Between-treatment Differences Research Articles

Effects of a 30-min rest with a nap chair on task performance, sleepiness, and neurophysiological measures in men with suspected brain fatigue: a randomized controlled crossover trial

BackgroundIt has been suggested that a short nap in the afternoon may improve sleepiness, alertness, and task performance. The present study evaluated the effects of a 30-min rest with a new nap chair on task performance, sleepiness, and neurophysiological measures.MethodsA randomized controlled crossover trial with a 1-week interval was carried out at the BOOCS Clinic Fukuoka in Japan. The subjects were male workers aged 20 to 64 years with suspected brain fatigue, which was defined by the Profile of Mood Status 2. The intervention was a 30-min rest with an office chair or a nap chair. The primary outcome was the performance in the Uchida-Kraepelin test. The secondary outcomes included the Karolinska Sleepiness Scale and 15-min heart rate variability (HRV). The changes after the nap-chair rest and office-chair rest were compared. Repeated measures analysis of variance with nesting was used in the statistical analysis.ResultsTwenty participants were eligible and entered the crossover trial. The overall 15-min score in the Uchida-Kraepelin test improved after the nap-chair rest and after the office-chair rest to almost the same extent (5.9 vs. 5.5 points, P = 0.68). The Karolinska Sleepiness score significantly decreased after the nap-chair rest, and the between-treatment difference in the decrease was highly significant (P = 0.0004). The average duration of sleep during rest was prominently longer in the nap-chair rest than in the office-chair rest (19.0 vs. 7.6 min, P = 0.002). No participants experienced REM sleep during the rest. LF and HF powers of the HRV were greater during the nap-chair rest than during the office-chair rest, the difference in the HF power being substantial.ConclusionA 30-min rest with the nap chair did not appreciably improve the performance in the Uchida-Kraepelin test as compared with the office-chair rest. The nap-chair rest induced a substantially longer sleep accompanied with a parasympathetic activation, thereby resulting in a material improvement in sleepiness after the rest.

Postprandial plasma aminoacidemia and indices of appetite regulation following pea-rice blend, pea isolate and whey protein ingestion in healthy young adults.

Plant-derived proteins are often deficient in essential amino acids and have lower rates of digestibility than animal-derived proteins. Blending different plant-derived proteins could compensate for these deficiencies and may augment postprandial aminoacidemia over single-source plant proteins. This study assessed plasma amino acids and appetite hormones, appetite sensations and ad libitum energy intake following ingestion of a pea-rice protein blend (BLEND), compared with pea-only (PEA) and whey (WHEY) protein. In a randomised, double-blind, crossover design, ten healthy adults (M n 4, F n 6; mean (sd) age 22 (sd 3) years; BMI 24 (sd 3) kg·m2) ingested 0·3 g·kg·body mass-1 of BLEND, PEA or WHEY. Arterialised venous blood samples and appetite ratings were obtained in the fasted state and over 240 min postprandially. Energy intake was measured via an ad libitum buffet-style test meal. Mean plasma essential amino acid incremental AUC was higher in WHEY, compared with PEA (P < 0·01; mean diff (95 % CI): 44218 (15806, 72631) μmol·240 min·l-1) and BLEND (P < 0·01; 14358 (16031, 101121) μmol·240 min·l-1), with no differences between PEA and BLEND (P = 0·67). Plasma ghrelin and glucagon-like peptide-1, appetite ratings and ad libitum energy intake responses did not differ between treatments (P > 0·05 for all). Ingestion of a pea-rice protein blend did not augment postprandial aminoacidemia above pea protein, perhaps attributable to marginal differences in essential amino acid composition. No between-treatment differences in appetite or energy intake responses were apparent, suggesting that the influence of protein ingestion on perceived appetite ratings and orexigenic hormonal responses may not be solely determined by postprandial plasma aminoacidemia.

Patient-reported outcomes in the subpopulation of patients with mismatch repair-deficient/microsatellite instability-high primary advanced or recurrent endometrial cancer treated with dostarlimab plus chemotherapy compared with chemotherapy alone in the ENGOT-EN6-NSGO/GOG3031/RUBY trial

ObjectiveIn the ENGOT-EN6-NSGO/GOG3031/RUBY trial, dostarlimab+carboplatin–paclitaxel demonstrated significant improvement in progression free survival and a positive trend in overall survival compared with placebo+carboplatin–paclitaxel, with manageable toxicity, in patients with primary advanced...

P148 EFFICACY AND SAFETY OF SACUBITRIL/ALLISARTAN FOR THE TREATMENT OF PRIMARY HYPERTENSION: A PHASE 3 RANDOMIZED, DOUBLE-BLIND STUDY

Background: This randomized, double-blind, phase 3 study assessed the efficacy and safety of sacubitril/allisartan, an angiotensin receptor neprilysin inhibitor, compared with olmesartan in Chinese patients with mild to moderate hypertension. Methods: Eligible patients aged 18-75 years (n=1197) with mild to moderate hypertension were randomized to receive sacubitril/allisartan 240 mg (n=399), sacubitril/allisartan 480 mg (n=399), or olmesartan 20 mg (n=399) once daily for 12 weeks. Patients who completed the 12-week treatment then received another 12-week extended treatment (n=1084) and 28-week prolonged treatment (n=189). The primary end point was a reduction in clinic mean sitting systolic blood pressure (msSBP) from baseline with various doses of sacubitril/allisartan versus olmesartan at 12 weeks. Secondary efficacy variables included clinic and 24-h ambulatory blood pressure for the comparison between sacubitril/allisartan and olmesartan at week 12, 24, and 52. Results: Sacubitril/allisartan 240 mg/day provided a greater reduction in msSBP than olmesartan at 12 weeks (between-group difference: -1.9 mmHg [95% confidence interval -4.2 to 0.4 mmHg], P=0.0007, for non-inferiority). Sacubitril/allisartan 480 mg/day provided a significantly greater reduction in msSBP than olmesartan at 12 weeks (between-treatment difference: -5.0 mmHg [95% confidence interval -7.3 to -2.8 mmHg], P&lt;0.001, for superiority). Greater reductions in 24-h, daytime and nighttime systolic and diastolic blood pressure were also observed with both doses of sacubitril/allisartan compared with olmesartan (P≤0.001 for 480 mg/day). The blood pressure reductions tended to be dose-dependent for sacubitril/allisartan. Sacubitril/allisartan was well tolerated, and no cases of angioedema or death were reported. Conclusions: Sacubitril/allisartan is effective for the treatment of hypertension and well tolerated in Chinese patients.

Zibotentan in Microvascular Angina: A Randomized, Placebo-Controlled, Crossover Trial.

Background: Microvascular angina is associated with dysregulation of the endothelin system and impairments in myocardial blood flow, exercise capacity, and health-related quality of life. The G allele of the noncoding single nucleotide polymorphism RS9349379 enhances expression of the endothelin-1 gene (EDN1) in human vascular cells, potentially increasing circulating concentrations of Endothelin-1 (ET-1). Whether zibotentan, an oral ET-A receptor selective antagonist, is efficacious and safe for the treatment of microvascular angina is unknown. Methods: Patients with microvascular angina were enrolled in this double-blind, placebo-controlled, sequential crossover trial of zibotentan (10 mg daily for 12 weeks). The trial population was enriched to ensure a G allele frequency of 50% for the RS9349379 single nucleotide polymorphism. Participants and investigators were blinded to genotype. The primary outcome was treadmill exercise duration (seconds) using the Bruce protocol. The primary analysis estimated the mean within-participant difference in exercise duration after treatment with zibotentan versus placebo. Results: A total of 118 participants (mean ±SD; years of age 63.5 [9.2 ]; 71 [60.2% ] females; 25 [21.2% ] with diabetes) were randomized. Among 103 participants with complete data, the mean exercise duration with zibotentan treatment compared with placebo was not different (between-treatment difference, -4.26 seconds [95 ] CI, -19.60 to 11.06] P=0.5871). Secondary outcomes showed no improvement with zibotentan. Zibotentan reduced blood pressure and increased plasma concentrations of ET-1. Adverse events were more common with zibotentan (60.2%) compared with placebo (14.4%; P<0.001). Conclusions: Among patients with microvascular angina, short-term treatment with a relatively high dose (10 mg daily) of zibotentan was not beneficial. Target-related adverse effects were common.

P147 EFFICACY AND SAFETY OF SACUBITRIL/VALSARTAN VERSUS AMLODIPINE IN JAPANESE PATIENTS WITH ESSENTIAL HYPERTENSION: A RANDOMIZED, OPEN-LABEL, MULTICENTER STUDY (PARASOL STUDY)

Background and Objective: Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, is shown to be superior to renin-angiotensin system inhibitors in terms of blood pressure (BP) lowering effect in several clinical trials. However, there is limited evidence on the BP-lowering effect of sacubitril/valsartan in comparison with amlodipine, a widely used calcium channel blocker (CCB), and potent BP-lowering effect. This study is to investigate the efficacy and safety of sacubitril/valsartan monotherapy compared with amlodipine monotherapy in Japanese patients with essential hypertension. (jRCTs051220165) Methods: This was a multicenter, randomized, open-label, parallel-group, and active-controlled study conducted in Japan. Male or female Japanese patients aged 18 to 79 with either treated or untreated mild to moderate essential hypertension were eligible for this study and randomly assigned to the sacubitril/valsartan 200 mg group or amlodipine 5 mg group. Each study drugs were administered once daily for eight weeks. The primary endpoint was to demonstrate the non-inferiority of sacubitril/valsartan versus amlodipine in mean change from baseline for 24-h systolic blood pressure (SBP) after eight weeks of treatment. Results: A total of 359 patients were randomized in this study (sacubitril/valsartan group n=182, amlodipine group n=177; mean age was 58.3 and 58.1 years, 75.3% and 74.0% were male, baseline BPs were described in Table). At week 8, mean reductions from baseline for mean 24-h SBP in sacubitril/valsartan were non-inferior to that in amlodipine (between-treatment difference: −0.6 mmHg [95% CI: −3.2 to 2.0; P=0.003 for non-inferiority, independent t-test]). In addition, other BP parameters in sacubitril/valsartan were comparable to those in amlodipine (Table). For the investigator-reported adverse events, seven hypotension-related events (3.8%) were observed in sacubitril/valsartan and three events (1.7%) in amlodipine. Conclusions: In Japanese patients with essential hypertension, the BP-lowering effect of sacubitril/valsartan was non-inferior to that of amlodipine, and no marked differences in tolerability were observed. Early initiation of sacubitril/valsartan in hypertensive patients is expected to achieve good BP control, similar to the widely used CCB.

Efficacy and Safety of Sacubitril/Allisartan for the Treatment of Primary Hypertension

BackgroundThe prevalence of hypertension still increases with the very rapidly increasing longevity in some countries, such as China. The control rate remains low. ObjectivesThis randomized, double-blind, phase 3 study assessed the efficacy and safety of sacubitril/allisartan, compared with olmesartan in Chinese patients with mild-to-moderate hypertension. MethodsEligible patients aged 18 to 75 years (n = 1,197) with mild-to-moderate hypertension were randomized to receive sacubitril/allisartan 240 mg (n = 399), sacubitril/allisartan 480 mg (n = 399), or olmesartan 20 mg (n = 399) once daily for 12 weeks. Patients who completed the 12-week treatment then received another 12-week extended treatment (n = 1,084) and 28-week prolonged treatment (n = 189). The primary end point was a reduction in clinic mean sitting systolic blood pressure (msSBP) from baseline at 12 weeks. ResultsSacubitril/allisartan 240 mg/d provided a greater reduction in msSBP than olmesartan at 12 weeks (between-group difference: −1.9 mm Hg [95% CI: −4.2 to 0.4 mm Hg]; P = 0.0007, for noninferiority). Sacubitril/allisartan 480 mg/d provided a significantly greater reduction in msSBP than olmesartan at 12 weeks (between-treatment difference: −5.0 mm Hg [95% CI: −7.3 to −2.8 mm Hg]; P < 0.001, for superiority). Greater reductions in 24-hour, and daytime and nighttime systolic and diastolic blood pressure were also observed with both doses of sacubitril/allisartan compared with olmesartan (P ≤ 0.001 for 480 mg/d). The blood pressure reductions tended to be dose-dependent for sacubitril/allisartan. Sacubitril/allisartan was well tolerated, and no cases of angioedema or death were reported. ConclusionsSacubitril/allisartan is effective for the treatment of hypertension and well tolerated in Chinese patients.

Efficacy and safety of hypertonic saline therapy in ambulatory patients with heart failure: The SALT-HF trial.

Combination of hypertonic saline solution (HSS) with intravenous loop diuretics has been suggested to improve diuretic response in patients hospitalized for heart failure (HF). The efficacy and safety of this approach in the ambulatory setting remain unexplored. In this multicentre, double-blind, randomized study, we allocated ambulatory patients with worsening heart failure (WHF) to a 1-h infusion of intravenous furosemide (ivFurosemide)-HSS versus ivFurosemide. The primary endpoint was the volume of diuresis at 3 h. Secondary endpoints included 3-h natriuresis and weight variation, 7-day congestion data, kidney function and electrolytes, and 30-day clinical events. Overall, 167 participants (median age: 81 years, 30.5% female) were randomized across 13 sites between December 2020 and March 2023. There were no differences in 3-h diuresis between treatments (ivFurosemide-HSS: 1099 ml vs. ivFurosemide: 1103 ml, p = 0.963), 3-h natriuresis (∆ +2.642 mEq/L, p = 0.559), or 3-h weight (∆ +0.012 kg, p = 0.920). Patients in the ivFurosemide-HSS arm experienced significant weight decrease at 7 days (Δ -0.586 kg, p = 0.048). There were no between-treatment differences in clinical congestion score, biomarkers, inferior vena cava diameter, or the presence of lung ultrasound B-lines. At 30 days, 26.5% of the patients in the ivFurosemide-HSS group versus 33.3% in the ivFurosemide group experienced WHF (hazard ratio 0.76, p = 0.330). The incidence of death from any cause or HF hospitalization was 6% of patients in the ivFurosemide-HSS group and 8.3% of patients in the ivFurosemide group (hazard ratio 0.69, p = 0.521). The incidence of worsening kidney function or metabolic derangements was not significantly different in the two arms. A single infusion of ivFurosemide-HSS did not improve 3-h diuresis or congestion parameters in patients with ambulatory WHF. This therapy showed an appropriate safety profile.

Effect of Sacubitril/Valsartan on Cognitive Function in Patients With Heart Failure With Preserved Ejection Fraction: A Prespecified Analysis of PARAGON-HF.

A hypothetical concern has been raised that sacubitril/valsartan might cause cognitive impairment because neprilysin is one of several enzymes degrading amyloid-β peptides in the brain, some of which are neurotoxic and linked to Alzheimer-type dementia. To address this, we examined the effect of sacubitril/valsartan compared with valsartan on cognitive function in patients with heart failure with preserved ejection fraction in a prespecified substudy of PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). In PARAGON-HF, serial assessment of cognitive function was conducted in a subset of patients with the Mini-Mental State Examination (MMSE; score range, 0-30, with lower scores reflecting worse cognitive function). The prespecified primary analysis of this substudy was the change from baseline in MMSE score at 96 weeks. Other post hoc analyses included cognitive decline (fall in MMSE score of ≥3 points), cognitive impairment (MMSE score <24), or the occurrence of dementia-related adverse events. Among 2895 patients included in the MMSE substudy with baseline MMSE score measured, 1453 patients were assigned to sacubitril/valsartan and 1442 to valsartan. Their mean age was 73 years, and the median follow-up was 32 months. The mean±SD MMSE score at randomization was 27.4±3.0 in the sacubitril/valsartan group, with 10% having an MMSE score <24; the corresponding numbers were nearly identical in the valsartan group. The mean change from baseline to 96 weeks in the sacubitril/valsartan group was -0.05 (SE, 0.07); the corresponding change in the valsartan group was -0.04 (0.07). The mean between-treatment difference at week 96 was -0.01 (95% CI, -0.20 to 0.19; P=0.95). Analyses of a ≥3-point decline in MMSE, decrease to a score <24, dementia-related adverse events, and combinations of these showed no difference between sacubitril/valsartan and valsartan. No difference was found in the subgroup of patients tested for apolipoprotein E ε4 allele genotype. Patients with heart failure with preserved ejection fraction in PARAGON-HF had relatively low baseline MMSE scores. Cognitive change, measured by MMSE, did not differ between treatment with sacubitril/valsartan and treatment with valsartan in patients with heart failure with preserved ejection fraction. URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

Efficacy of a synbiotic in the management of adults with Attention-Deficit and Hyperactivity Disorder and/or Borderline Personality Disorder and high levels of irritability: Results from a multicenter, randomized, placebo-controlled, “basket” trial

Irritability worsens prognosis and increases mortality in individuals with Attention-Deficit and Hyperactivity Disorder (ADHD) and/or Borderline Personality Disorder (BPD). However, treatment options are still insufficient. The aim of this randomized, double blind, placebo-controlled study was to investigate the superiority of a synbiotic over placebo in the management of adults with ADHD and/or BPD and high levels of irritability. The study was conducted between February 2019 and October 2020 at three European clinical centers located in Hungary, Spain and Germany. Included were patients aged 18–65 years old diagnosed with ADHD and/or BPD and high levels of irritability (i.e., an Affectivity Reactivity Index (ARI-S) ≥ 5, plus a Clinical Global Impression-Severity Scale (CGI-S) score ≥ 4). Subjects were randomized 1(synbiotic):1(placebo); the agent was administered each day, for 10 consecutive weeks. The primary outcome measure was end-of-treatment response (i.e., a reduction ≥ 30 % in the ARI-S total score compared to baseline, plus a Clinical Global Impression-Improvement (CGI-I) total score of < 3 (very much, or much improved) at week 10). Between-treatment differences in secondary outcomes, as well as safety were also investigated. Of the 231 included participants, 180 (90:90) were randomized and included in the intention-to-treat-analyses. Of these, 117 (65 %) were females, the mean age was 38 years, ADHD was diagnosed in 113 (63 %), BPD in 44 (24 %), both in 23 (13 %). The synbiotic was well tolerated. At week 10, patients allocated to the synbiotic experienced a significantly higher response rate compared to those allocated to placebo (OR: 0.2, 95 % CI:0.1 to 0.7; P = 0.01). These findings suggest that that (add-on) treatment with a synbiotic may be associated with a clinically meaningful improvement in irritability in, at least, a subgroup of adults with ADHD and/or BPD. A superiority of the synbiotic over placebo in the management of emotional dysregulation (−3.6, 95 % CI:-6.8 to −0.3; P = 0.03), emotional symptoms (−0.6, 95 % CI:-1.2 to −0.05; P = 0.03), inattention (−1.8, 95 % CI: −3.2 to −0.4; P = 0.01), functioning (−2.7, 95 % CI: −5.2 to −0.2; P = 0.03) and perceived stress levels (−0.6, 95 % CI: −1.2 to −0.05; P = 0.03) was also suggested. Higher baseline RANK-L protein levels were associated with a significantly lower response rate, but only in the synbiotic group (OR: 0.1, 95 % CI: −4.3 to – 0.3, P = 0.02). In the placebo group, higher IL-17A levels at baseline were significantly associated with a higher improvement in in particular, emotional dysregulation (P = 0.04), opening a door for new (targeted) drug intervention. However, larger prospective studies are warranted to confirm the findings. Trial RegistrationClinicalTrials.gov Identifier: NCT03495375.

INTerpath-001: Pembrolizumab with V940 (mRNA-4157) versus pembrolizumab with placebo for adjuvant treatment of high-risk stage II-IV melanoma.

TPS9616 Background: The anti−PD-1 antibody pembrolizumab is approved as adjuvant therapy for stage IIB-C and stage III melanoma by AJCC 8th ed, following complete resection. Adjuvant pembrolizumab has improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with high-risk melanoma, but many patients experience disease recurrence. In the randomized phase 2b KEYNOTE-942 study, the individualized neoantigen therapy V940 showed improved RFS and DMFS when used in combination with pembrolizumab versus pembrolizumab monotherapy in patients with stage III or IV melanoma. INTerpath-001 (NCT05933577) is a double-blind phase 3 randomized controlled trial designed to evaluate the efficacy and safety of adjuvant pembrolizumab plus V940 versus pembrolizumab plus placebo in patients with resected high-risk stage II-IV melanoma. Methods: Eligible patients are aged ≥18 years with surgically resected stage IIB or IIC (pathologic or clinical), III, or IV cutaneous melanoma per AJCC 8th ed and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients are ineligible if they have received any prior systemic therapy and if more than 13 weeks has elapsed between last surgical resection and first dose of pembrolizumab. Patients with ocular or mucosal melanoma and past or current in-transit metastases or satellitosis are excluded. All patients must provide a blood sample and a formalin-fixed, paraffin-embedded tumor sample for sequencing. Patients will be stratified by risk (IIB, IIC, IIIA, and IIIB vs IIIC/D and IV) and age (&lt;65 years vs ≥65 years). Approximately 1089 patients will be randomly assigned 2:1 to receive pembrolizumab 400 mg plus V940 1 mg or pembrolizumab 400 mg with placebo. Pembrolizumab will be administered intravenously every 6 weeks and v940 or placebo will be administered intramuscularly every 3 weeks. Treatment will continue for up to 9 doses or until disease recurrence, unacceptable toxicity, or patient withdrawal. The primary end point is RFS by investigator review. Secondary end points are DMFS by investigator review, overall survival, safety and tolerability, and quality of life. Hazard ratios and 95% CIs will be estimated using a stratified Cox regression model with the Efron method of handling ties. Between-treatment differences will be evaluated using a stratified log-rank test. Enrollment is ongoing. Clinical trial information: NCT05933577 .

EFFICACY AND SAFETY OF SACUBITRIL/ALLISARTAN FOR THE TREATMENT OF PRIMARY HYPERTENSION: A PHASE 3 RANDOMIZED, DOUBLE-BLIND STUDY

Objective: This randomized, double-blind, phase 3 study assessed the efficacy and safety of sacubitril/allisartan, an angiotensin receptor neprilysin inhibitor, compared with olmesartan in Chinese patients with mild to moderate hypertension. Design and method: Eligible patients aged 18-75 years (n=1197) with mild to moderate hypertension were randomized to receive sacubitril/allisartan 240 mg (n=399), sacubitril/allisartan 480 mg (n=399), or olmesartan 20 mg (n=399) once daily for 12 weeks. Patients who completed the 12-week treatment then received another 12-week extended treatment (n=1084) and 28-week prolonged treatment (n=189). The primary end point was a reduction in clinic mean sitting systolic blood pressure (msSBP) from baseline with various doses of sacubitril/allisartan versus olmesartan at 12 weeks. Secondary efficacy variables included clinic and 24-h ambulatory blood pressure for the comparison between sacubitril/allisartan and olmesartan at week 12, 24, and 52. Results: Sacubitril/allisartan 240 mg/day provided a greater reduction in msSBP than olmesartan at 12 weeks (between-group difference: -1.9 mmHg [95% confidence interval -4.2 to 0.4 mmHg], P=0.0007, for non-inferiority). Sacubitril/allisartan 480 mg/day provided a significantly greater reduction in msSBP than olmesartan at 12 weeks (between-treatment difference: -5.0 mmHg [95% confidence interval -7.3 to -2.8 mmHg], P&lt;0.001, for superiority). Greater reductions in 24-h, daytime and nighttime systolic and diastolic blood pressure were also observed with both doses of sacubitril/allisartan compared with olmesartan (P&lt;=0.001 for 480 mg/day). The blood pressure reductions tended to be dose-dependent for sacubitril/allisartan. Sacubitril/allisartan was well tolerated, and no cases of angioedema or death were reported. Conclusions: Sacubitril/allisartan is effective for the treatment of hypertension and well tolerated in Chinese patients.

Efficacy and Safety of Sacubitril/Valsartan in Chronic Type B Aortic Dissection Combined With Mild Hypertension.

Optimal antihypertensive medication for chronic type B aortic dissection (AD) remains undecided. This study compared the efficacy and safety of sacubitril/valsartan with valsartan to determine suitable antihypertensive drug combinations. In this single-center, open-label, randomized, controlled trial, patients with chronic Stanford type B AD and mild hypertension were randomized to receive sacubitril/valsartan 100/200 mg or valsartan 80/160 mg. The primary endpoint was the reduction in mean sitting systolic blood pressure (msSBP) at week 8 in patients with sacubitril/valsartan vs. valsartan. Key secondary endpoints included changes in (i) mean sitting diastolic blood pressure (msDBP); (ii) pulse pressure (PP); and (iii) mean ambulatory blood pressure (BP) for 24-hour, daytime, and nighttime. Safety assessments included adverse events (AEs) and serious AEs. This trial was registered with the Chinese Clinical Trial Registry, identifier: ChiCTR2300073399. A total of 315 patients completed the study. Sacubitril/valsartan provided a significantly greater reduction in msSBP than valsartan at week 8 (between-treatment difference: -5.1 mm Hg [95% confidence interval -5.8 to -4.5], P < 0.001). Reductions in msSBP, msDBP, and PP as well as the mean ambulatory BP for 24-hour, daytime, and nighttime, were significantly greater in sacubitril/valsartan compared with valsartan (all P < 0.001). No excessive episodes of AEs occurred in the sacubitril/valsartan group. Sacubitril/valsartan and valsartan reduced BP compared with baseline values. However, sacubitril/valsartan improved BP control to a greater extent than valsartan. It may offer a new treatment option for patients with mild hypertension and chronic type B AD.

Dapagliflozin and Days of Full Health Lost in the DAPA-HF Trial

BackgroundConventional time-to-first-event analyses cannot incorporate recurrent hospitalizations and patient well-being in a single outcome. ObjectivesTo overcome this limitation, we tested an integrated measure that includes days lost from death and hospitalization, and additional days of full health lost through diminished well-being. MethodsThe effect of dapagliflozin on this integrated measure was assessed in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial, which examined the efficacy of dapagliflozin, compared with placebo, in patients with NYHA functional class II to IV heart failure and a left ventricular ejection fraction ≤40%. ResultsOver 360 days, patients in the dapagliflozin group (n = 2,127) lost 10.6 ± 1.0 (2.9%) of potential follow-up days through cardiovascular death and heart failure hospitalization, compared with 14.4 ± 1.0 days (4.0%) in the placebo group (n = 2,108), and this component of all measures of days lost accounted for the greatest between-treatment difference (−3.8 days [95% CI: −6.6 to −1.0 days]). Patients receiving dapagliflozin also had fewer days lost to death and hospitalization from all causes vs placebo (15.5 ± 1.1 days [4.3%] vs 20.3 ± 1.1 days [5.6%]). When additional days of full health lost (ie, adjusted for Kansas City Cardiomyopathy Questionnaire–overall summary score) were added, total days lost were 110.6 ± 1.6 days (30.7%) with dapagliflozin vs 116.9 ± 1.6 days (32.5%) with placebo. The difference in all measures between the 2 groups increased over time (ie, days lost by death and hospitalization −0.9 days [−0.7%] at 120 days, −2.3 days [−1.0%] at 240 days, and −4.8 days [−1.3%] at 360 days). ConclusionsDapagliflozin reduced the total days of potential full health lost due to death, hospitalizations, and impaired well-being, and this benefit increased over time during the first year. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure; NCT03036124)

The Effect of Niacinamide Supplementation on Phosphate Concentrations in Dutch Dialysis Patients: A Randomized Crossover Trial

ObjectiveHyperphosphatemia is a common complication in patients with kidney failure, despite the use of phosphate binders (PBs). Vitamin B3, either in the form of niacin or niacinamide (NAM), shows potential as “add-on” treatment to reduce serum phosphate concentrations in this population. NAM seems to lack many of the side-effects that are observed with niacin. The aim of this study was to investigate whether NAM is an effective and acceptable treatment in reducing serum phosphate concentrations in patients with kidney failure. MethodsDiaNia was a double-blind placebo-controlled randomised crossover trial, comparing NAM (250-500 mg/day) to placebo as “add-on” treatment to an individual treatment with approved PBs for 12 weeks in patients receiving hemodialysis. The primary outcome was serum phosphate concentrations, and the secondary outcomes were platelet counts as well as drop-outs due to side-effects. Data was analysed using both per-protocol (PP) and intention-to-treat (ITT) analyses. ResultsMean age of the PP population (n=26) was 63.6 ± 17.2 years and 53.8% were men. NAM treatment significantly reduced serum phosphate with 0.59 mg/dL (p=0.03). Linear mixed models (LMMs) demonstrated superiority of 12 weeks NAM over 12 weeks placebo with a between-treatment difference of 0.77 mg/dL (95% CI 0.010, 1.43; p=0.03). Similar results, although not significant, were found in the ITT population. We found no between-treatment differences in platelet counts and during the NAM treatment we observed three drop-outs due to side effects (8.6%). ConclusionNAM is effective in reducing serum phosphate concentrations in patients with kidney failure receiving hemodialysis. In addition, NAM is well-tolerated and seems not to increase the risk of thrombocytopenia. Thus, NAM can be valuable as “add-on” treatment to combat hyperphosphatemia in patients with kidney failure. However, more research in larger populations is needed to confirm this.

Ipragliflozin and sitagliptin differentially affect lipid and apolipoprotein profiles in type 2 diabetes: the SUCRE study

BackgroundSGLT2 inhibitors and DPP4 inhibitors have been suggested to affect lipid metabolism. However, there are few randomized controlled trials comparing the effects on the lipid metabolism between the two types of antidiabetic drugs. The SUCRE study (UMIN ID: 000018084) was designed to compare the effects of ipragliflozin and sitagliptin on serum lipid and apolipoprotein profiles and other clinical parameters.MethodsThis is a multicenter, open-label, randomized, controlled trial. Patients with type 2 diabetes (20–74 years old) with HbA1c levels of 7.0-10.5% and serum triglyceride levels of 120–399 mg/dL (1.35–4.50 mmol/L) on diet and/or oral hypoglycemic agents were enrolled. Subjects were randomized to treatment with ipragliflozin (50 mg/day, n = 77) or sitagliptin (50 mg/day, n = 83). Laboratory measurements were performed at 0, 1, 3, and 6 months of treatment.ResultsIpragliflozin and sitagliptin reduced fasting plasma glucose, glycoalbumin, and HbA1c almost equally. Ipragliflozin increased HDL-C and decreased apo E. Sitagliptin decreased TG, apo B48, CII, and CIII, but increased LDL-C. The between-treatment differences were significant for HDL-C (P = 0.02) and apo B48 (P = 0.006), and nearly significant for apo A1 (P = 0.06). In addition, ipragliflozin reduced body weight, blood pressure, serum liver enzymes, uric acid, and leptin, and increased serum ketones compared with sitagliptin.ConclusionsWhile ipragliflozin and sitagliptin showed similar effects on glycemic parameters, the effects on serum lipid and apolipoprotein profiles were different. Ipragliflozin may have an anti-atherogenic effect through modulation of HDL-C and apo E compared to sitagliptin through TG and apo B48, CII, and CIII in patients with type 2 diabetes.

A green tea extract confection decreases circulating endotoxin and fasting glucose by improving gut barrier function but without affecting systemic inflammation: A double-blind, placebo-controlled randomized trial in healthy adults and adults with metabolic syndrome

Anti-inflammatory activities of catechin-rich green tea extract (GTE) in obese rodents protect against metabolic endotoxemia by decreasing intestinal permeability and absorption of gut-derived endotoxin. However, translation to human health has not been established. We hypothesized that GTE would reduce endotoxemia by decreasing gut permeability and intestinal and systemic inflammation in persons with metabolic syndrome (MetS) compared with healthy persons. A randomized, double-blind, placebo-controlled, crossover trial in healthy adults (n = 19, 34 ± 2 years) and adults with MetS (n = 21, 40 ± 3 years) examined 4-week administration of a decaffeinated GTE confection (890 mg/d total catechins) on serum endotoxin, intestinal permeability, gut and systemic inflammation, and cardiometabolic parameters. Compared with the placebo, the GTE confection decreased serum endotoxin (P = .023) in both healthy persons and those with MetS, while increasing concentrations of circulating catechins (P < .0001) and γ-valerolactones (P = .0001). Fecal calprotectin (P = .029) and myeloperoxidase (P = .048) concentrations were decreased by GTE regardless of health status. Following the ingestion of gut permeability probes, urinary lactose/mannitol (P = .043) but not sucralose/erythritol (P > .05) was decreased by GTE regardless of health status. No between-treatment differences (P > .05) were observed for plasma aminotransferases, blood pressure, plasma lipids, or body mass nor were plasma tumor necrosis factor-α, interleukin-6, or the ratio of lipopolysaccharide-binding protein/soluble cluster of differentiation-14 affected. However, fasting glucose in both study groups was decreased (P = .029) by the GTE confection compared with within-treatment arm baseline concentrations. These findings demonstrate that catechin-rich GTE is effective to decrease circulating endotoxin and improve glycemic control in healthy adults and those with MetS, likely by reducing gut inflammation and small intestinal permeability but without affecting systemic inflammation.

A quality-adjusted time without symptoms and toxicity (Q-TWiST) analysis comparing nivolumab plus ipilimumab (N+I) or nivolumab plus chemotherapy (N+CT) versus CT in patients (pts) with advanced esophageal squamous cell carcinoma (ESCC): CheckMate 648.

251 Background: In CheckMate 648, pts with advanced ESCC treated with first-line N+I or N+CT had significantly longer overall survival (OS) vs CT and maintained quality of life (QoL) with no new safety signals. Here we compare between-treatment differences in quality-adjusted survival using a Q-TWiST analysis in all randomized pts (29-month minimum follow-up). Methods: Survival time was partitioned into 3 health states: toxicity (TOX), time without symptoms of disease progression or toxicity (TWiST), and relapse (REL). TOX was defined as time spent with all-cause grade 3/4 adverse events after randomization, prior to disease progression. TWiST was defined as time prior to REL where pts did not experience TOX. REL was defined as time between disease progression and death, or the last known date alive. Mean duration of time in each state was calculated for each treatment group using descriptive statistics and Kaplan-Meier analysis. Utility values from the 3-level EQ-5D (EQ-5D-3L) questionnaire were used to adjust the time spent within each health state for QoL and to calculate Q-TWiST as the utility-weighted sum of the mean health state durations. Bootstrapping (500 samples) was used to estimate time in each health state and to compare mean Q-TWiST estimates between treatments. A between-group difference in Q-TWiST of 5 weeks was prespecified as being clinically important (defined as 10% of OS; based on a median OS in CT group of 10.7 months). Sensitivity analyses were conducted using different combinations of prespecified utility weights for each health state. Results: 970 pts were randomized 1:1:1 to N+I (n = 325), N+CT (n = 321), or CT (n = 324) and included in the Q-TWiST analysis. Median duration of follow-up for survivors was 155 weeks. Mean time in each health state was significantly longer for pts treated with N+I or N+CT compared to CT (Table). Between-group differences in Q-TWiST score were considered clinically important: 5.7 weeks (95% CI 5.5–6.0) favoring N+I vs CT and 7.6 weeks (95% CI 7.4–7.9) favoring N+CT vs CT. Sensitivity analyses supported these findings. Conclusions: In CheckMate 648, pts with unresectable advanced ESCC treated with N+I or N+CT had significantly longer OS compared with those treated with CT. Quality-adjusted survival using Q-TWiST also significantly favored N+I and N+CT compared to CT alone. Pts treated with N+I and N+CT not only experienced increased survival time, but also better QoL during their survival time. Clinical trial information: NCT03143153 . [Table: see text]

Effects of short-term, high-dose cocoa-derived flavanol supplementation on gut microbiota composition: secondary findings from a randomized, double-blind, placebo-controlled crossover study

Abstract Cocoa-derived flavanols (CDF) may act as prebiotics. However, evidence is inconsistent, and the duration and dose of CDF intake needed to elicit any prebiotic effect are undefined. This randomized, double-blind, crossover study determined the effects of short-term, high-dose dietary supplementation with CDF versus matched placebo on gut microbiota composition in 8 healthy adults. A single faecal sample was collected 8 d after supplementation with 900 mg/d CDF or placebo. Gut microbiota composition and Bifidobacterium spp. and Lactobacillus spp. abundance were measured as secondary outcomes by 16S ribosomal ribonucleic acid (rRNA) amplicon sequencing and quantitative polymerase chain reaction, respectively. No between-treatment differences in the relative or absolute abundance of Bifidobacterium spp. (Cohen’s d = 0.89, P = 0.22) or Lactobacillus spp. (Cohen’s d = 0.42, P = 0.65) were detected. Shannon diversity (Cohen’s d = 0.38, P = 0.04) and overall community richness (Cohen’s d = 0.34, P = 0.06) were lower following CDF supplementation versus placebo, but no between-treatment differences in β-diversity or taxa relative abundances were observed. Findings are not consistent with a clear prebiotic effect of this short-term, high-dose CDF supplementation strategy relative to placebo.

Durable Symptom Improvement for Patients with Non-Transfusion Dependent Thalassemia Treated with Luspatercept: Patient-Reported Outcomes from the BEYOND Study

Background: Patients with non-transfusion dependent beta-thalassemia (NTDT) suffer from chronic anemia due to ineffective erythropoiesis. The phase 2, randomized, placebo-controlled BEYOND study demonstrated that luspatercept increased hemoglobin (Hb), reduced transfusion burden, and improved NTDT-related symptoms based on the data with 48 weeks of follow-up (Taher A, et al. Lancet Haematol. 2022;9(10):E733). Objective: The purpose of this analysis was to investigate the long-term effect of luspatercept + best supportive care (BSC) vs placebo + BSC on NTDT-related symptoms through 96 weeks using data collected in the BEYOND study. Methods: 145 patients with NTDT were randomized 2:1 to luspatercept (Q3W) + BSC or placebo + BSC. BSC included red blood cell (RBC) transfusions and iron chelation therapy as deemed necessary by investigators. Patients completed the NTDT Patient Reported Outcome (NTDT-PRO) and Patient Global Impression of Severity (PGI-S) in a daily electronic diary starting 7 days prior to the first dosing day until Week 24, and thereafter over the 7 days prior to dosing at every other dosing visit. The Patient Global Impression of Change (PGI-C) was administered at every other dosing visit, starting with the first dosing day. The NTDT-PRO consists of 6 questions measuring 2 NTDT anemia-related symptom domains: Tiredness/Weakness (T/W) and Shortness of Breath (SoB), each with a score range of 0 (no symptoms) to 10 (extreme symptoms). The PGI-S asks patients to rate the overall severity of their NTDT-related symptoms (range of 0 to 10, with a higher score indicating greater severity), whereas the PGI-C asks patients to rate the overall change in their NTDT-related symptoms since the start of the study (7-level verbal rating scale ranging from “a great deal better” to “a great deal worse”). Least squares (LS) mean changes from baseline at each visit (up to Week 96) in NTDT-PRO T/W and SoB scores, as well as the PGI-S score, were estimated using a mixed model for repeated measures (MMRM). Responses to the PGI-C were descriptively summarized by treatment group. All analyses were performed in the health-related quality of life (HRQoL)-evaluable population, defined as all randomized patients with a valid QoL assessment and at least 1 post-baseline assessment. All p-values reported from the analyses were nominal. Results: The HRQoL-evaluable population consisted of 95 of the 96 patients randomized to the luspatercept arm and all 49 patients randomized to the placebo arm. LS mean changes from baseline in both the NTDT-PRO T/W and SoB scores for the luspatercept arm consistently demonstrated greater improvement (i.e., lower scores) than the placebo arm across visits. Improvement in both T/W and SoB domains were more pronounced starting at Week 24 and sustained through Week 96, with differences in LS mean changes from baseline ranging from -0.89 to -0.21 in the T/W domain and from -0.80 to -0.45 in the SoB domain over this time period (both domains on a 0 to 10 scale). Between-treatment differences were significant (p&amp;lt;0.05) at Week 30 (between-treatment difference in LS mean change from baseline, 95% confidence interval: -0.76, -1.42 to -0.10), Week 36 (-0.89, -1.55 to -0.22), and Week 72 (-0.81, -1.54 to -0.09) in the T/W domain and at Week 30 (-0.71, -1.36 to -0.06), Week 48 (-0.77, -1.43 to -0.10), and Week 72 (-0.80, -1.51 to -0.10) in the SoB domain. LS mean changes from baseline in the severity of overall NTDT-related symptoms, assessed by the PGI-S, showed a marked improvement through Week 96 in the luspatercept arm ( Figure 1), whereas patients receiving placebo tended to worsen over time. The between-treatment difference was statistically significant (p&amp;lt;0.05) across most assessment visits from Weeks 18 to 96. For the PGI-C, most patients treated with luspatercept reported “a little better” or more on their overall NTDT-related symptoms at Weeks 72 (89%) and 96 (87%), whereas most patients receiving placebo reported no change at either Week 72 (61%) or 96 (75%) ( Figure 2). Conclusions: Analysis of the PRO data collected in BEYOND suggests that, in addition to improvements in Hb, patients with NTDT treated with luspatercept experienced durable improvement in NTDT-related symptoms, from a patient perspective, through at least 96 weeks of treatment.