A proactive approach across several departments and business units ensured the successful delivery of this complex study, mitigated operational challenges, achieved client timelines, and enabled the client to make key strategic program decisions to advance their larger Phase 2 trial.

This successful delivery was achieved through a collaborative effort between ICON’s expert Scientific and Medical Affairs teams with the Early Patient Solutions (EPS) Project Management and Clinical Operations teams, who redesigned the protocol and adapted the operational setting while still meeting project timelines.

A randomised, double-blind, placebo-controlled, cross-over Phase 2 study of continuous 8-hour intravenous infusions of investigational medicinal product (IMP) in patients with heart failure and impaired systolic function given a standard dose of loop diuretic.

A top pharma company with which ICON maintained a formal partnership requested that ICON conduct a complex Phase 2 cardiovascular study at a single site in the UK, already selected by the client. The client protocol included a complex assessment and sampling scheme. Following enrollment of the first patient, it was evident that protocol amendments to enable successful study completion would be required.

ICON’s scientific and medical experts provided intensive input to the required protocol amendments, allowing study enrollment to be completed on time. The bioanalytical samples had to be analysed in seven different laboratories, adding to the complexity of the operational setup. ICON’s Clinical Operations team focused on intensive site training, provided detailed sample documentation and handling sheets, and closely monitored the shipment logistics.

Based on the client’s strategic decision, the study became a high priority. An interim analysis was added to provide topline results for a board meeting. At ICON’s suggestion, a second site was quickly established, and enrollment was completed one month ahead of schedule. ICON’s dedicated Data Management and Biostats team delivered topline results two weeks after DBL to the client.

Challenge 

IMP administration methodology and patient inclusion criteria clearly required adjustment following enrollment of the first patient, and ICON implemented swift mitigation strategies to address this before dosing additional patients.

The IMP required a slow-infusion administration for 8 hours with frequent urine samples and blood samples taken. Extensive monitoring of vital signs throughout the infusion period was required due to the blood pressure-lowering effect of the IMP. In addition, the operational implementation of these requirements in the targeted patient population (mean age of enrolled participants was 68 years, comprising a broad definition of chronic heart failure patients) and strict withholding of diuretics and water intake during dosing days proved to be unfeasible.

Solution

A protocol amendment was prepared. The initial protocol was written by a consultant to the client without ICON’s input. ICON took over the preparation of the protocol amendment, employing our internal expert Therapeutic Expertise (TE) and Clinical Pharmacology (CP) groups. This granted more flexibility to the principal investigator in withholding standard diuretics and water intake restrictions and implementing a more specific definition of the patient population to patients with stable chronic HFrEF without signs of decompensation.

Challenge

When the screen failure rate was higher than expected—83% vs the 50% projected by the site—ICON quickly determined that the contracted timelines were at risk, thus impacting the planned enrollment rate.

Solution

A second protocol amendment was prepared by ICON’s Medical Writing team with adapted inclusion criteria to increase enrollment, e.g., allowing lower initial b-natriuretic peptide levels (BNP, 200 pg/ml instead of 500 pg/ml) and increasing allowed estimated glomerular filtration rate (eGFR, from < 60 to < 80 mL/min/1.73m2). After the implementation of the new inclusion criteria, the screening failure rate reduced from 83% to 44%.

Challenge

The client favoured a single-site approach for the study to minimise data variability. At the time of study award, the site had already been selected by the client based on an established relationship. ICON had no previous experience with the site and had not been involved in establishing their enrollment potential, which was lower than the site’s initial prediction.

Solution

ICON suggested opening an additional site in the UK. Supported by the established EPS site network, the new site was promptly activated within 3 months from first site contact to the site initiation visit (SIV), demonstrating the benefits of known site enrollment potential, rapid contract execution based on previous contracting experience, and EPS’ lean start-up processes. By adding the second site, the enrollment target date was met a month ahead of schedule.

Challenge

ICON established that additional specialist equipment and training were needed at sites to “explore effects on whole body bio-impedance,” a stated exploratory goal.

Solution

The PM engaged ICON’s Vendor Management (VM) group early in the study start-up phase to identify an appropriate vendor for equipment supply and site training, enabling vendor contracting, equipment delivery, and site training to be completed before the planned clinical start.

Challenge

Several secondary endpoints (3) and exploratory endpoints (7) were defined in the protocol. This translated into a highly complex sampling scheme in which up to 8 blood samples and 7 urine samples had to be taken per timepoint using various types of sampling and processing tubes. The sample analysis was performed at 7 different laboratories in the UK (2), US (4), and NL(1), amplifying the study’s operational complexity.

Solution

Sample shipment preparation and tracking required careful management and collaboration between the operational team and the sites. To ensure clarity on sample handling, processing, and shipment procedures, ICON’s project manager (PM) managed the preparation of a laboratory manual, which stipulated that the clinical team manager (CTM) generate detailed sampling source data sheets, sample handling/processing sheets, and sample tracking logs to provide to the sites. This ensured the proper implementation of the laboratory manual’s details into the clinical study routine. Specific training sessions conducted by the CTM and PM were provided to the site staff. After the first patient was dosed, the CTM visited the site to gain firsthand knowledge of challenges that occurred, to provide additional support and guidance to site staff, and to identify lessons learned early on in the clinical conduct. ICON’s added support to the study planning and execution was key for success; as all samples could be analysed, and complete datasets from all patients were available.

Our selected shipment service vendor (World Courier) provided accurate shipment tracking, temperature monitoring during transit, and a smooth importation process, each of which ensured the safety and integrity of samples in transit.

Challenge

When the study was underway, the client’s strategic decision compelled the addition of an interim analysis of the data. This study became a high priority project and would determine the overall development program. Topline results were needed to plan the larger Phase 2 study.

Solution

The added interim analysis demonstrated the need for data cleaning, which required additional clinical research associate (CRA) and data management (DM) resources. CRA resources were increased to expedite the source data verification (SDV), which was simultaneously performed at both UK sites. In addition, the CTM supported the CRAs and visited the sites for two co-monitoring visits (requiring travel from Germany to the UK). The DM and Stats teams reallocated resources internally to accelerate the interim analysis, and topline results were delivered only two weeks after DBL.

20 patients with heart failure and impaired systolic function were enrolled ahead of target despite an initial delay caused by the submission of protocol amendments. Topline results were delivered to the client in time for a board meeting which required an interim analysis that was added to the study on short notice.

"This has been a tremendous work; huge thanks and congratulations to the entire team! The meeting today with the Executive Committee went very well, everybody agreed on the great quality of the data! So congrats to you all, well done!”

Head of Clinical Evaluations and Collaborations

"Congratulations and thank you for all of your hard work and dedication to this project. It was a challenge from the beginning, but as a great team working together, you made it a success!”

Director, Operations Portfolio Lead–Cardiovascular