A Study of Sotatercept for Patients With Eisenmenger Syndrome or Unrepaired Shunt-Associated Pulmonary Arterial Hypertension Resistant to Vasodilator Therapy (SuMILE)

An Open-label, Randomized, Controlled Trial to Evaluate the Efficacy of Sotatercept Add-on Therapy Compared to Standard PAH Therapy With Pulmonary Vasodilators for Pulmonary Arterial Hypertension Associated With Pulmonary Vasodilator-resistant, Unrepaired Congenital Shunts (ASD, VSD, PDA) Including Eisenmenger Syndrome：SuMILE Trial

What is this study about? This study will test whether adding sotatercept to usual medicines for pulmonary arterial hypertension (PAH) can help adults who have PAH due to unrepaired congenital heart defects (atrial or ventricular septal defect, or patent ductus arteriosus), including Eisenmenger syndrome. These conditions often cause long-standing changes in the lung blood vessels and low oxygen levels.

Who can join? About 36 adults (age ≥18 years) in Japan whose PAH has not improved enough with pulmonary vasodilators may join. People with very severe symptoms (WHO class IV) or other serious illnesses will not be enrolled.

What will happen if I join?

Participants will be randomly assigned (like a coin flip, in a 2:1 ratio) to:

Sotatercept + vasodilator-based PAH care, or

vasodilator-based PAH care alone. The study lasts 24 weeks. Those who receive sotatercept will have injections every 3 weeks. All participants will have clinic visits and tests at the start, week 12, and week 24, including a 6-minute walk test (how far you can walk in 6 minutes), blood tests, questionnaires, and other heart-lung assessments used in routine PAH care.

What are the possible benefits? Sotatercept improved exercise capacity and heart-lung measures in other PAH studies, but people with unrepaired heart defects were not included. This study may or may not help you directly, but it may help doctors learn how to use sotatercept safely in this group.

What are the possible risks? Side effects seen with sotatercept include increase in haemoglobin, low platelets, nosebleeds, telangiectasia (small dilated blood vessels), bleeding, and blood clots. People with Eisenmenger syndrome can have both bleeding (for example, haemoptysis) and clotting risks. The study will check complete blood counts (CBC) regularly and adjust or pause dosing using label-based rules. Other risks are those of standard PAH care and blood tests.

Time and location The study is conducted at multiple hospitals in Japan. Study participation lasts about 6 months.

Costs and payments The study drug and study-specific tests will be provided at no cost. Usual medical care not required by the study will follow each hospital's standard billing. There is no required payment to join. Any travel reimbursement or stipends will follow site policy.

Privacy Your information will be kept confidential. Results will be shared in journals and at meetings without using your name.

Who to contact If you are interested or have questions, please contact the study team at the participating hospital.

Study Overview

• Status: Recruiting
• Conditions: Eisenmenger Syndrome; Pulmonary Arterial Hypertension of Congenital Heart Disease
• Intervention / Treatment: Drug: Sotatercept; Drug: vasodilator-based PAH therapy

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Kazuya Hosokawa, MD, PhD; Phone Number: +81-92-642-5360; Email: hosokawa.kazuya.712@m.kyushu-u.ac.jp
• Study Contact Backup: Name: Keimei Yoshida, MD, PhD; Email: yoshida.keimei.713@m.kyushu-u.ac.jp

Study Locations

• Japan
  • Fukuoka, Japan
    • Recruiting
    • The Second Department of Internal Medicine, University of Occupational and Environmental Health
    • Contact: Masaharu Kataoka; Phone Number: +81--603-1611; Email: mkataoka@med.uoeh-u.ac.jp
    • Principal Investigator: Masaharu Kataoka
  • Kobe, Japan
    • Recruiting
    • Division of Cardiovascular Medicine, Kobe University Hospital
    • Contact: Yu Taniguchi; Phone Number: +81-78-382-5111; Email: yu.taniguchi007@gmail.com
    • Principal Investigator: Yu Taniguchi
  • Kyoto, Japan
    • Recruiting
    • Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
    • Contact: Naohiko Nakanishi; Phone Number: +81-75-703-5101; Email: naka-nao@koto.kpu-m.ac.jp
    • Principal Investigator: Naohiko Nakanishi
  • Nagoya, Japan
    • Recruiting
    • Department of Cardiology, Nagoya University Hospital
    • Principal Investigator: Shiro Adachi
    • Contact: Shiro Adachi; Phone Number: +81-52-741-2111; Email: adachi.shiro.b6@f.mail.nagoya-u.ac.jp
  • Okayama, Japan
    • Recruiting
    • Department of Cardiovascular Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University
    • Contact: Satoshi Akagi; Phone Number: +81-86-223-7151; Email: akagi-s@cc.okayama-u.ac.jp
    • Principal Investigator: Satoshi Akagi
  • Sendai, Japan
    • Recruiting
    • Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine
    • Contact: Taijyu Sato; Phone Number: +81-22-717-7000; Email: s-taiju@cardio.med.tohoku.ac.jp
    • Principal Investigator: Taijyu Sato
  • Tokyo, Japan
    • Recruiting
    • Department of Cardiology, Keio University School of Medicine
    • Contact: Takahiro Hiraide; Phone Number: +81-3-3353-1211; Email: t.hiraide.a6@keio.jp
    • Principal Investigator: Takahiro Hiraide
  • Tokyo, Japan
    • Recruiting
    • Department of Cardiovascular Medicine, Kyorin University School of Medicine
    • Contact: Takumi Inami; Phone Number: +81-22-47-5511; Email: tinami@ks.kyorin-u.ac.jp
    • Principal Investigator: Takumi Inami
  • Tokyo, Japan
    • Recruiting
    • Division of Cardiovascular Medicine, Department of Internal Medicine, Showa University Graduate School of Medicine
    • Contact: Toshiro Shinke; Email: shinke@med.showa-u.ac.jp
    • Principal Investigator: Toshiro Shinke
  • Not Required For This Country
    • Fukuoka, Not Required For This Country, Japan, 8150014
      • Recruiting
      • Kyushu University Hospital
      • Contact: Kazuya Hosokawa; Phone Number: +81-92-642-1151; Email: hosokawa.kazuya.712@m.kyushu-u.ac.jp
      • Sub-Investigator: Ayako Ishikita
      • Sub-Investigator: Keimei Yoshida
      • Principal Investigator: Kazuya Hosokawa

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• adults (≥18 years)
• unrepaired ASD, VSD or PDA
• ≥90 days of pulmonary vasodilator therapy; and either (i) pulmonary vascular resistance (PVR) ≥5 Wood units and mean pulmonary arterial pressure (mPAP) > 20 mm Hg on right heart catheterization within 180 days, or (ii) echocardiographic tricuspid regurgitation velocity >3.4 m/s with right-to-left/bidirectional shunt plus resting SpO₂ ≤92% consistent with cyanosis
• baseline 6MWD ≥100 m
• ability to complete questionnaires

Exclusion Criteria:

• WHO functional class IV; other unrepaired intracardiac shunts
• severe renal/hepatic/parenchymal lung disease or LVEF <40%
• prior sotatercept use
• contraindication to sotatercept per label
• investigator-judged unsuitability

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sotatercept add-on + vasodilator-based PAH therapy	Drug: Sotatercept; Sotatercept will be administered subcutaneously every 3 weeks for 24 weeks (total 8 injections): 0.3 mg/kg lead-in at Visit 1, then 0.7 mg/kg from Visit 2 if safety criteria are met. Dose holds/reductions follow label-concordant rules based on complete blood count (CBC) prior to each dose (e.g., hemoglobin rise >4.0 g/dL from baseline; or >2.0 g/dL from the previous dose and above ULN; or >2.0 g/dL above ULN; and platelet count <50,000/µL). Participants continue stable background PAH therapy (endothelin, nitric-oxide, prostacyclin pathways) per protocol; initiation or up-titration of PAH drugs during the 24-week treatment period is generally not permitted unless clinically mandated for safety and recorded as a protocol deviation.; Drug: vasodilator-based PAH therapy; Participants receive no sotatercept. They continue site-standard, stable PAH therapy for 24 weeks (endothelin receptor antagonist, PDE5 inhibitor/riociguat, and/or prostacyclin class as clinically indicated). Changes to background therapy are discouraged during the 24-week period unless required for safety; any changes are captured for analysis. The same visit schedule and assessments (e.g., 6-minute walk test, biomarkers, clinical events) apply as in the sotatercept arm.
Active Comparator: vasodilator-based PAH therapy alone	Drug: vasodilator-based PAH therapy; Participants receive no sotatercept. They continue site-standard, stable PAH therapy for 24 weeks (endothelin receptor antagonist, PDE5 inhibitor/riociguat, and/or prostacyclin class as clinically indicated). Changes to background therapy are discouraged during the 24-week period unless required for safety; any changes are captured for analysis. The same visit schedule and assessments (e.g., 6-minute walk test, biomarkers, clinical events) apply as in the sotatercept arm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change in 6-minute walk distance at 24 weeks from baseline	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality or lung transplantation		24 weeks
PH-related hospitalisation or initiation of parenteral prostacyclin		24 weeks
Change in WHO functional class at 24-week from baseline	A higher score indicates more severe symptom	24 weeks
Change in NT-pro BNP at 24-week from baseline		24 weeks
Change in emPHasis-10 at 24-week from baseline	A higher score indicates more severe symptom	24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
PAH specific genetic test		0 week
Changes in blood pressure (systolic and diastolic)	Office resting BP	0, 12, 24 weeks
Changes in pulse rate	bpm	0, 12, 24 weeks
Changes in oxygen saturation	Pulse Oxygen Saturation (Office, Resting)	0, 12, 24 weeks
Changes in hemoglobin	g per dL	0, 12, 24 weeks
Changes in platlet counts		0, 12, 24 weeks
Changes in catheter-based mPAP	mm Hg	0, 24 weeks
Changes in catheter-based PVR	Wood units	0, 24 weeks
Changes in catheter-based Qp/Qs		0, 24 weeks

Collaborators and Investigators

• Sponsor: Kazuya Hosokawa

Study record dates

Study Major Dates

• Study Start (Actual): October 7, 2025
• Primary Completion (Estimated): August 31, 2027
• Study Completion (Estimated): April 30, 2028

Study Registration Dates

• First Submitted: September 20, 2025
• First Submitted That Met QC Criteria: January 20, 2026
• First Posted (Actual): January 21, 2026

Study Record Updates

• Last Update Posted (Actual): January 21, 2026
• Last Update Submitted That Met QC Criteria: January 20, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: pulmonary arterial hypertension; sotatercept; Eisenmenger syndrome; Congential heart disease
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Respiratory Tract Diseases; Lung Diseases; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Defects, Congenital; Hypertension, Pulmonary; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pulmonary Arterial Hypertension; Eisenmenger Complex; ACE-011
• Other Study ID Numbers: CTR-2025-Sep

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No