Analysis Of Secondary Endpoints Research Articles

Circulating tumor DNA for detection of molecular residual disease (MRD) in patients (pts) with stage II/III colorectal cancer (CRC): Final analysis of the BESPOKE CRC sub-cohort.

15 Background: BESPOKE CRC, a multicenter, prospective, observational study investigated the clinical utility of ctDNA for detecting MRD-based early recurrence in pts with surgically resected CRC. The primary endpoint was to assess the impact of ctDNA testing on treatment decisions and asymptomatic recurrence rates. The secondary endpoint was to assess the MRD clearance rate, survival of MRD-negative pts, overall survival, and patient-reported outcomes. Methods: Complete clinical and laboratory data were available for 1001 pts with stages II–III CRC. Longitudinal ctDNA testing was performed prospectively using a clinically validated, personalized, tumor-informed 16-plex mPCR-NGS assay (Signatera, Natera, Inc.). Plasma time points (n=8,536) were collected during the MRD (2-12 weeks postoperatively) and surveillance (post-adjuvant chemotherapy [ACT] completion/12 weeks postoperatively for pts observed) windows. We evaluated the correlation between ctDNA status and disease-free survival (DFS) as part of exploratory analysis. Results: Following curative resection, 62.4% (625/1001) pts received ACT: 25.9% (115/443) stage II, and 91.3% (510/558) stage III.Among pts with ctDNA results available during the MRD window with a median follow-up of 23.15 (range: 2.89-33.45) months, ctDNA-positivity was observed in 8.1% (34/420) of stage II and 24.9% (126/505) of stage III pts. A significant association between ctDNA positivity and inferior DFS was observed in stage II (HR=10.4; p<0.0001), and stage III (HR=10.1, p<0.0001) pts. 18/24 month DFS estimates for stages II-III combined were: (MRD-negative: 93.0%/91.7%; MRD-positive: 44.4%/41.4%). Analysis of surveillance was performed separately for pts observed (N=368) vs. ACT-treated (N=597). During surveillance, in the observation cohort, 6.8% (22/323) of stage II, and 33.3% of stage III (15/45) pts tested ctDNA-positive correlating with significantly worse DFS (stage II: HR=34.9; p<0.0001, stage III: HR=34.1; p=0.0008). Likewise, in the ACT cohort, 10.9% (12/110) of stage II and 21.1% of stage III (103/487) pts turned ctDNA-positive and had significantly worse DFS (stage II: HR=131.4; p<0.0001, stage III: HR=54.6; p<0.0001). Analysis of primary and secondary endpoints will be presented. Conclusions: ctDNA positivity was highly prognostic of DFS within MRD and surveillance windows in a subset of stages II-III pts enrolled in the BESPOKE CRC study. Our results highlight the potential value of ctDNA-based MRD detection for treatment-decision making, and findings relevant to clinical utility will be reported in the conference presentation. Clinical trial information: NCT04264702 .

Preliminary effectiveness of social prescription and virtual patient information in increasing tertiary prevention among cancer patients (ESPRIT): protocol for a single-centre, randomised controlled pilot trial

IntroductionTertiary prevention through physical activity and psychosocial support can positively impact patient outcomes, such as physical function and quality of life (QoL). However, more research is required on the effectiveness...

Overall Survival of Patients with Metastatic Renal Cell Carcinoma Following the Introduction of Targeted and Immunotherapies: A Norwegian Retrospective, Real-World Registry Data Study (RECON3).

In Norway, 5-year survival rates of patients with renal cell carcinoma (RCC) are increasing. The objective of this study was to describe the survival of real-world patients with metastatic RCC (mRCC) across Norway and to identify associated factors. The results may provide additional information on the benefits of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) in clinical practice. We performed a longitudinal, retrospective, non-interventional cohort study using data from four national registries. The study included adults diagnosed with mRCC between 1 January 1995 and 31 December 2018. Primary endpoint was to evaluate overall survival (OS) in all included patients. Secondary endpoints included further analysis of treatment patterns and possible impact on OS. Secondary endpoint analysis was performed in patients diagnosed with mRCC between 1 January 2008 and 31 December 2018, as complete data on systemic therapies were available from 2008 and onwards. In total, 4078 patients were diagnosed with mRCC in the period from 1995 to 2018. The median OS since initial mRCC diagnosis was 1.17 years. OS appeared to improve over time, 5-year OS was 10% in patients diagnosed in the period 1995-2001 compared to 25% in 2012-2015. The secondary analysis included 2338 patients. Fifty-five percent (55%) of the patients received systemic treatment. No differences were observed in the number of treatment lines administered over time or in the number of lines of treatment administered according to tumor histology. Among 343 patients who received ≥3 treatment lines, we observed longer OS in patients who received an ICI as a part of their treatment, with a median OS of 4.51 compared to 2.31 years. Provision of information into registries is mandatory in Norway. This retrospective, registry-based study provides real-world evidence on patient outcomes and treatments of the Norwegian patients with mRCC in the period from 1995 to 2018.

Fixed-dose Combination of Dapagliflozin and Linagliptin in Individuals with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin: A Randomized Double-blind Multicenter Trial

Abstract Context: Combining dipeptidyl peptidase 4 inhibitors and sodium-glucose cotransporter-2 inhibitors in therapy could be beneficial for those with metformin intolerance or not achieving adequate control. Aims: To evaluate the efficacy, safety, and tolerability of a fixed-dose combination (FDC) of dapagliflozin plus linagliptin in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin. Settings and Design: It is a phase III, prospective, randomized, double-blind, multicenter study. Materials and Methods: Patients with T2DM, with a stable dose of metformin ≥1000 mg/day as monotherapy for at least 3 months before screening, with inadequate glycemic control at screening were randomly assigned to either arm A (dapagliflozin 10 mg + linagliptin 5 mg) or arm B (linagliptin 5 mg) in a 1:1 ratio. Statistical Analysis Used: The primary and secondary efficacy endpoint analyses were done using repeated measures analysis of covariance or a two-sample t test. All safety parameters were analyzed using a two-sample t test and descriptive statistics. Results: A total of 232 patients were randomized in arm A (n = 112) and arm B (n = 110). At week 16, arm A showed a significant mean reduction in glycated hemoglobin (HbA1c) than arm B (−1.35% vs. −0.92%; P≤0.0001). Similarly, the mean reductions in fasting plasma glucose (−26.13 mg/dL vs. −22.59 mg/dL; P = 0.0492), 2-h postprandial plasma glucose (−52.29 mg/dL vs. −30.35 mg/dL; P≤0.0001), and body weight (−1.32 kg vs. −0.42 kg; P≤0.0001) were significantly higher in arm A than in arm B. Arm A had a higher proportion of patients achieving HbA1c <7.0% (42.24% vs. 22.41%; P = 0.0012). Adverse events were comparable between study arms. Conclusions: The FDC of dapagliflozin and linagliptin was superior in terms of improvement in glycemic control and a higher proportion of patients achieving target HbA1c level, with both treatment arms being well-tolerated.

Efficacy and Safety of Sacubitril/Valsartan Versus Amlodipine in Japanese Patients With Essential Hypertension: A Randomized, Multicenter, Open-Label, Noninferiority Study (PARASOL Study).

Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, has demonstrated a superior blood pressure-lowering effect compared with renin-angiotensin system inhibitors in several clinical trials. However, there has been no available evidence on the comparison between sacubitril/valsartan and calcium channel blockers (CCBs), a well-established class of antihypertensive drugs. In this open-label, multicenter study, we aimed to demonstrate the efficacy and safety of sacubitril/valsartan versus amlodipine, one of the most widely used CCBs, after 8 weeks of treatment. A total of 359 Japanese patients with essential hypertension (office systolic blood pressure [SBP] ≥150 to <180mmHg), aged 18-79, were randomly assigned to receive either once-daily sacubitril/valsartan 200mg or once-daily amlodipine 5mg in a 1:1 allocation ratio. The primary endpoint was the noninferiority of sacubitril/valsartan compared with amlodipine in mean change in 24-h SBP from baseline to Week 8, followed by a significance test as a secondary endpoint analysis. The mean change in 24-h SBP in sacubitril/valsartan was noninferior to that in amlodipine (between-treatment difference -0.62mmHg [95% confidential interval: -3.23 to 1.98; p = 0.003 for noninferiority; independent t-test with noninferiority margin 3.0mmHg]), with no significant difference observed (p=0.637). There was no significant difference in the incidence of adverse events (AEs). These results suggested that the blood pressure-lowering effect of sacubitril/valsartan is comparable to that of amlodipine, with no marked differences in tolerability between the two groups. Sacubitril/valsartan, a potent antihypertensive drug comparable to amlodipine, is expected to improve blood pressure control in clinical practice.

Effect of vitamin D, omega-3 supplementation, or a home exercise program on muscle mass and sarcopenia: DO-HEALTH trial.

We aimed to investigate the effect of daily supplemental vitamin D, omega-3s, and a thrice-weekly home exercise program, alone or in combination, on change of appendicular lean muscle mass index (ALMI) and incident sarcopenia in older adults. This is a secondary endpoint analysis of a 3-year randomized, double-blind, placebo-controlled trial with a 2 × 2 × 2 factorial design among 2157 community-dwelling, healthy adults aged 70 + years, from 2012 to 2018 (DO-HEALTH). Participants were randomized to 2000 IU/d vitamin D and/or 1 g/d marine omega-3s and/or exercise. Change in ALMI over 3 years was calculated in all participants who underwent dual energy X-ray absorptiometry (DXA) (n = 1495) using mixed effect models. Incident sarcopenia was analyzed based on the Sarcopenia Definitions and Outcomes Consortium in all non-sarcopenic participants (n = 1940). Among 1495 participants (mean age 74.9 (sd 4.4); 63.3% were women; 80.5% were at least moderately physically active at baseline) mean gait speed at baseline was 1.2 m/s (sd 0.3), mean ALMI at baseline was 6.65 (SD 0.95) in women, and 8.01 (SD 0.88) kg/m2 in men. At year 3, average change of ALMI was -0.09 (sd 0.34) kg/m2 (-1.35%) in women and - 0.17 (sd 0.33) kg/m2 (-2.0%) in men. None of the treatments individually or in combination had a benefit on ALMI change compared to control over 3 years, with omega-3s showing a small protective effect on ALMI at year 1 only (-0.021 vs. no-omega-3s -0.066 kg/m2, p = 0.001). Of 1940 non-sarcopenic participants at baseline, 88 (4.5%) developed incident sarcopenia over 3 years. None of the treatments individually or in combination reduced the odds of incident sarcopenia compared with placebo. Among healthy, physically active older adults, ALMI and incidence of sarcopenia were not improved by treatment of daily 2000 IU vitamin D, daily 1 g omega-3s, or a simple home exercise program compared with control over 3 years.

Safety of abdominal paracentesis in hospitalised patients receiving uninterrupted therapeutic or prophylactic anticoagulants.

Abdominal paracentesis is a frequently performed procedure in hospitalised patients with ascites. Concurrently, most hospitalised adult patients receive pharmacologic anticoagulation, either for therapeutic purposes or prophylactically to prevent venous thromboembolism. Despite this, minimal evidence exists to guide management of anticoagulant therapy pre- and post-paracentesis. The authors aimed to investigate the safety of abdominal paracentesis in hospitalised patients receiving therapeutic or prophylactic anticoagulation, including in patients for whom these medications were withheld periprocedurally. TriNetX, an electronic health record data set, was queried to identify patients between the ages of 18 and 80 years who received an abdominal paracentesis while hospitalised at the authors' institution between September 2017 and June 2022. Patients receiving prophylactic anticoagulation (137), therapeutic anticoagulation (74) and no anticoagulation because of coagulopathy or thrombocytopenia (15) were compared. Rates of withholding anticoagulation, performing service, pre- and post-paracentesis haemoglobin, bleeding complications, thrombotic complications and need for red blood cell transfusion were analysed. Procedure-related bleeding complications occurred in two (1.4%) patients in the prophylactic group and 0 (0%) patients in the therapeutic group (P = 0.54). No thrombotic complications occurred. Rates of red blood cell transfusions post-paracentesis were similar between groups. Analysis of secondary end-points identified significant differences in rates of withholding anticoagulation and mean change in haemoglobin between performing services. Performance of abdominal paracentesis in patients receiving therapeutic or prophylactic anticoagulation appears to be safe regardless of whether anticoagulation was interrupted periprocedurally, with low rates of bleeding complications, thrombotic complications or need for red blood cell transfusions post-paracentesis.

Anticoagulation, photoselective vaporization of the prostate and safety : a propensity score-matched study.

We compared surgical complications after laser prostatic photovaporization in anticoagulated versus non-anticoagulated patients. A propensity score was calculated and patients were matched, to compare postoperative complications using the Clavien-Dindo classification between the anticoagulated and non-anticoagulated groups. We also identified factors associated with complications, and perform an analysis of secondary endpoint with categories of urological complications. We included all patients that benefited a photovaporization between 2013 and 2022, either 811 patients, reducing to 245 after propensity score matching for anticoagulation. After propensity score matching, there were no differences in baseline characteristics between groups. Ninety five patients (38%) were receiving anticoagulants; 162 (66%) had an ASA score ≥ 3. Among 86 patients (35%) who experienced complications within 3 months postoperatively, 92% had a Clavien Dindo score ≤ 2. By multivariate analysis, anticoagulation was not statistically significant, the only significant risk factor for complications was ASA score ≥ 3 (Odds ratio (OR) 2.2; 95% confidence interval (CI) [1.2-4.1]). Secondary endpoint analysis for hematuria found ASA score of 3 or higher and anticoagulant treatment statistically significant in univariate and multivariate analysis, with OR of 2.9 (95% CI [1.1-7.4]) and OR of 3.5 (95% CI [1.7-7.5]), respectively. Green light laser photovaporization of the prostate demonstrates significant safety, even in frail patients on anticoagulant therapy.

Effect of integrated medicines management on quality of discharge medication information-a secondary endpoint in a randomized controlled trial.

High-quality discharge information is important to promote patient safety when patients are transferred from hospital to primary care. Patients with multiple long-term conditions are especially vulnerable to insufficient transfer of medication information, as they use many medications and have complex interactions with the healthcare services. The aim of this study was to investigate the effect of integrated medicines management provided to hospitalized multimorbid patients on the quality of the discharge medication information. Multimorbid patients ≥18 years, using a minimum of four regular medications from a minimum of two therapeutic medication classes were recruited from the Internal Medicine ward, Oslo University Hospital, Norway, from August 2014 to March 2016 and randomly assigned, 1:1, to the intervention or control group. Intervention patients received integrated medicines management throughout the hospital stay. Control patients received standard care. This paper reports the results of a prespecified secondary endpoint analysis of the randomized controlled trial; the difference between the intervention and control group in the quality of discharge medication information. The analysis population comprised 384 patients. Integrated medicines management improved the discharge summary quality score of the medication information from 5.8 ± 1.5 to 8.6 ± 2.6 [mean difference 2.7, 95% confidence interval (CI) 2.3-3.2, P < .001]. In total, 171 intervention patients (89%) received a patient discharge information letter, compared to 66 control patients (35%), P < .001. The quality score of the medication information in the patient discharge information letter was improved from 6.0 ± 1.8 in the control group to 10.0 ± 1.3 in the intervention group (mean difference 4.0, 95% CI 3.6-4.4, P < .001). Integrated medicines management delivered to multimorbid patients during a hospital stay improved the quality of the medication information in discharge summaries as well as patient discharge information letters and ensured that a discharge information letter in lay language was prepared for almost all patients who were involved in the management of their medications after discharge.

Long-term outcomes of cardiogenic shock survivors: a contemporary retrospective analysis from a tertiary center

Abstract Background Cardiogenic shock (CS) is a complex syndrome that still portends a dismal short-term prognosis. However, in patients that survive the initial admission and are later discharged, the long-term prognosis remains ill-characterized. Aim We aimed to describe the long-term morbidity and mortality outcomes of patients surviving the index admission for CS. Methods Retrospective analysis of all consecutive patients admitted to a cardiac intensive care unit (CICU) between December 2016 and December 2022 with a diagnosis of CS. All etiologies were included and further categorized as: acute myocardial infarction (AMI-CS), acute-on-chronic heart failure (HF-CS) and secondary causes [(S-CS): myocarditis, arrhythmic storm, acute pulmonary embolism, among others]. Our primary endpoint was defined as all-cause death, conditional to being discharged alive. Secondary endpoints comprised heart transplant, durable left ventricular assist device (LVAD) implantation, implantable cardioverter-defibrillator (ICD) insertion and hospital readmission during follow-up. Results A total of 208 patients were included [median age 68 years (IQR 57-80), 66% males, mean Charlson comorbidity index 4±3], of whom 52% (n=108) had AMI-CS, 27% (n=56) HF-CS and 21% (n=44) S-CS. During the index admission, mean SAPS II score was 49±18 and most patients were in SCAI-C (66%, n=137) stage. Organ support in the form of invasive mechanical ventilation, renal replacement therapy or temporary mechanical circulatory assist devices was necessary in 62% (n=129), 27% (n=56) and 26% (n=55) of patients, respectively. 53% of patients (n=110) survived the index admission [median CICU length of stay 8 (IQR 3-15) days; median hospital length of stay 13 (IQR 4-25) days]. At discharge, mean left ventricular ejection fraction was 38±16% and 28% (n=26) of patients underwent ICD implantation. Median follow-up after discharge was 679 (IQR 373-1056) days, with 4 (4%) patients lost to follow-up. Overall mortality was 22% (n=24) and was numerically higher for AMI-CS when compared to HF-CS and S-CS (9% vs 7% vs 6% respectively, p=0.640). Secondary endpoint analysis showed that 10% (n=11) had a heart transplant, 2% (n=2) received a durable LVAD, 9% (n=10) received an ICD and 26% (n=28) were re-hospitalized during that period. Conclusions Although the long-term mortality of patients discharged alive after the index admission for CS is not overwhelming, one in every four will be readmitted and a small proportion will be eligible for advanced heart failure therapies. Healthcare strategies to improve the morbidity and mortality of many CS survivors should be devised.

Alternative Complement Pathway Inhibition with Iptacopan in IgA Nephropathy.

The alternative complement pathway plays a key role in the pathogenesis of IgA nephropathy. Iptacopan specifically binds to factor B and inhibits the alternative pathway. In this phase 3, double-blind, randomized, placebo-controlled trial, we enrolled adults with biopsy-confirmed IgA nephropathy and proteinuria (defined as a 24-hour urinary protein-to-creatinine ratio of ≥1 [with protein and creatinine both measured in grams]) despite optimized supportive therapy. Patients were randomly assigned, in a 1:1 ratio, to receive oral iptacopan (200 mg) or placebo twice daily for 24 months while continuing to receive supportive therapy. The primary objective of this prespecified interim analysis was to assess the efficacy of iptacopan as compared with that of placebo in reducing proteinuria at month 9; the primary end point was the change from baseline in the 24-hour urinary protein-to-creatinine ratio at month 9. The proportion of patients who had a 24-hour urinary protein-to-creatinine ratio of less than 1 at month 9 without receiving rescue or alternative medication or undergoing kidney-replacement therapy (dialysis or transplantation) was a secondary end point. Safety was also assessed. The effect of iptacopan on kidney function will be assessed at the end of the 2-year double-blind treatment period. The main trial population included 222 patients in the iptacopan group and 221 in the placebo group. The interim efficacy analysis included the first 250 patients who underwent randomization in the main trial population (125 patients in each group) and who remained in the trial until month 9 or discontinued the trial by month 9. Safety was assessed in all the patients in the main trial population. At month 9, the adjusted geometric mean 24-hour urinary protein-to-creatinine ratio was 38.3% (95% confidence interval, 26.0 to 48.6; two-sided P<0.001) lower with iptacopan than with placebo. The reduction in proteinuria was supported by consistent results in secondary end point analyses. There were no unexpected safety findings with iptacopan. The incidence of adverse events that occurred during the treatment period was similar in the two groups; most events were mild to moderate in severity and reversible. No increased risk of infection was observed. Among patients with IgA nephropathy, treatment with iptacopan resulted in a significant and clinically meaningful reduction in proteinuria as compared with placebo. (Funded by Novartis; APPLAUSE-IgAN ClinicalTrials.gov number, NCT04578834.).

Pancreatic Enzyme Replacement Leads to Increased Vitamin D Uptake in Patients Undergoing Sleeve-gastrectomy — A Prospective, Monocentric Trial

PurposeMetabolic and bariatric surgery (MBS) is often considered to be associated with macro- and micronutrient deficiency. A possible treatment option can be the implementation of pancreatic enzyme replacement (PERT) and may lead to better outcomes. We designed a prospective trial investigating the possible impact of PERT in patients undergoing MBS at a high-volume center.Materials and MethodsA prospective two-arm randomized controlled trial was conducted on patients who underwent either sleeve gastrectomy or gastric bypass procedures at a high-volume center. Patients underwent bariatric surgery and follow-up examinations at 3, 6, and 12 months after surgery. Patients were stratified either to the treatment group with PERT or to the control group. The primary endpoint of the study was a change in BMI. Lab testing was carried out to measure secondary endpoints, including albumin and vitamin D levels.ResultsOverall, 204 patients were enrolled. Due to missing follow-ups, surgical complications, and side effects due to Kreon medication, 65 were excluded. Analysis of primary endpoints indicates that PERT does not lead to slower weight loss or BMI reduction. Analysis of secondary endpoints showed significantly better vitamin D levels in patients undergoing MBS and PERT. No statistical difference was seen regarding albumin. In both arms, fatty liver disease improved. Quality of life is positively judged as comparable by patients in both groups.ConclusionHerein, we show an association between PERT and higher vitamin D levels in patients undergoing MBS. An optimized enzymatic environment due to PERT may therefore result in higher vitamin D levels and may improve clinical outcomes in patients undergoing MBS.Graphical

Liberal versus restrictive transfusion strategies in acute myocardial infarction: a systematic review and comparative frequentist and Bayesian meta-analysis of randomized controlled trials

BackgroundThe transfusion strategy in the acute phase of myocardial infarction (AMI) remains a debated topic with non-standardized guidelines. This study aimed to evaluate the impact of liberal versus restrictive transfusion strategies on mortality during AMI.MethodsA systematic search was conducted across MEDLINE, EMBASE, and the COCHRANE library databases, focusing on randomized controlled trials (RCTs). The primary endpoint was the latest measured mortality within 90 days following myocardial infarction (MI). Secondary endpoints included recurrence of MI, cardiovascular mortality, stroke occurrence, unplanned revascularization, and a composite endpoint of death or recurrent MI. Mixed and random-effects models were employed to estimate relative risks. Sensitivity analyses were conducted using two approaches: one incorporating only studies assessed as low risk of bias according to the Rob2 tool, and another employing a Bayesian analysis.ResultsFour RCTs including a total of 4324 participants were analyzed. Neither the fixed-effect nor random-effects models demonstrated a significant reduction in mortality, with risk ratios (RR) of 1.16 (95% CI 0.95–1.40) for the fixed-effect model and 1.13 (95% CI 0.67–1.91) for the random-effects model (GRADE: low certainty of evidence). Sensitivity analyses, including the exclusion of two high-risk-of-bias studies and a Bayesian analysis, were consistent with the primary analysis. For the composite outcome death or MI both fixed-effect and random-effects models showed a statistically significant RR of 1.18 (95% CI 1.01–1.37) with negligible heterogeneity (I2 = 0%, p = 0.46), indicating results unfavorable to restrictive transfusion (GRADE: very low certainty of evidence). However, this result was primarily driven by a single study. For cardiac mortality, the fixed-effects model indicated a significant RR of 1.42 (95% CI 1.07–1.88), whereas the random-effects model showed non-significant RR of 1.05 (95% CI 0.36–3.80). Analyses of other secondary endpoints did not show statistically significant results.ConclusionsOur analysis did not demonstrate a significant benefit in early mortality with a liberal transfusion strategy compared to a restrictive strategy for AMI, low certainty of evidence. Liberal transfusion may reduce the risk of the composite outcome death or MI, with very low certainty of evidence. These findings should be interpreted with caution in critically ill patients.

Closed-Loop Insulin Therapy for People With Type 2 Diabetes Treated With an Insulin Pump: A 12-Week Multicenter, Open-Label Randomized, Controlled, Crossover Trial.

Continuous glucose monitoring (CGM) combined with continuous subcutaneous insulin infusion (CSII) achieves better glycemic control than multi-injection therapy in people with type 2 diabetes. The effectiveness of closed-loop therapy needs to be further evaluated in this population. The study objective was to measure the impact of a hybrid closed-loop device (DBLG1) compared with CSII + CGM on glycemic control in people with type 2 diabetes previously treated with CSII. The randomized, controlled, crossover, two-period, open-label, and multicenter study was conducted from August 2022 to July 2023 in 17 individuals (9 to receive 6 weeks of CSII + CGM first and 8 to receive 6 weeks of closed-loop therapy first). The primary end point was the percentage time in range (TIR: 70-180 mg/dL). Secondary outcomes were other CGM-glucose metrics, physical activity, and sleep objectively measured using 1-week actimetry. Data were analyzed using a modified intention-to-treat approach. Mean age was 63 (SD 9) years and 35% were women. Mean HbA1c at inclusion was 7.9% (SD 0.9). TIR increased to 76.0% (interquartile range 69.0-84.0) during the closed-loop condition vs. 61.0% (interquartile range 55.0-70.0) during the CSII + CGM condition; mean difference was 15.0 percentage points (interquartile range 8.0-22.0; P < 0.001). Analyses of secondary end points showed a decrease in time above range, in glucose management indicator, in glucose variability, and an increase in daily insulin dose. Actimetric sleep analysis showed an improvement in sleep fragmentation during closed-loop treatment. Closed-loop therapy improved glycemic control more than did CSII + CGM in people with type 2 diabetes.

Efficacy of early administration of sacubitril/valsartan after coronary artery revascularization in patients with acute myocardial infarction complicated by moderate-to-severe mitral regurgitation: a randomized controlled trial.

Effects of angiotensin receptor/neprilysin inhibitors (ARNI) on ventricular remodeling in patients with heart failure, especially heart failure with reduced ejection fraction (HFrEF), are better than those of angiotensin-converting enzyme inhibitors (ACEI). Acute myocardial infarction (AMI) complicated by mitral regurgitation exacerbates ventricular remodeling and increases the risk of heart failure. There is limited evidence on the effects of early administration of ARNI in patients with AMI complicated by mitral regurgitation. The aim of this trial was to examine the effectiveness and the safety of early administration of sacubitril/valsartan after coronary artery revascularization in patients with AMI complicated by moderate-to-severe mitral regurgitation. This was a randomized, single-blind, parallel-group, controlled trial. From June 2021 to June 2022, we enrolled 142 consecutive patients with AMI complicated by moderate-to-severe mitral regurgitation and followed them for 12months. The patients received standard treatment for AMI and were randomly assigned to receive ARNI or benazepril. The primary efficacy end points were the differences in mitral regurgitant jet area (MRJA), mitral regurgitant volume (MRV), concentration of n-terminal pro-brain natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), and left ventricular end-diastolic volume and end-systolic volume (LVEDV and LVESV) between groups and within groups at baseline, 1, 3, 6, and 12months. Secondary end points included the rates of heart failure hospitalization, all-cause mortality, refractory angina, malignant arrhythmias, recurrent myocardial infarction, and stroke. Safety end points included the rates of hyperkalemia, renal dysfunction, hypotension, angioedema, and cough. The ARNI group had significantly lower NT-proBNP levels than the benazepril group at 1month and later (P < 0.001). MRJA and MRV significantly improved in the ARNI group compared with the benazepril group at 12months (MRJA: - 3.21 ± 2.18 cm2 vs. - 1.83 ± 2.81 cm2, P < 0.05; MRV: - 27.22 ± 15.22mL vs. - 13.67 ± 21.02mL, P < 0.001). The ARNI group also showed significant reductions in LVEDV and LVESV (P < 0.05) and improvement in LVEF (P < 0.05). Secondary end point analysis showed a significantly higher rate of heart failure hospitalization in the benazepril group compared with the ARNI group (HR = 2.03, 95% CI 1.12-3.68, P = 0.021). Safety end point analysis showed a higher rate of hypotension in the ARNI group (P < 0.05). Early use of sacubitril/valsartan after coronary artery revascularization in patients with AMI complicated by moderate-to-severe mitral regurgitation can significantly reduce mitral regurgitation, improve ventricular remodeling, and decrease heart failure hospitalization. Nevertheless, caution is needed to avoid hypotension. Chinese Clinical Trial Registry (ChiCTR2100054255) registered on December 11, 2021.

A Randomized, Placebo-Controlled Trial to Evaluate the Safety and Efficacy of VIR-2482 in Healthy Adults for Prevention of Influenza A Illness (PENINSULA).

Influenza A results in significant morbidity and mortality. VIR-2482, an engineered human monoclonal antibody with extended half-life, targets a highly conserved epitope on the stem region of influenza A hemagglutinin and may protect against seasonal and pandemic influenza. This double-blind, randomized, placebo-controlled, phase 2 study examined the safety and efficacy of VIR-2482 for seasonal influenza A illness prevention in unvaccinated healthy adults. Participants (N = 2977) were randomized 1:1:1 to receive VIR-2482 450 mg, VIR-2482 1200 mg, or placebo via intramuscular injection. Primary and secondary efficacy endpoints were the proportions of participants with reverse transcriptase-polymerase chain reaction-confirmed influenza A infection and either protocol-defined influenza-like illness (ILI) and Centers for Disease Control and Prevention-defined ILI or World Health Organization-defined ILI, respectively. VIR-2482 450 mg and 1200 mg prophylaxis did not reduce the risk of protocol-defined ILI with reverse transcriptase-polymerase chain reaction-confirmed influenza A versus placebo (relative risk reduction, 3.8% [95% confidence interval (CI), -67.3 to 44.6] and 15.9% [95% CI, -49.3 to 52.3], respectively). At the 1200-mg dose, the relative risk reductions in influenza A illness were 57.2% (95% CI: -2.5 to 82.2) using Centers for Disease Control and Prevention ILI and 44.1% (95% CI: -50.5 to 79.3) using World Health Organization ILI definitions, respectively. Serum VIR-2482 levels were similar regardless of influenza status; variants with reduced VIR-2482 susceptibility were not detected. Local injection site reactions were mild and similar across groups. VIR-2482 1200 mg intramuscular was well tolerated but did not significantly prevent protocol-defined ILI. Secondary endpoint analyses suggest this dose may have reduced influenza A illness. Trial registration: ClinicalTrials.gov identifier, NCT05567783.

The effect of exercise and educational programs for breast cancer patients on the development of breast cancer-related lymphoedema: secondary endpoint from a randomized controlled trial in the Setouchi Breast Project-10.

Although the association between higher physical activity and preventive effect on breast-cancer-related lymphoedema (BCRL) has been reported, it is unclear what intervention is optimal. We aimed to investigate the effect of exercise and educational programs on BCRL development. This study was a secondary endpoint analysis from a prospective randomized controlled trial. We enrolled patients with stage 0-III breast cancer from March 2016 to March 2020 and randomly assigned them to the control (n = 111), education (n = 115), or exercise (n = 104) group. As secondary endpoint, we assessed the incidence of and preventive effect on BCRL at 12months post-intervention. There were no significant differences in the incidence of BCRL at 12months post-intervention between the exercise and control groups (9.8% and 10.8%, P = 0.83) and the education and control groups (11.6% and 10.8%, P = 1.00). There were no significant differences in time to BCRL onset from the day of surgery between the exercise and control groups (event rate at 12months: 20.7% and 17.2%, log-rank, P = 0.54) and the education and control groups (18.8% and 17.2%, log-rank, P = 0.57). The multivariable analyses indicated that axillary dissection and obesity significantly increased the risk of BCRL [hazard ratio (HR): 2.36, 95% confidence interval (CI) 1.52-3.67 and HR: 1.68, 95% CI 1.07-2.63, respectively]. The intervention did not decrease the risk of BCRL, and axillary dissection and obesity were the risk factors of BCRL. UMIN000020595 at UMIN Clinical Trial Registry.

Lomitapide in Pediatric Patients with Homozygous Familial Hypercholesterolemia – Analysis of Secondary and Safety Endpoints from the APH-19 Study

Lomitapide in Pediatric Patients with Homozygous Familial Hypercholesterolemia – Analysis of Secondary and Safety Endpoints from the APH-19 Study

Prevalence of Acute on Chronic Liver Failure in Autoimmune Hepatitis, Treatment Response and Mortality Burden Assessment: A Region-Predominant Systematic Review and Meta-Analysis.

Acute-on-chronic liver failure (ACLF) is a global health problem. Little scientific evidence exists on its prevalence in autoimmune hepatitis. Treatment response and mortality outcomes have also been reported differently. The study was conducted to estimate the overall prevalence of ACLF among patients with autoimmune hepatitis (AIH) and determine the associated treatment response and mortality. We scrutinized wide literature in Scopus, PubMed, Embase, Web of Science, and Cochrane, and assessed published articles completely, studies performed and reported from around the globe, until December 07, 2023, according to the PROSPERO registered protocol (CRD42023412176). Studies (retrospective and prospective cohort study type) that stated the ACLF development among established AIH cases were considered. Features of the study, duration of follow-up, and numeric patient information were retrieved from the studies included. The research paper quality was checked for risk of bias. Random effect meta-analysis with metaregression and subsection scrutinies were performed with R. The main outcome was the collective prevalence of ACLF in the AIH patients, whereas treatment response and mortality in AIH-associated ACLF were secondary outcomes. Six studies were involved with confirmed diagnoses in 985 AIH patients for the data synthesis. The pooled prevalence of ACLF in the explored patients was 12% (95% CI: 8-17) ( P =0.01). Heterogeneity was found to be high in the present meta-analysis ( I2 =72%; P < 0.01). For the secondary endpoint analysis, the pooled prevalence of complete remission at 1-year follow-up was 71% (0.52; 0.85), and mortality from the ACLF-AIH patient population was 32% (95% CI: 18-50). Sensitivity analysis showed no influence on the overall estimations of the pooled prevalence of ACLF by omitting studies one by one. One in 10 AIH patients likely present with ACLF. The response to treatment is seen in two-thirds of patients, and mortality is high.

Establishing Optimal Control Cohorts for Phase 1 Trials: Retrospective Analysis of Clinical and Biological Outcomes in Neonates and Infants Undergoing Two-Ventricle Repair.

Phase 1 trials are primarily conducted to evaluate the safety and feasibility of new interventions, usually without recruiting control patients. This retrospective study aims to characterize clinical and biological outcomes in historical and contemporary cases of neonates and infants undergoing two-ventricle repair to facilitate future secondary endpoint analyses for such trials. This retrospective study included neonates/infants (ages ≤ 6months) who underwent two-ventricle repair between 2015 and 2021 using the same criteria as our phase 1 trial (n = 199). Patients were allocated into the ventricular septal defect (n = 61), the Tetralogy of Fallot (TOF, n = 88), and the transposition of the great arteries (n = 50) groups with an additional comparison between two eras (2015-2019 vs. 2020-2021). Patient characteristics and most variables assessed were different between the three diagnostic groups indicating the importance of diagnostic matching for secondary analyses. Although the era did not alter cerebral/somatic oxygenation, ventricular function, neuroimaging findings, and complication rates, we observed improvement of inotropic and/or vasoactive-inotropic scores in all groups during the more recent era. In 2020-2021, the age and the body weight at the operation were higher, and hospital stay was shorter in the TOF group, suggesting the possible impact of the pandemic. Results also indicated that matching altered characteristics such as age at operation that may limit the temporal effects and optimize secondary analyses. Using optimal contemporary cases and historical data based on this study will assist in developing a comprehensive study design for a future efficacy/effectiveness trial.