disease‐specific outcome measure is available for use by researchers, clinicians, patient organizations, and companies to measure changes in disease burden during therapeutic trials.

Assessment of Minimal Clinically Important Difference in Patient-Reported Myelofibrosis-Associated Symptoms Using an Anchor-Based Analysis Based on MANIFEST Arm 3 Data

Background Myelofibrosis (MF) is a life-threatening hematologic neoplasm that can arise as a primary condition or as a progression from polycythemia vera or essential thrombocythemia. The MF Symptom Assessment Form (MFSAF) v4.0 is a seven-item questionnaire that assesses symptom severity from the patients' (pts) perspective. Each item is rated on a scale from 0 (Absent) to 10 (Worst Imaginable). The MFSAF Total Symptom Score (TSS) ranges from 0 to 70, with higher scores indicating worse symptoms. A ≥50% reduction in TSS (TSS50) is a commonly used binary endpoint in clinical trials. However, the clinical meaningfulness of the dichotomization of response at 50% cutoff across the spectrum of responses remains uncertain. The relevance of considering TSS as a continuous endpoint in MF studies is assessed here to capture the full spectrum of symptom changes, enabling a potentially more accurate assessment of treatment effects. Pelabresib (CPI-0610) is an investigational oral small-molecule BET inhibitor, while the Janus kinase inhibitors (JAKis) ruxolitinib or fedratinib are the current standard of care for intermediate- or high-risk pts with MF.InArm 3 of the Phase 2 MANIFEST trial of JAKi treatment-naïve pts with MF treated with pelabresib and ruxolitinib, 56% achieved TSS50 response at Week (Wk) 24. Aims This anchor-based analysis aims to determine the minimal clinically important difference (MCID) of change in TSS as a continuous endpoint, based on data from JAKi treatment-naïve pts with MF treated with pelabresib and ruxolitinib, to better evaluate the incremental clinical benefit of treatment effects. Methods Data from Arm 3 of the MANIFEST Phase 2 study of treatment-naïve pts with MF treated with pelabresib combined with ruxolitinib were used (July 29, 2022 data cut). Anchor-based methods compare the change in a scale-based outcome measure with that of an established patient-reported outcome (PRO). These methods are commonly used to establish the MCID, defined as the smallest difference in score that pts consider beneficial. In this analysis, the Patient Global Impression of Change (PGIC), a seven-point scale reflecting overall improvement compared with baseline (BL), was used as the anchor PRO. On the PGIC, pts rated their change from ‘very much improved’ to ‘very much worse’ (Table 1). The relationship between TSS changes (percentage and absolute) at Wk 24 and PGIC categories was examined using correlation and graphical analyses. Linear and quantile regressions were applied to assess the impact of a one-point difference in PGIC score on TSS change at Wk 24, adjusting for BL TSS score. Only pts with available TSS and PGIC data at Wk 24 were included, with no imputation for missing values. Results In Arm 3 of the MANIFEST trial, 78 of 84 pts treated with pelabresib and ruxolitinib had complete TSS data and PGIC at Wk 24. At BL, mean TSS was 16.4 (SD=8.4), and median TSS was 15.5 (range 2.0-38.3). A -58.8% and -7.7 median percentage and absolute reduction in TSS at Wk 24 was observed, respectively. For PGIC at Wk 24 (Table 1), only six pts (7.7%) scored in the three worsening PGIC categories. Percentage and absolute changes in TSS, and the percentage TSS50 responders for each PGIC category are shown in Table 1. Linear regression demonstrated that a one-category increase in PGIC (indicating worsening) corresponded to an 11.89% increase (95% CI 3.12-20.65) in TSS (indicating worsening) at Wk 24. The quantile regression estimate for this relationship was 11.36% (3.53-19.19). For absolute change at Wk 24, a one-category increase in PGIC resulted in a 1.67 (range 0.74-2.60) increase in mean TSS, with a 1.87 (range 0.62-3.12) increase in median TSS. Conclusion Assuming a one-category change in the seven-category PGIC represents a clinically meaningful difference, the analyses suggest that the MCID in TSS for JAKi treatment-naïve pts with MF could be approximately 11-12% for percentage change from BL and approximately 1.5-2 points for absolute change from BL. These findings provide valuable guidance for assessing treatment outcomes and evaluating symptom improvements' clinical significance in this patient population. Further exploration of these findings requires larger data sets, which will be addressed in the forthcoming Phase 3 MANIFEST-2 study evaluating pelabresib and ruxolitinib versus placebo and ruxolitinib in JAKi treatment-naïve pts with MF.

Comparison of relative change with effect size metrics in Alzheimer’s disease clinical trials

BackgroundPer cent slowing of decline is frequently used as a metric of outcome in Alzheimer’s disease (AD) clinical trials, but it may be misleading. Our objective was to determine whether...

Is Dental Anxiety Associated with Oral Health-Related Quality of Life? Assessment of Statistical Significance and Clinical Meaningfulness in a Sample of Russian Medical and Dental Students.

Information about oral health-related quality of life (OHRQoL) and dental anxiety (DA) in Russian young adults is scarce. We investigated how DA is associated with OHRQoL in a group of medical and dental students in North-West Russia. The study had a cross-sectional design and included 807 students aged 18-25 years who attended the Northern State Medical University in Arkhangelsk. OHRQoL and DA were measured by the Oral Health Impact Profile (OHIP-14) and Corah's Dental Anxiety Scale (DAS), respectively. A questionnaire collected information on socio-demographics and self-reported oral health (OH) characteristics. A dental examination was executed to assess dental caries and oral hygiene. We observed differences in the OHIP-14 scores between dentally anxious and non-anxious students: unadjusted incidence rate ratio [IRR] = 1.65, 95% confidence interval [CI]: 1.29-2.12; after adjustment for socio-demographics and clinically assessed OH: IRR = 1.58, 95% CI: 1.23-2.02; after adjustment for socio-demographics, clinically assessed OH, and self-reported OH characteristics: IRR = 1.27, 95% CI: 0.99-1.63. The differences between estimated marginal means for the DAS categories in the models were 2.92, 2.51, and 1.24, respectively. Minimal clinically important differences of OHIP-14 fell between 1.68 and 2.51. We found a negative statistical association between DA and OHRQoL in our study sample, but after adjustment for potential confounders, the association lost its clinical importance.

Patient-centered collaborative research: Exploring perspectives on clinical meaningfulness in metastatic breast cancer with clinicians, patients, and caregivers.

338 Background: In metastatic breast cancer (mBC), treatment decision-making is informed by many factors including patient values, preferences, and care goals. Important to treatment decision-making is clinical meaningfulness, or the degree to which a treatment for mBC results in a meaningful change in the patient’s daily life, and clinically meaningful outcomes that are relevant to patients (e.g., survival, quality of life). However, patient and clinician perspectives and alignment on these concepts have not been well elucidated. Engaging patients and other key stakeholders as research collaborators is vital to guiding the delivery of high-quality cancer care focused on outcomes that patients considered meaningful. The aim of this work is to describe the implementation of an innovative multi-collaborator engagement with patient advocates and professional oncology societies to support a study examining perspectives on clinical meaningfulness in mBC treatment among clinicians, patients, and caregivers in the United States. Methods: This mixed-methods study utilizes qualitative semi-structured in-person and virtual focus groups to inform the development of collaborator-specific surveys on clinical meaningfulness in mBC. A multi-collaborator engagement approach was selected to support the conception, implementation, and completion of this study. Specifically, we have convened a collaboration with patient advocacy groups and professional membership organizations to engage researchers, patients, caregivers, and clinicians. The collaboration is designed to: i) facilitate the development of study protocols and key data collection documents; ii) review and reflect on findings and salience for relevant populations; and iii) participate in dissemination activities whereby collaborators co-create, co-present and discuss findings and their impact on clinical practice. Results: To date, we have partnered with four breast cancer patient advocacy groups representing sociodemographic diverse constituencies throughout the US and three oncology professional membership organizations. By describing how to implement these partnerships, we seek to present a collaboration roadmap that can be replicated and adapted to similar studies in oncology care delivery. Such a comprehensive and rigorous approach aims to enhance the quality of data collection and interpretation, generating evidence that will optimally improve patient-centered mBC care delivery and meaningful patient outcomes. Conclusions: Engaging patients and other key collaborators in research is important to generate clinically meaningful evidence to those involved in mBC treatment decision-making. This study offers a robust methodological approach for gaining insights into the delivery of patient-centered cancer care.

Symposium 08: Neuropsychological Considerations for Alzheimer's Disease Clinical Trials

Summary Abstract:The 2011 National Institute on Aging and Alzheimer's Association (NIA-AA) criteria for the diagnosis of Alzheimer's disease (AD) focused on clinical signs and symptoms to make a diagnosis of probable or possible AD. Under these criteria, emphasis was placed on gathering objective evidence of cognitive decline, which gave neuropsychologists a central role as diagnosticians in AD clinical trials. The release of the 2018 NIA-AA research framework put greater emphasis on the use of biomarkers, especially measures of amyloid, tau, and neurodegeneration, to define AD. Once AD is defined based on these biomarkers, it is staged via clinical signs and symptoms. Thus, the role of neuropsychologists has shifted from being central to diagnosis to a possibly more ancillary role of staging the disease once it is determined to be present. The move away from clinical signs towards biomarkers only became more prominent with the recent, controversial Food and Drug Administration approval of Aducanumab as an AD treatment based on evidence of change in biomarkers without clear evidence of clinical benefit. In this landscape, the fit of neuropsychologists in AD clinical trial research has become less clear.This symposium will address the role of neuropsychologists in modern AD clinical trial research. The presenters will highlight varied ways in which neuropsychologists can enrich and improve AD clinical trials. First, Dr. Dustin Hammers from Indiana University will discuss how neuropsychological methods can help us to understand which participants do, and perhaps more importantly, do not get enrolled in clinical trials. Second, Dr. Mirella Diaz-Santos from the University of California Los Angeles will summarize her work to enroll Hispanic individuals in the Human Connectome Project, improving inclusivity. Third, Dr. Tamar Gollan from the University of California San Diego will summarize her work on novel behavioral markers of AD risk discovered from the study of Spanish-English bilingual patients. Fourth, Dr. Andrew Kiselica from the University of Missouri will highlight psychometric considerations in interpreting clinically meaningfully change in AD clinical trials using data from the National Alzheimer's Coordinating Center. Fifth, Dr. Samantha John from the University of Nevada at Las Vegas will discuss the influence of race/ethnicity on how clinically meaningful change is defined using data from a diverse cohort.Dr. Kevin Duff will serve as discussant for this series of studies. He will highlight the important roles that neuropsychologists can play in improving AD clinical trial screening processes, expanding inclusion of diverse patients into trials, and enhancing interpretation of the clinical meaningfulness of trial results. He will also reflect on the future of neuropsychology's role in the AD clinical trial landscape and encourage audience questions and responses to the research presented.

Burosumab Improves Patient-Reported Outcomes in Adults With Tumor-Induced Osteomalacia: Mixed-Methods Analysis.

Tumor-induced osteomalacia (TIO) is an ultra-rare disease caused by tumors that secrete fibroblast growth factor 23, leading to chronic hypophosphatemia, poor skeletal health, and impaired physical function. In a phase 2 trial (UX023T-CL201; NCT02304367; n = 14), 48 weeks of burosumab treatment restored phosphate homeostasis, with improvements in skeletal health, functional mobility, and patient-reported pain, fatigue, and health-related quality of life (HRQL) (SF-36 v2). Here, we report an exploratory mixed-methods analysis of change from baseline after 144 weeks of burosumab treatment alongside qualitative data from exit interviews with 8 of 14 trial participants to evaluate meaningful treatment effects from a patient perspective. The interview subset (n = 8) reported pain and fatigue and compromised HRQL at baseline. In the interviews, participants reported that compromised HRQL and pain were the most important aspects of the disease to treat; both were considered more bothersome than fatigue and compromised physical function and activities of daily living. Improvements in pain and fatigue after treatment were reported, some of which achieved statistically and/or clinically meaningful thresholds. Furthermore, improvements in SF-36 v2 scores were most pronounced in the Physical Component Score and its Physical Function and Bodily Pain domains. Overall, the interview subset provided descriptions of symptomatic improvement and its clinical meaningfulness, including physical function, participation in activities of daily living, and mental well-being. Thus, this exploratory mixed-methods analysis provides deeper understanding of patients' perception of clinical meaningfulness beyond that articulated in validated patient-reported outcome instruments. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

3 Ethnoracial Differences in Anchor Agreement and MCID Estimation in Alzheimer’s Disease

Objective:Alzheimer’s disease (AD) clinical trials lack diverse representation, limiting their generalizability. In addition, the clinical meaningfulness of observed changes during treatment may vary as a function of participant characteristics. Defining meaningful change in AD within diverse ethnoracial groups is therefore greatly needed. Meaningful change in AD trials can be assessed by three different anchors: participants, informants, or clinicians. Previous research has suggested that estimations of the minimal clinically important difference (MCID) vary by disease severity, choice of anchor, and anchor agreement. These relationships have been studied primarily within non-Hispanic white (NHW) samples. This project evaluates anchor-based MCID within and across the three most prevalent ethnoracial groups in the United States, non-Hispanic White (NHW), Hispanic/Latino (H/L), and Black/African-American (B/AA).Participants and Methods:Data from the National Alzheimer’s Coordinating Center Uniform Dataset (NACC UDS) were used to investigate MCID within older adults (ages 50+) diagnosed as cognitively normal or cognitively impaired due to suspected AD. Data were taken from all versions of the UDS and consisted of all available participants with two consecutive annual visits. The identified sample (N=22,043) is approximately 83.6% NHW, 4.7% H/L, and 11.7% B/AA. Participant, informant, and clinician anchor variables were utilized to compare proportions of anchor agreement within and across ethnoracial groups. MCID on the Mini-Mental State Exam (MMSE) was estimated within each ethnoracial group and compared across the independent variables of anchor agreement and disease severity (cognitively normal (CN), mild cognitive impairment (MCI), and dementia) in 2x3 ANOVAs.Results:Participant age (M = 71.56, SD = 9.03) did not significantly differ across ethnoracial groups; years of education significantly differed across groups, p < .001, with NHW (M=15.83 SD=3.05), H/L (M=12.49, SD=5.01), and B/AA (M=14.42, SD=3.22). Across all three anchors (participant, informant, clinician), unanimous agreement about the presence or absence of a decline in functioning was present in about 75.1% of the full sample. To further explore agreement differences across groups, anchor agreement was classified into a 3-level variable: 1) agreement that the participant remained stable over time, 2) agreement that the participant declined, and 3) disagreement. The proportion of each level within each ethnoracial group was significantly different, (x2(4, n = 22,043) = 179.16, p < .001, phi = .09, NHW (34.5% agreement-stable, 41.4% agreement-declined, 24.1% disagreement), H/L (30.5%, 42.6%, 26.9%, respectively), and B/AA (42.2%, 28.1%, 29.7%, respectively). MCID estimates on the MMSE followed similar trends within each ethnoracial group. There was a significant main effect of disease severity, such that MCID estimates increased in magnitude with increasing disease severity. There were no significant main effects of anchor agreement for any ethnoracial group. Within the NHW sample only, an interaction effect between diagnostic severity and anchor agreement was significant (p = .007).Conclusions:Across ethnoracial groups, MCID estimates on the MMSE are reliably influenced by the severity of disease. However, the benefit of anchor-based MCID estimates may vary by ethnoracial group with respect to both anchor choice and use of anchor agreement. The origins of anchor disagreement and perceived stability in functioning warrant further exploration.

Impact of walk advice alone or in combination with supervised or home-based structured exercise on patient-reported physical function and generic and disease-specific health related quality of life in patients with intermittent claudication, a secondary analysis in a randomized clinical trial

BackgroundSupervised exercise is an integral part of the recommended first-line treatment for patients with intermittent claudication (IC). By reflecting the patients’ perspectives, patient-reported outcome measurements provide additional knowledge to the biomedical endpoints and are important outcomes to include when evaluating exercise interventions in patients with IC. We aimed to evaluate the one-year impact of three strategies: unsupervised Nordic pole walk advice (WA), WA + six months of home-based structured exercise (HSEP) or WA + six months of hospital-based supervised exercise (SEP) on health-related quality of life and patient-reported physical function in patients with IC.MethodsThis secondary exploratory analysis of a multi-center, randomized clinical trial compared three exercise strategies. The primary outcome of the secondary analysis was the one-year change in the 36-Item Short-Form (SF-36). Secondary outcomes were three- and six-months SF-36 changes alongside three, six- and 12-months changes in the disease-specific Vascular Quality of Life instrument (VascuQoL) and the Patient-Specific Functional Scale (PSFS). The Kruskal–Wallis test with Bonferroni-adjusted post-hoc tests were used for between-group comparisons. Effect size calculations were used to describe the size of observed treatment effects, and the clinical meaningfulness of observed changes in the VascuQoL summary score at one year was studied using established minimally important difference (MID) thresholds.ResultsA total of 166 patients with IC, mean age: 72.1 (SD 7.4) years, 41% women, were randomized. No significant between-group differences were observed over time for the SF-36 or the PSFS scores whereas some significant between-group differences were observed in the VascuQoL domain and summary scores over time, favoring SEP and/or HSEP over WA. The observed SF-36 and VascuQoL domain and summary score effect sizes were small to moderate, and many domain score effect sizes also remained unchanged over time. A significantly higher proportion of the patients in the SEP group reached the VascuQoL summary score MID of improvement in one year.ConclusionClinically important improvements were observed in SEP using the VascuQoL, while we did not observe any significant between-group differences using the SF-36. Whereas effect sizes for the observed changes over time were generally small, a significantly higher proportion of patients in SEP reached the VascuQoL MID of improvement.Trial registrationNCT02341716, January 19, 2015 (retrospectively registered).