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NCT Number: NCT07700303

Withdrawal of Prostacyclin Pathway Therapy in Patients With Pulmonary Arterial Hypertension Receiving Sotatercept (WATERLOO)

Pulmonary arterial hypertension (PAH) is a rare lung disease that 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, investigators 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 participant is doing well on sotatercept is safe. Investigators 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.

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Key information

Conditions

Pulmonary Arterial Hypertension Hypertension, Pulmonary Lung Diseases Respiratory Tract Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

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

  • Adults ≥ 18 years old diagnosed with PAH.
  • Treatment with sotatercept for ≥6 months.
  • Background therapy with ≥2 PAH vasodilator therapies, one of which is a parenteral prostacyclin or selexipag.
  • At low or intermediate-low risk, defined using the 2022 ESC/ERS guidelines 4-strata risk assessment tool (Table 1).
  • 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
  • The ability to adhere to the study visit schedule and to comprehend and comply with all protocol requirements.
  • 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:

  • Known intolerance to sotatercept
  • 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.
  • Hospitalization for worsening PAH or right heart failure within the 3 months prior to screening.
  • Active listing for lung or heart/lung transplantation.
  • Metastatic cancer or any other condition with a life expectancy < 6 months,
  • Female patients who are pregnant or who are of childbearing age and are unwilling to use contraception during the study.
  • History of ≥ 3 interruptions or missed doses of sotatercept for any reason within the previous 6 months prior to screening.
  • 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.

Treatment and study plan

Discontinuation of parenteral prostacyclins analogues or selexipag

Procedure

Discontinuation of parenteral prostacyclins analogues or selexipag

Primary outcomes

  1. Change in Mean Pulmonary Arterial Pressure (mPAP) From Baseline to 24 Weeks

    Time frame: 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.

Secondary outcomes

  1. Time to First Occurrence of All-Cause Death or Clinical Worsening

    Time frame: Baseline to 24 weeks

    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.

  2. Change in EmPHasis-10 Score From Baseline to Week 24

    Time frame: Baseline to 24 weeks

    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.

  3. Change in EQ-5D-5L Index Score From Baseline to Week 24

    Time frame: 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.

  4. Change in EQ Visual Analogue Scale (EQ VAS) Score From Baseline to Week 24

    Time frame: 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.

  5. Change in Living with Medicines Questionnaire Version 3 (LMQ-3) Score From Baseline to Week 24

    Time frame: 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.

  6. Number of Participants Reporting Prostanoid-Associated Side Effects

    Time frame: Baseline to 24 weeks

    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.

Other outcomes

  1. Number of Participants Experiencing Adverse Events (AEs)

    Time frame: Baseline to 24, 52 and 104 (End of Study) weeks

    Difference between the prostacyclin pathway therapy withdrawal group and the continuation group in the number of participants experiencing one or more adverse events.

  2. Number of Participants Experiencing Serious Adverse Events (SAEs)

    Time frame: Baseline to 24, 52 and 104 (End of Study) weeks

    Difference between the prostacyclin pathway therapy withdrawal group and the continuation group in the number of participants experiencing one or more serious adverse events.

  3. Participant Enrollment Rate

    Time frame: Baseline to 24 weeks

    Number of participants enrolled per site per month during the 24-week recruitment period.

  4. Protocol Adherence Rate

    Time frame: Baseline to Week 24

    Proportion of participants who complete study procedures according to protocol through Week 24 without major protocol deviations.

  5. Completeness of Secondary and Exploratory Outcome Data

    Time frame: Baseline to Week 24

    Proportion of expected secondary and exploratory outcome data points successfully collected through Week 24.

Study contacts

Contact information is provided by the study sponsor or research team.

Canadian VIGOUR Centre Clinical Trial Project Lead

CONTACT

[email protected]

1-800-707-9098

Sponsors and collaborators

Lead sponsor

University of Alberta

Other

Registry information

Official study title

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

Acronym: WATERLOO

Important dates

Study start
2026
Primary completion
2028
Study completion
2030
First posted
Jul 14, 2026
Registry last updated
Jul 15, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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