Keimei Yoshida, Kazuya Hosokawa, Takahiro Hiraide, Satoshi Akagi, Kentaro Ejiri, Yu Taniguchi, Shiro Adachi, Takumi Inami, Naohiko Nakanishi, Masaharu Kataoka, Taijyu Satoh, Shunsuke Tatebe, Toshiro Shinke, Hideshi Tomita, Yusuke Akazawa, Takashi Higaki, Koshiro Tagawa, Ayako Ishikita, Soshun Asakawa, Kohtaro Abe
Kyushu University and Kyushu University Hospital. Keio University School of Medicine. Okayama University. Kobe University Hospital. Nagoya University Hospital. Kyorin University School of Medicine. Kyoto Prefectural University of Medicine. University of Occupational and Environmental Health. Tohoku University and Tohoku University Graduate School of Medicine. Showa Medical University Hospital. Ehime University Graduate School of Medicine.
Japan
British Medical Journal Open
BMJ Open 2026;
DOI: 10.1136/bmjopen-2025-113430
Abstract
Introduction: Eisenmenger syndrome and pulmonary arterial hypertension (PAH) due to unrepaired congenital shunts, including atrial septal defect (ASD), ventricular septal defect (VSD) and patent ductus arteriosus (PDA), remain life-threatening conditions despite advances in congenital heart disease (CHD) care. In this population, vasodilator-based therapies effective in other forms of PAH have shown limited benefit, and no disease-modifying treatment has been established. Sotatercept, an activin-signalling inhibitor, improved exercise capacity and haemodynamics in phase 2/3 PAH trials; however, patients with unrepaired CHD, including Eisenmenger syndrome, were excluded. The efficacy and safety of sotatercept in this population remain unknown.
Methods and analysis: The SuMILE trial is a prospective, exploratory, multicentre, open-label, randomised, controlled trial conducted at 11 Japanese tertiary centres. 36 adults with vasodilator-resistant PAH due to unrepaired ASD, VSD or PDA, including Eisenmenger syndrome, will be randomised 2:1 to sotatercept add-on therapy plus vasodilator-based PAH therapy versus vasodilator-based PAH therapy alone. Sotatercept will be administered subcutaneously every 3 weeks in accordance with label-approved dose-modification rules for haemoglobin and platelet changes. The primary endpoint is the change in 6-min walk distance from baseline to week 24. Key clinical events will be independently adjudicated. Secondary endpoints include all-cause mortality or lung transplantation; pulmonary hypertension-related hospitalisation or initiation of parenteral prostacyclin and changes in WHO functional class, N-terminal pro-brain natriuretic peptide and emPHasis-10. Exploratory endpoints include genotype, right heart catheterisation and cardiac MRI parameters. The primary analysis will use ANCOVA, adjusting for baseline 6-min walk distance and randomisation stratum in the intention-to-treat population.
Ethics and dissemination: The protocol has been reviewed and approved by the certified central review board (Kyushu University Hospital Clinical Ethics Review Board) and participating institutions. Written informed consent will be obtained from all participants. Findings will be disseminated through peer-reviewed journals, scientific conferences and trial registries.
Trial registration number: Japan Registry of Clinical Trials no. 1071250069; ClinicalTrials.gov NCT07356778. Protocol version and date: V.1.3; 23 October 2025.
Category
Class I. Pulmonary Hypertension Associated with Congenital Cardiovascular Disease
Diagnostic Testing for Pulmonary Vascular Disease. Non-invasive Testing
Medical Therapy. Efficacy or Lack of Efficacy
Medical Therapy. Adverse Effects or Lack of Adverse Effects
Age Focus: Adult Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes