Four operational changes lifted average global enrollment by 128% across 103 sites in 19 countries.
The trial was already open, running a Phase III program for pulmonary arterial hypertension (PAH) across 19 countries and 103 sites. With an average global enrollment of only 3.2 patients per month, the program moved slowly. In a disease with real mortality stakes and a narrow patient pool, this continued pace would have cost the sponsor months.
Adding sites was not the answer, because sites in the wrong locations would have made the problem worse. Instead, the solution was to work differently with the right sites by directly utilizing PAH specialists, providing regional recruitment training, and engaging in earlier site interaction than the original protocol had planned. Furthermore, a partnership with patient advocacy organizations made an impactful difference. As a result, over the last seven months of the study, the average global monthly enrollment was 9.6 patients. This 128% increase in enrollment and 50% rise in the study’s randomization rate were achieved solely through operational changes.
That scenario is worth examining in detail; it illustrates the specific operational demands that make PAH trials run differently from other cardiovascular indications, and it shows how those demands translate into decisions a sponsor and CRO need to make together before the first patient is enrolled.
Efficient PAH Enrollment Is Driven by Selecting the Right Sites — Not More Sites
PAH patients are not distributed evenly across the cardiovascular care system. They are managed at cardiology centers and at Pulmonary Hypertension Care Centers. The functional assessments PAH protocols depend on, such as six-minute walk testing and right heart catheterization, are performed at these centers as part of routine clinical operations.
That distribution shapes how a study performs. A broad network of cardiovascular sites with marginal PAH caseloads will yield per-site monthly rates of one patient or fewer. The sites that move PAH enrollment are specialist centers with ongoing relationships in the PAH advocacy community, the patient referral pathways those relationships open up, and the clinical teams that already run the protocol-required assessments routinely. PAH trials demand proven expertise, making it a poor fit for general cardiology or pulmonary sites without that foundation.
In the Phase III optimization above, the four interventions worked because they focused on identifying and activating sites that already had the right caseload and clinical infrastructure, thereby improving enrollment velocity.
Standard of Care Is Moving, & PAH Protocols Need To Keep Up
Background therapy in PAH is evolving as Phase III programs run. Sotatercept (WinrevairTM) was approved by the FDA in March 2024 and by the EMA in August 2024 based on the Phase III STELLAR trial, in which adding sotatercept to background therapy reduced the risk of death or PAH clinical worsening events by 84% compared with background therapy alone.
The Phase III ZENITH trial in 172 high-risk PAH patients was stopped early at interim analysis after sotatercept produced a 76% relative risk reduction in major morbidity and mortality events versus placebo. The HYPERION trial in newly diagnosed patients was terminated early in 2025 once the strength of the ZENITH and broader program data made continued placebo control ethically unjustifiable. Patients from those studies are transitioning to active treatment through SOTERIA, the open-label extension study running at 196 sites across 21 countries.
For sponsors with a competing PAH protocol still in the field, the practical effect is significant. Patients now have access to an additional approved therapy through routine clinical care, which changes how patients and investigators weigh participation in a placebo-controlled trial.
At the site level, this compounds an already constrained enrollment environment. Disease prevalence is low. Screen failure rates run high, and the patient population is medically fragile. What counts as standard-of-care background therapy at study start may look different 18 months in. Composite morbidity and mortality endpoints are replacing the six-minute walk test as primary efficacy measures, and enriched-population designs add eligibility complexity to an already narrow patient pool.
PAH protocols built today need to plan for that. Amending a protocol mid-study without losing enrollment momentum requires a team that has done it before, with the regulatory and project-management infrastructure to execute the amendment cleanly. Building this flexibility into the study at design is materially different from trying to retrofit it once enrollment begins to lag.
Devices & Data Architecture Are Design Decisions, Not Implementation Details
Worldwide’s CardioMEMS work in PAH helped address the practical issues commonly encountered with these devices. CardioMEMS provides continuous pulmonary artery pressure data, but it is not a routine standard-of-care procedure in PAH, and some patients decline participation due to uncertainty about an implanted device. Sites without the workflows and tactical experience to support the procedure and integrate device-generated signals into protocol assessments will slow a study.
Identifying sites with the technical infrastructure and clinical workflows already in place, and reinforcing those relationships before the protocol is final, works better than mitigating gaps after the study is underway. Data management architecture is a foundational decision. If it is wrong at study launch, it undermines execution downstream.
Retention in a Severely Ill Population Requires a Unique Operational Model
Dropout in PAH trials is not purely administrative. Patients face disease progression, clinical decline, and, in some cases, death, all while studies are ongoing. A retention plan for this population requires more than standard engagement. It requires site teams that can balance data collection obligations with clinical care realities. It requires upfront knowledge of which sites have the infrastructure to support patients over longer periods of participation. And it requires defined escalation pathways for when a patient’s clinical status changes.
Lost-to-follow-up or discretionary withdrawal in a high-risk PAH population signals that the retention model was not designed for the indication. This is a fixable problem at design, but a costly one to address mid-study.
Advocacy Engagement Is a Recruitment Driver, Not a Courtesy
PAH patient advocacy organizations shape how patients find clinical trials. They support site access and sit close to referral pathways that impact enrollment trajectory. The PHA International Conference brings together PAH trial investigators, KOLs, advocacy organizations, and patients in a single forum. It is a working venue for the people who move PAH enrollment.
In the Phase III enrollment optimization described above, partnership with patient advocacy organizations was one of the four operational interventions that boosted enrollment. Worldwide’s cardiovascular team maintains relationships with the PAH advocacy community in North America and Europe, including the Pulmonary Hypertension Association, the Pulmonary Hypertension Association of Canada, phaware, PHA Europe, and AIPI. These relationships were part of how the enrollment challenge was tackled, not a downstream benefit of a study already going well.
What This Means for Sponsors Designing PAH Trials
PAH has rare disease complexity within a cardiovascular indication, layered on top of a clinical environment where background therapy can shift mid-study. The decisions that determine whether a trial finishes on plan are made before the first patient is enrolled:
- Which sites are selected
- How advocacy is engaged
- How device and data workflows are built
- How the protocol accommodates a moving standard of care
Worldwide Clinical Trials has run PAH studies from Phase II through Phase IV, including programs that are active today. Our cardiovascular team includes PAH-specific medical expertise and site relationships built across multiple PAH programs in North America and Europe. The case described above is one of those programs, and the operational model that produced the recovery is the one we bring to PAH trials by default.
If you are designing a PAH trial, or working to understand why one is not performing as planned, we are open to a practical conversation about the operational model, contact us today.
