Meaningful Threshold Research Articles

Validation of the Peak Pruritus Numerical Rating Scale as a Patient-Reported Outcome Measure in Prurigo Nodularis.

Validated patient report tools for quantifying patient experiences of itch in prurigo nodularis (PN) are limited. This study aimed to evaluate the validity of the 11-point peak pruritus numerical rating scale (PP NRS) as a single-item patient-reported outcome (PRO) measure for assessing itch severity in PN. Content validity of the PP NRS was evaluated through qualitative interviews with adults with PN. The PP NRS was then psychometrically evaluated using data from a placebo-controlled trial of nemolizumab in adults with PN, during which patients completed the PP NRS daily. Meaningful within-patient change was estimated from the qualitative interviews and by anchor- and distribution-based analyses of trial data. The interview participants (N = 21) all understood the PP NRS and reported itch as their worst symptom overall. The PP NRS showed good test-retest reliability and demonstrated convergent validity and known-groups validity. PP NRS scores improved more in patients classified as "improved" on other clinical outcome measures than in those classified as "worsened/unchanged". Triangulation of the different estimates identified a 2- to 5-point decrease in PP NRS score as a meaningful within-patient change threshold. The PP NRS is a content-valid and reliable PRO measure for quantifying itch severity in adults with PN in clinical trials. NCT03181503.

VRE acquisition in hospital and its association with hospital antimicrobial usage -a non-linear analysis of an extended time series.

Vancomycin resistant enterococci (VRE) have become endemic pathogens in many Australian hospitals causing significant morbidity. There are few observational studies that have evaluated the effect of antibiotic usage on VRE acquisition. This study examined VRE acquisition and its association with antimicrobial use. The setting was a NSW tertiary hospital with 800 beds over a 63 month period up to March 2020, straddling piperacillin-tazobactam (PT) shortages that occurred from in September 2017. The primary outcome was monthly inpatient hospital onset Vancomycin-resistant Enterococci (VRE) acquisitions. Multivariate adaptive regression splines (MARS) were used to estimate hypothetical thresholds, where antimicrobial use above threshold is associated with increased incidence of hospital onset VRE acquisition. Specific antimicrobials and categorised usage (broad, less broad and narrow spectrum) were modelled. There were 846 hospital onset VRE detections over the study period. Hospital onset vanB and vanA VRE acquisitions fell significantly by 64% and 36% respectively after the PT shortage. MARS modelling indicated that PT usage was the only antibiotic found to exhibit a meaningful threshold. PT usage greater than 17.4 defined daily doses/1000 occupied bed-days (95%C I: 13.4, 20.5) was associated with higher onset of hospital VRE. This paper highlights the large, sustained impact that reduced broad spectrum antimicrobial use had on VRE acquisition and showed that PT use in particular was a major driver with a relatively low threshold. It raises the question as to whether hospitals should be determining local antimicrobial usage targets based on direct evidence from local data analysed with non-linear methods.

Shor–Laflamme distributions of graph states and noise robustness of entanglement

The Shor–Laflamme distribution (SLD) of a quantum state is a collection of local unitary invariants that quantify k-body correlations. We show that the SLD of graph states can be derived by solving a graph-theoretical problem. In this way, the mean and variance of the SLD are obtained as simple functions of efficiently computable graph properties. Furthermore, this formulation enables us to derive closed expressions of SLDs for some graph state families. For cluster states, we observe that the SLD is very similar to a binomial distribution, and we argue that this property is typical for graph states in general. Finally, we derive an SLD-based entanglement criterion from the purity criterion and apply it to derive meaningful noise thresholds for entanglement. Our new entanglement criterion is easy to use and also applies to the case of higher-dimensional qudits. In the bigger picture, our results foster the understanding both of quantum error-correcting codes, where a closely related notion of SLDs plays an important role, and of the geometry of quantum states, where SLDs are known as sector length distributions.

Identifying thresholds for clinically meaningful change among clients of drug and alcohol services using the Australian Treatment Outcomes Profile.

The Austraian Treatment Outcomes Profile (ATOP) is a brief clinical outcomes tool used widely in the Australian alcohol and other drugs treatment sector to monitor clients' substance use, health, wellbeing and clinical risk factors. It has demonstrated reliability and validity, and has recommended clinical cut-offs for assessing single-occasion client-rated health scores. This study determined clinically meaningful change thresholds for ATOP substance use and health and wellbeing variables for use by clinicians in monitoring client progress, and for quality improvement and service evaluation. A framework for assessing clinically meaningful changes scores was developed by (1) calculating statistically reliable change thresholds using data-driven techniques with a reference sample of clinical ATOP data and (2) conducting a multi-disciplinary subject matter expert group to review the utility and validity of data-derived clinically meaningful change. The study was conducted within Outpatient Alcohol and Other Drug treatment services in New South Wales, Australia. The reference sample comprised 6100 ATOPs from clients at entry to public outpatient Alcohol and Other Drug treatment services; the subject matter expert group comprised 29 key stakeholders from the specialist alcohol and other drug treatment sector. We used the Reliable Change Index method to calculate clinically meaningful change thresholds for ATOP variables. For substance use variables, a change of 30% in days of use in the last 28 (minimum 4days) was the threshold for clinically meaningful change for substance use; for health and wellbeing variables, a change of 2 or more points in psychological health, physical health or quality of life scores (measured on 0-10 scales) was the minimum clinically meaningful change. Clinically meaningful change thresholds have been proposed for Australian Treatment Outcomes Profile substance use and health and wellbeing items, based on statistical reliability and subject matter expert assessment. These will be used in the development of an outcomes metric for assessing change and assigning meaning in aggregated data for evaluation of services.

Establishing clinically meaningful within-individual improvement thresholds for eight patient-reported outcome measures in people with relapsing-remitting multiple sclerosis

BackgroundAs disease-modifying therapies do not reverse the course of multiple sclerosis (MS), assessment of therapeutic success involves documenting patient-reported outcomes (PROs) concerning health-related quality of life, disease and treatment-related symptoms, and the impact of symptoms on function. Interpreting PRO data involves going beyond statistical significance to calculate within-patient meaningful change scores. These thresholds are needed for each PRO in order to fully interpret the PRO data. This analysis of PRO data from the PROMiS AUBAGIO study, which utilized 8 PRO instruments in teriflunomide-treated relapsing-remitting MS (RRMS) patients, was designed to estimate clinically meaningful within-individual improvement thresholds in the same manner, for 8 PRO instruments.ResultsThe analytical approach followed a triangulation exercise that considered results from anchor- and distribution-based methods and graphical representations of empirical cumulative distribution functions in PRO scores in groups defined by anchor variables. Data from 8 PRO instruments (MSIS-29 v2, FSMC, MSPS, MSNQ, TSQM v1.4, PDDS, HRPQ-MS v2, and HADS) were assessed from 434 RRMS patients. For MSIS-29 v2, FSMC, MSPS, and MSNQ total scores, available anchor variables enabled both anchor- and distribution-based methods to be applied. For instruments with no appropriate anchor available, distribution-based methods were applied. A recommended value for meaningful within-individual improvement was defined by comparing mean change in PRO scores between participants showing improvement of one or two categories in the anchor variable or those showing no change. A “lower bound” estimate was calculated using distribution-based methods. An improvement greater than the lower-bound estimate was considered “clinically meaningful”.ConclusionThis analysis produced estimates for assessing meaningful within-individual improvements for 8 PRO instruments used in MS studies. These estimates should be useful for interpreting scores and communicating study results and should facilitate decision-making by regulatory and healthcare authorities where these 8 PROs are commonly employed.

P71 Dupilumab improves patient-reported itch and other signs and symptoms of disease in adults with prurigo nodularis (LIBERTY-PN PRIME and PRIME2)

Abstract Prurigo nodularis (PN) is characterized by the presence of itchy nodules on the trunk/extremities and is often accompanied by skin pain and sleep disruption. Patient needs are highest regarding symptom control and improvement of itch, which is one of the main hallmarks of PN. Using pooled blinded data from two randomized, double-blind, placebo-controlled phase III trials of dupilumab in adults with PN uncontrolled on topical therapies, LIBERTY-PN PRIME (NCT04183335) and PRIME2 (NCT04202679), the psychometric validation and within-patient meaningful change thresholds for three patient-reported outcome (PRO) instruments of the trial were assessed in patients with PN: Worst Itch Numerical Rating Scale (WI-NRS), Skin Pain-NRS and Sleep-NRS. The proportion of patients achieving clinically meaningful improvement in these PRO scores in LIBERTY-PN PRIME and PRIME2 was investigated in this post hoc analysis. Adults with PN inadequately controlled on topical prescription therapies, or when those therapies were not advisable, were randomized 1 : 1 to dupilumab 300 mg every 2 weeks or matched placebo. Here, we report the proportion of patients meeting a defined improvement threshold in weekly averages from baseline to week 24 of ≥ 4 points in WI-NRS, ≥ 4 points in Skin Pain-NRS and ≥ 2 points in Sleep-NRS (within-patient meaningful improvement thresholds defined in the context of the LIBERTY-PN PRIME and PRIME2 studies, range 0–10), and the proportion of patients who achieved a new composite endpoint, meaningful improvement in WI-NRS and either Skin Pain-NRS or Sleep-NRS at week 24. A total of 311 patients were randomized (dupilumab, n = 153; placebo, n = 158). Baseline scores for WI-NRS, Skin Pain-NRS and Sleep-NRS were balanced between treatment groups. Significantly more patients treated with dupilumab vs. placebo achieved in-­patient meaningful improvement in WI-NRS (58.8% vs. 19.0%; P < 0.001), Skin Pain-NRS (49.7% vs. 20.9%; P < 0.001) and Sleep-NRS (42.5% vs. 23.4%; P < 0.001) from baseline to week 24. More patients treated with dupilumab experienced clinically meaningful improvement in WI-NRS and either Skin Pain-NRS or Sleep-NRS vs. placebo (53.6% vs. 18.4%; P < 0.001). Adults with PN uncontrolled on topical therapies treated with dupilumab achieved statistically significant and clinically meaningful improvement in itch, skin pain and sleep quality individually, and in itch combined with either skin pain or sleep. The safety profile of dupilumab was consistent with the known safety profile in its approved indications. Funding sources: research sponsored by Sanofi and Regeneron Pharmaceuticals Inc.

GOunder/Desmoid Tumor Research Foundation DEsmoid Symptom/Impact Scale (GODDESS©): psychometric properties and clinically meaningful thresholds as assessed in the Phase 3 DeFi randomized controlled clinical trial

PurposeThe GODDESS© tool was developed to assess Desmoid Tumor/Aggressive Fibromatosis (DT/AF) symptom severity and impact on patients’ lives. This study evaluated GODDESS©’s cross-sectional and longitudinal measurement properties.MethodsThe Phase 3, randomized placebo-controlled, DeFi study (NCT03785964) of nirogacestat in DT/AF was used to assess GODDESS©’s reliability, construct validity, responsiveness, and estimate of meaningful change thresholds (MCTs). Other patient-reported outcome (PRO) measures included Patient Global Impression of Severity (PGIS) in DT/AF symptoms, EORTC QLQ-C30, Brief Pain Inventory Short Form, and PROMIS Physical Function short-form 10a v2.0 plus 3 items.ResultsDeFi participants (N = 142) had a median age of 34 years (range: 18–76) and were mostly female (64.8%), with extra-abdominal (76.8%) or intra-abdominal tumors (23.2%). The GODDESS© symptom/impact scales showed internal consistency at baseline, cycles 4 and 7 (Cronbach’s α > 0.70) and test–retest reliability (intra-class correlation coefficient > 0.85). GODDESS© scales correlated moderately to highly with PRO measures capturing similar content and differentiated among PGIS and Eastern Cooperative Oncology Group groups. GODDESS© scales detected improvement over time. For the total symptom score, a 1.30-point decrease was estimated as the within-person MCT and a 1.00-point decrease as the between-group MCT. For the physical functioning impact score, estimated within- and between-group MCTs were 0.60-point and 0.50-point decreases, respectively. Few participants exhibited symptom worsening.ConclusionGODDESS© was found to be reliable, valid, responsive, and interpretable as a clinical trial endpoint in the pooled sample of DT/AF patients. Estimated MCTs can be used to define responders and assess group-level differences in future, unblinded, efficacy analyses.Trial registration number and registration dateNCT03785964; December 24, 2018.

Tracking between cardiovascular-related measures at 4 and 8years of age in the INMA-Asturias cohort.

Identifying cardiovascular-related measures that track from early childhood into later ages may help inform early prevention targets for cardiovascular disease. In this study, the tracking of triglycerides (TG), high-density cholesterol (HDL-c), atherogenic coefficient (AC), waist circumference to height ratio (WC/Height), mean arterial pressure (MAP), and homeostatic model assessment of insulin resistance (HOMA-IR) was examined in the INMA-Asturias cohort between 4 and 8years of age. The analysis was conducted in 307 children who participated in the INMA-Asturias cohort (Spain) at 4 and at 8years of age. Quantile regression models were used to evaluate tracking between measures at both ages, with each measure at 8years as the dependent variable and the rank transformation of the same measure at 4years as the independent variable. We found a positive association between HDL-c rank at 4years and higher quantiles of the HDL-c distribution at 8years, with an increase of 2.93mg/dL (95% CI: 1.98, 3.87) per decile in the 0.9 quantile. A positive association was also found for WC/Height, with an increase of 0.008 (95% CI: 0.004, 0.012) per decile in the 0.9 quantile. We observed that tracking for AC increased in the higher quantiles of the distribution at 8years, with an increase of 0.11 (95% CI: 0.09, 0.14) in the 0.6 quantile compared to an effect of 0.15 (95% CI: 0.09, 0.21) in the 0.9 quantile. Conclusions: Adult markers of dyslipidemia and central obesity tracked between ages 4 and 8years. For AC, tracking increased in the higher quantiles of the distribution. What is Known: • Atherosclerosis begins in early life, so preventive efforts that start in childhood may delay progression to clinical disease. Determine what cardiovascular risk factors track into time since childhood bring the opportunity to identified those subjects at risk for later cardiovascular disease. • The study of risk factors in health populations and, particularly in children, copes with not clear and/or controversial thresholds definition. This makes it challenging to study tracking in pediatric ages. What is New: • Quantile regression is a useful tool for assessing the tracking of risk factors for which there are no clinically meaningful thresholds. The increasing trend observed in the tracking of dyslipidemia suggests the possible difficulty that children with abnormal values at 4 years of age might have in normalizing them in future years. • The findings of this article may help to determine which cardiovascular-related measures could be screened and followed-up in children.

Study to Assess Content Validity and Interrater and Intrarater Reliability of the Inclusion Body Myositis Functional Rating Scale.

Sporadic inclusion body myositis (IBM) is a rare, muscle-wasting disease that negatively affects health-related quality of life. Although a measure that has been developed to assess the impact of IBM, the IBM Functional Rating Scale (IBMFRS) has limited evidence of content validity or reliability, and what constitutes a meaningful change threshold; this study was conducted to address these gaps. Adult patients with a clinical diagnosis of IBM from the United Kingdom and disease area expert health care professionals from the United States and United Kingdom took part in this study. This study consisted of 5 stages including phone interviews (physicians), face-to-face interviews (patients), face-to-face ratings, phone ratings, and ratings of videos using the IBMFRS. The IBMFRS adequately captures all core functional impacts of IBM, which was corroborated by both patient participants and physicians when debriefing the measure. Physicians and patient participants all thought any change on the measure would be meaningful change for a patient, either improvement or worsening. The quantitative analysis demonstrated good interrater reliability for face-to-face ratings (intraclass correlation coefficient [ICC] >0.7) and for video ratings (ICC >0.9). Intrarater reliability was excellent for face-to-face and video ratings (ICC >0.9). Equivalence between the modes of administration, face-to-face vs phone, was also excellent (ICC >0.9). The IBMFRS is content valid in assessing the key functional impacts of IBM, and any change would be meaningful. It is reliable both within and across raters, and there is equivalence between different modes of administration (face-to-face vs phone).

Psychometric Validation and Meaningful Change Thresholds of the New Nasal Polyposis Symptom Diary.

The Nasal Polyposis Symptom Diary (NPSD) is a novel and short patient-reported outcome (PRO) tool specifically developed to assess important and relevant symptoms reported by patients with chronic rhinosinusitis with nasal polyposis (CRSwNP). We evaluated the psychometric properties of 4 predefined NPSD-derived scores intended to support symptom-improvement assessments of investigational therapies for inclusion in product labeling. Five hundred eighteen patients with severe CRSwNP from a Phase III clinical trial (NCT03401229) completed the NPSD, comprising 11 items: 8 symptom-specific, 2 symptom-impact, and 1 optional medication-compliance. The psychometric characteristics of 3 single-item symptom scores (Nasal Blockage Score [NBS], Nasal Congestion Score [NCS], and Difficulty with Sense of Smell Score [DSS]) and a Total Symptom Score (TSS, summary of the 8 symptom-specific items) were evaluated for reliability, validity, and ability to detect change. Within-patient meaningful change thresholds (MCTs) were established using anchor- and distribution-based methods. Comparative PROs included the 22-item Sino-Nasal Outcome Test (SNOT-22) and Patient Global Impression of Severity (PGI-S). The TSS exhibited strong internal consistency (Cronbach α = .88) and test-retest reliability (intraclass correlation coefficient >.80). Correlation between the TSS and SNOT-22 total score indicated good convergent validity (r = .70). All 4 NPSD scores demonstrated known-groups validity (significant differences among subgroups of patients with predetermined disease severity levels based on PGI-S categories) and were sensitive to detect change in patients' clinical status (significant differences among subgroups of patients with reported changes between 2 time-points in PGI-S and Patient Global Impression of Change scores). MCTs for improvement were established at 1.0 point for NBS, NCS, and DSS, and 4.0 points for TSS. These findings support the reliability, validity, and suitability of the 4 NPSD-derived scores for evaluating treatment effect on CRSwNP symptoms and their use in clinical trials with predetermined MCTs for improvement.

CO168 Defining Clinically Meaningful Thresholds (CMT) for Forced Vital Capacity (FVC) and Six-Minute Walk Test (6MWT) in Patients with Late-Onset Pompe Disease (LOPD)

Interpretation of clinical trial results is limited without a defined CMT for within-patient change or between-group differences of study endpoints. Pooled data (n =100) from COMET trial (NCT02782741) comparing avalglucosidase alfa (AVA) vs. alglucosidase alfa (ALG) in LOPD was used to estimate within-patient and between-group CMTs for FVC (%predicted) and 6MWT.

Health-related quality of life (HRQOL) in patients (pts) with advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC) or esophageal adenocarcinoma (EAC): 36-month results of nivolumab plus chemotherapy (N+C) versus (C) from CheckMate 649.

4038 Background: CheckMate 649 (NCT02872116) is a randomized, open-label, phase 3 study in first-line treatment of pts with advanced GC/GEJC/EAC. Primary results showed statistically significant improvement in overall survival (OS) for N+C versus C in all randomized pts. Prior analyses conducted for 24-month follow-up (FUP) showed pts receiving N+C maintained HRQOL and experienced delayed deterioration in HRQOL compared with pts receiving C. Here we report additional analyses of HRQOL with 36-month FUP data. Methods: Functional Assessment of Cancer Therapy–Gastric Cancer (FACT-Ga) and EQ-5D-3L results were collected at baseline (BL) and every 6 weeks while on treatment. Change from BL in FACT-Ga, EQ-5D Visual Analog Scale (VAS), and Utility Index (UI) scores were analyzed using mixed models. Time to first symptom deterioration (TTSD), time until definitive deterioration (TuDD), and time to improvement (TTI) were estimated with Kaplan-Meier estimators and stratified Cox models; deterioration/improvement events were based on prespecified meaningful thresholds for change scores. Results: A total of 1,581 pts were randomized to N+C (n = 789) and C (n = 792); of those, 1,360 pts had BL and post-BL PROs and were included in the PRO population (N+C [n = 694] and C [n = 666]). With additional follow-up, least-squares mean differences from BL remained comparable between groups across visits for HRQOL measurements with exceptions. FACT-Ga total score, GaCS, physical well-being (WB), and emotional WB tended to favor N+C; social WB tended to favor C. For all randomized pts, most time-to-event endpoints favored N+C; like the 24-month analysis, statistically significant delays in deterioration were maintained for TuDD (except FACT-G Social WB) and TTSD (only FACT-GaCS and FACT-Ga total). Conclusions: These results confirm the earlier 24-month FUP findings. Compared with C alone, N+C maintained HRQOL with decreased risk of deterioration in pts with previously untreated advanced or metastatic GC/GEJC/EAC. Together with improved OS, data continue to support N+C as a first-line standard treatment for GC/GEJC/EAC. Clinical trial information: NCT02872116 . [Table: see text]

Percentage of negative urine drug screens as a clinically meaningful endpoint for RCTs evaluating treatment for cocaine use

BackgroundThis study examined a threshold based on the percentage of cocaine-negative (CN) urine drug screens (UDS) collected during treatment as a potential meaningful endpoint for clinical trials. We hypothesized that individuals providing at least 75% CN UDS would have better long-term outcomes than those providing less than 75% CN UDS. MethodsTwo separate pooled datasets of randomized clinical trials conducted at different institutions were used for analyses: one composed of eight trials (N = 760) and the other composed of three trials (N = 416), all evaluating behavioral and/or pharmacological treatments for cocaine use. UDS were collected at least once per week (up to three times per week) during the 8- or 12-week treatment period across all trials, with substance use and psychosocial functioning measured up to 12 months following treatment. Chi-squares and ANOVAs compared within-treatment and follow-up outcomes between the groups. ResultsCompared to those who did not achieve the threshold, participants who achieved the 75%-CN threshold were retained in treatment longer and had a longer period of continuous abstinence, and were more likely to report problem-free functioning. Additionally, participants who achieved the 75%-CN threshold were more likely to report sustained abstinence and better psychosocial functioning throughout a follow-up period up to 12 months than those who did not achieve the threshold. ConclusionsA threshold of 75%-CN UDS is associated with short- and long-term clinical benefits. Future clinical trials may consider this a meaningful threshold for defining treatment responders.

Using bookmarking methods with orthopedic clinicians and patients with fractures produces score interpretation labels for patient-reported outcome measures

ObjectiveThe objective of this study was to determine the patient-reported outcome measure (PROM) score ranges associated with descriptive labels (i.e., within normal limits, mild, moderate, severe) by using bookmarking methods with orthopedic clinicians and patients who have experienced a bone fracture.Study design and settingWe created vignettes comprised of six items and responses from the Patient-Reported Outcomes Measurement Information System (PROMIS) Upper Extremity Function, Physical Function, and Pain Interference item banks reflecting different levels of severity. Two groups of patients with fractures (n = 11) and two groups of orthopedic clinicians (n = 16) reviewed the vignettes and assigned descriptive labels independently and then discussed as a group until reaching consensus via a videoconference platform.ResultsPROMIS Physical Function and Pain Interference thresholds (T = 50, 40, 25/30 and T = 50/55, 60, 65/70, respectively) for patients with bone fractures were consistent with the results from other patient populations. Upper Extremity thresholds were about 10 points (1 SD) more severe (T = 40, 30, 25/20) compared to the other measures. Patient and clinician perspectives were similar.ConclusionBookmarking methods generated meaningful score thresholds for PROMIS measures. These thresholds between severity categories varied by domain. Threshold values for severity represent important supplemental information to interpret PROMIS scores clinically.

Psychometric evaluation of the Symptoms of Infection with Coronavirus-19 (SIC): results from a cross-sectional study and a phase 3 clinical trial

BackgroundThe Symptoms of Infection with Coronavirus-19 (SIC) is a 30-item patient-reported outcome (PRO) measure scored by body system composites to assess signs/symptoms of coronavirus disease 2019 (COVID-19). In addition to cross-sectional and longitudinal psychometric evaluations, qualitative exit interviews were conducted to support the content validity of the SIC.MethodsIn a cross-sectional study, adults diagnosed with COVID-19 in the United States completed the web-based SIC and additional PRO measures. A subset was invited to participate in phone-based exit interviews. Longitudinal psychometric properties were assessed in ENSEMBLE2, a multinational, randomized, double-blind, placebo-controlled, phase 3 trial of the Ad26.COV2.S COVID-19 vaccine. Psychometric properties evaluated included structure, scoring, reliability, construct validity, discriminating ability, responsiveness, and meaningful change thresholds of SIC items and composite scores.ResultsIn the cross-sectional study, 152 participants completed the SIC (mean age, 51.0 ± 18.6 years) and 20 completed follow-up interviews. Fatigue (77.6%), feeling unwell (65.8%), and cough (60.5%) were symptoms most frequently reported. SIC inter-item correlations were all positive and mostly moderate (r ≥ 0.3) and statistically significant. SIC items and Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) scores correlated as hypothesized (all r ≥ 0.32). Internal consistency reliabilities of all SIC composite scores were satisfactory (Cronbach’s alpha, 0.69–0.91). SIC composite scores correlated moderately (r = 0.30–0.49) to strongly (r ≥ 0.50) with PROMIS-29 scores and Patient Global Impression of Severity (PGIS) ratings (all P < 0.01). A variety of signs/symptoms were cited in exit interviews, and participants considered the SIC straightforward, comprehensive, and easy to use. From ENSEMBLE2, 183 participants with laboratory-confirmed moderate to severe/critical COVID-19 were included (51.5 ± 14.8 years). Strong test-retest reliabilities were observed for most SIC composite scores (intraclass correlations ≥ 0.60). Statistically significant differences across PGIS severity levels were found for all but 1 composite score, supporting known-groups validity. All SIC composite scores demonstrated responsiveness based on changes in PGIS.ConclusionsThe psychometric evaluations provided strong evidence for the reliability and validity of the SIC for measuring COVID-19 symptoms, supporting its use in vaccine and treatment trials. In exit interviews, participants described a broad range of signs/symptoms consistent with previous research, further supporting the content validity and format of the SIC.

Health-Related Quality of Life Instruments for Clinical Trials in AL Amyloidosis: Report from the Amyloidosis Forum HRQOL Working Group.

Systemic AL (light chain) amyloidosis is a rare protein misfolding disorder associated with plasma cell dyscrasia affecting various organs leading to organ dysfunction and failure. The Amyloidosis Forum is a public-private partnership between the Amyloidosis Research Consortium and the US Food and Drug Administration Center for Drug Evaluation and Research with the goal of accelerating the development of effective treatments for AL amyloidosis. In recognition of this goal, 6 individual working groups were formed to identify and/or provide recommendations related to various aspects of patient-relevant clinical trial endpoints. This review summarizes the methods, findings, and recommendations of the Health-Related Quality of Life (HRQOL) Working Group. The HRQOL Working Group sought to identify existing patient-reported outcome (PRO) assessments of HRQOL for use in clinical trials and practice deemed relevant across a broad spectrum of patients with AL amyloidosis. A systematic review of the AL amyloidosis literature identified 1) additional signs/symptoms not currently part of an existing conceptual model, and 2) relevant PRO instruments used to measure HRQOL. The Working Group mapped content from each identified instrument to areas of impact in the conceptual model to determine which instrument(s) provide coverage of relevant concepts. The SF-36v2® Health Survey (SF-36v2; QualityMetric Incorporated, LLC) and Patient-Reported Outcomes Measurement Information System-29 Profile (PROMIS-29; HealthMeasures) were identified as instruments relevant to patients with AL amyloidosis. Existing evidence of reliability and validity was evaluated with a recommendation for future work focused on estimating clinically meaningful within-patient change thresholds for these instruments. For sponsors, the context of use-including specific research objectives, trial population, and investigational product under study-should inherently drive selection of the appropriate PRO instrument and endpoint definitions to detect meaningful change and enable patient-focused drug development.

Meaningful changes for efficacy outcomes in patients with chronic rhinosinusitis with nasal polyps

ObjectiveNasal Polyp Score (NPS) and Nasal Congestion Score (NCS) are commonly used clinical trial endpoints to determine improvements in response to treatment in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). However, limited information is available on within-patient meaningful change thresholds (MCTs) and between-group minimal important differences (MIDs) for NPS and NCS, which would aid interpretation of results. MethodsData from phase 3 placebo-controlled trials of omalizumab in patients with CRSwNP (POLYP 1 and POLYP 2) were used to estimate MCTs and MIDs for both NPS and NCS using anchor-based methods. Sino-Nasal Outcome Test-22 (SNOT-22) and SNOT-22 Sino-Nasal Symptoms Subscale (SNSS) scores were used as anchors (≥0.35 correlation with NPS and NCS). Within- and between-group differences in NPS and NCS change scores were used to estimate MCTs and MIDs, respectively. Identified MCTs were used in unblinded responder analyses to compare the proportions of patients per treatment group achieving a meaningful improvement. ResultsMCTs and MIDs were estimated at −1.0 and −0.5 for NPS and −0.50 and −0.35 for NCS, respectively, and were consistent across studies. Overall, 57.0% of patients achieved the MCT in NPS with omalizumab vs 29.9% with placebo (p < 0.0001). Similarly, 58.9% of patients achieved the MCT in NCS with omalizumab vs 30.7% with placebo (p < 0.0001). Group differences in mean change were statistically significant and exceeded the estimated MIDs. ConclusionsMeaningful change estimates for NPS and NCS could be used to assess response to treatment for patients with chronic rhinosinusitis with nasal polyps.Trial registration: POLYP1: clinicaltrails.gov NCT03280550; registered September 12, 2017; https://clinicaltrials.gov/ct2/show/NCT03280550). POLYP2 (clinicaltrials.gov NCT03280537; registered September 12, 2017; https://clinicaltrials.gov/ct2/show/NCT03280537).

PO-04-209 A NOVEL MACHINE LEARNING (ML) ALGORITHM TO MEASURE THE CORRECTED QT INTERVAL FROM MOBILE ECGS WITH HIGH ACCURACY AND PRECISION

The heart rate-corrected QT interval (QTc) is an important feature of the electrocardiogram (ECG), as it is an important prognosticator for ventricular arrhythmia and sudden cardiac death. The 12-lead (12L) ECG is used most often for assessment of QTc, and algorithms that have extended QTc detection to mobile ECGs with fewer than 12 leads are prone to wide sample size deviation. For clinical applications requiring serial QTc monitoring, such as titration of QTc-prolonging drugs, both accuracy and precision are critical. The aim was to develop a novel machine-learning (ML) algorithm that measures QTc from mobile ECG data formats with high accuracy as well as precision. The acceptance criteria was defined as error and standard deviation within 20 milliseconds (ms), the human interobserver variability observed for manual ECG measurements (gold standard). The ML algorithm was trained using a database of 13,000 cardiologist-annotated 12L ECG heartbeats, including the following steps: 1) pre-processing including resampling to 300 Hz, 2) normalization of amplitudes using min-max scaling 3) noisy beats with excessive baseline wander were discarded, and 4) applying TabNet and XGBoost models for detection of the end of T-Wave. This ML model for detection of the T-wave endpoint was merged with a signal processing method for detection of the Q-point. The algorithm was then validated on a subset of 1,239 cardiologist-annotated heartbeats, sufficient to assess strong agreement between software and manual methods (95% CI ± 0.2 std, Bland-Altman approach). Results showed high AUC, sensitivity, and specificity for detecting QTc above clinically meaningful thresholds. Mean QTc error was 5.24±7.22 ms, meeting predefined acceptance criteria. The ML algorithm was then applied to a dataset of 150 6L mECGs (AliveCor; Mountain View, CA), which comprise an all-comer population of a combination of healthy (∼40%), outpatient clinic (30%), and hospitalized patients (30%), with error 13.7±7.78 ms, again meeting acceptance criteria. Algorithm validation surpassed the defined acceptance criteria and demonstrated that the algorithm can provide and potentially surpass human QTc measurement capabilities. By enabling automated, dynamic QTc analysis, the algorithm offered the precision required for outpatient use.

Sustained antibody persistence for at least 15years after a booster vaccination against tick-borne encephalitis following different primary vaccination schedules: Third 5-year follow-up.

Vaccination is the best mode of protection against tick-borne encephalitis (TBE) and its sequelae. The duration of protection and the optimal interval of repeat booster doses are still debated. The current study evaluated the persistence of the antibody response 11-15years after a first booster vaccination following different primary vaccination schedules with a TBE vaccine (Encepur Adults, manufactured by Bavarian Nordic, previously by GSK). This phase IV, open-label, mono-centric extension study enrolled adults who had received (at≥12years of age) primary vaccination with one of three randomly assigned TBE vaccine schedules (rapid [group R], conventional [group C], or accelerated conventional schedule [group A]) followed by a booster dose 3years later. The antibody response was measured annually from 11 to 15years post-booster using a TBE virus neutralization test (NT). An NT titer of≥10 was considered as a clinically meaningful threshold and surrogate for protection. In total, 194 participants were enrolled and included in the per-protocol set; 188 completed the study. The percentage of participants with an NT titer≥10 was 100% in group R and 99.0% in group A at all visits and ranged from 100% (year 11) to 95.8% (year 15) in group C. NT geometric mean titers were similar in the three study groups (181-267 in group R, 142-227 in group C, 141-209 in group A). NT geometric mean titers also remained high among participants≥50years old (98-206) and≥60years old (91-191) across study groups and time points. This study showed neutralizing antibody persistence for at least 15years after a first booster dose of the Encepur Adults TBE vaccine in all age groups evaluated, regardless of which primary vaccination schedule was given to adolescents or adults. Trialregistry: ClinicalTrials.gov: NCT03294135.

Psychometrics of patient-reported bother from side effects of treatment single-items in industry-sponsored oncology trials.

Improvements in cancer treatment have increased the number of cancer survivors, but also increased the long-term and late effects from cancer therapy. Patient reported "side effect bother" could be used to measure the burden of treatment, and the risk for negative outcomes such as dose reduction, treatment delay or discontinuation. The current study addresses the psychometric properties of a single item, determines what represents a "meaningful change", and evaluates the correlation to safety endpoints and functioning. Results from 5911 patients enrolled in 8 clinical trials representing 5 disease types in oncology and hematology who completed either the Functional Assessment of Cancer Therapy (FACT) GP5 item or a modified bother item (MBI) were assessed. Patients ranged in age from 18 to 93years, with all cancer stages represented and approximately equal numbers of males and females. Test-retest reliability was acceptable, as were convergent and known groups validity. The GP5 and MBI effectively demonstrated sensitivity to change over time and established meaningful thresholds. The results indicate that these single-items are psychometrically sound, capable of distinguishing known groups, responsive to change and can identify meaningful change over time in terms of treatment-related symptoms. It extends the findings of recent scientific groups by providing analyses not included in prior studies, and further supports the FDA's recommendation to include a single item question in clinical trials.