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Establishing clinically meaningful changes in pain experiences remains important for clinical trials of chronic pain treatments. Regulatory guidance and pain measurement initiatives have recommended including patient-reported global assessment measures (eg, Patient-Global Impression of Change [PGIC]) to aid interpretation of within-patient differences in domain-specific clinical trial outcomes (eg, pain intensity). The objectives of this systematic review were to determine the frequency of global assessment measures inclusion, types of measures, domains assessed, number and types of response options, and how measures were analyzed. Of 4172 abstracts screened across 6 pain specialty journals, we reviewed 96 clinical trials of chronic pain treatments. Fiftytwo (54.2%) studies included a global assessment measure. The PGIC was most common (n 5 28; 53.8%), with relatively infrequent use of other measures. The majority of studies that used a global assessment measure (n 5 31; 59.6%) assessed change or improvement in an unspecified domain. Others assessed overall condition severity (n 5 9; 17.3%), satisfaction (n 5 8; 15.4%), or overall health status/recovery (n 5 5; 9.6%). The number, range, and type of response options were variable and frequently not reported. Response options and reference periods even differed within the PGIC. Global assessment measures were most commonly analyzed as continuous variables (n 5 24; 46.2%) or as dichotomous variables with positive categories combined to calculate the proportion of participants with a positive response to treatment (n 5 18; 34.6%). This review highlights the substantial work necessary to clarify measurement and use of patient global assessment in chronic pain trials and provides short- and long-term considerations for measure selection, reporting and analysis, and measure development. [ABSTRACT FROM AUTHOR]

The emergence of the United States Food and Drug Administration (FDA)‐approved amyloid‐targeting therapies for Alzheimer's disease challenges clinicians and healthcare providers with a transformative landscape. Effectively communicating the risks, benefits, burdens, costs, and available support associated with these novel disease‐modifying treatments to patients, families, and other healthcare providers is essential but complex. In response, the Alzheimer's Association's Clinical Meaningfulness Workgroup has proposed language surrounding treatment eligibility, benefits, amyloid‐related imaging abnormalities (ARIA), apolipoprotein E (APOE) genotyping, and treatment costs, serving as a resource to healthcare professionals in navigating discussions with patients and their families. As the landscape evolves with the approval of new Alzheimer's therapies, this resource stands poised for updates, ensuring its continued relevance in facilitating informed and meaningful patient‐provider dialogues. Highlights: Effective communication of risks, benefits, burdens, and costs of FDA‐approved amyloid‐targeting antibodies is essential to patients, families, and healthcare providers.The Alzheimer's Association's Clinical Meaningfulness Workgroup provides language for physicians and healthcare providers around treatment eligibility, benefits, ARIA, APOE genotyping, and treatment costs.This supplementary resource may be updated as new AD therapies become approved. [ABSTRACT FROM AUTHOR]

Incorporating person-centered outcomes into clinical trials for neurodegenerative diseases has been challenging due to a deficiency in quantitative measures. Meanwhile, the integration of personally meaningful treatment targets in clinical practice remains qualitative, failing to truly inform evaluations, therapeutic interventions and longitudinal monitoring and support. We discuss the current advances and future directions in capturing individualized brain health outcomes and present an approach to integrate person-centered outcome in a scalable manner. Our approach stems from the evidence-based electronic Person-Specific Outcome Measure (ePSOM) program which prompts an individual to define personally meaningful treatment priorities and report level of confidence in managing items that matter to the individual the most (e.g., "Do I feel confident in my ability to contribute to a conversation?"). Deployed either as a single version (person only) or a dyad version (person and care partner), our proposed tool could be used as an endpoint in clinical trials, offering proof of meaningful intervention benefits and in clinical practice, by establishing an anchor for the therapeutic objectives sought by the individual. [ABSTRACT FROM AUTHOR]

Incorporating person-centered outcomes into clinical trials for neurodegenerative diseases has been challenging due to a deficiency in quantitative measures. Meanwhile, the integration of personally meaningful treatment targets in clinical practice remains qualitative, failing to truly inform evaluations, therapeutic interventions and longitudinal monitoring and support. We discuss the current advances and future directions in capturing individualized brain health outcomes and present an approach to integrate person-centered outcome in a scalable manner. Our approach stems from the evidence-based electronic Person-Specific Outcome Measure (ePSOM) program which prompts an individual to define personally meaningful treatment priorities and report level of confidence in managing items that matter to the individual the most (e.g., “Do I feel confident in my ability to contribute to a conversation?”). Deployed either as a single version (person only) or a dyad version (person and care partner), our proposed tool could be used as an endpoint in clinical trials, offering proof of meaningful intervention benefits and in clinical practice, by establishing an anchor for the therapeutic objectives sought by the individual.

The efficient and accurate execution of clinical trials testing novel treatments for Alzheimer's disease (AD) is a critical component of the field's collective efforts to develop effective disease‐modifying treatments for AD. The lengthy and heterogeneous nature of clinical progression in AD contributes to the challenges inherent in demonstrating a clinically meaningful benefit of any potential new AD therapy. The failure of many large and expensive clinical trials to date has prompted a focus on optimizing all aspects of decision making, to not only expedite the development of new treatments, but also maximize the value of the information that each clinical trial yields, so that all future clinical trials (including those that are negative) will contribute toward advancing the field. To address this important topic the Alzheimer's Association Research Roundtable convened December 1–2, 2020. The goals focused around identifying new directions and actionable steps to enhance clinical trial decision making in planned future studies. [ABSTRACT FROM AUTHOR]

Abstract Introduction In this phase of the ongoing What Matters Most study series, designed to evaluate concepts that are meaningful to people affected by Alzheimer’s disease (AD), we quantified the importance of symptoms, impacts, and outcomes of AD to people at risk for or with AD and care partners of people with AD. Methods We administered a web-based survey to individuals at risk for or with AD (Group 1: unimpaired cognition with evidence of AD pathology; Group 2: AD risk factors and subjective cognitive complaints/mild cognitive impairment; Group 3: mild AD) and to care partners of individuals with moderate AD (Group 4) or severe AD (Group 5). Respondents rated the importance of 42 symptoms, impacts, and outcomes on a scale ranging from 1 (“not at all important”) to 5 (“extremely important”). Results Among the 274 respondents (70.4% female; 63.1% white), over half of patient respondents rated all 42 items as “very important” or “extremely important,” while care partners rated fewer items as “very important” or “extremely important.” Among the three patient groups, the minimum (maximum) mean importance rating for any item was 3.4 (4.6), indicating that all items were at least moderately to very important. Among care partners of people with moderate or severe AD, the minimum (maximum) mean importance rating was 2.1 (4.4), indicating that most items were rated as at least moderately important. Overall, taking medications correctly, not feeling down or depressed, and staying safe had the highest importance ratings among both patients and care partners, regardless of AD phase. Conclusion Concepts of importance to individuals affected by AD go beyond the common understanding of “cognition” or “function” alone, reflecting a desire to maintain independence, overall physical and mental health, emotional well-being, and safety. Preservation of these attributes may be key to understanding whether interventions deliver clinically meaningful outcomes.

Abstract The efficient and accurate execution of clinical trials testing novel treatments for Alzheimer's disease (AD) is a critical component of the field's collective efforts to develop effective disease‐modifying treatments for AD. The lengthy and heterogeneous nature of clinical progression in AD contributes to the challenges inherent in demonstrating a clinically meaningful benefit of any potential new AD therapy. The failure of many large and expensive clinical trials to date has prompted a focus on optimizing all aspects of decision making, to not only expedite the development of new treatments, but also maximize the value of the information that each clinical trial yields, so that all future clinical trials (including those that are negative) will contribute toward advancing the field. To address this important topic the Alzheimer's Association Research Roundtable convened December 1–2, 2020. The goals focused around identifying new directions and actionable steps to enhance clinical trial decision making in planned future studies.

Alzheimer's disease (AD) clinical trials are designed and powered to detect the impact of a therapeutic intervention, and there has been considerable discussion on what constitutes a clinically meaningful change in those receiving treatment versus placebo. The pathology of AD is complex, beginning many years before clinical symptoms are detectable, with multiple potential opportunities for therapeutic engagement. Introducing treatment strategies early in the disease and assessing meaningful change over the course of an 18‐month clinical trial are critical to understanding the value to an effective intervention. With new clinical trial data expected soon on emerging therapeutics from several AD studies, the Alzheimer's Association convened a work group of experts to discuss key considerations for interpreting data from cognitive and functional measures and what is considered a clinically meaningful benefit or meaningful slowing of this fatal disease. Our expectations of outcomes from therapeutic interventions in AD may need to be modified. [ABSTRACT FROM AUTHOR]

Introduction: In this phase of the ongoing What Matters Most study series, designed to evaluate concepts that are meaningful to people affected by Alzheimer's disease (AD), we quantified the importance of symptoms, impacts, and outcomes of AD to people at risk for or with AD and care partners of people with AD. Methods: We administered a web-based survey to individuals at risk for or with AD (Group 1: unimpaired cognition with evidence of AD pathology; Group 2: AD risk factors and subjective cognitive complaints/mild cognitive impairment; Group 3: mild AD) and to care partners of individuals with moderate AD (Group 4) or severe AD (Group 5). Respondents rated the importance of 42 symptoms, impacts, and outcomes on a scale ranging from 1 ("not at all important") to 5 ("extremely important"). Results: Among the 274 respondents (70.4% female; 63.1% white), over half of patient respondents rated all 42 items as "very important" or "extremely important," while care partners rated fewer items as "very important" or "extremely important." Among the three patient groups, the minimum (maximum) mean importance rating for any item was 3.4 (4.6), indicating that all items were at least moderately to very important. Among care partners of people with moderate or severe AD, the minimum (maximum) mean importance rating was 2.1 (4.4), indicating that most items were rated as at least moderately important. Overall, taking medications correctly, not feeling down or depressed, and staying safe had the highest importance ratings among both patients and care partners, regardless of AD phase. Conclusion: Concepts of importance to individuals affected by AD go beyond the common understanding of "cognition" or "function" alone, reflecting a desire to maintain independence, overall physical and mental health, emotional well-being, and safety. Preservation of these attributes may be key to understanding whether interventions deliver clinically meaningful outcomes. [ABSTRACT FROM AUTHOR]

Abstract Background The need for preventive therapies that interrupt the progression of Alzheimer’s disease (AD) before the onset of symptoms or when symptoms are emerging is urgent and has spurred the ongoing development of disease-modifying therapies (DMTs) in preclinical and early AD (mild cognitive impairment [MCI] to mild dementia). Assessing the meaningfulness of what are likely small initial treatment effects in these earlier stages of the AD patho-clinical disease continuum is a major challenge and warrants further consideration. Body To accommodate a shift towards earlier intervention in AD, we propose meaningful benefits as a new umbrella concept that encapsulates the spectrum of potentially desirable outcomes that may be demonstrated in clinical trials and other studies across the AD continuum, with an emphasis on preclinical AD and early AD (i.e., MCI due to AD and mild AD dementia). The meaningful benefits framework applies to data collection, assessment, and communication across three dimensions: (1) multidimensional clinical outcome assessments (COAs) including not only core disease outcomes related to cognition and function but also patient- and caregiver-reported outcomes, health and economic outcomes, and neuropsychiatric symptoms; (2) complementary analyses that help contextualize and expand the understanding of COA-based assessments, such as number-needed-to-treat or time-to-event analyses; and (3) assessment of both cumulative benefit and predictive benefit, where early changes on cognitive, functional, or biomarker assessments predict longer-term clinical benefit. Conclusion The concept of meaningful benefits emphasizes the importance of multidimensional reporting of clinical trial data while, conceptually, it advances our understanding of treatment effects in preclinical AD and mild cognitive impairment due to AD. We propose that such an approach will help bridge the gap between the emergence of DMTs and their clinical use, particularly now that a DMT is available for patients diagnosed with MCI due to AD and mild AD dementia.

Abstract Background Everyday functioning is a clinically relevant concept in dementia, yet little is known about the clinical meaningfulness of scores on functional outcome measures. We aimed to establish clinically meaningful scoring categories for the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q), representing no, mild, moderate and severe problems in daily functioning. Methods Informal caregivers (n = 6) of memory-clinic patients and clinicians (n = 13), including neurologists and nurse specialists, working at various memory clinics in The Netherlands. In focus groups, participants individually ranked nine summaries of fictional patients from least to most impairment in daily functioning. Then, they placed bookmarks to demarcate the thresholds for mild, moderate and severe problems. Individual bookmark placements were then discussed to reach consensus. Clinicians completed a survey in which they placed bookmarks, individually. Results While individual categorizations varied somewhat, caregivers and clinicians generally agreed on the thresholds, particularly about the distinction between ‘no’ and ‘mild’ problems. Score categories were no problems (T-score ≥ 60), mild problems (T-score 50–59), moderate problems (T-score 40–49), and severe problems in daily functioning (T-score

What is this summary about? This is a plain language summary of an article published in the journal Advances in Therapy. In 2020, the US Food and Drug Administration (also called the FDA) approved a medicine called vibegron to treat overactive bladder, also called OAB. The key results used to approve vibegron were from the EMPOWUR study. In the EMPOWUR study, participants who took vibegron had fewer urination episodes, urgency episodes, and bladder leaks each day than those who took a pill containing no medicine, called a placebo. At the end of the study, participants also rated how much their overactive bladder symptoms changed overall during EMPOWUR by responding to a survey. Many participants rated their overactive bladder symptoms as improved overall. This study asked if improvements in the number of urination episodes, urgency episodes, and bladder leaks caused by urgency were associated with feeling better overall. This study also looked at how many participants in the EMPOWUR study had improvements in the number of urination episodes, urgency episodes, and bladder leaks that were big enough to matter. A separate group of people with overactive bladder were asked about the magnitude of improvements that would be important to them. This group had not participated in the EMPOWUR study. What were the results? EMPOWUR participants who reported that taking medicine resulted in their overactive bladder symptoms getting better overall also generally reported fewer daily urinations, urgency episodes, and bladder leaks after treatment. Many had changes in their symptoms that were meaningful. Meaningful was defined for each symptom as: at least 15% fewer urinations, 50% fewer urgency episodes, and 75% fewer bladder leaks. Participants who received vibegron had meaningful reductions in the daily number of episodes of urination, urgency, and bladder leaks more often than those who received the placebo (pill with no active medicine). People with overactive bladder who did not participate in the study were interviewed and said that improvements to those symptoms, similar to those seen in the EMPOWUR study, would be important to them. What do the results mean? This study suggests that the results we measured in the EMPOWUR study may also reflect changes in overactive bladder symptoms that are big enough to be important to people with overactive bladder. Many participants who took vibegron in the EMPOWUR study felt that it helped to improve their individual overactive bladder symptoms. This may also help improve quality of life of participants.

To understand the potential benefits of emerging Alzheimer's disease (AD) therapies within and beyond clinical trial settings, there is a need to advance current outcome measurements into meaningful information relevant to all stakeholders. The relationship between the impact on disease biology and clinically measurable outcomes in cognition, function, and behavior must be considered when defining the meaningful benefit of early AD therapies. In this review, we discuss: (1) the lack of consideration for biomarkers in the current concept of meaningfulness in AD; (2) the lack of gold standards for determining minimal biologically and clinically important differences (MBCIDs) in AD trials; (3) how the treatment benefits of disease-modifying treatments are cumulative and increase over time; and (4) the different concepts of meaningfulness among key stakeholders. This review utilizes the future clinical biological framework of AD and aims to further integrate and expand the parameters of meaningful benefits toward a precision medicine framework. HIGHLIGHTS: Definition of meaningful benefit from Alzheimer's disease (AD) treatment varies across disease stage and stakeholder perspectives. Observable and meaningful outcomes must consider the clinical-biological nature of AD. Statistically significant effects or outcomes do not always equate to clinically meaningfulness. Assessment tools must reflect stage-specific subtle changes following treatment. Real-world evidence will support consensus, definition, and interpretation of clinical meaningfulness., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Alzheimer's disease is the most prevalent form of dementia in the elderly, which is clinically characterized by a gradual and progressive deterioration of cognitive functions. The central and early role of β-amyloid in the pathogenesis of Alzheimer's disease is supported by a plethora of studies including genetic analyses, biomarker research and genome-wide association studies in both familial (early-onset) and sporadic (late-onset) forms of Alzheimer's. Monoclonal antibodies directed against β-amyloid demonstrate slowing of the clinical deterioration of patients with early Alzheimer's disease. Aducanumab, lecanemab and donanemab clinical trials showed slowing of Alzheimer's disease progression on composite scores by 25-40% based on the measure used. Anti-β-amyloid antibodies can cause side effects of bleeding and swelling in the brain, called amyloid-related imaging abnormalities. Amyloid-related imaging abnormalities typically occur early in treatment and are often asymptomatic, and though in rare cases, they can lead to serious or life-threatening events. The aim of this review is to evaluate the clinical meaningfulness of anti-β-amyloid therapies amidst amyloid-related imaging abnormalities concern in Alzheimer's disease., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The emergence of the United States Food and Drug Administration (FDA)-approved amyloid-targeting therapies for Alzheimer's disease challenges clinicians and healthcare providers with a transformative landscape. Effectively communicating the risks, benefits, burdens, costs, and available support associated with these novel disease-modifying treatments to patients, families, and other healthcare providers is essential but complex. In response, the Alzheimer's Association's Clinical Meaningfulness Workgroup has proposed language surrounding treatment eligibility, benefits, amyloid-related imaging abnormalities (ARIA), apolipoprotein E (APOE) genotyping, and treatment costs, serving as a resource to healthcare professionals in navigating discussions with patients and their families. As the landscape evolves with the approval of new Alzheimer's therapies, this resource stands poised for updates, ensuring its continued relevance in facilitating informed and meaningful patient-provider dialogues. HIGHLIGHTS: Effective communication of risks, benefits, burdens, and costs of FDA-approved amyloid-targeting antibodies is essential to patients, families, and healthcare providers. The Alzheimer's Association's Clinical Meaningfulness Workgroup provides language for physicians and healthcare providers around treatment eligibility, benefits, ARIA, APOE genotyping, and treatment costs. This supplementary resource may be updated as new AD therapies become approved., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Abstract Background The 32-item Motor Function Measure (MFM32) is a clinician-reported outcome measure used to assess the functional abilities of individuals with neuromuscular diseases, including those with spinal muscular atrophy (SMA). This two-part study explored the relationship between the functional abilities assessed in the MFM32 and activities of daily living (ADLs) from the perspective of individuals with Type 2 and Type 3 (non-ambulant and ambulant) SMA and their caregivers through qualitative interviews and a quantitative online survey. Methods In-depth, semi-structured, qualitative interviews were conducted with individuals with SMA and caregivers from the US. Subsequently, a quantitative online survey was completed by individuals with SMA or their caregivers from France, Germany, Italy, Poland, Spain, Canada, the United States (US) and the UK. In both parts of the study, participants were asked to describe the ADLs considered to be related to the functional abilities assessed in the MFM32. Results from the qualitative interviews informed the content of the quantitative online survey. Results Qualitative interviews were conducted with 15 adult participants, and 217 participants completed the quantitative online survey. From the qualitative interviews, all of the functional abilities assessed in the patient-friendly MFM32 were deemed as related to one or more ADL. The specific ADLs that participants considered related to the patient-friendly MFM32 items could be grouped into 10 key ADL domains: dressing, mobility/transferring, self-care, self-feeding, reaching, picking up and holding objects, physical activity, writing and technology use, social contact/engagement, toileting and performing work/school activities. These results were confirmed by the quantitative online survey whereby the ADLs reported to be related to each patient-friendly MFM32 item were consistent and could be grouped into the same 10 ADL domains. Conclusion This study provides in-depth evidence from the patient/caregiver perspective supporting the relevance of the patient-friendly MFM32 items to the ADLs of individuals with Type 2 and Type 3 SMA.

Background: The need for preventive therapies that interrupt the progression of Alzheimer's disease (AD) before the onset of symptoms or when symptoms are emerging is urgent and has spurred the ongoing development of disease-modifying therapies (DMTs) in preclinical and early AD (mild cognitive impairment [MCI] to mild dementia). Assessing the meaningfulness of what are likely small initial treatment effects in these earlier stages of the AD patho-clinical disease continuum is a major challenge and warrants further consideration. Body: To accommodate a shift towards earlier intervention in AD, we propose meaningful benefits as a new umbrella concept that encapsulates the spectrum of potentially desirable outcomes that may be demonstrated in clinical trials and other studies across the AD continuum, with an emphasis on preclinical AD and early AD (i.e., MCI due to AD and mild AD dementia). The meaningful benefits framework applies to data collection, assessment, and communication across three dimensions: (1) multidimensional clinical outcome assessments (COAs) including not only core disease outcomes related to cognition and function but also patient- and caregiver-reported outcomes, health and economic outcomes, and neuropsychiatric symptoms; (2) complementary analyses that help contextualize and expand the understanding of COA-based assessments, such as number-needed-to-treat or time-to-event analyses; and (3) assessment of both cumulative benefit and predictive benefit, where early changes on cognitive, functional, or biomarker assessments predict longer-term clinical benefit. Conclusion: The concept of meaningful benefits emphasizes the importance of multidimensional reporting of clinical trial data while, conceptually, it advances our understanding of treatment effects in preclinical AD and mild cognitive impairment due to AD. We propose that such an approach will help bridge the gap between the emergence of DMTs and their clinical use, particularly now that a DMT is available for patients diagnosed with MCI due to AD and mild AD dementia. [ABSTRACT FROM AUTHOR]

Background: Everyday functioning is a clinically relevant concept in dementia, yet little is known about the clinical meaningfulness of scores on functional outcome measures. We aimed to establish clinically meaningful scoring categories for the Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q), representing no, mild, moderate and severe problems in daily functioning.Methods: Informal caregivers (n = 6) of memory-clinic patients and clinicians (n = 13), including neurologists and nurse specialists, working at various memory clinics in The Netherlands. In focus groups, participants individually ranked nine summaries of fictional patients from least to most impairment in daily functioning. Then, they placed bookmarks to demarcate the thresholds for mild, moderate and severe problems. Individual bookmark placements were then discussed to reach consensus. Clinicians completed a survey in which they placed bookmarks, individually.Results: While individual categorizations varied somewhat, caregivers and clinicians generally agreed on the thresholds, particularly about the distinction between 'no' and 'mild' problems. Score categories were no problems (T-score ≥ 60), mild problems (T-score 50-59), moderate problems (T-score 40-49), and severe problems in daily functioning (T-score < 40), on a scale ranging 20-80.Conclusions: Our findings provide categories for determining the level of functional impairment, which can facilitate interpretation of A-IADL-Q scores. These categories can subsequently be used by clinicians to improve communication with patients and caregivers. [ABSTRACT FROM AUTHOR]

In order for patients to gain the benefit of innovation in cardiac CT, it is necessary for coding, coverage, and payment to adapt to the novelty of algorithm-based healthcare procedures and services (ABHS). Appendix S to the CPT Code Set, the "AI Taxonomy", enables creation of discrete and differentiable codes for reimbursement of ABHS which has been clinically validated and FDA-labeled. Payment policy in OPPS and PFS is evolving to take account of the unique opportunities and issues arising from the clinical adoption of ABHS., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2024 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Introduction: Consensus definitions of meaningful within-patient change (MWPC) on the Clinical Dementia Rating-Sum of Boxes (CDR-SB) are needed. Existing estimates use clinician-rated anchors in clinically diagnosed Alzheimer's disease (AD) populations. Incorporating the care partner perspective offers important insights, and evaluating biomarker-confirmed cohorts aligns estimates with ongoing trials., Methods: Anchor-based analyses were conducted to evaluate MWPC on the CDR-SB in early AD (Tauriel; NCT03289143) using Caregiver Global Impression of Change in memory or daily activities., Results: Across time points and anchors, mean CDR-SB changes associated with the "somewhat worse" category ranged from 1.50 to 2.12 in early AD, 1.07 to 2.06 in mild cognitive impairment-AD, and 1.79 to 2.25 in mild AD., Discussion: The proposed ranges are appropriate to define meaningful progression on the CDR-SB in similar cohorts and support the interpretation of treatment benefit through MWPC analyses. Thresholds should be calibrated to the context of use; lower/higher thresholds may be applicable in studies of earlier/later disease over shorter/longer durations., Highlights: Within-patient CDR-SB change thresholds are provided using caregiver-rated anchors. 1.5 to 2.5 points may be an appropriate range in early AD trials of similar durations. Cumulative distribution function plots illustrate the benefit of a given treatment. When selecting thresholds, the target population and study design should be considered., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Abstract Introduction The Integrated Alzheimer's Disease Rating Scale (iADRS) has been used to detect differences in disease progression in early Alzheimer's disease (AD). The objectives of this study were to enhance understanding of iADRS point changes within the context of clinical trials, and to establish a minimal clinically important difference (MCID) on the iADRS. Methods Data from AMARANTH and EXPEDITION3 were analyzed using various approaches, including anchor‐based, distribution‐based, regression analyses, and cumulative distribution function (CDF) plots. Three potential anchors were examined, including the Clinical Dementia Rating—Sum of Boxes, Mini‐Mental State Examination, and Functional Activities Questionnaire. Triangulation of all results was used to determine the MCID for participants with mild cognitive impairment (MCI) due to AD and AD with mild dementia. Results All three anchors met criteria for “sufficiently associated” (|r| = 0.4–0.7). Cumulatively, results from anchor‐based and distribution‐based results converged to suggest an iADRS MCID of 5 points for MCI due to AD and 9 points for AD with mild dementia. Regression analyses and CDF plots supported these values. Discussion These findings suggest the iADRS can be used in clinical trials to detect a clinically meaningful outcome of AD progression.

Introduction: The Integrated Alzheimer's Disease Rating Scale (iADRS) has been used to detect differences in disease progression in early Alzheimer's disease (AD). The objectives of this study were to enhance understanding of iADRS point changeswithin the context of clinical trials, and to establish a minimal clinically important difference (MCID) on the iADRS. Methods: Data from AMARANTH and EXPEDITION3 were analyzed using various approaches, including anchor-based, distribution-based, regression analyses, and cumulative distribution function (CDF) plots. Three potential anchors were examined, including theClinical Dementia Rating--Sum of Boxes, Mini-Mental State Examination, and Functional Activities Questionnaire. Triangulation of all results was used to determine the MCID for participants with mild cognitive impairment (MCI) due to AD and AD with mild dementia. Results: All three anchors met criteria for "sufficiently associated" (|r| = 0.4-0.7). Cumulatively, results from anchor-based and distribution-based results converged to suggest an iADRS MCID of 5 points for MCI due to AD and 9 points for AD with mild dementia. Regression analyses and CDF plots supported these values. Discussion: These findings suggest the iADRS can be used in clinical trials to detect a clinically meaningful outcome of AD progression. [ABSTRACT FROM AUTHOR]

Background: The 32-item Motor Function Measure (MFM32) is a clinician-reported outcome measure used to assess the functional abilities of individuals with neuromuscular diseases, including those with spinal muscular atrophy (SMA). This two-part study explored the relationship between the functional abilities assessed in the MFM32 and activities of daily living (ADLs) from the perspective of individuals with Type 2 and Type 3 (non-ambulant and ambulant) SMA and their caregivers through qualitative interviews and a quantitative online survey. Methods: In-depth, semi-structured, qualitative interviews were conducted with individuals with SMA and caregivers from the US. Subsequently, a quantitative online survey was completed by individuals with SMA or their caregivers from France, Germany, Italy, Poland, Spain, Canada, the United States (US) and the UK. In both parts of the study, participants were asked to describe the ADLs considered to be related to the functional abilities assessed in the MFM32. Results from the qualitative interviews informed the content of the quantitative online survey. Results: Qualitative interviews were conducted with 15 adult participants, and 217 participants completed the quantitative online survey. From the qualitative interviews, all of the functional abilities assessed in the patient-friendly MFM32 were deemed as related to one or more ADL. The specific ADLs that participants considered related to the patient-friendly MFM32 items could be grouped into 10 key ADL domains: dressing, mobility/transferring, self-care, self-feeding, reaching, picking up and holding objects, physical activity, writing and technology use, social contact/engagement, toileting and performing work/school activities. These results were confirmed by the quantitative online survey whereby the ADLs reported to be related to each patient-friendly MFM32 item were consistent and could be grouped into the same 10 ADL domains. Conclusion: This study provides in-depth evidence from the patient/caregiver perspective supporting the relevance of the patient-friendly MFM32 items to the ADLs of individuals with Type 2 and Type 3 SMA. [ABSTRACT FROM AUTHOR]

Background: The Progressive Supranuclear Palsy Rating Scale is a prospectively validated physician‐rated measure of disease severity for progressive supranuclear palsy. We hypothesized that, according to experts' opinion, individual scores of items would differ in relevance for patients' quality of life, functionality in daily living, and mortality. Thus, changes in the score may not equate to clinically meaningful changes in the patient's status. Objective: The aim of this work was to establish a condensed modified version of the scale focusing on meaningful disease milestones. Methods: Sixteen movement disorders experts evaluated each scale item for its capacity to capture disease milestones (0 = no, 1 = moderate, 2 = severe milestone). Items not capturing severe milestones were eliminated. Remaining items were recalibrated in proportion to milestone severity by collapsing across response categories that yielded identical milestone severity grades. Items with low sensitivity to change were eliminated, based on power calculations using longitudinal 12‐month follow‐up data from 86 patients with possible or probable progressive supranuclear palsy. Results: The modified scale retained 14 items (yielding 0–2 points each). The items were rated as functionally relevant to disease milestones with comparable severity. The modified scale was sensitive to change over 6 and 12 months and of similar power for clinical trials of disease‐modifying therapy as the original scale (achieving 80% power for two‐sample t test to detect a 50% slowing with n = 41 and 25% slowing with n = 159 at 12 months). Conclusions: The modified Progressive Supranuclear Palsy Rating Scale may serve as a clinimetrically sound scale to monitor disease progression in clinical trials and routine. © 2021 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Abstract Demonstrating that treatments are clinically meaningful across the Alzheimer's disease (AD) continuum is critical for meeting our goals of accelerating a cure by 2025. While this topic has been a focus of several Alzheimer's Association Research Roundtable (AARR) meetings, there remains no consensus as to what constitutes a “clinically meaningful outcome” in the eyes of patients, clinicians, care partners, policymakers, payers, and regulatory bodies. Furthermore, the field has not come to agreement as to what constitutes a clinically meaningful treatment effect at each stage of disease severity. The AARR meeting on November 19–20, 2019, reviewed current approaches to defining clinical meaningfulness from various perspectives including those of patients and care partners, clinicians, regulators, health economists, and public policymakers. Participants discussed approaches that may confer clinical relevance at each stage of the disease continuum and fostered discussion about what should guide us in the future.

Demonstrating that treatments are clinically meaningful across the Alzheimer’s disease (AD) continuum is critical for meeting our goals of accelerating a cure by 2025. While this topic has been a focus of several Alzheimer’s Association Research Roundtable (AARR) meetings, there remains no consensus as to what constitutes a “clinically meaningful outcome” in the eyes of patients, clinicians, care partners, policymakers, payers, and regulatory bodies. Furthermore, the field has not come to agreement as to what constitutes a clinically meaningful treatment effect at each stage of disease severity. The AARR meeting on November 19–20, 2019, reviewed current approaches to defining clinical meaningfulness from various perspectives including those of patients and care partners, clinicians, regulators, health economists, and public policymakers. Participants discussed approaches that may confer clinical relevance at each stage of the disease continuum and fostered discussion about what should guide us in the future. [ABSTRACT FROM AUTHOR]

Introduction: Demonstrating the "clinical meaningfulness" of slowing early cognitive decline in clinically normal (CN) older adults with elevated amyloid‐β (Aβ+) is critical for Alzheimer's disease secondary prevention trials and for understanding early cognitive progression. Methods: Cox regression analyses were used to determine whether 3‐year slopes on the preclinical Alzheimer's cognitive composite predicted MCI diagnosis and global Clinical Dementia Rating>0 in 267 Aβ+ CN individuals participating in the Harvard Aging Brain Study, Australian Imaging, Biomarker and Lifestyle Study, and Alzheimer's Disease Neuroimaging Initiative. Results: Steeper preclinical Alzheimer's cognitive composite decline over 3 years was associated with increased risk for MCI diagnosis and global Clinical Dementia Rating>0 in the following years across all cohorts. Hazard ratios using meta‐analytic estimates were 5.47 (95% CI: 3.25–9.18) for MCI diagnosis and 4.49 (95% CI: 2.84–7.09) for Clinical Dementia Rating>0 in those with subtle decline (>−.14 to −.26 preclinical Alzheimer's cognitive composite standard deviations/year) on longitudinal cognitive testing. Discussion: Early "subtle cognitive decline" among Aβ+ CN on a sensitive cognitive composite demonstrably increases risk for imminent clinical disease progression and functional impairment. [ABSTRACT FROM AUTHOR]

Objective: To determine the overall effectiveness of instrument-assisted soft tissue mobilization (IASTM) in improving range of motion (ROM), pain, strength, and patient-reported function in order to provide recommendations for use. We also sought to examine the influence of IASTM on injured and healthy participants, body part treated, and product used. Data Sources: We searched the Academic Search Premier, Alt Healthwatch, CINAHL Complete, Cochrane Library, MEDLINE with full text, NLM PubMed, Physical Education Index, Physiotherapy Evidence Database (PEDro), SPORTDiscus with full text, and Web of Science databases for articles published from 1997 through 2016. The Boolean string advantEDGE OR astym OR graston OR iastm OR "instrument assist* soft tissue mobil*" OR "augment* soft tissue mobil*" OR "myofascial release" OR "instrument assist* massage" OR "augment* massage" OR "instrument assist* cross fiber massage" was used. Study Selection: Included articles were randomized controlled trials that measured ROM, pain, strength, or patient-reported function and compared IASTM treatment with at least 1 other group. Data Extraction: Thirteen articles met the inclusion criteria. Four independent reviewers assessed study quality using the PEDro and Centre for Evidence-Based Medicine scales. Twelve articles were included in the effect-size analysis. Data Synthesis: The average PEDro score for studies of uninjured participants was 5.83 (range = 5 to 7) and that for studies of injured participants was 5.86 (range = 3 to 7). Large effect sizes were found in outcomes for ROM (uninjured participants), pain (injured participants), and patient-reported function (injured participants). The different IASTM tools used in these studies revealed similar effect sizes in the various outcomes. Conclusions: The current literature provides support for IASTM in improving ROM in uninjured individuals as well as pain and patient-reported function (or both) in injured patients. More high-quality research involving a larger variety of patients and products is needed to further. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the analgesic effect of duloxetine in Chinese patients with osteoarthritis (OA) of the knee/hip at individual patient level and report the relationship between pain intensity reduction, overall improvement, and physical functioning. Patients and methods: Post hoc analysis of 13-week, phase 3, parallel-group, randomized, placebo-controlled study of duloxetine in Chinese patients with OA pain. Patients were randomized (1:1, computer-generated, interactive web-response system) to duloxetine (60 mg once daily, n=202) or placebo (n=207). Patients, investigators, and study staff were blinded throughout the study. Duloxetine's efficacy was evaluated using the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) and the Osteoarthritis Research Society International and Outcome Measures in Rheumatology (OARSI-OMERACT) responder criteria. Analyses were conducted on all randomized patients with a baseline and at least one post-baseline observation. Results: At study endpoint, the percentage of patients experiencing ≥30% pain intensity reduction (30% responders) was significantly higher in the duloxetine group than in the placebo group (63.4% vs 49.7%; P=0.008). The percentage of patients experiencing ≥50% pain intensity reduction (50% responders) in the duloxetine group was numerically higher than in the placebo group (42.8% vs 34.5%; P=0.098). Most of the 30% and 50% responders to duloxetine treatment felt either "very much improved" or "much improved" on the Patient Global Impression-Improvement at endpoint. The 30% and 50% responders to duloxetine treatment also experienced greater improvements in the Western Ontario and McMaster Universities Osteoarthritis Index physical function scores at endpoint compared with non-responders. The overall percentage of OARSI-OMERACT responders was significantly higher in the duloxetine group vs the placebo group (70.1% vs 54.9%; P=0.003). Conclusion: Based on IMMPACT and OARSI-OMERACT criteria, the analgesic effect of duloxetine was associated with clinically relevant benefits in Chinese patients with OA of the knee/hip. ClinicalTrials.gov identifier: NCT01931475. [ABSTRACT FROM AUTHOR]

There has been a paradigm shift in medicine away from tradition, anecdote and theoretical reasoning from the basic sciences towards evidence-based medicine (EBM). In palliative care however, statistically significant benefits may be marginal and may not be related to clinical meaningfulness. The typical treatment vs. placebo comparison necessitated by ‘gold standard’ randomised controlled trials (RCTs) is not necessarily applicable. The complex multimorbidity of end of life care involves considerations of the patient's physical, psychological, social and spiritual needs. In addition, the field of palliative care covers a heterogeneous group of chronic and incurable diseases no longer limited to cancer. Adequate sample sizes can be difficult to achieve, reducing the power of studies and high attrition rates can result in inadequate follow up periods. This review uses examples of the management of cancer-related fatigue and death rattle (noisy breathing) to demonstrate the current state of EBM in palliative care. The future of EBM in palliative care needs to be as diverse as the patients who ultimately derive benefit. Non-RCT methodologies of equivalent quality, validity and size conducted by collaborative research networks using a ‘mixed methods approach’ are likely to pose the correct clinical questions and derive evidencebased yet clinically relevant outcomes.

Understanding the results and statistics reported in original research remains a large challenge for many sports medicine practitioners and, in turn, may be among one of the biggest barriers to integrating research into sports medicine practice. The purpose of this article is to provide minimal essentials a sports medicine practitioner needs to know about interpreting statistics and research results to facilitate the incorporation of the latest evidence into practice. Topics covered include the difference between statistical significance and clinical meaningfulness; effect sizes and confidence intervals; reliability statistics, including the minimal detectable difference and minimal important difference; and statistical power. [ABSTRACT FROM AUTHOR]

Introduction The clinical meaningfulness of Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS-Cog) subscale change is disputed. We compared 2- to 4-point ADAS-Cog changes with changes in Goal Attainment Scaling (GAS) and everyday function across initial ADAS-Cog scores and treatment responses. Methods This exploratory analysis evaluated mild-moderate Alzheimer's disease patients treated with donepezil (12 months) or galantamine (8 months). Clinical meaningfulness was defined as concomitant ADAS-Cog and GAS changes of ±3 points and/or functional improvement. Results Patients with ≥3-point ADAS-Cog improvement significantly improved on GAS but not on standard tests of everyday function. ADAS-Cog “no change” (≤±3 points) was seen with mean GAS improvement. Initial ADAS-Cog improvement made endpoint improvement (ADAS-Cog 3 points and GAS 1 point) more likely (odds ratio = 6.9; 95% confidence interval = 2.5–19.5). In contrast, initial deterioration made endpoint improvement unlikely (0.33; 0.14–0.64). Discussion ADAS-Cog improvement and no change were each associated with GAS improvement. Initial ADAS-Cog worsening was unlikely to result in later improvement. Clinical trial registration number ISRCTN26167328. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) clinical trials are designed and powered to detect the impact of a therapeutic intervention, and there has been considerable discussion on what constitutes a clinically meaningful change in those receiving treatment versus placebo. The pathology of AD is complex, beginning many years before clinical symptoms are detectable, with multiple potential opportunities for therapeutic engagement. Introducing treatment strategies early in the disease and assessing meaningful change over the course of an 18-month clinical trial are critical to understanding the value to an effective intervention. With new clinical trial data expected soon on emerging therapeutics from several AD studies, the Alzheimer's Association convened a work group of experts to discuss key considerations for interpreting data from cognitive and functional measures and what is considered a clinically meaningful benefit or meaningful slowing of this fatal disease. Our expectations of outcomes from therapeutic interventions in AD may need to be modified., (© 2023 Alzheimer's Association. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: In psoriasis clinical trials, treatment success is often defined as achieving a static Physician Global Assessment (sPGA) score of 0 (clear) or 1 (almost clear). Patients with clear versus almost clear skin may experience psoriasis differently. This study assessed whether aggregating these patients underestimates subjective improvements associated with total skin clearance.Methods: Patients with plaque psoriasis with stable sPGA 0 or 1 currently treated with adalimumab, etanercept, infliximab, or ustekinumab reported Psoriasis Symptom Inventory (PSI) scores for seven days and Dermatology Life Quality Index (DLQI) scores on day 8. The PSI measures psoriasis signs and symptom severity; the DLQI measures the impact of skin disease on quality of life. This analysis compared PSI and DLQI outcomes between patients with sPGA 0 and 1.Results: This study assessed 230 patients: 79 sPGA 0 and 151 sPGA 1. A greater percentage with sPGA 0 than sPGA 1 achieved a total PSI score of 0 (“best”; 61% vs. 5%,p < 0.0001) and DLQI 0 (“no effect”; 79% vs. 24%,p < 0.001). Patients with sPGA 0 reported better scores than sPGA 1 on all other PSI and DLQI assessments.Conclusions:Achieving total skin clearance, compared with almost clear skin, provides clinically meaningful improvements in psoriasis. [ABSTRACT FROM AUTHOR]

There has been a paradigm shift in medicine away from tradition, anecdote and theoretical reasoning from the basic sciences towards evidence-based medicine (EBM). In palliative care however, statistically significant benefits may be marginal and may not be related to clinical meaningfulness. The typical treatment vs. placebo comparison necessitated by 'gold standard' randomised controlled trials (RCTs) is not necessarily applicable. The complex multimorbidity of end of life care involves considerations of the patient's physical, psychological, social and spiritual needs. In addition, the field of palliative care covers a heterogeneous group of chronic and incurable diseases no longer limited to cancer. Adequate sample sizes can be difficult to achieve, reducing the power of studies and high attrition rates can result in inadequate follow up periods. This review uses examples of the management of cancer-related fatigue and death rattle (noisy breathing) to demonstrate the current state of EBM in palliative care. The future of EBM in palliative care needs to be as diverse as the patients who ultimately derive benefit. Non-RCT methodologies of equivalent quality, validity and size conducted by collaborative research networks using a 'mixed methods approach' are likely to pose the correct clinical questions and derive evidence-based yet clinically relevant outcomes. [ABSTRACT FROM AUTHOR]

In addition to headache, persons with chronic migraine (CM) experience multiple symptoms, both ictal and interictal, that may contribute to their suffering. Translating clinical trial results into practice requires assessment of the results' clinical meaningfulness. When examining treatment benefit in this disabled patient population, multiple headache-symptom measures should be considered to fully reflect clinical relevance. Currently, only onabotulinumtoxinA is approved specifically for headache prophylaxis in adults with CM. Topiramate is the only other therapeutic agent with double-blind, placebo-controlled evidence in this population. Herein we evaluate the clinical meaningfulness of onabotulinumtoxinA and topiramate as headache prophylaxis in CM by comparing primary endpoints from the placebo-controlled, double-blind phase of the Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program and the topiramate clinical trial (frequency of headache days [primary endpoint in PREEMPT; secondary in topiramate trial] and migraine/ migrainous days [primary in topiramate trial, or "migraine/probable-migraine days"; secondary in PREEMPT]). Additionally, outcome measures such as responder rates, health-related quality of life, discontinuation rates, safety, and tolerability profiles are important clinical considerations. The clinical data indicate that statistically significant, clinically relevant treatment benefits exist for both onabotu-linumtoxinA and topiramate. These data support these treatments as meaningful headache prophylaxis in adults with CM. [ABSTRACT FROM AUTHOR]

Background and Objective: Minimal clinically important difference (MCID) values of 4 and 6 points have been proposed for interpreting meaningful change in Multiple Sclerosis Walking Scale-12 (MSWS-12) scores.This study examined the validity of those MCID values based on capturing corresponding changes in other walking outcomes in persons with multiple sclerosis (MS). Methods: On 2 occasions separated by 6 months, 82 persons with MS completed the MSWS-12, timed 25-ft walk (T25FW), 6-min walk (6MW), and gait analysis, and then wore an accelerometer over a 7-day period. We generated change scores for the MSWS-12 and formed groups of stable, worsened, and improved perceived walking based on both 4- and 6-point changes. The groups were compared for corresponding changes in other walking measures over time using mixed-model ANOVAs. Results: The mixed-model ANOVAs did not identify statistically significant group-by-time interactions on the T25FW (p = 0.98 and p = 0.67), the 6MW (p = 0.89 and p = 0.72), gait (p = 0.54 and p = 0.21), or accelerometry (p = 0.40 and p = 0.68) for MCID values of 4- or 6-point changes in MSWS-12 scores. Conclusions: We did not confirm that MCID values of 4 and 6 points for the MSWS-12 correspond with changes in performance, gait, and free-living assessments of walking in MS. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objectives To highlight the utility of using an effect size analysis to communicate the effectiveness of treatment interventions. Design Secondary analysis. Setting Previously published systematic review on cholinesterase inhibitors (Ch EIs) in Alzheimer's disease. Participants Individuals with mild to moderate Alzheimer's disease. Intervention Six-month randomized controlled trials involving a placebo group and a Ch EI group (donepezil, galantamine, or rivastigmine). Measurements Cognitive function was assessed according to performance on the cognition subscale of the Alzheimer's Disease Assessment Scale ( ADAS-Cog). Global Function was quantified using the Clinician's Interview- Based Impression of Change- Plus ( CIBIC-Plus). Harm was defined as withdrawal from a trial because of an adverse event. Several effect size indices were computed based on these domains: the success rate difference ( SRD), the harm rate difference ( HRD), the number needed to treat ( NNT) or harm ( NNH), and the area under the curve ( AUC). Harm:benefit ratios were also computed to compare effect size indices across domains of function. Results In terms of benefit, the NNT for cognition ranged from 4 to 14 (corresponding AUC values: 0.64-0.54), and the NNT for global function ranged from 6 to 100 (corresponding AUC 0.59-0.51). In terms of harm, the NNH ranged from 6 to 20 (corresponding AUC 0.58-0.53). Only one of the four studies had favorable harm:benefit ratios in both the cognition and global function domains. Conclusion Effect size indices should be reported in clinical trials because they provide important insight into the clinical meaningfulness of results. Additional benefit is gained by comparing effect size indices across domains of function to reveal harm:benefit ratios. [ABSTRACT FROM AUTHOR]

In new drug development, demonstrating a clinically important effect of the new drug is a key element of efficacy evaluations instead of simply showing a statistical significance. However, approaches to demonstrate clinically important effects are unclear and not wall recognized among many investigators and sponsors. The minimal clinically important change from baseline (MCIC) and minimal clinically important difference between groups (MCID) are used to assess the clinically important effect. We state the roles of MCIC and MCID in each phase of new drug development and common approaches to establishing MCIC and MCID. Furthermore, we provide some common approaches on how to practically compare the clinical trial results with the MCIC and MCID and interpret the clinical importance from applications in new drug development. We also suggest incorporating the clinical importance at the planning phase of trials. [ABSTRACT FROM AUTHOR]