Effect of Multinutrient Supplementation and Food-2 Related Behavioral Activation Therapy on 3 Prevention of Major Depressive Disorder Among 4 Overweight or Obese Adults With Subsyndromal 5 Depressive Symptoms

This is the author accepted manuscript. The final version is available from the American Medical Association via the DOI in this record.Importance: Effects of nutritional interventions on the prevention of major depressive disorder (MDD) in overweight adults are unknown. Objective: To examine the effect of two nutritional strategies (multi-nutrient supplementation, food-related behavioral activation (F-BA) therapy) and their combination for prevention of a new MDD episode in overweight adults with subsyndromal depressive symptoms. Design, setting, participants: This multicenter 2x2 factorial randomized clinical trial included overweight adults (BMI 25-40kg/m2) aged 18-75years with elevated depressive symptoms (Patient Health Questionnaire-9 (PHQ-9) scores≥5) not meeting criteria for MDD episodes in the past 6 months from 4 European countries. 1025 adults were randomized between July-30-2015 and October-12-2016, and followed for 1 year (until October-13-2017). Interventions: Daily multi-nutrient supplements (1412mg omega-3 fatty acids, 30μg selenium, 400μg folic acid, and 20μg D-3 vitamin plus 100mg calcium) versus placebo (blinded), and/or 21 individual and group F-BA sessions versus no F-BA (blinded to researchers), for one year. Participants were allocated to placebo without F-BA (n=257), placebo with F-BA (n=256), supplements without F-BA (n=256), and supplements with F-BA (n=256). Main Outcomes and Measures: Primary outcome was cumulative 1-year onset of MDD measured with the Mini International Neuropsychiatric Interview after 3, 6 and 12 months. Logistic regression using effect-coded variables (-1 indicating control, +1 indicating intervention) evaluated intervention effects both individually and in combination (interaction) on MDD onset. Results: Among 1025 participants (mean age 46.5y; 772 (75%) women; mean BMI 31.4kg/m2), 779 (76%) completed the trial. During 12 month follow-up, 105 (10%) developed MDD (placebo without F-BA: 25 (9.7%), placebo with F-BA: 26 (10.2%), supplements without F-BA: 32 (12.5%), supplements with F-BA: 22 (8.6%).. Neither supplements (odds ratio (OR)=1.06; 95%-confidence interval (CI)=0.87-1.29), F-BA (OR=0.93; 95%CI=0.76-1.13), nor their combination (OR=0.93; 95%CI=0.76-1.14, p for interaction=0.48) affected MDD onset. Number of deaths/hospitalizations were for placebo without F-BA (n=0,n=24), placebo with F-BA (n=0,n=24), supplements without F-BA (n=0,n=26) and supplements with F-BA (n=1,n=24), respectively. Conclusions and Relevance: Among overweight or obese adults with depressive symptoms, multi-nutrient supplementation compared with placebo and food-related behavioral activation therapy compared with no therapy did not reduce episodes of major depressive disorder during 1 year. These findings do not support the use of these interventions for prevention of major depressive disorder. Trial registration: https://www.clinicaltrials.gov/ct2/show/NCT02529423. August-2015.European CommissionNational Institute for Health Research (NIHR

Exercise Capacity in Patients With Obstructive Hypertrophic Cardiomyopathy:SEQUOIA-HCM Baseline Characteristics and Study Design

Patients with obstructive hypertrophic cardiomyopathy (oHCM) have increased risk of arrhythmia, stroke, heart failure, and sudden death. Contemporary management of oHCM has decreased annual hospitalization and mortality rates, yet patients have worsening health-related quality of life due to impaired exercise capacity and persistent residual symptoms. Here we consider the design of clinical trials evaluating potential oHCM therapies in the context of SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). This large, phase 3 trial is now fully enrolled (N = 282). Baseline characteristics reflect an ethnically diverse population with characteristics typical of patients encountered clinically with substantial functional and symptom burden. The study will assess the effect of aficamten vs placebo, in addition to standard-of-care medications, on functional capacity and symptoms over 24 weeks. Future clinical trials could model the approach in SEQUOIA-HCM to evaluate the effect of potential therapies on the burden of oHCM. (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM [SEQUOIA-HCM]; NCT05186818).</p

Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy:Results From SEQUOIA-HCM

BACKGROUND: Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). METHODS AND RESULTS: A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5-20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site-interpreted Valsalva left ventricular outflow tract gradient &lt;30 mm Hg with left ventricular ejection fraction (LVEF) ≥50%. End points were evaluated during titration (day 1 to week 8), maintenance (weeks 8-24), and washout (weeks 24-28), and included major adverse cardiac events, new-onset atrial fibrillation, implantable cardioverter-defibrillator discharges, LVEF &lt;50%, and treatment-emergent adverse events. At week 8, 3.6%, 12.9%, 35%, and 48.6% of patients achieved 5-, 10-, 15-, and 20-mg doses, respectively. Baseline characteristics were similar across groups. Aficamten concentration increased by dose and remained stable during maintenance. During the treatment period, LVEF decreased by -0.9% (95% CI, -1.3 to -0.6) per 100 ng/mL aficamten exposure. Seven (4.9%) patients taking aficamten underwent per-protocol dose reduction for site-interpreted LVEF &lt;50%. There were no treatment interruptions or heart failure worsening for LVEF &lt;50%. No major adverse cardiovascular events were associated with aficamten, and treatment-emergent adverse events were similar between treatment groups, including atrial fibrillation.CONCLUSIONS: A site-based dosing algorithm targeting the lowest effective aficamten dose reduced left ventricular outflow tract gradient with a favorable safety profile throughout SEQUOIA-HCM. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05186818.</p

Aficamten for drug-refractory severe obstructive hypertrophic cardiomyopathy in patients receiving Disopyramide: REDWOOD-HCM Cohort 3

No abstract available

Phase 2 study of aficamten in patients with obstructive hypertrophic cardiomyopathy

Background: Left ventricular outflow tract (LVOT) obstruction is a major determinant of heart failure symptoms in obstructive hypertrophic cardiomyopathy (oHCM). Aficamten, a next-in-class cardiac myosin inhibitor, may lower gradients and improve symptoms in these patients. Objectives: This study aims to evaluate the safety and efficacy of aficamten in patients with oHCM. Methods: Patients with oHCM and LVOT gradients ≥30 mm Hg at rest or ≥50 mm Hg with Valsalva were randomized 2:1 to receive aficamten (n = 28) or placebo (n = 13) in 2 dose-finding cohorts. Doses were titrated based on gradients and ejection fraction (EF). Safety and changes in gradient, EF, New York Heart Association functional class, and cardiac biomarkers were assessed over a 10-week treatment period and after a 2-week washout. Results: From baseline to 10 weeks, aficamten reduced gradients at rest (mean difference: −40 ± 27 mm Hg, and −43 ± 37 mm Hg in Cohorts 1 and 2, P = 0.0003 and P = 0.0004 vs placebo, respectively) and with Valsalva (−36 ± 27 mm Hg and −53 ± 44 mm Hg, P = 0.001 and &lt;0.0001 vs placebo, respectively). There were modest reductions in EF (−6% ± 7.5% and −12% ± 5.9%, P = 0.007 and P &lt; 0.0001 vs placebo, respectively). Symptomatic improvement in ≥1 New York Heart Association functional class was observed in 31% on placebo, and 43% and 64% on aficamten in Cohorts 1 and 2, respectively (nonsignificant). With aficamten, N-terminal pro–B-type natriuretic peptide was reduced (62% relative to placebo, P = 0.0002). There were no treatment interruptions and adverse events were similar between treatment arms. Conclusions: Aficamten resulted in substantial reductions in LVOT gradients with most patients experiencing improvement in biomarkers and symptoms. These results highlight the potential of sarcomere-targeted therapy for treatment of oHCM

Cardiac biomarkers and effects of aficamten in obstructive hypertrophic cardiomyopathy: the SEQUOIA-HCM trial

Background and Aims: The role of biomarker testing in the management of obstructive hypertrophic cardiomyopathy is not well defined. This pre-specified analysis of SEQUOIA-HCM (NCT05186818) sought to define the associations between clinical characteristics and baseline concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-cTnI), and to evaluate the effect of treatment with aficamten on biomarker concentrations. Methods: Cardiac biomarkers were measured at baseline and serially throughout the study. Regression analyses determined predictors of baseline NT-proBNP and hs-cTnI concentrations, and evaluated whether early changes in these biomarkers relate to later changes in left ventricular outflow tract gradient (LVOT-G), other echocardiographic measures, health status, and functional capacity. Results: Baseline concentration of NT-proBNP was associated with LVOT-G and measures of diastolic function, while hs-cTnI was associated with left ventricular thickness. Within 8 weeks of treatment with aficamten, NT-proBNP was reduced by 79% (95% confidence interval 76%–83%, P &lt; .001) and hs-cTnI by 41% (95% confidence interval 32%–49%, P &lt; .001); both biomarkers reverted to baseline after washout. Reductions in NT-proBNP and hs-cTnI by 24 weeks were strongly associated with a lowering of LVOT-G, improvement in health status, and increased peak oxygen uptake. N-Terminal pro-B-type natriuretic peptide reduction strongly correlated with the majority of improvements in exercise capacity. Furthermore, the change in NT-proBNP by Week 2 was associated with the 24-week change in key endpoints. Conclusions: N-Terminal pro-B-type natriuretic peptide and hs-cTnI concentrations are associated with key variables in obstructive hypertrophic cardiomyopathy. Serial measurement of NT-proBNP and hs-cTnI appears to reflect clinical response to aficamten therapy

Efficacy and safety of aficamten in symptomatic non-obstructive hypertrophic cardiomyopathy: results from the REDWOOD-HCM trial, cohort 4

Background This open-label phase 2 trial evaluated the safety and efficacy of aficamten in patients with nonobstructive hypertrophic cardiomyopathy (nHCM). Methods Patients with symptomatic nHCM (left ventricular outflow tract obstruction gradient ≤ 30 mmHg, left ventricular ejection fraction [LVEF] ≥ 60%, N-terminal pro-B-type natriuretic peptide [NT-proBNP] &gt; 300 pg/mL) received aficamten 5–15 mg once daily (doses adjusted according to echocardiographic LVEF) for 10 weeks. Results We enrolled 41 patients (mean ± SD age 56 ± 16 years; 59% female). At Week 10, 22 (55%) patients experienced an improvement of ≥ 1 New York Heart Association class; 11 (29%) became asymptomatic. Clinically relevant improvements in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores occurred in 22 (55%) patients. Symptom relief was paralleled by reductions in NT-proBNP levels (56%; P &lt; 0.001) and high-sensitivity cardiac troponin I (22%; P &lt; 0.005). Modest reductions in LVEF (mean ± SD) of −5.4% ± 10 to 64.6% ± 9.1 were observed. Three (8%) patients had asymptomatic reduction in LVEF &lt; 50% (range: 41%–48%), all returning to normal after 2 weeks of washout. One patient with prior history of aborted sudden cardiac death experienced a fatal arrhythmia during the study. Conclusions Aficamten administration for symptomatic nHCM was generally safe and was associated with improvements in heart failure symptoms and cardiac biomarkers

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies