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.
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).
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.
Parallel
Discontinuation of parenteral prostacyclins analogues or selexipag
Procedure/SurgeryDiscontinuation of parenteral prostacyclins analogues or selexipag
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.
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.
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.
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.
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.
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.
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.
Participant Enrollment Rate
Number of participants enrolled per site per month during the 24-week recruitment period.
Protocol Adherence Rate
Proportion of participants who complete study procedures according to protocol through Week 24 without major protocol deviations.
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