Rationale and design of the CADENCE trial: evaluating sotatercept in Cpc-PH secondary to HFpEF
Bibliographic record
Abstract
Abstract Background/Introduction Combined post- and precapillary pulmonary hypertension (Cpc-PH) complicates heart failure with preserved ejection fraction (HFpEF), contributing to an increase in morbidity and mortality. There is no approved therapy for this condition, in addition to recommended treatment for the underlying disorder. Sotatercept, a first-in-class activin signaling inhibitor, may offer a novel therapeutic approach. Purpose The ongoing CADENCE trial evaluates the efficacy and safety of sotatercept in Cpc-PH associated with HFpEF, aiming to improve clinical outcomes. Methods This phase 2, randomized, double-blind, placebo-controlled study enrolled approximately 150 adults (18-85 years) with Cpc-PH associated with HFpEF, who were on stable doses (≥30 days) of guideline-directed medical therapies for HF and other chronic conditions. Inclusion criteria mandated left ventricular ejection fraction (LVEF) ≥50%, mean pulmonary artery pressure (mPAP) >20 mmHg, pulmonary vascular resistance (PVR) ≥4 Wood units, and pulmonary artery wedge pressure (PAWP) >15 mmHg but <30 mmHg. Participants were also required to have New York Heart Association functional class (NYHA-FC) II or III and a 6-minute walk distance (6MWD) ≥100 m. Key exclusion criteria included significant lung disease, severe valvular conditions, uncontrolled hypertension, recent coronary events, and prior use of PAH-related therapies. Participants were stratified by NYHA-FC and randomized 1:1:1 to receive subcutaneous sotatercept (0.3 mg/kg or 0.3 mg/kg escalating to 0.7 mg/kg) or placebo every 3 weeks for 24 weeks. The primary endpoint is the change in PVR at week 24, with 6MWD a key secondary endpoint. Other secondary endpoints include time-to-clinical worsening (TTCW; a composite endpoint of all-cause mortality, heart failure- or PH-related hospitalizations, intravenous diuretic initiation, or ≥15% decrease in 6MWD), echocardiographic and hemodynamic parameters, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and NYHA-FC. Exploratory outcomes include patient-reported outcomes and biomarkers. An interim analysis is planned. Those initially assigned to placebo will be re-randomized to one of the sotatercept dose groups in an open-label extension study. An independent data monitoring committee (DMC) oversees periodic safety reviews. Conclusion The ongoing CADENCE trial aims to demonstrate whether sotatercept improves pulmonary hemodynamics, exercise capacity, and reduces risk of fatal and non-fatal clinical worsening events in patients with Cpc-PH associated with HFpEF, potentially addressing a need for effective treatments in this high-risk population.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.036 | 0.027 |
| Meta-epidemiology (narrow) | 0.004 | 0.002 |
| Meta-epidemiology (broad) | 0.005 | 0.003 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.002 | 0.003 |
| Scholarly communication | 0.003 | 0.002 |
| Open science | 0.003 | 0.001 |
| Research integrity | 0.005 | 0.004 |
| Insufficient payload (model declined to judge) | 0.015 | 0.004 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".