Withdrawal of Background Prostacyclin Pathway Therapy in Patients With Pulmonary Arterial Hypertension Receiving Sotatercept: an Open Label Non-inferiority Trial (WATERLOO)

Pulmonary arterial hypertension (PAH) is a rare lung disease which leads to elevated blood pressure in the lungs and strain on the right side of the heart. For many years, treatments for PAH have included drugs that target the prostacyclin pathway using intravenous, subcutaneous, oral and inhaled drugs. These drugs help widen the blood vessels in the lungs so the heart does not have to work as hard. However, these medicines can cause side effects - such as jaw pain, flushing, diarrhea, and nausea - and the pump therapy can be very hard to manage day-to-day.

A newer medicine called sotatercept works in a different way. It helps fix some of the root causes of PAH. Early reports suggest that some people do very well on sotatercept and may not need to keep taking their prostacyclin therapy. However, we do not yet know if it is safe to stop prostacyclin therapies or how to do so. This study - called WATERLOO - is designed to find out whether slowly stopping prostacyclin therapy while the patient is doing well on sotatercept is safe. We will compare people who stop their prostacyclin therapy to people who keep taking it. This study is being done at PAH expert centres in Canada and Europe.

Study Overview

• Status: Not yet recruiting
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Procedure: Discontinuation of parenteral prostacyclins analogues or selexipag

• Study Type: Interventional
• Enrollment (Estimated): 78
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Canadian VIGOUR Centre Clinical Trial Project Lead; Phone Number: 1-800-707-9098; Email: waterloo@ualberta.ca

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada
      • University of Alberta Hospital
      • Contact: CVC Clinical Trial Project Lead; Phone Number: 1-800-707-9098; Email: waterloo@ualberta.ca

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria: In order to be eligible for this study, a participant must meet all of the following criteria:

1. Adults ≥ 18 years old diagnosed with PAH.
2. Treatment with sotatercept for ≥6 months.
3. Background therapy with ≥2 PAH vasodilator therapies, one of which is a parenteral prostacyclin or selexipag.
4. At low or intermediate-low risk, defined using the 2022 ESC/ERS guidelines 4-strata risk assessment tool (Table 1).
5. RHC at screening or historical within 8 weeks of screening, and after at least 6 months of sotatercept treatment, demonstrating a mPAP ≤40 mmHg and PVR ≤5 WU
6. The ability to adhere to the study visit schedule and to comprehend and comply with all protocol requirements.
7. Ability to provide informed consent.

Exclusion Criteria: A potential participant who meets any of the following criteria will be excluded from participation in this study:

1. Known intolerance to sotatercept
2. A RHC at screening or historical within 8 weeks of screening and after ≥6 months of sotatercept treatment demonstrating mPAP > 40 mmHg or PVR > 5 WU.
3. Hospitalization for worsening PAH or right heart failure within the 3 months prior to screening.
4. Active listing for lung or heart/lung transplantation.
5. Metastatic cancer or any other condition with a life expectancy < 6 months,
6. Female patients who are pregnant or who are of childbearing age and are unwilling to use contraception during the study.
7. History of ≥ 3 interruptions or missed doses of sotatercept for any reason within the previous 6 months prior to screening.
8. Patients who received any investigational medication within 1 month prior to screening (unless known to be placebo) or who are scheduled to receive another investigational drug during the course of this study.

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
No Intervention: Control group / no change to therapy; The control group will continue prostacyclin pathway therapies as per their authorized indications, with no change in dosage.
Experimental: Prostacyclin pathway therapy withdrawal; Dose de-escalation and discontinuation of parenteral prostacyclins analogues or selexipag	Procedure: Discontinuation of parenteral prostacyclins analogues or selexipag; Discontinuation of parenteral prostacyclins analogues or selexipag

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Mean Pulmonary Arterial Pressure (mPAP) From Baseline to 24 Weeks	Difference between the prostacyclin pathway therapy withdrawal group and the continuation group in the change in mean pulmonary arterial pressure (mPAP), measured in mmHg, from baseline to Week 24 by right heart catheterization.	Baseline to 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to First Occurrence of All-Cause Death or Clinical Worsening	Comparison between the prostacyclin pathway therapy withdrawal group and the continuation group in the time to first occurrence of the composite endpoint of all-cause death or clinical worsening. Clinical worsening is defined as any of the following: hospitalization for worsening PAH, decline in 6-minute walk distance (6MWD) ≥10% from baseline on two consecutive tests at least 4 hours apart accompanied by worsening WHO functional class, or worsening ESC/ERS 4-strata risk status.	Baseline to 24 weeks
Change in EmPHasis-10 Score From Baseline to Week 24	Difference between the prostacyclin pathway therapy withdrawal group and the continuation group in the change from baseline to Week 24 Unit of Measure: Score Range: 0-50 Higher scores indicate worse pulmonary hypertension-related quality of life.	Baseline to 24 weeks
Change in EQ-5D-5L Index Score From Baseline to Week 24	Difference between the prostacyclin pathway therapy withdrawal group and the continuation group in the change from baseline to Week 24 in the EQ-5D-5L Index Score. Unit of Measure: Index score Country-specific value set; Higher scores indicate better health status.	Baseline to Week 24
Change in EQ Visual Analogue Scale (EQ VAS) Score From Baseline to Week 24	Difference between the prostacyclin pathway therapy withdrawal group and the continuation group in the change from baseline to Week 24 in the EQ-5D-5L Index Score. Unit of Measure: score Range: 0-100 Higher scores indicate better perceived health.	Baseline to Week 24
Change in Living with Medicines Questionnaire Version 3 (LMQ-3) Score From Baseline to Week 24	Difference between the prostacyclin pathway therapy withdrawal group and the continuation group in the change from baseline to Week 24 in the EQ-5D-5L Index Score. Unit of Measure: Score Range: 41-205 Higher scores indicate a greater medication burden.	Baseline to Week 24
Number of Participants Reporting Prostanoid-Associated Side Effects	Difference between the prostacyclin pathway therapy withdrawal group and the continuation group in the number of participants reporting prostanoid-associated side effects, including jaw pain, flushing, nausea, diarrhea, and myalgia.	Baseline to 24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing Adverse Events (AEs)	Difference between the prostacyclin pathway therapy withdrawal group and the continuation group in the number of participants experiencing one or more adverse events.	Baseline to 24, 52 and 104 (End of Study) weeks
Number of Participants Experiencing Serious Adverse Events (SAEs)	Difference between the prostacyclin pathway therapy withdrawal group and the continuation group in the number of participants experiencing one or more serious adverse events.	Baseline to 24, 52 and 104 (End of Study) weeks
Participant Enrollment Rate	Number of participants enrolled per site per month during the 24-week recruitment period.	Baseline to 24 weeks
Protocol Adherence Rate	Proportion of participants who complete study procedures according to protocol through Week 24 without major protocol deviations.	Baseline to Week 24
Completeness of Secondary and Exploratory Outcome Data	Proportion of expected secondary and exploratory outcome data points successfully collected through Week 24.	Baseline to Week 24

Collaborators and Investigators

• Sponsor: University of Alberta
• Investigators: Principal Investigator: Dr. Jason Weatherald, MD, MSc, FRCPC, University of Alberta

Publications and helpful links

General Publications

• Souza R, Badesch DB, Ghofrani HA, Gibbs JSR, Gomberg-Maitland M, McLaughlin VV, Preston IR, Waxman AB, Grunig E, Kopec G, Meyer G, Olsson KM, Rosenkranz S, Lin J, Johnson-Levonas AO, de Oliveira Pena J, Humbert M, Hoeper MM. Effects of sotatercept on haemodynamics and right heart function: analysis of the STELLAR trial. Eur Respir J. 2023 Sep 21;62(3):2301107. doi: 10.1183/13993003.01107-2023. Print 2023 Sep.
• Hoeper MM, Badesch DB, Ghofrani HA, Gibbs JSR, Gomberg-Maitland M, McLaughlin VV, Preston IR, Souza R, Waxman AB, Grunig E, Kopec G, Meyer G, Olsson KM, Rosenkranz S, Xu Y, Miller B, Fowler M, Butler J, Koglin J, de Oliveira Pena J, Humbert M; STELLAR Trial Investigators. Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2023 Apr 20;388(16):1478-1490. doi: 10.1056/NEJMoa2213558. Epub 2023 Mar 6.
• Weatherald J, Iqbal H, Mielniczuk L, Syed AR, Legkaia L, Howard J, Dempsey N, Rader T, Swiston J, Provencher S. Priorities for pulmonary hypertension research: A James Lind Alliance priority setting partnership. J Heart Lung Transplant. 2023 Jan;42(1):1-6. doi: 10.1016/j.healun.2022.09.015. Epub 2022 Oct 3.
• Olsson KM, Fuge J, Park DH, Kamp JC, Hoeper MM. Withdrawal of prostacyclin pathway therapies after initiation of sotatercept treatment in patients with pulmonary arterial hypertension. Eur Respir J. 2025 Jun 5;65(6):2500064. doi: 10.1183/13993003.00064-2025. Print 2025 Jun.
• Preston IR, Badesch D, Ghofrani HA, Gibbs JSR, Gomberg-Maitland M, Hoeper MM, Humbert M, McLaughlin VV, Waxman AB, Manimaran S, Mikhailova E, Reddy M, Lau A, de Oliveira Pena J, Souza R. A long-term follow-up study of sotatercept for treatment of pulmonary arterial hypertension: interim results of SOTERIA. Eur Respir J. 2025 Jul 24;66(1):2401435. doi: 10.1183/13993003.01435-2024. Print 2025 Jul.

Study record dates

Study Major Dates

• Study Start (Estimated): September 30, 2026
• Primary Completion (Estimated): March 30, 2028
• Study Completion (Estimated): March 30, 2030

Study Registration Dates

• First Submitted: June 15, 2026
• First Submitted That Met QC Criteria: July 8, 2026
• First Posted (Actual): July 14, 2026

Study Record Updates

• Last Update Posted (Actual): July 14, 2026
• Last Update Submitted That Met QC Criteria: July 8, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Prostacyclin; open label; CVC; pulmonary arterial hypertension; non-inferiority; sotatercept; Canadian VIGOUR Centre; Weatherald
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; selexipag
• Other Study ID Numbers: WATERLOO

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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