Categorized Hematologic Response to Pegcetacoplan and Correlations with Quality of Life in Patients with Paroxysmal Nocturnal Hemoglobinuria: Post Hoc Analysis of Data from Phase 1b, Phase 2a, and Phase 3 Trials

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a complement-mediated, hematologic disease characterized by hemolysis, anemia, and fatigue that impairs quality of life. Pegcetacoplan (PEG), a C3-inhibitor recently approved by the Food and Drug Administration for treatment of PNH, controls intravascular hemolysis (IVH) and prevents extravascular hemolysis (EVH). The PADDOCK and PALOMINO trials demonstrated PEG's improvement of key hematologic and clinical parameters, including hemoglobin (Hb) level and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score. The PEGASUS trial demonstrated that PEG was more effective than eculizumab (ECU) in improving these parameters in PNH patients with suboptimal response to prior ECU treatment. Aims: This post hoc analysis categorized hematologic response to PEG in 3 trials: PADDOCK (phase 1b, open-label, two-cohort [NCT02588833]), PALOMINO (phase 2a, open-label, single-cohort [NCT03593200]), and PEGASUS (phase 3, randomized, open-label, active-comparator controlled [NCT03500549]). Methods: PADDOCK and PALOMINO included adult complement inhibitor-naïve patients, while PEGASUS included adult patients with Hb <10.5 g/dL despite ≥3 months of ECU treatment. PADDOCK was a multiple ascending dose pilot study of 2 cohorts: cohort 1 received a suboptimal PEG dose (180 mg/day subcutaneously [SQ]) for 28 days; cohort 2 received a PEG dose of 270-360 mg/day SQ for up to one year. Patients could be enrolled in both cohorts. PALOMINO patients received a PEG dose of 270-360 mg/day SQ for up to one year. PEGASUS comprised a 4-week run-in period where patients received both ECU (continued dosing regimen) and PEG (1080 mg SQ twice-weekly), 16-week randomized controlled period (PEG or ECU monotherapy), and 32-week open-label period (PEG monotherapy) including a 4-week run-in period for the ECU-to-PEG group. Hematologic response category was assessed at Days 113/337 for patients in the combined PADDOCK/PALOMINO trials (N=24) via manual categorization by two independent, blinded observers. Categorization was assessed at Weeks 16/48 for PEGASUS patients (N=80) using SAS 9.4M5. Statistical significance for hematologic response categories within arms at Week 16 vs. 48, and between arms at Week 48, was evaluated using Wilcoxon-Mann-Whitney and Chi-square testing. FACIT-Fatigue scores for PEGASUS patients, summarized using descriptive statistics, were also correlated to hematologic response category. Response categories were defined per the following criteria (Risitano A, et al., Front Immunol, 2019;10:1157): complete- no transfusions required, stable Hb (normal range), no evidence of hemolysis (lactate dehydrogenase [LDH]≤1.5×upper limit of normal [ULN] U/L, absolute reticulocyte count [ARC]≤150,000/µL); major- no transfusion, normal Hb, but with evidence of hemolysis (LDH>1.5×ULN U/L and/or ARC>150,000/µL); good- no transfusions, but with chronic mild anemia or evidence of hemolysis; partial- chronic moderate anemia and/or occasional transfusions (<3 units/6 months); minor- regular transfusions required (3-6 units/6 months); no response- regular and frequent transfusions required (>6 units/6 months). PADDOCK/PALOMINO patients missing data at an assessment timepoint, or PEGASUS patients missing data within 6 weeks prior to an assessment timepoint, were not evaluated. Results: Most PADDOCK/PALOMINO patients achieved at least a good hematologic response at Days 113 and 337 (Table 1). At Week 48, most patients in both PEGASUS arms achieved a good/major/complete hematologic response (inter-arm p=0.4390), with a significant increase in the percent of ECU-to-PEG patients achieving at least a good response after switching to PEG at Week 16 (Week 16 vs. 48: intra-arm p<0.0001; Table 1). In PEGASUS, patients with better response categories had higher FACIT-Fatigue scores when compared to the rest of the cohort (Week 16: p<0.001, Week 48: p=0.028; Table 2). Conclusions: In post hoc analyses of PADDOCK, PALOMINO, and PEGASUS trial data, a substantial proportion of patients achieved and maintained good, major, or complete hematologic responses to PEG, suggesting that PEG can lead to sustained improvements in hematologic parameters. PEGASUS data also demonstrated correlation of improved hematologic response category with clinically meaningful improvements in quality of life, as measured by FACIT-Fatigue. Figure 1 Figure 1. Disclosures Risitano: Jazz: Other: Lecture fees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees; Biocryst: Membership on an entity's Board of Directors or advisory committees; RA Pharma: Research Funding; Amyndas: Consultancy; Samsung: Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd.: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Lecture fees, Speakers Bureau; Apellis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Speakers Bureau. Wong: Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Apellis Pharmaceuticals: Research Funding, Speakers Bureau; Alexion: Consultancy, Honoraria, Research Funding, Speakers Bureau. Al-Adhami: Apellis Pharmaceuticals: Current Employment. Chen: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Peffault De Latour: Swedish Orphan Biovitrum AB: Consultancy, Honoraria; Apellis Pharmaceuticals: Consultancy, Honoraria; Alexion Pharmaceuticals: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

Response Category Functioning on the Health Care Engagement Measure Using the Nominal Response Model

As part of a scale development project, we fit a nominal response item response theory model to responses to the Health Care Engagement Measure (HEM). When using the original 5-point response format, categories were not ordered as intended for six of the 23 items. For the remaining, the category boundary discrimination between Categories 0 ( not at all true) and 1 ( a little bit true) was only weakly discriminating, suggesting uninformative categories. When the lowest two categories were collapsed, psychometric properties improved greatly. Category boundary discriminations within items, however, varied significantly. Specifically, higher response category distinctions, such as responding 3 ( very true) versus 2 ( mostly true) were considerably more discriminating than lower response category distinctions. Implications for HEM scoring and for improving measurement precision at lower levels of the construct are presented as is the unique role of the nominal response model in category analysis.

378 Use of a Clinician’s Global Impression of Severity scale to measure insomnia severity in Alzheimer’s disease-dementia patients

Introduction Full montage polysomnography (PSG) is the gold standard for the objective evaluation of sleep but is time consuming and inaccessible to most clinicians. A Clinician’s Global Impression of Severity (CGI-S) scale can be used in clinical practice to provide a subjective assessment of patients’ insomnia severity. However, the utility of a CGI-S scale for assessing insomnia in patients with Alzheimer’s disease (AD)-dementia is not well understood. In a recent Phase III randomized, placebo-controlled clinical trial (NCT02750306), patients on suvorexant with AD-dementia and insomnia showed improvements in both PSG total sleep time (TST) and CGI-S scores. We conducted additional analyses to examine the association between CGI-S and PSG-TST to inform on the possible use of a CGI-S scale to assess insomnia severity in patients with AD-dementia in real-world settings. Methods Patients (N=285) met clinical diagnostic criteria for both probable mild-to-moderate AD-dementia and insomnia. The primary endpoint was change-from-baseline in overnight PSG-TST at Week-4. A single-item CGI-S rating of insomnia with responses of 1 (normal, not ill at all) to 7 (among the most extremely ill patients) was completed by a trained rater at baseline and after 2 and 4 weeks. CGI-S was an exploratory endpoint. Post-hoc correlational analyses and analyses of distribution of change-from-baseline to Week-4 in CGI-S response categories were performed. Results Pearson correlation indicated a significant association at baseline between PSG-TST and CGI-S (r=-0.18, nominal p=0.004). A correlation of change-from-baseline to Week-4 also indicated an association between PSG-TST and CGI-S (r=-0.24, nominal p<.0001). The distribution of change in CGI-S response category results at Week-4 showed that, compared to placebo, numerically less patients on suvorexant remained stable or worsened by >1 response category (21.8% vs. 29.4%, respectively) and numerically more improved by ≥1 response category (73.3% vs. 67.9%, respectively). Conclusion Our findings suggest that a CGI-S scale may be a useful tool for assessing insomnia severity in mild-to-moderate AD-dementia patients. Future studies with these patients are needed to determine the utility of a CGI-S scale in real-world settings. Support (if any) This study was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA

Aflibercept for treatment-naïve diabetic macula oedema in a multi-ethnic population: Real-world outcomes from North West London

Purpose To evaluate the clinical outcomes of patients with treatment–naïve diabetic macula oedema (DMO) treated with Aflibercept in routine clinic settings in ethnically diverse North West London (NWL) and compare to outcomes reported in the VIVID and VISTA clinical trials Methods This was a retrospective multicentre interventional case series. Two hundred and seventy eyes of 221 treatment-naïve patients at three NWL hospitals initiated on Aflibercept and who had at least 12 months follow-up were included in the study. Visual acuity, central subfield thickness and macula volume were recorded at baseline, month 3, 6 and 12. Results There were significant differences between the NWL cohort and participants in the VIVID and VISTA trials at baseline including higher HbA1c and a higher proportion of eyes with proliferative diabetic retinopathy in the NWL cohort. The mean VA, mean CSFT and mean MV at baseline was 66.4 (± 14.6) letters, 417 (± 94) μm and 10.3 (± 1.9) mm3. The mean VA gain at 12 months was 4.0 (± 11.8) letters (p < 0.001); a total of 26% of eyes gained ≥ 10 letters, 15% of eyes gained ≥ 15 letters and 6% lost ≥15 letters. At 12-months, the mean reduction in CSFT was 108 (± 96) μm (p<0.001) and the mean reduction in MV was 1.05 (± 1.21) mm3 (p<0.001). An average of 6.2 (± 2.3) injections was given over 12 months. There was a significant association between functional and anatomical response category at 3 months and response category at 12 months (p<0.001). Conclusion The effectiveness of treatment with Aflibercept for patients in NWL was meaningfully lower than was reported in the VIVID and VISTA clinical trials. A high proportion of patients with good visual acuity at baseline, poorer glycaemic control, worse diabetic retinopathy and under-treatment likely contributed to lower functional and anatomical outcomes.

Team Activity of Robot Competition of Simulated Robot in World Robot Summit 2020

World Robot Summit (WRS) has several robot competitions, and we will participate it in the infrastructure and disaster response category. Participating teams develop their robot system by teleoperation and/or autonomous operation and run it in a set of courses modelling and simplifying disaster responding situations. The authors will attend the challenge of the tunnel disaster response and recovery, in which we are requested to achieve an investigation and rescue scenario of a tunnel fire with simulated robots. As preparation, we develop simulated robot models and corresponding software as a team. In this article, we report out activity to the robot competition and student’s project-based learning by joining it.

MEASUREMENT OF ORGANIZATIONAL EXCELLENCE IN INDIAN CONTEXT: AN EXPLORATORY STUDY

Organizational excellence is the most recognized organizational concept of the twenty first century. This study aims at exploring the criteria for measuring organizational excellence in the Indian context. The study is basically based on primary data collected from a sample of 50 executives using structured questionnaire. Judgment sampling technique is used for conducting the survey. The five point response category of Likert type has been employed to examine the responses of respondents. The percentage of respondents responded against each response category has been used to measure the extent of positive, neutral and negative responses. The data sorted out and Cronbach’s alpha computed using Excel-07 and SPSS-20. The response analysis indicated that the organization under study has achieved satisfactory level of organizational excellence at the present time. The results are quite consistent to the saga of the organization. The study emphasizes the need for long-term strategy for achieving the goal of sustained excellence of the organization. Key contribution and limitations also indicated.

Structural validity of the Boston Carpal Tunnel Questionnaire and its short version, the 6-Item CTS symptoms scale: a Rasch analysis one year after surgery

Background The Boston Carpal Tunnel Questionnaire (BCTQ) and its shorter version, the Six-Item Carpal Tunnel Symptoms Scale (CTS-6), are widely used for assessing function and/or symptoms in patients with carpal tunnel syndrome. This study examined the structural validity of the BCTQ and CTS-6 among patients who had undergone surgery for treatment of carpal tunnel syndrome. Methods The data for this cross-sectional analysis were obtained from 217 adult patients who had undergone carpal tunnel release surgery 1 year earlier. All patients completed the CTS-6, Symptom Severity Scale (SSS) and Functional Status Scale (FSS) of the BCTQ at 12 months after surgery. The Rasch Measurement Theory (RMT) was applied to investigate the unidimensionality, residual correlation, differential item functioning, scale coverage/targeting, and person separation of the CTS-6, SSS and FSS of the BCTQ. Results The FSS showed unidimensionality and good scale and item fit. All items showed ordered response category thresholds. Eight of the FSS items displayed differential item functioning favoring age or gender. The multidimensional structure of the CTS-6 was absorbed by creating a testlet for frequency of symptoms or testlets for pain and numbness. The testlets supported unidimensionality in the BCTQ SSS. One item in the CTS-6 and two items in the BCTQ SSS showed differential item functioning favoring age or gender. Four items in the BCTQ SSS and two items in the CTS-6 exhibited disordered response category thresholds. Merging of the relevant response categories led to ordered response category thresholds. The person separation indices were 0.73, 0.86 and 0.77 for the CTS-6, BCTQ SSS and FSS, respectively. Conclusions Based on the RMT analysis, the CTS-6 has superior psychometric properties compared to the BCTQ SSS in surgically treated patients. The CTS-6 might be more accurate when separated into item sets measuring pain or numbness. The FSS of the BCTQ has acceptable construct validity, although gender differences at some ages were observed in responses.

Structural validity of the Boston Carpal Tunnel Questionnaire and its short version, the 6-Item CTS Symptoms Scale: A Rasch analysis one year after surgery

Background: The Boston Carpal Tunnel Questionnaire (BCTQ) and its shorter version, the Six-Item Carpal Tunnel Symptoms Scale (CTS-6), are widely used for assessing function and/or symptoms in patients with carpal tunnel syndrome. This study examined the structural validity of the BCTQ and CTS-6 among patients who had undergone surgery for treatment of carpal tunnel syndrome. Methods: The data for this cross-sectional analysis were obtained from 217 adult patients who had undergone carpal tunnel release surgery one year earlier. All patients completed the CTS-6, Symptom Severity Scale (SSS) and Functional Status Scale (FSS) of the BCTQ at 12 months after surgery. The Rasch Measurement Theory (RMT) was applied to investigate the unidimensionality, residual correlation, differential item functioning, scale coverage/targeting, and person separation of the CTS-6, SSS and FSS of the BCTQ.Results: The FSS showed unidimensionality and good scale and item fit. All items showed ordered response category thresholds. Eight of the FSS items displayed differential item functioning favoring age or gender. The multidimensional structure of the CTS-6 was absorbed by creating a testlet for frequency of symptoms or testlets for pain and numbness. The testlets supported unidimensionality in the BCTQ SSS. One item in the CTS-6 and two items in the BCTQ SSS showed differential item functioning favoring age or gender. Four items in the BCTQ SSS and two items in the CTS-6 exhibited disordered response category thresholds. Merging of the relevant response categories led to ordered response category thresholds. The person separation indices were 0.73, 0.86 and 0.77 for the CTS-6, BCTQ SSS and FSS, respectively.Conclusions: Based on the RMT analysis, the CTS-6 has superior psychometric properties compared to the BCTQ SSS in surgically treated patients. The CTS-6 might be more accurate when separated into item sets measuring pain or numbness. The FSS of the BCTQ has acceptable construct validity, although gender differences at some ages were observed in responses.