{
  "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",
  "authors": [
    {
      "affiliations": [
        "Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan"
      ],
      "name": "Keimei Yoshida"
    },
    {
      "affiliations": [
        "Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan",
        "Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan"
      ],
      "name": "Kazuya Hosokawa"
    },
    {
      "affiliations": [
        "Department of Cardiology, Keio University School of Medicine, Tokyo, Japan"
      ],
      "name": "Takahiro Hiraide"
    },
    {
      "affiliations": [
        "Department of Cardiovascular Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan"
      ],
      "name": "Satoshi Akagi"
    },
    {
      "affiliations": [
        "Department of Cardiovascular Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan"
      ],
      "name": "Kentaro Ejiri"
    },
    {
      "affiliations": [
        "Division of Cardiovascular Medicine, Kobe University Hospital, Kobe, Japan"
      ],
      "name": "Yu Taniguchi"
    },
    {
      "affiliations": [
        "Department of Cardiology, Nagoya University Hospital, Nagoya, Japan"
      ],
      "name": "Shiro Adachi"
    },
    {
      "affiliations": [
        "Department of Cardiovascular Medicine, Kyorin University School of Medicine, Tokyo, Japan"
      ],
      "name": "Takumi Inami"
    },
    {
      "affiliations": [
        "Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan"
      ],
      "name": "Naohiko Nakanishi"
    },
    {
      "affiliations": [
        "The Second Department of Internal Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan"
      ],
      "name": "Masaharu Kataoka"
    },
    {
      "affiliations": [
        "Department of Medical Science and Innovation, SiRIUS Institute of Medical Research, Tohoku University, Sendai, Japan",
        "Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan"
      ],
      "name": "Taijyu Satoh"
    },
    {
      "affiliations": [
        "Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan"
      ],
      "name": "Shunsuke Tatebe"
    },
    {
      "affiliations": [
        "Division of Cardiology, Department of Medicine, Showa Medical University Hospital, Tokyo, Japan"
      ],
      "name": "Toshiro Shinke"
    },
    {
      "affiliations": [
        "Periatric Heart Disease and Adult Congenital Heart Disease Center, Showa Medical University Hospital, Tokyo, Japan"
      ],
      "name": "Hideshi Tomita"
    },
    {
      "affiliations": [
        "Department of Cardiology, Pulmonology, Hypertension and Nephrology, Ehime University Graduate School of Medicine, Toon, Japan"
      ],
      "name": "Yusuke Akazawa"
    },
    {
      "affiliations": [
        "Department of Pediatric and Adolescent Therapeutic and Developmental Education, Ehime University Graduate School of Medicine, Toon, Japan"
      ],
      "name": "Takashi Higaki"
    },
    {
      "affiliations": [
        "Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan"
      ],
      "name": "Koshiro Tagawa"
    },
    {
      "affiliations": [
        "Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan"
      ],
      "name": "Ayako Ishikita"
    },
    {
      "affiliations": [
        "Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan"
      ],
      "name": "Soshun Asakawa"
    },
    {
      "affiliations": [
        "Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan"
      ],
      "name": "Kohtaro Abe"
    }
  ],
  "title": "Protocol for an open-label, randomised, controlled trial to evaluate the efficacy and safety of sotatercept add-on therapy compared with pulmonary vasodilator-based standard of care for pulmonary vasodilator-resistant pulmonary arterial hypertension associated with unrepaired congenital shunts (atrial septal defect, ventricular septal defect or patent ductus arteriosus), including Eisenmenger syndrome: the SuMILE trial",
  "uid": "261b5850-fe3a-5a18-944c-36e7803a6b0e"
}