Meaningful Threshold Research Articles

Maintenance of zilucoplan efficacy in patients with generalised myasthenia gravis up to 24 weeks: a model-informed analysis.

Clinical efficacy of zilucoplan has been demonstrated in a 12-week, placebo-controlled, phase III study in patients with acetylcholine receptor autoantibody-positive generalised myasthenia gravis (gMG). However, placebo-controlled zilucoplan data past 12 weeks are not available. Predict the treatment effect of zilucoplan versus control (placebo or standard of care) in patients with gMG up to 24 weeks. A model-informed analysis (MIA) within a Bayesian framework. Part 1 of the MIA comprised a control meta-regression using aggregate data on control response over time from randomised studies and a national myasthenia gravis (MG) registry. In Part 2, a combined Bayesian analysis of individual patient-level data from the phase II (NCT03315130), RAISE (NCT04115293) and RAISE-XT (NCT04225871) studies of zilucoplan was conducted using posterior distributions from Part 1 as informative priors. Population mean treatment effect in the change from baseline (CFB) at week 24 in MG-Activities of Daily Living (MG-ADL) and quantitative MG (QMG) scores for zilucoplan versus control were assessed. At week 24, the predicted mean CFB in MG-ADL score was -4.55 (95% credible interval: -6.04, -3.13) with zilucoplan versus -2.00 (-3.35, -0.64) with control (difference: -2.55 [-3.76, -1.40]). The probability of a favourable treatment effect as measured by MG-ADL score at week 24 with zilucoplan versus control was >99.9%. There was an 82.8% probability that the difference in the predicted mean CFB in MG-ADL score at week 24 was greater than the clinically meaningful threshold (⩾2.0-point improvement). Comparable results were observed with QMG. This MIA demonstrates the maintenance of efficacy with zilucoplan versus control up to 24 weeks. Through combining real-world evidence with data from randomised studies, this novel method to estimate long-term treatment efficacy facilitated reduced exposure to placebo in the phase III RAISE study. This methodology could be used to reduce the length of future placebo-controlled studies.

Effect of avalglucosidase alfa on disease-specific and general patient-reported outcomes in treatment-naïve adults with late-onset Pompe disease compared with alglucosidase alfa: Meaningful change analyses from the Phase 3 COMET trial

BackgroundThe Phase 3 COMET trial (NCT02782741) comparing avalglucosidase alfa and alglucosidase alfa included health-related quality of life (HRQoL) assessments in treatment-naïve patients with late-onset Pompe disease (LOPD). Here, we further characterize results from disease-specific and general patient-reported outcome (PRO) measures. MethodsAdults who participated in the COMET trial receiving avalglucosidase alfa or alglucosidase alfa (both 20 mg/kg biweekly) during the 49-week double-blind treatment period were included in the analysis. Proportions of patients exceeding meaningful change thresholds at Week 49 were compared post hoc between treatment groups. PROs and their meaningful change thresholds included: Pompe Disease Severity Scale (PDSS; decrease 1.0–1.5 points), Pompe Disease Impact Scale (PDIS; decrease 1.0–1.5 points), Rasch-built Pompe-specific Activity Scale (R-PAct; change from unable to able to complete activity), 12-item Short Form Health Survey (SF-12; physical component summary [PCS] score: increase ≥6 points, mental component summary [MCS] score: increase ≥7 points), EuroQol 5 Dimension 5 Level (EQ-5D-5L; improvement of ≥1 category), and Patient Global Impression of Change (PGIC; any improvement). ResultsThe analysis included 99 adult patients (avalglucosidase alfa n = 50; alglucosidase alfa n = 49). Patients who received avalglucosidase alfa had significantly greater odds of achieving a meaningful change versus alglucosidase alfa for the PDSS Shortness of Breath (OR [95% CI] 11.79 [2.24; 62.18]), Fatigue/Pain (6.24 [1.20; 32.54]), Morning Headache (13.98 [1.71; 114.18]), and Overall Fatigue (5.88 [1.37; 25.11]) domains, and were significantly more likely to meet meaningful change thresholds across multiple PDSS domains (all nominal p < 0.05). A numerically greater proportion of patients in the avalglucosidase alfa group were able to complete selected activities of the R-PAct compared with the alglucosidase alfa group. Significantly greater proportions of patients who received avalglucosidase alfa achieved meaningful improvements for EQ-5D-5L usual activities dimension, EQ visual analog scale, and all four PGIC domains. The proportion of patients with improvements in SF-12 PCS and MCS was greater in the avalglucosidase alfa group versus alglucosidase alfa group, but was not significant (p > 0.05). ConclusionsThese analyses show that avalglucosidase alfa improves multiple symptoms and aspects of daily functioning, including breathing and mobility. This supports the clinical relevance of the effects of avalglucosidase alfa on HRQoL for patients with LOPD.

Systematic Literature Review: Ability of the IBDQ-32 to Detect Meaningful Change in Ulcerative Colitis Health Indicators.

Previous reviews produced weak evidence regarding the responsiveness of the Inflammatory Bowel Disease Questionnaire (IBDQ-32) to changes in ulcerative colitis (UC) health indicators. This systematic review and meta-analysis provide an updated synthesis on IBDQ-32 responsiveness. A systematic literature review identified 11 articles reporting IBDQ-32 responder analyses in randomized control trials, which were included in a random effects meta-analysis, and 15 articles linking IBDQ-32 change to change in UC health indicators, which were summarized narratively. Meta-analysis compared differences between IBDQ-32 responder proportions in efficacious and nonefficacious treatment arms relative to placebo. Linear meta-regression examined the association of treatment efficacy and proportions of IBDQ-32 responders in active treatment compared with placebo. Meta-analysis showed larger differences in IBDQ-32 response proportions between active treatment and placebo for efficacious treatments (pooled OR, 2.19; 95% CI, 1.83-2.63) than nonefficacious treatments (pooled OR, 1.21; 95% CI, 0.84-1.74; Cochran's Q[df = 1] = 8.26, P = .004). Meta-regression showed that the magnitude of treatment efficacy positively predicted IBDQ-32 response in active treatments relative to placebo (β = 0.21, P < .001). Moderate to strong correlations were found between change in IBDQ-32 and change in health indicators (eg, patient-reported measures, disease activity, endoscopic indices; correlations, 0.37-0.64 in absolute values). Patients achieving clinical response or remission showed greater change in IBDQ-32 total scores (range, 22.3-50.1 points) and more frequently met clinically meaningful thresholds on the IBDQ-32 than those not achieving clinical response or remission (all P < .05). The IBDQ-32 is responsive to changes in UC health indicators and disease activity, including in response to efficacious treatment (relative to placebo).

Atypical Mitotic Figures Are Prognostically Meaningful for Canine Cutaneous Mast Cell Tumors.

Cell division through mitosis (microscopically visible as mitotic figures, MFs) is a highly regulated process. However, neoplastic cells may exhibit errors in chromosome segregation (microscopically visible as atypical mitotic figures, AMFs) resulting in aberrant chromosome structures. AMFs have been shown to be of prognostic relevance for some neoplasms in humans but not in animals. In this study, the prognostic relevance of AMFs was evaluated for canine cutaneous mast cell tumors (ccMCT). Histological examination was conducted by one pathologist in whole slide images of 96 cases of ccMCT with a known survival time. Tumor-related death occurred in 11/18 high-grade and 2/78 low-grade cases (2011 two-tier system). The area under the curve (AUC) was 0.859 for the AMF count and 0.880 for the AMF to MF ratio with regard to tumor-related mortality. In comparison, the AUC for the mitotic count was 0.885. Based on our data, a prognostically meaningful threshold of ≥3 per 2.37 mm2 for the AMF count (sensitivity: 76.9%, specificity: 98.8%) and >7.5% for the AMF:MF ratio (sensitivity: 76.9%, specificity: 100%) is suggested. While the mitotic count of ≥ 6 resulted in six false positive cases, these could be eliminated when combined with the AMF to MF ratio. In conclusion, the results of this study suggests that AMF enumeration is a prognostically valuable test, particularly due to its high specificity with regard to tumor-related mortality. Additional validation and reproducibility studies are needed to further evaluate AMFs as a prognostic criterion for ccMCT and other tumor types.

Responsiveness and meaningful thresholds of PROMIS pain interference, fatigue, and physical function forms in adults with idiopathic inflammatory myopathies: Report from the OMERACT Myositis Working Group

BackgroundA series of qualitative studies conducted by the OMERACT Myositis Working Group identified pain interference, fatigue, and physical function as highly important life impact domains for adults with idiopathic inflammatory myositis (IIM). In this study, our goal was to assess the responsiveness and minimal important difference of PROMIS pain interference (6a), fatigue (7a), and physical function (8b). MethodsAdults with IIM from USA, Netherlands, Korea, Sweden, and Australia with two "clinical" visits were enrolled in this prospective study. Anchor questions on a Likert scale were collected at baseline, and manual muscle testing (MMT), physician and patient reported global disease activity, and PROMIS instruments were collected at both visits. Responsiveness was assessed with i) ANOVA, ii) paired t-test, effect size and standardized response mean, and iii) Pearson correlation. Minimal important difference (MID), minimal important change (MIC) and minimal detectable change (MDC) values were calculated. Results114 patients with IIM (median age 60, 60 % female) completed both visits. Changes in PROMIS instruments were significantly different among anchor categories. Patients who reported improvement had a significant improvement in their PROMIS scores with at least medium effect size, while patients who reported worsening and stability did not show a significant change with weak effect size. PROMIS instruments had weak to moderate correlations with MMT, patient and physician global disease activity. MID was approximately 2–3 points for Pain Interference and 3–4 points for Fatigue and Physical Functionforms based on the method used. MIC was approximately 4–5 for improvement of all the instruments, while MDC was 1.7–2 points for Pain Interference and Physical Function and 3.2–3.9 for Fatigue. ConclusionThis study provides evidence towards the responsiveness of the PROMIS instruments in a large international prospective cohort of adults with IIM supporting their use as PROMs in adult myositis.

PCR149 Determination of Ranges of HiSQOL Scores Defining Clinically Meaningful Within-Patient Improvement Thresholds and Severity Levels

PCR149 Determination of Ranges of HiSQOL Scores Defining Clinically Meaningful Within-Patient Improvement Thresholds and Severity Levels

Assessing Treatment Burden in Pediatric Hemophilia: Validation of the Observer-Reported Child Hemophilia Treatment Experience Measure (Child Hemo-TEM)

Background: Despite treatment safety and efficacy advancements for children with hemophilia (CwH), home treatment can be complicated and burdensome. Treatment burdens are major contributing factors to adherence issues. The Child Hemo-TEM is a patient-centric outcome measure developed following the United States (US) Food and Drug Administration guidance for patient-reported outcome measure development. Designed to assess the treatment burden for CwH, the measure is a caregiver observer-reported outcome (ObsRO) measure where questions are answered by the caregiver about the child's treatment experience based on what the caregiver has seen, heard, or been told by the child. Aim: The purpose of this study was to psychometrically validate the Child Hemo-TEM ObsRO. Methods: Data was collected through a cross-sectional, web survey from a population of caregivers of CwH aged 2 to &amp;lt; 12 years in the US. The survey consisted of the Child Hemo-TEM, sociodemographic items, child's hemophilia medical history, and supporting items/measures required to assess the measure's psychometric properties. The survey took up to 45 minutes to complete and was administered at a single time point. To be eligible for the study, caregivers needed to be: aged ≥ 18 years; a caregiver of a male child with a diagnosis of severe to moderate hemophilia A or B, with a factor level of &amp;lt; 2%, with or without an inhibitor, and currently receiving either prophylactic or on-demand treatment; and living in the same residence as the child over the past 2 weeks. Recruitment was conducted by a patient advocacy group and a professional market research firm. Recruitment quotas were targeted to ensure a diverse population and mix of frequency of prophylactic treatment(s) and treatment administration type. All psychometric analyses were conducted following an a-priori statistical analysis plan, which included examination of measurement characteristics, item reduction, factor analysis, measure scoring, internal consistency, reliability, and validity. Results: Caregivers ( n=187) of CwH completed the web survey. The respondents were, on average, 37.8 years of age, mothers (84.0%), and predominantly White/Caucasian (74.3%). Twelve items were dropped from the validation-ready, 19-item measure: 5 items due to high ceiling effects at baseline (&amp;gt;50%) mirrored by the Rasch results and 1 item as it was highly correlated with a retained item. Further, as there were only a small number of children who self-injected, 6 items designed to assess child self-injection were removed. The remaining items underwent further psychometric testing. An exploratory factor analysis generated a single, 7-item factor. The Child Hemo-TEM was found to be internally consistent with a Cronbach's α of 0.855. A-priori validity hypotheses were adapted to match the final factor structure. Hypothesized associations were predominantly confirmed with a few exceptions. For convergent validity (Pearson's r significance set at α = 0.05), a few of the associations, although significant, were below 0.30 (Table 1). The Child Hemo-TEM was able to discriminate between levels of self-complaining about their infusions (p &amp;lt; 0.001), psychological stress reported by parent (p &amp;lt; 0.001), and ease/difficulty of their medication in its current form, among other variables. Based on psychometric findings and taking into consideration learnings from the concept elicitation during measure development, the brief, 7-item Child Hemo-TEM was finalized with 1 domain capturing information from all the hypothesized concepts of treatment concerns (3 items), adherence (1 item), physical impact (1 item), and interference with daily life (2 items) (Figure 1). A five-point Likert response scale with ranges from “Never” to “Always”, or a “Don't know” option, is used. Conclusion: The Child Hemo-TEM ObsRO has been found to be conceptually sound with adequate evidence to support its reliability and validity. Incorporation of the measure into both clinical and research settings will help assess the pediatric patient's experience of living with hemophilia as well as aid clinicians in tailoring treatments to patient characteristics and situations. Future studies are needed to assess test-retest reproducibility, sensitivity to change, and meaningful change thresholds of this new measure.

Establishing Content Validity of the FACIT-Fatigue Scale in Patients Living with Warm Autoimmune Hemolytic Anemia: Results from Qualitative Interview Studies

Introduction: Warm autoimmune hemolytic anemia (wAIHA) is a rare, life-threatening autoimmune disorder caused by autoantibodies that bind to and prematurely destroy red blood cells. Patients with wAIHA can experience acute worsening of anemia which can be a medical emergency and have an increased risk of thromboembolic events and premature death. Fatigue is the primary patient-reported symptom for many individuals living with wAIHA. The patient-reported Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale is supported by robust psychometric evidence and has been used to support efficacy assessments of improvement in anemia-related fatigue. However, evidence of content validity of this scale has not been established in the wAIHA patient population. The objective of this research was to examine whether the FACIT-Fatigue is fit for purpose to assess wAIHA-related fatigue. Methods: Twenty hybrid concept elicitation/cognitive debriefing interviews were conducted with adults living with wAIHA across two sequential studies. All participants were recruited from the United States via research partners following IRB approval. The studies aimed to understand the symptoms and impacts of wAIHA on participants' daily lives with a specific focus on fatigue and to evaluate the FACIT-Fatigue scale in a wAIHA patient population. The last 10 interviews also included a qualitative evaluation of meaningful change on the FACIT-Fatigue individual items. Interviews were recorded and transcribed verbatim, and data were coded. Content and descriptive analysis methods were used to examine data at the item and participant level. Thematic analysis was conducted to identify emerging patterns across items and participants and to identify key constructs from concept elicitation. Results: Interview participants were primarily non-Hispanic white (n=16, 80%), female (n=11, 55%), and had a mean age of 47.5 ± 14.7 years. Fatigue was reported as a core symptom of wAIHA by all participants. Several participants noted that fatigue was their most bothersome symptom. Participants summarized the extensive impact fatigue had on their daily functioning, including reduced ability to work or volunteer, disruptions to their social lives, and negative changes to their emotional wellbeing. Cognitive debriefing affirmed that the instructions and items comprising the FACIT-Fatigue were well understood and relevant to their experiences with wAIHA, the 7-day timeframe was easy to recall, and participants were easily able to rate their experiences using the response scale (see Table 1 for item-level insights).The majority of participants who were asked about meaningful change identified a 1-point change as meaningful for each of the FACIT-Fatigue items. Analysis of participants' perspectives on meaningful changes at the item level indicated that a 3 point change in the total score would be meaningful for all participants. This aligns with previous studies that have published meaningful change thresholds of 3-6 points on the FACIT-Fatigue total score in populations with chronic conditions that cause fatigue. Conclusions: Fatigue is a debilitating symptom of wAIHA which impacts functioning across multiple domains. The content validity of the FACIT Fatigue scale is well supported by the results of the qualitative interviews as its items capture constructs that are relevant to evaluating fatigue and important to people living with wAIHA. These research findings support the use of the FACIT-Fatigue scale in clinical trials of treatments for wAIHA and suggest that a 3-point change of the total score would represent meaningful change in this patient population. Future work will focus on evaluating the psychometric properties of the FACIT-Fatigue scale in a wAIHA population.

Health-Related Quality of Life and Symptoms in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma Treated with Odronextamab Monotherapy in the Phase 2 ELM-2 Study

Background. Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) have poor prognosis and significant impairment of health-related quality of life (HRQoL). CD20xCD3 bispecific antibodies show promise in the management of R/R DLBCL. ELM-2 (NCT03888105), a Phase 2, open-label, multicohort, multicenter study of the CD20xCD3 bispecific antibody odronextamab, demonstrated deep and durable responses and generally manageable safety in patients with R/R DLBCL. We report herein, for the first time, patient-reported outcome (PRO) results for patients in the R/R DLBCL cohort in ELM-2. Methods. In ELM-2, patients with R/R DLBCLafter 2 or more prior lines of therapy received odronextamab IV weekly in 21-day cycles in Cycles (C) 1-4. Revisions to the step-up dosing regimen to mitigate cytokine release syndrome (CRS) were reported previously. Odronextamab was administered with steroid prophylaxis and step-up doses of 0.7/4/20 mg in C1, then 160 mg on Days 1, 8, and 15 of C2-4 (the DLBCL 160 mg cohort). After C4, odronextamab maintenance treatment continued at 320 mg every 2 weeks until disease progression or unacceptable toxicity. Patients with durable complete response for ≥9 months transitioned to dosing every 4 weeks. PRO data were collected via the FACT-Lym, EORTC QLQ-C30, and EQ-5D-3L questionnaires at Weeks 1 (baseline), 2, 3, 4, and 10, then every 8 weeks in the first year and every 12 weeks in the second year. Pre-specified PRO analyses reported here are FACT-Lym lymphoma symptoms (LymS), FACT-G total, Trial Outcome Index (TOI), FACT-Lym total, EORTC QLQ-C30 general health status/quality of life (GHS/QoL), and EQ-5D-3L visual analog scale (VAS). PRO longitudinal analysis using mixed models for repeated measures (MMRM) were conducted through Week 42, the last visit with ≥10 patients with PRO data, and changes from baseline were statistically significant if the 95% confidence interval did not contain zero. No adjustment for multiplicity was performed, hence all statistical significance is nominal. Published ranges for minimum important difference (MID) for clinically meaningful thresholds are: GHS/QoL, 10; LymS, 2.9-5.4; FACT-G total, 3-7; TOI: 5.5-11; FACT-Lym total, 6.5-11.2; and EQ-5D-3L VAS, 7-12. Responder analysis and time to definitive deterioration (TTDD) used the upper end of these MID ranges to define clinically meaningful changes. Results. The final analysis of the DLBCL 160 mg cohort in ELM-2 assessed 141 patients. Median age was 66.0 (range, 24-88) years, with 56.0% ≥65 years, 59.6% male, 43.3% White, 47.5% Asian, 32.6% ECOG=0, and 67.4% ECOG=1. Median duration of follow-up was 26.2 (range, 8.5-34.3) months. PRO completion rates for FACT-Lym, EORTC QLQ-C30, and EQ-5D-3L were high at baseline and for most assessments through Week 42. Patients reported statistically significant and clinically meaningful improvements from Weeks 10 through 42 for FACT-Lym LymS (Figure), and from Weeks 18 through 42 for FACT-G total, FACT-Lym TOI, and FACT-Lym total (except Week 34 for FACT-G total and FACT-Lym total). Additionally, patients reported statistically significant and clinically meaningful improvements for EORTC QLQ-C30 GHS/QoL at Week 42, and for EQ-5D-3L VAS at Week 26. In responder analyses, the proportion of patients reporting clinically meaningful improvement or stability was higher than the proportion reporting meaningful worsening at each assessment through Week 42 for all scales/summary scores. Median TTDD was not reached for FACT-Lym LymS, FACT-Lym TOI, or EQ-5D-3L VAS. Conclusions. In the Phase 2 ELM-2 study, patients with R/R DLBCL reported favorable HRQoL during odronextamab treatment; patient-reported symptoms, functioning, and overall quality of life were maintained or improved from baseline through Week 42. Odronextamab treatment until disease progression may have benefits on HRQoL for heavily pretreated patients with R/R DLBCL and potentially addresses unmet needs in a challenging treatment setting. Collection of PROs was consistently high and the results offer important patient-centered insights into the overall benefit-risk profile of odronextamab in R/R DLBCL.

Establishing Meaningful Change Thresholds in Patient-Reported Outcomes Among Patients With Anaplastic Lymphoma Kinase-Positive Non–Small Cell Lung Cancer in ALTA-1L Trial

ObjectivesAn earlier study from the ALTA-1L trial of patients with anaplastic lymphoma kinase-positive non–small cell lung cancer demonstrated that brigatinib produces superior health-related quality of life (QoL) outcomes over crizotinib. This study aimed to derive meaningful change thresholds (MCTs) for European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 and EORTC QLQ-LC13 to refine the earlier results. MethodsPatients from the ALTA-1L trial were administered the EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires. Responses were analyzed using anchor-based analysis, graphical analysis, distribution-based analysis, longitudinal responder analysis, and time to deterioration. ResultsThe patient-reported outcome population comprised 262 patients who completed the EORTC QLQ-C30 at baseline and at least 1 follow-up timepoint. Both anchors (QLQ-C30 items for overall health and QoL) had correlations >0.40 or < −0.40 with all functioning domains, fatigue, pain, appetite loss, and all dyspnea scores. Within-group analysis for most scales found the derived MCT was consistent with a cutoff of 10 points for classifying individual-patient change, except for 3-item dyspnea. The probability of improvement/remaining stable was significantly greater in the brigatinib group over crizotinib for the EORTC QLQ-C30 emotional functioning, appetite loss, and constipation domains. ConclusionsThis study derived MCTs for EORTC QLQ-C30 and QLQ-LC13 domains that may be applied in future studies and again demonstrated the superiority of brigatinib over crizotinib in health-related QoL outcomes in patients with non–small cell lung cancer.

Abstract 12112: Establishing a Minimally Clinically Important Difference Threshold for Health-Related Quality of Life in Atrial Fibrillation: The SAGE-AF Study

Introduction: Health related quality of life (HRQoL) is increasingly recognized as an important patient reported outcome but few research has focused on HRQoL meaningful changes overtime. Using data from Systematic Assessment of Geriatric Elements in Atrial Fibrillation, we identified clinically meaningful change over 1-year in older patients with AF and examined sociodemographic and geriatric factors associated with change. Methods and Results: Between 2016-18, 1,244 patients aged 65+ with atrial fibrillation (AF) were recruited from medical centers in Massachusetts and Georgia. At baseline and 1-year follow-up, patients completed validated HRQoL measure. We used a distribution-based approach to calculate a clinically meaningful threshold (9 points) and to define three groups: improve (N=154, 14%), stable, (N=617, 56%), and decline (N=326, 30%). Logistic regression was used to examine factors associated with clinically meaningful improvement and decline in HRQoL. CHA2DS2-VASC score was associated with an increased odds of HRQoL decline (adjusted odds ratio [AOR]= 1.16, 95% CI: 1.03, 1.32). Frailty (AOR= 1.89, 95% CI: 1.20, 2.92) and depression, (AOR=1.62, 95% CI: 1.17, 2.25) were associated with an increased odds of HRQoL improvement, while cognitive impairment (AOR= 0.72, 95% CI: 0.52, 0.99) was associated with a decreased odds of improvement in HRQoL. Conclusions: A change in HRQoL of 9-points was identified as clinically meaningful over 1-year in our cohort. The majority of patients remained stable in HRQoL over a year of follow-up. Understanding meaningful change in HRQoL can assist providers with knowing how to best treat their patients and develop strategies to improved or stabilize HRQoL.

Abstract 252: End-Tidal CO2 and Glasgow Coma Scale in Non-Intubated Traumatic Brain Injury Patients: Evaluation of Prehospital Nasal Capnography and Level of Consciousness

Background: The EMS traumatic brain injury (TBI) guidelines recommend limiting intubation (ETI) to patients with profoundly-depressed level of consciousness (LOC) and who cannot protect their airway or adequately ventilate with basic maneuvers. Thus, many major TBIs are managed without ETI in the field. Monitoring ETCO2 via nasal sensors (NC-CO2) in non-ETI patients may provide valuable information about ventilatory status and trends. However, EMS NC-CO2 remains unstudied. Objective: To evaluate the association between LOC and NC-CO2 in non-intubated TBI. Methods: Cases from 7 EMS agencies reporting continuous monitor data (Philips MRx™) in the EPIC TBI Study (NIH 1R01NS071049) were evaluated (4/13-4/18). Comparisons in patient-level mean, median, lowest and highest NC-CO2 levels were made across GCS categories using clinically meaningful thresholds: &lt;15, &lt;12, &lt;9, 3. Results: Included: 177 cases [median age: 52 (range: 9-94), 66% male]. Overall, while not statistically significant, NC-CO2 tended to be lower in patients with lower GCS (Table). In addition, minimum NC-CO2 was significantly lower (p=0.01) in patients with compromised LOC (Table). O2 management (Hi-flow/Lo-flow/No O2) was documented in 176 patients (99.4%). Among the 107 patients with all GCS = 15, 44 (41%) had Hi-flow administered compared to 47/69 (68%) with any GCS &lt;15 (p=0.0008). Conclusion: The utility of prehospital capnography in non-intubated patients is unknown. In this study, NC-CO2 tended to be lower in TBI patients with lower GCS. Whether this reflects physiological/respiratory differences with changes in LOC, or variations in methods of managing oxygenation is unclear. These intriguing new findings require future study to determine if NC-CO2 is directly reflective of LOC-related ventilatory patterns. Furthermore, studies are needed to evaluate whether NC-CO2 monitoring has clinical utility as a non-invasive adjunct to care in spontaneously-breathing, non-ETI patients.

Patient-reported outcomes in high-risk HR+ /HER2- early breast cancer patients treated with endocrine therapy with or without palbociclib within the randomized PENELOPEB study

BackgroundThe PENELOPEB trial investigating efficacy and safety of additional 1-year post-neoadjuvant palbociclib to standard endocrine therapy (ET) high-risk hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) early breast cancer patients failed to improve invasive disease-free survival (iDFS). This analysis compared patient-reported outcomes (PROs) between treatment groups. Patients and methodsPatients received 13 cycles of palbociclib 125 mg/day (n = 631) or placebo (n = 619) orally for 3 out of 4 weeks + ET. European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30), its breast cancer (BR23) and fatigue (FA13) modules, mood questionnaire GAD7 and European Quality of Life 5 Dimensions (EQ-5D) instruments were used for the assessment of quality of life (QoL). Repeated-measures mixed-effects models were used to evaluate differences in PRO, changes of PRO over time, and treatment-by-time interactions. Results924 of 1250 patients (73.9%) completed baseline and at least one post-baseline questionnaire of all PRO instruments. General health status (GHS)/QoL based on EORTC QLQ-C30 was high in both arms (mean [SD]: palbociclib 70.1 [19.3], placebo 71.4 [18.8]) and was slightly higher in the placebo arm (LeastSquare mean difference: 0.82, p < 0.001). Higher fatigue was reported in the palbociclib arm (mean [SD]: 30.3 [23.8] vs. placebo 28.3 [22.7]; p < 0.001). No statistically significant differences were observed among FA13 physical, cognitive, and emotional fatigue subscales. ConclusionPatient-reported global QoL and fatigue did not substantially change in both treatment arms. Slight differences in GHS, physical functioning, and fatigue favored the placebo arm statistically without achieving clinically meaningful thresholds.

Patient-Reported Improvements in Fatigue and Health-Related Quality of Life in the Phase 3 Studies Apply-PNH and Appoint-PNH Evaluating the Use of Iptacopan in C5 Inhibitor-Treated and Treatment-Naïve Patients with Paroxysmal Nocturnal Hemoglobinuria

Introduction: Iptacopan is a first-in-class, oral, selective complement factor B inhibitor that recently demonstrated efficacy and safety as monotherapy in both C5 inhibitor-treated (APPLY-PNH [NCT04558918], Peffault de Latour et al) and treatment-naïve (APPOINT-PNH [NCT04820530], Risitano et al) patients with paroxysmal nocturnal hemoglobinuria (PNH). The primary results of active-comparator controlled APPLY-PNH and single-arm APPOINT-PNH have been reported, showing clinically meaningful increases in hemoglobin levels while controlling intravascular hemolysis and preventing extravascular hemolysis. As patient-perceived benefits of therapies are increasingly important, we present here additional results of the patient-reported outcomes measures (PROMs) including responder analyses of changes from baseline in these two studies based on meaningful within-patient thresholds. Methods: The PROMs included an assessment of fatigue (FACIT-Fatigue) as the basis of a secondary endpoint, a health-related quality of life questionnaire (EORTC QLQ-C30), and a Patient Global Impression of Severity (PGIS) of Fatigue. Both studies analyzed change from baseline in PROMs between Day 1 and Day 168. In APPLY-PNH, another focus was on comparing treatments on the average of model-derived estimates for visits between Day 126 and Day 168. While 5 points on the FACIT-Fatigue was prespecified in the protocol, anchor-based meaningful within-patient change analyses utilizing the PGIS as the anchor determined the range for the magnitude of meaningful change for the FACIT-Fatigue to be 7.5 to 9.5 points (derived from APPLY-PNH); 9 points within the upper segment of the range was chosen as the threshold value used in this analysis. Analyses of the EORTC QLQ C-30 focused on the Physical and Role Functioning subscales and symptoms subscales evaluating Fatigue and Dyspnea. Responder analysis thresholds were determined for all 4 subscales using a combination of anchors including PGIS to determine meaningful change thresholds for each subscale. The ranges and threshold choices were based on the assessment of empirical cumulative distribution function (eCDF) of the scores by scale levels of the anchor and used the visit median values as representative levels to determine the range supporting threshold choices. Results: Ninety-five patients were from APPLY-PNH, of whom 62 received iptacopan and 33 received anti-C5 treatment, and 40 patients were from APPOINT-PNH. In APPLY-PNH, responder analysis showed that more patients in the iptacopan group achieved the threshold of ≥9 points compared with the anti-C5 group (51% vs 11%) ( Table 1). The strength of this result was confirmed by a non-parametric Mann-Whitney test with P values ≤0.0039. In APPOINT-PNH, 56% (95% CI, 43-68) achieved the threshold of ≥9 points and approximately half reached a higher threshold of 11 points ( Table 1). Analyses of EORTC QLQ-C30 further corroborated the results for both trials. Responder analyses in APPLY-PNH of the four subscales using internally derived thresholds showed average proportions of responders in the iptacopan group 39% to 49% and in the anti-C5 group ranging from 9% to 20% ( Table 2). The strength of these results was confirmed by a non-parametric assessment of cumulative distribution functions and Mann-Whitney with P values ≤0.0088. In APPOINT-PNH, the estimated average proportions of responders for EORTC QLQ C30 ranged from 41% to 55% ( Table 2). Conclusion: Both anti-C5-experienced and treatment-naïve patients receiving iptacopan exhibited clinically meaningful improvements in fatigue, health-related quality of life, and disease-related symptoms as measured by predetermined meaningful thresholds of response in FACIT-Fatigue and EORTC QLQ-C30. Together with previous presented primary efficacy data from APPLY-PNH and APPOINT-PNH, these results indicate that iptacopan not only results in clinically meaningful improvements in markers of disease control but provides meaningful improvements in aspects that are important to patients (ie, fatigue and other aspects of health-related quality of life, such as physical functioning and role functioning).

Real-World Treatment Patterns and Outcomes in Patients with Immune Thrombocytopenia Treated with Avatrombopag in the United States: Real-AVA 2.0 Study Design

Background: Thrombopoietin-receptor agonists (TPO-RAs) are used in the treatment of chronic immune thrombocytopenia (ITP), a disorder characterized by prolonged low platelet counts (PCs) that pose a risk of serious bleeding events. The TPO-RAs eltrombopag (ELT) and romiplostim (ROMI) have been available for more than 10 years. ELT is an oral medication with food restrictions and carries a boxed warning for hepatoxicity, requiring hepatic laboratory monitoring and a potential need for statin dosing adjustments. ROMI, an injectable, is typically administered in a health care practitioner's office on a weekly basis without food restrictions. Avatrombopag (AVA), an oral medication taken with food, is the most recently approved TPO-RA for the treatment of chronic ITP (2019 by FDA and 2021 by EMA). Hence, the real-world evidence on AVA treatment and its clinical effectiveness in broader and more diverse ITP patient populations have been limited, and additional studies are warranted. REAL-AVA 2.0 is a retrospective chart review which will gather a substantially greater amount of platelet counts per patient than either a claims database review or an electronic medical record review. More granular efficacy data with more patients, more platelet counts per patient, and in a broader population will be used to better assess the clinical effectiveness of AVA in the real-world. This study will also describe the demographic and clinical characteristics of adult patients with primary ITP treated with AVA in the United States (US), and assess treatment patterns and clinical outcomes of these patients. Methods: This retrospective, observational medical chart review study will include patients treated in the US with AVA in a non-clinical trial setting from approximately 20 centers (both academic and community). The study aims to include approximately 200 ITP patients (at least 25 with an ITP disease duration &amp;lt; 12 months) treated with at least one dose of AVA between July 2019 and March 2023. The date the patient initiated treatment with AVA is defined as the index date. The period from the index date through the study end date, end of data availability for the patient or date of death, whichever occurs first, is defined as the post-index period. Results: The primary objective of the study is to describe treatment patterns and response to AVA. Primary outcome measures to be assessed include: achievement of meaningful PC thresholds (PC ≥ 30 X10 9/µL and ≥ 50 X10 9/µL) at any time during AVA treatment, time to achieve an initial platelet response with AVA based on achieving meaningful PC thresholds (PC ≥ 30X10 9/µL and ≥ 50 X10 9/µL) after AVA index date and before AVA discontinuation, durability of platelet response among patients who respond to AVA, and reduction in the use of concomitant steroids or immunosuppressant agents from the index date. The secondary objectives include: assessment of the demographic and clinical characteristics of patients treated with AVA, assessment of changes in PCs following the index date, ITP-related medication use prior to and following the index date, and treatment patterns with AVA (including treatment persistence and changes in dose/frequency). The exploratory objectives include assessment of AVA effectiveness in specific subpopulations (e.g. prior number of ITP treatments, persistent vs chronic ITP, switch from particular ITP treatments, gender, race, age) and, if feasible, to evaluate social determinants of health among ITP patients treated with AVA (including assessment of treatment response among those subpopulations of interest) [ Table 1]. Summary/Conclusions: The study aims to fill current gaps in knowledge by assessing treatment patterns and outcomes, clinical, and demographic characteristics of patients treated with AVA in a real-world clinical setting in the US. We look forward to presenting this data at upcoming scientific meetings.

Patient-Reported Outcomes in the Phase 3 CARTITUDE-4 Study of Ciltacabtagene Autoleucel Vs Standard of Care in Patients with Lenalidomide-Refractory Multiple Myeloma after 1-3 Lines of Therapy

Introduction: The phase 3 CARTITUDE-4 trial (NCT04181827) in patients with multiple myeloma (MM) after 1-3 lines of therapy compared ciltacabtagene autoleucel (cilta-cel) with standard of care (SOC; pomalidomide, bortezomib, and dexamethasone or daratumumab, pomalidomide, and dexamethasone). In the primary analysis, a single cilta-cel infusion significantly improved progression-free survival (hazard ratio [HR], 0.26; P&amp;lt;0.0001) and increased the rate and depth of response vs SOC. Here, we present adjusted comparisons of patient-reported outcomes (PROs) from patients randomized to cilta-cel vs SOC in CARTITUDE-4. Methods:419 patients with lenalidomide-refractory MM and 1-3 prior lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, were randomized (intent-to-treat [ITT] population) to receive cilta-cel (N=208) or SOC (N=211). European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30; 100-point scale), EuroQoL 5-Dimension 5-Level (EQ-5D-5L; 100-point scale), and Multiple Myeloma Symptom and Impact Questionnaire (MySIm-Q; 5-point scale) questionnaires were administered to all patients until disease progression. PRO compliance was calculated as the number of patients whose PROs were received divided by the number whose PROs were expected (ie, all patients on study pre disease progression and before subsequent therapy for each time point). Mixed-model for repeated measures analyses were performed on the ITT population to analyze changes from baseline for each arm and included the baseline PRO score and prognostic characteristics as covariates to balance arms and to adjust for confounders. Assessments after the start of subsequent therapy were excluded. Time to symptom worsening, defined as a clinically meaningful increase (≥0.5 standard deviation of pooled baseline values) without a subsequent reduction in MM symptoms, was assessed using the Kaplan-Meier method. Results: At clinical cut-off on November 1, 2022, 99 patients in the cilta-cel arm and 66 in the SOC arm had both baseline and 12-month PRO assessments, representing data prior to progression. PRO compliance was 100% at baseline and decreased with subsequent visits to 74% in the cilta-cel arm and 81% in the SOC arm at month 12. Patients reported improved functioning and symptom reduction from baseline in the cilta-cel arm, while PRO scores in the SOC arm trended towards worsening or lower degrees of improvement from baseline for most domains and symptoms. The average improvement from baseline to month 12 (least squares [LS] mean change) for patients who received cilta-cel exceeded clinically meaningful thresholds for global health status (10.1 points), pain (-10.2 points), and the visual analogue scale (8.0 points); improvements in fatigue (-9.1 points) and emotional functioning (9.5 points) neared clinically meaningful thresholds (Table). For all other EORTC QLQ-C30 domains, results numerically favored cilta-cel. On the MySIm-Q total symptom scale, the median time until MM symptom worsening in the cilta-cel arm was 23.7 months (95% CI, 22.1-not estimable) and was 18.9 months (95% CI, 16.8-not estimable) in the SOC arm (HR, 0.42). Conclusions:Patients with lenalidomide-refractory MM who had 1-3 prior lines of therapy demonstrated clinically meaningful improvements in health-related quality of life and meaningful reductions in disease-specific symptoms on multiple PRO endpoints after a single cilta-cel infusion. Improvements in health-related quality of life were numerically greater with cilta-cel than with continuously administered SOC treatments across all scales. With previously reported data showing that cilta-cel significantly improves PFS, response rate, and depth of response, these results strengthen the potential for cilta-cel to be a new SOC for patients with lenalidomide-refractory MM after first relapse.

Quantitative and Qualitative Exploration of Meaningful Change on the Vineland Adaptive Behavior Scales (Vineland™-II) in Children and Adolescents with Autism Without Intellectual Disability Following Participation in a Clinical Trial.

The VinelandTM Adaptive Behavior Scale is often used in autism spectrum disorder (ASD) trials. The Adaptive Behavior Composite Score (VABS-ABC) is the standardized overall score (the average of the Socialization, Communication and Daily Living skills domains), and the standardized 2-Domain Composite Score (VABS-2DC) is a novel outcome measure (average of the Socialization and Communication domains). A within-person meaningful change threshold (MCT) has not been established for the VABS-2DC. This paper presents a quantitative and qualitative interpretation of what constitutes a meaningful change in these scores to individuals with ASD without Intellectual Disability (ID; IQ≥70) and their families, as reported by their study partners (SPs). Data were obtained from the aV1ation clinical trial in children and adolescents with ASD and associated exit interviews. The intent-to-treat (ITT) clinical trial population included 308 individuals with autism (85.4% male; average age: 12.4 years [standard deviation (SD)=2.97]); 124 in the child cohort (aged 5 to 12 years; average age: 9.4 years [SD=1.86]), and 184 in the adolescent cohort (aged 13 to 17 years; average age: 14.5 years [SD=1.39]). Study partners of 86 trial participants were included in the Exit Interview Population (EIP): participants represented were 83.7% male, average age: 12.3 years [SD=2.98]). Anchor and distribution-based methods were used to estimate within-person change to support a responder definition, to aid interpretation of the clinical trial data; qualitative data were used to contextualize the meaning of changes observed. A within-person MCT range of 4 to 8 points was proposed for both VABS-ABC and VABS-2DC, which was associated with at least a 1-point improvement on 4 different anchors. Evidence for this within-person MCT was further supported by qualitative data, which suggested any change was considered meaningful to the individual with ASD, as reported by their SP, no matter what the magnitude. A change in standardized score of 4 to 8 points constitutes a within-person MCT on both VABS-ABC and novel VABS-2DC in those with ASD and no ID. A change of this, or more, was reported by the SPs in this trial to be meaningful and highly impactful upon the individuals with ASD and their family.

Harmonization of patient-reported outcome measurement across four academic medical centers: Multi-site clinician focus group results from the Carolinas Collaborative Initiative.

336 Background: Use of patient-reported outcomes (PROs) to monitor symptoms in cancer care demonstrates clinical benefit, but implementation of PROs across healthcare settings remains low. We conducted focus groups (FGs) with stakeholders from four academic medical centers (AMCs) to identify perceived barriers and facilitators to implementing PROs in routine care. Methods: Stakeholders were recruited to participate in FGs and asked to identify barriers and facilitators of future PRO implementation in their respective healthcare setting. Transcripts were coded and synthesized via thematic content analysis. Results: Seventy stakeholders participated in one of 14 FGs (leadership groups, n = 5; nurse groups, n = 4; physician groups, n = 5) stratified by role and site. The mean FG size was 5 (range = 2 to 14). Three overarching domains were identified: Workflow, Training and Implementation, and Data-Driven Action. Table 1 shows the relative frequency of notable codes associated with each domain across FGs aggregated by stakeholder role. Themes within each domain are: Workflow: current workflow dynamics inhibit PRO implementation (code = Workflow, Table 1); more resources are necessary to adjust clinical workflow and the EMR to facilitate administration and clinicians’ ability to respond to concerning symptoms (code = Resources needed, Table 1). Training and Implementation: clinicians may be unaware of the utility of PROs; training about the clinical relevance of PROs may help facilitate integration (code = Training needs, Table 1). Data-Driven Action: data derived from PROs must be interpretable and actionable to promote sustained utility (code = How to display PROs, Table 1). Tailored measures for specific clinical populations are needed, along with information on clinically significant scores, meaningful change thresholds, predictive value, and whether integration of PROs improves healthcare quality. Conclusions: Similar barriers to PRO implementation were identified across four AMCs. Infrastructure is needed in each AMC to help clinics integrate PROs. Resources to address workflow inefficiencies, EMR integration, clinician training, and follow-up support may help facilitate integration. Academic medical centers must also ensure that data derived from PROs are relevant and actionable.[Table: see text]

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).

Clinically meaningful change threshold in health‐related quality of life among patients aged 6 months to 5 years with atopic dermatitis and their caregiver(s)/family

AbstractBackgroundAtopic dermatitis (AD) significantly impacts health‐related quality of life (HRQoL) in children and their caregiver(s)/family. Measures to assess HRQoL include the Children's Dermatology Life Quality Index (CDLQI), Infants' Dermatitis Quality of Life Index (IDQoL) and Dermatitis Family Impact (DFI) questionnaire. Currently, there are no established clinically meaningful within‐person change thresholds for these measures in young children (6 months to 5 years) and their caregiver(s)/family.ObjectivesTo determine the clinically meaningful within‐person change thresholds for CDLQI (4–5 years), IDQoL (&lt;4 years) and DFI scores in children aged 6 months to 5 years with moderate‐to‐severe AD and their caregiver(s)/family.MethodsData from the 16‐week, randomised, double‐blind, placebo‐controlled, phase 3 LIBERTY AD PRESCHOOL part B study in children aged 6 months to 5 years were used. The anchor‐based method was used to assess meaningful change thresholds for the three instruments, using the Caregiver Global Impression of Disease (CGID; range: ‘no symptoms’ to ‘very severe’) as the primary anchor, and Caregiver Global Impression of Change (CGIC; range: ‘much better’ to ‘much worse’) as a supportive anchor.ResultsThe mean CDLQI change scores were −6.3 and −9.5 based on CGID 1‐point improvement and CGIC improvement of ‘a little better’, respectively. The mean IDQoL change scores were −5.6 and −3.4 based on the CGID and CGIC anchors. The mean DFI change scores were −7.0 and −6.7 based on the CGID and CGIC anchors.ConclusionsBased on primary anchor findings, improvements of ≥6 points on the CDLQI total score for children aged 4–5 years and on the IDQoL total score for children aged &lt;4 years were recommended as the clinically meaningful within‐person change thresholds in children with moderate‐to‐severe AD. A 7‐point improvement on the DFI total score may be considered as the meaningful threshold for the caregiver(s)/family of children aged 6 months to 5 years with moderate‐to‐severe AD.