Responder Definition Research Articles

P1739: HEALTH-RELATED QUALITY OF LIFE IN PATIENTS WITH TRIPLE-CLASS EXPOSED RELAPSED/REFRACTORY MULTIPLE MYELOMA TREATED WITH IBERDOMIDE PLUS DEXAMETHASONE IN A PHASE 1B/2A OPEN-LABEL DOSE ESCALATION STUDY

Background: Patients with relapsed/refractory multiple myeloma (RRMM) who are triple-class exposed (TCE) have limited treatment options and experience poor health-related quality of life (HRQoL). Iberdomide (IBER), a novel cereblon E3 ligase modulator (CELMoD®) compound, has shown an overall response rate of 26% in this population when administered with dexamethasone (DEX) in the open-label, single-arm, phase 1b/2a dose-escalation CC-220-MM-001 clinical trial (NCT02773030). Here, we assess the exploratory endpoint of HRQoL for patients enrolled in this clinical trial. Aims: To assess HRQoL in patients with RRMM who received IBER + DEX in cohorts D and I of the CC-220-MM-001 trial. Methods: In this pooled analysis of cohorts D and I, cohort D patients had RRMM; had received ≥3 prior lines of therapy, including lenalidomide, pomalidomide, a proteasome inhibitor, a glucocorticoid, and an anti-CD38 monoclonal antibody; had experienced disease progression within 60 days of last myeloma therapy; and were triple-class refractory. Patients who had received prior anti-B-cell maturation antigen (BCMA) therapy were excluded from cohort D but included in cohort I. In both cohorts, IBER (1.6 mg) was given orally on days 1–21, in combination with DEX (40 mg; 20 mg if >75 years) on day 1, 8, 15, and 22 of each 28-day cycle. The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30), EORTC QLQ-Multiple Myeloma Module (QLQ-MY20), and EuroQoL 5 dimensions 5 levels (EQ-5D-5L) were administered before treatment, on day 1 of each treatment cycle, and at end of treatment. The HRQoL-evaluable population included all patients who received IBER + DEX and who had evaluable assessments of a given HRQoL measure at baseline (cycle 1 day 1) and at ≥1 post-baseline time point. Minimally important differences were prespecified for each domain to interpret whether a mean within-group change from baseline was meaningful. Overall, least square mean HRQoL score changes from baseline were estimated from a mixed-effects model for repeated measures. Proportions of patients who experienced clinically meaningful HRQoL deterioration and improvement were calculated using prespecified responder definitions. Results: A total of 133 patients received IBER + DEX; 99 patients were included in the QLQ-C30-evaluable population (TCE n=79, TCE + anti-BCMA n=20). Median (range) age was 63 (44–82) years, 57% were male, and 95% had ≥4 prior MM regimens (median 6 prior MM regimens). Completion rates for most time points were ≥70%. Mean HRQoL scores were generally stable over time during treatment in all the HRQoL domains, including fatigue, pain, disease symptoms, and side effects. However, the EORTC QLQ-MY20 body image showed clinically meaningful improvement from baseline (Table). At individual level, most patients (≥60%) experienced either clinically meaningful improvement or no change while on treatment in all domains. Image:Summary/Conclusion: HRQoL scores among IBER + DEX patients in cohorts D and I were generally stable in all domains across 3 HRQoL measures. Most patients experienced either clinically meaningful improvement or no change in each domain. This suggests the IBER + DEX treatment maintained HRQoL in heavily pretreated patients with TCE RRMM, while demonstrating a promising clinical response.

Development of the Hypertrophic Cardiomyopathy Symptom Questionnaire (HCMSQ): A New Patient-Reported Outcome (PRO) Instrument.

BackgroundCurrently, there is no patient-reported outcome (PRO) instrument specifically designed to evaluate hypertrophic cardiomyopathy (HCM).ObjectiveWe present the development and psychometric validation of a novel PRO measure, the HCM Symptom Questionnaire version 1.0 (HCMSQv1.0).MethodsCognitive debriefing interviews and a card-sorting task were conducted in 33 patients with HCM to support development of the HCMSQv1.0, showing the scale to be interpretable and relevant to patients’ experiences. Baseline blinded data from two trials (EXPLORER-HCM and MAVERICK-HCM) were pooled (N = 299) to develop the scoring algorithm of HCMSQv1.0. Measurement properties were examined, followed by a meaningful-change analysis to interpret scores. Rasch modeling, mixed-model repeated measures, exploratory factor analysis, confirmatory factor analysis, and missing-data simulation analysis informed the number of domains and the items in each domain.ResultsThe scoring algorithm for HCMSQv1.0 consists of four domains: shortness of breath, tiredness, cardiovascular symptoms, and syncope; plus a total score, with higher scores indicating more severe symptoms. Item characteristics, internal consistency, test–retest reliability, construct validity, and responsiveness were acceptable. A clinically meaningful responder definition of 1–2 points on the HCMSQv1.0 score for shortness of breath and total score, and approximately 1 point on the tiredness and cardiovascular symptom scores, was calculated based on distribution- and anchor-based methods.ConclusionOur findings support the HCMSQv1.0 as a fit-for-purpose PRO instrument for assessing treatment benefit in patients with HCM. Studies in larger patient populations are ongoing to confirm responder definition and scoring approaches encompassing key HCM symptoms.Supplementary InformationThe online version contains supplementary material available at 10.1007/s41669-022-00335-5.

Lisocabtagene maraleucel (liso-cel) as second-line (2L) treatment (tx) for R/R large B-cell lymphoma (LBCL) in patients (pt) not intended for hematopoietic stem cell transplantation (HSCT): Patient-reported outcomes (PRO) from the phase 2 PILOT study.

6567 Background: PILOT (NCT03483103) evaluated liso-cel, an autologous, CD19-directed, CAR T cell product, as 2L tx in pts with R/R LBCL not intended for HSCT. We analyzed changes in health-related quality of life (QOL) with respect to functioning and symptoms in PILOT. Methods: Adults with R/R LBCL after first-line tx were eligible. Pts were deemed not candidates for high-dose chemotherapy and HSCT by their physician and met ≥ 1 frailty criteria: age ≥ 70 yr, ECOG PS = 2, DLCO ≤ 60%, LVEF < 50%, CrCl < 60 mL/min, or ALT/AST > 2 × ULN. Pts completed EORTC QLQ-C30, FACT-LymS, and EQ-5D-5L (health utility index [HUI] and VAS) at screening (baseline [BL]), pre-tx (within 7 days before lymphodepletion), preinfusion on day of liso-cel infusion (Day 1), post-tx on Days 29, 60, 90, 180, 270, 365, 545, and 730/end of study, or at PD. The PRO-evaluable set included all pts with BL and ≥ 1 post-BL assessments. Linear mixed-effects models for repeated measures assessed the least squares (LS) mean change from BL for visits with ≥ 10 pts. Meaningful change from BL was calculated using responder definitions (in points): 10 for EORTC QLQ-C30, 3 for FACT-LymS, 0.08 for EQ-5D-5L HUI, and 7 for EQ-VAS. Results: Among the PRO-evaluable set, completion rates were high (≥ 80%) across most visits for all measures. For EORTC QLQ-C30, mean BL fatigue was meaningfully worse than in a general noncancer population (difference of > 10 points). Overall LS mean changes through Day 545 showed significant improvements in EORTC QLQ-C30 fatigue and pain, FACT-LymS, and EQ-VAS (Table). Improvement for lymphoma symptoms was also clinically meaningful. Fatigue improvement was clinically meaningful with a more sensitive minimal important difference of 4 (Cocks et al, 2012). Significant worsening was not observed for any outcome. In individual patient-level analysis, 70% of pts demonstrated meaningful improvement in FACT-LymS at month 6. Conclusions: Liso-cel meaningfully improved fatigue and FACT-LymS scores without negatively impacting other QOL measures. These data support the clinical evidence of liso-cel as a potential new 2L tx in pts with R/R LBCL not intended for HSCT. Clinical trial information: NCT03483103. [Table: see text]

0455 The Insomnia Daytime Symptoms and Impacts Questionnaire: An Analysis of Clinically Meaningful Change Using Phase 3 Clinical Trial Data

Abstract Introduction The Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) is a new validated patientreported outcome (PRO) instrument evaluating daytime functioning in people with insomnia. It comprises 14 items grouped into 3 domains: Alert/Cognition, Mood, and Sleepiness. To further explore the ability of the IDSIQ to capture clinically meaningful changes in daytime functioning resulting from treatment, we estimated withinsubject changes in IDSIQ scores using phase 3 trial data. Methods A randomized double-blind placebocontrolled trial of daridorexant in adults with insomnia (NCT03545191), in which subjects completed the IDSIQ daily during treatment, provided data for blinded analyses. Spearman correlations were calculated for changes in IDSIQ scores and potential anchors: Insomnia Severity Index, Patient Global Assessment of Disease Severity, Patient Global Impression of Severity, and Patient Global Impression of Change, applying a prespecified threshold of 0.30 (moderate association). Anchor-based analyses of weekly average IDSIQ total and domain scores were used to estimate responder definitions (RDs). The various RD estimates were triangulated to identify values where they converged. Distribution-based and receiver operating characteristic analyses calculated standard error of measurement (SEM), 0.5 standard deviation (SD), and Youden’s index as supportive evidence for anchor-based RD estimates. Results The analysis included 930 subjects (18-88 years). Score change correlations for the potential anchors and IDSIQ at month 1 (0.36–0.44) and month 3 (0.45–0.57) were all >0.30. Triangulation of mean IDSIQ score changes in subjects with clinically relevant improvement on the different anchors supported RD thresholds for clinically meaningful change of 17 points for the IDSIQ total score, 9 points for the Alert/Cognition domain, 4 points for the Mood domain, and 4 points for the Sleepiness domain. SEM and 0.5 SD values were within the ranges of anchor-based IDSIQ score changes, and Youden’s index was maximized or near-maximized when the RD estimates were used as thresholds for identifying responders based on the anchors. Conclusion The IDSIQ is sensitive to changes in patients who experience daytime impacts of insomnia and can be used to assess treatment efficacy on daytime functioning in patients with insomnia. Support (If Any) This work was funded by Idorsia Pharmaceuticals Ltd.

Deciphering radiological stable disease to immune checkpoint inhibitors

'Stable disease (SD)' as per RECIST is a common but ambiguous outcome in patients receiving immune checkpoint inhibitors (ICIs). This study aimed to characterize SD and identify the subset of patients with SD who are benefiting from treatment. Understanding SD would facilitate drug development and improve precision in correlative research. A systematic review was carried out to characterize SD in ICI trials. SD and objective response were compared to proliferation index using The Cancer Genome Atlas gene expression data. To identify a subgroup of SD with outcomes mirroring responders, we examined a discovery cohort of non-small-cell lung cancer (NSCLC). Serial cutpoints of two variables, % best overall response and progression-free survival (PFS), were tested to define a subgroup of patients with SD with similar survival as responders. Results were then tested in external validation cohorts. Among trials of ICIs (59 studies, 14 280 patients), SD ranged from 16% to 42% in different tumor types and was associated with disease-specific proliferation index (ρ=-0.75, P= 0.03), a proxy of tumor kinetics, rather than relative response to ICIs. In a discovery cohort of NSCLC [1220 patients, 313 (26%) with SD to ICIs], PFS ranged widely in SD (0.2-49 months, median 4.9 months). The subset with PFS >6 months and no tumor growth mirrored partial response (PR) minor (overall survival hazard ratio 1.0) and was proposed as the definition of SD responder. This definition was confirmed in two validation cohorts from trials of NSCLC treated with durvalumab and found to apply in tumor types treated with immunotherapy in which depth and duration of benefit were correlated. RECIST-defined SD to immunotherapy is common, heterogeneous, and may largely reflect tumor growth rate rather than ICI response. In patients with NSCLC and SD to ICIs, PFS >6 months and no tumor growth may be considered 'SD responders'. This definition may improve the efficiency of and insight derivable from clinical and translational research.

Functionality, satisfaction, and global impression of change with ubrogepant for the acute treatment of migraine in triptan insufficient responders: a post hoc analysis of the ACHIEVE I and ACHIEVE II randomized trials

BackgroundTriptans are the first-line option for the acute treatment of migraine attacks; however, triptans are contraindicated in people with certain underlying cardiovascular risk factors and are associated with inadequate efficacy or poor tolerability in some individuals. Ubrogepant is an oral calcitonin gene–related peptide receptor antagonist approved for the acute treatment of migraine.MethodsThis post hoc analysis of the phase 3 ACHIEVE trials examined the impact of ubrogepant on the Functional Disability Scale (FDS), satisfaction with medication, and Patient Global Impression of Change (PGIC) in participants who were self-reported triptan insufficient responders (TIRs), defined as those who are unable to take triptans due to contraindications, tolerability issues, or insufficient efficacy. Responder definitions for the FDS, satisfaction measures, and PGIC were based on qualitative interpretation of the respective response options for the pooled ubrogepant 50 mg and placebo groups.ResultsIn the pooled analysis population (n = 1799), 451 (25%) participants were TIRs, with most (80%) reporting insufficient efficacy with triptan use. A significantly higher proportion of TIRs treated with ubrogepant vs placebo reported being able to function normally from 2 to 8 h post dose (P < 0.05). Notably, significance was demonstrated at the time of the primary outcome assessments (2 h post dose), where rates of normal function were 38% for ubrogepant vs 29% for placebo (P = 0.048). A greater proportion of TIRs in the ubrogepant arm vs the placebo arm were satisfied with treatment at 2 (33% vs 21%, P = 0.006) and 24 h (58% vs 28%, P < 0.001) and indicated that their migraine improved at 2 h vs placebo (30% vs 18%, P = 0.006). Results were generally similar in the insufficient efficacy subpopulation of TIRs as in the overall TIRs group. Ubrogepant was safe and well tolerated in TIRs, with no new safety signals identified.ConclusionsIn people with migraine who are TIRs, individuals treated with ubrogepant had favorable 2-h outcomes, as measured by the FDS, satisfaction with medication, and PGIC, compared with placebo.Trial registrationClinicalTrials.gov: NCT02828020 (ACHIEVE I), registered July 11, 2016; NCT02867709 (ACHIEVE II), registered August 16, 2016.

USING PAIN TOLERABILITY THRESHOLDS TO CHARACTERIZE CLINICALLY MEANINGFUL TREATMENT OUTCOMES IN KNEE OSTEOARTHRITIS: POST HOC ANALYSIS OF A PHASE 2B TRIAL OF INTRA-ARTICULAR LORECIVIVINT

Purpose: To evaluate the performance of responder definitions using cut-offs in the pain NRS that correlate with patient-reported pain tolerability for randomized clinical trials. The construct of pain tolerability reveals the complex burden of chronic knee osteoarthritis (OA) pain that informs decisions regarding clinically meaningful treatment effects in clinical trials. A recent survey of 537 patients with chronic pain demonstrated that respondents who reported pain numeric rating scale (NRS) scores of 4 and below almost exclusively report their pain as tolerable.

An Office-Based, Point-of-Care Test Predicts Treatment Outcomes With Community-Based Pelvic Floor Physical Therapy in Patients With Chronic Constipation

Rectal evacuation disorders are common among constipated patients. We aimed to evaluate the accuracy of an investigational point-of-care test (rectal expulsion device [RED]) to predict outcomes with community-based pelvic floor physical therapy. We enrolled patients meeting Rome IV criteria for functional constipation failing fiber/laxatives for more than 2 weeks. RED was inserted and self-inflated, and then time-to-expel was measured in a left lateral position. All patients underwent empiric community-based pelvic floor physical therapy in routine care with outcomes measured at 12 weeks. The primary end point was global clinical response (Patient Assessment of Constipation Symptoms score reduction, >0.75 vs baseline). Secondary end points included improvement in health-related quality-of-life (Patient Assessment of Constipation Quality of Life score reduction, >1.0) and complete spontaneous bowel movement frequency (Food and Drug Administration complete spontaneous bowel movement responder definition). Thirty-nine patients enrolled in a feasibility phase to develop the use-case protocol. Sixty patients enrolled in a blinded validation phase; 52 patients (mean, 46.9 y; 94.2% women) were included in the intention-to-treat analysis. In the left lateral position, RED predicted global clinical response (generalized area under the curve [gAUC], 0.67; 95% CI, 0.58-0.76]), health-related quality-of-life response (gAUC, 0.67; 95% CI, 0.58-0.77; P < .001), and complete spontaneous bowel movement response (gAUC, 0.63; 95% CI, 0.57-0.71; P < .001). As a screening test, a normal RED effectively rules out evacuation disorders (expected clinical response, 8.9%; P= .042). Abnormal RED in the left lateral position (defined as expulsion within 5 seconds or >120 seconds) predicted 48.9% clinical response to physical therapy. A seated maneuver enhanced the likelihood of clinical response (71.1% response with seated RED retained >13 seconds) but likely is unnecessary in most settings. RED offers an opportunity to disrupt the paradigm by offering a personalized approach to managing chronic constipation in the community (Clinicaltrials.gov: NCT04159350).

Global Expert Opinion on Cryolipolysis Treatment Recommendations and Considerations: A Modified Delphi Study.

BackgroundCryolipolysis is an increasingly popular nonsurgical fat-reduction procedure. Published treatment guidance and adverse event (AE) management protocols are limited.ObjectiveA modified Delphi study aimed to establish global expert consensus on the use of CoolSculpting (Allergan Aesthetics, an AbbVie Company, Irvine, CA), a noninvasive cryolipolysis treatment system.MethodsA literature search informed survey topics for an 11-expert Delphi panel. Panelists completed an online 39-question survey. An interim panel discussion, with open-ended questions and yes/no voting, informed a second survey containing 61 statements, for which panelists rated agreement using a 5-point Likert scale. Topics included treatment outcome and responder definitions, patient evaluation and selection, treatment protocols, patient satisfaction, and AEs.ResultsPanelists achieved consensus on 38 final guidelines and recommendations. They reached moderate to complete consensus on 4 statements on defining responders (ie, patients with a range of visible improvement) and 6 statements on patient factors contributing to treatment outcomes (eg, how well the applicator conforms to patient body region). Panelists defined minimum numbers of treatment cycles to achieve visible clinical outcomes for 12 body regions, with moderate to complete consensus on 31 statements. They achieved a strong to complete consensus on 7 statements about patient satisfaction (eg, importance of patient expectations, visible improvement, and before-and-after photographs). Panelists defined management strategies for AEs, with moderate to complete consensus on 15 statements.ConclusionsA modified Delphi process yielded multiple guideline recommendations for cryolipolysis, providing a needed resource for the broad range of clinicians who perform this noninvasive fat-reduction procedure.Level of Evidence: 5

Abstract PO-002: Initial retrospective analysis of mechanisms of FOLFIRINOX resistance using clinical and molecular data from the Know Your Tumor (KYT) pancreatic ductal adenocarcinoma (PDAC) cohort

Abstract Introduction: The Know Your Tumor (KYT) pancreas cancer program enables molecular analysis of both tumor DNA and mRNA to characterize tumor phenotypes and guide potential treatment options. The primary objective of the current study was to develop and apply criteria to establish treatment response from real-world clinical data and to characterize the matching molecular and immunologic features of the pancreatic ductal adenocarcinoma (PDAC) tumor biopsies to identify tumor phenotypes that associate with treatment response. Experimental Procedures: Formalin-fixed, paraffin-embedded tumor samples and related clinical data were collected from n=240 patients diagnosed with PDAC and treated at medical centers in the United States. Samples underwent retrospective mutation analysis using the Tempus xT targeted panel of 648 genes and whole transcriptome RNA-sequencing also from Tempus. To identify molecular profiles associated with tumor treatment response, the duration of first therapy and CA19-9 levels taken after the start of first therapy were analyzed to establish consensus responder and non-responder criteria. Mutation associations using Fisher exact tests and differential gene expression and immune signature analysis using Wilcoxon tests were performed on all FOLFIRINOX-treated subjects that meet consensus responder (n = 12) or non-responder (n = 10) definitions to identify molecular underpinnings of FOLFIRINOX resistance. Gene expression analysis initially focused on tumor intrinsic genes (TIGs) because the expression of these genes may specifically reflect PDAC tumor biology. Differentially expressed TIGs with an unadjusted p-value &amp;lt; 0.05 were submitted for gene set enrichment analysis (GSEA) and manual investigation. Results: No association between DNA mutations and response to FOLFIRINOX was observed in this small dataset. In contrast, results from RNA-based gene expression analysis suggested that differences in tumor biology may contribute to response. GSEA and manual interrogation of differentially expressed TIGs revealed non-responder tumors may have high expression of apoptosis-related genes and genes associated with energetics. GSEA of all differentially expressed genes (unadjusted p-value &amp;lt; 0.05) refined this interpretation and corroborated initial findings by suggesting non-responders may have high expression of hypoxia, glycolysis- and apoptosis-related genes and low expression of SMAD4 and its associated target genes. Summary and Conclusions: These results support the testable hypothesis that FOLFIRINOX non-responders evade apoptosis through hypoxia adaptations and autophagic flux. These hypotheses may warrant further investigation with preclinical models such as cell culture, PDX or organoid models. Finally, the analysis plan provides a roadmap for using the KYT cohort and other real-world datasets to generate hypotheses about molecular mechanisms of treatment response. Citation Format: James M. Davison, Greg Mayhew, Kirk Beebe, Joel R. Eisner, Dennis Ladnier, Eric A. Collisson, Lynn M. Matrisian. Initial retrospective analysis of mechanisms of FOLFIRINOX resistance using clinical and molecular data from the Know Your Tumor (KYT) pancreatic ductal adenocarcinoma (PDAC) cohort [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-002.

Humoral response to SARS-CoV-2 and seasonal coronaviruses in COVID-19 patients.

We used enzyme‐linked immunoassay methods to measure the prevalence and the levels of antibody responses to the nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and four seasonal human coronaviruses (HCoV‐OC43, HCoV‐HKU1, HCoV 229E, and HCoV‐NL63) in a cohort of 115 convalescent plasma donors infected with SARS‐CoV‐2 (1–61 days after symptom onset) compared to antibody levels in 114 individuals with no evidence of a recent infection with SARS‐CoV‐2. In the humoral response to the four seasonal coronaviruses, only HCoV‐HKU1‐ and HCoV‐229E‐assays showed slightly elevated antibody levels in the COVID group compared to the control group. While in the COVID‐group the levels of SARS‐CoV‐2 antibodies correlated significantly with disease severity, no association was found in the levels of antibodies against the seasonal coronaviruses. The most striking result in both groups was that the levels of antibodies against all tested coronaviruses, including the new SARS‐CoV‐2 showed a highly significant correlation with each other. There seems to be an individual predisposition to a weaker or stronger humoral immune response against all known seasonal human coronaviruses including the new SARS‐CoV‐2, which could lead to a definition of low and high responders against human coronaviruses with potential impact on the assessment of postinfection antibody levels and protection.

Impact of Elotuzumab Plus Pomalidomide/Dexamethasone on Health-Related Quality of Life for Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Final Data from the Phase 2 ELOQUENT-3 Trial

Impact of Elotuzumab Plus Pomalidomide/Dexamethasone on Health-Related Quality of Life for Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Final Data from the Phase 2 ELOQUENT-3 Trial

Measurement of specific organ domains in lupus randomized controlled trials: a scoping review.

Randomized controlled trials (RCTs) in SLE (lupus) typically adopt composite responder definitions as primary efficacy endpoints; however, outcomes within individual organ domains are also important to understand. The aim of this scoping review was to evaluate how organ-specific disease activity and therapeutic responses have been measured and reported in lupus RCTs. We searched MEDLINE, EMBASE, Cochrane registry and clinicaltrials.gov. Eligible studies were RCTs investigating efficacy of an immune-directed drug therapy in active SLE, published January 2000-March 2021, excluding studies limited to lupus nephritis. Data were extracted independently in duplicate into a template and summarized descriptively. Thirty-four RCTs were included, of which 32 (94%) reported activity and/or responses in at least one organ domain. Study populations had a high, although variable, frequency of baseline musculoskeletal and mucocutaneous activity and low, but also variable, representation of other domains. Definitions of organ-specific responses were inconsistent, even within individual instruments. Response in most organ domains were evaluated using BILAG and SLEDAI components but meaningful comparison between treatment arms was limited by small subgroups analysed in a post hoc fashion. Specific mucocutaneous and arthritis instruments were also used, including within pre-specified organ-specific endpoints, which discriminated between treatment arms in some studies. Mucocutaneous and musculoskeletal manifestations predominate in SLE RCTs. Organ-specific outcome measures are commonly reported, but definitions of involvement and response are inconsistent. Research into the development of new outcome measures for key organ domains, and validation and comparison of response definitions using existing instruments, is needed.

The impact of extended half‐life factor concentrates on patient reported health outcome measures in persons with hemophilia A and hemophilia B

BackgroundRecombinant factors VIII and IX Fc (rFVIIIFc/rFIXFc) were the only available extended half‐life (EHL) products in Canada during 2016 to 2018. ObjectivesTo evaluate if patient‐reported outcome measures (PROMs) improved in Canadian persons with hemophilia who switched from standard half‐life (SHL) to EHL products (rFVIIIFc/rFIXFc). Patients/MethodsThis prospective cohort study enrolled persons with moderate or severe hemophilia aged ≥6 years who switched to rFVIIIFc/rFIXFc (2016‐2018) and those who remained on SHL. Health‐related quality of life (HRQoL) was assessed using the Haemophilia‐specific Quality of Life (Haem‐A‐QoL) and 36‐item Short‐Form Survey (SF‐36) at baseline, 3‐months, 12 months, and 24 months. Other PROMs included the Work Productivity and Impairment Questionnaire, chronic pain scale, partner/parent ratings of mood, International Physical Activity Questionnaire, and Treatment Satisfaction Questionnaire for Medication. We identified meaningful changes using minimally important difference for SF‐36 and responder definition for Haem‐A‐QoL. ResultsWe enrolled 25 switchers (16 rFVIIIFc, 9 rFIXFc) and 33 nonswitchers. Those switched to rFVIIIFc/rFIXFc had improved overall HRQoL, and improved subscale physical activity, mental health, and social functioning at 3 months. The rFIXFc switchers had improved chronic pain and ability to engage in normal activities while the rFVIIIFc switchers had improved treatment satisfaction. There was no change in work impairment after the switch. Observed improvement disappeared by 24 months in most domains. ConclusionSwitching from SHL to rFVIIIFc/rFIXFc resulted in short‐term meaningful improvement in overall HRQoL and other PROMs in a small proportion. Longitudinal changes on PROMs are affected by ceiling effects and response shift, warranting further studies in instrument optimization in the era of EHL and nonfactor products.

Strength Training Volume to Increase Muscle Mass Responsiveness in Older Individuals: Weekly Sets Based Approach.

Currently, strength training (ST) is widely recommended to promote healthy aging. This reflects efforts made over the past three decades through which the role of ST as a sarcopenia countermeasure, preventing physical disability and other poor outcomes, has become evident. However, in recent years, considerable attention has been directed to the phenomenon of ST response heterogeneity. Different adaptive patterns among individuals submitted to the same intervention have increasingly led scholars to conventionally label non-responders or low responders those who do not respond appropriately, either for lack of meaningful improvements or even for worsening parameters. In the latter case, such individuals are specifically classified generally as adverse responders since they present responses in opposite direction to a threshold theoretically or empirically determined (Bouchard et al., 2012; Hecksteden et al., 2018). Although there is still no consensus on the definition of non-responders or low responders to ST, showing that their study is in its infancy, an interesting review by Atkinson et al. (2019) suggests that the categorization of a given response should be rationalized by the researcher after analyzing which threshold is clinically or practically relevant, changing the notion that minimal detectable change is imperative to determine who respond or not to an intervention. In this scenario, the phenomenon of non- or low-responsiveness indirectly favored the development of a more restrictive and less important perspective regarding the role of ST. However, reaffirming the ST relevance in aging, Churchward-Venne et al. (2015) have claimed that there are no older non-responders. In that study, it has been shown that all older adults submitted to ST improve at least one analyzed parameter (e.g., functional capacity and muscle strength), defended its widespread application. As suggested by Pickering and Kiely (2019), there are likely no individuals totally unresponsive to training. Nevertheless, the reason why some individuals show less expressive results than others in apparently homogeneous samples remains unclear, especially concerning muscle hypertrophy. It can be noticed in the study conduct by Churchward-Venne et al. (2015) that more than 35 and 30% of the older individuals had a maximum lean mass increase of 0.5 kg after 12 and 24 weeks of ST, respectively. In addition, about 20% had a decrease in lean mass, regardless of protocol duration. Despite the inherent physiological changes of aging, Ahtiainen et al. (2016) demonstrate that the variability of muscle mass response to ST is not affected by age. Although such changes may indeed lead older individuals to a decreased skeletal muscle tissue sensitivity to anabolic stimuli (Yang et al., 2012), it prohibits putting on account of aging the occurrence of inexpressive morphological adaptations in response to training exclusively. Regarding this muscle mass response heterogeneity, while some scholars (Atkinson et al., 2019; Dankel and Loenneke, 2020) recommend cautiousness when claiming its existence, emphasizing that individual differences need to be attested in studies that consider the random error, verified from a matched control group, many others widely recognize it (Hubal et al., 2005; Davidsen et al., 2011; Sparks, 2017; Stec et al., 2017; Camera, 2018; Rantila et al., 2021). Although more studies need to be conducted to demonstrate the true variability of the response, the body of evidence indicates that such heterogeneity should not be ignored. In this context, it is inevitable to admit that more efforts should be made to clarify the reasons behind the low-responsiveness of some individuals, which, in turn, might assist in planning more effective ST programs.

A Simple Predictive Marker in Cardiac Resynchronization Therapy Recipients: Prominent S-Wave in Right Precordial Leads.

Background and objectives: Current guidelines criteria do not satisfactorily discriminate responders to cardiac resynchronization therapy (CRT). QRS amplitude is an established index to recognize the severity of myocardial disturbance and might be a key to optimal patient selection for CRT. Materials and Methods: (1) Initial R-wave amplitude, (2) S-wave amplitude, and (3) a summation of maximal R- or R′-wave amplitude and S-wave amplitude were measured at baseline. These parameters were averaged according to right (V1 to V3) or left (V4 to V6) precordial leads. The impact of these parameters on response to CRT, which was defined as a decrease in left ventricular end-systolic volume ≥15% at six-month follow-up, was investigated. Results: Among 47 patients (71 years old, 28 men) who received guideline-indicated CRT implantation, 25 (53%) achieved the definition of CRT responder. Among baseline electrocardiogram parameters, only the higher S-wave amplitude in right precordial leads was an independent predictor of CRT responders (odds ratio: 2.181, 95% confidence interval: 1.078–4.414, p = 0.030) at a cutoff of 1.44 mV. The cutoff was independently associated with cumulative incidence of heart failure readmission and appropriate electrical defibrillation following CRT implantation (p < 0.05, respectively). Conclusions: Prominent S-wave in right precordial leads might be a promising index to predict left ventricular reverse remodeling and greater clinical outcomes following CRT implantation.

Blood eosinophil count and FeNO to predict benralizumab effectiveness in real-life severe asthma patients

Objective Benralizumab is a promising drug for severe uncontrolled asthma. This study aimed to clarify the effectiveness of benralizumab in a real-life setting. Methods Subjects included 24 patients with severe type 2 asthma who received benralizumab between April 2018 and July 2019. Changes in parameters, exacerbation frequency, and oral corticosteroid (OCS) use after 4 and 24 weeks of administration were examined. The parameters included the Global Evaluation of Treatment Effectiveness (GETE) scale, Asthma Control Questionnaire (ACQ), Asthma Control Test (ACT), blood eosinophils, fractional exhaled nitric oxide (FeNO), and spirometry. The response to treatment was defined as follows: for patients with exacerbations or OCS use before treatment initiation, a reduction of ≥50% in exacerbation frequency or OCS use; and for patients without exacerbations or OCS use, an improvement of ≥0.5 in ACQ scores and ≥3 in ACT scores, or of ≥10.38% in FEV1. Results Twenty-one patients completed the treatment for 24 weeks. Excellent and good GETE scales and ACQ and ACT improvement were found in 67% of the patients at 4 weeks, and the effect continued until 24 weeks. The patients’ rate with exacerbations was significantly reduced compared to the previous 24 weeks before administration. In 17 patients receiving OCS, the use could be reduced or quit in 14 patients. Overall, 16 patients (76.2%) met the responder definition and could be predicted by the baseline eosinophil count and FeNO levels with the best cutoff values of 100/μL and 40 ppb, respectively. Conclusions Blood eosinophil and FeNO could predict benralizumab effectiveness.

Clinician-reported outcome measures in lupus trials: a problem worth solving.

Systemic lupus erythematosus (SLE) remains a disease of high unmet clinical need. Because of substantial patient heterogeneity, the execution of clinical trials that successfully determine the efficacy of novel therapeutics compared with placebo is a continuous challenge. Clinician-reported outcome measures of treatment response used in SLE trials have evolved from the use of individual disease activity indices, including the SLE Disease Activity Index (SLEDAI) and British Isles Lupus Assessment Group (BILAG), to composite responder definitions such as the SLE Responder Index (SRI) and BILAG-Based Composite Lupus Assessment (BICLA), which are based on these indices. However, these approaches have notable drawbacks and defining the optimal clinical trial outcome measure for SLE remains a research goal. In this Viewpoint, we explore the strengths and limitations of existing indices and composite assessments, illustrating features which should be investigated in future analysis of trial data. Further, we provide a platform from which to advance new approaches to endpoint design, which is crucial to improve the interpretability and success of subsequent clinical trials in SLE.

Psychometric Validation of the Psoriasis Symptoms and Impacts Measure (P-SIM), a Novel Patient-Reported Outcome Instrument for Patients with Plaque Psoriasis, Using Data from the BEVIVID and BEREADY Phase3 Trials.

IntroductionPlaque psoriasis can significantly impact patients’ quality of life. We assessed psychometric properties of the Psoriasis Symptoms and Impacts Measure (P-SIM), developed to capture patients’ experiences of signs, symptoms and impacts of psoriasis.MethodsPooled, blinded, 16-week data from 1002 patients in the BE VIVID and BE READY bimekizumab phase 3 trials were analysed. The suitability of the P-SIM missing score rule (weekly scores considered missing if ≥ 4 daily scores were missing) was assessed. Test–retest reliability was evaluated using intraclass correlation coefficients (ICCs). Convergent validity was assessed between P-SIM and relevant patient-reported outcome (PRO) (Dermatology Life Quality Index [DLQI], DLQI item 1 [skin symptoms], Patient Global Assessment of Psoriasis) and clinician-reported outcome (ClinRO) scores (Psoriasis Area and Severity Index [PASI], Investigator’s Global Assessment [IGA]) at baseline and week 16. Known-groups validity was assessed, comparing P-SIM scores between patient subgroups predefined using PASI/IGA scores. Sensitivity to change over 16 weeks was evaluated; responder definition (RD) thresholds were explored.ResultsThe missing score rule used did not impact P-SIM scores. Test–retest reliability analyses demonstrated excellent score reproducibility (ICC 0.91–0.98). Inter-item correlations at baseline and week 16 were strong (> 0.5), apart from “choice of clothing” with “skin pain” and “burning” at baseline (both 0.49). All P-SIM scores were moderately to strongly correlated with other outcomes, demonstrating convergent validity, apart from ClinROs (PASI, IGA) at baseline that had low variability. P-SIM scores discriminated known groups at week 16, confirming known-groups validity. Changes from baseline to week 16 in P-SIM and other clinically relevant outcomes were strongly correlated (> 0.5; weaker with ClinROs), establishing sensitivity to change. Anchor-based RD analyses determined a four-point P-SIM item score decrease as indicative of marked clinically meaningful improvement.ConclusionP-SIM scores demonstrated good reliability, validity and sensitivity to change. A four-point RD threshold could be used to assess 16-week treatment effects.Trial RegistrationBE VIVID: NCT03370133; BE READY: NCT03410992.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13555-021-00570-4.

Platelet Response to Lusutrombopag, a Thrombopoietin Receptor Agonist, in Patients with Chronic Liver Disease and Thrombocytopenia Undergoing Non-Emergency Invasive Procedures: Results from a Phase 3 Randomized, Double-Blind, Placebo-Controlled Study

Thrombocytopenia is a common complication of chronic liver disease (CLD), which may be caused by multiple factors including decreased production of thrombopoietin (TPO). The presence of thrombocytopenia may complicate the conduct of routine invasive procedures that are commonly performed in CLD patients, leading to delayed or cancelled procedures. Lusutrombopag (formerly S-888711) is an orally available, small molecule agonist of human TPO receptor. Here we report the platelet response data from a confirmatory global phase 3, randomized, double-blind, placebo-controlled study (L-PLUS 2 study) evaluating lusutrombopag for the treatment of thrombocytopenia in patients with CLD who were undergoing non-emergency invasive procedures.Key eligibility criteria included 18 years of age or older, platelet count < 50 × 109/L at baseline, Child-Pugh Class A or Class B, and expecting to undergo a non-emergency invasive procedure. Patients with existing or history of portal vein thrombosis (PVT), or with past or present thrombosis or prothrombotic conditions were excluded. Patients were randomized 1:1 to receive oral lusutrombopag 3 mg once daily or placebo for up to 7 days. Stopping criteria based upon platelet count measurement on days 5, 6 and 7 were used to prevent platelet overshoot. Invasive procedures were performed between Day 9 and Day 14. Platelet transfusion was mandated by the study protocol if a patient's platelet count prior to the invasive procedure was < 50×109/L. The primary efficacy endpoint was proportion of patients who require no platelet transfusion prior to the primary invasive procedure and no rescue therapy for bleeding from randomization to 7 days after the primary procedure. Safety assessment included adverse events, physical exams, laboratory tests and imaging for detection of PVT.A total of 215 patients were randomized, constituting the ITT population (lusutrombopag 108, placebo 107). Baseline patient characteristics were similar between the two treatment groups. The most common invasive procedures included endoscopic variceal ligation (28%), endoscopy with or without polypectomy/biopsy (27%), dental extraction (11%), and transarterial chemoembolization (9%). The study met its primary efficacy endpoint: 64.8% of patients in lusutrombopag group required no platelet transfusion prior to their procedures and no rescue therapy for bleeding up to 7 day after the procedure, compared to 29.0% of patients in the placebo group (p<0.0001). The proportion of patients who met the definition of platelet responder (platelet count ≥ 50×109/L and an increase from baseline of ≥ 20×109/L at least once during the study) was 64.8% in lusutrombopag group and 13.1% in placebo group (p<0.0001). Figure 1 shows the median platelet count over the study period for both treatment groups. Among patients in the lusutrombopag group who did not receive platelet transfusion, the mean peak platelet count was 86.9×109/L (mean increase from baseline 47.1×109/L) which occurred on average around Day 12, and the median duration of platelet count maintained at ≥ 50×109/L was 19 days. Treatment-emergent adverse events (TEAEs) were reported for 47.7% of patients in lusutrombopag group and 48.6% in placebo group, with serious TEAEs at 6.5% in each treatment group. Three PVT events were observed, 1 in lusutrombopag group and 2 in placebo group; all were incomplete occlusion considered not clinically significant and all events resolved with therapy. Bleeding-related TEAEs occurred in 3 patients of lusutrombopag group and 6 patients in placebo group.In conclusion, oral lusutrombopag 3 mg once daily demonstrated superiority over placebo as treatment for thrombocytopenia in patients with CLD undergoing invasive procedures in this global phase 3 study, meeting all pre-specified primary and secondary endpoints. Lusutrombopag was well tolerated, with a safety profile similar to that of placebo. [Display omitted] DisclosuresAfdhal:Shionogi: Consultancy; Merck: Consultancy; Ligand: Consultancy; Jansen: Consultancy; Gilead: Consultancy; Echosens: Consultancy; Spring Bank Pharmaceuticals: Employment, Equity Ownership; Allurion: Equity Ownership; TRIO Healthcare: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Duggal:Shionogi: Consultancy. Ochiai:Shionogi: Employment. Motomiya:Shionogi: Employment. Kano:Shionogi: Employment. Nagata:Shionogi: Employment. Peck-Radosavljevic:Shionogi: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria; Boehringer-Ingelheim: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Jansen: Consultancy, Honoraria; MSD: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Takeda: Research Funding.