Strategic site selection and endpoint integrity drive success in two pivotal hypertrophic cardiomyopathy trials

A late-stage biopharmaceutical organisation planned to enroll 650 patients across two phase 3 pivotal trials in hypertrophic cardiomyopathy (HCM): 230 patients in obstructive HCM (oHCM) and 420 in non-obstructive HCM (nHCM), spanning 150 global sites.

From the outset, the recruitment strategy faced significant challenges. HCM is a rare condition, making patient enrolment inherently difficult. Further complicating recruitment, a major pharmaceutical competitor was conducting a parallel program targeting the same indication and mechanism of action — competing for the same investigators, sites, and patient population.

The trials also featured a complex primary endpoint: cardiopulmonary exercise testing (CPET). While CPET is a reliable measure when properly standardised, its accuracy depends on consistent execution across sites. With short treatment durations (24 weeks for oHCM and 36 weeks for nHCM) and relatively small sample sizes, maintaining data integrity was critical.

In this highly competitive and technically challenging environment, ICON’s role was critical. Our strategic leadership, operational precision, and therapeutic expertise enabled the client to overcome these challenges and move the programs forward successfully.

ICON partnered closely with the sponsor to develop and execute a highly targeted site selection and activation strategy, identifying only the most experienced and well-equipped sites. The main selection criteria included:

• Investigators with proven experience in HCM clinical trials, including Centers of Excellence in HCM (HCMA)
• Sites with dedicated, active HCM clinics
• Sites with onsite CPET facilities and strong collaboration between clinical and diagnostic teams

To protect the integrity of the CPET primary endpoint, ICON implemented the following critical measures:

• CPET equipment certification was required for site activation, ensuring calibration and compliance with protocol standards
• Consistent test administration by requiring, whenever possible, the same technician to conduct CPET for each subject, minimizing intrasubject variability
• Subject-specific CPET reminders were sent to each site before each CPET clinic visit to reinforce reproducibility and protocol adherence
• Timely and continuous QC of incoming CPET data
• Travel and lodging reimbursement were offered for long-distance participants, reducing potential barriers to completing the final CPET assessments

Both trials offered an opportunity to roll over into an open-label long-term extension trial after completing the parent trial, making participation more appealing. ICON managed the extension study, focusing on ensuring smooth and timely transitions for all eligible subjects.

ICON’s strategic planning and flawless execution led to exceptional trial performance across both studies:

• The oHCM study achieved a recruitment rate of 0.5 patients per site per month (p/s/m) versus historical rates of 0.25 p/s/m, and nHCM also achieved 0.5 p/s/m. In the absence of meaningful historical data, 0.13 p/s/m was assumed, with 35% of HCM subjects diagnosed with nHCM
• Both trials overenrolled (oHCM: N=282, 123%; nHCM: N=467, 148%) and completed ahead of contracted timelines (refer to graphs below)
• Enrollment was driven primarily by targeted outreach to site-held patient databases
• The CPET primary endpoint was safeguarded, with low discontinuation rates observed: 2% for oHCM and 8% for nHCM (ongoing), versus 15% planned for both trials