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

Official title

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

Overview

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.

Interventions

• Procedure Discontinuation of parenteral prostacyclins analogues or selexipag
  Discontinuation of parenteral prostacyclins analogues or selexipag

Primary outcome measures

• Change in Mean Pulmonary Arterial Pressure (mPAP) From Baseline to 24 Weeks [Time frame: Baseline to 24 weeks]

Secondary outcome measures (6)

• Time to First Occurrence of All-Cause Death or Clinical Worsening [Time frame: Baseline to 24 weeks]
• Change in EmPHasis-10 Score From Baseline to Week 24 [Time frame: Baseline to 24 weeks]
• Change in EQ-5D-5L Index Score From Baseline to Week 24 [Time frame: Baseline to Week 24]
• Change in EQ Visual Analogue Scale (EQ VAS) Score From Baseline to Week 24 [Time frame: Baseline to Week 24]
• Change in Living with Medicines Questionnaire Version 3 (LMQ-3) Score From Baseline to Week 24 [Time frame: Baseline to Week 24]
• Number of Participants Reporting Prostanoid-Associated Side Effects [Time frame: Baseline to 24 weeks]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Canada · 1 center

• University of Alberta Hospital — Edmonton

Publications

• 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. PMID 36283952
• 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. PMID 40268508
• 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. PMID 39978862
• 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. Pri PMID 37696565
• 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 PMID 36877098

Identifiers

NCT: NCT07700303 · WATERLOO

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗