Difference In Mean Change Research Articles

The effect of increased plasma potassium on myocardial function; a randomized POTCAST substudy

Plasma potassium (p-K) in the high-normal range has been suggested to reduce risk of cardiovascular arrythmias and mortality through electrophysiological and mechanical effects on the myocardium. In this study, it was to investigated if increasing p-K to high-normal levels improves systolic- and diastolic myocardial function in patients with low-normal to moderately reduced left ventricular ejection fraction (LVEF). The study included 50 patients (mean age 58 years (SD 14), 81% men), with a mean p-K 3.95 mmol/l (SD 0.19), mean LVEF 48% (SD 7), and mean Global Longitudinal Strain (GLS) -14.6% (SD 3.1) patients with LVEF 35–55% from “Targeted potassium levels to decrease arrhythmia burden in high-risk patients with cardiovascular diseases trial” (POTCAST). Patients were given standard therapy and randomized (1:1) to an intervention that included guidance on potassium-rich diets, potassium supplements, and mineralocorticoid receptor antagonists targeting high-normal p-K levels (4.5-5.0 mmol/l). Echocardiography was done at baseline and after a mean follow-up of 44 days (SD 18) and the echocardiograms were analyzed for changes in GLS, mechanical dispersion, E/A, e’, and E/e’. At follow-up, mean difference in changes in p-K was 0.52 mmol/l (95%CI 0.35;0.69), P<0.001 in the intervention group compared to controls. GLS was improved with a mean difference in changes of -1.0% (-2;-0.02), P<0.05 and e’ and E/e’ were improved with a mean difference in changes of 0.9 cm/s (0.02;1.7), P = 0.04 and ? 1.5 (-2.9;-0.14), P = 0.03, respectively. Thus, induced increase in p-K to the high-normal range improved indices of systolic and diastolic function in patients with low-normal to moderately reduced LVEF.

Effects of intermittent fasting on quality of life tolerance of chemotherapy in patients with gynecological cancers: study protocol of a randomized-controlled multi-center trial.

https://drks.de, identifier DRKS00031429.

Is fixed dose combination of rosuvastatin with fenofibrate more effective than high dose Rosuvastatin inpatients with stable coronary artery disease with mixed dyslipidemia? A study

: We aimed to compare lipid lowering efficacy and safety of fixed dose combination (FDC) of rosuvastatin and fenofibrate with high dose rosuvastatin (HDR) in patients of stable coronary artery disease (CAD) with mixed dyslipidemia.: 165 patients with stable CAD with mixed dyslipidaemia were randomly assigned to HDR group, 40mg per day (n=79) and FDC group; fenofibrate with rosuvastatin, 145 mg and 20 mg per day respectively (n=88). The lipid profile was measured at baseline and at 12 weeks. The safety profile was measured by recording self-reported adverse reactions during follow up visits and by measuring serum levels of transaminases, creatinine phosphokinase (CPK) at 4 weeks. The lipid lowering efficacy was compared by estimating differences in percentage mean change from baseline values of the lipid fractions and percentage of patients achieving target goals between study groups using unpaired t test and Xtest respectively. : The FDC achieved greater reduction compared to HDR in LDL-C, -11.0% 95% C.I. (-17.7% to -4.3%) p&amp;#60;0.001, NHDL-C levels, -10.1% (-16.0% to -4.2%) p&amp;#60;0.001, triglyceride, -18.4% (-32.0% to -4.7%) p&amp;#60;0.0001. The increase in HDL-C was significantly higher in FDC arm, 14.9% (8.3% to 21.4%) p&amp;#60;0.001.The percentage of patients achieving LDL-C and Non HDL-C target goals were higher in FDC arm but difference was statistically not significant. The FDC was tolerated well than HDR regimen. : The combination of moderate dose rosuvastatin and fenofibrate is more effective in reducing atherogenic lipid fractions and increasing the HDL-C level compared to high dose rosuvastatin and had better safety profile.

Efficacy and safety of CM310 in severe eosinophilic chronic rhinosinusitis with nasal polyps (CROWNS-1): a multicentre, randomised, double-blind, placebo-controlled phase 2 clinical trial.

Severe eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) remains the most relapsed subtype of uncontrolled CRSwNP. CM310, a humanised anti-interleukin (IL)-4 receptor alpha monoclonal antibody, inhibits IL-4 and IL-13 signaling which underlying eosinophilic inflammation. This study aims to evaluate the efficacy and safety of CM310 in patients with severe ECRSwNP. A multicentre, randomised, double-blind, and placebo-controlled phase 2 clinical trial was conducted. 56 eligible adult patients with severe ECRSwNP were randomised 1:1 to receive subcutaneously either CM310 (300mg) or placebo every 2 weeks under the background therapy of mometasone furoate nasal spray (MFNS) for 16 weeks, with 8 weeks of follow-up. Coprimary endpoints included the changes from baseline in nasal polyp score (NPS) and nasal congestion score (NCS) at week 16. Key secondary endpoints included sinus Lund-Mackay CTscore, change in sinus volume occupied by disease, University of Pennsylvania Smell Identification Test score, 22-item Sino-nasal Outcome Test score, and total symptom score. Safety, pharmacodynamics, and changes in type 2 inflammation biomarkers were assessed. This study is registered with ClinicalTrials.gov, NCT04805398. Between April 6, 2021, and March 18, 2022, 27 patients respectively in both the CM310 and placebo groups completed the study. Findings suggested that CM310 improved the coprimary efficacy endpoints of decreasing nasal polyp size and alleviating nasal congestion compared with the placebo. Least squares (LS) mean differences (CM310 vs placebo) of change from baseline in NPS and NCS at week 16 were-2.1 (95% CI-2.9,-1.4; p<0.0001) and-0.9 (95%CI-1.4,-0.5; p<0.0001), respectively. Sinus CT scan revealed that Lund-Mackay CT score (LS mean difference [95%CI]-7.6, [-9.4,-5.8]; p<0.0001) and sinus volume occupied by disease (LS mean difference [95% CI]-37%, [-47%,-28%]; p<0.0001) were significantly improved with CM310 compared with placebo. In addition, CM310 significantly relieved the daily symptoms of patients with CRSwNP and improved their quality of life reflected by the improvements in the TSS (-2.6 [95% CI-3.5,-1.6]), UPSIT (10.4 [95% CI 6.8, 14.0]) and SNOT-22 score (-19.1 [95% CI-29.8,-8.5]). Compared with placebo, CM310 administration significantly reduced type 2-related biomarkers including the serum TARC and total IgE, and tissue eosinophils. The most common adverse events were upper respiratory tract infection, blood cholesterol increased, and tinnitus, but none were considered drug-related. These findings support CM310 as an effective additional treatment option to the standard of care in patients with severe ECRSwNP. KeyMed Biosciences (Chengdu) Limited.

The VA National Teleneurology Program (NTNP): Implementing Teleneurology to Improve Equitable Access to Outpatient Neurology Care

BackgroundTelehealth is increasingly utilized in many healthcare systems to improve access to specialty care and better allocate limited resources, especially for rurally residing persons who face unique barriers to care.ObjectivesThe VHA sought to address critical gaps in access to neurology care by developing and implementing the first outpatient National Teleneurology Program (NTNP).DesignPre-post evaluation of intervention and control sites.ParticipantsNTNP sites and VA control sites; Veterans completing an NTNP consult and their referring providers.InterventionImplementation of the NTNP at participating sites.Main MeasuresNTNP and community care neurology (CCN) volume of consults before and after implementation; time to schedule and complete consults; Veteran satisfaction.Key ResultsIn FY2021, the NTNP was implemented at 12 VA sites; 1521 consults were placed and 1084 (71.3%) were completed. NTNP consults were scheduled (10.1 vs 29.0 days, p < 0.001) and completed (44.0 vs 96.9 days, p < 0.001) significantly faster than CCN consults. Post-implementation, monthly CCN consult volume was unchanged at NTNP sites compared to pre-implementation (mean change of 4.6 consults per month, [95% CI − 4.3, 13.6]), but control sites had a significant increase (mean change of 24.4 [5.2, 43.7]). The estimated difference in mean change in CCN consults between NTNP and control sites persisted after adjusting for local neurology availability (p < 0.001). Veterans (N = 259) were highly satisfied with NTNP care (mean (SD) overall satisfaction score 6.3 (1.2) on a 7-point Likert scale).ConclusionsImplementation of NTNP resulted in more timely neurologic care than care in the community. The observed significant increase in monthly CCN consults at non-participating sites during the post-implementation period was not seen at NTNP sites. Veterans were highly satisfied with Teleneurology care.

850-P: The Efficacy of Imeglimin in Diabetes Subgroups Stratified by Data-Driven Cluster Analysis—A Post Hoc Analysis of Imeglimin Clinical Trial Data

Objectives: We performed a post-hoc analysis of clinical trial data with the goal of investigating whether diabetic subgroups identified by data-driven clustering respond differently to imeglimin. Methods: Data from randomized, double-blind clinical trials of imeglimin as monotherapy or add-on to insulin therapy were included in the analysis. For monotherapy, 1) duration of type 2 diabetes, 2) baseline BMI, 3) baseline HbA1c, and 4) baseline HOMA-β, and for add-on to insulin therapy, the first three and 4) insulin total daily dose were applied as coordinates to form clusters by the non-hierarchical k-means method. The efficacy of imeglimin were examined for each cluster. Results: We identified four clusters of patients with diabetes, which had significantly different patient characteristics. Cluster 1 was a group with lower values of all four indices compared to the total patient population before cluster segregation, cluster 2 was a group with longer duration of diabetes, cluster 3 was a group with higher baseline BMI and higher HOMA-β (for monotherapy) or higher insulin total daily dose (for add-on to insulin therapy), and cluster 4 was a group with higher baseline HbA1c. The improvement in HbA1c with imeglimin differed significantly among the four clusters. The mean change differences versus placebo for imeglimin in monotherapy ranged from -0.64% to -1.27%, and add-on to insulin therapy ranged from -0.31% to -0.82%. In all clusters except for cluster 3 in the add-on to insulin therapy, imeglimin showed statistically significant HbA1c improvement compared to placebo. Conclusion: Data-driven clustering of patients with type 2 diabetes allowed us to identify subgroups that respond differently to imeglimin in improving HbA1c. This new stratification might help to tailor and target the imeglimin treatment to patients who would benefit most. Disclosure K.Hagi: Employee; Sumitomo Pharma. K.Kochi: Employee; Sumitomo Dainippon Pharma Co., Ltd., Sumitomo Pharma Co., Ltd. H.Watada: Research Support; Boehringer Ingelheim Japan, Inc., Mitsubishi Tanabe Pharma Corporation, LifeScan Diabetes Institute, Eli Lilly Japan K.K., Sun Pharmaceutical Industries Ltd., Teijin Pharma Limited, Taisho Pharmaceutical Holdings Co., Ltd., Ono Pharmaceutical Co., Ltd., Kowa Company, Ltd., Merck Sharp &amp; Dohme Corp., Sanwa Kagaku Kenkyusho, Speaker's Bureau; Mitsubishi Tanabe Pharma Corporation, Taiho Pharmaceutical Co. Ltd., Novo Nordisk, Abbott Japan Co., Ltd., Astellas Pharma Inc., Merck Sharp &amp; Dohme Corp., Kissei Pharmaceutical Co., Ltd., AstraZeneca, Ono Pharmaceutical Co., Ltd., Boehringer Ingelheim Japan, Inc., Sanofi, Sun Pharmaceutical Industries Ltd., Eli Lilly Japan K.K. K.Kaku: Advisory Panel; Novo Nordisk, Consultant; Sanwa Kagaku Kenkyusho, Speaker's Bureau; Astellas Pharma Inc., Daiichi Sankyo, Eli Lilly Japan K.K., Boehringer Ingelheim Japan, Inc., Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation, Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co., Ltd. K.Ueki: Advisory Panel; Abbott Japan Co., Ltd., Research Support; Abbott Japan Co., Ltd., Boehringer Ingelheim Japan, Inc., Eli Lilly Japan K.K., Sumitomo Dainippon Pharma Co., Ltd., Novo Nordisk, Sanofi K.K., MSD Life Science Foundation, Takeda Pharmaceutical Co., Ltd., Speaker's Bureau; Boehringer Ingelheim Japan, Inc., Eli Lilly Japan K.K., Astellas Pharma Inc., AstraZeneca, Sumitomo Dainippon Pharma Co., Ltd., Novo Nordisk, Taiho Pharmaceutical Co. Ltd., Kowa Company, Ltd., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd.

#5534 HIFS AND BUTS: A NETWORK META-ANALYSIS OF HIF-PH INHIBITORS AND ESAS IN NDD-CKD PATIENTS WITH ANEMIA COMPARING THEIR SAFETY AND EFFICACY

Abstract Background and Aims Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are a new class of oral medicines for the management of anemia in CKD patients. These agents are found to be efficacious in the management of renal anemia, however safety is still under scrutiny. While, ESAs (Erythropoietin stimulating agents) are available since long with a well-established clinical profile. This network meta-analysis aimed to compare the safety and efficacy of HIF-PHI vs ESA in CKD patients with anemia not undergoing dialysis. Method An electronic database search was carried out in EBM (Evidence Based Medicine) Reviews, Cochrane Library and PubMed from inception to July 2022 for phase III clinical trials comparing six different HIF-PHIs and ESA for treating anemia in non-dialysis-dependent (NDD) CKD patients. The outcomes included the serious adverse events (SAEs) and change in hemoglobin (Hb) levels. Results Total 163 records were identified out of which 6 studies involving a total of 6847 patients were eligible for analysis. Compared to ESA, all HIF-PHIs increased risk for SAEs (daprodustat of RR, 1.21[95% CI, 0.825–1.77]; desidustat, 1.38[95% CI, 0.695–2.76]; enarodustat, 1.29[95% CI, 0.568–3.02]; molidustat, 1.02[95% CI, 0.585–1.74]; roxadustat, 1.29[95% CI, 0.674–2.57] and vadadustat, 1.01[95% CI, 0.693–1.47]) although these differences were statistically non-significant. When change in Hb was analyzed, there was no statistically significant difference between the two groups. The mean difference in change in HB with various HIFs as compared to ESA were: daprodustat (MD: 0.0796, 95% CI −0.676–0.838), desidustat (MD: 0.120, 95% CI: −0.626–0.883), enarodustat (MD: -0.600, 95% CI: −1.36–0.157), molidustat (MD: -0.309, 95% CI: −1.07–0.449), roxadustat (MD: -0.0702, 95% CI: −0.831–0.692) and vadadustat (MD: -0.0402, 95% CI: −0.802–0.720). Conclusion In terms of safety, HIF PHIs were associated with more SAEs compared to ESA although these differences are not statistically significant. Comparing efficacy, HIF-PHIs and ESA both effectively increase Hb level in NDD-CKD patients without any significant difference. Results of our network meta-analysis suggest the need for larger and long-term studies comparing HIF-PHIs with ESAs to have better understanding of their comparative efficacy and safety profiles.

Effects of new hypoglycemic drugs on cardiac remodeling: a systematic review and network meta-analysis

BackgroundIn recent years, the incidence of diabetes mellitus has been increasing annually, and cardiovascular complications secondary to diabetes mellitus have become the leading cause of death in diabetic patients. Considering the high incidence of type 2 diabetes (T2DM) combined with cardiovascular disease (CVD), some new hypoglycemic agents with cardiovascular protective effects have attracted extensive attention. However, the specific role of these regimens in ventricular remodeling remains unknown. The purpose of this network meta-analysis was to compare the effects of sodium glucose cotransporter type 2 inhibitor (SGLT-2i), glucagon-like peptide 1 receptor agonist (GLP-1RA) and dipeptidyl peptidase-4 inhibitor (DPP-4i) on ventricular remodeling in patients with T2DM and/or CVD.MethodsArticles published prior to 24 August 2022 were retrieved in four electronic databases: the Cochrane Library, Embase, PubMed, and Web of Science. This meta-analysis included randomized controlled trials (RCTs) and a small number of cohort studies. The differences in mean changes of left ventricular ultrasonic parameters between the treatment and control groups were compared.ResultsA total of 31 RCTs and 4 cohort studies involving 4322 patients were analyzed. GLP-1RA was more significantly associated with improvement in left ventricular end-systolic diameter (LVESD) [MD = -0.38 mm, 95% CI (-0.66, -0.10)] and LV mass index (LVMI) [MD = -1.07 g/m2, 95% CI (-1.71, -0.42)], but significantly decreased e' [MD = -0.43 cm/s 95% CI (-0.81, -0.04)]. DPP-4i was more strongly associated with improvement in e' [MD = 3.82 cm/s, 95% CI (2.92,4.7)] and E/e'[MD = -5.97 95% CI (-10.35, -1.59)], but significantly inhibited LV ejection fraction (LVEF) [MD = -0.89% 95% CI (-1.76, -0.03)]. SGLT-2i significantly improved LVMI [MD = -0.28 g/m2, 95% CI (-0.43, -0.12)] and LV end-diastolic diameter (LVEDD) [MD = -0.72 ml, 95% CI (-1.30, -0.14)] in the overall population, as well as E/e' and SBP in T2DM patients combined with CVD, without showing any negative effect on left ventricular function.ConclusionThe results of the network meta-analysis provided high certainty to suggest that SGLT-2i may be more effective in cardiac remodeling compared to GLP-1RA and DPP-4i. While GLP-1RA and DPP-4i may have a tendency to improve cardiac systolic and diastolic function respectively. SGLT-2i is the most recommended drug for reversing ventricular remodeling in this meta-analysis.

An interventional study of the impact of digital patient monitoring (DPM) on health outcomes, healthcare resource utilization, and feasibility of a combination with at-home treatment (tx) for delivery of systemic anticancer tx in clinical practice.

TPS1617 Background: Disease- and tx-related symptoms negatively affect quality of life and may become life-threatening. There is a need for improved understanding, prevention, reduction and mitigation of symptoms, and tools to facilitate remote tracking of pt-reported outcomes (PROs) and support self-management of symptoms. As anticancer txs are increasingly given outside of the clinical settings, DPM tools are becoming more important to support remote symptom management. DPM can improve clinical care and pt outcomes; however, broad adoption requires proven usability and demonstration of real-world clinical utility/impact. ORIGAMA (NCT05694013) is an interventional, open-label, multi-country platform study investigating the clinical utility of DPM tools with specific txs. ORIGAMA will assess atezolizumab (atezo)-specific Roche DPM Modules (F. Hoffmann-La Roche Ltd, Basel, Switzerland; hosted on Kaiku Health DPM platform [Helsinki, Finland]) in two cohorts, to study the impact of DPM on clinical outcomes and healthcare resource utilization, and its feasibility to support at-home tx administration. Methods: Adult pts with ECOG PS of 0–2, an email address, and access to an internet-capable device and internet connection are eligible. In Cohort A, systemic tx-naive pts with metastatic non-small cell lung cancer (NSCLC), extensive-stage SCLC, or Child–Pugh A unresectable hepatocellular carcinoma, with a life expectancy of ≥ 12 weeks (wks) will be randomized 1:1 to a locally approved anticancer regimen of intravenous atezo and local standard-of-care (SoC) support with/without access to the Roche DPM Module. Pts will receive tx until progressive disease or per local SoC. Cohort B will assess the Roche DPM Module in pts receiving 3 cycles of subcutaneous atezo in a hospital setting, followed by 13 cycles of at-home administration by a healthcare professional. Eligible pts have programmed-death ligand 1-positive (expression on ≥ 1% of tumor cells), NSCLC (Stages IIB, IIIA, IIIB [T3–N2]), have completed adjuvant chemotherapy 4–12 wks prior to randomization, and must have a complete resection. Future cohorts may be added to investigate digital health solutions in other tx settings. The primary endpoints are the mean difference in change of the pt-reported Total Symptom Interference Score at Wk 12 from baseline (Cohort A), and flexible care adoption rate at Cycle 6 (Cohort B). The primary analysis for Cohort A will occur when all randomized pts have been followed for ≥ 12 wks and for Cohort B when all pts have completed 16 cycles of tx. Other endpoints include safety and PROs. An exploratory analysis of overall survival will be performed. ~400 pts in Cohort A and 40 pts in Cohort B will be enrolled. Recruitment has started; the first pt to be enrolled in February 2023. Clinical trial information: NCT05694013 .

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Zanubrutinib (zanu) is a potent and highly selective next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target effects. In the ALPINE study (NCT03734016), zanu demonstrated superiority to ibrutinib (ibr) in both progression-free survival (PFS) and overall response rate and a more favorable safety profile in R/R CLL/SLL. The purpose of this analysis was to assess health-related quality of life (HRQOL) in patients (pts) treated with zanu and ibr. Results from the data cutoff related to recent PFS analysis (8 Aug 2022) are reported here. Methods: HRQOL was measured by EORTC QLQ-C30 and EQ-5D-5L at baseline, cycle 1, and every 3rd 28-day cycle until end of treatment. Key pt-reported outcome (PRO) endpoints included global health status (GHS), physical and role functions, fatigue, pain, diarrhea, and nausea/vomiting. Descriptive analysis was conducted on all the scales; a mixed-model repeated-measure analysis using key PRO endpoints at the key clinical cycles of cycles 7 (6 months) and 13 (12 months) was performed. Adjusted completion rates were defined as the number of pts who completed the questionnaires at each cycle divided by number still on treatment. Clinically meaningful was defined as a ≥5% mean change difference from baseline. Results: A total of 652 pts were randomized to receive zanu (n = 327) or ibr (n = 325); baseline characteristics were generally similar between arms, although the zanu arm had fewer males versus ibr arm (65.1% vs. 71.4%). At baseline, GHS, functional, and symptom scales scores were similar between arms. Although more ibr-treated pts discontinued treatment due to adverse events versus zanu (22.2% vs. 15.4%), adjusted PRO completion rates were high at cycles 7 and 13 in both the zanu (89.6% and 94.3%) and ibr arm (87.7% and 92.3%), respectively. By cycle 7, GHS scores were improved with zanu versus ibr and by cycle 13, the difference in GHS scores from baseline was no longer significant (Table). Pts in the zanu arm experienced clinically meaningful improvements in physical and role functioning as well as pain and fatigue at cycles 7 and 13, but the difference between arms was not significant. Although pts in the zanu arm reported lower diarrhea scores, the difference between treatments was not significant. Nausea/vomiting scores were maintained in both arms with no measurable difference. VAS scores showed greater improvement from baseline at both cycle 7 (7.92 vs. 3.44) and cycle 13 (7.75 vs. 3.92) of treatment with zanu versus ibr, respectively. Conclusions: In ALPINE, pts with R/R CLL/SLL treated with zanu demonstrated improvement versus ibr in the QLQ-C30 GHS/QoL scale at cycle 7. Other endpoints continued to improve, suggesting treatment with zanu positively affected and improved HRQOL over time. As expected, given the generally good HRQOL at baseline in both arms, the differences between the arms were small and not significant. Encore Abstract - previously submitted to EHA 2023 The research was funded by: BeiGene Keyword: Chronic Lymphocytic Leukemia (CLL) Conflicts of interests pertinent to the abstract. B. Eichhorst Consultant or advisory role: Janssen, AbbVie, Gilead, AstraZeneca, BeiGene, MSD, Lilly Honoraria: Roche, AbbVie, BeiGene, AstraZeneca, MSD Research funding: Janssen, Gilead, Roche, AbbVie, BeiGene, AstraZeneca Educational grants: BeiGene N. Lamanna Consultant or advisory role: Abbvie, AstraZeneca, BeiGene, Eli Lily/Loxo, Genentech, Janssen, Pharmacyclics Research funding: Abbvie, AstraZeneca, BeiGene, Eli Lily/Loxo, Genentech, Octapharma, Oncternal, MingSight, TG Therapeutics S. M. O'Brien Consultant or advisory role: AbbVie, Alexion, Amgen, Aptose Biosciences Inc., Astellas, AstraZeneca, Autolus, BMS, Celgene, DynaMed, Eli Lilly and Company, Gilead, GSK, Janssen Oncology, Johnson and Johnson, Juno Therapeutics, MEI Pharma Inc., Merck, NOVA Research Company, Pfizer, Pharmacyclics, TG Therapeutics, Vaniam Group Inc., Verastem, Vida Ventures Research funding: TG Therapeutics, Pharmacyclics, Pfizer, Nurix Therapeutics, Inc., Mustang, Loxo Oncology Inc., Kite, Gilead, Caribou Biosciences, Inc. BeiGene, Ltd., Alliance, Acerta C. S. Tam Honoraria: BeiGene, AbbVie, Janssen Research funding: Janssen, AbbVie Other remuneration: BeiGene L. Qiu Consultant or advisory role: Janssen, Astra Zeneca, Takeda, Roche, Abbvie, Beigene K. Yang Employment or leadership position: BeiGene Stock ownership: BeiGene Research funding: BeiGene K. Wu Employment or leadership position: BeiGene (Self), Roche/Genentech (Spouse) Stock ownership: BeiGene (Self), Roche/Genentech (Spouse) T. Salmi Employment or leadership position: BeiGene G. Barnes Employment or leadership position: BeiGene Stock ownership: BeiGene J. R. Brown Consultant or advisory role: Abbvie, AstraZeneca, BeiGene, Eli Lily/Loxo, Genentech, Octapharma, Oncternal, MingSight, TG Therapeutics Research funding: BeiGene, Gilead, iOnctura, Loxo/Lilly, MEI Pharma, SecuraBio, Sun, TG Therapeutics

Nucleoside/nucleotide reverse transcriptase inhibitor sparing regimen with once daily integrase inhibitor plus boosted darunavir is non-inferior to standard of care in virologically-suppressed children and adolescents living with HIV - Week 48 results of the randomised SMILE Penta-17-ANRS 152 clinical trial.

Integrase inhibitor (INSTI) with boosted darunavir (DRV/r), a regimen with a high-resistance barrier, avoiding NRTI toxicities, might be a switching option in children living with HIV (CLWHIV). SMILE is a randomised non-inferiority trial evaluating safety and antiviral efficacy of once-daily INSTI+DRV/r vs. continuing on current standard-of-care (SOC) triple ART (2NRTI+boosted PI/NNRTI) in virologically-suppressed CLWHIV aged 6-18 years. The primary outcome is the proportion with confirmed HIV-RNA ≥50 copies/mL by week 48, estimated by Kaplan-Meier method. Non-inferiority margin was 10%. Registration number for SMILE are: ISRCTN11193709, NCT #: NCT02383108. Between 10th June 2016 and 30th August 2019, 318 participants were enrolled from Africa 53%, Europe 24%, Thailand 15% and Latin America 8%, 158 INSTI+DRV/r [153 Dolutegravir (DTG); 5 Elvitegravir (EVG)], 160 SOC. Median (range) age was 14.7 years (7.6-18.0); CD4 count 782cells/mm3 (227-1647); 61% female. Median follow-up was 64.3 weeks with no loss to follow-up. By 48 weeks, 8 INSTI+DRV/r vs. 12 SOC had confirmed HIV-RNA ≥50 copies/mL; difference (INSTI+DRV/r-SOC)-2.5% (95% CI:-7.6, 2.5%), showing non-inferiority. No major PI or INSTI resistance mutations were observed. There were no differences in safety between arms. By week 48, difference (INSTI+DRV/r-SOC) in mean CD4 count change from baseline was-48.3cells/mm3 (95% CI:-93.4,-3.2; p=0.036). Difference (INSTI+DRV/r-SOC) in mean HDL change from baseline was-4.1mg/dL (95% CI:-6.7,-1.4; p=0.003). Weight and Body Mass Index (BMI) increased more in INSTI+DRV/r than SOC [difference: 1.97kg (95% CI: 1.1, 2.9; p<0.001), 0.66kg/m2 (95% CI: 0.3, 1.0; p<0.001)]. In virologically-suppressed children, switching to INSTI+DRV/r was non-inferior virologically, with similar safety profile, to continuing SOC. Small but significant differences in CD4, HDL-cholesterol, weight and BMI were observed between INSTI+DRV/r vs. SOC although clinical relevance needs further investigation. SMILE data corroborate adult findings and provide evidence for this NRTI-sparing regimen for children and adolescents. Fondazione Penta Onlus, Gilead, Janssen, INSERM/ANRS and UK MRC. ViiV-Healthcare provided Dolutegravir.

Glucagon-like peptide-1 receptor agonists as a disease-modifying therapy for knee osteoarthritis mediated by weight loss: findings from the Shanghai Osteoarthritis Cohort

ObjectiveObesity is a risk factor for knee osteoarthritis (KOA) development and progression. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are indicated for type 2 diabetes mellitus (T2DM) and obesity. However, whether KOA...

0642 Effect of Iloperidone on Sleep Symptoms in Bipolar Patients with Manic and Mixed Episodes: A Randomized, Placebo Controlled Study

Abstract Introduction Iloperidone, a dopamine D2 receptor and serotonin 5HT2A receptor antagonist, was evaluated for the treatment of acute manic and mixed episodes associated with bipolar I disorder in adults in a phase 3 clinical trial. A core symptom of bipolar I disorder is disturbance in sleep. During manic episodes this commonly presents as reduced need for sleep with studies finding that 69%–99% of bipolar individuals report a lessened need for sleep or difficulties in falling and/or staying asleep. Here we present a post hoc analysis evaluating iloperidone effects on the sleep component of the Young Mania Rating Scale (YMRS) in patients with bipolar I disorder which addresses both sleep and the reduced need for sleep in that component. Methods This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study of iloperidone in patients with acute manic or mixed episodes associated with bipolar I disorder. Patients received four weeks of double-blind treatment. The primary analysis demonstrating an overall improvement from baseline YMRS score in iloperidone assigned patients versus placebo assigned patients (p = 0.000008) at the end of the study (week 4). A YMRS item level analysis evaluated changes on YMRS single items including the sleep component in the intent-to-treat population (N = 392) using a mixed-effects model for repeated measures approach. Results The least squares mean difference (LSMD) in change from baseline to day 28 was statistically significant on the YMRS sleep component in favor of iloperidone versus placebo (iloperidone = -1.26, placebo = -0.95; p = 0.008). Conclusion In addition to improving overall mania symptoms as reported by the YMRS, improvements were also seen in iloperidone treated patients in the sleep component which at baseline included assessments of both decreased sleep and decreased need or denial of the need for sleep. Support (if any) This work was supported by Vanda Pharmaceuticals Inc.

Effect of Phacoemulsification on Sub Foveal Choroidal and Central Macular Thickness as measured by Swept Source Optical Coherence Tomography.

To study the effect of Phacoemulsification on Sub Foveal Choroidal Thickness (SFCT) and Central Macular Thickness (CMT) as measured by Swept Source Optical Coherence Tomography (OCT). This experimental study was conducted at Armed Forces Institute of Ophthalmology (AFIO), Rawalpindi from April 2021 to February 2022. One hundred eyes of 100 patients with age related cataract underwent uneventful phacoemulsification surgery. Pre-operative SFCT and CMT was measured and compared with SFCT and CMT at one week, one month and three months after surgery using swept source OCT. Mean age of study population was 56.76±8.31 years. Out of 100 patients, 46 (46%) were males and 54 (54%) were females. Mean pre-operative CMT, one week, one month and three months post-operative CMT was 233.95±9.46 μm, 232.88±8.59 μm, 230.38±10.62 μm and 230.67±7.55 μm respectively. Mean pre-operative SFCT, one week, one month and three months post-operative SFCT was 337.14±8.41 μm, 339.14±9.63 μm, 339.39±11.96 μm and 351.39±9.19 μm respectively. The difference of mean change in CMT from baseline at one week, one month and three months post-operatively was not statistically significant. The difference of mean change in SFCT from baseline at one week and one month post-operatively was not statistically significant. However, the difference of mean change in SFCT from baseline at three months post-operatively was statistically significant (p<0.05). Uneventful phacoemulsification surgery does not have any effect on central macular thickness, however there is a significant increase in subfoveal choroidal thickness at three months after surgery.

Remote haemodynamic monitoring of pulmonary artery pressures in patients with chronic heart failure (MONITOR-HF): a randomised clinical trial

The effect of haemodynamic monitoring of pulmonary artery pressure has predominantly been studied in the USA. There is a clear need for randomised trial data from patients treated with contemporary guideline-directed-medical-therapy with long-term follow-up in a different health-care system. MONITOR-HF was an open-label, randomised trial, done in 25 centres in the Netherlands. Eligible patients had chronic heart failure of New York Heart Association class III and a previous heart failure hospitalisation, irrespective of ejection fraction. Patients were randomly assigned (1:1) to haemodynamic monitoring (CardioMEMS-HF system, Abbott Laboratories, Abbott Park, IL, USA) or standard care. All patients were scheduled to be seen by their clinician at 3 months and 6 months, and every 6 months thereafter, up to 48 months. The primary endpoint was the mean difference in the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score at 12 months. All analyses were by intention-to-treat. This trial was prospectively registered under the clinical trial registration number NTR7673 (NL7430) on the International Clinical Trials Registry Platform. Between April 1, 2019, and Jan 14, 2022, we randomly assigned 348 patients to either the CardioMEMS-HF group (n=176 [51%]) or the control group (n=172 [49%]). The median age was 69 years (IQR 61-75) and median ejection fraction was 30% (23-40). The difference in mean change in KCCQ overall summary score at 12 months was 7·13 (95% CI 1·51-12·75; p=0·013) between groups (+7·05 in the CardioMEMS group, p=0·0014, and -0·08 in the standard care group, p=0·97). In the responder analysis, the odds ratio (OR) of an improvement of at least 5 points in KCCQ overall summary score was OR 1·69 (95% CI 1·01-2·83; p=0·046) and the OR of a deterioration of at least 5 points was 0·45 (0·26-0·77; p=0·0035) in the CardioMEMS-HF group compared with in the standard care group. The freedom of device-related or system-related complications and sensor failure were 97·7% and 98·8%, respectively. Haemodynamic monitoring substantially improved quality of life and reduced heart failure hospitalisations in patients with moderate-to-severe heart failure treated according to contemporary guidelines. These findings contribute to the aggregate evidence for this technology and might have implications for guideline recommendations and implementation of remote pulmonary artery pressure monitoring. The Dutch Ministry of Health, Health Care Institute (Zorginstituut), and Abbott Laboratories.

Self-monitoring of blood glucose two-weekly versus weekly in gestational diabetes on nutrition therapy: A randomized trial.

To evaluate 4-point per day self-monitoring of blood glucose (SMBG) every 2 weeks compared with every week. A total of 104 patients with lifestyle-controlled gestational diabetes (GDMA1) were randomized to 2-weekly or weekly 4-point per day (fasting on awakening and 2-h post-meals) SMBG. Primary outcome was the change in glycated hemoglobin (HbA1c) level from enrollment to 36 weeks of pregnancy across trial arms. The non-inferiority margin was an HbA1c increase of 0.2%. The mean difference for change in HbA1c from enrollment to 36 weeks was 0.003% (95% confidence interval [CI] -0.098% to +0.093%), within the 0.2% non-inferiority margin. The change in HbA1c level increased significantly within both trial arms-0.275% ± 0.241% (P < 0.001) in 2-weekly arm versus 0.277% ± 0.236% (P < 0.001) in the weekly arm. Participants randomized to 2-weekly SMBG were significantly less likely to receive anti-glycemic treatment-5/52 (9.6%) versus 14/50 (28.0%) (relative risk 0.34, 95% CI 0.13-0.88; P = 0.017). All secondary outcomes-maternal weight gain, preterm delivery, cesarean delivery, birthweight, and neonatal admission-were not significantly different. In GDMA1, 2-weekly is non-inferior to weekly SMBG on the change in HbA1c level. Two-weekly SMBG appeared to be adequate for monitoring women with GDMA1. This study was registered in ISRCTN registry on March 25, 2022 with trial identification number: ISRCTN13404790 (https://doi.org/10.1186/ISRCTN13404790). The first participant was recruited on April 12, 2022.

Randomized Trial of Biosimilar XSB-001 versus Reference Ranibizumab in Patients with Neovascular Age-Related Macular Degeneration

To evaluate the efficacy, safety, and immunogenicity of a ranibizumab biosimilar candidate (XSB-001) versus reference product (Lucentis) for neovascular age-related macular degeneration (nAMD). Phase III, multicenter, randomized, double-masked, parallel-group study. Patients with nAMD. Eligible patients were randomized (1:1) to receive intravitreal injections of XSB-001 or reference ranibizumab (0.5 mg [0.05 ml]) in the study eye once every 4 weeks for 52 weeks. Efficacy and safety assessments continued through 52 weeks of treatment. Primary end point was change from baseline in best-corrected visual acuity (BCVA) by ETDRS letters at week 8. Biosimilarity was concluded if the 2-sided 90% confidence interval (CI) (United States) or 95% CI (rest of world) for the difference in least-squares (LS) mean change in BCVA at week 8 between treatment groups was within the predefined equivalence margin of ± 3.5 letters. In total, 582 patients (n= 292 XSB-001, n= 290 reference ranibizumab) were randomized. Mean age was 74.1 years, most patients (85.2%) were White, and 55.8% were women. Mean BCVA score at baseline was 61.7 and 61.5 ETDRS letters in the XSB-001 and reference ranibizumab groups, respectively. At week 8, the LS mean (standard error [SE]) change in BCVA from baseline was 4.6 (0.5) ETDRS letters in the XSB-001 group and 6.4 (0.5) letters in the reference ranibizumab group (LS mean [SE] treatment difference:-1.8 [0.7] ETDRS letters; 90% CI,-2.9 to-0.7; 95% CI,-3.1 to-0.5). The 90% CI and 95% CI for LS mean difference in change from baseline were within the predefined equivalence margin. At week 52, LS mean (SE) change in BCVA was 6.4 (0.8) and 7.8 (0.8) letters, respectively (LS mean [SE] treatment difference,-1.5 [1.1] ETDRS letters; 90% CI,-3.3 to 0.4; 95% CI,-3.6 to 0.7). There were no clinically meaningful differences between treatments in anatomical, safety, or immunogenicity end points through week52. XSB-001 demonstrated biosimilarity to reference ranibizumab in patients with nAMD. Treatment with XSB-001 for 52 weeks was generally safe and well tolerated, with a safety profile similar to the reference product. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Antenatal mobile-delivered mindfulness-based intervention to reduce perinatal depression risk and improve obstetric and neonatal outcomes: A randomized controlled trial

ObjectivesOne in five mothers will experience perinatal depression (PND) during pregnancy and within their first year following childbirth. Current evidence suggests the short-term efficacy of Mindfulness-based interventions (MBI) for perinatal women, but the extent to which this positive impact remains the early postpartum period is unclear. This study investigated the short- and maintenance efficacy of a mobile-delivered four-immeasurable MBI on PND, and obstetric and neonatal outcomes. MethodsSeventy-five adult pregnant women suffering from heightened distress were randomized to receive a mobile-delivered four-immeasurable MBI (n = 38) or a web-based perinatal education program (n = 37). PND was measured by Edinburgh Postnatal Depression Scale at baseline, post-intervention, 37th-week gestation, and 4–6 weeks postpartum. Outcomes also included obstetric and neonatal outcomes, trait mindfulness, self-compassion, and positive affect. ResultsParticipants reported an average age of 30.6 (SD = 3.1) years with a mean gestational age of 18.8 (SD = 4.6) weeks. In intention-to-treat analyses, women in the mindfulness group showed a significantly greater reduction in depression from baseline to post-intervention (adjusted mean change difference [β] = −3.9; 95%CI = [−6.05, −1.81]; d = −0.6), and the reduction sustained until 4–6 weeks postpartum (β = −6.3; 95%CI = [−8.43, −4.12]; d = −1.0), compared with control. They had a significantly reduced risk of emergent cesarean section (relative risk = 0.5) and gave birth to infants with higher Apgar scores (β = 0.6;p = .03; d = 0.7). Depression reduction before giving birth significantly mediated the intervention effect on lowering the emergency cesarean risk. ConclusionsWith a reasonably low dropout rate (13.2 %), the mobile-delivered MBI can be an acceptable and effective intervention for reducing depression throughout pregnancy and postpartum. Our study also suggests the potential benefits of early prevention for mitigating emergent cesarean section risk and enhancing neonatal health.

Brain Stimulation and Constraint Induced Movement Therapy in Children With Unilateral Cerebral Palsy: A Randomized Controlled Trial

Background There is a crucial need to devise optimum rehabilitation programs for children with cerebral palsy (CP). Objective This study aimed to assess the feasibility, safety, and efficacy of combining 6-Hz primed, low-frequency, repetitive transcranial magnetic stimulation (rTMS) with modified constraint-induced movement therapy (mCIMT) in improving upper limb function in children with unilateral CP. Methods Children aged 5 to 18 years with unilateral CP were randomized (23 in each arm) to receive 10 sessions of mCIMT with real rTMS (intervention arm) or mCIMT with sham rTMS (control arm), on alternate weekdays over 4 weeks. The primary outcome was the difference in mean change in Quality of Upper Extremity Skills Test (QUEST) scores. Secondary outcomes were changes in QUEST domain scores, speed and strength measures, CP quality of life (CP-QOL) scale scores, and safety of rTMS. Results All 46 children completed the trial except one. At 4 weeks, the mean change in total QUEST scores was significantly higher in the intervention arm as compared to the control arm (11.66 ± 6.97 vs 6.56 ± 4.3, d = 5.1, 95% CI 1.7-8.5, P = .004). Change in “weight bearing” and “protective extension” domain score was significantly higher for children in the intervention arm. These improvements were sustained at 12 weeks (P = .028). CP-QOL scores improved at 12 weeks. No serious adverse events were seen. Conclusion A 6-Hz primed rTMS combined with mCIMT is safe, feasible, and superior to mCIMT alone in improving the upper limb function of children with unilateral CP. Trial Registration: ClinicalTrials.gov Identifier: NCT03792789.

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).